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c06bcc5adb5035de3647424d03d4b94f2a85d4df | wikidoc | Homeobox A1 | Homeobox A1
Homeobox protein Hox-A1 is a protein that in humans is encoded by the HOXA1 gene.
# Gene
Two transcript variants encoding two different isoforms have been found for this gene, with only one of the isoforms containing the homeodomain region.
# Function
In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on four separate chromosomes. Expression of these proteins is spatially and temporally regulated during embryonic development. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which may regulate gene expression, morphogenesis, and cellular differentiation. The homeobox protein Hox-A1 may be involved in the placement of hindbrain segments in the proper location along the anterior-posterior axis during development.
# Clinical significance
A common polymorphism in the HOXA1 gene is associated with a susceptibility to autism spectrum disorder, with individuals possessing these gene variant have an approximately doubled risk of developing the disorder. Studies on knockout mice have indicated that the gene can alter embryological development of the brain stem (specifically the facial and superior olivary nuclei), as well as induce several other physical changes such as in ear shape. Both of these sets of changes can also be seen in patients with autism.
Other HOXA1 mutations are associated with Bosley-Salih-Alorainy syndrome (BSAS) or the Athabascan brainstem dysgenesis syndrome (ABDS).
# Regulation
The HOXA1 gene is repressed by the microRNA miR-10a. | Homeobox A1
Homeobox protein Hox-A1 is a protein that in humans is encoded by the HOXA1 gene.[1][2][3]
# Gene
Two transcript variants encoding two different isoforms have been found for this gene, with only one of the isoforms containing the homeodomain region.[4]
# Function
In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on four separate chromosomes. Expression of these proteins is spatially and temporally regulated during embryonic development. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which may regulate gene expression, morphogenesis, and cellular differentiation. The homeobox protein Hox-A1 may be involved in the placement of hindbrain segments in the proper location along the anterior-posterior axis during development.[4]
# Clinical significance
A common polymorphism in the HOXA1 gene is associated with a susceptibility to autism spectrum disorder, with individuals possessing these gene variant have an approximately doubled risk of developing the disorder.[5] Studies on knockout mice have indicated that the gene can alter embryological development of the brain stem (specifically the facial and superior olivary nuclei), as well as induce several other physical changes such as in ear shape.[6] Both of these sets of changes can also be seen in patients with autism.
Other HOXA1 mutations are associated with Bosley-Salih-Alorainy syndrome (BSAS) or the Athabascan brainstem dysgenesis syndrome (ABDS).[7]
# Regulation
The HOXA1 gene is repressed by the microRNA miR-10a.[8] | https://www.wikidoc.org/index.php/Homeobox_A1 | |
99790814df9ec38cbb122a81a9a9e1d252741588 | wikidoc | Homeostasis | Homeostasis
# Overview
Homeostasis is the property of either an open system or a closed system, especially a living organism, that regulates its internal environment so as to maintain a stable, constant condition. Multiple dynamic equilibrium adjustments and regulation mechanisms make homeostasis possible. The concept was created by Claude Bernard, often considered as the father of physiology, and published in 1865. The term was coined in 1932 by Walter Bradford Cannon from the Greek homoios (same, like, resembling) and stasis (to stand, posture).
# Biological homeostasis
With regard to any given life system parameter, an organism may be a conformer or a regulator. Regulators try to maintain the parameter at a constant level over possibly wide ambient environmental variations. On the other hand, conformers allow the environment to determine the parameter. For instance, endothermic animals maintain a constant body temperature, while ectothermic animals exhibit wide body temperature variation. Examples of endothermic animals include mammals and birds, examples of ectothermic animals include reptiles and some sea animals.
This is not to say that conformers don't have behavioural adaptations allowing them to exert some control over a given parameter. For instance, reptiles often rest on sun-heated rocks in the morning to raise their body temperature. Likewise, regulators' behaviors may contribute to their internal stability: The same sun-baked rock may host a ground squirrel, also basking in the morning sun.
An advantage of homeostatic regulation is that it allows an organism to function effectively in a broad range of environmental conditions. For example, ectotherms tend to become sluggish at low temperatures, whereas a co-located endotherm may be fully active. That thermal stability comes at a price since an automatic regulation system requires additional energy. One reason snakes may eat only once a week is that they use much less energy to maintain homeostasis.
Most homeostatic regulation is controlled by the release of hormones into the bloodstream. However other regulatory processes rely on simple diffusion to maintain a balance.
Homeostatic regulation extends far beyond the control of temperature. All animals also regulate their blood glucose, as well as the concentration of their blood. Mammals regulate their blood glucose with insulin and glucagon. These hormones are released by the pancreas. If the pancreas is for any reason unable to produce enough of these two hormones diabetes results. The kidneys are used to remove excess water and ions from the blood. These are then expelled as urine. The kidneys perform a vital role in homeostatic regulation in mammals removing excess water, salt and urea from the blood. These are the body's main waste products.
Sleep timing depends upon a balance between homeostatic sleep propensity, the need for sleep as a function of the amount of time elapsed since the last adequate sleep episode, and circadian rhythms which determine the ideal timing of a correctly structured and restorative sleep episode.
## Control Mechanisms
All homeostatic control mechanisms have at least three interdependent components for the variable being regulated: The receptor is the sensing component that monitors and responds to changes in the environment. When the receptor senses a stimulus, it sends information to a control center, the component that sets the range at which a variable is maintained. The control center determines an appropriate response to the stimulus. The result of that response feeds to the effector, either enhancing it with positive feedback or depressing it with negative feedback
### Negative Feedback Mechanisms
Negative feedback mechanisms reduce or suppress the original stimulus, given the effector’s output. Most homeostatic control mechanisms require a negative feedback loop to keep conditions from exceeding tolerable limits. The purpose is to prevent sudden severe changes within a complex organism. There are hundreds of negative feedback mechanisms in the human body. Among the most important regulatory functions are thermoregulation, osmoregulation, and glucoregulation. The kidneys contribute to homeostasis in five important ways: regulation of blood water levels, re-absorption of substances into the blood, maintenance of salt and ion levels in the blood, regulation of blood pH, and excretion of urea and other wastes.
A negative feedback mechanism example is the typical home heating system. Its thermostat houses a thermometer, the receptor that senses when the temperature is too low. The control center, also housed in the thermostat, senses and responds to the thermometer when the temperature drops below a specified set point. Below that target level, the thermostat sends a message to the effector, the furnace. The furnace then produces heat, which warms the house. Once the thermostat senses a target level of heat has been reached, it will signal the furnace to turn off, thus maintaining a comfortable temperature - not too hot nor cold.
### Positive Feedback Mechanisms
Positive feedback mechanisms are designed to accelerate or enhance the output created by a stimulus that has already been activated.
Unlike negative feedback mechanisms that initiate to maintain or regulate physiological functions within a set and narrow range, the positive feedback mechanisms are designed to push levels out of normal ranges. To achieve this purpose, a series of events initiates a cascading process that builds to increase the effect of the stimulus. This process can be beneficial but is rarely used by the body due to risks of the acceleration becoming uncontrollable.
One positive feedback example event in the body is blood platelet accumulation, which, in turn, causes blood clotting in response to a break or tear in the lining of blood vessels. Another example is the release of oxytocin to intensify the contractions that take place during childbirth.
Positive feedback can also be harmful. One particular example is when a fever causes a positive feedback within homeostasis that pushes the temperature continually higher. Body temperature can reach extremes of 45°C (113°F), at which cellular proteins denature, causing the active site in proteins to change, thus causing metabolism to stop, resulting in death.
## Homeostatic Imbalance
Much disease results from disturbance of homeostasis, a condition known as homeostatic imbalance. As it ages, every organism will lose efficiency in its control systems. The inefficiencies gradually result in an unstable internal environment that increases the risk for illness. In addition, homeostatic imbalance is also responsible for the physical changes associated with aging. Even more serious than illness and other characteristics of aging, is death. Heart failure has been seen where nominal negative feedback mechanisms become overwhelmed, and destructive positive feedback mechanisms then take over.
Diseases that result from a homeostatic imbalance include diabetes, dehydration, hypoglycemia, hyperglycemia, gout, and any disease caused by a toxin present in the bloodstream. All of these conditions result from the presence of an increased amount of a particular substance. In ideal circumstances, homeostatic control mechanisms should prevent this imbalance from occurring, but, in some people, the mechanisms do not work efficiently enough or the quantity of the substance exceeds the levels at which it can be managed. In these cases, medical intervention is necessary to restore the imbalance, or permanent damage to the organs may result.
## Varieties of homeostasis
The dynamic energy budget theory for metabolic organisation delineates structure and (one or more) reserves in an organism. Its formulation is based on three forms of homeostasis:
- Strong homeostasis, wherein structure and reserve do not change in composition. Since the amount of reserve and structure can vary, this allows a particular change in the composition of the whole body (as explained by the dynamic energy budget theory).
- Weak homeostasis, wherein the ratio of the amounts of reserve and structure becomes constant as long as food availability is constant, even when the organism grows. This means that the whole body composition is constant during growth in constant environments.
- Structural homeostasis, wherein the sub-individual structures grow in harmony with the whole individual; the relative proportions of the individuals remain constant.
# Reactive homeostasis
Example of use: "Reactive homeostasis is an immediate response to a homeostatic challenge such as predation."
However, any homeostasis is impossible without reaction - because homeostasis is and must be a "feedback" phenomenon.
The phrase "reactive homeostasis" is simply short for: "reactive compensation reestablishing homeostasis", that is to say, "reestablishing a point of homeostasis." - it should not be confused with a separate kind of homeostasis or a distinct phenomenon from homeostasis; it is simply the compensation (or compensatory) phase of homeostasis.
# Other fields
The term has come to be used in other fields, as well.
### Metabolic homeostasis
Some herbal medicines, known as adaptogens, have been defined to function as non-toxic metabolic regulators that can enhance metabolic homeostasis during stress. | Homeostasis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Homeostasis is the property of either an open system or a closed system, especially a living organism, that regulates its internal environment so as to maintain a stable, constant condition. Multiple dynamic equilibrium adjustments and regulation mechanisms make homeostasis possible. The concept was created by Claude Bernard, often considered as the father of physiology, and published in 1865. The term was coined in 1932 by Walter Bradford Cannon from the Greek homoios (same, like, resembling) and stasis (to stand, posture).
# Biological homeostasis
With regard to any given life system parameter, an organism may be a conformer or a regulator. Regulators try to maintain the parameter at a constant level over possibly wide ambient environmental variations. On the other hand, conformers allow the environment to determine the parameter. For instance, endothermic animals maintain a constant body temperature, while ectothermic animals exhibit wide body temperature variation. Examples of endothermic animals include mammals and birds, examples of ectothermic animals include reptiles and some sea animals.
This is not to say that conformers don't have behavioural adaptations allowing them to exert some control over a given parameter. For instance, reptiles often rest on sun-heated rocks in the morning to raise their body temperature. Likewise, regulators' behaviors may contribute to their internal stability: The same sun-baked rock may host a ground squirrel, also basking in the morning sun.
An advantage of homeostatic regulation is that it allows an organism to function effectively in a broad range of environmental conditions. For example, ectotherms tend to become sluggish at low temperatures, whereas a co-located endotherm may be fully active. That thermal stability comes at a price since an automatic regulation system requires additional energy. One reason snakes may eat only once a week is that they use much less energy to maintain homeostasis.
Most homeostatic regulation is controlled by the release of hormones into the bloodstream. However other regulatory processes rely on simple diffusion to maintain a balance.
Homeostatic regulation extends far beyond the control of temperature. All animals also regulate their blood glucose, as well as the concentration of their blood. Mammals regulate their blood glucose with insulin and glucagon. These hormones are released by the pancreas. If the pancreas is for any reason unable to produce enough of these two hormones diabetes results. The kidneys are used to remove excess water and ions from the blood. These are then expelled as urine. The kidneys perform a vital role in homeostatic regulation in mammals removing excess water, salt and urea from the blood. These are the body's main waste products.
Sleep timing depends upon a balance between homeostatic sleep propensity, the need for sleep as a function of the amount of time elapsed since the last adequate sleep episode, and circadian rhythms which determine the ideal timing of a correctly structured and restorative sleep episode.[1]
## Control Mechanisms
All homeostatic control mechanisms have at least three interdependent components for the variable being regulated: The receptor is the sensing component that monitors and responds to changes in the environment. When the receptor senses a stimulus, it sends information to a control center, the component that sets the range at which a variable is maintained. The control center determines an appropriate response to the stimulus. The result of that response feeds to the effector, either enhancing it with positive feedback or depressing it with negative feedback [2]
### Negative Feedback Mechanisms
Negative feedback mechanisms reduce or suppress the original stimulus, given the effector’s output. Most homeostatic control mechanisms require a negative feedback loop to keep conditions from exceeding tolerable limits. The purpose is to prevent sudden severe changes within a complex organism. There are hundreds of negative feedback mechanisms in the human body. Among the most important regulatory functions are thermoregulation, osmoregulation, and glucoregulation. The kidneys contribute to homeostasis in five important ways: regulation of blood water levels, re-absorption of substances into the blood, maintenance of salt and ion levels in the blood, regulation of blood pH, and excretion of urea and other wastes.
A negative feedback mechanism example is the typical home heating system. Its thermostat houses a thermometer, the receptor that senses when the temperature is too low. The control center, also housed in the thermostat, senses and responds to the thermometer when the temperature drops below a specified set point. Below that target level, the thermostat sends a message to the effector, the furnace. The furnace then produces heat, which warms the house. Once the thermostat senses a target level of heat has been reached, it will signal the furnace to turn off, thus maintaining a comfortable temperature - not too hot nor cold. [2]
### Positive Feedback Mechanisms
Positive feedback mechanisms are designed to accelerate or enhance the output created by a stimulus that has already been activated.
Unlike negative feedback mechanisms that initiate to maintain or regulate physiological functions within a set and narrow range, the positive feedback mechanisms are designed to push levels out of normal ranges. To achieve this purpose, a series of events initiates a cascading process that builds to increase the effect of the stimulus. This process can be beneficial but is rarely used by the body due to risks of the acceleration becoming uncontrollable.
One positive feedback example event in the body is blood platelet accumulation, which, in turn, causes blood clotting in response to a break or tear in the lining of blood vessels. Another example is the release of oxytocin to intensify the contractions that take place during childbirth.[2]
Positive feedback can also be harmful. One particular example is when a fever causes a positive feedback within homeostasis that pushes the temperature continually higher. Body temperature can reach extremes of 45°C (113°F), at which cellular proteins denature, causing the active site in proteins to change, thus causing metabolism to stop, resulting in death.
## Homeostatic Imbalance
Much disease results from disturbance of homeostasis, a condition known as homeostatic imbalance. As it ages, every organism will lose efficiency in its control systems. The inefficiencies gradually result in an unstable internal environment that increases the risk for illness. In addition, homeostatic imbalance is also responsible for the physical changes associated with aging. Even more serious than illness and other characteristics of aging, is death. Heart failure has been seen where nominal negative feedback mechanisms become overwhelmed, and destructive positive feedback mechanisms then take over.[2]
Diseases that result from a homeostatic imbalance include diabetes, dehydration, hypoglycemia, hyperglycemia, gout, and any disease caused by a toxin present in the bloodstream. All of these conditions result from the presence of an increased amount of a particular substance. In ideal circumstances, homeostatic control mechanisms should prevent this imbalance from occurring, but, in some people, the mechanisms do not work efficiently enough or the quantity of the substance exceeds the levels at which it can be managed. In these cases, medical intervention is necessary to restore the imbalance, or permanent damage to the organs may result.
## Varieties of homeostasis
The dynamic energy budget theory for metabolic organisation delineates structure and (one or more) reserves in an organism. Its formulation is based on three forms of homeostasis:
- Strong homeostasis, wherein structure and reserve do not change in composition. Since the amount of reserve and structure can vary, this allows a particular change in the composition of the whole body (as explained by the dynamic energy budget theory).
- Weak homeostasis, wherein the ratio of the amounts of reserve and structure becomes constant as long as food availability is constant, even when the organism grows. This means that the whole body composition is constant during growth in constant environments.
- Structural homeostasis, wherein the sub-individual structures grow in harmony with the whole individual; the relative proportions of the individuals remain constant.
# Reactive homeostasis
Example of use: "Reactive homeostasis is an immediate response to a homeostatic challenge such as predation."
However, any homeostasis is impossible without reaction - because homeostasis is and must be a "feedback" phenomenon.
The phrase "reactive homeostasis" is simply short for: "reactive compensation reestablishing homeostasis", that is to say, "reestablishing a point of homeostasis." - it should not be confused with a separate kind of homeostasis or a distinct phenomenon from homeostasis; it is simply the compensation (or compensatory) phase of homeostasis.
# Other fields
The term has come to be used in other fields, as well.
### Metabolic homeostasis
Some herbal medicines, known as adaptogens, have been defined to function as non-toxic metabolic regulators that can enhance metabolic homeostasis during stress.[3] | https://www.wikidoc.org/index.php/Homeostasis | |
e47f83f6e5c6c15c1b725ea2a7d1c9bdcc706963 | wikidoc | Homogeneity | Homogeneity
Generally, homogeneity means being the same throughout. For various specialized meanings, see:
- Homogeneous (mathematics), a variety of meanings
- In statistics homogeneity can refer to
Homogeneity of variance: Homoscedasticity
Logically consistent data matrices: homogeneity (statistics)
- Homogeneity of variance: Homoscedasticity
- Logically consistent data matrices: homogeneity (statistics)
- homogeneity (physics), in physics, two particular meanings: On one hand, translational invariance. On the other, homogeneity of units in equations, related to dimensional analysis
- Homogenetic or homoplastic, in biology, applied both to animals and plants, of having a resemblance in structure, due to descent from a common progenitor with subsequent modification
- Homogenization is intensive mixing of mutually insoluble phases (sometimes with addition of surfactants) to obtain a soluble suspension or emulsion, for example homogenizing milk so that the cream doesn't separate out
- In physical chemistry, homogeneous describes a single-phase system as opposed to a heterogeneous system. See also phase diagrams and the classification of catalysts
- In the context of procurement/purchasing, homogeneous is used to describe goods that do not vary in their essential characteristic irrespective of the source of supply
cs:Homogenita
it:Omogeneità
nl:Homogeniteit
sl:Homogenost | Homogeneity
Generally, homogeneity means being the same throughout. For various specialized meanings, see:
- Homogeneous (mathematics), a variety of meanings
- In statistics homogeneity can refer to
Homogeneity of variance: Homoscedasticity
Logically consistent data matrices: homogeneity (statistics)
- Homogeneity of variance: Homoscedasticity
- Logically consistent data matrices: homogeneity (statistics)
- homogeneity (physics), in physics, two particular meanings: On one hand, translational invariance. On the other, homogeneity of units in equations, related to dimensional analysis
- Homogenetic or homoplastic, in biology, applied both to animals and plants, of having a resemblance in structure, due to descent from a common progenitor with subsequent modification
- Homogenization is intensive mixing of mutually insoluble phases (sometimes with addition of surfactants) to obtain a soluble suspension or emulsion, for example homogenizing milk so that the cream doesn't separate out
- In physical chemistry, homogeneous describes a single-phase system as opposed to a heterogeneous system. See also phase diagrams and the classification of catalysts
- In the context of procurement/purchasing, homogeneous is used to describe goods that do not vary in their essential characteristic irrespective of the source of supply
Template:Disambig
cs:Homogenita
it:Omogeneità
nl:Homogeniteit
sl:Homogenost
Template:WS | https://www.wikidoc.org/index.php/Homogeneity | |
92eb14039dc603c40db4546ce436cf93462f96b6 | wikidoc | Homotherium | Homotherium
Homotherium is a machairodontine saber-toothed cat genus that lived approximately 3 million to 10,000 years ago in North America, Eurasia and Africa. It first became extinct in Africa some 1.5 million years ago. In Eurasia it survived until about 30,000 years ago . The last scimitar cat survived in North America until 10,000 years ago.
# Anatomy
Homotherium reached 1,1 m at the shoulder and was therefore about the size of a lion. Compared to some other machairodonts, like Smilodon or Megantereon, Homotherium had relatively shorter upper canines, but they were flat, serrated and longer than those of any living cat. Incisors and lower canines formed a powerful puncturing and gripping device. Among living cats, only the tiger (Panthera tigris) has such large incisors, which aid in lifting and carrying prey. The molars of Homotherium were rather weak and not adapted for bone crushing. The skull was longer than in Smilodon and had a well-developed crest, where muscles were attached to power the lower jaw. This jaw had down-turned forward flanges to protect the scimitars. Its large canine teeth were crenulated and designed for slashing rather than purely stabbing.
It had the general appereance of a cat, but some of its physical characteristics are rather unusual for a large cat. The limb proportions of Homotherium gave it a hyena-like appearance. The forelegs were elongated, while the hind quarters were rather squat with feet perhaps partially plantigrade, causing the back to slope towards the short tail. Features of the hindlimbs indicate that this cat was moderately capable of leaping. The pelvic region, including the sacral vertebrae, were bear-like, as was the short tail composed of 13 vertebrae — about half the number in long-tailed cats.
The unusually large, square nasal opening, like that of the cheetah (Acinonyx jubatus), presumably allowed quicker oxygen intake, which aided in rapid running and in cooling the brain. As in the cheetah, too, the brain's visual cortex was large and complex, emphasizing the scimitar cat's ability to see well and function in the day, rather than the night, as in most cats.
# Range and species
Homotherium probably derived from Machairodus. During the Pleistocene it occurred in vast parts of Eurasia, North America and until the middle pleistocene (about 1.5 million years) even in Africa. Homotherium survived in Eurasia until about 30,000 , in North America even until 10,000 years ago.
Several species (nestianus, sainzelli, creantidens, nihowanensis, ultimum) are recognized from Eurasia, which differ mainly in the shape of the canines and in body size. But facing the fluctuation range of the size of modern large cats, it is highly probable, that all belong to just one species, Homotherium latidens.
Two species described form the early Pleistocene of Africa are Homotherium ethiopicum and Homotherium hadarensis. But they also differ hardly from the Eurasian forms. On the African continent the genus dissapeared about 1,5 million years ago.
In North America, a very similar species, Homotherium serum occurred from the latest Pliocene until the latest Pleistocene. Their relicts were found at various sites between Alaska and Texas. In the southern parts of its range the American Homotherium occurred beneath Smilodon, in the northern parts it was the only species of saber toothed cats. The american Homotherium was originally described under the name Dinobastis.
Despite Homotheriums vast range and the large amount of fossil remains from Eurasia, Africa and North America, complete skeletons of this cat are relatively rare. One of the most famous sites of Homotherium remains is the Friesenhahn cave in Texas, where 30 Homotherium were found, besides hundreds of young mammoths and several dire wolves.
# Diet and habitat
The Friesenhahn cave in Texas contained the remains of over 30 Homotherium, which were discovered along with the remains of between 300 and 400 juvenile American mammoths (Mammuthus columbii) . Besides mammoth, there where found only very few other potential prey species in the cave. Therefore it is unlikely that Homotherium carried carcasses of already dead animals in the cave. Such a specialism of prey in species and age structure is not covenant with a scavenging lifestyle. Because of the same reason it is also very unlikely, that the dire wolves carried the mammoths into the cave.
The worldwide association of Homotherium species with proboscideans (elephants and mastodons) and rhino remains, mainly those of juveniles, suggests that Homotherium preyed selectively on these tough-skinned animals and probably hunted in packs, carrying away the large animals it brought down.
The decline of Homotherium could be due to the dissapereance of large herbivorous mammals like mammoths in America at the end of the Pleistocene.
In North America fossil remains of Homotherium are less abundant than those of its contemporary Smilodon. For the most part it probably inhabited higher latitudes and altitudes, and therefore was likely to be well adapted to the colder conditions of the mammoth steppe environment.
The suggested large prey species, make it probable, that Homotherium hunted in packs. Reduced claws, relatively slender limbs and the sloping back indicate adaptions for endurance running in open habitats. | Homotherium
Homotherium is a machairodontine saber-toothed cat genus that lived approximately 3 million to 10,000 years ago in North America, Eurasia and Africa. It first became extinct in Africa some 1.5 million years ago. In Eurasia it survived until about 30,000 years ago [1]. The last scimitar cat survived in North America until 10,000 years ago.
# Anatomy
Homotherium reached 1,1 m at the shoulder and was therefore about the size of a lion. Compared to some other machairodonts, like Smilodon or Megantereon, Homotherium had relatively shorter upper canines, but they were flat, serrated and longer than those of any living cat. Incisors and lower canines formed a powerful puncturing and gripping device. Among living cats, only the tiger (Panthera tigris) has such large incisors, which aid in lifting and carrying prey. The molars of Homotherium were rather weak and not adapted for bone crushing. The skull was longer than in Smilodon and had a well-developed crest, where muscles were attached to power the lower jaw. This jaw had down-turned forward flanges to protect the scimitars. Its large canine teeth were crenulated and designed for slashing rather than purely stabbing.
It had the general appereance of a cat, but some of its physical characteristics are rather unusual for a large cat. The limb proportions of Homotherium gave it a hyena-like appearance. The forelegs were elongated, while the hind quarters were rather squat with feet perhaps partially plantigrade, causing the back to slope towards the short tail. Features of the hindlimbs indicate that this cat was moderately capable of leaping. The pelvic region, including the sacral vertebrae, were bear-like, as was the short tail composed of 13 vertebrae — about half the number in long-tailed cats.
The unusually large, square nasal opening, like that of the cheetah (Acinonyx jubatus), presumably allowed quicker oxygen intake, which aided in rapid running and in cooling the brain. As in the cheetah, too, the brain's visual cortex was large and complex, emphasizing the scimitar cat's ability to see well and function in the day, rather than the night, as in most cats.
# Range and species
Homotherium probably derived from Machairodus. During the Pleistocene it occurred in vast parts of Eurasia, North America and until the middle pleistocene (about 1.5 million years) even in Africa. Homotherium survived in Eurasia until about 30,000 [1], in North America even until 10,000 years ago.
Several species (nestianus, sainzelli, creantidens, nihowanensis, ultimum) are recognized from Eurasia, which differ mainly in the shape of the canines and in body size. But facing the fluctuation range of the size of modern large cats, it is highly probable, that all belong to just one species, Homotherium latidens.
Two species described form the early Pleistocene of Africa are Homotherium ethiopicum and Homotherium hadarensis. But they also differ hardly from the Eurasian forms[2]. On the African continent the genus dissapeared about 1,5 million years ago.
In North America, a very similar species, Homotherium serum occurred from the latest Pliocene until the latest Pleistocene. Their relicts were found at various sites between Alaska and Texas. In the southern parts of its range the American Homotherium occurred beneath Smilodon, in the northern parts it was the only species of saber toothed cats. The american Homotherium was originally described under the name Dinobastis.
Despite Homotheriums vast range and the large amount of fossil remains from Eurasia, Africa and North America, complete skeletons of this cat are relatively rare. One of the most famous sites of Homotherium remains is the Friesenhahn cave in Texas, where 30 Homotherium were found, besides hundreds of young mammoths and several dire wolves.
# Diet and habitat
The Friesenhahn cave in Texas contained the remains of over 30 Homotherium, which were discovered along with the remains of between 300 and 400 juvenile American mammoths (Mammuthus columbii) [3]. Besides mammoth, there where found only very few other potential prey species in the cave. Therefore it is unlikely that Homotherium carried carcasses of already dead animals in the cave. Such a specialism of prey in species and age structure is not covenant with a scavenging lifestyle. Because of the same reason it is also very unlikely, that the dire wolves carried the mammoths into the cave.
The worldwide association of Homotherium species with proboscideans (elephants and mastodons) and rhino remains, mainly those of juveniles, suggests that Homotherium preyed selectively on these tough-skinned animals and probably hunted in packs, carrying away the large animals it brought down.
The decline of Homotherium could be due to the dissapereance of large herbivorous mammals like mammoths in America at the end of the Pleistocene.
In North America fossil remains of Homotherium are less abundant than those of its contemporary Smilodon. For the most part it probably inhabited higher latitudes and altitudes, and therefore was likely to be well adapted to the colder conditions of the mammoth steppe environment.
The suggested large prey species, make it probable, that Homotherium hunted in packs. Reduced claws, relatively slender limbs and the sloping back indicate adaptions for endurance running in open habitats.[4] | https://www.wikidoc.org/index.php/Homotherium | |
5bdc170e57dc43b06a012e6c9690261803ddb607 | wikidoc | Hop (plant) | Hop (plant)
The hop (Humulus) is a small genus of flowering plants, native to the temperate Northern Hemisphere. The female flowers, commonly called hops, are used as flavoring and stabilizers during beer brewing. The hop is part of the family Cannabaceae, which also includes the genus cannabis (also known as hemp).
Although frequently referred to as the hop vine, it is technically a bine; unlike vines, which use tendrils, suckers, and other appendages for attaching themselves, bines have stout stems with stiff hairs to aid in climbing. It is a perennial herbaceous plant which sends up new shoots in early spring and dies back to the cold-hardy rhizome in autumn. Hop shoots grow very rapidly and at the peak of growth can grow 20–50 cm per week (1 to 3 inches per day). Hop bines climb by wrapping clockwise around anything within reach, and individual bines typically grow between 2 to 15 m (6.5 to 50 feet) depending on what is available to grow on. The leaves are opposite, with a 7–12 cm (2 3/4 to 4 3/4 inch) Petiole and a cordate-based, palmately lobed blade 12–25 cm long (4 3/4 to 10 inch) and broad; the edges are coarsely toothed. When the hop bines run out of material to climb, horizontal shoots sprout between the leaves of the main stem to form a network of stems wound round each other.
# Species
There are three species, one with five varieties:
- Humulus japonicus (syn. H. scandens). Asian Hop. Leaves with 5–7 lobes. Eastern Asia.
- Humulus lupulus. Common Hop. Leaves with 3–5 lobes. Europe, western Asia, North America.
Humulus lupulus var. lupulus. Europe, western Asia.
Humulus lupulus var. cordifolius. Eastern Asia.
Humulus lupulus var. lupuloides (syn. H. americanus). Eastern North America.
Humulus lupulus var. neomexicanus. Western North America.
Humulus lupulus var. pubescens. Midwest North America.
- Humulus lupulus var. lupulus. Europe, western Asia.
- Humulus lupulus var. cordifolius. Eastern Asia.
- Humulus lupulus var. lupuloides (syn. H. americanus). Eastern North America.
- Humulus lupulus var. neomexicanus. Western North America.
- Humulus lupulus var. pubescens. Midwest North America.
- Humulus yunnanensis. Yunnan Hop. Leaves with 3–5 lobes, densely hairy below. Southeast Asia (endemic in Yunnan, China).
Brewers' hops are specific cultivars, propagated by asexual reproduction.
# Cultivation
## History
The first documented instance of hop cultivation was in 736, in the Hallertau region of present-day Germany (which is today the most important production centre with about 25% of the worldwide production), although the first mention of the use of hops in brewing was in 1067 by Abbess Hildegard of Bingen. Hops were introduced to British beers in the early 1500s, and hop cultivation began in the present-day United States in 1629.
Today, the principal production centres for the UK are in Kent (which produces Kent Golding hops) and Worcestershire, and Washington state for the USA; other important production areas include Belgium, as mentioned Germany and the Czech Republic. Other major areas of production include Xinjiang (China), Tasmania (Australia), the Lublin area (Poland) and Chuvashia (Russia). New Zealand is a leading centre for organic hop production.
Until mechanisation (in the late 1960s for the UK), the need for massed labour at harvest time meant hop-growing had a big social impact. Many of those hopping in Kent were Eastenders, for whom the annual migration meant not just money in the family pocket but a welcome break from the grime and smoke of London. Whole families would come down on special trains and live in hoppers' huts for most of September, even the smallest children helping in the fields. In Kent, hops areas had Oast houses built for drying the hops; many now are converted to homes. The image of Cockney hoppers beneath the blue September skies of the Battle of Britain in 1940 has become part of British national mythology. Romany travellers were another very large group among the hoppers.
## Propagation and pests
The European Hop is propagated either by nursery plants or by cuttings. These are set in "hills", formed by digging holes in the spring, which are filled with fine leaf mould. The density of the holes varies from 3–5 holes per m². One, two, or three plants are put in each hill; although, if hops are designed to be raised from cuttings, four or five of these, ranging from 7 to 10 cm (3–4 inches) in length, are planted 3–5 cm deep in fine leaf mould.
Hop growing, though profitable when it succeeds, is risky, with several significant insect pests causing damage, including the European Corn Borer Ostrinia nubilalis and the Hop froghopper Aphrophora interrupta. Hop gardens on chalky soils are particularly subject to damage. In June and July, the hops are liable to be damaged by an aphid, Myzus humuli. This insect, however, does not endanger the growth of the plant, unless it is already in a weak state from root damage by the larvae of the ottermoth, Phalaena humuli. The roots are also attacked by the larvae of Common Swift, Ghost Moth and Orange Swift. The foliage is sometimes eaten by the larvae of other Lepidoptera including Peacock Butterfly, Angle Shades, Currant Pug, Emperor Moth, The Gothic and Hebrew Character.
## Diseases
## Harvest
At the end of the first year it becomes necessary to put poles into the hills, around which the bines reared from plants are wound; at the expiration of the second year, full-sized poles, from 5–6 m long, are set (though the hop bines will run to the height of 15 m) in the proportion of two poles to each hill, and a similar number of hop-plants are fastened loosely round each pole, by means of withered rushes.
In the northern hemisphere, hops begin to flower about the latter end of June or the beginning of July, at which point the poles are now entirely covered with foliage, and the pendent flowers are appearing in clusters. The hops themselves, which are the scaly seed-vessels of the female plants, are picked off by hand when the seed is formed around the end of August; for this purpose the poles are often taken down with the plants clinging to them. The seed-vessels are then dried, exposed to the air for a few days, and packed in sacks and sent to market.
# Production
The 2005 world production of hops according to FAOSTAT was as follows;
- Germany 29,000 tonnes
- USA 26,180 tonnes
- China 20,000 tonnes
- Czech Republic 6,800 tonnes
- Poland 3,355 tonnes
- Australia 2,000 tonnes
- North Korea 2,000 tonnes
- UK 2,000 tonnes
- Slovenia 1,500 tonnes
- France 1,400 tonnes
The total world production for 2005 was 102,216 tonnes.
# Uses
## Beer
Hop resins are composed of two main acids: alpha and beta acids. Alpha acids have a mild antibiotic/bacteriostatic effect against Gram-positive bacteria, and favours the exclusive activity of brewing yeast in the fermentation of beer. The flavour imparted by hops varies greatly by variety and use: hops boiled with the beer (known as "bittering hops") produce bitterness, while hops added to beer later impart some degree of "hop flavour" (if during the final 10 minutes of boil) or "hop aroma" (if during the final 3 minutes, or less, of boil) and a lesser degree of bitterness. Adding hops after the boil, a process known as "dry hopping", adds hop aroma, but very little bitterness. The degree of bitterness imparted by hops depends on the degree to which otherwise insoluble alpha acids (AAs) are isomerised during the boil, and the impact of a given amount of hops is specified in International Bitterness Units. Unboiled hops are only mildly bitter. Beta acids do not isomerise during the boil of wort, and have a negligible effect on beer flavour. Instead they contribute to beer's bitter aroma, and high beta acid hop varieties are often added at the end of the wort boil for aroma. Beta acids oxidise and oxidised beta acids form sulphur compounds such as DMS (dimethyl-sulfide) that can give beer off-flavours of rotten vegetables or cooked corn.
"Noble hops" are low in bitterness and high in aroma, and traditionally consist of four central European cultivars, 'Hallertauer Mittelfrueh', 'Tettnanger', 'Spalter', and 'Saaz'. They contain high amounts of the hop oil humulene and low amounts of alpha acids cohumulone and adhumulone, as well as lower amounts of the harsher-tasting beta acids lupulone, colupulone, and adlupulone. Humulene imparts an elegant, refined taste and aroma to beers containing it. These hops are used in pale lagers.
English ales use hop varieties such as Fuggle, Golding and Bullion. North American varieties include Cascade, Columbia, and Willamette. Certain beers (particularly the highly-hopped style known as India Pale Ale) can have high levels of bitterness.
Flavours and aromas are described using terms which include "grassy", "floral", "citrus", "spicy", and "earthy".
## Medicinal use
Hops have long-established and well-studied medicinal properties and uses, although new uses and properties are also being explored. Two of the many medically active ingredients in Hops are humulene and lupuline.
Dried female buds have a high methylbutenol content, which has a mild sedative effect on the central nervous system; it is used in the treatment for insomnia, stress and anxiety. If one has trouble getting sleep, hop tea before going to bed may help, though a quantity of beer has similar results.
Hops' antibacterial qualities also stimulate gastric juice production.
Hops have been studied for anti-viral properties and antimycobacterial properties. They also contain numerous various flavonoids, and they have been studied for containing Estrogen precursors as well.
## Fibre
The stem is flexible and very tough, with a tenacious fibre that has been used in some cases to make cloth and paper. It may be noted that hops are closely related to hemp, which is also used for fibre.
## Julmust
Hops are an ingredient in Julmust, a carbonated beverage popular in Sweden during the month of December.
## Other uses
Tender young hop shoots, which are only available for about three weeks during spring, were mainly eaten by the poor in medieval times, and were a substitute for asparagus. Only recently have they been rediscovered as a delicacy in parts of Germany, Belgium and England. They are served raw with vinaigrette, or boiled with fresh herbs or fried in batter. In the italian region of Veneto, they are called bruscàndołi and are used to prepare risotto or frittata.
Wild hops are also relished by cows, horses, goats, sheep, and pigs.
Another use for the hop bine once it has reached full growth is to be cut down and used as a decoration in public houses or in kitchens. In the old wives' tale, the hop bine is supposed to bring good luck. In some parts of Kent and Sussex there are signs alongside the road advertising the sale of hop bines. Because of fierce competition in the hop trade, some farms find that sale of bines for this purpose is better than selling the hops themselves, since a pint of beer only requires one and a half hops.
Hops has also been used to increase breast milk production between woman with a low milk supply.
# Notes | Hop (plant)
The hop (Humulus) is a small genus of flowering plants, native to the temperate Northern Hemisphere. The female flowers, commonly called hops, are used as flavoring and stabilizers during beer brewing. The hop is part of the family Cannabaceae, which also includes the genus cannabis (also known as hemp).
Although frequently referred to as the hop vine, it is technically a bine; unlike vines, which use tendrils, suckers, and other appendages for attaching themselves, bines have stout stems with stiff hairs to aid in climbing. It is a perennial herbaceous plant which sends up new shoots in early spring and dies back to the cold-hardy rhizome in autumn. Hop shoots grow very rapidly and at the peak of growth can grow 20–50 cm per week (1 to 3 inches per day). Hop bines climb by wrapping clockwise around anything within reach, and individual bines typically grow between 2 to 15 m (6.5 to 50 feet) depending on what is available to grow on. The leaves are opposite, with a 7–12 cm (2 3/4 to 4 3/4 inch) Petiole and a cordate-based, palmately lobed blade 12–25 cm long (4 3/4 to 10 inch) and broad; the edges are coarsely toothed. When the hop bines run out of material to climb, horizontal shoots sprout between the leaves of the main stem to form a network of stems wound round each other.
# Species
There are three species, one with five varieties:
- Humulus japonicus (syn. H. scandens). Asian Hop. Leaves with 5–7 lobes. Eastern Asia.
- Humulus lupulus. Common Hop. Leaves with 3–5 lobes. Europe, western Asia, North America.
Humulus lupulus var. lupulus. Europe, western Asia.
Humulus lupulus var. cordifolius. Eastern Asia.
Humulus lupulus var. lupuloides (syn. H. americanus). Eastern North America.
Humulus lupulus var. neomexicanus. Western North America.
Humulus lupulus var. pubescens. Midwest North America.
- Humulus lupulus var. lupulus. Europe, western Asia.
- Humulus lupulus var. cordifolius. Eastern Asia.
- Humulus lupulus var. lupuloides (syn. H. americanus). Eastern North America.
- Humulus lupulus var. neomexicanus. Western North America.
- Humulus lupulus var. pubescens. Midwest North America.
- Humulus yunnanensis. Yunnan Hop. Leaves with 3–5 lobes, densely hairy below. Southeast Asia (endemic in Yunnan, China).
Brewers' hops are specific cultivars, propagated by asexual reproduction.
# Cultivation
## History
The first documented instance of hop cultivation was in 736, in the Hallertau region of present-day Germany (which is today the most important production centre with about 25% of the worldwide production), although the first mention of the use of hops in brewing was in 1067 by Abbess Hildegard of Bingen. Hops were introduced to British beers in the early 1500s, and hop cultivation began in the present-day United States in 1629.
Today, the principal production centres for the UK are in Kent (which produces Kent Golding hops) and Worcestershire, and Washington state for the USA; other important production areas include Belgium, as mentioned Germany and the Czech Republic. Other major areas of production include Xinjiang (China), Tasmania (Australia), the Lublin area (Poland) and Chuvashia (Russia). New Zealand is a leading centre for organic hop production.
Until mechanisation (in the late 1960s for the UK), the need for massed labour at harvest time meant hop-growing had a big social impact. Many of those hopping in Kent were Eastenders, for whom the annual migration meant not just money in the family pocket but a welcome break from the grime and smoke of London. Whole families would come down on special trains and live in hoppers' huts for most of September, even the smallest children helping in the fields. In Kent, hops areas had Oast houses built for drying the hops; many now are converted to homes. The image of Cockney hoppers beneath the blue September skies of the Battle of Britain in 1940 has become part of British national mythology. Romany travellers were another very large group among the hoppers.
## Propagation and pests
The European Hop is propagated either by nursery plants or by cuttings. These are set in "hills", formed by digging holes in the spring, which are filled with fine leaf mould. The density of the holes varies from 3–5 holes per m². One, two, or three plants are put in each hill; although, if hops are designed to be raised from cuttings, four or five of these, ranging from 7 to 10 cm (3–4 inches) in length, are planted 3–5 cm deep in fine leaf mould.
Hop growing, though profitable when it succeeds, is risky, with several significant insect pests causing damage, including the European Corn Borer Ostrinia nubilalis and the Hop froghopper Aphrophora interrupta. Hop gardens on chalky soils are particularly subject to damage. In June and July, the hops are liable to be damaged by an aphid, Myzus humuli. This insect, however, does not endanger the growth of the plant, unless it is already in a weak state from root damage by the larvae of the ottermoth, Phalaena humuli. The roots are also attacked by the larvae of Common Swift, Ghost Moth and Orange Swift. The foliage is sometimes eaten by the larvae of other Lepidoptera including Peacock Butterfly, Angle Shades, Currant Pug, Emperor Moth, The Gothic and Hebrew Character.
## Diseases
## Harvest
At the end of the first year it becomes necessary to put poles into the hills, around which the bines reared from plants are wound; at the expiration of the second year, full-sized poles, from 5–6 m long, are set (though the hop bines will run to the height of 15 m) in the proportion of two poles to each hill, and a similar number of hop-plants are fastened loosely round each pole, by means of withered rushes.
In the northern hemisphere, hops begin to flower about the latter end of June or the beginning of July, at which point the poles are now entirely covered with foliage, and the pendent flowers are appearing in clusters. The hops themselves, which are the scaly seed-vessels of the female plants, are picked off by hand when the seed is formed around the end of August; for this purpose the poles are often taken down with the plants clinging to them. The seed-vessels are then dried, exposed to the air for a few days, and packed in sacks and sent to market.
# Production
The 2005 world production of hops according to FAOSTAT was as follows;
- Germany 29,000 tonnes
- USA 26,180 tonnes
- China 20,000 tonnes
- Czech Republic 6,800 tonnes
- Poland 3,355 tonnes
- Australia 2,000 tonnes
- North Korea 2,000 tonnes
- UK 2,000 tonnes
- Slovenia 1,500 tonnes
- France 1,400 tonnes
The total world production for 2005 was 102,216 tonnes.
# Uses
## Beer
Hop resins are composed of two main acids: alpha and beta acids. Alpha acids have a mild antibiotic/bacteriostatic effect against Gram-positive bacteria, and favours the exclusive activity of brewing yeast in the fermentation of beer. The flavour imparted by hops varies greatly by variety and use: hops boiled with the beer (known as "bittering hops") produce bitterness, while hops added to beer later impart some degree of "hop flavour" (if during the final 10 minutes of boil) or "hop aroma" (if during the final 3 minutes, or less, of boil) and a lesser degree of bitterness. Adding hops after the boil, a process known as "dry hopping", adds hop aroma, but very little bitterness. The degree of bitterness imparted by hops depends on the degree to which otherwise insoluble alpha acids (AAs) are isomerised during the boil, and the impact of a given amount of hops is specified in International Bitterness Units. Unboiled hops are only mildly bitter. Beta acids do not isomerise during the boil of wort, and have a negligible effect on beer flavour. Instead they contribute to beer's bitter aroma, and high beta acid hop varieties are often added at the end of the wort boil for aroma. Beta acids oxidise and oxidised beta acids form sulphur compounds such as DMS (dimethyl-sulfide) that can give beer off-flavours of rotten vegetables or cooked corn.
"Noble hops" are low in bitterness and high in aroma, and traditionally consist of four central European cultivars, 'Hallertauer Mittelfrueh', 'Tettnanger', 'Spalter', and 'Saaz'. They contain high amounts of the hop oil humulene and low amounts of alpha acids cohumulone and adhumulone, as well as lower amounts of the harsher-tasting beta acids lupulone, colupulone, and adlupulone. Humulene imparts an elegant, refined taste and aroma to beers containing it. These hops are used in pale lagers.
English ales use hop varieties such as Fuggle, Golding and Bullion. North American varieties include Cascade, Columbia, and Willamette. Certain beers (particularly the highly-hopped style known as India Pale Ale) can have high levels of bitterness.
Flavours and aromas are described using terms which include "grassy", "floral", "citrus", "spicy", and "earthy".
## Medicinal use
Hops have long-established and well-studied medicinal properties and uses, although new uses and properties are also being explored. Two of the many medically active ingredients in Hops are humulene and lupuline.
Dried female buds have a high methylbutenol content, which has a mild sedative effect on the central nervous system; it is used in the treatment for insomnia, stress and anxiety. If one has trouble getting sleep, hop tea before going to bed may help, though a quantity of beer has similar results.
Hops' antibacterial qualities also stimulate gastric juice production.
Hops have been studied for anti-viral properties [1] and antimycobacterial properties[2]. They also contain numerous various flavonoids[3], and they have been studied for containing Estrogen precursors as well. [4]
## Fibre
The stem is flexible and very tough, with a tenacious fibre that has been used in some cases to make cloth and paper. It may be noted that hops are closely related to hemp, which is also used for fibre.
## Julmust
Hops are an ingredient in Julmust, a carbonated beverage popular in Sweden during the month of December.
## Other uses
Tender young hop shoots, which are only available for about three weeks during spring, were mainly eaten by the poor in medieval times, and were a substitute for asparagus. Only recently have they been rediscovered as a delicacy in parts of Germany, Belgium and England. They are served raw with vinaigrette, or boiled with fresh herbs or fried in batter. In the italian region of Veneto, they are called bruscàndołi and are used to prepare risotto or frittata.
Wild hops are also relished by cows, horses, goats, sheep, and pigs.
Another use for the hop bine once it has reached full growth is to be cut down and used as a decoration in public houses or in kitchens. In the old wives' tale, the hop bine is supposed to bring good luck. In some parts of Kent and Sussex there are signs alongside the road advertising the sale of hop bines. Because of fierce competition in the hop trade, some farms find that sale of bines for this purpose is better than selling the hops themselves, since a pint of beer only requires one and a half hops.
Hops has also been used to increase breast milk production between woman with a low milk supply.
# Notes
- ↑ http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_uids=15550272&dopt=Citation
- ↑ http://www3.interscience.wiley.com/cgi-bin/abstract/109675877/ABSTRACT?CRETRY=1&SRETRY=0
- ↑ http://cat.inist.fr/?aModele=afficheN&cpsidt=1731712
- ↑ http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1815392 | https://www.wikidoc.org/index.php/Hop_(plant) | |
a2cfeac65b83a46950bbeb35a4ba64596aa4d38e | wikidoc | Horseradish | Horseradish
Horseradish (Armoracia rusticana, syn. Cochlearia armoracia) is a perennial plant of the Brassicaceae family, which includes mustard, wasabi, and cabbages. The plant is probably native to southeastern Europe and western Asia, but is popular around the world today. It grows up to 1.5 metres (five feet) tall and is mainly cultivated for its large white, tapered root.
The horseradish root itself has hardly any aroma. When cut or grated, however, enzymes from the damaged plant cells break down sinigrin (a glucosinolate) to produce allyl isothiocyanate (mustard oil), which irritates the sinuses and eyes. Once grated, if not used immediately or mixed in vinegar, the root darkens and loses its pungency and becomes unpleasantly bitter when exposed to air and heat.
# History
Horseradish was cultivated in antiquity. According to Greek mythology, the Delphic Oracle told Apollo that the horseradish was worth its weight in gold. Horseradish was known in Egypt in 1500 BC and has traditionally been used by Jews from eastern Europe in Passover Seders. Cato discusses the plant in his treatises on agriculture, and a mural in Pompeii showing the plant has survived until today. Horseradish is probably the plant mentioned by Pliny the Elder in his Natural History under the name of Amoracia, and recommended by him for its medicinal qualities, and possibly the Wild Radish, or raphanos agrios of the Greeks.
Both root and leaves were used as a medicine during the Middle Ages and the root was used as a condiment on meats in Germany, Scandinavia, and Britain. It was brought to North America during Colonial times.
William Turner mentions horseradish as Red Cole in his "Herbal" (1551-1568), but not as a condiment. In "The Herball, or Generall Historie of Plantes" (1597), John Gerard describes it under the name of raphanus rusticanus, stating that it occurs wild in several parts of England. After referring to its medicinal uses, he says: "the Horse Radish stamped with a little vinegar put thereto, is commonly used among the Germans for sauce to eate fish with and such like meates as we do mustarde."
# Cultivation
Horseradish is perennial in hardiness zones 2 - 9 and can be grown as an annual in other zones, though not as successfully as in zones with both a long growing season and winter temperatures cold enough to ensure plant dormancy. After the first frost in the autumn kills the leaves, the root is dug and divided. The main root is harvested and one or more large offshoots of the main root are replanted to produce next year's crop. Horseradish left undisturbed in the garden spreads via underground shoots and can become invasive. Older roots left in the ground become woody, after which they are no longer culinarily useful, although older plants can be dug and redivided to start new plants.
## Pests and Diseases
Imported cabbageworms (Artogeia rapae) are a common caterpillar pest in horseradish. The adults are white butterflies with black spots on the forewings that are commonly seen flying around plants during the day. The caterpillars are velvety green with faint yellow stripes running lengthwise down the back and sides. Full grown caterpillars are about 1 inch in length. They move sluggishly when prodded. They overwinter in green pupal cases. Adults start appearing in gardens after the last frost and are a problem through the remainder of the growing season. There are 3 to 5 overlapping generations a year. Mature caterpillars chew large, ragged holes in the leaves leaving the large veins intact. Handpicking is an effective control strategy.
## Commercial Production
Collinsville, Illinois is the self-proclaimed "Horseradish Capital of the World" and hosts an annual International Horseradish Festival each June. Collinsville produces 60% and the surrounding area of Southwestern Illinois 85% of the world's commercially grown horseradish. Other major US growing regions include Wisconsin and Northern California.
# Culinary uses
Cooks use the terms 'horseradish' or 'prepared horseradish' to refer to the grated root of the horseradish plant mixed with vinegar. Prepared horseradish is white to creamy-beige in color. It will keep for months refrigerated but eventually will start to darken, indicating it is losing flavor and should be replaced. The leaves of the plant, which while edible aren't commonly eaten, are referred to as 'horseradish greens.' Although technically a root, horseradish is generally treated as a condiment or ingredient.
In the USA, prepared horseradish is commonly used as an ingredient in Bloody Mary cocktails, in cocktail sauce, as a sauce or spread on meat, chicken, and fish, and in sandwiches. The American fast-food restaurant chain Arby's uses horseradish in its "Horsey Sauce", which is provided as a regular condiment, alongside ketchup, mustard, and mayonnaise. This is not a common practice at its major competitors.
There are several manufacturers of prepared horseradish in the United States. The largest is Gold's Horseradish in New York which sells about 2.5 million jars each year. The company was founded during the 1930s by Hyman and Tillie Gold and later expanded by their three sons Morris, Manny & Herbert.
Horseradish sauce made from grated horseradish root and cream is a popular condiment in the United Kingdom. It is often served with roast beef, but can be used in a number of other dishes also. Also popular in the UK is Tewkesbury mustard, a blend of mustard and grated horseradish originally created in medieval times and mentioned by Shakespeare.
In Eastern European Jewish cuisine, a sweetened horseradish-vinegar sauce called chrain in Yiddish traditionally accompanies gefilte fish. There are two varieties of chrain. "Red" chrain is mixed with red beet (beetroot) and "white" chrain contains no beet. It is also popular in Poland (under the name of chrzan), in Hungary (torma), in Romania (hrean), and in Bulgaria (хрян). Having this on the Easter table is a part of Easter tradition in Eastern and Central Europe. A variety with red beet also exists and it is called ćwikła z chrzanem or simply ćwikła in Poland. Horseradish (often grated and mixed with cream, hardboiled eggs, or apples) is also a traditional Easter dish in Slovenia and in the adjacent Italian region of Friuli Venezia Giulia.
Horseradish is also used as a main ingredient for soups. In Polish Silesia region, horseradish soup is a main Easter Sunday dish.
Horseradish dyed green is often substituted for the more expensive wasabi traditionally served with sushi, even in Japan. The Japanese botanical name for horseradish is Template:Nihongo, or "Western wasabi".
Horseradish contains 2 glucosinolates (sinigrin and gluconasturtiin) which are responsible for its pungent taste.
# Nutritional value
Horseradish contains potassium, calcium, magnesium and phosphorus, as well as volatile oils, such as mustard oil, which is an antibiotic. Fresh, the plant contains average 79.31 mg of vitamin C per 100 g of raw horseradish .
# Research applications
The enzyme horseradish peroxidase, found in the plant, is used extensively in molecular biology for antibody detection, among other things. It is increasingly important in biochemical research fields.
Horseradish peroxidase (HRP) is commonly used for specifically coloring of thin (~5 micrometer) slices of tissue biopsies from patients suspected to have cancer. This is an area of human pathology called immunohistochemistry (IHC). Many molecules of HRP are bound to a polymer together with immunoglobulins that will bind to a primary immunoglobulin that recognizes a specific biomarker in cells in the tissue slices. The HRP will convert 3,3-diaminobenzidin (DAB) to a yellowish brown insoluble compound. This compound is visible in a microscope and helps the pathologist to diagnose the cancer. For more information see Histochemistry. Horseradish peroxidase has been employed in materials used to test for the presence of glucose in blood or urine.
# Medicinal applications
Known to have diuretic properties, the roots have been used to treat various minor health problems, including urinary tract infections, bronchitis, sinus congestion, and coughs. Compounds found in horseradish have been found to kill some bacterial strains. | Horseradish
Horseradish (Armoracia rusticana, syn. Cochlearia armoracia) is a perennial plant of the Brassicaceae family, which includes mustard, wasabi, and cabbages. The plant is probably native to southeastern Europe and western Asia, but is popular around the world today. It grows up to 1.5 metres (five feet) tall and is mainly cultivated for its large white, tapered root.
The horseradish root itself has hardly any aroma. When cut or grated, however, enzymes from the damaged plant cells break down sinigrin (a glucosinolate) to produce allyl isothiocyanate (mustard oil), which irritates the sinuses and eyes. Once grated, if not used immediately or mixed in vinegar, the root darkens and loses its pungency and becomes unpleasantly bitter when exposed to air and heat.
# History
Horseradish was cultivated in antiquity. According to Greek mythology, the Delphic Oracle told Apollo that the horseradish was worth its weight in gold.[verification needed] Horseradish was known in Egypt in 1500 BC and has traditionally been used by Jews from eastern Europe in Passover Seders.[1] Cato discusses the plant in his treatises on agriculture, and a mural in Pompeii showing the plant has survived until today. Horseradish is probably the plant mentioned by Pliny the Elder in his Natural History under the name of Amoracia, and recommended by him for its medicinal qualities, and possibly the Wild Radish, or raphanos agrios of the Greeks.[verification needed]
Both root and leaves were used as a medicine during the Middle Ages and the root was used as a condiment on meats in Germany, Scandinavia, and Britain.[2] It was brought to North America during Colonial times.[3]
William Turner mentions horseradish as Red Cole in his "Herbal" (1551-1568), but not as a condiment. In "The Herball, or Generall Historie of Plantes" (1597), John Gerard describes it under the name of raphanus rusticanus, stating that it occurs wild in several parts of England. After referring to its medicinal uses, he says: "the Horse Radish stamped with a little vinegar put thereto, is commonly used among the Germans for sauce to eate fish with and such like meates as we do mustarde."[verification needed]
# Cultivation
Horseradish is perennial in hardiness zones 2 - 9 and can be grown as an annual in other zones, though not as successfully as in zones with both a long growing season and winter temperatures cold enough to ensure plant dormancy. After the first frost in the autumn kills the leaves, the root is dug and divided. The main root is harvested and one or more large offshoots of the main root are replanted to produce next year's crop. Horseradish left undisturbed in the garden spreads via underground shoots and can become invasive. Older roots left in the ground become woody, after which they are no longer culinarily useful, although older plants can be dug and redivided to start new plants.[4][5]
## Pests and Diseases
Imported cabbageworms (Artogeia rapae) are a common caterpillar pest in horseradish. The adults are white butterflies with black spots on the forewings that are commonly seen flying around plants during the day. The caterpillars are velvety green with faint yellow stripes running lengthwise down the back and sides. Full grown caterpillars are about 1 inch in length. They move sluggishly when prodded. They overwinter in green pupal cases. Adults start appearing in gardens after the last frost and are a problem through the remainder of the growing season. There are 3 to 5 overlapping generations a year. Mature caterpillars chew large, ragged holes in the leaves leaving the large veins intact. Handpicking is an effective control strategy.[6]
## Commercial Production
Collinsville, Illinois is the self-proclaimed "Horseradish Capital of the World" and hosts an annual International Horseradish Festival each June. Collinsville produces 60% and the surrounding area of Southwestern Illinois 85% of the world's commercially grown horseradish. Other major US growing regions include Wisconsin and Northern California.[7]
# Culinary uses
Cooks use the terms 'horseradish' or 'prepared horseradish' to refer to the grated root of the horseradish plant mixed with vinegar. Prepared horseradish is white to creamy-beige in color. It will keep for months refrigerated but eventually will start to darken, indicating it is losing flavor and should be replaced. The leaves of the plant, which while edible aren't commonly eaten, are referred to as 'horseradish greens.' Although technically a root, horseradish is generally treated as a condiment or ingredient.
In the USA, prepared horseradish is commonly used as an ingredient in Bloody Mary cocktails, in cocktail sauce, as a sauce or spread on meat, chicken, and fish, and in sandwiches. The American fast-food restaurant chain Arby's uses horseradish in its "Horsey Sauce", which is provided as a regular condiment, alongside ketchup, mustard, and mayonnaise. This is not a common practice at its major competitors.
There are several manufacturers of prepared horseradish in the United States. The largest is Gold's Horseradish in New York which sells about 2.5 million jars each year. The company was founded during the 1930s by Hyman and Tillie Gold and later expanded by their three sons Morris, Manny & Herbert.
Horseradish sauce made from grated horseradish root and cream is a popular condiment in the United Kingdom. It is often served with roast beef, but can be used in a number of other dishes also. Also popular in the UK is Tewkesbury mustard, a blend of mustard and grated horseradish originally created in medieval times and mentioned by Shakespeare.
In Eastern European Jewish cuisine, a sweetened horseradish-vinegar sauce called chrain in Yiddish [8] traditionally accompanies gefilte fish. There are two varieties of chrain. "Red" chrain is mixed with red beet (beetroot) and "white" chrain contains no beet. It is also popular in Poland (under the name of chrzan), in Hungary (torma), in Romania (hrean), and in Bulgaria (хрян). Having this on the Easter table is a part of Easter tradition in Eastern and Central Europe. A variety with red beet also exists and it is called ćwikła z chrzanem or simply ćwikła in Poland. Horseradish (often grated and mixed with cream, hardboiled eggs, or apples) is also a traditional Easter dish in Slovenia and in the adjacent Italian region of Friuli Venezia Giulia.
Horseradish is also used as a main ingredient for soups. In Polish Silesia region, horseradish soup is a main Easter Sunday dish[9].
Horseradish dyed green is often substituted for the more expensive wasabi traditionally served with sushi, even in Japan.[10] The Japanese botanical name for horseradish is Template:Nihongo, or "Western wasabi".
Horseradish contains 2 glucosinolates (sinigrin and gluconasturtiin) which are responsible for its pungent taste.[11]
# Nutritional value
Horseradish contains potassium, calcium, magnesium and phosphorus, as well as volatile oils, such as mustard oil, which is an antibiotic. Fresh, the plant contains average 79.31 mg of vitamin C per 100 g of raw horseradish [12].
# Research applications
The enzyme horseradish peroxidase, found in the plant, is used extensively in molecular biology for antibody detection, among other things. It is increasingly important in biochemical research fields.[13]
Horseradish peroxidase (HRP) is commonly used for specifically coloring of thin (~5 micrometer) slices of tissue biopsies from patients suspected to have cancer. This is an area of human pathology called immunohistochemistry (IHC). Many molecules of HRP are bound to a polymer together with immunoglobulins that will bind to a primary immunoglobulin that recognizes a specific biomarker in cells in the tissue slices. The HRP will convert 3,3-diaminobenzidin (DAB) to a yellowish brown insoluble compound. This compound is visible in a microscope and helps the pathologist to diagnose the cancer. For more information see Histochemistry. Horseradish peroxidase has been employed in materials used to test for the presence of glucose in blood or urine[citation needed].
# Medicinal applications
Known to have diuretic properties, the roots have been used to treat various minor health problems, including urinary tract infections, bronchitis, sinus congestion, and coughs. Compounds found in horseradish have been found to kill some bacterial strains.[14]
Template:Herbs & spices | https://www.wikidoc.org/index.php/Horseradish | |
4be3725af7674a89b886e59eca969d1bd9ed6933 | wikidoc | Hot springs | Hot springs
A hot spring is a spring that is produced by the emergence of geothermally-heated groundwater from the earth's crust. There are hot springs all over the earth, on every continent and even under the oceans and seas.
# Definitions
There is no universally accepted definition of a hot spring. For example, one can find the phrase hot spring defined as
- any geothermal spring
- a spring with water temperatures above its surroundings
- a natural spring with water temperature above body temperature – normally between 36.5 °C (97.7 °F) and 37.5 °C (99.5 °F)
- a natural spring with warm water above body temperature
- a thermal spring with water warmer than 36.7 °C (98.1 °F)
- a natural spring of water greater than 21.1 °C (70 °F) (synonymous with thermal spring)
- a natural discharge of groundwater with elevated temperatures
- a type of thermal spring in which hot water is brought to the surface. The water temperature of a hot spring is usually 6.5 °C (11.7 °F) or more above mean air temperature. Note that by this definition, "thermal spring" is not synonymous with the term "hot spring".
- a spring whose hot water is brought to the surface (synonymous with a thermal spring). The water temperature of the spring is usually 8.3 °C (14.9 °F) or more above the mean air temperature.
- a spring with water above the core human body temperature – 36.7 °C (98.1 °F).
- a spring with water above average ambient ground temperature, a definition favored by some.
- a spring with water temperatures above 50 °C (122 °F)
The related term "warm spring" is defined as a spring with water temperature less than a hot spring by many sources, although Pentecost et al (2003) suggest that the phrase "warm spring" is not useful and should be avoided. The US NOAA Geophysical Data Center defines a "warm spring" as a spring with water between 20 °C (68 °F) and 50 °C (122 °F). The ♨ symbol is commonly used on maps to denote a hot spring.
# Sources of heat
The water issuing from a hot spring is heated by geothermal heat, i.e., heat from the Earth's interior. In general, the temperature of rocks within the earth increases with depth. The rate of temperature increase with depth is known as the geothermal gradient. If water percolates deeply enough into the crust, it will be heated as it comes into contact with hot rocks. The water from hot springs in non-volcanic areas is heated in this manner.
In volcanic zones such as Yellowstone National Park, water may be heated by coming into contact with magma (molten rock). The high temperature gradient near magma may cause water to be heated enough that it boils or becomes superheated. If the water becomes so hot that it builds steam pressure and erupts in a jet above the surface of the Earth, it is called a geyser. If the water only reaches the surface in the form of steam, it is called a fumarole. If the water is mixed with mud and clay, it is called a mud pot.
Note that hot springs in volcanic areas are often at or near the boiling point. People have been seriously burned and even killed by accidentally or intentionally entering these springs.
Warm springs are sometimes the result of hot and cold springs mixing but may also occur outside of volcanic areas, such as Warm Springs, Georgia (frequented for its therapeutic effects by paraplegic U.S. President Franklin D. Roosevelt, who built the Little White House there).
# Flow rates
Hot springs range in flow rate from the tiniest "seeps" to veritable rivers of hot water. Sometimes there is enough pressure that the water shoots upward in a geyser, or fountain.
A very low flow rate hot spring fed the closed resort, Fales Hot Ditch, which is north of Bridgeport, California. There is a huge subterranean lake below Tonopah, Arizona, which provides natural hot mineral waters to several hot springs. These hot springs were used by the seven or more hot spring spas that once operated in Tonopah. The ruins of two such spas are still visible in Tonopah.
## High flow hot springs
There are many claims in the literature about the flow rates of hot springs. Some of the hot springs with high flow rates and high claimed flow rates. It should be noted that there are many more very high flow nonthermal springs than geothermal springs. For example, there are 33 recognized "magnitude one springs" (having a flow in excess of 2,800 liters/second) in Florida alone. Silver Springs, Florida has a flow of more than 21,000 liters/second. Springs with high flow rates include:
- The combined flow of the 47 hot springs in Hot Springs, Arkansas is 35 liters/second.
- The combined flow of the hot springs complex in Truth or Consequences, New Mexico is estimated at 99 liters/second.
- Lava Hot Springs in Idaho has a flow of 130 liters/second.
- Glenwood Springs in Colorado has a flow of 143 liters/second.
- Elizabeth Springs in western Queensland, Australia might have had a flow of 158 liters/second in the late 1800s, but now has a flow of about 5 liters/second
- Deildartunguhver in Iceland has a flow of 180 liters/second.
- The hot springs of Brazil's Caldas Novas ("Hot River" in Portuguese) are tapped by 86 wells, from which 333 liters/second are pumped for 14 hours per day. This corresponds to a peak average flow rate of 3.89 liters/second per well.
- The 2,850 hot springs of Beppu in Japan are the highest flow hot spring complex in Japan. Together the Beppu hot springs produce about 1,592 liters/second, or corresponding to an average hot spring flow of 0.56 liters/second.
- The 303 hot springs of Kokonoe in Japan produce 1,028 liters/second, which gives the average hot spring a flow of 3.39 liters/second.
- The Oita Prefecture has 4,762 hot springs, with a total flow of 4,437 liters/second, so the average hot spring flow is 0.93 liters/second.
- The highest flow rate hot spring in Japan is the Tamagawa Hot Spring in Akita Prefecture, which has a flow rate of 150 liters/second. The Tamagawa Hot Spring feeds a 3 m (9.8425197 ft) wide stream with a temperature of 98 °C (208.4 °F).
- There are at least three hot springs in the Nage region 8 km (4.970969536 mi) south west of Bajawa City in Indonesia that collectively produce more than 453.6 liters/second.
- There are another three large hot springs (Mengeruda, Wae Bana and Piga) 18 km (11.184681456 mi) north east of Bajawa City, Indonesia that together produce more than 450 liters/second of hot water.
- The Dalhousie Springs complex in Australia had a peak total flow of more than 23,000 liters/second in 1915, giving the average spring in the complex an output of more than 325 liters/second. This has been reduced now to a peak total fow of 17,370 liters/second so the average spring has a peak output of about 250 liters/second.
# Therapeutic uses
Because heated water can hold more dissolved solids, warm and especially hot springs also often have a very high mineral content, containing everything from simple calcium to lithium, and even radium. Because of both the folklore and the claimed medical value some of these springs have, they are often popular tourist destinations, and locations for rehabilitation clinics for those with disabilities.
# Infections from hot springs
Unfortunately, hot springs can create ideal conditions to spread infections. For example:
- Naegleria fowleri, an amoeba, lives in warm waters and soils worldwide and can be a cause of meningitis. Several deaths have been attributed to this amoeba, which enters the brain through the nasal passages.
- Acanthamoeba also can spread through hot springs, according to the US Centers for Disease Control.
- Legionella bacteria have been spread through hot springs.
- A bather may have been infected by the herpes simplex virus in his toe from a hot spring in Japan.
- Viruses have been collected from very extreme environments, for example, a hot spring with a temperature of 87 °C (188.6 °F) to 93 °C (199.4 °F) and an incredibly acidic pH of 1.5 in Pozzuoli, Italy. These viruses were observed to infect cells in the laboratory.
# Hot springs around the world
There are hot springs on all continents and in many countries around the world. Countries that are renowned for their hot springs include Iceland, New Zealand, Chile, Canada, Taiwan,
and Japan, but there are interesting and unique hot springs in many other places as well:
- The town of Spa, Belgium is the origin of the word "spa" and features springs with water temperatures of 32 °C (89.6 °F). Casanova visited Spa in 1783 looking for business opportunities but was disappointed.
- Aachen, Germany has the hottest springs of Central Europe with water temperatures of 74 °C (165.2 °F).
- There are more than 275 hot springs registered in Chile including South America's largest hot spring source in Liquiñe.
- The Yangbajing hot springs field about 87 km. north of Lhasa in Tibet is several square kilometers in size, and used to supply a large fraction of the electricity of Lhasa. At an altitude between 4,290 m (14,074.803171 ft) and 4,500 m (14,763.77955 ft), this is a strong candidate for the highest altitude set of hot springs on earth.
- Taiwan, is ranked among one of the world's top hot spring sites, harboring a great variety of springs, including hot springs, cold springs, mud springs, and seabed hot springs.
- Icaria, Greece features a radioactive hot water spring that has been used since the fourth century BCE.
- There are numerous hot springs in Greenland, such as in Uunartoq. There are over 2000 hot springs just on Disko Island, which has an area only 0.4% of that of Greenland.
- The Geysir hot springs in Iceland are the source of the word "geyser".
- The closest town to Machu Picchu in Peru is Machu Picchu Pueblo, which features several hot springs. The local name for Machu Picchu Pueblo is Aguas Calientes.
- Iceland has many famous hot springs, including the one feeding the Blue Lagoon spa in Grindavík, Iceland, and Europe's highest flow rate hot spring Deildartunguhver. Deildartunguhver's water emerges at 97 °C (206.6 °F) and is piped many miles to heat neighboring towns.
- Shiretoko National Park in Hokkaidō, Japan has a hot springs waterfall called Kamuiwakkayu-no-taki, which translates as "river of the gods" in the Ainu language.
- Northwest Spitsbergen National Park, Spitsbergen at 80 degrees north, contains two of earth's most northerly hot springs.
- There are many geothermal springs in the UK, but the thermal springs found in the town of Bath produce the highest temperature geothermal water in the UK. The Bath hot springs are only true hot springs in the UK, by some definitions.
- Oymyakon in eastern Siberia is a candidate for the coldest permanently-inhabited location in the Northern Hemisphere and another hot springs site. The Yakut language word "oymyakon" means "river doesn't freeze" after the local tributary of the Indigirka River fed by the hot springs which continues to flow year round in this permafrost region.
- Being located in the "Pacific Ring of Fire", Japan is in a volcanic region, and is home to many hot springs. The onsen (a Japanese word for "hot spring") plays a notable role in Japanese culture. Visiting an onsen is a quintessential Japanese experience and is a popular tourist activity.
- Chutsen Chugang Hot Springs are located on the grounds of the Zhoto Terdrom / Tidro Nunnery, at an altitude of 4400 meters in Maldrogongkar / Mozhugongka County, Lhasa, Tibet. Buddhist nuns and the "hot spring snake" both live near this set of high altitude hot springs.
- there is a hot spring on Deception Island in Antarctica.
- Champaign Hot Springs is a shallow submarine geothermal spring system along the coast of the island of Dominica, Lesser Antilles. | Hot springs
A hot spring is a spring that is produced by the emergence of geothermally-heated groundwater from the earth's crust. There are hot springs all over the earth, on every continent and even under the oceans and seas.
# Definitions
There is no universally accepted definition of a hot spring. For example, one can find the phrase hot spring defined as
- any geothermal spring[1]
- a spring with water temperatures above its surroundings[2]
- a natural spring with water temperature above body temperature – normally between 36.5 °C (97.7 °F) and 37.5 °C (99.5 °F)[3]
- a natural spring with warm water above body temperature[4]
- a thermal spring with water warmer than 36.7 °C (98.1 °F)[5] [6]
- a natural spring of water greater than 21.1 °C (70 °F) (synonymous with thermal spring) [7][8][9][10]
- a natural discharge of groundwater with elevated temperatures[11]
- a type of thermal spring in which hot water is brought to the surface. The water temperature of a hot spring is usually 6.5 °C (11.7 °F) or more above mean air temperature. [12][13] Note that by this definition, "thermal spring" is not synonymous with the term "hot spring".
- a spring whose hot water is brought to the surface (synonymous with a thermal spring). The water temperature of the spring is usually 8.3 °C (14.9 °F) or more above the mean air temperature.[14]
- a spring with water above the core human body temperature – 36.7 °C (98.1 °F).[15]
- a spring with water above average ambient ground temperature[16], a definition favored by some.
- a spring with water temperatures above 50 °C (122 °F)[17]
The related term "warm spring" is defined as a spring with water temperature less than a hot spring by many sources, although Pentecost et al (2003) suggest that the phrase "warm spring" is not useful and should be avoided.[18] The US NOAA Geophysical Data Center defines a "warm spring" as a spring with water between 20 °C (68 °F) and 50 °C (122 °F). The ♨ symbol is commonly used on maps to denote a hot spring.
# Sources of heat
The water issuing from a hot spring is heated by geothermal heat, i.e., heat from the Earth's interior. In general, the temperature of rocks within the earth increases with depth. The rate of temperature increase with depth is known as the geothermal gradient. If water percolates deeply enough into the crust, it will be heated as it comes into contact with hot rocks. The water from hot springs in non-volcanic areas is heated in this manner.
In volcanic zones such as Yellowstone National Park, water may be heated by coming into contact with magma (molten rock). The high temperature gradient near magma may cause water to be heated enough that it boils or becomes superheated. If the water becomes so hot that it builds steam pressure and erupts in a jet above the surface of the Earth, it is called a geyser. If the water only reaches the surface in the form of steam, it is called a fumarole. If the water is mixed with mud and clay, it is called a mud pot.
Note that hot springs in volcanic areas are often at or near the boiling point. People have been seriously burned and even killed by accidentally or intentionally entering these springs.
Warm springs are sometimes the result of hot and cold springs mixing but may also occur outside of volcanic areas, such as Warm Springs, Georgia (frequented for its therapeutic effects by paraplegic U.S. President Franklin D. Roosevelt, who built the Little White House there).
# Flow rates
Hot springs range in flow rate from the tiniest "seeps" to veritable rivers of hot water. Sometimes there is enough pressure that the water shoots upward in a geyser, or fountain.
A very low flow rate hot spring fed the closed resort, Fales Hot Ditch, which is north of Bridgeport, California. There is a huge subterranean lake below Tonopah, Arizona, which provides natural hot mineral waters to several hot springs. These hot springs were used by the seven or more hot spring spas that once operated in Tonopah. The ruins of two such spas are still visible in Tonopah.
## High flow hot springs
There are many claims in the literature about the flow rates of hot springs. Some of the hot springs with high flow rates and high claimed flow rates. It should be noted that there are many more very high flow nonthermal springs than geothermal springs. For example, there are 33 recognized "magnitude one springs" (having a flow in excess of 2,800 liters/second) in Florida alone. Silver Springs, Florida has a flow of more than 21,000 liters/second. Springs with high flow rates include:
- The combined flow of the 47 hot springs in Hot Springs, Arkansas is 35 liters/second.
- The combined flow of the hot springs complex in Truth or Consequences, New Mexico is estimated at 99 liters/second.[19]
- Lava Hot Springs in Idaho has a flow of 130 liters/second.
- Glenwood Springs in Colorado has a flow of 143 liters/second.
- Elizabeth Springs in western Queensland, Australia might have had a flow of 158 liters/second in the late 1800s, but now has a flow of about 5 liters/second
- Deildartunguhver in Iceland has a flow of 180 liters/second.
- The hot springs of Brazil's Caldas Novas ("Hot River" in Portuguese) are tapped by 86 wells, from which 333 liters/second are pumped for 14 hours per day. This corresponds to a peak average flow rate of 3.89 liters/second per well.
- The 2,850 hot springs of Beppu in Japan are the highest flow hot spring complex in Japan. Together the Beppu hot springs produce about 1,592 liters/second, or corresponding to an average hot spring flow of 0.56 liters/second.
- The 303 hot springs of Kokonoe in Japan produce 1,028 liters/second, which gives the average hot spring a flow of 3.39 liters/second.
- The Oita Prefecture has 4,762 hot springs, with a total flow of 4,437 liters/second, so the average hot spring flow is 0.93 liters/second.
- The highest flow rate hot spring in Japan is the Tamagawa Hot Spring in Akita Prefecture, which has a flow rate of 150 liters/second. The Tamagawa Hot Spring feeds a 3 m (9.8425197 ft) wide stream with a temperature of 98 °C (208.4 °F).
- There are at least three hot springs in the Nage region 8 km (4.970969536 mi) south west of Bajawa City in Indonesia that collectively produce more than 453.6 liters/second.
- There are another three large hot springs (Mengeruda, Wae Bana and Piga) 18 km (11.184681456 mi) north east of Bajawa City, Indonesia that together produce more than 450 liters/second of hot water.
- The Dalhousie Springs complex in Australia had a peak total flow of more than 23,000 liters/second in 1915, giving the average spring in the complex an output of more than 325 liters/second. This has been reduced now to a peak total fow of 17,370 liters/second so the average spring has a peak output of about 250 liters/second.[20]
# Therapeutic uses
Because heated water can hold more dissolved solids, warm and especially hot springs also often have a very high mineral content, containing everything from simple calcium to lithium, and even radium. Because of both the folklore and the claimed medical value some of these springs have, they are often popular tourist destinations, and locations for rehabilitation clinics for those with disabilities.[21][22]
# Infections from hot springs
Unfortunately, hot springs can create ideal conditions to spread infections. For example:
- Naegleria fowleri, an amoeba, lives in warm waters and soils worldwide and can be a cause of meningitis.[23][24] Several deaths have been attributed to this amoeba, which enters the brain through the nasal passages.[25][26]
- Acanthamoeba also can spread through hot springs, according to the US Centers for Disease Control.[27]
- Legionella bacteria have been spread through hot springs.[28][29]
- A bather may have been infected by the herpes simplex virus in his toe from a hot spring in Japan.[30]
- Viruses have been collected from very extreme environments, for example, a hot spring with a temperature of 87 °C (188.6 °F) to 93 °C (199.4 °F) and an incredibly acidic pH of 1.5 in Pozzuoli, Italy. These viruses were observed to infect cells in the laboratory.[31]
# Hot springs around the world
There are hot springs on all continents and in many countries around the world. Countries that are renowned for their hot springs include Iceland, New Zealand, Chile, Canada, Taiwan,
and Japan, but there are interesting and unique hot springs in many other places as well:
- The town of Spa, Belgium is the origin of the word "spa" and features springs with water temperatures of 32 °C (89.6 °F). Casanova visited Spa in 1783 looking for business opportunities but was disappointed.[32]
- Aachen, Germany has the hottest springs of Central Europe with water temperatures of 74 °C (165.2 °F).
- There are more than 275 hot springs registered in Chile including South America's largest hot spring source in Liquiñe.[citation needed]
- The Yangbajing hot springs field about 87 km. north of Lhasa in Tibet is several square kilometers in size, and used to supply a large fraction of the electricity of Lhasa. At an altitude between 4,290 m (14,074.803171 ft) and 4,500 m (14,763.77955 ft), this is a strong candidate for the highest altitude set of hot springs on earth.
- Taiwan, is ranked among one of the world's top hot spring sites, harboring a great variety of springs, including hot springs, cold springs, mud springs, and seabed hot springs.
- Icaria, Greece features a radioactive hot water spring that has been used since the fourth century BCE.
- There are numerous hot springs in Greenland, such as in Uunartoq. There are over 2000 hot springs just on Disko Island, which has an area only 0.4% of that of Greenland.
- The Geysir hot springs in Iceland are the source of the word "geyser".
- The closest town to Machu Picchu in Peru is Machu Picchu Pueblo, which features several hot springs. The local name for Machu Picchu Pueblo is Aguas Calientes.
- Iceland has many famous hot springs, including the one feeding the Blue Lagoon spa in Grindavík, Iceland, and Europe's highest flow rate hot spring Deildartunguhver. Deildartunguhver's water emerges at 97 °C (206.6 °F) and is piped many miles to heat neighboring towns.
- Shiretoko National Park in Hokkaidō, Japan has a hot springs waterfall called Kamuiwakkayu-no-taki, which translates as "river of the gods" in the Ainu language.
- Northwest Spitsbergen National Park, Spitsbergen at 80 degrees north, contains two of earth's most northerly hot springs.
- There are many geothermal springs in the UK, but the thermal springs found in the town of Bath produce the highest temperature geothermal water in the UK. The Bath hot springs are only true hot springs in the UK, by some definitions.
- Oymyakon in eastern Siberia is a candidate for the coldest permanently-inhabited location in the Northern Hemisphere and another hot springs site. The Yakut language word "oymyakon" means "river doesn't freeze" after the local tributary of the Indigirka River fed by the hot springs which continues to flow year round in this permafrost region.
- Being located in the "Pacific Ring of Fire", Japan is in a volcanic region, and is home to many hot springs. The onsen (a Japanese word for "hot spring") plays a notable role in Japanese culture. Visiting an onsen is a quintessential Japanese experience and is a popular tourist activity.
- Chutsen Chugang Hot Springs are located on the grounds of the Zhoto Terdrom / Tidro Nunnery, at an altitude of 4400 meters in Maldrogongkar / Mozhugongka County, Lhasa, Tibet. Buddhist nuns and the "hot spring snake" both live near this set of high altitude hot springs.
- there is a hot spring on Deception Island in Antarctica.
- Champaign Hot Springs is a shallow submarine geothermal spring system along the coast of the island of Dominica, Lesser Antilles.[33] | https://www.wikidoc.org/index.php/Hot_springs | |
47afedc647ab88d244a3245c05682ce6ddae88b9 | wikidoc | Human feces | Human feces
# Overview
Human feces (also faeces — see spelling differences), also known as stools, vary significantly in appearance, depending on the state of the whole digestive system, influenced by diet and health. Normally they are semisolid, with mucus coating. Small pieces of harder, less moist feces can sometimes be seen impacted on the distal end (a normal occurrence when a prior bowel movement is incomplete, and faeces are returned from the rectum to the intestine, where water is absorbed).
Meconium (sometimes erroneously spelled merconium) is a newborn baby's first feces.
Due to its taboo, feces are a subject of toilet humour.
# Composition
The main composition of human feces is water, indigestible food material (fiber), i like to crap on my hands then lick my hands, sloughed-off intestinal cells, bacteria and various organic compounds. One of the main purposes of defecation is to discharge waste and toxic substances from the body, thus these substances (such as bile pigments) attribute to the composition of human feces. Although fecal material in the human colon contains more water than other matter, 90% of the water will be absorbed by the large intestine before being expelled. This percentage changes however; and diarrhoea patients have more water than average and the longer the piece is in the bowels, the more water is taken out. The colon contains large numbers of bacteria that make up about one-third to one-half of the dry weight of the feces. As fecal matter moves along the colon, dead cells are sloughed off and added to the fecal matter and, in some cases can cause anal bleeding or bloody stools due to excessive abrasiveness within the colon.
# Fecal management
The problem of efficient management of feces has existed since the times when people started to live in permanent settlements, primarily for the reasons of cleanliness and odor. Toilets were known in ancient India (dated as early as 2,500 BC), in Ancient Rome, Egypt and China.
The use of feces is an issue of hygiene, since feces contribute to spreading of diseases and intestinal parasites. It is a matter of attention and education in developing countries.
Until the end of the 19th century, the primary concern of sewage collection and disposal in the Western world was to remove waste away from inhabited places, and it was common to use waterflows and larger bodies of water as a destination of sewage, where waste could be naturally dissipated and neutralized. With the increased population density this is no longer a viable solution, and special processing of sewage is required. The lack of the latter is a grave sanitary and public health problem in developing countries.
The urge to defecate after eating a meal is a natural reflex called the gastrocolic reflex.
## Tourism
Nature reserve organizations, parks, and tourist agencies often issue regulations for tourists aimed at the prevention of the pollution of the nature. In particular, catholes (cat holes), i.e., pits for feces, must be located at a reasonable distance (at least 60 m/200 feet) from water sources (rivers, lakes, etc.), to avoid possible bacterial contamination of water via precipitation, as well as away from trails. For faster feces decomposition, organic soil is preferred over sandy mineral soil. It is also recommended to avoid concentration of catholes around campsites. Filled catholes must be covered with a reasonably thick layer of soil, to prevent access by animals, some of which are coprophagous.
Some areas require special instructions on human waste disposal. In rocky places, with the absence of soil, it is advised to spread feces thinly by smearing over rocks with good sun access for faster sterilization by UV radiation and drying. In larger snow fields, a larger distance (e.g., 200 m/650 feet) from trails and campsites may be mandated, if the waste is being disposed under snow.
# Laboratory testing of feces
Feces will sometimes be required for microbiological testing, looking for an intestinal pathogen or other parasite or disease.
Biochemical tests done on feces include faecal elastase and faecal fat measurements, as well as tests for faecal occult blood.
It is recommended that the clinician correlate the symptoms and submit specimens according to laboratory guidelines to obtain results that are clinically significant. Formed stools often do not give satisfactory results and suggest little of actual pathologic conditions.
Three main types of microbiological tests are commonly done on feces:
- Antibody-antigen type tests, that look for a specific virus (e.g. rotavirus).
- Microscopic examination for intestinal parasites and their ova (eggs).
- Routine culture.
Routine culture involves streaking the sample onto agar plates containing special additives, such as MacConkey agar, that will inhibit the growth of Gram-positive organisms and will selectively allow enteric pathogens to grow, and incubating them for a period, and observing the bacterial colonies that have grown.
# Color variations of feces
Yellowing of feces can be caused by an infection known as Giardiasis, which derives its name from Giardia, a tiny parasitic organism. If Giardia infects the intestines it can cause severe yellow diarrhea. This is a dangerous communicable infection and must be reported.
Another cause of yellowing is a condition known as Gilbert's Syndrome. This condition is characterized by jaundice and hyperbilirubinemia. Hyperbilirubinemia occurs when too much bilirubin is present in the circulating blood.
Feces can be black due to the presence of blood that has been in the intestines long enough to be broken down by digestive enzymes. This is known as melena, and is typically due to bleeding in the upper digestive tract, such as from a bleeding peptic ulcer. The black color is caused by oxidation of the iron in the blood's hemoglobin. Black feces can also be caused by a number of medications, such as bismuth subsalicylate, and dietary iron supplements. Hematochezia is similarly the passage of feces that are bright red due to the presence of undigested blood, either from lower in the digestive tract, or from a more active source in the upper digestive tract.
In children with certain illnesses, feces can be blue or green. Eating green or leafy food can turn feces green. Babies when digesting solid food for the first time also produce feces which tends to be green and of unusual consistency because of the presence of cells discarded during development of the digestive tract.
Food with large amounts of food color can cause feces to be colored. An example is FDA Blue #5, which turns feces green when it reacts with bile in the intestine. The effect is considered harmless, and there have been no reports of ill effects.
# Fecal contamination
A quick test for fecal contamination of water sources or soil is a check for the presence of E. coli bacteria performed with the help of MacConkey agar plates or Petri dishes. E. coli bacteria uniquely develop red colonies at temperature of approximately 43 °C (110 °F) overnight. While most strains of E. coli are harmless, their presence is indicative of more serious fecal contamination, and hence a high possibility of more dangerous organisms.
Fecal contamination of water sources is highly prevalent worldwide, accounting for the majority of unsafe drinking water, which is the only water available to 1.1 billion people. In developing countries most sewage is discharged without treatment. Even in developed countries events of sanitary sewer overflow are not uncommon and regularly pollute the Seine River (France) and the River Thames (England), for example.
The main pathogens that are commonly looked for in feces include:
- Salmonella and Shigella
- Yersinia (this tends to be incubated at 30 °C, which is cooler than usual.)
- Campylobacter (incubated at 42 °C, in a special environment.)
- Aeromonas
- Candida (if the person is immunosuppressed e.g. cancer treatment.)
- E. coli O157 (if blood is visible in the stool sample.)
- Cryptosporidium | Human feces
# Overview
Human feces (also faeces — see spelling differences), also known as stools, vary significantly in appearance, depending on the state of the whole digestive system, influenced by diet and health. Normally they are semisolid, with mucus coating. Small pieces of harder, less moist feces can sometimes be seen impacted on the distal end (a normal occurrence when a prior bowel movement is incomplete, and faeces are returned from the rectum to the intestine, where water is absorbed).
Meconium (sometimes erroneously spelled merconium) is a newborn baby's first feces.
Due to its taboo, feces are a subject of toilet humour.
# Composition
The main composition of human feces is water, indigestible food material (fiber), i like to crap on my hands then lick my hands, sloughed-off intestinal cells, bacteria and various organic compounds. One of the main purposes of defecation is to discharge waste and toxic substances from the body, thus these substances (such as bile pigments) attribute to the composition of human feces. Although fecal material in the human colon contains more water than other matter, 90% of the water will be absorbed by the large intestine before being expelled. This percentage changes however; and diarrhoea patients have more water than average and the longer the piece is in the bowels, the more water is taken out. The colon contains large numbers of bacteria that make up about one-third to one-half of the dry weight of the feces. As fecal matter moves along the colon, dead cells are sloughed off and added to the fecal matter and, in some cases can cause anal bleeding or bloody stools due to excessive abrasiveness within the colon.
# Fecal management
The problem of efficient management of feces has existed since the times when people started to live in permanent settlements, primarily for the reasons of cleanliness and odor. Toilets were known in ancient India (dated as early as 2,500 BC), in Ancient Rome, Egypt and China.
The use of feces is an issue of hygiene, since feces contribute to spreading of diseases and intestinal parasites. It is a matter of attention and education in developing countries.
Until the end of the 19th century, the primary concern of sewage collection and disposal in the Western world was to remove waste away from inhabited places, and it was common to use waterflows and larger bodies of water as a destination of sewage, where waste could be naturally dissipated and neutralized. With the increased population density this is no longer a viable solution, and special processing of sewage is required. The lack of the latter is a grave sanitary and public health problem in developing countries.
The urge to defecate after eating a meal is a natural reflex called the gastrocolic reflex.
## Tourism
Nature reserve organizations, parks, and tourist agencies often issue regulations for tourists aimed at the prevention of the pollution of the nature. In particular, catholes (cat holes), i.e., pits for feces, must be located at a reasonable distance (at least 60 m/200 feet) from water sources (rivers, lakes, etc.), to avoid possible bacterial contamination of water via precipitation, as well as away from trails. For faster feces decomposition, organic soil is preferred over sandy mineral soil. It is also recommended to avoid concentration of catholes around campsites. Filled catholes must be covered with a reasonably thick layer of soil, to prevent access by animals, some of which are coprophagous.
Some areas require special instructions on human waste disposal. In rocky places, with the absence of soil, it is advised to spread feces thinly by smearing over rocks with good sun access for faster sterilization by UV radiation and drying. In larger snow fields, a larger distance (e.g., 200 m/650 feet) from trails and campsites may be mandated, if the waste is being disposed under snow.
# Laboratory testing of feces
Feces will sometimes be required for microbiological testing, looking for an intestinal pathogen or other parasite or disease.
Biochemical tests done on feces include faecal elastase and faecal fat measurements, as well as tests for faecal occult blood.
It is recommended that the clinician correlate the symptoms and submit specimens according to laboratory guidelines to obtain results that are clinically significant. Formed stools often do not give satisfactory results and suggest little of actual pathologic conditions.
Three main types of microbiological tests are commonly done on feces:
- Antibody-antigen type tests, that look for a specific virus (e.g. rotavirus).
- Microscopic examination for intestinal parasites and their ova (eggs).
- Routine culture.
Routine culture involves streaking the sample onto agar plates containing special additives, such as MacConkey agar, that will inhibit the growth of Gram-positive organisms and will selectively allow enteric pathogens to grow, and incubating them for a period, and observing the bacterial colonies that have grown.
# Color variations of feces
Yellowing of feces can be caused by an infection known as Giardiasis, which derives its name from Giardia, a tiny parasitic organism. If Giardia infects the intestines it can cause severe yellow diarrhea. This is a dangerous communicable infection and must be reported.
Another cause of yellowing is a condition known as Gilbert's Syndrome. This condition is characterized by jaundice and hyperbilirubinemia. Hyperbilirubinemia occurs when too much bilirubin is present in the circulating blood.
Feces can be black due to the presence of blood that has been in the intestines long enough to be broken down by digestive enzymes. This is known as melena, and is typically due to bleeding in the upper digestive tract, such as from a bleeding peptic ulcer. The black color is caused by oxidation of the iron in the blood's hemoglobin. Black feces can also be caused by a number of medications, such as bismuth subsalicylate, and dietary iron supplements. Hematochezia is similarly the passage of feces that are bright red due to the presence of undigested blood, either from lower in the digestive tract, or from a more active source in the upper digestive tract.
In children with certain illnesses, feces can be blue or green. Eating green or leafy food can turn feces green. Babies when digesting solid food for the first time also produce feces which tends to be green and of unusual consistency because of the presence of cells discarded during development of the digestive tract.
Food with large amounts of food color can cause feces to be colored. An example is FDA Blue #5, which turns feces green when it reacts with bile in the intestine. The effect is considered harmless, and there have been no reports of ill effects.
# Fecal contamination
A quick test for fecal contamination of water sources or soil is a check for the presence of E. coli bacteria performed with the help of MacConkey agar plates or Petri dishes. E. coli bacteria uniquely develop red colonies at temperature of approximately 43 °C (110 °F) overnight. While most strains of E. coli are harmless, their presence is indicative of more serious fecal contamination, and hence a high possibility of more dangerous organisms.
Fecal contamination of water sources is highly prevalent worldwide, accounting for the majority of unsafe drinking water, which is the only water available to 1.1 billion people. In developing countries most sewage is discharged without treatment. Even in developed countries events of sanitary sewer overflow are not uncommon and regularly pollute the Seine River (France) and the River Thames (England), for example.
The main pathogens that are commonly looked for in feces include:
- Salmonella and Shigella
- Yersinia (this tends to be incubated at 30 °C, which is cooler than usual.)
- Campylobacter (incubated at 42 °C, in a special environment.)
- Aeromonas
- Candida (if the person is immunosuppressed e.g. cancer treatment.)
- E. coli O157 (if blood is visible in the stool sample.)
- Cryptosporidium | https://www.wikidoc.org/index.php/Human_feces | |
f4869f9bfe4798e385e52057ec9ffb3848224a6b | wikidoc | Human flora | Human flora
The human body contains a large number of microrganisms, such as bacteria, fungi and archaea, some of these organisms perform tasks that are useful, while the majority have no beneficial or harmful effect. Those that are expected to be present, and that under normal circumstances do not cause disease, are termed normal flora.
# Bacterial flora
It is estimated that 500 to 100,000 species of bacteria live in the human body . Bacterial cells are much smaller than human cells, and there are about ten times as many bacteria as human cells in the body (1000 trillion (1015) versus 100 trillion (1014)). Though normal flora are found on all surfaces exposed to the environment (on the skin and eyes, in the mouth, nose, small intestine, and colon), the vast majority of bacteria live in the large intestine.
Many of the bacteria in the digestive tract, collectively referred to as gut flora, are able to break down certain nutrients such as carbohydrates that humans otherwise could not digest. The majority of these commensal bacteria are anaerobes, meaning they survive in an environment with no oxygen. Bacteria of the normal flora can act as opportunistic pathogens at times of lowered immunity.
Escherichia coli is a bacterium that lives in the colon; it is an extensively studied model organism and probably the best understood bacterium of all. Certain mutated strands of these gut bacteria do cause disease; an example is E. coli O157:H7.
A number of types of bacteria, such as Actinomyces viscosus and A. naeslundii, live in the mouth, where they are part of a sticky substance called plaque. If this is not removed by brushing, it hardens into calculus (also called tartar). The same bacteria also secrete acids that dissolve tooth enamel, causing tooth decay.
The vaginal microflora consist mostly of various lactobacillus species. It was long thought that the most common of these species was Lactobacillus acidophilus, but it has later been shown that the most common one is L. iners followed by L. crispatus. Other lactobacilli found in the vagina are L. delbruekii and L. gasseri. Disturbance of the vaginal flora can lead to bacterial vaginosis.
## Bacteria and human health
Bacteria are vital for the maintenance of human health, but some also pose a significant health threat by causing diseases. Large numbers of bacteria live on the skin and in the digestive tract. Their growth can be increased by warmth and sweat. Large populations of these organisms on humans are the cause of body odor and thought to play a part in acne. There are more than 500 bacterial species present in the normal human gut and are generally beneficial: they synthesize vitamins such as folic acid, vitamin K and biotin, and they ferment complex indigestible carbohydrates. Other beneficial bacteria in the normal flora include Lactobacillus species, which convert milk protein to lactic acid in the gut. The presence of such bacterial colonies also inhibits the growth of potentially pathogenic bacteria (usually through competitive exclusion) and some beneficial bacteria are consequently sold as probiotic dietary supplements.
Although the vast majority of bacteria are harmless or beneficial, a few pathogenic bacteria cause infectious diseases. The most common bacterial disease is tuberculosis, caused by the bacterium Mycobacterium tuberculosis, which kills about 2 million people a year, mostly in sub-Saharan Africa. Pathogenic bacteria contribute to other globally important diseases, such as pneumonia, which can be caused by bacteria such as Streptococcus and Pseudomonas, and foodborne illnesses, which can be caused by bacteria such as Shigella, Campylobacter and Salmonella. Pathogenic bacteria also cause infections such as tetanus, typhoid fever, diphtheria, syphilis and leprosy.
Koch's postulates, proposed by Robert Koch in 1890, are criteria designed to establish a causal relationship between a causative microbe and a disease. A pathogenic cause for a known medical disease may only be discovered many years after, as was the case with Helicobacter pylori and peptic ulcer disease.
Each pathogenic species has a characteristic spectrum of interactions with its human hosts. Some organisms, such as Staphylococcus or Streptococcus, can cause skin infections, pneumonia, meningitis and even overwhelming sepsis, a systemic inflammatory response producing shock, massive vasodilation and death. Yet these organisms are also part of the normal human flora and usually exist on the skin or in the nose without causing any disease at all. Other organisms invariably cause disease in humans, such as the Rickettsia, which are obligate intracellular parasites able to grow and reproduce only within the cells of other organisms. One species of Rickettsia causes typhus, while another causes Rocky Mountain spotted fever. Chlamydia, another phylum of obligate intracellular parasites, contains species that can cause pneumonia, or urinary tract infection and may be involved in coronary heart disease. Finally, some species, such as Pseudomonas aeruginosa, Burkholderia cenocepacia, and Mycobacterium avium, are opportunistic pathogens and cause disease mainly in people suffering from immunosuppression or cystic fibrosis.
Bacterial infections may be treated with antibiotics, which are classified as bacteriocidal if they kill bacteria, or bacteriostatic if they just prevent bacterial growth. There are many types of antibiotics and each class inhibits a process that is different in the pathogen from that found in the host. For example, the antibiotics, chloramphenicol and tetracyclin inhibit the bacterial ribosome, but not the structurally-different eukaryotic ribosome, and so exhibit selective toxicity. Antibiotics are used both in treating human disease and in intensive farming to promote animal growth. Both uses may be contributing to the rapid development of antibiotic resistance in bacterial populations. Infections can be prevented by antiseptic measures such as sterilizating the skin prior to piercing it with the needle of a syringe, and by proper care of indwelling catheters. Surgical and dental instruments are also sterilized to prevent contamination and infection by bacteria. Disinfectants such as bleach are used to kill bacteria or other pathogens on surfaces to prevent contamination and further reduce the risk of infection. Most bacteria in food are killed by cooking to temperatures above 60°C (140°F).
# Archean flora
Archaea are present in the human gut, but in contrast to the enormous variety of bacteria in this organ, the number of archaeal species are much more limited. The dominant group is the methanogens, particularly Methanobrevibacter smithii and Methanosphaera stadtmanae. However, colonization by methanogens is variable and only about 50% of humans have easily-detectable populations or these organisms.
## Archaea and human health
As of 2007, no clear examples of archaeal pathogens are known, although a relationship has been proposed between the presence of some methanogens and human periodontal disease.
# Fungal flora
Fungi, particularly yeasts are present in the human gut. The best studied of these are Candida species, due to their ability to become pathogenic in immunocompromised hosts. Yeasts are also present on the skin, particularly Malassezia species, where they consume oils secreted from the sebaceous glands. | Human flora
The human body contains a large number of microrganisms, such as bacteria, fungi and archaea, some of these organisms perform tasks that are useful, while the majority have no beneficial or harmful effect. Those that are expected to be present, and that under normal circumstances do not cause disease, are termed normal flora.[1]
# Bacterial flora
It is estimated that 500 to 100,000 species of bacteria live in the human body [2]. Bacterial cells are much smaller than human cells, and there are about ten times as many bacteria as human cells in the body (1000 trillion (1015) versus 100 trillion (1014)).[2] Though normal flora are found on all surfaces exposed to the environment (on the skin and eyes, in the mouth, nose, small intestine, and colon), the vast majority of bacteria live in the large intestine.
Many of the bacteria in the digestive tract, collectively referred to as gut flora, are able to break down certain nutrients such as carbohydrates that humans otherwise could not digest. The majority of these commensal bacteria are anaerobes, meaning they survive in an environment with no oxygen. Bacteria of the normal flora can act as opportunistic pathogens at times of lowered immunity. [1]
Escherichia coli is a bacterium that lives in the colon; it is an extensively studied model organism and probably the best understood bacterium of all.[citation needed] Certain mutated strands of these gut bacteria do cause disease; an example is E. coli O157:H7.
A number of types of bacteria, such as Actinomyces viscosus and A. naeslundii, live in the mouth, where they are part of a sticky substance called plaque. If this is not removed by brushing, it hardens into calculus (also called tartar). The same bacteria also secrete acids that dissolve tooth enamel, causing tooth decay.
The vaginal microflora consist mostly of various lactobacillus species. It was long thought that the most common of these species was Lactobacillus acidophilus, but it has later been shown that the most common one is L. iners followed by L. crispatus. Other lactobacilli found in the vagina are L. delbruekii and L. gasseri. Disturbance of the vaginal flora can lead to bacterial vaginosis.
## Bacteria and human health
Bacteria are vital for the maintenance of human health, but some also pose a significant health threat by causing diseases. Large numbers of bacteria live on the skin and in the digestive tract. Their growth can be increased by warmth and sweat. Large populations of these organisms on humans are the cause of body odor and thought to play a part in acne. There are more than 500 bacterial species present in the normal human gut and are generally beneficial: they synthesize vitamins such as folic acid, vitamin K and biotin, and they ferment complex indigestible carbohydrates.[3][4] Other beneficial bacteria in the normal flora include Lactobacillus species, which convert milk protein to lactic acid in the gut.[5] The presence of such bacterial colonies also inhibits the growth of potentially pathogenic bacteria (usually through competitive exclusion) and some beneficial bacteria are consequently sold as probiotic dietary supplements.[6]
Although the vast majority of bacteria are harmless or beneficial, a few pathogenic bacteria cause infectious diseases. The most common bacterial disease is tuberculosis, caused by the bacterium Mycobacterium tuberculosis, which kills about 2 million people a year, mostly in sub-Saharan Africa. Pathogenic bacteria contribute to other globally important diseases, such as pneumonia, which can be caused by bacteria such as Streptococcus and Pseudomonas, and foodborne illnesses, which can be caused by bacteria such as Shigella, Campylobacter and Salmonella. Pathogenic bacteria also cause infections such as tetanus, typhoid fever, diphtheria, syphilis and leprosy.
Koch's postulates, proposed by Robert Koch in 1890, are criteria designed to establish a causal relationship between a causative microbe and a disease. A pathogenic cause for a known medical disease may only be discovered many years after, as was the case with Helicobacter pylori and peptic ulcer disease.
Each pathogenic species has a characteristic spectrum of interactions with its human hosts. Some organisms, such as Staphylococcus or Streptococcus, can cause skin infections, pneumonia, meningitis and even overwhelming sepsis, a systemic inflammatory response producing shock, massive vasodilation and death.[7] Yet these organisms are also part of the normal human flora and usually exist on the skin or in the nose without causing any disease at all. Other organisms invariably cause disease in humans, such as the Rickettsia, which are obligate intracellular parasites able to grow and reproduce only within the cells of other organisms. One species of Rickettsia causes typhus, while another causes Rocky Mountain spotted fever. Chlamydia, another phylum of obligate intracellular parasites, contains species that can cause pneumonia, or urinary tract infection and may be involved in coronary heart disease.[8] Finally, some species, such as Pseudomonas aeruginosa, Burkholderia cenocepacia, and Mycobacterium avium, are opportunistic pathogens and cause disease mainly in people suffering from immunosuppression or cystic fibrosis.[9][10]
Bacterial infections may be treated with antibiotics, which are classified as bacteriocidal if they kill bacteria, or bacteriostatic if they just prevent bacterial growth. There are many types of antibiotics and each class inhibits a process that is different in the pathogen from that found in the host. For example, the antibiotics, chloramphenicol and tetracyclin inhibit the bacterial ribosome, but not the structurally-different eukaryotic ribosome, and so exhibit selective toxicity.[11] Antibiotics are used both in treating human disease and in intensive farming to promote animal growth. Both uses may be contributing to the rapid development of antibiotic resistance in bacterial populations.[12] Infections can be prevented by antiseptic measures such as sterilizating the skin prior to piercing it with the needle of a syringe, and by proper care of indwelling catheters. Surgical and dental instruments are also sterilized to prevent contamination and infection by bacteria. Disinfectants such as bleach are used to kill bacteria or other pathogens on surfaces to prevent contamination and further reduce the risk of infection. Most bacteria in food are killed by cooking to temperatures above 60°C (140°F).
# Archean flora
Archaea are present in the human gut, but in contrast to the enormous variety of bacteria in this organ, the number of archaeal species are much more limited.[13] The dominant group is the methanogens, particularly Methanobrevibacter smithii and Methanosphaera stadtmanae.[14] However, colonization by methanogens is variable and only about 50% of humans have easily-detectable populations or these organisms.[15]
## Archaea and human health
As of 2007, no clear examples of archaeal pathogens are known,[16][17] although a relationship has been proposed between the presence of some methanogens and human periodontal disease.[18]
# Fungal flora
Fungi, particularly yeasts are present in the human gut. The best studied of these are Candida species, due to their ability to become pathogenic in immunocompromised hosts.[19] Yeasts are also present on the skin, particularly Malassezia species, where they consume oils secreted from the sebaceous glands.[20][21] | https://www.wikidoc.org/index.php/Human_flora | |
6d1a6771e8ad7bb9d32a5f3fbc047cdea82d4963 | wikidoc | Human teeth | Human teeth
Teeth of humans are small, calcified, hard, whitish structures found in the mouth. They function in mastication mechanically breaking down items of food by cutting and crushing them in preparation for swallowing and digestion. The roots of teeth are embedded in the maxilla (upper jaw) or the mandible (lower jaw) and are covered by gingiva gums. Teeth are made of multiple tissues of varying density and hardness.
# Theory of teeth
Def. a "hard, calcareous structure present in the mouth of many vertebrate animals, generally used for eating" is called a tooth.
The image on the right is a model of a human molar-like tooth. Its components are labeled:
- Tooth:
- Enamel
- Dentin
- Dental pulp:
- cameral pulp
- root pulp
- Cementum
- Crown
- Cusp
- Sulcus
- Cementoenamel junction or Neck
- Root
- Furcation
- Root apex
- Apical foramen
- Gingival sulcus
- Periodontium:
- Gingiva:
- free or interdental
- marginal
- alveolar
- Periodontal ligament
- Alveolar bone
- Vessels and nerves:
- dental
- periodontal
- alveolar through alveolar canals.
# Genetics
Genetics involves the identification, expression, transmission, and variation of inherited characteristics.
Def. a "branch of biology that deals with the transmission and variation of inherited characteristics, in particular chromosomes and DNA" is called genetics.
# Sources
"Enamel cells ultimately determine the properties of dental enamel."
# Objects
Def. the "hard covering on the exposed part of a tooth" is called the enamel.
Def. the "hard, dense calcareous material that makes up the bulk of a tooth" is called the dentin.
Def. the "soft center of a tooth" is called the pulp.
# Liquid objects
"Pulp cells from human permanent molars were isolated and established in culture; 40% showed positive alkaline phosphatase staining."
The "cells formed a mineralized extracellular matrix; they could thus have the potential to differentiate into odontoblast-like cells in vitro."
The "cells produced predominantly (~99%) type I collagen and only trace amount of type III collagen. The ratio of α1(I) to α2(I) procollagen chains was about 68:32, indicating that no significant amount of collagen type I trimer was synthesized in this system. The ratios of α1(I), α2(I) and α1(III) procollagen mRNAs were about 61:25:1; these were compatible with the ratios of corresponding procollagen a chains. In addition, a novel 5.8 kb proα1(III) mRNA was detected. These observations indicate that collagen synthesis in these cultured pulp cells was regulated at the transcriptional level."
GeneID: 765 carbonic anhydrase 6 .
"We also found that the haplotype (ACA) (rs2274328, rs17032907 and rs11576766) of the carbonic anhydrase VI was associated with a low number of decayed, missing, and filled teeth index with an odds ratio (95% confidence interval) of 0.635 (0.440-0.918)."
"The rs17032907 genetic variant and the haplotype (ACA) of CA VI may be associated with dental caries susceptibility."
GeneID: 3479 IGF1 insulin like growth factor 1 .
"The protein encoded by this gene is similar to insulin in function and structure and is a member of a family of proteins involved in mediating growth and development. The encoded protein is processed from a precursor, bound by a specific receptor, and secreted. Defects in this gene are a cause of insulin-like growth factor I deficiency. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar processing to generate mature protein."
GeneID: 3480 IGF1R insulin like growth factor 1 receptor .
"IGF-1 regulates the metabolism of hard dental tissue through binding to the IGF-1 receptor on target cells. Furthermore, IGF-binding-protein-3 promotes the accessibility of IGF-1."
"The teeth showed significantly stronger expression of IGF-1 and IGF-1R. The major sources of all of the proteins investigated immunohistochemically in sections of wisdom teeth were odontoblasts, cementoblasts and cell colonies in the pulpal mesenchyme. members of the IGF-1 family are involved in the late stage of tooth development and the process of pulpal differentiation."
GeneID: 7124 TNF tumor necrosis factor .
"Tumor necrosis factor-α (TNF-α) is involved in various inflammatory processes, including periodontitis. Although the influences of TNF-α on periodontal ligament fibroblasts and osteoblasts have been widely documented, its effects on cementoblasts, the cells responsible for cementum production, remain largely unknown."
"TNF-α suppressed the mineralization ability of cementoblasts by inhibiting differentiation and inducing apoptosis."
"Various signaling pathways , such as p53, PP2AC, p38, Erk1/2, JNK, PI3K-Akt, and NF-κB, were activated during this process. The use of a specific inhibitor and siRNA transfection confirmed that the effects of TNF-α on differentiation and apoptosis in cementoblasts were partially abrogated by inhibiting p53 activity. By contrast, the effects of TNF-α were even exacerbated by the inhibition of the p38, Erk1/2, JNK, PI3K-Akt, and NF-κB pathways. Moreover, p53 activity was further enhanced by blocking the p38, Erk1/2, JNK, and PI3K-Akt signaling pathways."
The "differentiation inhibition and apoptosis in cementoblasts induced by TNF-α were partially dependent on p53 activity. The p38, Erk1/2, JNK, PI3K-Akt, and NF-κB pathways were also activated but acted as balancing players to limit rather than conduct the negative effects of TNF-α. These balancing effects were dependent, or at least partially dependent, on p53, except for the NF-κB pathway."
# Rocky objects
GeneID: 860 RUNX2 runt-related transcription factor 2 .
"This gene is a member of the RUNX family of transcription factors and encodes a nuclear protein with an Runt DNA-binding domain. This protein is essential for osteoblastic differentiation and skeletal morphogenesis and acts as a scaffold for nucleic acids and regulatory factors involved in skeletal gene expression. The protein can bind DNA both as a monomer or, with more affinity, as a subunit of a heterodimeric complex. Mutations in this gene have been associated with the bone development disorder cleidocranial dysplasia (CCD). Transcript variants that encode different protein isoforms result from the use of alternate promoters as well as alternate splicing."
"Cleidocranial dysplasia (CCD) is characterized by the runt-related transcription factor 2 (RUNX2) mutation, which results in delayed tooth eruption due to disturbed functions of dental follicle. Accumulating evidence has revealed a key regulatory circuit, including RUNX2, miR-31, and special AT-rich binding protein 2 (SATB2) acting in concert in mesenchymal stem cell homeostasis and functions. However, whether such a regulatory loop works in dental follicle cells (DFCs) remains unknown."
A "novel mutation on exon 5 (c.634T>G, p.T212P) in RUNX2 via exome sequencing in the CCD patient typical clinical presentations."
"Compared with DFCs from healthy donors, DFCs-CCD displayed significantly lower osteogenic, osteoclast-inductive, and matrix-degrading capacities and had lower RUNX2 (a transcriptional inhibitor of miR-31), higher miR-31, and downregulated SATB2. Lower ratios of RANKL/OPG and RANKL/RANK, as well as decreased expression of matrix metalloproteinase 9 (MMP9) and matrix metalloproteinase 2 (MMP2), would lead to inactivation of osteoclasts and suppression of bone matrix remodeling in DFCs-CCD. Furthermore, the roles of the RUNX2-miR-31-SATB2 loop in DFCs-CCD were revealed by endogenous miR-31 knockdown, which resulted in increased SATB2 and RUNX2, as well as osteoclast-inductive and matrix degradation capacities. Conversely, SATB2, RUNX2, MMP9, MMP2, and osteoclast-inductive factors expression declined upon ectopic miR-31 overexpression in normal DFCs. Importantly, neonatal mice with in vivo siRUNX2 delivery exhibited less activated osteoclasts around dental follicles and delayed tooth eruption."
GeneID: 1277 COL1A1 collagen, type I, alpha 1 .
"This gene encodes the pro-alpha1 chains of type I collagen whose triple helix comprises two alpha1 chains and one alpha2 chain. Type I is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis and tendon. Mutations in this gene are associated with osteogenesis imperfecta types I-IV, Ehlers-Danlos syndrome type VIIA, Ehlers-Danlos syndrome Classical type, Caffey Disease and idiopathic osteoporosis. Two transcripts, resulting from the use of alternate polyadenylation signals, have been identified for this gene."
# Matrix metalloproteinases
"Matrix metalloproteinases (MMPs) are a group of proteolytic enzymes capable of degrading most components of the extracellular matrix."
"MMPs may play a role in tissue degradation in inflamed dental pulp."
Gene ID: 4313 MMP2 matrix metallopeptidase 2 .
"The main gelatinase secreted by human pulp and PDL cells migrated at 72 kDa and represented MMP-2."
Gene ID: 4318 MMP9 matrix metallopeptidase 9 .
"Minor gelatinolytic bands were also observed at 92 kDa regions that correspond to MMP-9."
# Alkaline phosphatases
GeneID: 249 ALPL alkaline phosphatase, liver/bone/kidney .
ALPL is an alkaline phosphatase, liver/bone/kidney in humans. "The product of this gene is a membrane bound glycosylated enzyme that is not expressed in any particular tissue and is, therefore, referred to as the tissue-nonspecific form of the enzyme. The exact physiological function of the alkaline phosphatases is not known. A proposed function of this form of the enzyme is matrix mineralization; however, mice that lack a functional form of this enzyme show normal skeletal development. This enzyme has been linked directly to hypophosphatasia, a disorder that is characterized by hypercalcemia and includes skeletal defects. The character of this disorder can vary, however, depending on the specific mutation since this determines age of onset and severity of symptoms." Bold added.
"Mutations in hypophosphatasia reduce the function of tissue nonspecific alkaline phosphatase, and the resulting increase in pyrophosphate contributes to bone and tooth mineralization defects by inhibiting physiologic calcium-phosphate precipitation."
"Cementum is critical for anchoring the insertion of periodontal ligament fibers to the tooth root. Several aspects of cementogenesis remain unclear, including differences between acellular cementum and cellular cementum, and between cementum and bone. Biomineralization is regulated by the ratio of inorganic phosphate (Pi) to mineral inhibitor pyrophosphate (PPi), where local Pi and PPi concentrations are controlled by phosphatases including tissue-nonspecific alkaline phosphatase (TNAP) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (NPP1)."
"TNAP was associated with earliest cementoblasts near forming acellular and cellular cementum. With loss of TNAP in the Alpl null mouse, acellular cementum was inhibited, while cellular cementum production increased, albeit as hypomineralized cementoid. In contrast, NPP1 was detected in cementoblasts after acellular cementum formation, and at low levels around cellular cementum. Loss of NPP1 in the Enpp1 null mouse increased acellular cementum, with little effect on cellular cementum. Developmental patterns were recapitulated in a mouse model for acellular cementum regeneration, with early TNAP expression and later NPP1 expression. In vitro, cementoblasts expressed Alpl gene/protein early, whereas Enpp1 gene/protein expression was significantly induced only under mineralization conditions. These patterns were confirmed in human teeth, including widespread TNAP, and NPP1 restricted to cementoblasts lining acellular cementum. These studies suggest that early TNAP expression creates a low PPi environment promoting acellular cementum initiation, while later NPP1 expression increases PPi, restricting acellular cementum apposition. Alterations in PPi have little effect on cellular cementum formation, though matrix mineralization is affected."
# Transcription factors
GeneID: 860 RUNX2 runt-related transcription factor 2 .
RUNX2 "is a member of the RUNX family of transcription factors and encodes a nuclear protein with an Runt DNA-binding domain. This protein is essential for osteoblastic differentiation and skeletal morphogenesis and acts as a scaffold for nucleic acids and regulatory factors involved in skeletal gene expression. The protein can bind DNA both as a monomer or, with more affinity, as a subunit of a heterodimeric complex. Mutations in this gene have been associated with the bone development disorder cleidocranial dysplasia (CCD)."
RUNX2 is involved in "odontogenesis of dentin-containing tooth regulation of odontogenesis of dentin-containing tooth".
# Homeoboxes
GeneID: 4487 MSX1 msh homeobox 1 .
MSX1 "encodes a member of the muscle segment homeobox gene family. The encoded protein functions as a transcriptional repressor during embryogenesis through interactions with components of the core transcription complex and other homeoproteins. It may also have roles in limb-pattern formation, craniofacial development, particularly odontogenesis, and tumor growth inhibition. Mutations in this gene, which was once known as homeobox 7, have been associated with nonsyndromic cleft lip with or without cleft palate 5, Witkop syndrome, Wolf-Hirschom syndrome, and autosomoal dominant hypodontia."
"Novel nonsense mutation in MSX1 causes tooth agenesis with cleft lip in a Chinese family. ... he nonsense mutation in MSX1 might have resulted in rapid degradation of the mutated transcript and caused the phenotype of tooth agenesis with cleft lip in the Chinese family."
"PAX9 and MSX1 gene mutation can cause different phenotypes of tooth agenesis."
MSX1 is involved in "odontogenesis of dentin-containing tooth".
Gene ID: 5083 PAX9 paired box 9 .
"This gene is a member of the paired box (PAX) family of transcription factors."
"Mice lacking this gene exhibit impaired development of organs, musculature and the skeleton, including absent and abnormally developed teeth, and neonatal lethality. Mutations in the human gene are associated with selective tooth agenesis-3."
"PAX9 and MSX1 gene mutation can cause different phenotypes of tooth agenesis."
# Tachykinin peptide hormones
GeneID: 6863 TAC1 tachykinin precursor 1 .
TAC1 tachykinin, precursor 1 "encodes four products of the tachykinin peptide hormone family, substance P and neurokinin A, as well as the related peptides, neuropeptide K and neuropeptide gamma. These hormones are thought to function as neurotransmitters which interact with nerve receptors and smooth muscle cells. They are known to induce behavioral responses and function as vasodilators and secretagogues. Multiple transcript variants encoding different isoforms have been found for this gene."
"Transcript variant beta encodes the full-length form of this gene. It encodes hormones substance P, neurokinin A, as well as the neuropeptide K."
"As compared to the full-length transcript variant beta, variant alpha lacks exon 6, and therefore does not encode neuropeptide K, neurokinin A, or neuropeptide gamma. This transcript does encode the hormone substance P located on exon 3."
"As compared to the full-length transcript variant beta, variant gamma lacks exon 4, and therefore does not encode neuropeptide K. This transcript does encode substance P, neurokinin A, and is the only variant that encodes neuropeptide gamma."
"As compared to the full-length transcript variant beta, variant delta lacks both exons 4 and 6; therefore, it does not encode neurokinin A, neuropeptide K, or neuropeptide gamma. It does encode the hormone substance P located on exon 3."
Notation: let CGRP stand for Calcitonin Gene-Related Peptide.
Notation: let NKA represent neurokinin A.
"Substance P and CGRP present in and NKA detected in 96% of the pulps. CGRP present in much higher concentrations than SP and NKA in both painful and non-painful teeth. The painful teeth had significantly higher concentrations of SP ..., NKA ... and CGRP ... than non-painful teeth. The concentration of CGRP significantly higher in the pulps of smokers compared with non-smokers ...."
# Gene transcriptions
GeneID: 8091 HMGA2 high mobility group AT-hook 2 .
A genome-wide "association study identifies four loci associated with eruption of permanent teeth."
# Acknowledgements
The content on this page was first contributed by: Henry A. Hoff.
Initial content for this page in some instances came from Wikiversity.
# Hypotheses
- When the genome within each tooth is properly signaled, it will begin to heal the tooth from the inside out against caries and any other illness of the teeth. | Human teeth
Editor-In-Chief: Henry A. Hoff
Teeth of humans are small, calcified, hard, whitish structures found in the mouth. They function in mastication mechanically breaking down items of food by cutting and crushing them in preparation for swallowing and digestion. The roots of teeth are embedded in the maxilla (upper jaw) or the mandible (lower jaw) and are covered by gingiva gums. Teeth are made of multiple tissues of varying density and hardness.
# Theory of teeth
Def. a "hard, calcareous structure present in the mouth of many vertebrate animals, generally used for eating"[1] is called a tooth.
The image on the right is a model of a human molar-like tooth. Its components are labeled:
- Tooth:
- Enamel
- Dentin
- Dental pulp:
- cameral pulp
- root pulp
- Cementum
- Crown
- Cusp
- Sulcus
- Cementoenamel junction or Neck
- Root
- Furcation
- Root apex
- Apical foramen
- Gingival sulcus
- Periodontium:
- Gingiva:
- free or interdental
- marginal
- alveolar
- Periodontal ligament
- Alveolar bone
- Vessels and nerves:
- dental
- periodontal
- alveolar through alveolar canals.
# Genetics
Genetics involves the identification, expression, transmission, and variation of inherited characteristics.
Def. a "branch of biology that deals with the transmission and variation of inherited characteristics, in particular chromosomes and DNA"[2] is called genetics.
# Sources
"Enamel cells ultimately determine the properties of dental enamel."[3]
# Objects
Def. the "hard covering on the exposed part of a tooth"[4] is called the enamel.
Def. the "hard, dense calcareous material that makes up the bulk of a tooth"[5] is called the dentin.
Def. the "soft center of a tooth"[6] is called the pulp.
# Liquid objects
"Pulp cells from human permanent molars were isolated and established in culture; 40% showed positive alkaline phosphatase staining."[7]
The "cells formed a mineralized extracellular matrix; they could thus have the potential to differentiate into odontoblast-like cells in vitro."[7]
The "cells produced predominantly (~99%) type I collagen and only trace amount of type III collagen. The ratio of α1(I) to α2(I) procollagen chains was about 68:32, indicating that no significant amount of collagen type I trimer was synthesized in this system. The ratios of α1(I), α2(I) and α1(III) procollagen mRNAs were about 61:25:1; these were compatible with the ratios of corresponding procollagen a chains. In addition, a novel 5.8 kb proα1(III) mRNA was detected. These observations indicate that collagen synthesis in these cultured pulp cells was regulated at the transcriptional level."[7]
GeneID: 765 carbonic anhydrase 6 [ Homo sapiens (human) ].
"We also found that the haplotype (ACA) (rs2274328, rs17032907 and rs11576766) of the carbonic anhydrase VI was associated with a low number of decayed, missing, and filled teeth index with an odds ratio (95% confidence interval) of 0.635 (0.440-0.918)."[8]
"The rs17032907 genetic variant and the haplotype (ACA) of CA VI may be associated with dental caries susceptibility."[8]
GeneID: 3479 IGF1 insulin like growth factor 1 [ Homo sapiens (human) ].
"The protein encoded by this gene is similar to insulin in function and structure and is a member of a family of proteins involved in mediating growth and development. The encoded protein is processed from a precursor, bound by a specific receptor, and secreted. Defects in this gene are a cause of insulin-like growth factor I deficiency. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar processing to generate mature protein."[9]
GeneID: 3480 IGF1R insulin like growth factor 1 receptor [ Homo sapiens (human) ].
"IGF-1 regulates the metabolism of hard dental tissue through binding to the IGF-1 receptor on target cells. Furthermore, IGF-binding-protein-3 promotes the accessibility of IGF-1."[10]
"The teeth [showing ongoing development] showed significantly stronger expression of IGF-1 and IGF-1R. The major sources of all of the proteins investigated immunohistochemically in sections of wisdom teeth were odontoblasts, cementoblasts and cell colonies in the pulpal mesenchyme. [...] members of the IGF-1 family are involved in the late stage of tooth development and the process of pulpal differentiation."[10]
GeneID: 7124 TNF tumor necrosis factor [ Homo sapiens (human) ].
"Tumor necrosis factor-α (TNF-α) is involved in various inflammatory processes, including periodontitis. Although the influences of TNF-α on periodontal ligament fibroblasts and osteoblasts have been widely documented, its effects on cementoblasts, the cells responsible for cementum production, remain largely unknown."[11]
"TNF-α suppressed the mineralization ability of cementoblasts by inhibiting differentiation and inducing apoptosis."[11]
"Various signaling pathways [image on the right], such as p53, PP2AC, p38, Erk1/2, JNK, PI3K-Akt, and NF-κB, were activated during this process. The use of a specific inhibitor and siRNA transfection confirmed that the effects of TNF-α on differentiation and apoptosis in cementoblasts were partially abrogated by inhibiting p53 activity. By contrast, the effects of TNF-α were even exacerbated by the inhibition of the p38, Erk1/2, JNK, PI3K-Akt, and NF-κB pathways. Moreover, p53 activity was further enhanced by blocking the p38, Erk1/2, JNK, and PI3K-Akt signaling pathways."[11]
The "differentiation inhibition and apoptosis in cementoblasts induced by TNF-α were partially dependent on p53 activity. The p38, Erk1/2, JNK, PI3K-Akt, and NF-κB pathways were also activated but acted as balancing players to limit rather than conduct the negative effects of TNF-α. These balancing effects were dependent, or at least partially dependent, on p53, except for the NF-κB pathway."[11]
# Rocky objects
GeneID: 860 RUNX2 runt-related transcription factor 2 [ Homo sapiens (human) ].
"This gene is a member of the RUNX family of transcription factors and encodes a nuclear protein with an Runt DNA-binding domain. This protein is essential for osteoblastic differentiation and skeletal morphogenesis and acts as a scaffold for nucleic acids and regulatory factors involved in skeletal gene expression. The protein can bind DNA both as a monomer or, with more affinity, as a subunit of a heterodimeric complex. Mutations in this gene have been associated with the bone development disorder cleidocranial dysplasia (CCD). Transcript variants that encode different protein isoforms result from the use of alternate promoters as well as alternate splicing."[12]
"Cleidocranial dysplasia (CCD) is characterized by the runt-related transcription factor 2 (RUNX2) mutation, which results in delayed tooth eruption due to disturbed functions of dental follicle. Accumulating evidence has revealed a key regulatory circuit, including RUNX2, miR-31, and special AT-rich binding protein 2 (SATB2) acting in concert in mesenchymal stem cell homeostasis and functions. However, whether such a regulatory loop works in dental follicle cells (DFCs) remains unknown."[13]
A "novel mutation on exon 5 (c.634T>G, p.T212P) in RUNX2 via exome sequencing in the [cleidocranial dysplasia] CCD patient [has] typical clinical presentations."[13]
"Compared with [dental follicle cells] DFCs from healthy donors, DFCs-CCD displayed significantly lower osteogenic, osteoclast-inductive, and matrix-degrading capacities and had lower RUNX2 (a transcriptional inhibitor of miR-31), higher miR-31, and downregulated [special AT-rich binding protein 2] SATB2. Lower ratios of RANKL/OPG and RANKL/RANK, as well as decreased expression of matrix metalloproteinase 9 (MMP9) and matrix metalloproteinase 2 (MMP2), would lead to inactivation of osteoclasts and suppression of bone matrix remodeling in DFCs-CCD. Furthermore, the roles of the RUNX2-miR-31-SATB2 loop in DFCs-CCD were revealed by endogenous miR-31 knockdown, which resulted in increased SATB2 and RUNX2, as well as osteoclast-inductive and matrix degradation capacities. Conversely, SATB2, RUNX2, MMP9, MMP2, and osteoclast-inductive factors expression declined upon ectopic miR-31 overexpression in normal DFCs. Importantly, neonatal mice with in vivo siRUNX2 delivery exhibited less activated osteoclasts around dental follicles and delayed tooth eruption."[13]
GeneID: 1277 COL1A1 collagen, type I, alpha 1 [ Homo sapiens (human) ].
"This gene encodes the pro-alpha1 chains of type I collagen whose triple helix comprises two alpha1 chains and one alpha2 chain. Type I is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis and tendon. Mutations in this gene are associated with osteogenesis imperfecta types I-IV, Ehlers-Danlos syndrome type VIIA, Ehlers-Danlos syndrome Classical type, Caffey Disease and idiopathic osteoporosis. [...] Two transcripts, resulting from the use of alternate polyadenylation signals, have been identified for this gene."[14]
# Matrix metalloproteinases
"Matrix metalloproteinases (MMPs) are a group of proteolytic enzymes capable of degrading most components of the extracellular matrix."[15]
"MMPs may play a role in tissue degradation in inflamed dental pulp."[15]
Gene ID: 4313 MMP2 matrix metallopeptidase 2 [ Homo sapiens (human) ].
"The main gelatinase secreted by human pulp and [periodontal ligament] PDL cells migrated at 72 kDa and represented MMP-2."[15]
Gene ID: 4318 MMP9 matrix metallopeptidase 9 [ Homo sapiens (human) ].
"Minor gelatinolytic bands were also observed at 92 kDa regions that correspond to MMP-9."[15]
# Alkaline phosphatases
GeneID: 249 ALPL alkaline phosphatase, liver/bone/kidney [ Homo sapiens (human) ].
ALPL is an alkaline phosphatase, liver/bone/kidney in humans. "The product of this gene is a membrane bound glycosylated enzyme that is not expressed in any particular tissue and is, therefore, referred to as the tissue-nonspecific form of the enzyme. The exact physiological function of the alkaline phosphatases is not known. A proposed function of this form of the enzyme is matrix mineralization; however, mice that lack a functional form of this enzyme show normal skeletal development. This enzyme has been linked directly to hypophosphatasia, a disorder that is characterized by hypercalcemia and includes skeletal defects. The character of this disorder can vary, however, depending on the specific mutation since this determines age of onset and severity of symptoms."[16] Bold added.
"Mutations in hypophosphatasia reduce the function of tissue nonspecific alkaline phosphatase, and the resulting increase in pyrophosphate contributes to bone and tooth mineralization defects by inhibiting physiologic calcium-phosphate precipitation."[16]
"Cementum is critical for anchoring the insertion of periodontal ligament fibers to the tooth root. Several aspects of cementogenesis remain unclear, including differences between acellular cementum and cellular cementum, and between cementum and bone. Biomineralization is regulated by the ratio of inorganic phosphate (Pi) to mineral inhibitor pyrophosphate (PPi), where local Pi and PPi concentrations are controlled by phosphatases including tissue-nonspecific alkaline phosphatase (TNAP) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (NPP1)."[17]
"TNAP was associated with earliest cementoblasts near forming acellular and cellular cementum. With loss of TNAP in the Alpl null mouse, acellular cementum was inhibited, while cellular cementum production increased, albeit as hypomineralized cementoid. In contrast, NPP1 was detected in cementoblasts after acellular cementum formation, and at low levels around cellular cementum. Loss of NPP1 in the Enpp1 null mouse increased acellular cementum, with little effect on cellular cementum. Developmental patterns were recapitulated in a mouse model for acellular cementum regeneration, with early TNAP expression and later NPP1 expression. In vitro, cementoblasts expressed Alpl gene/protein early, whereas Enpp1 gene/protein expression was significantly induced only under mineralization conditions. These patterns were confirmed in human teeth, including widespread TNAP, and NPP1 restricted to cementoblasts lining acellular cementum. These studies suggest that early TNAP expression creates a low PPi environment promoting acellular cementum initiation, while later NPP1 expression increases PPi, restricting acellular cementum apposition. Alterations in PPi have little effect on cellular cementum formation, though matrix mineralization is affected."[17]
# Transcription factors
GeneID: 860 RUNX2 runt-related transcription factor 2 [ Homo sapiens (human) ].
RUNX2 "is a member of the RUNX family of transcription factors and encodes a nuclear protein with an Runt DNA-binding domain. This protein is essential for osteoblastic differentiation and skeletal morphogenesis and acts as a scaffold for nucleic acids and regulatory factors involved in skeletal gene expression. The protein can bind DNA both as a monomer or, with more affinity, as a subunit of a heterodimeric complex. Mutations in this gene have been associated with the bone development disorder cleidocranial dysplasia (CCD)."[18]
RUNX2 is involved in "odontogenesis of [any] dentin-containing tooth [and] regulation of odontogenesis of [any] dentin-containing tooth".[18]
# Homeoboxes
GeneID: 4487 MSX1 msh homeobox 1 [ Homo sapiens (human) ].
MSX1 "encodes a member of the muscle segment homeobox gene family. The encoded protein functions as a transcriptional repressor during embryogenesis through interactions with components of the core transcription complex and other homeoproteins. It may also have roles in limb-pattern formation, craniofacial development, particularly odontogenesis, and tumor growth inhibition. Mutations in this gene, which was once known as homeobox 7, have been associated with nonsyndromic cleft lip with or without cleft palate 5, Witkop syndrome, Wolf-Hirschom syndrome, and autosomoal dominant hypodontia."[19]
"Novel nonsense mutation in MSX1 causes tooth agenesis with cleft lip in a Chinese family. ... [T]he nonsense mutation in MSX1 might have resulted in rapid degradation of the mutated transcript and caused the phenotype of tooth agenesis with cleft lip in the Chinese family."[20]
"PAX9 and MSX1 gene mutation can cause different phenotypes of tooth agenesis."[20]
MSX1 is involved in "odontogenesis of [any] dentin-containing tooth".[20]
Gene ID: 5083 PAX9 paired box 9 [ Homo sapiens (human) ].
"This gene is a member of the paired box (PAX) family of transcription factors."[21]
"Mice lacking this gene exhibit impaired development of organs, musculature and the skeleton, including absent and abnormally developed teeth, and neonatal lethality. Mutations in the human gene are associated with selective tooth agenesis-3."[21]
"PAX9 and MSX1 gene mutation can cause different phenotypes of tooth agenesis."[20]
# Tachykinin peptide hormones
GeneID: 6863 TAC1 tachykinin precursor 1 [ Homo sapiens (human) ].
TAC1 tachykinin, precursor 1 "encodes four products of the tachykinin peptide hormone family, substance P and neurokinin A, as well as the related peptides, neuropeptide K and neuropeptide gamma. These hormones are thought to function as neurotransmitters which interact with nerve receptors and smooth muscle cells. They are known to induce behavioral responses and function as vasodilators and secretagogues. Multiple transcript variants encoding different isoforms have been found for this gene."[22]
"Transcript variant beta encodes the full-length form of this gene. It encodes hormones substance P, neurokinin A, as well as the neuropeptide K."[23]
"As compared to the full-length transcript variant beta, variant alpha lacks exon 6, and therefore does not encode neuropeptide K, neurokinin A, or neuropeptide gamma. This transcript does encode the hormone substance P located on exon 3."[23]
"As compared to the full-length transcript variant beta, variant gamma lacks exon 4, and therefore does not encode neuropeptide K. This transcript does encode substance P, neurokinin A, and is the only variant that encodes neuropeptide gamma."[23]
"As compared to the full-length transcript variant beta, variant delta lacks both exons 4 and 6; therefore, it does not encode neurokinin A, neuropeptide K, or neuropeptide gamma. It does encode the hormone substance P located on exon 3."[23]
Notation: let CGRP stand for Calcitonin Gene-Related Peptide.
Notation: let NKA represent neurokinin A.
"Substance P and CGRP [are] present in [painful and healthy pulp tissue from human adult teeth] and NKA [is] detected in 96% of the pulps. CGRP [is] present in much higher concentrations than SP and NKA in both painful and non-painful teeth. The painful teeth had significantly higher concentrations of SP ..., NKA ... and CGRP ... than non-painful teeth. The concentration of CGRP [are] significantly higher in the pulps of smokers compared with non-smokers ...."[24]
# Gene transcriptions
GeneID: 8091 HMGA2 high mobility group AT-hook 2 [ Homo sapiens (human) ].
A genome-wide "association study identifies four loci [of GeneID: 8091 HMGA2 high mobility group AT-hook 2] associated with eruption of permanent teeth."[25]
# Acknowledgements
The content on this page was first contributed by: Henry A. Hoff.
Initial content for this page in some instances came from Wikiversity.
# Hypotheses
- When the genome within each tooth is properly signaled, it will begin to heal the tooth from the inside out against caries and any other illness of the teeth. | https://www.wikidoc.org/index.php/Human_teeth | |
7372cc832fdbf179fb81dc718389e3748f3dbab1 | wikidoc | Human voice | Human voice
The human voice consists of sound made by a human being using the vocal folds for talking, singing, laughing, crying, screaming, etc. Human voice is specifically that part of human sound production in which the vocal folds (vocal cords) are the primary noise source. Generally speaking, the voice can be subdivided into three parts; the lungs, the vocal folds, and the articulators. The lung (the pump) must produce adequate airflow to vibrate vocal folds (air is the fuel of the voice). The vocal folds (vocal cords) are the vibrators, neuromuscular units that ‘fine tune’ pitch & tone. The articulators (vocal tract consisting of tongue, palate, cheek, lips, etc.) articulate and filter the sound.
The vocal folds, in combination with the articulators, are capable of producing highly intricate arrays of sound.
The tone of voice may be modulated to suggest emotions such as anger, surprise, or happiness.
Singers use the human voice as an instrument for creating music.
# Voice types and the folds (cords) themselves
Men and women have different vocal folds sizes; adult male voices are usually lower-pitched and have larger folds. The male vocal folds (which would be measured vertically in the opposite diagram), are between 17 mm and 25 mm in length.
Matching the female body, which on the whole has less muscle than the male, females have smaller folds. The female vocal folds are between 12.5 mm and 17.5 mm in length.
As seen in the illustration, the folds are located just above the trachea (the windpipe which travels from the lungs). Food and drink do not pass through the cords but instead pass through the esophagus, an unlinked tube. Both tubes are separated by the epiglottis, a "flap" that covers the opening of the trachea while swallowing. When food goes down through the cords and trachea (can occur when a person inhales while swallowing), aspiration and possibly choking result.
The folds in both sexes are within the larynx. They are attached at the back (side nearest the spinal cord) to the arytenoid cartilages, and at the front (side under the chin) to the thyroid cartilage. They have no outer edge as they blend into the side of the breathing tube (the illustration is out of date and does not show this well) while their inner edges or "margins" are free to vibrate (the hole). They have a three layer construction of an epithelium, vocal ligament, then muscle (vocalis muscle), which can shorten and bulge the folds. They are flat triangular bands and are pearly white in color. Above both sides of the vocal cord is the vestibular fold or false vocal cord, which has a small sac between its two folds (not illustrated).
The difference in vocal folds size between men and women means that they have differently pitched voices. Additionally, genetics also causes variances amongst the same sex, with men and women's singing voices being categorized into types. For example, among men, there are basses, baritones and tenors, and contraltos, mezzo-sopranos and sopranos among women. There are additional categories for operatic voices, see voice type. This is not the only source of difference between male and female voice. Men, generally speaking, have a larger vocal tract, which essentially gives the resultant voice a lower tonal quality. This is mostly independent of the vocal folds themselves.
# Physiology and vocal timbre
The sound of each individual's voice is entirely unique not only because of the actual shape and size of an individual's vocal cords but also due to the size and shape of the rest of that person's body. Humans have vocal folds which can loosen, tighten, or change their thickness, and over which breath can be transferred at varying pressures. The shape of chest and neck, the position of the tongue, and the tightness of otherwise unrelated muscles can be altered. Any one of these actions results in a change in pitch, volume, timbre, or tone of the sound produced. Sound also resonates within different parts of the body, and an individual's size and bone structure can affect the sound produced by an individual.
Singers can also learn to project sound in certain ways so that it resonates better within their vocal tract. This is known as vocal resonation. Another major influence on vocal sound and production is the function of the larynx which people can manipulate in different ways to produce different sounds. These different kinds of laryngeal function are described as different kinds of vocal registers. The primary method for singers to accomplish this is through the use of the Singer's Formant; which has been shown to match particularly well to the most sensitive part of the ear's frequency range.
## Vocal registration
Vocal registration refers to the system of vocal registers within the human voice. A register in the human voice is a particular series of tones, produced in the same vibratory pattern of the vocal folds, and possessing the same quality. Registers originate in laryngeal function. They occur because the vocal folds are capable of producing several different vibratory patterns. Each of these vibratory patterns appears within a particular range of pitches and produces certain characteristic sounds. The term register can be somewhat confusing at it encompasses several aspects of the human voice. The term register can be used to refer to any of the following:
- A particular part of the vocal range such as the upper, middle, or lower registers.
- A resonance area such as chest voice or head voice.
- A phonatory process
- A certain vocal timbre
- A region of the voice which is defined or delimited by vocal breaks.
- A subset of a language used for a particular purpose or in a particular social setting.
In linguistics, a register language is a language which combines tone and vowel phonation into a single phonological system.
Within speech pathology the term vocal register has three constituent elements: a certain vibratory pattern of the vocal folds, a certain series of pitches, and a certain type of sound. Speech pathologists identify four vocal registers based on the physiology of laryngeal function: the vocal fry register, the modal register, the falsetto register, and the whistle register. This view is also adopted by many vocal pedagogists.
## Vocal resonation
Vocal resonation is the process by which the basic product of phonation is enhanced in timbre and/or intensity by the air-filled cavities through which it passes on its way to the outside air. Various terms related to the resonation process include amplification, enrichment, enlargement, improvement, intensification, and prolongation, although in strictly scientific usage acoustic authorities would question most of them. The main point to be drawn from these terms by a singer or speaker is that the end result of resonation is, or should be, to make a better sound.
There are seven areas that may be listed as possible vocal resonators. In sequence from the lowest within the body to the highest, these areas are the chest, the tracheal tree, the larynx itself, the pharynx, the oral cavity, the nasal cavity, and the sinuses.
# Influences of the human voice
The twelve tone musical scale, upon which the majority of the world's music is based, may have its roots in the sound of the human voice during the course of evolution, according to a study published by the New Scientist. Analysis of recorded speech samples found peaks in acoustic energy that mirrored the distances between notes in the twelve-tone scale.
# Voice disorders
There are many disorders which affect the human voice; these include speech impediments, and growths and |lesions on the vocal folds. Talking improperly for long periods of time causes vocal loading which is stress inflicted on the speech organs. When vocal injury is done, often a ENT specialist may be able to help, but the best treatment is the prevention of injuries through good vocal production. Voice therapy is generally delivered by a Speech-language pathologist
Hoarseness or breathiness that lasts for more than two weeks is a common symptom for an underlying voice disorder and should be investigated medically.
# Footnotes
- ↑ Titze, I. R. (2008). The human instrument. Sci.Am. 298 (1):94-101. PM 18225701
- ↑ Titze, I.R. (1994). Principles of Voice Production, Prentice Hall (currently published by NCVS.org), ISBN 978-0137178933.
- ↑ Titze, I. R. (2006).The Myoelatic Aerodynamic Theory of Phonation, Iowa City:National Center for Voice and Speech, 2006.
- ↑ Smith BL, Brown BL, Strong WJ, Rencher AC. (1975) Effects of speech rate on personality perception. Lang Speech. 18(2):145-52 PMID: 1195957
- ↑ Williams CE, Stevens KN.(1972). Emotions and speech: some acoustical correlates. J Acoust Soc Am. 52(4):1238-50 PMID: 4638039
- ↑ I. R. Titze, S. Mapes, and B. Story. (1994) Acoustics of the Tenor High Voice. J.Acoust.Soc.Am. 95 (2):1133-1142. PMID: 8132903
- ↑ Thurman, Leon & Welch, ed., Graham (2000), Bodymind & voice: Foundations of voice education (revised ed.), Collegeville, Minnesota: The VoiceCare Network et al., ISBN 0874141230
- ↑ Vennard, William (1967). Singing: The Mechanism and the Technic. Carl Fischer. ISBN 13: 978-0825800559 Check |isbn= value: invalid character (help)..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ E. J. Hunter and I. R. Titze. Overlap of Hearing and Voicing Ranges in Singing. J.Singing 61 (4):387-392, 2004.
- ↑ E. J. Hunter, J. G. Svec, and I. R. Titze. Comparison of the Produced and Perceived Voice Range Profiles in Untrained and Trained Classical Singers. J.Voice 2005.
- ↑ Large, John (1972). "Towards an Integrated Physiologic-Acoustic Theory of Vocal Registers". The NATS Bulletin. 28: 30–35. Unknown parameter |month= ignored (help)
- ↑ Jump up to: 12.0 12.1 12.2 McKinney, James (1994). The Diagnosis and Correction of Vocal Faults. Genovex Music Group. ISBN 13: 978-1565939400 Check |isbn= value: invalid character (help).
- ↑ Greene, Margaret (2001). The Voice and its Disorders. John Wiley & Sons; 6th Edition edition. ISBN 13: 978-1861561961 Check |isbn= value: invalid character (help). Unknown parameter |coauthors= ignored (help)
- ↑ Musical roots may lie in human voice - 06 August 2003 - New Scientist
# Further reading
- Puts, D. A., Gaulin, S. J. C., & Verdolini, K. (2006). Dominance and the evolution of sexual dimorphism in human voice pitch. Evolution and Human Behavior, 27: 283-296. Full text
- Titze, I. R. (2008). The human instrument. Sci.Am. 298 (1):94-101. PM 18225701
- Thurman, Leon & Welch, ed., Graham (2000), Bodymind & voice: Foundations of voice education (revised ed.), Collegeville, Minnesota: The VoiceCare Network et al., ISBN 0874141230 | Human voice
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The human voice consists of sound made by a human being using the vocal folds for talking, singing, laughing, crying, screaming, etc. Human voice is specifically that part of human sound production in which the vocal folds (vocal cords) are the primary noise source. Generally speaking, the voice can be subdivided into three parts; the lungs, the vocal folds, and the articulators. The lung (the pump) must produce adequate airflow to vibrate vocal folds (air is the fuel of the voice). The vocal folds (vocal cords) are the vibrators, neuromuscular units that ‘fine tune’ pitch & tone. The articulators (vocal tract consisting of tongue, palate, cheek, lips, etc.) articulate and filter the sound.
The vocal folds, in combination with the articulators, are capable of producing highly intricate arrays of sound.[1][2][3]
The tone of voice may be modulated to suggest emotions such as anger, surprise, or happiness.[4][5]
Singers use the human voice as an instrument for creating music.[6]
# Voice types and the folds (cords) themselves
Men and women have different vocal folds sizes; adult male voices are usually lower-pitched and have larger folds. The male vocal folds (which would be measured vertically in the opposite diagram), are between 17 mm and 25 mm in length.[7]
Matching the female body, which on the whole has less muscle than the male, females have smaller folds. The female vocal folds are between 12.5 mm and 17.5 mm in length.
As seen in the illustration, the folds are located just above the trachea (the windpipe which travels from the lungs). Food and drink do not pass through the cords but instead pass through the esophagus, an unlinked tube. Both tubes are separated by the epiglottis, a "flap" that covers the opening of the trachea while swallowing. When food goes down through the cords and trachea (can occur when a person inhales while swallowing), aspiration and possibly choking result.
The folds in both sexes are within the larynx. They are attached at the back (side nearest the spinal cord) to the arytenoid cartilages, and at the front (side under the chin) to the thyroid cartilage. They have no outer edge as they blend into the side of the breathing tube (the illustration is out of date and does not show this well) while their inner edges or "margins" are free to vibrate (the hole). They have a three layer construction of an epithelium, vocal ligament, then muscle (vocalis muscle), which can shorten and bulge the folds. They are flat triangular bands and are pearly white in color. Above both sides of the vocal cord is the vestibular fold or false vocal cord, which has a small sac between its two folds (not illustrated).
The difference in vocal folds size between men and women means that they have differently pitched voices. Additionally, genetics also causes variances amongst the same sex, with men and women's singing voices being categorized into types. For example, among men, there are basses, baritones and tenors, and contraltos, mezzo-sopranos and sopranos among women. There are additional categories for operatic voices, see voice type. This is not the only source of difference between male and female voice. Men, generally speaking, have a larger vocal tract, which essentially gives the resultant voice a lower tonal quality. This is mostly independent of the vocal folds themselves.
# Physiology and vocal timbre
The sound of each individual's voice is entirely unique not only because of the actual shape and size of an individual's vocal cords but also due to the size and shape of the rest of that person's body. Humans have vocal folds which can loosen, tighten, or change their thickness, and over which breath can be transferred at varying pressures. The shape of chest and neck, the position of the tongue, and the tightness of otherwise unrelated muscles can be altered. Any one of these actions results in a change in pitch, volume, timbre, or tone of the sound produced. Sound also resonates within different parts of the body, and an individual's size and bone structure can affect the sound produced by an individual.
Singers can also learn to project sound in certain ways so that it resonates better within their vocal tract. This is known as vocal resonation. Another major influence on vocal sound and production is the function of the larynx which people can manipulate in different ways to produce different sounds. These different kinds of laryngeal function are described as different kinds of vocal registers.[8] The primary method for singers to accomplish this is through the use of the Singer's Formant; which has been shown to match particularly well to the most sensitive part of the ear's frequency range.[9][10]
## Vocal registration
Vocal registration refers to the system of vocal registers within the human voice. A register in the human voice is a particular series of tones, produced in the same vibratory pattern of the vocal folds, and possessing the same quality. Registers originate in laryngeal function. They occur because the vocal folds are capable of producing several different vibratory patterns. Each of these vibratory patterns appears within a particular range of pitches and produces certain characteristic sounds.[11] The term register can be somewhat confusing at it encompasses several aspects of the human voice. The term register can be used to refer to any of the following[12]:
- A particular part of the vocal range such as the upper, middle, or lower registers.
- A resonance area such as chest voice or head voice.
- A phonatory process
- A certain vocal timbre
- A region of the voice which is defined or delimited by vocal breaks.
- A subset of a language used for a particular purpose or in a particular social setting.
In linguistics, a register language is a language which combines tone and vowel phonation into a single phonological system.
Within speech pathology the term vocal register has three constituent elements: a certain vibratory pattern of the vocal folds, a certain series of pitches, and a certain type of sound. Speech pathologists identify four vocal registers based on the physiology of laryngeal function: the vocal fry register, the modal register, the falsetto register, and the whistle register. This view is also adopted by many vocal pedagogists.[12]
## Vocal resonation
Vocal resonation is the process by which the basic product of phonation is enhanced in timbre and/or intensity by the air-filled cavities through which it passes on its way to the outside air. Various terms related to the resonation process include amplification, enrichment, enlargement, improvement, intensification, and prolongation, although in strictly scientific usage acoustic authorities would question most of them. The main point to be drawn from these terms by a singer or speaker is that the end result of resonation is, or should be, to make a better sound.[12]
There are seven areas that may be listed as possible vocal resonators. In sequence from the lowest within the body to the highest, these areas are the chest, the tracheal tree, the larynx itself, the pharynx, the oral cavity, the nasal cavity, and the sinuses.[13]
# Influences of the human voice
The twelve tone musical scale, upon which the majority of the world's music is based, may have its roots in the sound of the human voice during the course of evolution, according to a study published by the New Scientist. Analysis of recorded speech samples found peaks in acoustic energy that mirrored the distances between notes in the twelve-tone scale.[14]
# Voice disorders
There are many disorders which affect the human voice; these include speech impediments, and growths and |lesions on the vocal folds. Talking improperly for long periods of time causes vocal loading which is stress inflicted on the speech organs. When vocal injury is done, often a ENT specialist may be able to help, but the best treatment is the prevention of injuries through good vocal production. Voice therapy is generally delivered by a Speech-language pathologist
Hoarseness or breathiness that lasts for more than two weeks is a common symptom for an underlying voice disorder and should be investigated medically.
# Footnotes
- ↑ Titze, I. R. (2008). The human instrument. Sci.Am. 298 (1):94-101. PM 18225701
- ↑ Titze, I.R. (1994). Principles of Voice Production, Prentice Hall (currently published by NCVS.org), ISBN 978-0137178933.
- ↑ Titze, I. R. (2006).The Myoelatic Aerodynamic Theory of Phonation, Iowa City:National Center for Voice and Speech, 2006.
- ↑ Smith BL, Brown BL, Strong WJ, Rencher AC. (1975) Effects of speech rate on personality perception. Lang Speech. 18(2):145-52 PMID: 1195957
- ↑ Williams CE, Stevens KN.(1972). Emotions and speech: some acoustical correlates. J Acoust Soc Am. 52(4):1238-50 PMID: 4638039
- ↑ I. R. Titze, S. Mapes, and B. Story. (1994) Acoustics of the Tenor High Voice. J.Acoust.Soc.Am. 95 (2):1133-1142. PMID: 8132903
- ↑ Thurman, Leon & Welch, ed., Graham (2000), Bodymind & voice: Foundations of voice education (revised ed.), Collegeville, Minnesota: The VoiceCare Network et al., ISBN 0874141230
- ↑ Vennard, William (1967). Singing: The Mechanism and the Technic. Carl Fischer. ISBN 13: 978-0825800559 Check |isbn= value: invalid character (help)..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ E. J. Hunter and I. R. Titze. Overlap of Hearing and Voicing Ranges in Singing. J.Singing 61 (4):387-392, 2004.
- ↑ E. J. Hunter, J. G. Svec, and I. R. Titze. Comparison of the Produced and Perceived Voice Range Profiles in Untrained and Trained Classical Singers. J.Voice 2005.
- ↑ Large, John (1972). "Towards an Integrated Physiologic-Acoustic Theory of Vocal Registers". The NATS Bulletin. 28: 30–35. Unknown parameter |month= ignored (help)
- ↑ Jump up to: 12.0 12.1 12.2 McKinney, James (1994). The Diagnosis and Correction of Vocal Faults. Genovex Music Group. ISBN 13: 978-1565939400 Check |isbn= value: invalid character (help).
- ↑ Greene, Margaret (2001). The Voice and its Disorders. John Wiley & Sons; 6th Edition edition. ISBN 13: 978-1861561961 Check |isbn= value: invalid character (help). Unknown parameter |coauthors= ignored (help)
- ↑ Musical roots may lie in human voice - 06 August 2003 - New Scientist
# Further reading
- Puts, D. A., Gaulin, S. J. C., & Verdolini, K. (2006). Dominance and the evolution of sexual dimorphism in human voice pitch. Evolution and Human Behavior, 27: 283-296. Full text
- Titze, I. R. (2008). The human instrument. Sci.Am. 298 (1):94-101. PM 18225701
- Thurman, Leon & Welch, ed., Graham (2000), Bodymind & voice: Foundations of voice education (revised ed.), Collegeville, Minnesota: The VoiceCare Network et al., ISBN 0874141230 | https://www.wikidoc.org/index.php/Human_voice | |
b05b9a4691942da0d913216bcb78dd706c9ccd43 | wikidoc | Hyaluronate | Hyaluronate
# Overview
Hyaluronan /haɪˈæljʊrənən/ (also called hyaluronic acid Template:IPA, hyaluronate Template:IPA or Template:IPA, or HA) is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues. It is unique among glycosaminoglycans in that it is nonsulfated, forms in the plasma membrane instead of the Golgi, and can be very large, with its molecular weight often reaching the millions.
One of the chief components of the extracellular matrix, hyaluronan contributes significantly to cell proliferation and migration, and may also be involved in the progression of some malignant tumors.
The average 70 kg (154 lb) person has roughly 15 grams of hyaluronan in the body, one-third of which is turned over (degraded and synthesized) every day. Hyaluronic acid is also a component of the group A streptococcal extracellular capsule, and is believed to play a role in virulence.
# Medical uses
Hyaluronan has been used in attempts to treat osteoarthritis of the knee via injecting it into the joint. It has not been proven, however, to generate significant benefit and has potentially severe adverse effects.
Dry, scaly skin (xerosis) such as that caused by atopic dermatitis (eczema) may be treated with a prescription skin lotion containing sodium hyaluronate as its active ingredient.
In some cancers, hyaluronan levels correlate well with malignancy and poor prognosis. Hyaluronan is, thus, often used as a tumor marker for prostate and breast cancer. It may also be used to monitor the progression of the disease.
Hyaluronan may also be used postoperatively to induce tissue healing, notably after cataract surgery. Current models of wound healing propose the larger polymers of hyaluronic acid appear in the early stages of healing to physically make room for white blood cells, which mediate the immune response.
Hyaluronan has also been used in the synthesis of biological scaffolds for wound-healing applications. These scaffolds typically have proteins such as fibronectin attached to the hyaluronan to facilitate cell migration into the wound. This is particularly important for individuals with diabetes suffering from chronic wounds.
# Functions
Until the late 1970s, hyaluronan was described as a "goo" molecule, a ubiquitous carbohydrate polymer that is part of the extracellular matrix. For example, hyaluronan is a major component of the synovial fluid, and was found to increase the viscosity of the fluid. Along with lubricin, it is one of the fluid's main lubricating components.
Hyaluronan is an important component of articular cartilage, where it is present as a coat around each cell (chondrocyte). When aggrecan monomers bind to hyaluronan in the presence of link protein, large, highly negatively charged aggregates form. These aggregates imbibe water and are responsible for the resilience of cartilage (its resistance to compression). The molecular weight (size) of hyaluronan in cartilage decreases with age, but the amount increases.
Hyaluronan is also a major component of skin, where it is involved in tissue repair. When skin is exposed to excessive UVB rays, it becomes inflamed (sunburn) and the cells in the dermis stop producing as much hyaluronan, and increase the rate of its degradation. Hyaluronan degradation products then accumulate in the skin after UV exposure.
While it is abundant in extracellular matrices, hyaluronan also contributes to tissue hydrodynamics, movement and proliferation of cells, and participates in a number of cell surface receptor interactions, notably those including its primary receptors, CD44 and RHAMM. Upregulation of CD44 itself is widely accepted as a marker of cell activation in lymphocytes. Hyaluronan's contribution to tumor growth may be due to its interaction with CD44. Receptor CD44 participates in cell adhesion interactions required by tumor cells.
Although hyaluronan binds to receptor CD44, there is evidence hyaluronan degradation products transduce their inflammatory signal through toll-like receptor 2 (TLR2), TLR4 or both TLR2, and TLR4 in macrophages and dendritic cells. TLR and hyaluronan play a role in innate immunity.
There are limitations including the in vivo loss of this compound limiting the duration of effect.
# Structure
Properties of hyaluronan were first determined in the 1930s in the laboratory of Karl Meyer.
Hyaluronan is a polymer of disaccharides, themselves composed of D-glucuronic acid and D-N-acetylglucosamine, linked via alternating β-1,4 and β-1,3 glycosidic bonds. Hyaluronan can be 25,000 disaccharide repeats in length. Polymers of hyaluronan can range in size from 5,000 to 20,000,000 Da in vivo. The average molecular weight in human synovial fluid is 3–4 million Da, and hyaluronan purified from human umbilical cord is 3,140,000 Da.
Hyaluronan is energetically stable, in part because of the stereochemistry of its component disaccharides. Bulky groups on each sugar molecule are in sterically favored positions, whereas the smaller hydrogens assume the less-favorable axial positions.
# Biological synthesis
Hyaluronan is synthesized by a class of integral membrane proteins called hyaluronan synthases, of which vertebrates have three types: HAS1, HAS2, and HAS3. These enzymes lengthen hyaluronan by repeatedly adding glucuronic acid and N-acetylglucosamine to the nascent polysaccharide as it is extruded via ABC-transporter through the cell membrane into the extracellular space.
Hyaluronan synthesis (HAS) has been shown to be inhibited by 4-methylumbelliferone (hymecromone, heparvit), a 7-hydroxy-4-methylcoumarin derivative.
This selective inhibition (without inhibiting other glycosaminoglycans) may prove useful in preventing metastasis of malignant tumor cells.
Bacillus subtilis recently has been genetically modified (GMO) to culture a proprietary formula to yield hyaluronans, in a patented process producing human-grade product.
# Cell receptors for hyaluronan
So far, cell receptors that have been identified for HA fall into three main groups: CD44, Receptor for HA-mediated motility (RHAMM) and intercellular adhesion molecule-1 (ICAM-1). CD44 and ICAM-1 were already known as cell adhesion molecules with other recognized ligands before their HA binding was discovered.
CD44 is widely distributed throughout the body, and the formal demonstration of HA-CD44 binding was proposed by Aruffo et al. in 1990. To date, it is recognized as the main cell surface receptor for HA. CD44 mediates cell interaction with HA and the binding of the two functions as an important part in various physiologic events, such as cell aggregation, migration, proliferation and activation; cell–cell and cell–substrate adhesion; endocytosis of HA, which leads to HA catabolism in macrophages; and assembly of pericellular matrices from HA and proteoglycan. Two significant roles of CD44 in skin were proposed by Kaya et al. The first is regulation of keratinocyte proliferation in response to extracellular stimuli, and the second is the maintenance of local HA homeostasis.
ICAM-1 is known mainly as a metabolic cell surface receptor for HA, and this protein may be responsible mainly for the clearance of HA from lymph and blood plasma, which accounts for perhaps most of its whole-body turnover. Ligand binding of this receptor, thus, triggers a highly coordinated cascade of events that includes the formation of an endocytotic vesicle, its fusion with primary lysosomes, enzymatic digestion to monosaccharides, active transmembrane transport of these sugars to cell sap, phosphorylation of GlcNAc and enzymatic deacetylation. Like its name, ICAM-1 may also serve as a cell adhesion molecule, and the binding of HA to ICAM-1 may contribute to the control of ICAM-1-mediated inflammatory activation.
# Degradation
Hyaluronan is degraded by a family of enzymes called hyaluronidases. In humans, there are at least seven types of hyaluronidase-like enzymes, several of which are tumor suppressors. The degradation products of hyaluronan, the oligosaccharides and very low-molecular-weight hyaluronan, exhibit pro-angiogenic properties. In addition, recent studies showed hyaluronan fragments, not the native high-molecular mass of hyaluronan, can induce inflammatory responses in macrophages and dendritic cells in tissue injury and in skin transplant
# Wound repair
Skin provides a mechanical barrier to the external environment and acts to prevent the ingress of infectious agents. Once injured, the tissues beneath are exposed to infection; therefore, rapid and effective healing is of crucial significance to reconstruct a barrier function. Skin wound healing is a complex process, and includes many interacting processes initiated by haemostasis and the release of platelet-derived factors. The following stages are inflammation, granulation tissue formation, reepithelization and remodeling. HA is likely to play a multifaceted role in mediation of these cellular and matrix events. The proposed roles of HA in this sequence of skin wound healing events are elucidated in details below.
## Inflammation
Many biological factors, such as growth factors, cytokines, eicosanoids etc., are generated in the inflammation process. These factors are necessary for the subsequent steps of wound healing due to their roles in promoting migration of inflammatory cells, fibroblasts, and endothelial cells into the wound site.
The wound tissue in the early inflammatory phase of wound repair is abundant in HA, probably a reflection of increased synthesis. HA acts as a promoter of early inflammation, which is crucial in the whole skin wound-healing process. In a murine air pouch model of carrageenan/IL-1-induced inflammation, HA was observed to enhance cellular infiltration. showed a dose-dependent increase of the proinflammatory cytokines TNF-α and IL-8 production by human uterine fibroblasts at HA concentrations of 10 μg/mL to 1 mg/mL via a CD44-mediated mechanism. Endothelial cells, in response to inflammatory cytokines such as TNF-α, and bacterial lipopolysaccharide, also synthesize HA, which has been shown to facilitate primary adhesion of cytokine-activated lymphocytes expressing the HA-binding variants of CD44 under laminar and static flow conditions. It is interesting to note that HA has contradictory dual functions in the inflammatory process. It not only can promote the inflammation, as stated above, but also can moderate the inflammatory response, which may contribute to the stabilization of granulation tissue matrix, as described in the following part.
## Granulation and organization of the granulation tissue matrix
Granulation tissue is the perfused, fibrous connective tissue that replaces a fibrin clot in healing wounds. It typically grows from the base of a wound and is able to fill wounds of almost any size it heals. HA is abundant in granulation tissue matrix. A variety of cell functions that are essential for tissue repair may attribute to this HA-rich network. These functions include facilitation of cell migration into the provisional wound matrix, cell proliferation and organization of the granulation tissue matrix. Initiation of inflammation is crucial for the formation of granulation tissue, therefore the pro-inflammatory role of HA as discussed above also contributes to this stage of wound healing.
## HA and cell migration
Cell migration is essential for the formation of granulation tissue. The early stage of granulation tissue is dominated by a HA-rich extracellular matrix, which is regarded as a conducive environment for migration of cells into this temporary wound matrix. Contributions of HA to cell migration may attribute to its physicochemical properties as stated above, as well as its direct interactions with cells. For the former scenario, HA provides an open hydrated matrix that facilitates cell migration, whereas, in the latter scenario, directed migration and control of the cell locomotory mechanisms are mediated via the specific cell interaction between HA and cell surface HA receptors. As discussed before, the three principal cell surface receptors for HA are CD44, RHAMM, and ICAM-1. RHAMM is more related to cell migration. It forms links with several protein kinases associated with cell locomotion, for example, extracellular signal-regulated protein kinase (ERK), p125fak, and pp60c-src. During fetal development, the migration path through which neural crest cells migrate is rich in HA. HA is closely associated with the cell migration process in granulation tissue matrix, and studies show that cell movement can be inhibited, at least partially, by HA degradation or blocking HA receptor occupancy.
By providing the dynamic force to the cell, HA synthesis has also been shown to associate with cell migration. Basically, HA is synthesized at the plasma membrane and released directly into the extracellular environment. This may contribute to the hydrated microenvironment at sites of synthesis, and is essential for cell migration by facilitating cell detachment.
## Role of HA in moderation of the inflammatory response
Although inflammation is an integral part of granulation tissue formation, for normal tissue repair to proceed, inflammation needs to be moderated. The initial granulation tissue formed is highly inflammatory with a high rate of tissue turnover mediated by matrix degrading enzymes and reactive oxygen metabolites that are products of inflammatory cells. Stabilization of granulation tissue matrix can be achieved by moderating inflammation. HA functions as an important moderator in this moderation process, which contradicts its role in inflammatory stimulation, as described above. HA can protect against free-radical damage to cells. This may attribute to its free-radical scavenging property, a physicochemical characteristic shared by large polyionic polymers. In a rat model of free-radical scavenging property investigated by Foschi D. and colleagues, HA has been shown to reduce damage to the granulation tissue.
In addition to the free-radical scavenging role, HA may also function in the negative feedback loop of inflammatory activation through its specific biological interactions with the biological constituents of inflammation. TNF-α, an important cytokine generated in inflammation, stimulates the expression of TSG-6 (TNF-stimulated gene 6) in fibroblasts and inflammatory cells. TSG-6, a HA-binding protein, also forms a stable complex with the serum proteinase inhibitor IαI (Inter-α-inhibitor) with a synergistic effect on the latter’s plasmin-inhibitory activity. Plasmin is involved in activation of the proteolytic cascade of matrix metalloproteinases and other proteinases leading to inflammatory tissue damage. Therefore, the action of TSG-6/ IαI complex, which may be additionally organized by binding to HA in the extracellular matrix, may serve as a potent negative feedback loop to moderate inflammation and stabilize the granulation tissue as healing progresses. In the murine air pouch model of carragenan/IL-1 (Interleukin-1β)-induced inflammation, where HA has been shown to have a proinflammatory property, reduction of inflammation can be achieved by administrating TSG-6, and the result is comparable with systemic dexamethasone treatment.
## Re-epithelization
HA plays an important role in the normal epidermis. HA also has crucial functions in the reepithelization process due to several of its properties. It serves as an integral part of the extracellular matrix of basal keratinocytes, which are major constituents of the epidermis; its free-radical scavenging function and its role in keratinocyte proliferation and migration.
In normal skin, HA is found in relative high concentrations in the basal layer of the epidermis where proliferating keratinocytes are found. CD44 is collocated with HA in the basal layer of epidermis where additionally it has been shown to be preferentially expressed on plasma membrane facing the HA-rich matrix pouches. Maintaining the extracellular space and providing an open, as well as hydrated, structure for the passage of nutrients are the main functions of HA in epidermis. Tammi R. and other colleagues found HA content increases at the presence of retinoic acid (vitamin A). The proposed effects of retinoic acid against skin photo-damage and aging may be correlated, at least in part, with an increase of skin HA content, giving rise to increase of tissue hydration. It has been suggested the free-radical scavenging property of HA contributes to protection against solar radiation, supporting the role of CD44 acting as a HA receptor in the epidermis.
Epidermal HA also functions as a manipulator in the process of keratinocyte proliferation, which is essential in normal epidermal function, as well as during reepithelization in tissue repair. In the wound healing process, HA is expressed in the wound margin, in the connective tissue matrix, and collocating with CD44 expression in migrating keratinocytes.Kaya G, Rodriguez I, Jorcano JL, Vassalli P, Stamenkovic I (1997). "Selective suppression of CD44 in keratinocytes of mice bearing an antisense CD44 transgene driven by a tissue-specific promoter disrupts hyaluronate metabolism in the skin and impairs keratinocyte proliferation". Genes Dev. 11 (8): 996–1007. doi:10.1101/gad.11.8.996. PMID 9136928..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} Kaya et al. found suppression of CD44 expression by an epidermis-specific antisense transgene resulted in animals with defective HA accumulation in the superficial dermis, accompanied by distinct morphologic alterations of basal keratinocytes and defective keratinocyte proliferation in response to mitogen and growth factors. Decrease in skin elasticity, impaired local inflammatory response, and impaired tissue repair were also observed. Their observations are strongly supportive of the important roles HA and CD44 have in skin physiology and tissue repair.
## Fetal wound healing and scarring
Lack of fibrous scarring is the primary feature of fetal wound healing. Even for longer periods, HA content in fetal wounds is still higher than that in adult wounds, which suggests that HA may, at least in part, reduce collagen deposition and therefore lead to reduced scarring. This suggestion is in agreement with the research of West et al., who showed in adult and late gestation fetal wound healing, removal of HA results in fibrotic scarring.
# Role in cancer metastasis
As shown in Figure 1, the various types of molecules that interact with hyaluronan can contribute to many of the stages of cancer metastasis, i.e. further the spread of cancer.
Hyaluronan synthases (HAS) play roles in all of the stages of cancer metastasis. By producing anti-adhesive HA, HAS can allow tumor cells to release from the primary tumor mass, and if HA associates with receptors such as CD44, the activation of Rho GTPases can promote epithelial-mesenchymal transition (EMT) of the cancer cells. During the processes of intravasation or extravasation, the interaction of HAS produced HA with receptors such as CD44 or RHAMM promote the cell changes that allow for the cancer cells to infiltrate the vascular or lymphatic systems. While traveling in these systems, HA produced by HAS protects the cancer cell from physical damage. Finally, in the formation of a metastatic lesion, HAS produces HA to allow the cancer cell to interact with native cells at the secondary site and to produce a tumor for itself.
Hyaluronidases (HAase or HYAL) also play many roles in cancer metastasis. By helping to degrade the extracellular matrix surrounding the tumor, hyaluronidases help the cancer cell escape from the primary tumor mass and play a major role in intravasation by allowing degradation of the basement membrane of the lymph or blood vessel. Hyaluronidases again play these roles in establishment of a metastatic lesion by helping with extravasation and clearing the extracellular matrix (ECM) of the secondary site. Finally, hyaluronidases play a key role in the process of angiogenesis. HA fragments promote angiogenesis and hyaluronidases produce these fragments. Interestingly, hypoxia also increases production of HA and activity of hyaluronidases.
The hyaluronan receptors, CD44 and RHAMM, are most thoroughly studied in terms of their roles in cancer metastasis. Increased clinical CD44 expression has been positively correlated to metastasis in a number of tumor types. In terms of mechanics, CD44 affects adhesion of cancer cells to each other and to endothelial cells, rearranges the cytoskeleton through the Rho GTPases, and increases the activity of ECM degrading enzymes. Increased RHAMM expression has also been clinically correlated with cancer metastasis. In terms of mechanics, RHAMM promotes cancer cell motility through a number of pathways including focal adhesion kinase (FAK), Map kinase (MAPK), pp60(c-src), and the downstream targets of Rho kinase (ROK). RHAMM can also cooperate with CD44 to promote angiogenesis toward the metastatic lesion.
# Cosmetic uses
Hyaluronan is a common ingredient in skin-care products.
Until recently, hyaluronic acid fillers were injected using a classic sharp hypodermic needle, cutting through nerves and vessels, causing pain and bruising.
In certain cases, the hyaluronic acid fillers results in a granulomatous foreign body reaction.
# Equine applications
Hyaluronan is used in treatment of articular disorders in horses, in particular those in competition or heavy work. It is indicated for carpal and fetlock joint dysfunctions, but not when joint sepsis or fracture are suspected. It is especially used for synovitis associated with equine osteoarthritis. It can be injected directly into an affected joint, or intravenously for less localized disorders. It may cause mild heating of the joint if directly injected, but this does not affect the clinical outcome. Intra-articularly administered medicine is fully metabolized in less than a week.
Note that, according to Canadian regulation, hyaluronan in HY-50 preparation should not be administered to animals to be slaughtered for horse meat. In Europe, however, the same preparation is not considered to have any such effect, and edibility of the horse meat is not affected.
# Etymology
Hyaluronic acid is derived from hyalos (Greek for vitreous) and uronic acid because it was first isolated from the vitreous humour and possesses a high uronic acid content.
The term hyaluronate refers to the conjugate base of hyaluronic acid. Because the molecule typically exists in vivo in its polyanionic form, it is most commonly referred to as hyaluronan.
# History
Hyaluronan is found in many tissues of the body, such as skin, cartilage, and the vitreous humour. Therefore, it is well suited to biomedical applications targeting these tissues. The first hyaluronan biomedical product, Healon, was developed in the 1970s and 1980s by Pharmacia, and is approved for use in eye surgery (i.e., corneal transplantation, cataract surgery, glaucoma surgery, and surgery to repair retinal detachment). Other biomedical companies also produce brands of hyaluronan for ophthalmic surgery.
Native hyaluronan has a relatively short half-life (shown in rabbits) so various manufacturing techniques have been deployed to extend the length of the chain and stabilise the molecule for its use in medical applications. The introduction of protein based cross-links, the introduction of free-radical scavenging molecules such as sorbitol, and minimal stabilisation of the HA chains through chemical agents e.g. NASHA stabilisation are all techniques that have been used.
In the late 1970s, intraocular lens implantation was often followed by severe corneal edema, due to endothelial cell damage during the surgery. It was evident that a viscous, clear, physiologic lubricant to prevent such scraping of the endothelial cells was needed.
# Approval
FDA approved formulations are available. In 2007, the EMA extended its approval of Hylan GF-20 as a treatment for ankle and shoulder osteoarthritis pain.
# Research
Due to its high biocompatibility and its common presence in the extracellular matrix of tissues, hyaluronan is gaining popularity as a biomaterial scaffold in tissue engineering research. In particular, a number of research groups have found hyaluronan's properties for tissue engineering and regenerative medicine are significantly improved with crosslinking, producing a hydrogel. This added feature allows a researcher to form a desired shape, as well as to deliver therapeutic molecules, into a host. Hyaluronan can be crosslinked by attaching thiols (trade names: Extracel, HyStem),methacrylates, hexadecylamides (trade name: Hymovis), and tyramines (trade name: Corgel). Hyaluronan can also be crosslinked directly with formaldehyde (trade name: Hylan-A) or with divinylsulfone (trade name: Hylan-B).
Due to its ability to regulate angiogenesis by stimulating endothelial cells to proliferate, hyaluronic acid can be used to create hydrogels to study vascular morphogenesis. These hydrogels have properties similar to human soft tissue, but are also easily controlled and modified, making HA very suitable for tissue engineering studies. For example, HA hydrogels are appealing for engineering vasculature from endothelial progenitor cells by using appropriate growth factors such as VEGF and Ang-1 to promote proliferation and vascular network formation. Vacuole and lumen formation have been observed in these gels, followed by branching and sprouting through degradation of the hydrogel and finally complex network formation. The ability to generate vascular networks using HA hydrogels leads to opportunities for in vivo and clinical applications. One in vivo study, where HA hydrogels with endothelial colony forming cells were implanted into mice three days after hydrogel formation, saw evidence that the host and engineered vessels joined within 2 weeks of implantation, indicating viability and functionality of the engineered vasculature. | Hyaluronate
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Hyaluronan /haɪˈæljʊrənən/ (also called hyaluronic acid Template:IPA, hyaluronate Template:IPA or Template:IPA, or HA) is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues. It is unique among glycosaminoglycans in that it is nonsulfated, forms in the plasma membrane instead of the Golgi, and can be very large, with its molecular weight often reaching the millions.[2]
One of the chief components of the extracellular matrix, hyaluronan contributes significantly to cell proliferation and migration, and may also be involved in the progression of some malignant tumors.[3]
The average 70 kg (154 lb) person has roughly 15 grams of hyaluronan in the body, one-third of which is turned over (degraded and synthesized) every day.[4] Hyaluronic acid is also a component of the group A streptococcal extracellular capsule,[5] and is believed to play a role in virulence.[6][7]
# Medical uses
Hyaluronan has been used in attempts to treat osteoarthritis of the knee via injecting it into the joint. It has not been proven, however, to generate significant benefit and has potentially severe adverse effects.[8]
Dry, scaly skin (xerosis) such as that caused by atopic dermatitis (eczema) may be treated with a prescription skin lotion containing sodium hyaluronate as its active ingredient.[9]
In some cancers, hyaluronan levels correlate well with malignancy and poor prognosis. Hyaluronan is, thus, often used as a tumor marker for prostate and breast cancer. It may also be used to monitor the progression of the disease.[10][11]
Hyaluronan may also be used postoperatively to induce tissue healing, notably after cataract surgery.[12] Current models of wound healing propose the larger polymers of hyaluronic acid appear in the early stages of healing to physically make room for white blood cells, which mediate the immune response.
Hyaluronan has also been used in the synthesis of biological scaffolds for wound-healing applications. These scaffolds typically have proteins such as fibronectin attached to the hyaluronan to facilitate cell migration into the wound. This is particularly important for individuals with diabetes suffering from chronic wounds.[13]
# Functions
Until the late 1970s, hyaluronan was described as a "goo" molecule, a ubiquitous carbohydrate polymer that is part of the extracellular matrix.[14] For example, hyaluronan is a major component of the synovial fluid, and was found to increase the viscosity of the fluid. Along with lubricin, it is one of the fluid's main lubricating components.
Hyaluronan is an important component of articular cartilage, where it is present as a coat around each cell (chondrocyte). When aggrecan monomers bind to hyaluronan in the presence of link protein, large, highly negatively charged aggregates form. These aggregates imbibe water and are responsible for the resilience of cartilage (its resistance to compression). The molecular weight (size) of hyaluronan in cartilage decreases with age, but the amount increases.[15]
Hyaluronan is also a major component of skin, where it is involved in tissue repair. When skin is exposed to excessive UVB rays, it becomes inflamed (sunburn) and the cells in the dermis stop producing as much hyaluronan, and increase the rate of its degradation. Hyaluronan degradation products then accumulate in the skin after UV exposure.[16]
While it is abundant in extracellular matrices, hyaluronan also contributes to tissue hydrodynamics, movement and proliferation of cells, and participates in a number of cell surface receptor interactions, notably those including its primary receptors, CD44 and RHAMM. Upregulation of CD44 itself is widely accepted as a marker of cell activation in lymphocytes. Hyaluronan's contribution to tumor growth may be due to its interaction with CD44. Receptor CD44 participates in cell adhesion interactions required by tumor cells.
Although hyaluronan binds to receptor CD44, there is evidence hyaluronan degradation products transduce their inflammatory signal through toll-like receptor 2 (TLR2), TLR4 or both TLR2, and TLR4 in macrophages and dendritic cells. TLR and hyaluronan play a role in innate immunity.
There are limitations including the in vivo loss of this compound limiting the duration of effect.[17][18]
# Structure
Properties of hyaluronan were first determined in the 1930s in the laboratory of Karl Meyer.[19]
Hyaluronan is a polymer of disaccharides, themselves composed of D-glucuronic acid and D-N-acetylglucosamine, linked via alternating β-1,4 and β-1,3 glycosidic bonds. Hyaluronan can be 25,000 disaccharide repeats in length. Polymers of hyaluronan can range in size from 5,000 to 20,000,000 Da in vivo. The average molecular weight in human synovial fluid is 3–4 million Da, and hyaluronan purified from human umbilical cord is 3,140,000 Da.[20]
Hyaluronan is energetically stable, in part because of the stereochemistry of its component disaccharides. Bulky groups on each sugar molecule are in sterically favored positions, whereas the smaller hydrogens assume the less-favorable axial positions.
# Biological synthesis
Hyaluronan is synthesized by a class of integral membrane proteins called hyaluronan synthases, of which vertebrates have three types: HAS1, HAS2, and HAS3. These enzymes lengthen hyaluronan by repeatedly adding glucuronic acid and N-acetylglucosamine to the nascent polysaccharide as it is extruded via ABC-transporter through the cell membrane into the extracellular space.[21]
Hyaluronan synthesis (HAS) has been shown to be inhibited by 4-methylumbelliferone (hymecromone, heparvit), a 7-hydroxy-4-methylcoumarin derivative.[22]
This selective inhibition (without inhibiting other glycosaminoglycans) may prove useful in preventing metastasis of malignant tumor cells.[23]
Bacillus subtilis recently has been genetically modified (GMO) to culture a proprietary formula to yield hyaluronans,[24] in a patented process producing human-grade product.
# Cell receptors for hyaluronan
So far, cell receptors that have been identified for HA fall into three main groups: CD44, Receptor for HA-mediated motility (RHAMM) and intercellular adhesion molecule-1 (ICAM-1). CD44 and ICAM-1 were already known as cell adhesion molecules with other recognized ligands before their HA binding was discovered.[25]
CD44 is widely distributed throughout the body, and the formal demonstration of HA-CD44 binding was proposed by Aruffo et al.[26] in 1990. To date, it is recognized as the main cell surface receptor for HA. CD44 mediates cell interaction with HA and the binding of the two functions as an important part in various physiologic events,[25][27] such as cell aggregation, migration, proliferation and activation; cell–cell and cell–substrate adhesion; endocytosis of HA, which leads to HA catabolism in macrophages; and assembly of pericellular matrices from HA and proteoglycan. Two significant roles of CD44 in skin were proposed by Kaya et al.[28] The first is regulation of keratinocyte proliferation in response to extracellular stimuli, and the second is the maintenance of local HA homeostasis.[27]
ICAM-1 is known mainly as a metabolic cell surface receptor for HA, and this protein may be responsible mainly for the clearance of HA from lymph and blood plasma, which accounts for perhaps most of its whole-body turnover.[25][29] Ligand binding of this receptor, thus, triggers a highly coordinated cascade of events that includes the formation of an endocytotic vesicle, its fusion with primary lysosomes, enzymatic digestion to monosaccharides, active transmembrane transport of these sugars to cell sap, phosphorylation of GlcNAc and enzymatic deacetylation.[25][30][31] Like its name, ICAM-1 may also serve as a cell adhesion molecule, and the binding of HA to ICAM-1 may contribute to the control of ICAM-1-mediated inflammatory activation.[27]
# Degradation
Hyaluronan is degraded by a family of enzymes called hyaluronidases. In humans, there are at least seven types of hyaluronidase-like enzymes, several of which are tumor suppressors. The degradation products of hyaluronan, the oligosaccharides and very low-molecular-weight hyaluronan, exhibit pro-angiogenic properties.[32] In addition, recent studies showed hyaluronan fragments, not the native high-molecular mass of hyaluronan, can induce inflammatory responses in macrophages and dendritic cells in tissue injury and in skin transplant[33][34]
# Wound repair
Skin provides a mechanical barrier to the external environment and acts to prevent the ingress of infectious agents.[35] Once injured, the tissues beneath are exposed to infection; therefore, rapid and effective healing is of crucial significance to reconstruct a barrier function. Skin wound healing is a complex process, and includes many interacting processes initiated by haemostasis and the release of platelet-derived factors.[36] The following stages are inflammation, granulation tissue formation, reepithelization and remodeling. HA is likely to play a multifaceted role in mediation of these cellular and matrix events. The proposed roles of HA in this sequence of skin wound healing events are elucidated in details below.
## Inflammation
Many biological factors, such as growth factors, cytokines, eicosanoids etc., are generated in the inflammation process. These factors are necessary for the subsequent steps of wound healing due to their roles in promoting migration of inflammatory cells, fibroblasts, and endothelial cells into the wound site.[27]
The wound tissue in the early inflammatory phase of wound repair is abundant in HA, probably a reflection of increased synthesis.[27] HA acts as a promoter of early inflammation, which is crucial in the whole skin wound-healing process. In a murine air pouch model of carrageenan/IL-1-induced inflammation, HA was observed to enhance cellular infiltration.[27][37] showed a dose-dependent increase of the proinflammatory cytokines TNF-α and IL-8 production by human uterine fibroblasts at HA concentrations of 10 μg/mL to 1 mg/mL via a CD44-mediated mechanism. Endothelial cells, in response to inflammatory cytokines such as TNF-α, and bacterial lipopolysaccharide, also synthesize HA, which has been shown to facilitate primary adhesion of cytokine-activated lymphocytes expressing the HA-binding variants of CD44 under laminar and static flow conditions.[27][38] It is interesting to note that HA has contradictory dual functions in the inflammatory process. It not only can promote the inflammation, as stated above, but also can moderate the inflammatory response, which may contribute to the stabilization of granulation tissue matrix, as described in the following part.
## Granulation and organization of the granulation tissue matrix
Granulation tissue is the perfused, fibrous connective tissue that replaces a fibrin clot in healing wounds. It typically grows from the base of a wound and is able to fill wounds of almost any size it heals. HA is abundant in granulation tissue matrix. A variety of cell functions that are essential for tissue repair may attribute to this HA-rich network. These functions include facilitation of cell migration into the provisional wound matrix, cell proliferation and organization of the granulation tissue matrix.[27] Initiation of inflammation is crucial for the formation of granulation tissue, therefore the pro-inflammatory role of HA as discussed above also contributes to this stage of wound healing.[27]
## HA and cell migration
Cell migration is essential for the formation of granulation tissue.[27] The early stage of granulation tissue is dominated by a HA-rich extracellular matrix, which is regarded as a conducive environment for migration of cells into this temporary wound matrix. Contributions of HA to cell migration may attribute to its physicochemical properties as stated above, as well as its direct interactions with cells. For the former scenario, HA provides an open hydrated matrix that facilitates cell migration,[27] whereas, in the latter scenario, directed migration and control of the cell locomotory mechanisms are mediated via the specific cell interaction between HA and cell surface HA receptors. As discussed before, the three principal cell surface receptors for HA are CD44, RHAMM, and ICAM-1. RHAMM is more related to cell migration. It forms links with several protein kinases associated with cell locomotion, for example, extracellular signal-regulated protein kinase (ERK), p125fak, and pp60c-src.[39][40][41] During fetal development, the migration path through which neural crest cells migrate is rich in HA.[27] HA is closely associated with the cell migration process in granulation tissue matrix, and studies show that cell movement can be inhibited, at least partially, by HA degradation or blocking HA receptor occupancy.[42]
By providing the dynamic force to the cell, HA synthesis has also been shown to associate with cell migration.[43] Basically, HA is synthesized at the plasma membrane and released directly into the extracellular environment.[27] This may contribute to the hydrated microenvironment at sites of synthesis, and is essential for cell migration by facilitating cell detachment.
## Role of HA in moderation of the inflammatory response
Although inflammation is an integral part of granulation tissue formation, for normal tissue repair to proceed, inflammation needs to be moderated. The initial granulation tissue formed is highly inflammatory with a high rate of tissue turnover mediated by matrix degrading enzymes and reactive oxygen metabolites that are products of inflammatory cells.[27] Stabilization of granulation tissue matrix can be achieved by moderating inflammation. HA functions as an important moderator in this moderation process, which contradicts its role in inflammatory stimulation, as described above. HA can protect against free-radical damage to cells.[44] This may attribute to its free-radical scavenging property, a physicochemical characteristic shared by large polyionic polymers. In a rat model of free-radical scavenging property investigated by Foschi D. and colleagues, HA has been shown to reduce damage to the granulation tissue.[45]
In addition to the free-radical scavenging role, HA may also function in the negative feedback loop of inflammatory activation through its specific biological interactions with the biological constituents of inflammation.[27] TNF-α, an important cytokine generated in inflammation, stimulates the expression of TSG-6 (TNF-stimulated gene 6) in fibroblasts and inflammatory cells. TSG-6, a HA-binding protein, also forms a stable complex with the serum proteinase inhibitor IαI (Inter-α-inhibitor) with a synergistic effect on the latter’s plasmin-inhibitory activity. Plasmin is involved in activation of the proteolytic cascade of matrix metalloproteinases and other proteinases leading to inflammatory tissue damage. Therefore, the action of TSG-6/ IαI complex, which may be additionally organized by binding to HA in the extracellular matrix, may serve as a potent negative feedback loop to moderate inflammation and stabilize the granulation tissue as healing progresses.[27][46] In the murine air pouch model of carragenan/IL-1 (Interleukin-1β)-induced inflammation, where HA has been shown to have a proinflammatory property, reduction of inflammation can be achieved by administrating TSG-6, and the result is comparable with systemic dexamethasone treatment.
## Re-epithelization
HA plays an important role in the normal epidermis. HA also has crucial functions in the reepithelization process due to several of its properties. It serves as an integral part of the extracellular matrix of basal keratinocytes, which are major constituents of the epidermis; its free-radical scavenging function and its role in keratinocyte proliferation and migration.[27]
In normal skin, HA is found in relative high concentrations in the basal layer of the epidermis where proliferating keratinocytes are found.[47] CD44 is collocated with HA in the basal layer of epidermis where additionally it has been shown to be preferentially expressed on plasma membrane facing the HA-rich matrix pouches.[27][48] Maintaining the extracellular space and providing an open, as well as hydrated, structure for the passage of nutrients are the main functions of HA in epidermis. Tammi R. and other colleagues found HA content increases at the presence of retinoic acid (vitamin A).[47] The proposed effects of retinoic acid against skin photo-damage and aging may be correlated, at least in part, with an increase of skin HA content, giving rise to increase of tissue hydration. It has been suggested the free-radical scavenging property of HA contributes to protection against solar radiation, supporting the role of CD44 acting as a HA receptor in the epidermis.[27]
Epidermal HA also functions as a manipulator in the process of keratinocyte proliferation, which is essential in normal epidermal function, as well as during reepithelization in tissue repair. In the wound healing process, HA is expressed in the wound margin, in the connective tissue matrix, and collocating with CD44 expression in migrating keratinocytes.[27]Kaya G, Rodriguez I, Jorcano JL, Vassalli P, Stamenkovic I (1997). "Selective suppression of CD44 in keratinocytes of mice bearing an antisense CD44 transgene driven by a tissue-specific promoter disrupts hyaluronate metabolism in the skin and impairs keratinocyte proliferation". Genes Dev. 11 (8): 996–1007. doi:10.1101/gad.11.8.996. PMID 9136928..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} Kaya et al. found suppression of CD44 expression by an epidermis-specific antisense transgene resulted in animals with defective HA accumulation in the superficial dermis, accompanied by distinct morphologic alterations of basal keratinocytes and defective keratinocyte proliferation in response to mitogen and growth factors. Decrease in skin elasticity, impaired local inflammatory response, and impaired tissue repair were also observed.[27] Their observations are strongly supportive of the important roles HA and CD44 have in skin physiology and tissue repair.[27]
## Fetal wound healing and scarring
Lack of fibrous scarring is the primary feature of fetal wound healing. Even for longer periods, HA content in fetal wounds is still higher than that in adult wounds, which suggests that HA may, at least in part, reduce collagen deposition and therefore lead to reduced scarring.[49] This suggestion is in agreement with the research of West et al., who showed in adult and late gestation fetal wound healing, removal of HA results in fibrotic scarring.[27]
# Role in cancer metastasis
As shown in Figure 1, the various types of molecules that interact with hyaluronan can contribute to many of the stages of cancer metastasis, i.e. further the spread of cancer.[citation needed]
Hyaluronan synthases (HAS) play roles in all of the stages of cancer metastasis. By producing anti-adhesive HA, HAS can allow tumor cells to release from the primary tumor mass, and if HA associates with receptors such as CD44, the activation of Rho GTPases can promote epithelial-mesenchymal transition (EMT) of the cancer cells. During the processes of intravasation or extravasation, the interaction of HAS produced HA with receptors such as CD44 or RHAMM promote the cell changes that allow for the cancer cells to infiltrate the vascular or lymphatic systems. While traveling in these systems, HA produced by HAS protects the cancer cell from physical damage. Finally, in the formation of a metastatic lesion, HAS produces HA to allow the cancer cell to interact with native cells at the secondary site and to produce a tumor for itself.[50]
Hyaluronidases (HAase or HYAL) also play many roles in cancer metastasis. By helping to degrade the extracellular matrix surrounding the tumor, hyaluronidases help the cancer cell escape from the primary tumor mass and play a major role in intravasation by allowing degradation of the basement membrane of the lymph or blood vessel. Hyaluronidases again play these roles in establishment of a metastatic lesion by helping with extravasation and clearing the extracellular matrix (ECM) of the secondary site.[51] Finally, hyaluronidases play a key role in the process of angiogenesis. HA fragments promote angiogenesis and hyaluronidases produce these fragments.[52] Interestingly, hypoxia also increases production of HA and activity of hyaluronidases.[53]
The hyaluronan receptors, CD44 and RHAMM, are most thoroughly studied in terms of their roles in cancer metastasis. Increased clinical CD44 expression has been positively correlated to metastasis in a number of tumor types.[54] In terms of mechanics, CD44 affects adhesion of cancer cells to each other and to endothelial cells, rearranges the cytoskeleton through the Rho GTPases, and increases the activity of ECM degrading enzymes.[55] Increased RHAMM expression has also been clinically correlated with cancer metastasis. In terms of mechanics, RHAMM promotes cancer cell motility through a number of pathways including focal adhesion kinase (FAK), Map kinase (MAPK), pp60(c-src), and the downstream targets of Rho kinase (ROK).[56] RHAMM can also cooperate with CD44 to promote angiogenesis toward the metastatic lesion.[57]
# Cosmetic uses
Hyaluronan is a common ingredient in skin-care products.
Until recently, hyaluronic acid fillers were injected using a classic sharp hypodermic needle, cutting through nerves and vessels, causing pain and bruising.
In certain cases, the hyaluronic acid fillers results in a granulomatous foreign body reaction.[58]
# Equine applications
Hyaluronan is used in treatment of articular disorders in horses, in particular those in competition or heavy work. It is indicated for carpal and fetlock joint dysfunctions, but not when joint sepsis or fracture are suspected. It is especially used for synovitis associated with equine osteoarthritis. It can be injected directly into an affected joint, or intravenously for less localized disorders. It may cause mild heating of the joint if directly injected, but this does not affect the clinical outcome. Intra-articularly administered medicine is fully metabolized in less than a week.[59]
Note that, according to Canadian regulation, hyaluronan in HY-50 preparation should not be administered to animals to be slaughtered for horse meat.[60] In Europe, however, the same preparation is not considered to have any such effect, and edibility of the horse meat is not affected.[61]
# Etymology
Hyaluronic acid is derived from hyalos (Greek for vitreous) and uronic acid because it was first isolated from the vitreous humour and possesses a high uronic acid content.
The term hyaluronate refers to the conjugate base of hyaluronic acid. Because the molecule typically exists in vivo in its polyanionic form, it is most commonly referred to as hyaluronan.
# History
Hyaluronan is found in many tissues of the body, such as skin, cartilage, and the vitreous humour. Therefore, it is well suited to biomedical applications targeting these tissues. The first hyaluronan biomedical product, Healon, was developed in the 1970s and 1980s by Pharmacia, and is approved for use in eye surgery (i.e., corneal transplantation, cataract surgery, glaucoma surgery, and surgery to repair retinal detachment). Other biomedical companies also produce brands of hyaluronan for ophthalmic surgery.[62][63][64]
Native hyaluronan has a relatively short half-life (shown in rabbits)[65] so various manufacturing techniques have been deployed to extend the length of the chain and stabilise the molecule for its use in medical applications. The introduction of protein based cross-links,[66] the introduction of free-radical scavenging molecules such as sorbitol,[67] and minimal stabilisation of the HA chains through chemical agents e.g. NASHA stabilisation are all techniques that have been used.[68]
In the late 1970s, intraocular lens implantation was often followed by severe corneal edema, due to endothelial cell damage during the surgery. It was evident that a viscous, clear, physiologic lubricant to prevent such scraping of the endothelial cells was needed.[69][70]
# Approval
FDA approved formulations are available.[18] In 2007, the EMA extended its approval of Hylan GF-20 as a treatment for ankle and shoulder osteoarthritis pain.[71]
# Research
Due to its high biocompatibility and its common presence in the extracellular matrix of tissues, hyaluronan is gaining popularity as a biomaterial scaffold in tissue engineering research.[72][73][74] In particular, a number of research groups have found hyaluronan's properties for tissue engineering and regenerative medicine are significantly improved with crosslinking, producing a hydrogel. This added feature allows a researcher to form a desired shape, as well as to deliver therapeutic molecules, into a host.[75] Hyaluronan can be crosslinked by attaching thiols (trade names: Extracel, HyStem),[75]methacrylates,[76] hexadecylamides (trade name: Hymovis), [77] and tyramines (trade name: Corgel).[78] Hyaluronan can also be crosslinked directly with formaldehyde (trade name: Hylan-A) or with divinylsulfone (trade name: Hylan-B).[79]
Due to its ability to regulate angiogenesis by stimulating endothelial cells to proliferate, hyaluronic acid can be used to create hydrogels to study vascular morphogenesis.[80] These hydrogels have properties similar to human soft tissue, but are also easily controlled and modified, making HA very suitable for tissue engineering studies. For example, HA hydrogels are appealing for engineering vasculature from endothelial progenitor cells by using appropriate growth factors such as VEGF and Ang-1 to promote proliferation and vascular network formation. Vacuole and lumen formation have been observed in these gels, followed by branching and sprouting through degradation of the hydrogel and finally complex network formation. The ability to generate vascular networks using HA hydrogels leads to opportunities for in vivo and clinical applications. One in vivo study, where HA hydrogels with endothelial colony forming cells were implanted into mice three days after hydrogel formation, saw evidence that the host and engineered vessels joined within 2 weeks of implantation, indicating viability and functionality of the engineered vasculature.[81] | https://www.wikidoc.org/index.php/Hyaluronate | |
2b88d58e117ae2755b1b20abc2bb2550dbc7db40 | wikidoc | Hydrocodone | Hydrocodone
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Hydrocodone is a that is FDA approved for the {{{indicationType}}} of . There is a Black Box Warning for this drug as shown here. Common adverse reactions include .
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Dosage
- Dosing Information
- Dosage
- Dosing Information
- Dosage
- Dosing Information
- Dosage
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by:
- Class of Recommendation:
- Strength of Evidence:
- Dosing Information
- Dosage
There is limited information regarding Off-Label Guideline-Supported Use of Hydrocodone in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Dosage
There is limited information regarding Off-Label Non–Guideline-Supported Use of Hydrocodone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- Dosage
There is limited information regarding FDA-Labeled Use of Hydrocodone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- Developed by:
- Class of Recommendation:
- Strength of Evidence:
- Dosing Information
- Dosage
There is limited information regarding Off-Label Guideline-Supported Use of Hydrocodone in pediatric patients.
### Non–Guideline-Supported Use
- Dosing Information
- Dosage
There is limited information regarding Off-Label Non–Guideline-Supported Use of Hydrocodone in pediatric patients.
# Contraindications
- Condition1
# Warnings
- Description
### Precautions
- Description
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Hydrocodone in the drug label.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Hydrocodone in the drug label.
# Drug Interactions
- Drug
- Description
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Hydrocodone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Hydrocodone during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Hydrocodone with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Hydrocodone with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Hydrocodone with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Hydrocodone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Hydrocodone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Hydrocodone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Hydrocodone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Hydrocodone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Hydrocodone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Hydrocodone in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Hydrocodone in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Description
### Management
- Description
## Chronic Overdose
There is limited information regarding Chronic Overdose of Hydrocodone in the drug label.
# Pharmacology
There is limited information regarding Hydrocodone Pharmacology in the drug label.
## Mechanism of Action
## Structure
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Hydrocodone in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Hydrocodone in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Hydrocodone in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Hydrocodone in the drug label.
# How Supplied
## Storage
There is limited information regarding Hydrocodone Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Hydrocodone in the drug label.
# Precautions with Alcohol
- Alcohol-Hydrocodone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Hydrocodone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Hydrocodone is a that is FDA approved for the {{{indicationType}}} of . There is a Black Box Warning for this drug as shown here. Common adverse reactions include .
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Dosage
- Dosing Information
- Dosage
- Dosing Information
- Dosage
- Dosing Information
- Dosage
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by:
- Class of Recommendation:
- Strength of Evidence:
- Dosing Information
- Dosage
There is limited information regarding Off-Label Guideline-Supported Use of Hydrocodone in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Dosage
There is limited information regarding Off-Label Non–Guideline-Supported Use of Hydrocodone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- Dosage
There is limited information regarding FDA-Labeled Use of Hydrocodone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- Developed by:
- Class of Recommendation:
- Strength of Evidence:
- Dosing Information
- Dosage
There is limited information regarding Off-Label Guideline-Supported Use of Hydrocodone in pediatric patients.
### Non–Guideline-Supported Use
- Dosing Information
- Dosage
There is limited information regarding Off-Label Non–Guideline-Supported Use of Hydrocodone in pediatric patients.
# Contraindications
- Condition1
# Warnings
- Description
### Precautions
- Description
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Hydrocodone in the drug label.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Hydrocodone in the drug label.
# Drug Interactions
- Drug
- Description
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Hydrocodone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Hydrocodone during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Hydrocodone with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Hydrocodone with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Hydrocodone with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Hydrocodone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Hydrocodone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Hydrocodone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Hydrocodone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Hydrocodone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Hydrocodone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Hydrocodone in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Hydrocodone in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Description
### Management
- Description
## Chronic Overdose
There is limited information regarding Chronic Overdose of Hydrocodone in the drug label.
# Pharmacology
There is limited information regarding Hydrocodone Pharmacology in the drug label.
## Mechanism of Action
-
## Structure
-
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Hydrocodone in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Hydrocodone in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Hydrocodone in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Hydrocodone in the drug label.
# How Supplied
-
## Storage
There is limited information regarding Hydrocodone Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Hydrocodone in the drug label.
# Precautions with Alcohol
- Alcohol-Hydrocodone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ®[1]
# Look-Alike Drug Names
- A® — B®[2]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Hydrocodone | |
cf652f6c5edfc485e282452abbfd0b6c464499ab | wikidoc | Hydrothorax | Hydrothorax
# Overview
A hydrothorax is a condition that results from fluid accumulating in the pleural cavity. In hemothorax this fluid is blood (as in major chest injuries), in pyothorax the fluid is pus (resulting from chest infections), in chylothorax it is lymph fluid (resulting from rupture of the thoracic duct).
# Historical Perspective
- was first discovered by , a , in during/following .
- In , mutations were first identified in the pathogenesis of .
- In , the first was developed by to treat/diagnose .
# Classification
- may be classified according to into subtypes/groups:
- Other variants of include , , and .
# Pathophysiology
- The pathogenesis of is characterized by , , and .
- The gene/Mutation in has been associated with the development of , involving the pathway.
- On gross pathology, , , and are characteristic findings of .
- On microscopic histopathological analysis, , , and are characteristic findings of .
# Causes
- may be caused by either , , or .
- is caused by a mutation in the , , or gene.
- There are no established causes for .
# Differentiating from other Diseases
- must be differentiated from other diseases that cause , , and , such as:
# Epidemiology and Demographics
- The prevalence of is approximately per 100,000 individuals worldwide.
- In , the incidence of was estimated to be cases per 100,000 individuals in .
## Age
- Patients of all age groups may develop .
- is more commonly observed among patients aged years old.
- is more commonly observed among .
## Gender
- affects men and women equally.
- are more commonly affected with than .
- The to ratio is approximately to 1.
## Race
- There is no racial predilection for .
- usually affects individuals of the race.
- individuals are less likely to develop .
# Risk Factors
- Common risk factors in the development of are , , , and .
# Natural History, Complications and Prognosis
- The majority of patients with remain asymptomatic for .
- Early clinical features include , , and .
- If left untreated, of patients with may progress to develop , , and .
- Common complications of include , , and .
- Prognosis is generally , and the of patients with is approximately .
# Diagnosis
## Diagnostic Criteria
- The diagnosis of is made when at least of the following diagnostic criteria are met:
## Symptoms
- is usually asymptomatic.
- Symptoms of may include the following:
## Physical Examination
- Patients with usually appear .
- Physical examination may be remarkable for:
## Laboratory Findings
- There are no specific laboratory findings associated with .
- A is diagnostic of .
- An concentration of is diagnostic of .
- Other laboratory findings consistent with the diagnosis of include , , and .
## Imaging Findings
- There are no findings associated with .
- is the imaging modality of choice for .
- On , is characterized by , , and .
- may demonstrate , , and .
## Other Diagnostic Studies
- may also be diagnosed using .
- Findings on include , , and .
# Treatment
## Medical Therapy
- There is no treatment for ; the mainstay of therapy is supportive care.
- The mainstay of therapy for is and .
- acts by .
- Response to can be monitored with every .
## Surgery
- Surgery is the mainstay of therapy for .
- in conjunction with is the most common approach to the treatment of .
- can only be performed for patients with .
## Prevention
- There are no primary preventive measures available for .
- Effective measures for the primary prevention of include , , and .
- Once diagnosed and successfully treated, patients with are followed-up every . Follow-up testing includes , , and .
# Related links
- Pleural effusion
- Pneumothorax | Hydrothorax
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A hydrothorax is a condition that results from fluid accumulating in the pleural cavity. In hemothorax this fluid is blood (as in major chest injuries), in pyothorax the fluid is pus (resulting from chest infections), in chylothorax it is lymph fluid (resulting from rupture of the thoracic duct).
# Historical Perspective
- [Disease name] was first discovered by [scientist name], a [nationality + occupation], in [year] during/following [event].
- In [year], [gene] mutations were first identified in the pathogenesis of [disease name].
- In [year], the first [discovery] was developed by [scientist] to treat/diagnose [disease name].
# Classification
- [Disease name] may be classified according to [classification method] into [number] subtypes/groups:
- [group1]
- [group2]
- [group3]
- Other variants of [disease name] include [disease subtype 1], [disease subtype 2], and [disease subtype 3].
# Pathophysiology
- The pathogenesis of [disease name] is characterized by [feature1], [feature2], and [feature3].
- The [gene name] gene/Mutation in [gene name] has been associated with the development of [disease name], involving the [molecular pathway] pathway.
- On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
- On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
# Causes
- [Disease name] may be caused by either [cause1], [cause2], or [cause3].
- [Disease name] is caused by a mutation in the [gene1], [gene2], or [gene3] gene[s].
- There are no established causes for [disease name].
# Differentiating [disease name] from other Diseases
- [Disease name] must be differentiated from other diseases that cause [clinical feature 1], [clinical feature 2], and [clinical feature 3], such as:
- [Differential dx1]
- [Differential dx2]
- [Differential dx3]
# Epidemiology and Demographics
- The prevalence of [disease name] is approximately [number or range] per 100,000 individuals worldwide.
- In [year], the incidence of [disease name] was estimated to be [number or range] cases per 100,000 individuals in [location].
## Age
- Patients of all age groups may develop [disease name].
- [Disease name] is more commonly observed among patients aged [age range] years old.
- [Disease name] is more commonly observed among [elderly patients/young patients/children].
## Gender
- [Disease name] affects men and women equally.
- [Gender 1] are more commonly affected with [disease name] than [gender 2].
- The [gender 1] to [Gender 2] ratio is approximately [number > 1] to 1.
## Race
- There is no racial predilection for [disease name].
- [Disease name] usually affects individuals of the [race 1] race.
- [Race 2] individuals are less likely to develop [disease name].
# Risk Factors
- Common risk factors in the development of [disease name] are [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4].
# Natural History, Complications and Prognosis
- The majority of patients with [disease name] remain asymptomatic for [duration/years].
- Early clinical features include [manifestation 1], [manifestation 2], and [manifestation 3].
- If left untreated, [#%] of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].
- Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].
- Prognosis is generally [excellent/good/poor], and the [1/5/10year mortality/survival rate] of patients with [disease name] is approximately [#%].
# Diagnosis
## Diagnostic Criteria
- The diagnosis of [disease name] is made when at least [number] of the following [number] diagnostic criteria are met:
- [criterion 1]
- [criterion 2]
- [criterion 3]
- [criterion 4]
## Symptoms
- [Disease name] is usually asymptomatic.
- Symptoms of [disease name] may include the following:
- [symptom 1]
- [symptom 2]
- [symptom 3]
- [symptom 4]
- [symptom 5]
- [symptom 6]
## Physical Examination
- Patients with [disease name] usually appear [general appearance].
- Physical examination may be remarkable for:
- [finding 1]
- [finding 2]
- [finding 3]
- [finding 4]
- [finding 5]
- [finding 6]
## Laboratory Findings
- There are no specific laboratory findings associated with [disease name].
- A [positive/negative] [test name] is diagnostic of [disease name].
- An [elevated/reduced] concentration of [serum/blood/urinary/CSF/other] [lab test] is diagnostic of [disease name].
- Other laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3].
## Imaging Findings
- There are no [imaging study] findings associated with [disease name].
- [Imaging study 1] is the imaging modality of choice for [disease name].
- On [imaging study 1], [disease name] is characterized by [finding 1], [finding 2], and [finding 3].
- [Imaging study 2] may demonstrate [finding 1], [finding 2], and [finding 3].
## Other Diagnostic Studies
- [Disease name] may also be diagnosed using [diagnostic study name].
- Findings on [diagnostic study name] include [finding 1], [finding 2], and [finding 3].
# Treatment
## Medical Therapy
- There is no treatment for [disease name]; the mainstay of therapy is supportive care.
- The mainstay of therapy for [disease name] is [medical therapy 1] and [medical therapy 2].
- [Medical therapy 1] acts by [mechanism of action 1].
- Response to [medical therapy 1] can be monitored with [test/physical finding/imaging] every [frequency/duration].
## Surgery
- Surgery is the mainstay of therapy for [disease name].
- [Surgical procedure] in conjunction with [chemotherapy/radiation] is the most common approach to the treatment of [disease name].
- [Surgical procedure] can only be performed for patients with [disease stage] [disease name].
## Prevention
- There are no primary preventive measures available for [disease name].
- Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3].
- Once diagnosed and successfully treated, patients with [disease name] are followed-up every [duration]. Follow-up testing includes [test 1], [test 2], and [test 3].
# Related links
- Pleural effusion
- Pneumothorax | https://www.wikidoc.org/index.php/Hydrothorax | |
4381f0ee084f520f7b782e5e4e431de83f8eda12 | wikidoc | Hydroxyurea | Hydroxyurea
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Hydroxyurea is an antimetabolite, antineoplastic agent that is FDA approved for the treatment of sicle cell anemia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include myelosuppression.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Procedures for proper handling and disposal of cytotoxic drugs should be considered. Several guidelines on this subject have been published. To minimize the risk of dermal exposure, always wear impervious gloves when handling bottles containing Hydroxyurea capsules. Hydroxyurea capsules should not be opened. Personnel should avoid exposure to crushed or opened capsules. If contact with crushed or opened capsules occurs, wash immediately and thoroughly. More information is available in the references listed below.
- Dosage should be based on the patient’s actual or ideal weight, whichever is less. The initial dose of Hydroxyurea is 15 mg/kg/day as a single dose. The patient’s blood count must be monitored every two weeks. If blood counts are in an acceptable range, the dose may be increased by 5 mg/kg/day every 12 weeks until a maximum tolerated dose (the highest dose that does not produce toxic blood counts over 24 consecutive weeks), or 35 mg/kg/day, is reached.
- If blood counts are between the acceptable rangeand toxic, the dose is not increased. If blood counts are considered toxic, Hydroxyurea should be discontinued until hematologic recovery. Treatment may then be resumed after reducing the dose by 2.5 mg/kg/day from the dose associated with hematologic toxicity. Hydroxyurea may then be titrated up or down, every 12 weeks in 2.5 mg/kg/day increments, until the patient is at a stable dose that does not result in hematologic toxicity for 24 weeks. Any dosage on which a patient develops hematologic toxicity twice should not be tried again.
Acceptable range
- Neutrophils ≥2500 cells/
- Platelets ≥95,000/
- Hemoglobin >5.3 g/dL
- Reticulocytes ≥95,000/mm3 if the hemoglobin concentration <9 g/dL.
Toxic
- Neutrophils <2000 cells/mm3,
- Platelets <80,000/mm3,
- Hemoglobin <4.5 g/dL and
- Reticulocytes <80,000/mm3 if the hemoglobin concentration <9 g/dL.
Since hydroxyurea may raise the serum uric acid level, dosage adjustment of uricosuric medication may be necessary.
- Used as Alternative for the primary regimen of Busulfan and Interferon.
- Dosage: 20-30 mg/kg administered orally as a single dose daily, for 6 weeks
- Dosage: 1 gram PO q12h, starting the day before radiation. 11 doses in total.
- Dosage: 80 mg/kg administered orally as a single dose every third day.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Hydroxyurea (patient information) in adult patients.
### Non–Guideline-Supported Use
- Dosage
Initial dose: 15 milligrams/kilogram/day
Maintenance dose: Dose which allowed platelet count be bellow 600, 000/mm3
- Initial dose: 15 milligrams/kilogram/day
- Maintenance dose: Dose which allowed platelet count be bellow 600, 000/mm3
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Procedures for proper handling and disposal of cytotoxic drugs should be considered. Several guidelines on this subject have been published. To minimize the risk of dermal exposure, always wear impervious gloves when handling bottles containing Hydroxyurea capsules. Hydroxyurea capsules should not be opened. Personnel should avoid exposure to crushed or opened capsules. If contact with crushed or opened capsules occurs, wash immediately and thoroughly. More information is available in the references listed below.
- Dosage should be based on the patient’s actual or ideal weight, whichever is less. The initial dose of Hydroxyurea is 15 mg/kg/day as a single dose. The patient’s blood count must be monitored every two weeks. If blood counts are in an acceptable range, the dose may be increased by 5 mg/kg/day every 12 weeks until a maximum tolerated dose (the highest dose that does not produce toxic blood counts over 24 consecutive weeks), or 35 mg/kg/day, is reached.
- If blood counts are between the acceptable rangeand toxic, the dose is not increased. If blood counts are considered toxic, Hydroxyurea should be discontinued until hematologic recovery. Treatment may then be resumed after reducing the dose by 2.5 mg/kg/day from the dose associated with hematologic toxicity. Hydroxyurea may then be titrated up or down, every 12 weeks in 2.5 mg/kg/day increments, until the patient is at a stable dose that does not result in hematologic toxicity for 24 weeks. Any dosage on which a patient develops hematologic toxicity twice should not be tried again.
Acceptable range
- Neutrophils ≥2500 cells/
- Platelets ≥95,000/
- Hemoglobin >5.3 g/dL
- Reticulocytes ≥95,000/mm3 if the hemoglobin concentration <9 g/dL.
Toxic
- Neutrophils <2000 cells/mm3,
- Platelets <80,000/mm3,
- Hemoglobin <4.5 g/dL and
- Reticulocytes <80,000/mm3 if the hemoglobin concentration <9 g/dL.
Since hydroxyurea may raise the serum uric acid level, dosage adjustment of uricosuric medication may be necessary.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Hydroxyurea (patient information) in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Hydroxyurea (patient information) in pediatric patients.
# Contraindications
- Hydroxyurea is contraindicated in patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation.
# Warnings
- Hydroxyurea is a cytotoxic and myelosuppressive agent. Hydroxyurea should not be given if bone marrow function is markedly depressed, as indicated by neutrophils below 2000 cells/mm3; a platelet count below 80,000/mm3; a hemoglobin level below 4.5 g/dL; or reticulocytes below 80,000/mm3 when the hemoglobin concentration is below 9 g/dL. Neutropenia is generally the first and most common manifestation of hematologic suppression. Thrombocytopenia and anemia occur less often, and are seldom seen without a preceding leukopenia. Recovery from myelosuppression is usually rapid when therapy is interrupted. Hydroxyurea causes macrocytosis, which may mask the incidental development of folic acid deficiency. Prophylactic administration of folic acid is recommended.
- In HIV-infected patients during therapy with hydroxyurea and didanosine, with or without stavudine, fatal and nonfatal pancreatitis have occurred. Hepatotoxicity and hepatic failure resulting in death have been reported during postmarketing surveillance in HIV-infected patients treated with hydroxyurea and other antiretroviral agents. *Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. This combination should be avoided.
- Peripheral neuropathy, which was severe in some cases, has been reported in HIV-infected patients receiving hydroxyurea in combination with antiretroviral agents, including didanosine, with or without stavudine.
- Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients with myeloproliferative disorders during therapy with hydroxyurea. These vasculitic toxicities were reported most often in patients with a history of, or currently receiving, interferon therapy. Due to potentially severe clinical outcomes for the cutaneous vasculitic ulcers reported in patients with myeloproliferative disease, hydroxyurea should be discontinued if cutaneous vasculitic ulcerations develop.
- Hydroxyurea is genotoxic in a wide range of test systems and is thus presumed to be a human carcinogen. In patients receiving long-term hydroxyurea for myeloproliferative disorders, such as polycythemia vera and thrombocythemia, secondary leukemia has been reported. It is unknown whether this leukemogenic effect is secondary to hydroxyurea or is associated with the patient’s underlying disease. Skin cancer has also been reported in patients receiving long-term hydroxyurea.
- Conventional long-term studies to evaluate the carcinogenic potential of Hydroxyurea have not been performed. However, intraperitoneal administration of 125 to 250 mg/kg hydroxyurea (about 0.6-1.2 times the maximum recommended human oral daily dose on a mg/m2 basis) thrice weekly for 6 months to female rats increased the incidence of mammary tumors in rats surviving to 18 months compared to control. Hydroxyurea is mutagenic in vitro to bacteria, fungi, protozoa, and mammalian cells. Hydroxyurea is clastogenic in vitro (hamster cells, human lymphoblasts) and in vivo (SCE assay in rodents, mouse micronucleus assay). Hydroxyurea causes the transformation of rodent embryo cells to a tumorigenic phenotype.
# Adverse Reactions
## Clinical Trials Experience
- In patients treated for sickle cell anemia in the Multicenter Study of Hydroxyurea in Sickle Cell Anemia, the most common adverse reactions were hematologic, with neutropenia, and low reticulocyte and platelet levels necessitating temporary cessation in almost all patients. Hematologic recovery usually occurred in two weeks.
- Non-hematologic events that possibly were associated with treatment include hair loss, skin rash, fever, gastrointestinal disturbances, weight gain, bleeding, and parvovirus B-19 infection; however, these non-hematologic events occurred with similar frequencies in the hydroxyurea and placebo treatment groups. Melanonychia has also been reported in patients receiving Hydroxyurea for SCA.
- Adverse events associated with the use of hydroxyurea in the treatment of neoplastic diseases, in addition to hematologic effects include: gastrointestinal symptoms (stomatitis, anorexia, nausea, vomiting, diarrhea, and constipation), and dermatological reactions such as maculopapular rash, skin ulceration, dermatomyositis-like skin changes, peripheral erythema, and facial erythema. Hyperpigmentation, atrophy of skin and nails, scaling, and violet papules have been observed in some patients after several years of long-term daily maintenance therapy with hydroxyurea. Skin cancer has been reported. Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients with myeloproliferative disorders during therapy with hydroxyurea. These vasculitic toxicities were reported most often in patients with a history of, or currently receiving, interferon therapy. Dysuria and alopecia have been reported. Large doses may produce drowsiness. Neurological disturbances have occurred and were limited to headache, dizziness, disorientation, hallucinations, and convulsions. Hydroxyurea may cause temporary impairment of renal tubular function accompanied by elevations in serum uric acid, blood urea nitrogen (BUN), and creatinine levels. Abnormal bromsulphalein (BSP) retention has been reported. Fever, chills, malaise, edema, asthenia, and elevation of hepatic enzymes have also been reported.
- The association of hydroxyurea with the development of acute pulmonary reactions consisting of diffuse pulmonary infiltrates, fever, and dyspnea has been reported. Pulmonary fibrosis also has been reported.
- In HIV-infected patients who received hydroxyurea in combination with antiretroviral agents, in particular, didanosine plus stavudine, fatal and nonfatal pancreatitis and hepatotoxicity, and severe peripheral neuropathy have been reported. Patients treated with hydroxyurea in combination with didanosine, stavudine, and indinavir in Study ACTG 5025 showed a median decline in CD4 cells of approximately 100/mm3.
## Postmarketing Experience
There is limited information regarding Hydroxyurea Postmarketing Experience in the drug label.
# Drug Interactions
- Prospective studies on the potential for hydroxyurea to interact with other drugs have not been performed. Studies have shown that there is an analytical interference of hydroxyurea with the enzymes (urease, uricase, and lactate dehydrogenase) used in the determination of urea, uric acid and lactic acid, rendering falsely elevated results of these in patients treated with hydroxyurea.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Hydroxyurea can cause fetal harm when administered to a pregnant woman. Hydroxyurea has been demonstrated to be a potent teratogen in a wide variety of animal models, including mice, hamsters, cats, miniature swine, dogs, and monkeys at doses within 1-fold of the human dose given on a mg/m2 basis. Hydroxyurea is embryotoxic and causes fetal malformations (partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, missing lumbar vertebrae) at 180 mg/kg/day (about 0.8 times the maximum recommended human daily dose on a mg/m2 basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m2 basis) in rabbits. Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. Hydroxyurea crosses the placenta. Single doses of ≥375 mg/kg (about 1.7 times the maximum recommended human daily dose on a mg/m2 basis) to rats caused growth retardation and impaired learning ability. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Hydroxyurea in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Hydroxyurea during labor and delivery.
### Nursing Mothers
- Hydroxyurea is excreted in human milk. Because of the potential for serious adverse reactions with hydroxyurea, a decision should be made either to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
There is no FDA guidance on the use of Hydroxyurea in geriatric settings.
### Gender
There is no FDA guidance on the use of Hydroxyurea with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Hydroxyurea with respect to specific racial populations.
### Renal Impairment
- As renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage of hydroxyurea in patients with renal impairment. In adult patients with sickle cell disease, an open-label, non-randomized, single-dose, multicenter study was conducted to assess the influence of renal function on the pharmacokinetics of hydroxyurea. Patients in the study with normal renal function (creatinine clearance >80 mL/min), mild (CrCl 50-80 mL/min), moderate (CrCl = 30-<50 mL/min), or severe (<30 mL/min) renal impairment received hydroxyurea as a single oral dose of 15 mg/kg, achieved by using combinations of the 200 mg, 300 mg, or 400 mg capsules. Patients with end-stage renal disease (ESRD) received two doses of 15 mg/kg separated by 7 days, the first was given following a 4-hour hemodialysis session, the second prior to hemodialysis. In this study, the mean exposure (AUC) in patients whose creatinine clearance was <60 mL/min (or ESRD) was approximately 64% higher than in patients with normal renal function. The results suggest that the initial dose of hydroxyurea should be reduced when used to treat patients with renal impairment. The table below describes the recommended dosage modification.
### Hepatic Impairment
- There are no data that support specific guidance for dosage adjustment in patients with hepatic impairment. Close monitoring of hematologic parameters is advised in these patients.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Hydroxyurea in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Hydroxyurea in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Hydroxyurea Administration in the drug label.
### Monitoring
Close monitoring of hematologic parameters is advised in patients with renal impairment.
# IV Compatibility
There is limited information regarding the compatibility of Hydroxyurea and IV administrations.
# Overdosage
- Acute mucocutaneous toxicity has been reported in patients receiving hydroxyurea at dosages several times the therapeutic dose. Soreness, violet erythema, edema on palms and soles followed by scaling of hands and feet, severe generalized hyperpigmentation of the skin, and stomatitis have been observed.
# Pharmacology
## Mechanism of Action
- The precise mechanism by which hydroxyurea produces its cytotoxic and cytoreductive effects is not known. However, various studies support the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein.
- The mechanisms by which Hydroxyurea produces its beneficial effects in patients with sickle cell anemia (SCA) are uncertain. Known pharmacologic effects of Hydroxyurea that may contribute to its beneficial effects include increasing hemoglobin F levels in RBCs, decreasing neutrophils, increasing the water content of RBCs, increasing deformability of sickled cells, and altering the adhesion of RBCs to endothelium.
## Structure
- Hydroxyurea is an essentially tasteless, white crystalline powder. Its structural formula is:
## Pharmacodynamics
There is limited information regarding Hydroxyurea Pharmacodynamics in the drug label.
## Pharmacokinetics
- Hydroxyurea is readily absorbed after oral administration. Peak plasma levels are reached in 1 to 4 hours after an oral dose. With increasing doses, disproportionately greater mean peak plasma concentrations and AUCs are observed. There are no data on the effect of food on the absorption of hydroxyurea.
- Hydroxyurea distributes rapidly and widely in the body with an estimated volume of distribution approximating total body water. Plasma to ascites fluid ratios range from 2:1 to 7.5:1. Hydroxyurea concentrates in leukocytes and erythrocytes.
- Up to 60% of an oral dose undergoes conversion through metabolic pathways that are not fully characterized. One pathway is probably saturable hepatic metabolism. Another minor pathway may be degradation by urease found in intestinal bacteria. Acetohydroxamic acid was found in the serum of three leukemic patients receiving hydroxyurea and may be formed from hydroxylamine resulting from action of urease on hydroxyurea.
- Excretion of hydroxyurea in humans is likely a linear first-order renal process. In adults with SCA, mean cumulative urinary recovery of hydroxyurea was about 40% of the administered dose.
## Nonclinical Toxicology
There is limited information regarding Hydroxyurea Nonclinical Toxicology in the drug label.
# Clinical Studies
- The efficacy of hydroxyurea in sickle cell anemia was assessed in a large clinical study (Multicenter Study of Hydroxyurea in Sickle Cell Anemia).
- The study was a randomized, double-blind, placebo-controlled trial that evaluated 299 adult patients (≥18 years) with moderate to severe disease (≥3 painful crises yearly). The trial was stopped by the Data Safety Monitoring Committee, after accrual was completed but before the scheduled 24 months of follow-up was completed in all patients, based on observations of fewer painful crises among patients receiving hydroxyurea.
- Compared to placebo treatment, treatment with hydroxyurea resulted in a significant decrease in the yearly rate of painful crises, the yearly rate of painful crises requiring hospitalization, the incidence of chest syndrome, the number of patients transfused, and units of blood transfused. Hydroxyurea treatment significantly increased the median time to both first and second painful crises.
- Although patients with 3 or more painful crises during the preceding 12 months were eligible for the study, most of the benefit in crisis reduction was seen in the patients with 6 or more painful crises during the preceding 12 months.
- No deaths were attributed to treatment with hydroxyurea, and none of the patients developed neoplastic disorders during the study. Treatment was permanently stopped for medical reasons in 14 hydroxyurea-treated (2 patients with myelotoxicity) and 6 placebo-treated patients.
- In patients with SCA treated with hydroxyurea, fetal hemoglobin (HbF) increases 4 to 12 weeks after initiation of treatment. In general, average HbF levels correlate with dose and plasma level with possible plateauing at higher dosages.
- A clear relation between reduction in crisis frequency and increased HbF or F-cell levels has not been demonstrated. The dose-related cytoreductive effects of hydroxyurea, particularly on neutrophils, was the factor most strongly correlated with reduced crisis frequency.
# How Supplied
- 200 mg capsules packaged in HDPE bottles of 60 with a plastic safety screw cap. (NDC 0003-6335-17). The cap and body are opaque blue-green. The capsule is marked in black ink on both the cap and body with “Hydroxyurea” and “6335”.
- 300 mg capsules packaged in HDPE bottles of 60 with a plastic safety screw cap. (NDC 0003-6336-17). The cap and body are opaque purple. The capsule is marked in black ink on both the cap and body with “Hydroxyurea” and “6336”.
- 400 mg capsules packaged in HDPE bottles of 60 with a plastic safety screw cap. (NDC 0003-6337-17). The cap and body are opaque reddish-orange. The capsule is marked in black ink on both the cap and body with “Hydroxyurea” and “6337”.
## Storage
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Keep Tightly closed.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Hydroxyurea Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Hydroxyurea (patient information) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Hydroxyurea
- Hydrea
# Look-Alike Drug Names
There is limited information regarding Hydroxyurea Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Hydroxyurea
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
# Disclaimer
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# Black Box Warning
# Overview
Hydroxyurea is an antimetabolite, antineoplastic agent that is FDA approved for the treatment of sicle cell anemia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include myelosuppression.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Procedures for proper handling and disposal of cytotoxic drugs should be considered. Several guidelines on this subject have been published. To minimize the risk of dermal exposure, always wear impervious gloves when handling bottles containing Hydroxyurea capsules. Hydroxyurea capsules should not be opened. Personnel should avoid exposure to crushed or opened capsules. If contact with crushed or opened capsules occurs, wash immediately and thoroughly. More information is available in the references listed below.
- Dosage should be based on the patient’s actual or ideal weight, whichever is less. The initial dose of Hydroxyurea is 15 mg/kg/day as a single dose. The patient’s blood count must be monitored every two weeks. If blood counts are in an acceptable range, the dose may be increased by 5 mg/kg/day every 12 weeks until a maximum tolerated dose (the highest dose that does not produce toxic blood counts over 24 consecutive weeks), or 35 mg/kg/day, is reached.
- If blood counts are between the acceptable rangeand toxic, the dose is not increased. If blood counts are considered toxic, Hydroxyurea should be discontinued until hematologic recovery. Treatment may then be resumed after reducing the dose by 2.5 mg/kg/day from the dose associated with hematologic toxicity. Hydroxyurea may then be titrated up or down, every 12 weeks in 2.5 mg/kg/day increments, until the patient is at a stable dose that does not result in hematologic toxicity for 24 weeks. Any dosage on which a patient develops hematologic toxicity twice should not be tried again.
Acceptable range
- Neutrophils ≥2500 cells/
- Platelets ≥95,000/
- Hemoglobin >5.3 g/dL
- Reticulocytes ≥95,000/mm3 if the hemoglobin concentration <9 g/dL.
Toxic
- Neutrophils <2000 cells/mm3,
- Platelets <80,000/mm3,
- Hemoglobin <4.5 g/dL and
- Reticulocytes <80,000/mm3 if the hemoglobin concentration <9 g/dL.
Since hydroxyurea may raise the serum uric acid level, dosage adjustment of uricosuric medication may be necessary.
- Used as Alternative for the primary regimen of Busulfan and Interferon[1].
- Dosage: 20-30 mg/kg administered orally as a single dose daily, for 6 weeks[2]
- Dosage: 1 gram PO q12h, starting the day before radiation. 11 doses in total[3].
- Dosage: 80 mg/kg administered orally as a single dose every third day[4].
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Hydroxyurea (patient information) in adult patients.
### Non–Guideline-Supported Use
- Dosage
Initial dose: 15 milligrams/kilogram/day
Maintenance dose: Dose which allowed platelet count be bellow 600, 000/mm3[5]
- Initial dose: 15 milligrams/kilogram/day
- Maintenance dose: Dose which allowed platelet count be bellow 600, 000/mm3[5]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Procedures for proper handling and disposal of cytotoxic drugs should be considered. Several guidelines on this subject have been published. To minimize the risk of dermal exposure, always wear impervious gloves when handling bottles containing Hydroxyurea capsules. Hydroxyurea capsules should not be opened. Personnel should avoid exposure to crushed or opened capsules. If contact with crushed or opened capsules occurs, wash immediately and thoroughly. More information is available in the references listed below.
- Dosage should be based on the patient’s actual or ideal weight, whichever is less. The initial dose of Hydroxyurea is 15 mg/kg/day as a single dose. The patient’s blood count must be monitored every two weeks. If blood counts are in an acceptable range, the dose may be increased by 5 mg/kg/day every 12 weeks until a maximum tolerated dose (the highest dose that does not produce toxic blood counts over 24 consecutive weeks), or 35 mg/kg/day, is reached.
- If blood counts are between the acceptable rangeand toxic, the dose is not increased. If blood counts are considered toxic, Hydroxyurea should be discontinued until hematologic recovery. Treatment may then be resumed after reducing the dose by 2.5 mg/kg/day from the dose associated with hematologic toxicity. Hydroxyurea may then be titrated up or down, every 12 weeks in 2.5 mg/kg/day increments, until the patient is at a stable dose that does not result in hematologic toxicity for 24 weeks. Any dosage on which a patient develops hematologic toxicity twice should not be tried again.
Acceptable range
- Neutrophils ≥2500 cells/
- Platelets ≥95,000/
- Hemoglobin >5.3 g/dL
- Reticulocytes ≥95,000/mm3 if the hemoglobin concentration <9 g/dL.
Toxic
- Neutrophils <2000 cells/mm3,
- Platelets <80,000/mm3,
- Hemoglobin <4.5 g/dL and
- Reticulocytes <80,000/mm3 if the hemoglobin concentration <9 g/dL.
Since hydroxyurea may raise the serum uric acid level, dosage adjustment of uricosuric medication may be necessary.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Hydroxyurea (patient information) in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Hydroxyurea (patient information) in pediatric patients.
# Contraindications
- Hydroxyurea is contraindicated in patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation.
# Warnings
- Hydroxyurea is a cytotoxic and myelosuppressive agent. Hydroxyurea should not be given if bone marrow function is markedly depressed, as indicated by neutrophils below 2000 cells/mm3; a platelet count below 80,000/mm3; a hemoglobin level below 4.5 g/dL; or reticulocytes below 80,000/mm3 when the hemoglobin concentration is below 9 g/dL. Neutropenia is generally the first and most common manifestation of hematologic suppression. Thrombocytopenia and anemia occur less often, and are seldom seen without a preceding leukopenia. Recovery from myelosuppression is usually rapid when therapy is interrupted. Hydroxyurea causes macrocytosis, which may mask the incidental development of folic acid deficiency. Prophylactic administration of folic acid is recommended.
- In HIV-infected patients during therapy with hydroxyurea and didanosine, with or without stavudine, fatal and nonfatal pancreatitis have occurred. Hepatotoxicity and hepatic failure resulting in death have been reported during postmarketing surveillance in HIV-infected patients treated with hydroxyurea and other antiretroviral agents. *Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. This combination should be avoided.
- Peripheral neuropathy, which was severe in some cases, has been reported in HIV-infected patients receiving hydroxyurea in combination with antiretroviral agents, including didanosine, with or without stavudine.
- Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients with myeloproliferative disorders during therapy with hydroxyurea. These vasculitic toxicities were reported most often in patients with a history of, or currently receiving, interferon therapy. Due to potentially severe clinical outcomes for the cutaneous vasculitic ulcers reported in patients with myeloproliferative disease, hydroxyurea should be discontinued if cutaneous vasculitic ulcerations develop.
- Hydroxyurea is genotoxic in a wide range of test systems and is thus presumed to be a human carcinogen. In patients receiving long-term hydroxyurea for myeloproliferative disorders, such as polycythemia vera and thrombocythemia, secondary leukemia has been reported. It is unknown whether this leukemogenic effect is secondary to hydroxyurea or is associated with the patient’s underlying disease. Skin cancer has also been reported in patients receiving long-term hydroxyurea.
- Conventional long-term studies to evaluate the carcinogenic potential of Hydroxyurea have not been performed. However, intraperitoneal administration of 125 to 250 mg/kg hydroxyurea (about 0.6-1.2 times the maximum recommended human oral daily dose on a mg/m2 basis) thrice weekly for 6 months to female rats increased the incidence of mammary tumors in rats surviving to 18 months compared to control. Hydroxyurea is mutagenic in vitro to bacteria, fungi, protozoa, and mammalian cells. Hydroxyurea is clastogenic in vitro (hamster cells, human lymphoblasts) and in vivo (SCE assay in rodents, mouse micronucleus assay). Hydroxyurea causes the transformation of rodent embryo cells to a tumorigenic phenotype.
# Adverse Reactions
## Clinical Trials Experience
- In patients treated for sickle cell anemia in the Multicenter Study of Hydroxyurea in Sickle Cell Anemia, the most common adverse reactions were hematologic, with neutropenia, and low reticulocyte and platelet levels necessitating temporary cessation in almost all patients. Hematologic recovery usually occurred in two weeks.
- Non-hematologic events that possibly were associated with treatment include hair loss, skin rash, fever, gastrointestinal disturbances, weight gain, bleeding, and parvovirus B-19 infection; however, these non-hematologic events occurred with similar frequencies in the hydroxyurea and placebo treatment groups. Melanonychia has also been reported in patients receiving Hydroxyurea for SCA.
- Adverse events associated with the use of hydroxyurea in the treatment of neoplastic diseases, in addition to hematologic effects include: gastrointestinal symptoms (stomatitis, anorexia, nausea, vomiting, diarrhea, and constipation), and dermatological reactions such as maculopapular rash, skin ulceration, dermatomyositis-like skin changes, peripheral erythema, and facial erythema. Hyperpigmentation, atrophy of skin and nails, scaling, and violet papules have been observed in some patients after several years of long-term daily maintenance therapy with hydroxyurea. Skin cancer has been reported. Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients with myeloproliferative disorders during therapy with hydroxyurea. These vasculitic toxicities were reported most often in patients with a history of, or currently receiving, interferon therapy. Dysuria and alopecia have been reported. Large doses may produce drowsiness. Neurological disturbances have occurred and were limited to headache, dizziness, disorientation, hallucinations, and convulsions. Hydroxyurea may cause temporary impairment of renal tubular function accompanied by elevations in serum uric acid, blood urea nitrogen (BUN), and creatinine levels. Abnormal bromsulphalein (BSP) retention has been reported. Fever, chills, malaise, edema, asthenia, and elevation of hepatic enzymes have also been reported.
- The association of hydroxyurea with the development of acute pulmonary reactions consisting of diffuse pulmonary infiltrates, fever, and dyspnea has been reported. Pulmonary fibrosis also has been reported.
- In HIV-infected patients who received hydroxyurea in combination with antiretroviral agents, in particular, didanosine plus stavudine, fatal and nonfatal pancreatitis and hepatotoxicity, and severe peripheral neuropathy have been reported. Patients treated with hydroxyurea in combination with didanosine, stavudine, and indinavir in Study ACTG 5025 showed a median decline in CD4 cells of approximately 100/mm3.
## Postmarketing Experience
There is limited information regarding Hydroxyurea Postmarketing Experience in the drug label.
# Drug Interactions
- Prospective studies on the potential for hydroxyurea to interact with other drugs have not been performed. Studies have shown that there is an analytical interference of hydroxyurea with the enzymes (urease, uricase, and lactate dehydrogenase) used in the determination of urea, uric acid and lactic acid, rendering falsely elevated results of these in patients treated with hydroxyurea.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Hydroxyurea can cause fetal harm when administered to a pregnant woman. Hydroxyurea has been demonstrated to be a potent teratogen in a wide variety of animal models, including mice, hamsters, cats, miniature swine, dogs, and monkeys at doses within 1-fold of the human dose given on a mg/m2 basis. Hydroxyurea is embryotoxic and causes fetal malformations (partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, missing lumbar vertebrae) at 180 mg/kg/day (about 0.8 times the maximum recommended human daily dose on a mg/m2 basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m2 basis) in rabbits. Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. Hydroxyurea crosses the placenta. Single doses of ≥375 mg/kg (about 1.7 times the maximum recommended human daily dose on a mg/m2 basis) to rats caused growth retardation and impaired learning ability. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Hydroxyurea in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Hydroxyurea during labor and delivery.
### Nursing Mothers
- Hydroxyurea is excreted in human milk. Because of the potential for serious adverse reactions with hydroxyurea, a decision should be made either to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
There is no FDA guidance on the use of Hydroxyurea in geriatric settings.
### Gender
There is no FDA guidance on the use of Hydroxyurea with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Hydroxyurea with respect to specific racial populations.
### Renal Impairment
- As renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage of hydroxyurea in patients with renal impairment. In adult patients with sickle cell disease, an open-label, non-randomized, single-dose, multicenter study was conducted to assess the influence of renal function on the pharmacokinetics of hydroxyurea. Patients in the study with normal renal function (creatinine clearance [CrCl] >80 mL/min), mild (CrCl 50-80 mL/min), moderate (CrCl = 30-<50 mL/min), or severe (<30 mL/min) renal impairment received hydroxyurea as a single oral dose of 15 mg/kg, achieved by using combinations of the 200 mg, 300 mg, or 400 mg capsules. Patients with end-stage renal disease (ESRD) received two doses of 15 mg/kg separated by 7 days, the first was given following a 4-hour hemodialysis session, the second prior to hemodialysis. In this study, the mean exposure (AUC) in patients whose creatinine clearance was <60 mL/min (or ESRD) was approximately 64% higher than in patients with normal renal function. The results suggest that the initial dose of hydroxyurea should be reduced when used to treat patients with renal impairment. The table below describes the recommended dosage modification.
### Hepatic Impairment
- There are no data that support specific guidance for dosage adjustment in patients with hepatic impairment. Close monitoring of hematologic parameters is advised in these patients.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Hydroxyurea in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Hydroxyurea in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Hydroxyurea Administration in the drug label.
### Monitoring
Close monitoring of hematologic parameters is advised in patients with renal impairment.
# IV Compatibility
There is limited information regarding the compatibility of Hydroxyurea and IV administrations.
# Overdosage
- Acute mucocutaneous toxicity has been reported in patients receiving hydroxyurea at dosages several times the therapeutic dose. Soreness, violet erythema, edema on palms and soles followed by scaling of hands and feet, severe generalized hyperpigmentation of the skin, and stomatitis have been observed.
# Pharmacology
## Mechanism of Action
- The precise mechanism by which hydroxyurea produces its cytotoxic and cytoreductive effects is not known. However, various studies support the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein.
- The mechanisms by which Hydroxyurea produces its beneficial effects in patients with sickle cell anemia (SCA) are uncertain. Known pharmacologic effects of Hydroxyurea that may contribute to its beneficial effects include increasing hemoglobin F levels in RBCs, decreasing neutrophils, increasing the water content of RBCs, increasing deformability of sickled cells, and altering the adhesion of RBCs to endothelium.
## Structure
- Hydroxyurea is an essentially tasteless, white crystalline powder. Its structural formula is:
## Pharmacodynamics
There is limited information regarding Hydroxyurea Pharmacodynamics in the drug label.
## Pharmacokinetics
- Hydroxyurea is readily absorbed after oral administration. Peak plasma levels are reached in 1 to 4 hours after an oral dose. With increasing doses, disproportionately greater mean peak plasma concentrations and AUCs are observed. There are no data on the effect of food on the absorption of hydroxyurea.
- Hydroxyurea distributes rapidly and widely in the body with an estimated volume of distribution approximating total body water. Plasma to ascites fluid ratios range from 2:1 to 7.5:1. Hydroxyurea concentrates in leukocytes and erythrocytes.
- Up to 60% of an oral dose undergoes conversion through metabolic pathways that are not fully characterized. One pathway is probably saturable hepatic metabolism. Another minor pathway may be degradation by urease found in intestinal bacteria. Acetohydroxamic acid was found in the serum of three leukemic patients receiving hydroxyurea and may be formed from hydroxylamine resulting from action of urease on hydroxyurea.
- Excretion of hydroxyurea in humans is likely a linear first-order renal process. In adults with SCA, mean cumulative urinary recovery of hydroxyurea was about 40% of the administered dose.
## Nonclinical Toxicology
There is limited information regarding Hydroxyurea Nonclinical Toxicology in the drug label.
# Clinical Studies
- The efficacy of hydroxyurea in sickle cell anemia was assessed in a large clinical study (Multicenter Study of Hydroxyurea in Sickle Cell Anemia).
- The study was a randomized, double-blind, placebo-controlled trial that evaluated 299 adult patients (≥18 years) with moderate to severe disease (≥3 painful crises yearly). The trial was stopped by the Data Safety Monitoring Committee, after accrual was completed but before the scheduled 24 months of follow-up was completed in all patients, based on observations of fewer painful crises among patients receiving hydroxyurea.
- Compared to placebo treatment, treatment with hydroxyurea resulted in a significant decrease in the yearly rate of painful crises, the yearly rate of painful crises requiring hospitalization, the incidence of chest syndrome, the number of patients transfused, and units of blood transfused. Hydroxyurea treatment significantly increased the median time to both first and second painful crises.
- Although patients with 3 or more painful crises during the preceding 12 months were eligible for the study, most of the benefit in crisis reduction was seen in the patients with 6 or more painful crises during the preceding 12 months.
- No deaths were attributed to treatment with hydroxyurea, and none of the patients developed neoplastic disorders during the study. Treatment was permanently stopped for medical reasons in 14 hydroxyurea-treated (2 patients with myelotoxicity) and 6 placebo-treated patients.
- In patients with SCA treated with hydroxyurea, fetal hemoglobin (HbF) increases 4 to 12 weeks after initiation of treatment. In general, average HbF levels correlate with dose and plasma level with possible plateauing at higher dosages.
- A clear relation between reduction in crisis frequency and increased HbF or F-cell levels has not been demonstrated. The dose-related cytoreductive effects of hydroxyurea, particularly on neutrophils, was the factor most strongly correlated with reduced crisis frequency.
# How Supplied
- 200 mg capsules packaged in HDPE bottles of 60 with a plastic safety screw cap. (NDC 0003-6335-17). The cap and body are opaque blue-green. The capsule is marked in black ink on both the cap and body with “Hydroxyurea” and “6335”.
- 300 mg capsules packaged in HDPE bottles of 60 with a plastic safety screw cap. (NDC 0003-6336-17). The cap and body are opaque purple. The capsule is marked in black ink on both the cap and body with “Hydroxyurea” and “6336”.
- 400 mg capsules packaged in HDPE bottles of 60 with a plastic safety screw cap. (NDC 0003-6337-17). The cap and body are opaque reddish-orange. The capsule is marked in black ink on both the cap and body with “Hydroxyurea” and “6337”.
## Storage
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Keep Tightly closed.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Hydroxyurea Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Hydroxyurea (patient information) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Hydroxyurea
- Hydrea
# Look-Alike Drug Names
There is limited information regarding Hydroxyurea Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Hydroxyurea | |
13afab662b01015e0d961697f230e89d21cf000f | wikidoc | Hyoscyamine | Hyoscyamine
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Hyoscyamine is an antimuscarinic that is FDA approved for the {{{indicationType}}} of adjunctive therapy in the treatment of peptic ulcer and irritable bowel syndrome (irritable colon, spastic colon, mucous colitis), acute entercolitis and other functional gastrointestinal disorders, in symptomatic relief of biliary and renal colic and drying agent in the relief of symptoms of acute rhinitis. Common adverse reactions include diminished sweating, xerostomia, dizziness, somnolence, blurred vision, mydriasis, delay when starting to pass urine.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- 1 or 2 tablets every four hours or as needed. Do not exceed 12 tablets in 24 hours.
- Dosing Information
- 1 or 2 tablets every four hours or as needed. Do not exceed 12 tablets in 24 hours.
- Dosing Information
- 1 or 2 tablets every four hours or as needed. Do not exceed 12 tablets in 24 hours.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Hyoscyamine in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Hyoscyamine sulfate injection is used in adults for the reduction of drug-induced bradycardia during surgery.
- Dosing Information
- Hyoscyamine sulfate injection is used in adults during induction of anesthesia and intubation as a pre-operative medication for reduction of salivary, tracheobronchial, and pharyngeal secretions.
- Dosing Information
- Hyoscyamine sulfate is used as an adjunct with morphine or other narcotics in the symptomatic treatment of biliary colic .
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- Children 12 years of age and older: 1 or 2 tablets every four hours or as needed. Do not exceed 12 tablets in 24 hours. Children 2 to under 12 years of age: 1/2 to 1 tablet every four hours or as needed. Do not exceed 6 tablets in 24 hours.
- Dosing Information
- Children 12 years of age and older: 1 or 2 tablets every four hours or as needed. Do not exceed 12 tablets in 24 hours. Children 2 to under 12 years of age: 1/2 to 1 tablet every four hours or as needed. Do not exceed 6 tablets in 24 hours.
- Dosing Information
- Children 12 years of age and older: 1 or 2 tablets every four hours or as needed. Do not exceed 12 tablets in 24 hours. Children 2 to under 12 years of age: 1/2 to 1 tablet every four hours or as needed. Do not exceed 6 tablets in 24 hours.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Hyoscyamine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Hyoscyamine in pediatric patients.
# Contraindications
- Glaucoma, obstructive uropathy (for example, bladder neck obstruction due to prostatic hypertrophy); obstructive disease of the gastrointestinal tract (as in achalasia, pyloroduodenal stenosis); paralytic ileus; intestinal atony of elderly or debilitated patients; unstable cardiovascular status; severe ulcerative colitis; toxic megacolon; myasthenia gravis; myocardial ischemia.
# Warnings
### Precautions
- In the presence of high environmental temperature, heat prostration can occur with drug use (fever and heat stroke due to decreased sweating). Diarrhea may be an early symptom of incomplete intestinal obstruction, especially in patients with ileostomy or colostomy. In this instance, treatment with this drug would be inappropriate and possibly harmful. Like other anticholinergic agents, ANASPAZ may produce drowsiness or blurred vision. In this event, the patient should be warned not to engage in activities requiring mental alertness such as operating a motor vehicle or other machinery or to perform hazardous work while taking this drug.
- Anticholinergic psychosis has been reported in sensitive individuals given anticholinergic drugs. CNS signs and symptoms include confusion, disorientation, short term memory loss, hallucinations, dysarthria, ataxia, coma, euphoria, decreased anxiety, fatigue, insomnia, agitation and mannerisms, and inappropriate affect. These CNS signs and symptoms usually resolve 12 to 48 hours after drug discontinuation.
- Elderly patients may react with excitement, agitation, drowsiness, and other unfavorable manifestations to even small doses of ANASPAZ.
# Adverse Reactions
## Clinical Trials Experience
- Not all the following adverse reactions have been associated with ANASPAZ, but have been reported for drugs in the same pharmacological class, with anticholinergic / antispasmodic action. Adverse reactions may include dryness of the mouth, urinary hesitancy, urinary retention, tachycardia, palpitations, blurred vision, mydriasis, cycloplegia, increased intraocular pressure, dry eyes, headache, nervousness, drowsiness, dizziness, weakness, mental confusion and/or excitement (especially in geriatric patients), flushing, insomnia, fever, altered sense of taste, nausea, vomiting, dysphagia, heartburn, constipation, bloated feeling, suppression of lactation, impotence, and decreased sweating. Allergic reactions or drug idiosyncrasies such as anaphylaxis, urticaria and other dermal manifestations may also occur.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Hyoscyamine in the drug label.
# Drug Interactions
- Additive adverse effects resulting from cholinergic blockade may occur when ANASPAZ is administered concomitantly with other anti-muscarinics, amantadine, haloperidol, phenothiazines, monoamine oxidase (MAO) inhibitors, tricyclic antidepressants or some antihistamines.
- Antacids may interfere with the absorption of ANASPAZ; take ANASPAZ before meals and antacids after meals.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Animal reproduction studies have not been conducted with ANASPAZ. It is also not known whether ANASPAZ can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. ANASPAZ should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Hyoscyamine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Hyoscyamine during labor and delivery.
### Nursing Mothers
- ANASPAZ is excreted in human milk. Caution should be exercised when ANASPAZ is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 2 have not been established.
### Geriatic Use
- This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
- Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of ANASPAZ and observed closely.
### Gender
There is no FDA guidance on the use of Hyoscyamine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Hyoscyamine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Hyoscyamine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Hyoscyamine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Hyoscyamine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Hyoscyamine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Hyoscyamine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Hyoscyamine in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- The signs and symptoms of overdose include headache, nausea, vomiting, dizziness, dry mouth, difficulty in swallowing, dilated pupils, blurred vision, urinary retention, hot dry and flushed skin, tachycardia, hypertension, hypotension, respiratory depression, CNS stimulation, fever, ataxia, excitation, lethargy, stupor, coma, and paralysis (with large overdoses).
- The LD50 for hyoscyamine in rats is 375 mg/kg.
### Management
- General measures such as emesis or gastric lavage and administration of activated charcoal should be undertaken immediately. Supportive therapy is given as needed, including artificial respiration if required. Physostigmine may be given by intravenous injection to reverse severe anticholinergic symptoms.
- Hyoscyamine sulfate is dialyzable.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Hyoscyamine in the drug label.
# Pharmacology
## Mechanism of Action
- ANASPAZ inhibits specifically the actions of acetylcholine on structures innervated by postganglionic cholinergic nerves and on smooth muscles that respond to acetylcholine but lack cholinergic innervation. These peripheral cholinergic receptors are present in the autonomic effector cells of smooth muscle, cardiac muscle, the sino-atrial node, the atrioventricular node and exocrine glands. At therapeutic doses, it is completely devoid of any action in the autonomic ganglia. ANASPAZ inhibits gastrointestinal propulsive motility and decreases gastric acid secretion. ANASPAZ also controls excessive pharyngeal, tracheal and bronchial secretions. ANASPAZ is absorbed totally and completely by sublingual administration as well as oral administration. Once absorbed, ANASPAZ disappears rapidly from the blood and is distributed throughout the entire body. The half-life of ANASPAZ is 3.5 hours and the majority of drug is excreted in the urine unchanged within the first 12 hours, with a small amount hydrolyzed to tropic acid and tropine. Only traces of this drug are found in breast milk. ANASPAZ passes the blood-brain and placental barriers.
## Structure
- Each ANASPAZ orally disintegrating tablet contains 1-hyoscyamine sulfate 0.125 mg. ANASPAZ may be taken orally (swallowed or chewed) or sublingually. ANASPAZ tablets are compressed, light yellow and scored with the Ascher logo on one side and 225/295 on the other. Inactive ingredients: DC Yellow #10, FDC yellow #6, lactose NF, magnesium stearate NF, mannitol USP, sorbitol NF, pre-gelatinized starch NF, stearic acid NF.
- ANASPAZ is chemically pure 1-hyoscyamine sulfate, one of the principal anticholinergic/antispasmodic components of belladonna alkaloids. Chemically, it is benzeneacetic acid, α-(hydroxymethyl)-, 8-methyl-8-azabicyclooct-3-yl ester, -, sulfate (2:1), dihydrate with the chemical formula (C17H23NO3)2H2SO42H2O
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Hyoscyamine in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Hyoscyamine in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Hyoscyamine in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Hyoscyamine in the drug label.
# How Supplied
- ANASPAZ (l-hyoscyamine sulfate orally disintegrating tablets) 0.125mg is available as a compressed, light yellow, scored tablet, imprinted with the Ascher logo and 225/295 in bottles of 100 tablets (NDC 0225-0295-15) and 500 tablets (NDC 0225-0295-20).
- Store at room temperature - 59º - 86º F (15º - 30º C) in a dry place.
- Dispense in tight, amber glass or opaque PE plastic containers.
## Storage
There is limited information regarding Hyoscyamine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- ANASPAZ may produce drowsiness, dizziness or blurred vision. Patients should observe caution before operating a motor vehicle or other machinery or performing other tasks requiring mental alertness.
- Use of ANASPAZ may decrease sweating resulting in heat prostration, fever or heat stroke; febrile patients or those who may be exposed to elevated environmental temperatures should use caution.
# Precautions with Alcohol
- Alcohol-Hyoscyamine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ANASPAZ®
# Look-Alike Drug Names
There is limited information regarding Hyoscyamine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Hyoscyamine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Hyoscyamine is an antimuscarinic that is FDA approved for the {{{indicationType}}} of adjunctive therapy in the treatment of peptic ulcer and irritable bowel syndrome (irritable colon, spastic colon, mucous colitis), acute entercolitis and other functional gastrointestinal disorders, in symptomatic relief of biliary and renal colic and drying agent in the relief of symptoms of acute rhinitis. Common adverse reactions include diminished sweating, xerostomia, dizziness, somnolence, blurred vision, mydriasis, delay when starting to pass urine.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- 1 or 2 tablets every four hours or as needed. Do not exceed 12 tablets in 24 hours.
- Dosing Information
- 1 or 2 tablets every four hours or as needed. Do not exceed 12 tablets in 24 hours.
- Dosing Information
- 1 or 2 tablets every four hours or as needed. Do not exceed 12 tablets in 24 hours.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Hyoscyamine in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Hyoscyamine sulfate injection is used in adults for the reduction of drug-induced bradycardia during surgery.
- Dosing Information
- Hyoscyamine sulfate injection is used in adults during induction of anesthesia and intubation as a pre-operative medication for reduction of salivary, tracheobronchial, and pharyngeal secretions.
- Dosing Information
- Hyoscyamine sulfate is used as an adjunct with morphine or other narcotics in the symptomatic treatment of biliary colic .
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- Children 12 years of age and older: 1 or 2 tablets every four hours or as needed. Do not exceed 12 tablets in 24 hours. Children 2 to under 12 years of age: 1/2 to 1 tablet every four hours or as needed. Do not exceed 6 tablets in 24 hours.
- Dosing Information
- Children 12 years of age and older: 1 or 2 tablets every four hours or as needed. Do not exceed 12 tablets in 24 hours. Children 2 to under 12 years of age: 1/2 to 1 tablet every four hours or as needed. Do not exceed 6 tablets in 24 hours.
- Dosing Information
- Children 12 years of age and older: 1 or 2 tablets every four hours or as needed. Do not exceed 12 tablets in 24 hours. Children 2 to under 12 years of age: 1/2 to 1 tablet every four hours or as needed. Do not exceed 6 tablets in 24 hours.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Hyoscyamine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Hyoscyamine in pediatric patients.
# Contraindications
- Glaucoma, obstructive uropathy (for example, bladder neck obstruction due to prostatic hypertrophy); obstructive disease of the gastrointestinal tract (as in achalasia, pyloroduodenal stenosis); paralytic ileus; intestinal atony of elderly or debilitated patients; unstable cardiovascular status; severe ulcerative colitis; toxic megacolon; myasthenia gravis; myocardial ischemia.
# Warnings
### Precautions
- In the presence of high environmental temperature, heat prostration can occur with drug use (fever and heat stroke due to decreased sweating). Diarrhea may be an early symptom of incomplete intestinal obstruction, especially in patients with ileostomy or colostomy. In this instance, treatment with this drug would be inappropriate and possibly harmful. Like other anticholinergic agents, ANASPAZ may produce drowsiness or blurred vision. In this event, the patient should be warned not to engage in activities requiring mental alertness such as operating a motor vehicle or other machinery or to perform hazardous work while taking this drug.
- Anticholinergic psychosis has been reported in sensitive individuals given anticholinergic drugs. CNS signs and symptoms include confusion, disorientation, short term memory loss, hallucinations, dysarthria, ataxia, coma, euphoria, decreased anxiety, fatigue, insomnia, agitation and mannerisms, and inappropriate affect. These CNS signs and symptoms usually resolve 12 to 48 hours after drug discontinuation.
- Elderly patients may react with excitement, agitation, drowsiness, and other unfavorable manifestations to even small doses of ANASPAZ.
# Adverse Reactions
## Clinical Trials Experience
- Not all the following adverse reactions have been associated with ANASPAZ, but have been reported for drugs in the same pharmacological class, with anticholinergic / antispasmodic action. Adverse reactions may include dryness of the mouth, urinary hesitancy, urinary retention, tachycardia, palpitations, blurred vision, mydriasis, cycloplegia, increased intraocular pressure, dry eyes, headache, nervousness, drowsiness, dizziness, weakness, mental confusion and/or excitement (especially in geriatric patients), flushing, insomnia, fever, altered sense of taste, nausea, vomiting, dysphagia, heartburn, constipation, bloated feeling, suppression of lactation, impotence, and decreased sweating. Allergic reactions or drug idiosyncrasies such as anaphylaxis, urticaria and other dermal manifestations may also occur.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Hyoscyamine in the drug label.
# Drug Interactions
- Additive adverse effects resulting from cholinergic blockade may occur when ANASPAZ is administered concomitantly with other anti-muscarinics, amantadine, haloperidol, phenothiazines, monoamine oxidase (MAO) inhibitors, tricyclic antidepressants or some antihistamines.
- Antacids may interfere with the absorption of ANASPAZ; take ANASPAZ before meals and antacids after meals.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Animal reproduction studies have not been conducted with ANASPAZ. It is also not known whether ANASPAZ can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. ANASPAZ should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Hyoscyamine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Hyoscyamine during labor and delivery.
### Nursing Mothers
- ANASPAZ is excreted in human milk. Caution should be exercised when ANASPAZ is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 2 have not been established.
### Geriatic Use
- This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
- Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of ANASPAZ and observed closely.
### Gender
There is no FDA guidance on the use of Hyoscyamine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Hyoscyamine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Hyoscyamine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Hyoscyamine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Hyoscyamine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Hyoscyamine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Hyoscyamine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Hyoscyamine in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- The signs and symptoms of overdose include headache, nausea, vomiting, dizziness, dry mouth, difficulty in swallowing, dilated pupils, blurred vision, urinary retention, hot dry and flushed skin, tachycardia, hypertension, hypotension, respiratory depression, CNS stimulation, fever, ataxia, excitation, lethargy, stupor, coma, and paralysis (with large overdoses).
- The LD50 for hyoscyamine in rats is 375 mg/kg.
### Management
- General measures such as emesis or gastric lavage and administration of activated charcoal should be undertaken immediately. Supportive therapy is given as needed, including artificial respiration if required. Physostigmine may be given by intravenous injection to reverse severe anticholinergic symptoms.
- Hyoscyamine sulfate is dialyzable.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Hyoscyamine in the drug label.
# Pharmacology
## Mechanism of Action
- ANASPAZ inhibits specifically the actions of acetylcholine on structures innervated by postganglionic cholinergic nerves and on smooth muscles that respond to acetylcholine but lack cholinergic innervation. These peripheral cholinergic receptors are present in the autonomic effector cells of smooth muscle, cardiac muscle, the sino-atrial node, the atrioventricular node and exocrine glands. At therapeutic doses, it is completely devoid of any action in the autonomic ganglia. ANASPAZ inhibits gastrointestinal propulsive motility and decreases gastric acid secretion. ANASPAZ also controls excessive pharyngeal, tracheal and bronchial secretions. ANASPAZ is absorbed totally and completely by sublingual administration as well as oral administration. Once absorbed, ANASPAZ disappears rapidly from the blood and is distributed throughout the entire body. The half-life of ANASPAZ is 3.5 hours and the majority of drug is excreted in the urine unchanged within the first 12 hours, with a small amount hydrolyzed to tropic acid and tropine. Only traces of this drug are found in breast milk. ANASPAZ passes the blood-brain and placental barriers.
## Structure
- Each ANASPAZ orally disintegrating tablet contains 1-hyoscyamine sulfate 0.125 mg. ANASPAZ may be taken orally (swallowed or chewed) or sublingually. ANASPAZ tablets are compressed, light yellow and scored with the Ascher logo on one side and 225/295 on the other. Inactive ingredients: DC Yellow #10, FDC yellow #6, lactose NF, magnesium stearate NF, mannitol USP, sorbitol NF, pre-gelatinized starch NF, stearic acid NF.
- ANASPAZ is chemically pure 1-hyoscyamine sulfate, one of the principal anticholinergic/antispasmodic components of belladonna alkaloids. Chemically, it is benzeneacetic acid, α-(hydroxymethyl)-, 8-methyl-8-azabicyclo[3.2.1.]oct-3-yl ester, [3(S)-endo]-, sulfate (2:1), dihydrate with the chemical formula (C17H23NO3)2•H2SO4•2H2O
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Hyoscyamine in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Hyoscyamine in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Hyoscyamine in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Hyoscyamine in the drug label.
# How Supplied
- ANASPAZ (l-hyoscyamine sulfate orally disintegrating tablets) 0.125mg is available as a compressed, light yellow, scored tablet, imprinted with the Ascher logo and 225/295 in bottles of 100 tablets (NDC 0225-0295-15) and 500 tablets (NDC 0225-0295-20).
- Store at room temperature - 59º - 86º F (15º - 30º C) in a dry place.
- Dispense in tight, amber glass or opaque PE plastic containers.
## Storage
There is limited information regarding Hyoscyamine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- ANASPAZ may produce drowsiness, dizziness or blurred vision. Patients should observe caution before operating a motor vehicle or other machinery or performing other tasks requiring mental alertness.
- Use of ANASPAZ may decrease sweating resulting in heat prostration, fever or heat stroke; febrile patients or those who may be exposed to elevated environmental temperatures should use caution.
# Precautions with Alcohol
- Alcohol-Hyoscyamine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ANASPAZ®[1]
# Look-Alike Drug Names
There is limited information regarding Hyoscyamine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Hyoscyamine | |
45a4c8daa31d9fd26c81a8572237470f4d435c93 | wikidoc | Hyperacusis | Hyperacusis
# Overview
Hyperacusis is a condition characterized by an over-sensitivity to a specific frequency of sound or intolerance to reasonable environmental sounds. A person with hyperacusis has difficulty accepting everyday sounds; some sounds may seem offensively loud to that person but not to others. In hyperacusis, a person gives inappropriate or exaggerated responses to sounds that are neither uncomfortable nor threatening loud to an average person; even low-intensity sounds can elicit the reaction.
# Classification
Based on the symptoms, hyperacusis may be classified as cochlear and vestibular hyperacusis.
### Cochlear hyperacusis:
- The most common form of hyperacusis
- Presents with ear pain and general intolerance to any sounds that most people don't notice or consider unpleasant.
- Crying spells or panic attacks may result from cochlear hyperacusis.
- Most of the time cochlear hyperacusis is associated with tinnitus.
### Vestibular hyperacusis:
- Associated with dizziness, nausea, or a loss of balance triggered by certain pitch sounds.
- Anxiety, stress, and phonophobia may be present in both types of hyperacusis.
- High risk for developing avoidant behavior to avoid a stressful sound situation.
# Pathophysiology
- Hyperacusis can be developed because of damage to the inner ear or hearing apparatus, affecting efferent part of the auditory nerve, and fibers that come out from the brain that control sounds.
- In this process, tissues of the auditory nerve are damaged, though the hair cells that permit us to hear pure tones remain integral.
- It can be as a result of injury to the neurological system of the brain. In some cases, hyperacusis may be triggered by a vestibular disorder.
- Stapes hypermobility can also be one of the causes of peripheral hyperacusis.
- Situations that comprise paralysis of the facial nerve (i.e., Ramsay-Hunt syndrome, Bell’s palsy, and Lyme disease) are involved in the causes of the condition.
- Hyperacusis increases in extent during anxiety, tiredness, or stress.
- The mechanism involved during stress, include endogenous dynorphins release into the synaptic region underneath inner hair cells.
- It potentiates the neurotransmitter glutamate, triggering sound to be seeming with excessive noise.
# Causes
Common causes of hyperacusis include:
- Severe head trauma
- Facial nerve dysfunction (to Stapedius)
- Surgery
- Ear irrigation
- TMJ (Temporomandibular joint disorder)
- Adverse drug reaction
- Williams Syndrome
- Autism
- Bell's palsy
- Ménière's disease
- Asperger syndrome
- Superior Canal Dehiscence Syndrome
- Chronic ear infections
- Minor Head Injury
- A vestibular disorder
## Differentiating hyperacusis from other diseases
On the basis of signs and symptoms, hyperacusis must be differentiated from misophonia, phonophobia, tinnitus, William syndrome, Lyme disease, migraine..
# Epidemiology and Demographics
Incidence
- The incidence of hyperacusis is approximately 1 in 50,000 people.
Prevalence
- The overall prevalence of hyperacusis among children and adolescents is between 3.2% to 1.7%. In adults, prevalence rate is between 8% to 15.2%.
Age
- Hyperacusis is commonly seen in individuals with any age group.
Gender
- Hyperacusis affects men and women equally.
Race
- There is no racial predilection to hyperacusis.
# Natural History, Complications, and Prognosis
Natural History
- In the case of a hyperacusis, patients can present with.
- Ear pain
- Annoyance
- Fear
- General intolerance to many sounds
- Crying spells
- Panic attacks
- Tinnitus
- Anxiety
- Stress
- Phonophobia
- Avoidant behavior
- Dizziness
- Nausea
Complications
- Common complications of hyperacusis depend on the etiology.
Prognosis
- Depending on the extent of the disease progression at the time of diagnosis, the prognosis may vary. However, the prognosis is generally regarded as good.
- Patients with hyperacusis have profound psychological influence, patients presenting with self-harm or suicidal ideation.
# Hyperausis Diagnosis
## Diagnostic study of choice
Pure tone audiometry is the gold standard test for the diagnosis of hyperacusis.
- Loudness discomfort level( LDL) measured in decibels (dB); LDL decreased by 16–18 dB than the general population is diagnostic of hyperacusis.
- 95% of patients with hyperacusis have LDL ≤ 77 dB (average LDL in a normal person is 100 dB).
## History and Symptoms
- The hallmark of hyperacusis is sensitivity to sounds.
- A positive history of over-sensitivity or distress to particular sounds is suggestive of hyperacusis.
- The most common symptoms of hyperacusis include annoyance, ear pain, loudness, and tinnitus.
## Physical Examination
Physical examination of patients' hyperacusis is usually remarkable for fear, irritability, and avoidance behavior.
## Laboratory Findings
There are no diagnostic laboratory findings associated with hyperacusis.
## CT scan
There are no CT scan findings associated with hyperacusis.
## MRI
There are no MRI findings associated with hyperacusis.
## Other Diagnostic Studies
Health questionnaires may be helpful in the diagnosis of hyperacusis. Findings suggestive of hyperacusis include:
- HQ score of ≥ 22 is diagnostic of hyperacusis.
- Disability
- Functional impact
- Psychological factors
- Impacted quality of life
# Treatment
The most common treatment for hyperacusis is retraining therapy that includes:
- Tinnitus Retraining Therapy (TRT), a treatment originally used to treat tinnitus, uses broadband noise to treat hyperacusis. By listening to broadband noise at soft levels for a disciplined period of time each day, patients can rebuild (i.e., re-establish) their tolerances to sound.
- Pink noise can also be used to treat hyperacusis.
Another possible treatment include:
# People
- Stephen Merritt, of The Magnetic Fields, suffers from this condition. | Hyperacusis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Norina Usman, M.B.B.S[2]
# Overview
Hyperacusis is a condition characterized by an over-sensitivity to a specific frequency of sound or intolerance to reasonable environmental sounds. A person with hyperacusis has difficulty accepting everyday sounds; some sounds may seem offensively loud to that person but not to others. In hyperacusis, a person gives inappropriate or exaggerated responses to sounds that are neither uncomfortable nor threatening loud to an average person; even low-intensity sounds can elicit the reaction.
# Classification
Based on the symptoms, hyperacusis may be classified as cochlear and vestibular hyperacusis.[1]
### Cochlear hyperacusis:
- The most common form of hyperacusis
- Presents with ear pain and general intolerance to any sounds that most people don't notice or consider unpleasant.
- Crying spells or panic attacks may result from cochlear hyperacusis.
- Most of the time cochlear hyperacusis is associated with tinnitus.
### Vestibular hyperacusis:
- Associated with dizziness, nausea, or a loss of balance triggered by certain pitch sounds.
- Anxiety, stress, and phonophobia may be present in both types of hyperacusis.
- High risk for developing avoidant behavior to avoid a stressful sound situation.
# Pathophysiology
- Hyperacusis can be developed because of damage to the inner ear or hearing apparatus, affecting efferent part of the auditory nerve, and fibers that come out from the brain that control sounds.[2][3]
- In this process, tissues of the auditory nerve are damaged, though the hair cells that permit us to hear pure tones remain integral.
- It can be as a result of injury to the neurological system of the brain. In some cases, hyperacusis may be triggered by a vestibular disorder.
- Stapes hypermobility can also be one of the causes of peripheral hyperacusis.
- Situations that comprise paralysis of the facial nerve (i.e., Ramsay-Hunt syndrome, Bell’s palsy, and Lyme disease) are involved in the causes of the condition.
- Hyperacusis increases in extent during anxiety, tiredness, or stress.
- The mechanism involved during stress, include endogenous dynorphins release into the synaptic region underneath inner hair cells.
- It potentiates the neurotransmitter glutamate, triggering sound to be seeming with excessive noise.
# Causes
Common causes of hyperacusis include:[4]
- Severe head trauma
- Facial nerve dysfunction (to Stapedius)
- Surgery
- Ear irrigation
- TMJ (Temporomandibular joint disorder)
- Adverse drug reaction
- Williams Syndrome
- Autism
- Bell's palsy
- Ménière's disease
- Asperger syndrome
- Superior Canal Dehiscence Syndrome
- Chronic ear infections
- Minor Head Injury
- A vestibular disorder
## Differentiating hyperacusis from other diseases
On the basis of signs and symptoms, hyperacusis must be differentiated from misophonia, phonophobia, tinnitus, William syndrome, Lyme disease, migraine.[5][6][7][8].
# Epidemiology and Demographics
Incidence
- The incidence of hyperacusis is approximately 1 in 50,000 people.
Prevalence
- The overall prevalence of hyperacusis among children and adolescents is between 3.2% to 1.7%. In adults, prevalence rate is between 8% to 15.2%.
Age
- Hyperacusis is commonly seen in individuals with any age group.
Gender
- Hyperacusis affects men and women equally.
Race
- There is no racial predilection to hyperacusis.
# Natural History, Complications, and Prognosis
Natural History
- In the case of a hyperacusis, patients can present with.[9][3]
- Ear pain
- Annoyance
- Fear
- General intolerance to many sounds
- Crying spells
- Panic attacks
- Tinnitus
- Anxiety
- Stress
- Phonophobia
- Avoidant behavior
- Dizziness
- Nausea
Complications
- Common complications of hyperacusis depend on the etiology.
Prognosis
- Depending on the extent of the disease progression at the time of diagnosis, the prognosis may vary. However, the prognosis is generally regarded as good.
- Patients with hyperacusis have profound psychological influence, patients presenting with self-harm or suicidal ideation.
# Hyperausis Diagnosis
## Diagnostic study of choice
Pure tone audiometry is the gold standard test for the diagnosis of hyperacusis.
- Loudness discomfort level( LDL) measured in decibels (dB); LDL decreased by 16–18 dB than the general population is diagnostic of hyperacusis.
- 95% of patients with hyperacusis have LDL ≤ 77 dB (average LDL in a normal person is 100 dB).
## History and Symptoms
- The hallmark of hyperacusis is sensitivity to sounds.
- A positive history of over-sensitivity or distress to particular sounds is suggestive of hyperacusis.
- The most common symptoms of hyperacusis include annoyance, ear pain, loudness, and tinnitus.
## Physical Examination
Physical examination of patients' hyperacusis is usually remarkable for fear, irritability, and avoidance behavior.
## Laboratory Findings
There are no diagnostic laboratory findings associated with hyperacusis.
## CT scan
There are no CT scan findings associated with hyperacusis.
## MRI
There are no MRI findings associated with hyperacusis.
## Other Diagnostic Studies
Health questionnaires may be helpful in the diagnosis of hyperacusis. Findings suggestive of hyperacusis include:
- HQ score of ≥ 22 is diagnostic of hyperacusis.
- Disability
- Functional impact
- Psychological factors
- Impacted quality of life
# Treatment
The most common treatment for hyperacusis is retraining therapy that includes:[10][11][12]
- Tinnitus Retraining Therapy (TRT), a treatment originally used to treat tinnitus, uses broadband noise to treat hyperacusis. By listening to broadband noise at soft levels for a disciplined period of time each day, patients can rebuild (i.e., re-establish) their tolerances to sound.
- Pink noise can also be used to treat hyperacusis.
Another possible treatment include:[1]
# People
- Stephen Merritt, of The Magnetic Fields, suffers from this condition. | https://www.wikidoc.org/index.php/Hyperacusia | |
e5476e2d721cdfaa63662277db71da54fe073a17 | wikidoc | Nephropathy | Nephropathy
# Overview
Nephropathy refers to damage to or disease of the kidney. An older term for this is nephrosis.
# Causes
The main causes of nephropathy are administration of analgesics, xanthine oxidase deficiency, and long-term exposure to Lead or its salts.
## Analgesics
One cause of nephropathy is the long term usage of analgesics. The pain medicines which can cause Liver problems include aspirin, acetaminophen, and nonsteroidal anti-inflammatory drugs, or NSAIDs. This form of nephropathy is "chronic analgesic nephritis," a chronic inflammatory change characterized by loss and atrophy of tubules and interstitial fibrosis and inflammation (BRS Pathology, 2nd edition).
Specifically, long term use of the analgesic phenacetin has been linked to renal papillary necrosis (necrotizing papillitis).
## Xanthine oxidase deficiency
A second possible cause of nephropathy is due to decreased function of xanthine oxidase in the purine degradation pathway. Xanthine oxidase will degrade hypoxanthine to xanthine and then to uric acid. Xanthine is not very soluble in water; therefore, an increase in xanthine forms crystals (which can lead to kidney stones) and result in damage of the kidney. Drugs like allopurinol that are used to inhibit xanthine oxidase can therefore cause possible nephropathy.
# Related Chapters
- Diabetic nephropathy
- Hypertensive nephropathy
- Nephritis
- IgA nephropathy
de:Nephropathie | Nephropathy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Nephropathy refers to damage to or disease of the kidney. An older term for this is nephrosis.
# Causes
The main causes of nephropathy are administration of analgesics, xanthine oxidase deficiency, and long-term exposure to Lead or its salts.
## Analgesics
One cause of nephropathy is the long term usage of analgesics. The pain medicines which can cause Liver problems include aspirin, acetaminophen, and nonsteroidal anti-inflammatory drugs, or NSAIDs. This form of nephropathy is "chronic analgesic nephritis," a chronic inflammatory change characterized by loss and atrophy of tubules and interstitial fibrosis and inflammation (BRS Pathology, 2nd edition).
Specifically, long term use of the analgesic phenacetin has been linked to renal papillary necrosis (necrotizing papillitis).
## Xanthine oxidase deficiency
A second possible cause of nephropathy is due to decreased function of xanthine oxidase in the purine degradation pathway. Xanthine oxidase will degrade hypoxanthine to xanthine and then to uric acid. Xanthine is not very soluble in water; therefore, an increase in xanthine forms crystals (which can lead to kidney stones) and result in damage of the kidney. Drugs like allopurinol that are used to inhibit xanthine oxidase can therefore cause possible nephropathy.
# Related Chapters
- Diabetic nephropathy
- Hypertensive nephropathy
- Nephritis
- IgA nephropathy
de:Nephropathie
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Hypercalcemic_nephropathy | |
c6098f5f9c0bfd8434381807808d53ec3cfc76d4 | wikidoc | Polydactyly | Polydactyly
# Overview
Polydactyly or polydactylism (from the Greek poly = "many" + daktylos = "finger"), also known as hyperdactyly, is a congenital physical anomaly consisting of supernumerary fingers or toes. When each hand or foot has six digits, it is sometimes called "sexdactyly", "hexadactyly", or "hexadactylism". Although the condition is usually not life-threatening or even particularly debilitating, most people in Western societies have the extra digits removed surgically.
The extra digit is usually a small piece of soft tissue; occasionally it may contain bone without joints; rarely it may be a complete, functioning digit. The extra digit is most common on the ulnar (little finger) side of the hand, less common on the radial (thumb) side, and very rarely within the middle three digits. The extra digit is most commonly an abnormal fork in an existing digit, or it may rarely originate at the wrist like a normal digit does.
Polydactyly can occur by itself, or more commonly, as one feature of a syndrome of congenital anomalies. When it occurs by itself, it is associated with autosomal dominant mutations in single genes, i.e. it is not a multifactorial trait. But mutation in a variety of genes can give rise to polydactyly. Typically the mutated gene is involved in developmental patterning, and a syndrome of congenital anomalies results, of which polydactyly is one feature.
The condition has an incidence of 1 in every 500 live births although the frequency is higher in some groups (an example is the Amish in the United States, due to the founder effect).
# Types of polydactyly
- Polydactyly with cleft lip/palate and psychomotor retardation (Varadi-Papp Syndrome)
- Polydactyly myopia syndrome
- Polydactyly postaxial dental and vertebral
- Polydactyly postaxial with median cleft of upper lip
- Polydactyly postaxial
- Polydactyly preaxial type 1
- Polydactyly syndrome middle ray duplication
- Polydactyly visceral anomalies cleft lip palate
# Diagnosis
## Physical Examination
- Rudimentary polydactyly. Adapted from Dermatology Atlas.
- Rudimentary polydactyly. Adapted from Dermatology Atlas.
- Rudimentary polydactyly. Adapted from Dermatology Atlas.
- Rudimentary polydactyly. Adapted from Dermatology Atlas.
- Rudimentary polydactyly. Adapted from Dermatology Atlas.
- Rudimentary polydactyly. Adapted from Dermatology Atlas.
- Rudimentary polydactyly. Adapted from Dermatology Atlas.
- Rudimentary polydactyly. Adapted from Dermatology Atlas.
- Rudimentary polydactyly. Adapted from Dermatology Atlas.
- Rudimentary polydactyly. Adapted from Dermatology Atlas.
- Rudimentary polydactyly. Adapted from Dermatology Atlas.
# Examples
- Ellis-Van Creveld syndrome
- Left foot with postaxial polydactyly of 5th ray
- Right hand with mid-ray duplication | Polydactyly
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2] Kiran Singh, M.D. [3]
# Overview
Polydactyly or polydactylism (from the Greek poly = "many" + daktylos = "finger"), also known as hyperdactyly, is a congenital physical anomaly consisting of supernumerary fingers or toes. When each hand or foot has six digits, it is sometimes called "sexdactyly", "hexadactyly", or "hexadactylism". Although the condition is usually not life-threatening or even particularly debilitating, most people in Western societies have the extra digits removed surgically.
The extra digit is usually a small piece of soft tissue; occasionally it may contain bone without joints; rarely it may be a complete, functioning digit. The extra digit is most common on the ulnar (little finger) side of the hand, less common on the radial (thumb) side, and very rarely within the middle three digits. The extra digit is most commonly an abnormal fork in an existing digit, or it may rarely originate at the wrist like a normal digit does.
Polydactyly can occur by itself, or more commonly, as one feature of a syndrome of congenital anomalies. When it occurs by itself, it is associated with autosomal dominant mutations in single genes, i.e. it is not a multifactorial trait. [4] But mutation in a variety of genes can give rise to polydactyly. Typically the mutated gene is involved in developmental patterning, and a syndrome of congenital anomalies results, of which polydactyly is one feature.
The condition has an incidence of 1 in every 500 live births[1] although the frequency is higher in some groups (an example is the Amish in the United States, due to the founder effect).
# Types of polydactyly
- Polydactyly with cleft lip/palate and psychomotor retardation (Varadi-Papp Syndrome)
- Polydactyly myopia syndrome
- Polydactyly postaxial dental and vertebral
- Polydactyly postaxial with median cleft of upper lip
- Polydactyly postaxial
- Polydactyly preaxial type 1
- Polydactyly syndrome middle ray duplication
- Polydactyly visceral anomalies cleft lip palate
# Diagnosis
## Physical Examination
- Rudimentary polydactyly. Adapted from Dermatology Atlas.[2]
- Rudimentary polydactyly. Adapted from Dermatology Atlas.[2]
- Rudimentary polydactyly. Adapted from Dermatology Atlas.[2]
- Rudimentary polydactyly. Adapted from Dermatology Atlas.[2]
- Rudimentary polydactyly. Adapted from Dermatology Atlas.[2]
- Rudimentary polydactyly. Adapted from Dermatology Atlas.[2]
- Rudimentary polydactyly. Adapted from Dermatology Atlas.[2]
- Rudimentary polydactyly. Adapted from Dermatology Atlas.[2]
- Rudimentary polydactyly. Adapted from Dermatology Atlas.[2]
- Rudimentary polydactyly. Adapted from Dermatology Atlas.[2]
- Rudimentary polydactyly. Adapted from Dermatology Atlas.[2]
# Examples
- Ellis-Van Creveld syndrome
- Left foot with postaxial polydactyly of 5th ray
- Right hand with mid-ray duplication | https://www.wikidoc.org/index.php/Hyperdactyly | |
6344ce71673399f47d9c0d4feb2173b0f6eeef8b | wikidoc | Hyperdontia | Hyperdontia
Hyperdontia is the condition of having supernumerary teeth, or teeth which appear in addition to the regular number of teeth. The most common supernumerary tooth is a mesiodens, which is a mal-formed, peg-like tooth that occurs between the maxillary central incisors.
There is evidence of hereditary factors along with some evidence of environmental factors leading to this condition. Many supernumerary teeth never erupt, but they may delay eruption of nearby teeth or cause other dental problems. Molar-type extra teeth are the rarest form. Dental X-rays are often used to diagnose hyperdontia.
A similar condition is hypodontia, in which there are fewer than the usual number of teeth.
Hyperdontia is seen in a number of disorders, including Gardner's syndrome and cleidocranial dysostosis where multiple supernumerary teeth are seen that are usually impacted.
It is suggested that supernumerary teeth develop from a third tooth bud arising from the dental lamina near the permanent tooth bud or possibly from splitting the permanent tooth bud itself.
Supernumerary teeth in deciduous dentition are less common than in permanent dentition.
zh-min-nan:To-khí-chèng
he:שן עודפת
hu:Hyperodontia | Hyperdontia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Hyperdontia is the condition of having supernumerary teeth, or teeth which appear in addition to the regular number of teeth. The most common supernumerary tooth is a mesiodens, which is a mal-formed, peg-like tooth that occurs between the maxillary central incisors.
There is evidence of hereditary factors along with some evidence of environmental factors leading to this condition. Many supernumerary teeth never erupt, but they may delay eruption of nearby teeth or cause other dental problems. Molar-type extra teeth are the rarest form. Dental X-rays are often used to diagnose hyperdontia.
A similar condition is hypodontia, in which there are fewer than the usual number of teeth.
Hyperdontia is seen in a number of disorders, including Gardner's syndrome and cleidocranial dysostosis where multiple supernumerary teeth are seen that are usually impacted.
It is suggested that supernumerary teeth develop from a third tooth bud arising from the dental lamina near the permanent tooth bud or possibly from splitting the permanent tooth bud itself.
Supernumerary teeth in deciduous dentition are less common than in permanent dentition.
Template:Oral pathology
zh-min-nan:To-khí-chèng
he:שן עודפת
hu:Hyperodontia
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Hyperdontia | |
4638cb068a4b2419e283deed9d722cca440da148 | wikidoc | Hyperplasia | Hyperplasia
Synonyms and keywords: Physiologic hyperplasia; Pathologic hyperplasia; Hypergenesis
# Overview
Hyperplasia (or "hypergenesis") is a general term referring to the proliferation of cells within an organ or tissue. Hyperplasia may result in the gross enlargement of an organ, the formation of a benign tumor. Hyperplasia is considered to be a physiological response to a specific stimulus, and the cells of a hyperplastic growth remain subject to normal regulatory control mechanisms. This stands in contrast to neoplasia (the process underlying cancer and some benign tumors), in which genetically abnormal cells proliferate in a non-physiological manner which is unresponsive to normal stimuli.
# Classification
- Hyperplasia may be classified into 2 groups:
Physiologic hyperplasia
- Normal stressor (eg. pregnancy)
Pathologic hyperplasia
- Abnormal stressor (eg. pituitary adenoma)
# Pathophysiology
- The pathogenesis of hyperplasia is characterized by an increase in the number of cells.
- Hyperplasia is the result of growth factor driven proliferation of mature cells.
- The pathogenesis of hyperplasia is limited to cells that have the capability of reproduction, excluding primarily myocytes and neurons.
- On gross pathology, findings of hyperplasia will depend on the anatomical site.
# Causes
- Hyperplasia may be caused by either increased metabolic demand, chronic inflammatory response, or compensation for damage.
# Differentiating Hyperplasia from other Diseases
- Hyperplasia must be differentiated from other diseases that cause abnormal tissue growth such as:
- Cancer
- Hypertrophy
- Metaplasia
- Some examples of hyperplasia, include:
- Congenital adrenal hyperplasia
- Endometrial hyperplasia
- Benign prostatic hyperplasia
- Hyperplasia of the breast
- Focal epithelial hyperplasia
- Sebaceous hyperplasia
- Compensatory liver hyperplasia
# Risk Factors
- Common risk factors in the development of hyperplasia are genetic mutations, chronic inflammation, increased metabolic demand, and hormonal stimulation. | Hyperplasia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]
Synonyms and keywords: Physiologic hyperplasia; Pathologic hyperplasia; Hypergenesis
# Overview
Hyperplasia (or "hypergenesis") is a general term referring to the proliferation of cells within an organ or tissue. Hyperplasia may result in the gross enlargement of an organ, the formation of a benign tumor. Hyperplasia is considered to be a physiological response to a specific stimulus, and the cells of a hyperplastic growth remain subject to normal regulatory control mechanisms. This stands in contrast to neoplasia (the process underlying cancer and some benign tumors), in which genetically abnormal cells proliferate in a non-physiological manner which is unresponsive to normal stimuli.[1]
# Classification
- Hyperplasia may be classified into 2 groups:[2]
Physiologic hyperplasia
- Normal stressor (eg. pregnancy)
Pathologic hyperplasia
- Abnormal stressor (eg. pituitary adenoma)
# Pathophysiology
- The pathogenesis of hyperplasia is characterized by an increase in the number of cells.[2]
- Hyperplasia is the result of growth factor driven proliferation of mature cells.[1]
- The pathogenesis of hyperplasia is limited to cells that have the capability of reproduction, excluding primarily myocytes and neurons.
- On gross pathology, findings of hyperplasia will depend on the anatomical site.
# Causes
- Hyperplasia may be caused by either increased metabolic demand, chronic inflammatory response, or compensation for damage.
# Differentiating Hyperplasia from other Diseases
- Hyperplasia must be differentiated from other diseases that cause abnormal tissue growth such as:[2]
- Cancer
- Hypertrophy
- Metaplasia
- Some examples of hyperplasia, include:
- Congenital adrenal hyperplasia
- Endometrial hyperplasia
- Benign prostatic hyperplasia
- Hyperplasia of the breast
- Focal epithelial hyperplasia
- Sebaceous hyperplasia
- Compensatory liver hyperplasia
# Risk Factors
- Common risk factors in the development of hyperplasia are genetic mutations, chronic inflammation, increased metabolic demand, and hormonal stimulation.[2] | https://www.wikidoc.org/index.php/Hypergenesis | |
96415d2cc0a28bc3717483e9b271b09efecf1d39 | wikidoc | Menorrhagia | Menorrhagia
# Overview
Menorrhagia is an abnormally heavy and prolonged menstrual period at regular intervals. Causes may be due to abnormal blood clotting, disruption of normal hormonal regulation of periods or disorders of the endometrial lining of the uterus. Depending upon the cause, it may be associated with abnormally painful periods (dysmenorrhea).
# Definition
A normal menstrual cycle is 21-35 days in duration, with bleeding lasting an average of 5 days and total blood flow between 25 and 80 mL. A blood loss of greater than 80 ml or lasting longer than 7 days constitutes menorrhagia (also called hypermenorrhea). In practice this is not usually directly measured by patients or doctors. Menorrhagia also occurs at predictable and normal (usually about 28 days) intervals, distinguishing it from menometrorrhagia, which occurs at irregular and more frequent intervals. It is possible to estimate the amount of bleeding by the number of tampons or pads a woman uses during her period. As a guide a regular tampon fully soaked will hold about 5ml of blood.
# Complications
Aside from the social distress of dealing with a prolonged and heavy period, over time the blood loss may prove to be greater than the body iron reserves or the rate of blood replenishment, leading to anemia. Symptoms attributable to the anemia may include tiredness, weakness, tingling and numbness in fingers and toes, headaches, depression, becoming cold more easily, and poor concentration.
# Etiology
Usually no causative abnormality can be identified and treatment is directed at the symptom, rather than a specific mechanism. A brief overview of causes is given below, followed by a more formal medical list based on the nature of the menstrual cycle experienced.
## Disorders of coagulation
With the shedding of the endometrial lining's blood vessels, normal coagulation process must occur to limit and eventually stop the blood flow. Blood disorders of platelets (such as ITP) or coagulation (such as von Willebrand disease) or use of anticoagulant medication (such as warfarin) are therefore possible causes, although a rare minority of cases.
## Excessive build up in endometrial lining
Periods soon after the onset of menstruation in girls (the menarche) and just before menopause may in some women be particularly heavy. Hormonal disorders involving the ovaries-pituitary-hypothalamus (the 'ovarian endocrine axis') account for many cases, and hormonal-based treatments may regulate effectively.
The lining of the womb builds up naturally under the hormonal effects of pregnancy, and an early spontaneous miscarriage may be mistaken for a heavier than normal period.
Irritation of the endometrium may result in increased blood flow, e.g. from infection (acute or chronic pelvic inflammatory disease) or the contraceptive intrauterine device (note the distinction from the IntraUterine System which is used to treat this condition).
Fibroids in the wall of the womb sometimes can cause increase menstrual loss if they protrude into the central cavity and so thereby increase endometrium's surface area.
Abnormalities of the endometrium such as adenomyosis (so called "internal endometriosis") where there is extension into the wall of the womb gives rise to enlarged tender uterus. Note, true endometriosis is a cause of pain (dysmenorrhoea) but usually not alteration in menstrual blood loss.
Endometrial carcinoma (cancer of the uterine lining) usually causes irregular bleeding, rather than the cyclical pattern of menorrhagia. Bleeding in between periods (intermenstrual bleeding or IMB) or after the menopause (postmenopausal bleeding or PMB) should always be considered suspicious.
## Consideration by nature of the menstrual cycle
- Excessive menses but normal cycle:
Painless:
Fibroids
Ovarian endocrine disorder (dysfunctional uterine bleeding or DUB)(the most common cause)
Coagulation defects (rare)
Painful:
Pelvic inflammatory disease
Endometriosis
- Painless:
Fibroids
Ovarian endocrine disorder (dysfunctional uterine bleeding or DUB)(the most common cause)
Coagulation defects (rare)
- Fibroids
- Ovarian endocrine disorder (dysfunctional uterine bleeding or DUB)(the most common cause)
- Coagulation defects (rare)
- Painful:
Pelvic inflammatory disease
Endometriosis
- Pelvic inflammatory disease
- Endometriosis
- Short cycle (<21 days) but normal menses (epimenorrhoea or polymenorrhoea). These are always anovulatory cycles due to hormonal disorders.
- Short cycle and excessive menses (epimenorrhagia) due to ovarian dysfunction and may be secondary to blockage of blood vessels by tumours.
- Excessive menses and long intervals.
Anovular ovarian disorder due to prolonged oestrogen production.
This may occur following prolonged continuous courses of the combined oral contraceptive pill (e.g. where several packets are taken without a withdrawal gap in order to defer menstruation).
- Anovular ovarian disorder due to prolonged oestrogen production.
- This may occur following prolonged continuous courses of the combined oral contraceptive pill (e.g. where several packets are taken without a withdrawal gap in order to defer menstruation).
## Differential Diagnosis
- Pregnancy complications:
Ectopic pregnancy
Incomplete abortion
Miscarriage
Threatened abortion
- Ectopic pregnancy
- Incomplete abortion
- Miscarriage
- Threatened abortion
- Nonuterine bleeding:
Cervical ectropion/erosion
Cervical neoplasia/polyp
Cervical or vaginal trauma
Condylomata
Atrophic vaginitis
Foreign bodies
- Cervical ectropion/erosion
- Cervical neoplasia/polyp
- Cervical or vaginal trauma
- Condylomata
- Atrophic vaginitis
- Foreign bodies
- Pelvic inflammatory disease (PID):
Endometritis
Tuberculosis
- Endometritis
- Tuberculosis
- Hypothyroidism
## Risk Factors
- Obesity
- Anovulation
- Estrogen administration (without progestogens)
- Prior treatment with progestational agents or oral contraceptives increases the risk of endometrial atrophy, but decreases the risk of endometrial hyperplasia or neoplasia
## Drug Side Effect
- Estradiol valerate and estradiol valerate/dienogest
- Misoprostol
- Olsalazine
## ICD-9 codes
# Investigation
- Pelvic and rectal examination
- Pap smear
- Pelvic ultrasound scan is the first line diagnostic tool for identifying structural abnormalities.
- Endometrial biopsy to exclude endometrial cancer or atypical hyperplasia
- Hysteroscopy
# Treatment
Where an underlying cause can be identified, treatment may be directed at this. Clearly heavy periods at the start and end of a women's reproductive years may settle spontaneously (the menopause being the cessation of periods).
If the degree of bleeding is mild, all that may be sought by the woman is the reassurance that there is no sinister underlying cause. If anaemia occurs then iron tablets may be used to help restore normal hemoglobin levels. Treatment may be given for a fixed period of time to replenish the body stores. Alternatively therapy may be continued long-term, often in a cyclical regimen on the days of menstruation.
The condition is often be treated with hormones, particularly as dysfunctional uterine bleeding commonly occurs in the early and late menstrual years when contraception is also sought. Usually oral combined contraceptive or progesterone only pills may be taken for a few months, but for longer-term treatment the alternatives of injected Depo Provera or the more recent progesterone releasing IntraUterine System may be used. Fibroids may respond to hormonal treatment, else require surgical removal.
Anti-inflammatory medication has previously been used, although it has a greater effect on dysmenorrhoea excess pain than on the heaviness of the period (typically 30% reduction in flow). More effective is the use of tranexamic acid tablets that may reduce loss by up to 50%. This may be combined with hormonal medication previously mentioned.
A definitive treatment for menorrhagia is to perform hysterectomy (removal of the uterus). This historically has been associated with issues of male domination within medicine and patient's subservient roles. The risks of the procedure have been reduced with measures to reduce the risk of deep vein thrombosis after surgery, and the switch from the front abdominal to vaginal approach greatly minimising the discomfort and recuperation time for the patient; however extensive fibroids may make the womb too large for removal by the vaginal approach. Small fibroids may be dealt with by local removal (myomectomy). A further surgical technique is endometrial ablation (destruction) by the use of applied heat (thermoablation). A non-surgical approach has been the introduction and use of the IntraUterine System.
In the UK the use of hysterectomy for menorrhagia has been almost halved between 1989 and 2003. This has a number of causes: better medical management, endometrial ablation and particularly the introduction of IUS which may be inserted in the community and avoid the need for specialist referral; in one study up to 64% of women cancelled surgery.
## Treatment Options
NOTE: Management of bleeding in pregnancy requires gynaecology referral and potential hospital admission especially if bleeding does not stop or is substantial and surgical intervention is required.
Blood transfusions may be required for blood loss resulting in compromised hemodynamic stability.
Treatment options include pharmaceutical or surgical and radiological options:
These have been ranked by the UK's National Institute for Health and Clinical Excellence:Template:Ref label
- First line
IntraUterine System insertion
- IntraUterine System insertion
- Second Line
Tranexamic acid an antifibrinolytic agent
Non-steroidal anti-inflammatory drugs (NSAIDs)
Combined oral contraceptive pills to prevent proliferation of the endometrium
- Tranexamic acid an antifibrinolytic agent
- Non-steroidal anti-inflammatory drugs (NSAIDs)
- Combined oral contraceptive pills to prevent proliferation of the endometrium
- Third line
Oral progestogen (e.g. norethisterone), to prevent proliferation of the endometrium
Injected progestogen (e.g. Depo provera)
- Oral progestogen (e.g. norethisterone), to prevent proliferation of the endometrium
- Injected progestogen (e.g. Depo provera)
- Other options
Gonadotrophin-releasing hormone (GnRH) agonists (e.g. Goserelin)
- Gonadotrophin-releasing hormone (GnRH) agonists (e.g. Goserelin)
- Dilation and curettage (D&C) is no longer performed for cases of simple menorrhagia, having a reserved role if a spontaneous abortion is incomplete
- Endometrial ablation
- Uterine artery embolisation (UAE)
- Hysteroscopic myomectomy to remove fibroids over 3 cm in diameter
- Hysterectomy | Menorrhagia
For patient information, click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Menorrhagia is an abnormally heavy and prolonged menstrual period at regular intervals. Causes may be due to abnormal blood clotting, disruption of normal hormonal regulation of periods or disorders of the endometrial lining of the uterus. Depending upon the cause, it may be associated with abnormally painful periods (dysmenorrhea).
# Definition
A normal menstrual cycle is 21-35 days in duration, with bleeding lasting an average of 5 days and total blood flow between 25 and 80 mL. A blood loss of greater than 80 ml or lasting longer than 7 days constitutes menorrhagia (also called hypermenorrhea). In practice this is not usually directly measured by patients or doctors. Menorrhagia also occurs at predictable and normal (usually about 28 days) intervals, distinguishing it from menometrorrhagia, which occurs at irregular and more frequent intervals. It is possible to estimate the amount of bleeding by the number of tampons or pads a woman uses during her period. As a guide a regular tampon fully soaked will hold about 5ml of blood.
# Complications
Aside from the social distress of dealing with a prolonged and heavy period, over time the blood loss may prove to be greater than the body iron reserves or the rate of blood replenishment, leading to anemia. Symptoms attributable to the anemia may include tiredness, weakness, tingling and numbness in fingers and toes, headaches, depression, becoming cold more easily, and poor concentration.
# Etiology
Usually no causative abnormality can be identified and treatment is directed at the symptom, rather than a specific mechanism. A brief overview of causes is given below, followed by a more formal medical list based on the nature of the menstrual cycle experienced.
## Disorders of coagulation
With the shedding of the endometrial lining's blood vessels, normal coagulation process must occur to limit and eventually stop the blood flow. Blood disorders of platelets (such as ITP) or coagulation (such as von Willebrand disease) or use of anticoagulant medication (such as warfarin) are therefore possible causes, although a rare minority of cases.
## Excessive build up in endometrial lining
Periods soon after the onset of menstruation in girls (the menarche) and just before menopause may in some women be particularly heavy. Hormonal disorders involving the ovaries-pituitary-hypothalamus (the 'ovarian endocrine axis') account for many cases, and hormonal-based treatments may regulate effectively.
The lining of the womb builds up naturally under the hormonal effects of pregnancy, and an early spontaneous miscarriage may be mistaken for a heavier than normal period.
Irritation of the endometrium may result in increased blood flow, e.g. from infection (acute or chronic pelvic inflammatory disease) or the contraceptive intrauterine device (note the distinction from the IntraUterine System which is used to treat this condition).
Fibroids in the wall of the womb sometimes can cause increase menstrual loss if they protrude into the central cavity and so thereby increase endometrium's surface area.
Abnormalities of the endometrium such as adenomyosis (so called "internal endometriosis") where there is extension into the wall of the womb gives rise to enlarged tender uterus. Note, true endometriosis is a cause of pain (dysmenorrhoea) but usually not alteration in menstrual blood loss.
Endometrial carcinoma (cancer of the uterine lining) usually causes irregular bleeding, rather than the cyclical pattern of menorrhagia. Bleeding in between periods (intermenstrual bleeding or IMB) or after the menopause (postmenopausal bleeding or PMB) should always be considered suspicious.
## Consideration by nature of the menstrual cycle
- Excessive menses but normal cycle:
Painless:
Fibroids
Ovarian endocrine disorder (dysfunctional uterine bleeding or DUB)(the most common cause)
Coagulation defects (rare)
Painful:
Pelvic inflammatory disease
Endometriosis
- Painless:
Fibroids
Ovarian endocrine disorder (dysfunctional uterine bleeding or DUB)(the most common cause)
Coagulation defects (rare)
- Fibroids
- Ovarian endocrine disorder (dysfunctional uterine bleeding or DUB)(the most common cause)
- Coagulation defects (rare)
- Painful:
Pelvic inflammatory disease
Endometriosis
- Pelvic inflammatory disease
- Endometriosis
- Short cycle (<21 days) but normal menses (epimenorrhoea or polymenorrhoea). These are always anovulatory cycles due to hormonal disorders.
- Short cycle and excessive menses (epimenorrhagia) due to ovarian dysfunction and may be secondary to blockage of blood vessels by tumours.
- Excessive menses and long intervals.
Anovular ovarian disorder due to prolonged oestrogen production.
This may occur following prolonged continuous courses of the combined oral contraceptive pill (e.g. where several packets are taken without a withdrawal gap in order to defer menstruation).
- Anovular ovarian disorder due to prolonged oestrogen production.
- This may occur following prolonged continuous courses of the combined oral contraceptive pill (e.g. where several packets are taken without a withdrawal gap in order to defer menstruation).
## Differential Diagnosis
- Pregnancy complications:
Ectopic pregnancy
Incomplete abortion
Miscarriage
Threatened abortion
- Ectopic pregnancy
- Incomplete abortion
- Miscarriage
- Threatened abortion
- Nonuterine bleeding:
Cervical ectropion/erosion
Cervical neoplasia/polyp
Cervical or vaginal trauma
Condylomata
Atrophic vaginitis
Foreign bodies
- Cervical ectropion/erosion
- Cervical neoplasia/polyp
- Cervical or vaginal trauma
- Condylomata
- Atrophic vaginitis
- Foreign bodies
- Pelvic inflammatory disease (PID):
Endometritis
Tuberculosis
- Endometritis
- Tuberculosis
- Hypothyroidism
## Risk Factors
- Obesity
- Anovulation
- Estrogen administration (without progestogens)
- Prior treatment with progestational agents or oral contraceptives increases the risk of endometrial atrophy, but decreases the risk of endometrial hyperplasia or neoplasia
## Drug Side Effect
- Estradiol valerate and estradiol valerate/dienogest
- Misoprostol
- Olsalazine
## ICD-9 codes
# Investigation
- Pelvic and rectal examination
- Pap smear
- Pelvic ultrasound scan is the first line diagnostic tool for identifying structural abnormalities.[2]
- Endometrial biopsy to exclude endometrial cancer or atypical hyperplasia
- Hysteroscopy
# Treatment
Where an underlying cause can be identified, treatment may be directed at this. Clearly heavy periods at the start and end of a women's reproductive years may settle spontaneously (the menopause being the cessation of periods).
If the degree of bleeding is mild, all that may be sought by the woman is the reassurance that there is no sinister underlying cause. If anaemia occurs then iron tablets may be used to help restore normal hemoglobin levels. Treatment may be given for a fixed period of time to replenish the body stores. Alternatively therapy may be continued long-term, often in a cyclical regimen on the days of menstruation.
The condition is often be treated with hormones, particularly as dysfunctional uterine bleeding commonly occurs in the early and late menstrual years when contraception is also sought. Usually oral combined contraceptive or progesterone only pills may be taken for a few months, but for longer-term treatment the alternatives of injected Depo Provera or the more recent progesterone releasing IntraUterine System may be used. Fibroids may respond to hormonal treatment, else require surgical removal.
Anti-inflammatory medication has previously been used, although it has a greater effect on dysmenorrhoea excess pain than on the heaviness of the period (typically 30% reduction in flow). More effective is the use of tranexamic acid tablets that may reduce loss by up to 50%. This may be combined with hormonal medication previously mentioned.
A definitive treatment for menorrhagia is to perform hysterectomy (removal of the uterus). This historically has been associated with issues of male domination within medicine and patient's subservient roles. The risks of the procedure have been reduced with measures to reduce the risk of deep vein thrombosis after surgery, and the switch from the front abdominal to vaginal approach greatly minimising the discomfort and recuperation time for the patient; however extensive fibroids may make the womb too large for removal by the vaginal approach. Small fibroids may be dealt with by local removal (myomectomy). A further surgical technique is endometrial ablation (destruction) by the use of applied heat (thermoablation). A non-surgical approach has been the introduction and use of the IntraUterine System.
In the UK the use of hysterectomy for menorrhagia has been almost halved between 1989 and 2003[3]. This has a number of causes: better medical management, endometrial ablation and particularly the introduction of IUS[4][5] which may be inserted in the community and avoid the need for specialist referral; in one study up to 64% of women cancelled surgery[6].
## Treatment Options
NOTE: Management of bleeding in pregnancy requires gynaecology referral and potential hospital admission especially if bleeding does not stop or is substantial and surgical intervention is required.
Blood transfusions may be required for blood loss resulting in compromised hemodynamic stability.
Treatment options include pharmaceutical or surgical and radiological options:
These have been ranked by the UK's National Institute for Health and Clinical Excellence:Template:Ref label
- First line
IntraUterine System insertion
- IntraUterine System insertion
- Second Line
Tranexamic acid an antifibrinolytic agent
Non-steroidal anti-inflammatory drugs (NSAIDs)
Combined oral contraceptive pills to prevent proliferation of the endometrium
- Tranexamic acid an antifibrinolytic agent
- Non-steroidal anti-inflammatory drugs (NSAIDs)
- Combined oral contraceptive pills to prevent proliferation of the endometrium
- Third line
Oral progestogen (e.g. norethisterone), to prevent proliferation of the endometrium
Injected progestogen (e.g. Depo provera)
- Oral progestogen (e.g. norethisterone), to prevent proliferation of the endometrium
- Injected progestogen (e.g. Depo provera)
- Other options
Gonadotrophin-releasing hormone (GnRH) agonists (e.g. Goserelin)
- Gonadotrophin-releasing hormone (GnRH) agonists (e.g. Goserelin)
- Dilation and curettage (D&C) is no longer performed for cases of simple menorrhagia, having a reserved role if a spontaneous abortion is incomplete
- Endometrial ablation
- Uterine artery embolisation (UAE)
- Hysteroscopic myomectomy to remove fibroids over 3 cm in diameter
- Hysterectomy | https://www.wikidoc.org/index.php/Hypermenorrhea | |
b218bf110d7c5b12022ffa399c8ecd268e6ebb9a | wikidoc | Hyperpathia | Hyperpathia
# Overview
Hyperpathia is a clinical symptom of certain neurological disorders wherein the patient experiences a greatly exaggerated pain sensation to nociceptive stimuli. This can be contrasted from allodynia in which the patient feels painful sensations from stimuli which are not painful to normal individuals.
# Mechanism
Hyperpathia describes the neuropathic pain which the pain threshold on one hand is elevated and the other hand is central hyperexcited whenever there is a loss of fibres. Hyperpathia is underlying the peripheral or central deafferentation when the afferent inputs are lost. Hyperpathia only occurs on neuropathic pain patients with the loss of fibres.
The International Association of the Study of Pain’s (IASP) definition of hyperpathia is that: A painful syndrome characterized by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased threshold. The definition also complies with a note which is: It may occur with allodynia, hyperesthesia, hyperalgesia, or dysesthesia. Faulty identification and localization of the stimulus, delay, radiating sensation, and after-sensation may be present, and the pain is often explosive in character. The changes in this note are the specification of allodynia and the inclusion of hyperalgesia explicitly. Previously hyperalgesia was implied, since hyperesthesia was mentioned in the previous note and hyperalgesia is a special case of hyperesthesia. | Hyperpathia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Hyperpathia is a clinical symptom of certain neurological disorders wherein the patient experiences a greatly exaggerated pain sensation to nociceptive stimuli. This can be contrasted from allodynia in which the patient feels painful sensations from stimuli which are not painful to normal individuals.
# Mechanism
Hyperpathia describes the neuropathic pain which the pain threshold on one hand is elevated and the other hand is central hyperexcited whenever there is a loss of fibres. Hyperpathia is underlying the peripheral or central deafferentation when the afferent inputs are lost.[1] Hyperpathia only occurs on neuropathic pain patients with the loss of fibres.
The International Association of the Study of Pain’s (IASP) definition of hyperpathia is that: A painful syndrome characterized by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased threshold. The definition also complies with a note which is: It may occur with allodynia, hyperesthesia, hyperalgesia, or dysesthesia. Faulty identification and localization of the stimulus, delay, radiating sensation, and after-sensation may be present, and the pain is often explosive in character. The changes in this note are the specification of allodynia and the inclusion of hyperalgesia explicitly. Previously hyperalgesia was implied, since hyperesthesia was mentioned in the previous note and hyperalgesia is a special case of hyperesthesia.[2] | https://www.wikidoc.org/index.php/Hyperpathia | |
ad991b57d54c03c4c4b1b94a6543f83e5fe9c1ee | wikidoc | Hypertropia | Hypertropia
Hypertropia is a condition of misalignment of the eyes (strabismus), whereby the visual axis of one eye is higher than the fellow fixating eye.
Hypotropia is the similar condition, focus being on the eye with the visual axis lower than the fellow fixating eye.
Dissociated vertical deviation is a special type of hypertropia leading to slow upward drift of one or rarely both eyes, usually when the patient is inattentive.
# Etiology
Hypertropia may be either congenital or acquired, and misalignment is due to imbalance in extraocular muscle function. The superior rectus, inferior rectus, superior oblique, and inferior oblique muscles affect the vertical movement of the eyes. These muscles may be either paretic, restrictive (fibrosis) or overactive effect of the muscles. Congenital cases may have developmental abnormality due to abnormal muscle structure, usually muscle atrophy / hypertrophy or rarely, absence of the muscle and incorrect placement.
Specific & common causes include:
- Superior Oblique Palsy / Congenital fourth nerve palsy
- Inferior Oblique overaction
- Brown's Syndrome
- Duane's Retraction Syndrome
- Double elevator palsy
- Fibrosis of rectus muscle in Graves Disease (most commonly inferior rectus is involved)
- Surgical trauma to the vertical muscles (e.g. during scleral buckling surgery or cataract surgery causing iatrogenic trauma to the vertical muscles).
Sudden onset hypertropia in a middle aged or elderly adult may be due to compression of the trochlear nerve and mass effect from a tumor, requiring urgent brain imaging using MRI to localise any space occupying lesion. It could also be due to infarction of blood vessels supplying the nerve, due to diabetes and atherosclerosis.
# Associated defects
Refractive errors such as hyperopia and Anisometropia may be associated abnormalities found in patients with vertical strabismus.
The vertical miscoordination between the two eyes may lead to
- Strabismic amblyopia, (due to deprivation / suppression of the deviating eye)
- cosmetic defect (most noticed by parents of a young child and in photographs)
- Face turn, depending on presence of binocular vision in a particular gaze
- diplopia or double vision - more seen in adults (maturity / plasticity of neural pathways) and suppression mechanisms of the brain in sorting out the images from the two eyes.
- Cyclotorsional deviation of the eyes (rotation around the visual axis), particularly when the root cause is an oblique muscle paresis causing the hypertropia.
# Treatment
In general, strabismus can be approached and treated with a variety of procedures. Depending on the individual case, treatment options include:
- Correction of refractive errors by Glasses
- Prism therapy (if tolerated, to manage diplopia)
- Patching (mainly to manage amblyopia in children and diplopia in adults)
- Botulinum Toxin Botox injection
- Surgical correction
Surgical correction of the hypertropia is desired to achieve binocularity, manage diplopia and/or correct the cosmetic defect. Steps to achieve the same depend on mechanism of the hypertropia and identification of the offending muscles causing the misalignment. Various surgical procedures have been described and should be offered after careful examination of eyes, including a detailed orthoptic examination focussing on the disturbances in ocular motility and visual status. Specialty fellowship trained pediatric ophthalmologists and strabismus surgeons are best equipped to deal with these complex procedures. | Hypertropia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Hypertropia is a condition of misalignment of the eyes (strabismus), whereby the visual axis of one eye is higher than the fellow fixating eye.
Hypotropia is the similar condition, focus being on the eye with the visual axis lower than the fellow fixating eye.
Dissociated vertical deviation is a special type of hypertropia leading to slow upward drift of one or rarely both eyes, usually when the patient is inattentive.
# Etiology
Hypertropia may be either congenital or acquired, and misalignment is due to imbalance in extraocular muscle function. The superior rectus, inferior rectus, superior oblique, and inferior oblique muscles affect the vertical movement of the eyes. These muscles may be either paretic, restrictive (fibrosis) or overactive effect of the muscles. Congenital cases may have developmental abnormality due to abnormal muscle structure, usually muscle atrophy / hypertrophy or rarely, absence of the muscle and incorrect placement.
Specific & common causes include:
- Superior Oblique Palsy / Congenital fourth nerve palsy
- Inferior Oblique overaction
- Brown's Syndrome
- Duane's Retraction Syndrome
- Double elevator palsy
- Fibrosis of rectus muscle in Graves Disease (most commonly inferior rectus is involved)
- Surgical trauma to the vertical muscles (e.g. during scleral buckling surgery or cataract surgery causing iatrogenic trauma to the vertical muscles).
Sudden onset hypertropia in a middle aged or elderly adult may be due to compression of the trochlear nerve and mass effect from a tumor, requiring urgent brain imaging using MRI to localise any space occupying lesion. It could also be due to infarction of blood vessels supplying the nerve, due to diabetes and atherosclerosis.
# Associated defects
Refractive errors such as hyperopia and Anisometropia may be associated abnormalities found in patients with vertical strabismus.
The vertical miscoordination between the two eyes may lead to
- Strabismic amblyopia, (due to deprivation / suppression of the deviating eye)
- cosmetic defect (most noticed by parents of a young child and in photographs)
- Face turn, depending on presence of binocular vision in a particular gaze
- diplopia or double vision - more seen in adults (maturity / plasticity of neural pathways) and suppression mechanisms of the brain in sorting out the images from the two eyes.
- Cyclotorsional deviation of the eyes (rotation around the visual axis), particularly when the root cause is an oblique muscle paresis causing the hypertropia.
# Treatment
In general, strabismus can be approached and treated with a variety of procedures. Depending on the individual case, treatment options include:
- Correction of refractive errors by Glasses
- Prism therapy (if tolerated, to manage diplopia)
- Patching (mainly to manage amblyopia in children and diplopia in adults)
- Botulinum Toxin Botox injection
- Surgical correction
Surgical correction of the hypertropia is desired to achieve binocularity, manage diplopia and/or correct the cosmetic defect. Steps to achieve the same depend on mechanism of the hypertropia and identification of the offending muscles causing the misalignment. Various surgical procedures have been described and should be offered after careful examination of eyes, including a detailed orthoptic examination focussing on the disturbances in ocular motility and visual status. Specialty fellowship trained pediatric ophthalmologists and strabismus surgeons are best equipped to deal with these complex procedures. | https://www.wikidoc.org/index.php/Hypertropia | |
7241dec74c167fbadc85738ee4cee31d4a3dd3e4 | wikidoc | Hypnic jerk | Hypnic jerk
# Overview
A hypnic or hypnagogic jerk is an involuntary muscle twitch (commonly known as a myoclonic twitch) which occurs during the transition into hypnagogia.
It is often described as an electric shock or falling sensation, and can cause movement of the body in bed. Hypnic jerks are experienced by most people, especially when exhausted or sleeping uncomfortably.
# Occurrence
Hypnic jerks are usually felt once or twice per night. More regular, and usually less intense, hypnic jerks often occur during normal sleep. In extreme cases, this may be classified as a disorder called periodic limb movement. The person with the disorder will usually sleep through the events.
When a subject is deprived of sleep and is trying to fight sleep, hypnic jerks can occur more often. This normally happens to subjects who have deprived themselves of sleep for longer than 24 hours, or to those who have recently woken up from insufficient amounts of sleep. | Hypnic jerk
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A hypnic or hypnagogic jerk is an involuntary muscle twitch (commonly known as a myoclonic twitch) which occurs during the transition into hypnagogia.
It is often described as an electric shock or falling sensation, and can cause movement of the body in bed. Hypnic jerks are experienced by most people, especially when exhausted or sleeping uncomfortably.
# Occurrence
Hypnic jerks are usually felt once or twice per night. More regular, and usually less intense, hypnic jerks often occur during normal sleep. In extreme cases, this may be classified as a disorder called periodic limb movement. The person with the disorder will usually sleep through the events.
When a subject is deprived of sleep and is trying to fight sleep, hypnic jerks can occur more often. This normally happens to subjects who have deprived themselves of sleep for longer than 24 hours, or to those who have recently woken up from insufficient amounts of sleep. | https://www.wikidoc.org/index.php/Hypnic_jerk | |
7eabd411c9c74a21f77c729c6bd4d410f06088fc | wikidoc | Hypoalgesia | Hypoalgesia
Hypoalgesia or hypalgesia denotes a decreased sensitivity to painful stimuli.
Hypoalgesia occurs when nociceptive (painful) stimuli are interrupted or decreased somewhere along the path between the input (nociceptors), and the places where they are processed and recognized as pain in the conscious mind. Hypoalgesic effects can be mild, such as massaging a stubbed toe to make it hurt less or taking aspirin to decrease a headache, or they can be severe, like being under strong anesthesia. Hypoalgesia can be caused by exogenous chemicals such as opioids, as well as by chemicals produced by the body in phenomenon such as fear- and exercise- induced hypoalgesia Hypoalgesia can also be associated with diseases, such as CIPA or in less severe cases with diabetes or other diseases associated with hypertension.
# Chemical causes
## Analgesics
Analgesics are a class of biochemicals that cause hypoalgesia. Analgesics can act on both the peripheral and central nervous systems to decrease pain. Certain analgesics also work to decrease the source of the pain by working to decrease swelling an inflammation, as in the case of NSAIDs.
## Opioids
Opioids refers to a specific group of analgesics - including morphine, codeine, and opium - that act on opioid receptors, which are located mainly in the central nervous system.
Endogenous opioids types of opioids produced by the body specifically to modulate pain. They include endorphins, enkephalins, dynorphins and endomorphins. These proteins are especially important for modulating pain in response to the environment. These can be released in response to a number of things, including increased blood pressure, pain and danger. It has been found that endogenous opioids are at least partially responsible for phenomena like “Runner’s high”, hypoalgesia in the fight-or-flight response, and even for the analgesic effects of acupuncture therapy. In all these cases, there is a certain level of signal processing that occurs in the CNS which leads to the release of these chemicals.
## Exercise induced hypoalgesia
There has been a great deal of research examining the link between exercise and hypoalgesia. Many studies have shown the direct link between the two by subjecting patients to exercise and rating their pain responses, but despite the great deal of research, the mechanism of action is still poorly understood. It has been shown that the triggering mechanism for the hypoalgesic effects is the increase in blood pressure that accompanies a good workout. The body senses the increased blood pressure, and it is hypothesized that in response, endogenous opioids are released . This hypothesis is well supported in human research, and it has been verified that it plays a part, but animal research implies that other mechanisms are also involved.
## Fear induced hypoalgesia
Fear induced hypoalgesia is another example of a mechanism controlled by opioids. It is postulated that fear is a defense mechanism that has evolved over time to provide protection. In the case of hypoalgesia, a decreased response to pain would be very beneficial in a situation where an organism’s life was at stake, since feeling pain would be a hindrance rather than a help. It has been well documented that fear does cause a decrease in pain response, however much like the exercise induced hypoalgesia, the exact mechanisms of action are not well understood. Studies have shown that opioids are definitely involved in the process, yet opiates alone do not completely explain the analgesic response. What the other mechanisms of action are is still unknown.
# Diseases
It has been demonstrated that many diseases can cause hypoalgesia. Some diseases, like CIPA, are hereditary disorders where genes essential for the correct functioning of nociceptors no longer work. There are many diseases like this, and they all fall under the category of hereditary sensory autonomic neuropathies. Alternatively, some diseases affect other functions in your body, which can activate the pathways that cause hypoalgesia. This effect happens in people with diabetes and other diseases associated with hypertension.
## Hereditary neuropathies
Hereditary sensory autonomic neuropathies (HSAN) (like CIPA), are hereditary disorders that are characterized by malfunctioning or nonfunctioning pain receptors. Most of these diseases are also associated with decreased temperature sensation as well. In some cases these diseases are also associated with other symptoms like mental retardation and diminished production of sweat and tears. Diseases like this can be very dangerous for the patients, because they are not able to judge what hurts, and therefore when they should stop doing something. A child with the disease might bite their finger clean off before they realized that what they were doing might harm them, or they might leave their hand on a hot stove without ever realizing it was on. Diseases like this show just how beneficial feeling pain is for our survival.
## Hypoalgesia and hypertension
Many studies have shown that hypertension in patients can cause hypoalgesia. Diseases like diabetes, which are associated with hypertension are also associated with hypoalgesia. Just like in Exercise-Induced Hypoalgesia, the increased blood pressure of hypertension works as a signal to the body to release opioids and activate other pain modulation pathways. Also, although the area is not widely studied, there is evidence that this is not the only cause. Diseases may lead to activation of any of these mechanisms, just like diabetes causing hypertension. A full study of the pathways regulating pain is desperately needed. | Hypoalgesia
Template:Distinguish2
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Hypoalgesia or hypalgesia denotes a decreased sensitivity to painful stimuli.
Hypoalgesia occurs when nociceptive (painful) stimuli are interrupted or decreased somewhere along the path between the input (nociceptors), and the places where they are processed and recognized as pain in the conscious mind. Hypoalgesic effects can be mild, such as massaging a stubbed toe to make it hurt less or taking aspirin to decrease a headache, or they can be severe, like being under strong anesthesia. Hypoalgesia can be caused by exogenous chemicals such as opioids, as well as by chemicals produced by the body in phenomenon such as fear- and exercise- induced hypoalgesia Hypoalgesia can also be associated with diseases, such as CIPA or in less severe cases with diabetes or other diseases associated with hypertension.
# Chemical causes
## Analgesics
Analgesics are a class of biochemicals that cause hypoalgesia. Analgesics can act on both the peripheral and central nervous systems to decrease pain. Certain analgesics also work to decrease the source of the pain by working to decrease swelling an inflammation, as in the case of NSAIDs[1].
## Opioids
Opioids refers to a specific group of analgesics - including morphine, codeine, and opium - that act on opioid receptors, which are located mainly in the central nervous system.
Endogenous opioids types of opioids produced by the body specifically to modulate pain. They include endorphins, enkephalins, dynorphins and endomorphins. These proteins are especially important for modulating pain in response to the environment. These can be released in response to a number of things, including increased blood pressure, pain and danger. It has been found that endogenous opioids are at least partially responsible for phenomena like “Runner’s high”, hypoalgesia in the fight-or-flight response, and even for the analgesic effects of acupuncture therapy[2]. In all these cases, there is a certain level of signal processing that occurs in the CNS which leads to the release of these chemicals.
## Exercise induced hypoalgesia
There has been a great deal of research examining the link between exercise and hypoalgesia. Many studies have shown the direct link between the two by subjecting patients to exercise and rating their pain responses, but despite the great deal of research, the mechanism of action is still poorly understood. It has been shown that the triggering mechanism for the hypoalgesic effects is the increase in blood pressure that accompanies a good workout. The body senses the increased blood pressure, and it is hypothesized that in response, endogenous opioids are released [3]. This hypothesis is well supported in human research, and it has been verified that it plays a part, but animal research implies that other mechanisms are also involved[4].
## Fear induced hypoalgesia
Fear induced hypoalgesia is another example of a mechanism controlled by opioids. It is postulated that fear is a defense mechanism that has evolved over time to provide protection. In the case of hypoalgesia, a decreased response to pain would be very beneficial in a situation where an organism’s life was at stake, since feeling pain would be a hindrance rather than a help. It has been well documented that fear does cause a decrease in pain response[5], however much like the exercise induced hypoalgesia, the exact mechanisms of action are not well understood. Studies have shown that opioids are definitely involved in the process, yet opiates alone do not completely explain the analgesic response[6][7]. What the other mechanisms of action are is still unknown.
# Diseases
It has been demonstrated that many diseases can cause hypoalgesia. Some diseases, like CIPA, are hereditary disorders where genes essential for the correct functioning of nociceptors no longer work. There are many diseases like this, and they all fall under the category of hereditary sensory autonomic neuropathies. Alternatively, some diseases affect other functions in your body, which can activate the pathways that cause hypoalgesia. This effect happens in people with diabetes and other diseases associated with hypertension.
## Hereditary neuropathies
Hereditary sensory autonomic neuropathies (HSAN) (like CIPA), are hereditary disorders that are characterized by malfunctioning or nonfunctioning pain receptors[8]. Most of these diseases are also associated with decreased temperature sensation as well. In some cases these diseases are also associated with other symptoms like mental retardation and diminished production of sweat and tears. Diseases like this can be very dangerous for the patients, because they are not able to judge what hurts, and therefore when they should stop doing something. A child with the disease might bite their finger clean off before they realized that what they were doing might harm them, or they might leave their hand on a hot stove without ever realizing it was on. Diseases like this show just how beneficial feeling pain is for our survival.
## Hypoalgesia and hypertension
Many studies have shown that hypertension in patients can cause hypoalgesia[9][10]. Diseases like diabetes, which are associated with hypertension are also associated with hypoalgesia. Just like in Exercise-Induced Hypoalgesia, the increased blood pressure of hypertension works as a signal to the body to release opioids and activate other pain modulation pathways. Also, although the area is not widely studied, there is evidence that this is not the only cause. Diseases may lead to activation of any of these mechanisms, just like diabetes causing hypertension. A full study of the pathways regulating pain is desperately needed. | https://www.wikidoc.org/index.php/Hypoalgesia | |
d585f6da8b7d0fce421d96116bf586f769fdb242 | wikidoc | Hypokinesia | Hypokinesia
# Overview
Hypokinesia refers to slow or diminished movement of body musculature. It may be associated with basal ganglia diseases; mental disorders; prolonged inactivity due to illness; experimental protocols used to evaluate the physiologic effects of immobility; and other conditions.
There are 4 types of this disorder:
- Bradykinesia: this is the slowness of movement and has been linked to Parkinson Disease
- Freezing: this is when you can't move your muscles how you want them too.
- Rigidity: the increase in muscle tension when moved by an outside force
- Postural instability: loss of ability to maintain an upright posture.
# Causes
## Common Causes
- Encephalitis
- Functional disorders
- Parkinsonism
- Parkinson's disease
- Primary affective disorder
## Causes by Organ System
## Causes in Alphabetical Order
- Bokhoror
- Dopamine depletion
- Dystonia 12
- Estazolam
- Functional disorders
- Inhibition of cortex glutamate
- Inhibition of gaba
- Pallidopyramidal syndrome
- Parkinson disease
- Parkinsonism
- Parkinson's disease
- Primary affective disorder
- Progressive supranuclear palsy
- Psychogenic movement disorders
- Viliuisk encephalitis
- Viliuisk encephalomyelitis
- Westphal disease | Hypokinesia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Luke Rusowicz-Orazem, B.S.
# Overview
Hypokinesia refers to slow or diminished movement of body musculature. It may be associated with basal ganglia diseases; mental disorders; prolonged inactivity due to illness; experimental protocols used to evaluate the physiologic effects of immobility; and other conditions.
There are 4 types of this disorder:[1] [2]
- Bradykinesia: this is the slowness of movement and has been linked to Parkinson Disease
- Freezing: this is when you can't move your muscles how you want them too.
- Rigidity: the increase in muscle tension when moved by an outside force
- Postural instability: loss of ability to maintain an upright posture.
# Causes
## Common Causes
- Encephalitis
- Functional disorders
- Parkinsonism
- Parkinson's disease
- Primary affective disorder
## Causes by Organ System
## Causes in Alphabetical Order
- Bokhoror
- Dopamine depletion
- Dystonia 12
- Estazolam
- Functional disorders
- Inhibition of cortex glutamate
- Inhibition of gaba
- Pallidopyramidal syndrome
- Parkinson disease
- Parkinsonism
- Parkinson's disease
- Primary affective disorder
- Progressive supranuclear palsy
- Psychogenic movement disorders
- Viliuisk encephalitis
- Viliuisk encephalomyelitis
- Westphal disease | https://www.wikidoc.org/index.php/Hypokinesia | |
f8205cccf886662e0a8e6a9dd536ddadb5a3b49e | wikidoc | Micromastia | Micromastia
# Overview
Micromastia, or breast hypoplasia, is a medical term describing the postpubertal underdevelopment of a woman's breast tissue. Just as it is impossible to define 'normal' breast size, there is no objective definition of micromastia. This condition may be a congenital defect as in the case of true hypoplasia, related to underlying abnormalities of the pectoral muscle (as in Poland's syndrome), or it may be a more subjective aesthetic description.
Self perceived micromastia involves a discrepancy between a person's body image, and her internalized images of appropriate or desirable breast size and shape. Societal ideals over breast size vary over time, but there exist many conceived ideas involving breasts and sexual attractiveness and identity across different cultures.
The procedure to remedy micromastia is most commonly augmentation mammplasty using breast implants. Other techniques available involve using muscle flap-based reconstructive surgery techniques (latissimus dorsi and rectus abdominus muscles), microsurgical reconstruction, or fat grafting. | Micromastia
Template:DiseaseDisorder infobox
# Overview
Micromastia, or breast hypoplasia, is a medical term describing the postpubertal underdevelopment of a woman's breast tissue.[1] Just as it is impossible to define 'normal' breast size, there is no objective definition of micromastia. This condition may be a congenital defect as in the case of true hypoplasia, related to underlying abnormalities of the pectoral muscle (as in Poland's syndrome[2]), or it may be a more subjective aesthetic description.
Self perceived micromastia involves a discrepancy between a person's body image, and her internalized images of appropriate or desirable breast size and shape. Societal ideals over breast size vary over time, but there exist many conceived ideas involving breasts and sexual attractiveness and identity across different cultures.
The procedure to remedy micromastia is most commonly augmentation mammplasty using breast implants. Other techniques available involve using muscle flap-based reconstructive surgery techniques (latissimus dorsi and rectus abdominus muscles), microsurgical reconstruction, or fat grafting. | https://www.wikidoc.org/index.php/Hypoplasia_of_breast | |
07156dd172aa9410c7e97c13c9a1bb5a8d86fa51 | wikidoc | Hypospermia | Hypospermia
Hypospermia is the medical term when a man has an unusually low ejaculate (or semen) volume. It should not be confused with azoospermia, which means low sperm count.
Normal ejaculate when a man is not drained from prior sex and is suitably aroused, is around 2 - 6 ml, although this varies greatly with mood, physical condition and sexual activity. Of this, around 1% by volume only is sperm cells. Hypospermia, a semen volume of under 1.5 ml, would only usually be a factor in infertility if the two conditions are combined.
The presence of high levels of fructose (a sugar) is normal in the semen and this comes almost entirely from the seminal vesicles. Obstruction of this accessory gland will result in low semen volumes since the seminal vesicles normally produce 70% of the seminal plasma. A test that showed low fructose levels combined with a low semen volume would therefore suggest an obstruction in this part of the body. | Hypospermia
Hypospermia is the medical term when a man has an unusually low ejaculate (or semen) volume. It should not be confused with azoospermia, which means low sperm count.
Normal ejaculate when a man is not drained from prior sex and is suitably aroused, is around 2 - 6 ml, although this varies greatly with mood, physical condition and sexual activity. Of this, around 1% by volume only is sperm cells. Hypospermia, a semen volume of under 1.5 ml, would only usually be a factor in infertility if the two conditions are combined.
The presence of high levels of fructose (a sugar) is normal in the semen and this comes almost entirely from the seminal vesicles. Obstruction of this accessory gland will result in low semen volumes since the seminal vesicles normally produce 70% of the seminal plasma. A test that showed low fructose levels combined with a low semen volume would therefore suggest an obstruction in this part of the body. [1]
Template:Disease-stub
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Hypospermia | |
e8c7875cf2f315d7b7628dc9afcded8fdc618bfa | wikidoc | ICPC-2 PLUS | ICPC-2 PLUS
# Overview
ICPC-2 PLUS is an extended terminology classified to ICPC-2 International Classification of Primary Care, which aids data entry, retrieval and analysis. ICPC-2 PLUS takes into account the frequency distribution of problems seen in primary care. It allows for the classification of the patient’s reason for encounter (RFE), the problems/diagnosis managed, primary care interventions, and the ordering of the data of the primary care session in an episode of care structure.
ICPC-2 PLUS provides a list of possible terms matching a keyword (or start of a keyword) entered by the user. The user then selects the most appropriate term. Each term is already classified to ICPC-2 rubrics and a system of additional groupers that may include terms from multiple ICPC-2 rubrics.
Each term has one or more keywords linked to it which may include abbreviations, synonyms, generics or specifics. The keyword searching is thus much broader, faster and better controlled than text mining of free text and labels. Instead of guessing what the doctor meant by a term (in free text) prior to classification, the doctor is actually prompted with a small list of terms to select from which are already classified.
The product also includes a 'natural language' label for each term which can be used for reports and letters.
Note: The PLUS extension mentioned here is not part of the ICPC-2 standard. WONCA and WICC have no control over it although they do have control over the ICPC classification which the PLUS extension makes use of. It’s similar to the difference between a car and fuel.
# History
ICPC-2 PLUS was the successor to 'ICPC PLUS' and were both designed by the Family Medicine Research Centre( FMRC]) for use in Australia. The FMRC continues to update and support ICPC-2 PLUS.
ICPC is being developed by the WONCA International Classification Committee (WICC), and the first version was published as ICPC-1 in 1987 by Oxford University Press (OUP), and a revision and inclusion of criteria and definitions, was published in 1998 as ICPC-2. | ICPC-2 PLUS
# Overview
ICPC-2 PLUS is an extended terminology classified to ICPC-2 International Classification of Primary Care, which aids data entry, retrieval and analysis. ICPC-2 PLUS takes into account the frequency distribution of problems seen in primary care. It allows for the classification of the patient’s reason for encounter (RFE), the problems/diagnosis managed, primary care interventions, and the ordering of the data of the primary care session in an episode of care structure.
ICPC-2 PLUS provides a list of possible terms matching a keyword (or start of a keyword) entered by the user. The user then selects the most appropriate term. Each term is already classified to ICPC-2 rubrics and a system of additional groupers that may include terms from multiple ICPC-2 rubrics.
Each term has one or more keywords linked to it which may include abbreviations, synonyms, generics or specifics. The keyword searching is thus much broader, faster and better controlled than text mining of free text and labels. Instead of guessing what the doctor meant by a term (in free text) prior to classification, the doctor is actually prompted with a small list of terms to select from which are already classified.
The product also includes a 'natural language' label for each term which can be used for reports and letters.
Note: The PLUS extension mentioned here is not part of the ICPC-2 standard. WONCA and WICC have no control over it although they do have control over the ICPC classification which the PLUS extension makes use of. It’s similar to the difference between a car and fuel.
# History
ICPC-2 PLUS was the successor to 'ICPC PLUS' and were both designed by the Family Medicine Research Centre([1] FMRC]) for use in Australia. The FMRC continues to update and support ICPC-2 PLUS.
ICPC is being developed by the WONCA International Classification Committee (WICC), and the first version was published as ICPC-1 in 1987 by Oxford University Press (OUP), and a revision and inclusion of criteria and definitions, was published in 1998 as ICPC-2. | https://www.wikidoc.org/index.php/ICPC-2_PLUS | |
29c6a82ff94906a0274adc96ae1596c2e48abf0f | wikidoc | IDEAL Trial | IDEAL Trial
# Objective
To compare the effects of two lipid lowering strategies (high dose atorvastatin and simvastatin 20 mg) on the risk of cardiovascular disease among patients with a previous myocardial infarction (MI).
# Methods
The Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL) trial was a prospective, randomized, open-label, blinded end-point evaluation trial which enrolled 8888 patients with past history of acute myocardial infarction, who were randomly assigned to treatment with high dose atorvastatin (80 mg) or simvastatin 20 mg. The primary endpoint was a major coronary event, defined as coronary death, confirmed nonfatal acute MI, or cardiac arrest with resuscitation.
# Results
After a median follow-up time of 4.8 years, compared with patients in simvastatin group those in atorvastatin group were associated with:
- Lower mean LDL-C levels (81 vs 104 mg/dL)
- Lowered primary end point rate (9.3% vs 10.4%)
- Lowered occurrence of any coronary event (898 vs 1059)
# Conclusion
Intensive lowering of LDL-C did not result in a significant reduction in the primary outcome of major coronary events, but did reduce the risk of other composite secondary end points and nonfatal acute MI. There were no differences in cardiovascular or all-cause mortality. | IDEAL Trial
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Objective
To compare the effects of two lipid lowering strategies (high dose atorvastatin [80 mg] and simvastatin 20 mg) on the risk of cardiovascular disease among patients with a previous myocardial infarction (MI).
# Methods
The Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL) trial was a prospective, randomized, open-label, blinded end-point evaluation trial which enrolled 8888 patients with past history of acute myocardial infarction, who were randomly assigned to treatment with high dose atorvastatin (80 mg) or simvastatin 20 mg. The primary endpoint was a major coronary event, defined as coronary death, confirmed nonfatal acute MI, or cardiac arrest with resuscitation.
# Results
After a median follow-up time of 4.8 years, compared with patients in simvastatin group those in atorvastatin group were associated with:
- Lower mean LDL-C levels (81 vs 104 mg/dL)
- Lowered primary end point rate (9.3% vs 10.4%)
- Lowered occurrence of any coronary event (898 vs 1059)
# Conclusion
Intensive lowering of LDL-C did not result in a significant reduction in the primary outcome of major coronary events, but did reduce the risk of other composite secondary end points and nonfatal acute MI. There were no differences in cardiovascular or all-cause mortality.[1][2] | https://www.wikidoc.org/index.php/IDEAL_Trial | |
c4558b5f84ad583a77861c9ba5d77926d41ecb6b | wikidoc | Phytic acid | Phytic acid
Phytic acid (known as inositol hexakisphosphate (IP6), or phytate when in salt form) is the principal storage form of phosphorus in many plant tissues, especially bran and seeds. Phosphorus in this form is generally not bioavailable to non-ruminant animals because they lack the digestive enzyme, phytase, required to separate phosphorus from the phytate molecule. On the other hand, ruminants readily utilize phytate because of the phytase produced by rumen microorganisms.
In most commercial agriculture, non-ruminant livestock such as swine and poultry are fed mainly grains such as soybeans and maize. Because phytate from these grains is unavailable for absorption, the unabsorbed phytate passes through the gastrointestinal tract, elevating the amount of phosphorus in the manure. Excess phosphorus excretion can lead to environmental problems such as eutrophication.
The bioavailability of phytate phosphorus can be increased by supplementation of the diet with phytase enzyme. Also, viable low phytic acid mutant lines have been developed in several crop species in which the seeds have drastically reduced levels of phytic acid and concomitant increases in inorganic phosphorus. However, reported germination problems have hindered the use of these cultivars thus far.
# Food science
Phytic acid is found within the hulls of nuts, seeds, and grains. In-home food preparation techniques can reduce the phytic acid in all of these foods. Simply cooking the food will reduce the phytic acid to some degree. More effective methods are soaking in an acid medium, lactic acid fermentation, and sprouting.
Phytic acid is a strong chelator of important minerals such as calcium, magnesium, iron and zinc and can therefore contribute to mineral deficiencies in people whose diets rely on these foods for their mineral intake such as those in developing countries. In this way, it is an anti-nutrient. For people with a particularly low intake of essential minerals, especially young children and those in developing countries, this effect can be undesirable.
Dietary mineral chelators helps, through reducing the available minerals, to prevent over-mineralization of joints, blood vessels, and other parts of the body, which is most common in older persons. They do not correct the disorder that causes this negative distribution of substances though, and can reduce the availability of these minerals for other essential processes.
# Therapeutic Use
Phytic acid may be considered a phytonutrient, providing an antioxidant effect.
Phytic acid's same mineral binding properties may also prevent colon cancer by reducing oxidative stress in the lumen of the intestinal tract. It may also reduce the risk of colon cancer. Researchers now believe that phytic acid, found in the fiber of legumes and grains, is the major ingredient responsible for preventing colon cancer and other cancers.
Phytic acid's chelating effect may serve to prevent, inhibit, or even cure some cancers by depriving those cells of the minerals (especially iron) they need to reproduce. The deprivation of essential minerals like iron would, much like other broad treatments for cancers, also have negative effects on non-cancerous cells. It is unknown if this would affect other cells in the body that require iron (such as red blood cells) or if the deprivation of minerals is more localized to the internal colon region.
Phytic acid has no known toxicity and is not known to cause mutagenic activity. It may have more therapeutic value when added to water rather than when naturally absorbed in foods as it is difficult to free from fiber.
Phytic acid is one of few chelating therapies for uranium removal.
As a food additive, phytic acid is used as a preservative with E number E391.
Food must be well cooked in order to free IP6 from the fiber and enable it to be absorbed in the system. IP6 rarely appears in soluble fiber. It's usually attached to the bran, the hard (insoluble) fiber, which is difficult to digest. IP6 is found in legumes, peas, wheat, barley, and oats. Of any studied legumes, whole soybeans have the highest levels of phytic acid.
Those who argue for the beneficial effects of phytic acid, and freeing it up for interaction with the system through cooking, do not argue that cooking destroys the phytic acid.This is a major deviation between those arguing for the merits of processed grain products. | Phytic acid
Template:Chembox new
Phytic acid (known as inositol hexakisphosphate (IP6), or phytate when in salt form) is the principal storage form of phosphorus in many plant tissues, especially bran and seeds.[1] Phosphorus in this form is generally not bioavailable to non-ruminant animals because they lack the digestive enzyme, phytase, required to separate phosphorus from the phytate molecule.[citation needed] On the other hand, ruminants readily utilize phytate because of the phytase produced by rumen microorganisms.[citation needed]
In most commercial agriculture, non-ruminant livestock such as swine and poultry are fed mainly grains such as soybeans and maize.[citation needed] Because phytate from these grains is unavailable for absorption, the unabsorbed phytate passes through the gastrointestinal tract, elevating the amount of phosphorus in the manure.[citation needed] Excess phosphorus excretion can lead to environmental problems such as eutrophication.[citation needed]
The bioavailability of phytate phosphorus can be increased by supplementation of the diet with phytase enzyme.[citation needed] Also, viable low phytic acid mutant lines have been developed in several crop species in which the seeds have drastically reduced levels of phytic acid and concomitant increases in inorganic phosphorus.[citation needed] However, reported germination problems have hindered the use of these cultivars thus far.[citation needed]
# Food science
Phytic acid is found within the hulls of nuts, seeds, and grains.[1] In-home food preparation techniques can reduce the phytic acid in all of these foods. Simply cooking the food will reduce the phytic acid to some degree. More effective methods are soaking in an acid medium, lactic acid fermentation, and sprouting.[2]
Phytic acid is a strong chelator of important minerals such as calcium, magnesium, iron and zinc and can therefore contribute to mineral deficiencies in people whose diets rely on these foods for their mineral intake such as those in developing countries.[3] In this way, it is an anti-nutrient.[1] For people with a particularly low intake of essential minerals, especially young children and those in developing countries, this effect can be undesirable.
Dietary mineral chelators helps, through reducing the available minerals, to prevent over-mineralization of joints, blood vessels, and other parts of the body, which is most common in older persons.[citation needed] They do not correct the disorder that causes this negative distribution of substances though, and can reduce the availability of these minerals for other essential processes.[citation needed]
# Therapeutic Use
Phytic acid may be considered a phytonutrient, providing an antioxidant effect.[4][1]
Phytic acid's same mineral binding properties may also prevent colon cancer by reducing oxidative stress in the lumen of the intestinal tract. It may also reduce the risk of colon cancer.[5] Researchers now believe that phytic acid, found in the fiber of legumes and grains, is the major ingredient responsible for preventing colon cancer and other cancers.[1][6]
Phytic acid's chelating effect may serve to prevent, inhibit, or even cure some cancers by depriving those cells of the minerals (especially iron) they need to reproduce.[1] The deprivation of essential minerals like iron would, much like other broad treatments for cancers, also have negative effects on non-cancerous cells. It is unknown if this would affect other cells in the body that require iron (such as red blood cells) or if the deprivation of minerals is more localized to the internal colon region.[citation needed]
Phytic acid has no known toxicity and is not known to cause mutagenic activity.[citation needed] It may have more therapeutic value when added to water rather than when naturally absorbed in foods as it is difficult to free from fiber.[citation needed]
Phytic acid is one of few chelating therapies for uranium removal.
As a food additive, phytic acid is used as a preservative with E number E391.[citation needed]
Food must be well cooked in order to free IP6 from the fiber and enable it to be absorbed in the system.[citation needed] IP6 rarely appears in soluble fiber. It's usually attached to the bran, the hard (insoluble) fiber, which is difficult to digest.[citation needed] IP6 is found in legumes, peas, wheat, barley, and oats.[citation needed] Of any studied legumes, whole soybeans have the highest levels of phytic acid.[citation needed]
Those who argue for the beneficial effects of phytic acid, and freeing it up for interaction with the system through cooking, do not argue that cooking destroys the phytic acid.[citation needed]This is a major deviation between those arguing for the merits of processed grain products.[citation needed] | https://www.wikidoc.org/index.php/IP6 | |
813dbd1114e2f861e78d42f94930148ee1199b16 | wikidoc | Iberiotoxin | Iberiotoxin
Iberiotoxin is an ion channel toxin purified from the Eastern Indian red scorpion Buthus tamulus.
Iberiotoxin selectively inhibits the flow of current through large-conductance calcium-activated potassium channels.
# Chemistry
Iberiotoxin is a 37-amino acid peptide. It is also known as "Potassium channel toxin alpha-KTx 1.3" or IbTx. The complete amino acid sequence has been defined and it displays 68% sequence homology with charybdotoxin.
# Target and mode of action
Iberiotoxin binds to the the outer face of the large-conductance calcium-activated potassium channels (maxiK or BK channels) with high affinity (Kd ~1 nM). It selectively inhibits the flow of current by decreasing both the probability of opening and the open time of the channel.
# Toxicity
The venom produces mainly cardiopulmonary abnormalities like circulatory derangements, myocarditis and changes in cardiac sarcolemmal ATPase and by these abnormalities it can finally cause death. In rural India the scorpion and its venom is a commonly known factor of children's death. The venom initially causes transient cholinergic stimulation (vomiting, profuse sweating, bradycardia, priapism, hypersalivation, and hypotension) which is followed by sustained adrenergic hyperactivity (hypertension, tachycardia, and myocardial failure). The adrenergic phase but not the cholinergic phase is a dose dependent phenomenon.
# Treatment
Treatment is mainly symptomatic. Local pain is treated by injecting dehydroemetine at the site of the sting. Hypovolaemia is corrected by oral rehydration solution. Agitated, confused and non-cooperative patients are given a 5% dextrose saline drip. Patients with hypertension on admission are given a single dose of 5 mg sublingual nifedipine and oral prazosin. The blood pressure in patients with hypertension is controlled with sublingual nifedipine alone. Patients with pulmonary oedema are propped up and given intravenous aminophylline, sodium bicarbonate, oral prazosin, and oxygen by mask. | Iberiotoxin
Iberiotoxin is an ion channel toxin purified from the Eastern Indian red scorpion Buthus tamulus.
Iberiotoxin selectively inhibits the flow of current through large-conductance calcium-activated potassium channels.
# Chemistry
Iberiotoxin is a 37-amino acid peptide.[2] It is also known as "Potassium channel toxin alpha-KTx 1.3" or IbTx. The complete amino acid sequence has been defined and it displays 68% sequence homology with charybdotoxin.[1]
# Target and mode of action
Iberiotoxin binds to the the outer face of the large-conductance calcium-activated potassium channels (maxiK or BK channels) with high affinity (Kd ~1 nM).[3] It selectively inhibits the flow of current by decreasing both the probability of opening and the open time of the channel.[3]
# Toxicity
The venom produces mainly cardiopulmonary abnormalities like circulatory derangements, myocarditis and changes in cardiac sarcolemmal ATPase and by these abnormalities it can finally cause death. In rural India the scorpion and its venom is a commonly known factor of children's death. The venom initially causes transient cholinergic stimulation (vomiting, profuse sweating, bradycardia, priapism, hypersalivation, and hypotension) which is followed by sustained adrenergic hyperactivity (hypertension, tachycardia, and myocardial failure). The adrenergic phase but not the cholinergic phase is a dose dependent phenomenon.[4]
# Treatment
Treatment is mainly symptomatic. Local pain is treated by injecting dehydroemetine at the site of the sting. Hypovolaemia is corrected by oral rehydration solution. Agitated, confused and non-cooperative patients are given a 5% dextrose saline drip. Patients with hypertension on admission are given a single dose of 5 mg sublingual nifedipine and oral prazosin. The blood pressure in patients with hypertension is controlled with sublingual nifedipine alone. Patients with pulmonary oedema are propped up and given intravenous aminophylline, sodium bicarbonate, oral prazosin, and oxygen by mask.[4] | https://www.wikidoc.org/index.php/Iberiotoxin | |
b607bcac525372bfff4fa8cc79b4fa100bd3bfd9 | wikidoc | Palbociclib | Palbociclib
- The recommended dose of Palbociclib is a 125 mg capsule taken orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days. Palbociclib should be taken with food in combination with letrozole 2.5 mg once daily given continuously throughout the 28-day cycle. Patients should be encouraged to take their dose at approximately the same time each day.
- If the patient vomits or misses a dose, an additional dose should not be taken that day. The next prescribed dose should be taken at the usual time. Palbociclib capsules should be swallowed whole (do not chew, crush or open them prior to swallowing). No capsule should be ingested if it is broken, cracked, or otherwise not intact.
# Dose Modification
- Dose modification of Palbociclib is recommended based on individual safety and tolerability.
- Management of some adverse reactions may require temporary dose interruptions/delays and/or dose reductions, or permanent discontinuation as per dose reduction schedules provided in Tables 1, 2 and 3.
See manufacturer's prescribing information for the coadministered product, letrozole, dose adjustment guidelines in the event of toxicity and other relevant safety information or contraindications.
# Dose Modifications for Use With Strong CYP3A Inhibitors
- Avoid concomitant use of strong CYP3A inhibitors and consider an alternative concomitant medication with no or minimal CYP3A inhibition. If patients must be coadministered a strong CYP3A inhibitor, reduce the Palbociclib dose to 75 mg once daily. If the strong inhibitor is discontinued, increase the Palbociclib dose (after 3–5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor.
- Decreased neutrophil counts have been observed in clinical trials with Palbociclib. Grade 3 (57%) or 4 (5%) decreased neutrophil counts were reported in patients receiving Palbociclib plus letrozole in the randomized clinical trial (Study 1). Median time to first episode of any grade neutropenia per laboratory data was 15 days (13–117 days). Median duration of Grade ≥3 neutropenia was 7 days.
- Febrile neutropenia events have been reported in the Palbociclib clinical program, although no cases of febrile neutropenia have been observed in Study 1. Monitor complete blood count prior to starting Palbociclib therapy and at the beginning of each cycle, as well as on Day 14 of the first two cycles, and as clinically indicated. Dose interruption, dose reduction or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.
# Infections
- Infections have been reported at a higher rate in patients treated with Palbociclib plus letrozole compared to patients treated with letrozole alone in Study 1. Grade 3 or 4 infections occurred in 5% of patients treated with Palbociclib plus letrozole whereas no patients treated with letrozole alone experienced a Grade 3 or 4 infection. Monitor patients for signs and symptoms of infection and treat as medically appropriate.
# Pulmonary Embolism
- Pulmonary embolism has been reported at a higher rate in patients treated with Palbociclib plus letrozole (5%) compared with no cases in patients treated with letrozole alone in Study 1. Monitor patients for signs and symptoms of pulmonary embolism and treat as medically appropriate.
# Embryo-Fetal Toxicity
- Based on findings in animals and mechanism of action, Palbociclib can cause fetal harm. Palbociclib caused embryo-fetal toxicities in rats and rabbits at maternal exposures that were greater than or equal to 4 times the human clinical exposure based on area under the curve (AUC). Advise females of reproductive potential to use effective contraception during therapy with Palbociclib and for at least two weeks after the last dose.
- Neutropenia.
- Infections.
- Pulmonary Embolism.
# Clinical Studies Experience
- Because clinical trials are conducted under varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.
- The safety of Palbociclib (125 mg/day) plus letrozole (2.5 mg/day) versus letrozole alone was evaluated in Study 1. The data described below reflect exposure to Palbociclib in 83 out of 160 patients with ER-positive, HER2-negative advanced breast cancer who received at least 1 dose of treatment in Study 1. The median duration of treatment for palbociclib was 13.8 months while the median duration of treatment for letrozole on the letrozole-alone arm was 7.6 months.
- Dose reductions due to an adverse reaction of any grade occurred in 36% of patients receiving Palbociclib plus letrozole. No dose reduction was allowed for letrozole in Study 1.
- Permanent discontinuation due to an adverse reaction occurred in 7 of 83 (8%) patients receiving Palbociclib plus letrozole and in 2 of 77 (3%) patients receiving letrozole alone. Adverse reactions leading to discontinuation for those patients receiving Palbociclib plus letrozole included neutropenia (6%), asthenia (1%), and fatigue (1%).
- The most common adverse reactions (≥10%) of any grade reported in patients in the Palbociclib plus letrozole arm were neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, asthenia, peripheral neuropathy, and epistaxis.
- The most frequently reported serious adverse reactions in patients receiving Palbociclib plus letrozole were pulmonary embolism (3 of 83; 4%) and diarrhea (2 of 83; 2%).
An increase incidence of infections events was observed in the palbociclib plus letrozole arm (55%) compared to the letrozole alone arm (34%). Febrile neutropenia events have been reported in the Palbociclib clinical program, although no cases were observed in Study 1. Grade ≥3 neutropenia was managed by dose reductions and/or dose delay or temporary discontinuation consistent with a permanent discontinuation rate of 6% due to neutropenia.
Adverse drug reactions (≥10%) reported in patients who received Palbociclib plus letrozole or letrozole alone in Study 1 are listed in Table 4.
# Agents That May Increase Palbociclib Plasma Concentrations
- Coadministration of a strong CYP3A inhibitor (itraconazole) increased the plasma exposure of palbociclib in healthy subjects by 87%. Avoid concomitant use of strong CYP3A inhibitors (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, and voriconazole). Avoid grapefruit or grapefruit juice during Palbociclib treatment. If coadministration of Palbociclib with a strong CYP3A inhibitor cannot be avoided, reduce the dose of Palbociclib.
# Agents That May Decrease Palbociclib Plasma Concentrations
- Coadministration of a strong CYP3A inducer (rifampin) decreased the plasma exposure of palbociclib in healthy subjects by 85%. Avoid concomitant use of strong CYP3A inducers (e.g., phenytoin, rifampin, carbamazepine and St John's Wort).
- Coadministration of moderate CYP3A inducers may also decrease the plasma exposure of Palbociclib. Avoid concomitant use of moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin).
# Drugs That May Have Their Plasma Concentrations Altered by Palbociclib
- Coadministration of midazolam with multiple doses of Palbociclib increased the midazolam plasma exposure by 61%, in healthy subjects, compared with administration of midazolam alone. The dose of the sensitive CYP3A substrate with a narrow therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus and tacrolimus) may need to be reduced as Palbociclib may increase their exposure.
- Based on findings in animals and mechanism of action, Palbociclib can cause fetal harm when administered to a pregnant woman. In animal studies, palbociclib was teratogenic and fetotoxic at maternal exposures that were ≥4 times the human clinical exposure based on AUC at the recommended human dose. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2–4% and of miscarriage is 15–20% of clinically recognized pregnancies.
- Animal Data: In a fertility and early embryonic development study in female rats, palbociclib was administered orally for 15 days before mating through to Day 7 of pregnancy, which did not cause embryo toxicity at doses up to 300 mg/kg/day with maternal systemic exposures approximately 4 times the human exposure (AUC) at the recommended dose. In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses up to 300 mg/kg/day and 20 mg/kg/day palbociclib, respectively, during the period of organogenesis. The maternally toxic dose of 300 mg/kg/day was fetotoxic in rats, resulting in reduced fetal body weights. At doses ≥100 mg/kg/day in rats, there was an increased incidence of a skeletal variation (increased incidence of a rib present at the seventh cervical vertebra). At the maternally toxic dose of 20 mg/kg/day in rabbits, there was an increased incidence of skeletal variations, including small phalanges in the forelimb. At 300 mg/kg/day in rats and 20 mg/kg/day in rabbits, the maternal systemic exposures were approximately 4 and 9 times the human exposure (AUC) at the recommended dose. CDK4/6 double knockout mice have been reported to die in late stages of fetal development (gestation Day 14.5 until birth) due to severe anemia. However, knockout mouse data may not be predictive of effects in humans due to differences in degree of target inhibition.
- Females: Advise females of reproductive potential to use effective contraception during treatment with Palbociclib and for at least two weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with Palbociclib.
# Infertility
- Males: Based on findings in animals, male fertility may be compromised by treatment with Palbociclib.
- The effect of palbociclib on the QTc interval was evaluated in 184 patients with advanced cancer. No large change (i.e., >20 ms) in the QTc interval was detected at the mean observed maximal steady-state palbociclib concentration following a therapeutic schedule (e.g., 125 mg daily for 21 consecutive days followed by 7 days off to comprise a complete cycle of 28 days).
# Absorption
- The mean Cmax of palbociclib is generally observed between 6 to 12 hours (time to reach maximum concentration, Tmax) following oral administration. The mean absolute bioavailability of Palbociclib after an oral 125 mg dose is 46%. In the dosing range of 25 mg to 225 mg, the AUC and Cmax increased proportionally with dose in general. Steady state was achieved within 8 days following repeated once daily dosing. With repeated once daily administration, palbociclib accumulated with a median accumulation ratio of 2.4 (range 1.5–4.2).
- Food effect: Palbociclib absorption and exposure were very low in approximately 13% of the population under the fasted condition. Food intake increased the palbociclib exposure in this small subset of the population, but did not alter palbociclib exposure in the rest of the population to a clinically relevant extent. Therefore, food intake reduced the intersubject variability of palbociclib exposure, which supports administration of Palbociclib with food. Compared to Palbociclib given under overnight fasted conditions, the population average AUCinf and Cmax of palbociclib increased by 21% and 38%, respectively, when given with high-fat, high-calorie food (approximately 800 to 1000 calories with 150, 250, and 500 to 600 calories from protein, carbohydrate and fat, respectively), by 12% and 27%, respectively, when given with low-fat, low-calorie food (approximately 400 to 500 calories with 120, 250, and 28 to 35 calories from protein, carbohydrate and fat, respectively), and by 13% and 24%, respectively, when moderate-fat, standard calorie food (approximately 500 to 700 calories with 75 to 105, 250 to 350 and 175 to 245 calories from protein, carbohydrate and fat, respectively) was given one hour before and two hours after Palbociclib dosing.
# Distribution
- Binding of palbociclib to human plasma proteins in vitro was approximately 85%, with no concentration dependence over the concentration range of 500 ng/mL to 5000 ng/mL. The geometric mean apparent volume of distribution (Vz/F) was 2583 L (26% CV).
# Metabolism
- In vitro and in vivo studies indicated that palbociclib undergoes hepatic metabolism in humans. Following oral administration of a single 125 mg dose of palbociclib to humans, the primary metabolic pathways for palbociclib involved oxidation and sulfonation, with acylation and glucuronidation contributing as minor pathways. Palbociclib was the major circulating drug-derived entity in plasma (23%). The major circulating metabolite was a glucuronide conjugate of palbociclib, although it only represented 1.5% of the administered dose in the excreta. Palbociclib was extensively metabolized with unchanged drug accounting for 2.3% and 6.9% of radioactivity in feces and urine, respectively. In feces, the sulfamic acid conjugate of palbociclib was the major drug-related component, accounting for 26% of the administered dose. In vitro studies with human hepatocytes, liver cytosolic and S9 fractions, and recombinant SULT enzymes indicated that CYP3A and SULT2A1 are mainly involved in the metabolism of palbociclib.
# Elimination
- The geometric mean apparent oral clearance (CL/F) of palbociclib was 63.1 L/hr (29% CV), and the mean (± standard deviation) plasma elimination half-life was 29 (±5) hours in patients with advanced breast cancer. In 6 healthy male subjects given a single oral dose of palbociclib, a median of 91.6% of the total administered radioactive dose was recovered in 15 days; feces (74.1% of dose) was the major route of excretion, with 17.5% of the dose recovered in urine. The majority of the material was excreted as metabolites.
- Carcinogenicity studies have not been conducted with palbociclib.
- Palbociclib was clastogenic in an in vitro micronucleus assay in Chinese Hamster Ovary cells and in vivo in the bone marrow of male rats that received doses ≥100 mg/kg/day for three weeks. Clastogenicity occurred via an aneugenic mechanism. Palbociclib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and did not induce structural chromosomal aberrations in the in vitro human lymphocyte chromosome aberration assay.
- In a fertility study in female rats, palbociclib did not affect mating or fertility at any dose up to 300 mg/kg/day (approximately 4 times human clinical exposure based on AUC) and no adverse effects were observed in the female reproductive tissues in repeat-dose toxicity studies up to 300 mg/kg/day in the rat and 3 mg/kg/day in the dog (approximately 6 times and similar to human exposure (AUC), at the recommended dose, respectively). Male fertility studies with palbociclib have not been conducted; however, in repeat-dose toxicity studies, testicular degeneration was observed in rats and dogs at 30 and 0.2 mg/kg/day, respectively (approximately 11 and 0.1 times human exposure (AUC), at the recommended dose, respectively), which was partially reversible in the rat and dog following a 12-week non-dosing period.
# Animal Toxicology and/or Pharmacology
- Altered glucose metabolism (glycosuria, hyperglycemia, decreased insulin) associated with changes in the pancreas (islet cell vacuolation), eye (cataracts, lens degeneration), teeth (degeneration/necrosis of ameloblasts in actively growing teeth), kidney (tubule vacuolation, chronic progressive nephropathy), and adipose tissue (atrophy) were identified in the 27-week repeat-dose toxicology study in rats and were most prevalent in males at doses ≥30 mg/kg/day (approximately 11 times the human exposure (AUC) at the recommended dose). Some of these findings (glycosuria/hyperglycemia, pancreatic islet cell vacuolation, and kidney tubule vacuolation) were present in the 15-week repeat-dose toxicology study in rats, but with lower incidence and severity. The rats used in these studies were approximately 7 weeks old at the beginning of the studies. Altered glucose metabolism or associated changes in pancreas, eye, teeth, kidney, and adipose tissue were not identified in dogs in repeat-dose toxicology studies up to 39 weeks duration.
- Patients enrolled in this study had a median age of 63 years (range 38 to 89). The majority of patients were Caucasian (90%) and all patients had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Forty-three percent of patients had received chemotherapy and 33% had received antihormonal therapy in the neoadjuvant or adjuvant setting prior to their diagnosis of advanced breast cancer. Forty-nine percent of patients had no prior systemic therapy in the neoadjuvant or adjuvant setting. The majority of patients (98%) had metastatic disease. Nineteen percent of patients had bone only disease and 48% of patients had visceral disease.
- The major efficacy outcome measure of the study was investigator-assessed PFS evaluated according to Response Evaluation Criteria in Solid Tumors Version 1.0 (RECIST). Major efficacy results from Study 1 are summarized in Table 6 and Figure 1. Consistent results were observed across patient subgroups of, disease-free interval, disease site and prior therapy. The treatment effect of the combination on PFS was also supported by a retrospective independent review of radiographs with an observed hazard ratio (HR) of 0.621 (95% CI: 0.378, 1.019). Overall response rate in patients with measurable disease as assessed by the investigator was higher in the Palbociclib plus letrozole compared to the letrozole alone arm (55.4% versus 39.4%). At the time of the final analysis of PFS, overall survival (OS) data was not mature with 37% of events. | Palbociclib
- The recommended dose of Palbociclib is a 125 mg capsule taken orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days. Palbociclib should be taken with food in combination with letrozole 2.5 mg once daily given continuously throughout the 28-day cycle. Patients should be encouraged to take their dose at approximately the same time each day.
- If the patient vomits or misses a dose, an additional dose should not be taken that day. The next prescribed dose should be taken at the usual time. Palbociclib capsules should be swallowed whole (do not chew, crush or open them prior to swallowing). No capsule should be ingested if it is broken, cracked, or otherwise not intact.
### Dose Modification
- Dose modification of Palbociclib is recommended based on individual safety and tolerability.
- Management of some adverse reactions may require temporary dose interruptions/delays and/or dose reductions, or permanent discontinuation as per dose reduction schedules provided in Tables 1, 2 and 3.
See manufacturer's prescribing information for the coadministered product, letrozole, dose adjustment guidelines in the event of toxicity and other relevant safety information or contraindications.
### Dose Modifications for Use With Strong CYP3A Inhibitors
- Avoid concomitant use of strong CYP3A inhibitors and consider an alternative concomitant medication with no or minimal CYP3A inhibition. If patients must be coadministered a strong CYP3A inhibitor, reduce the Palbociclib dose to 75 mg once daily. If the strong inhibitor is discontinued, increase the Palbociclib dose (after 3–5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor.
- Decreased neutrophil counts have been observed in clinical trials with Palbociclib. Grade 3 (57%) or 4 (5%) decreased neutrophil counts were reported in patients receiving Palbociclib plus letrozole in the randomized clinical trial (Study 1). Median time to first episode of any grade neutropenia per laboratory data was 15 days (13–117 days). Median duration of Grade ≥3 neutropenia was 7 days.
- Febrile neutropenia events have been reported in the Palbociclib clinical program, although no cases of febrile neutropenia have been observed in Study 1. Monitor complete blood count prior to starting Palbociclib therapy and at the beginning of each cycle, as well as on Day 14 of the first two cycles, and as clinically indicated. Dose interruption, dose reduction or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.
### Infections
- Infections have been reported at a higher rate in patients treated with Palbociclib plus letrozole compared to patients treated with letrozole alone in Study 1. Grade 3 or 4 infections occurred in 5% of patients treated with Palbociclib plus letrozole whereas no patients treated with letrozole alone experienced a Grade 3 or 4 infection. Monitor patients for signs and symptoms of infection and treat as medically appropriate.
### Pulmonary Embolism
- Pulmonary embolism has been reported at a higher rate in patients treated with Palbociclib plus letrozole (5%) compared with no cases in patients treated with letrozole alone in Study 1. Monitor patients for signs and symptoms of pulmonary embolism and treat as medically appropriate.
### Embryo-Fetal Toxicity
- Based on findings in animals and mechanism of action, Palbociclib can cause fetal harm. Palbociclib caused embryo-fetal toxicities in rats and rabbits at maternal exposures that were greater than or equal to 4 times the human clinical exposure based on area under the curve (AUC). Advise females of reproductive potential to use effective contraception during therapy with Palbociclib and for at least two weeks after the last dose.
- Neutropenia.
- Infections.
- Pulmonary Embolism.
### Clinical Studies Experience
- Because clinical trials are conducted under varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.
- The safety of Palbociclib (125 mg/day) plus letrozole (2.5 mg/day) versus letrozole alone was evaluated in Study 1. The data described below reflect exposure to Palbociclib in 83 out of 160 patients with ER-positive, HER2-negative advanced breast cancer who received at least 1 dose of treatment in Study 1. The median duration of treatment for palbociclib was 13.8 months while the median duration of treatment for letrozole on the letrozole-alone arm was 7.6 months.
- Dose reductions due to an adverse reaction of any grade occurred in 36% of patients receiving Palbociclib plus letrozole. No dose reduction was allowed for letrozole in Study 1.
- Permanent discontinuation due to an adverse reaction occurred in 7 of 83 (8%) patients receiving Palbociclib plus letrozole and in 2 of 77 (3%) patients receiving letrozole alone. Adverse reactions leading to discontinuation for those patients receiving Palbociclib plus letrozole included neutropenia (6%), asthenia (1%), and fatigue (1%).
- The most common adverse reactions (≥10%) of any grade reported in patients in the Palbociclib plus letrozole arm were neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, asthenia, peripheral neuropathy, and epistaxis.
- The most frequently reported serious adverse reactions in patients receiving Palbociclib plus letrozole were pulmonary embolism (3 of 83; 4%) and diarrhea (2 of 83; 2%).
An increase incidence of infections events was observed in the palbociclib plus letrozole arm (55%) compared to the letrozole alone arm (34%). Febrile neutropenia events have been reported in the Palbociclib clinical program, although no cases were observed in Study 1. Grade ≥3 neutropenia was managed by dose reductions and/or dose delay or temporary discontinuation consistent with a permanent discontinuation rate of 6% due to neutropenia.
Adverse drug reactions (≥10%) reported in patients who received Palbociclib plus letrozole or letrozole alone in Study 1 are listed in Table 4.
### Agents That May Increase Palbociclib Plasma Concentrations
- Coadministration of a strong CYP3A inhibitor (itraconazole) increased the plasma exposure of palbociclib in healthy subjects by 87%. Avoid concomitant use of strong CYP3A inhibitors (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, and voriconazole). Avoid grapefruit or grapefruit juice during Palbociclib treatment. If coadministration of Palbociclib with a strong CYP3A inhibitor cannot be avoided, reduce the dose of Palbociclib.
### Agents That May Decrease Palbociclib Plasma Concentrations
- Coadministration of a strong CYP3A inducer (rifampin) decreased the plasma exposure of palbociclib in healthy subjects by 85%. Avoid concomitant use of strong CYP3A inducers (e.g., phenytoin, rifampin, carbamazepine and St John's Wort).
- Coadministration of moderate CYP3A inducers may also decrease the plasma exposure of Palbociclib. Avoid concomitant use of moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin).
### Drugs That May Have Their Plasma Concentrations Altered by Palbociclib
- Coadministration of midazolam with multiple doses of Palbociclib increased the midazolam plasma exposure by 61%, in healthy subjects, compared with administration of midazolam alone. The dose of the sensitive CYP3A substrate with a narrow therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus and tacrolimus) may need to be reduced as Palbociclib may increase their exposure.
- Based on findings in animals and mechanism of action, Palbociclib can cause fetal harm when administered to a pregnant woman. In animal studies, palbociclib was teratogenic and fetotoxic at maternal exposures that were ≥4 times the human clinical exposure based on AUC at the recommended human dose. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2–4% and of miscarriage is 15–20% of clinically recognized pregnancies.
- Animal Data: In a fertility and early embryonic development study in female rats, palbociclib was administered orally for 15 days before mating through to Day 7 of pregnancy, which did not cause embryo toxicity at doses up to 300 mg/kg/day with maternal systemic exposures approximately 4 times the human exposure (AUC) at the recommended dose. In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses up to 300 mg/kg/day and 20 mg/kg/day palbociclib, respectively, during the period of organogenesis. The maternally toxic dose of 300 mg/kg/day was fetotoxic in rats, resulting in reduced fetal body weights. At doses ≥100 mg/kg/day in rats, there was an increased incidence of a skeletal variation (increased incidence of a rib present at the seventh cervical vertebra). At the maternally toxic dose of 20 mg/kg/day in rabbits, there was an increased incidence of skeletal variations, including small phalanges in the forelimb. At 300 mg/kg/day in rats and 20 mg/kg/day in rabbits, the maternal systemic exposures were approximately 4 and 9 times the human exposure (AUC) at the recommended dose. CDK4/6 double knockout mice have been reported to die in late stages of fetal development (gestation Day 14.5 until birth) due to severe anemia. However, knockout mouse data may not be predictive of effects in humans due to differences in degree of target inhibition.
- Females: Advise females of reproductive potential to use effective contraception during treatment with Palbociclib and for at least two weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with Palbociclib.
### Infertility
- Males: Based on findings in animals, male fertility may be compromised by treatment with Palbociclib.
- The effect of palbociclib on the QTc interval was evaluated in 184 patients with advanced cancer. No large change (i.e., >20 ms) in the QTc interval was detected at the mean observed maximal steady-state palbociclib concentration following a therapeutic schedule (e.g., 125 mg daily for 21 consecutive days followed by 7 days off to comprise a complete cycle of 28 days).
### Absorption
- The mean Cmax of palbociclib is generally observed between 6 to 12 hours (time to reach maximum concentration, Tmax) following oral administration. The mean absolute bioavailability of Palbociclib after an oral 125 mg dose is 46%. In the dosing range of 25 mg to 225 mg, the AUC and Cmax increased proportionally with dose in general. Steady state was achieved within 8 days following repeated once daily dosing. With repeated once daily administration, palbociclib accumulated with a median accumulation ratio of 2.4 (range 1.5–4.2).
- Food effect: Palbociclib absorption and exposure were very low in approximately 13% of the population under the fasted condition. Food intake increased the palbociclib exposure in this small subset of the population, but did not alter palbociclib exposure in the rest of the population to a clinically relevant extent. Therefore, food intake reduced the intersubject variability of palbociclib exposure, which supports administration of Palbociclib with food. Compared to Palbociclib given under overnight fasted conditions, the population average AUCinf and Cmax of palbociclib increased by 21% and 38%, respectively, when given with high-fat, high-calorie food (approximately 800 to 1000 calories with 150, 250, and 500 to 600 calories from protein, carbohydrate and fat, respectively), by 12% and 27%, respectively, when given with low-fat, low-calorie food (approximately 400 to 500 calories with 120, 250, and 28 to 35 calories from protein, carbohydrate and fat, respectively), and by 13% and 24%, respectively, when moderate-fat, standard calorie food (approximately 500 to 700 calories with 75 to 105, 250 to 350 and 175 to 245 calories from protein, carbohydrate and fat, respectively) was given one hour before and two hours after Palbociclib dosing.
### Distribution
- Binding of palbociclib to human plasma proteins in vitro was approximately 85%, with no concentration dependence over the concentration range of 500 ng/mL to 5000 ng/mL. The geometric mean apparent volume of distribution (Vz/F) was 2583 L (26% CV).
### Metabolism
- In vitro and in vivo studies indicated that palbociclib undergoes hepatic metabolism in humans. Following oral administration of a single 125 mg dose of [14C]palbociclib to humans, the primary metabolic pathways for palbociclib involved oxidation and sulfonation, with acylation and glucuronidation contributing as minor pathways. Palbociclib was the major circulating drug-derived entity in plasma (23%). The major circulating metabolite was a glucuronide conjugate of palbociclib, although it only represented 1.5% of the administered dose in the excreta. Palbociclib was extensively metabolized with unchanged drug accounting for 2.3% and 6.9% of radioactivity in feces and urine, respectively. In feces, the sulfamic acid conjugate of palbociclib was the major drug-related component, accounting for 26% of the administered dose. In vitro studies with human hepatocytes, liver cytosolic and S9 fractions, and recombinant SULT enzymes indicated that CYP3A and SULT2A1 are mainly involved in the metabolism of palbociclib.
### Elimination
- The geometric mean apparent oral clearance (CL/F) of palbociclib was 63.1 L/hr (29% CV), and the mean (± standard deviation) plasma elimination half-life was 29 (±5) hours in patients with advanced breast cancer. In 6 healthy male subjects given a single oral dose of [14C]palbociclib, a median of 91.6% of the total administered radioactive dose was recovered in 15 days; feces (74.1% of dose) was the major route of excretion, with 17.5% of the dose recovered in urine. The majority of the material was excreted as metabolites.
- Carcinogenicity studies have not been conducted with palbociclib.
- Palbociclib was clastogenic in an in vitro micronucleus assay in Chinese Hamster Ovary cells and in vivo in the bone marrow of male rats that received doses ≥100 mg/kg/day for three weeks. Clastogenicity occurred via an aneugenic mechanism. Palbociclib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and did not induce structural chromosomal aberrations in the in vitro human lymphocyte chromosome aberration assay.
- In a fertility study in female rats, palbociclib did not affect mating or fertility at any dose up to 300 mg/kg/day (approximately 4 times human clinical exposure based on AUC) and no adverse effects were observed in the female reproductive tissues in repeat-dose toxicity studies up to 300 mg/kg/day in the rat and 3 mg/kg/day in the dog (approximately 6 times and similar to human exposure (AUC), at the recommended dose, respectively). Male fertility studies with palbociclib have not been conducted; however, in repeat-dose toxicity studies, testicular degeneration was observed in rats and dogs at 30 and 0.2 mg/kg/day, respectively (approximately 11 and 0.1 times human exposure (AUC), at the recommended dose, respectively), which was partially reversible in the rat and dog following a 12-week non-dosing period.
### Animal Toxicology and/or Pharmacology
- Altered glucose metabolism (glycosuria, hyperglycemia, decreased insulin) associated with changes in the pancreas (islet cell vacuolation), eye (cataracts, lens degeneration), teeth (degeneration/necrosis of ameloblasts in actively growing teeth), kidney (tubule vacuolation, chronic progressive nephropathy), and adipose tissue (atrophy) were identified in the 27-week repeat-dose toxicology study in rats and were most prevalent in males at doses ≥30 mg/kg/day (approximately 11 times the human exposure (AUC) at the recommended dose). Some of these findings (glycosuria/hyperglycemia, pancreatic islet cell vacuolation, and kidney tubule vacuolation) were present in the 15-week repeat-dose toxicology study in rats, but with lower incidence and severity. The rats used in these studies were approximately 7 weeks old at the beginning of the studies. Altered glucose metabolism or associated changes in pancreas, eye, teeth, kidney, and adipose tissue were not identified in dogs in repeat-dose toxicology studies up to 39 weeks duration.
- Patients enrolled in this study had a median age of 63 years (range 38 to 89). The majority of patients were Caucasian (90%) and all patients had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Forty-three percent of patients had received chemotherapy and 33% had received antihormonal therapy in the neoadjuvant or adjuvant setting prior to their diagnosis of advanced breast cancer. Forty-nine percent of patients had no prior systemic therapy in the neoadjuvant or adjuvant setting. The majority of patients (98%) had metastatic disease. Nineteen percent of patients had bone only disease and 48% of patients had visceral disease.
- The major efficacy outcome measure of the study was investigator-assessed PFS evaluated according to Response Evaluation Criteria in Solid Tumors Version 1.0 (RECIST). Major efficacy results from Study 1 are summarized in Table 6 and Figure 1. Consistent results were observed across patient subgroups of, disease-free interval, disease site and prior therapy. The treatment effect of the combination on PFS was also supported by a retrospective independent review of radiographs with an observed hazard ratio (HR) of 0.621 (95% CI: 0.378, 1.019). Overall response rate in patients with measurable disease as assessed by the investigator was higher in the Palbociclib plus letrozole compared to the letrozole alone arm (55.4% versus 39.4%). At the time of the final analysis of PFS, overall survival (OS) data was not mature with 37% of events. | https://www.wikidoc.org/index.php/Ibrance | |
ba938b2f528dc987807cbd573045943c502f328a | wikidoc | Icosahedron | Icosahedron
An icosahedron (Greek: eikosaedron, from eikosi twenty + hedron seat; Template:IPA; plural: -drons, -dra Template:IPA) is
any polyhedron having 20 faces, but usually a regular icosahedron is implied, which has equilateral triangles as faces.
In geometry, the regular icosahedron is one of the five Platonic solids. It is a convex regular polyhedron composed of twenty triangular faces, with five meeting at each of the twelve vertices. It has 30 edges and 12 vertices.
Its dual polyhedron is the dodecahedron.
# Dimensions
If the edge length of a regular icosahedron is a, the radius of a circumscribed sphere (one that touches the icosahedron at all vertices) is
and the radius of an inscribed sphere (tangent to each of the icosahedron's faces) is
while the midradius, which touches the middle of each edge, is
where \tau (also called φ) is the golden ratio.
# Area and volume
The surface area A and the volume V of a regular icosahedron of edge length a are:
# Cartesian coordinates
The following Cartesian coordinates define the vertices of an icosahedron with edge-length 2, centered at the origin:
where φ = (1+√5)/2 is the golden ratio (also written τ).
Note that these vertices form five sets of three mutually centered, mutually orthogonal golden rectangles.
The 12 edges of a regular octahedron can be partitioned in the golden ratio so that the resulting vertices define a regular icosahedron. This is done by first placing vectors along the octahedron's edges such that each face is bounded by a cycle, then similarly partitioning each edge into the golden mean along the direction of its vector. The five octahedra defining any given icosahedron form a regular polyhedral compound, as do the two icosahedra that can be defined in this way from any given octahedron.
# Geometric relations
There are distortions of the icosahedron that, while no longer regular, are nevertheless vertex-uniform. These are invariant under the same rotations as the tetrahedron, and are somewhat analogous to the snub cube and snub dodecahedron, including some forms which are chiral and some with Th-symmetry, i.e. have different planes of symmetry from the tetrahedron. The icosahedron has a large number of stellations, including one of the Kepler-Poinsot polyhedra and some of the regular compounds, which could be discussed here.
The icosahedron is unique among the Platonic solids in possessing a dihedral angle not less than 120°. Its dihedral angle is approximately 138.19°. Thus, just as hexagons have angles not less than 120° and cannot be used as the faces of a convex regular polyhedron because such a construction would not meet the requirement that at least three faces meet at a vertex and leave a positive defect for folding in three dimensions, icosahedra cannot be used as the cells of a convex regular polychoron because, similarly, at least three cells must meet at an edge and leave a positive defect for folding in four dimensions (in general for a convex polytope in n dimensions, at least three facets must meet at a peak and leave a positive defect for folding in n-space). However, when combined with suitable cells having smaller dihedral angles, icosahedra can be used as cells in semi-regular polychora (for example the snub 24-cell), just as hexagons can be used as faces in semi-regular polyhedra (for example the truncated icosahedron). Finally, non-convex polytopes do not carry the same strict requirements as convex polytopes, and icosahedra are indeed the cells of the icosahedral 120-cell, one of the ten non-convex regular polychora.
An icosahedron can also be called a gyroelongated pentagonal bipyramid. It can be decomposed into a gyroelongated pentagonal pyramid and a pentagonal pyramid or into a pentagonal antiprism and two equal pentagonal pyramids.
The icosahedron can also be called a snub tetrahedron, as snubification of a regular tetrahedron gives a regular icosahedron. Alternatively, using the nomenclature for snub polyhedra that refers to a snub cube as a snub cuboctahedron (cuboctahedron = rectified cube) and a snub dodecahedron as a snub icosidodecahedron (icosidodecahedron = rectified dodecahedron), one may call the icosahedron the snub octahedron (octahedron = rectified tetrahedron).
A rectified icosahedron forms an icosidodecahedron.
## Icosahedron vs dodecahedron
When an icosahedron is inscribed in a sphere, it occupies less of the sphere's volume (60.54%)
than a dodecahedron inscribed in the same sphere (66.49%).
# Natural forms and uses
Many viruses, e.g. herpes virus, have the shape of an icosahedron. Viral structures are built of repeated identical protein subunits and the icosahedron is the easiest shape to assemble using these subunits. A regular polyhedron is used because it can be built from a single basic unit protein used over and over again; this saves space in the viral genome.
In 1904, Ernst Haeckel described a number of species of Radiolaria, including Circogonia icosahedra, whose skeleton is shaped like a regular icosahedron. A copy of Haeckel's illustration for this radiolarian appears in the article on regular polyhedra.
In some roleplaying games, the twenty-sided die (for short, d20) is used in determining success or failure of an action. This die is in the form of a regular icosahedron. It may be numbered from "0" to "9" twice (in which form it usually serves as a ten-sided die, or d10, but most modern versions are labeled from "1" to "20". See d20 System.
An icosahedron is the three-dimensional game board for Icosagame, formerly known as the Ico Crystal Game.
An icosahedron is used in the board game Scattergories to choose a letter of the alphabet. Six little-used letters, such as X, Q, and Z, are omitted.
Inside a Magic 8-Ball, various answers to yes-no questions are printed on a regular icosahedron.
The icosahedron displayed in a functional form is seen in the Sol de la Flor light shade. The rosette formed by the overlapping pieces show a resemblance to the Frangipani flower.
If each edge of an icosahedron is replaced by a one ohm resistor, the resistance between opposite vertices is 0.5 ohms, and that between adjacent vertices 11/30 ohms.
The symmetry group of the icosahedron is isomorphic to the alternating group on five letters. This nonabelian simple group is the only nontrivial normal subgroup of the symmetric group on five letters. Since the Galois group of the general quintic equation is isomorphic to the symmetric group on five letters, and the fact that the icosahedral group is simple and nonabelian means that quintic equations need not have a solution in radicals. The proof of the Abel-Ruffini theorem uses this simple fact, and Felix Klein wrote a book that made use of the theory of icosahedral symmetries to derive an analytical solution to the general quintic equation. | Icosahedron
Template:Reg polyhedra db
An icosahedron (Greek: eikosaedron, from eikosi twenty + hedron seat; Template:IPA; plural: -drons, -dra Template:IPA) is
any polyhedron having 20 faces, but usually a regular icosahedron is implied, which has equilateral triangles as faces.
In geometry, the regular icosahedron is one of the five Platonic solids. It is a convex regular polyhedron composed of twenty triangular faces, with five meeting at each of the twelve vertices. It has 30 edges and 12 vertices.
Its dual polyhedron is the dodecahedron.
# Dimensions
If the edge length of a regular icosahedron is <math>a</math>, the radius of a circumscribed sphere (one that touches the icosahedron at all vertices) is
and the radius of an inscribed sphere (tangent to each of the icosahedron's faces) is
while the midradius, which touches the middle of each edge, is
where <math> \tau </math> (also called φ) is the golden ratio.
# Area and volume
The surface area A and the volume V of a regular icosahedron of edge length a are:
# Cartesian coordinates
The following Cartesian coordinates define the vertices of an icosahedron with edge-length 2, centered at the origin:
where φ = (1+√5)/2 is the golden ratio (also written τ).
Note that these vertices form five sets of three mutually centered, mutually orthogonal golden rectangles.
The 12 edges of a regular octahedron can be partitioned in the golden ratio so that the resulting vertices define a regular icosahedron. This is done by first placing vectors along the octahedron's edges such that each face is bounded by a cycle, then similarly partitioning each edge into the golden mean along the direction of its vector. The five octahedra defining any given icosahedron form a regular polyhedral compound, as do the two icosahedra that can be defined in this way from any given octahedron.
# Geometric relations
There are distortions of the icosahedron that, while no longer regular, are nevertheless vertex-uniform. These are invariant under the same rotations as the tetrahedron, and are somewhat analogous to the snub cube and snub dodecahedron, including some forms which are chiral and some with Th-symmetry, i.e. have different planes of symmetry from the tetrahedron. The icosahedron has a large number of stellations, including one of the Kepler-Poinsot polyhedra and some of the regular compounds, which could be discussed here.
The icosahedron is unique among the Platonic solids in possessing a dihedral angle not less than 120°. Its dihedral angle is approximately 138.19°. Thus, just as hexagons have angles not less than 120° and cannot be used as the faces of a convex regular polyhedron because such a construction would not meet the requirement that at least three faces meet at a vertex and leave a positive defect for folding in three dimensions, icosahedra cannot be used as the cells of a convex regular polychoron because, similarly, at least three cells must meet at an edge and leave a positive defect for folding in four dimensions (in general for a convex polytope in n dimensions, at least three facets must meet at a peak and leave a positive defect for folding in n-space). However, when combined with suitable cells having smaller dihedral angles, icosahedra can be used as cells in semi-regular polychora (for example the snub 24-cell), just as hexagons can be used as faces in semi-regular polyhedra (for example the truncated icosahedron). Finally, non-convex polytopes do not carry the same strict requirements as convex polytopes, and icosahedra are indeed the cells of the icosahedral 120-cell, one of the ten non-convex regular polychora.
An icosahedron can also be called a gyroelongated pentagonal bipyramid. It can be decomposed into a gyroelongated pentagonal pyramid and a pentagonal pyramid or into a pentagonal antiprism and two equal pentagonal pyramids.
The icosahedron can also be called a snub tetrahedron, as snubification of a regular tetrahedron gives a regular icosahedron. Alternatively, using the nomenclature for snub polyhedra that refers to a snub cube as a snub cuboctahedron (cuboctahedron = rectified cube) and a snub dodecahedron as a snub icosidodecahedron (icosidodecahedron = rectified dodecahedron), one may call the icosahedron the snub octahedron (octahedron = rectified tetrahedron).
A rectified icosahedron forms an icosidodecahedron.
## Icosahedron vs dodecahedron
When an icosahedron is inscribed in a sphere, it occupies less of the sphere's volume (60.54%)
than a dodecahedron inscribed in the same sphere (66.49%).
# Natural forms and uses
Many viruses, e.g. herpes virus, have the shape of an icosahedron. Viral structures are built of repeated identical protein subunits and the icosahedron is the easiest shape to assemble using these subunits. A regular polyhedron is used because it can be built from a single basic unit protein used over and over again; this saves space in the viral genome.
In 1904, Ernst Haeckel described a number of species of Radiolaria, including Circogonia icosahedra, whose skeleton is shaped like a regular icosahedron. A copy of Haeckel's illustration for this radiolarian appears in the article on regular polyhedra.
In some roleplaying games, the twenty-sided die (for short, d20) is used in determining success or failure of an action. This die is in the form of a regular icosahedron. It may be numbered from "0" to "9" twice (in which form it usually serves as a ten-sided die, or d10, but most modern versions are labeled from "1" to "20". See d20 System.
An icosahedron is the three-dimensional game board for Icosagame, formerly known as the Ico Crystal Game.
An icosahedron is used in the board game Scattergories to choose a letter of the alphabet. Six little-used letters, such as X, Q, and Z, are omitted.
Inside a Magic 8-Ball, various answers to yes-no questions are printed on a regular icosahedron.
The icosahedron displayed in a functional form is seen in the Sol de la Flor light shade. The rosette formed by the overlapping pieces show a resemblance to the Frangipani flower.
If each edge of an icosahedron is replaced by a one ohm resistor, the resistance between opposite vertices is 0.5 ohms, and that between adjacent vertices 11/30 ohms.[1]
The symmetry group of the icosahedron is isomorphic to the alternating group on five letters. This nonabelian simple group is the only nontrivial normal subgroup of the symmetric group on five letters. Since the Galois group of the general quintic equation is isomorphic to the symmetric group on five letters, and the fact that the icosahedral group is simple and nonabelian means that quintic equations need not have a solution in radicals. The proof of the Abel-Ruffini theorem uses this simple fact, and Felix Klein wrote a book that made use of the theory of icosahedral symmetries to derive an analytical solution to the general quintic equation. | https://www.wikidoc.org/index.php/Icosahedral | |
89ebe97c134d148994cc946227dcc801c432b062 | wikidoc | Ida Noddack | Ida Noddack
Ida Noddack (25 February 1896 - 1978), née Ida Tacke, was a German chemist and physicist. She was among the first physicists to propose nuclear fission. With her husband Walter Noddack she discovered element 75 Rhenium.
# Background
Ida Noddack was born in Wesel.
She was one of the first women in Germany to study chemistry. She attained a doctorate in 1919 at the Technical University of Berlin "On higher aliphatic fatty acid anhydrides" and worked afterwards in the field being the first woman in the industry in Germany.
# Nuclear fission
Noddack correctly criticized Enrico Fermi's chemical proofs in his 1934 neutron bombardment experiments, from which he postulated that transuranic elements might have been produced, and which was widely accepted for a few years. Her paper, "On Element 93" suggested a number of possibilities, centering around Fermi's failure to chemically eliminate all lighter than uranium elements in his proofs, rather than only down to lead. The paper is considered historically significant today not simply because she correctly pointed out the flaw in Fermi's chemical proof but because she suggested the possibility that "it is conceivable that the nucleus breaks up into several large fragments, which would of course be isotopes of known elements but would not be neighbors of the irradiated element." In so doing she presaged what would become known a few years later as nuclear fission. However Noddack offered no theoretical basis for this possibility, which defied the understanding at the time, and her suggestion that the nucleus breaks into several large fragments is not what occurs in nuclear fission. The paper was generally ignored.
Later experiments along a similar line to Fermi's, by Irene Joliot-Curie, and Pavel Savitch in 1938 raised what they called "interpretational difficulties" when the supposed transuranics exhibited the properties of rare earths rather than those of adjacent elements. Ultimately in 1939 Otto Hahn and Fritz Strassmann, working in consultation with long term colleague Lise Meitner (who had been forced to flee Germany) provided chemical proof that the previously presumed transuranic elements were isotopes of Barium. It remained for Meitner and her nephew Otto Frisch utilizing Fritz Kalckar and Neils Bohr's liquid drop hypothesis (first proposed by George Gamow in 1935) to provide a theoretical model and mathematical proof of what they dubbed nuclear fission ( Frisch also experimentally verified the fission reaction by means of a cloud chamber, confirming the massive energy release).
# Element discovery priority
Noddack and her husband looked for the then still unknown elements 43 and 75 at the Physical Institute for Realm. In 1925, they published a paper (Zwei neue Elemente der Mangangruppe, Chemischer Teil) claiming to have done so, and called the new elements Rhenium and Masurium. Only the discovery of the rhenium was confirmed. They were unable to isolate any element 43 and their results were not reproducible. Their choice of the term Masurium was also considered unacceptably nationalistic and may have contributed to a poor reputation amongst scientists of the day.
Artificially produced Element 43 was definitively isolated in 1937 by Emilio Segrè and Carlo Perrier from a discarded piece of molybdenum foil from a cyclotron which had undergone beta decay. It is called Technetium. No isotope of technetium has a half-life longer than 4.2 million years and was presumed to have disappeared on earth in as a naturally occurring element. In 1961 of minute amounts of technetium in pitchblende produced from spontaneous 238U fission was discovered by B. T. Kenna and P. K. Kuroda.
Based on this discovery, Belgian physicist Pieter van Assche constructed an analysis of their data to show that the detection limit of Noddacks' analytical method could have been 1000 times lower than the 10-9 value reported in their paper, in order to show that the Noddacks could have been the first to find measurable amounts of element 43, as the ores they had analyzed contained uranium.
Using Van Assche's estimates of the Noddacks' residue compositions NIST scientist, John T. Armstrong, to simulated the original X-ray spectrum with a computer, and claimed that the results were "surprisingly close to their published spectrum!"
Gunter Herrmann from the University of Mainz examined van Assche's arguments, and concluded that they were developed ad hoc, and forced to a predetermined result.
According to Kenna and Kuroda 99technetium content expected in a typical pitchblende (50% uranium) is about 10 -10 g/kg of ore.
F. Habashi pointed out that uranium was never more than about 5% in Noddacks' columbite samples, and the amount of element 43 could not exceed 3 × 10 -11 µg/kg of ore. Such a low quantity could not be weighed, nor give X-ray lines of element 43 that could be clearly distinguished from the background noise. The only way to detect its presence is to carry out radioactive measurements, a technique that the
Noddacks did not use, but Segrè and Perrier did.
Following on the Van Assche and Armstrong claims, an investigation was made into the works of Masataka Ogawa who had made a prior claim to the Noddacks. In 1908 he claimed to have isolated element 43 calling it Nipponium. Using an actual original plate (not a simulation) Kenji Yoshihara determined that Ogawa had not found the Period 5 Group 7 element 43 ( eka-manganese), but had successfully separated Period 6 Group 7 element 73 ( dvi-manganese) (Rhenium), preceding the Noddacks by 17 years.
# Nobel nominations
Ida Noddack was nominated three times for Nobel Prize in Chemistry, once by Walter Nernst and K. L. Wagner for 1933; both Noddacks were nominated by W. J. Müller for 1935 and then by A. Skrabal for 1937.
# Bibliography
- Tacke, Ida, and D. Holde. 1921. Ueber Anhydride höherer aliphatischer Fettesäuren. Berlin, TeH., Diss., 1921. (On higher aliphatic fatty acid anhydrides )
- Noddack, Walter, Otto Berg, and Ida Tacke. 1925. Zwei neue Elemente der Mangangruppe, Chemischer Teil. . (Two new elements of the manganese chemical group)
- Noddack, Ida, and Walter Noddack. 1927. Das Rhenium. Ergebnisse Der Exakten Naturwissenschaften. 6. Bd. (1927) (Rhenium)
- Noddack, Ida, and Walter Noddack. 1933. Das Rhenium. Leipzig: Leopold Foss. (Rhenium)
- Noddack, Walter, and Ida Noddack. 1937. Aufgaben und Ziele der Geochemie. Freiburger wissenschaftliche Gesellschaft, Hft. 26. Freiburg im Breisgau: H. Speyer, H.F. Schulz. (Tasks and goals of Geochemistry)
- Noddack, Ida, and Walter Noddack. 1939. Die Häufigkeiten der Schwermetalle in Meerestieren. Arkiv för zoologi, Bd. 32, A, Nr. 4. Stockholm: Almqvist & Wiksell. (The frequency of heavy metals in marine animals)
- Noddack, Ida. 1942. Entwicklung und Aufbau der chemischen Wissenschaft. Freiburg i.Br: Schulz. (The development and structure of chemical science) | Ida Noddack
Ida Noddack (25 February 1896 - 1978), née Ida Tacke, was a German chemist and physicist. She was among the first physicists to propose nuclear fission. With her husband Walter Noddack she discovered element 75 Rhenium.
# Background
Ida Noddack was born in Wesel.
She was one of the first women in Germany to study chemistry. She attained a doctorate in 1919 at the Technical University of Berlin "On higher aliphatic fatty acid anhydrides" and worked afterwards in the field being the first woman in the industry in Germany.
# Nuclear fission
Noddack correctly criticized Enrico Fermi's chemical proofs in his 1934 neutron bombardment experiments, from which he postulated that transuranic elements might have been produced, and which was widely accepted for a few years. Her paper, "On Element 93" suggested a number of possibilities, centering around Fermi's failure to chemically eliminate all lighter than uranium elements in his proofs, rather than only down to lead. The paper is considered historically significant today not simply because she correctly pointed out the flaw in Fermi's chemical proof but because she suggested the possibility that "it is conceivable that the nucleus breaks up into several large fragments, which would of course be isotopes of known elements but would not be neighbors of the irradiated element." In so doing she presaged what would become known a few years later as nuclear fission. However Noddack offered no theoretical basis for this possibility, which defied the understanding at the time, and her suggestion that the nucleus breaks into several large fragments is not what occurs in nuclear fission. The paper was generally ignored.
Later experiments along a similar line to Fermi's, by Irene Joliot-Curie, and Pavel Savitch in 1938 raised what they called "interpretational difficulties" when the supposed transuranics exhibited the properties of rare earths rather than those of adjacent elements. Ultimately in 1939 Otto Hahn and Fritz Strassmann, working in consultation with long term colleague Lise Meitner (who had been forced to flee Germany) provided chemical proof that the previously presumed transuranic elements were isotopes of Barium. It remained for Meitner and her nephew Otto Frisch utilizing Fritz Kalckar and Neils Bohr's liquid drop hypothesis (first proposed by George Gamow in 1935) to provide a theoretical model and mathematical proof of what they dubbed nuclear fission ( Frisch also experimentally verified the fission reaction by means of a cloud chamber, confirming the massive energy release).
[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
# Element discovery priority
Noddack and her husband looked for the then still unknown elements 43 and 75 at the Physical Institute for Realm. In 1925, they published a paper (Zwei neue Elemente der Mangangruppe, Chemischer Teil) claiming to have done so, and called the new elements Rhenium and Masurium. Only the discovery of the rhenium was confirmed. They were unable to isolate any element 43 and their results were not reproducible. Their choice of the term Masurium was also considered unacceptably nationalistic and may have contributed to a poor reputation amongst scientists of the day.
Artificially produced Element 43 was definitively isolated in 1937 by Emilio Segrè and Carlo Perrier from a discarded piece of molybdenum foil from a cyclotron which had undergone beta decay. It is called Technetium. No isotope of technetium has a half-life longer than 4.2 million years and was presumed to have disappeared on earth in as a naturally occurring element. In 1961 of minute amounts of technetium in pitchblende produced from spontaneous 238U fission was discovered by B. T. Kenna and P. K. Kuroda.
[11]
Based on this discovery, Belgian physicist Pieter van Assche constructed an analysis of their data to show that the detection limit of Noddacks' analytical method could have been 1000 times lower than the 10-9 value reported in their paper, in order to show that the Noddacks could have been the first to find measurable amounts of element 43, as the ores they had analyzed contained uranium.
[12]
Using Van Assche's estimates of the Noddacks' residue compositions NIST scientist, John T. Armstrong, to simulated the original X-ray spectrum with a computer, and claimed that the results were "surprisingly close to their published spectrum!"
[13]
Gunter Herrmann from the University of Mainz examined van Assche's arguments, and concluded that they were developed ad hoc, and forced to a predetermined result.
[14]
According to Kenna and Kuroda 99technetium content expected in a typical pitchblende (50% uranium) is about 10 -10 g/kg of ore.
F. Habashi pointed out that uranium was never more than about 5% in Noddacks' columbite samples, and the amount of element 43 could not exceed 3 × 10 -11 µg/kg of ore. Such a low quantity could not be weighed, nor give X-ray lines of element 43 that could be clearly distinguished from the background noise. The only way to detect its presence is to carry out radioactive measurements, a technique that the
Noddacks did not use, but Segrè and Perrier did.
[15]
[16]
[17]
[18]
[19]
Following on the Van Assche and Armstrong claims, an investigation was made into the works of Masataka Ogawa who had made a prior claim to the Noddacks. In 1908 he claimed to have isolated element 43 calling it Nipponium. Using an actual original plate (not a simulation) Kenji Yoshihara determined that Ogawa had not found the Period 5 Group 7 element 43 ( eka-manganese), but had successfully separated Period 6 Group 7 element 73 ( dvi-manganese) (Rhenium), preceding the Noddacks by 17 years.
[20]
[21]
[22]
# Nobel nominations
Ida Noddack was nominated three times for Nobel Prize in Chemistry, once by Walter Nernst and K. L. Wagner for 1933; both Noddacks were nominated by W. J. Müller for 1935 and then by A. Skrabal for 1937.[23]
[24]
# Bibliography
- Tacke, Ida, and D. Holde. 1921. Ueber Anhydride höherer aliphatischer Fettesäuren. Berlin, TeH., Diss., 1921. (On higher aliphatic fatty acid anhydrides )
- Noddack, Walter, Otto Berg, and Ida Tacke. 1925. Zwei neue Elemente der Mangangruppe, Chemischer Teil. [Berlin: In Kommission bei W. de Gruyter]. (Two new elements of the manganese chemical group)
- Noddack, Ida, and Walter Noddack. 1927. Das Rhenium. Ergebnisse Der Exakten Naturwissenschaften. 6. Bd. (1927) (Rhenium)
- Noddack, Ida, and Walter Noddack. 1933. Das Rhenium. Leipzig: Leopold Foss. (Rhenium)
- Noddack, Walter, and Ida Noddack. 1937. Aufgaben und Ziele der Geochemie. Freiburger wissenschaftliche Gesellschaft, Hft. 26. Freiburg im Breisgau: H. Speyer, H.F. Schulz. (Tasks and goals of Geochemistry)
- Noddack, Ida, and Walter Noddack. 1939. Die Häufigkeiten der Schwermetalle in Meerestieren. Arkiv för zoologi, Bd. 32, A, Nr. 4. Stockholm: Almqvist & Wiksell. (The frequency of heavy metals in marine animals)
- Noddack, Ida. 1942. Entwicklung und Aufbau der chemischen Wissenschaft. Freiburg i.Br: Schulz. (The development and structure of chemical science)
- | https://www.wikidoc.org/index.php/Ida_Noddack | |
751d0cb3cc69d314f33a5c575b6fc7312fd899f3 | wikidoc | Idoxuridine | Idoxuridine
# Disclaimer
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# Overview
Idoxuridine is a Antiviral ophthalmologic Agent that is FDA approved for the treatment of keratitis caused by the virus of herpes simplex. Common adverse reactions include Acute ocular irritation including burning, corneal stippling, vascularization, and clouding.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- For the treatment of keratitis caused by the virus of herpes simplex.
### Dosage
- Instill one drop in the affected eye(s) every hour. In acute herpes, dosage may be tapered through every two hours to four times daily prior to discontinuation (treatment should be continued for at least seven days).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Idoxuridine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Idoxuridine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Idoxuridine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Idoxuridine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Idoxuridine in pediatric patients.
# Contraindications
- Hypersensitivity to the active ingredient or any other component of this drug.
# Warnings
### Precautions
- For topical use only. Do not exceed the frequency or duration of recommended dosage. The incidence of some adverse reactions increases with prolonged use. Idoxuridine is not effective in corneal inflammations following herpes simplex keratitis in which the virus is not present. Some strains of herpes simplex appear resistant to the action of Idoxuridine.
- Idoxuridine should be administered with caution in pregnancy or in women of childbearing potential. Idoxuridine has been reported to cross the placental barrier and to produce fetal malformations in rabbits when administered topically to the eyes of pregnant females in doses similar to those used clinically. Idoxuridine has also been reported to produce fetal malformations in the rat after intraperitoneal and oral administration and in the mouse after subcutaneous administration. Nursing should not be performed while a patient is undergoing IDU treatment as the drug and metabolites may be excreted in human milk.
- Idoxuridine has been reported to cause chromosome aberrations in mice and to be mutagenic in mammalian cells in culture (e.g., diploid human lymphoblasts and mouse lymphoma cells). Drosophila melanogaster and in a host-mediated assay system utilizing mammalian cells.
- The studies performed to date on idoxuridine are inadequate for assessment of carcinogenicity. This cytotoxic drug should be regarded as being potentially carcinogenic. It can inhibit DNA synthesis or function and is incorporated into the DNA of mammalian cells as well as into this genome of DNA viruses. Indoxuridine has been reported to induce RNA tumor virus (type C particles) production from virus negative mouse cells. The degree of oncogenic activity of idoxuridine induced oncornaviruses has not been documented. However, several idoxuridine activated oncornaviruses have caused in vitro cell transformation and induction of specific neoplasms (lymphatic leukemias and carcinomas) upon inoculation into syngenic mice.
# Adverse Reactions
## Clinical Trials Experience
- Acute ocular irritation including burning, corneal stippling, vascularization, and clouding has been reported. Following prolonged use of idoxuridine, ocular irritation characterized by follicular conjunctivitis, blepharitis with punctal swelling, bulbar conjunctival hyperemia, and corneal epithelial staining has also been reported. In either case, the drug should be discontinued.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Idoxuridine in the drug label.
# Drug Interactions
There is limited information regarding Idoxuridine Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Idoxuridine should be administered with caution in pregnancy or in women of childbearing potential. Idoxuridine has been reported to cross the placental barrier and to produce fetal malformations in rabbits when administered topically to the eyes of pregnant females in doses similar to those used clinically. Idoxuridine has also been reported to produce fetal malformations in the rat after intraperitoneal and oral administration and in the mouse after subcutaneous administration
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Idoxuridine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Idoxuridine during labor and delivery.
### Nursing Mothers
- Nursing should not be performed while a patient is undergoing IDU treatment as the drug and metabolites may be excreted in human milk.
### Pediatric Use
There is no FDA guidance on the use of Idoxuridine with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Idoxuridine with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Idoxuridine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Idoxuridine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Idoxuridine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Idoxuridine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Idoxuridine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Idoxuridine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical ophthalmic solution
### Monitoring
There is limited information regarding Monitoring of Idoxuridine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Idoxuridine in the drug label.
# Overdosage
There is limited information regarding Overdose of Idoxuridine in the drug label.
# Pharmacology
## Mechanism of Action
- Herpes simplex virus utilizes thymidine in the synthesis of deoxyribonucleic acid (DNA), a metabolite necessary for reproduction. Idoxuridine is identical in chemical structure to thymidine except that the 5-methyl group is replaced by iodine. When idoxuridine is substituted for thymidine in DNA, the cell is unable to utilize the DNA and reproduction ceases.
## Structure
- Dendrid® (idoxuridine) is an antiviral chemotherapeutic agent prepared in a sterile buffered isotonic solution. The active ingredient is represented by the chemical structure:
Established name:
Idoxuridine
Chemical name:
Uridine, 2’-deoxy-5-iodo-
Each ml contains: Active: Idoxuridine 0.1%. Preservative: Benzalkonium Chloride 0.01%. Inactive: Boric Acid, Edetate Disodium, Sodium Hydroxide and/or Hydrochloric Acid (to adjust pH), Purified Water. DM-01
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Idoxuridine in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Idoxuridine in the drug label.
## Nonclinical Toxicology
- Idoxuridine has been reported to cause chromosome aberrations in mice and to be mutagenic in mammalian cells in culture (e.g., diploid human lymphoblasts and mouse lymphoma cells). Drosophila melanogaster and in a host-mediated assay system utilizing mammalian cells.
# Clinical Studies
There is limited information regarding Clinical Studies of Idoxuridine in the drug label.
# How Supplied
- In a 15 ml plastic Drop-Tainer® dispenser.
NDC 0065-0029-15
## Storage
- Between 36°-80°F. Protect from light.
# Images
## Drug Images
## Package and Label Display Panel
### Ingredients and Appearance
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Idoxuridine in the drug label.
# Precautions with Alcohol
- Alcohol-Idoxuridine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- DENDRID®
# Look-Alike Drug Names
There is limited information regarding Idoxuridine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Idoxuridine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Idoxuridine is a Antiviral ophthalmologic Agent that is FDA approved for the treatment of keratitis caused by the virus of herpes simplex. Common adverse reactions include Acute ocular irritation including burning, corneal stippling, vascularization, and clouding.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- For the treatment of keratitis caused by the virus of herpes simplex.
### Dosage
- Instill one drop in the affected eye(s) every hour. In acute herpes, dosage may be tapered through every two hours to four times daily prior to discontinuation (treatment should be continued for at least seven days).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Idoxuridine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Idoxuridine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Idoxuridine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Idoxuridine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Idoxuridine in pediatric patients.
# Contraindications
- Hypersensitivity to the active ingredient or any other component of this drug.
# Warnings
### Precautions
- For topical use only. Do not exceed the frequency or duration of recommended dosage. The incidence of some adverse reactions increases with prolonged use. Idoxuridine is not effective in corneal inflammations following herpes simplex keratitis in which the virus is not present. Some strains of herpes simplex appear resistant to the action of Idoxuridine.
- Idoxuridine should be administered with caution in pregnancy or in women of childbearing potential. Idoxuridine has been reported to cross the placental barrier and to produce fetal malformations in rabbits when administered topically to the eyes of pregnant females in doses similar to those used clinically. Idoxuridine has also been reported to produce fetal malformations in the rat after intraperitoneal and oral administration and in the mouse after subcutaneous administration. Nursing should not be performed while a patient is undergoing IDU treatment as the drug and metabolites may be excreted in human milk.
- Idoxuridine has been reported to cause chromosome aberrations in mice and to be mutagenic in mammalian cells in culture (e.g., diploid human lymphoblasts and mouse lymphoma cells). Drosophila melanogaster and in a host-mediated assay system utilizing mammalian cells.
- The studies performed to date on idoxuridine are inadequate for assessment of carcinogenicity. This cytotoxic drug should be regarded as being potentially carcinogenic. It can inhibit DNA synthesis or function and is incorporated into the DNA of mammalian cells as well as into this genome of DNA viruses. Indoxuridine has been reported to induce RNA tumor virus (type C particles) production from virus negative mouse cells. The degree of oncogenic activity of idoxuridine induced oncornaviruses has not been documented. However, several idoxuridine activated oncornaviruses have caused in vitro cell transformation and induction of specific neoplasms (lymphatic leukemias and carcinomas) upon inoculation into syngenic mice.
# Adverse Reactions
## Clinical Trials Experience
- Acute ocular irritation including burning, corneal stippling, vascularization, and clouding has been reported. Following prolonged use of idoxuridine, ocular irritation characterized by follicular conjunctivitis, blepharitis with punctal swelling, bulbar conjunctival hyperemia, and corneal epithelial staining has also been reported. In either case, the drug should be discontinued.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Idoxuridine in the drug label.
# Drug Interactions
There is limited information regarding Idoxuridine Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Idoxuridine should be administered with caution in pregnancy or in women of childbearing potential. Idoxuridine has been reported to cross the placental barrier and to produce fetal malformations in rabbits when administered topically to the eyes of pregnant females in doses similar to those used clinically. Idoxuridine has also been reported to produce fetal malformations in the rat after intraperitoneal and oral administration and in the mouse after subcutaneous administration
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Idoxuridine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Idoxuridine during labor and delivery.
### Nursing Mothers
- Nursing should not be performed while a patient is undergoing IDU treatment as the drug and metabolites may be excreted in human milk.
### Pediatric Use
There is no FDA guidance on the use of Idoxuridine with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Idoxuridine with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Idoxuridine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Idoxuridine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Idoxuridine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Idoxuridine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Idoxuridine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Idoxuridine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical ophthalmic solution
### Monitoring
There is limited information regarding Monitoring of Idoxuridine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Idoxuridine in the drug label.
# Overdosage
There is limited information regarding Overdose of Idoxuridine in the drug label.
# Pharmacology
## Mechanism of Action
- Herpes simplex virus utilizes thymidine in the synthesis of deoxyribonucleic acid (DNA), a metabolite necessary for reproduction. Idoxuridine is identical in chemical structure to thymidine except that the 5-methyl group is replaced by iodine. When idoxuridine is substituted for thymidine in DNA, the cell is unable to utilize the DNA and reproduction ceases.
## Structure
- Dendrid® (idoxuridine) is an antiviral chemotherapeutic agent prepared in a sterile buffered isotonic solution. The active ingredient is represented by the chemical structure:
Established name:
Idoxuridine
Chemical name:
Uridine, 2’-deoxy-5-iodo-
Each ml contains: Active: Idoxuridine 0.1%. Preservative: Benzalkonium Chloride 0.01%. Inactive: Boric Acid, Edetate Disodium, Sodium Hydroxide and/or Hydrochloric Acid (to adjust pH), Purified Water. DM-01
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Idoxuridine in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Idoxuridine in the drug label.
## Nonclinical Toxicology
- Idoxuridine has been reported to cause chromosome aberrations in mice and to be mutagenic in mammalian cells in culture (e.g., diploid human lymphoblasts and mouse lymphoma cells). Drosophila melanogaster and in a host-mediated assay system utilizing mammalian cells.
# Clinical Studies
There is limited information regarding Clinical Studies of Idoxuridine in the drug label.
# How Supplied
- In a 15 ml plastic Drop-Tainer® dispenser.
NDC 0065-0029-15
## Storage
- Between 36°-80°F. Protect from light.
# Images
## Drug Images
## Package and Label Display Panel
### Ingredients and Appearance
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Idoxuridine in the drug label.
# Precautions with Alcohol
- Alcohol-Idoxuridine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- DENDRID®[1]
# Look-Alike Drug Names
There is limited information regarding Idoxuridine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Idoxuridine | |
ce98e58f7cf5aa3ffa04e83a653e706d7f09224d | wikidoc | Idraparinux | Idraparinux
# Overview
Idraparinux sodium is a novel long-acting synthetic indirect inhibitor of coagulation factor Xa. The agent is being developed by Sanofi-Aventis. It has a similar chemical structure and mechanism of action as fondaparinux, but its elimination half-life of 80 hours is 5 to 6 times longer than that of fondaparix (17 hours). Given its long half life, it can be injected subcutaneously once a week.
# Use in Atrial Fibrillation
## The AMADEUS study
The phase III AMADEUS study was a randomized, open label trial designed to compare the efficacy and safety of once-a-week idraparinux versus oral VKA treatment for the long-term prevention of thromboembolic events (stroke and non-central nervous system systemic embolism) in patients with AF and at least one additional risk factor for stroke. The predefined risk factors were previous ischemic stroke, transient ischemic attack or SE, hypertension requiring drug treatment, left ventricular dysfunction, age >75 years, age between 65-75 years plus diabetes mellitus, or age between 65-75 years plus symptomatic coronary heart disease.
Patients (n=4,576) with AF who were eligible for VKA treatment were randomized to receive either subcutaneous idraparinux 2.5 mg once a week (2,283) or VKA therapy (2,293) adjusted to achieve a target international normalized ratio (INR) of 2.5 (range 2 to 3) between September 2003 and July 2005. The study was powered to show non-inferior efficacy of idraparinux, compared with standard vitamin K antagonist (VKA) treatment in patients with AF who require prolonged oral anticoagulation. The primary efficacy endpoint was the composite of all strokes (ischemic, hemorrhagic and undefined) and non-CNS SE within the planned treatment period. The principal safety endpoint was the occurrence of major bleeding or clinically relevant non-major bleeding. The other safety outcome was all cause mortality.
A weekly subcutaneous administration of idraparinux was as effective as warfarin, a Vitamin K Antagonist (VKA), in reducing stroke and non Central Nervous System (CNS) systemic embolic events in patients with atrial fibrillation (AF), a population at risk of thromboembolic events (TE). The results of the AMADEUS study were presented at the XXI ISTH Congress (International Society on Thrombosis and Haemostasis) in Geneva.
The AMADEUS trial met its primary endpoint. The event rate of the composite endpoint of any strokes (ischemic, hemorrhagic, and undefined) and non-CNS systemic embolism was 0.9% with idraparinux and 1.3% with warfarin (p= 0.007), meeting the criteria for non-inferiority.
The incidence of clinically relevant bleeding, the primary safety outcome, was significantly higher in the idraparinux group than in the comparator group (19.7% vs. 11.3%, p<0.0001). There was an increase in fatal bleeds as well (13/1941 (0.7%) vs 2/2,131 (0.1%), HR =7.14, , although, overall no difference was observed in the all causes mortality between the two treatment groups. Intracranial hemorrhage was not increased (4/1,922 (0.2%) vs 5/2,107 (0.2%), HR= 0.88, ). Bleeding appeared over time and was more pronounced in patients with impaired renal function and in the elderly.
Given the increased risk of bleeding, future trials will adjust the dose of a reversible form of idraparinux depending on patient age and renal function. The BOREALIS-AF study will evaluate the safety and efficacy of a new neutralizable / reversible form of idraparinux (biotinylated idraparinux) to VKA in patients with atrial fibrillation and the dose will be adjusted depending on age and renal function after 7 weeks of treatment.
# Biotinylated Version of Idraparinux
Because idraparinux has a very long half life, a biotinylated version of this drug (SSR 126517) is also in clinical development. The addition of a biotin moiety to the structure allows the more rapid removal of the drug and reversal upon the addition of avidin. A bioequipotency study of biotinylated idraparinux vs. idraparinux for the treatment of DVT is ongoing.
Biotinylated idraparinux is being compared to warfarin for the treatment of pulmonary embolism in the phase III CASSIOPEA.
# The BOREALIS-AF study of Biotinylated Idraparinux
Once a week idraparinux treatment could represent a convenient alternative to cumbersome VKA treatment for AF patients. The goal of BOREALIS-AF is to improve the safety profile of Idraparinux using the reversible biotinylated idraparinux and adjusting the dose to patients renal function and age.
BOREALIS-AF is a multicenter, randomized, double-blind, assessor-blind, non-inferiority study comparing the efficacy and safety of once-a-week subcutaneous biotinylated idraparinux (whichis reversible) with adjusted-dose warfarin in the prevention of stroke and systemic thromboembolic events in patients with atrial fibrillation.
Treatment will be administrated for a period of 6 months to 2 years. All patients will start with biotinylated idraparinux 3 mg (equivalent to base idraparinux 2.5 mg) once-a-week for 7 weeks, and then the dose will be reduced depending on age and renal function. | Idraparinux
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Idraparinux sodium is a novel long-acting synthetic indirect inhibitor of coagulation factor Xa[1]. The agent is being developed by Sanofi-Aventis. It has a similar chemical structure and mechanism of action as fondaparinux, but its elimination half-life of 80 hours is 5 to 6 times longer than that of fondaparix (17 hours). Given its long half life, it can be injected subcutaneously once a week.
# Use in Atrial Fibrillation
## The AMADEUS study
The phase III AMADEUS study was a randomized, open label trial designed to compare the efficacy and safety of once-a-week idraparinux versus oral VKA treatment for the long-term prevention of thromboembolic events (stroke and non-central nervous system systemic embolism) in patients with AF and at least one additional risk factor for stroke. The predefined risk factors were previous ischemic stroke, transient ischemic attack or SE, hypertension requiring drug treatment, left ventricular dysfunction, age >75 years, age between 65-75 years plus diabetes mellitus, or age between 65-75 years plus symptomatic coronary heart disease.
Patients (n=4,576) with AF who were eligible for VKA treatment were randomized to receive either subcutaneous idraparinux 2.5 mg once a week (2,283) or VKA therapy (2,293) adjusted to achieve a target international normalized ratio (INR) of 2.5 (range 2 to 3) between September 2003 and July 2005. The study was powered to show non-inferior efficacy of idraparinux, compared with standard vitamin K antagonist (VKA) treatment in patients with AF who require prolonged oral anticoagulation. The primary efficacy endpoint was the composite of all strokes (ischemic, hemorrhagic and undefined) and non-CNS SE within the planned treatment period. The principal safety endpoint was the occurrence of major bleeding or clinically relevant non-major bleeding. The other safety outcome was all cause mortality.
A weekly subcutaneous administration of idraparinux was as effective as warfarin, a Vitamin K Antagonist (VKA), in reducing stroke and non Central Nervous System (CNS) systemic embolic events in patients with atrial fibrillation (AF), a population at risk of thromboembolic events (TE). The results of the AMADEUS study were presented at the XXI ISTH Congress (International Society on Thrombosis and Haemostasis) in Geneva.
The AMADEUS trial met its primary endpoint. The event rate of the composite endpoint of any strokes (ischemic, hemorrhagic, and undefined) and non-CNS systemic embolism was 0.9% with idraparinux and 1.3% with warfarin (p= 0.007), meeting the criteria for non-inferiority.
The incidence of clinically relevant bleeding, the primary safety outcome, was significantly higher in the idraparinux group than in the comparator group (19.7% vs. 11.3%, p<0.0001). There was an increase in fatal bleeds as well (13/1941 (0.7%) vs 2/2,131 (0.1%), HR =7.14, [95% CI =1.61;31.58], although, overall no difference was observed in the all causes mortality between the two treatment groups. Intracranial hemorrhage was not increased (4/1,922 (0.2%) vs 5/2,107 (0.2%), HR= 0.88, [95% CI = 0.24;3.26]). Bleeding appeared over time and was more pronounced in patients with impaired renal function and in the elderly.
Given the increased risk of bleeding, future trials will adjust the dose of a reversible form of idraparinux depending on patient age and renal function. The BOREALIS-AF study will evaluate the safety and efficacy of a new neutralizable / reversible form of idraparinux (biotinylated idraparinux) to VKA in patients with atrial fibrillation and the dose will be adjusted depending on age and renal function after 7 weeks of treatment.
# Biotinylated Version of Idraparinux
Because idraparinux has a very long half life, a biotinylated version of this drug (SSR 126517) is also in clinical development. The addition of a biotin moiety to the structure allows the more rapid removal of the drug and reversal upon the addition of avidin. A bioequipotency study of biotinylated idraparinux vs. idraparinux for the treatment of DVT is ongoing.
Biotinylated idraparinux is being compared to warfarin for the treatment of pulmonary embolism in the phase III CASSIOPEA.
# The BOREALIS-AF study of Biotinylated Idraparinux
Once a week idraparinux treatment could represent a convenient alternative to cumbersome VKA treatment for AF patients. The goal of BOREALIS-AF is to improve the safety profile of Idraparinux using the reversible biotinylated idraparinux and adjusting the dose to patients renal function and age.
BOREALIS-AF is a multicenter, randomized, double-blind, assessor-blind, non-inferiority study comparing the efficacy and safety of once-a-week subcutaneous biotinylated idraparinux (whichis reversible) with adjusted-dose warfarin in the prevention of stroke and systemic thromboembolic events in patients with atrial fibrillation.
Treatment will be administrated for a period of 6 months to 2 years. All patients will start with biotinylated idraparinux 3 mg (equivalent to base idraparinux 2.5 mg) once-a-week for 7 weeks, and then the dose will be reduced depending on age and renal function. | https://www.wikidoc.org/index.php/Idraparinux | |
fbb360f88ed0511aee73234584bdf59d9644b0ab | wikidoc | Paraprotein | Paraprotein
A paraprotein is an abnormal protein in the urine or blood, most often associated with benign MGUS (monoclonal gammopathy of undetermined significance), where they remain "silent", and multiple myeloma. An excess in the blood is known as paraproteinemia.
These are immunoglobulins or immunoglobulin light-chains that are produced by the clonal proliferation of plasma cells. Paraproteins form a narrow band, or 'spike' in protein electrophoresis as they are all exactly the same protein.
Monoclonal free light chains in the serum or urine are called Bence Jones proteins.
# History
The concept and term were introduced by the Berlin pathologist Dr Kurt Apitz in 1940, at that time the Oberarzt of the pathological institute at the Charité hospital.
Paraproteins allowed the detailed study of immunoglobulins, which eventually led to the production of monoclonal antibodies in 1975. | Paraprotein
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
A paraprotein is an abnormal protein in the urine or blood, most often associated with benign MGUS (monoclonal gammopathy of undetermined significance), where they remain "silent",[1] and multiple myeloma. An excess in the blood is known as paraproteinemia.
These are immunoglobulins or immunoglobulin light-chains that are produced by the clonal proliferation of plasma cells. Paraproteins form a narrow band, or 'spike' in protein electrophoresis as they are all exactly the same protein.
Monoclonal free light chains in the serum or urine are called Bence Jones proteins.
# History
The concept and term were introduced by the Berlin pathologist Dr Kurt Apitz in 1940,[2] at that time the Oberarzt of the pathological institute at the Charité hospital.[3]
Paraproteins allowed the detailed study of immunoglobulins, which eventually led to the production of monoclonal antibodies in 1975. | https://www.wikidoc.org/index.php/IgM_monoclonal_protein | |
c8f1269d309fac00c230024c5d5dd4d004ece4d5 | wikidoc | Illiciaceae | Illiciaceae
Illiciaceae is the botanical name of a family of flowering plants. Such a family has been recognized by most taxonomists, at least for the past several decades.
The APG II system, of 2003 does not recognize such a family, not as such. However, it does allow the option of segregating this from the family Schisandraceae. This (optional segregate) family then has the traditional circumscription, consisting of a single genus, Illicium, of a few dozen species occurring in Southeast Asia and the New World (the West Indies and the adjacent areas of North America).
For furter details of placement in various systems see the entry for family Schisandraceae. | Illiciaceae
Illiciaceae is the botanical name of a family of flowering plants. Such a family has been recognized by most taxonomists, at least for the past several decades.
The APG II system, of 2003 does not recognize such a family, not as such. However, it does allow the option of segregating this from the family Schisandraceae. This (optional segregate) family then has the traditional circumscription, consisting of a single genus, Illicium, of a few dozen species occurring in Southeast Asia and the New World (the West Indies and the adjacent areas of North America).
For furter details of placement in various systems see the entry for family Schisandraceae.
External links :
- Illiciaceae in L. Watson and M.J. Dallwitz (1992 onwards) The families of flowering plants: descriptions, illustrations, identification, information retrieval. Version: 3rd May 2006. http://delta-intkey.com.
- Illiciaceae in the Flora of North America
de:Sternanis (Gattung)
hu:Csillagánizsfélék
lt:Žvaigždanyžiniai
nl:Illiciaceae
Template:WS | https://www.wikidoc.org/index.php/Illiciaceae | |
a2295e554f5507ab9c26006aa73d0e84ba57462a | wikidoc | Iloperidone | Iloperidone
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Iloperidone is an atypical antipsychotic agent that is FDA approved for the {{{indicationType}}} of schizophrenia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include dizziness, dry mouth, fatigue, nasal congestion, orthostatic hypotension, somnolence, tachycardia, and weight increased.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- FANAPT must be titrated slowly from a low starting dose to avoid orthostatic hypotension due to its alpha-adrenergic blocking properties. The recommended starting dose for FANAPT tablets is 1 mg twice daily. Dose increases to reach the target range of 6 to 12 mg twice daily (12 to 24 mg/day) may be made with daily dosage adjustments not to exceed 2 mg twice daily (4 mg/day). The maximum recommended dose is 12 mg twice daily (24 mg/day). FANAPT doses above 24 mg/day have not been systematically evaluated in the clinical trials. Efficacy was demonstrated with FANAPT in a dose range of 6 to 12 mg twice daily. Prescribers should be mindful of the fact that patients need to be titrated to an effective dose of FANAPT. Thus, control of symptoms may be delayed during the first 1 to 2 weeks of treatment compared to some other antipsychotic drugs that do not require similar titration. Prescribers should also be aware that some adverse effects associated with FANAPT use are dose related.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Iloperidone in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Iloperidone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Iloperidone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Iloperidone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Iloperidone in pediatric patients.
# Contraindications
- FANAPT is contraindicated in individuals with a known hypersensitivity reaction to the product. Reactions have included pruritus and urticaria.
# Warnings
### Precautions
- Increased Risks in Elderly Patients with Dementia-Related Psychosis
- Increased Mortality
- Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. FANAPT is not approved for the treatment of patients with dementia-related psychosis.
- Cerebrovascular Adverse Events, Including Stroke
- In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly patients with dementia, there was a higher incidence of cerebrovascular adverse events (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated patients. FANAPT is not approved for the treatment of patients with dementia-related psychosis.
- QT Prolongation
- In an open-label QTc study in patients with schizophrenia or schizoaffective disorder (n=160), FANAPT was associated with QTc prolongation of 9 msec at an iloperidone dose of 12 mg twice daily. The effect of FANAPT on the QT interval was augmented by the presence of CYP450 2D6 or 3A4 metabolic inhibition (paroxetine 20 mg once daily and ketoconazole 200 mg twice daily, respectively). Under conditions of metabolic inhibition for both 2D6 and 3A4, FANAPT 12 mg twice daily was associated with a mean QTcF increase from baseline of about 19 msec.
- No cases of torsade de pointes or other severe cardiac arrhythmias were observed during the pre-marketing clinical program.
- The use of FANAPT should be avoided in combination with other drugs that are known to prolong QTc including Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications, antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval (e.g., pentamidine, levomethadyl acetate, methadone). FANAPT should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias.
- Certain circumstances may increase the risk of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval; (5) recent acute myocardial infarction; and/or (6) uncompensated heart failure.
- Caution is warranted when prescribing FANAPT with drugs that inhibit FANAPT metabolism, and in patients with reduced activity of CYP2D6.
- It is recommended that patients being considered for FANAPT treatment who are at risk for significant electrolyte disturbances have baseline serum potassium and magnesium measurements with periodic monitoring. Hypokalemia (and/or hypomagnesemia) may increase the risk of QT prolongation and arrhythmia. FANAPT should be avoided in patients with histories of significant cardiovascular illness, e.g., QT prolongation, recent acute myocardial infarction, uncompensated heart failure, or cardiac arrhythmia. FANAPT should be discontinued in patients who are found to have persistent QTc measurements >500 msec.
- If patients taking FANAPT experience symptoms that could indicate the occurrence of cardiac arrhythmias, e.g., dizziness, palpitations, or syncope, the prescriber should initiate further evaluation, including cardiac monitoring.
- Neuroleptic Malignant Syndrome (NMS)
- A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including FANAPT. Clinical manifestations include hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
- The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system (CNS) pathology.
- The management of this syndrome should include: (1) immediate discontinuation of the antipsychotic drugs and other drugs not essential to concurrent therapy, (2) intensive symptomatic treatment and medical monitoring, and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.
- If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
- Tardive Dyskinesia
- Tardive dyskinesia is a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, which may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely on prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
- The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic administered increases. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.
- There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
- Given these considerations, FANAPT should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.
- If signs and symptoms of tardive dyskinesia appear in a patient on FANAPT, drug discontinuation should be considered. However, some patients may require treatment with FANAPT despite the presence of the syndrome.
- Metabolic Changes
- Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all atypical antipsychotic drugs have been shown to produce some metabolic changes, each drug in the class has its own specific risk profile.
- Hyperglycemia and Diabetes Mellitus
- Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including FANAPT. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics included in these studies. Because FANAPT was not marketed at the time these studies were performed, it is not known if FANAPT is associated with this increased risk.
- Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.
- Data from a 4-week, fixed-dose study in adult subjects with schizophrenia, in which fasting blood samples were drawn, are presented in Table 1.
- Dyslipidemia
- Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
- Data from a placebo-controlled, 4-week, fixed-dose study, in which fasting blood samples were drawn, in adult subjects with schizophrenia are presented in Table 3.
- Pooled analyses of cholesterol and triglyceride data from clinical studies including longer term trials are shown in Tables 4 and 5.
- Weight Gain
- Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.
- Across all short- and long-term studies, the overall mean change from baseline at endpoint was 2.1 kg.
- Changes in body weight (kg) and the proportion of subjects with ≥7% gain in body weight from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies in adult subjects are presented in Table 6.
- Seizures
- In short-term placebo-controlled trials (4- to 6-weeks), seizures occurred in 0.1% (1/1344) of patients treated with FANAPT compared to 0.3% (2/587) on placebo. As with other antipsychotics, FANAPT should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer’s dementia. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.
- Orthostatic Hypotension and Syncope
- FANAPT can induce orthostatic hypotension associated with dizziness, tachycardia, and syncope. This reflects its alpha1-adrenergic antagonist properties. In double-blind placebo-controlled short-term studies, where the dose was increased slowly, as recommended above, syncope was reported in 0.4% (5/1344) of patients treated with FANAPT, compared with 0.2% (1/587) on placebo. Orthostatic hypotension was reported in 5% of patients given 20 to 24 mg/day, 3% of patients given 10 to 16 mg/day, and 1% of patients given placebo. More rapid titration would be expected to increase the rate of orthostatic hypotension and syncope.
- FANAPT should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history of myocardial infarction, ischemia, or conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications). Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to hypotension.
- Leukopenia, Neutropenia and Agranulocytosis
- In clinical trial and postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents. Agranulocytosis (including fatal cases) has also been reported.
- Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue FANAPT at the first sign of a decline in WBC in the absence of other causative factors.
- Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue FANAPT and have their WBC followed until recovery.
- Hyperprolactinemia
- As with other drugs that antagonize dopamine D2 receptors, FANAPT elevates prolactin levels.
- Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadalsteroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male patients.
- Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. Mammary gland proliferative changes and increases in serum prolactin were seen in mice and rats treated with FANAPT . Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time.
- In a short-term placebo-controlled trial (4-weeks), the mean change from baseline to endpoint in plasma prolactin levels for the FANAPT 24 mg/day-treated group was an increase of 2.6 ng/mL compared to a decrease of 6.3 ng/mL in the placebo-group. In this trial, elevated plasma prolactin levels were observed in 26% of adults treated with FANAPT compared to 12% in the placebo-group. In the short-term trials, FANAPT was associated with modest levels of prolactin elevation compared to greater prolactin elevations observed with some other antipsychotic agents. In pooled analysis from clinical studies including longer term trials, in 3210 adults treated with iloperidone, gynecomastia was reported in 2 male subjects (0.1%) compared to 0% in placebo-treated patients, and galactorrhea was reported in 8 female subjects (0.2%) compared to 3 female subjects (0.5%) in placebo-treated patients.
- Body Temperature Regulation
- Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing FANAPT for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.
- Dysphagia
- Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer’s dementia. FANAPT and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.
- Suicide
- The possibility of a suicide attempt is inherent in psychotic illness, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for FANAPT should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose.
- Priapism
- Three cases of priapism were reported in the premarketing FANAPT program. Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. FANAPT shares this pharmacologic activity. Severe priapism may require surgical intervention.
- Potential for Cognitive and Motor Impairment
- FANAPT, like other antipsychotics, has the potential to impair judgment, thinking or motor skills. In short-term, placebo-controlled trials, somnolence (including sedation) was reported in 11.9% (104/874) of adult patients treated with FANAPT at doses of 10 mg/day or greater versus 5.3% (31/587) treated with placebo. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with FANAPT does not affect them adversely.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trial of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The information below is derived from a clinical trial database for FANAPT consisting of 2070 patients exposed to FANAPT at doses of 10 mg/day or greater, for the treatment of schizophrenia. Of these, 806 received FANAPT for at least 6 months, with 463 exposed to FANAPT for at least 12 months. All of these patients who received FANAPT were participating in multiple-dose clinical trials. The conditions and duration of treatment with FANAPT varied greatly and included (in overlapping categories), open-label and double-blind phases of studies, inpatients and outpatients, fixed-dose and flexible-dose studies, and short-term and longer-term exposure.
- Adverse reactions during exposure were obtained by general inquiry and recorded by clinical investigators using their own terminology. Consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions, reactions were grouped in standardized categories using MedDRA terminology.
- The stated frequencies of adverse reactions represent the proportions of individuals who experienced a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.
- The information presented in these sections was derived from pooled data from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies in patients who received FANAPT at daily doses within a range of 10 to 24 mg (n=874).
- Adverse Reactions Occurring at an Incidence of 2% or More among FANAPT-Treated Patients and More Frequent than Placebo
- Table 7 enumerates the pooled incidences of treatment-emergent adverse reactions that were spontaneously reported in four placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies, listing those reactions that occurred in 2% or more of patients treated with FANAPT in any of the dose groups, and for which the incidence in FANAPT-treated patients in any dose group was greater than the incidence in patients treated with placebo.
- Dose-Related Adverse Reactions in Clinical Trials
- Based on the pooled data from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies, adverse reactions that occurred with a greater than 2% incidence in the patients treated with FANAPT, and for which the incidence in patients treated with FANAPT 20 to 24 mg/day were twice than the incidence in patients treated with FANAPT 10 to 16 mg/day were: abdominal discomfort, dizziness, hypotension, musculoskeletal stiffness, tachycardia, and weight increased.
- Common and Drug-Related Adverse Reactions in Clinical Trials
- Based on the pooled data from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies, the following adverse reactions occurred in ≥5% incidence in the patients treated with FANAPT and at least twice the placebo rate for at least 1 dose: dizziness, dry mouth, fatigue, nasal congestion, somnolence, tachycardia, orthostatic hypotension, and weight increased. Dizziness, tachycardia, and weight increased were at least twice as common on 20 to 24 mg/day as on 10 to 16 mg/day.
- Extrapyramidal Symptoms (EPS) in Clinical Trials
- Pooled data from the 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies provided information regarding treatment-emergent EPS. Adverse event data collected from those trials showed the following rates of EPS-related adverse events as shown in Table 8.
- Adverse Reactions Associated with Discontinuation of Treatment in Clinical Trials
- Based on the pooled data from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies, there was no difference in the incidence of discontinuation due to adverse events between FANAPT-treated (5%) and placebo-treated (5%) patients. The types of adverse events that led to discontinuation were similar for the FANAPT- and placebo-treated patients.
- Demographic Differences in Adverse Reactions in Clinical Trials
- An examination of population subgroups in the 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies did not reveal any evidence of differences in safety on the basis of age, gender or race.
- Laboratory Test Abnormalities in Clinical Trials
- There were no differences between FANAPT and placebo in the incidence of discontinuation due to changes in hematology, urinalysis, or serum chemistry.
- In short-term placebo-controlled trials (4- to 6-weeks), there were 1.0% (13/1342) iloperidone-treated patients with hematocrit at least one time below the extended normal range during post-randomization treatment, compared to 0.3% (2/585) on placebo. The extended normal range for lowered hematocrit was defined in each of these trials as the value 15% below the normal range for the centralized laboratory that was used in the trial.
- Other Reactions During the Premarketing Evaluation of FANAPT
- The following is a list of MedDRA terms that reflect treatment-emergent adverse reactions in patients treated with FANAPT at multiple doses ≥4 mg/day during any phase of a trial with the database of 3210 FANAPT-treated patients. All reported reactions are included except those already listed in Table 7, or other parts of the Adverse Reactions (6) section, those considered in the Warnings and Precautions (5), those reaction terms which were so general as to be uninformative, reactions reported in fewer than 3 patients and which were neither serious nor life-threatening, reactions that are otherwise common as background reactions, and reactions considered unlikely to be drug related. It is important to emphasize that, although the reactions reported occurred during treatment with FANAPT, they were not necessarily caused by it.
- Reactions are further categorized by MedDRA system organ class and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring in at least 1/100 patients (only those not listed in Table 7 appear in this listing); infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.
Infrequent – anemia, iron deficiency anemia; Rare – leukopenia
Frequent – palpitations; Rare – arrhythmia, atrioventricular block first degree, cardiac failure (including congestive and acute)
Infrequent – vertigo, tinnitus
Infrequent – hypothyroidism
Frequent - conjunctivitis (including allergic); Infrequent – dry eye, blepharitis, eyelid edema, eye swelling, lenticular opacities, cataract, hyperemia (including conjunctival)
Infrequent – gastritis, salivary hypersecretion, fecal incontinence, mouth ulceration; Rare - aphthous stomatitis, duodenal ulcer, hiatus hernia, hyperchlorhydria, lip ulceration, reflux esophagitis, stomatitis
Infrequent – edema (general, pitting, due to cardiac disease), difficulty in walking, thirst; Rare - hyperthermia
Infrequent – cholelithiasis
Frequent - weight decreased; Infrequent – hemoglobin decreased, neutrophil count increased, hematocrit decreased
Infrequent – increased appetite, dehydration, hypokalemia, fluid retention
Frequent – myalgia, muscle spasms; Rare – torticollis
Infrequent – paresthesia, psychomotor hyperactivity, restlessness, amnesia, nystagmus; Rare – restless legs syndrome
Frequent – restlessness, aggression, delusion; Infrequent – hostility, libido decreased, paranoia, anorgasmia, confusional state, mania, catatonia, mood swings, panic attack, obsessive-compulsive disorder, bulimia nervosa, delirium, polydipsia psychogenic, impulse-control disorder, major depression
Frequent – urinary incontinence; Infrequent – dysuria, pollakiuria, enuresis, nephrolithiasis; Rare – urinary retention, renal failure acute
Frequent – erectile dysfunction; Infrequent – testicular pain, amenorrhea, breast pain; Rare – menstruation irregular, gynecomastia, menorrhagia, metrorrhagia, postmenopausal hemorrhage, prostatitis.
Infrequent – epistaxis, asthma, rhinorrhea, sinus congestion, nasal dryness; Rare – dry throat, sleep apnea syndrome, dyspnea exertional
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of FANAPT: retrograde ejaculation. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
# Drug Interactions
- Potential for Other Drugs to Affect FANAPT
- Iloperidone is not a substrate for CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. This suggests that an interaction of iloperidone with inhibitors or inducers of these enzymes, or other factors, like smoking, is unlikely.
- Both CYP3A4 and CYP2D6 are responsible for iloperidone metabolism. Inhibitors of CYP3A4 (e.g., ketoconazole) or CYP2D6 (e.g., fluoxetine, paroxetine) can inhibit iloperidone elimination and cause increased blood levels.
- Ketoconazole: Co-administration of ketoconazole (200 mg twice daily for 4 days), a potent inhibitor of CYP3A4, with a 3 mg single dose of iloperidone to 19 healthy volunteers, ages 18 to 45 years, increased the area under the curve (AUC) of iloperidone and its metabolites P88 and P95 by 57%, 55% and 35%, respectively. Iloperidone doses should be reduced by about one-half when administered with ketoconazole or other strong inhibitors of CYP3A4 (e.g., itraconazole). Weaker inhibitors (e.g., erythromycin, grapefruit juice) have not been studied. When the CYP3A4 inhibitor is withdrawn from the combination therapy, the iloperidone dose should be returned to the previous level.
- Fluoxetine: Co-administration of fluoxetine (20 mg twice daily for 21 days), a potent inhibitor of CYP2D6, with a single 3 mg dose of iloperidone to 23 healthy volunteers, ages 29 to 44 years, who were classified as CYP2D6 extensive metabolizers, increased the AUC of iloperidone and its metabolite P88, by about 2- to 3-fold, and decreased the AUC of its metabolite P95 by one-half. Iloperidone doses should be reduced by one-half when administered with fluoxetine. When fluoxetine is withdrawn from the combination therapy, the iloperidone dose should be returned to the previous level. Other strong inhibitors of CYP2D6 would be expected to have similar effects and would need appropriate dose reductions. When the CYP2D6 inhibitor is withdrawn from the combination therapy, iloperidone dose could then be increased to the previous level.
- Paroxetine: Co-administration of paroxetine (20 mg/day for 5 to 8 days), a potent inhibitor of CYP2D6, with multiple doses of iloperidone (8 or 12 mg twice daily) to patients with schizophrenia ages 18 to 65 years resulted in increased mean steady-state peak concentrations of iloperidone and its metabolite P88, by about 1.6-fold, and decreased mean steady-state peak concentrations of its metabolite P95 by one-half. Iloperidone doses should be reduced by one-half when administered with paroxetine. When paroxetine is withdrawn from the combination therapy, the iloperidone dose should be returned to the previous level. Other strong inhibitors of CYP2D6 would be expected to have similar effects and would need appropriate dose reductions. When the CYP2D6 inhibitor is withdrawn from the combination therapy, iloperidone dose could then be increased to previous levels.
- Paroxetine and Ketoconazole: Co-administration of paroxetine (20 mg once daily for 10 days), a CYP2D6 inhibitor, and ketoconazole (200 mg twice daily) with multiple doses of iloperidone (8 or 12 mg twice daily) to patients with schizophrenia ages 18 to 65 years resulted in a 1.4-fold increase in steady-state concentrations of iloperidone and its metabolite P88 and a 1.4-fold decrease in the P95 in the presence of paroxetine. So giving iloperidone with inhibitors of both of its metabolic pathways did not add to the effect of either inhibitor given alone. Iloperidone doses should therefore be reduced by about one-half if administered concomitantly with both a CYP2D6 and CYP3A4 inhibitor.
- Potential for FANAPT to Affect Other Drugs
- In vitro studies in human liver microsomes showed that iloperidone does not substantially inhibit the metabolism of drugs metabolized by the following cytochrome P450 isozymes: CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, or CYP2E1. Furthermore, in vitro studies in human liver microsomes showed that iloperidone does not have enzyme inducing properties, specifically for the following cytochrome P450 isozymes: CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4 and CYP3A5.
- Dextromethorphan: A study in healthy volunteers showed that changes in the pharmacokinetics of dextromethorphan (80 mg dose) when a 3 mg dose of iloperidone was co-administered resulted in a 17% increase in total exposure and a 26% increase in the maximum plasma concentrations (Cmax)of dextromethorphan. Thus, an interaction between iloperidone and other CYP2D6 substrates is unlikely.
- Fluoxetine: A single 3 mg dose of iloperidone had no effect on the pharmacokinetics of fluoxetine (20 mg twice daily).
- Midazolam (a sensitive CYP 3A4 substrate): A study in patients with schizophrenia showed a less than 50% increase in midazolam total exposure at iloperidone steady state (14 days of oral dosing at up to 10 mg iloperidone twice daily) and no effect on midazolam Cmax. Thus, an interaction between iloperidone and other CYP3A4 substrates is unlikely.
- Drugs that Prolong the QT Interval
- FANAPT should not be used with any other drugs that prolong the QT interval.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- FANAPT caused developmental toxicity, but was not teratogenic, in rats and rabbits.
- In an embryo-fetal development study, pregnant rats were given 4, 16, or 64 mg/kg/day (1.6, 6.5, and 26 times the maximum recommended human dose (MRHD) of 24 mg/day on a mg/m2 basis) of iloperidone orally during the period of organogenesis. The highest dose caused increased early intrauterine deaths, decreased fetal weight and length, decreased fetal skeletal ossification, and an increased incidence of minor fetal skeletal anomalies and variations; this dose also caused decreased maternal food consumption and weight gain.
- In an embryo-fetal development study, pregnant rabbits were given 4, 10, or 25 mg/kg/day (3, 8, and 20 times the MRHD on a mg/m2 basis) of iloperidone during the period of organogenesis. The highest dose caused increased early intrauterine deaths and decreased fetal viability at term; this dose also caused maternal toxicity.
- In additional studies in which rats were given iloperidone at doses similar to the above beginning from either pre-conception or from day 17 of gestation and continuing through weaning, adverse reproductive effects included prolonged pregnancy and parturition, increased stillbirth rates, increased incidence of fetal visceral variations, decreased fetal and pup weights, and decreased post-partum pup survival. There were no drug effects on the neurobehavioral or reproductive development of the surviving pups. No-effect doses ranged from 4 to 12 mg/kg except for the increase in stillbirth rates which occurred at the lowest dose tested of 4 mg/kg, which is 1.6 times the MRHD on a mg/m2 basis. Maternal toxicity was seen at the higher doses in these studies.
- The iloperidone metabolite P95, which is a major circulating metabolite of iloperidone in humans but is not present in significant amounts in rats, was given to pregnant rats during the period of organogenesis at oral doses of 20, 80, or 200 mg/kg/day. No teratogenic effects were seen. Delayed skeletal ossification occurred at all doses. No significant maternal toxicity was produced. Plasma levels of P95 (AUC) at the highest dose tested were 2 times those in humans receiving the MRHD of iloperidone.
- There are no adequate and well-controlled studies in pregnant women.
- Non-teratogenic Effects
- Neonates exposed to antipsychotic drugs, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.
- FANAPT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Iloperidone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Iloperidone during labor and delivery.
### Nursing Mothers
- FANAPT was excreted in milk of rats during lactation. It is not known whether FANAPT or its metabolites are excreted in human milk. It is recommended that women receiving FANAPT should not breastfeed.
### Pediatric Use
- Safety and effectiveness in pediatric and adolescent patients have not been established.
### Geriatic Use
- Clinical Studies of FANAPT in the treatment of schizophrenia did not include sufficient numbers of patients aged 65 years and over to determine whether or not they respond differently than younger adult patients. Of the 3210 patients treated with FANAPT in premarketing trials, 25 (0.5%) were ≥65 years old and there were no patients ≥75 years old.
- Studies of elderly patients with psychosis associated with Alzheimer’s disease have suggested that there may be a different tolerability profile (i.e., increased risk in mortality and cerebrovascular events including stroke) in this population compared to younger patients with schizophrenia. The safety and efficacy of FANAPT in the treatment of patients with psychosis associated with Alzheimer’s disease has not been established. If the prescriber elects to treat such patients with FANAPT, vigilance should be exercised.
### Gender
There is no FDA guidance on the use of Iloperidone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Iloperidone with respect to specific racial populations.
### Renal Impairment
- Because FANAPT is highly metabolized, with less than 1% of the drug excreted unchanged, renal impairment alone is unlikely to have a significant impact on the pharmacokinetics of FANAPT. Renal impairment (creatinine clearance <30 mL/min) had minimal effect on Cmax of iloperidone (given in a single dose of 3 mg) and its metabolites P88 and P95 in any of the 3 analytes measured. AUC0–∞ was increased by 24%, decreased by 6%, and increased by 52% for iloperidone, P88 and P95, respectively, in subjects with renal impairment.
### Hepatic Impairment
- No dose adjustment to FANAPT is needed in patients with mild hepatic impairment. Exercise caution when administering it to patients with moderate hepatic impairment. FANAPT is not recommended for patients with severe hepatic impairment.
- In adult subjects with mild hepatic impairment no relevant difference in pharmacokinetics of iloperidone, P88 or P95 (total or unbound) was observed compared to healthy adult controls. In subjects with moderate hepatic impairment a higher (2-fold) and more variable free exposure to the active metabolites P88 was observed compared to healthy controls, whereas exposure to iloperidone and P95 was generally similar (less than 50% change compared to control). Since a study in severe liver impaired subjects has not been conducted, FANAPT is not recommended for patients with severe hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Iloperidone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Iloperidone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Iloperidone in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Iloperidone in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- In premarketing trials involving over 3210 patients, accidental or intentional overdose of FANAPT was documented in 8 patients ranging from 48 mg to 576 mg taken at once and 292 mg taken over a 3-day period. No fatalities were reported from these cases. The largest confirmed single ingestion of FANAPT was 576 mg; no adverse physical effects were noted for this patient. The next largest confirmed ingestion of FANAPT was 438 mg over a 4-day period; extrapyramidal symptoms and a QTc interval of 507 msec were reported for this patient with no cardiac sequelae. This patient resumed FANAPT treatment for an additional 11 months. In general, reported signs and symptoms were those resulting from an exaggeration of the known pharmacological effects (e.g., drowsiness and sedation, tachycardia and hypotension) of FANAPT.
### Management
- There is no specific antidote for FANAPT. Therefore appropriate supportive measures should be instituted. In case of acute overdose, the physician should establish and maintain an airway and ensure adequate oxygenation and ventilation. Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. The possibility of obtundation, seizures or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should commence immediately and should include continuous ECG monitoring to detect possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide and quinidine should not be used, as they have the potential for QT-prolonging effects that might be additive to those of FANAPT. Similarly, it is reasonable to expect that the alpha-blocking properties of bretylium might be additive to those of FANAPT, resulting in problematic hypotension. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of FANAPT-induced alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision should continue until the patient recovers.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Iloperidone in the drug label.
# Pharmacology
## Mechanism of Action
- The mechanism of action of FANAPT, as with other drugs having efficacy in schizophrenia, is unknown. However it is proposed that the efficacy of FANAPT is mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5-HT2) antagonisms.
## Structure
- FANAPT is a psychotropic agent belonging to the chemical class of piperidinyl-benzisoxazole derivatives. Its chemical name is 4’-propoxy]-3’-methoxyacetophenone. Its molecular formula is C24H27FN2O4 and its molecular weight is 426.48. The structural formula is:
- Iloperidone is a white to off-white finely crystalline powder. It is practically insoluble in water, very slightly soluble in 0.1 N HCl and freely soluble in chloroform, ethanol, methanol, and acetonitrile.
- FANAPT tablets are intended for oral administration only. Each round, uncoated tablet contains 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, or 12 mg of iloperidone. Inactive ingredients are: lactose monohydrate, microcrystalline cellulose, hydroxypropylmethylcellulose, crospovidone, magnesium stearate, colloidal silicon dioxide, and purified water (removed during processing). The tablets are white, round, flat, beveled-edged and identified with a logo “Tablet Imprint ” debossed on one side and tablet strength “1”, “2”, “4”, “6”, “8”, “10”, or “12” debossed on the other side.
## Pharmacodynamics
- FANAPT exhibits high (nM) affinity binding to serotonin 5-HT2A dopamine D2 and D3 receptors, and norepinephrine NEα1 receptors (Ki values of 5.6, 6.3, 7.1, and 0.36 nM, respectively). FANAPT has moderate affinity for dopamine D4, and serotonin 5-HT6 and 5-HT7 receptors (Ki values of 25, 43, and 22, nM respectively), and low affinity for the serotonin 5-HT1A, dopamine D1, and histamine H1 receptors (Ki values of 168, 216 and 437 nM, respectively). FANAPT has no appreciable affinity (Ki >1000 nM) for cholinergic muscarinic receptors. FANAPT functions as an antagonist at the dopamine D2, D3, serotonin 5-HT1A and norepinephrine α1/α2C receptors. The affinity of the FANAPT metabolite P88 is generally equal or less than that of the parent compound. In contrast, the metabolite P95 only shows affinity for 5-HT2A (Ki value of 3.91) and the NEα1A, NEα1B, NEα1D, and NEα2C receptors (Ki values of 4.7, 2.7, 8.8, and 4.7 nM respectively).
## Pharmacokinetics
- The observed mean elimination half-lives for iloperidone, P88 and P95 in CYP2D6 extensive metabolizers (EM) are 18, 26, and 23 hours, respectively, and in poor metabolizers (PM) are 33, 37, and 31 hours, respectively. Steady-state concentrations are attained within 3 to 4 days of dosing. Iloperidone accumulation is predictable from single-dose pharmacokinetics. The pharmacokinetics of iloperidone is more than dose proportional. Elimination of iloperidone is mainly through hepatic metabolism involving 2 P450 isozymes, CYP2D6 and CYP3A4.
- Absorption: Iloperidone is well absorbed after administration of the tablet with peak plasma concentrations occurring within 2 to 4 hours; while the relative bioavailability of the tablet formulation compared to oral solution is 96%. Administration of iloperidone with a standard high-fat meal did not significantly affect the Cmax or AUC of iloperidone, P88, or P95, but delayed Tmax by 1 hour for iloperidone, 2 hours for P88 and 6 hours for P95. FANAPT can be administered without regard to meals.
- Distribution: Iloperidone has an apparent clearance (clearance/bioavailability) of 47 to 102 L/h, with an apparent volume of distribution of 1340 to 2800 L. At therapeutic concentrations, the unbound fraction of iloperidone in plasma is ~3% and of each metabolite (P88 and P95) it is ~8%.
- Metabolism and Elimination: Iloperidone is metabolized primarily by 3 biotransformation pathways: carbonyl reduction, hydroxylation (mediated by CYP2D6) and O-demethylation (mediated by CYP3A4). There are 2 predominant iloperidone metabolites, P95 and P88. The iloperidone metabolite P95 represents 47.9% of the AUC of iloperidone and its metabolites in plasma at steady-state for extensive metabolizers (EM) and 25% for poor metabolizers (PM). The active metabolite P88 accounts for 19.5% and 34.0% of total plasma exposure in EM and PM, respectively.
- Approximately 7% to 10% of Caucasians and 3% to 8% of black/African Americans lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers (PM), whereas the rest are intermediate, extensive or ultrarapid metabolizers. Co-administration of FANAPT with known strong inhibitors of CYP2D6 like fluoxetine results in a 2.3-fold increase in iloperidone plasma exposure, and therefore one-half of the FANAPT dose should be administered.
- Similarly, PMs of CYP2D6 have higher exposure to iloperidone compared with EMs and PMs should have their dose reduced by one-half. Laboratory tests are available to identify CYP2D6 PMs.
- The bulk of the radioactive materials were recovered in the urine (mean 58.2% and 45.1% in EM and PM, respectively), with feces accounting for 19.9% (EM) to 22.1% (PM) of the dosed radioactivity.
- Transporter Interaction: Iloperidone and P88 are not substrates of P-gp and iloperidone is a weak P-gp inhibitor.
## Nonclinical Toxicology
- Carcinogenesis
- Lifetime carcinogenicity studies were conducted in CD-1 mice and Sprague Dawley rats. Iloperidone was administered orally at doses of 2.5, 5.0, and 10 mg/kg/day to CD-1 mice and 4, 8, and 16 mg/kg/day to Sprague Dawley rats (0.5, 1.0, and 2.0 times and 1.6, 3.2, and 6.5 times, respectively, the MRHD of 24 mg/day on a mg/m2 basis). There was an increased incidence of malignant mammary gland tumors in female mice treated with the lowest dose (2.5 mg/kg/day) only. There were no treatment-related increases in neoplasia in rats.
- The carcinogenic potential of the iloperidone metabolite P95, which is a major circulating metabolite of iloperidone in humans but is not present at significant amounts in mice or rats, was assessed in a lifetime carcinogenicity study in Wistar rats at oral doses of 25, 75, and 200 mg/kg/day in males and 50, 150, and 250 (reduced from 400) mg/kg/day in females.
- Drug-related neoplastic changes occurred in males, in the pituitary gland (pars distalis adenoma) at all doses and in the pancreas (islet cell adenoma) at the high dose. Plasma levels of P95 (AUC) in males at the tested doses (25, 75, and 200 mg/kg/day) were approximately 0.4, 3, and 23 times, respectively, the human exposure to P95 at the MRHD of iloperidone.
- An increase in mammary, pituitary and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be mediated by prolonged dopamine D2 antagonism and hyperprolactinemia. Increases in serum prolactin were seen in mice and rats treated with iloperidone. The relevance of these tumor findings in rodents in terms of human risk is unknown.
- Mutagenesis
- Iloperidone was negative in the Ames test and in the in vivo mouse bone marrow and rat liver micronucleus tests. Iloperidone induced chromosomal aberrations in Chinese Hamster Ovary (CHO) cells in vitro at concentrations which also caused some cytotoxicity.
- The iloperidone metabolite P95 was negative in the Ames test, the V79 chromosome aberration test, and an in vivo mouse bone marrow micronucleus test.
- Impairment of Fertility
- Iloperidone decreased fertility at 12 and 36 mg/kg in a study in which both male and female rats were treated. The no-effect dose was 4 mg/kg, which is 1.6 times the MRHD of 24 mg/day on a mg/m2 basis.
# Clinical Studies
- The efficacy of FANAPT in the treatment of schizophrenia was supported by 2 placebo- and active-controlled short-term (4- and 6-week) trials. Both trials enrolled patients who met the DSM-III/IV criteria for schizophrenia.
- Two instruments were used for assessing psychiatric signs and symptoms in these studies. The Positive and Negative Syndrome Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS) are both multi-item inventories of general psychopathology usually used to evaluate the effects of drug treatment in schizophrenia.
- A 6-week, placebo-controlled trial (n=706) involved 2 flexible dose ranges of FANAPT (12 to 16 mg/day or 20 to 24 mg/day) compared to placebo and an active-control (risperidone). For the 12 to 16 mg/day group, the titration schedule of FANAPT was 1 mg twice daily on Days 1 and 2, 2 mg twice daily on Days 3 and 4, 4 mg twice daily on Days 5 and 6, and 6 mg twice daily on Day 7. For the 20 to 24 mg/day group, the titration schedule of FANAPT was 1 mg twice daily on Day 1, 2 mg twice daily on Day 2, 4 mg twice daily on Day 3, 6 mg twice daily on Days 4 and 5, 8 mg twice daily on Day 6, and 10 mg twice daily on Day 7. The primary endpoint was change from baseline on the BPRS total score at the end of treatment (Day 42). Both the 12 to 16 mg/day and the 20 to 24 mg/day dose ranges of FANAPT were superior to placebo on the BPRS total score. The active-control antipsychotic drug appeared to be superior to FANAPT in this trial within the first 2 weeks, a finding that may in part be explained by the more rapid titration that was possible for that drug. In patients in this study who remained on treatment for at least 2 weeks, iloperidone appeared to have had comparable efficacy to the active-control.
- A 4-week, placebo-controlled trial (n=604) involved one fixed dose of FANAPT (24 mg/day) compared to placebo- and an active-control (ziprasidone). The titration schedule for this study was similar to that for the 6-week study. This study involved titration of FANAPT starting at 1 mg twice daily on Day 1 and increasing to 2, 4, 6, 8, 10, and 12 mg twice daily on Days 2, 3, 4, 5, 6, and 7. The primary endpoint was change from baseline on the PANSS total score at the end of treatment (Day 28). The 24 mg/day FANAPT dose was superior to placebo in the PANSS total score. FANAPT appeared to have similar efficacy to the active-control drug which also needed a slow titration to the target dose.
# How Supplied
- FANAPT tablets are white, round and identified with a logo “Tablet Imprint ” debossed on one side and tablet strength “1”, “2”, “4”, “6”, “8”, “10”, or “12” debossed on the other side. Tablets are supplied in the following strengths and package configurations:
- Storage
- Store FANAPT tablets at controlled room temperature, 25°C (77°F); excursions permitted to 15° to 30 °C (59° to 86°F). Protect FANAPT tablets from exposure to light and moisture.
## Storage
There is limited information regarding Iloperidone Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- QT Interval Prolongation
- Patients should be advised to consult their physician immediately if they feel faint, lose consciousness or have heart palpitations. Patients should be counseled not to take FANAPT with other drugs that cause QT interval prolongation. Patients should be told to inform physicians that they are taking FANAPT before any new drug is taken.
- Neuroleptic Malignant Syndrome
- Patients and caregivers should be counseled that a potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs, including FANAPT. Signs and symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia).
- Metabolic Changes
- Patients should be aware of the symptoms of hyperglycemia (high blood sugar) and diabetes mellitus. Patients who are diagnosed with diabetes, those with risk factors for diabetes, or those who develop these symptoms during treatment should have their blood glucose monitored at the beginning of and periodically during treatment. Patients should be counseled that weight gain has occurred during treatment with FANAPT. Clinical monitoring of weight is recommended.
- Orthostatic Hypotension
- Patients should be advised of the risk of orthostatic hypotension, particularly at the time of initiating treatment, reinitiating treatment, or increasing the dose.
- Interference with Cognitive and Motor Performance
- Because FANAPT may have the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that FANAPT therapy does not affect them adversely.
- Pregnancy
- Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy with FANAPT.
- Nursing
- Patients should be advised not to breastfeed an infant if they are taking FANAPT.
- Concomitant Medication
- Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions.
- Alcohol
- Patients should be advised to avoid alcohol while taking FANAPT.
- Heat Exposure and Dehydration
- Patients should be advised regarding appropriate care in avoiding overheating and dehydration.
# Precautions with Alcohol
- Alcohol-Iloperidone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- FANAPT®
# Look-Alike Drug Names
- Fanapt® — Xanax®
- Fanapt® — Zantac®
# Drug Shortage Status
# Price | Iloperidone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Black Box Warning
# Overview
Iloperidone is an atypical antipsychotic agent that is FDA approved for the {{{indicationType}}} of schizophrenia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include dizziness, dry mouth, fatigue, nasal congestion, orthostatic hypotension, somnolence, tachycardia, and weight increased.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- FANAPT must be titrated slowly from a low starting dose to avoid orthostatic hypotension due to its alpha-adrenergic blocking properties. The recommended starting dose for FANAPT tablets is 1 mg twice daily. Dose increases to reach the target range of 6 to 12 mg twice daily (12 to 24 mg/day) may be made with daily dosage adjustments not to exceed 2 mg twice daily (4 mg/day). The maximum recommended dose is 12 mg twice daily (24 mg/day). FANAPT doses above 24 mg/day have not been systematically evaluated in the clinical trials. Efficacy was demonstrated with FANAPT in a dose range of 6 to 12 mg twice daily. Prescribers should be mindful of the fact that patients need to be titrated to an effective dose of FANAPT. Thus, control of symptoms may be delayed during the first 1 to 2 weeks of treatment compared to some other antipsychotic drugs that do not require similar titration. Prescribers should also be aware that some adverse effects associated with FANAPT use are dose related.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Iloperidone in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Iloperidone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Iloperidone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Iloperidone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Iloperidone in pediatric patients.
# Contraindications
- FANAPT is contraindicated in individuals with a known hypersensitivity reaction to the product. Reactions have included pruritus and urticaria.
# Warnings
### Precautions
- Increased Risks in Elderly Patients with Dementia-Related Psychosis
- Increased Mortality
- Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. FANAPT is not approved for the treatment of patients with dementia-related psychosis.
- Cerebrovascular Adverse Events, Including Stroke
- In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly patients with dementia, there was a higher incidence of cerebrovascular adverse events (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated patients. FANAPT is not approved for the treatment of patients with dementia-related psychosis.
- QT Prolongation
- In an open-label QTc study in patients with schizophrenia or schizoaffective disorder (n=160), FANAPT was associated with QTc prolongation of 9 msec at an iloperidone dose of 12 mg twice daily. The effect of FANAPT on the QT interval was augmented by the presence of CYP450 2D6 or 3A4 metabolic inhibition (paroxetine 20 mg once daily and ketoconazole 200 mg twice daily, respectively). Under conditions of metabolic inhibition for both 2D6 and 3A4, FANAPT 12 mg twice daily was associated with a mean QTcF increase from baseline of about 19 msec.
- No cases of torsade de pointes or other severe cardiac arrhythmias were observed during the pre-marketing clinical program.
- The use of FANAPT should be avoided in combination with other drugs that are known to prolong QTc including Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications, antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval (e.g., pentamidine, levomethadyl acetate, methadone). FANAPT should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias.
- Certain circumstances may increase the risk of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval; (5) recent acute myocardial infarction; and/or (6) uncompensated heart failure.
- Caution is warranted when prescribing FANAPT with drugs that inhibit FANAPT metabolism, and in patients with reduced activity of CYP2D6.
- It is recommended that patients being considered for FANAPT treatment who are at risk for significant electrolyte disturbances have baseline serum potassium and magnesium measurements with periodic monitoring. Hypokalemia (and/or hypomagnesemia) may increase the risk of QT prolongation and arrhythmia. FANAPT should be avoided in patients with histories of significant cardiovascular illness, e.g., QT prolongation, recent acute myocardial infarction, uncompensated heart failure, or cardiac arrhythmia. FANAPT should be discontinued in patients who are found to have persistent QTc measurements >500 msec.
- If patients taking FANAPT experience symptoms that could indicate the occurrence of cardiac arrhythmias, e.g., dizziness, palpitations, or syncope, the prescriber should initiate further evaluation, including cardiac monitoring.
- Neuroleptic Malignant Syndrome (NMS)
- A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including FANAPT. Clinical manifestations include hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
- The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system (CNS) pathology.
- The management of this syndrome should include: (1) immediate discontinuation of the antipsychotic drugs and other drugs not essential to concurrent therapy, (2) intensive symptomatic treatment and medical monitoring, and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.
- If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
- Tardive Dyskinesia
- Tardive dyskinesia is a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, which may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely on prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
- The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic administered increases. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.
- There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
- Given these considerations, FANAPT should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.
- If signs and symptoms of tardive dyskinesia appear in a patient on FANAPT, drug discontinuation should be considered. However, some patients may require treatment with FANAPT despite the presence of the syndrome.
- Metabolic Changes
- Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all atypical antipsychotic drugs have been shown to produce some metabolic changes, each drug in the class has its own specific risk profile.
- Hyperglycemia and Diabetes Mellitus
- Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including FANAPT. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics included in these studies. Because FANAPT was not marketed at the time these studies were performed, it is not known if FANAPT is associated with this increased risk.
- Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.
- Data from a 4-week, fixed-dose study in adult subjects with schizophrenia, in which fasting blood samples were drawn, are presented in Table 1.
- Dyslipidemia
- Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
- Data from a placebo-controlled, 4-week, fixed-dose study, in which fasting blood samples were drawn, in adult subjects with schizophrenia are presented in Table 3.
- Pooled analyses of cholesterol and triglyceride data from clinical studies including longer term trials are shown in Tables 4 and 5.
- Weight Gain
- Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.
- Across all short- and long-term studies, the overall mean change from baseline at endpoint was 2.1 kg.
- Changes in body weight (kg) and the proportion of subjects with ≥7% gain in body weight from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies in adult subjects are presented in Table 6.
- Seizures
- In short-term placebo-controlled trials (4- to 6-weeks), seizures occurred in 0.1% (1/1344) of patients treated with FANAPT compared to 0.3% (2/587) on placebo. As with other antipsychotics, FANAPT should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer’s dementia. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.
- Orthostatic Hypotension and Syncope
- FANAPT can induce orthostatic hypotension associated with dizziness, tachycardia, and syncope. This reflects its alpha1-adrenergic antagonist properties. In double-blind placebo-controlled short-term studies, where the dose was increased slowly, as recommended above, syncope was reported in 0.4% (5/1344) of patients treated with FANAPT, compared with 0.2% (1/587) on placebo. Orthostatic hypotension was reported in 5% of patients given 20 to 24 mg/day, 3% of patients given 10 to 16 mg/day, and 1% of patients given placebo. More rapid titration would be expected to increase the rate of orthostatic hypotension and syncope.
- FANAPT should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history of myocardial infarction, ischemia, or conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications). Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to hypotension.
- Leukopenia, Neutropenia and Agranulocytosis
- In clinical trial and postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents. Agranulocytosis (including fatal cases) has also been reported.
- Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue FANAPT at the first sign of a decline in WBC in the absence of other causative factors.
- Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue FANAPT and have their WBC followed until recovery.
- Hyperprolactinemia
- As with other drugs that antagonize dopamine D2 receptors, FANAPT elevates prolactin levels.
- Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadalsteroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male patients.
- Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. Mammary gland proliferative changes and increases in serum prolactin were seen in mice and rats treated with FANAPT [see Nonclinical Toxicology (13.1)]. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time.
- In a short-term placebo-controlled trial (4-weeks), the mean change from baseline to endpoint in plasma prolactin levels for the FANAPT 24 mg/day-treated group was an increase of 2.6 ng/mL compared to a decrease of 6.3 ng/mL in the placebo-group. In this trial, elevated plasma prolactin levels were observed in 26% of adults treated with FANAPT compared to 12% in the placebo-group. In the short-term trials, FANAPT was associated with modest levels of prolactin elevation compared to greater prolactin elevations observed with some other antipsychotic agents. In pooled analysis from clinical studies including longer term trials, in 3210 adults treated with iloperidone, gynecomastia was reported in 2 male subjects (0.1%) compared to 0% in placebo-treated patients, and galactorrhea was reported in 8 female subjects (0.2%) compared to 3 female subjects (0.5%) in placebo-treated patients.
- Body Temperature Regulation
- Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing FANAPT for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.
- Dysphagia
- Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer’s dementia. FANAPT and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.
- Suicide
- The possibility of a suicide attempt is inherent in psychotic illness, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for FANAPT should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose.
- Priapism
- Three cases of priapism were reported in the premarketing FANAPT program. Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. FANAPT shares this pharmacologic activity. Severe priapism may require surgical intervention.
- Potential for Cognitive and Motor Impairment
- FANAPT, like other antipsychotics, has the potential to impair judgment, thinking or motor skills. In short-term, placebo-controlled trials, somnolence (including sedation) was reported in 11.9% (104/874) of adult patients treated with FANAPT at doses of 10 mg/day or greater versus 5.3% (31/587) treated with placebo. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with FANAPT does not affect them adversely.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trial of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The information below is derived from a clinical trial database for FANAPT consisting of 2070 patients exposed to FANAPT at doses of 10 mg/day or greater, for the treatment of schizophrenia. Of these, 806 received FANAPT for at least 6 months, with 463 exposed to FANAPT for at least 12 months. All of these patients who received FANAPT were participating in multiple-dose clinical trials. The conditions and duration of treatment with FANAPT varied greatly and included (in overlapping categories), open-label and double-blind phases of studies, inpatients and outpatients, fixed-dose and flexible-dose studies, and short-term and longer-term exposure.
- Adverse reactions during exposure were obtained by general inquiry and recorded by clinical investigators using their own terminology. Consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions, reactions were grouped in standardized categories using MedDRA terminology.
- The stated frequencies of adverse reactions represent the proportions of individuals who experienced a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.
- The information presented in these sections was derived from pooled data from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies in patients who received FANAPT at daily doses within a range of 10 to 24 mg (n=874).
- Adverse Reactions Occurring at an Incidence of 2% or More among FANAPT-Treated Patients and More Frequent than Placebo
- Table 7 enumerates the pooled incidences of treatment-emergent adverse reactions that were spontaneously reported in four placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies, listing those reactions that occurred in 2% or more of patients treated with FANAPT in any of the dose groups, and for which the incidence in FANAPT-treated patients in any dose group was greater than the incidence in patients treated with placebo.
- Dose-Related Adverse Reactions in Clinical Trials
- Based on the pooled data from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies, adverse reactions that occurred with a greater than 2% incidence in the patients treated with FANAPT, and for which the incidence in patients treated with FANAPT 20 to 24 mg/day were twice than the incidence in patients treated with FANAPT 10 to 16 mg/day were: abdominal discomfort, dizziness, hypotension, musculoskeletal stiffness, tachycardia, and weight increased.
- Common and Drug-Related Adverse Reactions in Clinical Trials
- Based on the pooled data from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies, the following adverse reactions occurred in ≥5% incidence in the patients treated with FANAPT and at least twice the placebo rate for at least 1 dose: dizziness, dry mouth, fatigue, nasal congestion, somnolence, tachycardia, orthostatic hypotension, and weight increased. Dizziness, tachycardia, and weight increased were at least twice as common on 20 to 24 mg/day as on 10 to 16 mg/day.
- Extrapyramidal Symptoms (EPS) in Clinical Trials
- Pooled data from the 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies provided information regarding treatment-emergent EPS. Adverse event data collected from those trials showed the following rates of EPS-related adverse events as shown in Table 8.
- Adverse Reactions Associated with Discontinuation of Treatment in Clinical Trials
- Based on the pooled data from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies, there was no difference in the incidence of discontinuation due to adverse events between FANAPT-treated (5%) and placebo-treated (5%) patients. The types of adverse events that led to discontinuation were similar for the FANAPT- and placebo-treated patients.
- Demographic Differences in Adverse Reactions in Clinical Trials
- An examination of population subgroups in the 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies did not reveal any evidence of differences in safety on the basis of age, gender or race.
- Laboratory Test Abnormalities in Clinical Trials
- There were no differences between FANAPT and placebo in the incidence of discontinuation due to changes in hematology, urinalysis, or serum chemistry.
- In short-term placebo-controlled trials (4- to 6-weeks), there were 1.0% (13/1342) iloperidone-treated patients with hematocrit at least one time below the extended normal range during post-randomization treatment, compared to 0.3% (2/585) on placebo. The extended normal range for lowered hematocrit was defined in each of these trials as the value 15% below the normal range for the centralized laboratory that was used in the trial.
- Other Reactions During the Premarketing Evaluation of FANAPT
- The following is a list of MedDRA terms that reflect treatment-emergent adverse reactions in patients treated with FANAPT at multiple doses ≥4 mg/day during any phase of a trial with the database of 3210 FANAPT-treated patients. All reported reactions are included except those already listed in Table 7, or other parts of the Adverse Reactions (6) section, those considered in the Warnings and Precautions (5), those reaction terms which were so general as to be uninformative, reactions reported in fewer than 3 patients and which were neither serious nor life-threatening, reactions that are otherwise common as background reactions, and reactions considered unlikely to be drug related. It is important to emphasize that, although the reactions reported occurred during treatment with FANAPT, they were not necessarily caused by it.
- Reactions are further categorized by MedDRA system organ class and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring in at least 1/100 patients (only those not listed in Table 7 appear in this listing); infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.
Infrequent – anemia, iron deficiency anemia; Rare – leukopenia
Frequent – palpitations; Rare – arrhythmia, atrioventricular block first degree, cardiac failure (including congestive and acute)
Infrequent – vertigo, tinnitus
Infrequent – hypothyroidism
Frequent - conjunctivitis (including allergic); Infrequent – dry eye, blepharitis, eyelid edema, eye swelling, lenticular opacities, cataract, hyperemia (including conjunctival)
Infrequent – gastritis, salivary hypersecretion, fecal incontinence, mouth ulceration; Rare - aphthous stomatitis, duodenal ulcer, hiatus hernia, hyperchlorhydria, lip ulceration, reflux esophagitis, stomatitis
Infrequent – edema (general, pitting, due to cardiac disease), difficulty in walking, thirst; Rare - hyperthermia
Infrequent – cholelithiasis
Frequent - weight decreased; Infrequent – hemoglobin decreased, neutrophil count increased, hematocrit decreased
Infrequent – increased appetite, dehydration, hypokalemia, fluid retention
Frequent – myalgia, muscle spasms; Rare – torticollis
Infrequent – paresthesia, psychomotor hyperactivity, restlessness, amnesia, nystagmus; Rare – restless legs syndrome
Frequent – restlessness, aggression, delusion; Infrequent – hostility, libido decreased, paranoia, anorgasmia, confusional state, mania, catatonia, mood swings, panic attack, obsessive-compulsive disorder, bulimia nervosa, delirium, polydipsia psychogenic, impulse-control disorder, major depression
Frequent – urinary incontinence; Infrequent – dysuria, pollakiuria, enuresis, nephrolithiasis; Rare – urinary retention, renal failure acute
Frequent – erectile dysfunction; Infrequent – testicular pain, amenorrhea, breast pain; Rare – menstruation irregular, gynecomastia, menorrhagia, metrorrhagia, postmenopausal hemorrhage, prostatitis.
Infrequent – epistaxis, asthma, rhinorrhea, sinus congestion, nasal dryness; Rare – dry throat, sleep apnea syndrome, dyspnea exertional
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of FANAPT: retrograde ejaculation. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
# Drug Interactions
- Potential for Other Drugs to Affect FANAPT
- Iloperidone is not a substrate for CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. This suggests that an interaction of iloperidone with inhibitors or inducers of these enzymes, or other factors, like smoking, is unlikely.
- Both CYP3A4 and CYP2D6 are responsible for iloperidone metabolism. Inhibitors of CYP3A4 (e.g., ketoconazole) or CYP2D6 (e.g., fluoxetine, paroxetine) can inhibit iloperidone elimination and cause increased blood levels.
- Ketoconazole: Co-administration of ketoconazole (200 mg twice daily for 4 days), a potent inhibitor of CYP3A4, with a 3 mg single dose of iloperidone to 19 healthy volunteers, ages 18 to 45 years, increased the area under the curve (AUC) of iloperidone and its metabolites P88 and P95 by 57%, 55% and 35%, respectively. Iloperidone doses should be reduced by about one-half when administered with ketoconazole or other strong inhibitors of CYP3A4 (e.g., itraconazole). Weaker inhibitors (e.g., erythromycin, grapefruit juice) have not been studied. When the CYP3A4 inhibitor is withdrawn from the combination therapy, the iloperidone dose should be returned to the previous level.
- Fluoxetine: Co-administration of fluoxetine (20 mg twice daily for 21 days), a potent inhibitor of CYP2D6, with a single 3 mg dose of iloperidone to 23 healthy volunteers, ages 29 to 44 years, who were classified as CYP2D6 extensive metabolizers, increased the AUC of iloperidone and its metabolite P88, by about 2- to 3-fold, and decreased the AUC of its metabolite P95 by one-half. Iloperidone doses should be reduced by one-half when administered with fluoxetine. When fluoxetine is withdrawn from the combination therapy, the iloperidone dose should be returned to the previous level. Other strong inhibitors of CYP2D6 would be expected to have similar effects and would need appropriate dose reductions. When the CYP2D6 inhibitor is withdrawn from the combination therapy, iloperidone dose could then be increased to the previous level.
- Paroxetine: Co-administration of paroxetine (20 mg/day for 5 to 8 days), a potent inhibitor of CYP2D6, with multiple doses of iloperidone (8 or 12 mg twice daily) to patients with schizophrenia ages 18 to 65 years resulted in increased mean steady-state peak concentrations of iloperidone and its metabolite P88, by about 1.6-fold, and decreased mean steady-state peak concentrations of its metabolite P95 by one-half. Iloperidone doses should be reduced by one-half when administered with paroxetine. When paroxetine is withdrawn from the combination therapy, the iloperidone dose should be returned to the previous level. Other strong inhibitors of CYP2D6 would be expected to have similar effects and would need appropriate dose reductions. When the CYP2D6 inhibitor is withdrawn from the combination therapy, iloperidone dose could then be increased to previous levels.
- Paroxetine and Ketoconazole: Co-administration of paroxetine (20 mg once daily for 10 days), a CYP2D6 inhibitor, and ketoconazole (200 mg twice daily) with multiple doses of iloperidone (8 or 12 mg twice daily) to patients with schizophrenia ages 18 to 65 years resulted in a 1.4-fold increase in steady-state concentrations of iloperidone and its metabolite P88 and a 1.4-fold decrease in the P95 in the presence of paroxetine. So giving iloperidone with inhibitors of both of its metabolic pathways did not add to the effect of either inhibitor given alone. Iloperidone doses should therefore be reduced by about one-half if administered concomitantly with both a CYP2D6 and CYP3A4 inhibitor.
- Potential for FANAPT to Affect Other Drugs
- In vitro studies in human liver microsomes showed that iloperidone does not substantially inhibit the metabolism of drugs metabolized by the following cytochrome P450 isozymes: CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, or CYP2E1. Furthermore, in vitro studies in human liver microsomes showed that iloperidone does not have enzyme inducing properties, specifically for the following cytochrome P450 isozymes: CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4 and CYP3A5.
- Dextromethorphan: A study in healthy volunteers showed that changes in the pharmacokinetics of dextromethorphan (80 mg dose) when a 3 mg dose of iloperidone was co-administered resulted in a 17% increase in total exposure and a 26% increase in the maximum plasma concentrations (Cmax)of dextromethorphan. Thus, an interaction between iloperidone and other CYP2D6 substrates is unlikely.
- Fluoxetine: A single 3 mg dose of iloperidone had no effect on the pharmacokinetics of fluoxetine (20 mg twice daily).
- Midazolam (a sensitive CYP 3A4 substrate): A study in patients with schizophrenia showed a less than 50% increase in midazolam total exposure at iloperidone steady state (14 days of oral dosing at up to 10 mg iloperidone twice daily) and no effect on midazolam Cmax. Thus, an interaction between iloperidone and other CYP3A4 substrates is unlikely.
- Drugs that Prolong the QT Interval
- FANAPT should not be used with any other drugs that prolong the QT interval.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- FANAPT caused developmental toxicity, but was not teratogenic, in rats and rabbits.
- In an embryo-fetal development study, pregnant rats were given 4, 16, or 64 mg/kg/day (1.6, 6.5, and 26 times the maximum recommended human dose (MRHD) of 24 mg/day on a mg/m2 basis) of iloperidone orally during the period of organogenesis. The highest dose caused increased early intrauterine deaths, decreased fetal weight and length, decreased fetal skeletal ossification, and an increased incidence of minor fetal skeletal anomalies and variations; this dose also caused decreased maternal food consumption and weight gain.
- In an embryo-fetal development study, pregnant rabbits were given 4, 10, or 25 mg/kg/day (3, 8, and 20 times the MRHD on a mg/m2 basis) of iloperidone during the period of organogenesis. The highest dose caused increased early intrauterine deaths and decreased fetal viability at term; this dose also caused maternal toxicity.
- In additional studies in which rats were given iloperidone at doses similar to the above beginning from either pre-conception or from day 17 of gestation and continuing through weaning, adverse reproductive effects included prolonged pregnancy and parturition, increased stillbirth rates, increased incidence of fetal visceral variations, decreased fetal and pup weights, and decreased post-partum pup survival. There were no drug effects on the neurobehavioral or reproductive development of the surviving pups. No-effect doses ranged from 4 to 12 mg/kg except for the increase in stillbirth rates which occurred at the lowest dose tested of 4 mg/kg, which is 1.6 times the MRHD on a mg/m2 basis. Maternal toxicity was seen at the higher doses in these studies.
- The iloperidone metabolite P95, which is a major circulating metabolite of iloperidone in humans but is not present in significant amounts in rats, was given to pregnant rats during the period of organogenesis at oral doses of 20, 80, or 200 mg/kg/day. No teratogenic effects were seen. Delayed skeletal ossification occurred at all doses. No significant maternal toxicity was produced. Plasma levels of P95 (AUC) at the highest dose tested were 2 times those in humans receiving the MRHD of iloperidone.
- There are no adequate and well-controlled studies in pregnant women.
- Non-teratogenic Effects
- Neonates exposed to antipsychotic drugs, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.
- FANAPT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Iloperidone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Iloperidone during labor and delivery.
### Nursing Mothers
- FANAPT was excreted in milk of rats during lactation. It is not known whether FANAPT or its metabolites are excreted in human milk. It is recommended that women receiving FANAPT should not breastfeed.
### Pediatric Use
- Safety and effectiveness in pediatric and adolescent patients have not been established.
### Geriatic Use
- Clinical Studies of FANAPT in the treatment of schizophrenia did not include sufficient numbers of patients aged 65 years and over to determine whether or not they respond differently than younger adult patients. Of the 3210 patients treated with FANAPT in premarketing trials, 25 (0.5%) were ≥65 years old and there were no patients ≥75 years old.
- Studies of elderly patients with psychosis associated with Alzheimer’s disease have suggested that there may be a different tolerability profile (i.e., increased risk in mortality and cerebrovascular events including stroke) in this population compared to younger patients with schizophrenia. The safety and efficacy of FANAPT in the treatment of patients with psychosis associated with Alzheimer’s disease has not been established. If the prescriber elects to treat such patients with FANAPT, vigilance should be exercised.
### Gender
There is no FDA guidance on the use of Iloperidone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Iloperidone with respect to specific racial populations.
### Renal Impairment
- Because FANAPT is highly metabolized, with less than 1% of the drug excreted unchanged, renal impairment alone is unlikely to have a significant impact on the pharmacokinetics of FANAPT. Renal impairment (creatinine clearance <30 mL/min) had minimal effect on Cmax of iloperidone (given in a single dose of 3 mg) and its metabolites P88 and P95 in any of the 3 analytes measured. AUC0–∞ was increased by 24%, decreased by 6%, and increased by 52% for iloperidone, P88 and P95, respectively, in subjects with renal impairment.
### Hepatic Impairment
- No dose adjustment to FANAPT is needed in patients with mild hepatic impairment. Exercise caution when administering it to patients with moderate hepatic impairment. FANAPT is not recommended for patients with severe hepatic impairment.
- In adult subjects with mild hepatic impairment no relevant difference in pharmacokinetics of iloperidone, P88 or P95 (total or unbound) was observed compared to healthy adult controls. In subjects with moderate hepatic impairment a higher (2-fold) and more variable free exposure to the active metabolites P88 was observed compared to healthy controls, whereas exposure to iloperidone and P95 was generally similar (less than 50% change compared to control). Since a study in severe liver impaired subjects has not been conducted, FANAPT is not recommended for patients with severe hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Iloperidone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Iloperidone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Iloperidone in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Iloperidone in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- In premarketing trials involving over 3210 patients, accidental or intentional overdose of FANAPT was documented in 8 patients ranging from 48 mg to 576 mg taken at once and 292 mg taken over a 3-day period. No fatalities were reported from these cases. The largest confirmed single ingestion of FANAPT was 576 mg; no adverse physical effects were noted for this patient. The next largest confirmed ingestion of FANAPT was 438 mg over a 4-day period; extrapyramidal symptoms and a QTc interval of 507 msec were reported for this patient with no cardiac sequelae. This patient resumed FANAPT treatment for an additional 11 months. In general, reported signs and symptoms were those resulting from an exaggeration of the known pharmacological effects (e.g., drowsiness and sedation, tachycardia and hypotension) of FANAPT.
### Management
- There is no specific antidote for FANAPT. Therefore appropriate supportive measures should be instituted. In case of acute overdose, the physician should establish and maintain an airway and ensure adequate oxygenation and ventilation. Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. The possibility of obtundation, seizures or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should commence immediately and should include continuous ECG monitoring to detect possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide and quinidine should not be used, as they have the potential for QT-prolonging effects that might be additive to those of FANAPT. Similarly, it is reasonable to expect that the alpha-blocking properties of bretylium might be additive to those of FANAPT, resulting in problematic hypotension. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of FANAPT-induced alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision should continue until the patient recovers.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Iloperidone in the drug label.
# Pharmacology
## Mechanism of Action
- The mechanism of action of FANAPT, as with other drugs having efficacy in schizophrenia, is unknown. However it is proposed that the efficacy of FANAPT is mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5-HT2) antagonisms.
## Structure
- FANAPT is a psychotropic agent belonging to the chemical class of piperidinyl-benzisoxazole derivatives. Its chemical name is 4’-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidino]propoxy]-3’-methoxyacetophenone. Its molecular formula is C24H27FN2O4 and its molecular weight is 426.48. The structural formula is:
- Iloperidone is a white to off-white finely crystalline powder. It is practically insoluble in water, very slightly soluble in 0.1 N HCl and freely soluble in chloroform, ethanol, methanol, and acetonitrile.
- FANAPT tablets are intended for oral administration only. Each round, uncoated tablet contains 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, or 12 mg of iloperidone. Inactive ingredients are: lactose monohydrate, microcrystalline cellulose, hydroxypropylmethylcellulose, crospovidone, magnesium stearate, colloidal silicon dioxide, and purified water (removed during processing). The tablets are white, round, flat, beveled-edged and identified with a logo “Tablet Imprint ” debossed on one side and tablet strength “1”, “2”, “4”, “6”, “8”, “10”, or “12” debossed on the other side.
## Pharmacodynamics
- FANAPT exhibits high (nM) affinity binding to serotonin 5-HT2A dopamine D2 and D3 receptors, and norepinephrine NEα1 receptors (Ki values of 5.6, 6.3, 7.1, and 0.36 nM, respectively). FANAPT has moderate affinity for dopamine D4, and serotonin 5-HT6 and 5-HT7 receptors (Ki values of 25, 43, and 22, nM respectively), and low affinity for the serotonin 5-HT1A, dopamine D1, and histamine H1 receptors (Ki values of 168, 216 and 437 nM, respectively). FANAPT has no appreciable affinity (Ki >1000 nM) for cholinergic muscarinic receptors. FANAPT functions as an antagonist at the dopamine D2, D3, serotonin 5-HT1A and norepinephrine α1/α2C receptors. The affinity of the FANAPT metabolite P88 is generally equal or less than that of the parent compound. In contrast, the metabolite P95 only shows affinity for 5-HT2A (Ki value of 3.91) and the NEα1A, NEα1B, NEα1D, and NEα2C receptors (Ki values of 4.7, 2.7, 8.8, and 4.7 nM respectively).
## Pharmacokinetics
- The observed mean elimination half-lives for iloperidone, P88 and P95 in CYP2D6 extensive metabolizers (EM) are 18, 26, and 23 hours, respectively, and in poor metabolizers (PM) are 33, 37, and 31 hours, respectively. Steady-state concentrations are attained within 3 to 4 days of dosing. Iloperidone accumulation is predictable from single-dose pharmacokinetics. The pharmacokinetics of iloperidone is more than dose proportional. Elimination of iloperidone is mainly through hepatic metabolism involving 2 P450 isozymes, CYP2D6 and CYP3A4.
- Absorption: Iloperidone is well absorbed after administration of the tablet with peak plasma concentrations occurring within 2 to 4 hours; while the relative bioavailability of the tablet formulation compared to oral solution is 96%. Administration of iloperidone with a standard high-fat meal did not significantly affect the Cmax or AUC of iloperidone, P88, or P95, but delayed Tmax by 1 hour for iloperidone, 2 hours for P88 and 6 hours for P95. FANAPT can be administered without regard to meals.
- Distribution: Iloperidone has an apparent clearance (clearance/bioavailability) of 47 to 102 L/h, with an apparent volume of distribution of 1340 to 2800 L. At therapeutic concentrations, the unbound fraction of iloperidone in plasma is ~3% and of each metabolite (P88 and P95) it is ~8%.
- Metabolism and Elimination: Iloperidone is metabolized primarily by 3 biotransformation pathways: carbonyl reduction, hydroxylation (mediated by CYP2D6) and O-demethylation (mediated by CYP3A4). There are 2 predominant iloperidone metabolites, P95 and P88. The iloperidone metabolite P95 represents 47.9% of the AUC of iloperidone and its metabolites in plasma at steady-state for extensive metabolizers (EM) and 25% for poor metabolizers (PM). The active metabolite P88 accounts for 19.5% and 34.0% of total plasma exposure in EM and PM, respectively.
- Approximately 7% to 10% of Caucasians and 3% to 8% of black/African Americans lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers (PM), whereas the rest are intermediate, extensive or ultrarapid metabolizers. Co-administration of FANAPT with known strong inhibitors of CYP2D6 like fluoxetine results in a 2.3-fold increase in iloperidone plasma exposure, and therefore one-half of the FANAPT dose should be administered.
- Similarly, PMs of CYP2D6 have higher exposure to iloperidone compared with EMs and PMs should have their dose reduced by one-half. Laboratory tests are available to identify CYP2D6 PMs.
- The bulk of the radioactive materials were recovered in the urine (mean 58.2% and 45.1% in EM and PM, respectively), with feces accounting for 19.9% (EM) to 22.1% (PM) of the dosed radioactivity.
- Transporter Interaction: Iloperidone and P88 are not substrates of P-gp and iloperidone is a weak P-gp inhibitor.
## Nonclinical Toxicology
- Carcinogenesis
- Lifetime carcinogenicity studies were conducted in CD-1 mice and Sprague Dawley rats. Iloperidone was administered orally at doses of 2.5, 5.0, and 10 mg/kg/day to CD-1 mice and 4, 8, and 16 mg/kg/day to Sprague Dawley rats (0.5, 1.0, and 2.0 times and 1.6, 3.2, and 6.5 times, respectively, the MRHD of 24 mg/day on a mg/m2 basis). There was an increased incidence of malignant mammary gland tumors in female mice treated with the lowest dose (2.5 mg/kg/day) only. There were no treatment-related increases in neoplasia in rats.
- The carcinogenic potential of the iloperidone metabolite P95, which is a major circulating metabolite of iloperidone in humans but is not present at significant amounts in mice or rats, was assessed in a lifetime carcinogenicity study in Wistar rats at oral doses of 25, 75, and 200 mg/kg/day in males and 50, 150, and 250 (reduced from 400) mg/kg/day in females.
- Drug-related neoplastic changes occurred in males, in the pituitary gland (pars distalis adenoma) at all doses and in the pancreas (islet cell adenoma) at the high dose. Plasma levels of P95 (AUC) in males at the tested doses (25, 75, and 200 mg/kg/day) were approximately 0.4, 3, and 23 times, respectively, the human exposure to P95 at the MRHD of iloperidone.
- An increase in mammary, pituitary and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be mediated by prolonged dopamine D2 antagonism and hyperprolactinemia. Increases in serum prolactin were seen in mice and rats treated with iloperidone. The relevance of these tumor findings in rodents in terms of human risk is unknown.
- Mutagenesis
- Iloperidone was negative in the Ames test and in the in vivo mouse bone marrow and rat liver micronucleus tests. Iloperidone induced chromosomal aberrations in Chinese Hamster Ovary (CHO) cells in vitro at concentrations which also caused some cytotoxicity.
- The iloperidone metabolite P95 was negative in the Ames test, the V79 chromosome aberration test, and an in vivo mouse bone marrow micronucleus test.
- Impairment of Fertility
- Iloperidone decreased fertility at 12 and 36 mg/kg in a study in which both male and female rats were treated. The no-effect dose was 4 mg/kg, which is 1.6 times the MRHD of 24 mg/day on a mg/m2 basis.
# Clinical Studies
- The efficacy of FANAPT in the treatment of schizophrenia was supported by 2 placebo- and active-controlled short-term (4- and 6-week) trials. Both trials enrolled patients who met the DSM-III/IV criteria for schizophrenia.
- Two instruments were used for assessing psychiatric signs and symptoms in these studies. The Positive and Negative Syndrome Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS) are both multi-item inventories of general psychopathology usually used to evaluate the effects of drug treatment in schizophrenia.
- A 6-week, placebo-controlled trial (n=706) involved 2 flexible dose ranges of FANAPT (12 to 16 mg/day or 20 to 24 mg/day) compared to placebo and an active-control (risperidone). For the 12 to 16 mg/day group, the titration schedule of FANAPT was 1 mg twice daily on Days 1 and 2, 2 mg twice daily on Days 3 and 4, 4 mg twice daily on Days 5 and 6, and 6 mg twice daily on Day 7. For the 20 to 24 mg/day group, the titration schedule of FANAPT was 1 mg twice daily on Day 1, 2 mg twice daily on Day 2, 4 mg twice daily on Day 3, 6 mg twice daily on Days 4 and 5, 8 mg twice daily on Day 6, and 10 mg twice daily on Day 7. The primary endpoint was change from baseline on the BPRS total score at the end of treatment (Day 42). Both the 12 to 16 mg/day and the 20 to 24 mg/day dose ranges of FANAPT were superior to placebo on the BPRS total score. The active-control antipsychotic drug appeared to be superior to FANAPT in this trial within the first 2 weeks, a finding that may in part be explained by the more rapid titration that was possible for that drug. In patients in this study who remained on treatment for at least 2 weeks, iloperidone appeared to have had comparable efficacy to the active-control.
- A 4-week, placebo-controlled trial (n=604) involved one fixed dose of FANAPT (24 mg/day) compared to placebo- and an active-control (ziprasidone). The titration schedule for this study was similar to that for the 6-week study. This study involved titration of FANAPT starting at 1 mg twice daily on Day 1 and increasing to 2, 4, 6, 8, 10, and 12 mg twice daily on Days 2, 3, 4, 5, 6, and 7. The primary endpoint was change from baseline on the PANSS total score at the end of treatment (Day 28). The 24 mg/day FANAPT dose was superior to placebo in the PANSS total score. FANAPT appeared to have similar efficacy to the active-control drug which also needed a slow titration to the target dose.
# How Supplied
- FANAPT tablets are white, round and identified with a logo “Tablet Imprint ” debossed on one side and tablet strength “1”, “2”, “4”, “6”, “8”, “10”, or “12” debossed on the other side. Tablets are supplied in the following strengths and package configurations:
- Storage
- Store FANAPT tablets at controlled room temperature, 25°C (77°F); excursions permitted to 15° to 30 °C (59° to 86°F). Protect FANAPT tablets from exposure to light and moisture.
## Storage
There is limited information regarding Iloperidone Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- QT Interval Prolongation
- Patients should be advised to consult their physician immediately if they feel faint, lose consciousness or have heart palpitations. Patients should be counseled not to take FANAPT with other drugs that cause QT interval prolongation. Patients should be told to inform physicians that they are taking FANAPT before any new drug is taken.
- Neuroleptic Malignant Syndrome
- Patients and caregivers should be counseled that a potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs, including FANAPT. Signs and symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia).
- Metabolic Changes
- Patients should be aware of the symptoms of hyperglycemia (high blood sugar) and diabetes mellitus. Patients who are diagnosed with diabetes, those with risk factors for diabetes, or those who develop these symptoms during treatment should have their blood glucose monitored at the beginning of and periodically during treatment. Patients should be counseled that weight gain has occurred during treatment with FANAPT. Clinical monitoring of weight is recommended.
- Orthostatic Hypotension
- Patients should be advised of the risk of orthostatic hypotension, particularly at the time of initiating treatment, reinitiating treatment, or increasing the dose.
- Interference with Cognitive and Motor Performance
- Because FANAPT may have the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that FANAPT therapy does not affect them adversely.
- Pregnancy
- Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy with FANAPT.
- Nursing
- Patients should be advised not to breastfeed an infant if they are taking FANAPT.
- Concomitant Medication
- Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions.
- Alcohol
- Patients should be advised to avoid alcohol while taking FANAPT.
- Heat Exposure and Dehydration
- Patients should be advised regarding appropriate care in avoiding overheating and dehydration.
# Precautions with Alcohol
- Alcohol-Iloperidone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- FANAPT®[1]
# Look-Alike Drug Names
- Fanapt® — Xanax®[2]
- Fanapt® — Zantac®[2]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Iloperidone | |
babd42bf22db24824b191286a37e47c3542e14a7 | wikidoc | Images page | Images page
Each uploaded file has an associated image page. This term is also applied in the case of other file types, notably sound files, e.g. Image:Schubert- Impromptu B-flat1.ogg.
In the case of an image proper, the image page shows the full image (elsewhere often only a reduced version is shown), or, depending on preferences, a reduced version with a link to the full version, labelled "Download high resolution version (..x.., .. KB)".
Also the page is used as image description page, giving info about the image.
If a family of projects has a Commons project, typically the file is uploaded on Commons. The image page there gives copyright info. In the internal image syntax ], ], or ], the filename is assumed to refer to the one in the same project if it exists there, otherwise to one on Commons. When choosing a name for a file on Commons, do not use a name that is already in use on any project on which the file may be used, unless the new file should replace the local ones, which will therefore be deleted, or unless the image from Commons should be replaced locally with a local version without changing the links.
An image on Commons can have a separate image page on every project that does not have another image with the same name (which would block access to the image on Commons). If the projects are distinguished by language, then the local image page can contain info about the image in the local language. It also allows categorizing the image within the local category system, and shows the local pages that use the image.
To find out on which pages of which projects an image on Commons is used, it is important to link the image page on Commons to all local image pages of that image. Even if the local image page has never been created explicitly and has therefore an empty editable part, a link to the page produces a page with an "image links" section showing the local pages that use the image.
The interlanguage link feature works on Commons, and produces links to the Wikipedias. Links to other projects are shown in-page. E.g. commons:Image:Blank Go board.png.
The image is linked to the local image description page, which, due to the contents of MediaWiki:Sharedupload, is linked to the one on Commons, where the image was uploaded. See a few local contents of ]: Meta-wiki, English, andItalian (Note that the link from the called contents to Commons cannot lead to a real image).
To make a link to the image description page of a sound file, or of an image without including the actual image, use a link like: ]or ]. In the case of an image, the leading colon prevents the image being embedded in the article, and instead makes an ordinary link. In the case of a sound, automatically playing the sound is not possible anyway.
The description page consists of four parts:
- in the case of an image: the image itself
- description of the image/sound
- "Image history", see page history
- "Image links" or "File links" (the name is the content of the local MediaWiki:Imagelinks. See a few local contents of ]:Meta-Wiki, English, and French): a list of pages that embed the image, if applicable, and of pages linking to the image/sound with "Media:"; however:
it does not list links to the image page
for an image in a template it lists only the template, not the pages in which the template occurs (for that see "What links here" of the template),
if an image in a template depends on a parameter with the whole image code or the url of the image, or depends on {{PAGENAME}} or {{PAGENAMEE}}, it does neither show the final page nor the template. If only the caption is a parameter, the template is listed.
it does not include the rare case of an uploaded html file linking to the image.
- it does not list links to the image page
- for an image in a template it lists only the template, not the pages in which the template occurs (for that see "What links here" of the template),
- if an image in a template depends on a parameter with the whole image code or the url of the image, or depends on {{PAGENAME}} or {{PAGENAMEE}}, it does neither show the final page nor the template. If only the caption is a parameter, the template is listed.
- it does not include the rare case of an uploaded html file linking to the image.
For an image on Commons, subsequently the following is shown on the local image page (see e.g. Image:Tst.png):
- the image
- the message in MediaWiki:Sharedupload
- the local editable content
- the rendering of the editable content on Commons, including content transcluded from other pages on Commons; sections are not numbered and not in the TOC; category tags are ignored; internal links within Commons are rendered in the style of internal links, but link to Commons; existence detection with regard to existence on Commons works; variables depending on the site refer to Commons.
- the local pages that use the image
The description part has also an edit history; it is labelled, somewhat confusingly, Image:xxx Revision history. It should not be confused with the Image history.
What follows refers to the description part, and is in particular about images. For sound, see also w:Wikipedia:Media.
# Useful things to include on an image description page
In the description part of the page you can put text. Initially the description part automatically contains the upload summary supplied by the user when uploading the first version (this text also shows up in the Image history section at the first upload line).
## Description of the image
Eg: "Image of a goldfish in a small tank". This should not be an alternative text (see alternative text for images), but rather a description. This is useful for users who do not have direct access to the image, and is a temporary substitute for a proper longdesc tag.
You could also include the proportions of the image, in pixels.
## Other versions
If other versions (especially a larger version) of the same image exists, link to them.
Textfree versions are useful for using across language versions.
# Categorizing images
Images can be in the same category as other pages, but are treated separately: on the category page they are not included in the count of articles in the category, and they are displayed in a separate section, with for each a thumbnail and the name, see category page.
On Commons there are essentially only images. On projects with real articles a category can either mix articles and images about a subject, or one has separate image categories. An image category is typically a subcategory of the general category about the same subject, and a subcategory of a wider image category.
For categorizing a new image, the image page does not even have to be edited: the category tag can simply be put in the upload summary.
Many images can be categorized in one of the subcategories of Category:Images by subject. You might need to poke around the category hierarchy a bit to find the right place.
# Nonexisting image
Nonexisting images show no image history section, see e.g. Image:Stop sign us.JPG.
# Editing
The preview of the edit page of an image page only shows the editable part, not the image itself, the image history or the image links.
Through this edit page one cannot edit the image file itself: a new image file requires a new upload.
# Protection
Protection of an image page is automatically also protection of the image itself: i.e. a new image under the name of the existing image can only be uploaded by a sysop. | Images page
Each uploaded file has an associated image page. This term is also applied in the case of other file types, notably sound files, e.g. Image:Schubert- Impromptu B-flat1.ogg.
In the case of an image proper, the image page shows the full image (elsewhere often only a reduced version is shown), or, depending on preferences, a reduced version with a link to the full version, labelled "Download high resolution version (..x.., .. KB)".
Also the page is used as image description page, giving info about the image.
If a family of projects has a Commons project, typically the file is uploaded on Commons. The image page there gives copyright info. In the internal image syntax [[Image:filename]], [[:Image:filename]], or [[Media:filename]], the filename is assumed to refer to the one in the same project if it exists there, otherwise to one on Commons. When choosing a name for a file on Commons, do not use a name that is already in use on any project on which the file may be used, unless the new file should replace the local ones, which will therefore be deleted, or unless the image from Commons should be replaced locally with a local version without changing the links.
An image on Commons can have a separate image page on every project that does not have another image with the same name (which would block access to the image on Commons). If the projects are distinguished by language, then the local image page can contain info about the image in the local language. It also allows categorizing the image within the local category system, and shows the local pages that use the image.
To find out on which pages of which projects an image on Commons is used, it is important to link the image page on Commons to all local image pages of that image. Even if the local image page has never been created explicitly and has therefore an empty editable part, a link to the page produces a page with an "image links" section showing the local pages that use the image.
The interlanguage link feature works on Commons, and produces links to the Wikipedias. Links to other projects are shown in-page. E.g. commons:Image:Blank Go board.png.
The image is linked to the local image description page, which, due to the contents of MediaWiki:Sharedupload, is linked to the one on Commons, where the image was uploaded. See a few local contents of [[MediaWiki:Sharedupload]]: Meta-wiki, English, andItalian (Note that the link from the called contents to Commons cannot lead to a real image).
To make a link to the image description page of a sound file, or of an image without including the actual image, use a link like: [[:Image:a_sound.ogg]]or [[:Image:an_image.jpg]]. In the case of an image, the leading colon prevents the image being embedded in the article, and instead makes an ordinary link. In the case of a sound, automatically playing the sound is not possible anyway.
The description page consists of four parts:
- in the case of an image: the image itself
- description of the image/sound
- "Image history", see page history
- "Image links" or "File links" (the name is the content of the local MediaWiki:Imagelinks. See a few local contents of [[MediaWiki:Imagelinks]]:Meta-Wiki, English, and French): a list of pages that embed the image, if applicable, and of pages linking to the image/sound with "Media:"; however:
it does not list links to the image page
for an image in a template it lists only the template, not the pages in which the template occurs (for that see "What links here" of the template),
if an image in a template depends on a parameter with the whole image code or the url of the image, or depends on {{PAGENAME}} or {{PAGENAMEE}}, it does neither show the final page nor the template. If only the caption is a parameter, the template is listed.
it does not include the rare case of an uploaded html file linking to the image.
- it does not list links to the image page
- for an image in a template it lists only the template, not the pages in which the template occurs (for that see "What links here" of the template),
- if an image in a template depends on a parameter with the whole image code or the url of the image, or depends on {{PAGENAME}} or {{PAGENAMEE}}, it does neither show the final page nor the template. If only the caption is a parameter, the template is listed.
- it does not include the rare case of an uploaded html file linking to the image.
For an image on Commons, subsequently the following is shown on the local image page (see e.g. Image:Tst.png):
- the image
- the message in MediaWiki:Sharedupload
- the local editable content
- the rendering of the editable content on Commons, including content transcluded from other pages on Commons; sections are not numbered and not in the TOC; category tags are ignored; internal links within Commons are rendered in the style of internal links, but link to Commons; existence detection with regard to existence on Commons works; variables depending on the site refer to Commons.
- the local pages that use the image
The description part has also an edit history; it is labelled, somewhat confusingly, Image:xxx Revision history. It should not be confused with the Image history.
What follows refers to the description part, and is in particular about images. For sound, see also w:Wikipedia:Media.
# Useful things to include on an image description page
In the description part of the page you can put text. Initially the description part automatically contains the upload summary supplied by the user when uploading the first version (this text also shows up in the Image history section at the first upload line).
## Description of the image
Eg: "Image of a goldfish in a small tank". This should not be an alternative text (see alternative text for images), but rather a description. This is useful for users who do not have direct access to the image, and is a temporary substitute for a proper longdesc tag.
You could also include the proportions of the image, in pixels.
## Other versions
If other versions (especially a larger version) of the same image exists, link to them.
- [[Media:Goldfish-in-tank2.jpg|different camera angle]] ([[:Image:Goldfish-in-tank2.jpg|info]])
- [[Media:Goldfish-in-tank-textfree.jpg|textfree version]] ([[:Image:Goldfish-in-tank-textfree.jpg|info]])
Textfree versions are useful for using across language versions.
# Categorizing images
Images can be in the same category as other pages, but are treated separately: on the category page they are not included in the count of articles in the category, and they are displayed in a separate section, with for each a thumbnail and the name, see category page.
On Commons there are essentially only images. On projects with real articles a category can either mix articles and images about a subject, or one has separate image categories. An image category is typically a subcategory of the general category about the same subject, and a subcategory of a wider image category.
For categorizing a new image, the image page does not even have to be edited: the category tag can simply be put in the upload summary.
Many images can be categorized in one of the subcategories of Category:Images by subject. You might need to poke around the category hierarchy a bit to find the right place.
# Nonexisting image
Nonexisting images show no image history section, see e.g. Image:Stop sign us.JPG.
# Editing
The preview of the edit page of an image page only shows the editable part, not the image itself, the image history or the image links.
Through this edit page one cannot edit the image file itself: a new image file requires a new upload.
# Protection
Protection of an image page is automatically also protection of the image itself: i.e. a new image under the name of the existing image can only be uploaded by a sysop. | https://www.wikidoc.org/index.php/Images_page | |
2850e5e938451ab66a73025fbf35b367191dc832 | wikidoc | Immortality | Immortality
Immortality (or eternal life) is the concept of living in physical or spiritual form for an infinite length of time
As immortality is the negation of mortality—not dying or not being subject to death—it has been a subject of the greatest fascination to mankind since at least the beginning of history. The Epic of Gilgamesh, one of the first literary works, dating back at least to the 22nd century BC, is primarily a quest of a hero seeking to become immortal. What form an unending human life would take, or whether the soul exists and possesses immortality, has been a fundamental point of focus of philosophy and religion, as well as the subject of speculation, fantasy, and debate.
As of May 2008, human physical immortality is not known to be an achievable possibility. Biological forms have inherent limitations in their design — for example, their fragility and slow adaptability to changing environments. Michael Shermer believes there is no significant scientific evidence for the proposed methods of achieving physical immortality, and says of them, "All have some basis in science, but none has achieved anything like scientific confirmation." Jacques-Yves Cousteau, in the preface to his book The Ocean World, expressed his meditations on physical immortality, as a part of life and its adaptive processes: "Death is fundamental to evolution," and "evolution is fundamental to survival." Cousteau concludes that, biologically speaking, "immortality does not present a possible means to avoid death... Mortal or immortal, an must die."
A timeless existence is also not known for certain to be achievable, or even definable, despite millennia of arguments for eternity. Wittgenstein, in a notably non-theological interpretation of eternal life, writes in the Tractatus that, "If we take eternity to mean not infinite temporal duration but timelessness, then eternal life belongs to those who live in the present."
# Definitions
## Spiritual
- The belief in an afterlife experienced by an immortal soul is a dogma of many branches of Christianity, Zoroastrianism, Hinduism, Islam, and Judaism. This belief is related to the philosophy of dualism.
Christian belief is that never die only our bodies and souls go to the grave and will be raised in God own order. Eternal life or eternal damnation is the choice that mankind will have to make.
## Hypothetical
- Fame itself has been described as a method to "achieve immortality", if only semantically, so that the name or works of a famous individual would "live on" after his or her death. This view of immortality places value on how one will be remembered by generations to come. For example, in Homer's Iliad, Achilles is already nigh-invincible, so his primary motive for fighting in the Trojan War is recognition and everlasting fame.
- Mystic approaches to immortality include those of the ancient Chinese Taoists and European medieval alchemists, seeking an elixir of life.
- Should metaphysical universals and abstract phenomena have an eternal existence, and if they can be interacted with by human beings, then a person might obtain a degree of immortality by interacting with them.
- Quantum immortality is not widely regarded by the scientific community as being a verifiable or even necessarily correct offshoot of the many worlds interpretation. In the many worlds interpretation of quantum mechanics, the wavefunction never collapses, and thus all possible outcomes of a quantum event exist simultaneously, with each event apparently spawning an entirely new universe in which a single possible outcome exists. In this theory, a person could hypothetically live forever as there might exist a string of possible quantum outcomes in which that individual never dies.
## Physical
- The persistence of life itself across time is a form of immortality, insofar as leaving surviving offspring or genetic material is a means of defeating death. Sociobiology and Richard Dawkins' theory of the selfish gene are related to this understanding of immortality.
- Life extension technologies promise a path to complete rejuvenation. Cryonics holds out the hope that the dead can be revived in the future, following sufficient medical advancements.
- Mind uploading is the concept of transference of consciousness from a human brain to an alternative media providing the same functionality. Assuming the process to be possible and repeatable, this would provide immortality to the consciousness, as predicted by futurists such as Ray Kurzweil.
# Physical immortality
Physical immortality is a state of life that allows a person to avoid death and maintain conscious thought, though it can mean the unending existence of a person from a physical source other than organic life, such as a computer. In the early 21st century, physical immortality remains a goal rather than a current reality. Active pursuit of physical immortality can either be based on scientific trends, such as predictions of an impending technological singularity, or because of a spiritual belief, such as those held by Rastafarians or Rebirthers.
## Causes of death
By definition, all causes of death must be overcome or avoided for physical immortality to be achieved. There are three main causes of death: aging, disease and trauma.
### Aging
Aubrey de Grey, a leading researcher in the field, defines aging as follows: “a collection of cumulative changes to the molecular and cellular structure of an adult organism, which result in essential metabolic processes, but which also, once they progress far enough, increasingly disrupt metabolism, resulting in pathology and death.” The current causes of aging in humans are cell loss (without replacement), oncogenic nuclear mutations and epimutations, cell senescence, mitochondrial mutations, lysosomal aggregates, extracellular aggregates, random extracellular cross-linking, immune system decline, and endocrine changes. Eliminating aging would require finding a solution to each of these causes.
### Disease
Disease is theoretically surmountable via technology. Human understanding of genetics is leading to cures and treatments of a myriad of previously incurable diseases.Template:Which The mechanisms by which other diseases do their damage are becoming better understood. Sophisticated methods of detecting diseases early are being developed. Preventative medicine is becoming better understood. Neurodegenerative diseases like Parkinson's and Alzheimer's may soon be curable with the use of stem cells. Breakthroughs in cell biology and telomere research are leading to treatments for cancer. Vaccines are being researched for AIDS and tuberculosis. Genes associated with type 1 diabetes and certain types of cancer have been discovered allowing for new therapies to be developed. Artificial devices attached directly to the nervous system may restore sight to the blind. Drugs are being developed to treat myriad other diseases and ailments.
### Trauma
Physical trauma would remain as a threat to perpetual physical life, even if the problems of aging and disease were overcome, as an otherwise immortal person would still be subject to unforeseen accidents or catastrophes. Ideally, any methods to achieve physical immortality would mitigate the risk of encountering trauma. Taking preventative measures by engineering inherent resistance to injury is thus relevant in addition to entirely reactive measures more closely associated with the paradigm of medical treatment.
The speed and quality of paramedic response remains a determining factor in surviving severe trauma. A body that could automatically treat itself from severe trauma, such as speculated uses for nanotechnology,Template:Who would mitigate this factor.
Being the seat of consciousness, the brain cannot be risked to trauma if a continuous physical life is to be maintained. Therefore, it cannot be replaced or repaired in the same way other organs can. A method of transferring consciousness would be required for an individual to survive trauma to the brain, and this transfer would have to anticipate and precede the damage itself.
## Biological immortality
Biological immortality is an absence of aging, specifically the absence of a sustained increase in rate of mortality as a function of chronological age. A cell or organism that does not experience aging, or ceases to age at some point, is biologically immortal.
Biologists have chosen the word immortal to designate cells that are not limited by the Hayflick limit, where cells no longer divide because of DNA damage or shortened telomeres. Prior to the work of Leonard Hayflick there was the erroneous belief fostered by Alexis Carrel that all normal somatic cells are immortal. By preventing cells from reaching senescence one can achieve biological immortality; telomeres, a “cap” at the end of DNA, are thought to be the cause of cell aging. Every time a cell divides the telomere becomes a bit shorter; when it is finally worn down, the cell is unable to split and dies. Telomerase is an enzyme which rebuilds the telomeres in stem cells and cancer cells, allowing them to replicate an infinite number of times. No definitive work has yet demonstrated that telomerase can be used in human somatic cells to prevent healthy tissues from aging. On the other hand, scientists hope to be able to grow organs with the help of stem cells, allowing organ transplants without the risk of rejection, another step in extending human life expectancy. These technologies are the subject of ongoing research, and are not yet realized.
### Biologically immortal species
Life defined as biologically immortal is still susceptible to causes of death besides aging, including disease and trauma, as defined above. Notable immortal species include:
- Bacteria (as a colony) — Bacteria reproduce through cell division. A parent bacterium splits itself into two identical daughter cells. These daughter cells then split themselves in half. This process repeats, thus making the bacterium colony essentially immortal.Recent research, however, suggests that even bacteria as a colony may eventually die since each succeeding generation is slightly smaller, weaker, and more likely to die than the previous.
- Hydra can be considered biologically immortal as they do not undergo senescence or aging.
- Turritopsis nutricula, a jellyfish, after becoming a sexually mature adult, can transform itself back into a child (the polyp stage) using the cell conversion process of transdifferentiation. Turritopsis nutricula repeats this cycle, meaning that it may have an indefinite lifespan.
- Bristlecone Pines are speculated to be potentially immortal; the oldest known living specimen is over 4800 years old.
### Evolution of aging
As the existence of biologically immortal species demonstrates, there is no thermodynamic necessity for senescence: a defining feature of life is that it takes in free energy from the environment and unloads its entropy as waste. Living systems can even build themselves up from seed, and routinely repair themselves. Aging is therefore presumed to be a byproduct of evolution, but why mortality should be selected for remains a subject of research and debate. Programmed cell death and the teleomere "end replication problem" are found even the earliest and simplest of organisms. This may be a tradeoff between selecting for cancer and selecting for aging.
Modern theories on the evolution of aging include the following:
Mutation accumulation is a theory formulated by Peter Medawar in 1952 to explain how evolution would select for aging. Essentially, aging is never selected against, as organisms have offspring before the mortal mutations surface in an individual.
Antagonistic pleiotropy is a theory proposed as an alternative by George C. Williams, a critic of Medawar, in 1957. In antagonistic pleiotropy, genes carry effects that are both beneficial and detrimental. In essence this refers to genes that offer benefits early in life, but exact a cost later on, i.e. decline and death.
The disposable soma theory was proposed in 1977 by Thomas Kirkwood, which states that an individual body must allocate energy for metabolism, reproduction, and maintenance, and must compromise when there is food scarcity. Compromise in allocating energy to the repair function is what causes the body gradually to deteriorate with age, according to Kirkwood.
## Prospects for human physical immortality
### Technological immortality
Technological immortality is the prospect for much longer life spans made possible by scientific advances in a variety of fields: nanotechnology, emergency room procedures, genetics, biological engineering, regenerative medicine, microbiology, and others. Contemporary life spans in the advanced industrial societies are already markedly longer than those of the past because of better nutrition, availability of health care, standard of living and bio-medical scientific advances. Technological immortality predicts further progress for the same reasons over the near term. An important aspect of current scientific thinking about immortality is that some combination of human cloning, cryonics or nanotechnology will play an essential role in extreme life extension. Robert Freitas, a nanorobotics theorist, suggests tiny medical nanorobots could be created to go through human bloodstreams, find dangerous things like cancer cells and bacteria, and destroy them. Freitas anticipates that gene-therapies and nanotechnology will eventually make the human body effectively self-sustainable and capable of living indefinitely, short of severe trauma. This supports the theory that we will be able to continually create biological or synthetic replacement parts to replace damaged or dying ones.
### Cryonics
Cryonics, the practice of preserving organisms (either intact specimens or only their brains) for possible future revival by storing them at cryogenic temperatures where metabolism and decay are almost completely stopped, is the answer for those who believe that nanotechnology or nanorobots will not develop sufficiently within their lifetime. Ideally, cryonics would allow clinically dead people to be brought back in the future after cures to the patients' diseases have been discovered and aging is reversible. Modern cryonics procedures use a process called vitrification which creates a glass-like state rather than freezing as the body is brought to low temperatures. This process reduces the risk of ice crystals damaging the brain structure. Many people who wish to become physically immortal think of cryonics as a backup plan in case the emerging life extension technologies don't develop rapidly enough.
### Mind-to-computer uploading
One interesting possibility involves uploading the personality and memories via direct mind-computer interface. Extropian futurists have proposed that, thanks to exponentially growing computing power, it will someday be possible to upload human consciousness onto a computer system, and live indefinitely in a virtual environment. This could be accomplished via advanced cybernetics, where computer hardware would initially be installed in the brain to help sort memory or accelerate thought processes. Gradually more and more components would be added until the person's entire brain functions were handled by artificial devices, without any sharp transitions that would lead to some identity issues mentioned below. At this point, the human body would become only an accessory and the mind could be transferred to any sufficiently powerful computer. A person in this state would then be essentially immortal, short of cataclysmic destruction of the entire civilization and their computers.
However, other futurists argue that it is impossible to truly move one's consciousness from one body to another;Template:Who it could be duplicated, but the original would still exist, creating two independent consciousnesses. Uploading is still only a hypothesis and has no scientific backing or proof that it is possible.
### Cyborgology
Transforming a human into a cyborg can include brain implants or extracting a human mind and placing it in a robotic life-support system. Even replacing biological organs with robotic ones could increase life span (ie pace makers) and depending on the definition many technological upgrades to the body, like genetic modifications or the addition of nanobots would qualify an individual as a cyborg. Such modifications would make one impervious to aging and disease and theoretically immortal unless killed or destroyed.
### Mystical and religious pursuits of physical immortality
Many Indian fables and tales include instances of metempsychosis — the ability to jump into another body — performed by advanced Yogis in order to live a longer life. There are also entire Hindu sects devoted to the attainment of physical immortality by various methods, namely the Naths and the Aghoras.
Long before modern science made such speculation feasible, people wishing to escape death turned to the supernatural world for answers. Examples include Chinese Taoists and the medieval alchemists and their search for the Philosopher's Stone, or more modern religious mystics such as Sri Aurobindo, who believed in the possibility of achieving physical immortality through spiritual transformation. In 18th century France, a man who called himself the Comte de Saint-Germain claimed to be centuries old; people who adhere to the Ascended Master Teachings are convinced of his physical immortality.
Rastafarians believe in physical immortality as a part of their religious doctrines. They believe that after God has called the Day of Judgment they will go to what they describe as Mount Zion in Africa to live in freedom for ever. They avoid the term "everlasting life"' and deliberately use "ever-living" instead.
Another group that believes in physical immortality are the Rebirthers, who believe that by following the connected breathing process of rebirthing they can physically live forever.
# Religious traditions
Until the late 20th century, there were no creditable scientific forecasts that physical immortality was obtainable. As late as 1952, the editorial staff of the Syntopicon found that in their compilation of the Great Books of the Western World, "The philosophical issue concerning immortality cannot be separated from issues concerning the existence and nature of man's soul." Thus, the vast majority of speculation regarding immortality before the 21st century was regarding the nature of the afterlife.
Spiritual immortality, also known as the immortality of the soul, is the unending existence of a person from a nonphysical source, or in a nonphysical state, such as a soul.
It is a belief that is expressed in nearly every religious tradition. In both Western and Eastern religions, the spirit is an energy or force that transcends the mortal body, and returns to: (1) the spirit realm whether to enjoy heavenly bliss or suffer eternal torment in hell, or; (2) the cycle of life, directly or indirectly depending on the tradition.
The world's major religions hold a number of perspectives on spiritual immortality.
## Hinduism
Hindus believe in an immortal soul which is reincarnated after death. According to Hinduism, people repeat a process of life, death, and rebirth in a cycle called samsara. If they live their life well, their karma improves and their station in the next life will be higher, and conversely lower if they live their life poorly. Eventually after many life times of perfecting its karma, the soul is freed from the cycle and lives in perpetual bliss. There is no eternal torment in Hinduism, temporal existence being harsh enough, although if a soul consistently lives very evil lives, it could work its way down to the very bottom of the cycle.
## Shintoism
Shintoists claim that except for those who choose or are dispatched to the underground world of Yomi, every living and non-living being may lose its body, but not its soul (tamashii), and that they live together with mortal souls as an immortal being called Kami. Shinto allows anything to attain Kami status regardless of its existence before becoming Kami. Therefore, even those that do not believe in Shinto may choose to become Kami, as well as things like a rock, a tree, or even a robot. Some may be reincarnated for various reasons.
## Zoroastrianism
Zoroastrians believe that on the fourth day after death, the human soul leaves the body and the body remains as an empty shell. Souls would go heaven or hell; these concepts of the afterlife in Zoroastrianism may have influenced Abrahamic religions.
## Buddhism
Buddhists believe that there is a cycle of birth, death, and rebirth and that the process is according to the qualities of their actions. This constant process of becoming ceases at the fruition of Bodhi (enlightenment) at which a being is no longer subject to causation (karma) but enters into a state that the Buddha called amata (deathlessness).
According to the philosophical premise of the Buddha, the initiate to Buddhism who is to be "shown the way to Immortality (amata)", wherein liberation of the mind (cittavimutta) is effectuated through the expansion of wisdom and the meditative practices of sati and samādhi, must first be educated away from his former ignorance-based (avijja) materialistic proclivities in that he "saw any of these forms, feelings, or this body, to be my Self, to be that which I am by nature".
Thus, desiring a soul or ego (ātman) to be permanent is a prime consequence of ignorance, itself the cause of all misery and the foundation of the cycle of reincarnation (saṃsāra). Form and consciousness being two of the five skandhas, or aggregates of ignorance, Buddhists believe that physical immortality is neither a path to enlightenment, nor an attainable goal: even the gods which can live for eons eventually die. Upon enlightenment, the "karmic seeds" (saṅkhāras or sanskaras) for all future becoming and rebirth are exhausted. After biological death an arhat, or buddha, enters into parinirvana, an everlasting state of transcendental happiness.
## Judaism
Judaism claims that the righteous dead will be resurrected in the Messianic age with the coming of the messiah. They will then be granted immortality in a perfect world. The wicked dead, on the other hand, will not be resurrected at all. This is not the only Jewish belief about the afterlife. The Tanakh is not specific about the afterlife, so there are wide differences in views and explanations among believers.
The Hebrew Bible speaks about sheol (שאול), the underworld to which the souls of the dead depart. The doctrine of resurrection is mentioned explicitly only in Template:Bibleverse although it may be implied in several other texts. Later Judaism accepted that there would be a resurrection of all men (cf. Template:Bibleverse) and the intertestamental literature describes in more detail what the dead experience in sheol. By the second century BC, Jews who accepted the Oral Torah had come to believe that those in sheol awaited the resurrection either in comfort (in the bosom of Abraham) or in torment.
## Christianity
Christian theology holds that Adam and Eve lost physical immortality for themselves and all their descendants in the Fall of Man, though this initial "imperishability of the bodily frame of man" was "a preternatural condition."
According to the book of Enoch, the righteous and wicked await the resurrection in separate divisions of sheol, a teaching which may have influenced Jesus' parable of Lazarus and Dives. Christians believe that every person that believes in Christ will be resurrected; Bible passages are interpreted as teaching that the resurrected body will, like the present body, be both physical (but a renewed and non-decaying physical body) and spiritual.
Specific imagery of resurrection into immortal form is found in the Pauline letters:
Behold, I shew you a mystery; We shall not all sleep, but we shall all be changed,
In a moment, in the twinkling of an eye, at the last trump: for the trumpet shall sound, and the dead shall be raised incorruptible, and we shall be changed.
For this corruptible must put on incorruption, and this mortal must put on immortality.
So when this corruptible shall have put on incorruption, and this mortal shall have put on immortality, then shall be brought to pass the saying that is written, Death is swallowed up in victory.
O death, where is thy sting? O grave, where is thy victory?
The sting of death is sin; and the strength of sin is the law.
But thanks be to God, which giveth us the victory through our Lord Jesus Christ.
Therefore, my beloved brethren, be ye stedfast, unmoveable, always abounding in the work of the Lord, forasmuch as ye know that your labour is not in vain in the Lord. —Template:Bibleverse
In Romans 2:6-7 Paul declares that God "will render to every man according to his deeds: To them who by patient continuance in well doing seek for glory and honour and immortality, eternal life", but then in Romans 3 warns that no one will ever meet this standard.
After the Last Judgment, those who have been born again will live forever in the presence of God, and those who were never born again will be abandoned to never-ending consciousness of guilt, separation from God, and punishment for sin. Eternal death is depicted in the Bible as a realm of constant physical and spiritual anguish in a lake of fire, and a realm of darkness away from God. Some see the fires of Hell as a theological metaphor, representing the inescapable presence of God endured in absence of love for God; others suggest that Hell represents complete destruction of both the physical body and of spiritual existence.
### Roman Catholicism
Roman Catholic dogmatic theology also used to teach that there is a supernatural realm called Purgatory where souls who have died in a state of grace but have yet to expiate venial sins or temporal punishments due to past sins are cleansed before they are admitted into Heaven.
### Jehovah's Witnesses
Jehovah's Witnesses believe the word soul (nephesh or psykhe) as used in the Bible is a person, an animal, or the life a person or animal enjoys. Hence, the soul is not part of man, but is the whole man — man as a living being. Hence, when a person or animal dies, the soul dies, and death is a state of non-existence, based on Ezekiel 18:4. Hell (hades or sheol) is not a place of fiery torment, but rather the common grave of humankind, a place of unconsciousness.
After the final judgment, it is expected that the righteous will receive eternal life and live forever in an earth turned into a paradise. Another group referenced as "the little flock" of 144,000 people will receive immortality and go to heaven to rule as Kings and Priests. Jehovah's Witnesses make the distinction that those with 'eternal life' can die though they do not succumb to disease or old age, whereas immortal ones cannot die by any cause. They teach that Jesus was the first to be rewarded with heavenly immortality, but that Revelation 7:4 and Revelation 14:1, 3 refer to a literal number (144,000) of additional people who will become "self-sustaining," that is, not needing anything outside themselves (food, sunlight, etc.) to maintain their own life.
### Mormonism
In Mormon theology, there are three degrees of glory which are the ultimate, eternal dwelling place for nearly all who lived on earth. Joseph Smith, Jr., the founder of the Latter Day Saint movement, provided a description of the afterlife based upon a vision he reportedly received, recorded within the Mormon canonical writings entitled Doctrine and Covenants. According to this section of LDS scripture, the afterlife consists of three degrees or kingdoms of glory, called the Celestial Kingdom, the Terrestrial Kingdom, and the Telestial Kingdom. The few who do not inherit any degree of glory (though they are resurrected) reside in a state called outer darkness, which, though not a degree of glory, is often discussed in this context. The only ones who go there are known as "Sons of Perdition".
Critics of the Latter Day Saint Movement argue that Joseph Smith used the ideas of Emanuel Swedenborg to formulate the theology surrounding the three degrees of glory.
### Other Christian beliefs
The doctrine of conditional immortality states the human soul is naturally mortal, and that immortality is granted by God as a gift. The doctrine is a "significant minority evangelical view" that has "grown within evangelicalism in recent years".
Some sects who hold to the doctrine of baptismal regeneration also believe in a third realm called Limbo, which is the final destination of souls who have not been baptised, but who have been innocent of mortal sin. Souls in Limbo include unbaptised infants and those who lived virtuously but were never exposed to Christianity in their lifetimes.
Christian Scientists believe that sin brought death, and that death will be overcome with the overcoming of sin.
## Islam
Muslims believe that everyone has an immortal soul which will live on after death. A soul undergoes correction in Hell if it has led an evil life, but once this correction is over, the soul is admitted to Heaven. Souls that commit unforgivable evil will never leave hell. Some souls will therefore never taste Heaven.
# Ethics of immortality
The possibility of clinical immortality raises a host of medical, philosophical, and religious issues and ethical questions. These include persistent vegetative states, the nature of personality over time, technology to mimic or copy the mind or its processes, social and economic disparities created by longevity, and survival of the heat death of the universe.
## Undesirability of immortality
Essential to many of the world's religions is a doctrine of an eternal afterlife. Narratives from Christianity and Islam assert that eternal afterlife is not desirable to the unfaithful:
The rich man also died, and was buried; And in hell he lift up his eyes, being in torments, and seeth Abraham afar off, and Lazarus in his bosom. And he cried and said, Father Abraham, have mercy on me, and send Lazarus, that he may dip the tip of his finger in water, and cool my tongue; for I am tormented in this flame. But Abraham said, Son, remember that thou in thy lifetime receivedst thy good things, and likewise Lazarus evil things: but now he is comforted, and thou art tormented. And beside all this, between us and you there is a great gulf fixed: so that they which would pass from hence to you cannot; neither can they pass to us, that would come from thence.
Those who are wretched shall be in the Fire: There will be for them therein (nothing but) the heaving of sighs and sobs: They will dwell therein for all the time that the heavens and the earth endure, except as thy Lord willeth: for thy Lord is the (sure) accomplisher of what He planneth. And those who are blessed shall be in the Garden: They will dwell therein for all the time that the heavens and the earth endure, except as thy Lord willeth: a gift without break.
Instances from other religions include the Buddhist concept of eternal rebirth, which considers that rebirth is caused by ignorance, an essentially undesirable condition that is to be overcome.
Physical immortality has also been imagined as a form of eternal torment, as in Mary Shelley's short story "The Mortal Immortal", the protagonist of which witnesses everyone he cares about dying around him. Jorge Luis Borges explored the idea that life gets its meaning from death in the short story "'The Immortal"; an entire society having achieved immortality, they found time becoming infinite, and so found no motivation for any action.
## Desirablity of immortality
Many religions promise their faithful an eternal paradise in an afterlife. These presume perfection, as they are part of a divine plan, and are categorically desirable.
Physical immortality is considered desirable over its counterpart, death, which to date has been inevitable for all human beings. This presumes tolerable living conditions as an incentive for perpetual life, as the prevalence of suicide demonstrates.
# Symbols
There are numerous symbols representing immortality. Pictured here is an Egyptian symbol of life that holds connotations of immortality when depicted in the hands of the gods and pharaohs who were seen as having control over the journey of life, the ankh (left). The Möbius strip in the shape of a trefoil knot is another symbol of immortality. Most symbolic representations of infinity or the life cycle are often used to represent immortality depending on the context they are placed in. Other examples include the Ouroboros, the Chinese fungus of longevity, the ten kanji, the phoenix, and the colors amaranth (in Western culture) and peach (in Chinese culture).
# Fiction
Immortal beings and species abound in fiction, especially fantasy fiction. | Immortality
Template:Otheruses3
Immortality (or eternal life) is the concept of living in physical or spiritual form for an infinite length of time
As immortality is the negation of mortality—not dying or not being subject to death—it has been a subject of the greatest fascination to mankind since at least the beginning of history.[citation needed] The Epic of Gilgamesh, one of the first literary works, dating back at least to the 22nd century BC, is primarily a quest of a hero seeking to become immortal. What form an unending human life would take, or whether the soul exists and possesses immortality, has been a fundamental point of focus of philosophy and religion,[citation needed] as well as the subject of speculation, fantasy, and debate.
As of May 2008, human physical immortality is not known to be an achievable possibility. Biological forms have inherent limitations in their design — for example, their fragility and slow adaptability to changing environments. Michael Shermer believes there is no significant scientific evidence for the proposed methods of achieving physical immortality, and says of them, "All have some basis in science, but none has achieved anything like scientific confirmation."[citation needed] Jacques-Yves Cousteau, in the preface to his book The Ocean World, expressed his meditations on physical immortality, as a part of life and its adaptive processes: "Death is fundamental to evolution," and "evolution is fundamental to survival." Cousteau concludes that, biologically speaking, "immortality does not present a possible means to avoid death... Mortal or immortal, an [organism] must die."
A timeless existence is also not known for certain to be achievable, or even definable, despite millennia of arguments for eternity. Wittgenstein, in a notably non-theological interpretation of eternal life, writes in the Tractatus that, "If we take eternity to mean not infinite temporal duration but timelessness, then eternal life belongs to those who live in the present."[citation needed]
Template:TOC right
# Definitions
## Spiritual
- The belief in an afterlife experienced by an immortal soul is a dogma of many branches of Christianity, Zoroastrianism, Hinduism, Islam, and Judaism. This belief is related to the philosophy of dualism.
Christian belief is that [spirits] never die only our bodies and souls go to the grave and will be raised in God own order. Eternal life or eternal damnation is the choice that mankind will have to make.
## Hypothetical
- Fame itself has been described as a method to "achieve immortality", if only semantically, so that the name or works of a famous individual would "live on" after his or her death. This view of immortality places value on how one will be remembered by generations to come. For example, in Homer's Iliad, Achilles is already nigh-invincible, so his primary motive for fighting in the Trojan War is recognition and everlasting fame.
- Mystic approaches to immortality include those of the ancient Chinese Taoists and European medieval alchemists, seeking an elixir of life.
- Should metaphysical universals and abstract phenomena have an eternal existence, and if they can be interacted with by human beings, then a person might obtain a degree of immortality by interacting with them.[citation needed]
- Quantum immortality is not widely regarded by the scientific community as being a verifiable or even necessarily correct offshoot of the many worlds interpretation. In the many worlds interpretation of quantum mechanics, the wavefunction never collapses, and thus all possible outcomes of a quantum event exist simultaneously, with each event apparently spawning an entirely new universe in which a single possible outcome exists. In this theory, a person could hypothetically live forever as there might exist a string of possible quantum outcomes in which that individual never dies.
## Physical
- The persistence of life itself across time is a form of immortality, insofar as leaving surviving offspring or genetic material is a means of defeating death. Sociobiology and Richard Dawkins' theory of the selfish gene are related to this understanding of immortality.[citation needed]
- Life extension technologies promise a path to complete rejuvenation. Cryonics holds out the hope that the dead can be revived in the future, following sufficient medical advancements.
- Mind uploading is the concept of transference of consciousness from a human brain to an alternative media providing the same functionality. Assuming the process to be possible and repeatable, this would provide immortality to the consciousness, as predicted by futurists such as Ray Kurzweil.[1]
# Physical immortality
Physical immortality is a state of life that allows a person to avoid death and maintain conscious thought, though it can mean the unending existence of a person from a physical source other than organic life, such as a computer. In the early 21st century, physical immortality remains a goal rather than a current reality. Active pursuit of physical immortality can either be based on scientific trends, such as predictions of an impending technological singularity, or because of a spiritual belief, such as those held by Rastafarians or Rebirthers.
## Causes of death
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By definition, all causes of death must be overcome or avoided for physical immortality to be achieved. There are three main causes of death: aging, disease and trauma.
### Aging
Aubrey de Grey, a leading researcher in the field, defines aging as follows: “a collection of cumulative changes to the molecular and cellular structure of an adult organism, which result in essential metabolic processes, but which also, once they progress far enough, increasingly disrupt metabolism, resulting in pathology and death.” The current causes of aging in humans are cell loss (without replacement), oncogenic nuclear mutations and epimutations, cell senescence, mitochondrial mutations, lysosomal aggregates, extracellular aggregates, random extracellular cross-linking, immune system decline, and endocrine changes. Eliminating aging would require finding a solution to each of these causes.
### Disease
Disease is theoretically surmountable via technology. Human understanding of genetics is leading to cures and treatments of a myriad of previously incurable diseases.Template:Which The mechanisms by which other diseases do their damage are becoming better understood. Sophisticated methods of detecting diseases early are being developed. Preventative medicine is becoming better understood. Neurodegenerative diseases like Parkinson's and Alzheimer's may soon be curable with the use of stem cells. Breakthroughs in cell biology and telomere research are leading to treatments for cancer. Vaccines are being researched for AIDS and tuberculosis. Genes associated with type 1 diabetes and certain types of cancer have been discovered allowing for new therapies to be developed. Artificial devices attached directly to the nervous system may restore sight to the blind. Drugs are being developed to treat myriad other diseases and ailments.
### Trauma
Physical trauma would remain as a threat to perpetual physical life, even if the problems of aging and disease were overcome, as an otherwise immortal person would still be subject to unforeseen accidents or catastrophes. Ideally, any methods to achieve physical immortality would mitigate the risk of encountering trauma. Taking preventative measures by engineering inherent resistance to injury is thus relevant in addition to entirely reactive measures more closely associated with the paradigm of medical treatment.
The speed and quality of paramedic response remains a determining factor in surviving severe trauma.[2] A body that could automatically treat itself from severe trauma, such as speculated uses for nanotechnology,Template:Who would mitigate this factor.
Being the seat of consciousness, the brain cannot be risked to trauma if a continuous physical life is to be maintained. Therefore, it cannot be replaced or repaired in the same way other organs can. A method of transferring consciousness would be required for an individual to survive trauma to the brain, and this transfer would have to anticipate and precede the damage itself.
## Biological immortality
Biological immortality is an absence of aging, specifically the absence of a sustained increase in rate of mortality as a function of chronological age. A cell or organism that does not experience aging, or ceases to age at some point, is biologically immortal.
Biologists have chosen the word immortal to designate cells that are not limited by the Hayflick limit, where cells no longer divide because of DNA damage or shortened telomeres. Prior to the work of Leonard Hayflick there was the erroneous belief fostered by Alexis Carrel that all normal somatic cells are immortal. By preventing cells from reaching senescence one can achieve biological immortality; telomeres, a “cap” at the end of DNA, are thought to be the cause of cell aging. Every time a cell divides the telomere becomes a bit shorter; when it is finally worn down, the cell is unable to split and dies. Telomerase is an enzyme which rebuilds the telomeres in stem cells and cancer cells, allowing them to replicate an infinite number of times.[3] No definitive work has yet demonstrated that telomerase can be used in human somatic cells to prevent healthy tissues from aging. On the other hand, scientists hope to be able to grow organs with the help of stem cells, allowing organ transplants without the risk of rejection, another step in extending human life expectancy. These technologies are the subject of ongoing research, and are not yet realized.[citation needed]
### Biologically immortal species
Life defined as biologically immortal is still susceptible to causes of death besides aging, including disease and trauma, as defined above. Notable immortal species include:
- Bacteria (as a colony) — Bacteria reproduce through cell division. A parent bacterium splits itself into two identical daughter cells. These daughter cells then split themselves in half. This process repeats, thus making the bacterium colony essentially immortal.Recent research, however, suggests that even bacteria as a colony may eventually die since each succeeding generation is slightly smaller, weaker, and more likely to die than the previous.[4]
- Hydra can be considered biologically immortal as they do not undergo senescence or aging.
- Turritopsis nutricula, a jellyfish, after becoming a sexually mature adult, can transform itself back into a child (the polyp stage) using the cell conversion process of transdifferentiation. Turritopsis nutricula repeats this cycle, meaning that it may have an indefinite lifespan.[5]
- Bristlecone Pines are speculated to be potentially immortal; the oldest known living specimen is over 4800 years old.
### Evolution of aging
As the existence of biologically immortal species demonstrates, there is no thermodynamic necessity for senescence: a defining feature of life is that it takes in free energy from the environment and unloads its entropy as waste. Living systems can even build themselves up from seed, and routinely repair themselves. Aging is therefore presumed to be a byproduct of evolution, but why mortality should be selected for remains a subject of research and debate. Programmed cell death and the teleomere "end replication problem" are found even the earliest and simplest of organisms.[6] This may be a tradeoff between selecting for cancer and selecting for aging.[7]
Modern theories on the evolution of aging include the following:
Mutation accumulation is a theory formulated by Peter Medawar in 1952 to explain how evolution would select for aging. Essentially, aging is never selected against, as organisms have offspring before the mortal mutations surface in an individual.
Antagonistic pleiotropy is a theory proposed as an alternative by George C. Williams, a critic of Medawar, in 1957. In antagonistic pleiotropy, genes carry effects that are both beneficial and detrimental. In essence this refers to genes that offer benefits early in life, but exact a cost later on, i.e. decline and death.[8]
The disposable soma theory was proposed in 1977 by Thomas Kirkwood, which states that an individual body must allocate energy for metabolism, reproduction, and maintenance, and must compromise when there is food scarcity. Compromise in allocating energy to the repair function is what causes the body gradually to deteriorate with age, according to Kirkwood.[9]
## Prospects for human physical immortality
Template:Inline
### Technological immortality
Technological immortality is the prospect for much longer life spans made possible by scientific advances in a variety of fields: nanotechnology, emergency room procedures, genetics, biological engineering, regenerative medicine, microbiology, and others. Contemporary life spans in the advanced industrial societies are already markedly longer than those of the past because of better nutrition, availability of health care, standard of living and bio-medical scientific advances. Technological immortality predicts further progress for the same reasons over the near term. An important aspect of current scientific thinking about immortality is that some combination of human cloning, cryonics or nanotechnology will play an essential role in extreme life extension. Robert Freitas, a nanorobotics theorist, suggests tiny medical nanorobots could be created to go through human bloodstreams, find dangerous things like cancer cells and bacteria, and destroy them.[10] Freitas anticipates that gene-therapies and nanotechnology will eventually make the human body effectively self-sustainable and capable of living indefinitely, short of severe trauma. This supports the theory that we will be able to continually create biological or synthetic replacement parts to replace damaged or dying ones.
### Cryonics
Cryonics, the practice of preserving organisms (either intact specimens or only their brains) for possible future revival by storing them at cryogenic temperatures where metabolism and decay are almost completely stopped, is the answer for those who believe that nanotechnology or nanorobots will not develop sufficiently within their lifetime. Ideally, cryonics would allow clinically dead people to be brought back in the future after cures to the patients' diseases have been discovered and aging is reversible. Modern cryonics procedures use a process called vitrification which creates a glass-like state rather than freezing as the body is brought to low temperatures. This process reduces the risk of ice crystals damaging the brain structure. Many people who wish to become physically immortal think of cryonics as a backup plan in case the emerging life extension technologies don't develop rapidly enough.
### Mind-to-computer uploading
One interesting possibility involves uploading the personality and memories via direct mind-computer interface. Extropian futurists have proposed that, thanks to exponentially growing computing power, it will someday be possible to upload human consciousness onto a computer system, and live indefinitely in a virtual environment. This could be accomplished via advanced cybernetics, where computer hardware would initially be installed in the brain to help sort memory or accelerate thought processes. Gradually more and more components would be added until the person's entire brain functions were handled by artificial devices, without any sharp transitions that would lead to some identity issues mentioned below. At this point, the human body would become only an accessory and the mind could be transferred to any sufficiently powerful computer. A person in this state would then be essentially immortal, short of cataclysmic destruction of the entire civilization and their computers.
However, other futurists argue that it is impossible to truly move one's consciousness from one body to another;Template:Who it could be duplicated, but the original would still exist, creating two independent consciousnesses. Uploading is still only a hypothesis and has no scientific backing or proof that it is possible.
### Cyborgology
Transforming a human into a cyborg can include brain implants or extracting a human mind and placing it in a robotic life-support system. Even replacing biological organs with robotic ones could increase life span (ie pace makers) and depending on the definition many technological upgrades to the body, like genetic modifications or the addition of nanobots would qualify an individual as a cyborg. Such modifications would make one impervious to aging and disease and theoretically immortal unless killed or destroyed.
### Mystical and religious pursuits of physical immortality
Many Indian fables and tales include instances of metempsychosis — the ability to jump into another body — performed by advanced Yogis in order to live a longer life. There are also entire Hindu sects devoted to the attainment of physical immortality by various methods, namely the Naths and the Aghoras.[citation needed]
Long before modern science made such speculation feasible, people wishing to escape death turned to the supernatural world for answers. Examples include Chinese Taoists[citation needed] and the medieval alchemists and their search for the Philosopher's Stone, or more modern religious mystics such as Sri Aurobindo, who believed in the possibility of achieving physical immortality through spiritual transformation. In 18th century France, a man who called himself the Comte de Saint-Germain claimed to be centuries old; people who adhere to the Ascended Master Teachings are convinced of his physical immortality.[citation needed]
Rastafarians believe in physical immortality as a part of their religious doctrines. They believe that after God has called the Day of Judgment they will go to what they describe as Mount Zion in Africa to live in freedom for ever. They avoid the term "everlasting life"' and deliberately use "ever-living" instead.
Another group that believes in physical immortality are the Rebirthers, who believe that by following the connected breathing process of rebirthing they can physically live forever.
# Religious traditions
Template:Globalize
Until the late 20th century, there were no creditable scientific forecasts that physical immortality was obtainable. As late as 1952, the editorial staff of the Syntopicon found that in their compilation of the Great Books of the Western World, "The philosophical issue concerning immortality cannot be separated from issues concerning the existence and nature of man's soul."[11] Thus, the vast majority of speculation regarding immortality before the 21st century was regarding the nature of the afterlife.
Spiritual immortality, also known as the immortality of the soul, is the unending existence of a person from a nonphysical source, or in a nonphysical state, such as a soul.
It is a belief that is expressed in nearly every religious tradition. In both Western and Eastern religions, the spirit is an energy or force that transcends the mortal body, and returns to: (1) the spirit realm whether to enjoy heavenly bliss or suffer eternal torment in hell, or; (2) the cycle of life, directly or indirectly depending on the tradition.
The world's major religions hold a number of perspectives on spiritual immortality.
## Hinduism
Hindus believe in an immortal soul which is reincarnated after death. According to Hinduism, people repeat a process of life, death, and rebirth in a cycle called samsara. If they live their life well, their karma improves and their station in the next life will be higher, and conversely lower if they live their life poorly. Eventually after many life times of perfecting its karma, the soul is freed from the cycle and lives in perpetual bliss. There is no eternal torment in Hinduism, temporal existence being harsh enough, although if a soul consistently lives very evil lives, it could work its way down to the very bottom of the cycle.
## Shintoism
Shintoists claim that except for those who choose or are dispatched to the underground world of Yomi, every living and non-living being may lose its body, but not its soul (tamashii), and that they live together with mortal souls as an immortal being called Kami. Shinto allows anything to attain Kami status regardless of its existence before becoming Kami. Therefore, even those that do not believe in Shinto may choose to become Kami, as well as things like a rock, a tree, or even a robot. Some may be reincarnated for various reasons.
## Zoroastrianism
Zoroastrians believe that on the fourth day after death, the human soul leaves the body and the body remains as an empty shell. Souls would go heaven or hell; these concepts of the afterlife in Zoroastrianism may have influenced Abrahamic religions.
## Buddhism
Buddhists believe that there is a cycle of birth, death, and rebirth and that the process is according to the qualities of their actions. This constant process of becoming ceases at the fruition of Bodhi (enlightenment) at which a being is no longer subject to causation (karma) but enters into a state that the Buddha called amata (deathlessness).
According to the philosophical premise of the Buddha, the initiate to Buddhism who is to be "shown the way to Immortality (amata)",[12] wherein liberation of the mind (cittavimutta) is effectuated through the expansion of wisdom and the meditative practices of sati and samādhi, must first be educated away from his former ignorance-based (avijja) materialistic proclivities in that he "saw any of these forms, feelings, or this body, to be my Self, to be that which I am by nature".
Thus, desiring a soul or ego (ātman) to be permanent is a prime consequence of ignorance, itself the cause of all misery and the foundation of the cycle of reincarnation (saṃsāra). Form and consciousness being two of the five skandhas, or aggregates of ignorance, Buddhists believe that physical immortality is neither a path to enlightenment, nor an attainable goal: even the gods which can live for eons eventually die. Upon enlightenment, the "karmic seeds" (saṅkhāras or sanskaras) for all future becoming and rebirth are exhausted. After biological death an arhat, or buddha, enters into parinirvana, an everlasting state of transcendental happiness.
## Judaism
Judaism claims that the righteous dead will be resurrected in the Messianic age with the coming of the messiah. They will then be granted immortality in a perfect world. The wicked dead, on the other hand, will not be resurrected at all. This is not the only Jewish belief about the afterlife. The Tanakh is not specific about the afterlife, so there are wide differences in views and explanations among believers.
The Hebrew Bible speaks about sheol (שאול), the underworld to which the souls of the dead depart. The doctrine of resurrection is mentioned explicitly only in Template:Bibleverse although it may be implied in several other texts. Later Judaism accepted that there would be a resurrection of all men (cf. Template:Bibleverse) and the intertestamental literature describes in more detail what the dead experience in sheol. By the second century BC, Jews who accepted the Oral Torah had come to believe that those in sheol awaited the resurrection either in comfort (in the bosom of Abraham) or in torment.
## Christianity
Christian theology holds that Adam and Eve lost physical immortality for themselves and all their descendants in the Fall of Man, though this initial "imperishability of the bodily frame of man" was "a preternatural condition."[13]
According to the book of Enoch, the righteous and wicked await the resurrection in separate divisions of sheol, a teaching which may have influenced Jesus' parable of Lazarus and Dives.[14] Christians believe that every person that believes in Christ will be resurrected; Bible passages are interpreted as teaching that the resurrected body will, like the present body, be both physical (but a renewed and non-decaying physical body) and spiritual.
Specific imagery of resurrection into immortal form is found in the Pauline letters:
Behold, I shew you a mystery; We shall not all sleep, but we shall all be changed,
In a moment, in the twinkling of an eye, at the last trump: for the trumpet shall sound, and the dead shall be raised incorruptible, and we shall be changed.
For this corruptible must put on incorruption, and this mortal must put on immortality.
So when this corruptible shall have put on incorruption, and this mortal shall have put on immortality, then shall be brought to pass the saying that is written, Death is swallowed up in victory.
O death, where is thy sting? O grave, where is thy victory?
The sting of death is sin; and the strength of sin is the law.
But thanks be to God, which giveth us the victory through our Lord Jesus Christ.
Therefore, my beloved brethren, be ye stedfast, unmoveable, always abounding in the work of the Lord, forasmuch as ye know that your labour is not in vain in the Lord. —Template:Bibleverse
In Romans 2:6-7 Paul declares that God "will render to every man according to his deeds: To them who by patient continuance in well doing seek for glory and honour and immortality, eternal life", but then in Romans 3 warns that no one will ever meet this standard.
After the Last Judgment, those who have been born again will live forever in the presence of God, and those who were never born again will be abandoned to never-ending consciousness of guilt, separation from God, and punishment for sin. Eternal death is depicted in the Bible as a realm of constant physical and spiritual anguish in a lake of fire, and a realm of darkness away from God. Some see the fires of Hell as a theological metaphor, representing the inescapable presence of God endured in absence of love for God; others suggest that Hell represents complete destruction of both the physical body and of spiritual existence.
### Roman Catholicism
Roman Catholic dogmatic theology also used to teach that there is a supernatural realm called Purgatory where souls who have died in a state of grace but have yet to expiate venial sins or temporal punishments due to past sins are cleansed before they are admitted into Heaven.
### Jehovah's Witnesses
Jehovah's Witnesses believe the word soul (nephesh or psykhe) as used in the Bible is a person, an animal, or the life a person or animal enjoys. Hence, the soul is not part of man, but is the whole man — man as a living being. Hence, when a person or animal dies, the soul dies, and death is a state of non-existence, based on Ezekiel 18:4.[15] Hell (hades or sheol) is not a place of fiery torment, but rather the common grave of humankind, a place of unconsciousness.[16][17]
After the final judgment, it is expected that the righteous will receive eternal life and live forever in an earth turned into a paradise. Another group referenced as "the little flock" of 144,000 people will receive immortality and go to heaven to rule as Kings and Priests. Jehovah's Witnesses make the distinction that those with 'eternal life' can die though they do not succumb to disease or old age, whereas immortal ones cannot die by any cause.[18] They teach that Jesus was the first to be rewarded with heavenly immortality, but that Revelation 7:4 and Revelation 14:1, 3 refer to a literal number (144,000) of additional people who will become "self-sustaining," that is, not needing anything outside themselves (food, sunlight, etc.) to maintain their own life.[19]
### Mormonism
In Mormon theology, there are three degrees of glory which are the ultimate, eternal dwelling place for nearly all who lived on earth. Joseph Smith, Jr., the founder of the Latter Day Saint movement, provided a description of the afterlife based upon a vision he reportedly received, recorded within the Mormon canonical writings entitled Doctrine and Covenants.[20] According to this section of LDS scripture, the afterlife consists of three degrees or kingdoms of glory, called the Celestial Kingdom, the Terrestrial Kingdom, and the Telestial Kingdom. The few who do not inherit any degree of glory (though they are resurrected) reside in a state called outer darkness, which, though not a degree of glory, is often discussed in this context. The only ones who go there are known as "Sons of Perdition".
Critics of the Latter Day Saint Movement argue that Joseph Smith used the ideas of Emanuel Swedenborg to formulate the theology surrounding the three degrees of glory.
### Other Christian beliefs
The doctrine of conditional immortality states the human soul is naturally mortal, and that immortality is granted by God as a gift. The doctrine is a "significant minority evangelical view" that has "grown within evangelicalism in recent years".
[21]
Some sects who hold to the doctrine of baptismal regeneration also believe in a third realm called Limbo, which is the final destination of souls who have not been baptised, but who have been innocent of mortal sin. Souls in Limbo include unbaptised infants and those who lived virtuously but were never exposed to Christianity in their lifetimes.
Christian Scientists believe that sin brought death, and that death will be overcome with the overcoming of sin.
## Islam
Muslims believe that everyone has an immortal soul which will live on after death. A soul undergoes correction in Hell if it has led an evil life, but once this correction is over, the soul is admitted to Heaven.[citation needed] Souls that commit unforgivable evil will never leave hell. Some souls will therefore never taste Heaven.
# Ethics of immortality
The possibility of clinical immortality raises a host of medical, philosophical, and religious issues and ethical questions. These include persistent vegetative states, the nature of personality over time, technology to mimic or copy the mind or its processes, social and economic disparities created by longevity, and survival of the heat death of the universe.
## Undesirability of immortality
Essential to many of the world's religions is a doctrine of an eternal afterlife. Narratives from Christianity and Islam assert that eternal afterlife is not desirable to the unfaithful:
The rich man also died, and was buried; And in hell he lift up his eyes, being in torments, and seeth Abraham afar off, and Lazarus in his bosom. And he cried and said, Father Abraham, have mercy on me, and send Lazarus, that he may dip the tip of his finger in water, and cool my tongue; for I am tormented in this flame. But Abraham said, Son, remember that thou in thy lifetime receivedst thy good things, and likewise Lazarus evil things: but now he is comforted, and thou art tormented. And beside all this, between us and you there is a great gulf fixed: so that they which would pass from hence to you cannot; neither can they pass to us, that would come from thence.
Those who are wretched shall be in the Fire: There will be for them therein (nothing but) the heaving of sighs and sobs: They will dwell therein for all the time that the heavens and the earth endure, except as thy Lord willeth: for thy Lord is the (sure) accomplisher of what He planneth. And those who are blessed shall be in the Garden: They will dwell therein for all the time that the heavens and the earth endure, except as thy Lord willeth: a gift without break.
Instances from other religions include the Buddhist concept of eternal rebirth, which considers that rebirth is caused by ignorance, an essentially undesirable condition that is to be overcome.[citation needed]
Physical immortality has also been imagined as a form of eternal torment, as in Mary Shelley's short story "The Mortal Immortal", the protagonist of which witnesses everyone he cares about dying around him. Jorge Luis Borges explored the idea that life gets its meaning from death in the short story "'The Immortal"; an entire society having achieved immortality, they found time becoming infinite, and so found no motivation for any action.
## Desirablity of immortality
Many religions promise their faithful an eternal paradise in an afterlife. These presume perfection, as they are part of a divine plan, and are categorically desirable.
Physical immortality is considered desirable over its counterpart, death, which to date has been inevitable for all human beings. This presumes tolerable living conditions as an incentive for perpetual life, as the prevalence of suicide demonstrates.
# Symbols
There are numerous symbols representing immortality. Pictured here is an Egyptian symbol of life that holds connotations of immortality when depicted in the hands of the gods and pharaohs who were seen as having control over the journey of life, the ankh (left). The Möbius strip in the shape of a trefoil knot is another symbol of immortality. Most symbolic representations of infinity or the life cycle are often used to represent immortality depending on the context they are placed in. Other examples include the Ouroboros, the Chinese fungus of longevity, the ten kanji, the phoenix, and the colors amaranth (in Western culture) and peach (in Chinese culture).
# Fiction
Immortal beings and species abound in fiction, especially fantasy fiction. | https://www.wikidoc.org/index.php/Immortality | |
c31ca5ed7be136dbcbf1edd2d6cf7ce02838536e | wikidoc | Vaccination | Vaccination
# Overview
Vaccination is the administration of agent-specific, but relatively harmless, antigenic components that can induce protective immunity against the corresponding infectious agent in those individuals who are vaccinated. In practice, the terms vaccination and immunization are often used interchangeably. Vaccination is highly effective in the prevention of some particular infections. Vaccines are safe and are associated with minimal adverse reactions. Vaccination can prevent illness, disability, and death from vaccine-preventable diseases, which includes cervical cancer, diphtheria, hepatitis B, measles, mumps, pertussis, pneumonia, polio, rotavirus diarrhea, rubella, and tetanus. Vaccines help develop immunity by imitating an infection. This type of infection, however, does not cause illness, though it does cause the immune system to produce T-lymphocytes and antibodies. Immunization currently prevents an estimated 2 to 3 million deaths every year. An additional 1.5 million deaths could be avoided, however, if global vaccination coverage is improved. An estimated 19.4 million infants worldwide are still missing out on basic vaccines. The material administered as a vaccine can either be live but weakened forms of pathogens such as bacteria or viruses; killed or inactivated forms of these pathogens; or purified material such as proteins.
Benjamin Jesty is notable for being perhaps the first person recorded to have been vaccinated with cowpox in order to artificially induce immunity to smallpox during the epidemic of 1774. The term vaccination was first used by Edward Jenner, an English physician, 22 years later in 1796. Louis Pasteur further adapted this principle in his pioneering work in microbiology. Vaccination (vacca in latin means cow) is so named because the first vaccine was derived from a virus affecting cows—the relatively benign cowpox virus, which provides a degree of immunity to smallpox, a contagious and deadly disease. The World Health Organization coordinated the global effort to eradicate smallpox. The last naturally occurring case of smallpox occurred in Somalia in 1977.
# Vaccine-preventable diseases
# Classification
## Passive immunization
Passive immunization is a method of disease prevention that functions by transferring pre-made antibodies to a person at risk of acquiring a certain disease. This type of immunity could be acquired naturally during pregnancy, via trans-placental maternal antibodies' transfer to the fetus. Artificial passive immunization is normally given by pre-made immunoglobulins to a person at risk of acquiring a certain disease.
### Human immune globulin (IG)
Human immune globulin is obtained from normal, healthy people; it is a concentrated solution of antibodies, mainly IgG antibodies. Human immune globulin is given intra-muscularly (IM). Up to 48 hours is required for IGs to reach the maximum serum concentration and their half-life is about 3 weeks. The sooner administration occurs, the more effective the prevention. IGs only provide temporary protection. Diseases with available human immune globulins include:
- Hepatitis A
- Measles
- Immunoglobulin deficiency
- Varicella (in immunocompromised patients when varicella-zoster IG is unavailable)
- Rubella exposure during the 1st trimester of pregnancy
IV immune globulin contains larger amounts of human immune globulin and is administered via the IV route. Diseases that may be prevented or ameliorated by using IVIGs include:
- Kawasaki disease
- HIV infection in children
- Chronic B-cell lymphocytic leukemia
- Primary immunodeficiencies
- Immune thrombocytopenia
- Prevention of graft-vs-host disease
Subcutaneous immune globulin (SCIG) is prepared for home-based use, especially for patients affected by primary immunodeficiency.
### Hyperimmune globulin
Hyperimmune globulin is derived from human plasma containing large amounts of antibodies. Those from whose plasma the globulin is derived are patients convalescing from natural infections or donors who are artificially immunized. Hyperimmune globulins are available for cytomegalovirus, varicella-zoster, hepatitis B, infant botulism, rabies, and tetanus.
### Monoclonal antibodies
Specific monoclonal antibodies can be used against infections. The only one that is currently available is palivizumab, which is active against RSV.
## Active immunization
### Live attenuated vaccines
Live attenuated vaccines are produced by modifying a disease-producing (wild) virus or bacterium in a laboratory. The resulting vaccine organism retains the ability to replicate and produce immunity, but usually does not cause illness. These vaccines are produced by growing the virus in tissue cultures that will select for less virulent strains, or by mutagenesis or targeted deletions in genes required for virulence. Attenuated vaccines can not be used by immunocompromised individuals. Examples of live attenuated vaccines include measles, mumps, and rubella vaccine (MMR) and varicella (chickenpox) vaccine.
### Inactivated vaccines
These vaccines are made by inactivating or killing the pathogen (mostly viruses). The inactivated polio vaccine is an example of this type of vaccine.
### Toxoid vaccines
Toxoid vaccines are effective against bacteria that produces toxins. The vaccines are weakened toxins produced by particular bacteria. The DTaP vaccine contains diphtheria and tetanus toxoids.
### Subunit vaccines
Subunit vaccines contain only some parts of bacteria or virus, not the entire germ. Because these vaccines contain only the essential antigens and not all the other molecules that make up the germ, side effects are less common. The pertussis component of the DTaP vaccine is an example of a subunit vaccine.
### Conjugate vaccines
Conjugate vaccines are effective against bacteria that have polysaccharides in their cell wall components. Polysaccharides may cause less stimulation of immune system and result in a defective immune response. Conjugate vaccines are effective for these types of bacteria because they connect (or conjugate) the polysaccharides to antigens that the immune system responds to very well. This linkage helps the immature immune system react to the coating and develop an immune response. An example of this type of vaccine is the Haemophilus influenzae type B (Hib) vaccine.
# Adverse reactions
Adverse reactions to vaccines can be divided into 2 major groups:
- Allergic reactions
- Severe reportable reactions
## Allergic reactions
- Immediate reactions: Immediate reactions are IgE-related reactions that begins within minutes.
- Delayed reactions: Delayed reactions appear several hours or even days after administration and they are mostly non-IgE related reactions.
### Immediate reactions
Anaphylaxis is rare but important among immediate reactions. Health care providers should be aware of its symptoms and signs and be prepared for prompt treatment.
Other common but less serious immediate reactions include:
- Cutaneous symptoms: Flushing, itching, urticaria, and angioedema
- Respiratory symptoms: Nasal discharge, nasal congestion, change in voice quality, sensation of throat closure or choking, stridor, cough, wheeze, and dyspnea
- Cardiovascular symptoms: Faintness, syncope, altered mental status, palpitations, and hypotension
### Delayed reactions
Common delayed reactions to vaccines include:
- Fever: Fever is common after vaccination and should not preclude vaccination in the future.
- Local reactions: Local reactions such as swelling and erythema are common and can be treated with a cold compress.
- Serum sickness and serum sickness-like reactions
### Vasovagal reactions
Vasovagal reactions such as fainting, hypotension, pallor, diaphoresis, weakness, nausea, vomiting, bradycardia, and if severe, loss of consciousness may be seen after vaccination.
### Reaction to vaccine components
Vaccine components such as gelatin, egg proteins, cow's milk, thimerosal, aluminum, and phenoxyethanol that are used as vaccine preservatives, and they may cause adverse reactions ranging from fever or skin reactions to severe reactions that may require skin testing before future administration.
## Severe reportable reactions
Anaphylaxis or anaphylactic shock within seven days of any vaccine should be reported. Other vaccine-specific reactions that must be reported include:
- Tetanus: Brachial neuritis within 28 days
- Pertussis: Encephalopathy or encephalitis within seven days
- Measles, mumps, and/or rubella (MMR): Encephalopathy or encephalitis within 15 days
- Rubella: Chronic arthritis within six weeks
- Measles: Thrombocytopenic purpura within 7 to 30 days; vaccine-strain measles infection in an immunodeficient recipient within six months of measles vaccination
- Oral polio: Paralytic polio or vaccine-strain polio within 30 days to 6 months (this vaccine is no longer used for routine childhood immunization)
- Rotavirus: Intussusception within 30 days of rotavirus immunization | Vaccination
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]
# Overview
Vaccination is the administration of agent-specific, but relatively harmless, antigenic components that can induce protective immunity against the corresponding infectious agent in those individuals who are vaccinated. In practice, the terms vaccination and immunization are often used interchangeably. Vaccination is highly effective in the prevention of some particular infections. Vaccines are safe and are associated with minimal adverse reactions. Vaccination can prevent illness, disability, and death from vaccine-preventable diseases, which includes cervical cancer, diphtheria, hepatitis B, measles, mumps, pertussis, pneumonia, polio, rotavirus diarrhea, rubella, and tetanus. Vaccines help develop immunity by imitating an infection. This type of infection, however, does not cause illness, though it does cause the immune system to produce T-lymphocytes and antibodies. Immunization currently prevents an estimated 2 to 3 million deaths every year. An additional 1.5 million deaths could be avoided, however, if global vaccination coverage is improved. An estimated 19.4 million infants worldwide are still missing out on basic vaccines. The material administered as a vaccine can either be live but weakened forms of pathogens such as bacteria or viruses; killed or inactivated forms of these pathogens; or purified material such as proteins.
Benjamin Jesty is notable for being perhaps the first person recorded to have been vaccinated with cowpox in order to artificially induce immunity to smallpox during the epidemic of 1774. The term vaccination was first used by Edward Jenner, an English physician, 22 years later in 1796. Louis Pasteur further adapted this principle in his pioneering work in microbiology. Vaccination (vacca in latin means cow) is so named because the first vaccine was derived from a virus affecting cows—the relatively benign cowpox virus, which provides a degree of immunity to smallpox, a contagious and deadly disease. The World Health Organization coordinated the global effort to eradicate smallpox. The last naturally occurring case of smallpox occurred in Somalia in 1977.
# Vaccine-preventable diseases
# Classification
## Passive immunization
Passive immunization is a method of disease prevention that functions by transferring pre-made antibodies to a person at risk of acquiring a certain disease. This type of immunity could be acquired naturally during pregnancy, via trans-placental maternal antibodies' transfer to the fetus. Artificial passive immunization is normally given by pre-made immunoglobulins to a person at risk of acquiring a certain disease.
### Human immune globulin (IG)
Human immune globulin is obtained from normal, healthy people; it is a concentrated solution of antibodies, mainly IgG antibodies. Human immune globulin is given intra-muscularly (IM). Up to 48 hours is required for IGs to reach the maximum serum concentration and their half-life is about 3 weeks. The sooner administration occurs, the more effective the prevention. IGs only provide temporary protection. Diseases with available human immune globulins include:
- Hepatitis A
- Measles
- Immunoglobulin deficiency
- Varicella (in immunocompromised patients when varicella-zoster IG is unavailable)
- Rubella exposure during the 1st trimester of pregnancy
IV immune globulin contains larger amounts of human immune globulin and is administered via the IV route. Diseases that may be prevented or ameliorated by using IVIGs include:
- Kawasaki disease
- HIV infection in children
- Chronic B-cell lymphocytic leukemia
- Primary immunodeficiencies
- Immune thrombocytopenia
- Prevention of graft-vs-host disease
Subcutaneous immune globulin (SCIG) is prepared for home-based use, especially for patients affected by primary immunodeficiency.
### Hyperimmune globulin
Hyperimmune globulin is derived from human plasma containing large amounts of antibodies. Those from whose plasma the globulin is derived are patients convalescing from natural infections or donors who are artificially immunized. Hyperimmune globulins are available for cytomegalovirus, varicella-zoster, hepatitis B, infant botulism, rabies, and tetanus.
### Monoclonal antibodies
Specific monoclonal antibodies can be used against infections. The only one that is currently available is palivizumab, which is active against RSV.
## Active immunization
### Live attenuated vaccines
Live attenuated vaccines are produced by modifying a disease-producing (wild) virus or bacterium in a laboratory. The resulting vaccine organism retains the ability to replicate and produce immunity, but usually does not cause illness. These vaccines are produced by growing the virus in tissue cultures that will select for less virulent strains, or by mutagenesis or targeted deletions in genes required for virulence. Attenuated vaccines can not be used by immunocompromised individuals. Examples of live attenuated vaccines include measles, mumps, and rubella vaccine (MMR) and varicella (chickenpox) vaccine.
### Inactivated vaccines
These vaccines are made by inactivating or killing the pathogen (mostly viruses). The inactivated polio vaccine is an example of this type of vaccine.
### Toxoid vaccines
Toxoid vaccines are effective against bacteria that produces toxins. The vaccines are weakened toxins produced by particular bacteria. The DTaP vaccine contains diphtheria and tetanus toxoids.
### Subunit vaccines
Subunit vaccines contain only some parts of bacteria or virus, not the entire germ. Because these vaccines contain only the essential antigens and not all the other molecules that make up the germ, side effects are less common. The pertussis component of the DTaP vaccine is an example of a subunit vaccine.
### Conjugate vaccines
Conjugate vaccines are effective against bacteria that have polysaccharides in their cell wall components. Polysaccharides may cause less stimulation of immune system and result in a defective immune response. Conjugate vaccines are effective for these types of bacteria because they connect (or conjugate) the polysaccharides to antigens that the immune system responds to very well. This linkage helps the immature immune system react to the coating and develop an immune response. An example of this type of vaccine is the Haemophilus influenzae type B (Hib) vaccine.
# Adverse reactions
Adverse reactions to vaccines can be divided into 2 major groups:[8]
- Allergic reactions
- Severe reportable reactions
## Allergic reactions
- Immediate reactions: Immediate reactions are IgE-related reactions that begins within minutes.
- Delayed reactions: Delayed reactions appear several hours or even days after administration and they are mostly non-IgE related reactions.
### Immediate reactions
Anaphylaxis is rare but important among immediate reactions. Health care providers should be aware of its symptoms and signs and be prepared for prompt treatment.[9][10]
Other common but less serious immediate reactions include:
- Cutaneous symptoms: Flushing, itching, urticaria, and angioedema
- Respiratory symptoms: Nasal discharge, nasal congestion, change in voice quality, sensation of throat closure or choking, stridor, cough, wheeze, and dyspnea
- Cardiovascular symptoms: Faintness, syncope, altered mental status, palpitations, and hypotension
### Delayed reactions
Common delayed reactions to vaccines include:
- Fever: Fever is common after vaccination and should not preclude vaccination in the future.[11]
- Local reactions: Local reactions such as swelling and erythema are common and can be treated with a cold compress.[11]
- Serum sickness and serum sickness-like reactions
### Vasovagal reactions
Vasovagal reactions such as fainting, hypotension, pallor, diaphoresis, weakness, nausea, vomiting, bradycardia, and if severe, loss of consciousness may be seen after vaccination.[12]
### Reaction to vaccine components
Vaccine components such as gelatin, egg proteins, cow's milk, thimerosal, aluminum, and phenoxyethanol that are used as vaccine preservatives, and they may cause adverse reactions ranging from fever or skin reactions to severe reactions that may require skin testing before future administration.[13][14][11][15][16]
## Severe reportable reactions
Anaphylaxis or anaphylactic shock within seven days of any vaccine should be reported. Other vaccine-specific reactions that must be reported include:[11]
- Tetanus: Brachial neuritis within 28 days
- Pertussis: Encephalopathy or encephalitis within seven days
- Measles, mumps, and/or rubella (MMR): Encephalopathy or encephalitis within 15 days
- Rubella: Chronic arthritis within six weeks
- Measles: Thrombocytopenic purpura within 7 to 30 days; vaccine-strain measles infection in an immunodeficient recipient within six months of measles vaccination
- Oral polio: Paralytic polio or vaccine-strain polio within 30 days to 6 months (this vaccine is no longer used for routine childhood immunization)
- Rotavirus: Intussusception within 30 days of rotavirus immunization | https://www.wikidoc.org/index.php/Immunization | |
f3eeebdca54eff8d6d56bbdc86f5d94efa9f9c86 | wikidoc | Light chain | Light chain
# Overview
A light chain is the small polypeptide subunit of an antibody (or immunoglobulin); a typical antibody is composed of two immunoglobulin (Ig) heavy chains and two Ig light chains.
# In humans
There are two types of light chain in mammals,
- lambda (λ) chain (1, 2, 3, and 4)
- kappa (κ) chain (only one type)
# In other animals
Other types of light chains can be found in lower vertebrates, such as the Ig-Light-Iota chain of Chondrichthyes and Teleostei.
Camelids are unique among mammals as they have fully functional antibodies which have two heavy chains, but lack the light chains usually paired with each heavy chain. The functional role of this separate repertoire is unknown as yet.
# Structure
Only one type of light chain is present in a typical antibody, thus the two light chains of an individual antibody are identical.
Each light chain is composed of two tandem immunoglobulin domains:
- one constant (IgC) domain
- one variable domain (IgV) that is important for binding antigen
The approximate length of a light chain protein is from 211 to 217 amino acids. | Light chain
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
# Overview
A light chain is the small polypeptide subunit of an antibody (or immunoglobulin); a typical antibody is composed of two immunoglobulin (Ig) heavy chains and two Ig light chains.
# In humans
There are two types of light chain in mammals,
- lambda (λ) chain (1, 2, 3, and 4)
- kappa (κ) chain (only one type)
# In other animals
Other types of light chains can be found in lower vertebrates, such as the Ig-Light-Iota chain of Chondrichthyes and Teleostei.[1][2]
Camelids are unique among mammals as they have fully functional antibodies which have two heavy chains, but lack the light chains usually paired with each heavy chain.[3] The functional role of this separate repertoire is unknown as yet.
# Structure
Only one type of light chain is present in a typical antibody, thus the two light chains of an individual antibody are identical.
Each light chain is composed of two tandem immunoglobulin domains:
- one constant (IgC) domain
- one variable domain (IgV) that is important for binding antigen
The approximate length of a light chain protein is from 211 to 217 amino acids.[1] | https://www.wikidoc.org/index.php/Immunoglobulin_light_chains | |
0aaaece5623187d9699732fc904e5c769b1ad59c | wikidoc | Miltefosine | Miltefosine
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Miltefosine is an antimicrobial drug that is FDA approved for the treatment of visceral leishmaniasis, cutaneous leishmaniasis,mucosal leishmaniasis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea,vomiting,asthenia, abdominal Pain, malaise, pyrexia, dizziness, headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
Miltefosine capsules are indicated in adults for the treatment of:
- Visceral leishmaniasis caused by Leishmania donovani.
- Cutaneous leishmaniasis caused by Leishmania braziliensis, Leishmania guyanensis, and Leishmania panamensis.
- Mucosal leishmaniasis caused by Leishmania braziliensis.
Limitations of Use:
- Leishmania species studied in clinical trials evaluating miltefosine were based on epidemiologic data.
- There may be geographic variation in clinical response of the same Leishmania species to miltefosine.
- The efficacy of miltefosine in the treatment of other Leishmania species has not been evaluated.
# Dosage
- The treatment duration is 28 consecutive days. Administer with food to ameliorate gastrointestinal adverse reactions.
# DOSAGE FORMS AND STRENGTHS
- Miltefosine oral capsules are opaque, red, hard gelatin capsules with “PLB” imprinted on the capsule body and “MILT 50” imprinted on the cap using a white ink. Each capsule contains 50 mg miltefosine.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Miltefosine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Miltefosine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
# Indications
Miltefosine capsules are indicated adolescents ≥12 years of age weighing ≥ 30 kg for the treatment of:
- Visceral leishmaniasis caused by Leishmania donovani.
- Cutaneous leishmaniasis caused by Leishmania braziliensis, Leishmania guyanensis, and Leishmania panamensis.
- Mucosal leishmaniasis caused by Leishmania braziliensis.
Limitations of Use:
- Leishmania species studied in clinical trials evaluating miltefosine were based on epidemiologic data.
- There may be geographic variation in clinical response of the same Leishmania species to miltefosine.
- The efficacy of miltefosine in the treatment of other Leishmania species has not been evaluated.
# Dosage
- The treatment duration is 28 consecutive days. Administer with food to ameliorate gastrointestinal adverse reactions.
# DOSAGE FORMS AND STRENGTHS
- Miltefosine oral capsules are opaque, red, hard gelatin capsules with “PLB” imprinted on the capsule body and “MILT 50” imprinted on the cap using a white ink. Each capsule contains 50 mg miltefosine.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Miltefosine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Miltefosine in pediatric patients.
# Contraindications
Pregnancy
Miltefosine may cause fetal harm. Miltefosine is contraindicated in pregnant women. Obtain a urine or serum pregnancy test prior to prescribing Miltefosine.
Sjögren-Larsson-Syndrome
Miltefosine is contraindicated in patients who have Sjögren-Larsson-Syndrome.
Hypersensitivity
Miltefosine is contraindicated in patients who are hypersensitive to miltefosine or any miltefosine excipients.
# Warnings
Embryo-Fetal Toxicity
- Miltefosine may cause fetal harm. Embryo-fetal toxicity, including death and teratogenicity, was observed in animals administered miltefosine prior to mating, during early pregnancy, and during organogenesis at doses lower than the maximum recommended human dose (MRHD). Do not use miltefosine in pregnant women. Obtain a urine or serum pregnancy test prior to prescribing miltefosine to females of reproductive potential. Advise females of reproductive potential to use effective contraception during miltefosine therapy and for 5 months after completion of therapy.
Reproductive Effects
Females
- Miltefosine caused impaired fertility in rats and reversible follicular atresia and diestrus in dogs at doses approximately 1.0 and 0.2 times respectively the MRHD based on body surface area comparisons. Effects on human female fertility have not been formally studied.
Males
- Miltefosine caused reduced viable sperm counts and impaired fertility in rats at doses approximately 0.4 times the MRHD. A higher dose in rats, approximately 1.0 times the MRHD, caused testicular atrophy and impaired fertility that did not fully reverse 10 weeks after drug administration ended.
- Scrotal pain and decreased or absent ejaculation during therapy have been reported during miltefosine therapy. The effects of miltefosine on human male fertility have not been adequately studied.
- Advise women and men of the animal fertility findings, and that the potential for impaired fertility with miltefosine therapy in humans has not been adequately evaluated.
Renal Effects
Elevations of serum creatinine (Cr) were noted in clinical trials evaluating miltefosine in the treatment of cutaneous, mucosal and visceral leishmaniasis. Monitor renal function weekly in patients receiving miltefosine during therapy and for 4 weeks after end of therapy.
Hepatic Effects
Elevations in liver transaminases (ALT, AST) and bilirubin were noted in clinical trials evaluating miltefosine in the treatment of visceral leishmaniasis. Monitor liver transaminases (ALT, AST) and bilirubin during therapy in patients receiving miltefosine.
Gastrointestinal Effects
Vomiting and/or diarrhea commonly occur during miltefosine administration and may result in volume depletion. Encourage fluid intake to avoid volume depletion.
Thrombocytopenia
Thrombocytopenia during therapy has been reported in patients treated for visceral leishmaniasis. Monitor platelet count during therapy for visceral leishmaniasis.
Absorption of Oral Contraceptives
- Vomiting and/or diarrhea occurring during miltefosine therapy may affect the absorption of oral contraceptives, and therefore compromise their efficacy. If vomiting and/or diarrhea occur during miltefosine therapy, advise females to use additional non-hormonal or alternative method(s) of effective contraception.
Stevens-Johnson Syndrome
Stevens-Johnson syndrome has been reported during miltefosine therapy.Discontinue miltefosine if an exfoliative or bullous rash is noted during therapy.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
## Clinical Trials Experience
Visceral Leishmaniasis
- One Phase 3 trial was conducted in patients ≥ 12 years of age in India. Two-hundred and ninety-nine (299) patients (211 men and 88 women) received oral miltefosine at a target dose of 2.5 mg/kg/day for 28 days (50 mg capsule once daily if weight was less than 25 kg and 50 mg capsule twice daily if weight was 25 kg or greater). Patients ranged between 12 and 64 years of age. Weight ranged between 15 and 67 kg (mean weight 38.6 kg) and BMI ranged between 8.2 and 24 (mean 16.1). Ninety-nine (99) patients received 1 mg/kg/day amphotericin B deoxycholate intravenously every other day for 15 doses. A statistically significant higher percentage of men received miltefosine compared to amphotericin B.
- Less than 1% of patients who received miltefosine died (2/299) and no patient who received amphotericin B died. Serious adverse reactions were reported in 2% of miltefosine recipients (6/299) and 1% of amphotericin B recipients (1/99). Approximately 3% of patients discontinued treatment in each treatment arm due to an adverse reaction. Serious adverse reactions and adverse reactions leading to drug discontinuation that were thought to be related or possibly related to miltefosine included Stevens-Johnson syndrome, melena and thrombocytopenia, arthritis and skin rash, CTCAE1 Grade 4 diarrhea (≥10 stools per day) and CTCAE Grade 4 hyperbilirubinemia (≥10x upper limit of normal ULN).
- In this study, creatinine (Cr) elevations ≥ 1.5 times above baseline occurred in approximately 10% of miltefosine recipients and in 40% of amphotericin B recipients at the end of therapy. Ten percent of subjects in each arm had Cr elevations ≥1.5 times above baseline at 6 months follow up. No miltefosine recipient discontinued therapy due to Cr elevation.
- Elevations of transaminases during therapy occurred in up to half of miltefosine recipients and up to a third of amphotericin B recipients. The elevations were mild (< 3x ULN) or moderate (3-5x ULN) in 94% and 6% respectively of miltefosine-treated patients who experienced an elevation. No patient discontinued therapy due to elevations in transaminases.
- At the end of therapy, 62% and 2.4% of miltefosine recipients and 54% and 2% of amphotericin B recipients had platelet count < 150,000 and < 50,000 respectively.
Cutaneous Leishmaniasis
- The efficacy of miltefosine in the treatment of cutaneous leishmaniasis was evaluated in one placebo-controlled trial conducted in Colombia and Guatemala and in two comparative trials conducted in Bolivia and Brazil respectively. In the placebo-controlled trial, eighty-nine (89) patients ≥12 years of age received a target miltefosine dose of 2.5 mg/kg/day for 28 days and forty-four (44) received placebo. In the comparative trials, one hundred and twenty (120) patients ≥12 years of age received a target miltefosine dose of 2.5 mg/kg/day for 28 days and fifty eight (58) patients received 20 mg/kg/day pentavalent antimony (meglumine) parenterally for 20 days.
- In the placebo controlled trial, 12/89 (13.4%) miltefosine subjects had Cr increases of 1.5-3 times above baseline, compared to 2/44 (4.5%) placebo subjects at end of therapy. In the comparative trial, a similar percentage of subjects who received miltefosine or pentavalent antimony had Cr elevations above baseline at 3 and 6 months after therapy (approximately 5%). Approximately 25% of miltefosine subjects and 11% of pentavalent antimony subjects had Cr elevations 1.5-3 times above baseline at the end of therapy in the two active controlled trials. The frequency of AST and ALT increase above upper limit of normal at end of therapy was similar in miltefosine and placebo recipients (approximately 5%).
- Other adverse events seen at <2% incidence in the miltefosine group included anemia, lymphadenopathy, abdominal distension, constipation, dysphagia, flatulence, fatigue, malaise, abscess, cellulitis, ecthyma, paresthesia, testicular pain, testicular swelling, Stevens-Johnson syndrome, urticaria, rash, pyoderma.
## Postmarketing Experience
- The following adverse reactions have been identified during use of miltefosine worldwide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Blood and Lymphatics Disorders: thrombocytopenia, agranulocytosis
- Gastrointestinal Disorders: melena
- General Disorders: generalized edema, peripheral edema
- Hepatobiliary Disorders: jaundice
- Nervous System Disorders: seizure
- Reproductive System and Breast Disorders: scrotal pain, decreased ejaculate volume, absent ejaculation.
- Vascular Disorders: epistaxis
# Drug Interactions
- In vitro and animal metabolism studies showed that miltefosine did not markedly induce or inhibit the activity of the major human cytochrome P450 enzymes. The potential of miltefosine to interact with drug transporters has not been evaluated.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Category D
Risk Summary
- miltefosine may cause fetal harm. Human pregnancy data are not available, however, embryo-fetal toxicity including death and teratogenicity, was observed in embryo-fetal studies in rats and rabbits administered oral miltefosine during organogenesis at doses that were respectively 0.06 and 0.2 times the maximum recommended human dose (MRHD), based on body surface area (BSA) comparison. Numerous visceral and skeletal fetal malformations were observed in a fertility study in female rats administered miltefosine prior to mating through day 7 of pregnancy at doses 0.3 times the MRHD. Do not administer miltefosine to pregnant women.
Clinical Considerations
- During pregnancy, visceral leishmaniasis may be life-threatening for the mother and may result in adverse fetal outcomes, including spontaneous abortion, congenital disease due to vertical transmission, small for gestational age newborn, and severe anemia. During pregnancy, cutaneous leishmaniasis may manifest with larger and atypical appearing lesions and may be associated with increased risk for adverse fetal outcomes, including preterm births and stillbirths.
Animal Data
- Miltefosine administration in rat embryo-fetal toxicity studies during early embryonic development (Day 6 to Day 15 of gestation) caused embryo-fetal toxicity including death and teratogenicity at dosages of ≥ 1.2 mg/kg/day (0.06 times the MRHD based on BSA comparison). Teratogenic effects included undeveloped cerebrum, hemorrhagic fluid filling the lumina of the skull, cleft palate and generalized edema. Embryo-fetal toxicity was also observed in rabbits after oral administration of miltefosine during organogenesis (Day 6 to Day 18 of gestation) at doses ≥ 2.4 mg/kg/day (0.2 times the MRHD based on BSA comparison). In both rats and rabbits, there were no viable litters at miltefosine doses ≥ 6.0 mg/kg/day (0.3 or 0.6 times the MRHD based on BSA comparisons for rats and rabbits respectively).
- In a separate female fertility study in rats, miltefosine doses ≥ 6.81 mg/kg/day (0.3 times the MRHD based on BSA comparison) administered for four weeks before mating and up to Day 7 of pregnancy produced numerous visceral (misshapen cerebral structures, dilated ventricles filled with brown masses, misshapen spinal cord, misshapen and malpositioned eyes, hypophysis, and absent inner ear) and skeletal (cleft palate, dumbbell-shaped ossification of thoracic vertebral centers, markedly enlarged skull bones, and markedly dilated suturae) fetal malformations.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Miltefosine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Miltefosine during labor and delivery.
### Nursing Mothers
- It is not known whether miltefosine is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from miltefosine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Breastfeeding should be avoided for 5 months after miltefosine therapy.
### Pediatric Use
- Safety and effectiveness in pediatric patients < 12 years have not been established. Juvenile rats were more sensitive to the miltefosine-induced effects, especially retinal and kidney effects, than adult rats.
### Geriatic Use
- Clinical studies of miltefosine did not include sufficient numbers of subjects 65 years of age and over to determine if they respond differently than younger subjects.
### Gender
Contraception
- Miltefosine may cause fetal harm when used during pregnancy. Advise females of reproductive potential to use effective contraception during miltefosine therapy and for 5 months after therapy is completed.
- Vomiting and/or diarrhea occurring during miltefosine therapy may affect absorption of oral contraceptives and therefore may compromise their efficacy. Advise females who use oral contraceptives to use additional non-hormonal or alternative method(s) of effective contraception during miltefosine therapy if vomiting and/or diarrhea occurs during therapy.
Infertility
Females
- Miltefosine caused impaired fertility in rats and caused reversible follicular atresia and diestrus in dogs at doses approximately 1.0 and 0.2 times respectively the MRHD. The effects of miltefosine on human female fertility have not been formally studied.
Males
- Miltefosine caused reduced viable sperm counts and impaired fertility in rats at doses approximately 0.4 times the MRHD . A higher dose in rats, approximately 1.0 times the MRHD, caused testicular atrophy and impaired fertility that did not fully reverse 10 weeks after drug administration ended. The effects of miltefosine on human male fertility have not been adequately studied.
- Advise women and men of the animal fertility findings, and that the potential for impaired fertility with miltefosine therapy has not been adequately evaluated.
### Race
There is no FDA guidance on the use of Miltefosine with respect to specific racial populations.
### Renal Impairment
- Patients with serum creatinine or BUN levels ≥1.5 times the upper limit of normal were excluded from the clinical studies. Miltefosine pharmacokinetics have not been studied in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Miltefosine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Miltefosine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Miltefosine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Miltefosine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Miltefosine in the drug label.
# Overdosage
- The common adverse effects of vomiting, diarrhea, and abdominal pain are likely in case of overdose. Institute adequate hydration to prevent the risk of impaired renal function, and replace electrolytes as necessary. Because miltefosine is only slightly excreted in the urine, forced diuresis will not increase miltefosine excretion. Gastrointestinal lavage is of unknown value. A specific antidote to treat miltefosine overdose is not known.
# Pharmacology
## Mechanism of Action
- The specific mode of action of miltefosine against Leishmania species is unknown. The mechanism of action of miltefosine is likely to involve interaction with lipids (phospholipids and sterols), including membrane lipids, inhibition of cytochrome c oxidase (mitochondrial function), and apoptosis-like cell death.
## Structure
- Miltefosine capsules contain the active ingredient miltefosine, an antileishmanial agent. The chemical name of miltefosine is 2-(hexadecyloxy)hydroxyphosphenyloxy-N,N,N-trimethylethylammonium inner salt. Miltefosine is a white powder that is freely soluble in water, 0.1 N HCl or NaOH, methanol, and ethanol. It has the empirical formula of C21H46NO4P with a molecular weight of 407.6 and the following structural formula:
- The inactive ingredients are colloidal silicon dioxide, microcrystalline cellulose, lactose monohydrate, talc, and magnesium stearate. The capsule shell contains gelatin, titanium dioxide, ferric oxide, and purified water.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Miltefosine in the drug label.
## Pharmacokinetics
- The pharmacokinetic parameters of miltefosine in patients with visceral and cutaneous leishmaniasis treated for 28 days with miltefosine are listed in Table 5. Due to the long half-life of miltefosine (> 6 days), trough plasma concentrations did not appear to reach a steady state at the end of treatment (i.e., Day 28).
Absorption
- Absolute bioavailability of miltefosine has not been determined. In patients with visceral leishmaniasis, maximum miltefosine concentrations following oral administration of miltefosine capsules were reached right before the next dose in many patients, indicating that the absorption of miltefosine may proceed throughout the dosing interval.
Distribution
- The distribution of miltefosine has not been studied in humans. Human plasma protein binding of miltefosine, evaluated by an ultracentrifugation method, was 98% over the drug concentration range from 0.1 to 10 µg/mL. In rats, radioactivity of miltefosine is widely distributed after both single and repeated oral administration with highest uptake of radioactivity in kidney, liver, and spleen. Placental transfer and excretion into milk have not been investigated.
Metabolism and Excretion
- No in vitro oxidative metabolism by 15 different human cytochrome P450 enzymes (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, 3A7, and 4A1) was observed.
- A slow metabolic breakdown could be shown in human hepatocytes, resulting in the release of choline by phospholipase D-like cleavage of the miltefosine molecule. The fatty alcohol-containing fragment of miltefosine can enter the metabolism of fatty acids after being oxidized to palmitic acid. This oxidation is blocked in patients with Sjögren-Larsson syndrome, which is caused by a genetic defect in fatty aldehyde dehydrogenase activity. Miltefosine is contraindicated in patients who have Sjögren-Larsson-Syndrome.
- There was little or no evidence of time or metabolism dependent inhibition of the cytochrome P450 enzymes examined at up to approximately 40 µg/mL miltefosine.
- Oral administration of miltefosine did not markedly induce the content of hepatic CYP3A assayed by demethylation activity of erythromycin in rats.
- In visceral leishmaniasis patients, <0.2% of the administered dose was excreted into the urine.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Mutagenicity/Carcinogenicity: Miltefosine tested negative in the AMES-Salmonella test, DNA-amplification test, chromosomal aberration test in vitro, UDS-test in vivo/in vitro, and oral mouse micronucleus test in vivo. The V 79 mammalian cell HPRT gene mutation test showed an increase in mutant frequency without dose dependency. In view of all mutagenicity test results, the single positive finding in the V 79 HPRT test is considered to be not of toxicological relevance with respect to a mutagenic risk to humans.
- Carcinogenicity studies were not performed. In a 52-week oral rat toxicity study, testicular Leydig cell adenoma was observed in 3 of 30 male rats with daily administration of 21.5 mg/kg/day miltefosine (1.0 times the MRHD based on BSA comparison). The carcinogenic potential of miltefosine in humans is unknown.
- In a Segment I fertility study in male rats, testicular atrophy, reduced numbers of viable sperm, and impaired fertility were observed in rats following daily oral doses of ≥ 8.25 mg/kg (0.4 times the MRHD based on BSA comparison). These findings were reversible within a recovery period of 10 weeks except at the highest dose tested, 21.5 mg/kg/day (1.0 times the MRHD based on BSA comparison), where effects were not fully reversible.
- In a female fertility study in rats, estrus cycle arrest in the metestrus or diestrus phases occurred with the high-dose of 21.5 mg/kg (1.0 times the MRHD based on BSA comparison). At doses of 6.81 and 21.5 mg/kg (0.3 and 1.0 times the MRHD respectively based on BSA comparison) increased numbers of embryonic and fetal resorptions and dead fetuses were observed. In a 52-week toxicology study in dogs, increased numbers of atretic follicles in the ovaries, and cycle arrest in the uterus, vagina, and mammary gland with morphology consistent with anestrus or diestrus was observed at doses ≥ 1 mg/kg/day (0.2 times the MRHD based on BSA comparison). The effects in dogs were fully reversible after a recovery period of 6 weeks.
Animal Toxicology and/or Pharmacology
- Toxicological studies with miltefosine have been performed in mice, rats, dogs, and rabbits. Adverse reactions not observed in clinical studies but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows:
- Acute and chronic toxicity: The oral administration of miltefosine in rats was associated with lesions affecting the eyes (retinal degeneration). Retinal degeneration was observed after 8-weeks treatment at doses of 10 mg/kg/day (0.5 times the MRHD based on BSA comparison). Juvenile rats were more sensitive to the miltefosine-induced effects, especially on eyes and kidneys, than adult rats with retinal degeneration occurring at doses ≥ 2.15 mg/kg/day (0.1 times the MRHD based on BSA comparison), and reversible damage to proximal tubule epithelium occurring at doses ≥ 4.64 mg/kg/day (0.2 times the MRHD based on BSA comparison).
# Clinical Studies
Treatment of Visceral Leishmaniasis
- One randomized, open-label, active-controlled study was conducted to evaluate the efficacy of miltefosine in the treatment of visceral leishmaniasis in Bihar, India, an area where L. donovani is known epidemiologically to be the prevalent infecting species. Patients ≥ 12 years of age with clinical signs and symptoms compatible with visceral leishmaniasis (fever, splenomegaly, and cytopenia) confirmed by the presence of Leishmania amastigotes in aspirates of spleen or bone marrow were randomized to receive oral miltefosine or intravenous amphotericin B deoxycholate in a 3:1 ratio. Patients weighing ≥ 25 kg received an miltefosine 50 mg capsule with meals twice a day. Patients weighing < 25 kg received an miltefosine 50 mg capsule with meals once a day in the morning. Weight ranged between 15 and 67 kg (mean weight 38.6 kg) and BMI ranged between 8.2 and 24 (mean 16.1). No patient weighed more than 70kg. Amphotericin B was administered intravenously over 6 continuous hours at 1 mg/kg every other day for 15 doses. Patients were hospitalized for the duration of therapy.
- Exclusion criteria included platelet count 1.5 times upper limit of the normal range, prothrombin time >5 seconds above control, and any non-compensated or uncontrolled condition including human immunodeficiency virus (HIV) infection. Women of reproductive potential were required to use effective contraception for the duration of therapy and for 2 months post therapy.
- Final cure was defined as initial cure at end of therapy plus absence of signs and symptoms of visceral leishmaniasis at 6 months follow up. Initial cure at the end of therapy was evaluated by repeat spleen or bone marrow aspiration. Patients with initial parasitologic cure were followed for 6 months; patients without absence of clinical signs and symptoms of visceral leishmaniasis were to be evaluated with repeat spleen or bone marrow aspiration to determine final cure.
- Two hundred and ninety nine (299) patients received miltefosine and 99 patients received amphotericin B. Approximately, 70% of patients in each arm had previously failed treatment with pentavalent antimony. Initial cure was achieved in 98% of patients in each treatment arm. At 6 months after therapy, 88 (29.5%) miltefosine recipients and 12 (12.1%) amphotericin B recipients continued to have signs and symptoms suggestive of visceral leishmaniasis. These signs or symptoms were attributed to alternative diagnosis in 73 patients. The remaining 27 patients, all in the miltefosine arm, underwent evaluation with splenic or bone marrow aspiration, and 9 (3.0%) were positive for Leishmania amastigotes, indicating relapse. The final cure rates for miltefosine and amphotericin B were 94% and 97%, respectively.
Treatment of Cutaneous Leishmaniasis
- A placebo controlled study was performed in Colombia where L. panamensis and L. braziliensis are epidemiologically known to be the prevalent infecting Leishmania species, and in Guatemala where L. braziliensis is epidemiologically known to be the prevalent infecting species. The study included male and female patients older than 12 years of age who had newly diagnosed or relapsing cutaneous leishmaniasis without mucosal involvement, parasitologically confirmed, presenting with at least one skin ulcer with minimum area of 50 mm2. Exclusion criteria were AST or ALT ≥2 times upper limit of normal range, bilirubin ≥1.5 times upper limit of normal range, and serum creatinine or BUN >1.5 times upper limit of normal range. Women of reproductive potential were required to use effective contraception for the duration of therapy and for 2 months post therapy.
- Patients were randomized to receive miltefosine or placebo in a 2:1 allocation. Patients who weighed 50% in lesions, no appearance of new lesions, and negative parasitology if done) at 2 weeks after end of therapy and complete epithelialization of all ulcers at 6 months after end of therapy. The definite cure rate for miltefosine was statistically significantly higher than the cure rate for placebo.
- An additional study of miltefosine was conducted in Bahia and Manaus, two regions in Brazil where respectively L. braziliensis and L. guyanensis are epidemiologically the prevalent infecting pathogens. Adolescent/adult patients aged 12-65 years received miltefosine orally for 28 days. Miltefosine target dose was 2.5 mg/kg/day: patients weighing 15-29 kg received 50 mg once daily, patients weighing 30-45 kg received 50 twice mg daily and patients weighing > 46 kg received 50 mg three times daily. The efficacy criteria were initial cure (complete re-epithelialization of the ulcer at 2 months after the end of therapy) followed by definite cure (complete re-epithelialization at 6 months after the end of therapy). Definite cure rate in patients aged ≥12 years was 27/40 (67.5%) for Manaus, Brazil and 34/40 (85%) for Bahia, Brazil.
Treatment of Mucosal Leishmaniasis
- A single arm study was conducted to evaluate the efficacy of miltefosine capsules for the treatment of mucosal leishmaniasis. The study was conducted in Bolivia where L. braziliensis is epidemiologically the prevalent species.
- Seventy nine (79) patients ≥18 years of age with a cutaneous leishmaniasis scar plus parasites observed or cultured from lesion material or a positive skin test, and no clinically significant concomitant disease received miltefosine at a target dose of 2.5 mg/kg/day for 28 days. By 12 months after the end of therapy, 49 of the patients (62%) had complete resolution of edema, erythema, infiltration and erosion from the involved mucosal sites.
# How Supplied
- Each miltefosine capsule contains 50 mg miltefosine in an opaque, red, hard gelatin capsule. Miltefosine capsules are supplied in a folded peel/push-through blister card. Each blister card contains 14 capsules. Each carton contains two blister cards (NDC 61744-050-01).
## Storage
- Store at 20-25 °C (68-77 °F); excursions permitted to 15-30 °C (59-86 °F). . Protect from moisture.
- Dispense only in the original carton.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Dosing Instructions'
- Miltefosine is administered with food to ameliorate gastrointestinal side effects.
Instruct the patient to swallow the capsule whole and not to chew it or break it apart. Instruct the patient to complete the full course of therapy.
- Inform the patient that abdominal pain, nausea, vomiting, and diarrhea are common side effects of therapy with miltefosine and instruct the patient to inform their healthcare provider if these gastrointestinal side effects are severe or persistent. Instruct the patient to consume sufficient fluids to avoid dehydration and, consequently, the risk of kidney injury.
Females and Males of Reproductive Potential
- Advise women of reproductive potential to use effective contraception during miltefosine therapy and for 5 months after therapy ends.
- Advise women who use oral contraceptives to use additional non-hormonal or alternative method(s) of effective contraception during miltefosine therapy if vomiting and/or diarrhea occurs .
Advise nursing mothers not to breastfeed during miltefosine therapy and for 5 months after therapy is completed.
- Advise women and men that miltefosine caused infertility in male rats, impaired fertility in female rats, and caused atresia in ovarian follicles in female dogs. Advise patients that the potential of impaired fertility in humans has not been adequately evaluated.
# Precautions with Alcohol
- Alcohol-Miltefosine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- IMPAVIDO
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Miltefosine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
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# Black Box Warning
# Overview
Miltefosine is an antimicrobial drug that is FDA approved for the treatment of visceral leishmaniasis, cutaneous leishmaniasis,mucosal leishmaniasis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea,vomiting,asthenia, abdominal Pain, malaise, pyrexia, dizziness, headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
Miltefosine capsules are indicated in adults for the treatment of:
- Visceral leishmaniasis caused by Leishmania donovani.
- Cutaneous leishmaniasis caused by Leishmania braziliensis, Leishmania guyanensis, and Leishmania panamensis.
- Mucosal leishmaniasis caused by Leishmania braziliensis.
Limitations of Use:
- Leishmania species studied in clinical trials evaluating miltefosine were based on epidemiologic data.
- There may be geographic variation in clinical response of the same Leishmania species to miltefosine.
- The efficacy of miltefosine in the treatment of other Leishmania species has not been evaluated.
# Dosage
- The treatment duration is 28 consecutive days. Administer with food to ameliorate gastrointestinal adverse reactions.
# DOSAGE FORMS AND STRENGTHS
- Miltefosine oral capsules are opaque, red, hard gelatin capsules with “PLB” imprinted on the capsule body and “MILT 50” imprinted on the cap using a white ink. Each capsule contains 50 mg miltefosine.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Miltefosine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Miltefosine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
# Indications
Miltefosine capsules are indicated adolescents ≥12 years of age weighing ≥ 30 kg for the treatment of:
- Visceral leishmaniasis caused by Leishmania donovani.
- Cutaneous leishmaniasis caused by Leishmania braziliensis, Leishmania guyanensis, and Leishmania panamensis.
- Mucosal leishmaniasis caused by Leishmania braziliensis.
Limitations of Use:
- Leishmania species studied in clinical trials evaluating miltefosine were based on epidemiologic data.
- There may be geographic variation in clinical response of the same Leishmania species to miltefosine.
- The efficacy of miltefosine in the treatment of other Leishmania species has not been evaluated.
# Dosage
- The treatment duration is 28 consecutive days. Administer with food to ameliorate gastrointestinal adverse reactions.
# DOSAGE FORMS AND STRENGTHS
- Miltefosine oral capsules are opaque, red, hard gelatin capsules with “PLB” imprinted on the capsule body and “MILT 50” imprinted on the cap using a white ink. Each capsule contains 50 mg miltefosine.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Miltefosine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Miltefosine in pediatric patients.
# Contraindications
Pregnancy
Miltefosine may cause fetal harm. Miltefosine is contraindicated in pregnant women. Obtain a urine or serum pregnancy test prior to prescribing Miltefosine.
Sjögren-Larsson-Syndrome
Miltefosine is contraindicated in patients who have Sjögren-Larsson-Syndrome.
Hypersensitivity
Miltefosine is contraindicated in patients who are hypersensitive to miltefosine or any miltefosine excipients.
# Warnings
Embryo-Fetal Toxicity
- Miltefosine may cause fetal harm. Embryo-fetal toxicity, including death and teratogenicity, was observed in animals administered miltefosine prior to mating, during early pregnancy, and during organogenesis at doses lower than the maximum recommended human dose (MRHD). Do not use miltefosine in pregnant women. Obtain a urine or serum pregnancy test prior to prescribing miltefosine to females of reproductive potential. Advise females of reproductive potential to use effective contraception during miltefosine therapy and for 5 months after completion of therapy.
Reproductive Effects
Females
- Miltefosine caused impaired fertility in rats and reversible follicular atresia and diestrus in dogs at doses approximately 1.0 and 0.2 times respectively the MRHD based on body surface area comparisons. Effects on human female fertility have not been formally studied.
Males
- Miltefosine caused reduced viable sperm counts and impaired fertility in rats at doses approximately 0.4 times the MRHD. A higher dose in rats, approximately 1.0 times the MRHD, caused testicular atrophy and impaired fertility that did not fully reverse 10 weeks after drug administration ended.
- Scrotal pain and decreased or absent ejaculation during therapy have been reported during miltefosine therapy. The effects of miltefosine on human male fertility have not been adequately studied.
- Advise women and men of the animal fertility findings, and that the potential for impaired fertility with miltefosine therapy in humans has not been adequately evaluated.
Renal Effects
Elevations of serum creatinine (Cr) were noted in clinical trials evaluating miltefosine in the treatment of cutaneous, mucosal and visceral leishmaniasis. Monitor renal function weekly in patients receiving miltefosine during therapy and for 4 weeks after end of therapy.
Hepatic Effects
Elevations in liver transaminases (ALT, AST) and bilirubin were noted in clinical trials evaluating miltefosine in the treatment of visceral leishmaniasis. Monitor liver transaminases (ALT, AST) and bilirubin during therapy in patients receiving miltefosine.
Gastrointestinal Effects
Vomiting and/or diarrhea commonly occur during miltefosine administration and may result in volume depletion. Encourage fluid intake to avoid volume depletion.
Thrombocytopenia
Thrombocytopenia during therapy has been reported in patients treated for visceral leishmaniasis. Monitor platelet count during therapy for visceral leishmaniasis.
Absorption of Oral Contraceptives
- Vomiting and/or diarrhea occurring during miltefosine therapy may affect the absorption of oral contraceptives, and therefore compromise their efficacy. If vomiting and/or diarrhea occur during miltefosine therapy, advise females to use additional non-hormonal or alternative method(s) of effective contraception.
Stevens-Johnson Syndrome
Stevens-Johnson syndrome has been reported during miltefosine therapy.Discontinue miltefosine if an exfoliative or bullous rash is noted during therapy.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
## Clinical Trials Experience
Visceral Leishmaniasis
- One Phase 3 trial was conducted in patients ≥ 12 years of age in India. Two-hundred and ninety-nine (299) patients (211 men and 88 women) received oral miltefosine at a target dose of 2.5 mg/kg/day for 28 days (50 mg capsule once daily if weight was less than 25 kg and 50 mg capsule twice daily if weight was 25 kg or greater). Patients ranged between 12 and 64 years of age. Weight ranged between 15 and 67 kg (mean weight 38.6 kg) and BMI ranged between 8.2 and 24 (mean 16.1). Ninety-nine (99) patients received 1 mg/kg/day amphotericin B deoxycholate intravenously every other day for 15 doses. A statistically significant higher percentage of men received miltefosine compared to amphotericin B.
- Less than 1% of patients who received miltefosine died (2/299) and no patient who received amphotericin B died. Serious adverse reactions were reported in 2% of miltefosine recipients (6/299) and 1% of amphotericin B recipients (1/99). Approximately 3% of patients discontinued treatment in each treatment arm due to an adverse reaction. Serious adverse reactions and adverse reactions leading to drug discontinuation that were thought to be related or possibly related to miltefosine included Stevens-Johnson syndrome, melena and thrombocytopenia, arthritis and skin rash, CTCAE1 Grade 4 diarrhea (≥10 stools per day) and CTCAE Grade 4 hyperbilirubinemia (≥10x upper limit of normal ULN).
- In this study, creatinine (Cr) elevations ≥ 1.5 times above baseline occurred in approximately 10% of miltefosine recipients and in 40% of amphotericin B recipients at the end of therapy. Ten percent of subjects in each arm had Cr elevations ≥1.5 times above baseline at 6 months follow up. No miltefosine recipient discontinued therapy due to Cr elevation.
- Elevations of transaminases during therapy occurred in up to half of miltefosine recipients and up to a third of amphotericin B recipients. The elevations were mild (< 3x ULN) or moderate (3-5x ULN) in 94% and 6% respectively of miltefosine-treated patients who experienced an elevation. No patient discontinued therapy due to elevations in transaminases.
- At the end of therapy, 62% and 2.4% of miltefosine recipients and 54% and 2% of amphotericin B recipients had platelet count < 150,000 and < 50,000 respectively.
Cutaneous Leishmaniasis
- The efficacy of miltefosine in the treatment of cutaneous leishmaniasis was evaluated in one placebo-controlled trial conducted in Colombia and Guatemala and in two comparative trials conducted in Bolivia and Brazil respectively. In the placebo-controlled trial, eighty-nine (89) patients ≥12 years of age received a target miltefosine dose of 2.5 mg/kg/day for 28 days and forty-four (44) received placebo. In the comparative trials, one hundred and twenty (120) patients ≥12 years of age received a target miltefosine dose of 2.5 mg/kg/day for 28 days and fifty eight (58) patients received 20 mg/kg/day pentavalent antimony (meglumine) parenterally for 20 days.
- In the placebo controlled trial, 12/89 (13.4%) miltefosine subjects had Cr increases of 1.5-3 times above baseline, compared to 2/44 (4.5%) placebo subjects at end of therapy. In the comparative trial, a similar percentage of subjects who received miltefosine or pentavalent antimony had Cr elevations above baseline at 3 and 6 months after therapy (approximately 5%). Approximately 25% of miltefosine subjects and 11% of pentavalent antimony subjects had Cr elevations 1.5-3 times above baseline at the end of therapy in the two active controlled trials. The frequency of AST and ALT increase above upper limit of normal at end of therapy was similar in miltefosine and placebo recipients (approximately 5%).
- Other adverse events seen at <2% incidence in the miltefosine group included anemia, lymphadenopathy, abdominal distension, constipation, dysphagia, flatulence, fatigue, malaise, abscess, cellulitis, ecthyma, paresthesia, testicular pain, testicular swelling, Stevens-Johnson syndrome, urticaria, rash, pyoderma.
## Postmarketing Experience
- The following adverse reactions have been identified during use of miltefosine worldwide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Blood and Lymphatics Disorders: thrombocytopenia, agranulocytosis
- Gastrointestinal Disorders: melena
- General Disorders: generalized edema, peripheral edema
- Hepatobiliary Disorders: jaundice
- Nervous System Disorders: seizure
- Reproductive System and Breast Disorders: scrotal pain, decreased ejaculate volume, absent ejaculation.
- Vascular Disorders: epistaxis
# Drug Interactions
- In vitro and animal metabolism studies showed that miltefosine did not markedly induce or inhibit the activity of the major human cytochrome P450 enzymes. The potential of miltefosine to interact with drug transporters has not been evaluated.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Category D
Risk Summary
- miltefosine may cause fetal harm. Human pregnancy data are not available, however, embryo-fetal toxicity including death and teratogenicity, was observed in embryo-fetal studies in rats and rabbits administered oral miltefosine during organogenesis at doses that were respectively 0.06 and 0.2 times the maximum recommended human dose (MRHD), based on body surface area (BSA) comparison. Numerous visceral and skeletal fetal malformations were observed in a fertility study in female rats administered miltefosine prior to mating through day 7 of pregnancy at doses 0.3 times the MRHD. Do not administer miltefosine to pregnant women.
Clinical Considerations
- During pregnancy, visceral leishmaniasis may be life-threatening for the mother and may result in adverse fetal outcomes, including spontaneous abortion, congenital disease due to vertical transmission, small for gestational age newborn, and severe anemia. During pregnancy, cutaneous leishmaniasis may manifest with larger and atypical appearing lesions and may be associated with increased risk for adverse fetal outcomes, including preterm births and stillbirths.
Animal Data
- Miltefosine administration in rat embryo-fetal toxicity studies during early embryonic development (Day 6 to Day 15 of gestation) caused embryo-fetal toxicity including death and teratogenicity at dosages of ≥ 1.2 mg/kg/day (0.06 times the MRHD based on BSA comparison). Teratogenic effects included undeveloped cerebrum, hemorrhagic fluid filling the lumina of the skull, cleft palate and generalized edema. Embryo-fetal toxicity was also observed in rabbits after oral administration of miltefosine during organogenesis (Day 6 to Day 18 of gestation) at doses ≥ 2.4 mg/kg/day (0.2 times the MRHD based on BSA comparison). In both rats and rabbits, there were no viable litters at miltefosine doses ≥ 6.0 mg/kg/day (0.3 or 0.6 times the MRHD based on BSA comparisons for rats and rabbits respectively).
- In a separate female fertility study in rats, miltefosine doses ≥ 6.81 mg/kg/day (0.3 times the MRHD based on BSA comparison) administered for four weeks before mating and up to Day 7 of pregnancy produced numerous visceral (misshapen cerebral structures, dilated ventricles filled with brown masses, misshapen spinal cord, misshapen and malpositioned eyes, hypophysis, and absent inner ear) and skeletal (cleft palate, dumbbell-shaped ossification of thoracic vertebral centers, markedly enlarged skull bones, and markedly dilated suturae) fetal malformations.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Miltefosine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Miltefosine during labor and delivery.
### Nursing Mothers
- It is not known whether miltefosine is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from miltefosine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Breastfeeding should be avoided for 5 months after miltefosine therapy.
### Pediatric Use
- Safety and effectiveness in pediatric patients < 12 years have not been established. Juvenile rats were more sensitive to the miltefosine-induced effects, especially retinal and kidney effects, than adult rats.
### Geriatic Use
- Clinical studies of miltefosine did not include sufficient numbers of subjects 65 years of age and over to determine if they respond differently than younger subjects.
### Gender
Contraception
- Miltefosine may cause fetal harm when used during pregnancy. Advise females of reproductive potential to use effective contraception during miltefosine therapy and for 5 months after therapy is completed.
- Vomiting and/or diarrhea occurring during miltefosine therapy may affect absorption of oral contraceptives and therefore may compromise their efficacy. Advise females who use oral contraceptives to use additional non-hormonal or alternative method(s) of effective contraception during miltefosine therapy if vomiting and/or diarrhea occurs during therapy.
Infertility
Females
- Miltefosine caused impaired fertility in rats and caused reversible follicular atresia and diestrus in dogs at doses approximately 1.0 and 0.2 times respectively the MRHD. The effects of miltefosine on human female fertility have not been formally studied.
Males
- Miltefosine caused reduced viable sperm counts and impaired fertility in rats at doses approximately 0.4 times the MRHD . A higher dose in rats, approximately 1.0 times the MRHD, caused testicular atrophy and impaired fertility that did not fully reverse 10 weeks after drug administration ended. The effects of miltefosine on human male fertility have not been adequately studied.
- Advise women and men of the animal fertility findings, and that the potential for impaired fertility with miltefosine therapy has not been adequately evaluated.
### Race
There is no FDA guidance on the use of Miltefosine with respect to specific racial populations.
### Renal Impairment
- Patients with serum creatinine or BUN levels ≥1.5 times the upper limit of normal were excluded from the clinical studies. Miltefosine pharmacokinetics have not been studied in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Miltefosine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Miltefosine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Miltefosine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Miltefosine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Miltefosine in the drug label.
# Overdosage
- The common adverse effects of vomiting, diarrhea, and abdominal pain are likely in case of overdose. Institute adequate hydration to prevent the risk of impaired renal function, and replace electrolytes as necessary. Because miltefosine is only slightly excreted in the urine, forced diuresis will not increase miltefosine excretion. Gastrointestinal lavage is of unknown value. A specific antidote to treat miltefosine overdose is not known.
# Pharmacology
## Mechanism of Action
- The specific mode of action of miltefosine against Leishmania species is unknown. The mechanism of action of miltefosine is likely to involve interaction with lipids (phospholipids and sterols), including membrane lipids, inhibition of cytochrome c oxidase (mitochondrial function), and apoptosis-like cell death.
## Structure
- Miltefosine capsules contain the active ingredient miltefosine, an antileishmanial agent. The chemical name of miltefosine is 2-(hexadecyloxy)hydroxyphosphenyloxy-N,N,N-trimethylethylammonium inner salt. Miltefosine is a white powder that is freely soluble in water, 0.1 N HCl or NaOH, methanol, and ethanol. It has the empirical formula of C21H46NO4P with a molecular weight of 407.6 and the following structural formula:
- The inactive ingredients are colloidal silicon dioxide, microcrystalline cellulose, lactose monohydrate, talc, and magnesium stearate. The capsule shell contains gelatin, titanium dioxide, ferric oxide, and purified water.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Miltefosine in the drug label.
## Pharmacokinetics
- The pharmacokinetic parameters of miltefosine in patients with visceral and cutaneous leishmaniasis treated for 28 days with miltefosine are listed in Table 5. Due to the long half-life of miltefosine (> 6 days), trough plasma concentrations did not appear to reach a steady state at the end of treatment (i.e., Day 28).
Absorption
- Absolute bioavailability of miltefosine has not been determined. In patients with visceral leishmaniasis, maximum miltefosine concentrations following oral administration of miltefosine capsules were reached right before the next dose in many patients, indicating that the absorption of miltefosine may proceed throughout the dosing interval.
Distribution
- The distribution of miltefosine has not been studied in humans. Human plasma protein binding of miltefosine, evaluated by an ultracentrifugation method, was 98% over the drug concentration range from 0.1 to 10 µg/mL. In rats, radioactivity of [14C] miltefosine is widely distributed after both single and repeated oral administration with highest uptake of radioactivity in kidney, liver, and spleen. Placental transfer and excretion into milk have not been investigated.
Metabolism and Excretion
- No in vitro oxidative metabolism by 15 different human cytochrome P450 enzymes (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, 3A7, and 4A1) was observed.
- A slow metabolic breakdown could be shown in human hepatocytes, resulting in the release of choline by phospholipase D-like cleavage of the miltefosine molecule. The fatty alcohol-containing fragment of miltefosine can enter the metabolism of fatty acids after being oxidized to palmitic acid. This oxidation is blocked in patients with Sjögren-Larsson syndrome, which is caused by a genetic defect in fatty aldehyde dehydrogenase activity. Miltefosine is contraindicated in patients who have Sjögren-Larsson-Syndrome.
- There was little or no evidence of time or metabolism dependent inhibition of the cytochrome P450 enzymes examined at up to approximately 40 µg/mL miltefosine.
- Oral administration of miltefosine did not markedly induce the content of hepatic CYP3A assayed by demethylation activity of erythromycin in rats.
- In visceral leishmaniasis patients, <0.2% of the administered dose was excreted into the urine.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Mutagenicity/Carcinogenicity: Miltefosine tested negative in the AMES-Salmonella test, DNA-amplification test, chromosomal aberration test in vitro, UDS-test in vivo/in vitro, and oral mouse micronucleus test in vivo. The V 79 mammalian cell HPRT gene mutation test showed an increase in mutant frequency without dose dependency. In view of all mutagenicity test results, the single positive finding in the V 79 HPRT test is considered to be not of toxicological relevance with respect to a mutagenic risk to humans.
- Carcinogenicity studies were not performed. In a 52-week oral rat toxicity study, testicular Leydig cell adenoma was observed in 3 of 30 male rats with daily administration of 21.5 mg/kg/day miltefosine (1.0 times the MRHD based on BSA comparison). The carcinogenic potential of miltefosine in humans is unknown.
- In a Segment I fertility study in male rats, testicular atrophy, reduced numbers of viable sperm, and impaired fertility were observed in rats following daily oral doses of ≥ 8.25 mg/kg (0.4 times the MRHD based on BSA comparison). These findings were reversible within a recovery period of 10 weeks except at the highest dose tested, 21.5 mg/kg/day (1.0 times the MRHD based on BSA comparison), where effects were not fully reversible.
- In a female fertility study in rats, estrus cycle arrest in the metestrus or diestrus phases occurred with the high-dose of 21.5 mg/kg (1.0 times the MRHD based on BSA comparison). At doses of 6.81 and 21.5 mg/kg (0.3 and 1.0 times the MRHD respectively based on BSA comparison) increased numbers of embryonic and fetal resorptions and dead fetuses were observed. In a 52-week toxicology study in dogs, increased numbers of atretic follicles in the ovaries, and cycle arrest in the uterus, vagina, and mammary gland with morphology consistent with anestrus or diestrus was observed at doses ≥ 1 mg/kg/day (0.2 times the MRHD based on BSA comparison). The effects in dogs were fully reversible after a recovery period of 6 weeks.
Animal Toxicology and/or Pharmacology
- Toxicological studies with miltefosine have been performed in mice, rats, dogs, and rabbits. Adverse reactions not observed in clinical studies but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows:
- Acute and chronic toxicity: The oral administration of miltefosine in rats was associated with lesions affecting the eyes (retinal degeneration). Retinal degeneration was observed after 8-weeks treatment at doses of 10 mg/kg/day (0.5 times the MRHD based on BSA comparison). Juvenile rats were more sensitive to the miltefosine-induced effects, especially on eyes and kidneys, than adult rats with retinal degeneration occurring at doses ≥ 2.15 mg/kg/day (0.1 times the MRHD based on BSA comparison), and reversible damage to proximal tubule epithelium occurring at doses ≥ 4.64 mg/kg/day (0.2 times the MRHD based on BSA comparison).
# Clinical Studies
Treatment of Visceral Leishmaniasis
- One randomized, open-label, active-controlled study was conducted to evaluate the efficacy of miltefosine in the treatment of visceral leishmaniasis in Bihar, India, an area where L. donovani is known epidemiologically to be the prevalent infecting species. Patients ≥ 12 years of age with clinical signs and symptoms compatible with visceral leishmaniasis (fever, splenomegaly, and cytopenia) confirmed by the presence of Leishmania amastigotes in aspirates of spleen or bone marrow were randomized to receive oral miltefosine or intravenous amphotericin B deoxycholate in a 3:1 ratio. Patients weighing ≥ 25 kg received an miltefosine 50 mg capsule with meals twice a day. Patients weighing < 25 kg received an miltefosine 50 mg capsule with meals once a day in the morning. Weight ranged between 15 and 67 kg (mean weight 38.6 kg) and BMI ranged between 8.2 and 24 (mean 16.1). No patient weighed more than 70kg. Amphotericin B was administered intravenously over 6 continuous hours at 1 mg/kg every other day for 15 doses. Patients were hospitalized for the duration of therapy.
- Exclusion criteria included platelet count <50 × 109/L, white cell count <1 × 109/L, hemoglobin <6 g/100 mL, AST or ALT ≥3 times upper limit of the normal range, bilirubin ≥2 times upper limit of the normal range, serum creatinine or BUN >1.5 times upper limit of the normal range, prothrombin time >5 seconds above control, and any non-compensated or uncontrolled condition including human immunodeficiency virus (HIV) infection. Women of reproductive potential were required to use effective contraception for the duration of therapy and for 2 months post therapy.
- Final cure was defined as initial cure at end of therapy plus absence of signs and symptoms of visceral leishmaniasis at 6 months follow up. Initial cure at the end of therapy was evaluated by repeat spleen or bone marrow aspiration. Patients with initial parasitologic cure were followed for 6 months; patients without absence of clinical signs and symptoms of visceral leishmaniasis were to be evaluated with repeat spleen or bone marrow aspiration to determine final cure.
- Two hundred and ninety nine (299) patients received miltefosine and 99 patients received amphotericin B. Approximately, 70% of patients in each arm had previously failed treatment with pentavalent antimony. Initial cure was achieved in 98% of patients in each treatment arm. At 6 months after therapy, 88 (29.5%) miltefosine recipients and 12 (12.1%) amphotericin B recipients continued to have signs and symptoms suggestive of visceral leishmaniasis. These signs or symptoms were attributed to alternative diagnosis in 73 patients. The remaining 27 patients, all in the miltefosine arm, underwent evaluation with splenic or bone marrow aspiration, and 9 (3.0%) were positive for Leishmania amastigotes, indicating relapse. The final cure rates for miltefosine and amphotericin B were 94% and 97%, respectively.
Treatment of Cutaneous Leishmaniasis
- A placebo controlled study was performed in Colombia where L. panamensis and L. braziliensis are epidemiologically known to be the prevalent infecting Leishmania species, and in Guatemala where L. braziliensis is epidemiologically known to be the prevalent infecting species. The study included male and female patients older than 12 years of age who had newly diagnosed or relapsing cutaneous leishmaniasis without mucosal involvement, parasitologically confirmed, presenting with at least one skin ulcer with minimum area of 50 mm2. Exclusion criteria were AST or ALT ≥2 times upper limit of normal range, bilirubin ≥1.5 times upper limit of normal range, and serum creatinine or BUN >1.5 times upper limit of normal range. Women of reproductive potential were required to use effective contraception for the duration of therapy and for 2 months post therapy.
- Patients were randomized to receive miltefosine or placebo in a 2:1 allocation. Patients who weighed < 45 kg received miltefosine 50 mg capsule twice a day, and patients who weighed ≥45 kg received miltefosine 50 mg capsule three times a day. No patient weighed more than 84 kg. Definite cure was defined as apparent (complete epithelialization of all lesions) or partial cure (incomplete epithelialization, no enlargement by > 50% in lesions, no appearance of new lesions, and negative parasitology if done) at 2 weeks after end of therapy and complete epithelialization of all ulcers at 6 months after end of therapy. The definite cure rate for miltefosine was statistically significantly higher than the cure rate for placebo.
- An additional study of miltefosine was conducted in Bahia and Manaus, two regions in Brazil where respectively L. braziliensis and L. guyanensis are epidemiologically the prevalent infecting pathogens. Adolescent/adult patients aged 12-65 years received miltefosine orally for 28 days. Miltefosine target dose was 2.5 mg/kg/day: patients weighing 15-29 kg received 50 mg once daily, patients weighing 30-45 kg received 50 twice mg daily and patients weighing > 46 kg received 50 mg three times daily. The efficacy criteria were initial cure (complete re-epithelialization of the ulcer at 2 months after the end of therapy) followed by definite cure (complete re-epithelialization at 6 months after the end of therapy). Definite cure rate in patients aged ≥12 years was 27/40 (67.5%) for Manaus, Brazil and 34/40 (85%) for Bahia, Brazil.
Treatment of Mucosal Leishmaniasis
- A single arm study was conducted to evaluate the efficacy of miltefosine capsules for the treatment of mucosal leishmaniasis. The study was conducted in Bolivia where L. braziliensis is epidemiologically the prevalent species.
- Seventy nine (79) patients ≥18 years of age with a cutaneous leishmaniasis scar plus parasites observed or cultured from lesion material or a positive skin test, and no clinically significant concomitant disease received miltefosine at a target dose of 2.5 mg/kg/day for 28 days. By 12 months after the end of therapy, 49 of the patients (62%) had complete resolution of edema, erythema, infiltration and erosion from the involved mucosal sites.
# How Supplied
- Each miltefosine capsule contains 50 mg miltefosine in an opaque, red, hard gelatin capsule. Miltefosine capsules are supplied in a folded peel/push-through blister card. Each blister card contains 14 capsules. Each carton contains two blister cards (NDC 61744-050-01).
## Storage
- Store at 20-25 °C (68-77 °F); excursions permitted to 15-30 °C (59-86 °F). [See USP Controlled Room Temperature]. Protect from moisture.
- Dispense only in the original carton.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Dosing Instructions'
- Miltefosine is administered with food to ameliorate gastrointestinal side effects.
Instruct the patient to swallow the capsule whole and not to chew it or break it apart. Instruct the patient to complete the full course of therapy.
- Inform the patient that abdominal pain, nausea, vomiting, and diarrhea are common side effects of therapy with miltefosine and instruct the patient to inform their healthcare provider if these gastrointestinal side effects are severe or persistent. Instruct the patient to consume sufficient fluids to avoid dehydration and, consequently, the risk of kidney injury.
Females and Males of Reproductive Potential
- Advise women of reproductive potential to use effective contraception during miltefosine therapy and for 5 months after therapy ends.
- Advise women who use oral contraceptives to use additional non-hormonal or alternative method(s) of effective contraception during miltefosine therapy if vomiting and/or diarrhea occurs .
Advise nursing mothers not to breastfeed during miltefosine therapy and for 5 months after therapy is completed.
- Advise women and men that miltefosine caused infertility in male rats, impaired fertility in female rats, and caused atresia in ovarian follicles in female dogs. Advise patients that the potential of impaired fertility in humans has not been adequately evaluated.
# Precautions with Alcohol
- Alcohol-Miltefosine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- IMPAVIDO
# Look-Alike Drug Names
- A® — B®[1]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Impavido | |
629c50bd4c92a221476a28c84f9426d1dc74cd24 | wikidoc | Impulsivity | Impulsivity
# Overview
Impulsivity (or impulsiveness) is a type of human behavior characterized by the inclination of an individual to act on impulse rather than thought. Although part of the normal behavior, impulsivity also plays a role in many mental illnesses.
As a personality trait, impulsivity is part of normal behavior as it contributes to adaptive functioning. However, psychological research has questioned impulsivity as a unitary psychological construct. Some authors have proposed a 3-factor model according to which impulsivity can be decomposed as a combination of attentional ("getting easily bored"), motor ("going into action") and cognitive ("inability to plan") factors. Recent theories have further decomposed impulsivity into 4 dimensions which partially map onto the five-factor model of personality:
- Urgency, the feeling of negative affects for resisting the urge, is linked to neuroticism
- Lack of premeditation, the inability to anticipate consequences, is linked to conscientiousness
- Lack of perseverance, the inability to stick to one's task, is also linked to conscientiousness
- Sensation-seeking, the experience positive feelings towards risky actions, is linked to extroversion
Increased impulsiveness is at the center of impulse control disorders such as obsessive-compulsive disorder. It may be linked to other psychopathological conditions like addiction, ADHD, bulimia, and borderline personality.
Recent evidence from neurobiological research seems to support these psychological theories as it has been shown that these different aspects of impulsivity can be independently manipulated by specific drugs. | Impulsivity
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Impulsivity (or impulsiveness) is a type of human behavior characterized by the inclination of an individual to act on impulse rather than thought.[1] Although part of the normal behavior, impulsivity also plays a role in many mental illnesses.
As a personality trait, impulsivity is part of normal behavior as it contributes to adaptive functioning. However, psychological research has questioned impulsivity as a unitary psychological construct[2]. Some authors have proposed a 3-factor model according to which impulsivity can be decomposed as a combination of attentional ("getting easily bored"), motor ("going into action") and cognitive ("inability to plan") factors. Recent theories[3] have further decomposed impulsivity into 4 dimensions which partially map onto the five-factor model of personality:
- Urgency, the feeling of negative affects for resisting the urge, is linked to neuroticism
- Lack of premeditation, the inability to anticipate consequences, is linked to conscientiousness
- Lack of perseverance, the inability to stick to one's task, is also linked to conscientiousness
- Sensation-seeking, the experience positive feelings towards risky actions, is linked to extroversion
Increased impulsiveness is at the center of impulse control disorders such as obsessive-compulsive disorder. It may be linked to other psychopathological conditions like addiction, ADHD, bulimia, and borderline personality.
Recent evidence from neurobiological research seems to support these psychological theories as it has been shown that these different aspects of impulsivity can be independently manipulated by specific drugs. | https://www.wikidoc.org/index.php/Impulsivity | |
27b5511968cdc3acd749da0b01eaba583dadddf7 | wikidoc | Indacaterol | Indacaterol
# Disclaimer
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# Black Box Warning
# Overview
Indacaterol is an adrenergic that is FDA approved for the treatment of Maintenance Treatment of COPD. There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, cough, nasopharynx.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- ARCAPTA NEOHALER is a long-acting beta2-agonist indicated for long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.
- ARCAPTA NEOHALER is not indicated to treat acute deteriorations of chronic obstructive pulmonary disease.
- ARCAPTA NEOHALER is not indicated to treat asthma. The safety and effectiveness of ARCAPTA NEOHALER in asthma have not been established.
- DO NOT SWALLOW ARCAPTA CAPSULES
- FOR USE WITH NEOHALER DEVICE ONLY
- FOR ORAL INHALATION ONLY
- ARCAPTA capsules must not be swallowed as the intended effects on the lungs will not be obtained. The contents of ARCAPTA capsules are only for oral inhalation and should only be used with the NEOHALER device.
- The recommended dosage of ARCAPTA NEOHALER is the once-daily inhalation of the contents of one 75 mcg ARCAPTA capsule using the NEOHALER inhaler.
- ARCAPTA NEOHALER should be administered once daily every day at the same time of the day by the orally inhaled route only. If a dose is missed, the next dose should be taken as soon as it is remembered. Do not use ARCAPTA NEOHALER more than one time every 24 hours.
- ARCAPTA capsules must always be stored in the blister, and only removed IMMEDIATELY BEFORE USE.
- No dosage adjustment is required for geriatric patients, patients with mild and moderate hepatic impairment, or renally impaired patients. No data are available for subjects with severe hepatic impairment.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Indacaterol in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Indacaterol in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Indacaterol in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Indacaterol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Indacaterol in pediatric patients.
# Contraindications
- ll LABA are contraindicated in patients with asthma without use of a long-term asthma control medication. ARCAPTA NEOHALER is not indicated for the treatment of asthma.
- ARCAPTA NEOHALER is contraindicated in patients with a history of hypersensitivity to indacaterol or to any of the ingredients.
# Warnings
- Data from a large placebo-controlled study in asthma patients showed that long-acting beta2-adrenergic agonists may increase the risk of asthma-related death. Data are not available to determine whether the rate of death in patients with COPD is increased by long-acting beta2-adrenergic agonists.
- A 28-week, placebo-controlled US study comparing the safety of another long-acting beta2-adrenergic agonist (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol (13/13,176 in patients treated with salmeterol vs.
- 3/13,179 in patients treated with placebo; RR 4.37, 95% CI 1.25, 15.34). The increased risk of asthma-related death is considered a class effect of the long-acting beta2-adrenergic agonists, including ARCAPTA NEOHALER. No study adequate to determine whether the rate of asthma-related death is increased in patients treated with ARCAPTA NEOHALER has been conducted. The safety and efficacy of ARCAPTA NEOHALER in patients with asthma have not been established. ARCAPTA NEOHALER is not indicated for the treatment of asthma.
- Serious asthma-related events, including death, were reported in clinical studies with ARCAPTA NEOHALER. The sizes of these studies were not adequate to precisely quantify the differences in serious asthma exacerbation rates between treatment groups.
- ARCAPTA NEOHALER should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition. ARCAPTA NEOHALER has not been studied in patients with acutely deteriorating COPD. The use of ARCAPTA NEOHALER in this setting is inappropriate.
- ARCAPTA NEOHALER should not be used for the relief of acute symptoms, i.e. as rescue therapy for the treatment of acute episodes of bronchospasm. ARCAPTA NEOHALER has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled short-acting beta2-agonist.
- When beginning ARCAPTA NEOHALER, patients who have been taking inhaled, short-acting beta2-agonists on a regular basis (e.g., four times a day) should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief of acute respiratory symptoms. When prescribing ARCAPTA NEOHALER, the healthcare provider should also prescribe an inhaled, short-acting beta2- agonist and instruct the patient on how it should be used. Increasing inhaled beta2-agonist use is a signal of deteriorating disease for which prompt medical attention is indicated.
- COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If ARCAPTA NEOHALER no longer controls the symptoms of bronchoconstriction, or the patient’s inhaled, short-acting beta2-agonist becomes less effective or the patient needs more inhalation of short-acting beta2-agonist than usual, these may be markers of deterioration of disease.
- In this setting, a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dosage of ARCAPTA NEOHALER beyond the recommended dose is not appropriate in this situation.
- As with other inhaled beta2-adrenergic drugs, ARCAPTA NEOHALER should not be used more often, at higher doses than recommended, or in conjunction with other medications containing long-acting beta2-agonists, as an overdose may result.
- Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.
- Immediate hypersensitivity reactions may occur after administration of ARCAPTA NEOHALER. If signs suggesting allergic reactions (in particular, difficulties in breathing or swallowing, swelling of tongue, lips and face, urticaria, skin rash) occur, ARCAPTA NEOHALER should be discontinued immediately and alternative therapy instituted.
- As with other inhaled beta2-agonists, ARCAPTA NEOHALER may produce paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs, ARCAPTA NEOHALER should be discontinued immediately and alternative therapy instituted.
- ARCAPTA NEOHALER, like other beta2-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, or symptoms. If such effects occur, ARCAPTA NEOHALER may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance of these findings is unknown. Therefore, ARCAPTA NEOHALER, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.
- ARCAPTA NEOHALER, like other sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis, and in patients who are unusually responsive to sympathomimetic amines. Doses of the related beta2-agonist albuterol, when administered intravenously, have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis.
- Beta2-agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. Inhalation of high doses of beta2-adrenergic agonists may produce increases in plasma glucose.
- Clinically notable decreases in serum potassium or changes in blood glucose were infrequent during clinical studies with long-term administration of ARCAPTA NEOHALER with the rates similar to those for placebo controls. ARCAPTA NEOHALER has not been investigated in patients whose diabetes mellitus is not well controlled.
# Adverse Reactions
## Clinical Trials Experience
- Long-acting beta2-adrenergic agonists, such as ARCAPTA NEOHALER, increase the risk of asthma-related death. ARCAPTA NEOHALER is not indicated for the treatment of asthma.
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The ARCAPTA NEOHALER safety database reflects exposure of 2516 patients to ARCAPTA NEOHALER at doses of 75 mcg or greater for at least 12 weeks in six confirmatory randomized, double-blind, placebo and active-controlled clinical trials. In these trials, 449 patients were exposed to the recommended dose of 75 mcg for up to 3 months, and 144, 583 and 425 COPD patients were exposed to a dose of 150, 300 or 600 mcg for one year, respectively. Overall, patients had a mean pre-bronchodilator forced expiratory volume in one second (FEV1) percent predicted of 54%. The mean age of patients was 64 years, with 47% of patients aged 65 years or older, and the majority (88%) was Caucasian.
- In these six clinical trials, 48% of patients treated with any dose of ARCAPTA NEOHALER reported an adverse reaction compared with 43% of patients treated with placebo. The proportion of patients who discontinued treatment due to adverse reaction was 5% for ARCAPTA NEOHALER-treated patients and 5% for placebo-treated patients. The most common adverse reactions that lead to discontinuation of ARCAPTA NEOHALER were COPD and dyspnea.
- The most common serious adverse reactions were COPD exacerbation, pneumonia, angina pectoris, and atrial fibrillation, which occurred at similar rates across treatment groups.
- Table 1 displays adverse drug reactions reported by at least 2% of patients (and higher than placebo) during a 3 month exposure at the recommended 75 mcg once daily dose. Adverse drug reactions are listed according to MedDRA (version 13.0) system organ class and sorted in descending order of frequency.
- In these trials the overall frequency of all cardiovascular adverse reactions was 2.5% for ARCAPTA NEOHALER 75 mcg and 1.6% for placebo during a 3 month exposure. There were no frequently occurring specific cardiovascular adverse reactions for ARCAPTA NEOHALER 75 mcg (frequency at least 1% and greater than placebo).
- Additional adverse drug reactions reported in greater than 2% (and higher than on placebo) in patients dosed with 150, 300 or 600 mcg for up to 12 months were as follows:
- Musculoskeletal and connective tissue disorders
- Muscle spasm, musculoskeletal pain
- General disorders and administration site conditions
- Edema peripheral
- Metabolism and nutrition disorder
- Diabetes mellitus, hyperglycemia
- Infections and infestations
- Sinusitis, upper respiratory tract infection
- Cough experienced post-inhalation
- In the clinical trials, health care providers observed during clinic visits that an average of 24% of patients experienced a cough on at least 20% of visits following inhalation of the recommended 75 mcg dose of ARCAPTA NEOHALER compared to 7% of patients receiving placebo. The cough usually occurred within 15 seconds following inhalation and lasted for no more than 15 seconds. Cough following inhalation in clinical trials was not associated with bronchospasm, exacerbations, deteriorations of disease or loss of efficacy.
- In a 6-month randomized, active controlled asthma safety trial, 805 adult patients with moderate to severe persistent asthma were treated with ARCAPTA NEOHALER 300 mcg (n=268), ARCAPTA NEOHALER 600 mcg (n=268), and salmeterol (n=269), all concomitant with inhaled corticosteroids, which were not co-randomized. Of these patients, there were 2 respiratory-related deaths in the ARCAPTA NEOHALER 300 mcg dose group. There were no deaths in the ARCAPTA NEOHALER 600 mcg dose group or in the salmeterol active control group. Serious adverse reactions related to asthma exacerbation were reported for 2 patients in the indacaterol 300 mcg group, 3 patients in the indacaterol 600 mcg group, and no patients in the salmeterol active control group.
- In addition, a two-week dose-ranging trial was conducted in 511 adult patients with mild persistent asthma taking inhaled corticosteroids. No deaths, intubations, or serious adverse reactions related to asthma exacerbation were reported in this trial.
## Postmarketing Experience
- The following adverse reactions have been identified during worldwide post-approval use of indacaterol, the active ingredient in ARCAPTA NEOHALER. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- These adverse reactions are: hypersensitivity reactions, paradoxical bronchospasm, tachycardia/heart rate increase/palpitations, pruritus/rash and dizziness.
# Drug Interactions
- If additional adrenergic drugs are to be administered by any route, they should be used with caution because the sympathetic effects of ARCAPTA NEOHALER may be potentiated.
- Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate any hypokalemic effect of ARCAPTA NEOHALER.
- The ECG changes or hypokalemia that may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical relevance of these effects is not known, caution is advised in the co-administration of ARCAPTA NEOHALER with non-potassium-sparing diuretics.
- Indacaterol, as with other beta2-agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or other drugs known to prolong the QTc interval because the action of adrenergic agonists on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval may have an increased risk of ventricular arrhythmias.
- Beta-adrenergic receptor antagonists (beta-blockers) and ARCAPTA NEOHALER may interfere with the effect of each other when administered concurrently. Beta-blockers not only block the therapeutic effects of beta-agonists, but may produce severe bronchospasm in COPD patients. Therefore, patients with COPD should not normally be treated with beta-blockers. However, under certain circumstances, e.g. as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-blockers in patients with COPD. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.
- Drug interaction studies were carried out using potent and specific inhibitors of CYP3A4 and P-gp (i.e., ketoconazole, erythromycin, verapamil and ritonavir). The data suggest that systemic clearance is influenced by modulation of both P-gp and CYP3A4 activities and that the 1.9-fold AUC0-24 increase caused by the strong dual inhibitor ketoconazole reflects the impact of maximal combined inhibition. ARCAPTA NEOHALER was evaluated in clinical trials for up to one year at doses up to 600 mcg. No dose adjustment is warranted at the 75 mcg dose.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies with ARCAPTA NEOHALER in pregnant women. ARCAPTA NEOHALER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Indacaterol was not teratogenic following subcutaneous administration to rats and rabbits at doses up to 1 mg/kg, approximately 130 and 260 times, respectively, the 75 mcg dose on a mg/m2 basis.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Indacaterol in women who are pregnant.
### Labor and Delivery
- There are no adequate and well-controlled human studies that have investigated effects of ARCAPTA NEOHALER on preterm labor or labor at term. Because of the potential for beta-agonist interference with uterine contractility, use of ARCAPTA NEOHALER during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.
### Nursing Mothers
- It is not known that the active component of ARCAPTA NEOHALER, indacaterol, is excreted in human milk. Because many drugs are excreted in human milk and because indacaterol has been detected in the milk of lactating rats, caution should be exercised when ARCAPTA NEOHALER is administered to nursing women.
### Pediatric Use
- ARCAPTA NEOHALER is not indicated for use in children. The safety and effectiveness of ARCAPTA NEOHALER in pediatric patients have not been established.
### Geriatic Use
- Based on available data, no adjustment of ARCAPTA NEOHALER dosage in geriatric patients is warranted. Of the total number of patients who received ARCAPTA NEOHALER at the recommended dose of 75 mcg once daily in the clinical studies from the pooled 3-month database, 239 were <65 years, 153 were 65–74 years and 57 were ≥75 years of age.
- No overall differences in effectiveness were observed, and in the 3-month pooled data, the adverse drug reaction profile was similar in the older population compared to the patient population overall. When treated at higher doses (300 mcg and 600 mcg) over the course of a year, the adverse drug reaction profiles for patients >65 years was similar to that of the general patient population.
### Gender
There is no FDA guidance on the use of Indacaterol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Indacaterol with respect to specific racial populations.
### Renal Impairment
- Patients with mild and moderate hepatic impairment showed no relevant changes in Cmax or AUC, nor did protein binding differ between mild and moderate hepatically impaired subjects and their healthy controls. Studies in subjects with severe hepatic impairment were not performed.
### Hepatic Impairment
Due to the very low contribution of the urinary pathway to total body elimination, a study in renally impaired subjects was not performed.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Indacaterol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Indacaterol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Inhaler
### Monitoring
- Cardiac monitoring is recommended in cases of overdosage.
# IV Compatibility
There is limited information regarding IV Compatibility of Indacaterol in the drug label.
# Overdosage
- In COPD patients single doses of 40 times the 75 mcg dose were associated with moderate increases in pulse rate, systolic blood pressure and QTc interval.
- The expected signs and symptoms associated with overdosage of ARCAPTA NEOHALER are those of excessive beta-adrenergic stimulation and occurrence or exaggeration of any of the signs and symptoms, e.g., angina, hypertension or hypotension, tachycardia, with rates up to 200 bpm, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, muscle cramps, nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, metabolic acidosis and insomnia. As with all inhaled sympathomimetic medications, cardiac arrest and even death may be associated with an overdose of ARCAPTA NEOHALER.
- Treatment of overdosage consists of discontinuation of ARCAPTA NEOHALER together with institution of appropriate symptomatic and supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm.
- There is insufficient evidence to determine if dialysis is beneficial for overdosage of ARCAPTA NEOHALER. Cardiac monitoring is recommended in cases of overdosage.
# Pharmacology
## Mechanism of Action
- Indacaterol is a long-acting beta2-adrenergic agonist.
- When inhaled, indacaterol acts locally in the lung as a bronchodilator. Although beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, there are also beta2-adrenergic receptors in the human heart comprising 10%-50% of the total adrenergic receptors. The precise function of these receptors is not known, but their presence raises the possibility that even highly selective beta2-adrenergic agonists may have cardiac effects.
- The pharmacological effects of beta2-adrenoceptor agonist drugs, including indacaterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3’, 5’-adenosine monophosphate (cyclic monophosphate). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle. In vitro studies have shown that indacaterol has more than 24-fold greater agonist activity at beta2-receptors compared to beta1-receptors and 20-fold greater agonist activity compared to beta3-receptors. This selectivity profile is similar to formoterol. The clinical significance of these findings is unknown.
## Structure
- ARCAPTA NEOHALER consists of a dry powder formulation of indacaterol maleate for oral inhalation only with the NEOHALER inhaler. The inhalation powder is packaged in clear gelatin capsules.
- Each clear, hard gelatin capsule contains a dry powder blend of 75 mcg of indacaterol (equivalent to 97 mcg of indacaterol maleate) with approximately 25 mg of lactose monohydrate (which contains trace levels of milk protein) as the carrier.
- The active component of ARCAPTA NEOHALER is indacaterol maleate, a (R) enantiomer. Indacaterol maleate is a selective beta2-adrenergic agonist. Its chemical name is (R)-5--8-hydroxy-1H-quinolin-2-one maleate; its structural formula is
- Indacaterol maleate has a molecular weight of 508.56, and its empirical formula is C24H28N2O3 - C4H4O4. Indacaterol maleate is a white to very slightly grayish or very slightly yellowish powder. Indacaterol maleate is freely soluble in N-methylpyrrolidone and dimethylformamide, slightly soluble in methanol, ethanol, propylene glycol and polyethylene glycol 400, very slightly soluble in water, isopropyl alcohol and practically insoluble in 0.9% sodium chloride in water, ethyl acetate and n-octanol.
- The NEOHALER inhaler is a plastic device used for inhaling ARCAPTA. The amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow rate and inspiratory time. Under standardized in vitro testing at a fixed flow rate of 60 L/min for 2 seconds, the NEOHALER inhaler delivered 57 mcg for the 75 mcg dose strength (equivalent to 73.9 mcg of indacaterol maleate) from the mouthpiece. Peak inspiratory flow rates (PIFR) achievable through the NEOHALER inhaler were evaluated in 26 adult patients with COPD of varying severity. Mean PIFR was 95 L/min (range 52-133 L/min) for adult patients. Approximately ninety-five percent of the population studied generated a PIFR through the device exceeding 60 L/min.
## Pharmacodynamics
- The major adverse effects of inhaled beta2-adrenergic agonists occur as a result of excessive activation of systemic beta-adrenergic receptors. The most common adverse effects in adults include skeletal muscle tremor and cramps, insomnia, tachycardia, decreases in serum potassium and increases in plasma glucose.
- Changes in serum potassium and plasma glucose were evaluated in COPD patients in double-blind Phase III studies. In pooled data, at the recommended 75 mcg dose, at 1 hour post-dose at week 12, there was no change compared to placebo in serum potassium, and change in mean plasma glucose was 0.07 mmol/L.
- The effect of ARCAPTA NEOHALER on the QT interval was evaluated in a double-blind, placebo- and active (moxifloxacin)-controlled study following multiple doses of indacaterol 150 mcg, 300 mcg or 600 mcg once-daily for 2 weeks in 404 healthy volunteers. Fridericia’s method for heart rate correction was employed to derive the corrected QT interval (QTcF). Maximum mean prolongation of QTcF intervals were <5 ms, and the upper limit of the 90% confidence interval was below 10 ms for all time-matched comparisons versus placebo. During these studies, there were no clinically meaningful QT-interval prolongations. There was no evidence of a clinically relevant concentration-delta QTc relationship in the range of doses evaluated.
- The effect of 150 mcg and 300 mcg once daily of ARCAPTA NEOHALER on heart rate and rhythm was assessed using continuous 24-hour ECG recording (Holter monitoring) in a subset of 605 patients with COPD from a 26-week, double-blind, placebo-controlled Phase III study. Holter monitoring occurred once at baseline and up to 3 times during the 26-week treatment period (at weeks 2, 12 and 26). A comparison of the mean heart rate over 24 hours showed no increase from baseline. The hourly heart rate analysis was similar compared to placebo. The pattern of diurnal variation over 24 hours was maintained and was similar to placebo. No difference from placebo was seen in the rates of atrial fibrillation, time spent in atrial fibrillation and also the maximum ventricular rate of atrial fibrillation. No clear patterns in the rates of single ectopic beats, couplets or runs were seen across visits. Because the summary data on rates of ventricular ectopic beats can be difficult to interpret, specific pro-arrhythmic criteria were analyzed. In this analysis, baseline occurrence of ventricular ectopic beats was compared to change from baseline, setting certain parameters for the change to describe the pro-arrhythmic response. The number of patients with a documented pro-arrhythmic response was very similar compared to placebo.
- Overall, there was no clinically relevant difference in the development of arrhythmic events in patients receiving indacaterol treatment over those patients who received placebo.
- Tolerance to the effects of inhaled beta-agonists can occur with regularly-scheduled, chronic use. In two 12-week clinical efficacy trials in 323 and 318 adult patients with COPD, ARCAPTA NEOHALER improvement in lung function (as measured by the forced expiratory volume in one second, FEV1) observed at Week 4 with ARCAPTA NEOHALER was consistently maintained over the 12-week treatment period in both trials.
## Pharmacokinetics
- The median time to reach peak serum concentrations of indacaterol was approximately 15 minutes after single or repeated inhaled doses. Systemic exposure to indacaterol increased with increasing dose (150 mcg to 600 mcg) in a dose proportional manner, and was about dose-proportional in the dose range of 75 mcg to 150 mcg. Absolute bioavailability of indacaterol after an inhaled dose was on average 43-45%. Systemic exposure results from a composite of pulmonary and intestinal absorption.
- Indacaterol serum concentrations increased with repeated once-daily administration. Steady-state was achieved within 12 to 15 days. The mean accumulation ratio of indacaterol, i.e. AUC over the 24-hour dosing interval on day 14 or day 15 compared to day 1, was in the range of 2.9 to 3.8 for once-daily inhaled doses between 75 mcg and 600 mcg.
- After intravenous infusion the volume of distribution (Vz) of indacaterol was 2,361 L to 2,557 L indicating an extensive distribution. The in vitro human serum and plasma protein binding was 94.1-95.3% and 95.1-96.2%, respectively.
- After oral administration of radiolabeled indacaterol in the human ADME (absorption, distribution, metabolism, excretion) study unchanged indacaterol was the main component in serum, accounting for about one third of total drug-related AUC over 24 hours. A hydroxylated derivative was the most prominent metabolite in serum. Phenolic O-glucuronides of indacaterol and hydroxylated indacaterol were further prominent metabolites. A diastereomer of the hydroxylated derivative, a N-glucuronide of indacaterol, and C- and N-dealkylated products were further metabolites identified.
- In vitro investigations indicated that UGT1A1 was the only UGT isoform that metabolized indacaterol to the phenolic O-glucuronide. The oxidative metabolites were found in incubations with recombinant CYP1A1, CYP2D6, and CYP3A4. CYP3A4 is concluded to be the predominant isoenzyme responsible for hydroxylation of indacaterol.
- In vitro investigations indicated that indacaterol is a low affinity substrate for the efflux pump P-gp.
- In vitro investigations indicated that indacaterol has negligible potential to cause metabolic interactions with medications (by inhibition or induction of cytochrome P450 enzymes, or induction of UGT1A1) at the systemic exposure levels achieved in clinical practice. In vitro investigation furthermore indicated that, in vivo, indacaterol is unlikely to significantly inhibit transporter proteins such as P-gp, MRP2, BCRP, the cationic substrate transporters hOCT1 and hOCT2, and the human multidrug and toxin extrusion transporters hMATE1 and hMATE2K, and that indacaterol has negligible potential to induce P-gp or MRP2.
- In clinical studies which included urine collection the amount of indacaterol excreted unchanged via urine was generally lower than 2% of the dose. Renal clearance of indacaterol was, on average, between 0.46 and 1.2 L/h. When compared with the serum clearance of indacaterol of 18.8 L/h to 23.3 L/h, it is evident that renal clearance plays a minor role (about 2 to 6% of systemic clearance) in the elimination of systemically available indacaterol.
- In a human ADME study where indacaterol was given orally, the fecal route of excretion was dominant over the urinary route. Indacaterol was excreted into human feces primarily as unchanged parent drug (54% of the dose) and, to a lesser extent, hydroxylated indacaterol metabolites (23% of the dose). Mass balance was complete with ≥90% of the dose recovered in the excreta.
- Indacaterol serum concentrations declined in a multi-phasic manner with an average terminal half-life ranging from 45.5 to 126 hours. The effective half-life, calculated from the accumulation of indacaterol after repeated dosing with once daily doses between 75 mcg and 600 mcg ranged from 40 to 56 hours which is consistent with the observed time-to-steady state of approximately 12-15 days.
- A population pharmacokinetic analysis was performed for indacaterol utilizing data from 3 controlled clinical trials that included 1,844 patients with COPD aged 40 to 88 years who received treatment with ARCAPTA NEOHALER.
- The population analysis showed that no dose adjustment is warranted based on the effect of age, gender and weight on systemic exposure in COPD patients after inhalation of ARCAPTA NEOHALER. The population pharmacokinetic analysis did not suggest any difference between ethnic subgroups in this population.
- Patients with mild and moderate hepatic impairment showed no relevant changes in Cmax or AUC of indacaterol, nor did protein binding differ between mild and moderate hepatically impaired subjects and their healthy controls. Studies in subjects with severe hepatic impairment were not performed.
- Due to the very low contribution of the urinary pathway to total body elimination, a study in renally impaired subjects was not performed.
- Drug interaction studies were carried out using potent and specific inhibitors of CYP3A4 and P-gp (i.e., ketoconazole, erythromycin, verapamil and ritonavir).
- Verapamil
- Co-administration of indacaterol 300 mcg (single dose) with verapamil (80 mg t.i.d for 4 days) showed 2-fold increase in indacaterol AUC0-24, and 1.5-fold increase in indacaterol Cmax.
- Erythromycin
- Co-administration of indacaterol inhalation powder 300 mcg (single dose) with erythromycin (400 mg q.i.d for 7 days) showed a 1.4-fold increase in indacaterol AUC0-24, and 1.2-fold increase in indacaterol Cmax
- Ketoconazole
- Co-administration of indacaterol inhalation powder 300 mcg (single dose) with ketoconazole (200 mg b.i.d for 7 days) caused a 1.9-fold increase in indacaterol AUC0-24, and 1.3-fold increase in indacaterol Cmax
- Ritonavir
- Co-administration of indacaterol 300 mcg (single dose) with ritonavir (300 mg b.i.d for 7.5 days) resulted in a 1.7-fold increase in indacaterol AUC0-24 whereas indacaterol Cmax was unaffected.
- The pharmacokinetics of indacaterol were prospectively investigated in subjects with the UGT1A1 (TA)7/(TA)7 genotype (low UGT1A1 expression; also referred to as *28) and the (TA)6, (TA)6 genotype. Steady-state AUC and Cmax of indacaterol were 1.2-fold higher in the genotype, suggesting no relevant effect of UGT1A1 genotype of indacaterol exposure.
## Nonclinical Toxicology
- Long-term studies were conducted in transgenic mice using oral administration and in rats using inhalation administration to evaluate the carcinogenic potential of indacaterol maleate. Indacaterol did not show a statistically significant increase in tumor formation in mice or rats.
- Lifetime treatment of rats resulted in increased incidences of benign ovarian leiomyoma and focal hyperplasia of ovarian smooth muscle in females at doses approximately 270-times the dose of 75 mcg once-daily for humans (on a mg/m2 basis).
- A 26-week oral (gavage) study in CB6F1/TgrasH2 hemizygous mice with indacaterol did not show any evidence of tumorigenicity at doses approximately 39,000-times the dose of 75 mcg once-daily for humans (on a mg/m2 basis).
- Increases in leiomyomas of the female rat genital tract have been similarly demonstrated with other beta2-adrenergic agonist drugs. The relevance of these findings to human use is unknown.
- Indacaterol was not mutagenic or clastogenic in Ames test, chromosome aberration test in V79 Chinese hamster cells, and bone marrow micronucleus test in rats.
- Indacaterol did not impair fertility of rats in reproduction studies.
# Clinical Studies
- The ARCAPTA NEOHALER COPD clinical development program included three dose-ranging trials and six confirmatory trials (Trial 3, a 26-week seamless adaptive design trial that included an initial 2 week dose ranging phase; Trials 4, 5, and 6, 12-week trials; Trial 7, a 26-week trial; and Trial 8, a 52 week trial).
- Dose selection for ARCAPTA NEOHALER for COPD was based on three dose-ranging trials (Trial 1, a 2-week dose- ranging trial in an asthma population; Trial 2, a 2-week dose-ranging trial in a COPD population; and Trial 3, a 26-week adaptive seamless design trial that included an initial 2-week dose ranging phase). Although ARCAPTA NEOHALER is not indicated for asthma, dose selection was primarily based upon the results from the dose-ranging trial in asthma patients (Trial 1) as an asthma population is the most responsive to beta-agonist bronchodilation and is most likely to demonstrate a dose response. Dose-ranging in COPD patients (Trials 2 and 3) provided supportive information.
- ARCAPTA NEOHALER is not indicated for asthma.
- Trial 1 was a 2-week, randomized, double-blinded, placebo-controlled design that enrolled 511 patients with persistent asthma 18 years of age and older. - All enrolled patients were required to be taking inhaled corticosteroids, had a forced expiratory volume in one second (FEV1) of ≥ 50% and ≤ 90% predicted, and FEV1 reversibility after albuterol of at least 12% and at least 200 mL. Trial 1 included ARCAPTA NEOHALER doses of 18.75, 37.5, 75, and 150 mcg once daily, a salmeterol active control group, and placebo. The trial showed that the effect on FEV1 in patients treated with ARCAPTA NEOHALER 18.75 and 37.5 mcg doses was lower compared to patients treated with other ARCAPTA NEOHALER doses, particularly after the first dose. The effect did not clearly differ between the 75 and 150 mcg doses.
- Results of the ARCAPTA NEOHALER and placebo treatment arms are as follows. After the first dose (Day 1), the peak (4 hour) FEV1 was 2.58L in the placebo group, with a treatment difference of 0.04L (95% CI -0.01, 0.09) in the 18.75 mcg ARCAPTA NEOHALER group, 0.04L (-0.01, 0.09) in the 37.5 mcg group, 0.12L (0.07, 0.17) in the 75 mcg group, and 0.15L (0.10, 0.20) in the 150 mcg group. The Day 2 trough FEV1 was 2.45L in the placebo group, with a treatment difference of 0.02L (95% CI -0.05, 0.08), 0.08L (0.01, 0.15), 0.09L (0.03, 0.16) and 0.16L (0.09, 0.22) in the ARCAPTA NEOHALER groups, respectively. At Day 14, the peak (4 hour) FEV1 was 2.55L in the placebo group, with a treatment difference of 0.12L (95% CI 0.05, 0.20) in the 18.75 mcg ARCAPTA NEOHALER group, 0.14L (0.06, 0.21) in the 37.5 mcg group, 0.23L (0.15, 0.30) in the 75 mcg group, and 0.20L (0.13, 0.27) in the 150 mcg group. The Day 15 FEV1 (primary endpoint) was 2.42L in the placebo group, with a treatment difference of 0.09L (95% CI 0.00, 0.17), 0.11L (0.02, 0.19), 0.17L (0.08, 0.26), and 0.12L (0.04, 0.21) in the ARCAPTA NEOHALER groups, respectively.
- Trial 2 was a 2-week, randomized, double-blinded, placebo-controlled design that enrolled 552 patients with a clinical diagnosis of COPD, who were 40 years or older, had a smoking history of at least 10 pack years, had a post-bronchodilator FEV1 less than 80% and at least 30% of the predicated normal value and a post-bronchodilator ratio of FEV1 over forced vital capacity (FEV1/FVC) of less than 70%. Trial 2 included ARCAPTA NEOHALER doses of 18.75, 37.5, 75 and 150 mcg once daily, a salmeterol active control group, and placebo. Results of the ARCAPTA NEOHALER and placebo arms are shown in Figure 1. The trial showed that the effect on FEV1 in patients treated with ARCAPTA NEOHALER 18.75 mcg dose was lower compared to patients treated with other ARCAPTA NEOHALER doses. Although a dose-response relationship was observed at Day 1, the effect did not clearly differ among the 37.5, 75 and 150 mcg doses by Day 15.
- The 2-week dose ranging phase of Trial 3 included ARCAPTA NEOHALER doses of 75, 150, 300, and 600 mcg once daily, placebo, and two active comparators. Although a dose-response relationship was observed at week 2, the effect did not clearly differ among the ARCAPTA NEOHALER doses.
- The ARCAPTA NEOHALER COPD development program included six confirmatory trials that were randomized, double-blinded placebo and active-controlled in design (Trial 3, a 26-week seamless adaptive design trial that included an initial 2 week dose-ranging phase; Trials 4, 5, and 6, 12-week trials; Trial 7, a 26-week trial; and Trial 8, a 52 week trial). After the initial 2-week dose-ranging portion of the design, Trial 3 was conducted with ARCAPTA NEOHALER doses of 150 mcg and 300 mcg once daily, placebo, and an active comparator. Trials 4 and 5 were conducted with ARCAPTA NEOHALER dose of 75 mcg once daily, and placebo. Trial 6 was conducted with ARCAPTA NEOHALER dose of 150 mcg once daily and placebo. Trial 7 was conducted with ARCAPTA NEOHALER dose of 150 mcg once daily, an active comparator, and placebo. Trial 8 was conducted with ARCAPTA NEOHALER doses of 300 mcg and 600 mcg once daily, an active comparator, and placebo.
- As Trials 3, 6, 7, and 8 were conducted with doses of ARCAPTA NEOHALER higher than 75 mcg, the results of Trials 4 and 5, which included ARCAPTA NEOHALER 75 mcg are the focus of this section.
- These six trials enrolled 5474 patients with a clinical diagnosis of COPD, who were 40 years or older, had a smoking history of at least 10 pack years, had a post-bronchodilator FEV1 less than 80% and at least 30% of the predicted normal value and a post-bronchodilator ratio of FEV1 over FVC of less than 70%.
- Assessment of efficacy in these six COPD trials was based on FEV1. The primary efficacy endpoint was 24-hour post-dose trough FEV1 (defined as the average of two FEV1 measurements taken after 23 hours 10 minutes and 23 hours and 45 minutes after the previous dose) after 12 weeks of treatment in all 6 trials. Other efficacy variables included other FEV1 and FVC time points, rescue medication use, symptoms, and health-related quality of life measured using the St. George’s Respiratory Questionnaire (SGRQ).
- In all six confirmatory COPD trials, all doses of ARCAPTA NEOHALER tested (75 mcg, 150 mcg, 300 mcg, and 600 mcg) showed significantly greater 24-hour post-dose trough FEV1 compared to placebo at 12 weeks. Results of Trials 4 and 5, which compared ARCAPTA NEOHALER at the dose of 75 mcg once daily to placebo are shown in Table 2.
- In both COPD clinical trials including the 75 mcg dose (Trials 4 and 5), patients treated with ARCAPTA NEOHALER used less daily rescue albuterol during the trial compared to patients treated with placebo.
- Health-related quality of life was measured using the St. George’s Respiratory Questionnaire (SGRQ) in all six confirmatory COPD clinical trials. SGRQ is a disease-specific patient reported instrument which measures symptoms, activities, and its impact on daily life. At week 12, pooled data from these trials demonstrated an improvement over placebo in SGRQ total score of -3.8 with a 95% CI of (-5.3, -2.3) for the ARCAPTA NEOHALER 75 mcg dose, -4.6 with a 95% CI of (-5.5, -3.6) for 150 mcg, and -3.8 with a 95% CI of (-4.9, -2.8) for 300 mcg. The confidence intervals for this change are widely overlapping with no dose ordering. Results from individual studies were variable, but are generally consistent with the pooled data results.
# How Supplied
- 75 mcg ARCAPTA NEOHALER contains ARCAPTA (indacaterol inhalation powder) capsules packaged in aluminum blister cards, one NEOHALER inhaler, and an FDA approved Medication Guide.
- Unit Dose (blister pack), Box of 30 (5 blister cards with 6 capsules each) NDC 0078-0619-15
- The NEOHALER inhaler consists of a white protective cap and a base with mouthpiece, capsule chamber and two translucent red push buttons.
## Storage
- Store in a dry place at 25°C (77°F); excursions permitted to 15-30°C (59-86° F).
- 75 mcg: Protect capsule from light and moisture.
- ARCAPTA capsules should be used with the NEOHALER inhaler only. The NEOHALER inhaler should not be used with any other capsules.
- Capsules should always be stored in the blister and only removed from the blister immediately before use.
- Always use the new NEOHALER inhaler provided with each new prescription.
Keep out of the reach of children.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be informed that LABA, such as ARCAPTA NEOHALER, increase the risk of asthma-related death. ARCAPTA NEOHALER is not indicated for the treatment of asthma.
- It is important for patients to understand how to correctly administer ARCAPTA capsules using the NEOHALER device. Patients should be instructed that ARCAPTA capsules should only be administered via the NEOHALER device and the NEOHALER device should not be used for administering other medications. The contents of ARCAPTA capsules are for oral inhalation only and must not be swallowed.
- ARCAPTA capsules should always be stored in sealed blisters. Only one ARCAPTA capsule should be removed immediately before use, or its effectiveness may be reduced. Additional ARCAPTA capsules that are exposed to air (i.e. not intended for immediate use) should be discarded.
- ARCAPTA NEOHALER is not meant to relieve acute symptoms or exacerbations of COPD and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist such as albuterol. (The healthcare provider should provide the patient with such medication and instruct the patient in how it should be used.)
- Patients should be instructed to notify their physician immediately if they experience any of the following:
- Worsening of symptoms
- Decreasing effectiveness of inhaled, short-acting beta2-agonists
Need for more inhalations than usual of inhaled, short-acting beta2-agonists
Significant decrease in lung function as outlined by the physician.
Patients should not stop therapy with ARCAPTA NEOHALER without physician/provider guidance since symptoms may recur after discontinuation.
- Patients who have been taking inhaled, short-acting beta2-agonists on a regular basis should be instructed to discontinue the regular use of these products and use them only for the symptomatic relief of acute symptoms.
- When patients are prescribed ARCAPTA NEOHALER, other inhaled medications containing long-acting beta2-agonists should not be used. Patients should not use more than the recommended once daily dose of ARCAPTA NEOHALER. Excessive use of sympathomimetics may cause significant cardiovascular effects, and may be fatal.
- Patients should be informed of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.
# Precautions with Alcohol
- Alcohol-Indacaterol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ARCAPTA NEOHALER®
# Look-Alike Drug Names
There is limited information regarding Indacaterol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Indacaterol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
# Disclaimer
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# Black Box Warning
# Overview
Indacaterol is an adrenergic that is FDA approved for the treatment of Maintenance Treatment of COPD. There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, cough, nasopharynx.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- ARCAPTA NEOHALER is a long-acting beta2-agonist indicated for long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.
- ARCAPTA NEOHALER is not indicated to treat acute deteriorations of chronic obstructive pulmonary disease.
- ARCAPTA NEOHALER is not indicated to treat asthma. The safety and effectiveness of ARCAPTA NEOHALER in asthma have not been established.
- DO NOT SWALLOW ARCAPTA CAPSULES
- FOR USE WITH NEOHALER DEVICE ONLY
- FOR ORAL INHALATION ONLY
- ARCAPTA capsules must not be swallowed as the intended effects on the lungs will not be obtained. The contents of ARCAPTA capsules are only for oral inhalation and should only be used with the NEOHALER device.
- The recommended dosage of ARCAPTA NEOHALER is the once-daily inhalation of the contents of one 75 mcg ARCAPTA capsule using the NEOHALER inhaler.
- ARCAPTA NEOHALER should be administered once daily every day at the same time of the day by the orally inhaled route only. If a dose is missed, the next dose should be taken as soon as it is remembered. Do not use ARCAPTA NEOHALER more than one time every 24 hours.
- ARCAPTA capsules must always be stored in the blister, and only removed IMMEDIATELY BEFORE USE.
- No dosage adjustment is required for geriatric patients, patients with mild and moderate hepatic impairment, or renally impaired patients. No data are available for subjects with severe hepatic impairment.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Indacaterol in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Indacaterol in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Indacaterol in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Indacaterol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Indacaterol in pediatric patients.
# Contraindications
- ll LABA are contraindicated in patients with asthma without use of a long-term asthma control medication. ARCAPTA NEOHALER is not indicated for the treatment of asthma.
- ARCAPTA NEOHALER is contraindicated in patients with a history of hypersensitivity to indacaterol or to any of the ingredients.
# Warnings
- Data from a large placebo-controlled study in asthma patients showed that long-acting beta2-adrenergic agonists may increase the risk of asthma-related death. Data are not available to determine whether the rate of death in patients with COPD is increased by long-acting beta2-adrenergic agonists.
- A 28-week, placebo-controlled US study comparing the safety of another long-acting beta2-adrenergic agonist (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol (13/13,176 in patients treated with salmeterol vs.
- 3/13,179 in patients treated with placebo; RR 4.37, 95% CI 1.25, 15.34). The increased risk of asthma-related death is considered a class effect of the long-acting beta2-adrenergic agonists, including ARCAPTA NEOHALER. No study adequate to determine whether the rate of asthma-related death is increased in patients treated with ARCAPTA NEOHALER has been conducted. The safety and efficacy of ARCAPTA NEOHALER in patients with asthma have not been established. ARCAPTA NEOHALER is not indicated for the treatment of asthma.
- Serious asthma-related events, including death, were reported in clinical studies with ARCAPTA NEOHALER. The sizes of these studies were not adequate to precisely quantify the differences in serious asthma exacerbation rates between treatment groups.
- ARCAPTA NEOHALER should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition. ARCAPTA NEOHALER has not been studied in patients with acutely deteriorating COPD. The use of ARCAPTA NEOHALER in this setting is inappropriate.
- ARCAPTA NEOHALER should not be used for the relief of acute symptoms, i.e. as rescue therapy for the treatment of acute episodes of bronchospasm. ARCAPTA NEOHALER has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled short-acting beta2-agonist.
- When beginning ARCAPTA NEOHALER, patients who have been taking inhaled, short-acting beta2-agonists on a regular basis (e.g., four times a day) should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief of acute respiratory symptoms. When prescribing ARCAPTA NEOHALER, the healthcare provider should also prescribe an inhaled, short-acting beta2- agonist and instruct the patient on how it should be used. Increasing inhaled beta2-agonist use is a signal of deteriorating disease for which prompt medical attention is indicated.
- COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If ARCAPTA NEOHALER no longer controls the symptoms of bronchoconstriction, or the patient’s inhaled, short-acting beta2-agonist becomes less effective or the patient needs more inhalation of short-acting beta2-agonist than usual, these may be markers of deterioration of disease.
- In this setting, a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dosage of ARCAPTA NEOHALER beyond the recommended dose is not appropriate in this situation.
- As with other inhaled beta2-adrenergic drugs, ARCAPTA NEOHALER should not be used more often, at higher doses than recommended, or in conjunction with other medications containing long-acting beta2-agonists, as an overdose may result.
- Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.
- Immediate hypersensitivity reactions may occur after administration of ARCAPTA NEOHALER. If signs suggesting allergic reactions (in particular, difficulties in breathing or swallowing, swelling of tongue, lips and face, urticaria, skin rash) occur, ARCAPTA NEOHALER should be discontinued immediately and alternative therapy instituted.
- As with other inhaled beta2-agonists, ARCAPTA NEOHALER may produce paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs, ARCAPTA NEOHALER should be discontinued immediately and alternative therapy instituted.
- ARCAPTA NEOHALER, like other beta2-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, or symptoms. If such effects occur, ARCAPTA NEOHALER may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance of these findings is unknown. Therefore, ARCAPTA NEOHALER, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.
- ARCAPTA NEOHALER, like other sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis, and in patients who are unusually responsive to sympathomimetic amines. Doses of the related beta2-agonist albuterol, when administered intravenously, have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis.
- Beta2-agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. Inhalation of high doses of beta2-adrenergic agonists may produce increases in plasma glucose.
- Clinically notable decreases in serum potassium or changes in blood glucose were infrequent during clinical studies with long-term administration of ARCAPTA NEOHALER with the rates similar to those for placebo controls. ARCAPTA NEOHALER has not been investigated in patients whose diabetes mellitus is not well controlled.
# Adverse Reactions
## Clinical Trials Experience
- Long-acting beta2-adrenergic agonists, such as ARCAPTA NEOHALER, increase the risk of asthma-related death. ARCAPTA NEOHALER is not indicated for the treatment of asthma.
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The ARCAPTA NEOHALER safety database reflects exposure of 2516 patients to ARCAPTA NEOHALER at doses of 75 mcg or greater for at least 12 weeks in six confirmatory randomized, double-blind, placebo and active-controlled clinical trials. In these trials, 449 patients were exposed to the recommended dose of 75 mcg for up to 3 months, and 144, 583 and 425 COPD patients were exposed to a dose of 150, 300 or 600 mcg for one year, respectively. Overall, patients had a mean pre-bronchodilator forced expiratory volume in one second (FEV1) percent predicted of 54%. The mean age of patients was 64 years, with 47% of patients aged 65 years or older, and the majority (88%) was Caucasian.
- In these six clinical trials, 48% of patients treated with any dose of ARCAPTA NEOHALER reported an adverse reaction compared with 43% of patients treated with placebo. The proportion of patients who discontinued treatment due to adverse reaction was 5% for ARCAPTA NEOHALER-treated patients and 5% for placebo-treated patients. The most common adverse reactions that lead to discontinuation of ARCAPTA NEOHALER were COPD and dyspnea.
- The most common serious adverse reactions were COPD exacerbation, pneumonia, angina pectoris, and atrial fibrillation, which occurred at similar rates across treatment groups.
- Table 1 displays adverse drug reactions reported by at least 2% of patients (and higher than placebo) during a 3 month exposure at the recommended 75 mcg once daily dose. Adverse drug reactions are listed according to MedDRA (version 13.0) system organ class and sorted in descending order of frequency.
- In these trials the overall frequency of all cardiovascular adverse reactions was 2.5% for ARCAPTA NEOHALER 75 mcg and 1.6% for placebo during a 3 month exposure. There were no frequently occurring specific cardiovascular adverse reactions for ARCAPTA NEOHALER 75 mcg (frequency at least 1% and greater than placebo).
- Additional adverse drug reactions reported in greater than 2% (and higher than on placebo) in patients dosed with 150, 300 or 600 mcg for up to 12 months were as follows:
- Musculoskeletal and connective tissue disorders
- Muscle spasm, musculoskeletal pain
- General disorders and administration site conditions
- Edema peripheral
- Metabolism and nutrition disorder
- Diabetes mellitus, hyperglycemia
- Infections and infestations
- Sinusitis, upper respiratory tract infection
- Cough experienced post-inhalation
- In the clinical trials, health care providers observed during clinic visits that an average of 24% of patients experienced a cough on at least 20% of visits following inhalation of the recommended 75 mcg dose of ARCAPTA NEOHALER compared to 7% of patients receiving placebo. The cough usually occurred within 15 seconds following inhalation and lasted for no more than 15 seconds. Cough following inhalation in clinical trials was not associated with bronchospasm, exacerbations, deteriorations of disease or loss of efficacy.
- In a 6-month randomized, active controlled asthma safety trial, 805 adult patients with moderate to severe persistent asthma were treated with ARCAPTA NEOHALER 300 mcg (n=268), ARCAPTA NEOHALER 600 mcg (n=268), and salmeterol (n=269), all concomitant with inhaled corticosteroids, which were not co-randomized. Of these patients, there were 2 respiratory-related deaths in the ARCAPTA NEOHALER 300 mcg dose group. There were no deaths in the ARCAPTA NEOHALER 600 mcg dose group or in the salmeterol active control group. Serious adverse reactions related to asthma exacerbation were reported for 2 patients in the indacaterol 300 mcg group, 3 patients in the indacaterol 600 mcg group, and no patients in the salmeterol active control group.
- In addition, a two-week dose-ranging trial was conducted in 511 adult patients with mild persistent asthma taking inhaled corticosteroids. No deaths, intubations, or serious adverse reactions related to asthma exacerbation were reported in this trial.
## Postmarketing Experience
- The following adverse reactions have been identified during worldwide post-approval use of indacaterol, the active ingredient in ARCAPTA NEOHALER. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- These adverse reactions are: hypersensitivity reactions, paradoxical bronchospasm, tachycardia/heart rate increase/palpitations, pruritus/rash and dizziness.
# Drug Interactions
- If additional adrenergic drugs are to be administered by any route, they should be used with caution because the sympathetic effects of ARCAPTA NEOHALER may be potentiated.
- Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate any hypokalemic effect of ARCAPTA NEOHALER.
- The ECG changes or hypokalemia that may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical relevance of these effects is not known, caution is advised in the co-administration of ARCAPTA NEOHALER with non-potassium-sparing diuretics.
- Indacaterol, as with other beta2-agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or other drugs known to prolong the QTc interval because the action of adrenergic agonists on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval may have an increased risk of ventricular arrhythmias.
- Beta-adrenergic receptor antagonists (beta-blockers) and ARCAPTA NEOHALER may interfere with the effect of each other when administered concurrently. Beta-blockers not only block the therapeutic effects of beta-agonists, but may produce severe bronchospasm in COPD patients. Therefore, patients with COPD should not normally be treated with beta-blockers. However, under certain circumstances, e.g. as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-blockers in patients with COPD. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.
- Drug interaction studies were carried out using potent and specific inhibitors of CYP3A4 and P-gp (i.e., ketoconazole, erythromycin, verapamil and ritonavir). The data suggest that systemic clearance is influenced by modulation of both P-gp and CYP3A4 activities and that the 1.9-fold AUC0-24 increase caused by the strong dual inhibitor ketoconazole reflects the impact of maximal combined inhibition. ARCAPTA NEOHALER was evaluated in clinical trials for up to one year at doses up to 600 mcg. No dose adjustment is warranted at the 75 mcg dose.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies with ARCAPTA NEOHALER in pregnant women. ARCAPTA NEOHALER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Indacaterol was not teratogenic following subcutaneous administration to rats and rabbits at doses up to 1 mg/kg, approximately 130 and 260 times, respectively, the 75 mcg dose on a mg/m2 basis.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Indacaterol in women who are pregnant.
### Labor and Delivery
- There are no adequate and well-controlled human studies that have investigated effects of ARCAPTA NEOHALER on preterm labor or labor at term. Because of the potential for beta-agonist interference with uterine contractility, use of ARCAPTA NEOHALER during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.
### Nursing Mothers
- It is not known that the active component of ARCAPTA NEOHALER, indacaterol, is excreted in human milk. Because many drugs are excreted in human milk and because indacaterol has been detected in the milk of lactating rats, caution should be exercised when ARCAPTA NEOHALER is administered to nursing women.
### Pediatric Use
- ARCAPTA NEOHALER is not indicated for use in children. The safety and effectiveness of ARCAPTA NEOHALER in pediatric patients have not been established.
### Geriatic Use
- Based on available data, no adjustment of ARCAPTA NEOHALER dosage in geriatric patients is warranted. Of the total number of patients who received ARCAPTA NEOHALER at the recommended dose of 75 mcg once daily in the clinical studies from the pooled 3-month database, 239 were <65 years, 153 were 65–74 years and 57 were ≥75 years of age.
- No overall differences in effectiveness were observed, and in the 3-month pooled data, the adverse drug reaction profile was similar in the older population compared to the patient population overall. When treated at higher doses (300 mcg and 600 mcg) over the course of a year, the adverse drug reaction profiles for patients >65 years was similar to that of the general patient population.
### Gender
There is no FDA guidance on the use of Indacaterol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Indacaterol with respect to specific racial populations.
### Renal Impairment
- Patients with mild and moderate hepatic impairment showed no relevant changes in Cmax or AUC, nor did protein binding differ between mild and moderate hepatically impaired subjects and their healthy controls. Studies in subjects with severe hepatic impairment were not performed.
### Hepatic Impairment
Due to the very low contribution of the urinary pathway to total body elimination, a study in renally impaired subjects was not performed.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Indacaterol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Indacaterol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Inhaler
### Monitoring
- Cardiac monitoring is recommended in cases of overdosage.
# IV Compatibility
There is limited information regarding IV Compatibility of Indacaterol in the drug label.
# Overdosage
- In COPD patients single doses of 40 times the 75 mcg dose were associated with moderate increases in pulse rate, systolic blood pressure and QTc interval.
- The expected signs and symptoms associated with overdosage of ARCAPTA NEOHALER are those of excessive beta-adrenergic stimulation and occurrence or exaggeration of any of the signs and symptoms, e.g., angina, hypertension or hypotension, tachycardia, with rates up to 200 bpm, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, muscle cramps, nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, metabolic acidosis and insomnia. As with all inhaled sympathomimetic medications, cardiac arrest and even death may be associated with an overdose of ARCAPTA NEOHALER.
- Treatment of overdosage consists of discontinuation of ARCAPTA NEOHALER together with institution of appropriate symptomatic and supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm.
- There is insufficient evidence to determine if dialysis is beneficial for overdosage of ARCAPTA NEOHALER. Cardiac monitoring is recommended in cases of overdosage.
# Pharmacology
## Mechanism of Action
- Indacaterol is a long-acting beta2-adrenergic agonist.
- When inhaled, indacaterol acts locally in the lung as a bronchodilator. Although beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, there are also beta2-adrenergic receptors in the human heart comprising 10%-50% of the total adrenergic receptors. The precise function of these receptors is not known, but their presence raises the possibility that even highly selective beta2-adrenergic agonists may have cardiac effects.
- The pharmacological effects of beta2-adrenoceptor agonist drugs, including indacaterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3’, 5’-adenosine monophosphate (cyclic monophosphate). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle. In vitro studies have shown that indacaterol has more than 24-fold greater agonist activity at beta2-receptors compared to beta1-receptors and 20-fold greater agonist activity compared to beta3-receptors. This selectivity profile is similar to formoterol. The clinical significance of these findings is unknown.
## Structure
- ARCAPTA NEOHALER consists of a dry powder formulation of indacaterol maleate for oral inhalation only with the NEOHALER inhaler. The inhalation powder is packaged in clear gelatin capsules.
- Each clear, hard gelatin capsule contains a dry powder blend of 75 mcg of indacaterol (equivalent to 97 mcg of indacaterol maleate) with approximately 25 mg of lactose monohydrate (which contains trace levels of milk protein) as the carrier.
- The active component of ARCAPTA NEOHALER is indacaterol maleate, a (R) enantiomer. Indacaterol maleate is a selective beta2-adrenergic agonist. Its chemical name is (R)-5-[2-(5,6-Diethylindan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one maleate; its structural formula is
- Indacaterol maleate has a molecular weight of 508.56, and its empirical formula is C24H28N2O3 • C4H4O4. Indacaterol maleate is a white to very slightly grayish or very slightly yellowish powder. Indacaterol maleate is freely soluble in N-methylpyrrolidone and dimethylformamide, slightly soluble in methanol, ethanol, propylene glycol and polyethylene glycol 400, very slightly soluble in water, isopropyl alcohol and practically insoluble in 0.9% sodium chloride in water, ethyl acetate and n-octanol.
- The NEOHALER inhaler is a plastic device used for inhaling ARCAPTA. The amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow rate and inspiratory time. Under standardized in vitro testing at a fixed flow rate of 60 L/min for 2 seconds, the NEOHALER inhaler delivered 57 mcg for the 75 mcg dose strength (equivalent to 73.9 mcg of indacaterol maleate) from the mouthpiece. Peak inspiratory flow rates (PIFR) achievable through the NEOHALER inhaler were evaluated in 26 adult patients with COPD of varying severity. Mean PIFR was 95 L/min (range 52-133 L/min) for adult patients. Approximately ninety-five percent of the population studied generated a PIFR through the device exceeding 60 L/min.
## Pharmacodynamics
- The major adverse effects of inhaled beta2-adrenergic agonists occur as a result of excessive activation of systemic beta-adrenergic receptors. The most common adverse effects in adults include skeletal muscle tremor and cramps, insomnia, tachycardia, decreases in serum potassium and increases in plasma glucose.
- Changes in serum potassium and plasma glucose were evaluated in COPD patients in double-blind Phase III studies. In pooled data, at the recommended 75 mcg dose, at 1 hour post-dose at week 12, there was no change compared to placebo in serum potassium, and change in mean plasma glucose was 0.07 mmol/L.
- The effect of ARCAPTA NEOHALER on the QT interval was evaluated in a double-blind, placebo- and active (moxifloxacin)-controlled study following multiple doses of indacaterol 150 mcg, 300 mcg or 600 mcg once-daily for 2 weeks in 404 healthy volunteers. Fridericia’s method for heart rate correction was employed to derive the corrected QT interval (QTcF). Maximum mean prolongation of QTcF intervals were <5 ms, and the upper limit of the 90% confidence interval was below 10 ms for all time-matched comparisons versus placebo. During these studies, there were no clinically meaningful QT-interval prolongations. There was no evidence of a clinically relevant concentration-delta QTc relationship in the range of doses evaluated.
- The effect of 150 mcg and 300 mcg once daily of ARCAPTA NEOHALER on heart rate and rhythm was assessed using continuous 24-hour ECG recording (Holter monitoring) in a subset of 605 patients with COPD from a 26-week, double-blind, placebo-controlled Phase III study. Holter monitoring occurred once at baseline and up to 3 times during the 26-week treatment period (at weeks 2, 12 and 26). A comparison of the mean heart rate over 24 hours showed no increase from baseline. The hourly heart rate analysis was similar compared to placebo. The pattern of diurnal variation over 24 hours was maintained and was similar to placebo. No difference from placebo was seen in the rates of atrial fibrillation, time spent in atrial fibrillation and also the maximum ventricular rate of atrial fibrillation. No clear patterns in the rates of single ectopic beats, couplets or runs were seen across visits. Because the summary data on rates of ventricular ectopic beats can be difficult to interpret, specific pro-arrhythmic criteria were analyzed. In this analysis, baseline occurrence of ventricular ectopic beats was compared to change from baseline, setting certain parameters for the change to describe the pro-arrhythmic response. The number of patients with a documented pro-arrhythmic response was very similar compared to placebo.
- Overall, there was no clinically relevant difference in the development of arrhythmic events in patients receiving indacaterol treatment over those patients who received placebo.
- Tolerance to the effects of inhaled beta-agonists can occur with regularly-scheduled, chronic use. In two 12-week clinical efficacy trials in 323 and 318 adult patients with COPD, ARCAPTA NEOHALER improvement in lung function (as measured by the forced expiratory volume in one second, FEV1) observed at Week 4 with ARCAPTA NEOHALER was consistently maintained over the 12-week treatment period in both trials.
## Pharmacokinetics
- The median time to reach peak serum concentrations of indacaterol was approximately 15 minutes after single or repeated inhaled doses. Systemic exposure to indacaterol increased with increasing dose (150 mcg to 600 mcg) in a dose proportional manner, and was about dose-proportional in the dose range of 75 mcg to 150 mcg. Absolute bioavailability of indacaterol after an inhaled dose was on average 43-45%. Systemic exposure results from a composite of pulmonary and intestinal absorption.
- Indacaterol serum concentrations increased with repeated once-daily administration. Steady-state was achieved within 12 to 15 days. The mean accumulation ratio of indacaterol, i.e. AUC over the 24-hour dosing interval on day 14 or day 15 compared to day 1, was in the range of 2.9 to 3.8 for once-daily inhaled doses between 75 mcg and 600 mcg.
- After intravenous infusion the volume of distribution (Vz) of indacaterol was 2,361 L to 2,557 L indicating an extensive distribution. The in vitro human serum and plasma protein binding was 94.1-95.3% and 95.1-96.2%, respectively.
- After oral administration of radiolabeled indacaterol in the human ADME (absorption, distribution, metabolism, excretion) study unchanged indacaterol was the main component in serum, accounting for about one third of total drug-related AUC over 24 hours. A hydroxylated derivative was the most prominent metabolite in serum. Phenolic O-glucuronides of indacaterol and hydroxylated indacaterol were further prominent metabolites. A diastereomer of the hydroxylated derivative, a N-glucuronide of indacaterol, and C- and N-dealkylated products were further metabolites identified.
- In vitro investigations indicated that UGT1A1 was the only UGT isoform that metabolized indacaterol to the phenolic O-glucuronide. The oxidative metabolites were found in incubations with recombinant CYP1A1, CYP2D6, and CYP3A4. CYP3A4 is concluded to be the predominant isoenzyme responsible for hydroxylation of indacaterol.
- In vitro investigations indicated that indacaterol is a low affinity substrate for the efflux pump P-gp.
- In vitro investigations indicated that indacaterol has negligible potential to cause metabolic interactions with medications (by inhibition or induction of cytochrome P450 enzymes, or induction of UGT1A1) at the systemic exposure levels achieved in clinical practice. In vitro investigation furthermore indicated that, in vivo, indacaterol is unlikely to significantly inhibit transporter proteins such as P-gp, MRP2, BCRP, the cationic substrate transporters hOCT1 and hOCT2, and the human multidrug and toxin extrusion transporters hMATE1 and hMATE2K, and that indacaterol has negligible potential to induce P-gp or MRP2.
- In clinical studies which included urine collection the amount of indacaterol excreted unchanged via urine was generally lower than 2% of the dose. Renal clearance of indacaterol was, on average, between 0.46 and 1.2 L/h. When compared with the serum clearance of indacaterol of 18.8 L/h to 23.3 L/h, it is evident that renal clearance plays a minor role (about 2 to 6% of systemic clearance) in the elimination of systemically available indacaterol.
- In a human ADME study where indacaterol was given orally, the fecal route of excretion was dominant over the urinary route. Indacaterol was excreted into human feces primarily as unchanged parent drug (54% of the dose) and, to a lesser extent, hydroxylated indacaterol metabolites (23% of the dose). Mass balance was complete with ≥90% of the dose recovered in the excreta.
- Indacaterol serum concentrations declined in a multi-phasic manner with an average terminal half-life ranging from 45.5 to 126 hours. The effective half-life, calculated from the accumulation of indacaterol after repeated dosing with once daily doses between 75 mcg and 600 mcg ranged from 40 to 56 hours which is consistent with the observed time-to-steady state of approximately 12-15 days.
- A population pharmacokinetic analysis was performed for indacaterol utilizing data from 3 controlled clinical trials that included 1,844 patients with COPD aged 40 to 88 years who received treatment with ARCAPTA NEOHALER.
- The population analysis showed that no dose adjustment is warranted based on the effect of age, gender and weight on systemic exposure in COPD patients after inhalation of ARCAPTA NEOHALER. The population pharmacokinetic analysis did not suggest any difference between ethnic subgroups in this population.
- Patients with mild and moderate hepatic impairment showed no relevant changes in Cmax or AUC of indacaterol, nor did protein binding differ between mild and moderate hepatically impaired subjects and their healthy controls. Studies in subjects with severe hepatic impairment were not performed.
- Due to the very low contribution of the urinary pathway to total body elimination, a study in renally impaired subjects was not performed.
- Drug interaction studies were carried out using potent and specific inhibitors of CYP3A4 and P-gp (i.e., ketoconazole, erythromycin, verapamil and ritonavir).
- Verapamil
- Co-administration of indacaterol 300 mcg (single dose) with verapamil (80 mg t.i.d for 4 days) showed 2-fold increase in indacaterol AUC0-24, and 1.5-fold increase in indacaterol Cmax.
- Erythromycin
- Co-administration of indacaterol inhalation powder 300 mcg (single dose) with erythromycin (400 mg q.i.d for 7 days) showed a 1.4-fold increase in indacaterol AUC0-24, and 1.2-fold increase in indacaterol Cmax
- Ketoconazole
- Co-administration of indacaterol inhalation powder 300 mcg (single dose) with ketoconazole (200 mg b.i.d for 7 days) caused a 1.9-fold increase in indacaterol AUC0-24, and 1.3-fold increase in indacaterol Cmax
- Ritonavir
- Co-administration of indacaterol 300 mcg (single dose) with ritonavir (300 mg b.i.d for 7.5 days) resulted in a 1.7-fold increase in indacaterol AUC0-24 whereas indacaterol Cmax was unaffected.
- The pharmacokinetics of indacaterol were prospectively investigated in subjects with the UGT1A1 (TA)7/(TA)7 genotype (low UGT1A1 expression; also referred to as *28) and the (TA)6, (TA)6 genotype. Steady-state AUC and Cmax of indacaterol were 1.2-fold higher in the [(TA)7, (TA)7] genotype, suggesting no relevant effect of UGT1A1 genotype of indacaterol exposure.
## Nonclinical Toxicology
- Long-term studies were conducted in transgenic mice using oral administration and in rats using inhalation administration to evaluate the carcinogenic potential of indacaterol maleate. Indacaterol did not show a statistically significant increase in tumor formation in mice or rats.
- Lifetime treatment of rats resulted in increased incidences of benign ovarian leiomyoma and focal hyperplasia of ovarian smooth muscle in females at doses approximately 270-times the dose of 75 mcg once-daily for humans (on a mg/m2 basis).
- A 26-week oral (gavage) study in CB6F1/TgrasH2 hemizygous mice with indacaterol did not show any evidence of tumorigenicity at doses approximately 39,000-times the dose of 75 mcg once-daily for humans (on a mg/m2 basis).
- Increases in leiomyomas of the female rat genital tract have been similarly demonstrated with other beta2-adrenergic agonist drugs. The relevance of these findings to human use is unknown.
- Indacaterol was not mutagenic or clastogenic in Ames test, chromosome aberration test in V79 Chinese hamster cells, and bone marrow micronucleus test in rats.
- Indacaterol did not impair fertility of rats in reproduction studies.
# Clinical Studies
- The ARCAPTA NEOHALER COPD clinical development program included three dose-ranging trials and six confirmatory trials (Trial 3, a 26-week seamless adaptive design trial that included an initial 2 week dose ranging phase; Trials 4, 5, and 6, 12-week trials; Trial 7, a 26-week trial; and Trial 8, a 52 week trial).
- Dose selection for ARCAPTA NEOHALER for COPD was based on three dose-ranging trials (Trial 1, a 2-week dose- ranging trial in an asthma population; Trial 2, a 2-week dose-ranging trial in a COPD population; and Trial 3, a 26-week adaptive seamless design trial that included an initial 2-week dose ranging phase). Although ARCAPTA NEOHALER is not indicated for asthma, dose selection was primarily based upon the results from the dose-ranging trial in asthma patients (Trial 1) as an asthma population is the most responsive to beta-agonist bronchodilation and is most likely to demonstrate a dose response. Dose-ranging in COPD patients (Trials 2 and 3) provided supportive information.
- ARCAPTA NEOHALER is not indicated for asthma.
- Trial 1 was a 2-week, randomized, double-blinded, placebo-controlled design that enrolled 511 patients with persistent asthma 18 years of age and older. * All enrolled patients were required to be taking inhaled corticosteroids, had a forced expiratory volume in one second (FEV1) of ≥ 50% and ≤ 90% predicted, and FEV1 reversibility after albuterol of at least 12% and at least 200 mL. Trial 1 included ARCAPTA NEOHALER doses of 18.75, 37.5, 75, and 150 mcg once daily, a salmeterol active control group, and placebo. The trial showed that the effect on FEV1 in patients treated with ARCAPTA NEOHALER 18.75 and 37.5 mcg doses was lower compared to patients treated with other ARCAPTA NEOHALER doses, particularly after the first dose. The effect did not clearly differ between the 75 and 150 mcg doses.
- Results of the ARCAPTA NEOHALER and placebo treatment arms are as follows. After the first dose (Day 1), the peak (4 hour) FEV1 was 2.58L in the placebo group, with a treatment difference of 0.04L (95% CI -0.01, 0.09) in the 18.75 mcg ARCAPTA NEOHALER group, 0.04L (-0.01, 0.09) in the 37.5 mcg group, 0.12L (0.07, 0.17) in the 75 mcg group, and 0.15L (0.10, 0.20) in the 150 mcg group. The Day 2 trough FEV1 was 2.45L in the placebo group, with a treatment difference of 0.02L (95% CI -0.05, 0.08), 0.08L (0.01, 0.15), 0.09L (0.03, 0.16) and 0.16L (0.09, 0.22) in the ARCAPTA NEOHALER groups, respectively. At Day 14, the peak (4 hour) FEV1 was 2.55L in the placebo group, with a treatment difference of 0.12L (95% CI 0.05, 0.20) in the 18.75 mcg ARCAPTA NEOHALER group, 0.14L (0.06, 0.21) in the 37.5 mcg group, 0.23L (0.15, 0.30) in the 75 mcg group, and 0.20L (0.13, 0.27) in the 150 mcg group. The Day 15 FEV1 (primary endpoint) was 2.42L in the placebo group, with a treatment difference of 0.09L (95% CI 0.00, 0.17), 0.11L (0.02, 0.19), 0.17L (0.08, 0.26), and 0.12L (0.04, 0.21) in the ARCAPTA NEOHALER groups, respectively.
- Trial 2 was a 2-week, randomized, double-blinded, placebo-controlled design that enrolled 552 patients with a clinical diagnosis of COPD, who were 40 years or older, had a smoking history of at least 10 pack years, had a post-bronchodilator FEV1 less than 80% and at least 30% of the predicated normal value and a post-bronchodilator ratio of FEV1 over forced vital capacity (FEV1/FVC) of less than 70%. Trial 2 included ARCAPTA NEOHALER doses of 18.75, 37.5, 75 and 150 mcg once daily, a salmeterol active control group, and placebo. Results of the ARCAPTA NEOHALER and placebo arms are shown in Figure 1. The trial showed that the effect on FEV1 in patients treated with ARCAPTA NEOHALER 18.75 mcg dose was lower compared to patients treated with other ARCAPTA NEOHALER doses. Although a dose-response relationship was observed at Day 1, the effect did not clearly differ among the 37.5, 75 and 150 mcg doses by Day 15.
- The 2-week dose ranging phase of Trial 3 included ARCAPTA NEOHALER doses of 75, 150, 300, and 600 mcg once daily, placebo, and two active comparators. Although a dose-response relationship was observed at week 2, the effect did not clearly differ among the ARCAPTA NEOHALER doses.
- The ARCAPTA NEOHALER COPD development program included six confirmatory trials that were randomized, double-blinded placebo and active-controlled in design (Trial 3, a 26-week seamless adaptive design trial that included an initial 2 week dose-ranging phase; Trials 4, 5, and 6, 12-week trials; Trial 7, a 26-week trial; and Trial 8, a 52 week trial). After the initial 2-week dose-ranging portion of the design, Trial 3 was conducted with ARCAPTA NEOHALER doses of 150 mcg and 300 mcg once daily, placebo, and an active comparator. Trials 4 and 5 were conducted with ARCAPTA NEOHALER dose of 75 mcg once daily, and placebo. Trial 6 was conducted with ARCAPTA NEOHALER dose of 150 mcg once daily and placebo. Trial 7 was conducted with ARCAPTA NEOHALER dose of 150 mcg once daily, an active comparator, and placebo. Trial 8 was conducted with ARCAPTA NEOHALER doses of 300 mcg and 600 mcg once daily, an active comparator, and placebo.
- As Trials 3, 6, 7, and 8 were conducted with doses of ARCAPTA NEOHALER higher than 75 mcg, the results of Trials 4 and 5, which included ARCAPTA NEOHALER 75 mcg are the focus of this section.
- These six trials enrolled 5474 patients with a clinical diagnosis of COPD, who were 40 years or older, had a smoking history of at least 10 pack years, had a post-bronchodilator FEV1 less than 80% and at least 30% of the predicted normal value and a post-bronchodilator ratio of FEV1 over FVC of less than 70%.
- Assessment of efficacy in these six COPD trials was based on FEV1. The primary efficacy endpoint was 24-hour post-dose trough FEV1 (defined as the average of two FEV1 measurements taken after 23 hours 10 minutes and 23 hours and 45 minutes after the previous dose) after 12 weeks of treatment in all 6 trials. Other efficacy variables included other FEV1 and FVC time points, rescue medication use, symptoms, and health-related quality of life measured using the St. George’s Respiratory Questionnaire (SGRQ).
- In all six confirmatory COPD trials, all doses of ARCAPTA NEOHALER tested (75 mcg, 150 mcg, 300 mcg, and 600 mcg) showed significantly greater 24-hour post-dose trough FEV1 compared to placebo at 12 weeks. Results of Trials 4 and 5, which compared ARCAPTA NEOHALER at the dose of 75 mcg once daily to placebo are shown in Table 2.
- In both COPD clinical trials including the 75 mcg dose (Trials 4 and 5), patients treated with ARCAPTA NEOHALER used less daily rescue albuterol during the trial compared to patients treated with placebo.
- Health-related quality of life was measured using the St. George’s Respiratory Questionnaire (SGRQ) in all six confirmatory COPD clinical trials. SGRQ is a disease-specific patient reported instrument which measures symptoms, activities, and its impact on daily life. At week 12, pooled data from these trials demonstrated an improvement over placebo in SGRQ total score of -3.8 with a 95% CI of (-5.3, -2.3) for the ARCAPTA NEOHALER 75 mcg dose, -4.6 with a 95% CI of (-5.5, -3.6) for 150 mcg, and -3.8 with a 95% CI of (-4.9, -2.8) for 300 mcg. The confidence intervals for this change are widely overlapping with no dose ordering. Results from individual studies were variable, but are generally consistent with the pooled data results.
# How Supplied
- 75 mcg ARCAPTA NEOHALER contains ARCAPTA (indacaterol inhalation powder) capsules packaged in aluminum blister cards, one NEOHALER inhaler, and an FDA approved Medication Guide.
- Unit Dose (blister pack), Box of 30 (5 blister cards with 6 capsules each) NDC 0078-0619-15
- The NEOHALER inhaler consists of a white protective cap and a base with mouthpiece, capsule chamber and two translucent red push buttons.
## Storage
- Store in a dry place at 25°C (77°F); excursions permitted to 15-30°C (59-86° F).
- 75 mcg: Protect capsule from light and moisture.
- ARCAPTA capsules should be used with the NEOHALER inhaler only. The NEOHALER inhaler should not be used with any other capsules.
- Capsules should always be stored in the blister and only removed from the blister immediately before use.
- Always use the new NEOHALER inhaler provided with each new prescription.
Keep out of the reach of children.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be informed that LABA, such as ARCAPTA NEOHALER, increase the risk of asthma-related death. ARCAPTA NEOHALER is not indicated for the treatment of asthma.
- It is important for patients to understand how to correctly administer ARCAPTA capsules using the NEOHALER device. Patients should be instructed that ARCAPTA capsules should only be administered via the NEOHALER device and the NEOHALER device should not be used for administering other medications. The contents of ARCAPTA capsules are for oral inhalation only and must not be swallowed.
- ARCAPTA capsules should always be stored in sealed blisters. Only one ARCAPTA capsule should be removed immediately before use, or its effectiveness may be reduced. Additional ARCAPTA capsules that are exposed to air (i.e. not intended for immediate use) should be discarded.
- ARCAPTA NEOHALER is not meant to relieve acute symptoms or exacerbations of COPD and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist such as albuterol. (The healthcare provider should provide the patient with such medication and instruct the patient in how it should be used.)
- Patients should be instructed to notify their physician immediately if they experience any of the following:
- Worsening of symptoms
- Decreasing effectiveness of inhaled, short-acting beta2-agonists
Need for more inhalations than usual of inhaled, short-acting beta2-agonists
Significant decrease in lung function as outlined by the physician.
Patients should not stop therapy with ARCAPTA NEOHALER without physician/provider guidance since symptoms may recur after discontinuation.
- Patients who have been taking inhaled, short-acting beta2-agonists on a regular basis should be instructed to discontinue the regular use of these products and use them only for the symptomatic relief of acute symptoms.
- When patients are prescribed ARCAPTA NEOHALER, other inhaled medications containing long-acting beta2-agonists should not be used. Patients should not use more than the recommended once daily dose of ARCAPTA NEOHALER. Excessive use of sympathomimetics may cause significant cardiovascular effects, and may be fatal.
- Patients should be informed of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.
# Precautions with Alcohol
- Alcohol-Indacaterol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ARCAPTA NEOHALER®[1]
# Look-Alike Drug Names
There is limited information regarding Indacaterol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Indacaterol | |
989db6429d5e286fc6cdd2c791475f7e1878b9e4 | wikidoc | Indolamines | Indolamines
Indolamines are a family of neurotransmitters that share a common molecular structure (namely, indolamine). A common example of an indolamine is serotonin, which is a neurotransmitter involved in mood and sleep. Another example of an indolamine is melatonin, which regulates the sleep-wake cycle (circadian rhythm) in humans.
In biochemistry, indoleamines are substituted indole compounds that contain an amino group. Examples of indoleamines are the tryptamines, such as 5-hydroxytryptamine (serotonin, 5-HT) and the lysergamides.
Also, histamines are a part of the indolamine family. Histamines are synthesized by the amino acid histidine.
# Synthesis
In humans, neurotransmitters in the indolamine family are believed to be produced in the pineal gland. Indolamines are biologically synthesized from the essential amino acid tryptophan. | Indolamines
Template:Unreferenced stub
Indolamines are a family of neurotransmitters that share a common molecular structure (namely, indolamine). A common example of an indolamine is serotonin, which is a neurotransmitter involved in mood and sleep. Another example of an indolamine is melatonin, which regulates the sleep-wake cycle (circadian rhythm) in humans.
In biochemistry, indoleamines are substituted indole compounds that contain an amino group. Examples of indoleamines are the tryptamines, such as 5-hydroxytryptamine (serotonin, 5-HT) and the lysergamides.
Also, histamines are a part of the indolamine family. Histamines are synthesized by the amino acid histidine.[citation needed]
# Synthesis
In humans, neurotransmitters in the indolamine family are believed to be produced in the pineal gland.[citation needed] Indolamines are biologically synthesized from the essential amino acid tryptophan. | https://www.wikidoc.org/index.php/Indolamines | |
dd28cf6013482ff0a67623162c031e6f3c1ad205 | wikidoc | Indospicine | Indospicine
# Overview
L-Indospicin is a toxic , non- proteinogenic amino acid from the legume Indigofera endecaphylla . There it comes in amounts of up to 0.15% in the herb and up to 2.0% in the seeds before.
This plant is used as a forage crop in tropical areas. The offspring of pregnant animals, which eat the plant suffered a embryopathisches syndrome characterized by cleft palate , dwarfism , and acute liver damage is characterized. Furthermore, even were liver cirrhosis was observed. In humans, but so far no known poisonings.
The toxic effects (eg it is made responsible for certain equine diseases) based on the action as L - arginine - an antimetabolite and a consequent impairment of protein biosynthesis. It also inhibits the constitutive and inducible NO synthase and is teratogenic .
L-Indospicin also occurs in other species such as Indigofera Indigofera mucronata and is suspected in several others. Because in addition to these poisons Indospicin the canavanine and Hiptagensäure are, there is some conflicting evidence in the literature about the nature and severity of the toxicity of the plant. | Indospicine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
L-Indospicin [synonym: (S)-Indospicin] is a toxic , non- proteinogenic amino acid from the legume Indigofera endecaphylla . There it comes in amounts of up to 0.15% in the herb and up to 2.0% in the seeds before.
This plant is used as a forage crop in tropical areas. The offspring of pregnant animals, which eat the plant suffered a embryopathisches syndrome characterized by cleft palate , dwarfism , and acute liver damage is characterized. Furthermore, even were liver cirrhosis was observed. In humans, but so far no known poisonings.
The toxic effects (eg it is made responsible for certain equine diseases) based on the action as L - arginine - an antimetabolite and a consequent impairment of protein biosynthesis. It also inhibits the constitutive and inducible NO synthase and is teratogenic .
L-Indospicin also occurs in other species such as Indigofera Indigofera mucronata and is suspected in several others. Because in addition to these poisons Indospicin the canavanine and Hiptagensäure are, there is some conflicting evidence in the literature about the nature and severity of the toxicity of the plant. | https://www.wikidoc.org/index.php/Indospicine | |
b0799b20621baf5f4ca3a8deada483de61a70ac8 | wikidoc | Pseudomonas | Pseudomonas
# Overview
Pseudomonas is a genus of gamma proteobacteria, belonging to the larger family of pseudomonads.
Recently, 16S rRNA sequence analysis has redefined the taxonomy of many bacterial species. As a result the genus Pseudomonas includes strains formerly classifed in the genera Chryseomonas and Flavimonas. Other strains previously classified in the genus Pseudomonas are now classified in the genera Burkholderia and Ralstonia.
# History
Pseudomonad literally means 'false unit', being derived from the Greek pseudo (ψευδο 'false') and monas (μονάς / μονάδα 'a single unit'). The term "monad" was used in the early history of microbiology to denote single-celled organisms.
Because of their widespread occurrence in nature, the pseudomonads were observed early in the history of microbiology. The generic name Pseudomonas created for these organisms was defined in rather vague terms in 1894 as a genus of Gram-negative, rod-shaped and polar-flagella bacteria. Soon afterwards, a very large number of species was assigned to the genus. Pseudomonads were isolated from many natural niches and a large number of species names was originally assigned to the genus. New methodology and the inclusion of approaches based on the studies of conservative macromolecules have reclassified many strains.
Pseudomonas aeruginosa is increasingly recognized as an emerging opportunistic pathogen of clinical relevance. Several different epidemiological studies indicate that antibiotic resistance is increasing in clinical isolates.
In the year 2000, the complete genome sequence of a Pseudomonas species was determined; more recently the sequence of other strains have been determined including P. aeruginosa strains PAO1 (2000), P. putida KT2440 (2002), P. fluorescens Pf-5 (2005), P. syringae pathovar tomato DC3000 (2003), P. syringae pathovar syringae B728a (2005), P. syringae pathovar phaseolica 1448A (2005), P. fluorescens PfO-1 and P. entomophila L48.
An article published in the journal Science in 2008 showed that Pseudomanas may be the most common nucleator of ice crystals in clouds, thereby being of utmost importance to the formation of snow and rain around the world.
# Characteristics
Members of the genus display the following defining characteristics:
- Rod shaped
- Gram-negative
- One or more polar flagella, providing motility
- Aerobic, although some species have been found to be facultative anaerobes (e.g. P. aeruginosa)
- Non–spore forming
- Positive catalase test
Other characteristics which tend to be associated with Pseudomonas species (with some exceptions) include secretion of pyoverdin (fluorescein), a fluorescent yellow-green siderophore under iron-limiting conditions. Certain Pseudomonas species may also produce additional types of siderophore, such as pyocyanin by Pseudomonas aeruginosa and thioquinolobactin by Pseudomonas fluorescens,. Pseudomonas species also typically give a positive result to the oxidase test, the absence of gas formation from glucose, glucose is oxidised in oxidation/fermentation test using Hugh and Leifson O/F test, beta hemolytic (on blood agar), indole negative, methyl red negative, Voges Proskauer test negative, citrate positive.
The genus demonstrates a great deal of metabolic diversity, and consequently are able to colonise a wide range of niches. Their ease of culture in vitro and availability of an increasing number of Pseudomonas strain genome sequences has made the genus an excellent focus for scientific research; the best studied species include P. aeruginosa in its role as an opportunistic human pathogen, the plant pathogen P. syringae, the soil bacterium P. putida, and the plant growth promoting P. fluorescens.
# Diagnosis
## Physical Examination
### Skin
- Pseudomonas infection. With permission from Dermatology Atlas.
## Biofilm formation
All species and strains of Pseudomonas are Gram-negative rods, and have historically been classified as strict aerobes. Exceptions to this classification have recently been discovered in Pseudomonas biofilms. A significant number can produce exopolysaccharides that are known as slime layers. Secretion of exopolysaccharide makes it difficult for Pseudomonads to be phagocytosed by mammalian white blood cells. Slime production also contributes to surface-colonising biofilms which are difficult to remove from food preparation surfaces. Growth of Pseudomonads on spoiling foods can generate a "fruity" odor.
Pseudomonas have the ability to metabolise a variety of diverse nutrients. Combined with the ability to form biofilms, they are thus able to survive in a variety of unexpected places. For example, they have been found in areas where pharmaceuticals are prepared. A simple carbon source, such as soap residue or cap liner-adhesives is a suitable place for the Pseudomonads to thrive. Other unlikely places where they have been found include antiseptics such as quaternary ammonium compounds and bottled mineral water.
## Antibiotic resistance
Being Gram-negative bacteria, most Pseudomonas spp. are naturally resistant to penicillin and the majority of related beta-lactam antibiotics, but a number are sensitive to piperacillin, imipenem, tobramycin, or ciprofloxacin.
This ability to thrive in harsh conditions is a result of their hardy cell wall that contains porins. Their resistance to most antibiotics is attributed to efflux pumps called ABC transporters, which pump out some antibiotics before they are able to act.
Pseudomonas aeruginosa is a highly relevant opportunistic pathogen. One of the most worrisome characteristics of P. aeruginosa consists in its low antibiotic susceptibility. This low susceptibility is attributable to a concerted action of multidrug efflux pumps with chromosomally-encoded antibiotic resistance genes and the low permeability of the bacterial cellular envelopes. Besides intrinsic resistance, P. aeruginosa easily develop acquired resistance either by mutation in chromosomally-encoded genes, either by the horizontal gene transfer of antibiotic resistance determinants. Development of multidrug resistance by P. aeruginosa isolates requires several different genetic events that include acquisition of different mutations and/or horizontal transfer of antibiotic resistance genes. Hypermutation favours the selection of mutation-driven antibiotic resistance in P. aeruginosa strains producing chronic infections, whereas the clustering of several different antibiotic resistance genes in integrons favours the concerted acquisition of antibiotic resistance determinants. Some recent studies have shown that phenotypic resistance associated to biofilm formation or to the emergence of small-colony-variants may be important in the response of P. aeruginosa populations to antibiotics treatment.
# Taxonomy
The studies on the taxonomy of this complicated genus groped their way in the dark while following the classical procedures developed for the description and identification of the organisms involved in sanitary bacteriology during the first decades of the twentieth century. This situation sharply changed with the proposal to introduce as the central criterion the similarities in the composition and sequences of macromolecules components of the ribosomal RNA. The new methodology clearly showed that the genus Pseudomonas, as classical defined, consisted in fact of a conglomerate of genera that could clearly be separated into five so-called rRNA homology groups. Moreover, the taxonomic studies suggested an approach that might proved useful in taxonomic studies of all other prokaryotic groups. A few decades after the proposal of the new genus Pseudomonas by Migula in 1894, the accumulation of species names assigned to the genus reached alarming proportions. At the present moment, the number of species in the current list has contracted more than tenfold. In fact, this approximated reduction may be even more dramatic if one considers that the present list contains many new names, i.e., relatively few names of the original list survived in the process. The new methodology and the inclusion of approaches based on the studies of conservative macromolecules other than rRNA components, constitutes an effective prescription that helped to reduce Pseudomonas nomenclatural hypertrophy to a manageable size.
# Pathogenicity
## Animal pathogens
P. aeruginosa is an opportunistic human pathogen, most commonly affecting immunocompromised patients, such as those with cystic fibrosis or AIDS. Infection can affect many different parts of the body, but infections typically target the respiratory tract (e.g. patients with CF or those on mechanical ventillation), causing bacterial pneumonia. Treatment of such infections can be difficult due to multiple antibiotic resistance.
P. oryzihabitans can also be a human pathogen, although infections are rare. It can cause peritonitis, endophthalmitis, septicemia and bacteremia. Similar symptoms although also very rare can be seen by infections of P. luteola.
P. plecoglossicida is a fish pathogenic species, causing hemorrhagic ascites in the ayu (Plecoglossus altivelis). P. anguilliseptica is also a fish pathogen.
Due to their hemolytic activity, even non-pathogenic species of Pseudomonas can occasionally become a problem in clinical settings, where they have been known to infect blood transfusions.
# Use as biocontrol agents
Since the mid 1980s, certain members of the Pseudomonas genus have been applied to cereal seeds or applied directly to soils as a way of preventing the growth or establishment of crop pathogens. This practice is generically referred to as biocontrol. The biocontrol properties of P. fluorescens strains (CHA0 or Pf-5 for example) are currently best understood, although it is not clear exactly how the plant growth promoting properties of P. fluorescens are achieved. Theories include: that the bacteria might induce systemic resistance in the host plant, so it can better resist attack by a true pathogen; the bacteria might out compete other (pathogenic) soil microbes, e.g. by siderophores giving a competitive advantage at scavenging for iron; the bacteria might produce compounds antagonistic to other soil microbes, such as phenazine-type antibiotics or hydrogen cyanide. There is experimental evidence to support all of these theories, in certain conditions; a good review of the topic is written by Haas and Defago.
Other notable Pseudomonas species with biocontrol properties include P. chlororaphis which produces a phenazine type antibiotic active agent against certain fungal plant pathogens, and the closely related species P. aurantiaca which produces di-2,4-diacetylfluoroglucylmethan, a compound antibiotically active against Gram-positive organisms.
# Use as bioremediation agents
Some members of the genus Pseudomonas are able to metabolise chemical pollutants in the environment, and as a result can be used for bioremediation. Notable species demonstrated as suitable for use as bioremediation agents include:
- P. alcaligenes, which can degrade polycyclic aromatic hydrocarbons.
- P. mendocina, which is able to degrade toluene.
- P. pseudoalcaligenes is able to use cyanide as a nitrogen source.
- P. resinovorans can degrade carbazole.
- P. veronii has been shown to degrade a variety of simple aromatic organic compounds.
- P. putida has the ability to degrade organic solvents such as toluene. At least one strain of this bacterium is able to convert morphine in aqueous solution into the stronger and somewhat expensive to manufacture drug hydromorphone (Dilaudid®).
- Strain KC of P. stutzeri is able to degrade carbon tetrachloride.
# Food spoilage agents
As a result of their metabolic diversity, ability to grow at low temperatures and ubiquitous nature, many Pseudomonas can cause food spoilage. Notable examples include dairy spoilage by P. fragi, mustiness in eggs caused by P. taetrolens and P. mudicolens, and P. lundensis, which causes spoilage of milk, cheese, meat, and fish.
# Species previously classified in the genus
Recently, 16S rRNA sequence analysis redefined the taxonomy of many bacterial species previously classified as being in the Pseudomonas genus. Species which moved from the Pseudomonas genus are listed below; clicking on a species will show its new classification. Note that the term 'Pseudomonad' does not apply strictly to just the Pseudomonas genus, and can be used to also include previous members such as the genera Burkholderia and Ralstonia.
α proteobacteria: P. abikonensis, P. aminovorans, P. azotocolligans, P. carboxydohydrogena, P. carboxidovorans, P. compransoris, P. diminuta, P. echinoides, P. extorquens, P. lindneri, P. mesophilica, P. paucimobilis, P. radiora, P. rhodos, P. riboflavina, P. rosea, P. vesicularis.
β proteobacteria: P. acidovorans, P. alliicola, P. antimicrobica, P. avenae, P. butanovorae, P. caryophylli, P. cattleyae, P. cepacia, P. cocovenenans, P. delafieldii, P. facilis, P. flava, P. gladioli, P. glathei, P. glumae, P. graminis, P. huttiensis, P. indigofera, P. lanceolata, P. lemoignei, P. mallei, P. mephitica, P. mixta, P. palleronii, P. phenazinium, P. pickettii, P. plantarii, P. pseudoflava, P. pseudomallei, P. pyrrocinia, P. rubrilineans, P. rubrisubalbicans, P. saccharophila]], P. solanacearum, P. spinosa, P. syzygii, P. taeniospiralis, P. terrigena, P. testosteroni.
γ-β proteobacteria: P. beteli, P. boreopolis, P. cissicola, P. geniculata, P. hibiscicola, P. maltophilia, P. pictorum.
γ proteobacteria: P. beijerinckii, P. diminuta, P. doudoroffii, P. elongata, P. flectens, P. halodurans, P. halophila, P. iners, P. marina, P. nautica, P. nigrifaciens, P. pavonacea, P. piscicida, P. stanieri.
δ proteobacteria: P. formicans | Pseudomonas
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
# Overview
Pseudomonas is a genus of gamma proteobacteria, belonging to the larger family of pseudomonads.
Recently, 16S rRNA sequence analysis has redefined the taxonomy of many bacterial species.[1] As a result the genus Pseudomonas includes strains formerly classifed in the genera Chryseomonas and Flavimonas.[2] Other strains previously classified in the genus Pseudomonas are now classified in the genera Burkholderia and Ralstonia.
# History
Pseudomonad literally means 'false unit', being derived from the Greek pseudo (ψευδο 'false') and monas (μονάς / μονάδα 'a single unit'). The term "monad" was used in the early history of microbiology to denote single-celled organisms.
Because of their widespread occurrence in nature, the pseudomonads were observed early in the history of microbiology. The generic name Pseudomonas created for these organisms was defined in rather vague terms in 1894 as a genus of Gram-negative, rod-shaped and polar-flagella bacteria. Soon afterwards, a very large number of species was assigned to the genus. Pseudomonads were isolated from many natural niches and a large number of species names was originally assigned to the genus. New methodology and the inclusion of approaches based on the studies of conservative macromolecules have reclassified many strains. [3]
Pseudomonas aeruginosa is increasingly recognized as an emerging opportunistic pathogen of clinical relevance. Several different epidemiological studies indicate that antibiotic resistance is increasing in clinical isolates[4].
In the year 2000, the complete genome sequence of a Pseudomonas species was determined; more recently the sequence of other strains have been determined including P. aeruginosa strains PAO1 (2000), P. putida KT2440 (2002), P. fluorescens Pf-5 (2005), P. syringae pathovar tomato DC3000 (2003), P. syringae pathovar syringae B728a (2005), P. syringae pathovar phaseolica 1448A (2005), P. fluorescens PfO-1 and P. entomophila L48.[3]
An article published in the journal Science in 2008 showed that Pseudomanas may be the most common nucleator of ice crystals in clouds, thereby being of utmost importance to the formation of snow and rain around the world.[5]
# Characteristics
Members of the genus display the following defining characteristics:[6]
- Rod shaped
- Gram-negative
- One or more polar flagella, providing motility
- Aerobic, although some species have been found to be facultative anaerobes (e.g. P. aeruginosa)
- Non–spore forming
- Positive catalase test
Other characteristics which tend to be associated with Pseudomonas species (with some exceptions) include secretion of pyoverdin (fluorescein), a fluorescent yellow-green siderophore[7] under iron-limiting conditions. Certain Pseudomonas species may also produce additional types of siderophore, such as pyocyanin by Pseudomonas aeruginosa[8] and thioquinolobactin by Pseudomonas fluorescens,[9]. Pseudomonas species also typically give a positive result to the oxidase test, the absence of gas formation from glucose, glucose is oxidised in oxidation/fermentation test using Hugh and Leifson O/F test, beta hemolytic (on blood agar), indole negative, methyl red negative, Voges Proskauer test negative, citrate positive.
The genus demonstrates a great deal of metabolic diversity, and consequently are able to colonise a wide range of niches[10]. Their ease of culture in vitro and availability of an increasing number of Pseudomonas strain genome sequences has made the genus an excellent focus for scientific research; the best studied species include P. aeruginosa in its role as an opportunistic human pathogen, the plant pathogen P. syringae, the soil bacterium P. putida, and the plant growth promoting P. fluorescens.
# Diagnosis
## Physical Examination
### Skin
- Pseudomonas infection. With permission from Dermatology Atlas.[11]
## Biofilm formation
All species and strains of Pseudomonas are Gram-negative rods, and have historically been classified as strict aerobes. Exceptions to this classification have recently been discovered in Pseudomonas biofilms[12]. A significant number can produce exopolysaccharides that are known as slime layers. Secretion of exopolysaccharide makes it difficult for Pseudomonads to be phagocytosed by mammalian white blood cells.[13] Slime production also contributes to surface-colonising biofilms which are difficult to remove from food preparation surfaces. Growth of Pseudomonads on spoiling foods can generate a "fruity" odor.
Pseudomonas have the ability to metabolise a variety of diverse nutrients. Combined with the ability to form biofilms, they are thus able to survive in a variety of unexpected places. For example, they have been found in areas where pharmaceuticals are prepared. A simple carbon source, such as soap residue or cap liner-adhesives is a suitable place for the Pseudomonads to thrive. Other unlikely places where they have been found include antiseptics such as quaternary ammonium compounds and bottled mineral water.
## Antibiotic resistance
Being Gram-negative bacteria, most Pseudomonas spp. are naturally resistant to penicillin and the majority of related beta-lactam antibiotics, but a number are sensitive to piperacillin, imipenem, tobramycin, or ciprofloxacin.[13]
This ability to thrive in harsh conditions is a result of their hardy cell wall that contains porins. Their resistance to most antibiotics is attributed to efflux pumps called ABC transporters, which pump out some antibiotics before they are able to act.
Pseudomonas aeruginosa is a highly relevant opportunistic pathogen. One of the most worrisome characteristics of P. aeruginosa consists in its low antibiotic susceptibility. This low susceptibility is attributable to a concerted action of multidrug efflux pumps with chromosomally-encoded antibiotic resistance genes and the low permeability of the bacterial cellular envelopes. Besides intrinsic resistance, P. aeruginosa easily develop acquired resistance either by mutation in chromosomally-encoded genes, either by the horizontal gene transfer of antibiotic resistance determinants. Development of multidrug resistance by P. aeruginosa isolates requires several different genetic events that include acquisition of different mutations and/or horizontal transfer of antibiotic resistance genes. Hypermutation favours the selection of mutation-driven antibiotic resistance in P. aeruginosa strains producing chronic infections, whereas the clustering of several different antibiotic resistance genes in integrons favours the concerted acquisition of antibiotic resistance determinants. Some recent studies have shown that phenotypic resistance associated to biofilm formation or to the emergence of small-colony-variants may be important in the response of P. aeruginosa populations to antibiotics treatment.[3]
# Taxonomy
The studies on the taxonomy of this complicated genus groped their way in the dark while following the classical procedures developed for the description and identification of the organisms involved in sanitary bacteriology during the first decades of the twentieth century. This situation sharply changed with the proposal to introduce as the central criterion the similarities in the composition and sequences of macromolecules components of the ribosomal RNA. The new methodology clearly showed that the genus Pseudomonas, as classical defined, consisted in fact of a conglomerate of genera that could clearly be separated into five so-called rRNA homology groups. Moreover, the taxonomic studies suggested an approach that might proved useful in taxonomic studies of all other prokaryotic groups. A few decades after the proposal of the new genus Pseudomonas by Migula in 1894, the accumulation of species names assigned to the genus reached alarming proportions. At the present moment, the number of species in the current list has contracted more than tenfold. In fact, this approximated reduction may be even more dramatic if one considers that the present list contains many new names, i.e., relatively few names of the original list survived in the process. The new methodology and the inclusion of approaches based on the studies of conservative macromolecules other than rRNA components, constitutes an effective prescription that helped to reduce Pseudomonas nomenclatural hypertrophy to a manageable size.[3]
# Pathogenicity
## Animal pathogens
P. aeruginosa is an opportunistic human pathogen, most commonly affecting immunocompromised patients, such as those with cystic fibrosis[14] or AIDS.[15] Infection can affect many different parts of the body, but infections typically target the respiratory tract (e.g. patients with CF or those on mechanical ventillation), causing bacterial pneumonia. Treatment of such infections can be difficult due to multiple antibiotic resistance.[16]
P. oryzihabitans can also be a human pathogen, although infections are rare. It can cause peritonitis,[17] endophthalmitis,[18] septicemia and bacteremia. Similar symptoms although also very rare can be seen by infections of P. luteola.[19]
P. plecoglossicida is a fish pathogenic species, causing hemorrhagic ascites in the ayu (Plecoglossus altivelis).[20] P. anguilliseptica is also a fish pathogen.[21]
Due to their hemolytic activity, even non-pathogenic species of Pseudomonas can occasionally become a problem in clinical settings, where they have been known to infect blood transfusions.[22]
# Use as biocontrol agents
Since the mid 1980s, certain members of the Pseudomonas genus have been applied to cereal seeds or applied directly to soils as a way of preventing the growth or establishment of crop pathogens. This practice is generically referred to as biocontrol. The biocontrol properties of P. fluorescens strains (CHA0 or Pf-5 for example) are currently best understood, although it is not clear exactly how the plant growth promoting properties of P. fluorescens are achieved. Theories include: that the bacteria might induce systemic resistance in the host plant, so it can better resist attack by a true pathogen; the bacteria might out compete other (pathogenic) soil microbes, e.g. by siderophores giving a competitive advantage at scavenging for iron; the bacteria might produce compounds antagonistic to other soil microbes, such as phenazine-type antibiotics or hydrogen cyanide. There is experimental evidence to support all of these theories, in certain conditions; a good review of the topic is written by Haas and Defago[23].
Other notable Pseudomonas species with biocontrol properties include P. chlororaphis which produces a phenazine type antibiotic active agent against certain fungal plant pathogens[24], and the closely related species P. aurantiaca which produces di-2,4-diacetylfluoroglucylmethan, a compound antibiotically active against Gram-positive organisms[25].
# Use as bioremediation agents
Some members of the genus Pseudomonas are able to metabolise chemical pollutants in the environment, and as a result can be used for bioremediation. Notable species demonstrated as suitable for use as bioremediation agents include:
- P. alcaligenes, which can degrade polycyclic aromatic hydrocarbons.[26]
- P. mendocina, which is able to degrade toluene.[27]
- P. pseudoalcaligenes is able to use cyanide as a nitrogen source.[28]
- P. resinovorans can degrade carbazole.[29]
- P. veronii has been shown to degrade a variety of simple aromatic organic compounds.[30][31]
- P. putida has the ability to degrade organic solvents such as toluene.[32] At least one strain of this bacterium is able to convert morphine in aqueous solution into the stronger and somewhat expensive to manufacture drug hydromorphone (Dilaudid®).
- Strain KC of P. stutzeri is able to degrade carbon tetrachloride.[33]
# Food spoilage agents
As a result of their metabolic diversity, ability to grow at low temperatures and ubiquitous nature, many Pseudomonas can cause food spoilage. Notable examples include dairy spoilage by P. fragi,[34] mustiness in eggs caused by P. taetrolens and P. mudicolens,[35] and P. lundensis, which causes spoilage of milk, cheese, meat, and fish.[36]
# Species previously classified in the genus
Recently, 16S rRNA sequence analysis redefined the taxonomy of many bacterial species previously classified as being in the Pseudomonas genus.[1] Species which moved from the Pseudomonas genus are listed below; clicking on a species will show its new classification. Note that the term 'Pseudomonad' does not apply strictly to just the Pseudomonas genus, and can be used to also include previous members such as the genera Burkholderia and Ralstonia.
α proteobacteria: P. abikonensis, P. aminovorans, P. azotocolligans, P. carboxydohydrogena, P. carboxidovorans, P. compransoris, P. diminuta, P. echinoides, P. extorquens, P. lindneri, P. mesophilica, P. paucimobilis, P. radiora, P. rhodos, P. riboflavina, P. rosea, P. vesicularis.
β proteobacteria: P. acidovorans, P. alliicola, P. antimicrobica, P. avenae, P. butanovorae, P. caryophylli, P. cattleyae, P. cepacia, P. cocovenenans, P. delafieldii, P. facilis, P. flava, P. gladioli, P. glathei, P. glumae, P. graminis, P. huttiensis, P. indigofera, P. lanceolata, P. lemoignei, P. mallei, P. mephitica, P. mixta, P. palleronii, P. phenazinium, P. pickettii, P. plantarii, P. pseudoflava, P. pseudomallei, P. pyrrocinia, P. rubrilineans, P. rubrisubalbicans, P. saccharophila]], P. solanacearum, P. spinosa, P. syzygii, P. taeniospiralis, P. terrigena, P. testosteroni.
γ-β proteobacteria: P. beteli, P. boreopolis, P. cissicola, P. geniculata, P. hibiscicola, P. maltophilia, P. pictorum.
γ proteobacteria: P. beijerinckii, P. diminuta, P. doudoroffii, P. elongata, P. flectens, P. halodurans, P. halophila, P. iners, P. marina, P. nautica, P. nigrifaciens, P. pavonacea, P. piscicida, P. stanieri.
δ proteobacteria: P. formicans | https://www.wikidoc.org/index.php/Infections_due_to_Pseudomonas_Species_and_Related_Organisms | |
93c59edbc3fd495752e73c363b8245b3614aa9fa | wikidoc | Inflamation | Inflamation
Inflammation (Latin, inflammatio, to set on fire) is the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue. Inflammation is not a synonym for infection. Even in cases where inflammation is caused by infection it is incorrect to use the terms as synonyms: infection is caused by an exogenous pathogen, while inflammation is the response of the organism to the pathogen.
In the absence of inflammation, wounds and infections would never heal and progressive destruction of the tissue would compromise the survival of the organism. However, inflammation which runs unchecked can also lead to a host of diseases, such as hay fever, atherosclerosis, and rheumatoid arthritis. It is for this reason that inflammation is normally tightly regulated by the body.
Inflammation can be classified as either acute or chronic. Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes from the blood into the injured tissues. A cascade of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells within the injured tissue. Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells which are present at the site of inflammation and is characterised by simultaneous destruction and healing of the tissue from the inflammatory process.
# Causes
- Burns
- Chemical irritants
- Frostbite
- Toxins
- Infection by pathogens
- Necrosis
- Physical injury, blunt or penetrating
- Immune reactions due to hypersensitivity
- Ionizing radiation
- Foreign bodies, including splinters and dirt
# Types
## Acute inflammation
Acute inflammation is a short-term process which is characterized by the classic signs of inflammation - swelling, redness, pain, heat, and loss of function - due to the infiltration of the tissues by plasma and leukocytes. It occurs as long as the injurious stimulus is present and ceases once the stimulus has been removed, broken down, or walled off by scarring (fibrosis). The first four characteristics have been known since ancient times and are attributed to Celsus. Loss of function was added to the definition of inflammation by Virchow in the 19th century (1870).
The process of acute inflammation is initiated by the blood vessels local to the injured tissue, which alter to allow the exudation of plasma proteins and leukocytes into the surrounding tissue. The increased flow of fluid into the tissue causes the characteristic swelling associated with inflammation since the lymphatic system doesn't have the capacity to compensate for it, and the increased blood flow to the area causes the reddened colour and increased heat. The blood vessels also alter to permit the extravasation of leukocytes through the endothelium and basement membrane constituting the blood vessel. Once in the tissue, the cells migrate along a chemotactic gradient to reach the site of injury, where they can attempt to remove the stimulus and repair the tissue.
Meanwhile, several biochemical cascade systems, consisting of chemicals known as plasma-derived inflammatory mediators, act in parallel to propagate and mature the inflammatory response. These include the complement system, coagulation system and fibrinolysis system.
Finally, down-regulation of the inflammatory response concludes acute inflammation. Removal of the injurious stimuli halts the response of the inflammatory mechanisms, which require constant stimulation to propagate the process. Additionally, many inflammatory mediators have short half lives and are quickly degraded in the tissue, helping to quickly cease the inflammatory response once the stimulus has been removed.
## Chronic inflammation
Chronic inflammation is a pathological condition characterised by concurrent active inflammation, tissue destruction, and attempts at repair. Chronic inflammation is not characterised by the classic signs of acute inflammation listed above. Instead, chronically inflamed tissue is characterised by the infiltration of mononuclear immune cells (monocytes, macrophages, lymphocytes, and plasma cells), tissue destruction, and attempts at healing, which include angiogenesis and fibrosis.
Endogenous causes include persistent acute inflammation. Exogenous causes are varied and include bacterial infection, especially by Mycobacterium tuberculosis, prolonged exposure to chemical agents such as silica, tobacco smoke, or autoimmune reactions such as rheumatoid arthritis.
In acute inflammation, removal of the stimulus halts the recruitment of monocytes (which become macrophages under appropriate activation) into the inflamed tissue, and existing macrophages exit the tissue via lymphatics. However in chronically inflamed tissue the stimulus is persistent, and therefore recruitment of monocytes is maintained, existing macrophages are tethered in place, and proliferation of macrophages is stimulated (especially in atheromatous plaques).
# Exudative component
The exudative component involves the movement of plasma fluid, containing important proteins such as fibrin and immunoglobulins (antibodies), into inflamed tissue. This movement is achieved via the chemically-induced dilation and increased permeability of blood vessels, which results in a net loss of blood plasma. The increased collection of fluid into the tissue causes it to swell (edema).
## Vascular changes
Acute inflammation is characterised by marked vascular changes, including vasodilation, increased permeability, and the slowing of blood flow, which are induced by the actions of various inflammatory mediators. Vasodilation occurs first at the arteriole level, progressing to the capillary level, and brings about a net increase in the amount of blood present, causing the redness and heat of inflammation. Increased permeability of the vessels results in the movement of plasma into the tissues, with resultant stasis due to the increase in the concentration of the cells within blood - a condition characterised by enlarged vessels packed with cells. Stasis allows leukocytes to marginate along the endothelium, a process critical to their recruitment into the tissues. Normal flowing blood prevents this, as the shearing force along the periphery of the vessels moves cells in the blood into the middle of the vessel.
## Plasma cascade systems
- The complement system, when activated, results in the increased removal of pathogens via opsonisation and phagocytosis.
- The kinin system generates proteins capable of sustaining vasodilation and other physical inflammatory effects.
- The coagulation system or clotting cascade which forms a protective protein mesh over sites of injury.
- The fibrinolysis system, which acts in opposition to the coagulation system, to counterbalance clotting and generate several other inflammatory mediators.
## Plasma derived mediators
- non-exhaustive list
# Cellular component
The cellular component involves leukocytes, which normally reside in blood and must move into the inflamed tissue via extravasation to aid in inflammation. Some act as phagocytes, ingesting bacteria, viruses, and cellular debris. Others release enzymatic granules which damage pathogenic invaders. Leukocytes also release inflammatory mediators which develop and maintain the inflammatory response. Generally speaking, acute inflammation is mediated by granulocytes, while chronic inflammation is mediated by mononuclear cells such as monocytes and lymphocytes.
## Leukocyte extravasation
Various leukocytes are critically involved in the initiation and maintenance of inflammation. These cells must be able to get to the site of injury from their usual location in the blood, therefore mechanisms exist to recruit and direct leukocytes to the appropriate place. The process of leukocyte movement from the blood to the tissues through the blood vessels is known as extravasation, and can be divided up into a number of broad steps:
- Leukocyte localisation and recruitment to the endothelium local to the site of inflammation – involving margination and adhesion to the endothelial cells: Recruitment of leukocytes is receptor-mediated. The products of inflammation, such as histamine, promote the immediate expression of P-selectin on endothelial cell surfaces. This receptor binds weakly to carbohydrate ligands on leukocyte surfaces and causes them to "roll" along the endothelial surface as bonds are made and broken. Cytokines from injured cells induce the expression of E-selectin on endothelial cells, which functions similarly to P-selectin. Cytokines also induce the expression of integrin ligands on endothelial cells, which further slow leukocytes down. These weakly bound leukocytes are free to detach if not activated by chemokines produced in injured tissue. Activation increases the affinity of bound integrin receptors for ligands on the endothelial cell surface, firmly binding the leukocytes to the endothelium.
- Migration across the endothelium, known as transmigration, via the process of diapedesis: Chemokine gradients stimulate the adhered leukocytes to move between endothelial cells and pass the basement membrane into the tissues.
- Movement of leukocytes within the tissue via chemotaxis: Leukocytes reaching the tissue interstitium bind to extracellular matrix proteins via expressed integrins and CD44 to prevent their loss from the site. Chemoattractants cause the leukocytes to move along a chemotactic gradient towards the source of inflammation.
## Cell derived mediators
- non-exhaustive list
# Morphologic patterns
Specific patterns of acute and chronic inflammation are seen during particular situations that arise in the body, such as when inflammation occurs on an epithelial surface, or pyogenic bacteria are involved.
- Granulomatous inflammation: characterised by the formation of granulomas, they are the result of a limited but diverse number of diseases, which include among others tuberculosis, leprosy, and syphilis.
- Fibrinous inflammation: Inflammation resulting in a large increase in vascular permeability allows the blood vessels to pass through fibrin. If an appropriate procoagulative stimulus is present, such as cancer cells, a fibrinous exudate is deposited. This is commonly seen in serous cavities, where the conversion of fibrinous exudate into a scar can occur between serous membranes, limiting their function.
- Purulent inflammation: Inflammation resulting in large amount of pus, which consists of neutrophils, dead cells, and fluid. Infection by pyogenic bacteria such as staphylococci is characteristic of this kind of inflammation. Large, localised collections of pus enclosed by surrounding tissues are called abscesses.
- Serous inflammation: Characterised by the copious effusion of non-viscous serous fluid, commonly produced by mesothelial cells of serous membranes, but may which also be derived from blood plasma. Skin blisters exemplify this pattern of inflammation.
- Ulcerative inflammation: Inflammation occurring near an epithelium can result in the necrotic loss of tissue from the surface, exposing lower layers. The subsequent excavation in the epithelium is known as an ulcer.
# Inflammatory disorders
Abnormalities associated with inflammation comprise a large, unrelated group of disorders which underly a variety of human diseases. The immune system is often involved with inflammatory disorders, demonstrated in both allergic reactions and some myopathies, with many immune system disorders resulting in abnormal inflammation. Non-immune diseases with aetiological origins in inflammatory processes are thought to include cancer, atherosclerosis, and ischaemic heart disease.
A large variety of proteins are involved in inflammation, and any one of them is open to a genetic mutation which impairs or otherwise dysregulates the normal function and expression of that protein.
Examples of disorders associated with inflammation include:
- Asthma
- Autoimmune diseases
- Chronic inflammation
- Chronic prostatitis
- Glomerulonephritis
- Hypersensitivities
- Inflammatory bowel diseases
- Pelvic inflammatory disease
- Reperfusion injury
- Rheumatoid arthritis
- Transplant rejection
- Vasculitis
## Allergies
An allergic reaction, formally known as type 1 hypersensitivity, is the result of an inappropriate immune response triggering inflammation. A common example is hay fever, which is caused by a hypersensitive response by skin mast cells to allergens. Pre-sensitised mast cells respond by degranulating, releasing vasoactive chemicals such as histamine. These chemicals propagate an excessive inflammatory response characterised by blood vessel dilation, production of pro-inflammatory molecules, cytokine release, and recruitment of leukocytes. Severe inflammatory response may mature into a systemic response known as anaphylaxis.
Other hypersensitivity reactions (type 2 and type 3) are mediated by antibody reactions and induce inflammation by attracting leukocytes which damage surrounding tissue.
## Myopathies
Inflammatory myopathies are caused by the immune system inappropriately attacking components of muscle, leading to signs of muscle inflammation. They may occur in conjunction with other immune disorders, such as systemic sclerosis, and include dermatomyositis, polymyositis, and inclusion body myositis.
## Leukocyte defects
Due to the central role of leukocytes in the development and propagation of inflammation, defects in leukocyte function often result in a decreased capacity for inflammatory defence with subsequent vulnerability to infection. Dysfunctional leukocytes may be unable to correctly bind to blood vessels due to surface receptor mutations, digest bacteria (Chediak-Higashi syndrome), or produce microbicides (chronic granulomatous disease). Additionally, diseases affecting the bone marrow may result in abnormal or few leukocytes.
## Pharmacological
Certain drugs or chemical compounds are known to affect inflammation. Vitamin A deficiency causes an increase in inflammatory responses, and anti-inflammatory drugs work specifically by inhibiting normal inflammatory components.
## Cancer
Inflammation orchestrates the microenvironment around tumours, contributing to proliferation, survival and migration. Cancer cells use selectins, chemokines and their receptors for invasion, migration and metastasis. On the other hand, many cells of the immune system contribute to cancer immunology, suppressing cancer.
# Termination
The inflammatory response must be actively terminated when no longer needed to prevent unnecessary "bystander" damage to tissues. Failure to do so results in chronic inflammation, cellular destruction, and attempts to heal the inflamed tissue. One intrinsic mechanism employed to terminate inflammation is the short half-life of inflammatory mediators in vivo. They have a limited time frame to affect their target before breaking down into non-functional components, therefore constant inflammatory stimulation is needed to propagate their effects.
Active mechanisms which serve to terminate inflammation include:
- TGF-β from macrophages
- Anti-inflammatory lipoxins
- Inhibition of pro-inflammatory molecules, such as leukotrienes
# Systemic effects
An organism can escape the confines of the immediate tissue via the circulatory system or lymphatic system, where it may spread to other parts of the body. If an organism is not contained by the actions of acute inflammation it may gain access to the lymphatic system via nearby lymph vessels. An infection of the lymph vessels is known as lymphangitis, and infection of a lymph node is known as lymphadenitis. A pathogen can gain access to the bloodstream through lymphatic drainage into the circulatory system.
When inflammation overwhelms the host, systemic inflammatory response syndrome is diagnosed. When it is due to infection, the term sepsis is applied, with bacteremia being applied specifically for bacterial sepsis and viremia specifically to viral sepsis. Vasodilation and organ dysfunction are serious problems associated with widespread infection that may lead to septic shock and death.
## Acute-phase proteins
Inflammation also induces high systemic levels of acute-phase proteins. In acute inflammation, these proteins prove beneficial, however in chronic inflammation they can contribute to amyloidosis These proteins include C-reactive protein, serum amyloid A, serum amyloid P, vasopressin, and glucocorticoids, which cause a range of systemic effects including:
- Fever
- Increased blood pressure
- Decreased sweating
- Malaise
- Loss of appetite
- Somnolence
## Leukocyte numbers
Inflammation often affects the numbers of leukocytes present in the body:
- Leukocytosis is often seen during inflammation induced by infection, where it results in a large increase in the amount of leukocytes in the blood, especially immature cells. Leukocyte numbers usually increase to between 15 000 and 20 000 cells per ml, but extreme cases can see it approach 100 000 cells per ml. Bacterial infection usually results in an increase of neutrophils, creating neutrophilia, whereas diseases such as asthma, hay fever, and parasite infestation result in an increase in eosinophils, creating eosinophilia.
- Leukopenia can be induced by certain infections and diseases, including viral infection, Rickettsia infection, some protozoa, tuberculosis, and some cancers.
## Systemic inflammation and obesity
With the discovery of interleukins (IL), the concept of systemic inflammation developed. Although the processes involved are identical to tissue inflammation, systemic inflammation is not confined to a particular tissue but involves the endothelium and other organ systems.
High levels of several inflammation-related markers such as IL-6, IL-8, and TNF-α are associated with obesity. During clinical studies, inflammatory-related molecule levels were reduced and increased levels of anti-inflammatory molecules were seen within four weeks after patients began a very low calorie diet. The association of systemic inflammation with insulin resistance and atherosclerosis is the subject of intense
research.
# Outcomes
The outcome in a particular circumstance will be determined by the tissue in which the injury has occurred and the injurious agent that is causing it. There are three possible outcomes to inflammation:
- ResolutionThe complete restoration of the inflamed tissue back to a normal status. Inflammatory measures such as vasodilation, chemical production, and leukocyte infiltration cease, and damaged parenchymal cells regenerate. In situations where limited or short lived inflammation has occurred this is usually the outcome.
- FibrosisLarge amounts of tissue destruction, or damage in tissues unable to regenerate, can not be regenerated completely by the body. Fibrous scarring occurs in these areas of damage, forming a scar composed primarily of collagen. The scar will not contain any specialized structures, such as parenchymal cells, hence functional impairment may occur.
- Abscess FormationA cavity is formed containing pus, an opaque liquid containing dead white blood cells and bacteria with general debris from destroyed cells.
- Chronic inflammationIn acute inflammation, if the injurious agent persists then chronic inflammation will ensue. This process, marked by inflammation lasting many days, months or even years, may lead to the formation of a chronic wound. Chronic inflammation is characterised by the dominating presence of macrophages in the injured tissue. These cells are powerful defensive agents of the body, but the toxins they release (including reactive oxygen species) are injurious to the organism's own tissues as well as invading agents. Consequently, chronic inflammation is almost always accompanied by tissue destruction.
# Examples
Inflammation is usually indicated by adding the suffix "-itis", as shown below. However, some conditions such as asthma and pneumonia do not follow this convention. More examples are available at list of types of inflammation.
- Acute appendicitis
- Acute dermatitis
- Acute infective meningitis
- Acute tonsillitis | Inflamation
Inflammation (Latin, inflammatio, to set on fire) is the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue. Inflammation is not a synonym for infection. Even in cases where inflammation is caused by infection it is incorrect to use the terms as synonyms: infection is caused by an exogenous pathogen, while inflammation is the response of the organism to the pathogen.
In the absence of inflammation, wounds and infections would never heal and progressive destruction of the tissue would compromise the survival of the organism. However, inflammation which runs unchecked can also lead to a host of diseases, such as hay fever, atherosclerosis, and rheumatoid arthritis. It is for this reason that inflammation is normally tightly regulated by the body.
Inflammation can be classified as either acute or chronic. Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes from the blood into the injured tissues. A cascade of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells within the injured tissue. Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells which are present at the site of inflammation and is characterised by simultaneous destruction and healing of the tissue from the inflammatory process.
# Causes
- Burns
- Chemical irritants
- Frostbite
- Toxins
- Infection by pathogens
- Necrosis
- Physical injury, blunt or penetrating
- Immune reactions due to hypersensitivity
- Ionizing radiation
- Foreign bodies, including splinters and dirt
# Types
## Acute inflammation
Acute inflammation is a short-term process which is characterized by the classic signs of inflammation - swelling, redness, pain, heat, and loss of function - due to the infiltration of the tissues by plasma and leukocytes. It occurs as long as the injurious stimulus is present and ceases once the stimulus has been removed, broken down, or walled off by scarring (fibrosis). The first four characteristics have been known since ancient times and are attributed to Celsus. Loss of function was added to the definition of inflammation by Virchow in the 19th century (1870).[3]
The process of acute inflammation is initiated by the blood vessels local to the injured tissue, which alter to allow the exudation of plasma proteins and leukocytes into the surrounding tissue. The increased flow of fluid into the tissue causes the characteristic swelling associated with inflammation since the lymphatic system doesn't have the capacity to compensate for it, and the increased blood flow to the area causes the reddened colour and increased heat. The blood vessels also alter to permit the extravasation of leukocytes through the endothelium and basement membrane constituting the blood vessel. Once in the tissue, the cells migrate along a chemotactic gradient to reach the site of injury, where they can attempt to remove the stimulus and repair the tissue.
Meanwhile, several biochemical cascade systems, consisting of chemicals known as plasma-derived inflammatory mediators, act in parallel to propagate and mature the inflammatory response. These include the complement system, coagulation system and fibrinolysis system.
Finally, down-regulation of the inflammatory response concludes acute inflammation. Removal of the injurious stimuli halts the response of the inflammatory mechanisms, which require constant stimulation to propagate the process. Additionally, many inflammatory mediators have short half lives and are quickly degraded in the tissue, helping to quickly cease the inflammatory response once the stimulus has been removed.[3]
## Chronic inflammation
Chronic inflammation is a pathological condition characterised by concurrent active inflammation, tissue destruction, and attempts at repair. Chronic inflammation is not characterised by the classic signs of acute inflammation listed above. Instead, chronically inflamed tissue is characterised by the infiltration of mononuclear immune cells (monocytes, macrophages, lymphocytes, and plasma cells), tissue destruction, and attempts at healing, which include angiogenesis and fibrosis.
Endogenous causes include persistent acute inflammation. Exogenous causes are varied and include bacterial infection, especially by Mycobacterium tuberculosis, prolonged exposure to chemical agents such as silica, tobacco smoke, or autoimmune reactions such as rheumatoid arthritis.
In acute inflammation, removal of the stimulus halts the recruitment of monocytes (which become macrophages under appropriate activation) into the inflamed tissue, and existing macrophages exit the tissue via lymphatics. However in chronically inflamed tissue the stimulus is persistent, and therefore recruitment of monocytes is maintained, existing macrophages are tethered in place, and proliferation of macrophages is stimulated (especially in atheromatous plaques).[3]
# Exudative component
The exudative component involves the movement of plasma fluid, containing important proteins such as fibrin and immunoglobulins (antibodies), into inflamed tissue. This movement is achieved via the chemically-induced dilation and increased permeability of blood vessels, which results in a net loss of blood plasma. The increased collection of fluid into the tissue causes it to swell (edema).
## Vascular changes
Acute inflammation is characterised by marked vascular changes, including vasodilation, increased permeability, and the slowing of blood flow, which are induced by the actions of various inflammatory mediators. Vasodilation occurs first at the arteriole level, progressing to the capillary level, and brings about a net increase in the amount of blood present, causing the redness and heat of inflammation. Increased permeability of the vessels results in the movement of plasma into the tissues, with resultant stasis due to the increase in the concentration of the cells within blood - a condition characterised by enlarged vessels packed with cells. Stasis allows leukocytes to marginate along the endothelium, a process critical to their recruitment into the tissues. Normal flowing blood prevents this, as the shearing force along the periphery of the vessels moves cells in the blood into the middle of the vessel.
## Plasma cascade systems
- The complement system, when activated, results in the increased removal of pathogens via opsonisation and phagocytosis.
- The kinin system generates proteins capable of sustaining vasodilation and other physical inflammatory effects.
- The coagulation system or clotting cascade which forms a protective protein mesh over sites of injury.
- The fibrinolysis system, which acts in opposition to the coagulation system, to counterbalance clotting and generate several other inflammatory mediators.
## Plasma derived mediators
* non-exhaustive list
# Cellular component
The cellular component involves leukocytes, which normally reside in blood and must move into the inflamed tissue via extravasation to aid in inflammation. Some act as phagocytes, ingesting bacteria, viruses, and cellular debris. Others release enzymatic granules which damage pathogenic invaders. Leukocytes also release inflammatory mediators which develop and maintain the inflammatory response. Generally speaking, acute inflammation is mediated by granulocytes, while chronic inflammation is mediated by mononuclear cells such as monocytes and lymphocytes.
## Leukocyte extravasation
Various leukocytes are critically involved in the initiation and maintenance of inflammation. These cells must be able to get to the site of injury from their usual location in the blood, therefore mechanisms exist to recruit and direct leukocytes to the appropriate place. The process of leukocyte movement from the blood to the tissues through the blood vessels is known as extravasation, and can be divided up into a number of broad steps:
- Leukocyte localisation and recruitment to the endothelium local to the site of inflammation – involving margination and adhesion to the endothelial cells: Recruitment of leukocytes is receptor-mediated. The products of inflammation, such as histamine, promote the immediate expression of P-selectin on endothelial cell surfaces. This receptor binds weakly to carbohydrate ligands on leukocyte surfaces and causes them to "roll" along the endothelial surface as bonds are made and broken. Cytokines from injured cells induce the expression of E-selectin on endothelial cells, which functions similarly to P-selectin. Cytokines also induce the expression of integrin ligands on endothelial cells, which further slow leukocytes down. These weakly bound leukocytes are free to detach if not activated by chemokines produced in injured tissue. Activation increases the affinity of bound integrin receptors for ligands on the endothelial cell surface, firmly binding the leukocytes to the endothelium.
- Migration across the endothelium, known as transmigration, via the process of diapedesis: Chemokine gradients stimulate the adhered leukocytes to move between endothelial cells and pass the basement membrane into the tissues.
- Movement of leukocytes within the tissue via chemotaxis: Leukocytes reaching the tissue interstitium bind to extracellular matrix proteins via expressed integrins and CD44 to prevent their loss from the site. Chemoattractants cause the leukocytes to move along a chemotactic gradient towards the source of inflammation.
## Cell derived mediators
* non-exhaustive list
# Morphologic patterns
Specific patterns of acute and chronic inflammation are seen during particular situations that arise in the body, such as when inflammation occurs on an epithelial surface, or pyogenic bacteria are involved.
- Granulomatous inflammation: characterised by the formation of granulomas, they are the result of a limited but diverse number of diseases, which include among others tuberculosis, leprosy, and syphilis.
- Fibrinous inflammation: Inflammation resulting in a large increase in vascular permeability allows the blood vessels to pass through fibrin. If an appropriate procoagulative stimulus is present, such as cancer cells,[3] a fibrinous exudate is deposited. This is commonly seen in serous cavities, where the conversion of fibrinous exudate into a scar can occur between serous membranes, limiting their function.
- Purulent inflammation: Inflammation resulting in large amount of pus, which consists of neutrophils, dead cells, and fluid. Infection by pyogenic bacteria such as staphylococci is characteristic of this kind of inflammation. Large, localised collections of pus enclosed by surrounding tissues are called abscesses.
- Serous inflammation: Characterised by the copious effusion of non-viscous serous fluid, commonly produced by mesothelial cells of serous membranes, but may which also be derived from blood plasma. Skin blisters exemplify this pattern of inflammation.
- Ulcerative inflammation: Inflammation occurring near an epithelium can result in the necrotic loss of tissue from the surface, exposing lower layers. The subsequent excavation in the epithelium is known as an ulcer.
# Inflammatory disorders
Abnormalities associated with inflammation comprise a large, unrelated group of disorders which underly a variety of human diseases. The immune system is often involved with inflammatory disorders, demonstrated in both allergic reactions and some myopathies, with many immune system disorders resulting in abnormal inflammation. Non-immune diseases with aetiological origins in inflammatory processes are thought to include cancer, atherosclerosis, and ischaemic heart disease.[3]
A large variety of proteins are involved in inflammation, and any one of them is open to a genetic mutation which impairs or otherwise dysregulates the normal function and expression of that protein.
Examples of disorders associated with inflammation include:
- Asthma
- Autoimmune diseases
- Chronic inflammation
- Chronic prostatitis
- Glomerulonephritis
- Hypersensitivities
- Inflammatory bowel diseases
- Pelvic inflammatory disease
- Reperfusion injury
- Rheumatoid arthritis
- Transplant rejection
- Vasculitis
## Allergies
An allergic reaction, formally known as type 1 hypersensitivity, is the result of an inappropriate immune response triggering inflammation. A common example is hay fever, which is caused by a hypersensitive response by skin mast cells to allergens. Pre-sensitised mast cells respond by degranulating, releasing vasoactive chemicals such as histamine. These chemicals propagate an excessive inflammatory response characterised by blood vessel dilation, production of pro-inflammatory molecules, cytokine release, and recruitment of leukocytes.[3] Severe inflammatory response may mature into a systemic response known as anaphylaxis.
Other hypersensitivity reactions (type 2 and type 3) are mediated by antibody reactions and induce inflammation by attracting leukocytes which damage surrounding tissue.[3]
## Myopathies
Inflammatory myopathies are caused by the immune system inappropriately attacking components of muscle, leading to signs of muscle inflammation. They may occur in conjunction with other immune disorders, such as systemic sclerosis, and include dermatomyositis, polymyositis, and inclusion body myositis.[3]
## Leukocyte defects
Due to the central role of leukocytes in the development and propagation of inflammation, defects in leukocyte function often result in a decreased capacity for inflammatory defence with subsequent vulnerability to infection.[3] Dysfunctional leukocytes may be unable to correctly bind to blood vessels due to surface receptor mutations, digest bacteria (Chediak-Higashi syndrome), or produce microbicides (chronic granulomatous disease). Additionally, diseases affecting the bone marrow may result in abnormal or few leukocytes.
## Pharmacological
Certain drugs or chemical compounds are known to affect inflammation. Vitamin A deficiency causes an increase in inflammatory responses,[4] and anti-inflammatory drugs work specifically by inhibiting normal inflammatory components.
## Cancer
Inflammation orchestrates the microenvironment around tumours, contributing to proliferation, survival and migration. Cancer cells use selectins, chemokines and their receptors for invasion, migration and metastasis.[5] On the other hand, many cells of the immune system contribute to cancer immunology, suppressing cancer.
# Termination
The inflammatory response must be actively terminated when no longer needed to prevent unnecessary "bystander" damage to tissues.[3] Failure to do so results in chronic inflammation, cellular destruction, and attempts to heal the inflamed tissue. One intrinsic mechanism employed to terminate inflammation is the short half-life of inflammatory mediators in vivo. They have a limited time frame to affect their target before breaking down into non-functional components, therefore constant inflammatory stimulation is needed to propagate their effects.
Active mechanisms which serve to terminate inflammation include[3]:
- TGF-β from macrophages
- Anti-inflammatory lipoxins
- Inhibition of pro-inflammatory molecules, such as leukotrienes
# Systemic effects
An organism can escape the confines of the immediate tissue via the circulatory system or lymphatic system, where it may spread to other parts of the body. If an organism is not contained by the actions of acute inflammation it may gain access to the lymphatic system via nearby lymph vessels. An infection of the lymph vessels is known as lymphangitis, and infection of a lymph node is known as lymphadenitis. A pathogen can gain access to the bloodstream through lymphatic drainage into the circulatory system.
When inflammation overwhelms the host, systemic inflammatory response syndrome is diagnosed. When it is due to infection, the term sepsis is applied, with bacteremia being applied specifically for bacterial sepsis and viremia specifically to viral sepsis. Vasodilation and organ dysfunction are serious problems associated with widespread infection that may lead to septic shock and death.
## Acute-phase proteins
Inflammation also induces high systemic levels of acute-phase proteins. In acute inflammation, these proteins prove beneficial, however in chronic inflammation they can contribute to amyloidosis[3] These proteins include C-reactive protein, serum amyloid A, serum amyloid P, vasopressin, and glucocorticoids, which cause a range of systemic effects including[3]:
- Fever
- Increased blood pressure
- Decreased sweating
- Malaise
- Loss of appetite
- Somnolence
## Leukocyte numbers
Inflammation often affects the numbers of leukocytes present in the body:
- Leukocytosis is often seen during inflammation induced by infection, where it results in a large increase in the amount of leukocytes in the blood, especially immature cells. Leukocyte numbers usually increase to between 15 000 and 20 000 cells per ml, but extreme cases can see it approach 100 000 cells per ml.[3] Bacterial infection usually results in an increase of neutrophils, creating neutrophilia, whereas diseases such as asthma, hay fever, and parasite infestation result in an increase in eosinophils, creating eosinophilia.[3]
- Leukopenia can be induced by certain infections and diseases, including viral infection, Rickettsia infection, some protozoa, tuberculosis, and some cancers.[3]
## Systemic inflammation and obesity
With the discovery of interleukins (IL), the concept of systemic inflammation developed. Although the processes involved are identical to tissue inflammation, systemic inflammation is not confined to a particular tissue but involves the endothelium and other organ systems.
High levels of several inflammation-related markers such as IL-6, IL-8, and TNF-α are associated with obesity.[7][8] During clinical studies, inflammatory-related molecule levels were reduced and increased levels of anti-inflammatory molecules were seen within four weeks after patients began a very low calorie diet.[9] The association of systemic inflammation with insulin resistance and atherosclerosis is the subject of intense
research.[10]
# Outcomes
The outcome in a particular circumstance will be determined by the tissue in which the injury has occurred and the injurious agent that is causing it. There are three possible outcomes to inflammation:[3]
- ResolutionThe complete restoration of the inflamed tissue back to a normal status. Inflammatory measures such as vasodilation, chemical production, and leukocyte infiltration cease, and damaged parenchymal cells regenerate. In situations where limited or short lived inflammation has occurred this is usually the outcome.
- FibrosisLarge amounts of tissue destruction, or damage in tissues unable to regenerate, can not be regenerated completely by the body. Fibrous scarring occurs in these areas of damage, forming a scar composed primarily of collagen. The scar will not contain any specialized structures, such as parenchymal cells, hence functional impairment may occur.
- Abscess FormationA cavity is formed containing pus, an opaque liquid containing dead white blood cells and bacteria with general debris from destroyed cells.
- Chronic inflammationIn acute inflammation, if the injurious agent persists then chronic inflammation will ensue. This process, marked by inflammation lasting many days, months or even years, may lead to the formation of a chronic wound. Chronic inflammation is characterised by the dominating presence of macrophages in the injured tissue. These cells are powerful defensive agents of the body, but the toxins they release (including reactive oxygen species) are injurious to the organism's own tissues as well as invading agents. Consequently, chronic inflammation is almost always accompanied by tissue destruction.
# Examples
Inflammation is usually indicated by adding the suffix "-itis", as shown below. However, some conditions such as asthma and pneumonia do not follow this convention. More examples are available at list of types of inflammation.
- Acute appendicitis
- Acute dermatitis
- Acute infective meningitis
- Acute tonsillitis | https://www.wikidoc.org/index.php/Inflamation | |
e07dc999868ea47da2cff0827a42c897a802dd47 | wikidoc | Informatics | Informatics
Informatics includes the science of information, the practice of information processing, and the engineering of information systems. Informatics studies the structure, behavior, and interactions of natural and artificial systems that store, process and communicate information. It also develops its own conceptual and theoretical foundations. Since computers, individuals and organizations all process information, informatics has computational, cognitive and social aspects, including study of the social impact of information technologies.
Used as a compound, in conjunction with the name of a discipline, as in medical informatics, bioinformatics, etc., it denotes the specialization of informatics to the management and processing of data, information and knowledge in the named discipline, and the incorporation of informatic concepts and theories to enrich the other discipline; it has a similar relationship to library science.
Informatics is broader in scope than: information theory—the study of a particular mathematical concept of information; information science—a field primarily concerned with the collection, classification, manipulation, storage, retrieval and dissemination of information in human society; artificial intelligence—the study and engineering of intelligent behavior, learning, and adaptation, in machines; or computer science—the study of the storage, processing, and communication of information using engineered computing devices.
# Etymology
In 1957 the German computer scientist Karl Steinbuch coined the word Informatik by publishing a paper called Informatik: Automatische Informationsverarbeitung (i.e. "Informatics: automatic information processing"). The English term Informatics is commonly misunderstood to be the same as computer science. But Informatics is theoretically oriented contrary to computer science and therefore is more oriented towards mathematics than computer science.
The French term informatique was coined in 1962 by Philippe Dreyfus together with various translations—informatics (English), also proposed independently and simultaneously by Walter F.Bauer who co-founded the company named Informatics General Inc., and informatica (Italian, Spanish, Portuguese), referring to the application of computers to store and process information.
The term was coined as a combination of "information" and "automation", to describe the science of automatic information processing.
The morphology—informat-ion + -ics—uses "the accepted form for names of sciences, as conics, linguistics, optics, or matters of practice, as economics, politics, tactics", and so, linguistically, the meaning extends easily to encompass both the science of information and the practice of information processing.
This new term was adopted across Western Europe, and, except in English, developed a meaning roughly translated by the English ‘computer science’, or ‘computing science’. Mikhailov et al. advocated the Russian term informatika (1966), and the English informatics (1967), as names for the theory of scientific information, and argued for a broader meaning, including study of the use of information technology in various communities (for example, scientific) and of the interaction of technology and human organizational structures.
Usage has since modified this definition in three ways. First, the restriction to scientific information is removed, as in business informatics or legal informatics. Second, since most information is now digitally stored, computation is now central to informatics. Third, the representation, processing and communication of information are added as objects of investigation, since they have been recognized as fundamental to any scientific account of information. Taking information as the central focus of study, then distinguishes informatics—which includes study of biological and social mechanisms of information processing, from computer science—where digital computation plays a distinguished central role. Similarly, in the study of representation and communication, informatics is indifferent to the substrate that carries information. For example, it encompasses the study of communication using gesture, speech and language, as well as digital communications and networking.
A broad interpretation of informatics, as "the study of the structure, behaviour, and interactions of natural and artificial computational systems," was introduced by the University of Edinburgh in 1994 when it formed the grouping that is now its School of Informatics. This meaning is now (2006) increasingly used in the United Kingdom. Informatics encompasses the study of systems that represent, process, and communicate information, including all computational, cognitive and social aspects. The central notion is the transformation of information — whether by computation or communication, whether by organisms or artifacts. In this sense, informatics can be considered as encompassing computer science, cognitive science, artificial intelligence, information science and related fields, and as extending the scope of computer science to encompass computation in natural, as well as engineered, computational systems. Arizona State University adopted this broader definition at the launch of its School of Computing and Informatics in September 2006.
The 2008 Research Assessment Exercise, of the UK Funding Councils, includes a new, Computer Science and Informatics, unit of assessment (UoA), whose scope is described as follows:
At the Indiana University School of Informatics, informatics is defined as "the art, science and human dimensions of information technology" and "the study, application, and social consequences of technology." These definitions are widely accepted in the United States, and differ from British usage in omitting the study of natural computation.
At the University of California, Irvine Department of Informatics, informatics is defined as "the interdisciplinary study of the design, application, use and impact of information technology. The discipline of informatics is based on the recognition that the design of this technology is not solely a technical matter, but must focus on the relationship between the technology and its use in real-world settings. That is, informatics designs solutions in context, and takes into account the social, cultural and organizational settings in which computing and information technology will be used."
In the English-speaking world the term informatics was first widely used in the compound, ‘medical informatics’, taken to include "the cognitive, information processing, and communication tasks of medical practice, education, and research, including information science and the technology to support these tasks". Many such compounds are now in use; they can be viewed as different areas of applied informatics.
A practitioner of informatics may be called an informatician.
# Trademark
Informatics was registered as a trademark in the United States by Informatics Inc., which traded from 1966 to 1985. This fact prevented the Association for Computing Machinery from becoming the Society for Informatics. As of October, 2006, a search of the United States Patent and Trademark database reveals no live trademarks on the word "informatics" alone (although many combinations including that word do appear).
# Contributing disciplines
- Artificial intelligence
- Computer science
- Cognitive science
- Information science
- Communication studies
- Didactics of Informatics / Didactics of computer science | Informatics
Informatics includes the science of information, the practice of information processing, and the engineering of information systems. Informatics studies the structure, behavior, and interactions of natural and artificial systems that store, process and communicate information. It also develops its own conceptual and theoretical foundations. Since computers, individuals and organizations all process information, informatics has computational, cognitive and social aspects, including study of the social impact of information technologies.
Used as a compound, in conjunction with the name of a discipline, as in medical informatics, bioinformatics, etc., it denotes the specialization of informatics to the management and processing of data, information and knowledge in the named discipline, and the incorporation of informatic concepts and theories to enrich the other discipline; it has a similar relationship to library science.
Informatics is broader in scope than: information theory—the study of a particular mathematical concept of information; information science—a field primarily concerned with the collection, classification, manipulation, storage, retrieval and dissemination of information in human society; artificial intelligence—the study and engineering of intelligent behavior, learning, and adaptation, in machines; or computer science—the study of the storage, processing, and communication of information using engineered computing devices.
# Etymology
In 1957 the German computer scientist Karl Steinbuch coined the word Informatik by publishing a paper called Informatik: Automatische Informationsverarbeitung (i.e. "Informatics: automatic information processing"). The English term Informatics is commonly misunderstood to be the same as computer science. But Informatics is theoretically oriented contrary to computer science and therefore is more oriented towards mathematics than computer science.
The French term informatique was coined in 1962 by Philippe Dreyfus[1] together with various translations—informatics (English), also proposed independently and simultaneously by Walter F.Bauer who co-founded the company named Informatics General Inc., and informatica (Italian, Spanish, Portuguese), referring to the application of computers to store and process information.
The term was coined as a combination of "information" and "automation", to describe the science of automatic information processing.
The morphology—informat-ion + -ics—uses "the accepted form for names of sciences, as conics, linguistics, optics, or matters of practice, as economics, politics, tactics",[2] and so, linguistically, the meaning extends easily to encompass both the science of information and the practice of information processing.
This new term was adopted across Western Europe, and, except in English, developed a meaning roughly translated by the English ‘computer science’, or ‘computing science’. Mikhailov et al. advocated the Russian term informatika (1966), and the English informatics (1967), as names for the theory of scientific information, and argued for a broader meaning, including study of the use of information technology in various communities (for example, scientific) and of the interaction of technology and human organizational structures.
Usage has since modified this definition in three ways. First, the restriction to scientific information is removed, as in business informatics or legal informatics. Second, since most information is now digitally stored, computation is now central to informatics. Third, the representation, processing and communication of information are added as objects of investigation, since they have been recognized as fundamental to any scientific account of information. Taking information as the central focus of study, then distinguishes informatics—which includes study of biological and social mechanisms of information processing, from computer science—where digital computation plays a distinguished central role. Similarly, in the study of representation and communication, informatics is indifferent to the substrate that carries information. For example, it encompasses the study of communication using gesture, speech and language, as well as digital communications and networking.
A broad interpretation of informatics, as "the study of the structure, behaviour, and interactions of natural and artificial computational systems," was introduced by the University of Edinburgh in 1994 when it formed the grouping that is now its School of Informatics. This meaning is now (2006) increasingly used in the United Kingdom.[4] Informatics encompasses the study of systems that represent, process, and communicate information, including all computational, cognitive and social aspects. The central notion is the transformation of information — whether by computation or communication, whether by organisms or artifacts. In this sense, informatics can be considered as encompassing computer science, cognitive science, artificial intelligence, information science and related fields, and as extending the scope of computer science to encompass computation in natural, as well as engineered, computational systems. Arizona State University adopted this broader definition at the launch of its School of Computing and Informatics in September 2006.
The 2008 Research Assessment Exercise, of the UK Funding Councils, includes a new, Computer Science and Informatics, unit of assessment (UoA),[5] whose scope is described as follows:
At the Indiana University School of Informatics, informatics is defined as "the art, science and human dimensions of information technology" and "the study, application, and social consequences of technology." These definitions are widely accepted in the United States, and differ from British usage in omitting the study of natural computation.
At the University of California, Irvine Department of Informatics, informatics is defined as "the interdisciplinary study of the design, application, use and impact of information technology. The discipline of informatics is based on the recognition that the design of this technology is not solely a technical matter, but must focus on the relationship between the technology and its use in real-world settings. That is, informatics designs solutions in context, and takes into account the social, cultural and organizational settings in which computing and information technology will be used."
In the English-speaking world the term informatics was first widely used in the compound, ‘medical informatics’, taken to include "the cognitive, information processing, and communication tasks of medical practice, education, and research, including information science and the technology to support these tasks".[6] Many such compounds are now in use; they can be viewed as different areas of applied informatics.
A practitioner of informatics may be called an informatician.
# Trademark
Informatics was registered as a trademark[7] in the United States by Informatics Inc.[8], which traded from 1966 to 1985. This fact prevented the Association for Computing Machinery from becoming the Society for Informatics. As of October, 2006, a search of the United States Patent and Trademark database reveals no live trademarks on the word "informatics" alone (although many combinations including that word do appear).
# Contributing disciplines
- Artificial intelligence
- Computer science
- Cognitive science
- Information science
- Communication studies
- Didactics of Informatics / Didactics of computer science | https://www.wikidoc.org/index.php/Informatics | |
f4b0eb8567732f75521c5e2c38bc8c9c9ff40e21 | wikidoc | Inner child | Inner child
Inner child is a concept used in popular psychology to denote the childlike aspect of a person's psyche, especially when viewed as an independent entity. Frequently, the term is used to address subjective childhood experiences and the remaining effects of one's childhood. The Inner Child also refers to all of the emotional memory and experiences stored in the brain from earliest memory. The Twelve-step program recovery movement considers healing the Inner Child to be one of the essential stages in recovery from addiction, abuse, trauma, or post-traumatic stress disorder. In the 1970s, the Inner Child concept emerged alongside the clinical concept of Codependency (first called Adult Children of Alcoholics Syndrome.)
Carl Jung referred to a similar concept as the 'Divine Child.' Emmet Fox called it the 'Wonder Child.' Charles Whitfield dubbed it the 'Child Within.' Some psychotherapists call it the 'True Self'. Transactional Analysis calls it simply Child. W. Missildine may have been the first to refer to this concept as the inner child in his 1963 book Your Inner Child of the Past. The "wounded inner child" is a modified application of the inner child concept popularized by American educator, and pop psychology and self help movement leader, John Bradshaw.
Other writers who have developed and expanded the concept and methods include Lucia Capacchione, Louise Hay, Dr. Margaret Paul, and Pia Mellody. Some recovery methods such as "radical forgiveness" disdain the inner child concept and teach that the idea of 'nurturing the inner child' actually holds one back from full recovery by encouraging a victim stance . | Inner child
Inner child is a concept used in popular psychology to denote the childlike aspect of a person's psyche, especially when viewed as an independent entity. Frequently, the term is used to address subjective childhood experiences and the remaining effects of one's childhood. The Inner Child also refers to all of the emotional memory and experiences stored in the brain from earliest memory. The Twelve-step program recovery movement considers healing the Inner Child to be one of the essential stages in recovery from addiction, abuse, trauma, or post-traumatic stress disorder. In the 1970s, the Inner Child concept emerged alongside the clinical concept of Codependency (first called Adult Children of Alcoholics Syndrome.)
Carl Jung referred to a similar concept as the 'Divine Child.' Emmet Fox called it the 'Wonder Child.' Charles Whitfield dubbed it the 'Child Within.' Some psychotherapists call it the 'True Self'. Transactional Analysis calls it simply Child. W. Missildine may have been the first to refer to this concept as the inner child in his 1963 book Your Inner Child of the Past. The "wounded inner child" is a modified application of the inner child concept popularized by American educator, and pop psychology and self help movement leader, John Bradshaw.
Other writers who have developed and expanded the concept and methods include Lucia Capacchione, Louise Hay, Dr. Margaret Paul, and Pia Mellody. Some recovery methods such as "radical forgiveness" disdain the inner child concept and teach that the idea of 'nurturing the inner child' actually holds one back from full recovery by encouraging a victim stance [1]. | https://www.wikidoc.org/index.php/Inner_child | |
1a70b2f7837f522c31fe13727ef2335f87d1bd0b | wikidoc | InnoCentive | InnoCentive
InnoCentive is an "open innovation" company that takes research and development problems in biology or chemistry, frames them as "challenge problems", and opens them up for anyone to solve them. It gives cash awards for the best solutions to scientists who meet the challenge criteria.
# History
The idea for InnoCentive came to Alpheus Bingham and Aaron Schacht after they attended a public lecture at the Santa Fe Institute. The company was launched in 2001 by Jill Panetta and Alpheus Bingham.
In December 2006 the company signed an agreement with the Rockefeller Foundation to add a non-profit area designed to generate science and technology solutions to pressing problems in the developing world.
As of early 2007, InnoCentive's web site features an award from the non-profit "Prize 4 Life" foundation for $1 million for finding a biomarker that measures ALS disease progression.
# The Company
InnoCentive is based in Andover, Massachusetts.
InnoCentive calls the scientists who attempt the problems "solvers" and the companies these problems come from as "seekers". As of 2005 InnoCentive had 34 of these "seekers" (including Procter & Gamble, Dow AgroSciences and Eli Lilly), which have posted more than 200 "challenges" in 40 scientific disciplines, of which more than 58 had been solved by over 120,000 "solvers".
The problems listed are categorized as biology or chemistry problems, but use a very liberal definition of these disciplines, for example challenges have been posted in the areas of system network theory, manufacturing engineering, design, materials science and nanotechnology.
Solutions have come from US, Europe, Russia, China, India and Argentina; the cash awards for solving challenge problems are typically in the $10,000 to $100,000 range.
InnoCentive provides a consultancy service to enable its clients to make the most of its "solver" network. "Science advisers" and "problem definers" help clients to identify a challenge appropriate for posting on its network. They then estimate an appropriate award fee by determining the complexity of the problem, the resources required find a solution, and the value transferred to the company. InnoCentive reserves the right to reject the award amounts that are deemed too low and its experts provide a solution vetting service to screen out ideas that do not meet the challenge criteria.
InnoCentive forces its "seeker" companies to agree to intellectual property audits so that once a solution is provided to the company it can guarantee that the intellectual property is not used if the company decides not to award it. The company may also force the "seeker" company to award the solution if it deems that it meets the requirements of the challenge.
InnoCentive also provides a consultancy service to its network of "solvers". Its "science experts" provide feedback to explain the terms of the challenges as well as why submitted solutions may be deficient. It provides the logistic and legal framework for maintaining their control over the intellectual property until its sale to the seeker company. All communication and submitted solutions remain confidential.
Competitors offering similar services to InnoCentive include Yet2.com, YourEncore and NineSigma. | InnoCentive
Template:Infobox Company
InnoCentive is an "open innovation" company that takes research and development problems in biology or chemistry, frames them as "challenge problems", and opens them up for anyone to solve them. It gives cash awards for the best solutions to scientists who meet the challenge criteria.[1]
# History
The idea for InnoCentive came to Alpheus Bingham and Aaron Schacht after they attended a public lecture at the Santa Fe Institute.[2] The company was launched in 2001 by Jill Panetta and Alpheus Bingham.
In December 2006 the company signed an agreement with the Rockefeller Foundation to add a non-profit area designed to generate science and technology solutions to pressing problems in the developing world.[3]
As of early 2007, InnoCentive's web site features an award from the non-profit "Prize 4 Life" foundation for $1 million for finding a biomarker that measures ALS disease progression.
# The Company
InnoCentive is based in Andover, Massachusetts.
InnoCentive calls the scientists who attempt the problems "solvers" and the companies these problems come from as "seekers". As of 2005 InnoCentive had 34 of these "seekers" (including Procter & Gamble, Dow AgroSciences and Eli Lilly), which have posted more than 200 "challenges" in 40 scientific disciplines, of which more than 58 had been solved by over 120,000 "solvers".[4]
The problems listed are categorized as biology or chemistry problems, but use a very liberal definition of these disciplines, for example challenges have been posted in the areas of system network theory, manufacturing engineering, design, materials science and nanotechnology.
Solutions have come from US, Europe, Russia, China, India and Argentina; the cash awards for solving challenge problems are typically in the $10,000 to $100,000 range.
InnoCentive provides a consultancy service to enable its clients to make the most of its "solver" network. "Science advisers" and "problem definers" help clients to identify a challenge appropriate for posting on its network. They then estimate an appropriate award fee by determining the complexity of the problem, the resources required find a solution, and the value transferred to the company. InnoCentive reserves the right to reject the award amounts that are deemed too low and its experts provide a solution vetting service to screen out ideas that do not meet the challenge criteria.
InnoCentive forces its "seeker" companies to agree to intellectual property audits so that once a solution is provided to the company it can guarantee that the intellectual property is not used if the company decides not to award it. The company may also force the "seeker" company to award the solution if it deems that it meets the requirements of the challenge.
InnoCentive also provides a consultancy service to its network of "solvers". Its "science experts" provide feedback to explain the terms of the challenges as well as why submitted solutions may be deficient. It provides the logistic and legal framework for maintaining their control over the intellectual property until its sale to the seeker company. All communication and submitted solutions remain confidential.
Competitors offering similar services to InnoCentive include Yet2.com, YourEncore and NineSigma. | https://www.wikidoc.org/index.php/InnoCentive | |
8f79828a1d7f86a3c602a62f648f66c504479512 | wikidoc | Inoculation | Inoculation
# Overview
The word "Inoculation" refers to the placement of something to where it will grow or reproduce, and is most commonly used in respect of the introduction of a serum, vaccine, or antigenic substance into the body of a person or animal, especially to produce or boost immunity to a specific disease; but also can be used to refer to the communication of a disease to a living organism by transferring its causative agent into the organism, to implant microorganisms or infectious material into a culture medium such as a brewers vat or a petri dish, to safeguard as if by inoculation, to introduce an idea or attitude into someone's mind, any placement of microorganisms or viruses at a site where infection is possible such as to increase soybeans' nitrogen fixation one can treat soybeans at planting with Rhizobium japonicum inoculant. The verb "to inoculate" is from Middle English "inoculaten", which meant "to graft a scion (a scion is a plant part to be grafted onto another plant); which in turn is from Latin "inoculre" or "inocult-".
This article covers variolation, inoculation as a method of purposefully infecting a person with smallpox (Variola) in a controlled manner so as to minimise the severity of the infection and also to induce immunity against further infection. See vaccination for post-variolation methods of
safeguarding as if by inoculation by administering weakened or dead pathogens to a healthy person or animal with the intent of conferring immunity against a targeted form of a related disease agent.
Today the terms inoculation, vaccination and immunization are used more or less interchangeably and popularly refer to the process of artificial induction of immunity against various infectious diseases. The microorganism used in an inoculation is called the inoculant or inoculum.
# Origins
The earliest use of inoculation was from the Chinese. It is recorded that the Chinese inoculated their patients by making them snort the powdered scabs of smallpox victims. Another method of their inoculation was by scratching the powder into their skin.,
Some scholars suggest that the practice originated in India.
Dr. J.Z. Holwell writes the most detailed account for the college of Physicians in London in 1767 (An account of the manner of inoculating for the smallpox in the East Indies, by J. Z. Holwell, F.R.S. addressed to the President and Members of the College of Physicians in London) ... Holwell's detailed account, not only describes inoculation, but also shows that the Indians knew that microbes caused such diseases:
# Importation to the West
The practice was introduced to the west by Lady Mary Wortley Montagu (May 26, 1689-August 21, 1762). Lady Montagu's husband, Edward Wortley Montagu, served as the British ambassador to the Ottoman Empire from 1716 to 1717. She witnessed inoculation in Constantinople, and was greatly impressed: she had lost a brother to smallpox and bore facial scars from the disease herself. In March 1718 she had the embassy surgeon, Charles Maitland, inoculate her five-year-old son. In 1721, after returning to England, she had her four-year-old daughter inoculated. She invited friends to see her daughter, including Sir Hans Sloane, the King's physician. Sufficient interest arose that Maitland gained permission to test inoculation at Newgate prison in exchange for their freedom on six prisoners due to be hanged, an experiment which was witnessed by a number of notable doctors. The experiment succeeded, and in 1722 the Prince of Wales' daughters received inoculations.
The practice of inoculation slowly spread amongst the royal families of Europe, usually followed by more general adoption amongst the people.
The practice is documented in America as early as 1721. Cotton Mather in Boston had a description of the African practice of inoculation from his slave Onesimus and encouraged its application, with considerable controversy and strife. Fearing the outbreak of an epidemic, the editor of the South Carolina Gazette published a detailed description of the inoculation process in the April 22 issue. In Boston, there was opposition from churchmen regarding the practice who regarded it as "bidding defiance to Heaven itself, even to the will of God", though one historian also notes that "...within a year or two after the first experiment nearly three hundred persons had been inoculated ... in Boston and neighbouring towns, and out of these only six had died; whereas, during the same period, out of nearly six thousand persons who had taken smallpox naturally, and had received only the usual medical treatment, nearly one thousand had died." (from A History Of The Warfare Of Science With Theology In Christendom by Andrew Dickson White.)
In France considerable opposition arose to the introduction of inoculation. Voltaire, in his Lettres Philosophiques, wrote a criticism of his countrymen for being opposed to inoculation and having so little regard for the welfare of their children, concluding that "had inoculation been practised in France it would have saved the lives of thousands.".
Inoculation grew in popularity in Europe through the 18th century. Given the high prevalence and often severe consequences of smallpox in Europe in the 18th century (according to Voltaire, there was a 60% incidence of first infection, a 20% mortality rate, and a 20% incidence of severe scarring), many parents felt that the benefits of inoculation outweighted the risks and so inoculated their children.
# Mechanism
Two forms of the disease of Smallpox were recognised, now known to be due to two strains of the Variola virus. Those contracting Variola Minor had a greatly reduced risk of death — 1-2% — compared to those contracting Variola Major with 20% mortality. Infection via inhaled viral particles in droplets spread the infection more widely than the deliberate infection through a small skin wound. The smaller, localised infection is adequate to stimulate the immune system to produce specific immunity to the virus, while requiring more generations of the virus to reach levels of infection likely to kill the patient. The rising immunity terminates the infection. So the twofold effect is to ensure the less fatal form of the disease is the one caught, and to give the immune system the best start possible in combating it.
Inoculation in the East was historically performed by blowing smallpox crusts into the nostril. In Britain, Europe and the American Colonies the preferred method was rubbing material from a smallpox pustule from a selected mild case (Variola minor) into a scratch between the thumb and forefinger. This would generally be performed when an individual was in normal good health, and thus at peak resistance. The recipient would develop smallpox; however, due to being introduced through the skin rather than the lungs, and possibly because of the inoculated individual's preexisting state of good health, the small inoculum, and the single point of initial infection, the resulting case of smallpox was generally milder than the naturally-occurring form, produced far less facial scarring, and had a far lower mortality rate. As with survivors of the natural disease, the inoculated individual was subsequently immune to re-infection.
# Supplanted by vaccination
In 1796, Edward Jenner introduced the far safer method of inoculation with the cowpox virus, a non-fatal virus that also induced immunity to smallpox. This led to smallpox inoculation falling into disuse and eventually being banned in England in 1840. | Inoculation
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]
# Overview
The word "Inoculation" refers to the placement of something to where it will grow or reproduce, and is most commonly used in respect of the introduction of a serum, vaccine, or antigenic substance into the body of a person or animal, especially to produce or boost immunity to a specific disease; but also can be used to refer to the communication of a disease to a living organism by transferring its causative agent into the organism, to implant microorganisms or infectious material into a culture medium such as a brewers vat or a petri dish, to safeguard as if by inoculation, to introduce an idea or attitude into someone's mind, any placement of microorganisms or viruses at a site where infection is possible such as to increase soybeans' nitrogen fixation one can treat soybeans at planting with Rhizobium japonicum inoculant. The verb "to inoculate" is from Middle English "inoculaten", which meant "to graft a scion (a scion is a plant part to be grafted onto another plant); which in turn is from Latin "inoculre" or "inocult-".[1][2]
This article covers variolation, inoculation as a method of purposefully infecting a person with smallpox (Variola) in a controlled manner so as to minimise the severity of the infection and also to induce immunity against further infection. See vaccination for post-variolation methods of
safeguarding as if by inoculation by administering weakened or dead pathogens to a healthy person or animal with the intent of conferring immunity against a targeted form of a related disease agent.
Today the terms inoculation, vaccination and immunization are used more or less interchangeably and popularly refer to the process of artificial induction of immunity against various infectious diseases. The microorganism used in an inoculation is called the inoculant or inoculum.
# Origins
The earliest use of inoculation was from the Chinese. It is recorded that the Chinese inoculated their patients by making them snort the powdered scabs of smallpox victims. Another method of their inoculation was by scratching the powder into their skin.[4],[5]
Some scholars suggest that the practice originated in India.
Dr. J.Z. Holwell writes the most detailed account for the college of Physicians in London in 1767 (An account of the manner of inoculating for the smallpox in the East Indies, by J. Z. Holwell, F.R.S. addressed to the President and Members of the College of Physicians in London) ... Holwell's detailed account, not only describes inoculation, but also shows that the Indians knew that microbes caused such diseases:
# Importation to the West
The practice was introduced to the west by Lady Mary Wortley Montagu (May 26, 1689-August 21, 1762). Lady Montagu's husband, Edward Wortley Montagu, served as the British ambassador to the Ottoman Empire from 1716 to 1717. She witnessed inoculation in Constantinople, and was greatly impressed[citation needed]: she had lost a brother to smallpox and bore facial scars from the disease herself. In March 1718 she had the embassy surgeon, Charles Maitland, inoculate her five-year-old son. In 1721, after returning to England, she had her four-year-old daughter inoculated[citation needed]. She invited friends to see her daughter, including Sir Hans Sloane, the King's physician. Sufficient interest arose that Maitland gained permission to test inoculation at Newgate prison in exchange for their freedom on six prisoners due to be hanged[citation needed], an experiment which was witnessed by a number of notable doctors. The experiment succeeded, and in 1722 the Prince of Wales' daughters received inoculations[citation needed].
The practice of inoculation slowly spread amongst the royal families of Europe, usually followed by more general adoption amongst the people.
The practice is documented in America as early as 1721. Cotton Mather in Boston had a description of the African practice of inoculation from his slave[3] Onesimus and encouraged its application, with considerable controversy and strife. Fearing the outbreak of an epidemic, the editor of the South Carolina Gazette published a detailed description of the inoculation process in the April 22 issue. In Boston, there was opposition from churchmen regarding the practice who regarded it as "bidding defiance to Heaven itself, even to the will of God", though one historian also notes that "...within a year or two after the first experiment nearly three hundred persons had been inoculated ... in Boston and neighbouring towns, and out of these only six had died; whereas, during the same period, out of nearly six thousand persons who had taken smallpox naturally, and had received only the usual medical treatment, nearly one thousand had died." (from A History Of The Warfare Of Science With Theology In Christendom by Andrew Dickson White.)
In France considerable opposition arose to the introduction of inoculation. Voltaire, in his Lettres Philosophiques, wrote a criticism of his countrymen for being opposed to inoculation and having so little regard for the welfare of their children, concluding that "had inoculation been practised in France it would have saved the lives of thousands.".[5]
Inoculation grew in popularity in Europe through the 18th century. Given the high prevalence and often severe consequences of smallpox in Europe in the 18th century (according to Voltaire, there was a 60% incidence of first infection, a 20% mortality rate, and a 20% incidence of severe scarring),[6] many parents felt that the benefits of inoculation outweighted the risks and so inoculated their children.[7]
# Mechanism
Two forms of the disease of Smallpox were recognised, now known to be due to two strains of the Variola virus. Those contracting Variola Minor had a greatly reduced risk of death — 1-2% — compared to those contracting Variola Major with 20% mortality. Infection via inhaled viral particles in droplets spread the infection more widely than the deliberate infection through a small skin wound. The smaller, localised infection is adequate to stimulate the immune system to produce specific immunity to the virus, while requiring more generations of the virus to reach levels of infection likely to kill the patient. The rising immunity terminates the infection. So the twofold effect is to ensure the less fatal form of the disease is the one caught, and to give the immune system the best start possible in combating it.
Inoculation in the East was historically performed by blowing smallpox crusts into the nostril. In Britain, Europe and the American Colonies the preferred method was rubbing material from a smallpox pustule from a selected mild case (Variola minor) into a scratch between the thumb and forefinger. [6] This would generally be performed when an individual was in normal good health, and thus at peak resistance. The recipient would develop smallpox; however, due to being introduced through the skin rather than the lungs, and possibly because of the inoculated individual's preexisting state of good health, the small inoculum, and the single point of initial infection, the resulting case of smallpox was generally milder than the naturally-occurring form, produced far less facial scarring, and had a far lower mortality rate. As with survivors of the natural disease, the inoculated individual was subsequently immune to re-infection.
# Supplanted by vaccination
In 1796, Edward Jenner introduced the far safer method of inoculation with the cowpox virus, a non-fatal virus that also induced immunity to smallpox. This led to smallpox inoculation falling into disuse and eventually being banned in England in 1840. | https://www.wikidoc.org/index.php/Inoculate | |
92b3039db06d808a1977d3e8ac9b645fd5be7706 | wikidoc | Insulin pen | Insulin pen
An insulin pen is an insulin injection system for the treatment of diabetes. A pen is comprised of disposable needles, a vial of insulin, and a "pen."
# Types of pens
A number of companies make insulin pens including Novo Nordisk, Aventis and Eli Lilly. These companies produce pens for most of their insulins, including novolog, humalog (also known as insulin lispro), levemir and lantus. However, there are really only two different types of systems: replaceable cartridge and prefilled.
A replaceable cartridge pens reuses the pen portion. When the insulin is empty, the vial is simply replaced by inserting a new one.
A prefilled pen is entirely disposable. When the insulin is gone, the entire unit is discarded.
# Use
The information given here is for guidance only and will not necessarily be exactly what your doctor has recommended you do. Please follow your doctor's advice.
One significant advantage of pens is their ease of use. To use a pen:
- Screw on a new needle
- If necessary, prime the pen to remove any air from the needle
- Turn the knob on the end of the pen (or "dial") to the number of units needed
- Insert the needle into the skin
- Press the button on the end of the pen to deliver the dose
- Count to five
- Remove
# Advantages
Insulin pens have a number of advantages:
- More convenient than traditional vial and syringe
- Repeatedly more accurate dosages
- Easier to use for those with visual or fine motor skills impairments.
- Less injection pain (as polished and coated needles are not dulled by insertion into a vial of insulin before a 2nd insertion into the skin)
# Disadvantages
Unlike the traditional syringe, pens are usually restricted to full or half unit dosing. In addition, insurance coverage for insulin pens in the United States may vary widely. | Insulin pen
An insulin pen is an insulin injection system for the treatment of diabetes. A pen is comprised of disposable needles, a vial of insulin, and a "pen."
# Types of pens
A number of companies make insulin pens including Novo Nordisk, Aventis and Eli Lilly. These companies produce pens for most of their insulins, including novolog, humalog (also known as insulin lispro), levemir and lantus. However, there are really only two different types of systems: replaceable cartridge and prefilled.
A replaceable cartridge pens reuses the pen portion. When the insulin is empty, the vial is simply replaced by inserting a new one.
A prefilled pen is entirely disposable. When the insulin is gone, the entire unit is discarded.
# Use
The information given here is for guidance only and will not necessarily be exactly what your doctor has recommended you do. Please follow your doctor's advice.
One significant advantage of pens is their ease of use. To use a pen:
- Screw on a new needle
- If necessary, prime the pen to remove any air from the needle
- Turn the knob on the end of the pen (or "dial") to the number of units needed
- Insert the needle into the skin
- Press the button on the end of the pen to deliver the dose
- Count to five
- Remove
# Advantages
Insulin pens have a number of advantages:
- More convenient than traditional vial and syringe
- Repeatedly more accurate dosages
- Easier to use for those with visual or fine motor skills impairments.
- Less injection pain (as polished and coated needles are not dulled by insertion into a vial of insulin before a 2nd insertion into the skin)
# Disadvantages
Unlike the traditional syringe, pens are usually restricted to full or half unit dosing. In addition, insurance coverage for insulin pens in the United States may vary widely. | https://www.wikidoc.org/index.php/Insulin_pen | |
68078f718b42269fe3526fa7b7ec8573d32f87cf | wikidoc | Interobject | Interobject
An interobject is a phenomenon of dreams, in which there is a perception of something that is “between” two objects. The term was coined by Blechner in his book The Dream Frontier. Interobjects differ from typical dream condensations in which two objects are fused into one. Instead the condensation is incomplete. Some examples from the literature on dreams include “a piece of hardware, something like the lock of a door or perhaps a pair of paint-frozen hinges,” and “something between a record-player and a balance scale.” Interobjects are new creations derived from partially-fused blends of other objects.
Interobjects, like disjunctive cognitions, would sound bizarre or psychotic as perceptions in waking life, but are accepted by most people as commonplace in dreams. They have implications for both the theory of dreaming and the theory of categorization. Interobjects show the dreaming mind grouping items together whose connection may not be apparent to the waking mind. “Something between an aqueduct or a swimming-pool” reveals the category of “large man-made architectural objects that contain water.” “Something between a cellphone and a baby” reveals a category combining a relatively new piece of technology and a live infant: both make noise when you don’t expect it, both are held close to your body, and both can give you a feeling of connectedness.
We do not know if interobjects occur only in dreamlife or may occur as unconscious categorizations during waking life. Freud called interobjects “intermediate and composite structures.” He thought they were inferior mental constructions and were scrupulously avoided in waking life.
Most adults tend to regularize interobjects when discussing them in waking life. Children are better able to sustain interobjects in their original form. A child told his father a dream in which he was in trouble at sea and “a seal swam up to them. They thought it was just a seal, but then they looked and under the water it was a whole boat, it was huge, so they climbed onto the seal/boat, and it brought them to the shore of the mainland.” When the boy told his father the dream in the morning, the father, speaking like an adult who cannot tolerate contradictions, said to him: “So really, it was a boat, a big, safe boat.” The child, holding fast to the integrity of his dream, said, “It was a boat, but it was still a big, friendly seal.” This child had not yet learned to regularize his perceptions to fit the way the world works. Adults may learn to reject interobjects in waking life, but still retain them in their dreams.
Interobjects may have an elementary function in human thought. By transgressing the normal mental categories described by Eleanor Rosch, interobjects may be the origin of new ideas that would be harder to come by using only fully-formed, secondary process formations. They may be one example of “Oneiric Darwinism” in which new thought-mutations are created during dream-life and rejected or retained in waking life depending on their usefulness.
Interobjects have been used creatively in advertising. A set of rules, known as a “Replacement template,” enabled a computer to create interobjects:
“Given a product (P) with a trait (T), the subject is asked to come up with a creative idea for an ad that conveys the message that P has T. In a visual format, an object S (symbol), which is universally identified with T, is replaced with P. The effect is enhanced if S is placed in a situation in which T is essential. Moreover, the replacement operation can be iterated: Rather than P one can use parts of it, or aspects of it, or objects associated with it, to replace the corresponding elements associated with S.” When asked to produce an ad for the World Tennis Cup tournament in Jerusalem,
the computer generated a mosque with a dome that had a tennis ball texture. In advertising on-time performance for an airline, the computer generated a cuckoo-clock in which a jumbo jet pops out of the clock instead of a cuckoo. Both of these creations – the mosque/tennis ball and the jumbo jet/cuckoo clock – are interobjects.
- ↑ Hobson, J. A. (1988) The Dreaming Brain. New York: Basic Books.
- ↑ Meltzer, D. (1984) Dream-Life. Perthshire, UK: Clunie Press.
- ↑ States, B. (1995) Dreaming “accidentally” of Harold Pinter: The interplay of metaphor and metonymy in dreams. Dreaming, 5:229-245
- ↑ Blechner, M. (2005) The grammar of irrationality: What psychoanalytic dream study can tell us about the brain. Contemporary Psychoanalysis, 41: 203-221.
- ↑ Freud, S. (1900) The Interpretation of Dreams. New York: Viking.
- ↑ Blechner, M. (2001) The Dream Frontier. Hillsdale, NJ: The Analytic Press.
- ↑ Goldenberg, J., Mazursky, D., & Solomon, S. (1999) Creative sparks. Science, 285:1495-1496. | Interobject
An interobject is a phenomenon of dreams, in which there is a perception of something that is “between” two objects. The term was coined by Blechner in his book The Dream Frontier. Interobjects differ from typical dream condensations in which two objects are fused into one. Instead the condensation is incomplete. Some examples from the literature on dreams include “a piece of hardware, something like the lock of a door or perhaps a pair of paint-frozen hinges,” [1] and “something between a record-player and a balance scale.” [2] Interobjects are new creations derived from partially-fused blends of other objects.
Interobjects, like disjunctive cognitions, would sound bizarre or psychotic as perceptions in waking life, but are accepted by most people as commonplace in dreams. They have implications for both the theory of dreaming and the theory of categorization. Interobjects show the dreaming mind grouping items together whose connection may not be apparent to the waking mind. “Something between an aqueduct or a swimming-pool” [3] reveals the category of “large man-made architectural objects that contain water.” “Something between a cellphone and a baby”[4] reveals a category combining a relatively new piece of technology and a live infant: both make noise when you don’t expect it, both are held close to your body, and both can give you a feeling of connectedness.
We do not know if interobjects occur only in dreamlife or may occur as unconscious categorizations during waking life. Freud [5] called interobjects “intermediate and composite structures.” He thought they were inferior mental constructions and were scrupulously avoided in waking life.
Most adults tend to regularize interobjects when discussing them in waking life. Children are better able to sustain interobjects in their original form. A child told his father a dream in which he was in trouble at sea and “a seal swam up to them. They thought it was just a seal, but then they looked and under the water it was a whole boat, it was huge, so they climbed onto the seal/boat, and it brought them to the shore of the mainland.” When the boy told his father the dream in the morning, the father, speaking like an adult who cannot tolerate contradictions, said to him: “So really, it was a boat, a big, safe boat.” The child, holding fast to the integrity of his dream, said, “It was a boat, but it was still a big, friendly seal.” This child had not yet learned to regularize his perceptions to fit the way the world works. Adults may learn to reject interobjects in waking life, but still retain them in their dreams.
Interobjects may have an elementary function in human thought. By transgressing the normal mental categories described by Eleanor Rosch, interobjects may be the origin of new ideas that would be harder to come by using only fully-formed, secondary process formations. They may be one example of “Oneiric Darwinism” [6] in which new thought-mutations are created during dream-life and rejected or retained in waking life depending on their usefulness.
Interobjects have been used creatively in advertising. A set of rules, known as a “Replacement template,” enabled a computer to create interobjects:
“Given a product (P) with a trait (T), the subject is asked to come up with a creative idea for an ad that conveys the message that P has T. In a visual format, an object S (symbol), which is universally identified with T, is replaced with P. The effect is enhanced if S is placed in a situation in which T is essential. Moreover, the replacement operation can be iterated: Rather than P one can use parts of it, or aspects of it, or objects associated with it, to replace the corresponding elements associated with S.”[7] When asked to produce an ad for the World Tennis Cup tournament in Jerusalem,
the computer generated a mosque with a dome that had a tennis ball texture. In advertising on-time performance for an airline, the computer generated a cuckoo-clock in which a jumbo jet pops out of the clock instead of a cuckoo. Both of these creations – the mosque/tennis ball and the jumbo jet/cuckoo clock – are interobjects.
- ↑ Hobson, J. A. (1988) The Dreaming Brain. New York: Basic Books.
- ↑ Meltzer, D. (1984) Dream-Life. Perthshire, UK: Clunie Press.
- ↑ States, B. (1995) Dreaming “accidentally” of Harold Pinter: The interplay of metaphor and metonymy in dreams. Dreaming, 5:229-245
- ↑ Blechner, M. (2005) The grammar of irrationality: What psychoanalytic dream study can tell us about the brain. Contemporary Psychoanalysis, 41: 203-221.
- ↑ Freud, S. (1900) The Interpretation of Dreams. New York: Viking.
- ↑ Blechner, M. (2001) The Dream Frontier. Hillsdale, NJ: The Analytic Press.
- ↑ Goldenberg, J., Mazursky, D., & Solomon, S. (1999) Creative sparks. Science, 285:1495-1496.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Interobject | |
45230f00a85d5a01628321f8c8b0f45b96524fc9 | wikidoc | Nasal spray | Nasal spray
# Overview
Nasal sprays are used for the nasal delivery of a drug or drugs, generally to alleviate cold or allergy symptoms such as nasal congestion. Although delivery methods vary, most nasal sprays function by instilling a fine mist into the nostril by action of a hand-operated pump mechanism. The three main types available are: antihistamines, corticosteroids, and topical decongestants.
# Antihistamines
Excessive histamine function is the primary cause of allergic reactions in people. Histamine is a chemical naturally produced by the body which creates an inflammatory effect to help the immune system remove foreign substances. Antihistamines work by competing for receptor sites to block the function of histamine, thereby reducing the inflammatory effect.
Astelin (Azelastin hydrocholoride) is the only local antihistamine available as a nasal spray. It is available by prescription only and has gained popularity with sufferers of allergic rhinitis.
# Steroids
Steroidal nasal sprays, also available only by prescription, use the anti-inflammatory effect of a corticosteroid to reduce swelling and congestion in the nasal passages and sinuses. Examples include Nasonex, Flonase, Nasacort, and Rhinocort. They generally take a week to ten days to reach their maximum effectiveness, and are considered safe for extended use.
# Topical decongestants
Oxymetazoline hydrochloride decongestant nasal sprays such as Afrin and Vicks Sinex, which are available over-the-counter in the United States and the UK, work to very quickly open up nasal passages by constricting blood vessels in the lining of the nose.
Prolonged use of these types of sprays can damage the delicate mucous membranes in the nose. Ironically, this causes increased inflammation, an effect known as rhinitis medicamentosa, or the "rebound effect". As a result, decongestant nasal sprays are advised for short-term use only.
# Unmedicated sprays
Saline sprays are also common and are typically unmedicated. A mist of saline solution is delivered to help moisturize dry or irritated nostrils.
Nasal salves have been shown to improve respiratory discomfort caused by the increased dryness of air in pressurized air flight and some air conditioned offices (sick building syndrome) They have been shown to reduce susceptibility to various flight related respiratory infections.
It is becoming increasingly common for a physicians to recommend nasal irrigation with saline solution (or Jala neti) as an alternative or combined treatment.
# Combined use
Frequently, a doctor or allergist will prescribe several types of nasal sprays in combination with each other or with other drugs. For example, a decongestant spray is often advised for the first few days of treatment in conjunction with an antihistamine or steroidal spray. The quick-acting effects of the decongestant allow for better initial delivery of the other sprays.
de:Nasenspray
nl:Neusspray
sv:Nässprej | Nasal spray
# Overview
Nasal sprays are used for the nasal delivery of a drug or drugs, generally to alleviate cold or allergy symptoms such as nasal congestion. Although delivery methods vary, most nasal sprays function by instilling a fine mist into the nostril by action of a hand-operated pump mechanism. The three main types available are: antihistamines, corticosteroids, and topical decongestants.
# Antihistamines
Excessive histamine function is the primary cause of allergic reactions in people. Histamine is a chemical naturally produced by the body which creates an inflammatory effect to help the immune system remove foreign substances. Antihistamines work by competing for receptor sites to block the function of histamine, thereby reducing the inflammatory effect.
Astelin (Azelastin hydrocholoride) is the only local antihistamine available as a nasal spray. It is available by prescription only and has gained popularity with sufferers of allergic rhinitis.
# Steroids
Steroidal nasal sprays, also available only by prescription, use the anti-inflammatory effect of a corticosteroid to reduce swelling and congestion in the nasal passages and sinuses. Examples include Nasonex, Flonase, Nasacort, and Rhinocort. They generally take a week to ten days to reach their maximum effectiveness, and are considered safe for extended use.
# Topical decongestants
Oxymetazoline hydrochloride decongestant nasal sprays such as Afrin and Vicks Sinex, which are available over-the-counter in the United States and the UK, work to very quickly open up nasal passages by constricting blood vessels in the lining of the nose.
Prolonged use of these types of sprays can damage the delicate mucous membranes in the nose. Ironically, this causes increased inflammation, an effect known as rhinitis medicamentosa, or the "rebound effect". As a result, decongestant nasal sprays are advised for short-term use only.
# Unmedicated sprays
Saline sprays are also common and are typically unmedicated. A mist of saline solution is delivered to help moisturize dry or irritated nostrils.
Nasal salves have been shown to improve respiratory discomfort caused by the increased dryness of air in pressurized air flight and some air conditioned offices (sick building syndrome) They have been shown to reduce susceptibility to various flight related respiratory infections.
It is becoming increasingly common for a physicians to recommend nasal irrigation with saline solution (or Jala neti) as an alternative or combined treatment.
# Combined use
Frequently, a doctor or allergist will prescribe several types of nasal sprays in combination with each other or with other drugs. For example, a decongestant spray is often advised for the first few days of treatment in conjunction with an antihistamine or steroidal spray. The quick-acting effects of the decongestant allow for better initial delivery of the other sprays.
Template:Treatment-stub
de:Nasenspray
nl:Neusspray
sv:Nässprej
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Intranasally | |
ce62ec77e1d26ce6c7ff3147deac621744e36786 | wikidoc | Intumescent | Intumescent
An intumescent is a substance which swells as a result of heat exposure, thus increasing in volume, and decreasing in density. Intumescents are typically used in passive fire protection and require listing and approval use and compliance in their installed configurations in order to comply with the law.
# Types of intumescents
## Soft char producers
These intumescents produce a light char, which is a poor conductor of heat, thus retarding heat transfer. Typically, these materials also contain a significant amount of hydrates. As the hydrates are spent, water vapour is released, which has a cooling effect. Once the water is spent, it is only the insulation characteristics of the char that was produced, which can slow down heat transfer from the exposed side to the unexposed side of an assembly. Soft char producers are typically used in thin film intumescents for fireproofing of structural steel as well as firestop pillows. Typically, the expansion pressure that is created for these products is very low, because the soft carbonaceous char has little substance, which is beneficial if the aim is to produce a layer of insulation.
## Hard expanding char producers
Harder chars are produced with sodium silicates and graphite. These products are suitable for use in plastic pipe firestops as well as exterior steel fireproofing. In those applications, it is necessary to produce a more substantial char, with a quantifiable expansion pressure. In the case of the firestops, a melting, burning plastic pipe must be squeezed together and shut so that there will be no hole for fire to go through an opening in an otherwise fire-resistance rated wall or floor assembly. In the case of the exterior fireproofing, a hydrocarbon fire must be held off with quite potentially more kinetic energy than a house fire. Intumescents that produce hard chars are not typically used for interior spray fireproofing as they are not suitable for that application.
# Uses of intumescents in passive fire protection
## Applications
- firestopping,
- fireproofing
- gasketing applications
- windows
## Occupancies
- buildings
- offshore construction
- ships
- aircraft.
# Problems with intumescents
Some intumescents are susceptible to environmental influences such as humidity, which can reduce or negate their ability to function. DIBt approvals quantify the ability of intumescents to stand the test of time against various environmental exposures. DIBt approved firestops and fireproofing materials are available in Canada and the U.S.
# Gallery
- Low Pressure Intumescent Resin: This product is suitable for use in passive fire protection in general, firestopping and interior fireproofing in particular. The small, orange chunk on the bottom right hand side is capable of growing into that large black shape. This type of intumescent is typically highly endothermic. It contains a lot of chemically bound water, in hydrates. As this is released, it cools adjacent materials. Such intumescents are useful as ingredients in firestop pillows and in paints, which are used for fireproofing purposes. These intumescents do not produce enough expansion force to be used in plastic pipe devices, where the intumescent must squeeze a melting plastic pipe or conduit shut.
Low Pressure Intumescent Resin: This product is suitable for use in passive fire protection in general, firestopping and interior fireproofing in particular. The small, orange chunk on the bottom right hand side is capable of growing into that large black shape. This type of intumescent is typically highly endothermic. It contains a lot of chemically bound water, in hydrates. As this is released, it cools adjacent materials. Such intumescents are useful as ingredients in firestop pillows and in paints, which are used for fireproofing purposes. These intumescents do not produce enough expansion force to be used in plastic pipe devices, where the intumescent must squeeze a melting plastic pipe or conduit shut.
- Pipes covered with a thin-film intumescent spray fireproofing product called unitherm. As the flame from the blow-torch is applied, the intumescent sodium silicate expands, forming a layer of insulation, which slows down heat transfer to the pipe below. Hydrates within the coating give up their water content, maintaining a temperature near the boiling point of 100°C. The critical steel temperature is ca. 540°C. Once the water is spent and enough heat has gone through the char, the steel can reach and exceed its critical temperature and then lose its strength. The time this takes determines the fire-resistance rating.
Pipes covered with a thin-film intumescent spray fireproofing product called unitherm. As the flame from the blow-torch is applied, the intumescent sodium silicate expands, forming a layer of insulation, which slows down heat transfer to the pipe below. Hydrates within the coating give up their water content, maintaining a temperature near the boiling point of 100°C. The critical steel temperature is ca. 540°C. Once the water is spent and enough heat has gone through the char, the steel can reach and exceed its critical temperature and then lose its strength. The time this takes determines the fire-resistance rating.
- In this picture, the flame has been removed after the thin-film intumescent spray fireproofing product has been completely expanded. Some intumescents can undergo shrinkage shortly after full expansion has taken place. The important thing to remember, however, is the need for listing and approval use and compliance of the installed configuration.
In this picture, the flame has been removed after the thin-film intumescent spray fireproofing product has been completely expanded. Some intumescents can undergo shrinkage shortly after full expansion has taken place. The important thing to remember, however, is the need for listing and approval use and compliance of the installed configuration.
- Intumescent gasketing used in passive fire protection, for fire door applications. Typically, such gasketing is needed to pass positive pressure furnace testing, a recent change in North America.
Intumescent gasketing used in passive fire protection, for fire door applications. Typically, such gasketing is needed to pass positive pressure furnace testing, a recent change in North America.
- Intumescent putty, permanently pliable, used in a cable penetration firestop. Permanently pliable putties are similar in consistency to play-dough used for children's toys. Putties of this nature also lend themselves to be used as pads to cover electrical outlet boxes inside drywall assemblies required to have a fire-resistance rating. The endothermic and insulative action of the pads reduce thermal transfer through the metallic outlet box to the unexposed side of the rated drywall assembly. All intumescents must be installed in a manner consistent with listing and approval use and compliance requirements.
Intumescent putty, permanently pliable, used in a cable penetration firestop. Permanently pliable putties are similar in consistency to play-dough used for children's toys. Putties of this nature also lend themselves to be used as pads to cover electrical outlet boxes inside drywall assemblies required to have a fire-resistance rating. The endothermic and insulative action of the pads reduce thermal transfer through the metallic outlet box to the unexposed side of the rated drywall assembly. All intumescents must be installed in a manner consistent with listing and approval use and compliance requirements.
- A passive fire protection example of an intumescent with strong expansion pressure. This intumescent is called Palusol. It is based on waterproofed sodium silicate. Another high-expansion intumescent popular for use in plastic pipe firestop devices is graphite. Graphite tends to be less affected by atmospheric conditions than many water-bearing intumescents.
A passive fire protection example of an intumescent with strong expansion pressure. This intumescent is called Palusol. It is based on waterproofed sodium silicate. Another high-expansion intumescent popular for use in plastic pipe firestop devices is graphite. Graphite tends to be less affected by atmospheric conditions than many water-bearing intumescents.
- Construction of a test sample, consisting of a mock-up concrete floor frame, complete with penetrants. The concrete frame measures approximately 5’ x 9’ x 4" (ca. 1.5m x 2.3m x 10cm). It has a large hole in the centre with many mechanical and electrical services traversing. The penetrants extend 1’ (30cm) into the furnace and 3’ (91cm) on the unexposed side. A firestop mortar is being applied here. Notice the intumescent wrap strip surrounding the fibreglass pipe insulation. When the fire starts, this embedded intumescent will swell to take up the place of the melting insulation. The test was conducted in accordance with the Canadian firestop test method ULC in Scarborough, Ontario.
Construction of a test sample, consisting of a mock-up concrete floor frame, complete with penetrants. The concrete frame measures approximately 5’ x 9’ x 4" (ca. 1.5m x 2.3m x 10cm). It has a large hole in the centre with many mechanical and electrical services traversing. The penetrants extend 1’ (30cm) into the furnace and 3’ (91cm) on the unexposed side. A firestop mortar is being applied here. Notice the intumescent wrap strip surrounding the fibreglass pipe insulation. When the fire starts, this embedded intumescent will swell to take up the place of the melting insulation. The test was conducted in accordance with the Canadian firestop test method ULC in Scarborough, Ontario. | Intumescent
An intumescent is a substance which swells as a result of heat exposure, thus increasing in volume, and decreasing in density. Intumescents are typically used in passive fire protection and require listing and approval use and compliance in their installed configurations in order to comply with the law.
# Types of intumescents
## Soft char producers
These intumescents produce a light char, which is a poor conductor of heat, thus retarding heat transfer. Typically, these materials also contain a significant amount of hydrates. As the hydrates are spent, water vapour is released, which has a cooling effect. Once the water is spent, it is only the insulation characteristics of the char that was produced, which can slow down heat transfer from the exposed side to the unexposed side of an assembly. Soft char producers are typically used in thin film intumescents for fireproofing of structural steel as well as firestop pillows. Typically, the expansion pressure that is created for these products is very low, because the soft carbonaceous char has little substance, which is beneficial if the aim is to produce a layer of insulation.
## Hard expanding char producers
Harder chars are produced with sodium silicates and graphite. These products are suitable for use in plastic pipe firestops as well as exterior steel fireproofing. In those applications, it is necessary to produce a more substantial char, with a quantifiable expansion pressure. In the case of the firestops, a melting, burning plastic pipe must be squeezed together and shut so that there will be no hole for fire to go through an opening in an otherwise fire-resistance rated wall or floor assembly. In the case of the exterior fireproofing, a hydrocarbon fire must be held off with quite potentially more kinetic energy than a house fire. Intumescents that produce hard chars are not typically used for interior spray fireproofing as they are not suitable for that application.
# Uses of intumescents in passive fire protection
## Applications
- firestopping,
- fireproofing
- gasketing applications
- windows
## Occupancies
- buildings
- offshore construction
- ships
- aircraft.
# Problems with intumescents
Some intumescents are susceptible to environmental influences such as humidity, which can reduce or negate their ability to function. DIBt approvals quantify the ability of intumescents to stand the test of time against various environmental exposures. DIBt approved firestops and fireproofing materials are available in Canada and the U.S.[1]
# Gallery
- Low Pressure Intumescent Resin: This product is suitable for use in passive fire protection in general, firestopping and interior fireproofing in particular. The small, orange chunk on the bottom right hand side is capable of growing into that large black shape. This type of intumescent is typically highly endothermic. It contains a lot of chemically bound water, in hydrates. As this is released, it cools adjacent materials. Such intumescents are useful as ingredients in firestop pillows and in paints, which are used for fireproofing purposes. These intumescents do not produce enough expansion force to be used in plastic pipe devices, where the intumescent must squeeze a melting plastic pipe or conduit shut.
Low Pressure Intumescent Resin: This product is suitable for use in passive fire protection in general, firestopping and interior fireproofing in particular. The small, orange chunk on the bottom right hand side is capable of growing into that large black shape. This type of intumescent is typically highly endothermic. It contains a lot of chemically bound water, in hydrates. As this is released, it cools adjacent materials. Such intumescents are useful as ingredients in firestop pillows and in paints, which are used for fireproofing purposes. These intumescents do not produce enough expansion force to be used in plastic pipe devices, where the intumescent must squeeze a melting plastic pipe or conduit shut.
- Pipes covered with a thin-film intumescent spray fireproofing product called unitherm. As the flame from the blow-torch is applied, the intumescent sodium silicate expands, forming a layer of insulation, which slows down heat transfer to the pipe below. Hydrates within the coating give up their water content, maintaining a temperature near the boiling point of 100°C. The critical steel temperature is ca. 540°C. Once the water is spent and enough heat has gone through the char, the steel can reach and exceed its critical temperature and then lose its strength. The time this takes determines the fire-resistance rating.
Pipes covered with a thin-film intumescent spray fireproofing product called unitherm. As the flame from the blow-torch is applied, the intumescent sodium silicate expands, forming a layer of insulation, which slows down heat transfer to the pipe below. Hydrates within the coating give up their water content, maintaining a temperature near the boiling point of 100°C. The critical steel temperature is ca. 540°C. Once the water is spent and enough heat has gone through the char, the steel can reach and exceed its critical temperature and then lose its strength. The time this takes determines the fire-resistance rating.
- In this picture, the flame has been removed after the thin-film intumescent spray fireproofing product has been completely expanded. Some intumescents can undergo shrinkage shortly after full expansion has taken place. The important thing to remember, however, is the need for listing and approval use and compliance of the installed configuration.
In this picture, the flame has been removed after the thin-film intumescent spray fireproofing product has been completely expanded. Some intumescents can undergo shrinkage shortly after full expansion has taken place. The important thing to remember, however, is the need for listing and approval use and compliance of the installed configuration.
- Intumescent gasketing used in passive fire protection, for fire door applications. Typically, such gasketing is needed to pass positive pressure furnace testing, a recent change in North America.
Intumescent gasketing used in passive fire protection, for fire door applications. Typically, such gasketing is needed to pass positive pressure furnace testing, a recent change in North America.
- Intumescent putty, permanently pliable, used in a cable penetration firestop. Permanently pliable putties are similar in consistency to play-dough used for children's toys. Putties of this nature also lend themselves to be used as pads to cover electrical outlet boxes inside drywall assemblies required to have a fire-resistance rating. The endothermic and insulative action of the pads reduce thermal transfer through the metallic outlet box to the unexposed side of the rated drywall assembly. All intumescents must be installed in a manner consistent with listing and approval use and compliance requirements.
Intumescent putty, permanently pliable, used in a cable penetration firestop. Permanently pliable putties are similar in consistency to play-dough used for children's toys. Putties of this nature also lend themselves to be used as pads to cover electrical outlet boxes inside drywall assemblies required to have a fire-resistance rating. The endothermic and insulative action of the pads reduce thermal transfer through the metallic outlet box to the unexposed side of the rated drywall assembly. All intumescents must be installed in a manner consistent with listing and approval use and compliance requirements.
- A passive fire protection example of an intumescent with strong expansion pressure. This intumescent is called Palusol. It is based on waterproofed sodium silicate. Another high-expansion intumescent popular for use in plastic pipe firestop devices is graphite. Graphite tends to be less affected by atmospheric conditions than many water-bearing intumescents.
A passive fire protection example of an intumescent with strong expansion pressure. This intumescent is called Palusol. It is based on waterproofed sodium silicate. Another high-expansion intumescent popular for use in plastic pipe firestop devices is graphite. Graphite tends to be less affected by atmospheric conditions than many water-bearing intumescents.
- Construction of a test sample, consisting of a mock-up concrete floor frame, complete with penetrants. The concrete frame measures approximately 5’ x 9’ x 4" (ca. 1.5m x 2.3m x 10cm). It has a large hole in the centre with many mechanical and electrical services traversing. The penetrants extend 1’ (30cm) into the furnace and 3’ (91cm) on the unexposed side. A firestop mortar is being applied here. Notice the intumescent wrap strip surrounding the fibreglass pipe insulation. When the fire starts, this embedded intumescent will swell to take up the place of the melting insulation. The test was conducted in accordance with the Canadian firestop test method ULC in Scarborough, Ontario.[2]
Construction of a test sample, consisting of a mock-up concrete floor frame, complete with penetrants. The concrete frame measures approximately 5’ x 9’ x 4" (ca. 1.5m x 2.3m x 10cm). It has a large hole in the centre with many mechanical and electrical services traversing. The penetrants extend 1’ (30cm) into the furnace and 3’ (91cm) on the unexposed side. A firestop mortar is being applied here. Notice the intumescent wrap strip surrounding the fibreglass pipe insulation. When the fire starts, this embedded intumescent will swell to take up the place of the melting insulation. The test was conducted in accordance with the Canadian firestop test method ULC in Scarborough, Ontario.[2] | https://www.wikidoc.org/index.php/Intumescent | |
add4cd6b480c787ee66a9aa2230854fd8fa80293 | wikidoc | Iodobenzene | Iodobenzene
Iodobenzene is an organic compound consisting of a benzene ring substitituted with one iodine atom. It is a useful as a synthetic intermediate in organic chemistry. Since the C-I bond is weaker than C-Br or C-Cl, it is more reactive than bromobenzene or chlorobenzene. Iodobenzene can react with magnesium to form a Grignard reagent, phenylmagnesium iodide. Phenylmagnesium iodide, like the bromide analog, is a synthetic equivalent for the phenyl synthon.
It can also serve as a substrate for the Sonogashira coupling, reacting it with an alkyne.
# Preparation
Iodobenzene is commercially available, but it may be prepared in the laboratory from aniline. In the first step, the amine functional group is diazotized with hydrochloric acid and sodium nitrite. Potassium iodide is added to the resultant diazonium chloride, causing nitrogen gas to evolve. Any excess nitrite is hydrolyzed with a strong base; the mixture is acidified and the desired product is separated by steam distillation.
Alternatively, it may be produced by refluxing iodine and nitric acid with benzene. | Iodobenzene
Iodobenzene is an organic compound consisting of a benzene ring substitituted with one iodine atom. It is a useful as a synthetic intermediate in organic chemistry. Since the C-I bond is weaker than C-Br or C-Cl, it is more reactive than bromobenzene or chlorobenzene. Iodobenzene can react with magnesium to form a Grignard reagent, phenylmagnesium iodide. Phenylmagnesium iodide, like the bromide analog, is a synthetic equivalent for the phenyl synthon.
It can also serve as a substrate for the Sonogashira coupling, reacting it with an alkyne.
# Preparation
Iodobenzene is commercially available, but it may be prepared in the laboratory from aniline. In the first step, the amine functional group is diazotized with hydrochloric acid and sodium nitrite. Potassium iodide is added to the resultant diazonium chloride, causing nitrogen gas to evolve. Any excess nitrite is hydrolyzed with a strong base; the mixture is acidified and the desired product is separated by steam distillation.[1]
Alternatively, it may be produced by refluxing iodine and nitric acid with benzene.[2] | https://www.wikidoc.org/index.php/Iodobenzene | |
619ed3b7c3652041696be5dab8709b09ba78d95b | wikidoc | Iodomethane | Iodomethane
# Overview
Iodomethane, commonly called methyl iodide and commonly abbreviated "MeI", is the chemical compound with the formula CH3I. This dense volatile liquid is related to methane by replacement of one hydrogen atom by an atom of iodine and its dipole moment is 1.59 D. Refractive index is 1.5304 (20 °C, D), 1.5293 (21 °C, D). It is miscible with common organic solvents. It is colourless, although upon exposure to light, samples develop a purplish tinge caused by the presence of I2. Storage over copper metal absorbs the iodine. Methyl iodide is widely used in organic synthesis to deliver a methyl group, via the transformation called methylation. It is naturally emitted by rice plantations in small amounts.
# Chemical properties
Methyl iodide is an excellent substrate for SN2 substitution reactions. It is sterically open for attack by nucleophiles, and iodide is a good leaving group. For example, it can be used for the methylation of phenols or carboxylic acids:
In these examples, the base (K2CO3 or Li2CO3) removes the acidic proton to form the carboxylate or phenoxide anion, which serves as the nucleophile in the SN2 substitution.
Iodide is a "soft" anion which means that methylation with MeI tends to occur at the "softer" end of an ambidentate nucleophile. For example, reaction with thiocyanate ion favours attack at Sulfur rather than "hard" Nitrogen, leading mainly to methyl thiocyanate (CH3SCN) rather than CH3NCS. This behavior is relevant to the methylation of stabilized enolates such as those derived from 1,3-dicarbonyl compounds. Methylation of these and related enolates can occur on the harder oxygen atom or the (usually desired) carbon atom. With methyl iodide, C-alkylation nearly always predominates.
MeI is also an important precursor to methylmagnesium iodide or "MeMgI", which is a common reagent. Because MeMgI forms readily, it is often prepared in instructional laboratories as an illustration of Grignard reagents. The use of MeMgI has been somewhat superseded by the commercially available methyl lithium.
In the Monsanto process, MeI forms in situ from the reaction of methanol and hydrogen iodide. The CH3I then reacts with carbon monoxide in the presence of a rhodium complex to form acetyl iodide, the precursor to acetic acid after hydrolysis. Most acetic acid is prepared by this method.
MeI hydrolyzes at 270 °C forming hydrogen iodide, carbon monoxide and carbon dioxide.
# Preparation
Iodomethane is formed via the exothermic reaction that occurs when iodine is added to a mixture of methanol with red phosphorus:
The iodinating reagent is phosphorus triiodide that is formed in situ. Alternatively, it is prepared from the reaction of dimethylsulfate with potassium iodide in the presence of calcium carbonate:
The CH3I can easily be purified by distillation followed by washing with Na2S2O3 (to remove iodine) and then water, aq. Na2CO3.
Methyl iodide can be formed during nuclear accidents by the reaction of organic matter with the "fission iodine."
# Choice of iodomethane as a methylating agent
Iodomethane is an excellent reagent for methylation, but there are some disadvantages to its use. It has a high equivalent weight: one mole of MeI weighs almost three times as much as one mole of methyl chloride. However, the chloride is a gas (as is methyl bromide), making it more awkward to work with than liquid MeI. Methyl chloride is a poorer methylating reagent than MeI, though it is often adequate.
Iodides are generally expensive relative to the more common chlorides and bromides, though iodomethane is reasonably affordable; on a commercial scale the toxic dimethyl sulfate is preferred, since it is both cheap and liquid. The iodide leaving group in MeI may cause side reactions, as it is a powerful nucleophile. Finally, being highly reactive, MeI is more dangerous for laboratory workers than related chlorides and bromides. When considering alternatives to MeI, it is necessary to consider cost, handling, risk, chemical selectivity, and ease of reaction work-up.
# Uses
Besides use as a methylation agent, there have been proposals of its use as a fungicide, herbicide, insecticide or nematicide and as a fire extinguisher. Further it can be used as a soil disinfectant, replacing bromomethane (which was banned under the Montreal Protocol), and in microscopy due to properties related to refraction index. In a controversial October 2007 decision, the United States Environmental Protection Agency approved its use as a soil fumigant in some cases, although it cannot yet be used in California (a major potential market) due to lack of state approval.
# Biological effects
Iodomethane has LD50 for oral administration to rats 76 mg/kg and in the liver it undergoes rapid conversion to S-methylglutathione.
Breathing iodomethane fumes can cause lung, liver, kidney and central nervous system damage. It causes nausea, dizziness, coughing and vomiting. Prolonged contact with skin causes burns. Massive inhalation causes pulmonary edema. | Iodomethane
Template:Chembox new
# Overview
Iodomethane, commonly called methyl iodide and commonly abbreviated "MeI", is the chemical compound with the formula CH3I. This dense volatile liquid is related to methane by replacement of one hydrogen atom by an atom of iodine and its dipole moment is 1.59 D. Refractive index is 1.5304 (20 °C, D), 1.5293 (21 °C, D). It is miscible with common organic solvents. It is colourless, although upon exposure to light, samples develop a purplish tinge caused by the presence of I2. Storage over copper metal absorbs the iodine. Methyl iodide is widely used in organic synthesis to deliver a methyl group, via the transformation called methylation. It is naturally emitted by rice plantations in small amounts.[1]
# Chemical properties
Methyl iodide is an excellent substrate for SN2 substitution reactions. It is sterically open for attack by nucleophiles, and iodide is a good leaving group. For example, it can be used for the methylation of phenols or carboxylic acids:[2]
In these examples, the base (K2CO3 or Li2CO3) removes the acidic proton to form the carboxylate or phenoxide anion, which serves as the nucleophile in the SN2 substitution.
Iodide is a "soft" anion which means that methylation with MeI tends to occur at the "softer" end of an ambidentate nucleophile. For example, reaction with thiocyanate ion favours attack at Sulfur rather than "hard" Nitrogen, leading mainly to methyl thiocyanate (CH3SCN) rather than CH3NCS. This behavior is relevant to the methylation of stabilized enolates such as those derived from 1,3-dicarbonyl compounds. Methylation of these and related enolates can occur on the harder oxygen atom or the (usually desired) carbon atom. With methyl iodide, C-alkylation nearly always predominates.
MeI is also an important precursor to methylmagnesium iodide or "MeMgI", which is a common reagent. Because MeMgI forms readily, it is often prepared in instructional laboratories as an illustration of Grignard reagents. The use of MeMgI has been somewhat superseded by the commercially available methyl lithium.
In the Monsanto process, MeI forms in situ from the reaction of methanol and hydrogen iodide. The CH3I then reacts with carbon monoxide in the presence of a rhodium complex to form acetyl iodide, the precursor to acetic acid after hydrolysis. Most acetic acid is prepared by this method.
MeI hydrolyzes at 270 °C forming hydrogen iodide, carbon monoxide and carbon dioxide.
# Preparation
Iodomethane is formed via the exothermic reaction that occurs when iodine is added to a mixture of methanol with red phosphorus:[3]
The iodinating reagent is phosphorus triiodide that is formed in situ. Alternatively, it is prepared from the reaction of dimethylsulfate with potassium iodide in the presence of calcium carbonate:[3]
The CH3I can easily be purified by distillation followed by washing with Na2S2O3 (to remove iodine) and then water, aq. Na2CO3.
Methyl iodide can be formed during nuclear accidents by the reaction of organic matter with the "fission iodine."
# Choice of iodomethane as a methylating agent
Iodomethane is an excellent reagent for methylation, but there are some disadvantages to its use. It has a high equivalent weight: one mole of MeI weighs almost three times as much as one mole of methyl chloride. However, the chloride is a gas (as is methyl bromide), making it more awkward to work with than liquid MeI. Methyl chloride is a poorer methylating reagent than MeI, though it is often adequate.
Iodides are generally expensive relative to the more common chlorides and bromides, though iodomethane is reasonably affordable; on a commercial scale the toxic dimethyl sulfate is preferred, since it is both cheap and liquid. The iodide leaving group in MeI may cause side reactions, as it is a powerful nucleophile. Finally, being highly reactive, MeI is more dangerous for laboratory workers than related chlorides and bromides. When considering alternatives to MeI, it is necessary to consider cost, handling, risk, chemical selectivity, and ease of reaction work-up.
# Uses
Besides use as a methylation agent, there have been proposals of its use as a fungicide, herbicide, insecticide or nematicide and as a fire extinguisher. Further it can be used as a soil disinfectant, replacing bromomethane (which was banned under the Montreal Protocol), and in microscopy due to properties related to refraction index. In a controversial October 2007 decision, the United States Environmental Protection Agency approved its use as a soil fumigant in some cases, although it cannot yet be used in California (a major potential market) due to lack of state approval.[4]
# Biological effects
Iodomethane has LD50 for oral administration to rats 76 mg/kg and in the liver it undergoes rapid conversion to S-methylglutathione.[5]
Breathing iodomethane fumes can cause lung, liver, kidney and central nervous system damage. It causes nausea, dizziness, coughing and vomiting. Prolonged contact with skin causes burns. Massive inhalation causes pulmonary edema. | https://www.wikidoc.org/index.php/Iodomethane | |
3d1b0d6ed2918779121ad7cda99a780ece52a667 | wikidoc | Ipecacuanha | Ipecacuanha
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies.
# Overview
Ipecacuanha is a OTC emetic that is FDA approved for the treatment of of Poisoning, acute by inducing vomiting. Common adverse reactions include Diarrhea, Stomach cramps, Myalgia and Lethargy.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Poisoning, acute
- to induce NAUSEA AND VOMITING
### Dosage
- Allow 3 or 4 pellets to dissolve in the mouth 3 times a day until symptoms are relieved or as directed by a health professional.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ipecacuanha in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ipecacuanha in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Indications
- Poisoning, acute
### Dosage
- Allow 3 or 4 pellets to dissolve in the mouth 3 times a day until symptoms are relieved or as directed by a health professional.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ipecacuanha in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ipecacuanha in pediatric patients.
# Contraindications
There is limited information regarding Ipecacuanha Contraindications in the drug label.
# Warnings
There is limited information regarding Ipecacuanha Warnings' in the drug label.
# Adverse Reactions
## Clinical Trials Experience
- Diarrhea
- Stomach cramps
- Myalgia
- Lethargy
## Postmarketing Experience
There is limited information regarding Ipecacuanha Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Ipecacuanha Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- If pregnant or breast-feeding, ask a health professional before use
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ipecacuanha in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ipecacuanha during labor and delivery.
### Nursing Mothers
- If pregnant or breast-feeding, ask a health professional before use
### Pediatric Use
There is no FDA guidance on the use of Ipecacuanha with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Ipecacuanha with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Ipecacuanha with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ipecacuanha with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ipecacuanha in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ipecacuanha in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ipecacuanha in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ipecacuanha in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Ipecacuanha in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Ipecacuanha in the drug label.
# Overdosage
There is limited information regarding Overdose of Ipecacuanha in the drug label.
# Pharmacology
There is limited information regarding Ipecacuanha Pharmacology in the drug label.
## Mechanism of Action
There is limited information regarding Ipecacuanha Mechanism of Action in the drug label.
## Structure
IPECACUANHA 3X
(Ipecac)
Lactose, sucrose.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Ipecacuanha in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Ipecacuanha in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Ipecacuanha in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Ipecacuanha in the drug label.
# How Supplied
There is limited information regarding Ipecacuanha How Supplied in the drug label.
## Storage
- Store at room temperature.
# Images
## Drug Images
## Package and Label Display Panel
### LABEL
### Ingredients and Appearance
# Patient Counseling Information
- QUESTIONS?
# Precautions with Alcohol
- Alcohol-Ipecacuanha interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- IPECACUANHA®
# Look-Alike Drug Names
There is limited information regarding Ipecacuanha Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Ipecacuanha
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies.
# Overview
Ipecacuanha is a OTC emetic that is FDA approved for the treatment of of Poisoning, acute by inducing vomiting. Common adverse reactions include Diarrhea, Stomach cramps, Myalgia and Lethargy.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Poisoning, acute[1][2]
- to induce NAUSEA AND VOMITING
### Dosage
- Allow 3 or 4 pellets to dissolve in the mouth 3 times a day until symptoms are relieved or as directed by a health professional.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ipecacuanha in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ipecacuanha in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Indications
- Poisoning, acute[1]
### Dosage
- Allow 3 or 4 pellets to dissolve in the mouth 3 times a day until symptoms are relieved or as directed by a health professional.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ipecacuanha in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ipecacuanha in pediatric patients.
# Contraindications
There is limited information regarding Ipecacuanha Contraindications in the drug label.
# Warnings
There is limited information regarding Ipecacuanha Warnings' in the drug label.
# Adverse Reactions
## Clinical Trials Experience
- Diarrhea[3]
- Stomach cramps
- Myalgia
- Lethargy[3]
## Postmarketing Experience
There is limited information regarding Ipecacuanha Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Ipecacuanha Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- If pregnant or breast-feeding, ask a health professional before use
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ipecacuanha in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ipecacuanha during labor and delivery.
### Nursing Mothers
- If pregnant or breast-feeding, ask a health professional before use
### Pediatric Use
There is no FDA guidance on the use of Ipecacuanha with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Ipecacuanha with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Ipecacuanha with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ipecacuanha with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ipecacuanha in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ipecacuanha in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ipecacuanha in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ipecacuanha in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Ipecacuanha in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Ipecacuanha in the drug label.
# Overdosage
There is limited information regarding Overdose of Ipecacuanha in the drug label.
# Pharmacology
There is limited information regarding Ipecacuanha Pharmacology in the drug label.
## Mechanism of Action
There is limited information regarding Ipecacuanha Mechanism of Action in the drug label.
## Structure
IPECACUANHA 3X
(Ipecac)
Lactose, sucrose.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Ipecacuanha in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Ipecacuanha in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Ipecacuanha in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Ipecacuanha in the drug label.
# How Supplied
There is limited information regarding Ipecacuanha How Supplied in the drug label.
## Storage
- Store at room temperature.
# Images
## Drug Images
## Package and Label Display Panel
### LABEL
### Ingredients and Appearance
# Patient Counseling Information
- QUESTIONS?
# Precautions with Alcohol
- Alcohol-Ipecacuanha interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- IPECACUANHA®[4]
# Look-Alike Drug Names
There is limited information regarding Ipecacuanha Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Ipecac_root | |
a23fbc9dd171667cf46d1238f7d0b464ae254ca3 | wikidoc | Ipriflavone | Ipriflavone
# Overview
Ipriflavone is a synthetic isoflavone which may be used to inhibit bone resorption, maintain bone density and to prevent osteoporosis in postmenopausal women. It is not used to treat osteoporosis. It slows down the action of the osteoclasts (bone-eroding cells), possibly allowing the osteoblasts (bone-building cells) to build up bone mass.
A clinical trial reported in 2001 that it was not effective in prevention or treatment of osteoporosis.
A double-blind study reveals that ipriflavone might be effective on reducing tinnitus on otosclerosis sufferers. | Ipriflavone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Ipriflavone is a synthetic isoflavone which may be used to inhibit bone resorption,[1] maintain bone density and to prevent osteoporosis in postmenopausal women. It is not used to treat osteoporosis. It slows down the action of the osteoclasts (bone-eroding cells), possibly allowing the osteoblasts (bone-building cells) to build up bone mass.
A clinical trial reported in 2001 that it was not effective in prevention or treatment of osteoporosis.[2]
A double-blind study reveals that ipriflavone might be effective on reducing tinnitus on otosclerosis sufferers.[3] | https://www.wikidoc.org/index.php/Ipriflavone | |
de59812eceb5e40d656b11988d33bff29be01786 | wikidoc | Iproniazide | Iproniazide
# Overview
Iproniazid (Marsilid, Rivivol, Euphozid, Iprazid, Ipronid, Ipronin) is a non-selective, irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine class. It was discontinued in most of the world in the 1960s, but remained in use in France up until fairly recently.
Iproniazid was originally developed for the treatment of tuberculosis, but in 1952, its antidepressant properties were discovered when researchers noted that patients given isoniazid became inappropriately happy. Subsequently N-isopropyl addition lead to development as an antidepressant and was approved for use in 1958. It was withdrawn a few years later in 1961 due to a high incidence of hepatitis, and was replaced by less hepatotoxic drugs such as phenelzine and isocarboxazid.
Although iproniazid was one of the first antidepressants ever marketed, amphetamine (marketed as Benzedrine from 1935, for "mild depression", amid other indications) predates it; and frankincense has been marketed traditionally for millennia for, among other things, altering mood, although it was not until 2012 that one of the components of its smoke was found to have antidepressant effects in mice.
# Synthesis
Condensation of isoniazid with acetone at the basic nitrogen gives the corresponding Schiff base. Catalytic hydrogenation affords the antidepressant iproniazid.
Prepd by treating isoniazid with isopropyl bromide in absolute alcohol in the presence of sodium.
- Presumably, a third way would be to react the isonicotinic acid ester with acetone hydrazone, the same reactant used in the production of etazolate. Iproniazid would then be obtained after a reduction step. | Iproniazide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Iproniazid (Marsilid, Rivivol, Euphozid, Iprazid, Ipronid, Ipronin) is a non-selective, irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine class.[1][2] It was discontinued in most of the world in the 1960s, but remained in use in France up until fairly recently.[3]
Iproniazid was originally developed for the treatment of tuberculosis,[1] but in 1952, its antidepressant properties were discovered when researchers noted that patients given isoniazid became inappropriately happy.[1] Subsequently N-isopropyl addition lead to development as an antidepressant and was approved for use in 1958.[1] It was withdrawn a few years later in 1961 due to a high incidence of hepatitis, and was replaced by less hepatotoxic drugs such as phenelzine and isocarboxazid.[1]
Although iproniazid was one of the first antidepressants ever marketed, amphetamine (marketed as Benzedrine from 1935, for "mild depression", amid other indications)[4] predates it; and frankincense has been marketed traditionally for millennia for, among other things, altering mood, although it was not until 2012 that one of the components of its smoke was found to have antidepressant effects in mice.[5]
[6]
[7]
# Synthesis
Condensation of isoniazid with acetone at the basic nitrogen gives the corresponding Schiff base. Catalytic hydrogenation affords the antidepressant iproniazid.
Prepd by treating isoniazid with isopropyl bromide in absolute alcohol in the presence of sodium.
- Presumably, a third way would be to react the isonicotinic acid ester with acetone hydrazone,[10] the same reactant used in the production of etazolate. Iproniazid would then be obtained after a reduction step. | https://www.wikidoc.org/index.php/Iproniazide | |
70040438d6e3f63d1ad709bf4b041067148d3870 | wikidoc | Irradiation | Irradiation
# Overview
Irradiation is the process by which an item is exposed to radiation. The exposure can be intentional, sometimes to serve a specific purpose, or it can be accidental. In common usage the term refers specifically to ionizing radiation, and to a level of radiation that will serve that specific purpose, rather than radiation exposure to normal levels of background radiation or abnormal levels of radiation due to accidental exposure.
# Usage
Small doses of radiation may be used to remove bacteria in food, or other organic material, including blood.
# Applications
If administered at appropriate levels, all of these forms of radiation can be used to sterilize objects, a technique used in the production of medical instruments and disposables, such as syringes as well as in the disinfestation and sterilization of food. Irradiation can furthermore be used in cross-polymerization of plastics or to improve material qualities of semi-precious stones. Irradiation is also employed to prevent sprouting of certain cereals, onions, potatoes and garlic. During the 2001 anthrax attacks, the US Postal Service irradiated mail to protect members of the US government and other possible targets. This can be of some concern to people, including artists; according to the ART in Embassies programme "incoming mail is irradiated, and the process destroys slides, transparencies and disks." | Irradiation
# Overview
Irradiation is the process by which an item is exposed to radiation. The exposure can be intentional, sometimes to serve a specific purpose, or it can be accidental. In common usage the term refers specifically to ionizing radiation, and to a level of radiation that will serve that specific purpose, rather than radiation exposure to normal levels of background radiation or abnormal levels of radiation due to accidental exposure.
# Usage
Small doses of radiation may be used to remove bacteria in food, or other organic material, including blood.
# Applications
If administered at appropriate levels, all of these forms of radiation can be used to sterilize objects, a technique used in the production of medical instruments and disposables, such as syringes as well as in the disinfestation and sterilization of food. Irradiation can furthermore be used in cross-polymerization of plastics or to improve material qualities of semi-precious stones. Irradiation is also employed to prevent sprouting of certain cereals, onions, potatoes and garlic. During the 2001 anthrax attacks, the US Postal Service irradiated mail to protect members of the US government and other possible targets. This can be of some concern to people, including artists; according to the ART in Embassies programme "incoming mail is irradiated, and the process destroys slides, transparencies and disks."[1] | https://www.wikidoc.org/index.php/Irradiate | |
746755a0f3737865781941260c3cc1a15f7f2e57 | wikidoc | Irvine Page | Irvine Page
Irvine Heinly Page (January 7, 1901 - June 10, 1991) was born in Indianapolis, Indiana and was an American physiologist who played an important part in the field of hypertension for almost 60 years.
His first contributions were published in the early 1930s and his most recent, "Hypertension Research: A Memoir : 1920-1960", in 1988. He is perhaps best know for the co-discovery of serotonin in 1948, although his pre-eminence is a matter of record in four other areas: the renin-angiotensin system, the mosaic theory of hypertension, treatment of hypertension and public and professional advocacy of the recognition of this condition and its effects in daily life. In earlier work he published on the neurochemistry of the brain.
Page received many honors for his work. He was president of the American Heart Association (1956-57); he received ten honorary degrees and a number of prestigious awards--the Ida B. Gould Memorial Award of the American Association for the Advancement of Science (1957); Albert Lasker Award (1958); Gairdner Foundation Award (1963); Distinguished Award of the American Medical Association (1964); Oscar B. Hunter Award (1966); Passano Foundation Award (1967); and the Stouffer Prize (now the Novartis Award) for Hypertension Research in 1970. He was elected to the National Academy of Sciences in 1971 and published his memoirs in 1988.
The American Heart Association Irvine H. Page Young Investigator Research Awardand the Irvine Page - Alva Bradley Lifetime Achievement Award are named in his honor.
# Footnotes
- ↑ Dustan HP. Irvine Page lecture. Legacies of Irvine H. Page. J Hypertens Suppl. 1990;8:S29-34. PMID 2095393.
- ↑ Dustan HP Irvine Heinly Page. The National Academies Press Biographical Memoirs.
- ↑ Frohlich ED, Dustan HP, Bumpus FM Irvine H. Page: 1901-1991. The Celebration of a Leader Hypertension 1991;18:443-445.
- ↑ Rapport MM, Green AA, Page IH (1948). "Serum vasoconstrictor (serotonin). IV. Isolation and characterization". J Biol Chem 176 (3): 1243–1251.
- ↑ Page IH (1967). "The mosaic theory of arterial hypertension--its interpretation." Perspect Biol Med. 10:325-33.PMID 6034593.
# Bibliography
- Page, Irvine (1987). Hypertension Mechanisms. Orlando, Fla.: Grune & Stratton. ISBN 0-808-91768-4..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- Page, Irvine (1988). Hypertension Research: A Memoir : 1920-1960. New York: Pergamon. ISBN 0-080-36079-3.
- Page, Irvine (1937). Chemistry of the brain. New York: C.C. Thomas. ASIN B-000-87D23-C. | Irvine Page
Irvine Heinly Page (January 7, 1901 - June 10, 1991) was born in Indianapolis, Indiana and was an American physiologist who played an important part in the field of hypertension for almost 60 years[1][2][3].
His first contributions were published in the early 1930s and his most recent, "Hypertension Research: A Memoir : 1920-1960", in 1988. He is perhaps best know for the co-discovery of serotonin in 1948[4], although his pre-eminence is a matter of record in four other areas: the renin-angiotensin system, the mosaic theory of hypertension[5], treatment of hypertension and public and professional advocacy of the recognition of this condition and its effects in daily life. In earlier work he published on the neurochemistry of the brain.
Page received many honors for his work. He was president of the American Heart Association (1956-57); he received ten honorary degrees and a number of prestigious awards--the Ida B. Gould Memorial Award of the American Association for the Advancement of Science (1957); Albert Lasker Award (1958); Gairdner Foundation Award (1963); Distinguished Award of the American Medical Association (1964); Oscar B. Hunter Award (1966); Passano Foundation Award (1967); and the Stouffer Prize (now the Novartis Award) for Hypertension Research in 1970. He was elected to the National Academy of Sciences in 1971 and published his memoirs in 1988.
The American Heart Association Irvine H. Page Young Investigator Research Awardand the Irvine Page - Alva Bradley Lifetime Achievement Award are named in his honor.
# Footnotes
- ↑ Dustan HP. Irvine Page lecture. Legacies of Irvine H. Page. J Hypertens Suppl. 1990;8:S29-34. PMID 2095393.
- ↑ Dustan HP Irvine Heinly Page. The National Academies Press Biographical Memoirs.
- ↑ Frohlich ED, Dustan HP, Bumpus FM Irvine H. Page: 1901-1991. The Celebration of a Leader Hypertension 1991;18:443-445.
- ↑ Rapport MM, Green AA, Page IH (1948). "Serum vasoconstrictor (serotonin). IV. Isolation and characterization". J Biol Chem 176 (3): 1243–1251.
- ↑ Page IH (1967). "The mosaic theory of arterial hypertension--its interpretation." Perspect Biol Med. 10:325-33.PMID 6034593.
# Bibliography
- Page, Irvine (1987). Hypertension Mechanisms. Orlando, Fla.: Grune & Stratton. ISBN 0-808-91768-4..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- Page, Irvine (1988). Hypertension Research: A Memoir : 1920-1960. New York: Pergamon. ISBN 0-080-36079-3.
- Page, Irvine (1937). Chemistry of the brain. New York: C.C. Thomas. ASIN B-000-87D23-C.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Irvine_Page | |
ac2c2c8dffed5ede5f5e73abd0d9b51e0d2d7bb3 | wikidoc | Raltegravir | Raltegravir
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# Overview
Raltegravir is a integrase inhibitor that is FDA approved for the {{{indicationType}}} of HIV-1 infection in patients 4 weeks of age and older. Common adverse reactions include insomnia, headache, dizziness, nausea and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- For the treatment of adult patients with HIV-1 infection, the dosage of ISENTRESS is one 400 mg film-coated tablet administered orally, twice daily.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Raltegravir in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Raltegravir in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- If at least 25 kg: One 400 mg film-coated tablet orally, twice daily.
- If unable to swallow a tablet, consider the chewable tablet, as specified in Table 1.
- If at least 4 weeks of age and weighing at least 3 kg to less than 25 kg: Weight based dosing, as specified in Table 2.
- For patients weighing between 11 and 20 kg, either the chewable tablet or oral suspension can be used, as specified in Table 2. Patients can remain on the oral suspension as long as their weight is below 20 kg. Refer to Table 2 for appropriate dosing.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Raltegravir in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Raltegravir in pediatric patients.
# Contraindications
None
# Warnings
### Precautions
- Severe Skin and Hypersensitivity Reactions
- Severe, potentially life-threatening, and fatal skin reactions have been reported. These include cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including hepatic failure. Discontinue ISENTRESS and other suspect agents immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema). Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping ISENTRESS treatment or other suspect agents after the onset of severe rash may result in a life-threatening reaction.
- Immune Reconstitution Syndrome
- Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including ISENTRESS. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, tuberculosis), which may necessitate further evaluation and treatment.
- Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.
- Phenylketonurics
- ISENTRESS Chewable Tablets contain phenylalanine, a component of aspartame. Each 25 mg ISENTRESS Chewable Tablet contains approximately 0.05 mg phenylalanine. Each 100 mg ISENTRESS Chewable Tablet contains approximately 0.10 mg phenylalanine. Phenylalanine can be harmful to patients with phenylketonuria.
# Adverse Reactions
## Clinical Trials Experience
- Treatment-Naïve Adults
- The following safety assessment of ISENTRESS in treatment-naïve subjects is based on the randomized double-blind active controlled study of treatment-naïve subjects, STARTMRK (Protocol 021) with ISENTRESS 400 mg twice daily in combination with a fixed dose of emtricitabine 200 mg (+) tenofovir 300 mg, (N=281) versus efavirenz (EFV) 600 mg at bedtime in combination with emtricitabine (+) tenofovir, (N=282). During double-blind treatment, the total follow-up for subjects receiving ISENTRESS 400 mg twice daily + emtricitabine (+) tenofovir was 1104 patient-years and 1036 patient-years for subjects receiving efavirenz 600 mg at bedtime + emtricitabine (+) tenofovir.
- In Protocol 021, the rate of discontinuation of therapy due to adverse events was 5% in subjects receiving ISENTRESS + emtricitabine (+) tenofovir and 10% in subjects receiving efavirenz + emtricitabine (+) tenofovir.
- The clinical adverse drug reactions (ADRs) listed below were considered by investigators to be causally related to ISENTRESS + emtricitabine (+) tenofovir or efavirenz + emtricitabine (+) tenofovir. Clinical ADRs of moderate to severe intensity occurring in ≥2% of treatment-naïve subjects treated with ISENTRESS are presented in Table 3.
- Laboratory Abnormalities
- The percentages of adult subjects treated with ISENTRESS 400 mg twice daily or efavirenz in Protocol 021 with selected Grades 2 to 4 laboratory abnormalities that represent a worsening Grade from baseline are presented in Table 4.
- Lipids, Change from Baseline
- Changes from baseline in fasting lipids are shown in Table 5.
- Treatment-Experienced Adults
- The safety assessment of ISENTRESS in treatment-experienced subjects is based on the pooled safety data from the randomized, double-blind, placebo-controlled trials, BENCHMRK 1 and BENCHMRK 2 (Protocols 018 and 019) in antiretroviral treatment-experienced HIV-1 infected adult subjects. A total of 462 subjects received the recommended dose of ISENTRESS 400 mg twice daily in combination with optimized background therapy (OBT) compared to 237 subjects taking placebo in combination with OBT. The median duration of therapy in these trials was 96 weeks for subjects receiving ISENTRESS and 38 weeks for subjects receiving placebo. The total exposure to ISENTRESS was 708 patient-years versus 244 patient-years on placebo. The rates of discontinuation due to adverse events were 4% in subjects receiving ISENTRESS and 5% in subjects receiving placebo.
- Clinical ADRs were considered by investigators to be causally related to ISENTRESS + OBT or placebo + OBT. Clinical ADRs of moderate to severe intensity occurring in ≥2% of subjects treated with ISENTRESS and occurring at a higher rate compared to placebo are presented in Table 6.
- Laboratory Abnormalities
- The percentages of adult subjects treated with ISENTRESS 400 mg twice daily or placebo in Protocols 018 and 019 with selected Grade 2 to 4 laboratory abnormalities representing a worsening Grade from baseline are presented in Table 7.
- Less Common Adverse Reactions Observed in Treatment-Naïve and Treatment-Experienced Studies
- The following ADRs occurred in <2% of treatment-naïve or treatment-experienced subjects receiving ISENTRESS in a combination regimen. These events have been included because of their seriousness, increased frequency on ISENTRESS compared with efavirenz or placebo, or investigator's assessment of potential causal relationship.
- Gastrointestinal Disorders: abdominal pain, gastritis, dyspepsia, vomiting
- General Disorders and Administration Site Conditions: asthenia
- Hepatobiliary Disorders: hepatitis
- Immune System Disorders: hypersensitivity
- Infections and Infestations: genital herpes, herpes zoster
- Psychiatric Disorders: depression (particularly in subjects with a pre-existing history of psychiatric illness), including suicidal ideation and behaviors
- Renal and Urinary Disorders: nephrolithiasis, renal failure
- Selected Adverse Events - Adults
- Cancers were reported in treatment-experienced subjects who initiated ISENTRESS or placebo, both with OBT, and in treatment-naïve subjects who initiated ISENTRESS or efavirenz, both with emtricitabine (+) tenofovir; several were recurrent. The types and rates of specific cancers were those expected in a highly immunodeficient population (many had CD4+ counts below 50 cells/mm3 and most had prior AIDS diagnoses). The risk of developing cancer in these studies was similar in the group receiving ISENTRESS and the group receiving the comparator.
- Grade 2-4 creatine kinase laboratory abnormalities were observed in subjects treated with ISENTRESS (see Table 6). Myopathy and rhabdomyolysis have been reported. Use with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medications known to cause these conditions and patients with a history of rhabdomyolysis, myopathy or increased serum creatine kinase.
- Rash occurred more commonly in treatment-experienced subjects receiving regimens containing ISENTRESS + darunavir/ritonavir compared to subjects receiving ISENTRESS without darunavir/ritonavir or darunavir/ritonavir without ISENTRESS. However, rash that was considered drug related occurred at similar rates for all three groups. These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash.
- Patients with Co-existing Conditions - Adults
- Patients Co-infected with Hepatitis B and/or Hepatitis C Virus
- In the randomized, double-blind, placebo-controlled trials, treatment-experienced subjects (N = 114/699 or 16%) and treatment-naïve subjects (N = 34/563 or 6%) with chronic (but not acute) active hepatitis B and/or hepatitis C virus co-infection were permitted to enroll provided that baseline liver function tests did not exceed 5 times the upper limit of normal (ULN). In general the safety profile of ISENTRESS in subjects with hepatitis B and/or hepatitis C virus co-infection was similar to that in subjects without hepatitis B and/or hepatitis C virus co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or hepatitis C virus co-infection for all treatment groups. At 96 weeks, in treatment-experienced subjects, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 29%, 34% and 13%, respectively, of co-infected subjects treated with ISENTRESS as compared to 11%, 10% and 9% of all other subjects treated with ISENTRESS. At 240 weeks, in treatment-naïve subjects, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 22%, 44% and 17%, respectively, of co-infected subjects treated with ISENTRESS as compared to 13%, 13% and 5% of all other subjects treated with ISENTRESS.
- Pediatrics
- 2 to 18 Years of Age
- ISENTRESS has been studied in 126 antiretroviral treatment-experienced HIV-1 infected children and adolescents 2 to 18 years of age, in combination with other antiretroviral agents in IMPAACT P1066. Of the 126 patients, 96 received the recommended dose of ISENTRESS.
- In these 96 children and adolescents, frequency, type and severity of drug related adverse reactions through Week 24 were comparable to those observed in adults.
- One patient experienced drug related clinical adverse reactions of Grade 3 psychomotor hyperactivity, abnormal behavior and insomnia; one patient experienced a Grade 2 serious drug related allergic rash.
- One patient experienced drug related laboratory abnormalities, Grade 4 AST and Grade 3 ALT, which were considered serious.
- 4 Weeks to less than 2 Years of Age
- ISENTRESS has also been studied in 26 HIV-1 infected infants and toddlers 4 weeks to less than 2 years of age, in combination with other antiretroviral agents in IMPAACT P1066.
- In these 26 infants and toddlers, the frequency, type and severity of drug-related adverse reactions through Week 48 were comparable to those observed in adults.
- One patient experienced a Grade 3 serious drug-related allergic rash that resulted in treatment discontinuation.
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of ISENTRESS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Blood and Lymphatic System Disorders: thrombocytopenia
- Gastrointestinal Disorders: diarrhea
- Hepatobiliary Disorders: hepatic failure (with and without associated hypersensitivity) in patients with underlying liver disease and/or concomitant medications
- Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis
- Nervous System Disorders: cerebellar ataxia
- Psychiatric Disorders: anxiety, paranoia
# Drug Interactions
- Effect of Raltegravir on the Pharmacokinetics of Other Agents
- Raltegravir does not inhibit (IC50>100 µM) CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A in vitro. Moreover, in vitro, raltegravir did not induce CYP1A2, CYP2B6 or CYP3A4. A midazolam drug interaction study confirmed the low propensity of raltegravir to alter the pharmacokinetics of agents metabolized by CYP3A4 in vivo by demonstrating a lack of effect of raltegravir on the pharmacokinetics of midazolam, a sensitive CYP3A4 substrate. Similarly, raltegravir is not an inhibitor (IC50>50 µM) of the UDP-glucuronosyltransferases (UGT) tested (UGT1A1, UGT2B7), and raltegravir does not inhibit P-glycoprotein-mediated transport. Based on these data, ISENTRESS is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or P-glycoprotein (e.g., protease inhibitors, NNRTIs, opioid analgesics, statins, azole antifungals, proton pump inhibitors and anti-erectile dysfunction agents).
- In drug interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of the following: hormonal contraceptives, methadone, lamivudine, tenofovir, etravirine, darunavir/ritonavir, telaprevir, boceprevir.
- Effect of Other Agents on the Pharmacokinetics of Raltegravir
- Raltegravir is not a substrate of cytochrome P450 (CYP) enzymes. Based on in vivo and in vitro studies, raltegravir is eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway.
- Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of ISENTRESS. Therefore, in adults the dose of ISENTRESS should be increased during coadministration with rifampin. There are no data to guide co-administration of ISENTRESS with rifampin in patients below 18 years of age. The impact of other inducers of drug metabolizing enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown.
- Coadministration of ISENTRESS with drugs that inhibit UGT1A1 may increase plasma levels of raltegravir.
- Coadministration of ISENTRESS with antacids containing divalent metal cations may reduce raltegravir absorption by chelation, resulting in a decrease of raltegravir plasma levels. Taking an aluminum and magnesium antacid within 2 hours of ISENTRESS administration significantly decreased raltegravir plasma levels. Therefore, coadministration of ISENTRESS with aluminum and/or magnesium-containing antacids is not recommended. Coadministration of ISENTRESS with a calcium carbonate antacid decreased raltegravir plasma levels; however, this interaction is not considered clinically meaningful. Therefore, when ISENTRESS is coadministered with calcium carbonate-containing antacids, no dose adjustment is recommended.
- Selected drug interactions are presented in Table 8.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- SENTRESS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. There are no adequate and well-controlled studies in pregnant women. In addition, there have been no pharmacokinetic studies conducted in pregnant patients.
- Developmental toxicity studies were performed in rabbits (at oral doses up to 1000 mg/kg/day) and rats (at oral doses up to 600 mg/kg/day). The reproductive toxicity study in rats was performed with pre-, peri-, and postnatal evaluation. The highest doses in these studies produced systemic exposures in these species approximately 3- to 4-fold the exposure at the recommended human dose. In both rabbits and rats, no treatment-related effects on embryonic/fetal survival or fetal weights were observed. In addition, no treatment-related external, visceral, or skeletal changes were observed in rabbits. However, treatment-related increases over controls in the incidence of supernumerary ribs were seen in rats at 600 mg/kg/day (exposures 3-fold the exposure at the recommended human dose).
- Placenta transfer of drug was demonstrated in both rats and rabbits. At a maternal dose of 600 mg/kg/day in rats, mean drug concentrations in fetal plasma were approximately 1.5- to 2.5-fold greater than in maternal plasma at 1 hour and 24 hours postdose, respectively. Mean drug concentrations in fetal plasma were approximately 2% of the mean maternal concentration at both 1 and 24 hours postdose at a maternal dose of 1000 mg/kg/day in rabbits.
- Antiretroviral Pregnancy Registry
- To monitor maternal-fetal outcomes of pregnant patients exposed to ISENTRESS, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Raltegravir in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Raltegravir during labor and delivery.
### Nursing Mothers
- Breastfeeding is not recommended while taking ISENTRESS. In addition, it is recommended that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1.
- It is not known whether raltegravir is secreted in human milk. However, raltegravir is secreted in the milk of lactating rats. Mean drug concentrations in milk were approximately 3-fold greater than those in maternal plasma at a maternal dose of 600 mg/kg/day in rats. There were no effects in rat offspring attributable to exposure of ISENTRESS through the milk.
### Pediatric Use
- The safety, tolerability, pharmacokinetic profile, and efficacy of ISENTRESS were evaluated in HIV-1 infected infants, children and adolescents 4 weeks to 18 years of age in an open-label, multicenter clinical trial, IMPAACT P1066. The safety profile was comparable to that observed in adults. The safety and dosing information for ISENTRESS have not been established in infants less than 4 weeks of age.
### Geriatic Use
- Clinical studies of ISENTRESS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Raltegravir with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Raltegravir with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Raltegravir in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Raltegravir in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Raltegravir in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Raltegravir in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Raltegravir in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Raltegravir in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- No specific information is available on the treatment of overdosage with ISENTRESS. Doses as high as 1600-mg single dose and 800-mg twice-daily multiple doses were studied in healthy volunteers without evidence of toxicity. Occasional doses of up to 1800 mg per day were taken in the clinical studies of HIV-1 infected subjects without evidence of toxicity.
### Management
- In the event of an overdose, it is reasonable to employ the standard supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy if required. The extent to which ISENTRESS may be dialyzable is unknown.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Raltegravir in the drug label.
# Pharmacology
## Mechanism of Action
- Raltegravir inhibits the catalytic activity of HIV-1 integrase, an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the covalent insertion, or integration, of unintegrated linear HIV-1 DNA into the host cell genome preventing the formation of the HIV-1 provirus. The provirus is required to direct the production of progeny virus, so inhibiting integration prevents propagation of the viral infection. Raltegravir did not significantly inhibit human phosphoryltransferases including DNA polymerases α, β, and γ.
## Structure
- ISENTRESS contains raltegravir potassium, a human immunodeficiency virus integrase strand transfer inhibitor. The chemical name for raltegravir potassium is N--1,6-dihydro-5-hydroxy-1-methyl-2-amino]ethyl]-6-oxo-4-pyrimidinecarboxamide monopotassium salt.
- The empirical formula is C20H20FKN6O5 and the molecular weight is 482.51. The structural formula is:
- Raltegravir potassium is a white to off-white powder. It is soluble in water, slightly soluble in methanol, very slightly soluble in ethanol and acetonitrile and insoluble in isopropanol.
- Each 400 mg film-coated tablet of ISENTRESS for oral administration contains 434.4 mg of raltegravir (as potassium salt), equivalent to 400 mg of raltegravir free phenol and the following inactive ingredients: calcium phosphate dibasic anhydrous, hypromellose 2208, lactose monohydrate, magnesium stearate, microcrystalline cellulose, poloxamer 407 (contains 0.01% butylated hydroxytoluene as antioxidant), sodium stearyl fumarate. In addition, the film coating contains the following inactive ingredients: black iron oxide, polyethylene glycol 3350, polyvinyl alcohol, red iron oxide, talc and titanium dioxide.
- Each 100 mg chewable tablet of ISENTRESS for oral administration contains 108.6 mg of raltegravir (as potassium salt), equivalent to 100 mg of raltegravir free phenol and the following inactive ingredients: ammonium hydroxide, crospovidone, ethylcellulose 20 cP, fructose, hydroxypropyl cellulose, hypromellose 2910/6cP, magnesium stearate, mannitol, medium chain triglycerides, monoammonium glycyrrhizinate, natural and artificial flavors (orange, banana, and masking that contains aspartame), oleic acid, PEG 400, red iron oxide, saccharin sodium, sodium citrate dihydrate, sodium stearyl fumarate, sorbitol, sucralose and yellow iron oxide.
- Each 25 mg chewable tablet of ISENTRESS for oral administration contains 27.16 mg of raltegravir (as potassium salt), equivalent to 25 mg of raltegravir free phenol and the following inactive ingredients: ammonium hydroxide, crospovidone, ethylcellulose 20 cP, fructose, hydroxypropyl cellulose, hypromellose 2910/6cP, magnesium stearate, mannitol, medium chain triglycerides, monoammonium glycyrrhizinate, natural and artificial flavors (orange, banana, and masking that contains aspartame), oleic acid, PEG 400, saccharin sodium, sodium citrate dihydrate, sodium stearyl fumarate, sorbitol, sucralose and yellow iron oxide.
- Each packet of ISENTRESS for oral suspension 100 mg, contains 108.6 mg of raltegravir (as potassium salt), equivalent to 100 mg of raltegravir free phenol and the following inactive ingredients: ammonium hydroxide, banana with other natural flavors, carboxymethylcellulose sodium, crospovidone, ethylcellulose 20 cP, fructose, hydroxypropyl cellulose, hypromellose 2910/6cP, macrogol/PEG 400, magnesium stearate, maltodextrin, mannitol, medium chain triglycerides, microcrystalline cellulose, monoammonium glycyrrhizinate, oleic acid, sorbitol, sucralose and sucrose.
## Pharmacodynamics
- In a monotherapy study raltegravir (400 mg twice daily) demonstrated rapid antiviral activity with mean viral load reduction of 1.66 log10 copies/mL by Day 10.
- In the randomized, double-blind, placebo-controlled, dose-ranging trial, Protocol 005, and Protocols 018 and 019, antiviral responses were similar among subjects regardless of dose.
- Effects on Electrocardiogram
- In a randomized, placebo-controlled, crossover study, 31 healthy subjects were administered a single oral supratherapeutic dose of raltegravir 1600 mg and placebo. Peak raltegravir plasma concentrations were approximately 4-fold higher than the peak concentrations following a 400 mg dose. ISENTRESS did not appear to prolong the QTc interval for 12 hours postdose. After baseline and placebo adjustment, the maximum mean QTc change was -0.4 msec (1-sided 95% upper Cl: 3.1 msec).
## Pharmacokinetics
- Adults
- Absorption
- Raltegravir (film-coated tablet) is absorbed with a Tmax of approximately 3 hours postdose in the fasted state. Raltegravir AUC and Cmax increase dose proportionally over the dose range 100 mg to 1600 mg. Raltegravir C12hr increases dose proportionally over the dose range of 100 to 800 mg and increases slightly less than dose proportionally over the dose range 100 mg to 1600 mg. With twice-daily dosing, pharmacokinetic steady state is achieved within approximately the first 2 days of dosing. There is little to no accumulation in AUC and Cmax. The average accumulation ratio for C12hr ranged from approximately 1.2 to 1.6.
- The absolute bioavailability of raltegravir has not been established. Based on a formulation comparison study in healthy adult volunteers, the chewable tablet and oral suspension have higher oral bioavailability compared to the 400 mg film-coated tablet.
- In subjects who received 400 mg twice daily alone, raltegravir drug exposures were characterized by a geometric mean AUC0-12hr of 14.3 µM∙hr and C12hr of 142 nM.
- Considerable variability was observed in the pharmacokinetics of raltegravir. For observed C12hr in Protocols 018 and 019, the coefficient of variation (CV) for inter-subject variability = 212% and the CV for intra-subject variability = 122%.
- Effect of Food on Oral Absorption
- ISENTRESS may be administered with or without food. Raltegravir was administered without regard to food in the pivotal safety and efficacy studies in HIV-1-infected patients. The effect of consumption of low-, moderate- and high-fat meals on steady-state raltegravir pharmacokinetics was assessed in healthy volunteers administered the 400 mg film-coated tablet. Administration of multiple doses of raltegravir following a moderate-fat meal (600 Kcal, 21 g fat) did not affect raltegravir AUC to a clinically meaningful degree with an increase of 13% relative to fasting. Raltegravir C12hr was 66% higher and Cmax was 5% higher following a moderate-fat meal compared to fasting. Administration of raltegravir following a high-fat meal (825 Kcal, 52 g fat) increased AUC and Cmax by approximately 2-fold and increased C12hr by 4.1-fold. Administration of raltegravir following a low-fat meal (300 Kcal, 2.5 g fat) decreased AUC and Cmax by 46% and 52%, respectively; C12hr was essentially unchanged. Food appears to increase pharmacokinetic variability relative to fasting.
- Administration of the chewable tablet with a high fat meal led to an average 6% decrease in AUC, 62% decrease in Cmax, and 188% increase in C12hr compared to administration in the fasted state. Administration of the chewable tablet with a high fat meal does not affect raltegravir pharmacokinetics to a clinically meaningful degree and the chewable tablet can be administered without regard to food.
- The effect of food on the formulation for oral suspension was not studied.
- Distribution
- Raltegravir is approximately 83% bound to human plasma protein over the concentration range of 2 to 10 µM.
- In one study of HIV-1 infected subjects who received raltegravir 400 mg twice daily, raltegravir was measured in the cerebrospinal fluid. In the study (n=18), the median cerebrospinal fluid concentration was 5.8% (range 1 to 53.5%) of the corresponding plasma concentration. This median proportion was approximately 3-fold lower than the free fraction of raltegravir in plasma. The clinical relevance of this finding is unknown.
- Metabolism and Excretion
- The apparent terminal half-life of raltegravir is approximately 9 hours, with a shorter α-phase half-life (~1 hour) accounting for much of the AUC. Following administration of an oral dose of radiolabeled raltegravir, approximately 51 and 32% of the dose was excreted in feces and urine, respectively. In feces, only raltegravir was present, most of which is likely derived from hydrolysis of raltegravir-glucuronide secreted in bile as observed in preclinical species. Two components, namely raltegravir and raltegravir-glucuronide, were detected in urine and accounted for approximately 9 and 23% of the dose, respectively. The major circulating entity was raltegravir and represented approximately 70% of the total radioactivity; the remaining radioactivity in plasma was accounted for by raltegravir-glucuronide. Studies using isoform-selective chemical inhibitors and cDNA-expressed UDP-glucuronosyltransferases (UGT) show that UGT1A1 is the main enzyme responsible for the formation of raltegravir-glucuronide. Thus, the data indicate that the major mechanism of clearance of raltegravir in humans is UGT1A1-mediated glucuronidation.
- Special Populations
- Pediatric
- Two pediatric formulations were evaluated in healthy adult volunteers, where the chewable tablet and oral suspension were compared to the 400 mg tablet. The chewable tablet and oral suspension demonstrated higher oral bioavailability, thus higher AUC, compared to the 400 mg tablet. In the same study, the oral suspension resulted in higher oral bioavailability compared to the chewable tablet. These observations resulted in proposed pediatric doses targeting 6 mg/kg/dose for the chewable tablets and oral suspension. As displayed in Table 9, the doses recommended for HIV-infected infants, children and adolescents 4 weeks to 18 years of age resulted in a pharmacokinetic profile of raltegravir similar to that observed in adults receiving 400 mg twice daily.
- Overall, dosing in pediatric patients achieved exposures (Ctrough) above 45 nM in the majority of subjects, but some differences in exposures between formulations were observed. Pediatric patients above 25 kg administered the chewable tablets had lower trough concentrations (113 nM) compared to pediatric patients above 25 kg administered the 400 mg tablet formulation (233 nM). As a result, the 400 mg film-coated tablet is the recommended dose in patients weighing at least 25 kg; however, the chewable tablet offers an alternative regimen in patients weighing at least 25 kg who are unable to swallow the film-coated tablet. In addition, pediatric patients weighing 11 to 25 kg who were administered the chewable tablets had the lowest trough concentrations (82 nM) compared to all other pediatric subgroups.
- The pharmacokinetics of raltegravir in infants under 4 weeks of age has not been established.
- Age
- The effect of age (18 years and older) on the pharmacokinetics of raltegravir was evaluated in the composite analysis. No dosage adjustment is necessary.
- Race
- The effect of race on the pharmacokinetics of raltegravir in adults was evaluated in the composite analysis. No dosage adjustment is necessary.
- Gender
- A study of the pharmacokinetics of raltegravir was performed in healthy adult males and females. Additionally, the effect of gender was evaluated in a composite analysis of pharmacokinetic data from 103 healthy subjects and 28 HIV-1 infected subjects receiving raltegravir monotherapy with fasted administration. No dosage adjustment is necessary.
- Hepatic Impairment
- Raltegravir is eliminated primarily by glucuronidation in the liver. A study of the pharmacokinetics of raltegravir was performed in adult subjects with moderate hepatic impairment. Additionally, hepatic impairment was evaluated in the composite pharmacokinetic analysis. There were no clinically important pharmacokinetic differences between subjects with moderate hepatic impairment and healthy subjects. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of raltegravir has not been studied.
- Renal Impairment
- Renal clearance of unchanged drug is a minor pathway of elimination. A study of the pharmacokinetics of raltegravir was performed in adult subjects with severe renal impairment. Additionally, renal impairment was evaluated in the composite pharmacokinetic analysis. There were no clinically important pharmacokinetic differences between subjects with severe renal impairment and healthy subjects. No dosage adjustment is necessary. Because the extent to which ISENTRESS may be dialyzable is unknown, dosing before a dialysis session should be avoided.
- UGT1A1 Polymorphism
- There is no evidence that common UGT1A1 polymorphisms alter raltegravir pharmacokinetics to a clinically meaningful extent. In a comparison of 30 adult subjects with *28/*28 genotype (associated with reduced activity of UGT1A1) to 27 adult subjects with wild-type genotype, the geometric mean ratio (90% CI) of AUC was 1.41 (0.96, 2.09).
- Mechanism of Action
- Raltegravir inhibits the catalytic activity of HIV-1 integrase, an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the covalent insertion, or integration, of unintegrated linear HIV-1 DNA into the host cell genome preventing the formation of the HIV-1 provirus. The provirus is required to direct the production of progeny virus, so inhibiting integration prevents propagation of the viral infection. Raltegravir did not significantly inhibit human phosphoryltransferases including DNA polymerases α, β, and γ.
- Antiviral Activity in Cell Culture
- Raltegravir at concentrations of 31 ± 20 nM resulted in 95% inhibition (EC95) of viral spread (relative to an untreated virus-infected culture) in human T-lymphoid cell cultures infected with the cell-line adapted HIV-1 variant H9IIIB. In addition, 5 clinical isolates of HIV-1 subtype B had EC95 values ranging from 9 to 19 nM in cultures of mitogen-activated human peripheral blood mononuclear cells. In a single-cycle infection assay, raltegravir inhibited infection of 23 HIV-1 isolates representing 5 non-B subtypes (A, C, D, F, and G) and 5 circulating recombinant forms (AE, AG, BF, BG, and cpx) with EC50 values ranging from 5 to 12 nM. Raltegravir also inhibited replication of an HIV-2 isolate when tested in CEMx174 cells (EC95 value = 6 nM). Additive to synergistic antiretroviral activity was observed when human T-lymphoid cells infected with the H9IIIB variant of HIV-1 were incubated with raltegravir in combination with non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, or nevirapine); nucleoside analog reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, tenofovir, zalcitabine, or zidovudine); protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, or saquinavir); or the entry inhibitor enfuvirtide.
- Resistance
- The mutations observed in the HIV-1 integrase coding sequence that contributed to raltegravir resistance (evolved either in cell culture or in subjects treated with raltegravir) generally included an amino acid substitution at either Y143 (changed to C, H, or R) or Q148 (changed to H, K, or R) or N155 (changed to H) plus one or more additional substitutions (i.e., L74M, E92Q, Q95K/R, T97A, E138A/K, G140A/S, V151I, G163R, H183P, Y226C/D/F/H, S230R, and D232N). E92Q and F121C are occasionally seen in the absence of substitutions at Y143, Q148, or N155 in raltegravir-treatment failure subjects.
- Treatment-Naïve Adult Subjects: By Week 96 in the STARTMRK trial, the primary raltegravir resistance-associated substitutions were observed in 4 (2 with Y143H/R and 2 with Q148H/R) of the 10 virologic failure subjects with evaluable genotypic data from paired baseline and raltegravir treatment-failure isolates.
- Treatment-Experienced Adult Subjects: By Week 96 in the BENCHMRK trials, at least one of the primary raltegravir resistance-associated substitutions, Y143C/H/R, Q148H/K/R, and N155H, was observed in 76 of the 112 virologic failure subjects with evaluable genotypic data from paired baseline and raltegravir treatment-failure isolates. The emergence of the primary raltegravir resistance-associated substitutions was observed cumulatively in 70 subjects by Week 48 and 78 subjects by Week 96, 15.2% and 17% of the raltegravir recipients, respectively. Some (n=58) of those HIV-1 isolates harboring one or more of the primary raltegravir resistance-associated substitutions were evaluated for raltegravir susceptibility yielding a median decrease of 26.3-fold (mean 48.9 ± 44.8-fold decrease, ranging from 0.8- to 159-fold) compared to the wild-type reference.
## Nonclinical Toxicology
- Carcinogenicity studies of raltegravir in mice did not show any carcinogenic potential. At the highest dose levels, 400 mg/kg/day in females and 250 mg/kg/day in males, systemic exposure was 1.8-fold (females) or 1.2-fold (males) greater than the AUC (54 µM∙hr) at the 400-mg twice daily human dose. Treatment-related squamous cell carcinoma of nose/nasopharynx was observed in female rats dosed with 600 mg/kg/day raltegravir for 104 weeks. These tumors were possibly the result of local irritation and inflammation due to local deposition and/or aspiration of drug in the mucosa of the nose/nasopharynx during dosing. No tumors of the nose/nasopharynx were observed in rats dosed with 150 mg/kg/day (males) and 50 mg/kg/day (females) and the systemic exposure in rats was 1.7-fold (males) to 1.4-fold (females) greater than the AUC (54 μM∙hr) at the 400-mg twice daily human dose.
- No evidence of mutagenicity or genotoxicity was observed in in vitro microbial mutagenesis (Ames) tests, in vitro alkaline elution assays for DNA breakage, and in vitro and in vivo chromosomal aberration studies.
- No effect on fertility was seen in male and female rats at doses up to 600 mg/kg/day which resulted in a 3-fold exposure above the exposure at the recommended human dose.
# Clinical Studies
- The evidence of durable efficacy of ISENTRESS is based on the analyses of 240-week data from a randomized, double-blind, active-control trial, STARTMRK (Protocol 021) in antiretroviral treatment-naïve HIV-1 infected adult subjects and 96-week data from 2 randomized, double-blind, placebo-controlled studies, BENCHMRK 1 and BENCHMRK 2 (Protocols 018 and 019), in antiretroviral treatment-experienced HIV-1 infected adult subjects.
- STARTMRK (Protocol 021) is a Phase 3 study to evaluate the safety and antiretroviral activity of ISENTRESS 400 mg twice daily + emtricitabine (+) tenofovir versus efavirenz 600 mg at bedtime plus emtricitabine (+) tenofovir in treatment-naïve HIV-1-infected subjects with HIV-1 RNA >5000 copies/mL. Randomization was stratified by screening HIV-1 RNA level (≤50,000 copies/mL; and >50,000 copies/mL) and by hepatitis status.
- Table 11 shows the demographic characteristics of subjects in the group receiving ISENTRESS 400 mg twice daily and subjects in the comparator group.
- Week 240 outcomes from Protocol 021 are shown in Table 12.
- The mean changes in CD4 count from baseline were 295 cells/mm3 in the group receiving ISENTRESS 400 mg twice daily and 236 cells/mm3 in the group receiving Efavirenz 600 mg at bedtime.
- BENCHMRK 1 and BENCHMRK 2 are Phase 3 studies to evaluate the safety and antiretroviral activity of ISENTRESS 400 mg twice daily in combination with an optimized background therapy (OBT), versus OBT alone, in HIV-1-infected subjects, 16 years or older, with documented resistance to at least 1 drug in each of 3 classes (NNRTIs, NRTIs, PIs) of antiretroviral therapies. Randomization was stratified by degree of resistance to PI (1PI vs. >1PI) and the use of enfuvirtide in the OBT. Prior to randomization, OBT was selected by the investigator based on genotypic/phenotypic resistance testing and prior ART history.
- Table 13 shows the demographic characteristics of subjects in the group receiving ISENTRESS 400 mg twice daily and subjects in the placebo group.
- Table 14 compares the characteristics of optimized background therapy at baseline in the group receiving ISENTRESS 400 mg twice daily and subjects in the control group.
- Week 96 outcomes for the 699 subjects randomized and treated with the recommended dose of ISENTRESS 400 mg twice daily or placebo in the pooled BENCHMRK 1 and 2 studies are shown in Table 15.
- The mean changes in CD4 count from baseline were 118 cells/mm3 in the group receiving ISENTRESS 400 mg twice daily and 47 cells/mm3 for the control group.
- Treatment-emergent CDC Category C events occurred in 4% of the group receiving ISENTRESS 400 mg twice daily and 5% of the control group.
- Virologic responses at Week 96 by baseline genotypic and phenotypic sensitivity score are shown in Table 16.
- Switch of Suppressed Subjects from Lopinavir (+) Ritonavir to Raltegravir
- The SWITCHMRK 1 & 2 Phase 3 studies evaluated HIV-1 infected subjects receiving suppressive therapy (HIV-1 RNA 3 months) and randomized them 1:1 to either continue lopinavir (+) ritonavir (n=174 and n=178, SWITCHMRK 1 & 2, respectively) or replace lopinavir (+) ritonavir with ISENTRESS 400 mg twice daily (n=174 and n=176, respectively). The primary virology endpoint was the proportion of subjects with HIV-1 RNA less than 50 copies/mL at Week 24 with a prespecified non-inferiority margin of -12% for each study; and the frequency of adverse events up to 24 weeks.
- Subjects with a prior history of virological failure were not excluded and the number of previous antiretroviral therapies was not limited.
- These studies were terminated after the primary efficacy analysis at Week 24 because they each failed to demonstrate non-inferiority of switching to ISENTRESS versus continuing on lopinavir (+) ritonavir. In the combined analysis of these studies at Week 24, suppression of HIV-1 RNA to less than 50 copies/mL was maintained in 82.3% of the ISENTRESS group versus 90.3% of the lopinavir (+) ritonavir group. Clinical and laboratory adverse events occurred at similar frequencies in the treatment groups.
- 2 to 18 Years of Age
- IMPAACT P1066 is a Phase I/II open label multicenter trial to evaluate the pharmacokinetic profile, safety, tolerability, and efficacy of raltegravir in HIV infected children. This study enrolled 126 treatment experienced children and adolescents 2 to 18 years of age. Subjects were stratified by age, enrolling adolescents first and then successively younger children. Subjects were enrolled into cohorts according to age and received the following formulations: Cohort I (12 to less than 18 years old), 400 mg film-coated tablet; Cohort IIa (6 to less than 12 years old), 400 mg film-coated tablet; Cohort IIb (6 to less than 12 years old), chewable tablet; Cohort III (2 to less than 6 years), chewable tablet. Raltegravir was administered with an optimized background regimen.
- The initial dose finding stage included intensive pharmacokinetic evaluation. Dose selection was based upon achieving similar raltegravir plasma exposure and trough concentration as seen in adults, and acceptable short term safety. After dose selection, additional subjects were enrolled for evaluation of long term safety, tolerability and efficacy. Of the 126 subjects, 96 received the recommended dose of ISENTRESS.
- These 96 subjects had a median age of 13 (range 2 to 18) years, were 51% Female, 34% Caucasian, and 59% Black. At baseline, mean plasma HIV-1 RNA was 4.3 log10 copies/mL, median CD4 cell count was 481 cells/mm3 (range: 0 – 2361) and median CD4% was 23.3% (range: 0 – 44). Overall, 8% had baseline plasma HIV-1 RNA >100,000 copies/mL and 59% had a CDC HIV clinical classification of category B or C. Most subjects had previously used at least one NNRTI (78%) or one PI (83%).
- Ninety-three (97%) subjects 2 to 18 years of age completed 24 weeks of treatment (3 discontinued due to non-compliance). At Week 24, 54% achieved HIV RNA <50 copies/mL; 66% achieved HIV RNA <400 copies/mL. The mean CD4 count (percent) increase from baseline to Week 24 was 119 cells/mm3 (3.8%).
- 4 Weeks to Less Than 2 Years of Age
- IMPAACT P1066 also enrolled HIV-infected, infants and toddlers 4 weeks to less than 2 years of age (Cohorts IV and V) who had received prior antiretroviral therapy either as prophylaxis for prevention of mother-to-child transmission (PMTCT) and/or as combination antiretroviral therapy for treatment of HIV infection. Raltegravir was administered as an oral suspension without regard to food in combination with an optimized background regimen.
- The 26 subjects had a median age of 28 weeks (range: 4 -100), were 35% female, 85% Black and 8% Caucasian. At baseline, mean plasma HIV-1 RNA was 5.7 log10 copies/mL (range: 3.1 – 7), median CD4 cell count was 1400 cells/mm3 (range: 131 – 3648) and median CD4% was 18.6% (range: 3.3 – 39.3). Overall, 69% had baseline plasma HIV-1 RNA exceeding 100,000 copies/mL and 23% had a CDC HIV clinical classification of category B or C. None of the 26 patients were completely treatment naïve. All infants under 6 months of age had received nevirapine or zidovudine for prevention of mother-to-infant transmission, and 43% of patients greater than 6 months of age had received two or more antiretrovirals.
- Of the 26 treated subjects, 23 subjects were included in the Week 24 and 48 efficacy analyses, respectively. All 26 treated subjects were included for safety analyses.
- At Week 24, 39% achieved HIV RNA <50 copies/mL and 61% achieved HIV RNA <400 copies/mL. The mean CD4 count (percent) increase from baseline to Week 24 was 500 cells/mm3 (7.5%).
- At Week 48, 44% achieved HIV RNA <50 copies/mL and 61% achieved HIV RNA <400 copies/mL. The mean CD4 count (percent) increase from baseline to Week 48 was 492 cells/mm3 (7.8%).
# How Supplied
- ISENTRESS tablets 400 mg are pink, oval-shaped, film-coated tablets with "227" on one side. They are supplied as follows:
- NDC 0006-0227-61 unit-of-use bottles of 60.
- No. 3894
- ISENTRESS tablets 100 mg are pale orange, oval-shaped, orange-banana flavored, chewable tablets scored on both sides and imprinted on one face with the Merck logo and "477" on opposite sides of the score. They are supplied as follows:
- NDC 0006-0477-61 unit-of-use bottles of 60.
- No. 3972
- ISENTRESS tablets 25 mg are pale yellow, round, orange-banana flavored, chewable tablets with the Merck logo on one side and "473" on the other side. They are supplied as follows:
- NDC 0006-0473-61 unit-of-use bottles of 60.
- No. 3965
- ISENTRESS for oral suspension 100 mg is a white to off-white granular powder that may contain yellow or beige to tan particles, in child resistant single-use foil packets, packaged as a kit with two 5 mL dosing syringes and two mixing cups. It is supplied as follows:
- NDC 0006-3603-60 unit of use carton with 60 packets.
- NDC 0006-3603-01 individual packet.
- No. 3603
- Storage and Handling
- 400 mg Film-coated Tablets, Chewable Tablets and For Oral Suspension
- Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F).
- Chewable Tablets
- Store in the original package with the bottle tightly closed. Keep the desiccant in the bottle to protect from moisture.
- For Oral Suspension
- Store in the original container. Do not open foil packet until ready for use.
## Storage
There is limited information regarding Raltegravir Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
- General Information
- Instruct patients to reread patient labeling each time the prescription is renewed.
- Patients should remain under the care of a physician when using ISENTRESS. Instruct patients to inform their physician or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.
- ISENTRESS is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection such as opportunistic infections. Tell patients that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain on continuous HIV therapy to control HIV infection and decrease HIV-related illnesses.
- Advise patients to avoid doing things that can spread HIV-1 infection to others.
- Do not share needles or other injection equipment.
- Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
- Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
- Do not breastfeed. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk. Also, it is unknown if ISENTRESS can be passed to the baby through breast milk and whether it could harm the baby.
- General Dosing Instructions
- Instruct patients that if they miss a dose of ISENTRESS, they should take it as soon as they remember. If they do not remember until it is time for the next dose, instruct them to skip the missed dose and go back to the regular schedule. Instruct patients not to double their next dose or take more than the prescribed dose.
- Film-Coated Tablets and Chewable Tablets
- Inform patients that the chewable tablet forms can be chewed or swallowed whole, but the film-coated tablets must be swallowed whole.
- For Oral Suspension
- Instruct parents and/or caregivers to read the Instructions for Use before preparing and administering ISENTRESS for oral suspension to pediatric patients. Instruct parents and/or caregivers that ISENTRESS for oral suspension should be administered within 30 minutes of mixing.
- Severe and Potentially Life-threatening Rash
- Inform patients that severe and potentially life-threatening rash has been reported. Advise patients to immediately contact their healthcare provider if they develop rash. Instruct patients to immediately stop taking ISENTRESS and other suspect agents, and seek medical attention if they develop a rash associated with any of the following symptoms as it may be a sign of a more serious reaction such as Stevens-Johnson syndrome, toxic epidermal necrolysis or severe hypersensitivity: fever, generally ill feeling, extreme tiredness, muscle or joint aches, blisters, oral lesions, eye inflammation, facial swelling, swelling of the eyes, lips, mouth, breathing difficulty, and/or signs and symptoms of liver problems (e.g., yellowing of the skin or whites of the eyes, dark or tea colored urine, pale colored stools/bowel movements, nausea, vomiting, loss of appetite, or pain, aching or sensitivity on the right side below the ribs). Inform patients that if severe rash occurs, their physician will closely monitor them, order laboratory tests and initiate appropriate therapy.
- Rhabdomyolysis
- Before patients begin ISENTRESS, ask them if they have a history of rhabdomyolysis, myopathy or increased creatine kinase or if they are taking medications known to cause these conditions such as statins, fenofibrate, gemfibrozil or zidovudine.
- Instruct patients to immediately report to their healthcare provider any unexplained muscle pain, tenderness, or weakness while taking ISENTRESS.
- Phenylketonuria
- Alert patients with phenylketonuria that ISENTRESS Chewable Tablets contain phenylalanine.
- Drug Interactions
- Instruct patients to avoid taking aluminum and/or magnesium containing antacids during treatment with ISENTRESS.
# Precautions with Alcohol
- Alcohol-Raltegravir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Isentress®
# Look-Alike Drug Names
There is limited information regarding Raltegravir Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Raltegravir
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Overview
Raltegravir is a integrase inhibitor that is FDA approved for the {{{indicationType}}} of HIV-1 infection in patients 4 weeks of age and older. Common adverse reactions include insomnia, headache, dizziness, nausea and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- For the treatment of adult patients with HIV-1 infection, the dosage of ISENTRESS is one 400 mg film-coated tablet administered orally, twice daily.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Raltegravir in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Raltegravir in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- If at least 25 kg: One 400 mg film-coated tablet orally, twice daily.
- If unable to swallow a tablet, consider the chewable tablet, as specified in Table 1.
- If at least 4 weeks of age and weighing at least 3 kg to less than 25 kg: Weight based dosing, as specified in Table 2.
- For patients weighing between 11 and 20 kg, either the chewable tablet or oral suspension can be used, as specified in Table 2. Patients can remain on the oral suspension as long as their weight is below 20 kg. Refer to Table 2 for appropriate dosing.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Raltegravir in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Raltegravir in pediatric patients.
# Contraindications
None
# Warnings
### Precautions
- Severe Skin and Hypersensitivity Reactions
- Severe, potentially life-threatening, and fatal skin reactions have been reported. These include cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including hepatic failure. Discontinue ISENTRESS and other suspect agents immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema). Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping ISENTRESS treatment or other suspect agents after the onset of severe rash may result in a life-threatening reaction.
- Immune Reconstitution Syndrome
- Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including ISENTRESS. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, tuberculosis), which may necessitate further evaluation and treatment.
- Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.
- Phenylketonurics
- ISENTRESS Chewable Tablets contain phenylalanine, a component of aspartame. Each 25 mg ISENTRESS Chewable Tablet contains approximately 0.05 mg phenylalanine. Each 100 mg ISENTRESS Chewable Tablet contains approximately 0.10 mg phenylalanine. Phenylalanine can be harmful to patients with phenylketonuria.
# Adverse Reactions
## Clinical Trials Experience
- Treatment-Naïve Adults
- The following safety assessment of ISENTRESS in treatment-naïve subjects is based on the randomized double-blind active controlled study of treatment-naïve subjects, STARTMRK (Protocol 021) with ISENTRESS 400 mg twice daily in combination with a fixed dose of emtricitabine 200 mg (+) tenofovir 300 mg, (N=281) versus efavirenz (EFV) 600 mg at bedtime in combination with emtricitabine (+) tenofovir, (N=282). During double-blind treatment, the total follow-up for subjects receiving ISENTRESS 400 mg twice daily + emtricitabine (+) tenofovir was 1104 patient-years and 1036 patient-years for subjects receiving efavirenz 600 mg at bedtime + emtricitabine (+) tenofovir.
- In Protocol 021, the rate of discontinuation of therapy due to adverse events was 5% in subjects receiving ISENTRESS + emtricitabine (+) tenofovir and 10% in subjects receiving efavirenz + emtricitabine (+) tenofovir.
- The clinical adverse drug reactions (ADRs) listed below were considered by investigators to be causally related to ISENTRESS + emtricitabine (+) tenofovir or efavirenz + emtricitabine (+) tenofovir. Clinical ADRs of moderate to severe intensity occurring in ≥2% of treatment-naïve subjects treated with ISENTRESS are presented in Table 3.
- Laboratory Abnormalities
- The percentages of adult subjects treated with ISENTRESS 400 mg twice daily or efavirenz in Protocol 021 with selected Grades 2 to 4 laboratory abnormalities that represent a worsening Grade from baseline are presented in Table 4.
- Lipids, Change from Baseline
- Changes from baseline in fasting lipids are shown in Table 5.
- Treatment-Experienced Adults
- The safety assessment of ISENTRESS in treatment-experienced subjects is based on the pooled safety data from the randomized, double-blind, placebo-controlled trials, BENCHMRK 1 and BENCHMRK 2 (Protocols 018 and 019) in antiretroviral treatment-experienced HIV-1 infected adult subjects. A total of 462 subjects received the recommended dose of ISENTRESS 400 mg twice daily in combination with optimized background therapy (OBT) compared to 237 subjects taking placebo in combination with OBT. The median duration of therapy in these trials was 96 weeks for subjects receiving ISENTRESS and 38 weeks for subjects receiving placebo. The total exposure to ISENTRESS was 708 patient-years versus 244 patient-years on placebo. The rates of discontinuation due to adverse events were 4% in subjects receiving ISENTRESS and 5% in subjects receiving placebo.
- Clinical ADRs were considered by investigators to be causally related to ISENTRESS + OBT or placebo + OBT. Clinical ADRs of moderate to severe intensity occurring in ≥2% of subjects treated with ISENTRESS and occurring at a higher rate compared to placebo are presented in Table 6.
- Laboratory Abnormalities
- The percentages of adult subjects treated with ISENTRESS 400 mg twice daily or placebo in Protocols 018 and 019 with selected Grade 2 to 4 laboratory abnormalities representing a worsening Grade from baseline are presented in Table 7.
- Less Common Adverse Reactions Observed in Treatment-Naïve and Treatment-Experienced Studies
- The following ADRs occurred in <2% of treatment-naïve or treatment-experienced subjects receiving ISENTRESS in a combination regimen. These events have been included because of their seriousness, increased frequency on ISENTRESS compared with efavirenz or placebo, or investigator's assessment of potential causal relationship.
- Gastrointestinal Disorders: abdominal pain, gastritis, dyspepsia, vomiting
- General Disorders and Administration Site Conditions: asthenia
- Hepatobiliary Disorders: hepatitis
- Immune System Disorders: hypersensitivity
- Infections and Infestations: genital herpes, herpes zoster
- Psychiatric Disorders: depression (particularly in subjects with a pre-existing history of psychiatric illness), including suicidal ideation and behaviors
- Renal and Urinary Disorders: nephrolithiasis, renal failure
- Selected Adverse Events - Adults
- Cancers were reported in treatment-experienced subjects who initiated ISENTRESS or placebo, both with OBT, and in treatment-naïve subjects who initiated ISENTRESS or efavirenz, both with emtricitabine (+) tenofovir; several were recurrent. The types and rates of specific cancers were those expected in a highly immunodeficient population (many had CD4+ counts below 50 cells/mm3 and most had prior AIDS diagnoses). The risk of developing cancer in these studies was similar in the group receiving ISENTRESS and the group receiving the comparator.
- Grade 2-4 creatine kinase laboratory abnormalities were observed in subjects treated with ISENTRESS (see Table 6). Myopathy and rhabdomyolysis have been reported. Use with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medications known to cause these conditions and patients with a history of rhabdomyolysis, myopathy or increased serum creatine kinase.
- Rash occurred more commonly in treatment-experienced subjects receiving regimens containing ISENTRESS + darunavir/ritonavir compared to subjects receiving ISENTRESS without darunavir/ritonavir or darunavir/ritonavir without ISENTRESS. However, rash that was considered drug related occurred at similar rates for all three groups. These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash.
- Patients with Co-existing Conditions - Adults
- Patients Co-infected with Hepatitis B and/or Hepatitis C Virus
- In the randomized, double-blind, placebo-controlled trials, treatment-experienced subjects (N = 114/699 or 16%) and treatment-naïve subjects (N = 34/563 or 6%) with chronic (but not acute) active hepatitis B and/or hepatitis C virus co-infection were permitted to enroll provided that baseline liver function tests did not exceed 5 times the upper limit of normal (ULN). In general the safety profile of ISENTRESS in subjects with hepatitis B and/or hepatitis C virus co-infection was similar to that in subjects without hepatitis B and/or hepatitis C virus co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or hepatitis C virus co-infection for all treatment groups. At 96 weeks, in treatment-experienced subjects, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 29%, 34% and 13%, respectively, of co-infected subjects treated with ISENTRESS as compared to 11%, 10% and 9% of all other subjects treated with ISENTRESS. At 240 weeks, in treatment-naïve subjects, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 22%, 44% and 17%, respectively, of co-infected subjects treated with ISENTRESS as compared to 13%, 13% and 5% of all other subjects treated with ISENTRESS.
- Pediatrics
- 2 to 18 Years of Age
- ISENTRESS has been studied in 126 antiretroviral treatment-experienced HIV-1 infected children and adolescents 2 to 18 years of age, in combination with other antiretroviral agents in IMPAACT P1066. Of the 126 patients, 96 received the recommended dose of ISENTRESS.
- In these 96 children and adolescents, frequency, type and severity of drug related adverse reactions through Week 24 were comparable to those observed in adults.
- One patient experienced drug related clinical adverse reactions of Grade 3 psychomotor hyperactivity, abnormal behavior and insomnia; one patient experienced a Grade 2 serious drug related allergic rash.
- One patient experienced drug related laboratory abnormalities, Grade 4 AST and Grade 3 ALT, which were considered serious.
- 4 Weeks to less than 2 Years of Age
- ISENTRESS has also been studied in 26 HIV-1 infected infants and toddlers 4 weeks to less than 2 years of age, in combination with other antiretroviral agents in IMPAACT P1066.
- In these 26 infants and toddlers, the frequency, type and severity of drug-related adverse reactions through Week 48 were comparable to those observed in adults.
- One patient experienced a Grade 3 serious drug-related allergic rash that resulted in treatment discontinuation.
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of ISENTRESS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Blood and Lymphatic System Disorders: thrombocytopenia
- Gastrointestinal Disorders: diarrhea
- Hepatobiliary Disorders: hepatic failure (with and without associated hypersensitivity) in patients with underlying liver disease and/or concomitant medications
- Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis
- Nervous System Disorders: cerebellar ataxia
- Psychiatric Disorders: anxiety, paranoia
# Drug Interactions
- Effect of Raltegravir on the Pharmacokinetics of Other Agents
- Raltegravir does not inhibit (IC50>100 µM) CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A in vitro. Moreover, in vitro, raltegravir did not induce CYP1A2, CYP2B6 or CYP3A4. A midazolam drug interaction study confirmed the low propensity of raltegravir to alter the pharmacokinetics of agents metabolized by CYP3A4 in vivo by demonstrating a lack of effect of raltegravir on the pharmacokinetics of midazolam, a sensitive CYP3A4 substrate. Similarly, raltegravir is not an inhibitor (IC50>50 µM) of the UDP-glucuronosyltransferases (UGT) tested (UGT1A1, UGT2B7), and raltegravir does not inhibit P-glycoprotein-mediated transport. Based on these data, ISENTRESS is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or P-glycoprotein (e.g., protease inhibitors, NNRTIs, opioid analgesics, statins, azole antifungals, proton pump inhibitors and anti-erectile dysfunction agents).
- In drug interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of the following: hormonal contraceptives, methadone, lamivudine, tenofovir, etravirine, darunavir/ritonavir, telaprevir, boceprevir.
- Effect of Other Agents on the Pharmacokinetics of Raltegravir
- Raltegravir is not a substrate of cytochrome P450 (CYP) enzymes. Based on in vivo and in vitro studies, raltegravir is eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway.
- Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of ISENTRESS. Therefore, in adults the dose of ISENTRESS should be increased during coadministration with rifampin. There are no data to guide co-administration of ISENTRESS with rifampin in patients below 18 years of age. The impact of other inducers of drug metabolizing enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown.
- Coadministration of ISENTRESS with drugs that inhibit UGT1A1 may increase plasma levels of raltegravir.
- Coadministration of ISENTRESS with antacids containing divalent metal cations may reduce raltegravir absorption by chelation, resulting in a decrease of raltegravir plasma levels. Taking an aluminum and magnesium antacid within 2 hours of ISENTRESS administration significantly decreased raltegravir plasma levels. Therefore, coadministration of ISENTRESS with aluminum and/or magnesium-containing antacids is not recommended. Coadministration of ISENTRESS with a calcium carbonate antacid decreased raltegravir plasma levels; however, this interaction is not considered clinically meaningful. Therefore, when ISENTRESS is coadministered with calcium carbonate-containing antacids, no dose adjustment is recommended.
- Selected drug interactions are presented in Table 8.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- SENTRESS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. There are no adequate and well-controlled studies in pregnant women. In addition, there have been no pharmacokinetic studies conducted in pregnant patients.
- Developmental toxicity studies were performed in rabbits (at oral doses up to 1000 mg/kg/day) and rats (at oral doses up to 600 mg/kg/day). The reproductive toxicity study in rats was performed with pre-, peri-, and postnatal evaluation. The highest doses in these studies produced systemic exposures in these species approximately 3- to 4-fold the exposure at the recommended human dose. In both rabbits and rats, no treatment-related effects on embryonic/fetal survival or fetal weights were observed. In addition, no treatment-related external, visceral, or skeletal changes were observed in rabbits. However, treatment-related increases over controls in the incidence of supernumerary ribs were seen in rats at 600 mg/kg/day (exposures 3-fold the exposure at the recommended human dose).
- Placenta transfer of drug was demonstrated in both rats and rabbits. At a maternal dose of 600 mg/kg/day in rats, mean drug concentrations in fetal plasma were approximately 1.5- to 2.5-fold greater than in maternal plasma at 1 hour and 24 hours postdose, respectively. Mean drug concentrations in fetal plasma were approximately 2% of the mean maternal concentration at both 1 and 24 hours postdose at a maternal dose of 1000 mg/kg/day in rabbits.
- Antiretroviral Pregnancy Registry
- To monitor maternal-fetal outcomes of pregnant patients exposed to ISENTRESS, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Raltegravir in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Raltegravir during labor and delivery.
### Nursing Mothers
- Breastfeeding is not recommended while taking ISENTRESS. In addition, it is recommended that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1.
- It is not known whether raltegravir is secreted in human milk. However, raltegravir is secreted in the milk of lactating rats. Mean drug concentrations in milk were approximately 3-fold greater than those in maternal plasma at a maternal dose of 600 mg/kg/day in rats. There were no effects in rat offspring attributable to exposure of ISENTRESS through the milk.
### Pediatric Use
- The safety, tolerability, pharmacokinetic profile, and efficacy of ISENTRESS were evaluated in HIV-1 infected infants, children and adolescents 4 weeks to 18 years of age in an open-label, multicenter clinical trial, IMPAACT P1066. The safety profile was comparable to that observed in adults. The safety and dosing information for ISENTRESS have not been established in infants less than 4 weeks of age.
### Geriatic Use
- Clinical studies of ISENTRESS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Raltegravir with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Raltegravir with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Raltegravir in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Raltegravir in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Raltegravir in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Raltegravir in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Raltegravir in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Raltegravir in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- No specific information is available on the treatment of overdosage with ISENTRESS. Doses as high as 1600-mg single dose and 800-mg twice-daily multiple doses were studied in healthy volunteers without evidence of toxicity. Occasional doses of up to 1800 mg per day were taken in the clinical studies of HIV-1 infected subjects without evidence of toxicity.
### Management
- In the event of an overdose, it is reasonable to employ the standard supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy if required. The extent to which ISENTRESS may be dialyzable is unknown.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Raltegravir in the drug label.
# Pharmacology
## Mechanism of Action
- Raltegravir inhibits the catalytic activity of HIV-1 integrase, an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the covalent insertion, or integration, of unintegrated linear HIV-1 DNA into the host cell genome preventing the formation of the HIV-1 provirus. The provirus is required to direct the production of progeny virus, so inhibiting integration prevents propagation of the viral infection. Raltegravir did not significantly inhibit human phosphoryltransferases including DNA polymerases α, β, and γ.
## Structure
- ISENTRESS contains raltegravir potassium, a human immunodeficiency virus integrase strand transfer inhibitor. The chemical name for raltegravir potassium is N-[(4-Fluorophenyl) methyl]-1,6-dihydro-5-hydroxy-1-methyl-2-[1-methyl-1-[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino]ethyl]-6-oxo-4-pyrimidinecarboxamide monopotassium salt.
- The empirical formula is C20H20FKN6O5 and the molecular weight is 482.51. The structural formula is:
- Raltegravir potassium is a white to off-white powder. It is soluble in water, slightly soluble in methanol, very slightly soluble in ethanol and acetonitrile and insoluble in isopropanol.
- Each 400 mg film-coated tablet of ISENTRESS for oral administration contains 434.4 mg of raltegravir (as potassium salt), equivalent to 400 mg of raltegravir free phenol and the following inactive ingredients: calcium phosphate dibasic anhydrous, hypromellose 2208, lactose monohydrate, magnesium stearate, microcrystalline cellulose, poloxamer 407 (contains 0.01% butylated hydroxytoluene as antioxidant), sodium stearyl fumarate. In addition, the film coating contains the following inactive ingredients: black iron oxide, polyethylene glycol 3350, polyvinyl alcohol, red iron oxide, talc and titanium dioxide.
- Each 100 mg chewable tablet of ISENTRESS for oral administration contains 108.6 mg of raltegravir (as potassium salt), equivalent to 100 mg of raltegravir free phenol and the following inactive ingredients: ammonium hydroxide, crospovidone, ethylcellulose 20 cP, fructose, hydroxypropyl cellulose, hypromellose 2910/6cP, magnesium stearate, mannitol, medium chain triglycerides, monoammonium glycyrrhizinate, natural and artificial flavors (orange, banana, and masking that contains aspartame), oleic acid, PEG 400, red iron oxide, saccharin sodium, sodium citrate dihydrate, sodium stearyl fumarate, sorbitol, sucralose and yellow iron oxide.
- Each 25 mg chewable tablet of ISENTRESS for oral administration contains 27.16 mg of raltegravir (as potassium salt), equivalent to 25 mg of raltegravir free phenol and the following inactive ingredients: ammonium hydroxide, crospovidone, ethylcellulose 20 cP, fructose, hydroxypropyl cellulose, hypromellose 2910/6cP, magnesium stearate, mannitol, medium chain triglycerides, monoammonium glycyrrhizinate, natural and artificial flavors (orange, banana, and masking that contains aspartame), oleic acid, PEG 400, saccharin sodium, sodium citrate dihydrate, sodium stearyl fumarate, sorbitol, sucralose and yellow iron oxide.
- Each packet of ISENTRESS for oral suspension 100 mg, contains 108.6 mg of raltegravir (as potassium salt), equivalent to 100 mg of raltegravir free phenol and the following inactive ingredients: ammonium hydroxide, banana with other natural flavors, carboxymethylcellulose sodium, crospovidone, ethylcellulose 20 cP, fructose, hydroxypropyl cellulose, hypromellose 2910/6cP, macrogol/PEG 400, magnesium stearate, maltodextrin, mannitol, medium chain triglycerides, microcrystalline cellulose, monoammonium glycyrrhizinate, oleic acid, sorbitol, sucralose and sucrose.
## Pharmacodynamics
- In a monotherapy study raltegravir (400 mg twice daily) demonstrated rapid antiviral activity with mean viral load reduction of 1.66 log10 copies/mL by Day 10.
- In the randomized, double-blind, placebo-controlled, dose-ranging trial, Protocol 005, and Protocols 018 and 019, antiviral responses were similar among subjects regardless of dose.
- Effects on Electrocardiogram
- In a randomized, placebo-controlled, crossover study, 31 healthy subjects were administered a single oral supratherapeutic dose of raltegravir 1600 mg and placebo. Peak raltegravir plasma concentrations were approximately 4-fold higher than the peak concentrations following a 400 mg dose. ISENTRESS did not appear to prolong the QTc interval for 12 hours postdose. After baseline and placebo adjustment, the maximum mean QTc change was -0.4 msec (1-sided 95% upper Cl: 3.1 msec).
## Pharmacokinetics
- Adults
- Absorption
- Raltegravir (film-coated tablet) is absorbed with a Tmax of approximately 3 hours postdose in the fasted state. Raltegravir AUC and Cmax increase dose proportionally over the dose range 100 mg to 1600 mg. Raltegravir C12hr increases dose proportionally over the dose range of 100 to 800 mg and increases slightly less than dose proportionally over the dose range 100 mg to 1600 mg. With twice-daily dosing, pharmacokinetic steady state is achieved within approximately the first 2 days of dosing. There is little to no accumulation in AUC and Cmax. The average accumulation ratio for C12hr ranged from approximately 1.2 to 1.6.
- The absolute bioavailability of raltegravir has not been established. Based on a formulation comparison study in healthy adult volunteers, the chewable tablet and oral suspension have higher oral bioavailability compared to the 400 mg film-coated tablet.
- In subjects who received 400 mg twice daily alone, raltegravir drug exposures were characterized by a geometric mean AUC0-12hr of 14.3 µM∙hr and C12hr of 142 nM.
- Considerable variability was observed in the pharmacokinetics of raltegravir. For observed C12hr in Protocols 018 and 019, the coefficient of variation (CV) for inter-subject variability = 212% and the CV for intra-subject variability = 122%.
- Effect of Food on Oral Absorption
- ISENTRESS may be administered with or without food. Raltegravir was administered without regard to food in the pivotal safety and efficacy studies in HIV-1-infected patients. The effect of consumption of low-, moderate- and high-fat meals on steady-state raltegravir pharmacokinetics was assessed in healthy volunteers administered the 400 mg film-coated tablet. Administration of multiple doses of raltegravir following a moderate-fat meal (600 Kcal, 21 g fat) did not affect raltegravir AUC to a clinically meaningful degree with an increase of 13% relative to fasting. Raltegravir C12hr was 66% higher and Cmax was 5% higher following a moderate-fat meal compared to fasting. Administration of raltegravir following a high-fat meal (825 Kcal, 52 g fat) increased AUC and Cmax by approximately 2-fold and increased C12hr by 4.1-fold. Administration of raltegravir following a low-fat meal (300 Kcal, 2.5 g fat) decreased AUC and Cmax by 46% and 52%, respectively; C12hr was essentially unchanged. Food appears to increase pharmacokinetic variability relative to fasting.
- Administration of the chewable tablet with a high fat meal led to an average 6% decrease in AUC, 62% decrease in Cmax, and 188% increase in C12hr compared to administration in the fasted state. Administration of the chewable tablet with a high fat meal does not affect raltegravir pharmacokinetics to a clinically meaningful degree and the chewable tablet can be administered without regard to food.
- The effect of food on the formulation for oral suspension was not studied.
- Distribution
- Raltegravir is approximately 83% bound to human plasma protein over the concentration range of 2 to 10 µM.
- In one study of HIV-1 infected subjects who received raltegravir 400 mg twice daily, raltegravir was measured in the cerebrospinal fluid. In the study (n=18), the median cerebrospinal fluid concentration was 5.8% (range 1 to 53.5%) of the corresponding plasma concentration. This median proportion was approximately 3-fold lower than the free fraction of raltegravir in plasma. The clinical relevance of this finding is unknown.
- Metabolism and Excretion
- The apparent terminal half-life of raltegravir is approximately 9 hours, with a shorter α-phase half-life (~1 hour) accounting for much of the AUC. Following administration of an oral dose of radiolabeled raltegravir, approximately 51 and 32% of the dose was excreted in feces and urine, respectively. In feces, only raltegravir was present, most of which is likely derived from hydrolysis of raltegravir-glucuronide secreted in bile as observed in preclinical species. Two components, namely raltegravir and raltegravir-glucuronide, were detected in urine and accounted for approximately 9 and 23% of the dose, respectively. The major circulating entity was raltegravir and represented approximately 70% of the total radioactivity; the remaining radioactivity in plasma was accounted for by raltegravir-glucuronide. Studies using isoform-selective chemical inhibitors and cDNA-expressed UDP-glucuronosyltransferases (UGT) show that UGT1A1 is the main enzyme responsible for the formation of raltegravir-glucuronide. Thus, the data indicate that the major mechanism of clearance of raltegravir in humans is UGT1A1-mediated glucuronidation.
- Special Populations
- Pediatric
- Two pediatric formulations were evaluated in healthy adult volunteers, where the chewable tablet and oral suspension were compared to the 400 mg tablet. The chewable tablet and oral suspension demonstrated higher oral bioavailability, thus higher AUC, compared to the 400 mg tablet. In the same study, the oral suspension resulted in higher oral bioavailability compared to the chewable tablet. These observations resulted in proposed pediatric doses targeting 6 mg/kg/dose for the chewable tablets and oral suspension. As displayed in Table 9, the doses recommended for HIV-infected infants, children and adolescents 4 weeks to 18 years of age resulted in a pharmacokinetic profile of raltegravir similar to that observed in adults receiving 400 mg twice daily.
- Overall, dosing in pediatric patients achieved exposures (Ctrough) above 45 nM in the majority of subjects, but some differences in exposures between formulations were observed. Pediatric patients above 25 kg administered the chewable tablets had lower trough concentrations (113 nM) compared to pediatric patients above 25 kg administered the 400 mg tablet formulation (233 nM). As a result, the 400 mg film-coated tablet is the recommended dose in patients weighing at least 25 kg; however, the chewable tablet offers an alternative regimen in patients weighing at least 25 kg who are unable to swallow the film-coated tablet. In addition, pediatric patients weighing 11 to 25 kg who were administered the chewable tablets had the lowest trough concentrations (82 nM) compared to all other pediatric subgroups.
- The pharmacokinetics of raltegravir in infants under 4 weeks of age has not been established.
- Age
- The effect of age (18 years and older) on the pharmacokinetics of raltegravir was evaluated in the composite analysis. No dosage adjustment is necessary.
- Race
- The effect of race on the pharmacokinetics of raltegravir in adults was evaluated in the composite analysis. No dosage adjustment is necessary.
- Gender
- A study of the pharmacokinetics of raltegravir was performed in healthy adult males and females. Additionally, the effect of gender was evaluated in a composite analysis of pharmacokinetic data from 103 healthy subjects and 28 HIV-1 infected subjects receiving raltegravir monotherapy with fasted administration. No dosage adjustment is necessary.
- Hepatic Impairment
- Raltegravir is eliminated primarily by glucuronidation in the liver. A study of the pharmacokinetics of raltegravir was performed in adult subjects with moderate hepatic impairment. Additionally, hepatic impairment was evaluated in the composite pharmacokinetic analysis. There were no clinically important pharmacokinetic differences between subjects with moderate hepatic impairment and healthy subjects. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of raltegravir has not been studied.
- Renal Impairment
- Renal clearance of unchanged drug is a minor pathway of elimination. A study of the pharmacokinetics of raltegravir was performed in adult subjects with severe renal impairment. Additionally, renal impairment was evaluated in the composite pharmacokinetic analysis. There were no clinically important pharmacokinetic differences between subjects with severe renal impairment and healthy subjects. No dosage adjustment is necessary. Because the extent to which ISENTRESS may be dialyzable is unknown, dosing before a dialysis session should be avoided.
- UGT1A1 Polymorphism
- There is no evidence that common UGT1A1 polymorphisms alter raltegravir pharmacokinetics to a clinically meaningful extent. In a comparison of 30 adult subjects with *28/*28 genotype (associated with reduced activity of UGT1A1) to 27 adult subjects with wild-type genotype, the geometric mean ratio (90% CI) of AUC was 1.41 (0.96, 2.09).
- Mechanism of Action
- Raltegravir inhibits the catalytic activity of HIV-1 integrase, an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the covalent insertion, or integration, of unintegrated linear HIV-1 DNA into the host cell genome preventing the formation of the HIV-1 provirus. The provirus is required to direct the production of progeny virus, so inhibiting integration prevents propagation of the viral infection. Raltegravir did not significantly inhibit human phosphoryltransferases including DNA polymerases α, β, and γ.
- Antiviral Activity in Cell Culture
- Raltegravir at concentrations of 31 ± 20 nM resulted in 95% inhibition (EC95) of viral spread (relative to an untreated virus-infected culture) in human T-lymphoid cell cultures infected with the cell-line adapted HIV-1 variant H9IIIB. In addition, 5 clinical isolates of HIV-1 subtype B had EC95 values ranging from 9 to 19 nM in cultures of mitogen-activated human peripheral blood mononuclear cells. In a single-cycle infection assay, raltegravir inhibited infection of 23 HIV-1 isolates representing 5 non-B subtypes (A, C, D, F, and G) and 5 circulating recombinant forms (AE, AG, BF, BG, and cpx) with EC50 values ranging from 5 to 12 nM. Raltegravir also inhibited replication of an HIV-2 isolate when tested in CEMx174 cells (EC95 value = 6 nM). Additive to synergistic antiretroviral activity was observed when human T-lymphoid cells infected with the H9IIIB variant of HIV-1 were incubated with raltegravir in combination with non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, or nevirapine); nucleoside analog reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, tenofovir, zalcitabine, or zidovudine); protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, or saquinavir); or the entry inhibitor enfuvirtide.
- Resistance
- The mutations observed in the HIV-1 integrase coding sequence that contributed to raltegravir resistance (evolved either in cell culture or in subjects treated with raltegravir) generally included an amino acid substitution at either Y143 (changed to C, H, or R) or Q148 (changed to H, K, or R) or N155 (changed to H) plus one or more additional substitutions (i.e., L74M, E92Q, Q95K/R, T97A, E138A/K, G140A/S, V151I, G163R, H183P, Y226C/D/F/H, S230R, and D232N). E92Q and F121C are occasionally seen in the absence of substitutions at Y143, Q148, or N155 in raltegravir-treatment failure subjects.
- Treatment-Naïve Adult Subjects: By Week 96 in the STARTMRK trial, the primary raltegravir resistance-associated substitutions were observed in 4 (2 with Y143H/R and 2 with Q148H/R) of the 10 virologic failure subjects with evaluable genotypic data from paired baseline and raltegravir treatment-failure isolates.
- Treatment-Experienced Adult Subjects: By Week 96 in the BENCHMRK trials, at least one of the primary raltegravir resistance-associated substitutions, Y143C/H/R, Q148H/K/R, and N155H, was observed in 76 of the 112 virologic failure subjects with evaluable genotypic data from paired baseline and raltegravir treatment-failure isolates. The emergence of the primary raltegravir resistance-associated substitutions was observed cumulatively in 70 subjects by Week 48 and 78 subjects by Week 96, 15.2% and 17% of the raltegravir recipients, respectively. Some (n=58) of those HIV-1 isolates harboring one or more of the primary raltegravir resistance-associated substitutions were evaluated for raltegravir susceptibility yielding a median decrease of 26.3-fold (mean 48.9 ± 44.8-fold decrease, ranging from 0.8- to 159-fold) compared to the wild-type reference.
## Nonclinical Toxicology
- Carcinogenicity studies of raltegravir in mice did not show any carcinogenic potential. At the highest dose levels, 400 mg/kg/day in females and 250 mg/kg/day in males, systemic exposure was 1.8-fold (females) or 1.2-fold (males) greater than the AUC (54 µM∙hr) at the 400-mg twice daily human dose. Treatment-related squamous cell carcinoma of nose/nasopharynx was observed in female rats dosed with 600 mg/kg/day raltegravir for 104 weeks. These tumors were possibly the result of local irritation and inflammation due to local deposition and/or aspiration of drug in the mucosa of the nose/nasopharynx during dosing. No tumors of the nose/nasopharynx were observed in rats dosed with 150 mg/kg/day (males) and 50 mg/kg/day (females) and the systemic exposure in rats was 1.7-fold (males) to 1.4-fold (females) greater than the AUC (54 μM∙hr) at the 400-mg twice daily human dose.
- No evidence of mutagenicity or genotoxicity was observed in in vitro microbial mutagenesis (Ames) tests, in vitro alkaline elution assays for DNA breakage, and in vitro and in vivo chromosomal aberration studies.
- No effect on fertility was seen in male and female rats at doses up to 600 mg/kg/day which resulted in a 3-fold exposure above the exposure at the recommended human dose.
# Clinical Studies
- The evidence of durable efficacy of ISENTRESS is based on the analyses of 240-week data from a randomized, double-blind, active-control trial, STARTMRK (Protocol 021) in antiretroviral treatment-naïve HIV-1 infected adult subjects and 96-week data from 2 randomized, double-blind, placebo-controlled studies, BENCHMRK 1 and BENCHMRK 2 (Protocols 018 and 019), in antiretroviral treatment-experienced HIV-1 infected adult subjects.
- STARTMRK (Protocol 021) is a Phase 3 study to evaluate the safety and antiretroviral activity of ISENTRESS 400 mg twice daily + emtricitabine (+) tenofovir versus efavirenz 600 mg at bedtime plus emtricitabine (+) tenofovir in treatment-naïve HIV-1-infected subjects with HIV-1 RNA >5000 copies/mL. Randomization was stratified by screening HIV-1 RNA level (≤50,000 copies/mL; and >50,000 copies/mL) and by hepatitis status.
- Table 11 shows the demographic characteristics of subjects in the group receiving ISENTRESS 400 mg twice daily and subjects in the comparator group.
- Week 240 outcomes from Protocol 021 are shown in Table 12.
- The mean changes in CD4 count from baseline were 295 cells/mm3 in the group receiving ISENTRESS 400 mg twice daily and 236 cells/mm3 in the group receiving Efavirenz 600 mg at bedtime.
- BENCHMRK 1 and BENCHMRK 2 are Phase 3 studies to evaluate the safety and antiretroviral activity of ISENTRESS 400 mg twice daily in combination with an optimized background therapy (OBT), versus OBT alone, in HIV-1-infected subjects, 16 years or older, with documented resistance to at least 1 drug in each of 3 classes (NNRTIs, NRTIs, PIs) of antiretroviral therapies. Randomization was stratified by degree of resistance to PI (1PI vs. >1PI) and the use of enfuvirtide in the OBT. Prior to randomization, OBT was selected by the investigator based on genotypic/phenotypic resistance testing and prior ART history.
- Table 13 shows the demographic characteristics of subjects in the group receiving ISENTRESS 400 mg twice daily and subjects in the placebo group.
- Table 14 compares the characteristics of optimized background therapy at baseline in the group receiving ISENTRESS 400 mg twice daily and subjects in the control group.
- Week 96 outcomes for the 699 subjects randomized and treated with the recommended dose of ISENTRESS 400 mg twice daily or placebo in the pooled BENCHMRK 1 and 2 studies are shown in Table 15.
- The mean changes in CD4 count from baseline were 118 cells/mm3 in the group receiving ISENTRESS 400 mg twice daily and 47 cells/mm3 for the control group.
- Treatment-emergent CDC Category C events occurred in 4% of the group receiving ISENTRESS 400 mg twice daily and 5% of the control group.
- Virologic responses at Week 96 by baseline genotypic and phenotypic sensitivity score are shown in Table 16.
- Switch of Suppressed Subjects from Lopinavir (+) Ritonavir to Raltegravir
- The SWITCHMRK 1 & 2 Phase 3 studies evaluated HIV-1 infected subjects receiving suppressive therapy (HIV-1 RNA <50 copies/mL on a stable regimen of lopinavir 200 mg (+) ritonavir 50 mg 2 tablets twice daily plus at least 2 nucleoside reverse transcriptase inhibitors for >3 months) and randomized them 1:1 to either continue lopinavir (+) ritonavir (n=174 and n=178, SWITCHMRK 1 & 2, respectively) or replace lopinavir (+) ritonavir with ISENTRESS 400 mg twice daily (n=174 and n=176, respectively). The primary virology endpoint was the proportion of subjects with HIV-1 RNA less than 50 copies/mL at Week 24 with a prespecified non-inferiority margin of -12% for each study; and the frequency of adverse events up to 24 weeks.
- Subjects with a prior history of virological failure were not excluded and the number of previous antiretroviral therapies was not limited.
- These studies were terminated after the primary efficacy analysis at Week 24 because they each failed to demonstrate non-inferiority of switching to ISENTRESS versus continuing on lopinavir (+) ritonavir. In the combined analysis of these studies at Week 24, suppression of HIV-1 RNA to less than 50 copies/mL was maintained in 82.3% of the ISENTRESS group versus 90.3% of the lopinavir (+) ritonavir group. Clinical and laboratory adverse events occurred at similar frequencies in the treatment groups.
- 2 to 18 Years of Age
- IMPAACT P1066 is a Phase I/II open label multicenter trial to evaluate the pharmacokinetic profile, safety, tolerability, and efficacy of raltegravir in HIV infected children. This study enrolled 126 treatment experienced children and adolescents 2 to 18 years of age. Subjects were stratified by age, enrolling adolescents first and then successively younger children. Subjects were enrolled into cohorts according to age and received the following formulations: Cohort I (12 to less than 18 years old), 400 mg film-coated tablet; Cohort IIa (6 to less than 12 years old), 400 mg film-coated tablet; Cohort IIb (6 to less than 12 years old), chewable tablet; Cohort III (2 to less than 6 years), chewable tablet. Raltegravir was administered with an optimized background regimen.
- The initial dose finding stage included intensive pharmacokinetic evaluation. Dose selection was based upon achieving similar raltegravir plasma exposure and trough concentration as seen in adults, and acceptable short term safety. After dose selection, additional subjects were enrolled for evaluation of long term safety, tolerability and efficacy. Of the 126 subjects, 96 received the recommended dose of ISENTRESS.
- These 96 subjects had a median age of 13 (range 2 to 18) years, were 51% Female, 34% Caucasian, and 59% Black. At baseline, mean plasma HIV-1 RNA was 4.3 log10 copies/mL, median CD4 cell count was 481 cells/mm3 (range: 0 – 2361) and median CD4% was 23.3% (range: 0 – 44). Overall, 8% had baseline plasma HIV-1 RNA >100,000 copies/mL and 59% had a CDC HIV clinical classification of category B or C. Most subjects had previously used at least one NNRTI (78%) or one PI (83%).
- Ninety-three (97%) subjects 2 to 18 years of age completed 24 weeks of treatment (3 discontinued due to non-compliance). At Week 24, 54% achieved HIV RNA <50 copies/mL; 66% achieved HIV RNA <400 copies/mL. The mean CD4 count (percent) increase from baseline to Week 24 was 119 cells/mm3 (3.8%).
- 4 Weeks to Less Than 2 Years of Age
- IMPAACT P1066 also enrolled HIV-infected, infants and toddlers 4 weeks to less than 2 years of age (Cohorts IV and V) who had received prior antiretroviral therapy either as prophylaxis for prevention of mother-to-child transmission (PMTCT) and/or as combination antiretroviral therapy for treatment of HIV infection. Raltegravir was administered as an oral suspension without regard to food in combination with an optimized background regimen.
- The 26 subjects had a median age of 28 weeks (range: 4 -100), were 35% female, 85% Black and 8% Caucasian. At baseline, mean plasma HIV-1 RNA was 5.7 log10 copies/mL (range: 3.1 – 7), median CD4 cell count was 1400 cells/mm3 (range: 131 – 3648) and median CD4% was 18.6% (range: 3.3 – 39.3). Overall, 69% had baseline plasma HIV-1 RNA exceeding 100,000 copies/mL and 23% had a CDC HIV clinical classification of category B or C. None of the 26 patients were completely treatment naïve. All infants under 6 months of age had received nevirapine or zidovudine for prevention of mother-to-infant transmission, and 43% of patients greater than 6 months of age had received two or more antiretrovirals.
- Of the 26 treated subjects, 23 subjects were included in the Week 24 and 48 efficacy analyses, respectively. All 26 treated subjects were included for safety analyses.
- At Week 24, 39% achieved HIV RNA <50 copies/mL and 61% achieved HIV RNA <400 copies/mL. The mean CD4 count (percent) increase from baseline to Week 24 was 500 cells/mm3 (7.5%).
- At Week 48, 44% achieved HIV RNA <50 copies/mL and 61% achieved HIV RNA <400 copies/mL. The mean CD4 count (percent) increase from baseline to Week 48 was 492 cells/mm3 (7.8%).
# How Supplied
- ISENTRESS tablets 400 mg are pink, oval-shaped, film-coated tablets with "227" on one side. They are supplied as follows:
- NDC 0006-0227-61 unit-of-use bottles of 60.
- No. 3894
- ISENTRESS tablets 100 mg are pale orange, oval-shaped, orange-banana flavored, chewable tablets scored on both sides and imprinted on one face with the Merck logo and "477" on opposite sides of the score. They are supplied as follows:
- NDC 0006-0477-61 unit-of-use bottles of 60.
- No. 3972
- ISENTRESS tablets 25 mg are pale yellow, round, orange-banana flavored, chewable tablets with the Merck logo on one side and "473" on the other side. They are supplied as follows:
- NDC 0006-0473-61 unit-of-use bottles of 60.
- No. 3965
- ISENTRESS for oral suspension 100 mg is a white to off-white granular powder that may contain yellow or beige to tan particles, in child resistant single-use foil packets, packaged as a kit with two 5 mL dosing syringes and two mixing cups. It is supplied as follows:
- NDC 0006-3603-60 unit of use carton with 60 packets.
- NDC 0006-3603-01 individual packet.
- No. 3603
- Storage and Handling
- 400 mg Film-coated Tablets, Chewable Tablets and For Oral Suspension
- Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F).
- Chewable Tablets
- Store in the original package with the bottle tightly closed. Keep the desiccant in the bottle to protect from moisture.
- For Oral Suspension
- Store in the original container. Do not open foil packet until ready for use.
## Storage
There is limited information regarding Raltegravir Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
- General Information
- Instruct patients to reread patient labeling each time the prescription is renewed.
- Patients should remain under the care of a physician when using ISENTRESS. Instruct patients to inform their physician or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.
- ISENTRESS is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection such as opportunistic infections. Tell patients that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain on continuous HIV therapy to control HIV infection and decrease HIV-related illnesses.
- Advise patients to avoid doing things that can spread HIV-1 infection to others.
- Do not share needles or other injection equipment.
- Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
- Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
- Do not breastfeed. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk. Also, it is unknown if ISENTRESS can be passed to the baby through breast milk and whether it could harm the baby.
- General Dosing Instructions
- Instruct patients that if they miss a dose of ISENTRESS, they should take it as soon as they remember. If they do not remember until it is time for the next dose, instruct them to skip the missed dose and go back to the regular schedule. Instruct patients not to double their next dose or take more than the prescribed dose.
- Film-Coated Tablets and Chewable Tablets
- Inform patients that the chewable tablet forms can be chewed or swallowed whole, but the film-coated tablets must be swallowed whole.
- For Oral Suspension
- Instruct parents and/or caregivers to read the Instructions for Use before preparing and administering ISENTRESS for oral suspension to pediatric patients. Instruct parents and/or caregivers that ISENTRESS for oral suspension should be administered within 30 minutes of mixing.
- Severe and Potentially Life-threatening Rash
- Inform patients that severe and potentially life-threatening rash has been reported. Advise patients to immediately contact their healthcare provider if they develop rash. Instruct patients to immediately stop taking ISENTRESS and other suspect agents, and seek medical attention if they develop a rash associated with any of the following symptoms as it may be a sign of a more serious reaction such as Stevens-Johnson syndrome, toxic epidermal necrolysis or severe hypersensitivity: fever, generally ill feeling, extreme tiredness, muscle or joint aches, blisters, oral lesions, eye inflammation, facial swelling, swelling of the eyes, lips, mouth, breathing difficulty, and/or signs and symptoms of liver problems (e.g., yellowing of the skin or whites of the eyes, dark or tea colored urine, pale colored stools/bowel movements, nausea, vomiting, loss of appetite, or pain, aching or sensitivity on the right side below the ribs). Inform patients that if severe rash occurs, their physician will closely monitor them, order laboratory tests and initiate appropriate therapy.
- Rhabdomyolysis
- Before patients begin ISENTRESS, ask them if they have a history of rhabdomyolysis, myopathy or increased creatine kinase or if they are taking medications known to cause these conditions such as statins, fenofibrate, gemfibrozil or zidovudine.
- Instruct patients to immediately report to their healthcare provider any unexplained muscle pain, tenderness, or weakness while taking ISENTRESS.
- Phenylketonuria
- Alert patients with phenylketonuria that ISENTRESS Chewable Tablets contain phenylalanine.
- Drug Interactions
- Instruct patients to avoid taking aluminum and/or magnesium containing antacids during treatment with ISENTRESS.
# Precautions with Alcohol
- Alcohol-Raltegravir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Isentress®[1]
# Look-Alike Drug Names
There is limited information regarding Raltegravir Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Isentress | |
3ed11e02b74272ec17aaad30784013a2803a2ada | wikidoc | Isomorphism | Isomorphism
In abstract algebra, an isomorphism (Greek: ison "equal", and morphe "shape") is a bijective map f such that both f and its inverse f −1 are homomorphisms, i.e., structure-preserving mappings.
In the more general setting of category theory, an isomorphism is a morphism f:X→Y in a category for which there exists an "inverse" f −1:Y→X, with the property that both f −1f=idX and ff −1=idY.
Informally, an isomorphism is a kind of mapping between objects, which shows a relationship between two properties or operations. If there exists an isomorphism between two structures, we call the two structures isomorphic. In a certain sense, isomorphic structures are structurally identical, if you choose to ignore finer-grained differences that may arise from how they are defined.
# Purpose
Isomorphisms are studied in mathematics in order to extend insights from one phenomenon to others: if two objects are isomorphic, then any property which is preserved by an isomorphism and which is true of one of the objects is also true of the other. If an isomorphism can be found from a relatively unknown part of mathematics into some well studied division of mathematics, where many theorems are already proved, and many methods are already available to find answers, then the function can be used to map whole problems out of unfamiliar territory over to "solid ground" where the problem is easier to understand and work with.
# Physical analogies
Here are some everyday examples of isomorphic structures:
- A standard deck of 52 playing cards with the four suits hearts, diamonds, spades, and clubs and a standard deck of 52 playing cards with four suits of triangles, circles, squares, and pentagons; although the suits of each deck differ, the decks are structurally isomorphic — if we wish to play cards, it doesn't matter which deck we choose to use.
- The Clock Tower in London (that contains Big Ben) and a wristwatch; although the clocks vary greatly in size, their mechanisms of reckoning time are isomorphic.
- A six-sided die and a bag from which a number 1 through 6 is chosen; although the method of obtaining a number is different, their random number generating abilities are isomorphic. This is an example of functional isomorphism, without the presumption of geometric isomorphism.
- There is a game which is isomorphic to tic-tac-toe, but on the surface appears completely different. Players take it in turn to say a number between one and nine. Numbers may not be repeated. Both players aim to say three numbers which add up to 15. Plotting these numbers on a 3×3 magic square will reveal the exact correspondence with the game of tic-tac-toe, given that three numbers will be arranged in a straight line if and only if they add up to 15.
# Practical example
The following are examples of isomorphisms from ordinary algebra.
- Consider the logarithm function: For any fixed base b, the logarithm function logb maps from the positive real numbers \mathbb{R}^+ onto the real numbers \mathbb{R}; formally:
\log_b : \mathbb{R}^+ \to \mathbb{R} \!
This mapping is one-to-one and onto, that is, it is a bijection from the domain to the codomain of the logarithm function.
In addition to being an isomorphism of sets, the logarithm function also preserves certain operations. Specifically, consider the group (\mathbb{R}^+,\times) of positive real numbers under ordinary multiplication. The logarithm function obeys the following identity:
\log_b(x \times y) = \log_b(x) + \log_b(y) \!
But the real numbers under addition also form a group. So the logarithm function is in fact a group isomorphism from the group (\mathbb{R}^+,\times) to the group (\mathbb{R},+).
Logarithms can therefore be used to simplify multiplication of real numbers. By working with logarithms, multiplication of positive real numbers is replaced by addition of logs. This way it is possible to multiply real numbers using a ruler and a table of logarithms, or using a slide rule with a logarithmic scale.
- Consider the group Z6, the numbers from 0 to 5 with addition modulo 6. Also consider the group Z2 × Z3, the ordered pairs where the x coordinates can be 0 or 1, and the y coordinates can be 0, 1, or 2, where addition in the x-coordinate is modulo 2 and addition in the y-coordinate is modulo 3.
These structures are isomorphic under addition, if you identify them using the following scheme:
-r in general (a,b) -> ( 3a + 4 b ) mod 6.
For example note that (1,1) + (1,0) = (0,1) which translates in the other system as 1 + 3 = 4.
Even though these two groups "look" different in that the sets contain different elements, they are indeed isomorphic: their structures are exactly the same. More generally, the direct product of two cyclic groups Zn and Zm is cyclic if and only if n and m are coprime.
# Abstract examples
## A relation-preserving isomorphism
If one object consists of a set X with a binary relation R and the other object consists of a set Y with a binary relation S then an isomorphism from X to Y is a bijective function f : X → Y such that
S is reflexive, irreflexive, symmetric, antisymmetric, asymmetric, transitive, total, Template:Ml, a partial order, total order, strict weak order, total preorder (weak order), an equivalence relation, or a relation with any other special properties, if and only if R is.
For example, R is an ordering ≤ and S an ordering \sqsubseteq, then an isomorphism from X to Y is a bijective function f : X → Y such that
Such an isomorphism is called an order isomorphism or (less commonly) an isotone isomorphism.
If X = Y we have a relation-preserving automorphism.
## An operation-preserving isomorphism
Suppose that on these sets X and Y, there are two binary operations \star and \Diamond which happen to constitute the groups (X,\star) and (Y,\Diamond). Note that the operators operate on elements from the domain and range, respectively, of the "one-to-one" and "onto" function f. There is an isomorphism from X to Y if the bijective function f : X → Y happens to produce results, that sets up a correspondence between the operator \star and the operator \Diamond.
for all u, v in X.
# Applications
In abstract algebra, two basic isomorphisms are defined:
- Group isomorphism, an isomorphism between groups
- Ring isomorphism, an isomorphism between rings. (Note that isomorphisms between fields are actually ring isomorphisms)
Just as the automorphisms of an algebraic structure form a group, the isomorphisms between two algebras sharing a common structure form a heap. Letting a particular isomorphism identify the two structures turns this heap into a group.
In mathematical analysis, the Legendre transform is an isomorphism mapping hard differential equations into easier algebraic equations.
In category theory, Iet the category C consist of two classes, one of objects and the other of morphisms. Then a general definition of isomorphism that covers the previous and many other cases is: an isomorphism is a morphism f : a → b that has an inverse, i.e. there exists a morphism g : b → a with fg = 1b and gf = 1a. For example, a bijective linear map is an isomorphism between vector spaces, and a bijective continuous function whose inverse is also continuous is an isomorphism between topological spaces, called a homeomorphism.
In graph theory, an isomorphism between two graphs G and H is a bijective map f from the vertices of G to the vertices of H that preserves the "edge structure" in the sense that there is an edge from vertex u to vertex v in G if and only if there is an edge from f(u) to f(v) in H. See graph isomorphism.
In early theories of logical atomism, the formal relationship between facts and true propositions was theorized by Bertrand Russell and Ludwig Wittgenstein to be isomorphic.
In cybernetics the Good Regulator or Conant-Ashby theorem is stated "Every Good Regulator of a system must be a model of that system". Whether regulated or self-regulating an isomorphism is required between regulator part and the processing part of the system. | Isomorphism
In abstract algebra, an isomorphism (Greek: ison "equal", and morphe "shape") is a bijective map f such that both f and its inverse f −1 are homomorphisms, i.e., structure-preserving mappings.
In the more general setting of category theory, an isomorphism is a morphism f:X→Y in a category for which there exists an "inverse" f −1:Y→X, with the property that both f −1f=idX and ff −1=idY.
Informally, an isomorphism is a kind of mapping between objects, which shows a relationship between two properties or operations. If there exists an isomorphism between two structures, we call the two structures isomorphic. In a certain sense, isomorphic structures are structurally identical, if you choose to ignore finer-grained differences that may arise from how they are defined.
# Purpose
Isomorphisms are studied in mathematics in order to extend insights from one phenomenon to others: if two objects are isomorphic, then any property which is preserved by an isomorphism and which is true of one of the objects is also true of the other. If an isomorphism can be found from a relatively unknown part of mathematics into some well studied division of mathematics, where many theorems are already proved, and many methods are already available to find answers, then the function can be used to map whole problems out of unfamiliar territory over to "solid ground" where the problem is easier to understand and work with.
# Physical analogies
Here are some everyday examples of isomorphic structures:
- A standard deck of 52 playing cards with the four suits hearts, diamonds, spades, and clubs and a standard deck of 52 playing cards with four suits of triangles, circles, squares, and pentagons; although the suits of each deck differ, the decks are structurally isomorphic — if we wish to play cards, it doesn't matter which deck we choose to use.
- The Clock Tower in London (that contains Big Ben) and a wristwatch; although the clocks vary greatly in size, their mechanisms of reckoning time are isomorphic.
- A six-sided die and a bag from which a number 1 through 6 is chosen; although the method of obtaining a number is different, their random number generating abilities are isomorphic. This is an example of functional isomorphism, without the presumption of geometric isomorphism.
- There is a game which is isomorphic to tic-tac-toe, but on the surface appears completely different. Players take it in turn to say a number between one and nine. Numbers may not be repeated. Both players aim to say three numbers which add up to 15. Plotting these numbers on a 3×3 magic square will reveal the exact correspondence with the game of tic-tac-toe, given that three numbers will be arranged in a straight line if and only if they add up to 15.
# Practical example
The following are examples of isomorphisms from ordinary algebra.
- Consider the logarithm function: For any fixed base b, the logarithm function logb maps from the positive real numbers <math>\mathbb{R}^+</math> onto the real numbers <math>\mathbb{R}</math>; formally:
<math>\log_b : \mathbb{R}^+ \to \mathbb{R} \!</math>
This mapping is one-to-one and onto, that is, it is a bijection from the domain to the codomain of the logarithm function.
In addition to being an isomorphism of sets, the logarithm function also preserves certain operations. Specifically, consider the group <math>(\mathbb{R}^+,\times)</math> of positive real numbers under ordinary multiplication. The logarithm function obeys the following identity:
<math>\log_b(x \times y) = \log_b(x) + \log_b(y) \!</math>
But the real numbers under addition also form a group. So the logarithm function is in fact a group isomorphism from the group <math>(\mathbb{R}^+,\times)</math> to the group <math>(\mathbb{R},+)</math>.
Logarithms can therefore be used to simplify multiplication of real numbers. By working with logarithms, multiplication of positive real numbers is replaced by addition of logs. This way it is possible to multiply real numbers using a ruler and a table of logarithms, or using a slide rule with a logarithmic scale.
- Consider the group Z6, the numbers from 0 to 5 with addition modulo 6. Also consider the group Z2 × Z3, the ordered pairs where the x coordinates can be 0 or 1, and the y coordinates can be 0, 1, or 2, where addition in the x-coordinate is modulo 2 and addition in the y-coordinate is modulo 3.
These structures are isomorphic under addition, if you identify them using the following scheme:
(0,0) -> 0
(1,1) -> 1
(0,2) -> 2
(1,0) -> 3
(0,1) -> 4
(1,2) -> 5
or in general (a,b) -> ( 3a + 4 b ) mod 6.
For example note that (1,1) + (1,0) = (0,1) which translates in the other system as 1 + 3 = 4.
Even though these two groups "look" different in that the sets contain different elements, they are indeed isomorphic: their structures are exactly the same. More generally, the direct product of two cyclic groups Zn and Zm is cyclic if and only if n and m are coprime.
# Abstract examples
## A relation-preserving isomorphism
If one object consists of a set X with a binary relation R and the other object consists of a set Y with a binary relation S then an isomorphism from X to Y is a bijective function f : X → Y such that
S is reflexive, irreflexive, symmetric, antisymmetric, asymmetric, transitive, total, Template:Ml, a partial order, total order, strict weak order, total preorder (weak order), an equivalence relation, or a relation with any other special properties, if and only if R is.
For example, R is an ordering ≤ and S an ordering <math>\sqsubseteq</math>, then an isomorphism from X to Y is a bijective function f : X → Y such that
Such an isomorphism is called an order isomorphism or (less commonly) an isotone isomorphism.
If X = Y we have a relation-preserving automorphism.
## An operation-preserving isomorphism
Suppose that on these sets X and Y, there are two binary operations <math>\star</math> and <math>\Diamond</math> which happen to constitute the groups (X,<math>\star</math>) and (Y,<math>\Diamond</math>). Note that the operators operate on elements from the domain and range, respectively, of the "one-to-one" and "onto" function f. There is an isomorphism from X to Y if the bijective function f : X → Y happens to produce results, that sets up a correspondence between the operator <math>\star</math> and the operator <math>\Diamond</math>.
for all u, v in X.
# Applications
In abstract algebra, two basic isomorphisms are defined:
- Group isomorphism, an isomorphism between groups
- Ring isomorphism, an isomorphism between rings. (Note that isomorphisms between fields are actually ring isomorphisms)
Just as the automorphisms of an algebraic structure form a group, the isomorphisms between two algebras sharing a common structure form a heap. Letting a particular isomorphism identify the two structures turns this heap into a group.
In mathematical analysis, the Legendre transform is an isomorphism mapping hard differential equations into easier algebraic equations.
In category theory, Iet the category C consist of two classes, one of objects and the other of morphisms. Then a general definition of isomorphism that covers the previous and many other cases is: an isomorphism is a morphism f : a → b that has an inverse, i.e. there exists a morphism g : b → a with fg = 1b and gf = 1a. For example, a bijective linear map is an isomorphism between vector spaces, and a bijective continuous function whose inverse is also continuous is an isomorphism between topological spaces, called a homeomorphism.
In graph theory, an isomorphism between two graphs G and H is a bijective map f from the vertices of G to the vertices of H that preserves the "edge structure" in the sense that there is an edge from vertex u to vertex v in G if and only if there is an edge from f(u) to f(v) in H. See graph isomorphism.
In early theories of logical atomism, the formal relationship between facts and true propositions was theorized by Bertrand Russell and Ludwig Wittgenstein to be isomorphic.[citation needed]
In cybernetics the Good Regulator or Conant-Ashby theorem is stated "Every Good Regulator of a system must be a model of that system". Whether regulated or self-regulating an isomorphism is required between regulator part and the processing part of the system. | https://www.wikidoc.org/index.php/Isomorphism | |
0ad7411b495dc964b40e961b1771b86b210a8562 | wikidoc | Isoprostane | Isoprostane
The isoprostanes are prostaglandin-like compounds formed in vivo from the free radical-catalyzed peroxidation
-f essential fatty acids (primarily arachidonic acid) without the direct action of cyclooxygenase (COX) enzyme.
These nonclassical eicosanoids possess potent biological activity as inflammatory mediators that augment the perception of pain. These compounds are accurate markers of lipid peroxidation in both animal and human models of oxidative stress.
# Abundance | Isoprostane
The isoprostanes are prostaglandin-like compounds formed in vivo from the free radical-catalyzed peroxidation
of essential fatty acids (primarily arachidonic acid) without the direct action of cyclooxygenase (COX) enzyme.
[1][2]
These nonclassical eicosanoids possess potent biological activity as inflammatory mediators that augment the perception of pain.[3] These compounds are accurate markers of lipid peroxidation in both animal and human models of oxidative stress.
# Abundance | https://www.wikidoc.org/index.php/Isoprostane | |
efd0a50cd2e0e34d9b98b614f1cd949b80444806 | wikidoc | Isotopomers | Isotopomers
# Overview
Isotopomers (isotopic isomers) are isomers having the same number of each isotopic atom but differing in their positions. For example, CH3CHDCH3 and CH3CH2CH2D are a pair of constitutional isotopomers. An isotopomer should not be confused with an isotopologue.
# 13C NMR
The peaks seen in a 13C NMR spectra are a result of different Isotopomers. For example consider ethanol (CH3CH2OH). Ethanol will have 2 simple isotopomers one in which the 13C atom is on the methyl group i.e. 13CH3CH2OH and one isotopomer in which the 13C atom is on the methylene i.e. CH313CH2OH.
This gives rise to 2 peaks in the 13C NMR spectrum.
Note the 12C atoms do not show up in the 13C NMR.
Also given that 13C is only present in 1% abundance, there is a very small chance of also seeing the isotopologue in the 13C NMR, wherein both carbon atoms are 13C atoms (i.e. 13CH313CH2OH). These atoms would couple, giving satellites off the main peaks in a normal 13C-NMR spectrum and forming the basis for INADEQUATE (13C–13C correlation) experiments.
# Uses
Isotopmers have been used to determine reaction pathways e.g. A m-Benzyne to o-Benzyne Conversion Through a 1,2-Shift of a Phenyl Group. Blake, M. E.; Bartlett, K. L.; Jones, M. Jr. J. Am. Chem. Soc. 2003, 125, 6485 | Isotopomers
# Overview
Isotopomers (isotopic isomers) are isomers having the same number of each isotopic atom but differing in their positions.[1] For example, CH3CHDCH3 and CH3CH2CH2D are a pair of constitutional isotopomers. An isotopomer should not be confused with an isotopologue.
# 13C NMR
The peaks seen in a 13C NMR spectra are a result of different Isotopomers. For example consider ethanol (CH3CH2OH). Ethanol will have 2 simple isotopomers one in which the 13C atom is on the methyl group i.e. 13CH3CH2OH and one isotopomer in which the 13C atom is on the methylene i.e. CH313CH2OH.
This gives rise to 2 peaks in the 13C NMR spectrum.
Note the 12C atoms do not show up in the 13C NMR.
Also given that 13C is only present in 1% abundance, there is a very small chance of also seeing the isotopologue in the 13C NMR, wherein both carbon atoms are 13C atoms (i.e. 13CH313CH2OH). These atoms would couple, giving satellites off the main peaks in a normal 13C-NMR spectrum and forming the basis for INADEQUATE (13C–13C correlation) experiments.
# Uses
Isotopmers have been used to determine reaction pathways e.g. A m-Benzyne to o-Benzyne Conversion Through a 1,2-Shift of a Phenyl Group. Blake, M. E.; Bartlett, K. L.; Jones, M. Jr. J. Am. Chem. Soc. 2003, 125, 6485 | https://www.wikidoc.org/index.php/Isotopomer | |
91c61b3e63a31dda785d0a118bfe0f7bf3ed5dc5 | wikidoc | Isoxsuprine | Isoxsuprine
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Isoxsuprine is a vasodilator that is FDA approved for the treatment of cerebral vascular insufficiency, arteriosclerosis obliterans, thromboangitis obliterans, and Raynaud's disease. Common adverse reactions include hypotension, tachyarrhythmia, rash, abdominal discomfort, nausea, and dizziness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- 10 to 20 mg three or four times daily
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Isoxsuprine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Isoxsuprine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Isoxsuprine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Isoxsuprine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Isoxsuprine in pediatric patients.
# Contraindications
- There are no known contraindications to oral use when administered in recommended doses.
# Warnings
- Should not be given immediately postpartum or in the presence of arterial bleeding.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Isoxsuprine in the drug label.
## Postmarketing Experience
- On rare occasions oral administration of the drug has been associated in time with the occurrences of hypotension, tachycardia, nausea, vomiting, dizziness, abdominal distress, and severe rash. If rash appears the drug should be discontinued.
- Although available evidence suggests a temporal association of these reactions with Isoxsuprine, a casual relationship can be neither confirmed nor refused.
- Maternal and fetal tachycardia may occur under such use. Hypocalcemia, hypoglycemia, hypotension and ileus have been reported to occur in infants whose mothers received Isoxsuprine Hydrochloride. Pulmonary edema has been reported in mothers treated with beta stimulants. Isoxsuprine Hydrochloride is neither approved nor recommended for use in the treatment of premature labor.
# Drug Interactions
There is limited information regarding Drug Interactions of Isoxsuprine in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on the use of Isoxsuprine with respect to pregnant patients.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Isoxsuprine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Isoxsuprine during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Isoxsuprine with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Isoxsuprine with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Isoxsuprine with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Isoxsuprine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Isoxsuprine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Isoxsuprine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Isoxsuprine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Isoxsuprine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Isoxsuprine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Isoxsuprine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Isoxsuprine in the drug label.
# Overdosage
## Acute Overdose
There is limited information regarding Acute Overdose of Isoxsuprine in the drug label.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Isoxsuprine in the drug label.
# Pharmacology
There is limited information regarding Isoxsuprine Pharmacology in the drug label.
## Mechanism of Action
There is limited information regarding Isoxsuprine Mechanism of Action in the drug label.
## Structure
- lsoxsuprine HCI occurs as a white odorless, crystalline powder, having a bitter taste, It has a following structural formula
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Isoxsuprine in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Isoxsuprine in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Isoxsuprine in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Isoxsuprine in the drug label.
# How Supplied
- lsoxsuprine HCI 20mg tablets are supplied in HDPE containers of 1,000's.
## Storage
There is limited information regarding Isoxsuprine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
Bi-Coastal
Pharmaceutical Corp.®
NDC 42582-100-10
Isoxsuprine
Hydrochloride
Tablets, USP
10 mg
Rx only
100 Tablets
Bi-Coastal
Pharmaceutical Corp.®
NDC 42582-200-10
Isoxsuprine
Hydrochloride
Tablets, USP
20 mg
Rx only
100 Tablets
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Isoxsuprine in the drug label.
# Precautions with Alcohol
- Alcohol-Isoxsuprine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Vasodilan®
# Look-Alike Drug Names
- N/A
# Drug Shortage Status
# Price | Isoxsuprine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]; Turky Alkathery, M.D. [3]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Isoxsuprine is a vasodilator that is FDA approved for the treatment of cerebral vascular insufficiency, arteriosclerosis obliterans, thromboangitis obliterans, and Raynaud's disease. Common adverse reactions include hypotension, tachyarrhythmia, rash, abdominal discomfort, nausea, and dizziness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- 10 to 20 mg three or four times daily
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Isoxsuprine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Isoxsuprine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Isoxsuprine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Isoxsuprine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Isoxsuprine in pediatric patients.
# Contraindications
- There are no known contraindications to oral use when administered in recommended doses.
# Warnings
- Should not be given immediately postpartum or in the presence of arterial bleeding.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Isoxsuprine in the drug label.
## Postmarketing Experience
- On rare occasions oral administration of the drug has been associated in time with the occurrences of hypotension, tachycardia, nausea, vomiting, dizziness, abdominal distress, and severe rash. If rash appears the drug should be discontinued.
- Although available evidence suggests a temporal association of these reactions with Isoxsuprine, a casual relationship can be neither confirmed nor refused.
- Maternal and fetal tachycardia may occur under such use. Hypocalcemia, hypoglycemia, hypotension and ileus have been reported to occur in infants whose mothers received Isoxsuprine Hydrochloride. Pulmonary edema has been reported in mothers treated with beta stimulants. Isoxsuprine Hydrochloride is neither approved nor recommended for use in the treatment of premature labor.
# Drug Interactions
There is limited information regarding Drug Interactions of Isoxsuprine in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on the use of Isoxsuprine with respect to pregnant patients.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Isoxsuprine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Isoxsuprine during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Isoxsuprine with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Isoxsuprine with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Isoxsuprine with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Isoxsuprine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Isoxsuprine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Isoxsuprine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Isoxsuprine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Isoxsuprine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Isoxsuprine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Isoxsuprine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Isoxsuprine in the drug label.
# Overdosage
## Acute Overdose
There is limited information regarding Acute Overdose of Isoxsuprine in the drug label.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Isoxsuprine in the drug label.
# Pharmacology
There is limited information regarding Isoxsuprine Pharmacology in the drug label.
## Mechanism of Action
There is limited information regarding Isoxsuprine Mechanism of Action in the drug label.
## Structure
- lsoxsuprine HCI occurs as a white odorless, crystalline powder, having a bitter taste, It has a following structural formula
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Isoxsuprine in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Isoxsuprine in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Isoxsuprine in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Isoxsuprine in the drug label.
# How Supplied
- lsoxsuprine HCI 20mg tablets are supplied in HDPE containers of 1,000's.
## Storage
There is limited information regarding Isoxsuprine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
Bi-Coastal
Pharmaceutical Corp.®
NDC 42582-100-10
Isoxsuprine
Hydrochloride
Tablets, USP
10 mg
Rx only
100 Tablets
Bi-Coastal
Pharmaceutical Corp.®
NDC 42582-200-10
Isoxsuprine
Hydrochloride
Tablets, USP
20 mg
Rx only
100 Tablets
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Isoxsuprine in the drug label.
# Precautions with Alcohol
- Alcohol-Isoxsuprine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Vasodilan®[1]
# Look-Alike Drug Names
- N/A[2]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Isoxsuprine | |
ff344973d55bcd47828be82f156b3eb1e16e119e | wikidoc | Itō's lemma | Itō's lemma
In mathematics, Itō's lemma is used in Itō stochastic calculus to find the differential of a function of a particular type of stochastic process. It is the stochastic calculus counterpart of the chain rule in ordinary calculus and is best memorized using the Taylor series expansion and retaining the second order term related to the stochastic component change. The lemma is widely employed in mathematical finance.
# Itō processes
In its simplest form, Itō's lemma states that for an Itō process
and any twice continuously differentiable function f on the real numbers, then f(X) is also an Itō process satisfying
\begin{align}
df(X_t) &= f^\prime(X_t)\,dX_t + \frac{1}{2}f^{\prime\prime}(X_t)\sigma^2_t\,dt\\
&= f^\prime(X_t)\sigma_t\,dB_t + \left(f^\prime(X_t)\mu_t+\frac{1}{2}f^{\prime\prime}(X_t)\sigma^2_t\right)\,dt.
\end{align}
# Continuous semimartingales
More generally, Itō's lemma applies for any continuous d-dimensional semimartingale X=(X1,X2,…,Xd), and twice continuously differentiable and real valued function f on Rd. Then, f(X) is a semimartingale satisfying
In this expression, the term f,i represents the partial derivative of f(x) with respect to xi, and is the quadratic covariation process of Xi and Xj.
# Non-continuous semimartingales
Itō's lemma can also be applied to general d-dimensional semimartingales, which need not be continuous. In general, a semimartingale is a cadlag process, and an additional term needs to be added to the formula to ensure that the jumps of the process are correctly given by Itō's lemma.
For any cadlag process Yt, the left limit in t is denoted by Yt-, which is a left-continuous process. The jumps are written as ΔYt = Yt - Yt-. Then, Itō's lemma states that if X = (X1,X2,…,Xd) is a d-dimensional semimartingale and f is a twice continuously differentiable real valued function on Rd then f(X) is a semimartingale, and
\begin{align}
f(X_t)= & f(X_0)+\sum_{i=1}^d\int_0^t f_{,i}(X_{s-})\,dX^i_s + \frac{1}{2}\sum_{i,j=1}^d \int_0^t f_{,ij}(X_{s-})\,d_s\\
&+\sum_{s\le t}\left(\Delta f(X_s)-\sum_{i=1}^df_{,i}(X_{s-})\Delta X^i_s-\frac{1}{2}\sum_{i,j=1}^d f_{,ij}(X_{s-})\Delta X^i_s\Delta X^j_s\right).
\end{align}
This differs from the formula for continuous semimartingales by the additional term summing over the jumps of X, which ensures that the jump of the right hand side at time t is Δf(Xt).
# Informal derivation
A formal proof of the lemma requires us to take the limit of a sequence of random variables, which is not done here. Instead, we can derive Ito's lemma by exampling a Taylor series and applying the rules of stochastic calculus.
Assume the Itō process is in the form of
Expanding f(x, t) in a Taylor series in x and t we have
and substituting a dt + b dB for dx gives
In the limit as dt tends to 0, the dt2 and dt dB terms disappear but the dB2 term tends to dt. The latter can be shown if we prove that
The proof of this statistical property is however beyond the scope of this article.
Deleting the dt2 and dt dB terms, substituting dt for dB2, and collecting the dt and dB terms, we obtain
as required.
The formal proof is beyond the scope of this article.
# Examples
## Geometric Brownian motion
A process S is said to follow a geometric Brownian motion with volatility σ and drift μ if it satisfies the stochastic differential equation dS = S(σdB + μdt), for a Brownian motion B.
Applying Itō's lemma with f(S) = log(S) gives
\begin{align}
d\log(S) &= f^\prime(S)\,dS + \frac{1}{2}f^{\prime\prime}(S)S^2\sigma^2\,dt \\
&= \frac{1}{S}\left( \sigma S\,dB + \mu S\,dt\right) - \frac{1}{2}\sigma^2\,dt \\
&= \sigma\,dB +(\mu-\sigma^2/2)\,dt.
\end{align}
It follows that log(St) = log(S0) + σBt + (μ - σ2/2)t, and exponentiating gives the expression for S,
## The Doléans exponential
The Doléans exponential (or stochastic exponential) of a continuous semimartingale X is defined to be the solution to the SDE dY = YdX with initial condition Y0 = 1. It is sometimes denoted by Template:Unicode(X).
Applying Itō's lemma with f(Y)=log(Y) gives
\begin{align}
d\log(Y) &= \frac{1}{Y}\,dY -\frac{1}{2Y^2}\,d \\
&= dX - \frac{1}{2}\,d.
\end{align}
Exponentiating gives the solution
## Black–Scholes formula
Itō's lemma can be used to derive the Black–Scholes formula for an option. Suppose a stock price follows an exponential Brownian motion given by the stochastic differential equation dS = S(σdB + μdt).
Then, if the value of an option at time t is f(t,St), Itō's lemma gives
The term (∂f/∂S) dS represents the change in value in time dt of the trading strategy consisting of holding an amount ∂f/∂S of the stock. If this trading strategy is followed, and any cash held is assumed to grow at the risk free rate r, then the total value V of this portfolio satisfies the SDE
This strategy replicates the option if V = f(t,S).
Combining these equations gives the Black-Scholes formula | Itō's lemma
In mathematics, Itō's lemma is used in Itō stochastic calculus to find the differential of a function of a particular type of stochastic process. It is the stochastic calculus counterpart of the chain rule in ordinary calculus and is best memorized using the Taylor series expansion and retaining the second order term related to the stochastic component change. The lemma is widely employed in mathematical finance.
# Itō processes
In its simplest form, Itō's lemma states that for an Itō process
and any twice continuously differentiable function f on the real numbers, then f(X) is also an Itō process satisfying
\begin{align}
df(X_t) &= f^\prime(X_t)\,dX_t + \frac{1}{2}f^{\prime\prime}(X_t)\sigma^2_t\,dt\\
&= f^\prime(X_t)\sigma_t\,dB_t + \left(f^\prime(X_t)\mu_t+\frac{1}{2}f^{\prime\prime}(X_t)\sigma^2_t\right)\,dt.
\end{align}
</math>
# Continuous semimartingales
More generally, Itō's lemma applies for any continuous d-dimensional semimartingale X=(X1,X2,…,Xd), and twice continuously differentiable and real valued function f on Rd. Then, f(X) is a semimartingale satisfying
In this expression, the term f,i represents the partial derivative of f(x) with respect to xi, and [Xi,Xj ] is the quadratic covariation process of Xi and Xj.
# Non-continuous semimartingales
Itō's lemma can also be applied to general d-dimensional semimartingales, which need not be continuous. In general, a semimartingale is a cadlag process, and an additional term needs to be added to the formula to ensure that the jumps of the process are correctly given by Itō's lemma.
For any cadlag process Yt, the left limit in t is denoted by Yt-, which is a left-continuous process. The jumps are written as ΔYt = Yt - Yt-. Then, Itō's lemma states that if X = (X1,X2,…,Xd) is a d-dimensional semimartingale and f is a twice continuously differentiable real valued function on Rd then f(X) is a semimartingale, and
\begin{align}
f(X_t)= & f(X_0)+\sum_{i=1}^d\int_0^t f_{,i}(X_{s-})\,dX^i_s + \frac{1}{2}\sum_{i,j=1}^d \int_0^t f_{,ij}(X_{s-})\,d[X^i,X^j]_s\\
&+\sum_{s\le t}\left(\Delta f(X_s)-\sum_{i=1}^df_{,i}(X_{s-})\Delta X^i_s-\frac{1}{2}\sum_{i,j=1}^d f_{,ij}(X_{s-})\Delta X^i_s\Delta X^j_s\right).
\end{align}
</math>
This differs from the formula for continuous semimartingales by the additional term summing over the jumps of X, which ensures that the jump of the right hand side at time t is Δf(Xt).
# Informal derivation
A formal proof of the lemma requires us to take the limit of a sequence of random variables, which is not done here. Instead, we can derive Ito's lemma by exampling a Taylor series and applying the rules of stochastic calculus.
Assume the Itō process is in the form of
Expanding f(x, t) in a Taylor series in x and t we have
and substituting a dt + b dB for dx gives
In the limit as dt tends to 0, the dt2 and dt dB terms disappear but the dB2 term tends to dt. The latter can be shown if we prove that
The proof of this statistical property is however beyond the scope of this article.
Deleting the dt2 and dt dB terms, substituting dt for dB2, and collecting the dt and dB terms, we obtain
as required.
The formal proof is beyond the scope of this article.
# Examples
## Geometric Brownian motion
A process S is said to follow a geometric Brownian motion with volatility σ and drift μ if it satisfies the stochastic differential equation dS = S(σdB + μdt), for a Brownian motion B.
Applying Itō's lemma with f(S) = log(S) gives
\begin{align}
d\log(S) &= f^\prime(S)\,dS + \frac{1}{2}f^{\prime\prime}(S)S^2\sigma^2\,dt \\
&= \frac{1}{S}\left( \sigma S\,dB + \mu S\,dt\right) - \frac{1}{2}\sigma^2\,dt \\
&= \sigma\,dB +(\mu-\sigma^2/2)\,dt.
\end{align}
</math>
It follows that log(St) = log(S0) + σBt + (μ - σ2/2)t, and exponentiating gives the expression for S,
## The Doléans exponential
The Doléans exponential (or stochastic exponential) of a continuous semimartingale X is defined to be the solution to the SDE dY = YdX with initial condition Y0 = 1. It is sometimes denoted by Template:Unicode(X).
Applying Itō's lemma with f(Y)=log(Y) gives
\begin{align}
d\log(Y) &= \frac{1}{Y}\,dY -\frac{1}{2Y^2}\,d[Y] \\
&= dX - \frac{1}{2}\,d[X].
\end{align}
</math>
Exponentiating gives the solution
## Black–Scholes formula
Itō's lemma can be used to derive the Black–Scholes formula for an option. Suppose a stock price follows an exponential Brownian motion given by the stochastic differential equation dS = S(σdB + μdt).
Then, if the value of an option at time t is f(t,St), Itō's lemma gives
The term (∂f/∂S) dS represents the change in value in time dt of the trading strategy consisting of holding an amount ∂f/∂S of the stock. If this trading strategy is followed, and any cash held is assumed to grow at the risk free rate r, then the total value V of this portfolio satisfies the SDE
This strategy replicates the option if V = f(t,S).
Combining these equations gives the Black-Scholes formula | https://www.wikidoc.org/index.php/It%C5%8D%27s_lemma | |
e8ae739fd3afdd9d0dadbaae4482c3528e02a29c | wikidoc | Ixabepilone | Ixabepilone
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Ixabepilone is an antineoplastic agent, epothilone and mitotic inhibitor that is FDA approved for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated.
Ixabepilone is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine. There is a Black Box Warning for this drug as shown here. Common adverse reactions include peripheral sensory neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
## General Dosing Information
- The recommended dosage of Ixabepilone is 40 mg/m2 administered intravenously over 3 hours every 3 weeks. Doses for patients with body surface area (BSA) greater than 2.2 m2 should be calculated based on 2.2 m2.
## Dose Modification
### Dose Adjustments During Treatment
- Patients should be evaluated during treatment by periodic clinical observation and laboratory tests including complete blood cell counts. If toxicities are present, treatment should be delayed to allow recovery. Dosing adjustment guidelines for monotherapy and combination therapy are shown in Table 1. If toxicities recur, an additional 20% dose reduction should be made.
- Re-treatment Criteria: Dose adjustments at the start of a cycle should be based on nonhematologic toxicity or blood counts from the preceding cycle following the guidelines in Table 1. Patients should not begin a new cycle of treatment unless the neutrophil count is at least 1500 cells/mm3, the platelet count is at least 100,000 cells/mm3, and nonhematologic toxicities have improved to grade 1 (mild) or resolved.
### Dose Adjustments in Special Populations - Hepatic Impairment
- Combination Therapy: Ixabepilone in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN. Patients receiving combination treatment who have AST and ALT ≤2.5 x ULN and bilirubin ≤1 x ULN may receive the standard dose of ixabepilone (40 mg/m2).
- Monotherapy: Patients with hepatic impairment should be dosed with Ixabepilone based on the guidelines in Table 2. Patients with moderate hepatic impairment should be started at 20 mg/m2, the dosage in subsequent cycles may be escalated up to, but not exceeding, 30 mg/m2 if tolerated. Use in patients with AST or ALT >10 x ULN or bilirubin >3 x ULN is not recommended. Limited data are available for patients with baseline AST or ALT >5 x ULN. Caution should be used when treating these patients.
### Strong CYP3A4 Inhibitors
- The use of concomitant strong CYP3A4 inhibitors should be avoided (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, amprenavir, indinavir, nelfinavir, delavirdine, or voriconazole). Grapefruit juice may also increase plasma concentrations of Ixabepilone and should be avoided. Based on pharmacokinetic studies, if a strong CYP3A4 inhibitor must be coadministered, a dose reduction to 20 mg/m2 is predicted to adjust the ixabepilone AUC to the range observed without inhibitors and should be considered. If the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the Ixabepilone dose is adjusted upward to the indicated dose.
### Strong CYP3A4 Inducers
- The use of concomitant strong CYP3A4 inducers should be avoided (eg, phenytoin, carbamazepine, rifampin, rifabutin, dexamethasone, and phenobarbital). Selection of an alternative concomitant medication with no or minimal enzyme induction potential should be considered. Based on extrapolation from a drug interaction study with rifampin, the following guidance may be considered for dosing in patients requiring coadministration of a strong CYP3A4 inducer, if no alternatives are feasible. Once patients have been maintained on a strong CYP3A4 inducer, the dose of Ixabepilone may be gradually increased from 40 mg/m2 to 60 mg/m2 depending on tolerance. If the dose is increased, Ixabepilone should be given as a 4-hour intravenous infusion. This 60 mg/m2 dose given intravenously over 4 hours is predicted to adjust the AUC to the range observed without inducers. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. Patients whose dose is increased above 40 mg/m2 should be monitored carefully for toxicities associated with Ixabepilone If the strong inducer is discontinued, the Ixabepilone dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer.
## Premedication
- To minimize the chance of occurrence of a hypersensitivity reaction, all patients must be premedicated approximately 1 hour before the infusion of Ixabepilone with:
- An H1 antagonist (eg, diphenhydramine 50 mg orally or equivalent)
- An H2 antagonist (eg, ranitidine 150 - 300 mg orally or equivalent).
- Patients who experienced a hypersensitivity reaction to Ixabepilone require premedication with corticosteroids (eg, dexamethasone 20 mg intravenously, 30 minutes before infusion or orally, 60 minutes before infusion) in addition to pretreatment with H1 and H2 antagonists.
## Instructions for Preparation and IV Administration
- Ixabepilone Kit contains two vials, a vial labeled Ixabepilone (ixabepilone) for injection which contains ixabepilone powder and a vial containing DILUENT for Ixabepilone Only supplied DILUENT must be used for constituting Ixabepilone (ixabepilone) for injection. Ixabepilone Kit must be stored in a refrigerator at 2° C - 8° C (36° F - 46° F) in the original package to protect from light. Prior to constituting Ixabepilone for injection, the Kit should be removed from the refrigerator and allowed to stand at room temperature for approximately 30 minutes. When the vials are first removed from the refrigerator, a white precipitate may be observed in the DILUENT vial. This precipitate will dissolve to form a clear solution once the DILUENT warms to room temperature. To allow for withdrawal losses, the vial labeled as 15 mg Ixabepilone for injection contains 16 mg of ixabepilone and the vial labeled as 45 mg Ixabepilone for injection contains 47 mg of ixabepilone. The 15-mg Ixabepilone Kit is supplied with a vial providing 8 mL of the DILUENT and the 45-mg Ixabepilone Kit is supplied with a vial providing 23.5 mL of the DILUENT. After constituting with the DILUENT, the concentration of ixabepilone is 2 mg/mL.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ixabepilone in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ixabepilone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Ixabepilone FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ixabepilone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ixabepilone in pediatric patients.
# Contraindications
- Ixabepilone is contraindicated in patients with a history of a severe (CTC grade 3/4) hypersensitivity reaction to agents containing Cremophor® EL or its derivatives (eg, polyoxyethylated castor oil).
- Ixabepilone is contraindicated in patients who have a neutrophil count <1500 cells/mm3 or a platelet count <100,000 cells/mm3.
- Ixabepilone in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN.
# Warnings
### Peripheral Neuropathy
- Peripheral neuropathy was common (see Table 3). Patients treated with Ixabepilone should be monitored for symptoms of neuropathy, such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, or neuropathic pain. Neuropathy occurred early during treatment; ~75% of new onset or worsening neuropathy occurred during the first 3 cycles. Patients experiencing new or worsening symptoms may require a reduction or delay in the dose of Ixabepilone In clinical studies, peripheral neuropathy was managed through dose reductions, dose delays, and treatment discontinuation. Neuropathy was the most frequent cause of treatment discontinuation due to drug toxicity. In Studies 046 and 081, 80% and 87%, respectively, of patients with peripheral neuropathy who received Ixabepilone had improvement or no worsening of their neuropathy following dose reduction. For patients with grade 3/4 neuropathy in Studies 046 and 081, 76% and 79%, respectively, had documented improvement to baseline or grade 1, twelve weeks after onset.
- A pooled analysis of 1540 cancer patients treated with Ixabepilone indicated that patients with diabetes mellitus or preexisting peripheral neuropathy may be at increased risk of severe neuropathy. Prior therapy with neurotoxic chemotherapy agents did not predict the development of neuropathy. Patients with moderate to severe neuropathy (grade 2 or greater) were excluded from studies with Ixabepilone. Caution should be used when treating patients with diabetes mellitus or preexisting peripheral neuropathy.
### Myelosuppression
- Myelosuppression is dose-dependent and primarily manifested as neutropenia. In clinical studies, grade 4 neutropenia (2.5 x ULN or bilirubin >1.5 x ULN. Neutropenia-related death occurred in 0.4% of 240 patients treated with Ixabepilone as monotherapy. No neutropenia-related deaths were reported in 24 patients with AST or ALT >2.5 x ULN or bilirubin >1.5 x ULN treated with Ixabepilone monotherapy. Ixabepilone must not be administered to patients with a neutrophil count <1500 cells/mm3. To monitor for myelosuppression, frequent peripheral blood cell counts are recommended for all patients receiving Ixabepilone Patients who experience severe neutropenia or thrombocytopenia should have their dose reduced.
## Hepatic Impairment
- Patients with baseline AST or ALT >2.5 x ULN or bilirubin >1.5 x ULN experienced greater toxicity than patients with baseline AST or ALT ≤2.5 x ULN or bilirubin ≤1.5 x ULN when treated with Ixabepilone at 40 mg/m2 in combination with capecitabine or as monotherapy in breast cancer studies. In combination with capecitabine, the overall frequency of grade 3/4 adverse reactions, febrile neutropenia, serious adverse reactions, and toxicity-related deaths was greater. With monotherapy, grade 4 neutropenia, febrile neutropenia, and serious adverse reactions were more frequent. The safety and pharmacokinetics of Ixabepilone as monotherapy were evaluated in a dose escalation study in 56 patients with varying degrees of hepatic impairment. Exposure was increased in patients with elevated AST or bilirubin.
- Ixabepilone in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN due to increased risk of toxicity- and neutropenia-related death. Patients who are treated with Ixabepilone as monotherapy should receive a reduced dose depending on the degree of hepatic impairment. Use in patients with AST or ALT >10 x ULN or bilirubin >3 x ULN is not recommended. Limited data are available for patients with AST or ALT >5 x ULN. Caution should be used when treating these patients.
### Hypersensitivity Reactions
- Patients with a history of a severe hypersensitivity reaction to agents containing Cremophor® EL or its derivatives (eg, polyoxyethylated castor oil) should not be treated with Ixabepilone. All patients should be premedicated with an H1 and an H2 antagonist approximately 1 hour before Ixabepilone infusion and be observed for hypersensitivity reactions (eg, flushing, rash, dyspnea, and bronchospasm). In case of severe hypersensitivity reactions, infusion of Ixabepilone should be stopped and aggressive supportive treatment (eg, epinephrine, corticosteroids) started. Of the 1323 patients treated with Ixabepilone in clinical studies, 9 patients (1%) had experienced severe hypersensitivity reactions (including anaphylaxis). Three of the 9 patients were able to be retreated. Patients who experience a hypersensitivity reaction in one cycle of Ixabepilone must be premedicated in subsequent cycles with a corticosteroid in addition to the H1 and H2 antagonists, and extension of the infusion time should be considered.
### Cardiac Adverse Reactions
- The frequency of cardiac adverse reactions (myocardial ischemia and ventricular dysfunction) was higher in the Ixabepilone in combination with capecitabine (1.9%) than in the capecitabine alone (0.3%) treatment group. Supraventricular arrhythmias were observed in the combination arm (0.5%) and not in the capecitabine alone arm. Caution should be exercised in patients with a history of cardiac disease. Discontinuation of Ixabepilone should be considered in patients who develop cardiac ischemia or impaired cardiac function.
### Potential for Cognitive Impairment from Excipients
Since Ixabepilone contains dehydrated alcohol USP, consideration should be given to the possibility of central nervous system and other effects of alcohol.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.
- Unless otherwise specified, assessment of adverse reactions is based on one randomized study (Study 046) and one single-arm study (Study 081). In Study 046, 369 patients with metastatic breast cancer were treated with Ixabepilone 40 mg/m2 administered intravenously over 3 hours every 21 days, combined with capecitabine 1000 mg/m2 twice daily for 2 weeks followed by a 1-week rest period. Patients treated with capecitabine as monotherapy (n=368) in this study received 1250 mg/m2 twice daily for 2 weeks every 21 days. In Study 081, 126 patients with metastatic or locally advanced breast cancer were treated with Ixabepilone 40 mg/m2 administered intravenously over 3 hours every 3 weeks.
- The most common adverse reactions (≥20%) reported by patients receiving Ixabepilone were peripheral sensory neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain. The following additional reactions occurred in ≥20% in combination treatment: palmar-plantar erythrodysesthesia (hand-foot) syndrome, anorexia, abdominal pain, nail disorder, and constipation. The most common hematologic abnormalities (>40%) include neutropenia, leukopenia, anemia, and thrombocytopenia.
- Table 4 presents nonhematologic adverse reactions reported in 5% or more of patients. Hematologic abnormalities are presented separately in Table 5.
The following serious adverse reactions were also reported in 1323 patients treated with Ixabepilone as monotherapy or in combination with other therapies in Phase 2 and 3 studies.
- Infections and Infestations: sepsis, pneumonia, infection, neutropenic infection, urinary tract infection, bacterial infection, enterocolitis, laryngitis, lower respiratory tract infection.
- Blood and Lymphatic System Disorders: coagulopathy, lymphopenia
- Metabolism and Nutrition Disorders: hyponatremia, metabolic acidosis, hypokalemia, hypovolemia.
- Nervous System Disorders: cognitive disorder, syncope, cerebral hemorrhage, abnormal coordination, lethargy.
- Cardiac Disorders: myocardial infarction, supraventricular arrhythmia, left ventricular dysfunction, angina pectoris, atrial flutter, cardiomyopathy, myocardial ischemia.
- Vascular Disorders: hypotension, thrombosis, embolism, hemorrhage, hypovolemic shock, vasculitis.
- Respiratory, Thoracic, and Mediastinal Disorders: pneumonitis, hypoxia, respiratory failure, acute pulmonary edema, dysphonia, pharyngolaryngeal pain.
- Gastrointestinal Disorders: ileus, colitis, impaired gastric emptying, esophagitis, dysphagia, gastritis, gastrointestinal hemorrhage.
- Hepatobiliary Disorders: acute hepatic failure, jaundice.
- Skin and Subcutaneous Tissue Disorders: erythema multiforme
- Musculoskeletal, Connective Tissue, and Bone Disorders: muscular weakness, muscle spasms, trismus.
- Renal and Urinary Disorders: nephrolithiasis, renal failure.
- General Disorders and Administration Site Conditions: chills
- Investigations: increased transaminases, increased blood alkaline phosphatase, increased gamma-glutamyltransferase.
## Postmarketing Experience
- Radiation recall has been reported during postmarketing use of Ixabepilone Because this reaction was reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.
# Drug Interactions
### Effect of Other Drugs on Ixabepilone
- CYP3A4 Inhibitors: Coadministration of ixabepilone with ketoconazole, a potent CYP3A4 inhibitor, increased ixabepilone AUC by 79% compared to ixabepilone treatment alone. If alternative treatment cannot be administered, a dose adjustment should be considered. The effect of mild or moderate inhibitors (eg, erythromycin, fluconazole, or verapamil) on exposure to ixabepilone has not been studied. Therefore, caution should be used when administering mild or moderate CYP3A4 inhibitors during treatment with Ixabepilone, and alternative therapeutic agents that do not inhibit CYP3A4 should be considered. Patients receiving CYP3A4 inhibitors during treatment with Ixabepilone should be monitored closely for acute toxicities (eg, frequent monitoring of peripheral blood counts between cycles of Ixabepilone).
- CYP3A4 Inducers: Ixabepilone is a CYP3A4 substrate. Coadministration of Ixabepilone with rifampin, a potent CYP3A4 inducer, decreased ixabepilone AUC by 43% compared to Ixabepilone treatment alone. Other strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifabutin, and phenobarbital) may also decrease ixabepilone concentrations leading to subtherapeutic levels. Therefore, therapeutic agents with low enzyme induction potential should be considered for coadministration with Ixabepilone. St. John’s Wort may decrease ixabepilone plasma concentrations unpredictably and should be avoided. If patients must be coadministered a strong CYP3A4 inducer, a gradual dose adjustment may be considered.
### Effect of Ixabepilone on Other Drugs
- Ixabepilone does not inhibit CYP enzymes at relevant clinical concentrations and is not expected to alter the plasma concentrations of other drugs.
### Capecitabine
- In patients with cancer who received ixabepilone (40 mg/m2) in combination with capecitabine (1000 mg/m2), ixabepilone Cmax decreased by 19%, capecitabine Cmax decreased by 27%, and 5-fluorouracil AUC increased by 14%, as compared to ixabepilone or capecitabine administered separately. The interaction is not clinically significant given that the combination treatment is supported by efficacy data.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Ixabepilone may cause fetal harm when administered to pregnant women. There are no adequate and well-controlled studies with Ixabepilone in pregnant women. Women should be advised not to become pregnant when taking Ixabepilone If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
- Ixabepilone was studied for effects on embryo-fetal development in pregnant rats and rabbits given IV doses of 0.02, 0.08, and 0.3 mg/kg/day and 0.01, 0.03, 0.11, and 0.3 mg/kg/day, respectively. There were no teratogenic effects. In rats, an increase in resorptions and post-implantation loss and a decrease in the number of live fetuses and fetal weight was observed at the maternally toxic dose of 0.3 mg/kg/day (approximately one-tenth the human clinical exposure based on AUC). Abnormalities included a reduced ossification of caudal vertebrae, sternebrae, and metacarpals. In rabbits, ixabepilone caused maternal toxicity (death) and embryo-fetal toxicity (resorptions) at 0.3 mg/kg/day (approximately one-tenth the human clinical dose based on body surface area). No fetuses were available at this dose for evaluation.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ixabepilone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ixabepilone during labor and delivery.
### Nursing Mothers
- It is not known whether ixabepilone is excreted into human milk. Following intravenous administration of radiolabeled ixabepilone to rats on days 7 to 9 postpartum, concentrations of radioactivity in milk were comparable with those in plasma and declined in parallel with the plasma concentrations. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ixabepilone, a decision must be made whether to discontinue nursing or to discontinue Ixabepilone taking into account the importance of the drug to the mother.
### Pediatric Use
- The effectiveness of Ixabepilone in pediatric patients has not been established. Ixabepilone was evaluated in one Phase 1 and one Phase 2 trial. The pediatric patients had a safety profile consistent with that seen in adults, and no new safety signals were identified.
- In the Phase 1 open-label, dose-finding trial, the safety of Ixabepilone was evaluated in 19 pediatric patients with advanced or refractory solid tumors and 2 with acute leukemias. Ixabepilone was administered as a one-hour IV infusion daily for the first five days of a 21-day cycle at one of 5 dose levels, ranging from 3 to 10 mg/m2. Among the 21 patients, 12 ranged in age from 2 to 12 years and 9 ranged from 13 to 18 years. The maximum tolerated dose was 8 mg/m2 IV daily for 5 days every 21 days. No significant activity was observed. The pharmacokinetics of ixabepilone were characterized by population pharmacokinetic analysis of data for 16 patients from this trial, who were aged 2 to 18 years (median 12 years). The pharmacokinetic parameters of ixabepilone in these pediatric patients were compared to the corresponding parameters of 130 adult patients enrolled in clinical trials using the same dosing schedule. The median BSA normalized clearance of ixabepilone in pediatric patients (17 L/h/m2) was similar to that in adult patients (20 L/h/m2).
- In the Phase 2 trial of 59 patients with advanced or refractory solid tumors, 28 ranged in age from 3 to 12 years and 19 ranged in age from 13 to 18 years. Twelve additional patients over the age of 18 were treated in this trial. Ixabepilone was administered at a dose of 8 mg/m2 IV daily for 5 days every 21 days. This trial was terminated early due to lack of efficacy.
### Geriatic Use
- Clinical studies of Ixabepilone did not include sufficient numbers of subjects aged sixty-five and over to determine whether they respond differently from younger subjects.
- Forty-five of 431 patients treated with Ixabepilone in combination with capecitabine were ≥65 years of age and 3 patients were ≥75. Overall, the incidence of grade 3/4 adverse reactions was higher in patients ≥65 years of age versus those <65 years of age (82% versus 68%) including grade 3/4 stomatitis (9% versus 1%), diarrhea (9% versus 6%), palmar-plantar erythrodysesthesia syndrome (27% versus 20%), peripheral neuropathy (24% versus 22%), febrile neutropenia (9% versus 3%), fatigue (16% versus 12%), and asthenia (11% versus 6%). Toxicity-related deaths occurred in 2 (4.7%) of 43 patients ≥65 years with normal baseline hepatic function or mild impairment.
- Thirty-two of 240 breast cancer patients treated with Ixabepilone as monotherapy were ≥65 years of age and 6 patients were ≥75. No overall differences in safety were observed in these patients compared to those <65 years of age.
### Gender
There is no FDA guidance on the use of Ixabepilone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ixabepilone with respect to specific racial populations.
### Renal Impairment
- Ixabepilone is minimally excreted via the kidney. No controlled pharmacokinetic studies were conducted with Ixabepilone in patients with renal impairment. Ixabepilone in combination with capecitabine has not been evaluated in patients with calculated creatinine clearance of 1.5 times ULN. In a population pharmacokinetic analysis of Ixabepilone as monotherapy, there was no meaningful effect of mild and moderate renal insufficiency (CrCL >30 mL/min) on the pharmacokinetics of ixabepilone.
### Hepatic Impairment
- Ixabepilone was evaluated in 56 patients with mild to severe hepatic impairment defined by bilirubin levels and AST levels. Compared to patients with normal hepatic function (n=17), the area under the curve (AUC0-infinity) of ixabepilone increased by:
22% in patients with a) bilirubin >1 – 1.5 x ULN or b) AST >ULN but bilirubin <1.5 x ULN;
30% in patients with bilirubin >1.5 – 3 x ULN and any AST level; and
81% in patients with bilirubin >3 x ULN and any AST level.
- 22% in patients with a) bilirubin >1 – 1.5 x ULN or b) AST >ULN but bilirubin <1.5 x ULN;
- 30% in patients with bilirubin >1.5 – 3 x ULN and any AST level; and
- 81% in patients with bilirubin >3 x ULN and any AST level.
- Doses of 10 and 20 mg/m2 as monotherapy were tolerated in 17 patients with severe hepatic impairment (bilirubin >3 x ULN).
- Ixabepilone in combination with capecitabine must not be given to patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN . Dose reduction is recommended when administering Ixabepilone as monotherapy to patients with hepatic impairment . Because there is a need for dosage adjustment based upon hepatic function, assessment of hepatic function is recommended before initiation of Ixabepilone and periodically thereafter.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ixabepilone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ixabepilone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
### To constitute:
- With a suitable syringe, aseptically withdraw the DILUENT and slowly inject it into the Ixabepilone for injection vial. The 15-mg Ixabepilone is constituted with 8 mL of DILUENT and the 45-mg Ixabepilone is constituted with 23.5 mL of DILUENT.
- Gently swirl and invert the vial until the powder in Ixabepilone is completely dissolved.
### To dilute:
- Before administration, the constituted solution must be further diluted with one of the specified infusion fluids listed below. The Ixabepilone infusion must be prepared in a DEHP free bag.
- The following infusion fluids have been qualified for use in the dilution of Ixabepilone:
Lactated Ringer’s Injection, USP
- Lactated Ringer’s Injection, USP
0.9% Sodium Chloride Injection, USP (pH adjusted with Sodium Bicarbonate Injection, USP)
- When using a 250 mL or a 500 mL bag of 0.9% Sodium Chloride Injection to prepare the infusion, the pH must be adjusted to a pH between 6.0 and 9.0 by adding 2 mEq (ie, 2 mL of an 8.4% w/v solution or 4 mL of a 4.2% w/v solution) of Sodium Bicarbonate Injection, prior to the addition of the constituted Ixabepilone solution.
PLASMA-LYTE A Injection pH 7.4®
- When using a 250 mL or a 500 mL bag of 0.9% Sodium Chloride Injection to prepare the infusion, the pH must be adjusted to a pH between 6.0 and 9.0 by adding 2 mEq (ie, 2 mL of an 8.4% w/v solution or 4 mL of a 4.2% w/v solution) of Sodium Bicarbonate Injection, prior to the addition of the constituted Ixabepilone solution.
- When using a 250 mL or a 500 mL bag of 0.9% Sodium Chloride Injection to prepare the infusion, the pH must be adjusted to a pH between 6.0 and 9.0 by adding 2 mEq (ie, 2 mL of an 8.4% w/v solution or 4 mL of a 4.2% w/v solution) of Sodium Bicarbonate Injection, prior to the addition of the constituted Ixabepilone solution.
- PLASMA-LYTE A Injection pH 7.4®
- For most doses, a 250 mL bag of infusion fluid is sufficient. However, it is necessary to check the final Ixabepilone infusion concentration of each dose based on the volume of infusion fluid to be used.
- The final concentration for infusion must be between 0.2 mg/mL and 0.6 mg/mL. To calculate the final infusion concentration, use the following formulas:
Total Infusion Volume = mL of Constituted Solution + mL of infusion fluid
Final Infusion Concentration = Dose of Ixabepilone (mg)/Total Infusion Volume (mL)
- Total Infusion Volume = mL of Constituted Solution + mL of infusion fluid
- Final Infusion Concentration = Dose of Ixabepilone (mg)/Total Infusion Volume (mL)
- Aseptically, withdraw the appropriate volume of constituted solution containing 2 mg of ixabepilone per mL.
- Aseptically, transfer to an intravenous (IV) bag containing an appropriate volume of infusion fluid to achieve the final desired concentration of Ixabepilone.
- Thoroughly mix the infusion bag by manual rotation.
- The infusion solution must be administered through an appropriate in-line filter with a microporous membrane of 0.2 to 1.2 microns. DEHP-free infusion containers and administration sets must be used. *Any remaining solution should be discarded according to institutional procedures for antineoplastics.
### Monitoring
There is limited information regarding Ixabepilone Monitoring in the drug label.
# IV Compatibility
- After constituting Ixabepilone the constituted solution should be further diluted with infusion fluid as soon as possible, but may be stored in the vial (not the syringe) for a maximum of 1 hour at room temperature and room light. Once diluted with infusion fluid, the solution is stable at room temperature and room light for a maximum of 6 hours. Administration of diluted Ixabepilone must be completed within this 6-hour period. The infusion fluids previously mentioned are specified because their pH is in the range of 6.0 to 9.0, which is required to maintain Ixabepilone stability. Other infusion fluids should not be used with Ixabepilone.
# Overdosage
- Experience with overdose of Ixabepilone is limited to isolated cases. The adverse reactions reported in these cases included peripheral neuropathy, fatigue, musculoskeletal pain/myalgia, and gastrointestinal symptoms (nausea, anorexia, diarrhea, abdominal pain, stomatitis). The highest dose mistakenly received was 100 mg/m2 (total dose 185 mg).
- There is no known antidote for overdosage of Ixabepilone In case of overdosage, the patient should be closely monitored and supportive treatment should be administered. Management of overdose should include supportive medical interventions to treat the presenting clinical manifestations.
# Pharmacology
## Mechanism of Action
- Ixabepilone is a semi-synthetic analog of epothilone B. Ixabepilone binds directly to β-tubulin subunits on microtubules, leading to suppression of microtubule dynamics. Ixabepilone suppresses the dynamic instability of αβ−II and αβ−III microtubules. Ixabepilone possesses low in vitro susceptibility to multiple tumor resistance mechanisms including efflux transporters, such as MRP-1 and P-glycoprotein (P-gp). Ixabepilone blocks cells in the mitotic phase of the cell division cycle, leading to cell death.
## Structure
- The chemical name for ixabepilone is (1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-(1E)-1-methyl-2-(2-methyl-4-thiazolyl)ethenyl-17-oxa-4-azabicyclo14.1.0 heptadecane-5,9-dione, and it has a molecular weight of 506.7. Ixabepilone has the following structural formula:
## Pharmacodynamics
- In cancer patients, ixabepilone has a plasma concentration-dependent effect on tubulin dynamics in peripheral blood mononuclear cells that is observed as the formation of microtubule bundles. Ixabepilone has antitumor activity in vivo against multiple human tumor xenografts, including drug-resistant types that overexpress P-gp, MRP-1, and βIII tubulin isoforms, or harbor tubulin mutations. Ixabepilone is active in xenografts that are resistant to multiple agents including taxanes, anthracyclines, and vinca alkaloids. Ixabepilone demonstrated synergistic antitumor activity in combination with capecitabine in vivo. In addition to direct antitumor activity, ixabepilone has antiangiogenic activity.
## Pharmacokinetics
### Absorption
- Following administration of a single 40 mg/m2 dose of Ixabepilone in patients with cancer, the mean Cmax was 252 ng/mL (coefficient of variation, CV 56%) and the mean AUC was 2143 nghr/mL (CV 48%). Typically, Cmax occurred at the end of the 3-hour infusion. In cancer patients, the pharmacokinetics of ixabepilone were linear at doses of 15 to 57 mg/m2.
### Distribution
- The mean volume of distribution of 40 mg/m2 ixabepilone at steady-state was in excess of 1000 L. In vitro, the binding of ixabepilone to human serum proteins ranged from 67 to 77%, and the blood-to-plasma concentration ratios in human blood ranged from 0.65 to 0.85 over a concentration range of 50 to 5000 ng/mL.
### Metabolism
- Ixabepilone is extensively metabolized in the liver. In vitro studies indicated that the main route of oxidative metabolism of ixabepilone is via CYP3A4. More than 30 metabolites of ixabepilone are excreted into human urine and feces. No single metabolite accounted for more than 6% of the administered dose. The biotransformation products generated from ixabepilone by human liver microsomes were not active when tested for in vitro cytotoxicity against a human tumor cell line.
- In vitro studies using human liver microsomes indicate that clinically relevant concentrations of ixabepilone do not inhibit CYP3A4, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. Ixabepilone does not induce the activity or the corresponding mRNA levels of CYP1A2, CYP2B6, CYP2C9, or CYP3A4 in cultured human hepatocytes at clinically relevant concentrations. Therefore, it is unlikely that ixabepilone will affect the plasma levels of drugs that are substrates of CYP enzymes.
### Elimination
- Ixabepilone is eliminated primarily as metabolized drug. After an intravenous 14-ixabepilone dose to patients, approximately 86% of the dose was eliminated within 7 days in feces (65% of the dose) and in urine (21% of the dose). Unchanged ixabepilone accounted for approximately 1.6% and 5.6% of the dose in feces and urine, respectively. Ixabepilone has a terminal elimination half-life of approximately 52 hours. No accumulation in plasma is expected for ixabepilone administered every 3 weeks
## Nonclinical Toxicology
There is limited information regarding Ixabepilone Nonclinical Toxicology in the drug label.
# Clinical Studies
### Combination Therapy
- In an open-label, multicenter, multinational, randomized trial of 752 patients with metastatic or locally advanced breast cancer, the efficacy and safety of Ixabepilone (40 mg/m2 every 3 weeks) in combination with capecitabine (at 1000 mg/m2 twice daily for 2 weeks followed by 1 week rest) were assessed in comparison with capecitabine as monotherapy (at 1250 mg/m2 twice daily for 2 weeks followed by 1 week rest). Patients were previously treated with anthracyclines and taxanes. Patients were required to have demonstrated tumor progression or resistance to taxanes and anthracyclines as follows:
- tumor progression within 3 months of the last anthracycline dose in the metastatic setting or recurrence within 6 months in the adjuvant or neoadjuvant setting, and
- tumor progression within 4 months of the last taxane dose in the metastatic setting or recurrence within 12 months in the adjuvant or neoadjuvant setting.
For anthracyclines, patients who received a minimum cumulative dose of 240 mg/m2 of doxorubicin or 360 mg/m2 of epirubicin were also eligible.
Sixty-seven percent of patients were White, 23% were Asian, and 3% were Black. Both arms were evenly matched with regards to race, age (median 53 years), baseline performance status (Karnofsky 70-100%), and receipt of prior adjuvant or neo-adjuvant chemotherapy (75%). Tumors were ER-positive in 47% of patients, ER-negative in 43%, HER2-positive in 15%, HER2-negative in 61%, and ER-negative, PR-negative, HER2-negative in 25%. The baseline disease characteristics and previous therapies for all patients (n=752) are shown in Table 6.
The patients in the combination treatment group received a median of 5 cycles of treatment and patients in the capecitabine monotherapy treatment group received a median of 4 cycles of treatment.
- The primary endpoint of the study was progression-free survival (PFS) defined as time from randomization to radiologic progression as determined by Independent Radiologic Review (IRR), clinical progression of measurable skin lesions or death from any cause. Other study endpoints included objective tumor response based on Response Evaluation Criteria in Solid Tumors (RECIST), time to response, response duration, and overall survival.
- Ixabepilone in combination with capecitabine resulted in a statistically significant improvement in PFS compared to capecitabine. The results of the study are presented in Table 7 and Figure 1.
- There was no statistically significant difference in overall survival between treatment arms in this study, as well as in a second similar study. In the study described above, the median overall survivals were 12.9 months (95% CI: 11.5, 14.2) in the combination therapy arm and 11.1 months (95% CI: 10.0, 12.5) in the capecitabine alone arm .
- In the second trial, comparing Ixabepilone in combination with capecitabine versus capecitabine alone, conducted in 1221 patients pretreated with an anthracycline and a taxane, the median overall survivals were 16.4 months (95% CI: 15.0, 17.9) in the combination therapy arm and 15.6 months (95% CI: 13.9, 17.0), in the capecitabine alone arm .
### Monotherapy
- Ixabepilone was evaluated as a single agent in a multicenter single-arm study in 126 women with metastatic or locally advanced breast cancer. The study enrolled patients whose tumors had recurred or had progressed following two or more chemotherapy regimens including an anthracycline, a taxane, and capecitabine. Patients who had received a minimum cumulative dose of 240 mg/m2 of doxorubicin or 360 mg/m2 of epirubicin were also eligible. Tumor progression or recurrence were prospectively defined as follows:
- Disease progression while on therapy in the metastatic setting (defined as progression while on treatment or within 8 weeks of last dose),
Recurrence within 6 months of the last dose in the adjuvant or neoadjuvant setting (only for anthracycline and taxane),
HER2-positive patients must also have progressed during or after discontinuation of trastuzumab.
- Disease progression while on therapy in the metastatic setting (defined as progression while on treatment or within 8 weeks of last dose),
- Recurrence within 6 months of the last dose in the adjuvant or neoadjuvant setting (only for anthracycline and taxane),
- HER2-positive patients must also have progressed during or after discontinuation of trastuzumab.
In this study, the median age was 51 years (range, 30-78), and 79% were White, 5% Black, and 2% Asian,
- Karnofsky performance status was 70-100%, 88% had received two or more prior chemotherapy regimens for metastatic disease, and 86% had liver and/or lung metastases. Tumors were ER-positive in 48% of patients, ER-negative in 44%, HER2-positive in 7%, HER2-negative in 72%, and ER-negative, PR-negative, HER2-negative in 33%.
- Ixabepilone was administered at a dose of 40 mg/m2 intravenously over 3 hours every 3 weeks. Patients received a median of 4 cycles (range 1 to 18) of Ixabepilone therapy.
- Objective tumor response was determined by independent radiologic and investigator review using RECIST. Efficacy results are presented in Table 8.
# How Supplied
Ixabepilone is supplied as a Kit containing one vial of Ixabepilone® (ixabepilone) for injection and one vial of DILUENT for Ixabepilone.
## Storage
Ixabepilone Kit must be stored in a refrigerator at 2° C to 8° C (36° F to 46° F). Retain in original package until time of use to protect from light.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Ixabepilone Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Ixabepilone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Ixempra
# Look-Alike Drug Names
There is limited information regarding Ixabepilone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Ixabepilone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
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# Black Box Warning
# Overview
Ixabepilone is an antineoplastic agent, epothilone and mitotic inhibitor that is FDA approved for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated.
Ixabepilone is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine. There is a Black Box Warning for this drug as shown here. Common adverse reactions include peripheral sensory neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
## General Dosing Information
- The recommended dosage of Ixabepilone is 40 mg/m2 administered intravenously over 3 hours every 3 weeks. Doses for patients with body surface area (BSA) greater than 2.2 m2 should be calculated based on 2.2 m2.
## Dose Modification
### Dose Adjustments During Treatment
- Patients should be evaluated during treatment by periodic clinical observation and laboratory tests including complete blood cell counts. If toxicities are present, treatment should be delayed to allow recovery. Dosing adjustment guidelines for monotherapy and combination therapy are shown in Table 1. If toxicities recur, an additional 20% dose reduction should be made.
- Re-treatment Criteria: Dose adjustments at the start of a cycle should be based on nonhematologic toxicity or blood counts from the preceding cycle following the guidelines in Table 1. Patients should not begin a new cycle of treatment unless the neutrophil count is at least 1500 cells/mm3, the platelet count is at least 100,000 cells/mm3, and nonhematologic toxicities have improved to grade 1 (mild) or resolved.
### Dose Adjustments in Special Populations - Hepatic Impairment
- Combination Therapy: Ixabepilone in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN. Patients receiving combination treatment who have AST and ALT ≤2.5 x ULN and bilirubin ≤1 x ULN may receive the standard dose of ixabepilone (40 mg/m2).
- Monotherapy: Patients with hepatic impairment should be dosed with Ixabepilone based on the guidelines in Table 2. Patients with moderate hepatic impairment should be started at 20 mg/m2, the dosage in subsequent cycles may be escalated up to, but not exceeding, 30 mg/m2 if tolerated. Use in patients with AST or ALT >10 x ULN or bilirubin >3 x ULN is not recommended. Limited data are available for patients with baseline AST or ALT >5 x ULN. Caution should be used when treating these patients.
### Strong CYP3A4 Inhibitors
- The use of concomitant strong CYP3A4 inhibitors should be avoided (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, amprenavir, indinavir, nelfinavir, delavirdine, or voriconazole). Grapefruit juice may also increase plasma concentrations of Ixabepilone and should be avoided. Based on pharmacokinetic studies, if a strong CYP3A4 inhibitor must be coadministered, a dose reduction to 20 mg/m2 is predicted to adjust the ixabepilone AUC to the range observed without inhibitors and should be considered. If the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the Ixabepilone dose is adjusted upward to the indicated dose.
### Strong CYP3A4 Inducers
- The use of concomitant strong CYP3A4 inducers should be avoided (eg, phenytoin, carbamazepine, rifampin, rifabutin, dexamethasone, and phenobarbital). Selection of an alternative concomitant medication with no or minimal enzyme induction potential should be considered. Based on extrapolation from a drug interaction study with rifampin, the following guidance may be considered for dosing in patients requiring coadministration of a strong CYP3A4 inducer, if no alternatives are feasible. Once patients have been maintained on a strong CYP3A4 inducer, the dose of Ixabepilone may be gradually increased from 40 mg/m2 to 60 mg/m2 depending on tolerance. If the dose is increased, Ixabepilone should be given as a 4-hour intravenous infusion. This 60 mg/m2 dose given intravenously over 4 hours is predicted to adjust the AUC to the range observed without inducers. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. Patients whose dose is increased above 40 mg/m2 should be monitored carefully for toxicities associated with Ixabepilone If the strong inducer is discontinued, the Ixabepilone dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer.
## Premedication
- To minimize the chance of occurrence of a hypersensitivity reaction, all patients must be premedicated approximately 1 hour before the infusion of Ixabepilone with:
- An H1 antagonist (eg, diphenhydramine 50 mg orally or equivalent)
- An H2 antagonist (eg, ranitidine 150 - 300 mg orally or equivalent).
- Patients who experienced a hypersensitivity reaction to Ixabepilone require premedication with corticosteroids (eg, dexamethasone 20 mg intravenously, 30 minutes before infusion or orally, 60 minutes before infusion) in addition to pretreatment with H1 and H2 antagonists.
## Instructions for Preparation and IV Administration
- Ixabepilone Kit contains two vials, a vial labeled Ixabepilone (ixabepilone) for injection which contains ixabepilone powder and a vial containing DILUENT for Ixabepilone Only supplied DILUENT must be used for constituting Ixabepilone (ixabepilone) for injection. Ixabepilone Kit must be stored in a refrigerator at 2° C - 8° C (36° F - 46° F) in the original package to protect from light. Prior to constituting Ixabepilone for injection, the Kit should be removed from the refrigerator and allowed to stand at room temperature for approximately 30 minutes. When the vials are first removed from the refrigerator, a white precipitate may be observed in the DILUENT vial. This precipitate will dissolve to form a clear solution once the DILUENT warms to room temperature. To allow for withdrawal losses, the vial labeled as 15 mg Ixabepilone for injection contains 16 mg of ixabepilone and the vial labeled as 45 mg Ixabepilone for injection contains 47 mg of ixabepilone. The 15-mg Ixabepilone Kit is supplied with a vial providing 8 mL of the DILUENT and the 45-mg Ixabepilone Kit is supplied with a vial providing 23.5 mL of the DILUENT. After constituting with the DILUENT, the concentration of ixabepilone is 2 mg/mL.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ixabepilone in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ixabepilone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Ixabepilone FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ixabepilone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ixabepilone in pediatric patients.
# Contraindications
- Ixabepilone is contraindicated in patients with a history of a severe (CTC grade 3/4) hypersensitivity reaction to agents containing Cremophor® EL or its derivatives (eg, polyoxyethylated castor oil).
- Ixabepilone is contraindicated in patients who have a neutrophil count <1500 cells/mm3 or a platelet count <100,000 cells/mm3.
- Ixabepilone in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN.
# Warnings
### Peripheral Neuropathy
- Peripheral neuropathy was common (see Table 3). Patients treated with Ixabepilone should be monitored for symptoms of neuropathy, such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, or neuropathic pain. Neuropathy occurred early during treatment; ~75% of new onset or worsening neuropathy occurred during the first 3 cycles. Patients experiencing new or worsening symptoms may require a reduction or delay in the dose of Ixabepilone In clinical studies, peripheral neuropathy was managed through dose reductions, dose delays, and treatment discontinuation. Neuropathy was the most frequent cause of treatment discontinuation due to drug toxicity. In Studies 046 and 081, 80% and 87%, respectively, of patients with peripheral neuropathy who received Ixabepilone had improvement or no worsening of their neuropathy following dose reduction. For patients with grade 3/4 neuropathy in Studies 046 and 081, 76% and 79%, respectively, had documented improvement to baseline or grade 1, twelve weeks after onset.
- A pooled analysis of 1540 cancer patients treated with Ixabepilone indicated that patients with diabetes mellitus or preexisting peripheral neuropathy may be at increased risk of severe neuropathy. Prior therapy with neurotoxic chemotherapy agents did not predict the development of neuropathy. Patients with moderate to severe neuropathy (grade 2 or greater) were excluded from studies with Ixabepilone. Caution should be used when treating patients with diabetes mellitus or preexisting peripheral neuropathy.
### Myelosuppression
- Myelosuppression is dose-dependent and primarily manifested as neutropenia. In clinical studies, grade 4 neutropenia (<500 cells/mm3) occurred in 36% of patients treated with Ixabepilone in combination with capecitabine and 23% of patients treated with Ixabepilone monotherapy. Febrile neutropenia and infection with neutropenia were reported in 5% and 6% of patients treated with Ixabepilone in combination with capecitabine, respectively, and 3% and 5% of patients treated with Ixabepilone as monotherapy, respectively. Neutropenia-related death occurred in 1.9% of 414 patients with normal hepatic function or mild hepatic impairment treated with Ixabepilone in combination with capecitabine. The rate of neutropenia-related deaths was higher (29%, 5 out of 17) in patients with AST or ALT >2.5 x ULN or bilirubin >1.5 x ULN. Neutropenia-related death occurred in 0.4% of 240 patients treated with Ixabepilone as monotherapy. No neutropenia-related deaths were reported in 24 patients with AST or ALT >2.5 x ULN or bilirubin >1.5 x ULN treated with Ixabepilone monotherapy. Ixabepilone must not be administered to patients with a neutrophil count <1500 cells/mm3. To monitor for myelosuppression, frequent peripheral blood cell counts are recommended for all patients receiving Ixabepilone Patients who experience severe neutropenia or thrombocytopenia should have their dose reduced.
## Hepatic Impairment
- Patients with baseline AST or ALT >2.5 x ULN or bilirubin >1.5 x ULN experienced greater toxicity than patients with baseline AST or ALT ≤2.5 x ULN or bilirubin ≤1.5 x ULN when treated with Ixabepilone at 40 mg/m2 in combination with capecitabine or as monotherapy in breast cancer studies. In combination with capecitabine, the overall frequency of grade 3/4 adverse reactions, febrile neutropenia, serious adverse reactions, and toxicity-related deaths was greater. With monotherapy, grade 4 neutropenia, febrile neutropenia, and serious adverse reactions were more frequent. The safety and pharmacokinetics of Ixabepilone as monotherapy were evaluated in a dose escalation study in 56 patients with varying degrees of hepatic impairment. Exposure was increased in patients with elevated AST or bilirubin.
- Ixabepilone in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN due to increased risk of toxicity- and neutropenia-related death. Patients who are treated with Ixabepilone as monotherapy should receive a reduced dose depending on the degree of hepatic impairment. Use in patients with AST or ALT >10 x ULN or bilirubin >3 x ULN is not recommended. Limited data are available for patients with AST or ALT >5 x ULN. Caution should be used when treating these patients.
### Hypersensitivity Reactions
- Patients with a history of a severe hypersensitivity reaction to agents containing Cremophor® EL or its derivatives (eg, polyoxyethylated castor oil) should not be treated with Ixabepilone. All patients should be premedicated with an H1 and an H2 antagonist approximately 1 hour before Ixabepilone infusion and be observed for hypersensitivity reactions (eg, flushing, rash, dyspnea, and bronchospasm). In case of severe hypersensitivity reactions, infusion of Ixabepilone should be stopped and aggressive supportive treatment (eg, epinephrine, corticosteroids) started. Of the 1323 patients treated with Ixabepilone in clinical studies, 9 patients (1%) had experienced severe hypersensitivity reactions (including anaphylaxis). Three of the 9 patients were able to be retreated. Patients who experience a hypersensitivity reaction in one cycle of Ixabepilone must be premedicated in subsequent cycles with a corticosteroid in addition to the H1 and H2 antagonists, and extension of the infusion time should be considered.
### Cardiac Adverse Reactions
- The frequency of cardiac adverse reactions (myocardial ischemia and ventricular dysfunction) was higher in the Ixabepilone in combination with capecitabine (1.9%) than in the capecitabine alone (0.3%) treatment group. Supraventricular arrhythmias were observed in the combination arm (0.5%) and not in the capecitabine alone arm. Caution should be exercised in patients with a history of cardiac disease. Discontinuation of Ixabepilone should be considered in patients who develop cardiac ischemia or impaired cardiac function.
### Potential for Cognitive Impairment from Excipients
Since Ixabepilone contains dehydrated alcohol USP, consideration should be given to the possibility of central nervous system and other effects of alcohol.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.
- Unless otherwise specified, assessment of adverse reactions is based on one randomized study (Study 046) and one single-arm study (Study 081). In Study 046, 369 patients with metastatic breast cancer were treated with Ixabepilone 40 mg/m2 administered intravenously over 3 hours every 21 days, combined with capecitabine 1000 mg/m2 twice daily for 2 weeks followed by a 1-week rest period. Patients treated with capecitabine as monotherapy (n=368) in this study received 1250 mg/m2 twice daily for 2 weeks every 21 days. In Study 081, 126 patients with metastatic or locally advanced breast cancer were treated with Ixabepilone 40 mg/m2 administered intravenously over 3 hours every 3 weeks.
- The most common adverse reactions (≥20%) reported by patients receiving Ixabepilone were peripheral sensory neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain. The following additional reactions occurred in ≥20% in combination treatment: palmar-plantar erythrodysesthesia (hand-foot) syndrome, anorexia, abdominal pain, nail disorder, and constipation. The most common hematologic abnormalities (>40%) include neutropenia, leukopenia, anemia, and thrombocytopenia.
- Table 4 presents nonhematologic adverse reactions reported in 5% or more of patients. Hematologic abnormalities are presented separately in Table 5.
The following serious adverse reactions were also reported in 1323 patients treated with Ixabepilone as monotherapy or in combination with other therapies in Phase 2 and 3 studies.
- Infections and Infestations: sepsis, pneumonia, infection, neutropenic infection, urinary tract infection, bacterial infection, enterocolitis, laryngitis, lower respiratory tract infection.
- Blood and Lymphatic System Disorders: coagulopathy, lymphopenia
- Metabolism and Nutrition Disorders: hyponatremia, metabolic acidosis, hypokalemia, hypovolemia.
- Nervous System Disorders: cognitive disorder, syncope, cerebral hemorrhage, abnormal coordination, lethargy.
- Cardiac Disorders: myocardial infarction, supraventricular arrhythmia, left ventricular dysfunction, angina pectoris, atrial flutter, cardiomyopathy, myocardial ischemia.
- Vascular Disorders: hypotension, thrombosis, embolism, hemorrhage, hypovolemic shock, vasculitis.
- Respiratory, Thoracic, and Mediastinal Disorders: pneumonitis, hypoxia, respiratory failure, acute pulmonary edema, dysphonia, pharyngolaryngeal pain.
- Gastrointestinal Disorders: ileus, colitis, impaired gastric emptying, esophagitis, dysphagia, gastritis, gastrointestinal hemorrhage.
- Hepatobiliary Disorders: acute hepatic failure, jaundice.
- Skin and Subcutaneous Tissue Disorders: erythema multiforme
- Musculoskeletal, Connective Tissue, and Bone Disorders: muscular weakness, muscle spasms, trismus.
- Renal and Urinary Disorders: nephrolithiasis, renal failure.
- General Disorders and Administration Site Conditions: chills
- Investigations: increased transaminases, increased blood alkaline phosphatase, increased gamma-glutamyltransferase.
## Postmarketing Experience
- Radiation recall has been reported during postmarketing use of Ixabepilone Because this reaction was reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.
# Drug Interactions
### Effect of Other Drugs on Ixabepilone
- CYP3A4 Inhibitors: Coadministration of ixabepilone with ketoconazole, a potent CYP3A4 inhibitor, increased ixabepilone AUC by 79% compared to ixabepilone treatment alone. If alternative treatment cannot be administered, a dose adjustment should be considered. The effect of mild or moderate inhibitors (eg, erythromycin, fluconazole, or verapamil) on exposure to ixabepilone has not been studied. Therefore, caution should be used when administering mild or moderate CYP3A4 inhibitors during treatment with Ixabepilone, and alternative therapeutic agents that do not inhibit CYP3A4 should be considered. Patients receiving CYP3A4 inhibitors during treatment with Ixabepilone should be monitored closely for acute toxicities (eg, frequent monitoring of peripheral blood counts between cycles of Ixabepilone).
- CYP3A4 Inducers: Ixabepilone is a CYP3A4 substrate. Coadministration of Ixabepilone with rifampin, a potent CYP3A4 inducer, decreased ixabepilone AUC by 43% compared to Ixabepilone treatment alone. Other strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifabutin, and phenobarbital) may also decrease ixabepilone concentrations leading to subtherapeutic levels. Therefore, therapeutic agents with low enzyme induction potential should be considered for coadministration with Ixabepilone. St. John’s Wort may decrease ixabepilone plasma concentrations unpredictably and should be avoided. If patients must be coadministered a strong CYP3A4 inducer, a gradual dose adjustment may be considered.
### Effect of Ixabepilone on Other Drugs
- Ixabepilone does not inhibit CYP enzymes at relevant clinical concentrations and is not expected to alter the plasma concentrations of other drugs.
### Capecitabine
- In patients with cancer who received ixabepilone (40 mg/m2) in combination with capecitabine (1000 mg/m2), ixabepilone Cmax decreased by 19%, capecitabine Cmax decreased by 27%, and 5-fluorouracil AUC increased by 14%, as compared to ixabepilone or capecitabine administered separately. The interaction is not clinically significant given that the combination treatment is supported by efficacy data.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Ixabepilone may cause fetal harm when administered to pregnant women. There are no adequate and well-controlled studies with Ixabepilone in pregnant women. Women should be advised not to become pregnant when taking Ixabepilone If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
- Ixabepilone was studied for effects on embryo-fetal development in pregnant rats and rabbits given IV doses of 0.02, 0.08, and 0.3 mg/kg/day and 0.01, 0.03, 0.11, and 0.3 mg/kg/day, respectively. There were no teratogenic effects. In rats, an increase in resorptions and post-implantation loss and a decrease in the number of live fetuses and fetal weight was observed at the maternally toxic dose of 0.3 mg/kg/day (approximately one-tenth the human clinical exposure based on AUC). Abnormalities included a reduced ossification of caudal vertebrae, sternebrae, and metacarpals. In rabbits, ixabepilone caused maternal toxicity (death) and embryo-fetal toxicity (resorptions) at 0.3 mg/kg/day (approximately one-tenth the human clinical dose based on body surface area). No fetuses were available at this dose for evaluation.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ixabepilone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ixabepilone during labor and delivery.
### Nursing Mothers
- It is not known whether ixabepilone is excreted into human milk. Following intravenous administration of radiolabeled ixabepilone to rats on days 7 to 9 postpartum, concentrations of radioactivity in milk were comparable with those in plasma and declined in parallel with the plasma concentrations. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ixabepilone, a decision must be made whether to discontinue nursing or to discontinue Ixabepilone taking into account the importance of the drug to the mother.
### Pediatric Use
- The effectiveness of Ixabepilone in pediatric patients has not been established. Ixabepilone was evaluated in one Phase 1 and one Phase 2 trial. The pediatric patients had a safety profile consistent with that seen in adults, and no new safety signals were identified.
- In the Phase 1 open-label, dose-finding trial, the safety of Ixabepilone was evaluated in 19 pediatric patients with advanced or refractory solid tumors and 2 with acute leukemias. Ixabepilone was administered as a one-hour IV infusion daily for the first five days of a 21-day cycle at one of 5 dose levels, ranging from 3 to 10 mg/m2. Among the 21 patients, 12 ranged in age from 2 to 12 years and 9 ranged from 13 to 18 years. The maximum tolerated dose was 8 mg/m2 IV daily for 5 days every 21 days. No significant activity was observed. The pharmacokinetics of ixabepilone were characterized by population pharmacokinetic analysis of data for 16 patients from this trial, who were aged 2 to 18 years (median 12 years). The pharmacokinetic parameters of ixabepilone in these pediatric patients were compared to the corresponding parameters of 130 adult patients enrolled in clinical trials using the same dosing schedule. The median BSA normalized clearance of ixabepilone in pediatric patients (17 L/h/m2) was similar to that in adult patients (20 L/h/m2).
- In the Phase 2 trial of 59 patients with advanced or refractory solid tumors, 28 ranged in age from 3 to 12 years and 19 ranged in age from 13 to 18 years. Twelve additional patients over the age of 18 were treated in this trial. Ixabepilone was administered at a dose of 8 mg/m2 IV daily for 5 days every 21 days. This trial was terminated early due to lack of efficacy.
### Geriatic Use
- Clinical studies of Ixabepilone did not include sufficient numbers of subjects aged sixty-five and over to determine whether they respond differently from younger subjects.
- Forty-five of 431 patients treated with Ixabepilone in combination with capecitabine were ≥65 years of age and 3 patients were ≥75. Overall, the incidence of grade 3/4 adverse reactions was higher in patients ≥65 years of age versus those <65 years of age (82% versus 68%) including grade 3/4 stomatitis (9% versus 1%), diarrhea (9% versus 6%), palmar-plantar erythrodysesthesia syndrome (27% versus 20%), peripheral neuropathy (24% versus 22%), febrile neutropenia (9% versus 3%), fatigue (16% versus 12%), and asthenia (11% versus 6%). Toxicity-related deaths occurred in 2 (4.7%) of 43 patients ≥65 years with normal baseline hepatic function or mild impairment.
- Thirty-two of 240 breast cancer patients treated with Ixabepilone as monotherapy were ≥65 years of age and 6 patients were ≥75. No overall differences in safety were observed in these patients compared to those <65 years of age.
### Gender
There is no FDA guidance on the use of Ixabepilone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ixabepilone with respect to specific racial populations.
### Renal Impairment
- Ixabepilone is minimally excreted via the kidney. No controlled pharmacokinetic studies were conducted with Ixabepilone in patients with renal impairment. Ixabepilone in combination with capecitabine has not been evaluated in patients with calculated creatinine clearance of <50 mL/min. Ixabepilone as monotherapy has not been evaluated in patients with creatinine >1.5 times ULN. In a population pharmacokinetic analysis of Ixabepilone as monotherapy, there was no meaningful effect of mild and moderate renal insufficiency (CrCL >30 mL/min) on the pharmacokinetics of ixabepilone.
### Hepatic Impairment
- Ixabepilone was evaluated in 56 patients with mild to severe hepatic impairment defined by bilirubin levels and AST levels. Compared to patients with normal hepatic function (n=17), the area under the curve (AUC0-infinity) of ixabepilone increased by:
22% in patients with a) bilirubin >1 – 1.5 x ULN or b) AST >ULN but bilirubin <1.5 x ULN;
30% in patients with bilirubin >1.5 – 3 x ULN and any AST level; and
81% in patients with bilirubin >3 x ULN and any AST level.
- 22% in patients with a) bilirubin >1 – 1.5 x ULN or b) AST >ULN but bilirubin <1.5 x ULN;
- 30% in patients with bilirubin >1.5 – 3 x ULN and any AST level; and
- 81% in patients with bilirubin >3 x ULN and any AST level.
- Doses of 10 and 20 mg/m2 as monotherapy were tolerated in 17 patients with severe hepatic impairment (bilirubin >3 x ULN).
- Ixabepilone in combination with capecitabine must not be given to patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN [see Boxed Warning, Contraindications (4), and Warnings and Precautions (5.3)]. Dose reduction is recommended when administering Ixabepilone as monotherapy to patients with hepatic impairment [see Dosage and Administration (2.3)]. Because there is a need for dosage adjustment based upon hepatic function, assessment of hepatic function is recommended before initiation of Ixabepilone and periodically thereafter.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ixabepilone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ixabepilone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
### To constitute:
- With a suitable syringe, aseptically withdraw the DILUENT and slowly inject it into the Ixabepilone for injection vial. The 15-mg Ixabepilone is constituted with 8 mL of DILUENT and the 45-mg Ixabepilone is constituted with 23.5 mL of DILUENT.
- Gently swirl and invert the vial until the powder in Ixabepilone is completely dissolved.
### To dilute:
- Before administration, the constituted solution must be further diluted with one of the specified infusion fluids listed below. The Ixabepilone infusion must be prepared in a DEHP [di-(2-ethylhexyl) phthalate] free bag.
- The following infusion fluids have been qualified for use in the dilution of Ixabepilone:
Lactated Ringer’s Injection, USP
- Lactated Ringer’s Injection, USP
0**.9% Sodium Chloride Injection, USP (pH adjusted with Sodium Bicarbonate Injection, USP)
- When using a 250 mL or a 500 mL bag of 0.9% Sodium Chloride Injection to prepare the infusion, the pH must be adjusted to a pH between 6.0 and 9.0 by adding 2 mEq (ie, 2 mL of an 8.4% w/v solution or 4 mL of a 4.2% w/v solution) of Sodium Bicarbonate Injection, prior to the addition of the constituted Ixabepilone solution.
PLASMA-LYTE A Injection pH 7.4®
- When using a 250 mL or a 500 mL bag of 0.9% Sodium Chloride Injection to prepare the infusion, the pH must be adjusted to a pH between 6.0 and 9.0 by adding 2 mEq (ie, 2 mL of an 8.4% w/v solution or 4 mL of a 4.2% w/v solution) of Sodium Bicarbonate Injection, prior to the addition of the constituted Ixabepilone solution.
- When using a 250 mL or a 500 mL bag of 0.9% Sodium Chloride Injection to prepare the infusion, the pH must be adjusted to a pH between 6.0 and 9.0 by adding 2 mEq (ie, 2 mL of an 8.4% w/v solution or 4 mL of a 4.2% w/v solution) of Sodium Bicarbonate Injection, prior to the addition of the constituted Ixabepilone solution.
- PLASMA-LYTE A Injection pH 7.4®
- For most doses, a 250 mL bag of infusion fluid is sufficient. However, it is necessary to check the final Ixabepilone infusion concentration of each dose based on the volume of infusion fluid to be used.
- The final concentration for infusion must be between 0.2 mg/mL and 0.6 mg/mL. To calculate the final infusion concentration, use the following formulas:
Total Infusion Volume = mL of Constituted Solution + mL of infusion fluid
Final Infusion Concentration = Dose of Ixabepilone (mg)/Total Infusion Volume (mL)
- Total Infusion Volume = mL of Constituted Solution + mL of infusion fluid
- Final Infusion Concentration = Dose of Ixabepilone (mg)/Total Infusion Volume (mL)
- Aseptically, withdraw the appropriate volume of constituted solution containing 2 mg of ixabepilone per mL.
- Aseptically, transfer to an intravenous (IV) bag containing an appropriate volume of infusion fluid to achieve the final desired concentration of Ixabepilone.
- Thoroughly mix the infusion bag by manual rotation.
- The infusion solution must be administered through an appropriate in-line filter with a microporous membrane of 0.2 to 1.2 microns. DEHP-free infusion containers and administration sets must be used. *Any remaining solution should be discarded according to institutional procedures for antineoplastics.
### Monitoring
There is limited information regarding Ixabepilone Monitoring in the drug label.
# IV Compatibility
- After constituting Ixabepilone the constituted solution should be further diluted with infusion fluid as soon as possible, but may be stored in the vial (not the syringe) for a maximum of 1 hour at room temperature and room light. Once diluted with infusion fluid, the solution is stable at room temperature and room light for a maximum of 6 hours. Administration of diluted Ixabepilone must be completed within this 6-hour period. The infusion fluids previously mentioned are specified because their pH is in the range of 6.0 to 9.0, which is required to maintain Ixabepilone stability. Other infusion fluids should not be used with Ixabepilone.
# Overdosage
- Experience with overdose of Ixabepilone is limited to isolated cases. The adverse reactions reported in these cases included peripheral neuropathy, fatigue, musculoskeletal pain/myalgia, and gastrointestinal symptoms (nausea, anorexia, diarrhea, abdominal pain, stomatitis). The highest dose mistakenly received was 100 mg/m2 (total dose 185 mg).
- There is no known antidote for overdosage of Ixabepilone In case of overdosage, the patient should be closely monitored and supportive treatment should be administered. Management of overdose should include supportive medical interventions to treat the presenting clinical manifestations.
# Pharmacology
## Mechanism of Action
- Ixabepilone is a semi-synthetic analog of epothilone B. Ixabepilone binds directly to β-tubulin subunits on microtubules, leading to suppression of microtubule dynamics. Ixabepilone suppresses the dynamic instability of αβ−II and αβ−III microtubules. Ixabepilone possesses low in vitro susceptibility to multiple tumor resistance mechanisms including efflux transporters, such as MRP-1 and P-glycoprotein (P-gp). Ixabepilone blocks cells in the mitotic phase of the cell division cycle, leading to cell death.
## Structure
- The chemical name for ixabepilone is (1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-(1E)-1-methyl-2-(2-methyl-4-thiazolyl)ethenyl-17-oxa-4-azabicyclo14.1.0 heptadecane-5,9-dione, and it has a molecular weight of 506.7. Ixabepilone has the following structural formula:
## Pharmacodynamics
- In cancer patients, ixabepilone has a plasma concentration-dependent effect on tubulin dynamics in peripheral blood mononuclear cells that is observed as the formation of microtubule bundles. Ixabepilone has antitumor activity in vivo against multiple human tumor xenografts, including drug-resistant types that overexpress P-gp, MRP-1, and βIII tubulin isoforms, or harbor tubulin mutations. Ixabepilone is active in xenografts that are resistant to multiple agents including taxanes, anthracyclines, and vinca alkaloids. Ixabepilone demonstrated synergistic antitumor activity in combination with capecitabine in vivo. In addition to direct antitumor activity, ixabepilone has antiangiogenic activity.
## Pharmacokinetics
### Absorption
- Following administration of a single 40 mg/m2 dose of Ixabepilone in patients with cancer, the mean Cmax was 252 ng/mL (coefficient of variation, CV 56%) and the mean AUC was 2143 ng•hr/mL (CV 48%). Typically, Cmax occurred at the end of the 3-hour infusion. In cancer patients, the pharmacokinetics of ixabepilone were linear at doses of 15 to 57 mg/m2.
### Distribution
- The mean volume of distribution of 40 mg/m2 ixabepilone at steady-state was in excess of 1000 L. In vitro, the binding of ixabepilone to human serum proteins ranged from 67 to 77%, and the blood-to-plasma concentration ratios in human blood ranged from 0.65 to 0.85 over a concentration range of 50 to 5000 ng/mL.
### Metabolism
- Ixabepilone is extensively metabolized in the liver. In vitro studies indicated that the main route of oxidative metabolism of ixabepilone is via CYP3A4. More than 30 metabolites of ixabepilone are excreted into human urine and feces. No single metabolite accounted for more than 6% of the administered dose. The biotransformation products generated from ixabepilone by human liver microsomes were not active when tested for in vitro cytotoxicity against a human tumor cell line.
- In vitro studies using human liver microsomes indicate that clinically relevant concentrations of ixabepilone do not inhibit CYP3A4, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. Ixabepilone does not induce the activity or the corresponding mRNA levels of CYP1A2, CYP2B6, CYP2C9, or CYP3A4 in cultured human hepatocytes at clinically relevant concentrations. Therefore, it is unlikely that ixabepilone will affect the plasma levels of drugs that are substrates of CYP enzymes.
### Elimination
- Ixabepilone is eliminated primarily as metabolized drug. After an intravenous 14[C]-ixabepilone dose to patients, approximately 86% of the dose was eliminated within 7 days in feces (65% of the dose) and in urine (21% of the dose). Unchanged ixabepilone accounted for approximately 1.6% and 5.6% of the dose in feces and urine, respectively. Ixabepilone has a terminal elimination half-life of approximately 52 hours. No accumulation in plasma is expected for ixabepilone administered every 3 weeks
## Nonclinical Toxicology
There is limited information regarding Ixabepilone Nonclinical Toxicology in the drug label.
# Clinical Studies
### Combination Therapy
- In an open-label, multicenter, multinational, randomized trial of 752 patients with metastatic or locally advanced breast cancer, the efficacy and safety of Ixabepilone (40 mg/m2 every 3 weeks) in combination with capecitabine (at 1000 mg/m2 twice daily for 2 weeks followed by 1 week rest) were assessed in comparison with capecitabine as monotherapy (at 1250 mg/m2 twice daily for 2 weeks followed by 1 week rest). Patients were previously treated with anthracyclines and taxanes. Patients were required to have demonstrated tumor progression or resistance to taxanes and anthracyclines as follows:
- tumor progression within 3 months of the last anthracycline dose in the metastatic setting or recurrence within 6 months in the adjuvant or neoadjuvant setting, and
- tumor progression within 4 months of the last taxane dose in the metastatic setting or recurrence within 12 months in the adjuvant or neoadjuvant setting.
For anthracyclines, patients who received a minimum cumulative dose of 240 mg/m2 of doxorubicin or 360 mg/m2 of epirubicin were also eligible.
Sixty-seven percent of patients were White, 23% were Asian, and 3% were Black. Both arms were evenly matched with regards to race, age (median 53 years), baseline performance status (Karnofsky 70-100%), and receipt of prior adjuvant or neo-adjuvant chemotherapy (75%). Tumors were ER-positive in 47% of patients, ER-negative in 43%, HER2-positive in 15%, HER2-negative in 61%, and ER-negative, PR-negative, HER2-negative in 25%. The baseline disease characteristics and previous therapies for all patients (n=752) are shown in Table 6.
The patients in the combination treatment group received a median of 5 cycles of treatment and patients in the capecitabine monotherapy treatment group received a median of 4 cycles of treatment.
- The primary endpoint of the study was progression-free survival (PFS) defined as time from randomization to radiologic progression as determined by Independent Radiologic Review (IRR), clinical progression of measurable skin lesions or death from any cause. Other study endpoints included objective tumor response based on Response Evaluation Criteria in Solid Tumors (RECIST), time to response, response duration, and overall survival.
- Ixabepilone in combination with capecitabine resulted in a statistically significant improvement in PFS compared to capecitabine. The results of the study are presented in Table 7 and Figure 1.
- There was no statistically significant difference in overall survival between treatment arms in this study, as well as in a second similar study. In the study described above, the median overall survivals were 12.9 months (95% CI: 11.5, 14.2) in the combination therapy arm and 11.1 months (95% CI: 10.0, 12.5) in the capecitabine alone arm [Hazard Ratio 0.90 (95% CI: 0.77, 1.05), p-value=0.19].
- In the second trial, comparing Ixabepilone in combination with capecitabine versus capecitabine alone, conducted in 1221 patients pretreated with an anthracycline and a taxane, the median overall survivals were 16.4 months (95% CI: 15.0, 17.9) in the combination therapy arm and 15.6 months (95% CI: 13.9, 17.0), in the capecitabine alone arm [Hazard Ratio 0.90 (95% CI: 0.78, 1.03), p-value=0.12].
### Monotherapy
- Ixabepilone was evaluated as a single agent in a multicenter single-arm study in 126 women with metastatic or locally advanced breast cancer. The study enrolled patients whose tumors had recurred or had progressed following two or more chemotherapy regimens including an anthracycline, a taxane, and capecitabine. Patients who had received a minimum cumulative dose of 240 mg/m2 of doxorubicin or 360 mg/m2 of epirubicin were also eligible. Tumor progression or recurrence were prospectively defined as follows:
- Disease progression while on therapy in the metastatic setting (defined as progression while on treatment or within 8 weeks of last dose),
Recurrence within 6 months of the last dose in the adjuvant or neoadjuvant setting (only for anthracycline and taxane),
HER2-positive patients must also have progressed during or after discontinuation of trastuzumab.
- Disease progression while on therapy in the metastatic setting (defined as progression while on treatment or within 8 weeks of last dose),
- Recurrence within 6 months of the last dose in the adjuvant or neoadjuvant setting (only for anthracycline and taxane),
- HER2-positive patients must also have progressed during or after discontinuation of trastuzumab.
In this study, the median age was 51 years (range, 30-78), and 79% were White, 5% Black, and 2% Asian,
- Karnofsky performance status was 70-100%, 88% had received two or more prior chemotherapy regimens for metastatic disease, and 86% had liver and/or lung metastases. Tumors were ER-positive in 48% of patients, ER-negative in 44%, HER2-positive in 7%, HER2-negative in 72%, and ER-negative, PR-negative, HER2-negative in 33%.
- Ixabepilone was administered at a dose of 40 mg/m2 intravenously over 3 hours every 3 weeks. Patients received a median of 4 cycles (range 1 to 18) of Ixabepilone therapy.
- Objective tumor response was determined by independent radiologic and investigator review using RECIST. Efficacy results are presented in Table 8.
# How Supplied
Ixabepilone is supplied as a Kit containing one vial of Ixabepilone® (ixabepilone) for injection and one vial of DILUENT for Ixabepilone.
## Storage
Ixabepilone Kit must be stored in a refrigerator at 2° C to 8° C (36° F to 46° F). Retain in original package until time of use to protect from light.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Ixabepilone Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Ixabepilone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Ixempra
# Look-Alike Drug Names
There is limited information regarding Ixabepilone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Ixabepilone | |
252ef80ac6d49ea224171f7dd82dce564d742238 | wikidoc | Ruxolitinib | Ruxolitinib
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# Overview
Ruxolitinib is a tyrosine Kinase Inhibitor that is FDA approved for the treatment of myelofibrosis and polycythemia vera. Common adverse reactions include bruising, dizziness, headache, thrombocytopenia and anemia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Myelofibrosis
- For Patients with intermediate or high-risk myelofibrosis, including:
- Primary myelofibrosis
- Post-polycythemia vera myelofibrosis
- Post-essential thrombocythemia myelofibrosis.
The recommended starting dose of ruxolitinib is based on platelet count (TABLE 1).
- Interrupt treatment for platelet counts less than 50 X 109/L or absolute neutrophil count (ANC) less than 0.5 X 109/L.
- If the response is insufficient and platelet and neutrophil counts are adequate, doses may be increased in 5 mg twice daily increments to a maximum of 25 mg twice daily. Doses should not be increased during the first 4 weeks of therapy and not more frequently than every 2 weeks.
Consider dose increases in patients who meet all of the following conditions:
- Failure to achieve a reduction from pretreatment baseline in either palpable spleen length of 50% or a 35% reduction in spleen volume as measured by computed tomography (CT) or magnetic resonance imaging (MRI);
- Platelet count greater than 125 X 10 9/L at 4 weeks and platelet count never below 100 X 10 9/L;
- ANC Levels greater than 0.75 X 10 9/L.
Based on limited clinical data, long-term maintenance at a 5 mg twice daily dose has not shown responses and continued use at this dose should be limited to patients in whom the benefits outweigh the potential risks. Discontinue ruxolitinib if there is no spleen size reduction or symptom improvement after 6 months of therapy.
Dose Modifications for Hematologic Toxicity for Patients with Myelofibrosis Starting Treatment with Platelet Counts of 50 X 109/L to Less Than 100 X 109/L
This section applies only to patients with platelet counts of 50 X 109/L to less than 100 X 109/L prior to any treatment with ruxolitinib. For dose modifications for hematological toxicity in patients whose platelet counts were 100 X 109/L or more prior to starting treatment with ruxolitinib.
Treatment Interruption and Restarting Dosing
Interrupt treatment for platelet counts less than 25 X 109/L or ANC less than 0.5 X 109/L.
After recovery of platelet counts above 35 X 109/L and ANC above 0.75 X 109/L, dosing may be restarted. Restart dosing at the higher of 5 mg once daily or 5 mg twice daily below the largest dose in the week prior to the decrease in platelet count below 25 X 109/L or ANC below 0.5 X 109/L that led to dose interruption.
Reduce the dose of ruxolitinib for platelet counts less than 35 X 109/L as described in TABLE 4.
Do not increase doses during the first 4 weeks of therapy, and do not increase the dose more frequently than every 2 weeks.
If the response is insufficient, doses may be increased by increments of 5 mg daily to a maximum of 10 mg twice daily if:
- Theplatelet count has remained at least 40 X 10 9/L, and
- The platelet count has not fallen by more than 20% in the prior 4 weeks, and
- The ANC is more than 1 X 10 9/L, and
- The dose has not been reduced or interrupted for an adverse event or hematological toxicity in the prior 4 weeks.
Continuation of treatment for more than 6 months should be limited to patients in whom the benefits outweigh the potential risks. Discontinue ruxolitinib if there is no spleen size reduction or symptom improvement after 6 months of therapy.
Interrupt treatment for bleeding requiring intervention regardless of current platelet count. Once the bleeding event has resolved, consider resuming treatment at the prior dose if the underlying cause of bleeding has been controlled. If the bleeding event has resolved but the underlying cause persists, consider resuming treatment with ruxolitinib at a lower dose.
### Polycythemia Vera
- For patients who have had an inadequate response to or are intolerant of hydroxyurea.
- Recommended starting dose of ruxolitinib is 10 mg twice daily. Doses may be titrated based on safety and efficacy.
- Interrupt treatment for hemoglobin less than 8 g/dL, platelet counts less than 50 X 109/L or ANC less than 1.0 X 109/L.
- After recovery of the hematologic parameter(s) to acceptable levels, dosing may be restarted.
Restarting Doses for ruxolitinib after Safety Interruption for Hematologic Parameter(s):
- Use the most severe category of a patient’s hemoglobin, platelet count, or ANC abnormality to determine the corresponding maximum restarting dose.
Patients who had required dose interruption while receiving a dose of 5 mg twice daily, may restart at a dose of 5 mg twice daily or 5 mg once daily, but not higher, once hemoglobin is greater than or equal to 10 g/dL, platelet count is greater than or equal to 75 X 109/L, and ANC is greater than or equal to 1.5 X 109/L.
After restarting ruxolitinib following treatment interruption, doses may be titrated, but the maximum total daily dose should not exceed 5 mg less than the dose that resulted in the dose interruption. An exception to this is dose interruption following phlebotomy-associated anemia, in which case the maximal total daily dose allowed after restarting ruxolitinib would not be limited.
If the response is insufficient and platelet, hemoglobin, and neutrophil counts are adequate, doses may be increased in 5 mg twice daily increments to a maximum of 25 mg twice daily. Doses should not be increased during the first 4 weeks of therapy and not more frequently than every two weeks.
Consider dose increases in patients who meet all of the following conditions:
Inadequate efficacy as demonstrated by one or more of the following:
- Continued need for phlebotomy
- WBC greater than the upper limit of normal range
- Platelet count greater than the upper limit of normal range
- Palpable spleen that is reduced by less than 25% from Baseline
Platelet count greater than or equal to 140 X 109/L
Hemoglobin greater than or equal to 12 g/dL
ANC greater than or equal to 1.5 X 109/L
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ruxolitinib in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ruxolitinib in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Ruxolitinib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ruxolitinib in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ruxolitinib in pediatric patients.
# Contraindications
- None
# Warnings
### Thrombocytopenia, Anemia and Neutropenia
- Treatment with ruxolitinib can cause thrombocytopenia, anemia and neutropenia.
- Manage thrombocytopenia by reducing the dose or temporarily interrupting ruxolitinib.
- Platelet transfusions may be necessary.
- Patients developing anemia may require blood transfusions and/or dose modifications of ruxolitinib.
- Severe neutropenia (ANC less than 0.5 X 109/L) was generally reversible by withholding ruxolitinib until recovery.
- Perform a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated.
### Risk of Infection
- Serious bacterial, mycobacterial, fungal and viral infections have occurred.
- Delay starting therapy with ruxolitinib until active serious infections have resolved.
- Observe patients receiving ruxolitinib for signs and symptoms of infection and manage promptly.
### Tuberculosis
- Tuberculosis infection has been reported in patients receiving ruxolitinib.
- Observe patients receiving ruxolitinib for signs and symptoms of active tuberculosis and manage promptly.
- Prior to initiating ruxolitinib, patients should be evaluated for tuberculosis risk factors, and those at higher risk should be tested for latent infection.
- Risk factors include, but are not limited to, prior residence in or travel to countries with a high prevalence of tuberculosis, close contact with a person with active tuberculosis, and a history of active or latent tuberculosis where an adequate course of treatment cannot be confirmed.
- For patients with evidence of active or latent tuberculosis, consult a physician with expertise in the treatment of tuberculosis before starting ruxolitinib.
- The decision to continue ruxolitinib during treatment of active tuberculosis should be based on the overall risk-benefit determination.
### PML
- Progressive multifocal leukoencephalopathy (PML) has occurred with ruxolitinib treatment for myelofibrosis.
- If PML is suspected, stop ruxolitinib and evaluate.
### Herpes Zoster
- Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible if suspected.
### Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Ruxolitinib
- Following discontinuation of ruxolitinib, symptoms from myeloproliferative neoplasms may return to pretreatment levels over a period of approximately one week.
- Some patients with myelofibrosis have experienced one or more of the following adverse events after discontinuing ruxolitinib: fever, respiratory distress, hypotension, DIC, or multi-organ failure.
- If one or more of these occur after discontinuation of, or while tapering the dose of ruxolitinib, evaluate for and treat any intercurrent illness and consider restarting or increasing the dose of ruxolitinib.
- Instruct patients not to interrupt or discontinue ruxolitinib therapy without consulting their physician.
- When discontinuing or interrupting therapy with ruxolitinib for reasons other than thrombocytopenia or neutropenia, consider tapering the dose of ruxolitinib gradually rather than discontinuing abruptly.
### Non-Melanoma Skin Cancer
- Non-melanoma skin cancer including basal cell, squamous cell, and Merkel cell carcinoma have occurred in patients treated with ruxolitinib.
- Perform periodic skin examinations.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
### Experience in Myelofibrosis
The safety of ruxolitinib was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 months, including 301 patients with myelofibrosis in two Phase 3 studies.
In these two Phase 3 studies, patients had a median duration of exposure to ruxolitinib of 9.5 months (range 0.5 to 17 months), with 89% of patients treated for more than 6 months and 25% treated for more than 12 months. One hundred and eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In patients starting treatment with 15 mg twice daily (pretreatment platelet counts of 100 to 200 X 109/L) and 20 mg twice daily (pretreatment platelet counts greater than 200 X 109/L), 65% and 25% of patients, respectively, required a dose reduction below the starting dose within the first 8 weeks of therapy.
In a double-blind, randomized, placebo-controlled study of ruxolitinib, among the 155 patients treated with ruxolitinib, the most frequent adverse drug reactions were thrombocytopenia and anemia . Thrombocytopenia, anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache .
Discontinuation for adverse events, regardless of causality, was observed in 11% of patients treated with ruxolitinib and 11% of patients treated with placebo.
TABLE 10 presents the most common adverse reactions occurring in patients who received ruxolitinib in the double-blind, placebo-controlled study during randomized treatment.
Description of Selected Adverse Drug Reactions
Anemia
In the two Phase 3 clinical studies, median time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (<1%) discontinued treatment because of anemia. In patients receiving ruxolitinib, mean decreases in hemoglobin reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern was observed in patients regardless of whether they had received transfusions during therapy.
In the randomized, placebo-controlled study, 60% of patients treated with ruxolitinib and 38% of patients receiving placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the median number of units transfused per month was 1.2 in patients treated with ruxolitinib and 1.7 in placebo treated patients.
Thrombocytopenia
In the two Phase 3 clinical studies, in patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts above 50 X 109/L was 14 days. Platelet transfusions were administered to 5% of patients receiving ruxolitinib and to 4% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in <1% of patients receiving ruxolitinib and <1% of patients receiving control regimens. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting ruxolitinib had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (17% versus 7%).
Neutropenia
In the two Phase 3 clinical studies, 1% of patients reduced or stopped ruxolitinib because of neutropenia.
TABLE 11 provides the frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with ruxolitinib or placebo in the placebo-controlled study.
Additional Data from the Placebo-controlled Study
25% of patients treated with ruxolitinib and 7% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transaminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 2% for ruxolitinib with 1% Grade 3 and no Grade 4 ALT elevations.
17% of patients treated with ruxolitinib and 6% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase (AST). The incidence of Grade 2 AST elevations was <1% for ruxolitinib with no Grade 3 or 4 AST elevations.
17% of patients treated with ruxolitinib and <1% of patients treated with placebo developed newly occurring or worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was <1% for ruxolitinib with no Grade 3 or 4 cholesterol elevations.
### Clinical Trial Experience in Polycythemia Vera
In a randomized, open-label, active-controlled study, 110 patients with polycythemia vera resistant to or intolerant of hydroxyurea received ruxolitinib and 111 patients received best available therapy. The most frequent adverse drug reaction was anemia. TABLE 12 presents the most frequent non-hematologic treatment emergent adverse events occurring up to Week 32.
Discontinuation for adverse events, regardless of causality, was observed in 4% of patients treated with ruxolitinib.
Other clinically important treatment emergent adverse events observed in less than 6% of patients treated with ruxolitinib were:
- Weight gain
- Hypertension
- Urinary tract infections
Clinically relevant laboratory abnormalities are shown in TABLE 13.
## Postmarketing Experience
There is limited information regarding Ruxolitinib Postmarketing Experience in the drug label.
# Drug Interactions
### Drugs That Inhibit or Induce Cytochrome P450 Enzymes
- Ruxolitinib is metabolized by CYP3A4 and to a lesser extent by CYP2C9.
- The Cmax and AUC of ruxolitinib increased 33% and 91%, respectively following concomitant administration with the strong CYP3A4 inhibitor ketoconazole in healthy subjects. *Concomitant administration with mild or moderate CYP3A4 inhibitors did not result in an exposure change requiring intervention..
- When administering ruxolitinib with strong CYP3A4 inhibitors, consider dose reduction.
- The AUC of ruxolitinib is predicted to increase by approximately 100% to 300% following concomitant administration with the combined CYP3A4 and CYP2C9 inhibitor fluconazole at doses of 100 mg to 400 mg once daily, respectively.
- Avoid the concomitant use of ruxolitinib with fluconazole doses of greater than 200 mg daily.
- The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, following concomitant administration with the strong CYP3A4
inducer rifampin in healthy subjects.
- No dose adjustment is recommended; however, monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
There are no adequate and well-controlled studies of ruxolitinib in pregnant women. In embryofetal toxicity studies, treatment with ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. ruxolitinib should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
### Animal Data
Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratogenicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times the clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose.
In a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implantation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ruxolitinib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ruxolitinib during labor and delivery.
### Nursing Mothers
It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ruxolitinib, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
The safety and effectiveness of ruxolitinib in pediatric patients have not been established.
### Geriatic Use
Of the total number of myelofibrosis patients in clinical studies with ruxolitinib, 52% were 65 years of age and older. No overall differences in safety or effectiveness of ruxolitinib were observed between these patients and younger patients.
### Gender
There is no FDA guidance on the use of Ruxolitinib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ruxolitinib with respect to specific racial populations.
### Renal Impairment
The safety and pharmacokinetics of single dose ruxolitinib (25 mg) were evaluated in a study in healthy subjects ] 72-164 mL/min (N=8)] and in subjects with mild , moderate ] 38-57 mL/min (N=8)], or severe renal impairment ] 15-51 mL/min (N=8)]. Eight (8) additional subjects with end stage renal disease requiring hemodialysis were also enrolled.
The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal of some active metabolites by dialysis cannot be ruled out.
When administering ruxolitinib to patients with myelofibrosis and moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count between 50 X 109/L and 150 X 109/L, a dose reduction is recommended. A dose reduction is also recommended for patients with polycythemia vera and moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min). In all patients with end stage renal disease on dialysis, a dose reduction is recommended.
### Hepatic Impairment
The safety and pharmacokinetics of single dose ruxolitinib (25 mg) were evaluated in a study in healthy subjects (N=8) and in subjects with mild, Child-Pugh A (N=8), moderate Child-Pugh B (N=8), or severe hepatic impairment, Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib.
When administering ruxolitinib to patients with myelofibrosis and any degree of hepatic impairment and with a platelet count between 50 X 109/L and 150 X 109/L, a dose reduction is recommended. A dose reduction is also recommended for patients with polycythemia vera and hepatic impairment
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ruxolitinib in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ruxolitinib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Monitor complete blood counts every 2 to 4 weeks until doses are stabilized
- In the concomitant administration with CYP3A4 inducers, monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy
# IV Compatibility
There is limited information regarding the compatibility of Ruxolitinib and IV administrations.
# Overdosage
There is no known antidote for overdoses with ruxolitinib. Single doses up to 200 mg have been given with acceptable acute tolerability. Higher than recommended repeat doses are associated with increased myelosuppression including leukopenia, anemia and thrombocytopenia. Appropriate supportive treatment should be given.
Hemodialysis is not expected to enhance the elimination of ruxolitinib.
# Pharmacology
## Mechanism of Action
Ruxolitinib, a kinase inhibitor, inhibits Janus Associated Kinases (JAKs) JAK1 and JAK2 which mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, activation and subsequent localization of STATs to the nucleus leading to modulation of gene expression.
Myelofibrosis (MF) and polycythemia vera (PV) are myeloproliferative neoplasms (MPN) known to be associated with dysregulated JAK1 and JAK2 signaling]. In a mouse model of JAK2V617F-positive MPN, oral administration of ruxolitinib prevented splenomegaly, preferentially decreased JAK2V617F mutant cells in the spleen and decreased circulating inflammatory cytokines (eg, TNF-α, IL-6).
## Structure
Ruxolitinib phosphate is a kinase inhibitor with the chemical name (R)-3-(4-(7H-pyrrolopyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate and a molecular weight of 404.36. Ruxolitinib phosphate has the following structural formula:
Ruxolitinib phosphate is a white to off-white to light pink powder and is soluble in aqueous buffers across a pH range of 1 to 8.
## Pharmacodynamics
Ruxolitinib inhibits cytokine induced STAT3 phosphorylation in whole blood from healthy subjects and MF and PV patients. ruxolitinib administration resulted in maximal inhibition of STAT3 phosphorylation 2 hours after dosing which returned to near baseline by 10 hours in both healthy subjects and MF and PV patients.
## Pharmacokinetics
### Absorption
In clinical studies, ruxolitinib is rapidly absorbed after oral ruxolitinib administration with maximal plasma concentration (Cmax) achieved within 1 to 2 hours post-dose. Based on a mass balance study in humans, oral absorption of ruxolitinib was estimated to be at least 95%. Mean ruxolitinib Cmax and total exposure (AUC) increased proportionally over a single dose range of 5 to 200 mg. There were no clinically relevant changes in the pharmacokinetics of ruxolitinib upon administration of ruxolitinib with a high-fat meal, with the mean Cmax moderately decreased (24%) and the mean AUC nearly unchanged (4% increase).
### Distribution
The mean volume of distribution at steady-state is 72 L in MF patients with an associated inter-subject variability of 29% and 75 L in PV patients with an associated inter-subject variability of 23%. |Binding to plasma proteins]] in vitro is approximately 97%, mostly to albumin.
### Metabolism
In vitro studies suggest that ruxolitinib is metabolized by CYP3A4 and to a lesser extent by CYP2C9.
### Elimination
Following a single oral dose of -labeled ruxolitinib in healthy adult subjects, elimination was predominately through metabolism with 74% of radioactivity excreted in urine and 22% excretion via feces. Unchanged drug accounted for less than 1% of the excreted total radioactivity. The mean elimination half-life of ruxolitinib is approximately 3 hours and the mean half-life of ruxolitinib + metabolites is approximately 5.8 hours.
### Effects of Age, Gender, or Race
In healthy subjects, no significant differences in ruxolitinib pharmacokinetics were observed with regard to gender and race. In a population pharmacokinetic evaluation in MF patients, no relationship was apparent between oral clearance and patient age or race, and in women, clearance was 17.7 L/h and in men, 22.1 L/h with 39% inter-subject variability. Clearance was 12.7 L/h in PV patients, with a 42% inter-subject variability, and no relationship was apparent between oral clearance and gender, patient age or race in this patient population.
### Drug Interactions
Strong CYP3A4 inhibitors
In a trial of 16 healthy volunteers, a single dose of 10 mg of ruxolitinib was administered alone on Day 1 and a single dose of 10 mg of ruxolitinib was administered on Day 5 in combination with 200 mg of ketoconazole (a strong CYP3A4 inhibitor' given twice daily on Days 2 to 5). Ketoconazole increased ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ketoconazole also prolonged ruxolitinib half-life from 3.7 to 6.0 hours.
Fluconazole
Simulations using physiologically-based pharmacokinetic (PBPK) models suggested that fluconazole (a dual CYP3A4 and CYP2C9 inhibitor) increases steady state ruxolitinib AUC by approximately 100% to 300% following concomitant administration of 10 mg of ruxolitinib twice daily with 100 mg to 400 mg of fluconazole once daily, respectively.
Mild or moderate CYP3A4 inhibitors
In a trial of 15 healthy volunteers, a single dose of 10 mg of ruxolitinib was administered alone on Day 1 and a single dose of 10 mg of ruxolitinib was administered on Day 5 in combination with 400 mg of erythromycin (a moderate CYP3A4 inhibitor, given twice daily on Days 2 to 5). Erythromycin increased ruxolitinib Cmax and AUC by 8% and 27%, respectively.
CYP3A4 inducers
In a trial of 12 healthy volunteers, a single dose of 50 mg of ruxolitinib was administered alone on Day 1 and a single dose of 50 mg of ruxolitinib was administered on Day 13 in combination with 600 mg of rifampin (a strong CYP3A4 inducer, given once daily on Days 3 to 13). Rifampin decreased ruxolitinib Cmax and AUC by 32% and 61%, respectively. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately 100%
In vitro studies
In vitro, ruxolitinib and its M18 metabolite do not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4. Ruxolitinib is not an inducer of CYP1A2, CYP2B6 or CYP3A4 at clinically relevant concentrations.
In vitro, ruxolitinib and its M18 metabolite do not inhibit the P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1 or OAT3 transport systems at clinically relevant concentrations. Ruxolitinib is not a substrate for the P-gp transporter.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
Ruxolitinib was not carcinogenic in the 6-month Tg.rasH2 transgenic mouse model or in a 2-year carcinogenicity study in the rat.
Ruxolitinib was not mutagenic in a bacterial mutagenicity assay (Ames test) or clastogenic in in vitro chromosomal aberration assay (cultured human peripheral blood lymphocytes) or in vivo in a rat bone marrow micronucleus test.
In a fertility study, ruxolitinib was administered to male rats prior to and throughout mating and to female rats prior to mating and up to the implantation day (gestation day 7). Ruxolitinib had no effect on fertility or reproductive function in male or female rats at doses of 10, 30 or 60 mg/kg/day. However, in female rats doses of greater than or equal to 30 mg/kg/day resulted in increased post-implantation loss. The exposure (AUC) at the dose of 30 mg/kg/day is approximately 34% the clinical exposure at the maximum recommended dose of 25 mg twice daily.
# Clinical Studies
### Myelofibrosis
Two randomized Phase 3 studies (Studies 1 and 2) were conducted in patients with myelofibrosis (either primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia-myelofibrosis). In both studies, patients had palpable splenomegaly at least 5 cm below the costal margin and risk category of intermediate 2 (2 prognostic factors) or high risk (3 or more prognostic factors) based on the International Working Group Consensus Criteria (IWG).
The starting dose of ruxolitinib was based on platelet counts. Patients with a platelet count between 100 and 200 X 109/L were started on ruxolitinib 15 mg twice daily and patients with a platelet count greater than 200 X 109/L were started on ruxolitinib 20 mg twice daily. Doses were then individualized based upon tolerability and efficacy with maximum doses of 20 mg twice daily for patients with platelet counts between 100 to less than or equal to 125 X 109/L, of 10 mg twice daily for patients with platelet counts between 75 to less than or equal to 100 X 109/L, and of 5 mg twice daily for patients with platelet counts between 50 to less than or equal to 75 X 109/L.
### Study 1
Study 1 was a double-blind, randomized, placebo-controlled study in 309 patients who were refractory to or were not candidates for available therapy. The median age was 68 years (range 40 to 91 years) with 61% of patients older than 65 years and 54% were male. Fifty percent (50%) of patients had primary myelofibrosis, 31% had post-polycythemia vera myelofibrosis and 18% had post-essential thrombocythemia myelofibrosis. Twenty-one percent (21%) of patients had red blood cell transfusions within 8 weeks of enrollment in the study. The median hemoglobin count was 10.5 g/dL and the median platelet count was 251 X 109/L. Patients had a median palpable spleen length of 16 cm below the costal margin, with 81% having a spleen length 10 cm or greater below the costal margin. Patients had a median spleen volume as measured by magnetic resonance imaging (MRI) or computed tomography (CT) of 2595 cm3 (range 478 cm3 to 8881 cm3). (The upper limit of normal is approximately 300 cm3).
Patients were dosed with ruxolitinib or matching placebo. The primary efficacy endpoint was the proportion of patients achieving greater than or equal to a 35% reduction from baseline in spleen volume at Week 24 as measured by MRI or CT.
Secondary endpoints included duration of a 35% or greater reduction in spleen volume and proportion of patients with a 50% or greater reduction in Total Symptom Score from baseline to Week 24 as measured by the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 diary.
### Study 2
Study 2 was an open-label, randomized study in 219 patients. Patients were randomized 2:1 to ruxolitinib versus best available therapy. Best available therapy was selected by the investigator on a patient-by-patient basis. In the best available therapy arm, the medications received by more than 10% of patients were hydroxyurea (47%) and glucocorticoids (16%). The median age was 66 years (range 35 to 85 years) with 52% of patients older than 65 years and 57% were male. Fifty-three percent (53%) of patients had primary myelofibrosis, 31% had post-polycythemia vera myelofibrosis and 16% had post-essential thrombocythemia myelofibrosis. Twenty-one percent (21%) of patients had red blood cell transfusions within 8 weeks of enrollment in the study. The median hemoglobin count was 10.4 g/dL and the median platelet count was 236 X 109/L. Patients had a median palpable spleen length of 15 cm below the costal margin, with 70% having a spleen length 10 cm or greater below the costal margin. Patients had a median spleen volume as measured by MRI or CT of 2381 cm3 (range 451 cm3 to 7765 cm3).
The primary efficacy endpoint was the proportion of patients achieving 35% or greater reduction from baseline in spleen volume at Week 48 as measured by MRI or CT.
A secondary endpoint in Study 2 was the proportion of patients achieving a 35% or greater reduction of spleen volume as measured by MRI or CT from baseline to Week 24.
### Study 1 and 2 Efficacy Results
Efficacy analyses of the primary endpoint in Studies 1 and 2 are presented in TABLE 14 below. A significantly larger proportion of patients in the ruxolitinib group achieved a 35% or greater reduction in spleen volume from baseline in both studies compared to placebo in Study 1 and best available therapy in Study 2. A similar proportion of patients in the ruxolitinib group achieved a 50% or greater reduction in palpable spleen length.
FIGURE 1 shows the percent change from baseline in spleen volume for each patient at Week 24 (ruxolitinib N=139, placebo N=106) or the last evaluation prior to Week 24 for patients who did not complete 24 weeks of randomized treatment (ruxolitinib N=16, placebo N=47). One (1) patient (placebo) with a missing baseline spleen volume is not included.
In Study 1, myelofibrosis symptoms were a secondary endpoint and were measured using the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 diary. The modified MFSAF is a daily diary capturing the core symptoms of myelofibrosis (abdominal discomfort, pain under left ribs, night sweats, itching, bone/muscle pain and early satiety). Symptom scores ranged from 0 to 10 with 0 representing symptoms "absent" and 10 representing "worst imaginable" symptoms. These scores were added to create the daily total score, which has a maximum of 60.
TABLE 15 presents assessments of Total Symptom Score from baseline to Week 24 in Study 1 including the proportion of patients with at least a 50% reduction (ie, improvement in symptoms). At baseline, the mean Total Symptom Score was 18.0 in the ruxolitinib group and 16.5 in the placebo group. A higher proportion of patients in the ruxolitinib group had a 50% or greater reduction in Total Symptom Score than in the placebo group, with a median time to response of less than 4 weeks.
FIGURE 2 shows the percent change from baseline in Total Symptom Score for each patient at Week 24 (ruxolitinib N=129, placebo N=103) or the last evaluation on randomized therapy prior to Week 24 for patients who did not complete 24 weeks of randomized treatment (ruxolitinib N=16, placebo N=42). Results are excluded for 5 patients with a baseline Total Symptom Score of zero, 8 patients with missing baseline and 6 patients with insufficient post-baseline data.
FIGURE 3 displays the proportion of patients with at least a 50% improvement in each of the individual symptoms that comprise the Total Symptom Score indicating that all 6 of the symptoms contributed to the higher Total Symptom Score response rate in the group treated with ruxolitinib.
Overall survival was a secondary endpoint in both Study 1 and Study 2. Patients in the control groups were eligible for crossover in both studies, and the median times to crossover were 9 months in Study 1 and 17 months in Study 2.
FIGURE 4 and FIGURE 5 show Kaplan-Meier curves of overall survival at prospectively planned analyses after all patients remaining on study had completed 144 weeks on study.
### Polycythemia Vera
Study 3 was a randomized, open-label, active-controlled Phase 3 study conducted in 222 patients with polycythemia vera. Patients had been diagnosed with polycythemia vera for at least 24 weeks, had an inadequate response to or were intolerant of hydroxyurea, required phlebotomy and exhibited splenomegaly. All patients were required to demonstrate hematocrit control between 40-45% prior to randomization. The age ranged from 33 to 90 years with 30% of patients over 65 years of age and 66% were male. Patients had a median spleen volume as measured by MRI or CT of 1272 cm3 (range 254 cm3 to 5147 cm3) and median palpable spleen length below the costal margin was 7 cm.
Patients were randomized to ruxolitinib or best available therapy. The starting dose of ruxolitinib was 10 mg twice daily. Doses were then individualized based upon tolerability and efficacy with a maximum dose of 25 mg twice daily. At Week 32, 98 patients were still on ruxolitinib with 8% receiving greater than 20 mg twice daily, 15% receiving 20 mg twice daily, 33% receiving 15 mg twice daily, 34% receiving 10 mg twice daily, and 10% receiving less than 10 mg twice daily. Best available therapy (BAT) was selected by the investigator on a patient-by-patient basis and included hydroxyurea (60%), interferon/pegylated interferon (12%), anagrelide (7%), pipobroman (2%), lenalidomide/thalidomide (5%), and observation (15%).
The primary endpoint was the proportion of subjects achieving a response at Week 32, with response defined as having achieved both hematocrit control (the absence of phlebotomy eligibility beginning at the Week 8 visit and continuing through Week 32) and spleen volume reduction (a greater than or equal to 35% reduction from baseline in spleen volume at Week 32). Phlebotomy eligibility was defined as a confirmed hematocrit greater than 45% that is at least 3 percentage points higher than the hematocrit obtained at baseline or a confirmed hematocrit greater than 48%, whichever was lower. Secondary endpoints included the proportion of all randomized subjects who achieved the primary endpoint and who maintained their response 48 weeks after randomization, and the proportion of subjects achieving complete hematological remission at Week 32 with complete hematological remission defined as achieving hematocrit control, platelet count less than or equal to 400 X 109/L, and white blood cell count less than or equal to 10 X 109/L.
Results of the primary and secondary endpoints are presented in TABLE 16. A significantly larger proportion of patients in the ruxolitinib group achieved a response for the primary endpoint compared to best available therapy at Week 32 and maintained their response 48 weeks after randomization. A significantly larger proportion of patients in the ruxolitinib group compared to best available therapy also achieved complete hematological remission at Week 32.
For the proportion of patients achieving each of the individual components that make up the primary endpoint at Week 32, there were 60% of the patients with hematocrit control in the ruxolitinib group vs. 20% of the patients in the best available therapy group. There were 38% of the patients with spleen volume reduction from baseline greater than or equal to 35% at Week 32 in the ruxolitinib group vs. less than 1% of the patients in the best available therapy group.
# How Supplied
- Ruxolitinib Tablets are available as follows:
## Storage
- Store at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and
30°C (59°F and 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Discuss the following with patients prior to and during treatment with ruxolitinib:
### Thrombocytopenia, Anemia and Neutropenia
Inform patients that ruxolitinib is associated with thrombocytopenia, anemia and neutropenia, and of the need to monitor complete blood counts before and during treatment. Advise patients to observe for and report bleeding.
### Infections
Inform patients of the signs and symptoms of infection and to report any such signs and symptoms promptly.
Inform patients regarding the early signs and symptoms of herpes zoster and of progressive multifocal leukoencephalopathy, and advise patients to seek advice of a clinician if such symptoms are observed.
Symptom Exacerbation Following Interruption or Discontinuation of Treatment with ruxolitinib
Inform patients that after discontinuation of treatment, signs and symptoms from myeloproliferative neoplasms are expected to return. Instruct patients not to interrupt or discontinue ruxolitinib therapy without consulting their physician.
### Non-Melanoma Skin Cancer
Inform patients that ruxolitinib may increase their risk of certain non-melanoma skin cancers. Advise patients to inform their healthcare provider if they have ever had any type of skin cancer or if they observe any new or changing skin lesions.
### Drug-drug Interactions
Advise patients to inform their healthcare providers of all medications they are taking, including over-the-counter medications, herbal products and dietary supplements.
### Dialysis
Inform patients on dialysis that their dose should not be taken before dialysis but only following dialysis.
### Compliance
Advise patients to continue taking ruxolitinib every day for as long as their physician tells them and that this is a long-term treatment. Patients should not change dose or stop taking ruxolitinib without first consulting their physician. Patients should be aware that after discontinuation of treatment, signs and symptoms from myeloproliferative neoplasms are expected to return.
# Precautions with Alcohol
Alcohol-Ruxolitinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- JAKAFI
# Look-Alike Drug Names
There is limited information regarding Ruxolitinib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Ruxolitinib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Stefano Giannoni [2];Aparna Vuppala, M.B.B.S. [3]
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# Overview
Ruxolitinib is a tyrosine Kinase Inhibitor that is FDA approved for the treatment of myelofibrosis and polycythemia vera. Common adverse reactions include bruising, dizziness, headache, thrombocytopenia and anemia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Myelofibrosis
- For Patients with intermediate or high-risk myelofibrosis, including:
- Primary myelofibrosis
- Post-polycythemia vera myelofibrosis
- Post-essential thrombocythemia myelofibrosis.
The recommended starting dose of ruxolitinib is based on platelet count (TABLE 1).
- Interrupt treatment for platelet counts less than 50 X 109/L or absolute neutrophil count (ANC) less than 0.5 X 109/L.
- If the response is insufficient and platelet and neutrophil counts are adequate, doses may be increased in 5 mg twice daily increments to a maximum of 25 mg twice daily. Doses should not be increased during the first 4 weeks of therapy and not more frequently than every 2 weeks.
Consider dose increases in patients who meet all of the following conditions:
- Failure to achieve a reduction from pretreatment baseline in either palpable spleen length of 50% or a 35% reduction in spleen volume as measured by computed tomography (CT) or magnetic resonance imaging (MRI);
- Platelet count greater than 125 X 10 9/L at 4 weeks and platelet count never below 100 X 10 9/L;
- ANC Levels greater than 0.75 X 10 9/L.
Based on limited clinical data, long-term maintenance at a 5 mg twice daily dose has not shown responses and continued use at this dose should be limited to patients in whom the benefits outweigh the potential risks. Discontinue ruxolitinib if there is no spleen size reduction or symptom improvement after 6 months of therapy.
Dose Modifications for Hematologic Toxicity for Patients with Myelofibrosis Starting Treatment with Platelet Counts of 50 X 109/L to Less Than 100 X 109/L
This section applies only to patients with platelet counts of 50 X 109/L to less than 100 X 109/L prior to any treatment with ruxolitinib. For dose modifications for hematological toxicity in patients whose platelet counts were 100 X 109/L or more prior to starting treatment with ruxolitinib.
Treatment Interruption and Restarting Dosing
Interrupt treatment for platelet counts less than 25 X 109/L or ANC less than 0.5 X 109/L.
After recovery of platelet counts above 35 X 109/L and ANC above 0.75 X 109/L, dosing may be restarted. Restart dosing at the higher of 5 mg once daily or 5 mg twice daily below the largest dose in the week prior to the decrease in platelet count below 25 X 109/L or ANC below 0.5 X 109/L that led to dose interruption.
Reduce the dose of ruxolitinib for platelet counts less than 35 X 109/L as described in TABLE 4.
Do not increase doses during the first 4 weeks of therapy, and do not increase the dose more frequently than every 2 weeks.
If the response is insufficient, doses may be increased by increments of 5 mg daily to a maximum of 10 mg twice daily if:
- Theplatelet count has remained at least 40 X 10 9/L, and
- The platelet count has not fallen by more than 20% in the prior 4 weeks, and
- The ANC is more than 1 X 10 9/L, and
- The dose has not been reduced or interrupted for an adverse event or hematological toxicity in the prior 4 weeks.
Continuation of treatment for more than 6 months should be limited to patients in whom the benefits outweigh the potential risks. Discontinue ruxolitinib if there is no spleen size reduction or symptom improvement after 6 months of therapy.
Interrupt treatment for bleeding requiring intervention regardless of current platelet count. Once the bleeding event has resolved, consider resuming treatment at the prior dose if the underlying cause of bleeding has been controlled. If the bleeding event has resolved but the underlying cause persists, consider resuming treatment with ruxolitinib at a lower dose.
### Polycythemia Vera
- For patients who have had an inadequate response to or are intolerant of hydroxyurea.
- Recommended starting dose of ruxolitinib is 10 mg twice daily. Doses may be titrated based on safety and efficacy.
- Interrupt treatment for hemoglobin less than 8 g/dL, platelet counts less than 50 X 109/L or ANC less than 1.0 X 109/L.
- After recovery of the hematologic parameter(s) to acceptable levels, dosing may be restarted.
Restarting Doses for ruxolitinib after Safety Interruption for Hematologic Parameter(s):
- Use the most severe category of a patient’s hemoglobin, platelet count, or ANC abnormality to determine the corresponding maximum restarting dose.
Patients who had required dose interruption while receiving a dose of 5 mg twice daily, may restart at a dose of 5 mg twice daily or 5 mg once daily, but not higher, once hemoglobin is greater than or equal to 10 g/dL, platelet count is greater than or equal to 75 X 109/L, and ANC is greater than or equal to 1.5 X 109/L.
After restarting ruxolitinib following treatment interruption, doses may be titrated, but the maximum total daily dose should not exceed 5 mg less than the dose that resulted in the dose interruption. An exception to this is dose interruption following phlebotomy-associated anemia, in which case the maximal total daily dose allowed after restarting ruxolitinib would not be limited.
If the response is insufficient and platelet, hemoglobin, and neutrophil counts are adequate, doses may be increased in 5 mg twice daily increments to a maximum of 25 mg twice daily. Doses should not be increased during the first 4 weeks of therapy and not more frequently than every two weeks.
Consider dose increases in patients who meet all of the following conditions:
Inadequate efficacy as demonstrated by one or more of the following:
- Continued need for phlebotomy
- WBC greater than the upper limit of normal range
- Platelet count greater than the upper limit of normal range
- Palpable spleen that is reduced by less than 25% from Baseline
Platelet count greater than or equal to 140 X 109/L
Hemoglobin greater than or equal to 12 g/dL
ANC greater than or equal to 1.5 X 109/L
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ruxolitinib in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ruxolitinib in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Ruxolitinib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ruxolitinib in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ruxolitinib in pediatric patients.
# Contraindications
- None
# Warnings
### Thrombocytopenia, Anemia and Neutropenia
- Treatment with ruxolitinib can cause thrombocytopenia, anemia and neutropenia.
- Manage thrombocytopenia by reducing the dose or temporarily interrupting ruxolitinib.
- Platelet transfusions may be necessary.
- Patients developing anemia may require blood transfusions and/or dose modifications of ruxolitinib.
- Severe neutropenia (ANC less than 0.5 X 109/L) was generally reversible by withholding ruxolitinib until recovery.
- Perform a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated.
### Risk of Infection
- Serious bacterial, mycobacterial, fungal and viral infections have occurred.
- Delay starting therapy with ruxolitinib until active serious infections have resolved.
- Observe patients receiving ruxolitinib for signs and symptoms of infection and manage promptly.
### Tuberculosis
- Tuberculosis infection has been reported in patients receiving ruxolitinib.
- Observe patients receiving ruxolitinib for signs and symptoms of active tuberculosis and manage promptly.
- Prior to initiating ruxolitinib, patients should be evaluated for tuberculosis risk factors, and those at higher risk should be tested for latent infection.
- Risk factors include, but are not limited to, prior residence in or travel to countries with a high prevalence of tuberculosis, close contact with a person with active tuberculosis, and a history of active or latent tuberculosis where an adequate course of treatment cannot be confirmed.
- For patients with evidence of active or latent tuberculosis, consult a physician with expertise in the treatment of tuberculosis before starting ruxolitinib.
- The decision to continue ruxolitinib during treatment of active tuberculosis should be based on the overall risk-benefit determination.
### PML
- Progressive multifocal leukoencephalopathy (PML) has occurred with ruxolitinib treatment for myelofibrosis.
- If PML is suspected, stop ruxolitinib and evaluate.
### Herpes Zoster
- Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible if suspected.
### Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Ruxolitinib
- Following discontinuation of ruxolitinib, symptoms from myeloproliferative neoplasms may return to pretreatment levels over a period of approximately one week.
- Some patients with myelofibrosis have experienced one or more of the following adverse events after discontinuing ruxolitinib: fever, respiratory distress, hypotension, DIC, or multi-organ failure.
- If one or more of these occur after discontinuation of, or while tapering the dose of ruxolitinib, evaluate for and treat any intercurrent illness and consider restarting or increasing the dose of ruxolitinib.
- Instruct patients not to interrupt or discontinue ruxolitinib therapy without consulting their physician.
- When discontinuing or interrupting therapy with ruxolitinib for reasons other than thrombocytopenia or neutropenia, consider tapering the dose of ruxolitinib gradually rather than discontinuing abruptly.
### Non-Melanoma Skin Cancer
- Non-melanoma skin cancer including basal cell, squamous cell, and Merkel cell carcinoma have occurred in patients treated with ruxolitinib.
- Perform periodic skin examinations.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
### Experience in Myelofibrosis
The safety of ruxolitinib was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 months, including 301 patients with myelofibrosis in two Phase 3 studies.
In these two Phase 3 studies, patients had a median duration of exposure to ruxolitinib of 9.5 months (range 0.5 to 17 months), with 89% of patients treated for more than 6 months and 25% treated for more than 12 months. One hundred and eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In patients starting treatment with 15 mg twice daily (pretreatment platelet counts of 100 to 200 X 109/L) and 20 mg twice daily (pretreatment platelet counts greater than 200 X 109/L), 65% and 25% of patients, respectively, required a dose reduction below the starting dose within the first 8 weeks of therapy.
In a double-blind, randomized, placebo-controlled study of ruxolitinib, among the 155 patients treated with ruxolitinib, the most frequent adverse drug reactions were thrombocytopenia and anemia . Thrombocytopenia, anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache [see TABLE 10].
Discontinuation for adverse events, regardless of causality, was observed in 11% of patients treated with ruxolitinib and 11% of patients treated with placebo.
TABLE 10 presents the most common adverse reactions occurring in patients who received ruxolitinib in the double-blind, placebo-controlled study during randomized treatment.
Description of Selected Adverse Drug Reactions
Anemia
In the two Phase 3 clinical studies, median time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (<1%) discontinued treatment because of anemia. In patients receiving ruxolitinib, mean decreases in hemoglobin reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern was observed in patients regardless of whether they had received transfusions during therapy.
In the randomized, placebo-controlled study, 60% of patients treated with ruxolitinib and 38% of patients receiving placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the median number of units transfused per month was 1.2 in patients treated with ruxolitinib and 1.7 in placebo treated patients.
Thrombocytopenia
In the two Phase 3 clinical studies, in patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts above 50 X 109/L was 14 days. Platelet transfusions were administered to 5% of patients receiving ruxolitinib and to 4% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in <1% of patients receiving ruxolitinib and <1% of patients receiving control regimens. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting ruxolitinib had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (17% versus 7%).
Neutropenia
In the two Phase 3 clinical studies, 1% of patients reduced or stopped ruxolitinib because of neutropenia.
TABLE 11 provides the frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with ruxolitinib or placebo in the placebo-controlled study.
Additional Data from the Placebo-controlled Study
25% of patients treated with ruxolitinib and 7% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transaminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 2% for ruxolitinib with 1% Grade 3 and no Grade 4 ALT elevations.
17% of patients treated with ruxolitinib and 6% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase (AST). The incidence of Grade 2 AST elevations was <1% for ruxolitinib with no Grade 3 or 4 AST elevations.
17% of patients treated with ruxolitinib and <1% of patients treated with placebo developed newly occurring or worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was <1% for ruxolitinib with no Grade 3 or 4 cholesterol elevations.
### Clinical Trial Experience in Polycythemia Vera
In a randomized, open-label, active-controlled study, 110 patients with polycythemia vera resistant to or intolerant of hydroxyurea received ruxolitinib and 111 patients received best available therapy. The most frequent adverse drug reaction was anemia. TABLE 12 presents the most frequent non-hematologic treatment emergent adverse events occurring up to Week 32.
Discontinuation for adverse events, regardless of causality, was observed in 4% of patients treated with ruxolitinib.
Other clinically important treatment emergent adverse events observed in less than 6% of patients treated with ruxolitinib were:
- Weight gain
- Hypertension
- Urinary tract infections
Clinically relevant laboratory abnormalities are shown in TABLE 13.
## Postmarketing Experience
There is limited information regarding Ruxolitinib Postmarketing Experience in the drug label.
# Drug Interactions
### Drugs That Inhibit or Induce Cytochrome P450 Enzymes
- Ruxolitinib is metabolized by CYP3A4 and to a lesser extent by CYP2C9.
- The Cmax and AUC of ruxolitinib increased 33% and 91%, respectively following concomitant administration with the strong CYP3A4 inhibitor ketoconazole in healthy subjects. *Concomitant administration with mild or moderate CYP3A4 inhibitors did not result in an exposure change requiring intervention..
- When administering ruxolitinib with strong CYP3A4 inhibitors, consider dose reduction.
- The AUC of ruxolitinib is predicted to increase by approximately 100% to 300% following concomitant administration with the combined CYP3A4 and CYP2C9 inhibitor fluconazole at doses of 100 mg to 400 mg once daily, respectively.
- Avoid the concomitant use of ruxolitinib with fluconazole doses of greater than 200 mg daily.
- The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, following concomitant administration with the strong CYP3A4
inducer rifampin in healthy subjects.
- No dose adjustment is recommended; however, monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
There are no adequate and well-controlled studies of ruxolitinib in pregnant women. In embryofetal toxicity studies, treatment with ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. ruxolitinib should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
### Animal Data
Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratogenicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times the clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose.
In a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implantation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ruxolitinib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ruxolitinib during labor and delivery.
### Nursing Mothers
It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ruxolitinib, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
The safety and effectiveness of ruxolitinib in pediatric patients have not been established.
### Geriatic Use
Of the total number of myelofibrosis patients in clinical studies with ruxolitinib, 52% were 65 years of age and older. No overall differences in safety or effectiveness of ruxolitinib were observed between these patients and younger patients.
### Gender
There is no FDA guidance on the use of Ruxolitinib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ruxolitinib with respect to specific racial populations.
### Renal Impairment
The safety and pharmacokinetics of single dose ruxolitinib (25 mg) were evaluated in a study in healthy subjects [[[CrCl]] 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], moderate [[[CrCl]] 38-57 mL/min (N=8)], or severe renal impairment [[[CrCl]] 15-51 mL/min (N=8)]. Eight (8) additional subjects with end stage renal disease requiring hemodialysis were also enrolled.
The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal of some active metabolites by dialysis cannot be ruled out.
When administering ruxolitinib to patients with myelofibrosis and moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count between 50 X 109/L and 150 X 109/L, a dose reduction is recommended. A dose reduction is also recommended for patients with polycythemia vera and moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min). In all patients with end stage renal disease on dialysis, a dose reduction is recommended.
### Hepatic Impairment
The safety and pharmacokinetics of single dose ruxolitinib (25 mg) were evaluated in a study in healthy subjects (N=8) and in subjects with mild, Child-Pugh A (N=8), moderate Child-Pugh B (N=8), or severe hepatic impairment, Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib.
When administering ruxolitinib to patients with myelofibrosis and any degree of hepatic impairment and with a platelet count between 50 X 109/L and 150 X 109/L, a dose reduction is recommended. A dose reduction is also recommended for patients with polycythemia vera and hepatic impairment
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ruxolitinib in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ruxolitinib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Monitor complete blood counts every 2 to 4 weeks until doses are stabilized
- In the concomitant administration with CYP3A4 inducers, monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy
# IV Compatibility
There is limited information regarding the compatibility of Ruxolitinib and IV administrations.
# Overdosage
There is no known antidote for overdoses with ruxolitinib. Single doses up to 200 mg have been given with acceptable acute tolerability. Higher than recommended repeat doses are associated with increased myelosuppression including leukopenia, anemia and thrombocytopenia. Appropriate supportive treatment should be given.
Hemodialysis is not expected to enhance the elimination of ruxolitinib.
# Pharmacology
## Mechanism of Action
Ruxolitinib, a kinase inhibitor, inhibits Janus Associated Kinases (JAKs) JAK1 and JAK2 which mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, activation and subsequent localization of STATs to the nucleus leading to modulation of gene expression.
Myelofibrosis (MF) and polycythemia vera (PV) are myeloproliferative neoplasms (MPN) known to be associated with dysregulated JAK1 and JAK2 signaling]. In a mouse model of JAK2V617F-positive MPN, oral administration of ruxolitinib prevented splenomegaly, preferentially decreased JAK2V617F mutant cells in the spleen and decreased circulating inflammatory cytokines (eg, TNF-α, IL-6).
## Structure
Ruxolitinib phosphate is a kinase inhibitor with the chemical name (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate and a molecular weight of 404.36. Ruxolitinib phosphate has the following structural formula:
Ruxolitinib phosphate is a white to off-white to light pink powder and is soluble in aqueous buffers across a pH range of 1 to 8.
## Pharmacodynamics
Ruxolitinib inhibits cytokine induced STAT3 phosphorylation in whole blood from healthy subjects and MF and PV patients. ruxolitinib administration resulted in maximal inhibition of STAT3 phosphorylation 2 hours after dosing which returned to near baseline by 10 hours in both healthy subjects and MF and PV patients.
## Pharmacokinetics
### Absorption
In clinical studies, ruxolitinib is rapidly absorbed after oral ruxolitinib administration with maximal plasma concentration (Cmax) achieved within 1 to 2 hours post-dose. Based on a mass balance study in humans, oral absorption of ruxolitinib was estimated to be at least 95%. Mean ruxolitinib Cmax and total exposure (AUC) increased proportionally over a single dose range of 5 to 200 mg. There were no clinically relevant changes in the pharmacokinetics of ruxolitinib upon administration of ruxolitinib with a high-fat meal, with the mean Cmax moderately decreased (24%) and the mean AUC nearly unchanged (4% increase).
### Distribution
The mean volume of distribution at steady-state is 72 L in MF patients with an associated inter-subject variability of 29% and 75 L in PV patients with an associated inter-subject variability of 23%. [[plasma proteins]|Binding to plasma proteins]] in vitro is approximately 97%, mostly to albumin.
### Metabolism
In vitro studies suggest that ruxolitinib is metabolized by CYP3A4 and to a lesser extent by CYP2C9.
### Elimination
Following a single oral dose of [14C]-labeled ruxolitinib in healthy adult subjects, elimination was predominately through metabolism with 74% of radioactivity excreted in urine and 22% excretion via feces. Unchanged drug accounted for less than 1% of the excreted total radioactivity. The mean elimination half-life of ruxolitinib is approximately 3 hours and the mean half-life of ruxolitinib + metabolites is approximately 5.8 hours.
### Effects of Age, Gender, or Race
In healthy subjects, no significant differences in ruxolitinib pharmacokinetics were observed with regard to gender and race. In a population pharmacokinetic evaluation in MF patients, no relationship was apparent between oral clearance and patient age or race, and in women, clearance was 17.7 L/h and in men, 22.1 L/h with 39% inter-subject variability. Clearance was 12.7 L/h in PV patients, with a 42% inter-subject variability, and no relationship was apparent between oral clearance and gender, patient age or race in this patient population.
### Drug Interactions
Strong CYP3A4 inhibitors
In a trial of 16 healthy volunteers, a single dose of 10 mg of ruxolitinib was administered alone on Day 1 and a single dose of 10 mg of ruxolitinib was administered on Day 5 in combination with 200 mg of ketoconazole (a strong CYP3A4 inhibitor' given twice daily on Days 2 to 5). Ketoconazole increased ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ketoconazole also prolonged ruxolitinib half-life from 3.7 to 6.0 hours.
Fluconazole
Simulations using physiologically-based pharmacokinetic (PBPK) models suggested that fluconazole (a dual CYP3A4 and CYP2C9 inhibitor) increases steady state ruxolitinib AUC by approximately 100% to 300% following concomitant administration of 10 mg of ruxolitinib twice daily with 100 mg to 400 mg of fluconazole once daily, respectively.
Mild or moderate CYP3A4 inhibitors
In a trial of 15 healthy volunteers, a single dose of 10 mg of ruxolitinib was administered alone on Day 1 and a single dose of 10 mg of ruxolitinib was administered on Day 5 in combination with 400 mg of erythromycin (a moderate CYP3A4 inhibitor, given twice daily on Days 2 to 5). Erythromycin increased ruxolitinib Cmax and AUC by 8% and 27%, respectively.
CYP3A4 inducers
In a trial of 12 healthy volunteers, a single dose of 50 mg of ruxolitinib was administered alone on Day 1 and a single dose of 50 mg of ruxolitinib was administered on Day 13 in combination with 600 mg of rifampin (a strong CYP3A4 inducer, given once daily on Days 3 to 13). Rifampin decreased ruxolitinib Cmax and AUC by 32% and 61%, respectively. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately 100%
In vitro studies
In vitro, ruxolitinib and its M18 metabolite do not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4. Ruxolitinib is not an inducer of CYP1A2, CYP2B6 or CYP3A4 at clinically relevant concentrations.
In vitro, ruxolitinib and its M18 metabolite do not inhibit the P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1 or OAT3 transport systems at clinically relevant concentrations. Ruxolitinib is not a substrate for the P-gp transporter.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
Ruxolitinib was not carcinogenic in the 6-month Tg.rasH2 transgenic mouse model or in a 2-year carcinogenicity study in the rat.
Ruxolitinib was not mutagenic in a bacterial mutagenicity assay (Ames test) or clastogenic in in vitro chromosomal aberration assay (cultured human peripheral blood lymphocytes) or in vivo in a rat bone marrow micronucleus test.
In a fertility study, ruxolitinib was administered to male rats prior to and throughout mating and to female rats prior to mating and up to the implantation day (gestation day 7). Ruxolitinib had no effect on fertility or reproductive function in male or female rats at doses of 10, 30 or 60 mg/kg/day. However, in female rats doses of greater than or equal to 30 mg/kg/day resulted in increased post-implantation loss. The exposure (AUC) at the dose of 30 mg/kg/day is approximately 34% the clinical exposure at the maximum recommended dose of 25 mg twice daily.
# Clinical Studies
### Myelofibrosis
Two randomized Phase 3 studies (Studies 1 and 2) were conducted in patients with myelofibrosis (either primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia-myelofibrosis). In both studies, patients had palpable splenomegaly at least 5 cm below the costal margin and risk category of intermediate 2 (2 prognostic factors) or high risk (3 or more prognostic factors) based on the International Working Group Consensus Criteria (IWG).
The starting dose of ruxolitinib was based on platelet counts. Patients with a platelet count between 100 and 200 X 109/L were started on ruxolitinib 15 mg twice daily and patients with a platelet count greater than 200 X 109/L were started on ruxolitinib 20 mg twice daily. Doses were then individualized based upon tolerability and efficacy with maximum doses of 20 mg twice daily for patients with platelet counts between 100 to less than or equal to 125 X 109/L, of 10 mg twice daily for patients with platelet counts between 75 to less than or equal to 100 X 109/L, and of 5 mg twice daily for patients with platelet counts between 50 to less than or equal to 75 X 109/L.
### Study 1
Study 1 was a double-blind, randomized, placebo-controlled study in 309 patients who were refractory to or were not candidates for available therapy. The median age was 68 years (range 40 to 91 years) with 61% of patients older than 65 years and 54% were male. Fifty percent (50%) of patients had primary myelofibrosis, 31% had post-polycythemia vera myelofibrosis and 18% had post-essential thrombocythemia myelofibrosis. Twenty-one percent (21%) of patients had red blood cell transfusions within 8 weeks of enrollment in the study. The median hemoglobin count was 10.5 g/dL and the median platelet count was 251 X 109/L. Patients had a median palpable spleen length of 16 cm below the costal margin, with 81% having a spleen length 10 cm or greater below the costal margin. Patients had a median spleen volume as measured by magnetic resonance imaging (MRI) or computed tomography (CT) of 2595 cm3 (range 478 cm3 to 8881 cm3). (The upper limit of normal is approximately 300 cm3).
Patients were dosed with ruxolitinib or matching placebo. The primary efficacy endpoint was the proportion of patients achieving greater than or equal to a 35% reduction from baseline in spleen volume at Week 24 as measured by MRI or CT.
Secondary endpoints included duration of a 35% or greater reduction in spleen volume and proportion of patients with a 50% or greater reduction in Total Symptom Score from baseline to Week 24 as measured by the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 diary.
### Study 2
Study 2 was an open-label, randomized study in 219 patients. Patients were randomized 2:1 to ruxolitinib versus best available therapy. Best available therapy was selected by the investigator on a patient-by-patient basis. In the best available therapy arm, the medications received by more than 10% of patients were hydroxyurea (47%) and glucocorticoids (16%). The median age was 66 years (range 35 to 85 years) with 52% of patients older than 65 years and 57% were male. Fifty-three percent (53%) of patients had primary myelofibrosis, 31% had post-polycythemia vera myelofibrosis and 16% had post-essential thrombocythemia myelofibrosis. Twenty-one percent (21%) of patients had red blood cell transfusions within 8 weeks of enrollment in the study. The median hemoglobin count was 10.4 g/dL and the median platelet count was 236 X 109/L. Patients had a median palpable spleen length of 15 cm below the costal margin, with 70% having a spleen length 10 cm or greater below the costal margin. Patients had a median spleen volume as measured by MRI or CT of 2381 cm3 (range 451 cm3 to 7765 cm3).
The primary efficacy endpoint was the proportion of patients achieving 35% or greater reduction from baseline in spleen volume at Week 48 as measured by MRI or CT.
A secondary endpoint in Study 2 was the proportion of patients achieving a 35% or greater reduction of spleen volume as measured by MRI or CT from baseline to Week 24.
### Study 1 and 2 Efficacy Results
Efficacy analyses of the primary endpoint in Studies 1 and 2 are presented in TABLE 14 below. A significantly larger proportion of patients in the ruxolitinib group achieved a 35% or greater reduction in spleen volume from baseline in both studies compared to placebo in Study 1 and best available therapy in Study 2. A similar proportion of patients in the ruxolitinib group achieved a 50% or greater reduction in palpable spleen length.
FIGURE 1 shows the percent change from baseline in spleen volume for each patient at Week 24 (ruxolitinib N=139, placebo N=106) or the last evaluation prior to Week 24 for patients who did not complete 24 weeks of randomized treatment (ruxolitinib N=16, placebo N=47). One (1) patient (placebo) with a missing baseline spleen volume is not included.
In Study 1, myelofibrosis symptoms were a secondary endpoint and were measured using the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 diary. The modified MFSAF is a daily diary capturing the core symptoms of myelofibrosis (abdominal discomfort, pain under left ribs, night sweats, itching, bone/muscle pain and early satiety). Symptom scores ranged from 0 to 10 with 0 representing symptoms "absent" and 10 representing "worst imaginable" symptoms. These scores were added to create the daily total score, which has a maximum of 60.
TABLE 15 presents assessments of Total Symptom Score from baseline to Week 24 in Study 1 including the proportion of patients with at least a 50% reduction (ie, improvement in symptoms). At baseline, the mean Total Symptom Score was 18.0 in the ruxolitinib group and 16.5 in the placebo group. A higher proportion of patients in the ruxolitinib group had a 50% or greater reduction in Total Symptom Score than in the placebo group, with a median time to response of less than 4 weeks.
FIGURE 2 shows the percent change from baseline in Total Symptom Score for each patient at Week 24 (ruxolitinib N=129, placebo N=103) or the last evaluation on randomized therapy prior to Week 24 for patients who did not complete 24 weeks of randomized treatment (ruxolitinib N=16, placebo N=42). Results are excluded for 5 patients with a baseline Total Symptom Score of zero, 8 patients with missing baseline and 6 patients with insufficient post-baseline data.
FIGURE 3 displays the proportion of patients with at least a 50% improvement in each of the individual symptoms that comprise the Total Symptom Score indicating that all 6 of the symptoms contributed to the higher Total Symptom Score response rate in the group treated with ruxolitinib.
Overall survival was a secondary endpoint in both Study 1 and Study 2. Patients in the control groups were eligible for crossover in both studies, and the median times to crossover were 9 months in Study 1 and 17 months in Study 2.
FIGURE 4 and FIGURE 5 show Kaplan-Meier curves of overall survival at prospectively planned analyses after all patients remaining on study had completed 144 weeks on study.
### Polycythemia Vera
Study 3 was a randomized, open-label, active-controlled Phase 3 study conducted in 222 patients with polycythemia vera. Patients had been diagnosed with polycythemia vera for at least 24 weeks, had an inadequate response to or were intolerant of hydroxyurea, required phlebotomy and exhibited splenomegaly. All patients were required to demonstrate hematocrit control between 40-45% prior to randomization. The age ranged from 33 to 90 years with 30% of patients over 65 years of age and 66% were male. Patients had a median spleen volume as measured by MRI or CT of 1272 cm3 (range 254 cm3 to 5147 cm3) and median palpable spleen length below the costal margin was 7 cm.
Patients were randomized to ruxolitinib or best available therapy. The starting dose of ruxolitinib was 10 mg twice daily. Doses were then individualized based upon tolerability and efficacy with a maximum dose of 25 mg twice daily. At Week 32, 98 patients were still on ruxolitinib with 8% receiving greater than 20 mg twice daily, 15% receiving 20 mg twice daily, 33% receiving 15 mg twice daily, 34% receiving 10 mg twice daily, and 10% receiving less than 10 mg twice daily. Best available therapy (BAT) was selected by the investigator on a patient-by-patient basis and included hydroxyurea (60%), interferon/pegylated interferon (12%), anagrelide (7%), pipobroman (2%), lenalidomide/thalidomide (5%), and observation (15%).
The primary endpoint was the proportion of subjects achieving a response at Week 32, with response defined as having achieved both hematocrit control (the absence of phlebotomy eligibility beginning at the Week 8 visit and continuing through Week 32) and spleen volume reduction (a greater than or equal to 35% reduction from baseline in spleen volume at Week 32). Phlebotomy eligibility was defined as a confirmed hematocrit greater than 45% that is at least 3 percentage points higher than the hematocrit obtained at baseline or a confirmed hematocrit greater than 48%, whichever was lower. Secondary endpoints included the proportion of all randomized subjects who achieved the primary endpoint and who maintained their response 48 weeks after randomization, and the proportion of subjects achieving complete hematological remission at Week 32 with complete hematological remission defined as achieving hematocrit control, platelet count less than or equal to 400 X 109/L, and white blood cell count less than or equal to 10 X 109/L.
Results of the primary and secondary endpoints are presented in TABLE 16. A significantly larger proportion of patients in the ruxolitinib group achieved a response for the primary endpoint compared to best available therapy at Week 32 and maintained their response 48 weeks after randomization. A significantly larger proportion of patients in the ruxolitinib group compared to best available therapy also achieved complete hematological remission at Week 32.
For the proportion of patients achieving each of the individual components that make up the primary endpoint at Week 32, there were 60% of the patients with hematocrit control in the ruxolitinib group vs. 20% of the patients in the best available therapy group. There were 38% of the patients with spleen volume reduction from baseline greater than or equal to 35% at Week 32 in the ruxolitinib group vs. less than 1% of the patients in the best available therapy group.
# How Supplied
- Ruxolitinib Tablets are available as follows:
## Storage
- Store at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and
30°C (59°F and 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Discuss the following with patients prior to and during treatment with ruxolitinib:
### Thrombocytopenia, Anemia and Neutropenia
Inform patients that ruxolitinib is associated with thrombocytopenia, anemia and neutropenia, and of the need to monitor complete blood counts before and during treatment. Advise patients to observe for and report bleeding.
### Infections
Inform patients of the signs and symptoms of infection and to report any such signs and symptoms promptly.
Inform patients regarding the early signs and symptoms of herpes zoster and of progressive multifocal leukoencephalopathy, and advise patients to seek advice of a clinician if such symptoms are observed.
Symptom Exacerbation Following Interruption or Discontinuation of Treatment with ruxolitinib
Inform patients that after discontinuation of treatment, signs and symptoms from myeloproliferative neoplasms are expected to return. Instruct patients not to interrupt or discontinue ruxolitinib therapy without consulting their physician.
### Non-Melanoma Skin Cancer
Inform patients that ruxolitinib may increase their risk of certain non-melanoma skin cancers. Advise patients to inform their healthcare provider if they have ever had any type of skin cancer or if they observe any new or changing skin lesions.
### Drug-drug Interactions
Advise patients to inform their healthcare providers of all medications they are taking, including over-the-counter medications, herbal products and dietary supplements.
### Dialysis
Inform patients on dialysis that their dose should not be taken before dialysis but only following dialysis.
### Compliance
Advise patients to continue taking ruxolitinib every day for as long as their physician tells them and that this is a long-term treatment. Patients should not change dose or stop taking ruxolitinib without first consulting their physician. Patients should be aware that after discontinuation of treatment, signs and symptoms from myeloproliferative neoplasms are expected to return.
# Precautions with Alcohol
Alcohol-Ruxolitinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- JAKAFI[2]
# Look-Alike Drug Names
There is limited information regarding Ruxolitinib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/JAKAFI | |
a63b13b4b78808c52d5d216fe93b0eb70a9029a4 | wikidoc | Sitagliptin | Sitagliptin
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# Overview
Sitagliptin is a dipeptidyl peptidase-4 inhibitor that is FDA approved for the {{{indicationType}}} of type 2 diabetes mellitus. Common adverse reactions include hypoglycemia, headache, nasopharyngitis, and upper respiratory infection.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended dose of Januvia is 100 mg once daily. Januvia can be taken with or without food.
- Patients with Renal Insufficiency
- For patients with mild renal insufficiency (creatinine clearance greater than or equal to 50 mL/min, approximately corresponding to serum creatinine levels of less than or equal to 1.7 mg/dL in men and less than or equal to 1.5 mg/dL in women), no dosage adjustment for Januvia is required.
- For patients with moderate renal insufficiency (CrCl greater than or equal to 30 to less than 50 mL/min, approximately corresponding to serum creatinine levels of greater than 1.7 to less than or equal to 3.0 mg/dL in men and greater than 1.5 to less than or equal to 2.5 mg/dL in women), the dose of Januvia is 50 mg once daily.
- For patients with severe renal insufficiency (CrCl less than 30 mL/min, approximately corresponding to serum creatinine levels of greater than 3.0 mg/dL in men and greater than 2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of Januvia is 25 mg once daily. Januvia may be administered without regard to the timing of dialysis.
- Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of Januvia and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. There have been postmarketing reports of worsening renal function in patients with renal insufficiency, some of whom were cascribed inappropriate doses of sitagliptin.
- Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin
- When Januvia is used in combination with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sitagliptin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sitagliptin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness of Januvia in pediatric patients under 18 years of age have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sitagliptin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sitagliptin in pediatric patients.
# Contraindications
- History of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema.
# Warnings
- Pancreatitis
- There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking Januvia. After initiation of Januvia, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, Januvia should promptly be discontinued and appropriate management should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using Januvia.
- Renal Impairment
- Assessment of renal function is recommended prior to initiating Januvia and periodically thereafter. A dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD requiring hemodialysis or peritoneal dialysis. Caution should be used to ensure that the correct dose of Januvia is prescribed for patients with moderate (creatinine clearance ≥30 to <50 mL/min) or severe (creatinine clearance <30 mL/min) renal impairment.
- There have been postmarketing reports of worsening renal function, including acute renal failure, sometimes requiring dialysis. A subset of these reports involved patients with renal insufficiency, some of whom were prescribed inappropriate doses of sitagliptin. A return to baseline levels of renal insufficiency has been observed with supportive treatment and discontinuation of potentially causative agents. Consideration can be given to cautiously reinitiating Januvia if another etiology is deemed likely to have precipitated the acute worsening of renal function.
- Januvia has not been found to be nephrotoxic in preclinical studies at clinically relevant doses, or in clinical trials.
- Use with Medications Known to Cause Hypoglycemia
- When Januvia was used in combination with a sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or with insulin. Therefore, a lower dose of sulfonylurea or insulin may be required to reduce the risk of hypoglycemia.
- Hypersensitivity Reactions
- There have been postmarketing reports of serious hypersensitivity reactions in patients treated with Januvia. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of treatment with Januvia, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue Januvia, assess for other potential causes for the event, and institute alternative treatment for diabetes.
- Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a history of angioedema with another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with Januvia.
- Macrovascular Outcomes
- There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Januvia or any other anti-diabetic drug.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- In controlled clinical studies as both monotherapy and combination therapy with metformin, pioglitazone, or rosiglitazone and metformin, the overall incidence of adverse reactions, hypoglycemia, and discontinuation of therapy due to clinical adverse reactions with Januvia were similar to placebo. In combination with glimepiride, with or without metformin, the overall incidence of clinical adverse reactions with Januvia was higher than with placebo, in part related to a higher incidence of hypoglycemia (see Table 3); the incidence of discontinuation due to clinical adverse reactions was similar to placebo.
- Two placebo-controlled monotherapy studies, one of 18- and one of 24-week duration, included patients treated with Januvia 100 mg daily, Januvia 200 mg daily, and placebo. Five placebo-controlled add-on combination therapy studies were also conducted: one with metformin; one with pioglitazone; one with metformin and rosiglitazone; one with glimepiride (with or without metformin); and one with insulin (with or without metformin). In these trials, patients with inadequate glycemic control on a stable dose of the background therapy were randomized to add-on therapy with Januvia 100 mg daily or placebo. The adverse reactions, excluding hypoglycemia, reported regardless of investigator assessment of causality in ≥5% of patients treated with Januvia 100 mg daily and more commonly than in patients treated with placebo, are shown in Table 1 for the clinical trials of at least 18 weeks duration. Incidences of hypoglycemia are shown in Table 3.
- In the 24-week study of patients receiving Januvia as add-on combination therapy with metformin, there were no adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo.
- In the 24-week study of patients receiving Januvia as add-on therapy to insulin (with or without metformin), there were no adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo, except for hypoglycemia (see Table 3).
- In the study of Januvia as add-on combination therapy with metformin and rosiglitazone (Table 1), through Week 54 the adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients treated with Januvia and more commonly than in patients treated with placebo were: upper respiratory tract infection (Januvia, 15.5%; placebo, 6.2%), nasopharyngitis (11.0%, 9.3%), peripheral edema (8.3%, 5.2%), and headache (5.5%, 4.1%).
- In a pooled analysis of the two monotherapy studies, the add-on to metformin study, and the add-on to pioglitazone study, the incidence of selected gastrointestinal adverse reactions in patients treated with Januvia was as follows: abdominal pain (Januvia 100 mg, 2.3%; placebo, 2.1%), nausea (1.4%, 0.6%), and diarrhea (3.0%, 2.3%).
- In an additional, 24-week, placebo-controlled factorial study of initial therapy with sitagliptin in combination with metformin, the adverse reactions reported (regardless of investigator assessment of causality) in ≥5% of patients are shown in Table 2.
- In a 24-week study of initial therapy with Januvia in combination with pioglitazone, there were no adverse reactions reported (regardless of investigator assessment of causality) in ≥5% of patients and more commonly than in patients given pioglitazone alone.
- No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed in patients treated with Januvia.
- In a pooled analysis of 19 double-blind clinical trials that included data from 10,246 patients randomized to receive sitagliptin 100 mg/day (N=5429) or corresponding (active or placebo) control (N=4817), the incidence of acute pancreatitis was 0.1 per 100 patient-years in each group (4 patients with an event in 4708 patient-years for sitagliptin and 4 patients with an event in 3942 patient-years for control).
- Hypoglycemia
- In all (N=9) studies, adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia. A concurrent blood glucose measurement was not required although most (74%) reports of hypoglycemia were accompanied by a blood glucose measurement ≤70 mg/dL. When Januvia was co-administered with a sulfonylurea or with insulin, the percentage of patients with at least one adverse reaction of hypoglycemia was higher than in the corresponding placebo group (Table 3).
- In a pooled analysis of the two monotherapy studies, the add-on to metformin study, and the add-on to pioglitazone study, the overall incidence of adverse reactions of hypoglycemia was 1.2% in patients treated with Januvia 100 mg and 0.9% in patients treated with placebo.
- In the study of Januvia as add-on combination therapy with metformin and rosiglitazone, the overall incidence of hypoglycemia was 2.2% in patients given add-on Januvia and 0.0% in patients given add-on placebo through Week 18. Through Week 54, the overall incidence of hypoglycemia was 3.9% in patients given add-on Januvia and 1.0% in patients given add-on placebo.
- In the 24-week, placebo-controlled factorial study of initial therapy with Januvia in combination with metformin, the incidence of hypoglycemia was 0.6% in patients given placebo, 0.6% in patients given Januvia alone, 0.8% in patients given metformin alone, and 1.6% in patients given Januvia in combination with metformin.
- In the study of Januvia as initial therapy with pioglitazone, one patient taking Januvia experienced a severe episode of hypoglycemia. There were no severe hypoglycemia episodes reported in other studies except in the study involving co-administration with insulin.
- Laboratory Tests
- Across clinical studies, the incidence of laboratory adverse reactions was similar in patients treated with Januvia 100 mg compared to patients treated with placebo. A small increase in white blood cell count (WBC) was observed due to an increase in neutrophils. This increase in WBC (of approximately 200 cells/microL vs placebo, in four pooled placebo-controlled clinical studies, with a mean baseline WBC count of approximately 6600 cells/microL) is not considered to be clinically relevant. In a 12-week study of 91 patients with chronic renal insufficiency, 37 patients with moderate renal insufficiency were randomized to Januvia 50 mg daily, while 14 patients with the same magnitude of renal impairment were randomized to placebo. Mean (SE) increases in serum creatinine were observed in patients treated with Januvia and in patients treated with placebo . The clinical significance of this added increase in serum creatinine relative to placebo is not known.
## Postmarketing Experience
- Additional adverse reactions have been identified during postapproval use of Januvia as monotherapy and/or in combination with other antihyperglycemic agents. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin conditions including Stevens-Johnson syndrome; hepatic enzyme elevations; acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis; worsening renal function, including acute renal failure (sometimes requiring dialysis); constipation; vomiting; headache; arthralgia; myalgia; pain in extremity; back pain.
# Drug Interactions
- Digoxin
- There was a slight increase in the area under the curve (AUC, 11%) and mean peak drug concentration (Cmax, 18%) of digoxin with the co-administration of 100 mg sitagliptin for 10 days. Patients receiving digoxin should be monitored appropriately. No dosage adjustment of digoxin or Januvia is recommended.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- Reproduction studies have been performed in rats and rabbits. Doses of sitagliptin up to 125 mg/kg (approximately 12 times the human exposure at the maximum recommended human dose) did not impair fertility or harm the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., maintains a registry to monitor the pregnancy outcomes of women exposed to Januvia while pregnant. Health care providers are encouraged to report any prenatal exposure to Januvia by calling the Pregnancy Registry at 1-800-986-8999.
- Sitagliptin administered to pregnant female rats and rabbits from gestation day 6 to 20 (organogenesis) was not teratogenic at oral doses up to 250 mg/kg (rats) and 125 mg/kg (rabbits), or approximately 30- and 20-times human exposure at the maximum recommended human dose (MRHD) of 100 mg/day based on AUC comparisons. Higher doses increased the incidence of rib malformations in offspring at 1000 mg/kg, or approximately 100 times human exposure at the MRHD.
- Sitagliptin administered to female rats from gestation day 6 to lactation day 21 decreased body weight in male and female offspring at 1000 mg/kg. No functional or behavioral toxicity was observed in offspring of rats.
- Placental transfer of sitagliptin administered to pregnant rats was approximately 45% at 2 hours and 80% at 24 hours postdose. Placental transfer of sitagliptin administered to pregnant rabbits was approximately 66% at 2 hours and 30% at 24 hours.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sitagliptin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Sitagliptin during labor and delivery.
### Nursing Mothers
- Sitagliptin is secreted in the milk of lactating rats at a milk to plasma ratio of 4:1. It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Januvia is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness of Januvia in pediatric patients under 18 years of age have not been established.
### Geriatic Use
- Of the total number of subjects (N=3884) in pre-approval clinical safety and efficacy studies of Januvia, 725 patients were 65 years and over, while 61 patients were 75 years and over. No overall differences in safety or effectiveness were observed between subjects 65 years and over and younger subjects. While this and other reported clinical experience have not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.
- This drug is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly, and it may be useful to assess renal function in these patients prior to initiating dosing and periodically thereafter.
### Gender
There is no FDA guidance on the use of Sitagliptin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Sitagliptin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Sitagliptin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Sitagliptin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sitagliptin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Sitagliptin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Patients receiving digoxin should be monitored appropriately.
- In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy as dictated by the patient's clinical status.
- Patients should also be informed about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and A1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications.
# IV Compatibility
There is limited information regarding IV Compatibility of Sitagliptin in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- During controlled clinical trials in healthy subjects, single doses of up to 800 mg Januvia were administered. Maximal mean increases in QTc of 8.0 msec were observed in one study at a dose of 800 mg Januvia, a mean effect that is not considered clinically important. There is no experience with doses above 800 mg in clinical studies. In Phase I multiple-dose studies, there were no dose-related clinical adverse reactions observed with Januvia with doses of up to 600 mg per day for periods of up to 10 days and 400 mg per day for up to 28 days.
### Management
- In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy as dictated by the patient's clinical status.
- Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5% of the dose was removed over a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Sitagliptin in the drug label.
# Pharmacology
## Mechanism of Action
- Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by Januvia, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, Januvia increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
## Structure
- Januvia Tablets contain sitagliptin phosphate, an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme.
- Sitagliptin phosphate monohydrate is described chemically as 7--5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolopyrazine phosphate (1:1) monohydrate.
- The empirical formula is C16H15F6N5OH3PO4H2O and the molecular weight is 523.32. The structural formula is:
- Sitagliptin phosphate monohydrate is a white to off-white, crystalline, non-hygroscopic powder. It is soluble in water and N,N-dimethyl formamide; slightly soluble in methanol; very slightly soluble in ethanol, acetone, and acetonitrile; and insoluble in isopropanol and isopropyl acetate.
- Each film-coated tablet of Januvia contains 32.13, 64.25, or 128.5 mg of sitagliptin phosphate monohydrate, which is equivalent to 25, 50, or 100 mg, respectively, of free base and the following inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, red iron oxide, and yellow iron oxide.
## Pharmacodynamics
- General
- In patients with type 2 diabetes, administration of Januvia led to inhibition of DPP-4 enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP-4 inhibition resulted in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased responsiveness of insulin release to glucose, resulting in higher C-peptide and insulin concentrations. The rise in insulin with the decrease in glucagon was associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.
- In a two-day study in healthy subjects, sitagliptin alone increased active GLP-1 concentrations, whereas metformin alone increased active and total GLP-1 concentrations to similar extents. Co-administration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations. Sitagliptin, but not metformin, increased active GIP concentrations. It is unclear how these findings relate to changes in glycemic control in patients with type 2 diabetes.
- In studies with healthy subjects, Januvia did not lower blood glucose or cause hypoglycemia.
- Cardiac Electrophysiology
- In a randomized, placebo-controlled crossover study, 79 healthy subjects were administered a single oral dose of Januvia 100 mg, Januvia 800 mg (8 times the recommended dose), and placebo. At the recommended dose of 100 mg, there was no effect on the QTc interval obtained at the peak plasma concentration, or at any other time during the study. Following the 800 mg dose, the maximum increase in the placebo-corrected mean change in QTc from baseline was observed at 3 hours postdose and was 8.0 msec. This increase is not considered to be clinically significant. At the 800 mg dose, peak sitagliptin plasma concentrations were approximately 11 times higher than the peak concentrations following a 100 mg dose.
- In patients with type 2 diabetes administered Januvia 100 mg (N=81) or Januvia 200 mg (N=63) daily, there were no meaningful changes in QTc interval based on ECG data obtained at the time of expected peak plasma concentration.
## Pharmacokinetics
- The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose. Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 μMhr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.
- Absorption
- The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with Januvia had no effect on the pharmacokinetics, Januvia may be administered with or without food.
- Distribution
- The mean volume of distribution at steady state following a single 100 mg intravenous dose of sitagliptin to healthy subjects is approximately 198 liters. The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).
- Metabolism
- Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.
- Following a sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.
- Excretion
- Following administration of an oral sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.
- Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.
- Renal Insufficiency
- A single-dose, open-label study was conducted to evaluate the pharmacokinetics of Januvia (50 mg dose) in patients with varying degrees of chronic renal insufficiency compared to normal healthy control subjects. The study included patients with renal insufficiency classified on the basis of creatinine clearance as mild (50 to <80 mL/min), moderate (30 to <50 mL/min), and severe (<30 mL/min), as well as patients with ESRD on hemodialysis. In addition, the effects of renal insufficiency on sitagliptin pharmacokinetics in patients with type 2 diabetes and mild or moderate renal insufficiency were assessed using population pharmacokinetic analyses. Creatinine clearance was measured by 24‑hour urinary creatinine clearance measurements or estimated from serum creatinine based on the Cockcroft-Gault formula.
- Compared to normal healthy control subjects, an approximate 1.1- to 1.6-fold increase in plasma AUC of sitagliptin was observed in patients with mild renal insufficiency. Because increases of this magnitude are not clinically relevant, dosage adjustment in patients with mild renal insufficiency is not necessary. Plasma AUC levels of sitagliptin were increased approximately 2-fold and 4-fold in patients with moderate renal insufficiency and in patients with severe renal insufficiency, including patients with ESRD on hemodialysis, respectively. Sitagliptin was modestly removed by hemodialysis (13.5% over a 3- to 4-hour hemodialysis session starting 4 hours postdose). To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, lower dosages are recommended in patients with moderate and severe renal insufficiency, as well as in ESRD patients requiring dialysis.
- Hepatic Insufficiency
- In patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9), mean AUC and Cmax of sitagliptin increased approximately 21% and 13%, respectively, compared to healthy matched controls following administration of a single 100 mg dose of Januvia. These differences are not considered to be clinically meaningful. No dosage adjustment for Januvia is necessary for patients with mild or moderate hepatic insufficiency.
- There is no clinical experience in patients with severe hepatic insufficiency (Child-Pugh score >9).
- Body Mass Index (BMI)
- No dosage adjustment is necessary based on BMI. Body mass index had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.
- Gender
- No dosage adjustment is necessary based on gender. Gender had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.
- Geriatric
- No dosage adjustment is required based solely on age. When the effects of age on renal function are taken into account, age alone did not have a clinically meaningful impact on the pharmacokinetics of sitagliptin based on a population pharmacokinetic analysis. Elderly subjects (65 to 80 years) had approximately 19% higher plasma concentrations of sitagliptin compared to younger subjects.
- Pediatric
- Studies characterizing the pharmacokinetics of sitagliptin in pediatric patients have not been performed.
- Race
- No dosage adjustment is necessary based on race. Race had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of available pharmacokinetic data, including subjects of white, Hispanic, black, Asian, and other racial groups.
- Drug Interactions
- In Vitro Assessment of Drug Interactions
- Sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, and is not an inducer of CYP3A4. Sitagliptin is a p-glycoprotein substrate, but does not inhibit p-glycoprotein mediated transport of digoxin. Based on these results, sitagliptin is considered unlikely to cause interactions with other drugs that utilize these pathways.
- Sitagliptin is not extensively bound to plasma proteins. Therefore, the propensity of sitagliptin to be involved in clinically meaningful drug-drug interactions mediated by plasma protein binding displacement is very low.
- In Vivo Assessment of Drug Interactions
- Effects of Sitagliptin on Other Drugs
- In clinical studies, as described below, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of a low propensity for causing drug interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic cationic transporter (OCT).
- Digoxin: Sitagliptin had a minimal effect on the pharmacokinetics of digoxin. Following administration of 0.25 mg digoxin concomitantly with 100 mg of Januvia daily for 10 days, the plasma AUC of digoxin was increased by 11%, and the plasma Cmax by 18%.
- Metformin: Co-administration of multiple twice-daily doses of sitagliptin with metformin, an OCT substrate, did not meaningfully alter the pharmacokinetics of metformin in patients with type 2 diabetes. Therefore, sitagliptin is not an inhibitor of OCT-mediated transport.
- Sulfonylureas: Single-dose pharmacokinetics of glyburide, a CYP2C9 substrate, was not meaningfully altered in subjects receiving multiple doses of sitagliptin. Clinically meaningful interactions would not be expected with other sulfonylureas (e.g., glipizide, tolbutamide, and glimepiride) which, like glyburide, are primarily eliminated by CYP2C9.
- Simvastatin: Single-dose pharmacokinetics of simvastatin, a CYP3A4 substrate, was not meaningfully altered in subjects receiving multiple daily doses of sitagliptin. Therefore, sitagliptin is not an inhibitor of CYP3A4-mediated metabolism.
- Thiazolidinediones: Single-dose pharmacokinetics of rosiglitazone was not meaningfully altered in subjects receiving multiple daily doses of sitagliptin, indicating that Januvia is not an inhibitor of CYP2C8-mediated metabolism.
- Warfarin: Multiple daily doses of sitagliptin did not meaningfully alter the pharmacokinetics, as assessed by measurement of S(-) or R(+) warfarin enantiomers, or pharmacodynamics (as assessed by measurement of prothrombin INR) of a single dose of warfarin. Because S(-) warfarin is primarily metabolized by CYP2C9, these data also support the conclusion that sitagliptin is not a CYP2C9 inhibitor.
- Oral Contraceptives: Co-administration with sitagliptin did not meaningfully alter the steady-state pharmacokinetics of norethindrone or ethinyl estradiol.
- Effects of Other Drugs on Sitagliptin
- Clinical data described below suggest that sitagliptin is not susceptible to clinically meaningful interactions by co-administered medications.
- Metformin: Co-administration of multiple twice-daily doses of metformin with sitagliptin did not meaningfully alter the pharmacokinetics of sitagliptin in patients with type 2 diabetes.
- Cyclosporine: A study was conducted to assess the effect of cyclosporine, a potent inhibitor of p-glycoprotein, on the pharmacokinetics of sitagliptin. Co-administration of a single 100 mg oral dose of Januvia and a single 600 mg oral dose of cyclosporine increased the AUC and Cmax of sitagliptin by approximately 29% and 68%, respectively. These modest changes in sitagliptin pharmacokinetics were not considered to be clinically meaningful. The renal clearance of sitagliptin was also not meaningfully altered. Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors.
## Nonclinical Toxicology
- A two-year carcinogenicity study was conducted in male and female rats given oral doses of sitagliptin of 50, 150, and 500 mg/kg/day. There was an increased incidence of combined liver adenoma/carcinoma in males and females and of liver carcinoma in females at 500 mg/kg. This dose results in exposures approximately 60 times the human exposure at the maximum recommended daily adult human dose (MRHD) of 100 mg/day based on AUC comparisons. Liver tumors were not observed at 150 mg/kg, approximately 20 times the human exposure at the MRHD. A two-year carcinogenicity study was conducted in male and female mice given oral doses of sitagliptin of 50, 125, 250, and 500 mg/kg/day. There was no increase in the incidence of tumors in any organ up to 500 mg/kg, approximately 70 times human exposure at the MRHD. Sitagliptin was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay, a Chinese hamster ovary (CHO) chromosome aberration assay, an in vitro cytogenetics assay in CHO, an in vitro rat hepatocyte DNA alkaline elution assay, and an in vivo micronucleus assay.
- In rat fertility studies with oral gavage doses of 125, 250, and 1000 mg/kg, males were treated for 4 weeks prior to mating, during mating, up to scheduled termination (approximately 8 weeks total) and females were treated 2 weeks prior to mating through gestation day 7. No adverse effect on fertility was observed at 125 mg/kg (approximately 12 times human exposure at the MRHD of 100 mg/day based on AUC comparisons). At higher doses, nondose-related increased resorptions in females were observed (approximately 25 and 100 times human exposure at the MRHD based on AUC comparison).
# Clinical Studies
- There were approximately 5200 patients with type 2 diabetes randomized in nine double-blind, placebo-controlled clinical safety and efficacy studies conducted to evaluate the effects of sitagliptin on glycemic control. In a pooled analysis of seven of these studies, the ethnic/racial distribution was approximately 59% white, 20% Hispanic, 10% Asian, 6% black, and 6% other groups. Patients had an overall mean age of approximately 55 years (range 18 to 87 years). In addition, an active (glipizide)-controlled study of 52-weeks duration was conducted in 1172 patients with type 2 diabetes who had inadequate glycemic control on metformin.
- In patients with type 2 diabetes, treatment with Januvia produced clinically significant improvements in hemoglobin A1C, fasting plasma glucose (FPG) and 2-hour post-prandial glucose (PPG) compared to placebo.
- A total of 1262 patients with type 2 diabetes participated in two double-blind, placebo-controlled studies, one of 18-week and another of 24-week duration, to evaluate the efficacy and safety of Januvia monotherapy. In both monotherapy studies, patients currently on an antihyperglycemic agent discontinued the agent, and underwent a diet, exercise, and drug washout period of about 7 weeks. Patients with inadequate glycemic control (A1C 7% to 10%) after the washout period were randomized after completing a 2-week single-blind placebo run-in period; patients not currently on antihyperglycemic agents (off therapy for at least 8 weeks) with inadequate glycemic control (A1C 7% to 10%) were randomized after completing the 2-week single-blind placebo run-in period. In the 18-week study, 521 patients were randomized to placebo, Januvia 100 mg, or Januvia 200 mg, and in the 24-week study 741 patients were randomized to placebo, Januvia 100 mg, or Januvia 200 mg. Patients who failed to meet specific glycemic goals during the studies were treated with metformin rescue, added on to placebo or Januvia.
- Treatment with Januvia at 100 mg daily provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo (Table 4). In the 18-week study, 9% of patients receiving Januvia 100 mg and 17% who received placebo required rescue therapy. In the 24-week study, 9% of patients receiving Januvia 100 mg and 21% of patients receiving placebo required rescue therapy. The improvement in A1C compared to placebo was not affected by gender, age, race, prior antihyperglycemic therapy, or baseline BMI. As is typical for trials of agents to treat type 2 diabetes, the mean reduction in A1C with Januvia appears to be related to the degree of A1C elevation at baseline. In these 18- and 24-week studies, among patients who were not on an antihyperglycemic agent at study entry, the reductions from baseline in A1C were -0.7% and -0.8%, respectively, for those given Januvia, and -0.1% and -0.2%, respectively, for those given placebo. Overall, the 200 mg daily dose did not provide greater glycemic efficacy than the 100 mg daily dose. The effect of Januvia on lipid endpoints was similar to placebo. Body weight did not increase from baseline with Januvia therapy in either study, compared to a small reduction in patients given placebo.
- Additional Monotherapy Study
- A multinational, randomized, double-blind, placebo-controlled study was also conducted to assess the safety and tolerability of Januvia in 91 patients with type 2 diabetes and chronic renal insufficiency (creatinine clearance <50 mL/min). Patients with moderate renal insufficiency received 50 mg daily of Januvia and those with severe renal insufficiency or with ESRD on hemodialysis or peritoneal dialysis received 25 mg daily. In this study, the safety and tolerability of Januvia were generally similar to placebo. A small increase in serum creatinine was reported in patients with moderate renal insufficiency treated with Januvia relative to those on placebo. In addition, the reductions in A1C and FPG with Januvia compared to placebo were generally similar to those observed in other monotherapy studies.
- Add-on Combination Therapy with Metformin
- A total of 701 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of Januvia in combination with metformin. Patients already on metformin (N=431) at a dose of at least 1500 mg per day were randomized after completing a 2-week single-blind placebo run-in period. Patients on metformin and another antihyperglycemic agent (N=229) and patients not on any antihyperglycemic agents (off therapy for at least 8 weeks, N=41) were randomized after a run-in period of approximately 10 weeks on metformin (at a dose of at least 1500 mg per day) in monotherapy. Patients with inadequate glycemic control (A1C 7% to 10%) were randomized to the addition of either 100 mg of Januvia or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with pioglitazone rescue.
- In combination with metformin, Januvia provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin (Table 5). Rescue glycemic therapy was used in 5% of patients treated with Januvia 100 mg and 14% of patients treated with placebo. A similar decrease in body weight was observed for both treatment groups.
- Initial Combination Therapy with Metformin
- A total of 1091 patients with type 2 diabetes and inadequate glycemic control on diet and exercise participated in a 24-week, randomized, double-blind, placebo-controlled factorial study designed to assess the efficacy of sitagliptin as initial therapy in combination with metformin. Patients on an antihyperglycemic agent (N=541) discontinued the agent, and underwent a diet, exercise, and drug washout period of up to 12 weeks duration. After the washout period, patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized after completing a 2-week single-blind placebo run-in period. Patients not on antihyperglycemic agents at study entry (N=550) with inadequate glycemic control (A1C 7.5% to 11%) immediately entered the 2-week single-blind placebo run-in period and then were randomized. Approximately equal numbers of patients were randomized to receive initial therapy with placebo, 100 mg of Januvia once daily, 500 mg or 1000 mg of metformin twice daily, or 50 mg of sitagliptin twice daily in combination with 500 mg or 1000 mg of metformin twice daily. Patients who failed to meet specific glycemic goals during the study were treated with glyburide (glibenclamide) rescue.
- Initial therapy with the combination of Januvia and metformin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo, to metformin alone, and to Januvia alone (Table 6, Figure 1). Mean reductions from baseline in A1C were generally greater for patients with higher baseline A1C values. For patients not on an antihyperglycemic agent at study entry, mean reductions from baseline in A1C were: Januvia 100 mg once daily, -1.1%; metformin 500 mg bid, -1.1%; metformin 1000 mg bid, -1.2%; sitagliptin 50 mg bid with metformin 500 mg bid, -1.6%; sitagliptin 50 mg bid with metformin 1000 mg bid, -1.9%; and for patients receiving placebo, -0.2%. Lipid effects were generally neutral. The decrease in body weight in the groups given sitagliptin in combination with metformin was similar to that in the groups given metformin alone or placebo.
- Initial combination therapy or maintenance of combination therapy may not be appropriate for all patients. These management options are left to the discretion of the health care provider.
- Active-Controlled Study vs Glipizide in Combination with Metformin
- The efficacy of Januvia was evaluated in a 52-week, double-blind, glipizide-controlled noninferiority trial in patients with type 2 diabetes. Patients not on treatment or on other antihyperglycemic agents entered a run-in treatment period of up to 12 weeks duration with metformin monotherapy (dose of ≥1500 mg per day) which included washout of medications other than metformin, if applicable. After the run-in period, those with inadequate glycemic control (A1C 6.5% to 10%) were randomized 1:1 to the addition of Januvia 100 mg once daily or glipizide for 52 weeks. Patients receiving glipizide were given an initial dosage of 5 mg/day and then electively titrated over the next 18 weeks to a maximum dosage of 20 mg/day as needed to optimize glycemic control. Thereafter, the glipizide dose was to be kept constant, except for down-titration to prevent hypoglycemia. The mean dose of glipizide after the titration period was 10 mg.
- After 52 weeks, Januvia and glipizide had similar mean reductions from baseline in A1C in the intent-to-treat analysis (Table 7). These results were consistent with the per protocol analysis (Figure 2). A conclusion in favor of the non-inferiority of Januvia to glipizide may be limited to patients with baseline A1C comparable to those included in the study (over 70% of patients had baseline A1C <8% and over 90% had A1C <9%).
- The incidence of hypoglycemia in the Januvia group (4.9%) was significantly (p<0.001) lower than that in the glipizide group (32.0%). Patients treated with Januvia exhibited a significant mean decrease from baseline in body weight compared to a significant weight gain in patients administered glipizide (-1.5 kg vs +1.1 kg).
- Add-on Combination Therapy with Pioglitazone
- A total of 353 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of Januvia in combination with pioglitazone. Patients on any oral antihyperglycemic agent in monotherapy (N=212) or on a PPARγ agent in combination therapy (N=106) or not on an antihyperglycemic agent (off therapy for at least 8 weeks, N=34) were switched to monotherapy with pioglitazone (at a dose of 30-45 mg per day), and completed a run-in period of approximately 12 weeks in duration. After the run-in period on pioglitazone monotherapy, patients with inadequate glycemic control (A1C 7% to 10%) were randomized to the addition of either 100 mg of Januvia or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with metformin rescue. Glycemic endpoints measured were A1C and fasting glucose.
- In combination with pioglitazone, Januvia provided significant improvements in A1C and FPG compared to placebo with pioglitazone (Table 8). Rescue therapy was used in 7% of patients treated with Januvia 100 mg and 14% of patients treated with placebo. There was no significant difference between Januvia and placebo in body weight change.
- Initial Combination Therapy with Pioglitazone
- A total of 520 patients with type 2 diabetes and inadequate glycemic control on diet and exercise participated in a 24-week, randomized, double-blind study designed to assess the efficacy of Januvia as initial therapy in combination with pioglitazone. Patients not on antihyperglycemic agents at study entry (<4 weeks cumulative therapy over the past 2 years, and with no treatment over the prior 4 months) with inadequate glycemic control (A1C 8% to 12%) immediately entered the 2-week single-blind placebo run-in period and then were randomized. Approximately equal numbers of patients were randomized to receive initial therapy with 100 mg of Januvia in combination with 30 mg of pioglitazone once daily or 30 mg of pioglitazone once daily as monotherapy. There was no glycemic rescue therapy in this study.
- Initial therapy with the combination of Januvia and pioglitazone provided significant improvements in A1C, FPG, and 2-hour PPG compared to pioglitazone monotherapy (Table 9). The improvement in A1C was generally consistent across subgroups defined by gender, age, race, baseline BMI, baseline A1C, or duration of disease. In this study, patients treated with Januvia in combination with pioglitazone had a mean increase in body weight of 1.1 kg compared to pioglitazone alone (3.0 kg vs. 1.9 kg). Lipid effects were generally neutral.
- Add-on Combination Therapy with Metformin and Rosiglitazone
- A total of 278 patients with type 2 diabetes participated in a 54-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of Januvia in combination with metformin and rosiglitazone. Patients on dual therapy with metformin ≥1500 mg/day and rosiglitazone ≥4 mg/day or with metformin ≥1500 mg/day and pioglitazone ≥30 mg/day (switched to rosiglitazone ≥4 mg/day) entered a dose-stable run-in period of 6 weeks. Patients on other dual therapy were switched to metformin ≥1500 mg/day and rosiglitazone ≥4 mg/day in a dose titration/stabilization run-in period of up to 20 weeks in duration. After the run-in period, patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized 2:1 to the addition of either 100 mg of Januvia or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the study were treated with glipizide (or other sulfonylurea) rescue. The primary time point for evaluation of glycemic parameters was Week 18.
- In combination with metformin and rosiglitazone, Januvia provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin and rosiglitazone (Table 10) at Week 18. At Week 54, mean reduction in A1C was -1.0% for patients treated with Januvia and -0.3% for patients treated with placebo in an analysis based on the intent-to-treat population. Rescue therapy was used in 18% of patients treated with Januvia 100 mg and 40% of patients treated with placebo. There was no significant difference between Januvia and placebo in body weight change.
- Add-on Combination Therapy with Glimepiride, with or without Metformin
- A total of 441 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of Januvia in combination with glimepiride, with or without metformin. Patients entered a run-in treatment period on glimepiride (≥4 mg per day) alone or glimepiride in combination with metformin (≥1500 mg per day). After a dose-titration and dose-stable run-in period of up to 16 weeks and a 2-week placebo run-in period, patients with inadequate glycemic control (A1C 7.5% to 10.5%) were randomized to the addition of either 100 mg of Januvia or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with pioglitazone rescue.
- In combination with glimepiride, with or without metformin, Januvia provided significant improvements in A1C and FPG compared to placebo (Table 11). In the entire study population (patients on Januvia in combination with glimepiride and patients on Januvia in combination with glimepiride and metformin), a mean reduction from baseline relative to placebo in A1C of -0.7% and in FPG of -20 mg/dL was seen. Rescue therapy was used in 12% of patients treated with Januvia 100 mg and 27% of patients treated with placebo. In this study, patients treated with Januvia had a mean increase in body weight of 1.1 kg vs. placebo (+0.8 kg vs. -0.4 kg). In addition, there was an increased rate of hypoglycemia.
- Add-on Combination Therapy with Insulin (with or without Metformin)
- A total of 641 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of Januvia as add-on to insulin therapy (with or without metformin). The racial distribution in this study was approximately 70% white, 18% Asian, 7% black, and 5% other groups. Approximately 14% of the patients in this study were Hispanic. Patients entered a 2-week, single-blind run-in treatment period on pre-mixed, long-acting, or intermediate-acting insulin, with or without metformin (≥1500 mg per day). Patients using short-acting insulins were excluded unless the short-acting insulin was administered as part of a pre-mixed insulin. After the run-in period, patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized to the addition of either 100 mg of Januvia or placebo, administered once daily. Patients were on a stable dose of insulin prior to enrollment with no changes in insulin dose permitted during the run-in period. Patients who failed to meet specific glycemic goals during the double-blind treatment period were to have uptitration of the background insulin dose as rescue therapy.
- The median daily insulin dose at baseline was 42 units in the patients treated with Januvia and 45 units in the placebo-treated patients. The median change from baseline in daily dose of insulin was zero for both groups at the end of the study. In combination with insulin (with or without metformin), Januvia provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo (Table 12). Both treatment groups had an adjusted mean increase in body weight of 0.1 kg from baseline to Week 24. There was an increased rate of hypoglycemia in patients treated with Januvia.
# How Supplied
- No. 6737 — Tablets Januvia, 25 mg, are pink, round, film-coated tablets with "221" on one side. They are supplied as follows:
- NDC 0006-0221-31 unit-of-use bottles of 30
- NDC 0006-0221-54 unit-of-use bottles of 90
- NDC 0006-0221-28 unit dose blister packages of 100.
- No. 6738 — Tablets Januvia, 50 mg, are light beige, round, film-coated tablets with "112" on one side. They are supplied as follows:
- NDC 0006-0112-31 unit-of-use bottles of 30
- NDC 0006-0112-54 unit-of-use bottles of 90
- NDC 0006-0112-28 unit dose blister packages of 100.
- No. 6739 — Tablets Januvia, 100 mg, are beige, round, film-coated tablets with "277" on one side. They are supplied as follows:
- NDC 0006-0277-31 unit-of-use bottles of 30
- NDC 0006-0277-54 unit-of-use bottles of 90
- NDC 0006-0277-33 unit-of-use blister calendar package of 30
- NDC 0006-0277-28 unit dose blister packages of 100
- NDC 0006-0277-82 bottles of 1000.
- Storage
- Store at 20-25°C (68-77°F), excursions permitted to 15-30°C (59-86°F).
## Storage
There is limited information regarding Sitagliptin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
# Precautions with Alcohol
- Alcohol-Sitagliptin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Januvia®
# Look-Alike Drug Names
- Januvia® — Enjuvia®
- Januvia® — Jantoven®
- Januvia® — Janumet®
- sitaGLIPtin® — SUMAtriptan®
- sitaGLIPtin® — ZOLMitriptan®
# Drug Shortage Status
# Price | Sitagliptin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Overview
Sitagliptin is a dipeptidyl peptidase-4 inhibitor that is FDA approved for the {{{indicationType}}} of type 2 diabetes mellitus. Common adverse reactions include hypoglycemia, headache, nasopharyngitis, and upper respiratory infection.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended dose of Januvia is 100 mg once daily. Januvia can be taken with or without food.
- Patients with Renal Insufficiency
- For patients with mild renal insufficiency (creatinine clearance [CrCl] greater than or equal to 50 mL/min, approximately corresponding to serum creatinine levels of less than or equal to 1.7 mg/dL in men and less than or equal to 1.5 mg/dL in women), no dosage adjustment for Januvia is required.
- For patients with moderate renal insufficiency (CrCl greater than or equal to 30 to less than 50 mL/min, approximately corresponding to serum creatinine levels of greater than 1.7 to less than or equal to 3.0 mg/dL in men and greater than 1.5 to less than or equal to 2.5 mg/dL in women), the dose of Januvia is 50 mg once daily.
- For patients with severe renal insufficiency (CrCl less than 30 mL/min, approximately corresponding to serum creatinine levels of greater than 3.0 mg/dL in men and greater than 2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of Januvia is 25 mg once daily. Januvia may be administered without regard to the timing of dialysis.
- Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of Januvia and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. There have been postmarketing reports of worsening renal function in patients with renal insufficiency, some of whom were cascribed inappropriate doses of sitagliptin.
- Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin
- When Januvia is used in combination with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sitagliptin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sitagliptin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness of Januvia in pediatric patients under 18 years of age have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sitagliptin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sitagliptin in pediatric patients.
# Contraindications
- History of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema.
# Warnings
- Pancreatitis
- There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking Januvia. After initiation of Januvia, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, Januvia should promptly be discontinued and appropriate management should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using Januvia.
- Renal Impairment
- Assessment of renal function is recommended prior to initiating Januvia and periodically thereafter. A dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD requiring hemodialysis or peritoneal dialysis. Caution should be used to ensure that the correct dose of Januvia is prescribed for patients with moderate (creatinine clearance ≥30 to <50 mL/min) or severe (creatinine clearance <30 mL/min) renal impairment.
- There have been postmarketing reports of worsening renal function, including acute renal failure, sometimes requiring dialysis. A subset of these reports involved patients with renal insufficiency, some of whom were prescribed inappropriate doses of sitagliptin. A return to baseline levels of renal insufficiency has been observed with supportive treatment and discontinuation of potentially causative agents. Consideration can be given to cautiously reinitiating Januvia if another etiology is deemed likely to have precipitated the acute worsening of renal function.
- Januvia has not been found to be nephrotoxic in preclinical studies at clinically relevant doses, or in clinical trials.
- Use with Medications Known to Cause Hypoglycemia
- When Januvia was used in combination with a sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or with insulin. Therefore, a lower dose of sulfonylurea or insulin may be required to reduce the risk of hypoglycemia.
- Hypersensitivity Reactions
- There have been postmarketing reports of serious hypersensitivity reactions in patients treated with Januvia. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of treatment with Januvia, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue Januvia, assess for other potential causes for the event, and institute alternative treatment for diabetes.
- Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a history of angioedema with another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with Januvia.
- Macrovascular Outcomes
- There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Januvia or any other anti-diabetic drug.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- In controlled clinical studies as both monotherapy and combination therapy with metformin, pioglitazone, or rosiglitazone and metformin, the overall incidence of adverse reactions, hypoglycemia, and discontinuation of therapy due to clinical adverse reactions with Januvia were similar to placebo. In combination with glimepiride, with or without metformin, the overall incidence of clinical adverse reactions with Januvia was higher than with placebo, in part related to a higher incidence of hypoglycemia (see Table 3); the incidence of discontinuation due to clinical adverse reactions was similar to placebo.
- Two placebo-controlled monotherapy studies, one of 18- and one of 24-week duration, included patients treated with Januvia 100 mg daily, Januvia 200 mg daily, and placebo. Five placebo-controlled add-on combination therapy studies were also conducted: one with metformin; one with pioglitazone; one with metformin and rosiglitazone; one with glimepiride (with or without metformin); and one with insulin (with or without metformin). In these trials, patients with inadequate glycemic control on a stable dose of the background therapy were randomized to add-on therapy with Januvia 100 mg daily or placebo. The adverse reactions, excluding hypoglycemia, reported regardless of investigator assessment of causality in ≥5% of patients treated with Januvia 100 mg daily and more commonly than in patients treated with placebo, are shown in Table 1 for the clinical trials of at least 18 weeks duration. Incidences of hypoglycemia are shown in Table 3.
- In the 24-week study of patients receiving Januvia as add-on combination therapy with metformin, there were no adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo.
- In the 24-week study of patients receiving Januvia as add-on therapy to insulin (with or without metformin), there were no adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo, except for hypoglycemia (see Table 3).
- In the study of Januvia as add-on combination therapy with metformin and rosiglitazone (Table 1), through Week 54 the adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients treated with Januvia and more commonly than in patients treated with placebo were: upper respiratory tract infection (Januvia, 15.5%; placebo, 6.2%), nasopharyngitis (11.0%, 9.3%), peripheral edema (8.3%, 5.2%), and headache (5.5%, 4.1%).
- In a pooled analysis of the two monotherapy studies, the add-on to metformin study, and the add-on to pioglitazone study, the incidence of selected gastrointestinal adverse reactions in patients treated with Januvia was as follows: abdominal pain (Januvia 100 mg, 2.3%; placebo, 2.1%), nausea (1.4%, 0.6%), and diarrhea (3.0%, 2.3%).
- In an additional, 24-week, placebo-controlled factorial study of initial therapy with sitagliptin in combination with metformin, the adverse reactions reported (regardless of investigator assessment of causality) in ≥5% of patients are shown in Table 2.
- In a 24-week study of initial therapy with Januvia in combination with pioglitazone, there were no adverse reactions reported (regardless of investigator assessment of causality) in ≥5% of patients and more commonly than in patients given pioglitazone alone.
- No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed in patients treated with Januvia.
- In a pooled analysis of 19 double-blind clinical trials that included data from 10,246 patients randomized to receive sitagliptin 100 mg/day (N=5429) or corresponding (active or placebo) control (N=4817), the incidence of acute pancreatitis was 0.1 per 100 patient-years in each group (4 patients with an event in 4708 patient-years for sitagliptin and 4 patients with an event in 3942 patient-years for control).
- Hypoglycemia
- In all (N=9) studies, adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia. A concurrent blood glucose measurement was not required although most (74%) reports of hypoglycemia were accompanied by a blood glucose measurement ≤70 mg/dL. When Januvia was co-administered with a sulfonylurea or with insulin, the percentage of patients with at least one adverse reaction of hypoglycemia was higher than in the corresponding placebo group (Table 3).
- In a pooled analysis of the two monotherapy studies, the add-on to metformin study, and the add-on to pioglitazone study, the overall incidence of adverse reactions of hypoglycemia was 1.2% in patients treated with Januvia 100 mg and 0.9% in patients treated with placebo.
- In the study of Januvia as add-on combination therapy with metformin and rosiglitazone, the overall incidence of hypoglycemia was 2.2% in patients given add-on Januvia and 0.0% in patients given add-on placebo through Week 18. Through Week 54, the overall incidence of hypoglycemia was 3.9% in patients given add-on Januvia and 1.0% in patients given add-on placebo.
- In the 24-week, placebo-controlled factorial study of initial therapy with Januvia in combination with metformin, the incidence of hypoglycemia was 0.6% in patients given placebo, 0.6% in patients given Januvia alone, 0.8% in patients given metformin alone, and 1.6% in patients given Januvia in combination with metformin.
- In the study of Januvia as initial therapy with pioglitazone, one patient taking Januvia experienced a severe episode of hypoglycemia. There were no severe hypoglycemia episodes reported in other studies except in the study involving co-administration with insulin.
- Laboratory Tests
- Across clinical studies, the incidence of laboratory adverse reactions was similar in patients treated with Januvia 100 mg compared to patients treated with placebo. A small increase in white blood cell count (WBC) was observed due to an increase in neutrophils. This increase in WBC (of approximately 200 cells/microL vs placebo, in four pooled placebo-controlled clinical studies, with a mean baseline WBC count of approximately 6600 cells/microL) is not considered to be clinically relevant. In a 12-week study of 91 patients with chronic renal insufficiency, 37 patients with moderate renal insufficiency were randomized to Januvia 50 mg daily, while 14 patients with the same magnitude of renal impairment were randomized to placebo. Mean (SE) increases in serum creatinine were observed in patients treated with Januvia [0.12 mg/dL (0.04)] and in patients treated with placebo [0.07 mg/dL (0.07)]. The clinical significance of this added increase in serum creatinine relative to placebo is not known.
## Postmarketing Experience
- Additional adverse reactions have been identified during postapproval use of Januvia as monotherapy and/or in combination with other antihyperglycemic agents. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin conditions including Stevens-Johnson syndrome; hepatic enzyme elevations; acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis; worsening renal function, including acute renal failure (sometimes requiring dialysis); constipation; vomiting; headache; arthralgia; myalgia; pain in extremity; back pain.
# Drug Interactions
- Digoxin
- There was a slight increase in the area under the curve (AUC, 11%) and mean peak drug concentration (Cmax, 18%) of digoxin with the co-administration of 100 mg sitagliptin for 10 days. Patients receiving digoxin should be monitored appropriately. No dosage adjustment of digoxin or Januvia is recommended.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- Reproduction studies have been performed in rats and rabbits. Doses of sitagliptin up to 125 mg/kg (approximately 12 times the human exposure at the maximum recommended human dose) did not impair fertility or harm the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., maintains a registry to monitor the pregnancy outcomes of women exposed to Januvia while pregnant. Health care providers are encouraged to report any prenatal exposure to Januvia by calling the Pregnancy Registry at 1-800-986-8999.
- Sitagliptin administered to pregnant female rats and rabbits from gestation day 6 to 20 (organogenesis) was not teratogenic at oral doses up to 250 mg/kg (rats) and 125 mg/kg (rabbits), or approximately 30- and 20-times human exposure at the maximum recommended human dose (MRHD) of 100 mg/day based on AUC comparisons. Higher doses increased the incidence of rib malformations in offspring at 1000 mg/kg, or approximately 100 times human exposure at the MRHD.
- Sitagliptin administered to female rats from gestation day 6 to lactation day 21 decreased body weight in male and female offspring at 1000 mg/kg. No functional or behavioral toxicity was observed in offspring of rats.
- Placental transfer of sitagliptin administered to pregnant rats was approximately 45% at 2 hours and 80% at 24 hours postdose. Placental transfer of sitagliptin administered to pregnant rabbits was approximately 66% at 2 hours and 30% at 24 hours.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sitagliptin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Sitagliptin during labor and delivery.
### Nursing Mothers
- Sitagliptin is secreted in the milk of lactating rats at a milk to plasma ratio of 4:1. It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Januvia is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness of Januvia in pediatric patients under 18 years of age have not been established.
### Geriatic Use
- Of the total number of subjects (N=3884) in pre-approval clinical safety and efficacy studies of Januvia, 725 patients were 65 years and over, while 61 patients were 75 years and over. No overall differences in safety or effectiveness were observed between subjects 65 years and over and younger subjects. While this and other reported clinical experience have not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.
- This drug is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly, and it may be useful to assess renal function in these patients prior to initiating dosing and periodically thereafter.
### Gender
There is no FDA guidance on the use of Sitagliptin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Sitagliptin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Sitagliptin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Sitagliptin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sitagliptin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Sitagliptin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Patients receiving digoxin should be monitored appropriately.
- In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy as dictated by the patient's clinical status.
- Patients should also be informed about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and A1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications.
# IV Compatibility
There is limited information regarding IV Compatibility of Sitagliptin in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- During controlled clinical trials in healthy subjects, single doses of up to 800 mg Januvia were administered. Maximal mean increases in QTc of 8.0 msec were observed in one study at a dose of 800 mg Januvia, a mean effect that is not considered clinically important. There is no experience with doses above 800 mg in clinical studies. In Phase I multiple-dose studies, there were no dose-related clinical adverse reactions observed with Januvia with doses of up to 600 mg per day for periods of up to 10 days and 400 mg per day for up to 28 days.
### Management
- In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy as dictated by the patient's clinical status.
- Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5% of the dose was removed over a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Sitagliptin in the drug label.
# Pharmacology
## Mechanism of Action
- Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by Januvia, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, Januvia increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
## Structure
- Januvia Tablets contain sitagliptin phosphate, an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme.
- Sitagliptin phosphate monohydrate is described chemically as 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine phosphate (1:1) monohydrate.
- The empirical formula is C16H15F6N5O•H3PO4•H2O and the molecular weight is 523.32. The structural formula is:
- Sitagliptin phosphate monohydrate is a white to off-white, crystalline, non-hygroscopic powder. It is soluble in water and N,N-dimethyl formamide; slightly soluble in methanol; very slightly soluble in ethanol, acetone, and acetonitrile; and insoluble in isopropanol and isopropyl acetate.
- Each film-coated tablet of Januvia contains 32.13, 64.25, or 128.5 mg of sitagliptin phosphate monohydrate, which is equivalent to 25, 50, or 100 mg, respectively, of free base and the following inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, red iron oxide, and yellow iron oxide.
## Pharmacodynamics
- General
- In patients with type 2 diabetes, administration of Januvia led to inhibition of DPP-4 enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP-4 inhibition resulted in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased responsiveness of insulin release to glucose, resulting in higher C-peptide and insulin concentrations. The rise in insulin with the decrease in glucagon was associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.
- In a two-day study in healthy subjects, sitagliptin alone increased active GLP-1 concentrations, whereas metformin alone increased active and total GLP-1 concentrations to similar extents. Co-administration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations. Sitagliptin, but not metformin, increased active GIP concentrations. It is unclear how these findings relate to changes in glycemic control in patients with type 2 diabetes.
- In studies with healthy subjects, Januvia did not lower blood glucose or cause hypoglycemia.
- Cardiac Electrophysiology
- In a randomized, placebo-controlled crossover study, 79 healthy subjects were administered a single oral dose of Januvia 100 mg, Januvia 800 mg (8 times the recommended dose), and placebo. At the recommended dose of 100 mg, there was no effect on the QTc interval obtained at the peak plasma concentration, or at any other time during the study. Following the 800 mg dose, the maximum increase in the placebo-corrected mean change in QTc from baseline was observed at 3 hours postdose and was 8.0 msec. This increase is not considered to be clinically significant. At the 800 mg dose, peak sitagliptin plasma concentrations were approximately 11 times higher than the peak concentrations following a 100 mg dose.
- In patients with type 2 diabetes administered Januvia 100 mg (N=81) or Januvia 200 mg (N=63) daily, there were no meaningful changes in QTc interval based on ECG data obtained at the time of expected peak plasma concentration.
## Pharmacokinetics
- The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose. Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 μM•hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.
- Absorption
- The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with Januvia had no effect on the pharmacokinetics, Januvia may be administered with or without food.
- Distribution
- The mean volume of distribution at steady state following a single 100 mg intravenous dose of sitagliptin to healthy subjects is approximately 198 liters. The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).
- Metabolism
- Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.
- Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.
- Excretion
- Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.
- Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.
- Renal Insufficiency
- A single-dose, open-label study was conducted to evaluate the pharmacokinetics of Januvia (50 mg dose) in patients with varying degrees of chronic renal insufficiency compared to normal healthy control subjects. The study included patients with renal insufficiency classified on the basis of creatinine clearance as mild (50 to <80 mL/min), moderate (30 to <50 mL/min), and severe (<30 mL/min), as well as patients with ESRD on hemodialysis. In addition, the effects of renal insufficiency on sitagliptin pharmacokinetics in patients with type 2 diabetes and mild or moderate renal insufficiency were assessed using population pharmacokinetic analyses. Creatinine clearance was measured by 24‑hour urinary creatinine clearance measurements or estimated from serum creatinine based on the Cockcroft-Gault formula.
- Compared to normal healthy control subjects, an approximate 1.1- to 1.6-fold increase in plasma AUC of sitagliptin was observed in patients with mild renal insufficiency. Because increases of this magnitude are not clinically relevant, dosage adjustment in patients with mild renal insufficiency is not necessary. Plasma AUC levels of sitagliptin were increased approximately 2-fold and 4-fold in patients with moderate renal insufficiency and in patients with severe renal insufficiency, including patients with ESRD on hemodialysis, respectively. Sitagliptin was modestly removed by hemodialysis (13.5% over a 3- to 4-hour hemodialysis session starting 4 hours postdose). To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, lower dosages are recommended in patients with moderate and severe renal insufficiency, as well as in ESRD patients requiring dialysis.
- Hepatic Insufficiency
- In patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9), mean AUC and Cmax of sitagliptin increased approximately 21% and 13%, respectively, compared to healthy matched controls following administration of a single 100 mg dose of Januvia. These differences are not considered to be clinically meaningful. No dosage adjustment for Januvia is necessary for patients with mild or moderate hepatic insufficiency.
- There is no clinical experience in patients with severe hepatic insufficiency (Child-Pugh score >9).
- Body Mass Index (BMI)
- No dosage adjustment is necessary based on BMI. Body mass index had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.
- Gender
- No dosage adjustment is necessary based on gender. Gender had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.
- Geriatric
- No dosage adjustment is required based solely on age. When the effects of age on renal function are taken into account, age alone did not have a clinically meaningful impact on the pharmacokinetics of sitagliptin based on a population pharmacokinetic analysis. Elderly subjects (65 to 80 years) had approximately 19% higher plasma concentrations of sitagliptin compared to younger subjects.
- Pediatric
- Studies characterizing the pharmacokinetics of sitagliptin in pediatric patients have not been performed.
- Race
- No dosage adjustment is necessary based on race. Race had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of available pharmacokinetic data, including subjects of white, Hispanic, black, Asian, and other racial groups.
- Drug Interactions
- In Vitro Assessment of Drug Interactions
- Sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, and is not an inducer of CYP3A4. Sitagliptin is a p-glycoprotein substrate, but does not inhibit p-glycoprotein mediated transport of digoxin. Based on these results, sitagliptin is considered unlikely to cause interactions with other drugs that utilize these pathways.
- Sitagliptin is not extensively bound to plasma proteins. Therefore, the propensity of sitagliptin to be involved in clinically meaningful drug-drug interactions mediated by plasma protein binding displacement is very low.
- In Vivo Assessment of Drug Interactions
- Effects of Sitagliptin on Other Drugs
- In clinical studies, as described below, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of a low propensity for causing drug interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic cationic transporter (OCT).
- Digoxin: Sitagliptin had a minimal effect on the pharmacokinetics of digoxin. Following administration of 0.25 mg digoxin concomitantly with 100 mg of Januvia daily for 10 days, the plasma AUC of digoxin was increased by 11%, and the plasma Cmax by 18%.
- Metformin: Co-administration of multiple twice-daily doses of sitagliptin with metformin, an OCT substrate, did not meaningfully alter the pharmacokinetics of metformin in patients with type 2 diabetes. Therefore, sitagliptin is not an inhibitor of OCT-mediated transport.
- Sulfonylureas: Single-dose pharmacokinetics of glyburide, a CYP2C9 substrate, was not meaningfully altered in subjects receiving multiple doses of sitagliptin. Clinically meaningful interactions would not be expected with other sulfonylureas (e.g., glipizide, tolbutamide, and glimepiride) which, like glyburide, are primarily eliminated by CYP2C9.
- Simvastatin: Single-dose pharmacokinetics of simvastatin, a CYP3A4 substrate, was not meaningfully altered in subjects receiving multiple daily doses of sitagliptin. Therefore, sitagliptin is not an inhibitor of CYP3A4-mediated metabolism.
- Thiazolidinediones: Single-dose pharmacokinetics of rosiglitazone was not meaningfully altered in subjects receiving multiple daily doses of sitagliptin, indicating that Januvia is not an inhibitor of CYP2C8-mediated metabolism.
- Warfarin: Multiple daily doses of sitagliptin did not meaningfully alter the pharmacokinetics, as assessed by measurement of S(-) or R(+) warfarin enantiomers, or pharmacodynamics (as assessed by measurement of prothrombin INR) of a single dose of warfarin. Because S(-) warfarin is primarily metabolized by CYP2C9, these data also support the conclusion that sitagliptin is not a CYP2C9 inhibitor.
- Oral Contraceptives: Co-administration with sitagliptin did not meaningfully alter the steady-state pharmacokinetics of norethindrone or ethinyl estradiol.
- Effects of Other Drugs on Sitagliptin
- Clinical data described below suggest that sitagliptin is not susceptible to clinically meaningful interactions by co-administered medications.
- Metformin: Co-administration of multiple twice-daily doses of metformin with sitagliptin did not meaningfully alter the pharmacokinetics of sitagliptin in patients with type 2 diabetes.
- Cyclosporine: A study was conducted to assess the effect of cyclosporine, a potent inhibitor of p-glycoprotein, on the pharmacokinetics of sitagliptin. Co-administration of a single 100 mg oral dose of Januvia and a single 600 mg oral dose of cyclosporine increased the AUC and Cmax of sitagliptin by approximately 29% and 68%, respectively. These modest changes in sitagliptin pharmacokinetics were not considered to be clinically meaningful. The renal clearance of sitagliptin was also not meaningfully altered. Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors.
## Nonclinical Toxicology
- A two-year carcinogenicity study was conducted in male and female rats given oral doses of sitagliptin of 50, 150, and 500 mg/kg/day. There was an increased incidence of combined liver adenoma/carcinoma in males and females and of liver carcinoma in females at 500 mg/kg. This dose results in exposures approximately 60 times the human exposure at the maximum recommended daily adult human dose (MRHD) of 100 mg/day based on AUC comparisons. Liver tumors were not observed at 150 mg/kg, approximately 20 times the human exposure at the MRHD. A two-year carcinogenicity study was conducted in male and female mice given oral doses of sitagliptin of 50, 125, 250, and 500 mg/kg/day. There was no increase in the incidence of tumors in any organ up to 500 mg/kg, approximately 70 times human exposure at the MRHD. Sitagliptin was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay, a Chinese hamster ovary (CHO) chromosome aberration assay, an in vitro cytogenetics assay in CHO, an in vitro rat hepatocyte DNA alkaline elution assay, and an in vivo micronucleus assay.
- In rat fertility studies with oral gavage doses of 125, 250, and 1000 mg/kg, males were treated for 4 weeks prior to mating, during mating, up to scheduled termination (approximately 8 weeks total) and females were treated 2 weeks prior to mating through gestation day 7. No adverse effect on fertility was observed at 125 mg/kg (approximately 12 times human exposure at the MRHD of 100 mg/day based on AUC comparisons). At higher doses, nondose-related increased resorptions in females were observed (approximately 25 and 100 times human exposure at the MRHD based on AUC comparison).
# Clinical Studies
- There were approximately 5200 patients with type 2 diabetes randomized in nine double-blind, placebo-controlled clinical safety and efficacy studies conducted to evaluate the effects of sitagliptin on glycemic control. In a pooled analysis of seven of these studies, the ethnic/racial distribution was approximately 59% white, 20% Hispanic, 10% Asian, 6% black, and 6% other groups. Patients had an overall mean age of approximately 55 years (range 18 to 87 years). In addition, an active (glipizide)-controlled study of 52-weeks duration was conducted in 1172 patients with type 2 diabetes who had inadequate glycemic control on metformin.
- In patients with type 2 diabetes, treatment with Januvia produced clinically significant improvements in hemoglobin A1C, fasting plasma glucose (FPG) and 2-hour post-prandial glucose (PPG) compared to placebo.
- A total of 1262 patients with type 2 diabetes participated in two double-blind, placebo-controlled studies, one of 18-week and another of 24-week duration, to evaluate the efficacy and safety of Januvia monotherapy. In both monotherapy studies, patients currently on an antihyperglycemic agent discontinued the agent, and underwent a diet, exercise, and drug washout period of about 7 weeks. Patients with inadequate glycemic control (A1C 7% to 10%) after the washout period were randomized after completing a 2-week single-blind placebo run-in period; patients not currently on antihyperglycemic agents (off therapy for at least 8 weeks) with inadequate glycemic control (A1C 7% to 10%) were randomized after completing the 2-week single-blind placebo run-in period. In the 18-week study, 521 patients were randomized to placebo, Januvia 100 mg, or Januvia 200 mg, and in the 24-week study 741 patients were randomized to placebo, Januvia 100 mg, or Januvia 200 mg. Patients who failed to meet specific glycemic goals during the studies were treated with metformin rescue, added on to placebo or Januvia.
- Treatment with Januvia at 100 mg daily provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo (Table 4). In the 18-week study, 9% of patients receiving Januvia 100 mg and 17% who received placebo required rescue therapy. In the 24-week study, 9% of patients receiving Januvia 100 mg and 21% of patients receiving placebo required rescue therapy. The improvement in A1C compared to placebo was not affected by gender, age, race, prior antihyperglycemic therapy, or baseline BMI. As is typical for trials of agents to treat type 2 diabetes, the mean reduction in A1C with Januvia appears to be related to the degree of A1C elevation at baseline. In these 18- and 24-week studies, among patients who were not on an antihyperglycemic agent at study entry, the reductions from baseline in A1C were -0.7% and -0.8%, respectively, for those given Januvia, and -0.1% and -0.2%, respectively, for those given placebo. Overall, the 200 mg daily dose did not provide greater glycemic efficacy than the 100 mg daily dose. The effect of Januvia on lipid endpoints was similar to placebo. Body weight did not increase from baseline with Januvia therapy in either study, compared to a small reduction in patients given placebo.
- Additional Monotherapy Study
- A multinational, randomized, double-blind, placebo-controlled study was also conducted to assess the safety and tolerability of Januvia in 91 patients with type 2 diabetes and chronic renal insufficiency (creatinine clearance <50 mL/min). Patients with moderate renal insufficiency received 50 mg daily of Januvia and those with severe renal insufficiency or with ESRD on hemodialysis or peritoneal dialysis received 25 mg daily. In this study, the safety and tolerability of Januvia were generally similar to placebo. A small increase in serum creatinine was reported in patients with moderate renal insufficiency treated with Januvia relative to those on placebo. In addition, the reductions in A1C and FPG with Januvia compared to placebo were generally similar to those observed in other monotherapy studies.
- Add-on Combination Therapy with Metformin
- A total of 701 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of Januvia in combination with metformin. Patients already on metformin (N=431) at a dose of at least 1500 mg per day were randomized after completing a 2-week single-blind placebo run-in period. Patients on metformin and another antihyperglycemic agent (N=229) and patients not on any antihyperglycemic agents (off therapy for at least 8 weeks, N=41) were randomized after a run-in period of approximately 10 weeks on metformin (at a dose of at least 1500 mg per day) in monotherapy. Patients with inadequate glycemic control (A1C 7% to 10%) were randomized to the addition of either 100 mg of Januvia or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with pioglitazone rescue.
- In combination with metformin, Januvia provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin (Table 5). Rescue glycemic therapy was used in 5% of patients treated with Januvia 100 mg and 14% of patients treated with placebo. A similar decrease in body weight was observed for both treatment groups.
- Initial Combination Therapy with Metformin
- A total of 1091 patients with type 2 diabetes and inadequate glycemic control on diet and exercise participated in a 24-week, randomized, double-blind, placebo-controlled factorial study designed to assess the efficacy of sitagliptin as initial therapy in combination with metformin. Patients on an antihyperglycemic agent (N=541) discontinued the agent, and underwent a diet, exercise, and drug washout period of up to 12 weeks duration. After the washout period, patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized after completing a 2-week single-blind placebo run-in period. Patients not on antihyperglycemic agents at study entry (N=550) with inadequate glycemic control (A1C 7.5% to 11%) immediately entered the 2-week single-blind placebo run-in period and then were randomized. Approximately equal numbers of patients were randomized to receive initial therapy with placebo, 100 mg of Januvia once daily, 500 mg or 1000 mg of metformin twice daily, or 50 mg of sitagliptin twice daily in combination with 500 mg or 1000 mg of metformin twice daily. Patients who failed to meet specific glycemic goals during the study were treated with glyburide (glibenclamide) rescue.
- Initial therapy with the combination of Januvia and metformin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo, to metformin alone, and to Januvia alone (Table 6, Figure 1). Mean reductions from baseline in A1C were generally greater for patients with higher baseline A1C values. For patients not on an antihyperglycemic agent at study entry, mean reductions from baseline in A1C were: Januvia 100 mg once daily, -1.1%; metformin 500 mg bid, -1.1%; metformin 1000 mg bid, -1.2%; sitagliptin 50 mg bid with metformin 500 mg bid, -1.6%; sitagliptin 50 mg bid with metformin 1000 mg bid, -1.9%; and for patients receiving placebo, -0.2%. Lipid effects were generally neutral. The decrease in body weight in the groups given sitagliptin in combination with metformin was similar to that in the groups given metformin alone or placebo.
- Initial combination therapy or maintenance of combination therapy may not be appropriate for all patients. These management options are left to the discretion of the health care provider.
- Active-Controlled Study vs Glipizide in Combination with Metformin
- The efficacy of Januvia was evaluated in a 52-week, double-blind, glipizide-controlled noninferiority trial in patients with type 2 diabetes. Patients not on treatment or on other antihyperglycemic agents entered a run-in treatment period of up to 12 weeks duration with metformin monotherapy (dose of ≥1500 mg per day) which included washout of medications other than metformin, if applicable. After the run-in period, those with inadequate glycemic control (A1C 6.5% to 10%) were randomized 1:1 to the addition of Januvia 100 mg once daily or glipizide for 52 weeks. Patients receiving glipizide were given an initial dosage of 5 mg/day and then electively titrated over the next 18 weeks to a maximum dosage of 20 mg/day as needed to optimize glycemic control. Thereafter, the glipizide dose was to be kept constant, except for down-titration to prevent hypoglycemia. The mean dose of glipizide after the titration period was 10 mg.
- After 52 weeks, Januvia and glipizide had similar mean reductions from baseline in A1C in the intent-to-treat analysis (Table 7). These results were consistent with the per protocol analysis (Figure 2). A conclusion in favor of the non-inferiority of Januvia to glipizide may be limited to patients with baseline A1C comparable to those included in the study (over 70% of patients had baseline A1C <8% and over 90% had A1C <9%).
- The incidence of hypoglycemia in the Januvia group (4.9%) was significantly (p<0.001) lower than that in the glipizide group (32.0%). Patients treated with Januvia exhibited a significant mean decrease from baseline in body weight compared to a significant weight gain in patients administered glipizide (-1.5 kg vs +1.1 kg).
- Add-on Combination Therapy with Pioglitazone
- A total of 353 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of Januvia in combination with pioglitazone. Patients on any oral antihyperglycemic agent in monotherapy (N=212) or on a PPARγ agent in combination therapy (N=106) or not on an antihyperglycemic agent (off therapy for at least 8 weeks, N=34) were switched to monotherapy with pioglitazone (at a dose of 30-45 mg per day), and completed a run-in period of approximately 12 weeks in duration. After the run-in period on pioglitazone monotherapy, patients with inadequate glycemic control (A1C 7% to 10%) were randomized to the addition of either 100 mg of Januvia or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with metformin rescue. Glycemic endpoints measured were A1C and fasting glucose.
- In combination with pioglitazone, Januvia provided significant improvements in A1C and FPG compared to placebo with pioglitazone (Table 8). Rescue therapy was used in 7% of patients treated with Januvia 100 mg and 14% of patients treated with placebo. There was no significant difference between Januvia and placebo in body weight change.
- Initial Combination Therapy with Pioglitazone
- A total of 520 patients with type 2 diabetes and inadequate glycemic control on diet and exercise participated in a 24-week, randomized, double-blind study designed to assess the efficacy of Januvia as initial therapy in combination with pioglitazone. Patients not on antihyperglycemic agents at study entry (<4 weeks cumulative therapy over the past 2 years, and with no treatment over the prior 4 months) with inadequate glycemic control (A1C 8% to 12%) immediately entered the 2-week single-blind placebo run-in period and then were randomized. Approximately equal numbers of patients were randomized to receive initial therapy with 100 mg of Januvia in combination with 30 mg of pioglitazone once daily or 30 mg of pioglitazone once daily as monotherapy. There was no glycemic rescue therapy in this study.
- Initial therapy with the combination of Januvia and pioglitazone provided significant improvements in A1C, FPG, and 2-hour PPG compared to pioglitazone monotherapy (Table 9). The improvement in A1C was generally consistent across subgroups defined by gender, age, race, baseline BMI, baseline A1C, or duration of disease. In this study, patients treated with Januvia in combination with pioglitazone had a mean increase in body weight of 1.1 kg compared to pioglitazone alone (3.0 kg vs. 1.9 kg). Lipid effects were generally neutral.
- Add-on Combination Therapy with Metformin and Rosiglitazone
- A total of 278 patients with type 2 diabetes participated in a 54-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of Januvia in combination with metformin and rosiglitazone. Patients on dual therapy with metformin ≥1500 mg/day and rosiglitazone ≥4 mg/day or with metformin ≥1500 mg/day and pioglitazone ≥30 mg/day (switched to rosiglitazone ≥4 mg/day) entered a dose-stable run-in period of 6 weeks. Patients on other dual therapy were switched to metformin ≥1500 mg/day and rosiglitazone ≥4 mg/day in a dose titration/stabilization run-in period of up to 20 weeks in duration. After the run-in period, patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized 2:1 to the addition of either 100 mg of Januvia or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the study were treated with glipizide (or other sulfonylurea) rescue. The primary time point for evaluation of glycemic parameters was Week 18.
- In combination with metformin and rosiglitazone, Januvia provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin and rosiglitazone (Table 10) at Week 18. At Week 54, mean reduction in A1C was -1.0% for patients treated with Januvia and -0.3% for patients treated with placebo in an analysis based on the intent-to-treat population. Rescue therapy was used in 18% of patients treated with Januvia 100 mg and 40% of patients treated with placebo. There was no significant difference between Januvia and placebo in body weight change.
- Add-on Combination Therapy with Glimepiride, with or without Metformin
- A total of 441 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of Januvia in combination with glimepiride, with or without metformin. Patients entered a run-in treatment period on glimepiride (≥4 mg per day) alone or glimepiride in combination with metformin (≥1500 mg per day). After a dose-titration and dose-stable run-in period of up to 16 weeks and a 2-week placebo run-in period, patients with inadequate glycemic control (A1C 7.5% to 10.5%) were randomized to the addition of either 100 mg of Januvia or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with pioglitazone rescue.
- In combination with glimepiride, with or without metformin, Januvia provided significant improvements in A1C and FPG compared to placebo (Table 11). In the entire study population (patients on Januvia in combination with glimepiride and patients on Januvia in combination with glimepiride and metformin), a mean reduction from baseline relative to placebo in A1C of -0.7% and in FPG of -20 mg/dL was seen. Rescue therapy was used in 12% of patients treated with Januvia 100 mg and 27% of patients treated with placebo. In this study, patients treated with Januvia had a mean increase in body weight of 1.1 kg vs. placebo (+0.8 kg vs. -0.4 kg). In addition, there was an increased rate of hypoglycemia.
- Add-on Combination Therapy with Insulin (with or without Metformin)
- A total of 641 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of Januvia as add-on to insulin therapy (with or without metformin). The racial distribution in this study was approximately 70% white, 18% Asian, 7% black, and 5% other groups. Approximately 14% of the patients in this study were Hispanic. Patients entered a 2-week, single-blind run-in treatment period on pre-mixed, long-acting, or intermediate-acting insulin, with or without metformin (≥1500 mg per day). Patients using short-acting insulins were excluded unless the short-acting insulin was administered as part of a pre-mixed insulin. After the run-in period, patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized to the addition of either 100 mg of Januvia or placebo, administered once daily. Patients were on a stable dose of insulin prior to enrollment with no changes in insulin dose permitted during the run-in period. Patients who failed to meet specific glycemic goals during the double-blind treatment period were to have uptitration of the background insulin dose as rescue therapy.
- The median daily insulin dose at baseline was 42 units in the patients treated with Januvia and 45 units in the placebo-treated patients. The median change from baseline in daily dose of insulin was zero for both groups at the end of the study. In combination with insulin (with or without metformin), Januvia provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo (Table 12). Both treatment groups had an adjusted mean increase in body weight of 0.1 kg from baseline to Week 24. There was an increased rate of hypoglycemia in patients treated with Januvia.
# How Supplied
- No. 6737 — Tablets Januvia, 25 mg, are pink, round, film-coated tablets with "221" on one side. They are supplied as follows:
- NDC 0006-0221-31 unit-of-use bottles of 30
- NDC 0006-0221-54 unit-of-use bottles of 90
- NDC 0006-0221-28 unit dose blister packages of 100.
- No. 6738 — Tablets Januvia, 50 mg, are light beige, round, film-coated tablets with "112" on one side. They are supplied as follows:
- NDC 0006-0112-31 unit-of-use bottles of 30
- NDC 0006-0112-54 unit-of-use bottles of 90
- NDC 0006-0112-28 unit dose blister packages of 100.
- No. 6739 — Tablets Januvia, 100 mg, are beige, round, film-coated tablets with "277" on one side. They are supplied as follows:
- NDC 0006-0277-31 unit-of-use bottles of 30
- NDC 0006-0277-54 unit-of-use bottles of 90
- NDC 0006-0277-33 unit-of-use blister calendar package of 30
- NDC 0006-0277-28 unit dose blister packages of 100
- NDC 0006-0277-82 bottles of 1000.
- Storage
- Store at 20-25°C (68-77°F), excursions permitted to 15-30°C (59-86°F).
## Storage
There is limited information regarding Sitagliptin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
# Precautions with Alcohol
- Alcohol-Sitagliptin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Januvia®[2]
# Look-Alike Drug Names
- Januvia® — Enjuvia®[3]
- Januvia® — Jantoven®[3]
- Januvia® — Janumet®[3]
- sitaGLIPtin® — SUMAtriptan®[3]
- sitaGLIPtin® — ZOLMitriptan®[3]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Januvia | |
3578de03e052158182daf9a832a5deea64029f7b | wikidoc | Joker venom | Joker venom
Joker venom is a fictional toxin, a favourite murder weapon utilised by The Joker in the Batman franchise of movies, comics, and cartoons.
# Analysis
Joker venom can exist in liquid and gas states and has been used to great effect. The gas form is slightly denser than air and in some portrayals dissipates over time.
The DC Technical Manual: S.T.A.R. Labs 1993 Annual Report (a sourcebook for Mayfair's DC Heroes Roleplaying Game) stated that Joker Venom is "a hellish mixture of hydrogen cyanide and Strychnodide (a strychnine derivative), the toxin causes immediate cessation of heart and brain functions. As a side effect, the victim's muscles contract in such a way as to severely tighten and discolor the victim's skin, especially in the facial area. This leaves the victim's corpse permanently scarred with a clown-like grin in tribute to his killer. Since the Joker Venom is just as deadly if absorbed through the pores as it is if inhaled, the Joker occasionally releases it in gas form throughout the central heating/cooling vents of a building."
How exactly Joker knows how to make the venom varies by story. In the graphic novel Batman: The Killing Joke, it was revealed that the man who would become the Joker once worked in a chemical plant, and may have had some chemical education as a result.
In the 1989 movie, when Bruce Wayne reads through the police file on Jack Napier, he learns that Napier, despite his criminal ways, is extremely intelligent and especially gifted in chemistry. Napier, who became the Joker, was inspired to make the poison after reading testing reports on a nerve-affecting chemical that was (presumably) a component in the vat mixture caused his metamorphosis.
The 2004 graphic novel Batman: The Man Who Laughs revealed that Joker, who was created via way of the chemicals, had stolen them in a plan to poison Gotham City's resevoir, but the plan was foiled by Batman. A story arc in Legends of the Dark Knight revealed that a cousin of the man who became the Joker, Melvin Reipan, a master chemist but an idiotic buffoon otherwise due to an idiot-savant condition, was persuaded to create the Joker Venom as a way to "make people laugh", in exchange for becoming "handsome". However, Reipan was in fact physically very attractive, only having been told by his abusive mother he was ugly. This story appeared in Batman: Legends of the Dark Knight #50 and not only revealed the origins of Joker Venom, but also told the first battle between Batman and the Joker after his first attempt to destroy the city.
In a 1980s comic book, the Joker facilitates one of his many escapes from Arkham Asylum using the venom - by mixing together the common cleaning chemicals found in a janitor's closet.
Marvel Comics has an apparent equivalent to Joker venom in the form of Red Skull's "dust of death", a chemical which turns the head of its victim into a "red skull" resembling that of Red Skull. In a crossover, the Red Skull and the Joker face off against one another, the Joker angry he had unwittingly worked for a Nazi(I'm a lunatic, but I'm an American lunatic!), and employ their favourite toxins on each other-realizing they are useless, as they are immune to their own, and both toxins are strikingly similar at chemical level.
# Effects
- Lethal version
Contact with Joker venom causes uncontrollable spasms of laughter and then causes a painful death. Some have speculated that the venom hyperstimulates the laughter functions of the brain and the victim is unable to breathe.
- Non-lethal version
Prolonged exposure to the non-fatal forms can cause permanent brain damage.
The venom causes uncontrollable laughter, but instead of dying, their faces are usually pulled into an unusually large grin. Artists often stylize the effects, adding yellowed teeth, bulging eyes, etc. similar to the features of the Joker himself.
# Usage
- Comics
Joker venom has been a part of the Joker's arsenal since his first appearance in Batman #1 (1940). The venom is often deployed as an airborne agent, but can also be used in its liquid form (used both to poison victims through their unwitting consumption of it, or in special darts). In Batman: The Killing Joke, Joker was seen to use a spike worn in his palm (similar to a Joy Buzzer) to administer the drug in a handshake manner. In Jeph Lobe's and Tim Sale's Catwoman: When in Rome Joker venom is duplicted by the Riddler to blame Catwoman for the murder a mafia king pin in Sicily. It is referred to as Joker Juice by both Catwoman and The Riddler.
- Batman: The Animated Series
In the 1990s animated series, Joker venom was almost exclusively a non-lethal gas, or, as seen more often, infected individuals are almost always revived before death (the venom doesn't kill as quickly in the series). It was also used as part of a binary compound in an episode called "The Laughing Fish", in which selected targets were exposed to part of the compound and later gassed with the second part, thus the venom would only affect the intended party. That same episode also featured a diluted version of the toxin, which only affected fish to make them smile (though as Joker later revealed in "Mad Love", the toxin was ineffective on piranha), as part of Joker's plan to sell "Joker Fish" and earn money off product sales (Joker also indicated a possible plan to alter the toxin to affect cattle should the fish plan not work- a hint that Joker could alter the toxin to affect any specific species of life he wished). In later movies and episodes, the venom became lethal (it was used to kill, among others, Sal Valestra in Mask of the Phantasm, a security guard in "Holiday Knights" and a government agent in the Justice League episode "Wild Cards"), although Joker also used the non-lethal variant as well. Joker did not appear to be immune to it, as evidenced by his protective helmet in "The Last Laugh" (although this may have been an oversight - later episodes showed him breathing and even talking while the gas is in the air around him). However, in the episode Harley & Ivy, Poison Ivy did display immunity towards it due to her immune system's resistance to toxins.
- Batman (1989 film)
Dubbed Smilex (sometimes spelled Smylex) by the Joker, the venom originated as did nerve gas, an experimental bioweapon developed by the U.S. Army and discontinued in 1977, according to a file seen in the Joker's lair (the date may have been chosen to coincide with President Jimmy Carter's order for the cessation of U.S. biological weapon production that year). Smilex was distributed both as a gas and in liquid form, mixed as separate components in various beauty and hygiene products which only took effect when the victim used a number of them in tandem, thus making the toxin impossible to trace. The Joker shows no immunity to it, and can be seen donning a gas mask during the mass gassing during Gotham City's 200th anniversary parade scene.
- The Batman (new TV series)
Both versions of the venom are used in the new cartoon. The non-lethal version is weaponized as a gas and seems to dissipate over time. The gas is called "laughing gas", and puts its victims into a coma. Batman provided an antidote to this laughing gas. However, Joker also has a lethal version which is a liquid. The effects of this venom are the same as the one used in the Joker's first appearance in the comics (a venom which takes 24 hours to kill.). In the meantime, the victim slowly has fits of laughter until they are unable to function and die with Joker's trademark grin. Batman was infected with the venom, and was able to make a cure for it as well before it was too late.
# Cures
It has been stated that the Joker constantly alters the formula to the Venom (which he is immune to) so no antidote can be prepared for it. However, there have been some antidotes concocted. Gotham Police Commissioner Jim Gordon had been poisoned with the venom; and was successfully saved. It took days for the effects of the venom to get completely out of his systems. During that time, he found black humor funny; although normally, that would be out of character for him.
Poison Ivy concocted a fast-acting antidote for Joker venom. In Harley Quinn #13, Harley asks Ivy why she did not save people under the venom's influence, to which Ivy replies, "I don't do that, Harley. I don't save people. I'm poison, remember?"
# Aliases
Joker Venom has had a variety of names depending on the writer. They include:
Smilex
Laughing Gas,
Joker Gas,
Joker Juice,
Laughing Toxin,
Laugh-A-loads
and Perma-Smile | Joker venom
Joker venom is a fictional toxin, a favourite murder weapon utilised by The Joker in the Batman franchise of movies, comics, and cartoons.
# Analysis
Joker venom can exist in liquid and gas states and has been used to great effect. The gas form is slightly denser than air and in some portrayals dissipates over time.
The DC Technical Manual: S.T.A.R. Labs 1993 Annual Report (a sourcebook for Mayfair's DC Heroes Roleplaying Game) stated that Joker Venom is "a hellish mixture of hydrogen cyanide and Strychnodide (a strychnine derivative), the toxin causes immediate cessation of heart and brain functions. As a side effect, the victim's muscles contract in such a way as to severely tighten and discolor the victim's skin, especially in the facial area. This leaves the victim's corpse permanently scarred with a clown-like grin in tribute to his killer. Since the Joker Venom is just as deadly if absorbed through the pores as it is if inhaled, the Joker occasionally releases it in gas form throughout the central heating/cooling vents of a building."
How exactly Joker knows how to make the venom varies by story. In the graphic novel Batman: The Killing Joke, it was revealed that the man who would become the Joker once worked in a chemical plant, and may have had some chemical education as a result.
In the 1989 movie, when Bruce Wayne reads through the police file on Jack Napier, he learns that Napier, despite his criminal ways, is extremely intelligent and especially gifted in chemistry. Napier, who became the Joker, was inspired to make the poison after reading testing reports on a nerve-affecting chemical that was (presumably) a component in the vat mixture caused his metamorphosis.
The 2004 graphic novel Batman: The Man Who Laughs revealed that Joker, who was created via way of the chemicals, had stolen them in a plan to poison Gotham City's resevoir, but the plan was foiled by Batman. A story arc in Legends of the Dark Knight revealed that a cousin of the man who became the Joker, Melvin Reipan, a master chemist but an idiotic buffoon otherwise due to an idiot-savant condition, was persuaded to create the Joker Venom as a way to "make people laugh", in exchange for becoming "handsome". However, Reipan was in fact physically very attractive, only having been told by his abusive mother he was ugly. This story appeared in Batman: Legends of the Dark Knight #50 and not only revealed the origins of Joker Venom, but also told the first battle between Batman and the Joker after his first attempt to destroy the city.
In a 1980s comic book, the Joker facilitates one of his many escapes from Arkham Asylum using the venom - by mixing together the common cleaning chemicals found in a janitor's closet.
Marvel Comics has an apparent equivalent to Joker venom in the form of Red Skull's "dust of death", a chemical which turns the head of its victim into a "red skull" resembling that of Red Skull. In a crossover, the Red Skull and the Joker face off against one another, the Joker angry he had unwittingly worked for a Nazi(I'm a lunatic, but I'm an American lunatic!), and employ their favourite toxins on each other-realizing they are useless, as they are immune to their own, and both toxins are strikingly similar at chemical level.
# Effects
- Lethal version
Contact with Joker venom causes uncontrollable spasms of laughter and then causes a painful death. Some have speculated that the venom hyperstimulates the laughter functions of the brain and the victim is unable to breathe.
- Non-lethal version
Prolonged exposure to the non-fatal forms can cause permanent brain damage.
The venom causes uncontrollable laughter, but instead of dying, their faces are usually pulled into an unusually large grin. Artists often stylize the effects, adding yellowed teeth, bulging eyes, etc. similar to the features of the Joker himself.
# Usage
- Comics
Joker venom has been a part of the Joker's arsenal since his first appearance in Batman #1 (1940). The venom is often deployed as an airborne agent, but can also be used in its liquid form (used both to poison victims through their unwitting consumption of it, or in special darts). In Batman: The Killing Joke, Joker was seen to use a spike worn in his palm (similar to a Joy Buzzer) to administer the drug in a handshake manner. In Jeph Lobe's and Tim Sale's Catwoman: When in Rome Joker venom is duplicted by the Riddler to blame Catwoman for the murder a mafia king pin in Sicily. It is referred to as Joker Juice by both Catwoman and The Riddler.
- Batman: The Animated Series
In the 1990s animated series, Joker venom was almost exclusively a non-lethal gas, or, as seen more often, infected individuals are almost always revived before death (the venom doesn't kill as quickly in the series). It was also used as part of a binary compound in an episode called "The Laughing Fish", in which selected targets were exposed to part of the compound and later gassed with the second part, thus the venom would only affect the intended party. That same episode also featured a diluted version of the toxin, which only affected fish to make them smile (though as Joker later revealed in "Mad Love", the toxin was ineffective on piranha), as part of Joker's plan to sell "Joker Fish" and earn money off product sales (Joker also indicated a possible plan to alter the toxin to affect cattle should the fish plan not work- a hint that Joker could alter the toxin to affect any specific species of life he wished). In later movies and episodes, the venom became lethal (it was used to kill, among others, Sal Valestra in Mask of the Phantasm, a security guard in "Holiday Knights" and a government agent in the Justice League episode "Wild Cards"), although Joker also used the non-lethal variant as well. Joker did not appear to be immune to it, as evidenced by his protective helmet in "The Last Laugh" (although this may have been an oversight - later episodes showed him breathing and even talking while the gas is in the air around him). However, in the episode Harley & Ivy, Poison Ivy did display immunity towards it due to her immune system's resistance to toxins.
- Batman (1989 film)
Dubbed Smilex (sometimes spelled Smylex) by the Joker, the venom originated as did nerve gas, an experimental bioweapon developed by the U.S. Army and discontinued in 1977, according to a file seen in the Joker's lair (the date may have been chosen to coincide with President Jimmy Carter's order for the cessation of U.S. biological weapon production that year). Smilex was distributed both as a gas and in liquid form, mixed as separate components in various beauty and hygiene products which only took effect when the victim used a number of them in tandem, thus making the toxin impossible to trace. The Joker shows no immunity to it, and can be seen donning a gas mask during the mass gassing during Gotham City's 200th anniversary parade scene.
- The Batman (new TV series)
Both versions of the venom are used in the new cartoon. The non-lethal version is weaponized as a gas and seems to dissipate over time. The gas is called "laughing gas", and puts its victims into a coma. Batman provided an antidote to this laughing gas. However, Joker also has a lethal version which is a liquid. The effects of this venom are the same as the one used in the Joker's first appearance in the comics (a venom which takes 24 hours to kill.). In the meantime, the victim slowly has fits of laughter until they are unable to function and die with Joker's trademark grin. Batman was infected with the venom, and was able to make a cure for it as well before it was too late.
# Cures
It has been stated that the Joker constantly alters the formula to the Venom (which he is immune to) so no antidote can be prepared for it. However, there have been some antidotes concocted. Gotham Police Commissioner Jim Gordon had been poisoned with the venom; and was successfully saved. It took days for the effects of the venom to get completely out of his systems. During that time, he found black humor funny; although normally, that would be out of character for him.
Poison Ivy concocted a fast-acting antidote for Joker venom. In Harley Quinn #13, Harley asks Ivy why she did not save people under the venom's influence, to which Ivy replies, "I don't do that, Harley. I don't save people. I'm poison, remember?"
# Aliases
Joker Venom has had a variety of names depending on the writer. They include:
Smilex
Laughing Gas,
Joker Gas,
Joker Juice,
Laughing Toxin,
Laugh-A-loads
and Perma-Smile
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Joker_venom | |
aa2448f54156fb36d5466e0a01ec1404177ce999 | wikidoc | Junin virus | Junin virus
# Morphology and Genome Structure
The Junín virus virion is enveloped with a variable diameter of between 50 and 300nm. The surface of the particle encompasses a layer of T-shaped glycoprotein extensions, extending upto 10nm from the envelope, which are important for mediating attachment and entry into host cells.
The Junín virus genome comprises two single stranded RNA molecules, each encoding two different genes in an ambisense orientation. The two segments are termed 'short (S)' and 'long (L)' due to their respective lengths. The short segment (around 3400 nucleotides in length) encodes the nucleocapsid protein and the glycoprotein precursor (GPC). The GPC is subsequently cleaved to form two viral glycoproteins, GP1 and GP2 which ultimately form the T-shaped glycoprotein spike which extends from the viral envelope. . The long segment (around 7200 nucleotides in length) encodes the viral polymerase and a zinc binding protein.
# Epidemiology and Disease
A member of the genus Arenavirus, Junín virus characteristically causes Argentine hemorrhagic fever (AHF). AHF leads to major alterations within the vascular, neurological and immune systems and has a mortality rate of between 20 and 30%. Symptoms of the disease are conjunctivitis, purpura, petechia and occasional sepsis. The symptoms of the disease are relatively indistinct and may therefore be mistaken for a different condition.
Since the discovery of the Junín virus in 1958, the geographical distribution of the pathogen, although still confined to Argentina, has risen. At the time of discovery, Junín virus was confined to an area of around 15,000km². At the beginning of 2000, the distribution had risen to around 150,000km².. The natural hosts of Junín virus are rodents, particularly Mus musculus, Calomys spp and Akodon azarae. Direct rodent to human transmission only transpires when contact is made with excrement of an infected rodent. This commonly occurs via ingestion of contaminated food or water, inhalation of particles within urine or via direct contact of broken skin with rodent excrement. | Junin virus
# Morphology and Genome Structure
The Junín virus virion is enveloped with a variable diameter of between 50 and 300nm. The surface of the particle encompasses a layer of T-shaped glycoprotein extensions, extending upto 10nm from the envelope, which are important for mediating attachment and entry into host cells.
The Junín virus genome comprises two single stranded RNA molecules, each encoding two different genes in an ambisense orientation. The two segments are termed 'short (S)' and 'long (L)' due to their respective lengths. The short segment (around 3400 nucleotides in length) encodes the nucleocapsid protein and the glycoprotein precursor (GPC). The GPC is subsequently cleaved to form two viral glycoproteins, GP1 and GP2 which ultimately form the T-shaped glycoprotein spike which extends from the viral envelope. [1]. The long segment (around 7200 nucleotides in length) encodes the viral polymerase and a zinc binding protein.
# Epidemiology and Disease
A member of the genus Arenavirus, Junín virus characteristically causes Argentine hemorrhagic fever (AHF). AHF leads to major alterations within the vascular, neurological and immune systems and has a mortality rate of between 20 and 30%[2]. Symptoms of the disease are conjunctivitis, purpura, petechia and occasional sepsis. The symptoms of the disease are relatively indistinct and may therefore be mistaken for a different condition.
Since the discovery of the Junín virus in 1958, the geographical distribution of the pathogen, although still confined to Argentina, has risen. At the time of discovery, Junín virus was confined to an area of around 15,000km². At the beginning of 2000, the distribution had risen to around 150,000km².[3]. The natural hosts of Junín virus are rodents, particularly Mus musculus, Calomys spp and Akodon azarae. Direct rodent to human transmission only transpires when contact is made with excrement of an infected rodent. This commonly occurs via ingestion of contaminated food or water, inhalation of particles within urine or via direct contact of broken skin with rodent excrement. | https://www.wikidoc.org/index.php/Junin | |
9279b731b0da0df7170e793038274b33aae1214f | wikidoc | KARS (gene) | KARS (gene)
Lysyl-tRNA synthetase is an enzyme that in humans is encoded by the KARS gene.
# Function
Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. Lysyl-tRNA synthetase is a homodimer localized to the cytoplasm which belongs to the class II family of tRNA synthetases. It has been shown to be a target of autoantibodies in the human autoimmune diseases, polymyositis or dermatomyositis
Besides its role in translation, Lysyl-tRNA synthetase is involved in a signaling pathway leading to gene activation. Following physiological stimulation of a variety of cells, Lysyl-tRNA synthetase binds to the transcription factors MITF and USF2 and can then influence their transcriptional activities. Such physiological stimulation includes immunological activation of mast cells, so this pathway maybe relevant to the allergic response.
# Interactions
KARS (gene) has been shown to interact with Multisynthetase complex auxiliary component p38. Physiological trigger such as immunological activation results in the phosphorylation of LysRS is on serine residues. It separates from the multisynthetase complex and initiates Ap4A production. | KARS (gene)
Lysyl-tRNA synthetase is an enzyme that in humans is encoded by the KARS gene.[1][2][3]
# Function
Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. Lysyl-tRNA synthetase is a homodimer localized to the cytoplasm which belongs to the class II family of tRNA synthetases. It has been shown to be a target of autoantibodies in the human autoimmune diseases, polymyositis or dermatomyositis[3]
Besides its role in translation, Lysyl-tRNA synthetase is involved in a signaling pathway leading to gene activation.[4] Following physiological stimulation of a variety of cells, Lysyl-tRNA synthetase binds to the transcription factors MITF[5] and USF2[6] and can then influence their transcriptional activities. Such physiological stimulation includes immunological activation of mast cells, so this pathway maybe relevant to the allergic response.
# Interactions
KARS (gene) has been shown to interact with Multisynthetase complex auxiliary component p38.[7][8] Physiological trigger such as immunological activation results in the phosphorylation of LysRS is on serine residues. It separates from the multisynthetase complex and initiates Ap4A production.[4] | https://www.wikidoc.org/index.php/KARS_(gene) | |
2886d3f9f19a2316975200b36a21d47a49cf1c89 | wikidoc | Nucleoplasm | Nucleoplasm
# Overview
Similar to the cytoplasm of a cell, the nucleus contains nucleoplasm or nuclear sap. The nucleoplasm is one of the types of protoplasm, and it is often enveloped by the nuclear membrane or nuclear envelope. The nucleoplasm is a highly viscous liquid that surrounds the chromosomes and nucleoli. Many substances such as nucleotides (necessary for purposes such as the replication of DNA) and enzymes (which direct activities that take place in the nucleus) are dissolved in the nucleoplasm. The nucleoplasm is not a disorganized mass of jelly but a highly structured cell compartment formed of a nucleoskeleton. For example, a network of fibers known as the nuclear matrix can be found in the nucleoplasm. The nucleoplasm is partly made up of nucleohyaloplasm and nucleosol. The nucleoplasm is also colorless.
# Introduction
A plasm is a formative or formed material; i.e., something molded. Usually a formed material keeps it shape once the mold is removed. Should something be glassy or transparent it can be said to be hyaloid. Whether a fluid is molded or liquid is often a matter of viscosity and whether a fluid is transparent, translucent, or opaque is often a matter of absorption or scattering.
# Visibility of the nucleoplasm
Factors that can increase the visibility of the nucleoplasm include the state of lateral aggregation of deoxyribonucleic acid and the presence of fibrils. In E. coli, for example, the nucleoplasm has a formed shape that can be altered by fixation.
# Nuclear localization
The subcellular distribution of a substance to or within the nucleus is often referred to as nuclear localization.
Nucleophosmin has been found to require ATP and/or CTP for translocation (taking approximately 2-4 hrs) from nucleoli into the nucleoplasm as verified by immunofluorescent localization. The redistribution of nucleophosmin into the nucleoplasm was considered uniform, occurs during interphase or differentiation, and is a normal cellular process.
# Binding to the nucleoplasm
As a molded material, the nucleoplasm can serve as a target for binding molecules. For example, thyroid hormones have been found to bind to it.
# Macromolecular crowding
The nucleoplasm contains large amounts of macromolecules, which can alter how molecules behave, through macromolecular crowding. Since some of these macromolecules have less volume to move in, their effective concentration is increased. This crowding effect can produce large changes in both the rates and chemical equilibrium for reactions in the nucleoplasm. It is particularly important in its ability to alter dissociation constants by favoring the association of macromolecules, such as when multiple proteins come together to form protein complexes, or when DNA-binding proteins bind to their targets in the genome.
Macromolecular crowding provides the nucleoplasm with strongly viscoeleastic properties and renders the diffusion of soluble proteins anomalous. The cytoplasm is somewhat more crowded than the nucleoplasm.
Using computer simulation, it has been shown that crowding significantly enhances the rate and extent of macromolecular associations of proteins and larger structures for small radii relative to normal diffusion, but for larger radii the probability of finding the target massively decreases below that of normal diffusion, which itself decreases quite rapidly and becomes <1% when starting at a distance that exceeds the target's 10-fold radius. | Nucleoplasm
Editor-In-Chief: Henry A. Hoff
# Overview
Similar to the cytoplasm of a cell, the nucleus contains nucleoplasm or nuclear sap. The nucleoplasm is one of the types of protoplasm, and it is often enveloped by the nuclear membrane or nuclear envelope. The nucleoplasm is a highly viscous liquid that surrounds the chromosomes and nucleoli. Many substances such as nucleotides (necessary for purposes such as the replication of DNA) and enzymes (which direct activities that take place in the nucleus) are dissolved in the nucleoplasm. The nucleoplasm is not a disorganized mass of jelly but a highly structured cell compartment formed of a nucleoskeleton. For example, a network of fibers known as the nuclear matrix can be found in the nucleoplasm. The nucleoplasm is partly made up of nucleohyaloplasm and nucleosol. The nucleoplasm is also colorless.
# Introduction
A plasm is a formative or formed material; i.e., something molded. Usually a formed material keeps it shape once the mold is removed. Should something be glassy or transparent it can be said to be hyaloid. Whether a fluid is molded or liquid is often a matter of viscosity and whether a fluid is transparent, translucent, or opaque is often a matter of absorption or scattering.
# Visibility of the nucleoplasm
Factors that can increase the visibility of the nucleoplasm include the state of lateral aggregation of deoxyribonucleic acid and the presence of fibrils.[1] In E. coli, for example, the nucleoplasm has a formed shape that can be altered by fixation.[1]
# Nuclear localization
The subcellular distribution of a substance to or within the nucleus is often referred to as nuclear localization.[2]
Nucleophosmin has been found to require ATP and/or CTP for translocation (taking approximately 2-4 hrs) from nucleoli into the nucleoplasm as verified by immunofluorescent localization.[3] The redistribution of nucleophosmin into the nucleoplasm was considered uniform, occurs during interphase or differentiation, and is a normal cellular process.[3]
# Binding to the nucleoplasm
As a molded material, the nucleoplasm can serve as a target for binding molecules. For example, thyroid hormones have been found to bind to it.[4]
# Macromolecular crowding
The nucleoplasm contains large amounts of macromolecules, which can alter how molecules behave, through macromolecular crowding. Since some of these macromolecules have less volume to move in, their effective concentration is increased. This crowding effect can produce large changes in both the rates and chemical equilibrium for reactions in the nucleoplasm.[5] It is particularly important in its ability to alter dissociation constants by favoring the association of macromolecules, such as when multiple proteins come together to form protein complexes, or when DNA-binding proteins bind to their targets in the genome.[6]
Macromolecular crowding provides the nucleoplasm with strongly viscoeleastic properties and renders the diffusion of soluble proteins anomalous.[7] The cytoplasm is somewhat more crowded than the nucleoplasm.[7]
Using computer simulation, it has been shown that crowding significantly enhances the rate and extent of macromolecular associations of proteins and larger structures for small radii relative to normal diffusion, but for larger radii the probability of finding the target massively decreases below that of normal diffusion, which itself decreases quite rapidly and becomes <1% when starting at a distance that exceeds the target's 10-fold radius.[8] | https://www.wikidoc.org/index.php/Karyoplasm | |
56f44f09b7b58258b099598bfd5cf4cd75cde766 | wikidoc | Kehr's sign | Kehr's sign
Kehr's sign is the occurrence of acute pain in the tip of the shoulder due to the presence of blood or other irritants in the peritoneal cavity when a person is lying down and the legs are elevated. Kehr's sign in the left shoulder is considered a classical symptom of a ruptured spleen. May result from diaphragmatic or peridiaphragmatic lesions, renal calculi, splenic injury or ectopic pregnancy.
Kehr's sign is a classical example of referred pain: irritation of the diaphragm is signalled by the phrenic nerve as pain in the area above the collarbone.
The discovery of this is often attributed to a German gall bladder surgeon named Hans Kehr, but extensive studies into research he conducted during his life shows inconclusive evidence as to whether or not he actually discovered it. | Kehr's sign
Kehr's sign is the occurrence of acute pain in the tip of the shoulder due to the presence of blood or other irritants in the peritoneal cavity when a person is lying down and the legs are elevated. Kehr's sign in the left shoulder is considered a classical symptom of a ruptured spleen. May result from diaphragmatic or peridiaphragmatic lesions, renal calculi, splenic injury or ectopic pregnancy.
Kehr's sign is a classical example of referred pain: irritation of the diaphragm is signalled by the phrenic nerve as pain in the area above the collarbone.
The discovery of this is often attributed to a German gall bladder surgeon named Hans Kehr, but extensive studies into research he conducted during his life shows inconclusive evidence as to whether or not he actually discovered it.[1] | https://www.wikidoc.org/index.php/Kehr%27s_sign | |
147b8cbf440c275de21f78a840f0af1d52e26cd0 | wikidoc | Keratoconus | Keratoconus
# Overview
Keratoconus (from Greek: kerato- horn, cornea; and konos cone), is a degenerative non-inflammatory disorder of the eye in which structural changes within the cornea cause it to thin and change to a more conical shape than its normal gradual curve. Keratoconus can cause substantial distortion of vision, with multiple images, streaking and sensitivity to light all often reported by the patient. Keratoconus is the most common dystrophy of the cornea, affecting around one person in a thousand, and it seems to occur in populations throughout the world, although some ethnic groups experience a greater prevalence than others. It is typically diagnosed in the patient's adolescent years and attains its most severe state in the twenties and thirties.
Keratoconus is a little-understood disease with an uncertain cause, and its progression following diagnosis is unpredictable. If afflicting both eyes, the deterioration in vision can affect the patient's ability to drive a car or read normal print. In most cases, corrective lenses are effective enough to allow the patient to continue to drive legally and likewise function normally. Further progression of the disease may require surgery including transplantation of the cornea. Despite its uncertainties, keratoconus can be successfully managed with a variety of clinical and surgical techniques, and often with little or no impairment to the patient's quality of life.
# History
In a 1748 doctoral dissertation, the German oculist Burchard Mauchart provided an early description of a case of keratoconus, which he called staphyloma diaphanum. However, it was not until 1854 that British physician John Nottingham clearly described keratoconus and distinguished it from other ectasias of the cornea. Nottingham reported the cases of "conical cornea" that had come to his attention, and described several classic features of the disease, including polyopia, weakness of the cornea, and difficulty matching corrective lenses to the patient's vision. In 1859 British surgeon William Bowman used an ophthalmoscope (recently invented by Hermann von Helmholtz) to diagnose keratoconus, and described how to angle the instrument's mirror so as to best see the conical shape of the cornea. Bowman also attempted to restore the vision by pulling on the iris with a fine hook inserted through the cornea and stretching the pupil into a vertical slit, like that of a cat. He reported that he had had a measure of success with the technique, restoring vision to an 18-year old woman who had previously been unable to count fingers at a distance of 8 inches (20 cm). By 1869, when the pioneering Swiss ophthalmologist Johann Horner wrote a thesis entitled On the treatment of keratoconus, the disorder had acquired its current name. The treatment at that time, endorsed by the leading German ophthalmologist Albrecht von Gräfe, was an attempt to physically reshape the cornea by chemical cauterization with a silver nitrate solution and application of a miosis-causing agent with a pressure dressing. In 1888 the treatment of keratoconus became one of the first practical applications of the then newly-invented contact lens, when the French physician Eugène Kalt manufactured a glass scleral shell which improved vision by compressing the cornea into a more regular shape. Since the start of the twentieth century, research on keratoconus has both improved understanding of the disease and greatly expanded the range of treatment options.
# Features
## Symptoms
People with early keratoconus typically notice a minor blurring of their vision and come to their clinician seeking corrective lenses for reading or driving. At early stages, the symptoms of keratoconus may be no different from those of any other refractive defect of the eye. As the disease progresses, vision deteriorates, sometimes rapidly. Visual acuity becomes impaired at all distances, and night vision is often quite poor. Some individuals have vision in one eye that is markedly worse than that in the other eye. Some develop photophobia (sensitivity to bright light), eye strain from squinting in order to read, or itching in the eye. There is however normally little or no sensation of pain.
The classic symptom of keratoconus is the perception of multiple 'ghost' images, known as monocular polyopia. This effect is most clearly seen with a high contrast field, such as a point of light on a dark background. Instead of seeing just one point, a person with keratoconus sees many images of the point, spread out in a chaotic pattern. This pattern does not typically change from day to day, but over time it often takes on new forms. Patients also commonly notice streaking and flaring distortion around light sources. Some even notice the images moving relative to one another in time with their heart beat.
## Signs and diagnosis
Prior to any physical examination, the diagnosis of keratoconus frequently begins with an ophthalmologist's or optometrist's assessment of the patient's medical history, particularly the chief complaint and other visual symptoms, the presence of any history of ocular disease or injury which might affect vision, and the presence of any family history of ocular disease. An eye chart, such as a standard Snellen chart of progressively smaller letters, is then used to determine the patient's visual acuity. The eye examination may proceed to measurement of the localised curvature of the cornea with a manual keratometer, with detection of irregular astigmatism suggesting a possibility of keratoconus. Severe cases can exceed the instrument's measuring ability. A further indication can be provided by retinoscopy, in which a light beam is focused on the patient's retina and the reflection, or reflex, observed as the examiner tilts the light source back and forth. Keratoconus is amongst the ophthalmic conditions that exhibit a scissor reflex action of two bands moving toward and away from each other like the blades of a pair of scissors.
If keratoconus is suspected, the ophthalmologist or optometrist will search for other characteristic findings of the disease by means of slit lamp examination of the cornea. An advanced case is usually readily apparent to the examiner, and can provide for an unambiguous diagnosis prior to more specialised testing. Under close examination, a ring of yellow-brown to olive-green pigmentation known as a Fleischer ring can be observed in around half of keratoconic eyes. The Fleischer ring, caused by deposition of the iron oxide hemosiderin within the corneal epithelium, is subtle and may not be readily detectable in all cases, but becomes more evident when viewed under a cobalt blue filter. Similarly, around 50% of subjects exhibit Vogt's striae, fine stress lines within the cornea caused by stretching and thinning. The striae temporarily disappear while slight pressure is applied to the eyeball. A highly pronounced cone can create a V-shaped indentation in the lower eyelid when the patient's gaze is directed downwards, known as Munson's sign. Other clinical signs of keratoconus will normally have presented themselves long before Munson's sign becomes apparent, and so this finding, though a classic sign of the disease, tends not to be of primary diagnostic importance.
A handheld keratoscope, sometimes known as Placido's disk, can provide a simple non-invasive visualization of the surface of the cornea by projecting a series of concentric rings of light onto the cornea. A more definitive diagnosis can be obtained using corneal topography, in which an automated instrument projects the illuminated pattern onto the cornea and determines its topology from analysis of the digital image. The topographical map indicates any distortions or scarring in the cornea, with keratoconus revealed by a characteristic steepening of curvature which is usually below the centreline of the eye. The technique can record a snapshot of the degree and extent of the deformation as a benchmark for assessing its rate of progression. It is of particular value in detecting the disorder in its early stages when other signs have not yet presented.
Once keratoconus has been diagnosed, its degree may be classified by several metrics:
- The steepness of greatest curvature from mild ( 52 D);
- The morphology of the cone: nipple (small: 5 mm and near-central), oval (larger, below-center and often sagging), or globus (more than 75% of cornea affected);
- The corneal thickness from mild (> 506 μm) to advanced (< 446 μm).
Increasing use of corneal topography has led to a decline in use of these terms.
## Epidemiology
The National Eye Institute reports that keratoconus is the most common corneal dystrophy in the United States, affecting approximately 1 in 2,000 Americans, but some reports place the figure as high as 1 in 500. The inconsistency may be due to variations in diagnostic criteria, with some cases of severe astigmatism interpreted as those of keratoconus, and vice versa. A long-term study found a mean incidence rate of 2.0 new cases per 100,000 population per year. It is suggested that males and females, and all ethnicities appear equally susceptible, though some recent studies have cast doubt upon this, suggesting a higher prevalence amongst females; the literature however varying as to its extent. Also, a study carried out in the UK suggests that people of an Asian heritage are 4.4 times as likely to suffer from keratoconus as Caucasians, and are also more likely to be affected with the condition earlier.
Keratoconus is normally bilateral (affecting both eyes) although the distortion is usually asymmetric and is rarely completely identical in both corneas. Unilateral cases tend to be uncommon, and may in fact be very rare if a very mild condition in the better eye is simply below the limit of clinical detection. It is common for keratoconus to be diagnosed first in one eye and not until later in the other. As the condition then progresses in both eyes, the vision in the earlier-diagnosed eye will often persist to be poorer than that in its fellow.
## Prognosis
Patients with keratoconus typically present initially with mild astigmatism, commonly at the onset of puberty, and are diagnosed as having the disease by the late teenage years or early 20s. In rare cases keratoconus can occur in children or not present until later adulthood. A diagnosis of the disease at an early age may indicate a greater risk of severity in later life. Patients' vision will seem to fluctuate over a period of months, driving them to change lens prescriptions frequently but as the condition worsens, contact lenses become required in the majority of cases. The course of the disorder can be quite variable, with some patients remaining stable for years or indefinitely, while others progress rapidly or experience occasional exacerbations over a long and otherwise steady course. Most commonly, keratoconus progresses for a period of ten to twenty years before the course of the disease generally ceases.
In advanced cases, bulging of the cornea can result in a localized rupture of Descemet's membrane, an inner layer of the cornea. Aqueous humor from the eye's anterior chamber seeps into the cornea before Descemet's membrane reseals. The patient experiences pain and a sudden severe clouding of vision, with the cornea taking on a translucent milky-white appearance known as a corneal hydrops. Although disconcerting to the patient, the effect is normally temporary and after a period of six to eight weeks the cornea usually returns to its former transparency. The recovery can be aided non-surgically by bandaging with an osmotic saline solution. Although a hydrops usually causes increased scarring of the cornea, occasionally it will benefit a patient by creating a flatter cone, aiding the fitting of contact lenses. Very occasionally, in extreme cases, the cornea thins to the point that a partial rupture occurs, resulting in a small, bead-like swelling on the cornea that has been filled with fluid. When this occurs, a corneal transplant can become urgently necessary to avoid complete rupture and resulting loss of the eye.
# Pathophysiology and cause
Despite considerable research, the etiology of keratoconus remains somewhat of a mystery. A number of sources suggest that keratoconus likely arises from a number of different factors: genetic, environmental or cellular, any of which may form the trigger for the onset of the disease. Once initiated, the disease normally develops by progressive dissolution of Bowman's layer, which lies between the corneal epithelium and stroma. As the two come into contact, cellular and structural changes in the cornea adversely affect its integrity and lead to the bulging and scarring that are characteristic of the disorder. Within any individual keratoconic cornea, there may be found regions of degenerative thinning coexisting with regions undergoing wound healing.
The visual distortion experienced by the patient comes from two sources, one being the irregular deformation of the surface of the cornea; the other being scarring that occurs on its exposed highpoints. These factors act to form regions on the cornea that map an image to different locations on the retina and give rise to the symptom of monocular polyopia. The effect can worsen in low light conditions as the dark-adapted pupil dilates to expose more of the irregular surface of the cornea. Scarring appears to be an aspect of the corneal degradation; however, a recent, large, multi-center study suggests that abrasion by contact lenses may increase the likelihood of this finding by a factor of over two.
A number of studies have indicated that keratoconic corneas show signs of increased activity by proteases, a class of enzymes that break some of the collagen cross-linkages in the stroma, with a simultaneous reduced expression of protease inhibitors. Other studies have suggested that reduced activity by the enzyme aldehyde dehydrogenase may be responsible for a build-up of free radicals and oxidising species in the cornea. It seems likely that, whatever the pathogenetical process, the damage caused by activity within the cornea results in a reduction in its thickness and biomechanical strength.
A genetic predisposition to keratoconus has been observed, with the disease running in certain families, and incidences reported of concordance in identical twins. The frequency of occurrence in close family members is not clearly defined, though it is known to be considerably higher than that in the general population, and studies have obtained estimates ranging between 6% and 19%. A responsible gene has not been identified: two studies involving isolated, largely homogenetic communities have contrarily mapped putative gene locations to chromosomes 16q and 20q. However, most genetic studies agree on an autosomal dominant model of inheritance. Keratoconus is also diagnosed more often in people with Down syndrome, though the reasons for this link have not yet been determined. Keratoconus has been associated with atopic diseases, which include asthma, allergies, and eczema, and it is not uncommon for several or all of these diseases to affect one person. A number of studies suggest that vigorous eye rubbing may contribute to the progression of keratoconus, and that patients should be discouraged from the practice.
# Treatment
## Contact lenses
In early stages of keratoconus, spectacles can suffice to correct for the mild astigmatism. As the condition progresses, spectacles may no longer provide the patient with a satisfactory degree of visual acuity, and most clinical practitioners will move to managing the condition with contact lenses.
In keratoconic patients, contact lenses improve vision by means of tear fluid filling the gap between the irregular corneal surface and the smooth regular inner surface of the lens, thereby creating the effect of a smoother cornea. Many specialized types of contact lenses have been developed for keratoconus, and affected people may seek out both doctors specialized in conditions of the cornea, and contact-lens fitters who have experience managing patients with keratoconus. The irregular cone presents a challenge and the fitter will endeavour to produce a lens with the optimal contact, stability and steepness. Some trial-and-error fitting may prove necessary.
Traditionally, contact lenses for keratoconus have been the 'hard' or rigid gas-permeable variety, although manufacturers have also produced specialized 'soft' or hydrophilic lenses. A soft lens has a tendency to conform to the conical shape of the cornea, thus diminishing its effect. To counter this, hybrid lenses have been developed which are hard in the centre and encompassed by a soft skirt. Soft or hybrid lenses do not however prove effective for every patient.
Some patients also find good vision correction and comfort with a "piggyback" lens combination, in which gas permeable rigid lenses are worn over soft lenses, both providing a degree of vision correction. One form of piggyback lens makes use of a soft lens with a countersunk central area to accept the rigid lens. Fitting a piggyback lens combination requires experience on the part of the lens fitter, and tolerance on the part of the keratoconic patient.
Scleral lenses are sometimes prescribed for cases of advanced or very irregular keratoconus; these lenses cover a greater proportion of the surface of the eye and hence can offer improved stability. The larger size of the lenses may make them unappealing or uncomfortable to some, however their easier handling can find favour with patients with reduced dexterity, such as the elderly.
## Surgical options
### Corneal transplant
Between 10% and 25% of cases of keratoconus will progress to a point where vision correction is no longer possible, thinning of the cornea becomes excessive, or scarring as a result of contact lens wear causes problems of its own, and a corneal transplantation or penetrating keratoplasty becomes required. Keratoconus is the most common grounds for conducting a penetrating keratoplasty, generally accounting for around a quarter of such procedures. The corneal transplant surgeon trephines a lenticule of corneal tissue and then grafts the donor cornea to the existing eye tissue, usually using a combination of running and individual sutures. The cornea does not have a direct blood supply, and so donor tissue is not required to be blood type matched. Eye banks check the donor corneas for any disease or cellular irregularities.
The acute recovery period can take four to six weeks and full post-operative vision stabilization often takes a year or more but most transplants are very stable in the long term. The National Keratoconus Foundation reports that penetrating keratoplasty has the most successful outcome of all transplant procedures, and when performed for keratoconus in an otherwise healthy eye, its success rate can be 95% or greater. The sutures used usually dissolve over a period of three to five years but individual sutures can be removed during the healing process if they are causing irritation to the patient.
In the USA, corneal transplants (also known as corneal grafts) for keratoconus are usually performed under sedation as outpatient surgery. In other countries, such as Australia and the UK, the operation is commonly performed with the patient undergoing a general anaesthetic. All cases a require careful follow-up with an eye surgeon (ophthalmologist) for a number of years. Frequently, vision is greatly improved after the surgery, but even if the actual visual acuity does not improve, because the cornea is a more normal shape after the healing is completed, patients can more easily be fitted with corrective lenses. Complications of corneal transplants are mostly related to vascularization of the corneal tissue and rejection of the donor cornea. Vision loss is very rare, though difficult-to-correct vision is possible. When rejection is severe, repeat transplants are often attempted, and are frequently successful. Keratoconus will not normally reoccur in the transplanted cornea; incidences of this have been observed, but are usually attributed to incomplete excision of the original cornea or inadequate screening of the donor tissue. The long-term outlook for corneal transplants performed for keratoconus is usually favorable once the initial healing period is completed and a few years have elapsed without problems.
### DALK transplants
One way of reducing the risk of rejection is to use a newer technique called a Deep Anterior Lamellar Keratoplasty, referred to as DALK. In a DALK graft, only the outermost epithelium and the main bulk of the cornea, the stroma, are replaced; the patient's rearmost endothelium layer is retained, giving some additional structural integrity to the post-graft cornea. Because a graft rejection usually begins in the endothelium, the chance of a rejection episode is greatly reduced. Furthermore, it is possible to transplant tissue from a donor which has been freeze-dried. The freeze-drying process ensures that this tissue is dead, so there is no chance of a rejection.
Some surgeons prefer to remove the donor epithelium, others leave the donor's cells in place. Removing it can cause a slight improvement in overall vision, but a corresponding increase in visual recovery time.
### Epikeratophakia
Rarely, a non-penetrating keratoplasty known as an epikeratophakia (or epikeratoplasty) may be performed in cases of keratoconus. The corneal epithelium is removed and a lenticule of donor cornea grafted on top of it. The procedure requires a greater level of skill on the part of the surgeon, and is less frequently performed than a penetrating keratoplasty as the outcome is generally less favorable. It may however be seen as an option in a number of cases, particularly for young patients.
### Corneal ring segment inserts
A recent surgical alternative to corneal transplant is the insertion of intrastromal corneal ring segments. A small incision is made in the periphery of the cornea and two thin arcs of polymethyl methacrylate are slid between the layers of the stroma on either side of the pupil before the incision is closed. The segments push out against the curvature of the cornea, flattening the peak of the cone and returning it to a more natural shape. The procedure, carried out on an outpatient basis under local anaesthesia, offers the benefit of being reversible and even potentially exchangeable as it involves no removal of eye tissue.
The two principal types of intrastromal rings available are known by the trade names of Intacs and Ferrara rings. Intacs are flatter and less centrally placed than the prismatic Ferrara rings. Intacs were first approved by the Food and Drug Administration (FDA) in the United States in 1999 for myopia; this was extended to the treatment of keratoconus in July 2004. Ferrara rings await FDA approval for keratoconus. A development on the concept involves the injection of a transparent synthetic gel into a channel bored through the stroma. As the gel polymerises, it stiffens and takes on similar properties to the pre-formed rings.
Clinical studies on the effectiveness of intrastromal rings on keratoconus are in their early stages, and results have so far been generally encouraging, though they have yet to enter into wide acceptance with the refractive surgery community. In common with penetrating keratoplasty, the requirement for some vision correction in the form of spectacles or hydrophilic contact lenses may remain subsequent to the operation. Potential complications of intrastromal rings include accidental penetration through to the anterior chamber when forming the channel, post-operative infection of the cornea, and migration or extrusion of the segments. The rings offer a good chance of vision improvement even in otherwise hard to manage eyes, but results are not guaranteed and in a few cases may worsen.
Early studies on intrastromal corneal rings involved use of two segments to cause global flattening of the cornea. A later study reported that better results could be obtained for those cones located more to the periphery of the cornea by using a single Intacs segment. This leads to preferential flattening of the cone below, but also to steepening the over-flat upper part of the cornea.
### Radial keratotomy
Radial keratotomy is a refractive surgery procedure where the surgeon makes a spoke-like pattern of incisions into the cornea to modify its shape. This early surgical option for myopia has been largely superseded by LASIK and other similar procedures. LASIK itself is absolutely contraindicated in keratoconus and other corneal thinning conditions as removal of corneal stromal tissue will further damage an already thin and weak cornea.
For similar reasons, radial keratotomy has also generally not been used for keratoconic patients. However, an Italian clinic has reported some success with a modified asymmetric radial keratotomy procedure, in which the incisions are confined to one sector of the eye. The corneal thickness is first measured using a pachymeter, then the surgeon makes cuts to a depth of 70–80% of the measured thickness. The patient may initially experience photophobia and fluctuation of vision, in common with other forms of refractive surgery.
## Corneal Collagen Crosslinking with Riboflavin (C3-R)
A innovative treatment which has shown early success is Corneal Collagen Crosslinking with Riboflavin (C3-R), which involves a one-time application of riboflavin eye drops to the eye. The riboflavin, when activated by approximately 30 minutes illumination with UV-A light, augments the collagen cross-links within the stroma and so recovers some of the cornea's mechanical strength. C3-R, developed at the Technische Universität Dresden and the Boxer Wachler Vision Institute, has been shown to slow or arrest the progression of keratoconus, and in some cases even reverse it, particularly when applied in combination with intracorneal ring segments. A recent study showed that when C3-R was combined with Intacs, twice as much improvement occurred compared to Intacs alone.
Clinical trials are continuing, and while relatively few procedures have been performed, the technique is showing promise in treating early cases of the disease. Corrective lenses may still be required after the treatment but it is hoped that it could limit further deterioration in the patient's vision and reduce the case for keratoplasty.
# Related disorders
Several other non-inflammatory eye disorders, generally rarer than keratoconus, also cause thinning of the cornea: | Keratoconus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
# Overview
Keratoconus (from Greek: kerato- horn, cornea; and konos cone), is a degenerative non-inflammatory disorder of the eye in which structural changes within the cornea cause it to thin and change to a more conical shape than its normal gradual curve. Keratoconus can cause substantial distortion of vision, with multiple images, streaking and sensitivity to light all often reported by the patient. Keratoconus is the most common dystrophy of the cornea, affecting around one person in a thousand, and it seems to occur in populations throughout the world, although some ethnic groups experience a greater prevalence than others. It is typically diagnosed in the patient's adolescent years and attains its most severe state in the twenties and thirties.
Keratoconus is a little-understood disease with an uncertain cause, and its progression following diagnosis is unpredictable. If afflicting both eyes, the deterioration in vision can affect the patient's ability to drive a car or read normal print. In most cases, corrective lenses are effective enough to allow the patient to continue to drive legally and likewise function normally. Further progression of the disease may require surgery including transplantation of the cornea. Despite its uncertainties, keratoconus can be successfully managed with a variety of clinical and surgical techniques, and often with little or no impairment to the patient's quality of life.
# History
In a 1748 doctoral dissertation, the German oculist Burchard Mauchart provided an early description of a case of keratoconus,[1] which he called staphyloma diaphanum. However, it was not until 1854 that British physician John Nottingham clearly described keratoconus and distinguished it from other ectasias of the cornea.[1] Nottingham reported the cases of "conical cornea" that had come to his attention, and described several classic features of the disease, including polyopia, weakness of the cornea, and difficulty matching corrective lenses to the patient's vision.[2] In 1859 British surgeon William Bowman used an ophthalmoscope (recently invented by Hermann von Helmholtz) to diagnose keratoconus, and described how to angle the instrument's mirror so as to best see the conical shape of the cornea.[3] Bowman also attempted to restore the vision by pulling on the iris with a fine hook inserted through the cornea and stretching the pupil into a vertical slit, like that of a cat. He reported that he had had a measure of success with the technique, restoring vision to an 18-year old woman who had previously been unable to count fingers at a distance of 8 inches (20 cm). By 1869, when the pioneering Swiss ophthalmologist Johann Horner wrote a thesis entitled On the treatment of keratoconus,[4] the disorder had acquired its current name. The treatment at that time, endorsed by the leading German ophthalmologist Albrecht von Gräfe, was an attempt to physically reshape the cornea by chemical cauterization with a silver nitrate solution and application of a miosis-causing agent with a pressure dressing.[1] In 1888 the treatment of keratoconus became one of the first practical applications of the then newly-invented contact lens, when the French physician Eugène Kalt manufactured a glass scleral shell which improved vision by compressing the cornea into a more regular shape.[5] Since the start of the twentieth century, research on keratoconus has both improved understanding of the disease and greatly expanded the range of treatment options.
# Features
## Symptoms
People with early keratoconus typically notice a minor blurring of their vision and come to their clinician seeking corrective lenses for reading or driving.[6][7] At early stages, the symptoms of keratoconus may be no different from those of any other refractive defect of the eye. As the disease progresses, vision deteriorates, sometimes rapidly. Visual acuity becomes impaired at all distances, and night vision is often quite poor. Some individuals have vision in one eye that is markedly worse than that in the other eye. Some develop photophobia (sensitivity to bright light), eye strain from squinting in order to read, or itching in the eye.[6] There is however normally little or no sensation of pain.
The classic symptom of keratoconus is the perception of multiple 'ghost' images, known as monocular polyopia. This effect is most clearly seen with a high contrast field, such as a point of light on a dark background. Instead of seeing just one point, a person with keratoconus sees many images of the point, spread out in a chaotic pattern. This pattern does not typically change from day to day, but over time it often takes on new forms. Patients also commonly notice streaking and flaring distortion around light sources. Some even notice the images moving relative to one another in time with their heart beat.
## Signs and diagnosis
Prior to any physical examination, the diagnosis of keratoconus frequently begins with an ophthalmologist's or optometrist's assessment of the patient's medical history, particularly the chief complaint and other visual symptoms, the presence of any history of ocular disease or injury which might affect vision, and the presence of any family history of ocular disease. An eye chart, such as a standard Snellen chart of progressively smaller letters, is then used to determine the patient's visual acuity. The eye examination may proceed to measurement of the localised curvature of the cornea with a manual keratometer,[8] with detection of irregular astigmatism suggesting a possibility of keratoconus. Severe cases can exceed the instrument's measuring ability.[7] A further indication can be provided by retinoscopy, in which a light beam is focused on the patient's retina and the reflection, or reflex, observed as the examiner tilts the light source back and forth. Keratoconus is amongst the ophthalmic conditions that exhibit a scissor reflex action of two bands moving toward and away from each other like the blades of a pair of scissors.[9][7]
If keratoconus is suspected, the ophthalmologist or optometrist will search for other characteristic findings of the disease by means of slit lamp examination of the cornea.[10] An advanced case is usually readily apparent to the examiner, and can provide for an unambiguous diagnosis prior to more specialised testing. Under close examination, a ring of yellow-brown to olive-green pigmentation known as a Fleischer ring can be observed in around half of keratoconic eyes.[11] The Fleischer ring, caused by deposition of the iron oxide hemosiderin within the corneal epithelium, is subtle and may not be readily detectable in all cases, but becomes more evident when viewed under a cobalt blue filter.[7] Similarly, around 50% of subjects exhibit Vogt's striae, fine stress lines within the cornea caused by stretching and thinning.[11] The striae temporarily disappear while slight pressure is applied to the eyeball.[7] A highly pronounced cone can create a V-shaped indentation in the lower eyelid when the patient's gaze is directed downwards, known as Munson's sign.[6] Other clinical signs of keratoconus will normally have presented themselves long before Munson's sign becomes apparent,[12] and so this finding, though a classic sign of the disease, tends not to be of primary diagnostic importance.
A handheld keratoscope, sometimes known as Placido's disk, can provide a simple non-invasive visualization of the surface of the cornea by projecting a series of concentric rings of light onto the cornea. A more definitive diagnosis can be obtained using corneal topography, in which an automated instrument projects the illuminated pattern onto the cornea and determines its topology from analysis of the digital image. The topographical map indicates any distortions or scarring in the cornea, with keratoconus revealed by a characteristic steepening of curvature which is usually below the centreline of the eye.[1] The technique can record a snapshot of the degree and extent of the deformation as a benchmark for assessing its rate of progression. It is of particular value in detecting the disorder in its early stages when other signs have not yet presented.[13]
Once keratoconus has been diagnosed, its degree may be classified by several metrics:[14]
- The steepness of greatest curvature from mild (< 45 D), advanced (up to 52 D) or severe (> 52 D);
- The morphology of the cone: nipple (small: 5 mm and near-central), oval (larger, below-center and often sagging), or globus (more than 75% of cornea affected);
- The corneal thickness from mild (> 506 μm) to advanced (< 446 μm).
Increasing use of corneal topography has led to a decline in use of these terms.[14]
## Epidemiology
The National Eye Institute reports that keratoconus is the most common corneal dystrophy in the United States, affecting approximately 1 in 2,000 Americans,[15][16] but some reports place the figure as high as 1 in 500.[17] The inconsistency may be due to variations in diagnostic criteria,[7] with some cases of severe astigmatism interpreted as those of keratoconus, and vice versa.[12] A long-term study found a mean incidence rate of 2.0 new cases per 100,000 population per year.[16] It is suggested that males and females, and all ethnicities appear equally susceptible, though some recent studies have cast doubt upon this,[18] suggesting a higher prevalence amongst females; the literature however varying as to its extent. Also, a study carried out in the UK[19] suggests that people of an Asian heritage are 4.4 times as likely to suffer from keratoconus as Caucasians, and are also more likely to be affected with the condition earlier.
Keratoconus is normally bilateral[16] (affecting both eyes) although the distortion is usually asymmetric and is rarely completely identical in both corneas.[7] Unilateral cases tend to be uncommon, and may in fact be very rare if a very mild condition in the better eye is simply below the limit of clinical detection.[12] It is common for keratoconus to be diagnosed first in one eye and not until later in the other. As the condition then progresses in both eyes, the vision in the earlier-diagnosed eye will often persist to be poorer than that in its fellow.
## Prognosis
Patients with keratoconus typically present initially with mild astigmatism, commonly at the onset of puberty, and are diagnosed as having the disease by the late teenage years or early 20s. In rare cases keratoconus can occur in children or not present until later adulthood.[7] A diagnosis of the disease at an early age may indicate a greater risk of severity in later life.[1][20] Patients' vision will seem to fluctuate over a period of months, driving them to change lens prescriptions frequently but as the condition worsens, contact lenses become required in the majority of cases. The course of the disorder can be quite variable, with some patients remaining stable for years or indefinitely, while others progress rapidly or experience occasional exacerbations over a long and otherwise steady course. Most commonly, keratoconus progresses for a period of ten to twenty years[12] before the course of the disease generally ceases.
In advanced cases, bulging of the cornea can result in a localized rupture of Descemet's membrane, an inner layer of the cornea. Aqueous humor from the eye's anterior chamber seeps into the cornea before Descemet's membrane reseals. The patient experiences pain and a sudden severe clouding of vision, with the cornea taking on a translucent milky-white appearance known as a corneal hydrops.[21] Although disconcerting to the patient, the effect is normally temporary and after a period of six to eight weeks the cornea usually returns to its former transparency. The recovery can be aided non-surgically by bandaging with an osmotic saline solution. Although a hydrops usually causes increased scarring of the cornea, occasionally it will benefit a patient by creating a flatter cone, aiding the fitting of contact lenses.[21] Very occasionally, in extreme cases, the cornea thins to the point that a partial rupture occurs, resulting in a small, bead-like swelling on the cornea that has been filled with fluid. When this occurs, a corneal transplant can become urgently necessary to avoid complete rupture and resulting loss of the eye.[21]
# Pathophysiology and cause
Despite considerable research, the etiology of keratoconus remains somewhat of a mystery.[1] A number of sources suggest that keratoconus likely arises from a number of different factors: genetic, environmental or cellular, any of which may form the trigger for the onset of the disease.[22][23] Once initiated, the disease normally develops by progressive dissolution of Bowman's layer,[7] which lies between the corneal epithelium and stroma. As the two come into contact, cellular and structural changes in the cornea adversely affect its integrity and lead to the bulging and scarring that are characteristic of the disorder. Within any individual keratoconic cornea, there may be found regions of degenerative thinning coexisting with regions undergoing wound healing.
The visual distortion experienced by the patient comes from two sources, one being the irregular deformation of the surface of the cornea; the other being scarring that occurs on its exposed highpoints. These factors act to form regions on the cornea that map an image to different locations on the retina and give rise to the symptom of monocular polyopia. The effect can worsen in low light conditions as the dark-adapted pupil dilates to expose more of the irregular surface of the cornea. Scarring appears to be an aspect of the corneal degradation; however, a recent, large, multi-center study suggests that abrasion by contact lenses may increase the likelihood of this finding by a factor of over two.[24]
A number of studies have indicated that keratoconic corneas show signs of increased activity by proteases,[22] a class of enzymes that break some of the collagen cross-linkages in the stroma, with a simultaneous reduced expression of protease inhibitors.[25] Other studies have suggested that reduced activity by the enzyme aldehyde dehydrogenase may be responsible for a build-up of free radicals and oxidising species in the cornea.[26] It seems likely that, whatever the pathogenetical process, the damage caused by activity within the cornea results in a reduction in its thickness and biomechanical strength.
A genetic predisposition to keratoconus has been observed,[27] with the disease running in certain families,[28] and incidences reported of concordance in identical twins.[10] The frequency of occurrence in close family members is not clearly defined, though it is known to be considerably higher than that in the general population,[1] and studies have obtained estimates ranging between 6% and 19%.[29] A responsible gene has not been identified: two studies involving isolated, largely homogenetic communities have contrarily mapped putative gene locations to chromosomes 16q and 20q.[29] However, most genetic studies agree on an autosomal dominant model of inheritance.[6] Keratoconus is also diagnosed more often in people with Down syndrome, though the reasons for this link have not yet been determined.[30] Keratoconus has been associated with atopic diseases, which include asthma, allergies, and eczema, and it is not uncommon for several or all of these diseases to affect one person. A number of studies suggest that vigorous eye rubbing may contribute to the progression of keratoconus, and that patients should be discouraged from the practice.[31][32][33][34][35]
# Treatment
## Contact lenses
In early stages of keratoconus, spectacles can suffice to correct for the mild astigmatism. As the condition progresses, spectacles may no longer provide the patient with a satisfactory degree of visual acuity, and most clinical practitioners will move to managing the condition with contact lenses.
In keratoconic patients, contact lenses improve vision by means of tear fluid filling the gap between the irregular corneal surface and the smooth regular inner surface of the lens, thereby creating the effect of a smoother cornea. Many specialized types of contact lenses have been developed for keratoconus, and affected people may seek out both doctors specialized in conditions of the cornea, and contact-lens fitters who have experience managing patients with keratoconus. The irregular cone presents a challenge[22] and the fitter will endeavour to produce a lens with the optimal contact, stability and steepness. Some trial-and-error fitting may prove necessary.[12]
Traditionally, contact lenses for keratoconus have been the 'hard' or rigid gas-permeable variety, although manufacturers have also produced specialized 'soft' or hydrophilic lenses. A soft lens has a tendency to conform to the conical shape of the cornea, thus diminishing its effect. To counter this, hybrid lenses have been developed which are hard in the centre and encompassed by a soft skirt. Soft or hybrid lenses do not however prove effective for every patient.[36]
Some patients also find good vision correction and comfort with a "piggyback" lens combination, in which gas permeable rigid lenses are worn over soft lenses, both providing a degree of vision correction.[37] One form of piggyback lens makes use of a soft lens with a countersunk central area to accept the rigid lens. Fitting a piggyback lens combination requires experience on the part of the lens fitter, and tolerance on the part of the keratoconic patient.
Scleral lenses are sometimes prescribed for cases of advanced or very irregular keratoconus; these lenses cover a greater proportion of the surface of the eye and hence can offer improved stability.[38] The larger size of the lenses may make them unappealing or uncomfortable to some, however their easier handling can find favour with patients with reduced dexterity, such as the elderly.
## Surgical options
### Corneal transplant
Between 10% and 25% of cases of keratoconus[23][39][40] will progress to a point where vision correction is no longer possible, thinning of the cornea becomes excessive, or scarring as a result of contact lens wear causes problems of its own, and a corneal transplantation or penetrating keratoplasty becomes required. Keratoconus is the most common grounds for conducting a penetrating keratoplasty, generally accounting for around a quarter of such procedures.[41] The corneal transplant surgeon trephines a lenticule of corneal tissue and then grafts the donor cornea to the existing eye tissue, usually using a combination of running and individual sutures. The cornea does not have a direct blood supply, and so donor tissue is not required to be blood type matched. Eye banks check the donor corneas for any disease or cellular irregularities.
The acute recovery period can take four to six weeks and full post-operative vision stabilization often takes a year or more but most transplants are very stable in the long term.[40] The National Keratoconus Foundation reports that penetrating keratoplasty has the most successful outcome of all transplant procedures, and when performed for keratoconus in an otherwise healthy eye, its success rate can be 95% or greater.[23] The sutures used usually dissolve over a period of three to five years but individual sutures can be removed during the healing process if they are causing irritation to the patient.
In the USA, corneal transplants (also known as corneal grafts) for keratoconus are usually performed under sedation as outpatient surgery. In other countries, such as Australia and the UK, the operation is commonly performed with the patient undergoing a general anaesthetic. All cases a require careful follow-up with an eye surgeon (ophthalmologist) for a number of years. Frequently, vision is greatly improved after the surgery, but even if the actual visual acuity does not improve, because the cornea is a more normal shape after the healing is completed, patients can more easily be fitted with corrective lenses. Complications of corneal transplants are mostly related to vascularization of the corneal tissue and rejection of the donor cornea. Vision loss is very rare, though difficult-to-correct vision is possible. When rejection is severe, repeat transplants are often attempted, and are frequently successful.[42] Keratoconus will not normally reoccur in the transplanted cornea; incidences of this have been observed, but are usually attributed to incomplete excision of the original cornea or inadequate screening of the donor tissue.[43] The long-term outlook for corneal transplants performed for keratoconus is usually favorable once the initial healing period is completed and a few years have elapsed without problems.
### DALK transplants
One way of reducing the risk of rejection is to use a newer technique called a Deep Anterior Lamellar Keratoplasty, referred to as DALK. In a DALK graft, only the outermost epithelium and the main bulk of the cornea, the stroma, are replaced; the patient's rearmost endothelium layer is retained, giving some additional structural integrity to the post-graft cornea.[44] Because a graft rejection usually begins in the endothelium, the chance of a rejection episode is greatly reduced. Furthermore, it is possible to transplant tissue from a donor which has been freeze-dried. The freeze-drying process ensures that this tissue is dead, so there is no chance of a rejection.[44]
Some surgeons prefer to remove the donor epithelium, others leave the donor's cells in place. Removing it can cause a slight improvement in overall vision, but a corresponding increase in visual recovery time.
### Epikeratophakia
Rarely, a non-penetrating keratoplasty known as an epikeratophakia (or epikeratoplasty) may be performed in cases of keratoconus. The corneal epithelium is removed and a lenticule of donor cornea grafted on top of it.[22] The procedure requires a greater level of skill on the part of the surgeon, and is less frequently performed than a penetrating keratoplasty as the outcome is generally less favorable. It may however be seen as an option in a number of cases, particularly for young patients.[45]
### Corneal ring segment inserts
A recent surgical alternative to corneal transplant is the insertion of intrastromal corneal ring segments. A small incision is made in the periphery of the cornea and two thin arcs of polymethyl methacrylate are slid between the layers of the stroma on either side of the pupil before the incision is closed.[46] The segments push out against the curvature of the cornea, flattening the peak of the cone and returning it to a more natural shape. The procedure, carried out on an outpatient basis under local anaesthesia, offers the benefit of being reversible and even potentially exchangeable as it involves no removal of eye tissue.[46]
The two principal types of intrastromal rings available are known by the trade names of Intacs and Ferrara rings. Intacs are flatter and less centrally placed than the prismatic Ferrara rings. Intacs were first approved by the Food and Drug Administration (FDA) in the United States in 1999 for myopia; this was extended to the treatment of keratoconus in July 2004.[47] Ferrara rings await FDA approval for keratoconus. A development on the concept involves the injection of a transparent synthetic gel into a channel bored through the stroma. As the gel polymerises, it stiffens and takes on similar properties to the pre-formed rings.[48]
Clinical studies on the effectiveness of intrastromal rings on keratoconus are in their early stages, and results have so far been generally encouraging,[49][50] though they have yet to enter into wide acceptance with the refractive surgery community. In common with penetrating keratoplasty, the requirement for some vision correction in the form of spectacles or hydrophilic contact lenses may remain subsequent to the operation. Potential complications of intrastromal rings include accidental penetration through to the anterior chamber when forming the channel, post-operative infection of the cornea, and migration or extrusion of the segments.[50] The rings offer a good chance of vision improvement even in otherwise hard to manage eyes, but results are not guaranteed and in a few cases may worsen.
Early studies on intrastromal corneal rings involved use of two segments to cause global flattening of the cornea.[51] A later study reported that better results could be obtained for those cones located more to the periphery of the cornea by using a single Intacs segment. This leads to preferential flattening of the cone below, but also to steepening the over-flat upper part of the cornea.[52]
### Radial keratotomy
Radial keratotomy is a refractive surgery procedure where the surgeon makes a spoke-like pattern of incisions into the cornea to modify its shape. This early surgical option for myopia has been largely superseded by LASIK and other similar procedures. LASIK itself is absolutely contraindicated in keratoconus and other corneal thinning conditions as removal of corneal stromal tissue will further damage an already thin and weak cornea.[53]
For similar reasons, radial keratotomy has also generally not been used for keratoconic patients.[54][55] However, an Italian clinic has reported some success with a modified asymmetric radial keratotomy procedure,[56] in which the incisions are confined to one sector of the eye. The corneal thickness is first measured using a pachymeter, then the surgeon makes cuts to a depth of 70–80% of the measured thickness. The patient may initially experience photophobia and fluctuation of vision, in common with other forms of refractive surgery.[56]
## Corneal Collagen Crosslinking with Riboflavin (C3-R)
A innovative treatment which has shown early success is Corneal Collagen Crosslinking with Riboflavin (C3-R), which involves a one-time application of riboflavin eye drops to the eye.[25][57] The riboflavin, when activated by approximately 30 minutes illumination with UV-A light, augments the collagen cross-links within the stroma and so recovers some of the cornea's mechanical strength. C3-R, developed at the Technische Universität Dresden and the Boxer Wachler Vision Institute[58], has been shown to slow or arrest the progression of keratoconus, and in some cases even reverse it, particularly when applied in combination with intracorneal ring segments. A recent study showed that when C3-R was combined with Intacs, twice as much improvement occurred compared to Intacs alone.[59]
Clinical trials are continuing, and while relatively few procedures have been performed, the technique is showing promise in treating early cases of the disease.[60] Corrective lenses may still be required after the treatment but it is hoped that it could limit further deterioration in the patient's vision and reduce the case for keratoplasty.
# Related disorders
Several other non-inflammatory eye disorders, generally rarer than keratoconus, also cause thinning of the cornea:[12] | https://www.wikidoc.org/index.php/Keratoconus | |
e834c2d2989ecae9702e119c5dd7493d3d568305 | wikidoc | Keratometer | Keratometer
A keratometer, also known as a ophthalmometer, is a diagnostic instrument for measuring the curvature of the anterior surface of the cornea, particularly for assessing the extent and axis of astigmatism. It was invented by the French ophthalmologist Samuel Hankins in 1880.
A keratometer uses the relationship between object size (O), image size (I), the distance between the reflective surface and the object (d), and the radius of the reflective surface (R). If three of these variables are known (or fixed), the fourth can calculated using the formula
R = 2dI/O
There are two distinct variants of determining R; Javal-Schiotz type keratometers have a fixed image size and are typically 'two position', whereas Bausch and Lomb type keratometers have a fixed object size and are usually 'one position'.
# Javal-Schiotz Principles
The Javal-Schiotz keratometer is a two position instrument which uses a fixed image and doubling size and adjustable object size to determine the radius of curvature of the reflective surface. It uses two self illuminated mires (the object), one a red square, the other a green staircase design, which are held on a circumferential track in order to maintain a fixed distance from the eye. The object size is adjusted by maneuvering the mires along this track, changing the distance between them. The reflected image is doubled through a Wollaston prism, which then allows either side of the doubled image to be aligned, and any eye movement to cancel out as both images move with the same magnitude and direction, the relative separation remaining constant. A Wollaston prism uses the polarising property of light in order to split a single image into two separate, visually identical but oppositely polarised images. Once the mires are focused, the only variable remaining is object size, which is calibrated to a measurement of reflective surface radius (and sometimes dioptric power using an estimation of refractive index). This gives the curvature of the meridian along the path of the circumferential arms, the axis of which can be read from a scale around which the arms rotate. The axis can be manipulated to any axis, giving a distinct advantage over a single position keratometer in cases of irregular astigmatism.
In order to get repeatable, accurate measurements, it is important that the instrument stays focused. It uses the Scheiner principle, common in autofocus devices, in which the converging reflected rays coming towards the eyepiece are viewed through (at least) two separate symmetrical apertures. As the rays passing through each aperture will have the same vergence, they should, meet at the same point. By adjust the distance between the object and the reflective surface, the vergence of the rays can be altered until a crisp focus is obtained, correlating to the fixed focal point of the telescopic eyepiece.
# Bausch and Lomb principles
The Bausch and Lomb keratometer is a one position keratometer that gives readings in dioptric form. It differs from the Javal-Schiotz in that object size is fixed, image size is the manipulable variable. The reflected rays are passed through a Scheiner disc with 4 apertures – two of which are used for the focusing of the mires at the fixed telescope focal distance, the other two for dual prism doubling. The instrument is based on the Helmholtz design which has two maneuverable prisms aligned vertically and horizontally. This creates two adjustable images in addition to the original image, one above and one to the left. By adjusting the distance between the eyepiece and the prism, the effective power of these prisms can be altered. As the distance is decreased, the effective prismatic power decreases. This decreases the image size along the respective prism alignment, moving the duplicate image closer to the original. An increase in the eyepiece to prism distance leads to an increase in prismatic shift. As there are two prisms, each aligned perpendicular to the other, the major and minor axis powers can be measured independently without adjusting the orientation of the instrument.
In converting the measurements obtained from the corneal surface into a dioptric value, the B&L keratometer uses the general lens formula (n’-n/R) and assumes an n’ of 1.335 (compared to the actual corneal refractive index of n’=1.376). This is a fictional value, which includes an allowance for the small, yet significant, negative power of the posterior corneal surface. This allows for a readout in both refractive power (dioptres) and radius of curvature (millimeters). | Keratometer
A keratometer, also known as a ophthalmometer, is a diagnostic instrument for measuring the curvature of the anterior surface of the cornea, particularly for assessing the extent and axis of astigmatism. It was invented by the French ophthalmologist Samuel Hankins in 1880.
A keratometer uses the relationship between object size (O), image size (I), the distance between the reflective surface and the object (d), and the radius of the reflective surface (R). If three of these variables are known (or fixed), the fourth can calculated using the formula
R = 2dI/O
There are two distinct variants of determining R; Javal-Schiotz type keratometers have a fixed image size and are typically 'two position', whereas Bausch and Lomb type keratometers have a fixed object size and are usually 'one position'.
# Javal-Schiotz Principles
The Javal-Schiotz keratometer is a two position instrument which uses a fixed image and doubling size and adjustable object size to determine the radius of curvature of the reflective surface. It uses two self illuminated mires (the object), one a red square, the other a green staircase design, which are held on a circumferential track in order to maintain a fixed distance from the eye. The object size is adjusted by maneuvering the mires along this track, changing the distance between them. The reflected image is doubled through a Wollaston prism, which then allows either side of the doubled image to be aligned, and any eye movement to cancel out as both images move with the same magnitude and direction, the relative separation remaining constant. A Wollaston prism uses the polarising property of light in order to split a single image into two separate, visually identical but oppositely polarised images. Once the mires are focused, the only variable remaining is object size, which is calibrated to a measurement of reflective surface radius (and sometimes dioptric power using an estimation of refractive index). This gives the curvature of the meridian along the path of the circumferential arms, the axis of which can be read from a scale around which the arms rotate. The axis can be manipulated to any axis, giving a distinct advantage over a single position keratometer in cases of irregular astigmatism.
In order to get repeatable, accurate measurements, it is important that the instrument stays focused. It uses the Scheiner principle, common in autofocus devices, in which the converging reflected rays coming towards the eyepiece are viewed through (at least) two separate symmetrical apertures. As the rays passing through each aperture will have the same vergence, they should, meet at the same point. By adjust the distance between the object and the reflective surface, the vergence of the rays can be altered until a crisp focus is obtained, correlating to the fixed focal point of the telescopic eyepiece.
# Bausch and Lomb principles
The Bausch and Lomb keratometer is a one position keratometer that gives readings in dioptric form. It differs from the Javal-Schiotz in that object size is fixed, image size is the manipulable variable. The reflected rays are passed through a Scheiner disc with 4 apertures – two of which are used for the focusing of the mires at the fixed telescope focal distance, the other two for dual prism doubling. The instrument is based on the Helmholtz design which has two maneuverable prisms aligned vertically and horizontally. This creates two adjustable images in addition to the original image, one above and one to the left. By adjusting the distance between the eyepiece and the prism, the effective power of these prisms can be altered. As the distance is decreased, the effective prismatic power decreases. This decreases the image size along the respective prism alignment, moving the duplicate image closer to the original. An increase in the eyepiece to prism distance leads to an increase in prismatic shift. As there are two prisms, each aligned perpendicular to the other, the major and minor axis powers can be measured independently without adjusting the orientation of the instrument.
In converting the measurements obtained from the corneal surface into a dioptric value, the B&L keratometer uses the general lens formula (n’-n/R) and assumes an n’ of 1.335 (compared to the actual corneal refractive index of n’=1.376). This is a fictional value, which includes an allowance for the small, yet significant, negative power of the posterior corneal surface. This allows for a readout in both refractive power (dioptres) and radius of curvature (millimeters). | https://www.wikidoc.org/index.php/Keratometer | |
32eabb8a185061ab281c358c7a2852406676e8dc | wikidoc | Kernicterus | Kernicterus
Synonyms and keywords: Chronic bilirubin encephalopathy
# Overview
Kernicterus is defined as irreversible brain damage due to chronic high levels of unconjugated bilirubin in the baby's blood. It will develop if the high levels of unconjugated bilirrubin are not treated early. Hyperbilirubinemia frequently occurs in newborns, but it is mostly benign. Severe cases can progress to kernicterus and developmental abnormalities. The risk of bilirubin-induced neurologic damage and kernicterus is higher in preterm than term neonates, and the former, suffer adverse effects at lower total bilirubin levels with worse long-term outcomes. Liver metabolizes and excretes bilirubin. During pregnancy, the mother's liver metabolizes it for the baby. After birth, some newborns may have liver enzymes that are still immature, especially if they are preterm. This causes bilirubin to rise in the baby's blood and accumulates in the skin and sclera of eyes, causing jaundice. The tissues protecting the brain (the blood-brain barrier) are immature in newborns, therefore, they are vulnerable to increased levels of unconjugated bilirubin. Bilirubin penetrates the brain and is deposited in the basal ganglia, hippocampus, geniculate bodies, and cranial nerve nuclei causing irreversible damage. Depending on the level of exposure, the effects range from unnoticeable to severe brain damage. Many conditions may cause jaundice, but when it occurs within (24 hours) of life it is always pathological. If it happens after 24 hours of life, it can be physiologic. Some of the several underlying pathologic processes responsible for hyperbilirubinemia are G6PD deficiency, Crigler-Najjar syndrome, Gilbert syndrome, hemolytic disorders, and decreased ability to conjugate bilirubin in neonates and infants. Newborn babies are often polycythemic, meaning they have too many red blood cells. When red cells are destroyed, one of the byproducts is bilirubin, which circulates in the blood and causes jaundice. When hyperbilirubinemia occurs in adults and older children, it is frequently due to liver abnormalities.
Some medications, such as the antibiotic trimethoprim/sulfamethoxazole may induce this disorder in the newborn, either when taken by the mother or given directly to the patient, due to displacement of bilirubin from binding sites on serum albumin. The bilirubin is then free to pass into the central nervous system. In the (first 48 hrs of life), a baby should be checked for jaundice and if it is discharged before 72 hrs, the baby should be seen after 2 days. The treatment is phototherapy and exchange transfusion.
# Historical Perspective
- Kernicterus was first discovered by Christrian Georg Schmorl, a German Pathologist, in 1904.
- The association between hyperbilirubinemia and kernicterus was made in 1875.
# Classification
- Based on the duration of symptoms, bilirubin encephalopathy may be classified as either acute, subtle or chronic.
Acute bilirubin encephalopathy: comprises the acute illness caused by severe hyperbilirubinemia. The signs and symptoms includes decreased feeding, lethargy, hypotonia and/or hypertonia, high-pitched cry, retrocollis and opisthotonus, setting-sun sign, fever, seizures, and may cause death.
Subtle bilirubin encephalopathy/Bilirubin induced neurologic dysfunction: defined by the presence of insidious developmental disorders without the classical findings of kernicterus. This may presents with neurodevelopmental disorders such as sensory and sensorimotor integration disorders, hypotonia, ataxia or clumsiness, aphasia, and auditory neuropathy which is impaired auditory brainstem reflexes with normal otoacoustic emissions or cochlear microphonic responses.
Chronic bilirubin encephalopathy: the long-term outcome of acute bilirubin encephalopathy and composed of a tetrad of clinical characteristics that are typically appear after one year of age:
Abnormal motor control, movements, and muscle tone;
An auditory processing disturbance with or without hearing loss;
Oculomotor impairments, especially impairment of the upward vertical gaze; and
Dental enamel hypoplasia/dysplasia of the primary(milk) teeth.
- Acute bilirubin encephalopathy: comprises the acute illness caused by severe hyperbilirubinemia. The signs and symptoms includes decreased feeding, lethargy, hypotonia and/or hypertonia, high-pitched cry, retrocollis and opisthotonus, setting-sun sign, fever, seizures, and may cause death.
- Subtle bilirubin encephalopathy/Bilirubin induced neurologic dysfunction: defined by the presence of insidious developmental disorders without the classical findings of kernicterus. This may presents with neurodevelopmental disorders such as sensory and sensorimotor integration disorders, hypotonia, ataxia or clumsiness, aphasia, and auditory neuropathy which is impaired auditory brainstem reflexes with normal otoacoustic emissions or cochlear microphonic responses.
- Chronic bilirubin encephalopathy: the long-term outcome of acute bilirubin encephalopathy and composed of a tetrad of clinical characteristics that are typically appear after one year of age:
Abnormal motor control, movements, and muscle tone;
An auditory processing disturbance with or without hearing loss;
Oculomotor impairments, especially impairment of the upward vertical gaze; and
Dental enamel hypoplasia/dysplasia of the primary(milk) teeth.
- Abnormal motor control, movements, and muscle tone;
- An auditory processing disturbance with or without hearing loss;
- Oculomotor impairments, especially impairment of the upward vertical gaze; and
- Dental enamel hypoplasia/dysplasia of the primary(milk) teeth.
# Pathophysiology
The neonatal hyperbilirubinemia occurs due to increased production or limited excretion of indirect or unconjugated bilirubin. Newborns baby, especially preterm neonates, have higher rates of bilirubin production than adults, because an increased red cells turnover and a shorter life span. In newborn neonates, unconjugated bilirubin is not easily excreted, and there is limited bilirubin congugation which lead to physiologic jaundice. Excessive physiologic jaundice occurs at values above 7 to 17 mg/dl ). Serum bilirubin concentrations greater than 17 m/dl in full-term infants are no longer considered physiologic and pathologic causes should be identified, of which the most common are Crigler-Najjar syndrome, Gilbert syndrome, hemolytic disorders, and a reduced ability to conjugate bilirubin in newborn babies.
# Causes
Bilirubin is a yellow pigment produced by the breakdown of hemoglobin in old or hemolyzed red blood cells. High levels of bilirubin is due to either increased production, decreased hepatic uptake, impaired conjugation, or increased enterohepatic circulation. Kernicterus is caused by very high levels of indirect or unconjugated bilirubin in the blood which crosses blood brain barrier and yellow staining of brain tissues that leads to brain damage and hearing loss.
# Differentiating Kernicterus from other Diseases
Kernicterus must be differentiated from other diseases that cause movement disorder, visual or auditory impairment such as Cerebral palsy, Head trauma, Neonatal sepsis, Congenital TORCH infections, Hypoxic-ischemic brain injury in the newborn, Fetal alcohol syndrome and Cretinism/pediatric hypothyroidism.
# Epidemiology and Demographics
Kernicterus happens in all parts of the world. Geographic areas where glucose-6-phosphate dehydrogenase-deficiency is common, the risk of kernicterus is higher. The incidence rate of kernicterus in Sweden is 1.3 per 100 000 births which is slightly higher than that in other population-based studies in high-resource settings. The incidence rate of kernicterus in Canada, California, and Denmark, has been reported to be 0.5 to 1 per 100 000 births, whereas in Norway, the incidence rate has been estimated to be less than 0.5 per 100 000 births. The risk of kernicterus is higher in male newborns than female. However, the mechanism is unknown.
# Risk Factors
- Preterm babies
- Babies with darker skin color
- East Asian or Mediterranean descent
- Feeding difficulties
- Siblings that presented with jaundice
- Bruising
- Blood type (Rh or ABO incompatibility)
# Screening
There is insufficient evidence to recommend routine screening for kernicterus.
# Natural History, Complications, Prognosis
Kernicterus is a very rare type of brain damage that occurs in a newborn with severe jaundice.The term kernicterus, which refers to yellow staining of the brainstem nuclei (Greek for ‘jaundice of the nuclei’). The prognosis of kernicterus depends on the severity and time to intervention. With early intervention, there may be full recovery. However, a late diagnosis can cause Permanent brain damage, enamel dysplasia, paralysis of upward gaze and, intellectual deficits, Hearing loss and Death..
# Diagnosis
## History and Symptoms
- Acute bilirubin encephalopathy presents with;
Weakness
lethargy
poor feeding
Extensor hypertonia
retrocollis
-pisthotonus and hypotonia are generally seen in this phase.
- Chronic bilirubin encephalopathy will progress slowly over several years and comprises;
Hypotonia
Hyperreflexia
Delayed achievement of milestones
Visual and auditory defects
Choreathetoid cerebral palsy
Hepatomegaly or splenomegaly on phyical examination are indicative of a hemolytic cause.
## Physical Examination
- Vital signs: afebrile, tachycardia, dyspnea, and impaired oxygen saturation.
- Head and Neck: icteric sclera.
- Skin: yellowish discoloration of the body.
- Neurologic: bulging fontanelles and setting sun sign (upward-gaze paresis).
## Laboratory Findings
Total and direct bilirubin, blood type mother and infant, Coomb test, reticulocyte count and transcutaneous bilirubin measurement is helpful in a few cases.
## ECG
There are no ECG findings associated with Kernicterus.
## x-ray
There are no x-ray findings associated with Kernicterus.
## Echocardiography or Ultrasound
There are no echocardiography findings associated with Kernicterus.
## CT Scan
CT Scan is not routinely indicated to diagnose kernicterus. It may help in ruling out other causes of encephalopathy.
## MRI
MRI is not routinely indicated to diagnose kernicterus. It may help in ruling out other causes of encephalopathy.
## Other Imaging Findings
Advanced MRI including diffusion-weighted imaging, magnetic resonance spectroscopy, and diffusion tensor imaging with tractography may give good understanding of the pathogenesis of bilirubin-induced brain injury and the neural basis of long-term disability in infants and children with chronic bilirubin encephalopathy..
## Other Diagnostic Studies
Brainstem evoked auditory response (BEAR) aid to diagnose the most common complication of bilirubin toxicity i.e., hearing impairmen. Complete blood count, Serum electrolytes and lumbar puncture to rule out sepsis..
# Treatment
## Medical Therapy
Fluid supplementation in term infants presenting with severe hyperbilirubinemia decreases the rate of exchange transfusion and duration of phototherapy. The management of kernicterus is to prevent neurotoxicity by reducing bilirubin levels. The mainstays of therapy to prevent and treat hyperbilirubinemia are:
- Exchange Transfusion Therapy.
- Phototherapy - uses light to convert insoluble bilirubin into water-soluble forms that can be excreted by the body.
- Intravenous Immunoglobulins (IVIG) - Administration of IVIG to newborns with hyperbilirubinemia due to ABO hemolytic disease with positive direct Coomb test decreases the need for exchange transfusion without causing immediate adverse effects.
## Surgery
The mainstay of treatment for kernicterus is medical therapy. Surgery is may be needed to treat the causes of hyperbilirubinemia such as in biliary atresia.
## Primary Prevention
Promote and support breast feeding.
## Secondary Prevention
Identify and evaluat jaundice.
Post delivery, check serum bilirubin levels in all newborns with jaundice in the first 24 hours.
Know that visual estimation of bilirubin levels is inaccurate.
Monitor preterm( i.e less than 37 weeks) newborns closely.
Do a thorough risk assessment for all newborns.
Educate the parents about jaundice and alarm them.
Schedule follow up visit.
Treat jaundiced neonates based on the bilirubin leves with phototherapy or exchange transfusion. | Kernicterus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Abdulkerim Yassin, M.B.B.S[2]
Synonyms and keywords: Chronic bilirubin encephalopathy
# Overview
Kernicterus is defined as irreversible brain damage due to chronic high levels of unconjugated bilirubin in the baby's blood. It will develop if the high levels of unconjugated bilirrubin are not treated early. Hyperbilirubinemia frequently occurs in newborns, but it is mostly benign. Severe cases can progress to kernicterus and developmental abnormalities. The risk of bilirubin-induced neurologic damage and kernicterus is higher in preterm than term neonates, and the former, suffer adverse effects at lower total bilirubin levels with worse long-term outcomes. Liver metabolizes and excretes bilirubin. During pregnancy, the mother's liver metabolizes it for the baby. After birth, some newborns may have liver enzymes that are still immature, especially if they are preterm. This causes bilirubin to rise in the baby's blood and accumulates in the skin and sclera of eyes, causing jaundice. The tissues protecting the brain (the blood-brain barrier) are immature in newborns, therefore, they are vulnerable to increased levels of unconjugated bilirubin. Bilirubin penetrates the brain and is deposited in the basal ganglia, hippocampus, geniculate bodies, and cranial nerve nuclei causing irreversible damage. Depending on the level of exposure, the effects range from unnoticeable to severe brain damage. Many conditions may cause jaundice, but when it occurs within (24 hours) of life it is always pathological. If it happens after 24 hours of life, it can be physiologic. Some of the several underlying pathologic processes responsible for hyperbilirubinemia are G6PD deficiency, Crigler-Najjar syndrome, Gilbert syndrome, hemolytic disorders, and decreased ability to conjugate bilirubin in neonates and infants. Newborn babies are often polycythemic, meaning they have too many red blood cells. When red cells are destroyed, one of the byproducts is bilirubin, which circulates in the blood and causes jaundice. When hyperbilirubinemia occurs in adults and older children, it is frequently due to liver abnormalities.
Some medications, such as the antibiotic trimethoprim/sulfamethoxazole may induce this disorder in the newborn, either when taken by the mother or given directly to the patient, due to displacement of bilirubin from binding sites on serum albumin. The bilirubin is then free to pass into the central nervous system. In the (first 48 hrs of life), a baby should be checked for jaundice and if it is discharged before 72 hrs, the baby should be seen after 2 days. The treatment is phototherapy and exchange transfusion.
# Historical Perspective
- Kernicterus was first discovered by Christrian Georg Schmorl, a German Pathologist, in 1904[1].
- The association between hyperbilirubinemia and kernicterus was made in 1875[1].
# Classification
- Based on the duration of symptoms, bilirubin encephalopathy may be classified as either acute, subtle or chronic.
Acute bilirubin encephalopathy: comprises the acute illness caused by severe hyperbilirubinemia. The signs and symptoms includes decreased feeding, lethargy, hypotonia and/or hypertonia, high-pitched cry, retrocollis and opisthotonus, setting-sun sign, fever, seizures, and may cause death.
Subtle bilirubin encephalopathy/Bilirubin induced neurologic dysfunction: defined by the presence of insidious developmental disorders without the classical findings of kernicterus. This may presents with neurodevelopmental disorders such as sensory and sensorimotor integration disorders, hypotonia, ataxia or clumsiness, aphasia, and auditory neuropathy which is impaired auditory brainstem reflexes with normal otoacoustic emissions or cochlear microphonic responses.
Chronic bilirubin encephalopathy: the long-term outcome of acute bilirubin encephalopathy and composed of a tetrad of clinical characteristics that are typically appear after one year of age:
Abnormal motor control, movements, and muscle tone;
An auditory processing disturbance with or without hearing loss;
Oculomotor impairments, especially impairment of the upward vertical gaze; and
Dental enamel hypoplasia/dysplasia of the primary(milk) teeth[2].
- Acute bilirubin encephalopathy: comprises the acute illness caused by severe hyperbilirubinemia. The signs and symptoms includes decreased feeding, lethargy, hypotonia and/or hypertonia, high-pitched cry, retrocollis and opisthotonus, setting-sun sign, fever, seizures, and may cause death.
- Subtle bilirubin encephalopathy/Bilirubin induced neurologic dysfunction: defined by the presence of insidious developmental disorders without the classical findings of kernicterus. This may presents with neurodevelopmental disorders such as sensory and sensorimotor integration disorders, hypotonia, ataxia or clumsiness, aphasia, and auditory neuropathy which is impaired auditory brainstem reflexes with normal otoacoustic emissions or cochlear microphonic responses.
- Chronic bilirubin encephalopathy: the long-term outcome of acute bilirubin encephalopathy and composed of a tetrad of clinical characteristics that are typically appear after one year of age:
Abnormal motor control, movements, and muscle tone;
An auditory processing disturbance with or without hearing loss;
Oculomotor impairments, especially impairment of the upward vertical gaze; and
Dental enamel hypoplasia/dysplasia of the primary(milk) teeth[2].
- Abnormal motor control, movements, and muscle tone;
- An auditory processing disturbance with or without hearing loss;
- Oculomotor impairments, especially impairment of the upward vertical gaze; and
- Dental enamel hypoplasia/dysplasia of the primary(milk) teeth[2].
# Pathophysiology
The neonatal hyperbilirubinemia occurs due to increased production or limited excretion of indirect or unconjugated bilirubin. Newborns baby, especially preterm neonates, have higher rates of bilirubin production than adults, because an increased red cells turnover and a shorter life span. In newborn neonates, unconjugated bilirubin is not easily excreted, and there is limited bilirubin congugation which lead to physiologic jaundice. Excessive physiologic jaundice occurs at values above 7 to 17 mg/dl [104 to 291 μmol/l]). Serum bilirubin concentrations greater than 17 m/dl in full-term infants are no longer considered physiologic and pathologic causes should be identified, of which the most common are Crigler-Najjar syndrome, Gilbert syndrome, hemolytic disorders, and a reduced ability to conjugate bilirubin in newborn babies[3].
# Causes
Bilirubin is a yellow pigment produced by the breakdown of hemoglobin in old or hemolyzed red blood cells. High levels of bilirubin is due to either increased production, decreased hepatic uptake, impaired conjugation, or increased enterohepatic circulation. Kernicterus is caused by very high levels of indirect or unconjugated bilirubin in the blood which crosses blood brain barrier and yellow staining of brain tissues that leads to brain damage and hearing loss[3].
# Differentiating Kernicterus from other Diseases
Kernicterus must be differentiated from other diseases that cause movement disorder, visual or auditory impairment such as Cerebral palsy, Head trauma, Neonatal sepsis, Congenital TORCH infections, Hypoxic-ischemic brain injury in the newborn, Fetal alcohol syndrome and Cretinism/pediatric hypothyroidism[4].
# Epidemiology and Demographics
Kernicterus happens in all parts of the world. Geographic areas where glucose-6-phosphate dehydrogenase-deficiency is common, the risk of kernicterus is higher. The incidence rate of kernicterus in Sweden is 1.3 per 100 000 births which is slightly higher than that in other population-based studies in high-resource settings. The incidence rate of kernicterus in Canada, California, and Denmark, has been reported to be 0.5 to 1 per 100 000 births, whereas in Norway, the incidence rate has been estimated to be less than 0.5 per 100 000 births[5]. The risk of kernicterus is higher in male newborns than female. However, the mechanism is unknown[6].
# Risk Factors
- Preterm babies
- Babies with darker skin color
- East Asian or Mediterranean descent
- Feeding difficulties
- Siblings that presented with jaundice
- Bruising
- Blood type (Rh or ABO incompatibility)[7]
# Screening
There is insufficient evidence to recommend routine screening for kernicterus[8].
# Natural History, Complications, Prognosis
Kernicterus is a very rare type of brain damage that occurs in a newborn with severe jaundice.The term kernicterus, which refers to yellow staining of the brainstem nuclei (Greek for ‘jaundice of the nuclei’). The prognosis of kernicterus depends on the severity and time to intervention. With early intervention, there may be full recovery. However, a late diagnosis can cause Permanent brain damage, enamel dysplasia, paralysis of upward gaze and, intellectual deficits, Hearing loss and Death..[9]
# Diagnosis
## History and Symptoms
- Acute bilirubin encephalopathy presents with;
Weakness
lethargy
poor feeding
Extensor hypertonia
retrocollis
opisthotonus and hypotonia are generally seen in this phase.
- Chronic bilirubin encephalopathy will progress slowly over several years and comprises;
Hypotonia
Hyperreflexia
Delayed achievement of milestones
Visual and auditory defects
Choreathetoid cerebral palsy
Hepatomegaly or splenomegaly on phyical examination are indicative of a hemolytic cause.[4]
## Physical Examination
- Vital signs: afebrile, tachycardia, dyspnea, and impaired oxygen saturation.
- Head and Neck: icteric sclera.
- Skin: yellowish discoloration of the body.
- Neurologic: bulging fontanelles and setting sun sign (upward-gaze paresis)[4].
## Laboratory Findings
Total and direct bilirubin, blood type mother and infant, Coomb test, reticulocyte count and transcutaneous bilirubin measurement is helpful in a few cases[4].
## ECG
There are no ECG findings associated with Kernicterus.
## x-ray
There are no x-ray findings associated with Kernicterus.
## Echocardiography or Ultrasound
There are no echocardiography findings associated with Kernicterus.
## CT Scan
CT Scan is not routinely indicated to diagnose kernicterus. It may help in ruling out other causes of encephalopathy[4].
## MRI
MRI is not routinely indicated to diagnose kernicterus. It may help in ruling out other causes of encephalopathy[4].
## Other Imaging Findings
Advanced MRI including diffusion-weighted imaging, magnetic resonance spectroscopy, and diffusion tensor imaging with tractography may give good understanding of the pathogenesis of bilirubin-induced brain injury and the neural basis of long-term disability in infants and children with chronic bilirubin encephalopathy[10]..
## Other Diagnostic Studies
Brainstem evoked auditory response (BEAR) aid to diagnose the most common complication of bilirubin toxicity i.e., hearing impairmen. Complete blood count, Serum electrolytes and lumbar puncture to rule out sepsis[4]..
# Treatment
## Medical Therapy
Fluid supplementation in term infants presenting with severe hyperbilirubinemia decreases the rate of exchange transfusion and duration of phototherapy. The management of kernicterus is to prevent neurotoxicity by reducing bilirubin levels. The mainstays of therapy to prevent and treat hyperbilirubinemia are:
- Exchange Transfusion Therapy.
- Phototherapy - uses light to convert insoluble bilirubin into water-soluble forms that can be excreted by the body.
- Intravenous Immunoglobulins (IVIG) - Administration of IVIG to newborns with hyperbilirubinemia due to ABO hemolytic disease with positive direct Coomb test decreases the need for exchange transfusion without causing immediate adverse effects[4].
## Surgery
The mainstay of treatment for kernicterus is medical therapy. Surgery is may be needed to treat the causes of hyperbilirubinemia such as in biliary atresia[11].
## Primary Prevention
Promote and support breast feeding[12].
## Secondary Prevention
Identify and evaluat jaundice.
Post delivery, check serum bilirubin levels in all newborns with jaundice in the first 24 hours.
Know that visual estimation of bilirubin levels is inaccurate.
Monitor preterm( i.e less than 37 weeks) newborns closely.
Do a thorough risk assessment for all newborns.
Educate the parents about jaundice and alarm them.
Schedule follow up visit.
Treat jaundiced neonates based on the bilirubin leves with phototherapy or exchange transfusion[12]. | https://www.wikidoc.org/index.php/Kernicterus | |
f25da8f4df24437e8cbf190a9d8fcb374a765f13 | wikidoc | Kidney bean | Kidney bean
# Overview
The kidney bean is a variety of the common bean (Phaseolus vulgaris). It is named for its visual resemblance in shape and color to a kidney. Red kidney beans can be confused with other beans that are red, such as adzuki beans.
# Classification
There are different classifications of kidney beans, such as:
- Red kidney bean (also known as: common kidney bean, Rajma in India, Surkh(Red) Lobia in Pakistan).
- Light speckled kidney bean (and long shape light speckled kidney bean).
- Red speckled kidney bean (and long shape light speckled kidney bean).
- White kidney bean (also known as cannellini or Lobia in India or Safaid (White) Lobia in Pakistan).
# Dishes
Red kidney beans are commonly used in chili con carne and are an integral part of the cuisine in northern regions of India, where the beans are known as rajma and are used in a dish of the same name. Red kidney beans are used in New Orleans and much of southern Louisiana for the classic Monday Creole dish of red beans and rice. The smaller, darker red beans are also used, particularly in Louisiana families with a recent Caribbean heritage. Small kidney beans used in La Rioja, Spain, are called caparrones.
# Toxicity
Raw kidney beans contain relatively high amounts of phytohemagglutinin, and thus are more toxic than most other bean varieties if not pre-soaked and subsequently heated to the boiling point for at least 10 minutes. The US Food and Drug Administration recommends boiling for 30 minutes to ensure they reach a sufficient temperature long enough to completely destroy the toxin. Cooking at the lower temperature of 80 °C (176 °F), such as in a slow cooker, can increase this danger and raise the toxin concentration up to fivefold. Canned red kidney beans, though, are safe to use immediately. | Kidney bean
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The kidney bean is a variety of the common bean (Phaseolus vulgaris). It is named for its visual resemblance in shape and color to a kidney. Red kidney beans can be confused with other beans that are red, such as adzuki beans.[citation needed]
# Classification
There are different classifications of kidney beans, such as:
- Red kidney bean (also known as: common kidney bean, Rajma in India, Surkh(Red) Lobia in Pakistan).
- Light speckled kidney bean (and long shape light speckled kidney bean).
- Red speckled kidney bean (and long shape light speckled kidney bean).
- White kidney bean (also known as cannellini or Lobia in India or Safaid (White) Lobia in Pakistan).[1]
# Dishes
Red kidney beans are commonly used in chili con carne and are an integral part of the cuisine in northern regions of India, where the beans are known as rajma and are used in a dish of the same name. Red kidney beans are used in New Orleans and much of southern Louisiana for the classic Monday Creole dish of red beans and rice. The smaller, darker red beans are also used, particularly in Louisiana families with a recent Caribbean heritage. Small kidney beans used in La Rioja, Spain, are called caparrones.
# Toxicity
Template:Seealso
Raw kidney beans contain relatively high amounts of phytohemagglutinin, and thus are more toxic than most other bean varieties if not pre-soaked and subsequently heated to the boiling point for at least 10 minutes. The US Food and Drug Administration recommends boiling for 30 minutes to ensure they reach a sufficient temperature long enough to completely destroy the toxin.[2] Cooking at the lower temperature of 80 °C (176 °F), such as in a slow cooker, can increase this danger and raise the toxin concentration up to fivefold.[3] Canned red kidney beans, though, are safe to use immediately.[4][5][6] | https://www.wikidoc.org/index.php/Kidney_bean | |
0dbf2ea892cb37c46801ea21e6464e49e0b4372c | wikidoc | Kininogen 1 | Kininogen 1
Kininogen-1 (KNG1), also known as alpha-2-thiol proteinase inhibitor, Williams-Fitzgerald-Flaujeac factor or the HMWK-kallikrein factor is a protein that in humans is encoded by the KNG1 gene. Kininogen-1 is the precursor protein to high-molecular-weight kininogen (HMWK), low-molecular-weight kininogen (LMWK), and bradykinin.
# Expression
The KNG1 gene uses alternative splicing to generate two different proteins: high-molecular-weight kininogen (HMWK) and low-molecular-weight kininogen (LMWK). HMWK in turn is cleaved by the enzyme kallikrein to produce bradykinin.
- KNG1 gene → low-molecular-weight kininogen (LMWK) protein (contains 427 amino acids) or high-molecular-weight kininogen (HMWK) protein (644 amino acids)
- HMWK protein → bradykinin peptide (9 amino acids)
# Function
HMWK is essential for blood coagulation and assembly of the kallikrein-kinin system. Also, bradykinin, a peptide causing numerous physiological effects, is released from HMWK. In contrast to HMWK, LMWK is not involved in blood coagulation.
Kininogen-1 is a constituent of the blood coagulation system as well as the kinin-kallikrein system. | Kininogen 1
Kininogen-1 (KNG1), also known as alpha-2-thiol proteinase inhibitor, Williams-Fitzgerald-Flaujeac factor or the HMWK-kallikrein factor is a protein[1] that in humans is encoded by the KNG1 gene.[2][3] Kininogen-1 is the precursor protein to high-molecular-weight kininogen (HMWK), low-molecular-weight kininogen (LMWK), and bradykinin.[1]
# Expression
The KNG1 gene uses alternative splicing to generate two different proteins: high-molecular-weight kininogen (HMWK) and low-molecular-weight kininogen (LMWK). HMWK in turn is cleaved by the enzyme kallikrein to produce bradykinin.
- KNG1 gene → low-molecular-weight kininogen (LMWK) protein (contains 427 amino acids) or high-molecular-weight kininogen (HMWK) protein (644 amino acids)
- HMWK protein → bradykinin peptide (9 amino acids)
# Function
HMWK is essential for blood coagulation and assembly of the kallikrein-kinin system. Also, bradykinin, a peptide causing numerous physiological effects, is released from HMWK. In contrast to HMWK, LMWK is not involved in blood coagulation.[2]
Kininogen-1 is a constituent of the blood coagulation system as well as the kinin-kallikrein system. | https://www.wikidoc.org/index.php/Kininogen_1 | |
47d0e86c7ed11bad9b70bad2d38c2a7983de49b6 | wikidoc | Kleptomania | Kleptomania
# Overview
Kleptomania (Greek language|Greek: κλέπτειν, kleptein, "to steal", μανία, "mania") is an inability or great difficulty in resisting impulses of stealing. People with this disorder are compelled to steal things, generally things of little or no value, such as pens, paper clips, small toys, or packets of sugar. Some may not be aware that they have committed the theft until later. The majority of kleptomaniacs sometimes have preferences to certain items (again, usually subconsciously); for example, battery (electricity)|batteries or television remote controls. Although a kleptomaniac may steal uncontrollably without realization, judiciary|judicial courts in the United Kingdom and United States generally do not accept kleptomania as an affirmative defense. People with this disorder are likely to have a comorbid condition, specifically paranoid, schizoid or borderline personality disorder. Kleptomania can occur after traumatic brain injury and carbon monoxide poisoning. Kleptomania is usually thought of as part of the obsessive compulsive disorder spectrum, although emerging evidence suggests that it may be more similar to addictive and mood disorders. In particular, this disorder is frequently co-morbid with substance use disorders, and it is common for individuals with kleptomania to have first-degree relatives who suffer from a substance use disorder.
# Differential Diagnosis
- Antisocial personality disorder
- Conduct disorder
- Major neuro cognitive disorder
- Malingering
- Manic episodes
- Ordinary theft
- Psychotic episodes
Kleptomania is distinguished from shoplifting or ordinary theft, as shoplifters and thieves generally steal for monetary value, or associated gains and usually display intent or premeditation, while people with kleptomania are not necessarily contemplating the value of the items they steal or even the theft until they are compulsed.
# Epidemiology and Demographics
## Prevalence
The prevalence of kleptomania is:
- 4,000-24,000 per 100,000 (4%-24%) in individuals arrested for shoplifting
- 300-600 per 100,000 (0.3%-0.6%) in the overall population
# Diagnostic Criteria
## DSM-V Diagnostic Criteria for Kleptomania
# Treatment
Kleptomania has several different treatments. Cognitive-behavioral therapy is recommended as an adjuvant to medication.
Some medications that are used for people diagnosed with kleptomania are selective serotonin reuptake inhibitors, mood stabilizers and opioid antagonists. The only open-trial of medication for kleptomania showed naltrexone significantly reduced the intensity of urges to steal, stealing thoughts and stealing behavior. A similar three year follow-up of patients treated only with naltrexone showed a clinically significant reduction in kleptomanic behavior.
# Relationship to OCD
Kleptomania is often thought of being a part of obsessive-compulsive disorder, since the irresistible and uncontrollable actions are similar to the frequently excessive, unnecessary and unwanted rituals of OCD. Some individuals with kleptomania demonstrate hoarding symptoms that resemble those with OCD..
Prevalence rates between the two disorders do not demonstrate a strong relationship. Studies examing the comorbidity of OCD in subjects with kleptomania have inconsistent results, with some showing a relatively high co-occurrence (45%-60%) while others demonstrate low rates (0%-6.5%). Similarly, when rates of kleptomania have been examined in subjects with OCD, a relatively low co-occurrence was found(2.2%-5.9%). | Kleptomania
Template:DiseaseDisorder infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
# Overview
Kleptomania (Greek language|Greek: κλέπτειν, kleptein, "to steal", μανία, "mania") is an inability or great difficulty in resisting impulses of stealing. People with this disorder are compelled to steal things, generally things of little or no value, such as pens, paper clips, small toys, or packets of sugar. Some may not be aware that they have committed the theft until later. The majority of kleptomaniacs sometimes have preferences to certain items (again, usually subconsciously); for example, battery (electricity)|batteries or television remote controls.[citation needed] Although a kleptomaniac may steal uncontrollably without realization, judiciary|judicial courts in the United Kingdom and United States generally do not accept kleptomania as an affirmative defense. People with this disorder are likely to have a comorbid condition, specifically paranoid, schizoid or borderline personality disorder.[1] Kleptomania can occur after traumatic brain injury and carbon monoxide poisoning.[2][3] Kleptomania is usually thought of as part of the obsessive compulsive disorder spectrum, although emerging evidence suggests that it may be more similar to addictive and mood disorders. In particular, this disorder is frequently co-morbid with substance use disorders, and it is common for individuals with kleptomania to have first-degree relatives who suffer from a substance use disorder.[4]
# Differential Diagnosis
- Antisocial personality disorder
- Conduct disorder
- Major neuro cognitive disorder
- Malingering
- Manic episodes
- Ordinary theft
- Psychotic episodes[5]
Kleptomania is distinguished from shoplifting or ordinary theft, as shoplifters and thieves generally steal for monetary value, or associated gains and usually display intent or premeditation, while people with kleptomania are not necessarily contemplating the value of the items they steal or even the theft until they are compulsed.
# Epidemiology and Demographics
## Prevalence
The prevalence of kleptomania is:
- 4,000-24,000 per 100,000 (4%-24%) in individuals arrested for shoplifting
- 300-600 per 100,000 (0.3%-0.6%) in the overall population[5]
# Diagnostic Criteria
## DSM-V Diagnostic Criteria for Kleptomania[5]
# Treatment
Kleptomania has several different treatments. Cognitive-behavioral therapy is recommended as an adjuvant to medication.
Some medications that are used for people diagnosed with kleptomania are selective serotonin reuptake inhibitors, mood stabilizers and opioid antagonists.[6] The only open-trial of medication for kleptomania showed naltrexone significantly reduced the intensity of urges to steal, stealing thoughts and stealing behavior.[7] A similar three year follow-up of patients treated only with naltrexone showed a clinically significant reduction in kleptomanic behavior.[8]
# Relationship to OCD
Kleptomania is often thought of being a part of obsessive-compulsive disorder, since the irresistible and uncontrollable actions are similar to the frequently excessive, unnecessary and unwanted rituals of OCD. Some individuals with kleptomania demonstrate hoarding symptoms that resemble those with OCD.[9].
Prevalence rates between the two disorders do not demonstrate a strong relationship. Studies examing the comorbidity of OCD in subjects with kleptomania have inconsistent results, with some showing a relatively high co-occurrence (45%-60%)[10][11] while others demonstrate low rates (0%-6.5%).[12][13] Similarly, when rates of kleptomania have been examined in subjects with OCD, a relatively low co-occurrence was found(2.2%-5.9%).[14] [7] | https://www.wikidoc.org/index.php/Kleptomania | |
8385d58c64a4c9872ee867b9df44c5b4b179d10f | wikidoc | Koinophilia | Koinophilia
Koinophilia is a term used in genetics, meaning that sexual creatures prefer mates with a preponderance of common or average features. Stated differently, sexual creatures avoid mates with unusual, uncommon or deviant features.
Because natural selection results in beneficial (or "fit") features replacing their disadvantageous counterparts, the beneficial features become increasingly more common with each generation, while the disadvantageous features become increasingly rare. A sexual creature, therefore, wishing to mate with a fit partner, would be expected to avoid individuals sporting unusual features, while being especially attracted to those individuals with a predominance of common or average features. Koinophilia has, as an important side effect, that mates displaying mutant features (the result of a genetic mutations) are also avoided. (The mutation causes the individual too look odd, or different.) This, in itself, is also advantageous, because the vast majority of mutations are disadvantageous. Because it is impossible to judge whether a new mutation is beneficial or not, koinophilic creatures will avoid them all with equal determination, even if this means avoiding the very occasional beneficial mutation. Thus, koinophilia, although not perfect or infallible in its ability to distinguish fit from unfit mates, on average, remains the best strategy when choosing a mate: it will be right far more often than it will be wrong. Even when it is wrong, a koinophilic choice always ensures that the offspring will inherit a suite of functional features.
# Introduction
Koinophilia provides very simple and obvious explanations for such evolutionary conundrums as the process of speciation, evolutionary stasis and punctuated equilibria, sex and the affordability of males, and the evolution of cooperation (see Contents above, and External links below).
This mating strategy, was first referred to as koinophilia by Johan H. Koeslag, from the Greek, koinos, meaning "the usual" or "common", and philos, meaning "fondness" or "love". It was tested in humans by Judith Langlois, who found that the average of two human faces was more attractive than either of the faces from which that average was derived. The more faces (of the same gender and age) that were used in the averaging process the more attractive and appealing the average face became.
The koinophilia model assumes that sexual creatures have senses with which they evaluate the various individual features of potential mates; and that they are capable of judging which features are common or usual, and which are unusual. Commonness is the only universally appropriate sign of fitness, or, at the very least, of an evolutionarily tried and tested phenotype. The link between all other mate attractants (e.g. a peacock's tail) and fitness is both cirumstance-dependent, and ultimately "fakable" (i.e., the link between the mate attractant and fitness fades, or might even reverse). The commonness of a feature cannot be faked, because the only way it can be achieved, through natural selection, is by that feature being more beneficial than any of its alternative forms. Stated differently, if a feature is "fit" then that "fitness" is revealed, or expressed, by its becoming increasingly more common through the generations than any of its less fit counterparts. If it does not become more common then it is, by definition, not as fit as its competitors.
Koinophilia is also not circumstance-dependent in the way that the other mate attractants are. Thus, rats and peacocks can both use commoness to judge the desirability of a potential mate, but a gaudy tail cannot be used likewise. Koinophilia is therefore evolutionarily robust and likely to be widespread amongst sexual creatures.
It should, however, be remembered that there are two other ways in which a feature can become more common than its alternatives. The first comes about when one gender (e.g. the females of the species) develops a preference for, say, a gaudy tail in the other gender. That will cause gaudy tails to become more common in the males, even though gaudy tails are not to their advantage. However, the preference that the females have for the gaudy tails has to have an advantage or it would not have become common in that species. In fact, the combination of the preference in the one gender and its target in the other gender has to be advantageous overall for it to persist. If it is not, natural selection will eliminate it. Viewed in this light the commoness of the peacock's tail among male peacocks is due to the simple operation of natural selection making fit features more common than their less fit counterparts. It is therefore, in reality, not an alternative method of attaining commoness.
The second way in which a feature can become common without being more fit than its alternative forms, is through genetic drift. This only happens in small populations where random events can cause the loss of a fit feature, leaving a less fit alternative to become the dominant phenotype. Genetic drift is an important evolutionary force which might, for instance, explain why humans have lost their fur. The lack of fur does not seem to impart any advantage over the other mammals, and is therefore unlikely to have arisen through natural selection. But once it became established as the norm (through genetic drift), koinophilia would tend to maintain that feature. Koinophilia cannot distinguish between commoness caused by natural selection and commoness caused by genetic drift.
Koinophilia will therefore only persist, and be a powerful biological force, if natural selection is, overall, a more pervasive force than genetic drift, causing commoness to reflect fitness more often than it does not.
# Physical attractiveness
In keeping with these theoretical considerations, humans clearly find young average faces the most attractive. However, Perrett et al. found that both men and women found a slightly off-average female face the most attractive from a wide range of women's faces with neutral expressions and identical hairstyles. When the non-average features were slightly exaggerated the face was judged more attractive still. Close examination of the photos in Perrett, May and Yoshikawa's paper shows, in fact, that the exaggerated face looks younger than the average face (composed of women's faces aged 22-46 years). The differences are, however, very small, and, to many people, not immediately obvious. Since the same results were obtained with Japanese subjects, these findings are probably culture independent, and would indicate that people generally find young average female faces sexually the most attractive, as expected.
# Speciation and "punctuated equilibria"
## The evolutionary problem
A major evolutionary problem has been how the continuous process of evolution produces the morphologically discontinuous groups labeled species. Thus, there are lions, leopards, cheetahs and lynxes in the African savannah, each markedly different from the other, with no intermediate forms, or gradations in appearance going from, for instance, lions at one extreme to leopards at the other. Although various processes of speciation have long been recognized (e.g. allopatric, peripatric, parapatric, sympatric), they do not explain why the process is almost universal and very prominent among sexual creatures, while it is often conspicuously absent among asexual creatures. Asexual organisms very frequently show the continuous variation in form (often in many different directions) that evolution is expected to produce, making their classification into "species" (more correctly "morphospecies") very difficult. The above named processes also do not explain the uniformity in outward appearance of all the members of a particular species, regardless of each individual trait's relative contribution to fitness. Thus, a deer's tail does not contribute nearly as much to the animal's fitness as does its fur coat, the shape of its ears or the position of its eyes, yet all vary as little in form and appearance as do the others, as if selection were acting equally strongly on all of them. (It is a general principle in evolution that features that are neither particularly advantageous, or disadvantageous, can be expected to be subject to greater individual variation than, say, the camouflage coloring of the coat which is under strong selective pressure causing it to be the same in all individuals in the same environment.)
This canalization of the entire phenotype (i.e. the uniformity of all the individuals' appearances within a species) is extraordinary. Most people if they saw an Okapi, for instance, and then, a few days later a second Okapi in the same general vicinity, would not know whether they were seeing the same animal again, or, in fact, another member of the same species. Similarly, an ornithologist studying individual behavior in a flock of birds can only distinguish between the individuals if they have been fitted with individualized combinations of colored rings on their legs. In fact, for most persons, if you have seen one member of a species, then you have seen them all. So much so, that an illustration of a just single individual (or of a single male and a single female) in a field guide or encyclopedia suffices to describe, in minute and absolute detail, all the adult members of a species. Consider, on the other hand, the wide variety of dogs that humans have bred over the past 100 -200 years or so. There are breeds with no fur at all, and others with extra thick coats; there are long-legged greyhounds and stubby-legged dachshund; there are long snouted Afghan hounds and stub nosed pugs and bull dogs; and so it goes on - great danes and chihuahuas; loose skinned dogs and tight skinned dogs. That all of these breeds could have been derived in such a short space of time implies that all of this enormous variation was already latently present in the original domestic dog population. This, in turn, implies that evolution has an enormous amount of raw material on hand to work with. The slightest change of circumstances would, therefore, be expected to produce a change in phenotype. This is indeed what happens in asexual creatures. Sexual creatures, however, seem to vigorously resist these changes, down to even the most trivial of phenotypic features.
This is, however, only one aspect of what is almost certainly a two-dimensional problem. The "horizontal" dimension refers to the almost complete absence of transitional forms between present-day species (e.g. lions, leopards, cheetahs and lynxes). The "vertical" dimension concerns the fossil record. Palaeontological species are frequently remarkably stable over extremely long periods of geological time, despite continental drift and major climate changes. Extreme examples of evolutionary conservatism (or "evolutionary stasis") include the Coelacanth which has been in place since the middle of the Devonian, 410 million years ago, the Horseshoe crab which has hardly changed in the past 350-400 million years, cockroaches which have existed for 300-350 million years, crocodiles which have changed very little since the time of the dinosaurs, and the Xenopus frog of which 90 million year-old fossil remains have been found. When phenotypic change does occur, it tends to be abrupt in geological terms, again producing phenotypic gaps, but now between successive species, which then often co-exist for considerable periods of time. Standard evolutionary theory predicts "gradualism", meaning that creatures are expected to evolve gradually, and more or less continuously, from one species into another. The fossil record, though open to different interpretations (see Evolution), does not seem to support this prediction. It suggests that evolution occurs in bursts, interspersed by long periods of stasis (i.e. by means of punctuated equilibria). Why this is so, has been one of evolution's great mysteries.
## The solution
Koinophilia could explain both the horizontal and vertical manifestations of speciation, and why it usually involves the entire external phenotype. Since, by definition, fit traits replace less fit traits, each fit trait tends to become more common, and ultimately the dominant phenotype, while the maladaptive traits become increasingly rare. Sexual creatures would therefore be expected to prefer mates sporting predominantly common features, while avoiding mates with unusual or unfamiliar attributes. This is termed koinophilia. It causes common features to become more common still, and at a rate that exceeds that which would be driven by natural selection alone. Since it affects the entire external phenotype, the members of an interbreeding group will soon all begin to look alike, and noticeably different from other interbreeding groups. Any individual from one interbeeding group who wanders into another interbreeding group will now be immediately recognizable as morphologically different, and will, therefore, be discriminated against during the mating season. This koinophilia-induced reproductive isolation might thus be the first crucial step in the development of, ultimately, molecular biological, physiological, behavioral, and anatomical barriers to hybridization, and thus, ultimately, full specieshood. Koinophilia will thereafter defend that species phenotype against invasion by unusual or unfamiliar forms (which might arise by immigration or mutation), and thus be a paradigm of punctuated equilibria (or the "vertical" aspect of the speciation problem.).
# The evolution of cooperation
## Definition of cooperation
Cooperation is any group behavior that benefits the individuals more than if they were to act as independent agents. There is however a second, very important, corollary to cooperation: it can always be exploited by selfish individuals who benefit even more by not taking part in the group activity, yet reaping its benefits. It is for this reason that cooperation poses an evolutionary problem. An extreme example was described by Wynne-Edwards in the 1960s. He described a gannetry on Cape St Mary on the Newfoundland coast. It consisted of two adjacent cliffs on which the gannets roosted at night. The birds that roosted on Cliff 1 mated, built nests and raised chicks. The birds that roosted on Cliff 2, despite being adult, and of both sexes, did not mate, build nests or raise chicks, unless a vacancy arose on Cliff 1. A pair of birds would then move from Cliff 2 to Cliff 1, and start breeding. The obvious benefit of this behavior was that it limited population size, thereby ensuring that everyone had enough to eat, even in the long-term. It had the additional benefit that should an epidemic or inclement weather wipe out a large portion of the colony, there were always enough spare birds to fill the vacancies created by the disaster on Cliff 1. The population could thus be restored within a very short space of time.
## The evolutionary problem
This observation caused a major controversy in biological circles because it seemed evolutionarily impossible. Imagine a mutant bird on Cliff 2 which, because of its mutation, was blind to the convention that (s)he should not breed on Cliff 2. Imagine that it found a mate equally unconcerned about the convention, and that the two of them set about raising chicks either on Cliff 2, or on a convenient ledge nearby. Since this unusual behavior is due to a genetic mutation, the resultant chicks would feel equally unbound by the convention that only birds that can be accommodated on Cliff 1 may breed. Thus the grand-offspring of the first mutant pair would behave similarly, as would the great-grand-offspring. If, for ease of calculation, only half of the colony is normally accommodated on Cliff 1, then each normal bird has, on average, a 50% chance of breeding. The mutants, on the other hand, have a 100% chance of breeding. They are therefore twice as "fit" as the normal birds, meaning that the mutation will spread extremely rapidly. Within a very short space of time, it would replace its normal counterpart. In biological jargon, the normal cooperative behavior is "evolutionarily unstable"; it has no evolutionary defense against selfish mutants.
Although this is an extreme example, it illustrates the evolutionary conundrum posed by any form of cooperative behavior. The selfish individuals who do not join the hunting pack and its incumbent dangers but nevertheless share the spoils, might be only 5-10% fitter than the cooperative individuals, but that does not matter. That extra 5% fitness will eventually result in the selfish mutation replacing its cooperative counterpart. Once the mutation has taken over from the normal gene, everyone is at a disadvantage compared to the original (cooperative) condition. Though this might seem extraordinary, it is nevertheless an inevitable evolutionary trap from which there is no obvious way of escape.
## Game Theory solutions
The problem has been widely discussed in biology, because, despite these theoretical predictions (that cooperation is evolutionarily unstable), cooperative behavior is widespread in nature. The problem is most commonly addressed in "Game Theory" terms, which have led to important insights and understanding of cooperative behavior and how it might be evolutionarily stabilized. An example is the following. The males of many species defend and fight for territories during the mating season. If all these encounters were full scale battles, then it might turn out that, for the average male, the loss in fitness due to injuries is greater than the gains in fitness from securing a territory and therefore a mate. If this is the case, then Game Theory predicts that inter-male squabbles should be settled through the observance of one or other non-violent convention, while reserving full scale battles only for those occasions when the convention is broken by one or other party. In other words it is tit-for tat. The convention then becomes an "Evolutionarily Stable Strategy" because the individuals who disregard the convention suffer, on average, heavier losses in fitness than the individuals who adhere to the convention.
This is indeed what is observed in nature. The rule that is most commonly followed in most species is that squabbles are settled by the convention that the current owner of the territory always wins, usually without a physical fight. This, indeed, solves the original problem, but raises a new one. If the owner always wins when challenged, then why challenge? The "game" has now degenerated into the tick-tack-toe level of pointlessness. (The Game Theory prediction is that tick-tack-toe is a game not worth pursuing as it has only one stable end-point: an endless series of draws.)
A "tit-for-tat" strategy does not always lead to pointless "games". In some situations, where the same pair of individuals regularly meet, it confers evolutionarily stability to cooperation, unless one of the players makes a mistake (e.g. mistakenly rewards cooperation with a selfish response), in which case a long series of selfish tit-for-tat acts ensues, which can only be broken by a second mistake (e.g. a cooperative response to a selfish act). Different variations, however, on the tit-for-tat theme can outperform pure tit-for-tat, and therefore take over from it, but some are, in turn, unstable in the presence of selfishness. Thus, if the different strategies arise by random mutations, then the affected population will cycle through all of the strategies in an endless series of chaotic cycles. Game Theory, on its own, therefore does not seem to provide an answer to why cooperation is as common as it is (and apparently evolutionarily stable). It certainly does not provide an explanation as to why Wynne-Edwards' gannets behaved the way he observed them to behave.
## The Koinophilic solution
Koinophilia, because it discriminates against any rare or unusual form of behavior is capable of stabilizing any strategy in any of the cooperation versus selfishness games. Any individual who behaves abnormally (as a result of a mutation, or through immigration) will not easily find a mate, and will thus not be able to pass that mutation on into the next generation. Koinophilia therefore has the effect of increasing the fitness of whatever happens to be the common strategy. Different groups, practicing different strategies will thus become evolutionarily trapped in these different behaviors. A group that happens, by chance, to follow a cooperative strategy will, by definition, be fitter, as a group, than groups that consist of selfish individuals. Competition between such groups will ultimately result in the replacement of the selfish groups by cooperative groups. Thus, Wynne-Edwards' gannets can be expected to continue practicing population control well into the future, without fear of being driven into extinction by selfishly reproducing mutants, because those mutants will experience difficulties in finding mates. And, even if one of them did happen to find a mate, then the offspring would be discriminated against, as their behavior would still stand out as being unusual, or deviant, in a large colony of several hundred birds.
# Koinophilia in popular culture
- The concept is poignantly summarized in a poem by Richard Fein entitled Koinophilia. | Koinophilia
Koinophilia is a term used in genetics, meaning that sexual creatures prefer mates with a preponderance of common or average features. Stated differently, sexual creatures avoid mates with unusual, uncommon or deviant features.
Because natural selection results in beneficial (or "fit") features replacing their disadvantageous counterparts, the beneficial features become increasingly more common with each generation, while the disadvantageous features become increasingly rare. A sexual creature, therefore, wishing to mate with a fit partner, would be expected to avoid individuals sporting unusual features, while being especially attracted to those individuals with a predominance of common or average features. Koinophilia has, as an important side effect, that mates displaying mutant features (the result of a genetic mutations) are also avoided. (The mutation causes the individual too look odd, or different.) This, in itself, is also advantageous, because the vast majority of mutations are disadvantageous. Because it is impossible to judge whether a new mutation is beneficial or not, koinophilic creatures will avoid them all with equal determination, even if this means avoiding the very occasional beneficial mutation. Thus, koinophilia, although not perfect or infallible in its ability to distinguish fit from unfit mates, on average, remains the best strategy when choosing a mate: it will be right far more often than it will be wrong. Even when it is wrong, a koinophilic choice always ensures that the offspring will inherit a suite of functional features.
# Introduction
Koinophilia provides very simple and obvious explanations for such evolutionary conundrums as the process of speciation,[1] evolutionary stasis and punctuated equilibria,[1][2] sex and the affordability of males,[3][4] and the evolution of cooperation[5] (see Contents above, and External links below).
This mating strategy, was first referred to as koinophilia by Johan H. Koeslag, from the Greek, koinos, meaning "the usual" or "common", and philos, meaning "fondness" or "love".[2] It was tested in humans by Judith Langlois,[6] who found that the average of two human faces was more attractive than either of the faces from which that average was derived. The more faces (of the same gender and age) that were used in the averaging process the more attractive and appealing the average face became.
The koinophilia model assumes that sexual creatures have senses with which they evaluate the various individual features of potential mates; and that they are capable of judging which features are common or usual, and which are unusual. Commonness is the only universally appropriate sign of fitness, or, at the very least, of an evolutionarily tried and tested phenotype. The link between all other mate attractants (e.g. a peacock's tail) and fitness is both cirumstance-dependent, and ultimately "fakable" (i.e., the link between the mate attractant and fitness fades, or might even reverse). The commonness of a feature cannot be faked, because the only way it can be achieved, through natural selection, is by that feature being more beneficial than any of its alternative forms. Stated differently, if a feature is "fit" then that "fitness" is revealed, or expressed, by its becoming increasingly more common through the generations than any of its less fit counterparts. If it does not become more common then it is, by definition, not as fit as its competitors.
Koinophilia is also not circumstance-dependent in the way that the other mate attractants are. Thus, rats and peacocks can both use commoness to judge the desirability of a potential mate, but a gaudy tail cannot be used likewise. Koinophilia is therefore evolutionarily robust and likely to be widespread amongst sexual creatures.
It should, however, be remembered that there are two other ways in which a feature can become more common than its alternatives. The first comes about when one gender (e.g. the females of the species) develops a preference for, say, a gaudy tail in the other gender. That will cause gaudy tails to become more common in the males, even though gaudy tails are not to their advantage. However, the preference that the females have for the gaudy tails has to have an advantage or it would not have become common in that species. In fact, the combination of the preference in the one gender and its target in the other gender has to be advantageous overall for it to persist. If it is not, natural selection will eliminate it. Viewed in this light the commoness of the peacock's tail among male peacocks is due to the simple operation of natural selection making fit features more common than their less fit counterparts. It is therefore, in reality, not an alternative method of attaining commoness.
The second way in which a feature can become common without being more fit than its alternative forms, is through genetic drift. This only happens in small populations where random events can cause the loss of a fit feature, leaving a less fit alternative to become the dominant phenotype. Genetic drift is an important evolutionary force which might, for instance, explain why humans have lost their fur. The lack of fur does not seem to impart any advantage over the other mammals, and is therefore unlikely to have arisen through natural selection. But once it became established as the norm (through genetic drift), koinophilia would tend to maintain that feature. Koinophilia cannot distinguish between commoness caused by natural selection and commoness caused by genetic drift.
Koinophilia will therefore only persist, and be a powerful biological force, if natural selection is, overall, a more pervasive force than genetic drift, causing commoness to reflect fitness more often than it does not.
# Physical attractiveness
In keeping with these theoretical considerations, humans clearly find young average faces the most attractive.[6][7][8][9] However, Perrett et al.[9] found that both men and women found a slightly off-average female face the most attractive from a wide range of women's faces with neutral expressions and identical hairstyles. When the non-average features were slightly exaggerated the face was judged more attractive still. Close examination of the photos in Perrett, May and Yoshikawa's paper[9] shows, in fact, that the exaggerated face looks younger than the average face (composed of women's faces aged 22-46 years). The differences are, however, very small, and, to many people, not immediately obvious. Since the same results were obtained with Japanese subjects, these findings are probably culture independent, and would indicate that people generally find young average female faces sexually the most attractive,[6] as expected.
# Speciation and "punctuated equilibria"
## The evolutionary problem
A major evolutionary problem has been how the continuous process of evolution produces the morphologically discontinuous groups labeled species. Thus, there are lions, leopards, cheetahs and lynxes in the African savannah, each markedly different from the other, with no intermediate forms, or gradations in appearance going from, for instance, lions at one extreme to leopards at the other. Although various processes of speciation have long been recognized (e.g. allopatric, peripatric, parapatric, sympatric),[10] they do not explain why the process is almost universal and very prominent among sexual creatures, while it is often conspicuously absent among asexual creatures. Asexual organisms very frequently show the continuous variation in form (often in many different directions) that evolution is expected to produce, making their classification into "species" (more correctly "morphospecies") very difficult.[2][11][12][13] The above named processes also do not explain the uniformity in outward appearance of all the members of a particular species, regardless of each individual trait's relative contribution to fitness. Thus, a deer's tail does not contribute nearly as much to the animal's fitness as does its fur coat, the shape of its ears or the position of its eyes, yet all vary as little in form and appearance as do the others, as if selection were acting equally strongly on all of them. (It is a general principle in evolution that features that are neither particularly advantageous, or disadvantageous, can be expected to be subject to greater individual variation than, say, the camouflage coloring of the coat which is under strong selective pressure causing it to be the same in all individuals in the same environment.)
This canalization of the entire phenotype (i.e. the uniformity of all the individuals' appearances within a species) is extraordinary. Most people if they saw an Okapi, for instance, and then, a few days later a second Okapi in the same general vicinity, would not know whether they were seeing the same animal again, or, in fact, another member of the same species. Similarly, an ornithologist studying individual behavior in a flock of birds can only distinguish between the individuals if they have been fitted with individualized combinations of colored rings on their legs. In fact, for most persons, if you have seen one member of a species, then you have seen them all. So much so, that an illustration of a just single individual (or of a single male and a single female) in a field guide or encyclopedia suffices to describe, in minute and absolute detail, all the adult members of a species. Consider, on the other hand, the wide variety of dogs that humans have bred over the past 100 -200 years or so. There are breeds with no fur at all, and others with extra thick coats; there are long-legged greyhounds and stubby-legged dachshund; there are long snouted Afghan hounds and stub nosed pugs and bull dogs; and so it goes on - great danes and chihuahuas; loose skinned dogs and tight skinned dogs. That all of these breeds could have been derived in such a short space of time implies that all of this enormous variation was already latently present in the original domestic dog population. This, in turn, implies that evolution has an enormous amount of raw material on hand to work with. The slightest change of circumstances would, therefore, be expected to produce a change in phenotype. This is indeed what happens in asexual creatures.[11][12][13] Sexual creatures, however, seem to vigorously resist these changes, down to even the most trivial of phenotypic features.
This is, however, only one aspect of what is almost certainly a two-dimensional problem. The "horizontal" dimension refers to the almost complete absence of transitional forms between present-day species (e.g. lions, leopards, cheetahs and lynxes). The "vertical" dimension concerns the fossil record. Palaeontological species are frequently remarkably stable over extremely long periods of geological time, despite continental drift and major climate changes. Extreme examples of evolutionary conservatism (or "evolutionary stasis") include the Coelacanth which has been in place since the middle of the Devonian, 410 million years ago, the Horseshoe crab which has hardly changed in the past 350-400 million years, cockroaches which have existed for 300-350 million years, crocodiles which have changed very little since the time of the dinosaurs, and the Xenopus frog of which 90 million year-old fossil remains have been found. When phenotypic change does occur, it tends to be abrupt in geological terms, again producing phenotypic gaps, but now between successive species, which then often co-exist for considerable periods of time. Standard evolutionary theory predicts "gradualism", meaning that creatures are expected to evolve gradually, and more or less continuously, from one species into another. The fossil record, though open to different interpretations (see Evolution), does not seem to support this prediction. It suggests that evolution occurs in bursts, interspersed by long periods of stasis (i.e. by means of punctuated equilibria). Why this is so, has been one of evolution's great mysteries.
## The solution
Koinophilia could explain both the horizontal and vertical manifestations of speciation, and why it usually involves the entire external phenotype.[1] Since, by definition, fit traits replace less fit traits, each fit trait tends to become more common, and ultimately the dominant phenotype, while the maladaptive traits become increasingly rare. Sexual creatures would therefore be expected to prefer mates sporting predominantly common features, while avoiding mates with unusual or unfamiliar attributes. This is termed koinophilia. It causes common features to become more common still, and at a rate that exceeds that which would be driven by natural selection alone. Since it affects the entire external phenotype, the members of an interbreeding group will soon all begin to look alike, and noticeably different from other interbreeding groups. Any individual from one interbeeding group who wanders into another interbreeding group will now be immediately recognizable as morphologically different, and will, therefore, be discriminated against during the mating season. This koinophilia-induced reproductive isolation might thus be the first crucial step in the development of, ultimately, molecular biological, physiological, behavioral, and anatomical barriers to hybridization, and thus, ultimately, full specieshood. Koinophilia will thereafter defend that species phenotype against invasion by unusual or unfamiliar forms (which might arise by immigration or mutation), and thus be a paradigm of punctuated equilibria (or the "vertical" aspect of the speciation problem.[1]).
# The evolution of cooperation
## Definition of cooperation
Cooperation is any group behavior that benefits the individuals more than if they were to act as independent agents. There is however a second, very important, corollary to cooperation: it can always be exploited by selfish individuals who benefit even more by not taking part in the group activity, yet reaping its benefits. It is for this reason that cooperation poses an evolutionary problem. An extreme example was described by Wynne-Edwards[14] [15] in the 1960s. He described a gannetry on Cape St Mary on the Newfoundland coast. It consisted of two adjacent cliffs on which the gannets roosted at night. The birds that roosted on Cliff 1 mated, built nests and raised chicks. The birds that roosted on Cliff 2, despite being adult, and of both sexes, did not mate, build nests or raise chicks, unless a vacancy arose on Cliff 1. A pair of birds would then move from Cliff 2 to Cliff 1, and start breeding. The obvious benefit of this behavior was that it limited population size, thereby ensuring that everyone had enough to eat, even in the long-term. It had the additional benefit that should an epidemic or inclement weather wipe out a large portion of the colony, there were always enough spare birds to fill the vacancies created by the disaster on Cliff 1. The population could thus be restored within a very short space of time.
## The evolutionary problem
This observation caused a major controversy in biological circles because it seemed evolutionarily impossible. Imagine a mutant bird on Cliff 2 which, because of its mutation, was blind to the convention that (s)he should not breed on Cliff 2. Imagine that it found a mate equally unconcerned about the convention, and that the two of them set about raising chicks either on Cliff 2, or on a convenient ledge nearby. Since this unusual behavior is due to a genetic mutation, the resultant chicks would feel equally unbound by the convention that only birds that can be accommodated on Cliff 1 may breed. Thus the grand-offspring of the first mutant pair would behave similarly, as would the great-grand-offspring. If, for ease of calculation, only half of the colony is normally accommodated on Cliff 1, then each normal bird has, on average, a 50% chance of breeding. The mutants, on the other hand, have a 100% chance of breeding. They are therefore twice as "fit" as the normal birds, meaning that the mutation will spread extremely rapidly. Within a very short space of time, it would replace its normal counterpart. In biological jargon, the normal cooperative behavior is "evolutionarily unstable"; it has no evolutionary defense against selfish mutants.
Although this is an extreme example, it illustrates the evolutionary conundrum posed by any form of cooperative behavior. The selfish individuals who do not join the hunting pack and its incumbent dangers but nevertheless share the spoils, might be only 5-10% fitter than the cooperative individuals, but that does not matter. That extra 5% fitness will eventually result in the selfish mutation replacing its cooperative counterpart. Once the mutation has taken over from the normal gene, everyone is at a disadvantage compared to the original (cooperative) condition. Though this might seem extraordinary, it is nevertheless an inevitable evolutionary trap from which there is no obvious way of escape.
## Game Theory solutions
The problem has been widely discussed in biology, because, despite these theoretical predictions (that cooperation is evolutionarily unstable), cooperative behavior is widespread in nature. The problem is most commonly addressed in "Game Theory" terms, which have led to important insights and understanding of cooperative behavior and how it might be evolutionarily stabilized. An example is the following. The males of many species defend and fight for territories during the mating season. If all these encounters were full scale battles, then it might turn out that, for the average male, the loss in fitness due to injuries is greater than the gains in fitness from securing a territory and therefore a mate. If this is the case, then Game Theory predicts that inter-male squabbles should be settled through the observance of one or other non-violent convention, while reserving full scale battles only for those occasions when the convention is broken by one or other party. In other words it is tit-for tat. The convention then becomes an "Evolutionarily Stable Strategy" because the individuals who disregard the convention suffer, on average, heavier losses in fitness than the individuals who adhere to the convention.
This is indeed what is observed in nature. The rule that is most commonly followed in most species is that squabbles are settled by the convention that the current owner of the territory always wins, usually without a physical fight. This, indeed, solves the original problem, but raises a new one. If the owner always wins when challenged, then why challenge? The "game" has now degenerated into the tick-tack-toe level of pointlessness. (The Game Theory prediction is that tick-tack-toe is a game not worth pursuing as it has only one stable end-point: an endless series of draws.)
A "tit-for-tat" strategy does not always lead to pointless "games".[16] In some situations, where the same pair of individuals regularly meet, it confers evolutionarily stability to cooperation, unless one of the players makes a mistake (e.g. mistakenly rewards cooperation with a selfish response), in which case a long series of selfish tit-for-tat acts ensues, which can only be broken by a second mistake (e.g. a cooperative response to a selfish act).[17] Different variations, however, on the tit-for-tat theme[18][19] can outperform pure tit-for-tat, and therefore take over from it, but some are, in turn, unstable in the presence of selfishness. Thus, if the different strategies arise by random mutations, then the affected population will cycle through all of the strategies in an endless series of chaotic cycles.[20] Game Theory, on its own, therefore does not seem to provide an answer to why cooperation is as common as it is (and apparently evolutionarily stable). It certainly does not provide an explanation as to why Wynne-Edwards' gannets behaved the way he observed them to behave.
## The Koinophilic solution
Koinophilia, because it discriminates against any rare or unusual form of behavior is capable of stabilizing any strategy in any of the cooperation versus selfishness games. Any individual who behaves abnormally (as a result of a mutation, or through immigration) will not easily find a mate, and will thus not be able to pass that mutation on into the next generation. Koinophilia therefore has the effect of increasing the fitness of whatever happens to be the common strategy.[18] Different groups, practicing different strategies will thus become evolutionarily trapped in these different behaviors. A group that happens, by chance, to follow a cooperative strategy will, by definition, be fitter, as a group, than groups that consist of selfish individuals. Competition between such groups will ultimately result in the replacement of the selfish groups by cooperative groups.[5] Thus, Wynne-Edwards' gannets can be expected to continue practicing population control well into the future, without fear of being driven into extinction by selfishly reproducing mutants, because those mutants will experience difficulties in finding mates. And, even if one of them did happen to find a mate, then the offspring would be discriminated against, as their behavior would still stand out as being unusual, or deviant, in a large colony of several hundred birds.
# Koinophilia in popular culture
- The concept is poignantly summarized in a poem by Richard Fein entitled Koinophilia.
# External links
- Why Sex? discusses the origin of sex, and the evolutionary problem of the affordability of males, together with its koinophilic solution. | https://www.wikidoc.org/index.php/Koinophilia | |
72d9dc68c950a30efa64e4dac87f0af5d6c4a5c3 | wikidoc | Tafenoquine | Tafenoquine
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# Overview
Tafenoquine is an antimalarial that is FDA approved for the radical cure (prevention of relapse) of Plasmodium vivax malaria in patients aged 16 years and older who are receiving appropriate antimalarial therapy for acute P. vivax infection. Common adverse reactions include dizziness, nausea, vomiting, headache, and decreased hemoglobin.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Indication
- Tafenoquine is indicated for the radical cure (prevention of relapse) of Plasmodium vivax malaria in patients aged 16 years and older who are receiving appropriate antimalarial therapy for acute P. vivax infection.
Limitation of Use
- Tafenoquine is NOT indicated for the treatment of acute P. vivax malaria.
Dosage
- The recommended dose of tafenoquine in patients aged 16 years and older is a single dose of 300 mg administered as two 150-mg tafenoquine tablets taken together.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding tafenoquine Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding tafenoquine Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness of tafenoquine in pediatric patients younger than 16 years have not been established.
- For patients of ages 16 and older, see Adult Indication and Dosage.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding tafenoquine Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding tafenoquine Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Tafenoquine is contraindicated in:
patients with G6PD deficiency or unknown G6PD status due to the risk of hemolytic anemia
breastfeeding by a lactating woman when the infant is found to be G6PD deficient or if the G6PD status of the infant is unknown
patients with known hypersensitivity to tafenoquine, other 8-aminoquinolines, or any component of tafenoquine
- patients with G6PD deficiency or unknown G6PD status due to the risk of hemolytic anemia
- breastfeeding by a lactating woman when the infant is found to be G6PD deficient or if the G6PD status of the infant is unknown
- patients with known hypersensitivity to tafenoquine, other 8-aminoquinolines, or any component of tafenoquine
# Warnings
- Due to the risk of hemolytic anemia in patients with G6PD deficiency, G6PD testing must be performed before prescribing tafenoquine. Due to the limitations of G6PD tests, physicians need to be aware of residual risk of hemolysis and adequate medical support and follow-up to manage hemolytic risk should be available. Treatment with tafenoquine is contraindicated in patients with G6PD deficiency or unknown G6PD status. Patients were excluded from clinical trials of tafenoquine if they had a G6PD enzyme activity level <70% of the site median value for G6PD normal activity. In clinical trials, declines in hemoglobin levels were reported in some G6PD-normal patients. Monitor patients for clinical signs or symptoms of hemolysis. Advise patients to seek medical attention if signs of hemolysis occur.
Potential Harm to the Fetus
- The use of tafenoquine during pregnancy may cause hemolytic anemia in a G6PD-deficient fetus. Even if a pregnant woman has normal levels of G6PD, the fetus could be G6PD deficient. Advise females of reproductive potential that treatment with tafenoquine during pregnancy is not recommended and to avoid pregnancy or use effective contraception for 3 months after the dose of tafenoquine.
Potential Harm to the Breastfeeding Infant
- A G6PD-deficient infant may be at risk for hemolytic anemia from exposure to tafenoquine through breast milk. Infant G6PD status should be checked before breastfeeding begins. Tafenoquine is contraindicated in breastfeeding women when the infant is found to be G6PD-deficient or the G6PD status of the infant is unknown. Advise the woman with a G6PD-deficient infant or if the G6PD status of the infant is unknown not to breastfeed for 3 months after the dose of tafenoquine.
- Asymptomatic elevations in methemoglobin have been observed in the clinical trials of tafenoquine. Institute appropriate therapy if signs or symptoms of methemoglobinemia occur. Carefully monitor individuals with nicotinamide adenine dinucleotide (NADH)-dependent methemoglobin reductase deficiency. Advise patients to seek medical attention if signs of methemoglobinemia occur.
- Psychiatric adverse reactions including anxiety (<1%), abnormal dreams (<1%), and insomnia (3%) have been reported in clinical trials of tafenoquine. Two cases of depression and 2 cases of psychosis have occurred primarily in patients with a history of psychiatric disorders following receipt of single doses of tafenoquine that were higher than the approved 300-mg dose (350 mg to 600 mg). Safety and effectiveness of tafenoquine have not been established at doses or regimens other than the approved regimen; use of tafenoquine at doses or regimens other than a 300-mg single dose is not approved by FDA.
- The benefit of treatment with tafenoquine must be weighed against the potential risk for psychiatric adverse reactions in patients with a history of psychiatric illness. Due to the long half-life of tafenoquine (approximately 15 days), signs or symptoms of psychiatric adverse reactions that may occur could be delayed in onset and/or duration.
- Serious hypersensitivity reactions (e.g., angioedema, urticaria) have been observed with administration of tafenoquine. Institute appropriate therapy if hypersensitivity reactions occur. Do not re-administer tafenoquine. Tafenoquine is contraindicated in patients who develop hypersensitivity to tafenoquine or any component of tafenoquine or other 8-aminoquinolines.
- Due to the long half-life of tafenoquine (approximately 15 days), signs or symptoms of hypersensitivity adverse reactions that may occur could be delayed in onset and/or duration. Advise patients to seek medical attention if signs of hypersensitivity occur.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The safety data described below reflect exposure to 4,129 subjects, of whom 810 received a 300-mg single dose of tafenoquine. Tafenoquine was evaluated in patients with P. vivax malaria (n = 483) in 3 randomized, double-blind trials including a placebo-controlled trial comparing tafenoquine plus chloroquine (n = 260) with chloroquine alone (Trial 1), a placebo-controlled dose-ranging trial (Trial 2) (n = 57), and a hematologic safety trial (Trial 3, NCT02216123) (n = 166).
- In Trial 1, in patients with P. vivax malaria, the most common adverse reactions reported in ≥5% of patients treated with tafenoquine are listed in TABLE 1. Patients included in the trial had a mean age of 35 (range: 16 to 79 years), were 75% male and from the following regions: 70% Latin America (Brazil and Peru), 19% Southeast (SE) Asia (Thailand, Cambodia, and the Philippines), and 11% Africa (Ethiopia).
Other Adverse Reactions Reported with tafenoquine
- Clinically significant adverse reactions with tafenoquine 300-mg single dose in clinical trials (n = 810) in ≤3% of subjects are listed below:
Psychiatric Disorders: Anxiety, insomnia, abnormal dreams.
Nervous System Disorders: Somnolence.
Laboratory Investigations: Increased blood creatinine, increased blood methemoglobin, increased alanine aminotransferase.
Immune System Disorders: Hypersensitivity reactions (e.g., angioedema, urticaria).
Eye Disorders: Vortex keratopathy, photophobia.
- Psychiatric Disorders: Anxiety, insomnia, abnormal dreams.
- Nervous System Disorders: Somnolence.
- Laboratory Investigations: Increased blood creatinine, increased blood methemoglobin, increased alanine aminotransferase.
- Immune System Disorders: Hypersensitivity reactions (e.g., angioedema, urticaria).
- Eye Disorders: Vortex keratopathy, photophobia.
## Postmarketing Experience
There is limited information regarding Tafenoquine Postmarketing Experience in the drug label.
# Drug Interactions
- The effect of coadministration of tafenoquine on the pharmacokinetics of OCT2 and MATE substrates in humans is unknown. However, in vitro, observations suggest the potential for increased concentrations of these substrates which may increase the risk of toxicity of these drugs.
- Avoid coadministration of tafenoquine with OCT2 and MATE substrates (e.g., dofetilide, metformin). If coadministration cannot be avoided, monitor for drug-related toxicities and consider dosage reduction if needed based on approved product labeling of the coadministered drug.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- The use of tafenoquine during pregnancy may cause hemolytic anemia in a fetus who is G6PD deficient. Treatment with tafenoquine during pregnancy is not recommended. Available data with use of tafenoquine in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal studies, there were increased abortions, with and without maternal toxicity, when tafenoquine was given orally to pregnant rabbits at and above doses equivalent to about 0.4 times the clinical exposure based on body surface area comparisons. No fetotoxicity was observed at doses equivalent to the clinical exposure (based on body surface area comparisons) in a similar study in rats.
- The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Clinical Considerations
- Disease-Associated Maternal and/or Embryo/Fetal Risk: Malaria during pregnancy increases the risk for adverse pregnancy outcomes, including maternal anemia, prematurity, spontaneous abortion, and stillbirth.
Data
- Animal Data: Tafenoquine resulted in dose-related abortions when given orally to pregnant rabbits during organogenesis (Gestation Days 6 to 18) at doses of 7 mg/kg (about 0.4 times the clinical exposure based on body surface area comparisons) and above. Doses higher than 7 mg/kg were also associated with maternal toxicity (mortality and reduced body weight gain). In a similar study in rats, doses of 3, 10, or 30 mg/kg/day resulted in maternal toxicity (enlarged spleen, reduced body weight, and reduced food intake) but no fetotoxicity at the high dose (equivalent to the clinical exposure based on body surface area comparisons). There was no evidence of malformations in either species. In a pre- and postnatal development study in rats, tafenoquine administered throughout pregnancy and lactation produced maternal toxicity and a reversible decrease in offspring body weight gain and decrease in motor activity at 18 mg/kg/day, which is equivalent to about 0.6 times the clinical dose based on body surface area comparisons.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tafenoquine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tafenoquine during labor and delivery.
### Nursing Mothers
Risk Summary
- A breastfed infant with G6PD deficiency is at risk for hemolytic anemia from exposure to tafenoquine. Infant G6PD status should be checked before breastfeeding begins. Tafenoquine is contraindicated in breastfeeding women when the infant is found to be G6PD deficient or the G6PD status of the infant is unknown.
- There is no information regarding the presence of tafenoquine in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. In a breastfed infant with normal G6PD, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for tafenoquine and any potential effects on the breastfed infant from tafenoquine or from the underlying maternal condition.
Clinical Considerations
- Check the infant’s G6PD status before maternal breastfeeding commences. If an infant is G6PD deficient, exposure to tafenoquine during breastfeeding may result in hemolytic anemia in the infant; therefore, advise the woman with an infant who has G6PD deficiency or whose G6PD status is unknown, not to breastfeed for 3 months after the dose of tafenoquine.
### Pediatric Use
- The safety and effectiveness of tafenoquine have been established in pediatric patients aged 16 years and older. Use of tafenoquine in these pediatric patients is supported by evidence from adequate and well-controlled studies of tafenoquine.
- Safety and effectiveness of tafenoquine in pediatric patients younger than 16 years have not been established.
### Geriatic Use
- Clinical trials of tafenoquine did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
### Gender
There is no FDA guidance on the use of Tafenoquine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tafenoquine with respect to specific racial populations.
### Renal Impairment
- The pharmacokinetics of tafenoquine have not been studied in patients with renal impairment. If tafenoquine is administered to such patients, monitoring for adverse reactions associated with tafenoquine is needed.
### Hepatic Impairment
- The pharmacokinetics of tafenoquine have not been studied in patients with hepatic impairment. If tafenoquine is administered to such patients, monitoring for adverse reactions associated with tafenoquine is needed.
### Females of Reproductive Potential and Males
Pregnancy Testing
- Verify the pregnancy status in females of reproductive potential prior to initiating treatment with tafenoquine.
Contraception
- Tafenoquine may cause hemolytic anemia in a G6PD-deficient fetus. Advise females of reproductive potential that treatment with tafenoquine during pregnancy is not recommended and to avoid pregnancy or use effective contraception for 3 months after the dose of tafenoquine.
### Immunocompromised Patients
There is no FDA guidance one the use of Tafenoquine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- All patients must be tested for glucose-6-phosphate dehydrogenase (G6PD) deficiency prior to prescribing tafenoquine.
- Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with tafenoquine.
- The recommended dose of tafenoquine in patients aged 16 years and older is a single dose of 300 mg administered as two 150-mg tablets taken together. Coadminister tafenoquine on the first or second day of the appropriate antimalarial therapy (e.g. chloroquine) for acute P. vivax malaria.
- Administer tafenoquine with food to increase systemic absorption.
- Swallow tablets whole. Do not break, crush, or chew the tablets.
- In the event of vomiting within 1 hour after dosing, a repeat dose should be given. Re-dosing should not be attempted more than once.
### Monitoring
There is limited information regarding Tafenoquine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Tafenoquine and IV administrations.
# Overdosage
- Hemoglobin decline and methemoglobinemia may be encountered in an overdose with tafenoquine. Treatment of overdosage consists of institution of appropriate symptomatic and/or supportive therapy.
# Pharmacology
## Mechanism of Action
- Tafenoquine is an 8-aminoquinoline antimalarial drug.
## Structure
- The molecular formula of tafenoquine succinate is C24H28F3N3O3 - C4H6O4, and its molecular mass is 581.6 as the succinate salt (463.5 as free base). The structural formula is shown below.
## Pharmacodynamics
Cardiac Electrophysiology
- The effect of tafenoquine on the QTc interval was evaluated in a Phase 1 randomized, single-blind, placebo- and positive-controlled, parallel-group thorough QTc study in 260 healthy adult subjects. At a cumulative dose of 1,200 mg (400 mg/day for 3 days; 4 times the maximum recommended dose), tafenoquine did not prolong the QTc interval to any clinically relevant extent.
Exposure-Response Relationships
- A saturable relationship between tafenoquine exposure (AUC) and clinical response (recurrence-free rate at 6 months) was identified. Tafenoquine exposures achieved with doses of 300 mg and higher are on the plateau of the exposure-response curve. Use of tafenoquine at doses or regimens other than a 300-mg single dose is not approved by the FDA.
## Pharmacokinetics
Absorption
- Maximum plasma concentrations were generally observed 12 to 15 hours following oral administration.
- Food Effect: Plasma tafenoquine AUC increased by 41% and Cmax increased by 31% when administered as an investigational capsule formulation with a high-calorie, high-fat meal (approximately 1,000 calories with 15% protein, 25% carbohydrate, and 60% fat) compared with the fasted state.
Distribution
- Protein binding of tafenoquine is >99.5%. The apparent oral volume of distribution is ~1,600 L. Following single- and multiple-oral-dose administration, tafenoquine whole blood concentrations were on average 67% higher than corresponding plasma values.
Elimination
- The apparent oral clearance of tafenoquine is approximately 3 L/h. The average terminal half-life is approximately 15 days.
- Metabolism: Tafenoquine undergoes slow metabolism. Unchanged tafenoquine represented the only notable drug-related component in human plasma after a single oral dose of tafenoquine.
- Excretion: The full excretion profile of tafenoquine in humans is unknown. Over a 6-day collection period, renal elimination of unchanged tafenoquine was low.
Specific Populations
- Pharmacokinetics of tafenoquine were not significantly impacted by age, sex, ethnicity, and body weight. The effect of renal or hepatic impairment on tafenoquine pharmacokinetics is unknown.
Drug Interaction Studies
- Clinical Studies: No clinically significant effects on tafenoquine pharmacokinetics were observed following coadministration with chloroquine, dihydroartemisinin-piperaquine, or artemether-lumefantrine in healthy subjects.
- No clinically significant effects on the pharmacokinetics of dihydroartemisinin, piperaquine, artemether, lumefantrine, or substrates of cytochrome P450 isoenzymes (CYP)1A2 (caffeine), CYP2D6 (desipramine), CYP2C8 (chloroquine), CYP2C9 (flurbiprofen), or CYP3A4 (midazolam, chloroquine) were observed following coadministration of tafenoquine in healthy subjects.
- In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically: Tafenoquine inhibited metformin transport via human OCT2, MATE-1, and MATE2-K transporters. Clinical drug interaction studies with tafenoquine and OCT2 and MATE substrates have not been conducted.
- The effect of tafenoquine on substrates of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptides 1B1/1B3 (OATP1B1/OATP1B3) is unknown.
Microbiology
Mechanism of Action
- Tafenoquine, an 8-aminoquinoline antimalarial, is active against the liver stages including the hypnozoite (dormant stage) of P. vivax. In addition to its effect on the parasite, tafenoquine causes red blood cell shrinkage in vitro. The molecular target of tafenoquine is not known.
Antimicrobial Activity
- Tafenoquine is active against pre-erythrocytic (liver) and erythrocytic (asexual) forms as well as gametocytes of P. vivax. The activity of tafenoquine against the pre-erythrocytic liver stages of the parasite prevents the development of the erythrocytic forms of the parasite, which are responsible for relapses in P. vivax malaria.
Resistance
- A potential for development of resistance of Plasmodium species to tafenoquine was not evaluated.
## Nonclinical Toxicology
Carcinogenesis
- Two-year oral carcinogenicity studies were conducted in rats and mice. Renal cell adenomas and carcinomas were increased in male rats at doses of 1 mg/kg/day and above (3 times the clinical exposure based on AUC comparisons). Tafenoquine was not carcinogenic in mice. Given the single-dose administration of tafenoquine, these findings may not represent a carcinogenicity risk to humans.
Mutagenesis
- Tafenoquine did not cause mutations or chromosomal damage in 2 definitive in vitro tests (bacterial mutation assay and mouse lymphoma L5178Y cell assay) or in an in vivo oral rat micronucleus test.
Impairment of Fertility
- In a rat fertility study, tafenoquine was given orally at 1.5, 5, and 15 mg/kg/day (up to about 0.5 times the human dose based on body surface area comparisons) to males for at least 67 days, including 29 days prior to mating, and to females from 15 days prior to mating through early pregnancy. Tafenoquine resulted in reduced number of viable fetuses, implantation sites, and corpora lutea at 15 mg/kg in the presence of maternal toxicity (mortality, piloerection, rough coat, and reduced body weight).
# Clinical Studies
- Trial 1 (NCT01376167) was a double-blind, controlled clinical trial of 522 adults positive for P. vivax across 3 regions (Asia, Africa, and Latin America). All patients received chloroquine phosphate (600-mg free base on Days 1 and 2 with 300-mg free base on Day 3) to treat the acute infection in addition to either a one-time dose of tafenoquine (two 150-mg tablets) on Day 1 or Day 2 (n = 260), an active control (n = 129), or placebo (n = 133) in a 2:1:1 fashion. Patients included in the trial had a mean age of 35 (range: 16 to 79 years), were 75% male and from the following regions: 70% Latin America (Brazil and Peru), 19% SE Asia (Thailand, Cambodia, and the Philippines), and 11% Africa (Ethiopia).
- Patients were considered recurrence-free at 6 months if they demonstrated initial parasite clearance, took no anti-malarial medications, and were confirmed parasite-free at the 6-month final assessment (i.e., absence of relapse or new infection).
- Due to the risk of hemolytic anemia, patients were excluded from the trial if they had a G6PD enzyme activity level <70% of the site median value for G6PD normals (8.2 IU/gHb). In this trial, the minimum G6PD enzyme level of any subject was 5.4 IU/gHb. Patients with severe malaria were excluded from the trial.
- The recurrence-free efficacy rates at 6 months among the tafenoquine and placebo groups are presented in TABLE 2. The risk of recurrence for tafenoquine plus chloroquine was reduced by 76% compared with placebo plus chloroquine.
- In Trial 2 (NCT01376167), a dose-ranging trial with a study design similar to Trial 1, 57 and 54 subjects were randomized to tafenoquine 300-mg single dose plus chloroquine (same dose as in Trial 1) and placebo plus chloroquine groups, respectively. Tafenoquine plus chloroquine demonstrated a statistically significantly higher rate of recurrence-free efficacy at 6 months compared with the placebo plus chloroquine control group (84% versus 39%, with a difference of 45% and 95% CI ).
# How Supplied
- Tafenoquine tablets contain 150 mg of tafenoquine (equivalent to 188.2 mg tafenoquine succinate) and are pink, film‑coated, capsule-shaped, and debossed with ‘GS J11’ on one side. Tafenoquine is supplied as follows:
Bottle of 30 tablets with child-resistant closure (NDC 0173-0889-13). Bottles contain a desiccant. Once opened, use within 3 months.
Unit Dose Pack of 2 tablets in a bottle with child-resistant closure (NDC 0173-0889-39). Bottles contain a desiccant.
- Bottle of 30 tablets with child-resistant closure (NDC 0173-0889-13). Bottles contain a desiccant. Once opened, use within 3 months.
- Unit Dose Pack of 2 tablets in a bottle with child-resistant closure (NDC 0173-0889-39). Bottles contain a desiccant.
## Storage
- Store at 20°C to 25°C (68°F to 77°F). Temperature excursions are permitted to 15°C to 30°C (59°F to 86°F).
- Store in the original package to protect from moisture. Keep the bottle tightly closed and do not remove the desiccant.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Patient Information).
G6PD Testing and Hemolytic Anemia
- Inform patients of the need for testing for G6PD deficiency before starting tafenoquine. Advise patients of the symptoms of hemolytic anemia and instruct them to seek medical advice promptly if such symptoms occur. Patients should contact their healthcare provider if they develop dark lips or urine as these may be signs of hemolysis or methemoglobinemia.
Important Administration Instructions
- Advise patients to take tafenoquine with food to increase absorption.
- Advise patients to swallow the tablet whole and not to break, crush, or chew it.
Potential Harm to the Fetus
- Advise females of reproductive potential of the potential risk of tafenoquine to a fetus and to inform their healthcare provider of a known or suspected pregnancy.
- Advise females of reproductive potential to avoid pregnancy or use effective contraception for 3 months after the dose of tafenoquine.
Lactation
- Advise women with a G6PD-deficient infant, or if they do not know the G6PD status of their infant, not to breastfeed for 3 months after the dose of tafenoquine.
Methemoglobinemia
- Inform patients that methemoglobinemia has occurred with tafenoquine. Advise patients of the symptoms of methemoglobinemia and instruct them to seek medical advice promptly if such symptoms occur.
Psychiatric Symptoms
- Advise patients with a history of psychiatric illness regarding the potential for new or worsening psychiatric symptoms with tafenoquine and instruct them to seek medical advice promptly if such symptoms occur.
Hypersensitivity Reactions
- Inform patients that hypersensitivity reactions have occurred with tafenoquine. Advise patients of the symptoms of hypersensitivity reactions and instruct them to seek medical advice promptly if such symptoms occur.
# Precautions with Alcohol
Alcohol-Tafenoquine interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
Krintafel
# Look-Alike Drug Names
There is limited information regarding Tafenoquine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Tafenoquine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Zach Leibowitz [2]
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# Overview
Tafenoquine is an antimalarial that is FDA approved for the radical cure (prevention of relapse) of Plasmodium vivax malaria in patients aged 16 years and older who are receiving appropriate antimalarial therapy for acute P. vivax infection. Common adverse reactions include dizziness, nausea, vomiting, headache, and decreased hemoglobin.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Indication
- Tafenoquine is indicated for the radical cure (prevention of relapse) of Plasmodium vivax malaria in patients aged 16 years and older who are receiving appropriate antimalarial therapy for acute P. vivax infection.
Limitation of Use
- Tafenoquine is NOT indicated for the treatment of acute P. vivax malaria.
Dosage
- The recommended dose of tafenoquine in patients aged 16 years and older is a single dose of 300 mg administered as two 150-mg tafenoquine tablets taken together.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding tafenoquine Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding tafenoquine Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness of tafenoquine in pediatric patients younger than 16 years have not been established.
- For patients of ages 16 and older, see Adult Indication and Dosage.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding tafenoquine Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding tafenoquine Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Tafenoquine is contraindicated in:
patients with G6PD deficiency or unknown G6PD status due to the risk of hemolytic anemia
breastfeeding by a lactating woman when the infant is found to be G6PD deficient or if the G6PD status of the infant is unknown
patients with known hypersensitivity to tafenoquine, other 8-aminoquinolines, or any component of tafenoquine
- patients with G6PD deficiency or unknown G6PD status due to the risk of hemolytic anemia
- breastfeeding by a lactating woman when the infant is found to be G6PD deficient or if the G6PD status of the infant is unknown
- patients with known hypersensitivity to tafenoquine, other 8-aminoquinolines, or any component of tafenoquine
# Warnings
- Due to the risk of hemolytic anemia in patients with G6PD deficiency, G6PD testing must be performed before prescribing tafenoquine. Due to the limitations of G6PD tests, physicians need to be aware of residual risk of hemolysis and adequate medical support and follow-up to manage hemolytic risk should be available. Treatment with tafenoquine is contraindicated in patients with G6PD deficiency or unknown G6PD status. Patients were excluded from clinical trials of tafenoquine if they had a G6PD enzyme activity level <70% of the site median value for G6PD normal activity. In clinical trials, declines in hemoglobin levels were reported in some G6PD-normal patients. Monitor patients for clinical signs or symptoms of hemolysis. Advise patients to seek medical attention if signs of hemolysis occur.
Potential Harm to the Fetus
- The use of tafenoquine during pregnancy may cause hemolytic anemia in a G6PD-deficient fetus. Even if a pregnant woman has normal levels of G6PD, the fetus could be G6PD deficient. Advise females of reproductive potential that treatment with tafenoquine during pregnancy is not recommended and to avoid pregnancy or use effective contraception for 3 months after the dose of tafenoquine.
Potential Harm to the Breastfeeding Infant
- A G6PD-deficient infant may be at risk for hemolytic anemia from exposure to tafenoquine through breast milk. Infant G6PD status should be checked before breastfeeding begins. Tafenoquine is contraindicated in breastfeeding women when the infant is found to be G6PD-deficient or the G6PD status of the infant is unknown. Advise the woman with a G6PD-deficient infant or if the G6PD status of the infant is unknown not to breastfeed for 3 months after the dose of tafenoquine.
- Asymptomatic elevations in methemoglobin have been observed in the clinical trials of tafenoquine. Institute appropriate therapy if signs or symptoms of methemoglobinemia occur. Carefully monitor individuals with nicotinamide adenine dinucleotide (NADH)-dependent methemoglobin reductase deficiency. Advise patients to seek medical attention if signs of methemoglobinemia occur.
- Psychiatric adverse reactions including anxiety (<1%), abnormal dreams (<1%), and insomnia (3%) have been reported in clinical trials of tafenoquine. Two cases of depression and 2 cases of psychosis have occurred primarily in patients with a history of psychiatric disorders following receipt of single doses of tafenoquine that were higher than the approved 300-mg dose (350 mg to 600 mg). Safety and effectiveness of tafenoquine have not been established at doses or regimens other than the approved regimen; use of tafenoquine at doses or regimens other than a 300-mg single dose is not approved by FDA.
- The benefit of treatment with tafenoquine must be weighed against the potential risk for psychiatric adverse reactions in patients with a history of psychiatric illness. Due to the long half-life of tafenoquine (approximately 15 days), signs or symptoms of psychiatric adverse reactions that may occur could be delayed in onset and/or duration.
- Serious hypersensitivity reactions (e.g., angioedema, urticaria) have been observed with administration of tafenoquine. Institute appropriate therapy if hypersensitivity reactions occur. Do not re-administer tafenoquine. Tafenoquine is contraindicated in patients who develop hypersensitivity to tafenoquine or any component of tafenoquine or other 8-aminoquinolines.
- Due to the long half-life of tafenoquine (approximately 15 days), signs or symptoms of hypersensitivity adverse reactions that may occur could be delayed in onset and/or duration. Advise patients to seek medical attention if signs of hypersensitivity occur.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The safety data described below reflect exposure to 4,129 subjects, of whom 810 received a 300-mg single dose of tafenoquine. Tafenoquine was evaluated in patients with P. vivax malaria (n = 483) in 3 randomized, double-blind trials including a placebo-controlled trial comparing tafenoquine plus chloroquine (n = 260) with chloroquine alone (Trial 1), a placebo-controlled dose-ranging trial (Trial 2) (n = 57), and a hematologic safety trial (Trial 3, NCT02216123) (n = 166).
- In Trial 1, in patients with P. vivax malaria, the most common adverse reactions reported in ≥5% of patients treated with tafenoquine are listed in TABLE 1. Patients included in the trial had a mean age of 35 (range: 16 to 79 years), were 75% male and from the following regions: 70% Latin America (Brazil and Peru), 19% Southeast (SE) Asia (Thailand, Cambodia, and the Philippines), and 11% Africa (Ethiopia).
Other Adverse Reactions Reported with tafenoquine
- Clinically significant adverse reactions with tafenoquine 300-mg single dose in clinical trials (n = 810) in ≤3% of subjects are listed below:
Psychiatric Disorders: Anxiety, insomnia, abnormal dreams.
Nervous System Disorders: Somnolence.
Laboratory Investigations: Increased blood creatinine, increased blood methemoglobin, increased alanine aminotransferase.
Immune System Disorders: Hypersensitivity reactions (e.g., angioedema, urticaria).
Eye Disorders: Vortex keratopathy, photophobia.
- Psychiatric Disorders: Anxiety, insomnia, abnormal dreams.
- Nervous System Disorders: Somnolence.
- Laboratory Investigations: Increased blood creatinine, increased blood methemoglobin, increased alanine aminotransferase.
- Immune System Disorders: Hypersensitivity reactions (e.g., angioedema, urticaria).
- Eye Disorders: Vortex keratopathy, photophobia.
## Postmarketing Experience
There is limited information regarding Tafenoquine Postmarketing Experience in the drug label.
# Drug Interactions
- The effect of coadministration of tafenoquine on the pharmacokinetics of OCT2 and MATE substrates in humans is unknown. However, in vitro, observations suggest the potential for increased concentrations of these substrates which may increase the risk of toxicity of these drugs.
- Avoid coadministration of tafenoquine with OCT2 and MATE substrates (e.g., dofetilide, metformin). If coadministration cannot be avoided, monitor for drug-related toxicities and consider dosage reduction if needed based on approved product labeling of the coadministered drug.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- The use of tafenoquine during pregnancy may cause hemolytic anemia in a fetus who is G6PD deficient. Treatment with tafenoquine during pregnancy is not recommended. Available data with use of tafenoquine in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal studies, there were increased abortions, with and without maternal toxicity, when tafenoquine was given orally to pregnant rabbits at and above doses equivalent to about 0.4 times the clinical exposure based on body surface area comparisons. No fetotoxicity was observed at doses equivalent to the clinical exposure (based on body surface area comparisons) in a similar study in rats.
- The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Clinical Considerations
- Disease-Associated Maternal and/or Embryo/Fetal Risk: Malaria during pregnancy increases the risk for adverse pregnancy outcomes, including maternal anemia, prematurity, spontaneous abortion, and stillbirth.
Data
- Animal Data: Tafenoquine resulted in dose-related abortions when given orally to pregnant rabbits during organogenesis (Gestation Days 6 to 18) at doses of 7 mg/kg (about 0.4 times the clinical exposure based on body surface area comparisons) and above. Doses higher than 7 mg/kg were also associated with maternal toxicity (mortality and reduced body weight gain). In a similar study in rats, doses of 3, 10, or 30 mg/kg/day resulted in maternal toxicity (enlarged spleen, reduced body weight, and reduced food intake) but no fetotoxicity at the high dose (equivalent to the clinical exposure based on body surface area comparisons). There was no evidence of malformations in either species. In a pre- and postnatal development study in rats, tafenoquine administered throughout pregnancy and lactation produced maternal toxicity and a reversible decrease in offspring body weight gain and decrease in motor activity at 18 mg/kg/day, which is equivalent to about 0.6 times the clinical dose based on body surface area comparisons.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tafenoquine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tafenoquine during labor and delivery.
### Nursing Mothers
Risk Summary
- A breastfed infant with G6PD deficiency is at risk for hemolytic anemia from exposure to tafenoquine. Infant G6PD status should be checked before breastfeeding begins. Tafenoquine is contraindicated in breastfeeding women when the infant is found to be G6PD deficient or the G6PD status of the infant is unknown.
- There is no information regarding the presence of tafenoquine in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. In a breastfed infant with normal G6PD, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for tafenoquine and any potential effects on the breastfed infant from tafenoquine or from the underlying maternal condition.
Clinical Considerations
- Check the infant’s G6PD status before maternal breastfeeding commences. If an infant is G6PD deficient, exposure to tafenoquine during breastfeeding may result in hemolytic anemia in the infant; therefore, advise the woman with an infant who has G6PD deficiency or whose G6PD status is unknown, not to breastfeed for 3 months after the dose of tafenoquine.
### Pediatric Use
- The safety and effectiveness of tafenoquine have been established in pediatric patients aged 16 years and older. Use of tafenoquine in these pediatric patients is supported by evidence from adequate and well-controlled studies of tafenoquine.
- Safety and effectiveness of tafenoquine in pediatric patients younger than 16 years have not been established.
### Geriatic Use
- Clinical trials of tafenoquine did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
### Gender
There is no FDA guidance on the use of Tafenoquine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tafenoquine with respect to specific racial populations.
### Renal Impairment
- The pharmacokinetics of tafenoquine have not been studied in patients with renal impairment. If tafenoquine is administered to such patients, monitoring for adverse reactions associated with tafenoquine is needed.
### Hepatic Impairment
- The pharmacokinetics of tafenoquine have not been studied in patients with hepatic impairment. If tafenoquine is administered to such patients, monitoring for adverse reactions associated with tafenoquine is needed.
### Females of Reproductive Potential and Males
Pregnancy Testing
- Verify the pregnancy status in females of reproductive potential prior to initiating treatment with tafenoquine.
Contraception
- Tafenoquine may cause hemolytic anemia in a G6PD-deficient fetus. Advise females of reproductive potential that treatment with tafenoquine during pregnancy is not recommended and to avoid pregnancy or use effective contraception for 3 months after the dose of tafenoquine.
### Immunocompromised Patients
There is no FDA guidance one the use of Tafenoquine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- All patients must be tested for glucose-6-phosphate dehydrogenase (G6PD) deficiency prior to prescribing tafenoquine.
- Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with tafenoquine.
- The recommended dose of tafenoquine in patients aged 16 years and older is a single dose of 300 mg administered as two 150-mg tablets taken together. Coadminister tafenoquine on the first or second day of the appropriate antimalarial therapy (e.g. chloroquine) for acute P. vivax malaria.
- Administer tafenoquine with food to increase systemic absorption.
- Swallow tablets whole. Do not break, crush, or chew the tablets.
- In the event of vomiting within 1 hour after dosing, a repeat dose should be given. Re-dosing should not be attempted more than once.
### Monitoring
There is limited information regarding Tafenoquine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Tafenoquine and IV administrations.
# Overdosage
- Hemoglobin decline and methemoglobinemia may be encountered in an overdose with tafenoquine. Treatment of overdosage consists of institution of appropriate symptomatic and/or supportive therapy.
# Pharmacology
## Mechanism of Action
- Tafenoquine is an 8-aminoquinoline antimalarial drug.
## Structure
- The molecular formula of tafenoquine succinate is C24H28F3N3O3 • C4H6O4, and its molecular mass is 581.6 as the succinate salt (463.5 as free base). The structural formula is shown below.
## Pharmacodynamics
Cardiac Electrophysiology
- The effect of tafenoquine on the QTc interval was evaluated in a Phase 1 randomized, single-blind, placebo- and positive-controlled, parallel-group thorough QTc study in 260 healthy adult subjects. At a cumulative dose of 1,200 mg (400 mg/day for 3 days; 4 times the maximum recommended dose), tafenoquine did not prolong the QTc interval to any clinically relevant extent.
Exposure-Response Relationships
- A saturable relationship between tafenoquine exposure (AUC) and clinical response (recurrence-free rate at 6 months) was identified. Tafenoquine exposures achieved with doses of 300 mg and higher are on the plateau of the exposure-response curve. Use of tafenoquine at doses or regimens other than a 300-mg single dose is not approved by the FDA.
## Pharmacokinetics
Absorption
- Maximum plasma concentrations were generally observed 12 to 15 hours following oral administration.
- Food Effect: Plasma tafenoquine AUC increased by 41% and Cmax increased by 31% when administered as an investigational capsule formulation with a high-calorie, high-fat meal (approximately 1,000 calories with 15% protein, 25% carbohydrate, and 60% fat) compared with the fasted state.
Distribution
- Protein binding of tafenoquine is >99.5%. The apparent oral volume of distribution is ~1,600 L. Following single- and multiple-oral-dose administration, tafenoquine whole blood concentrations were on average 67% higher than corresponding plasma values.
Elimination
- The apparent oral clearance of tafenoquine is approximately 3 L/h. The average terminal half-life is approximately 15 days.
- Metabolism: Tafenoquine undergoes slow metabolism. Unchanged tafenoquine represented the only notable drug-related component in human plasma after a single oral dose of tafenoquine.
- Excretion: The full excretion profile of tafenoquine in humans is unknown. Over a 6-day collection period, renal elimination of unchanged tafenoquine was low.
Specific Populations
- Pharmacokinetics of tafenoquine were not significantly impacted by age, sex, ethnicity, and body weight. The effect of renal or hepatic impairment on tafenoquine pharmacokinetics is unknown.
Drug Interaction Studies
- Clinical Studies: No clinically significant effects on tafenoquine pharmacokinetics were observed following coadministration with chloroquine, dihydroartemisinin-piperaquine, or artemether-lumefantrine in healthy subjects.
- No clinically significant effects on the pharmacokinetics of dihydroartemisinin, piperaquine, artemether, lumefantrine, or substrates of cytochrome P450 isoenzymes (CYP)1A2 (caffeine), CYP2D6 (desipramine), CYP2C8 (chloroquine), CYP2C9 (flurbiprofen), or CYP3A4 (midazolam, chloroquine) were observed following coadministration of tafenoquine in healthy subjects.
- In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically: Tafenoquine inhibited metformin transport via human OCT2, MATE-1, and MATE2-K transporters. Clinical drug interaction studies with tafenoquine and OCT2 and MATE substrates have not been conducted.
- The effect of tafenoquine on substrates of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptides 1B1/1B3 (OATP1B1/OATP1B3) is unknown.
Microbiology
Mechanism of Action
- Tafenoquine, an 8-aminoquinoline antimalarial, is active against the liver stages including the hypnozoite (dormant stage) of P. vivax. In addition to its effect on the parasite, tafenoquine causes red blood cell shrinkage in vitro. The molecular target of tafenoquine is not known.
Antimicrobial Activity
- Tafenoquine is active against pre-erythrocytic (liver) and erythrocytic (asexual) forms as well as gametocytes of P. vivax. The activity of tafenoquine against the pre-erythrocytic liver stages of the parasite prevents the development of the erythrocytic forms of the parasite, which are responsible for relapses in P. vivax malaria.
Resistance
- A potential for development of resistance of Plasmodium species to tafenoquine was not evaluated.
## Nonclinical Toxicology
Carcinogenesis
- Two-year oral carcinogenicity studies were conducted in rats and mice. Renal cell adenomas and carcinomas were increased in male rats at doses of 1 mg/kg/day and above (3 times the clinical exposure based on AUC comparisons). Tafenoquine was not carcinogenic in mice. Given the single-dose administration of tafenoquine, these findings may not represent a carcinogenicity risk to humans.
Mutagenesis
- Tafenoquine did not cause mutations or chromosomal damage in 2 definitive in vitro tests (bacterial mutation assay and mouse lymphoma L5178Y cell assay) or in an in vivo oral rat micronucleus test.
Impairment of Fertility
- In a rat fertility study, tafenoquine was given orally at 1.5, 5, and 15 mg/kg/day (up to about 0.5 times the human dose based on body surface area comparisons) to males for at least 67 days, including 29 days prior to mating, and to females from 15 days prior to mating through early pregnancy. Tafenoquine resulted in reduced number of viable fetuses, implantation sites, and corpora lutea at 15 mg/kg in the presence of maternal toxicity (mortality, piloerection, rough coat, and reduced body weight).
# Clinical Studies
- Trial 1 (NCT01376167) was a double-blind, controlled clinical trial of 522 adults positive for P. vivax across 3 regions (Asia, Africa, and Latin America). All patients received chloroquine phosphate (600-mg free base on Days 1 and 2 with 300-mg free base on Day 3) to treat the acute infection in addition to either a one-time dose of tafenoquine (two 150-mg tablets) on Day 1 or Day 2 (n = 260), an active control (n = 129), or placebo (n = 133) in a 2:1:1 fashion. Patients included in the trial had a mean age of 35 (range: 16 to 79 years), were 75% male and from the following regions: 70% Latin America (Brazil and Peru), 19% SE Asia (Thailand, Cambodia, and the Philippines), and 11% Africa (Ethiopia).
- Patients were considered recurrence-free at 6 months if they demonstrated initial parasite clearance, took no anti-malarial medications, and were confirmed parasite-free at the 6-month final assessment (i.e., absence of relapse or new infection).
- Due to the risk of hemolytic anemia, patients were excluded from the trial if they had a G6PD enzyme activity level <70% of the site median value for G6PD normals (8.2 IU/gHb). In this trial, the minimum G6PD enzyme level of any subject was 5.4 IU/gHb. Patients with severe malaria were excluded from the trial.
- The recurrence-free efficacy rates at 6 months among the tafenoquine and placebo groups are presented in TABLE 2. The risk of recurrence for tafenoquine plus chloroquine was reduced by 76% compared with placebo plus chloroquine.
- In Trial 2 (NCT01376167), a dose-ranging trial with a study design similar to Trial 1, 57 and 54 subjects were randomized to tafenoquine 300-mg single dose plus chloroquine (same dose as in Trial 1) and placebo plus chloroquine groups, respectively. Tafenoquine plus chloroquine demonstrated a statistically significantly higher rate of recurrence-free efficacy at 6 months compared with the placebo plus chloroquine control group (84% versus 39%, with a difference of 45% and 95% CI [29%, 61%]).
# How Supplied
- Tafenoquine tablets contain 150 mg of tafenoquine (equivalent to 188.2 mg tafenoquine succinate) and are pink, film‑coated, capsule-shaped, and debossed with ‘GS J11’ on one side. Tafenoquine is supplied as follows:
Bottle of 30 tablets with child-resistant closure (NDC 0173-0889-13). Bottles contain a desiccant. Once opened, use within 3 months.
Unit Dose Pack of 2 tablets in a bottle with child-resistant closure (NDC 0173-0889-39). Bottles contain a desiccant.
- Bottle of 30 tablets with child-resistant closure (NDC 0173-0889-13). Bottles contain a desiccant. Once opened, use within 3 months.
- Unit Dose Pack of 2 tablets in a bottle with child-resistant closure (NDC 0173-0889-39). Bottles contain a desiccant.
## Storage
- Store at 20°C to 25°C (68°F to 77°F). Temperature excursions are permitted to 15°C to 30°C (59°F to 86°F).
- Store in the original package to protect from moisture. Keep the bottle tightly closed and do not remove the desiccant.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Patient Information).
G6PD Testing and Hemolytic Anemia
- Inform patients of the need for testing for G6PD deficiency before starting tafenoquine. Advise patients of the symptoms of hemolytic anemia and instruct them to seek medical advice promptly if such symptoms occur. Patients should contact their healthcare provider if they develop dark lips or urine as these may be signs of hemolysis or methemoglobinemia.
Important Administration Instructions
- Advise patients to take tafenoquine with food to increase absorption.
- Advise patients to swallow the tablet whole and not to break, crush, or chew it.
Potential Harm to the Fetus
- Advise females of reproductive potential of the potential risk of tafenoquine to a fetus and to inform their healthcare provider of a known or suspected pregnancy.
- Advise females of reproductive potential to avoid pregnancy or use effective contraception for 3 months after the dose of tafenoquine.
Lactation
- Advise women with a G6PD-deficient infant, or if they do not know the G6PD status of their infant, not to breastfeed for 3 months after the dose of tafenoquine.
Methemoglobinemia
- Inform patients that methemoglobinemia has occurred with tafenoquine. Advise patients of the symptoms of methemoglobinemia and instruct them to seek medical advice promptly if such symptoms occur.
Psychiatric Symptoms
- Advise patients with a history of psychiatric illness regarding the potential for new or worsening psychiatric symptoms with tafenoquine and instruct them to seek medical advice promptly if such symptoms occur.
Hypersensitivity Reactions
- Inform patients that hypersensitivity reactions have occurred with tafenoquine. Advise patients of the symptoms of hypersensitivity reactions and instruct them to seek medical advice promptly if such symptoms occur.
# Precautions with Alcohol
Alcohol-Tafenoquine interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
Krintafel
# Look-Alike Drug Names
There is limited information regarding Tafenoquine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Krintafel | |
62c4781c2a3c512e736c498d4632d81783e9053a | wikidoc | Kyphoplasty | Kyphoplasty
# Overview
Kyphoplasty is a medical procedure developed by orthopedist Mark A. Reiley, MD, where the original height and angle of kyphosis of a fractured vertebra (of certain types) are restored, followed by its stabilization using injected bone filler material. The procedure is commonly done percutaneously. Height and angle restoration are currently carried out by using either hydraulic or mechanical intravertebral expansion.
Kyphoplasty is designed to stop the pain caused by the bone fracture, to stabilize the bone, and to restore some or all of the lost vertebral body height due to the compression fracture.
The procedure can be performed under either local or general anesthesia, on multiple levels, out-patient or in-patient, and is viewed as minimally invasive. It is most commonly performed for spinal compression fractures caused by osteoporosis, a condition that weakens the bone, and is also sometimes performed for certain other conditions that may have led to a spinal fracture.
The procedure is often carried out under fluoroscopy as an interventional radiographic procedure. It is most commonly done within eight weeks of when the fracture occurs.
# Benefits
One of the perceived benefits of kyphoplasty (developed primarily by a Sunnyvale, CA-based company called Kyphon) over vertebroplasty is that kyphoplasty uses a "balloon" to create a void in the cancellous part of the collapsed vertebral body that can then be filled with a more viscous bone cement (proprietary). The viscous properties of this bone cement decrease the likelihood that the cement will leak out of the vertebral body and affect other parts of the vertebra, especially the spinal cavity which contains the sensitive spinal nerves. It has never been shown, however, that there is any increased complication rate with vertebroplasty. Most practitioners who perform both procedures note that they are equally effective in treating the pain from compression fractures.
Inflating the balloon within the bone can also help reduce the deformity (which can lead to a hunchback appearance) created by the collapsed bone, as the balloon helps restore some or most of the vertebral height. It is hypothesized that helping restore the spine's natural geometry should help reduce the risk of future vertebral compression fractures. In theory, helping restore some percentage of the vertebral body's pre-fracture height should also alleviate any pain caused by compression of the thoracic cavity and decrease the associated risk of mortality. The degree of height restoration is, in the majority of patients, minimal.
# Criticism
One argument against kyphoplasty is the perception that this approach creates the potential for the vertebal body to open up existing voids in the cancellous bone. In fact, it has been established that the inflation of the balloon inside the vertebral body pushes cancellous bone to the fringes of the vertebral body, "compacting trabecular bone, which may seal osseous defects and venous pathways, thus preventing cement from leaking." (Phillips, et al., Spine, 2002;27:2173-8). The void created by the balloon inside of the vertebral body also allows for bone cement to be deposited under low pressure, thus decreasing the possibility of cement extravasation outside of the vertebral body. Cement extravasation rates observed with kyphoplasty are low, especially compared to those reported with vertebroplasty (Hadjipalvou, JBJS, (Br) 2005, Vol. 87-B, No. 12, Dec 2005). While successful at stabilizing fractured vertebrae, studies have shown that compared to vertebroplasty, kyphoplasty has only marginally greater success in restoring vertebral height. Procedure critics also point out that kyphoplasty's only true advantage over vertebroplasty is the slight reduction in the occurrence of extravasation, that coupled with kyphoplasty's significantly greater cost over vertebroplasty renders it somewhat redundant.
# Treatment alternatives to Kyphoplasty
In addition to Kyphoplasty, there are alternatives to treating bone fractures in the spine. Many spine fractures heal on their own and can be helped without surgery. This is especially true in the younger age group. Treatment options to aid healing include pain medication, dietary supplements (such as calcium supplements and a back brace. Another surgical alternative for spinal fractures is called Vertebroplasty, which is a procedure similar to Kyphoplasty.
One of the most notable treatments and prevention is exercise – specifically a type of exercise called “weight-bearing exercise”. In laymen’s terms, weight-bearing exercise is really just exercise you do while standing on your feet, so that your feet and legs bear the weight of your body. Examples include dancing, running, and walking. Resistance training is also important, which is exercise where you use the strength of your muscles to build muscle mass and bone strength. There are a wide range of exercises that fit into these exercise categories that are good for people who have had fractures, have osteoporosis or who have other back problems.
# Related Chapters
- Fracture
- Osteoporosis
- Bone healing
- vertebroplasty | Kyphoplasty
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Template:Cleanup
Kyphoplasty is a medical procedure developed by orthopedist Mark A. Reiley, MD, where the original height and angle of kyphosis of a fractured vertebra (of certain types) are restored, followed by its stabilization using injected bone filler material. The procedure is commonly done percutaneously. Height and angle restoration are currently carried out by using either hydraulic or mechanical intravertebral expansion.
Kyphoplasty is designed to stop the pain caused by the bone fracture, to stabilize the bone, and to restore some or all of the lost vertebral body height due to the compression fracture[2].
The procedure can be performed under either local or general anesthesia, on multiple levels, out-patient or in-patient, and is viewed as minimally invasive. It is most commonly performed for spinal compression fractures caused by osteoporosis, a condition that weakens the bone, and is also sometimes performed for certain other conditions that may have led to a spinal fracture.
The procedure is often carried out under fluoroscopy as an interventional radiographic procedure. It is most commonly done within eight weeks of when the fracture occurs.
-
-
# Benefits
One of the perceived benefits of kyphoplasty (developed primarily by a Sunnyvale, CA-based company called Kyphon) over vertebroplasty is that kyphoplasty uses a "balloon" to create a void in the cancellous part of the collapsed vertebral body that can then be filled with a more viscous bone cement (proprietary). The viscous properties of this bone cement decrease the likelihood that the cement will leak out of the vertebral body and affect other parts of the vertebra, especially the spinal cavity which contains the sensitive spinal nerves. It has never been shown, however, that there is any increased complication rate with vertebroplasty. Most practitioners who perform both procedures note that they are equally effective in treating the pain from compression fractures.
Inflating the balloon within the bone can also help reduce the deformity (which can lead to a hunchback appearance) created by the collapsed bone, as the balloon helps restore some or most of the vertebral height. It is hypothesized that helping restore the spine's natural geometry should help reduce the risk of future vertebral compression fractures[3]. In theory, helping restore some percentage of the vertebral body's pre-fracture height should also alleviate any pain caused by compression of the thoracic cavity and decrease the associated risk of mortality. The degree of height restoration is, in the majority of patients, minimal.
# Criticism
One argument against kyphoplasty is the perception that this approach creates the potential for the vertebal body to open up existing voids in the cancellous bone. In fact, it has been established that the inflation of the balloon inside the vertebral body pushes cancellous bone to the fringes of the vertebral body, "compacting trabecular bone, which may seal osseous defects and venous pathways, thus preventing cement from leaking." (Phillips, et al., Spine, 2002;27:2173-8). The void created by the balloon inside of the vertebral body also allows for bone cement to be deposited under low pressure, thus decreasing the possibility of cement extravasation outside of the vertebral body. Cement extravasation rates observed with kyphoplasty are low, especially compared to those reported with vertebroplasty (Hadjipalvou, JBJS, (Br) 2005, Vol. 87-B, No. 12, Dec 2005). While successful at stabilizing fractured vertebrae, studies have shown that compared to vertebroplasty, kyphoplasty has only marginally greater success in restoring vertebral height. Procedure critics also point out that kyphoplasty's only true advantage over vertebroplasty is the slight reduction in the occurrence of extravasation, that coupled with kyphoplasty's significantly greater cost over vertebroplasty renders it somewhat redundant.
# Treatment alternatives to Kyphoplasty
In addition to Kyphoplasty, there are alternatives to treating bone fractures in the spine. Many spine fractures heal on their own and can be helped without surgery. This is especially true in the younger age group. Treatment options to aid healing include pain medication, dietary supplements (such as calcium supplements and a back brace. Another surgical alternative for spinal fractures is called Vertebroplasty, which is a procedure similar to Kyphoplasty.
One of the most notable treatments and prevention is exercise – specifically a type of exercise called “weight-bearing exercise”. In laymen’s terms, weight-bearing exercise is really just exercise you do while standing on your feet, so that your feet and legs bear the weight of your body. Examples include dancing, running, and walking. Resistance training is also important, which is exercise where you use the strength of your muscles to build muscle mass and bone strength. There are a wide range of exercises that fit into these exercise categories that are good for people who have had fractures, have osteoporosis or who have other back problems.
# Related Chapters
- Fracture
- Osteoporosis
- Bone healing
- vertebroplasty | https://www.wikidoc.org/index.php/Kyphoplasty | |
f479516f03728b014c5f0600b6085311b50ebfd3 | wikidoc | Left atrium | Left atrium
The left atrium is one of the four chambers in the human heart. It receives oxygenated blood from the pulmonary veins, and pumps it into the left ventricle.
# Structure
Blood is pumped through the left atrioventricular orifice, which contains the mitral valve. A normal left atrium may be up to 5.5cm in maximum diameter; any larger than this is a sign of cardiac failure. This may occur in cases of mitral regurgitation.
The left atrium of a human faces more or less posteriorly. It is named 'left' based on the chamber's embryological and (putative) evolutionary origin. The term 'base' of the heart sometimes refers to the left atrium, though 'base' is an ambiguous term.
Attached to the left atrium is the left auricular appendix (auricle). This auricle is a common site for formation of thrombi, which may embolise causing stroke or ischemic gut. Atrial fibrillation makes this more likely.
# Foramen ovale
There is a foramen ovale (oval hole) between the right and left atrium in the fetus. After birth, this should close over and become the fossa ovale. If it does not, this is an atrial septal defect (hole in the heart). In the fetus, the right atrium pumps blood into the left atrium, bypassing the pulmonary circulation (which is useless in a fetus). In an adult, a septal defect would result in flow in the reverse direction - from the left atrium to the right - which will reduce cardiac output, potentially cause cardiac failure and in severe or untreated cases, death.
# Blood supply
The left atrium is supplied mainly by the left circumflex coronary artery, though the branches are too small to be identified in a cadaveric human heart and are not named.
The oblique vein of the left atrium is partly responsible for venous drainage; it derives from the embryonic left superior vena cava.
# Animals
Many other animals, including mammals, also have four-chambered hearts, and have a left atrium. The function in these animals is similar. Some animals (amphibians, reptiles) have a three-chambered heart, in which the blood from each atrium is mixed in the single ventricle before being pumped to the aorta. In these animals, the left atrium still serves the purpose of collecting blood from pulmonary veins.
# Additional images
- Heart seen from above.
- Base and diaphragmatic surface of heart. | Left atrium
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The left atrium is one of the four chambers in the human heart. It receives oxygenated blood from the pulmonary veins, and pumps it into the left ventricle.
# Structure
Blood is pumped through the left atrioventricular orifice, which contains the mitral valve. A normal left atrium may be up to 5.5cm in maximum diameter; any larger than this is a sign of cardiac failure. This may occur in cases of mitral regurgitation.
The left atrium of a human faces more or less posteriorly. It is named 'left' based on the chamber's embryological and (putative) evolutionary origin. The term 'base' of the heart sometimes refers to the left atrium, though 'base' is an ambiguous term.
Attached to the left atrium is the left auricular appendix (auricle). This auricle is a common site for formation of thrombi, which may embolise causing stroke or ischemic gut. Atrial fibrillation makes this more likely.
# Foramen ovale
There is a foramen ovale (oval hole) between the right and left atrium in the fetus. After birth, this should close over and become the fossa ovale. If it does not, this is an atrial septal defect (hole in the heart). In the fetus, the right atrium pumps blood into the left atrium, bypassing the pulmonary circulation (which is useless in a fetus). In an adult, a septal defect would result in flow in the reverse direction - from the left atrium to the right - which will reduce cardiac output, potentially cause cardiac failure and in severe or untreated cases, death.
# Blood supply
The left atrium is supplied mainly by the left circumflex coronary artery, though the branches are too small to be identified in a cadaveric human heart and are not named.
The oblique vein of the left atrium is partly responsible for venous drainage; it derives from the embryonic left superior vena cava.
# Animals
Many other animals, including mammals, also have four-chambered hearts, and have a left atrium. The function in these animals is similar. Some animals (amphibians, reptiles) have a three-chambered heart, in which the blood from each atrium is mixed in the single ventricle before being pumped to the aorta. In these animals, the left atrium still serves the purpose of collecting blood from pulmonary veins.
# Additional images
- Heart seen from above.
- Base and diaphragmatic surface of heart. | https://www.wikidoc.org/index.php/LA | |
d31fd72f3b67582ebd0e4d334426b3e146385327 | wikidoc | LIPID Study | LIPID Study
# Objective
To assess the efficacy of pravastatin in reducing mortality in known CAD patients.
# Methods
The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study was a randomized, double-blinded, placebo controlled trial wherein 9014 patients (young and old) with known CAD and total cholesterol levels in the range of 155 to 271 mg per deciliter were enrolled and randomly assigned to treatment with either 40 mg daily pravastatin or placebo. The patients were followed up for a mean period of 6.1 years.
# Results
- Pravastatin was associated with a lower rate of death from CAD compared with placebo (6.4% vs 8.3%)
- Overall mortality rate was lower in the pravastatin group compared with that in the placebo group (11% vs 14.1%)
- The incidence of all cardiovascular outcomes was consistently lower among patients assigned to receive pravastatin
# Conclusion
Treatment with pravastatin reduced mortality from coronary heart disease and overall mortality, as compared with the rates in the placebo group, as well as the incidence of all prespecified cardiovascular events in patients with a history of myocardial infarction or unstable angina who had a broad range of initial cholesterol levels. | LIPID Study
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Objective
To assess the efficacy of pravastatin in reducing mortality in known CAD patients.
# Methods
The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study was a randomized, double-blinded, placebo controlled trial wherein 9014 patients (young and old) with known CAD and total cholesterol levels in the range of 155 to 271 mg per deciliter were enrolled and randomly assigned to treatment with either 40 mg daily pravastatin or placebo. The patients were followed up for a mean period of 6.1 years.
# Results
- Pravastatin was associated with a lower rate of death from CAD compared with placebo (6.4% vs 8.3%)
- Overall mortality rate was lower in the pravastatin group compared with that in the placebo group (11% vs 14.1%)
- The incidence of all cardiovascular outcomes was consistently lower among patients assigned to receive pravastatin
# Conclusion
Treatment with pravastatin reduced mortality from coronary heart disease and overall mortality, as compared with the rates in the placebo group, as well as the incidence of all prespecified cardiovascular events in patients with a history of myocardial infarction or unstable angina who had a broad range of initial cholesterol levels.[1] | https://www.wikidoc.org/index.php/LIPID_Study | |
9168b246b03583fbf773afd5f6da974c8629610a | wikidoc | QRS complex | QRS complex
Synonyms and keywords: QRS interval
# Overview
The QRS complex represents electrical activation of the ventricle. Widening of the QRS complex may reflect delayed conduction in the His, bundle branch or purkinje conduction system.
# Morphology of the QRS Complex
## Q Wave
If the first deflection of the QRS is downward, it’s called a Q wave. The Q wave represents activation of the ventricular septum. The electricity spreads from right to left through the septum.
Q waves may be normal. For example in lead I, a Q less than 1/4 of the R height, and less than one box wide, is considered normal. This is the early activation of the septum. This activation goes left — away from lead I — and is therefore negative on the ECG. “Septal Qs” are normal in I, F, V5 and V6. Qs are also generally innocent in lead III and lead V1 if no other abnormality is seen.
Q waves are “significant” if they are greater than 1 box in width (longer than 0.04 msec) OR are larger than 1/4 of the R wave.
Q waves can be seen on the electrocardiogram following necrosis of the myocardium such as seen in acute MI or the replacement of electrically active tissue with electrically inert tissue as seen with Chagas disease. A Q wave may also reflect septal hypertrophy in hypertrophic cardiomyopathy (HCM).
## Pathological Q Wave
Pathological Q waves are defined as one of the following:
- Q waves in leads V2 or V3 ≥ 0.02s
OR
- Q wave ≥ 0.1 mV in depth and ≥ 0.03 s in duration in at least two contiguous leads (I, aVL, V5, V6; V2, V3; V3, V4; or II, III, aVF)
OR
- R wave ≥ 0.04s and R/S ≥ 1 in V1 and V2 with a concordant positive T wave without any conduction defect
### Causes of Q Waves in the Absence of Myocardial Infarction
- A QS complex in lead V1 is normal.
- A Q wave <0.03 s and <1/4 of the R wave amplitude in lead III is normal if the frontal QRS axis is between 30 and 0°.
- The Q wave may be normal in aVL if the frontal QRS axis is between 60 and 90°. Small septal Q waves are non pathological Q waves if <0.03 s and <1/4 of the R wave amplitude in leads I, aVL, aVF, and V4-V5-V6
- The following may be associated with Q/QS complexes in the absence of myocardial infarction:
### Conditions that Mask Q waves in the Presence of Myocardial Infarction
The following may be associated with masking of the Q waves despite the presence of a myocardial infarction:
- LBBB may mask or mimic the presence of Q waves and ST-T changes during the acute and late phases of ventricular depolarization
- The sensitivity of Q wave abnormalities on EKG in ischemia among patients with complete LBBB is only 31%
- VPR from the apical RV region may demonstrate a wide QRS complex or pseudo-Q waves
- Ventricular fusion may result in pseudoinfarction pattern
- The unmasking of early Q waves during MI may necessitate changing the position of the leads
- Preexcitation and presence of delta waves typical of WPW syndrome or WPW pattern may either mimic acute and chronic MI or may mask it
- Abolishment of delta waves may be necessary for the diagnosis of MI to be made on EKG
- Left posterolateral or lateral accessory pathways may mask inferior or anteroseptal MI
- Posteroseptal accessory pathways may mask an anterior MI
- Right anteroseptal and anterolateral accessory pathways may mask inferior or anterolateral MI
### EKG Changes of Prior Myocardial Infarction
- Any Q wave in V2-V3 ≥0.02 sec or presence of QS complex in V2 and V3.
- Q wave ≥0.03 sec and ≥0.1 mV deep or presence of QS complexes in leads I, II, aVL, aVF or V4-V5-V6 in any two leads of a contiguous lead grouping (I, aVL, V6; V4-V5-V6, II, III and aVF). The same criteria are used for supplemental leads V7-V8-V9, and for the Cabrera frontal plane leads.
- R wave ≥0.04 sec in V1-V2 and R/S >1 with a concordant positive T wave in the absence of a conduction defect.
## R wave
The first upward deflection of the QRS is called the R wave. Most of the ventricle is activated during the R wave. The R wave may be prolonged if the ventricle is enlarged, and may be abnormally high (indicating strong voltage) if the ventricular muscle tissue is hypertrophied.
Looking at the precordial leads, the r wave usually progresses from showing a rS-type complex in V1 with an increasing R and a decreasing S wave when moving towards the left side. There is usually an qR-type of complex in V5 and V6 with the R-wave amplitude usually taller in V5 than in V6. It is normal to have a narrow QS and rSr' patterns in V1, and so is also the case for qRs and R patterns in V5 and V6. The transition zone is where the QRS complex changes from predominately negative to predominately positive (R/S ratio becoming >1), and this usually occurs at V3 or V4. It is normal to have the transition zone at V2 (called "early transition"), and at V5 (called "delayed transition").
The definition of poor R wave progression (PRWP) varies in the literature, but a common one is when the R wave is less than 2–4 mm in leads V3 or V4 and/or there is presence of a reversed R wave progression, which is defined as R in V4 < R in V3 or R in V3 < R in V2 or R in V2 < R in V1, or any combination of these. Poor R wave progression is commonly attributed to anterior myocardial infarction, but it may also be caused by left bundle branch block, Wolff–Parkinson–White syndrome, right and left ventricular hypertrophy as well as
by faulty ECG recording technique.
Shown below is an EKG demonstrating poor R wave progression:
### Tall R waves in V1
Examples
- Tall r waves in V1
- Tall R waves in V1
Causes of tall R waves in V1
- Posterior MI
- RBBB
- Right Strain
PE
COPD
Cor Pulmonale
- PE
- COPD
- Cor Pulmonale
- RBBB mimics
PE
Brugada
ARVD
WPW
- PE
- Brugada
- ARVD
- WPW
- Pediatric EKG (tall R-wave and flipped t-wave V1-3)
## S wave
The S wave is any downward deflection following the R wave. Like the R wave, an abnormally large S wave may indicate hypertrophy of the ventricle.
If a second upward deflection is seen, it’s called an R-prime wave. R-prime waves are never normal, but indicate a problem in the ventricular conduction system.
QRS complexes may be described by naming the waves that form them. For example, a complex with an R, an S, and an R’ is called an RSR’ complex.
# QRS Duration
- The normal duration is less than 0.12 seconds
If the duation is > 0.12 seconds then either left bundle branch block (LBBB), right bundle branch block (RBBB) or a non-specific intraventricular conduction delay is present.
- If the duation is > 0.12 seconds then either left bundle branch block (LBBB), right bundle branch block (RBBB) or a non-specific intraventricular conduction delay is present.
- The precordial leads are approximately 0.01 or 0.02 seconds longer than the limb leads.
## Causes of a Wide QRS Interval or a Prolonged QRS Interval
- Hypothermia
- Incomplete left bundle branch block
- Incomplete right bundle branch block
- Left anterior fascicular block
- Left bundle branch block
- Left posterior fascicular block
- Non-specific intraventricular conduction delay (NSIVCD) (when the QRS is wide and the definitions of LBBB and RBBB are not met)
- Right bundle branch block
- Ventricular tachycardia
# QRS Amplitude
## Definitions of Low QRS Voltage:
- If the total amplitude above and below the isoelectric line is < 5 mm in all 3 standard leads.
- An average voltage in the limb leads of < 5 mm with an average of < 10 mm in the chest leads.
- Should be at least 5 mm in V1 and V6 , 7 mm in V2 and V5 and 9 mm in V3 and V4.
## Pathophysiology of Low QRS Voltage
Three general processes contribute to low QRS voltage:
- Damping of the electrical signal due to excess air (emphysema, COPD), fluid (pericardial effusion, pericardial constriction, pleural effusion), edema (anasarca), fat (obesity), physiologic variant, or amyloid cardiomyopathy
- Electrically inert myocardium due to a loss of viable myocardium such as in myocardial infarction and Chagas disease]]
- Infiltration of the myocardium (myxedematous, Chagas disease)
## Causes of Low QRS Voltage
The presence of low voltage on the EKG should prompt an evaluation to rule out life threatening emergencies such as cardiac tamponade or a large pericardial effusion. These two diagnoses are suggested by the presence of tachycardia and electrical alternans along with the low QRS voltage. In alphabetical order the differential diagnosis includes:
- Alcoholic cardiomyopathy
- Amyloidosis
- Anasarca
- Dilated cardiomyopathy
- Beriberi heart disease
- Cardiomyopathy
- Chagas disease
- Diffuse coronary artery disease
- Congestive heart failure
- Constrictive pericarditis
- COPD
- Dilated cardiomyopathy
- Generalized edema and pedal edema
- Emphysema
- Hemochromatosis
- Hypothermia
- Hypothyroidism
- Ischemic cardiomyopathy
- Prior myocardial infarction
- Myocarditis
- Myxedema
- Obesity
- Pericardial effusion
- Pneumothorax
- Rejection after heart transplantation
- Restrictive cardiomyopathy
- Sarcoidosis
- Scleroderma
- Tamponade
- Technical error in the settings on the ECG apparatus (sensitivity should be at 10 mm/mV)
## Definition of Maximal QRS Voltage:
Can be up to 20 to 30 mm in lead 2 and can be up to 25 to 30 mm in the precordial leads. | QRS complex
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [3]
Synonyms and keywords: QRS interval
# Overview
The QRS complex represents electrical activation of the ventricle. Widening of the QRS complex may reflect delayed conduction in the His, bundle branch or purkinje conduction system.
# Morphology of the QRS Complex
## Q Wave
If the first deflection of the QRS is downward, it’s called a Q wave. The Q wave represents activation of the ventricular septum. The electricity spreads from right to left through the septum.
Q waves may be normal. For example in lead I, a Q less than 1/4 of the R height, and less than one box wide, is considered normal. This is the early activation of the septum. This activation goes left — away from lead I — and is therefore negative on the ECG. “Septal Qs” are normal in I, F, V5 and V6. Qs are also generally innocent in lead III and lead V1 if no other abnormality is seen.
Q waves are “significant” if they are greater than 1 box in width (longer than 0.04 msec) OR are larger than 1/4 of the R wave.
Q waves can be seen on the electrocardiogram following necrosis of the myocardium such as seen in acute MI or the replacement of electrically active tissue with electrically inert tissue as seen with Chagas disease. A Q wave may also reflect septal hypertrophy in hypertrophic cardiomyopathy (HCM).
## Pathological Q Wave
Pathological Q waves are defined as one of the following:[1]
- Q waves in leads V2 or V3 ≥ 0.02s
OR
- Q wave ≥ 0.1 mV in depth and ≥ 0.03 s in duration in at least two contiguous leads (I, aVL, V5, V6; V2, V3; V3, V4; or II, III, aVF)
OR
- R wave ≥ 0.04s and R/S ≥ 1 in V1 and V2 with a concordant positive T wave without any conduction defect
### Causes of Q Waves in the Absence of Myocardial Infarction
- A QS complex in lead V1 is normal.
- A Q wave <0.03 s and <1/4 of the R wave amplitude in lead III is normal if the frontal QRS axis is between 30 and 0°.
- The Q wave may be normal in aVL if the frontal QRS axis is between 60 and 90°. Small septal Q waves are non pathological Q waves if <0.03 s and <1/4 of the R wave amplitude in leads I, aVL, aVF, and V4-V5-V6
- The following may be associated with Q/QS complexes in the absence of myocardial infarction:
### Conditions that Mask Q waves in the Presence of Myocardial Infarction
The following may be associated with masking of the Q waves despite the presence of a myocardial infarction:
- LBBB may mask or mimic the presence of Q waves and ST-T changes during the acute and late phases of ventricular depolarization[2]
- The sensitivity of Q wave abnormalities on EKG in ischemia among patients with complete LBBB is only 31%[2]
- VPR from the apical RV region may demonstrate a wide QRS complex or pseudo-Q waves[4]
- Ventricular fusion may result in pseudoinfarction pattern[4]
- The unmasking of early Q waves during MI may necessitate changing the position of the leads[4]
- Preexcitation and presence of delta waves typical of WPW syndrome or WPW pattern may either mimic acute and chronic MI or may mask it[5]
- Abolishment of delta waves may be necessary for the diagnosis of MI to be made on EKG[6]
- Left posterolateral or lateral accessory pathways may mask inferior or anteroseptal MI[7]
- Posteroseptal accessory pathways may mask an anterior MI[7]
- Right anteroseptal and anterolateral accessory pathways may mask inferior or anterolateral MI[7]
### EKG Changes of Prior Myocardial Infarction
- Any Q wave in V2-V3 ≥0.02 sec or presence of QS complex in V2 and V3.
- Q wave ≥0.03 sec and ≥0.1 mV deep or presence of QS complexes in leads I, II, aVL, aVF or V4-V5-V6 in any two leads of a contiguous lead grouping (I, aVL, V6; V4-V5-V6, II, III and aVF). The same criteria are used for supplemental leads V7-V8-V9, and for the Cabrera frontal plane leads.
- R wave ≥0.04 sec in V1-V2 and R/S >1 with a concordant positive T wave in the absence of a conduction defect.[8]
## R wave
The first upward deflection of the QRS is called the R wave. Most of the ventricle is activated during the R wave. The R wave may be prolonged if the ventricle is enlarged, and may be abnormally high (indicating strong voltage) if the ventricular muscle tissue is hypertrophied.
Looking at the precordial leads, the r wave usually progresses from showing a rS-type complex in V1 with an increasing R and a decreasing S wave when moving towards the left side. There is usually an qR-type of complex in V5 and V6 with the R-wave amplitude usually taller in V5 than in V6. It is normal to have a narrow QS and rSr' patterns in V1, and so is also the case for qRs and R patterns in V5 and V6. The transition zone is where the QRS complex changes from predominately negative to predominately positive (R/S ratio becoming >1), and this usually occurs at V3 or V4. It is normal to have the transition zone at V2 (called "early transition"), and at V5 (called "delayed transition").[9]
The definition of poor R wave progression (PRWP) varies in the literature, but a common one is when the R wave is less than 2–4 mm in leads V3 or V4 and/or there is presence of a reversed R wave progression, which is defined as R in V4 < R in V3 or R in V3 < R in V2 or R in V2 < R in V1, or any combination of these.[9] Poor R wave progression is commonly attributed to anterior myocardial infarction, but it may also be caused by left bundle branch block, Wolff–Parkinson–White syndrome, right and left ventricular hypertrophy as well as
by faulty ECG recording technique.[9]
Shown below is an EKG demonstrating poor R wave progression:
### Tall R waves in V1
Examples
- Tall r waves in V1
- Tall R waves in V1
Causes of tall R waves in V1
- Posterior MI
- RBBB
- Right Strain
PE
COPD
Cor Pulmonale
- PE
- COPD
- Cor Pulmonale
- RBBB mimics
PE
Brugada
ARVD
WPW
- PE
- Brugada
- ARVD
- WPW
- Pediatric EKG (tall R-wave and flipped t-wave V1-3)
## S wave
The S wave is any downward deflection following the R wave. Like the R wave, an abnormally large S wave may indicate hypertrophy of the ventricle.
If a second upward deflection is seen, it’s called an R-prime wave. R-prime waves are never normal, but indicate a problem in the ventricular conduction system.
QRS complexes may be described by naming the waves that form them. For example, a complex with an R, an S, and an R’ is called an RSR’ complex.
# QRS Duration
- The normal duration is less than 0.12 seconds
If the duation is > 0.12 seconds then either left bundle branch block (LBBB), right bundle branch block (RBBB) or a non-specific intraventricular conduction delay is present.
- If the duation is > 0.12 seconds then either left bundle branch block (LBBB), right bundle branch block (RBBB) or a non-specific intraventricular conduction delay is present.
- The precordial leads are approximately 0.01 or 0.02 seconds longer than the limb leads.
## Causes of a Wide QRS Interval or a Prolonged QRS Interval
- Hypothermia
- Incomplete left bundle branch block
- Incomplete right bundle branch block
- Left anterior fascicular block
- Left bundle branch block
- Left posterior fascicular block
- Non-specific intraventricular conduction delay (NSIVCD) (when the QRS is wide and the definitions of LBBB and RBBB are not met)
- Right bundle branch block
- Ventricular tachycardia
# QRS Amplitude
## Definitions of Low QRS Voltage:
- If the total amplitude above and below the isoelectric line is < 5 mm in all 3 standard leads.
- An average voltage in the limb leads of < 5 mm with an average of < 10 mm in the chest leads.
- Should be at least 5 mm in V1 and V6 , 7 mm in V2 and V5 and 9 mm in V3 and V4.
## Pathophysiology of Low QRS Voltage
Three general processes contribute to low QRS voltage:
- Damping of the electrical signal due to excess air (emphysema, COPD), fluid (pericardial effusion, pericardial constriction, pleural effusion), edema (anasarca), fat (obesity), physiologic variant, or amyloid cardiomyopathy
- Electrically inert myocardium due to a loss of viable myocardium such as in myocardial infarction and Chagas disease]]
- Infiltration of the myocardium (myxedematous, Chagas disease)
## Causes of Low QRS Voltage
The presence of low voltage on the EKG should prompt an evaluation to rule out life threatening emergencies such as cardiac tamponade or a large pericardial effusion. These two diagnoses are suggested by the presence of tachycardia and electrical alternans along with the low QRS voltage. In alphabetical order the differential diagnosis includes[10]:
- Alcoholic cardiomyopathy
- Amyloidosis
- Anasarca[11]
- Dilated cardiomyopathy[12]
- Beriberi heart disease
- Cardiomyopathy
- Chagas disease
- Diffuse coronary artery disease
- Congestive heart failure
- Constrictive pericarditis
- COPD
- Dilated cardiomyopathy
- Generalized edema and pedal edema[11]
- Emphysema
- Hemochromatosis
- Hypothermia
- Hypothyroidism
- Ischemic cardiomyopathy
- Prior myocardial infarction
- Myocarditis[13]
- Myxedema
- Obesity
- Pericardial effusion
- Pneumothorax
- Rejection after heart transplantation
- Restrictive cardiomyopathy
- Sarcoidosis
- Scleroderma
- Tamponade
- Technical error in the settings on the ECG apparatus (sensitivity should be at 10 mm/mV)
## Definition of Maximal QRS Voltage:
Can be up to 20 to 30 mm in lead 2 and can be up to 25 to 30 mm in the precordial leads. [14] [15] | https://www.wikidoc.org/index.php/LQRSV | |
b73945552d112b0cb7e37e00369e39b170557860 | wikidoc | LabelEditor | LabelEditor
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785d969a9c9dddc6bd2058840d538c37b2b5198c | wikidoc | Labiaplasty | Labiaplasty
# Overview
Labiaplasty (sometimes spelled labioplasty and sometimes referred to as labia minor reduction or labial reduction) is plastic surgery of the labia majora and/or the labia minora, which are the external folds of skin surrounding the vaginal opening. The procedure involves reducing elongated labium. When labia are created where there were none, it is usually part of a vaginoplasty.
# Surgical procedures
Labiaplasty reduces the size of one or both sets of labia. It may also be employed to repair the labia following disease or injury, or especially after childbirth. In addition, a hoodectomy may be performed at the same time, which exposes the clitoris in an attempt to increase sexual stimulation. Hoodectomy is sometimes used to treat sexual dysfunction such as anorgasmia.
As recently as 1999, surgeons usually performed labium reduction by straight amputation of the protuberant sections and then by suturing the edges together. However, this procedure sometimes created a fragile and stiff suture line as well as eliminating the natural contour and pigmentation of the labia minora. Moreover, other procedural and clinical problems existed with amputation that did not ensure a favorable outcome.
Several years later, more surgeons introduced lasers into their armamentarium and began using more refined surgical procedures like one known as inferior wedge resection and superior pedicle flap reconstruction. In one outcome study, surgeons studied the results of 20 patients undergoing labiaplasty via the procedure. 95.2 percent of patients at 46 months reported being very satisfied. While five complications cropped up, all but one were handled immediately postoperatively and did not require additional hospital stays or interfere with healing.
Labiaplasty is almost always an outpatient procedure performed under local anesthesia. After surgery, patients may experience some mild discomfort and swelling, which usually disappear completely after one to two weeks. Recovery times ranging from three days to one or two weeks are often listed on surgeons’ websites.
# Risks
While statistics on any botched plastic surgery procedures are rare, the comparable rate of satisfaction for other commonly performed cosmetic plastic surgery procedures in the United States is about the same or slightly less than labiaplasty. According to Jeffrey Rawnsley, an assistant professor and director the UCLA Facial Aesthetic Center at the University of California, Los Angeles, about 90 percent of patients report a positive outcome for breast augmentation. Experts report about an 85 percent positive outcome for rhinoplasty (the “nose job”), while liposuction patients in the late 1990s suffered a mortality rate of about 20 per 100,000, according to author Christine Rosen. While liposuction outcome rates have improved, many breast augmentation and rhinoplasty revisions are performed worldwide, because the procedure was not done correctly the first time.
Labiaplasty—in comparison to other popular rejuvenation surgeries—requires additional treatment in five to seven percent of cases. While the American Society of Plastic Surgeons (ASPS) listed only about 1000 “vaginal rejuvenations” during 2006, the most current year for which U.S. statistics have been compiled, surgeons in both the U.S. and the U.K.—as well as in other developed nations—report that the procedure seems to be growing exponentially. The professional plastic surgery organizations like ASPS, the American Society for Aesthetic Plastic Surgery, the British Association of Aesthetic Plastic Surgeons (BAAPS) and the International Society of Aesthetic Plastic Surgeons do not count labiaplasties among the other yearly statistics of plastic cosmetic procedures. | Labiaplasty
Editors-In-Chief: Martin I. Newman, M.D., FACS, Cleveland Clinic Florida, [1]; Michel C. Samson, M.D., FRCSC, FACS [2]
# Overview
Labiaplasty (sometimes spelled labioplasty and sometimes referred to as labia minor reduction or labial reduction)[1] is plastic surgery of the labia majora and/or the labia minora, which are the external folds of skin surrounding the vaginal opening. The procedure involves reducing elongated labium. When labia are created where there were none, it is usually part of a vaginoplasty.
# Surgical procedures
Labiaplasty reduces the size of one or both sets of labia. It may also be employed to repair the labia following disease or injury, or especially after childbirth. In addition, a hoodectomy may be performed at the same time, which exposes the clitoris in an attempt to increase sexual stimulation. Hoodectomy is sometimes used to treat sexual dysfunction such as anorgasmia.
As recently as 1999, surgeons usually performed labium reduction by straight amputation of the protuberant sections and then by suturing the edges together.[2] However, this procedure sometimes created a fragile and stiff suture line as well as eliminating the natural contour and pigmentation of the labia minora. Moreover, other procedural and clinical problems existed with amputation that did not ensure a favorable outcome.
Several years later, more surgeons introduced lasers into their armamentarium and began using more refined surgical procedures like one known as inferior wedge resection and superior pedicle flap reconstruction. In one outcome study, surgeons studied the results of 20 patients undergoing labiaplasty via the procedure. 95.2 percent of patients at 46 months reported being very satisfied. While five complications cropped up, all but one were handled immediately postoperatively and did not require additional hospital stays or interfere with healing.[3]
Labiaplasty is almost always an outpatient procedure performed under local anesthesia. After surgery, patients may experience some mild discomfort and swelling, which usually disappear completely after one to two weeks. Recovery times ranging from three days to one or two weeks are often listed on surgeons’ websites.
# Risks
While statistics on any botched plastic surgery procedures are rare, the comparable rate of satisfaction for other commonly performed cosmetic plastic surgery procedures in the United States is about the same or slightly less than labiaplasty. According to Jeffrey Rawnsley, an assistant professor and director the UCLA Facial Aesthetic Center at the University of California, Los Angeles, about 90 percent of patients report a positive outcome for breast augmentation.[4] Experts report about an 85 percent positive outcome for rhinoplasty (the “nose job”), while liposuction patients in the late 1990s suffered a mortality rate of about 20 per 100,000, according to author Christine Rosen.[5] While liposuction outcome rates have improved, many breast augmentation and rhinoplasty revisions are performed worldwide, because the procedure was not done correctly the first time.
Labiaplasty—in comparison to other popular rejuvenation surgeries—requires additional treatment in five to seven percent of cases. While the American Society of Plastic Surgeons (ASPS) listed only about 1000 “vaginal rejuvenations” during 2006, the most current year for which U.S. statistics have been compiled, surgeons in both the U.S. and the U.K.—as well as in other developed nations—report that the procedure seems to be growing exponentially. The professional plastic surgery organizations like ASPS, the American Society for Aesthetic Plastic Surgery, the British Association of Aesthetic Plastic Surgeons (BAAPS) and the International Society of Aesthetic Plastic Surgeons do not count labiaplasties among the other yearly statistics of plastic cosmetic procedures. | https://www.wikidoc.org/index.php/Labiaplasty | |
6e69a474c779ffa5d74dc32b4c355cbe933d191f | wikidoc | Lactic acid | Lactic acid
# Overview
Lactic acid (IUPAC systematic name: 2-hydroxypropanoic acid), also known as milk acid, is a chemical compound that plays a role in several biochemical processes. It was first isolated in 1780 by a Swedish chemist, Carl Wilhelm Scheele, and is a carboxylic acid with a chemical formula of C3H6O3. It has a hydroxyl group adjacent to the carboxyl group, making it an alpha hydroxy acid (AHA). In solution, it can lose a proton from the acidic group, producing the lactate ion CH3CH(OH)COO−. It is miscible with water or ethanol, and is hygroscopic.
Lactic acid is chiral and has two optical isomers. One is known as L-(+)-lactic acid or (S)-lactic acid and the other, its mirror image, is D-(-)-lactic acid or (R)-lactic acid. L-(+)-Lactic acid is the biologically important isomer.
In animals, L-lactate is constantly produced from pyruvate via the enzyme lactate dehydrogenase (LDH) in a process of fermentation during normal metabolism and exercise. It does not increase in concentration until the rate of lactate production exceeds the rate of lactate removal which is governed by a number of factors including: monocarboxylate transporters, concentration and isoform of LDH and oxidative capacity of tissues. The concentration of blood lactate is usually 1-2 mmol/L at rest, but can rise to over 20 mmol/L during intense exertion.
Industrially, lactic acid fermentation is performed by Lactobacillus bacteria, among others. These bacteria can operate in the mouth; the acid they produce is responsible for the tooth decay known as caries.
In medicine, lactate is one of the main components of Ringer's lactate or lactated Ringer's solution (Compound Sodium Lactate or Hartmann's Solution in the UK). This intravenous fluid consists of sodium and potassium cations, with lactate and chloride anions, in solution with distilled water in concentration so as to be isotonic compared to human blood. It is most commonly used for fluid resuscitation after blood loss due to trauma, surgery, or a burn injury.
# Exercise and lactate
During power-intensive exercises such as sprinting, when the rate of demand for energy is high, lactate is produced faster than the ability of the tissues to remove it and lactate concentration begins to rise. This is a beneficial process since the regeneration of NAD+ ensures that energy production is maintained and exercise can continue. The increased lactate produced can be removed in a number of ways including
- oxidation to pyruvate by well-oxygenated muscle cells which is then directly used to fuel the citric acid cycle
- conversion to glucose via the Cori cycle in the liver through the process of gluconeogenesis.
Contrary to popular belief, this increased concentration of lactate does not directly cause acidosis, nor is it responsible for delayed onset muscle soreness. This is because lactate itself is not capable of releasing a proton, and secondly, the acidic form of lactate, lactic acid, cannot be formed under normal circumstances in human tissues. Analysis of the glycolytic pathway in humans indicates that there are not enough hydrogen ions present in the glycolytic intermediates to produce lactic or any other acid.
The acidosis that is associated with increases in lactate concentration during heavy exercise arises from a separate reaction. When ATP is hydrolysed, a hydrogen ion is released. ATP-derived hydrogen ions are primarily responsible for the decrease in pH. During intense exercise, aerobic metabolism cannot produce ATP quickly enough to supply the demands of the muscle. As a result, anaerobic metabolism becomes the dominant energy producing pathway as it can form ATP at high rates. Due to the large amounts of ATP being produced and hydrolysed in a short period of time, the buffering systems of the tissues are overcome, causing pH to fall and creating a state of acidosis. This may be one factor, among many, that contributes to the acute muscular discomfort experienced shortly after intense exercise.
The effect of lactate on acidosis has been the topic of many recent conferences in the field of exercise physiology. Robergs et al. have accurately chased the proton movement that occurs during glycolysis. However, in doing so, they have suggested that is an independent variable that determines its own concentration. A recent review by Lindinger et al. has been written to rebut the stoichiometric approach used by Robergs et al (2004). In using this stoichiometric process, Robergs et al. have ignored the causative factors (independent variables) of the concentration of hydrogen ions (denoted ). These factors are strong ion difference , PCO2, and weak acid buffers. Lactate is a strong anion, and causes a reduction in which causes an increase in to maintain electroneutrality. PCO2 also causes an increase in . During exercise, the intramuscular lactate concentration and PCO2 increase, causing an increase in , and thus a decrease in pH. (See Le Chatelier's principle)
# Lactic acid as a polymer precursor
Two molecules of lactic acid can be dehydrated to lactide, a cyclic lactone. A variety of catalysts can polymerise lactide to either heterotactic or syndiotactic polylactide, which as biodegradable polyesters with valuable (inter alia) medical properties are currently attracting much attention.
Nowadays, lactic acid is used as a monomer for producing polylactic acid (PLA) which later has application as biodegradable plastic. This kind of plastic is a good option for substituting conventional plastic produced from petroleum oil because of low emission of carbon dioxide that can contribute to global warming.
The commonly used process in producing lactic acid is via fermentation, and later to obtain the polylactic acid, the polymerization process follows.
# Lactic acid in foods
Lactic acid is primarily found in sour milk products, such as: koumiss, leban, yogurt, kefir and some cottage cheeses. The casein in fermented milk is coagulated (curdled) by lactic acid.
Although it can be fermented from lactose (milk sugar), most commercially used lactic acid is derived by using bacteria such as Bacillus acidilacti, Lactobacillus delbueckii or Lactobacillus bulgaricus to ferment carbohydrates from nondairy sources such as cornstarch, potatoes and molasses. Thus, although it is commonly known as "milk acid", vegan products can contain lactic acid as an ingredient.
Lactic acid may also be found in various processed foods, usually either as a pH adjusting ingredient, or as a preservative (either as antioxidant or for control of pathogenic micro-organisms). It may also be used as a fermentation booster in rye and sourdough breads.
Lactic acid is also present in wheat beers, especially lambic, due to the activity of Pediococcus damnosus.
Lactic acid is widely used for inhibiting pathogenic bacteria like E.coli, Salmonella, Campylobacter and Listeria on animal carcasses like beef, pork and poultry during the slaughtering process.
Potassium lactate, sodium lactate and calcium lactate are the neutralized salts of lactic acid. Potassium lactate is used in many fresh and cooked meat products for shelf life control, color preservation and reduction of sodium content. Sodium lactate has a mild saline taste and is therefore suitable for flavour enhancement in meat products as well. Sodium lactate is being produced as liquids as well as powders. Calcium lactate is popular for fortification and improved texture in emulsified meat products like frankfurters. | Lactic acid
Template:Chembox new
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Lactic acid (IUPAC systematic name: 2-hydroxypropanoic acid), also known as milk acid, is a chemical compound that plays a role in several biochemical processes. It was first isolated in 1780 by a Swedish chemist, Carl Wilhelm Scheele, and is a carboxylic acid with a chemical formula of C3H6O3. It has a hydroxyl group adjacent to the carboxyl group, making it an alpha hydroxy acid (AHA). In solution, it can lose a proton from the acidic group, producing the lactate ion CH3CH(OH)COO−. It is miscible with water or ethanol, and is hygroscopic.
Lactic acid is chiral and has two optical isomers. One is known as L-(+)-lactic acid or (S)-lactic acid and the other, its mirror image, is D-(-)-lactic acid or (R)-lactic acid. L-(+)-Lactic acid is the biologically important isomer.
In animals, L-lactate is constantly produced from pyruvate via the enzyme lactate dehydrogenase (LDH) in a process of fermentation during normal metabolism and exercise. It does not increase in concentration until the rate of lactate production exceeds the rate of lactate removal which is governed by a number of factors including: monocarboxylate transporters, concentration and isoform of LDH and oxidative capacity of tissues. The concentration of blood lactate is usually 1-2 mmol/L at rest, but can rise to over 20 mmol/L during intense exertion.
Industrially, lactic acid fermentation is performed by Lactobacillus bacteria, among others. These bacteria can operate in the mouth; the acid they produce is responsible for the tooth decay known as caries.
In medicine, lactate is one of the main components of Ringer's lactate or lactated Ringer's solution (Compound Sodium Lactate or Hartmann's Solution in the UK). This intravenous fluid consists of sodium and potassium cations, with lactate and chloride anions, in solution with distilled water in concentration so as to be isotonic compared to human blood. It is most commonly used for fluid resuscitation after blood loss due to trauma, surgery, or a burn injury.
# Exercise and lactate
During power-intensive exercises such as sprinting, when the rate of demand for energy is high, lactate is produced faster than the ability of the tissues to remove it and lactate concentration begins to rise. This is a beneficial process since the regeneration of NAD+ ensures that energy production is maintained and exercise can continue. The increased lactate produced can be removed in a number of ways including
- oxidation to pyruvate by well-oxygenated muscle cells which is then directly used to fuel the citric acid cycle
- conversion to glucose via the Cori cycle in the liver through the process of gluconeogenesis.
Contrary to popular belief, this increased concentration of lactate does not directly cause acidosis, nor is it responsible for delayed onset muscle soreness.[1] This is because lactate itself is not capable of releasing a proton, and secondly, the acidic form of lactate, lactic acid, cannot be formed under normal circumstances in human tissues. Analysis of the glycolytic pathway in humans indicates that there are not enough hydrogen ions present in the glycolytic intermediates to produce lactic or any other acid.
The acidosis that is associated with increases in lactate concentration during heavy exercise arises from a separate reaction. When ATP is hydrolysed, a hydrogen ion is released. ATP-derived hydrogen ions are primarily responsible for the decrease in pH. During intense exercise, aerobic metabolism cannot produce ATP quickly enough to supply the demands of the muscle. As a result, anaerobic metabolism becomes the dominant energy producing pathway as it can form ATP at high rates. Due to the large amounts of ATP being produced and hydrolysed in a short period of time, the buffering systems of the tissues are overcome, causing pH to fall and creating a state of acidosis. This may be one factor, among many, that contributes to the acute muscular discomfort experienced shortly after intense exercise.
The effect of lactate on acidosis has been the topic of many recent conferences in the field of exercise physiology. Robergs et al. have accurately chased the proton movement that occurs during glycolysis. However, in doing so, they have suggested that [H+] is an independent variable that determines its own concentration. A recent review by Lindinger et al. has been written to rebut the stoichiometric approach used by Robergs et al (2004).[1] In using this stoichiometric process, Robergs et al. have ignored the causative factors (independent variables) of the concentration of hydrogen ions (denoted [H+]). These factors are strong ion difference [SID], PCO2, and weak acid buffers. Lactate is a strong anion, and causes a reduction in [SID] which causes an increase in [H+] to maintain electroneutrality. PCO2 also causes an increase in [H+]. During exercise, the intramuscular lactate concentration and PCO2 increase, causing an increase in [H+], and thus a decrease in pH. (See Le Chatelier's principle)
# Lactic acid as a polymer precursor
Two molecules of lactic acid can be dehydrated to lactide, a cyclic lactone. A variety of catalysts can polymerise lactide to either heterotactic or syndiotactic polylactide, which as biodegradable polyesters with valuable (inter alia) medical properties are currently attracting much attention.
Nowadays, lactic acid is used as a monomer for producing polylactic acid (PLA) which later has application as biodegradable plastic. This kind of plastic is a good option for substituting conventional plastic produced from petroleum oil because of low emission of carbon dioxide that can contribute to global warming.
The commonly used process in producing lactic acid is via fermentation, and later to obtain the polylactic acid, the polymerization process follows.
# Lactic acid in foods
Lactic acid is primarily found in sour milk products, such as: koumiss, leban, yogurt, kefir and some cottage cheeses. The casein in fermented milk is coagulated (curdled) by lactic acid.
Although it can be fermented from lactose (milk sugar), most commercially used lactic acid is derived by using bacteria such as Bacillus acidilacti, Lactobacillus delbueckii or Lactobacillus bulgaricus to ferment carbohydrates from nondairy sources such as cornstarch, potatoes and molasses. Thus, although it is commonly known as "milk acid", vegan products can contain lactic acid as an ingredient.
Lactic acid may also be found in various processed foods, usually either as a pH adjusting ingredient, or as a preservative (either as antioxidant or for control of pathogenic micro-organisms). It may also be used as a fermentation booster in rye and sourdough breads.[2]
Lactic acid is also present in wheat beers, especially lambic, due to the activity of Pediococcus damnosus.[3]
Lactic acid is widely used for inhibiting pathogenic bacteria like E.coli, Salmonella, Campylobacter and Listeria on animal carcasses like beef, pork and poultry during the slaughtering process.
Potassium lactate, sodium lactate and calcium lactate are the neutralized salts of lactic acid. Potassium lactate is used in many fresh and cooked meat products for shelf life control, color preservation and reduction of sodium content. Sodium lactate has a mild saline taste and is therefore suitable for flavour enhancement in meat products as well. Sodium lactate is being produced as liquids as well as powders. Calcium lactate is popular for fortification and improved texture in emulsified meat products like frankfurters.[4] | https://www.wikidoc.org/index.php/Lactate | |
e1ea248ad49a0c78f5c5fb2e175cce9fef49dc6a | wikidoc | Lactoferrin | Lactoferrin
Lactoferrin (LF), also known as lactotransferrin (LTF), is a multifunctional protein of the transferrin family. Lactoferrin is a globular glycoprotein with a molecular mass of about 80 kDa that is widely represented in various secretory fluids, such as milk, saliva, tears, and nasal secretions. Lactoferrin is also present in secondary granules of PMNs and is secreted by some acinar cells. Lactoferrin can be purified from milk or produced recombinantly. Human colostrum ("first milk") has the highest concentration, followed by human milk, then cow milk (150 mg/L).
Lactoferrin is one of the components of the immune system of the body; it has antimicrobial activity (bacteriocide, fungicide) and is part of the innate defense, mainly at mucoses. In particular, lactoferrin provides antibacterial activity to human infants. Lactoferrin interacts with DNA and RNA, polysaccharides and heparin, and shows some of its biological functions in complexes with these ligands.
# History
Occurrence of iron-containing red protein in bovine milk was reported as early as in 1939; however, the protein could not be properly characterized because it could not be extracted with sufficient purity. Its first detailed studies were reported around 1960. They documented the molecular weight, isoelectric point, optical absorption spectra and presence of two iron atoms per protein molecule. The protein was extracted from milk, contained iron and was structurally and chemically similar to serum transferrin. Therefore, it was named lactoferrin in 1961, though the name lactotransferrin was used in some earlier publications, and later studies demonstrated that the protein is not restricted to milk. The antibacterial action of lactoferrin was also documented in 1961, and was associated with its ability to bind iron.
# Structure
## Genes of lactoferrin
At least 60 gene sequences of lactoferrin have been characterized in 11 species of mammals. In most species, stop codon is TAA, and TGA in Mus musculus. Deletions, insertions and mutations of stop codons affect the coding part and its length varies between 2,055 and 2,190 nucleotide pairs. Gene polymorphism between species is much more diverse than the intraspecific polymorphism of lactoferrin. There are differences in amino acid sequences: 8 in Homo sapiens, 6 in Mus musculus, 6 in Capra hircus, 10 in Bos taurus and 20 in Sus scrofa. This variation may indicate functional differences between different types of lactoferrin.
In humans, lactoferrin gene LTF is located on the third chromosome in the locus 3q21-q23. In oxen, the coding sequence consists of 17 exons and has a length of about 34,500 nucleotide pairs. Exons of the lactoferrin gene in oxen have a similar size to the exons of other genes of the transferrin family, whereas the sizes of introns differ within the family. Similarity in the size of exons and their distribution in the domains of the protein molecule indicates that the evolutionary development of lactoferrin gene occurred by duplication. Study of polymorphism of genes that encode lactoferrin helps selecting livestock breeds that are resistant to mastitis.
## Molecular structure
Lactoferrin is one of the transferrin proteins that transfer iron to the cells and control the level of free iron in the blood and external secretions. It is present in the milk of humans and other mammals, in the blood plasma and neutrophils and is one of the major proteins of virtually all exocrine secretions of mammals, such as saliva, bile, tears and pancreas. Concentration of lactoferrin in the milk varies from 7 g/L in the colostrum to 1 g/L in mature milk.
X-ray diffraction reveals that lactoferrin is based on one polypeptide chain that contains about 700 amino acids and forms two homologous globular domains named N-and C-lobes. N-lobe corresponds to amino acid residues 1–333 and C-lobe to 345–692, and the ends of those domains are connected by a short α-helix. Each lobe consists of two subdomains, N1, N2 and C1, C2, and contains one iron binding site and one glycosylation site. The degree of glycosylation of the protein may be different and therefore the molecular weight of lactoferrin varies between 76 and 80 kDa. The stability of lactoferrin has been associated with the high glycosylation degree.
Lactoferrin belongs to the basic proteins, its isoelectric point is 8.7. It exists in two forms: iron-rich hololactoferrin and iron-free apolactoferrin. Their tertiary structures are different; apolactoferrin is characterized by "open" conformation of the N-lobe and the "closed" conformation of the C-lobe, and both lobes are closed in the hololactoferrin.
Each lactoferrin molecule can reversibly bind two ions of iron, zinc, copper or other metals. The binding sites are localized in each of the two protein globules. There, each ion is bonded with six ligands: four from the polypeptide chain (two tyrosine residues, one histidine residue and one aspartic acid residue) and two from carbonate or bicarbonate ions.
Lactoferrin forms reddish complex with iron; its affinity for iron is 300 times higher than that of transferrin. The affinity increases in weakly acidic medium. This facilitates the transfer of iron from transferrin to lactoferrin during inflammations, when the pH of tissues decreases due to accumulation of lactic and other acids. The saturated iron concentration in lactoferrin in human milk is estimated as 10 to 30% (100% corresponds to all lactoferrin molecules containing 2 iron atoms). It is demonstrated that lactoferrin is involved not only in the transport of iron, zinc and copper, but also in the regulation of their intake. Presence of loose ions of zinc and copper does not affect the iron binding ability of lactoferrin, and might even increase it.
## Polymeric forms
Both in blood plasma and in secretory fluids lactoferrin can exist in different polymeric forms ranging from monomers to tetramers. Lactoferrin tends to polymerize both in vitro and in vivo, especially at high concentrations. Several authors found that the dominant form of lactoferrin in physiological conditions is a tetramer, with the monomer:tetramer ratio of 1:4 at the protein concentrations of 10−5 M.
It is suggested that the oligomer state of lactoferrin is determined by its concentration and that polymerization of lactoferrin is strongly affected by the presence of Ca2+ ions. In particular, monomers were dominant at concentrations below 10−10−10−11 M in the presence of Ca2+, but they converted into tetramers at lactoferrin concentrations above 10−9−10−10 M. Titer of lactoferrin in the blood corresponds to this particular "transition concentration" and thus lactoferrin in the blood should be presented both as a monomer and tetramer. Many functional properties of lactoferrin depend on its oligomeric state. In particular, monomeric, but not tetrameric lactoferrin can strongly bind to DNA.
# Function
Lactoferrin belongs to the innate immune system. Apart from its main biological function, namely binding and transport of iron ions, lactoferrin also has antibacterial, antiviral, antiparasitic, catalytic, anti-cancer, and anti-allergic functions and properties.
## Enzymatic activity of lactoferrin
Lactoferrin hydrolyzes RNA and exhibits the properties of pyrimidine-specific secretory ribonucleases. In particular, by destroying the RNA genome, milk RNase inhibits reverse transcription of retroviruses that cause breast cancer in mice. Parsi women in West India have the milk RNase level markedly lower than in other groups, and their breast cancer rate is three times higher than average. Thus, ribonucleases of milk, and lactoferrin in particular, might play an important role in pathogenesis of diseases caused by various retroviruses.
## Lactoferrin receptor
The lactoferrin receptor plays an important role in the internalization of lactoferrin; it also facilitates absorption of iron ions by lactoferrin. It was shown that gene expression increases with age in the duodenum and decreases in the jejunum.
The moonlighting glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been demonstrated to function as a receptor for lactoferrin.
## Bone activity
Ribonuclease-enriched lactoferrin has been used to examine how lactoferrin affects bone. Lactoferrin has shown to have positive effects on bone turnover. It has aided in decreasing bone resorption and increasing bone formation. This was indicated by a decrease in the levels of two bone resorption markers (deoxypyridinoline and N-telopeptide) and an increase in the levels two bone formation markers (osteocalcin and alkaline phosphatase). It has reduced osteoclast formation, which signifies a decrease in pro-inflammatory responses and an increase in anti-inflammatory responses which indicates a reduction in bone resorption as well.
## Interaction with nucleic acids
One of the important properties of lactoferrin is its ability to bind with nucleic acids. The fraction of protein extracted from milk, contains 3.3% RNA,
but, the protein preferably binds to double-stranded DNA rather than single-stranded DNA. The ability of lactoferrin to bind DNA is used for its isolation and purification using affinity chromatography with columns containing immobilized DNA-containing sorbents, such as agarose with the immobilized single-stranded DNA.
# Clinical significance
## Antibacterial activity
Lactoferrin's primary role is to sequester free iron, and in doing so remove essential substrate required for bacterial growth. Antibacterial action of lactoferrin is also explained by the presence of specific receptors on the cell surface of microorganisms. Lactoferrin binds to lipopolysaccharide of bacterial walls, and the oxidized iron part of the lactoferrin oxidizes bacteria via formation of peroxides. This affects the membrane permeability and results in the cell breakdown (lysis).
Although lactoferrin also has other antibacterial mechanisms not related to iron, such as stimulation of phagocytosis, the interaction with the outer bacterial membrane described above is the most dominant and most studied. Lactoferrin not only disrupts the membrane, but even penetrates into the cell. Its binding to the bacteria wall is associated with the specific peptide lactoferricin, which is located at the N-lobe of lactoferrin and is produced by in vitro cleavage of lactoferrin with another protein, trypsin. A mechanism of the antimicrobial action of lactoferrin has been reported as lactoferrin targets H+-ATPase and interferes with proton translocation in the cell membrane, resulting in a lethal effect in vitro.
Lactoferrin prevents the attachment of H. pylori in the stomach, which in turn, aids in reducing digestive system disorders. Bovine lactoferrin has more activity against H. pylori than human lactoferrin.
## Antiviral activity
Lactoferrin in sufficient strength example;- 2 grams oral capsule daily acts, mostly in vivo, on a wide range of human and animal viruses based on DNA and RNA genomes, including the herpes simplex virus 1 and 2, cytomegalovirus, HIV, hepatitis C virus, hantaviruses, rotaviruses, poliovirus type 1, human respiratory syncytial virus, murine leukemia viruses and Mayaro virus.
The most studied mechanism of antiviral activity of lactoferrin is its diversion of virus particles from the target cells. Many viruses tend to bind to the lipoproteins of the cell membranes and then penetrate into the cell. Lactoferrin binds to the same lipoproteins thereby repelling the virus particles. Iron-free apolactoferrin is more efficient in this function than hololactoferrin; and lactoferricin, which is responsible for antimicrobial properties of lactoferrin, shows almost no antiviral activity.
Beside interacting with the cell membrane, lactoferrin also directly binds to viral particles, such as the hepatitis viruses. This mechanism is also confirmed by the antiviral activity of lactoferrin against rotaviruses, which act on different cell types.
Lactoferrin also suppresses virus replication after the virus penetrated into the cell. Such an indirect antiviral effect is achieved by affecting natural killer cells, granulocytes and macrophages – cells, which play a crucial role in the early stages of viral infections, such as severe acute respiratory syndrome (SARS).
## Antifungal activity
Lactoferrin and lactoferricin inhibit in vitro growth of Trichophyton mentagrophytes, which are responsible for several skin diseases such as ringworm. Lactoferrin also acts against the Candida albicans – a diploid fungus (a form of yeast) that causes opportunistic oral and genital infections in humans. Fluconazole has long been used against Candida albicans, which resulted in emergence of strains resistant to this drug. However, a combination of lactoferrin with fluconazole can act against fluconazole-resistant strains of Candida albicans as well as other types of Candida: C. glabrata, C. krusei, C. parapsilosis and C. tropicalis. Antifungal activity is observed for sequential incubation of Candida with lactoferrin and then with fluconazole, but not vice versa. The antifungal activity of lactoferricin exceeds that of lactoferrin. In particular, synthetic peptide 1–11 lactoferricin shows much greater activity against Candida albicans than native lactoferricin.
Administration of lactoferrin through drinking water to mice with weakened immune systems and symptoms of aphthous ulcer reduced the number of Candida albicans strains in the mouth and the size of the damaged areas in the tongue. Oral administration of lactoferrin to animals also reduced the number of pathogenic organisms in the tissues close to the gastrointestinal tract. Candida albicans could also be completely eradicated with a mixture containing lactoferrin, lysozyme and itraconazole in HIV-positive patients who were resistant to other antifungal drugs. Such antifungal action when other drugs deem inefficient is characteristic of lactoferrin and is especially valuable for HIV-infected patients. Contrary to the antiviral and antibacterial actions of lactoferrin, very little is known about the mechanism of its antifungal action. Lactoferrin seems to bind the plasma membrane of C. albicans inducing an apoptotic-like process.
## Anticarcinogenic activity
The anticancer activity of bovine lactoferrin (bLF) has been demonstrated in experimental lung, bladder, tongue, colon, and liver carcinogeneses on rats, possibly by suppression of phase I enzymes, such as cytochrome P450 1A2 (CYP1A2). Also, in another experiment done on hamsters, bovine lactoferrin decreased the incidence of oral cancer by 50%. Currently, bLF is used as an ingredient in yogurt, chewing gums, infant formulas, and cosmetics.
## Cystic fibrosis
The human lung and saliva contain a wide range of antimicrobial compound including lactoperoxidase system, producing hypothiocyanite and lactoferrin, with hypothiocyanite missing in cystic fibrosis patients. Lactoferrin, a component of innate immunity, prevents bacterial biofilm development. The loss of microbicidal activity and increased formation of biofilm due to decreased lactoferrin activity is observed in patients with cystic fibrosis. In cystic fibrosis, antibiotic susceptibility may be modified by lactoferrin These findings demonstrate the important role of lactoferrin in human host defense and especially in lung. Lactoferrin with hypothiocyanite has been granted orphan drug status by the EMEA and the FDA.
## Necrotizing enterocolitis
A 2017 Cochrane review with low quality suggests that oral lactoferrin with or without probiotic decreases late onset of sepsis and necrotizing enterocolitis (stage II or III) in preterm infants with no adverse effects.
## In diagnosis
Lactoferrin levels in tear fluid have been shown to decrease in dry eye diseases such as Sjögren's syndrome. A rapid, portable test utilizing microfluidic technology has been developed to enable measurement of lactoferrin levels in human tear fluid at the point-of-care with the aim of improving diagnosis of Sjögren's syndrome and other forms of dry eye disease.
# Nanotechnology
Lactotransferrin has been used in the synthesis of fluorescent gold quantum clusters, which has potential applications in nanotechnology. | Lactoferrin
Lactoferrin (LF), also known as lactotransferrin (LTF), is a multifunctional protein of the transferrin family. Lactoferrin is a globular glycoprotein with a molecular mass of about 80 kDa that is widely represented in various secretory fluids, such as milk, saliva, tears, and nasal secretions. Lactoferrin is also present in secondary granules of PMNs and is secreted by some acinar cells. Lactoferrin can be purified from milk or produced recombinantly. Human colostrum ("first milk") has the highest concentration, followed by human milk, then cow milk (150 mg/L).[1]
Lactoferrin is one of the components of the immune system of the body; it has antimicrobial activity (bacteriocide, fungicide) and is part of the innate defense, mainly at mucoses.[1] In particular, lactoferrin provides antibacterial activity to human infants.[2][3] Lactoferrin interacts with DNA and RNA, polysaccharides and heparin, and shows some of its biological functions in complexes with these ligands.
# History
Occurrence of iron-containing red protein in bovine milk was reported as early as in 1939;[4] however, the protein could not be properly characterized because it could not be extracted with sufficient purity. Its first detailed studies were reported around 1960. They documented the molecular weight, isoelectric point, optical absorption spectra and presence of two iron atoms per protein molecule.[5][6] The protein was extracted from milk, contained iron and was structurally and chemically similar to serum transferrin. Therefore, it was named lactoferrin in 1961, though the name lactotransferrin was used in some earlier publications, and later studies demonstrated that the protein is not restricted to milk. The antibacterial action of lactoferrin was also documented in 1961, and was associated with its ability to bind iron.[7]
# Structure
## Genes of lactoferrin
At least 60 gene sequences of lactoferrin have been characterized in 11 species of mammals.[8] In most species, stop codon is TAA, and TGA in Mus musculus. Deletions, insertions and mutations of stop codons affect the coding part and its length varies between 2,055 and 2,190 nucleotide pairs. Gene polymorphism between species is much more diverse than the intraspecific polymorphism of lactoferrin. There are differences in amino acid sequences: 8 in Homo sapiens, 6 in Mus musculus, 6 in Capra hircus, 10 in Bos taurus and 20 in Sus scrofa. This variation may indicate functional differences between different types of lactoferrin.[8]
In humans, lactoferrin gene LTF is located on the third chromosome in the locus 3q21-q23. In oxen, the coding sequence consists of 17 exons and has a length of about 34,500 nucleotide pairs. Exons of the lactoferrin gene in oxen have a similar size to the exons of other genes of the transferrin family, whereas the sizes of introns differ within the family. Similarity in the size of exons and their distribution in the domains of the protein molecule indicates that the evolutionary development of lactoferrin gene occurred by duplication.[9] Study of polymorphism of genes that encode lactoferrin helps selecting livestock breeds that are resistant to mastitis.[10]
## Molecular structure
Lactoferrin is one of the transferrin proteins that transfer iron to the cells and control the level of free iron in the blood and external secretions. It is present in the milk of humans and other mammals,[6] in the blood plasma and neutrophils and is one of the major proteins of virtually all exocrine secretions of mammals, such as saliva, bile, tears and pancreas.[11] Concentration of lactoferrin in the milk varies from 7 g/L in the colostrum to 1 g/L in mature milk.
X-ray diffraction reveals that lactoferrin is based on one polypeptide chain that contains about 700 amino acids and forms two homologous globular domains named N-and C-lobes. N-lobe corresponds to amino acid residues 1–333 and C-lobe to 345–692, and the ends of those domains are connected by a short α-helix.[12][13] Each lobe consists of two subdomains, N1, N2 and C1, C2, and contains one iron binding site and one glycosylation site. The degree of glycosylation of the protein may be different and therefore the molecular weight of lactoferrin varies between 76 and 80 kDa. The stability of lactoferrin has been associated with the high glycosylation degree.[14]
Lactoferrin belongs to the basic proteins, its isoelectric point is 8.7. It exists in two forms: iron-rich hololactoferrin and iron-free apolactoferrin. Their tertiary structures are different; apolactoferrin is characterized by "open" conformation of the N-lobe and the "closed" conformation of the C-lobe, and both lobes are closed in the hololactoferrin.[15]
Each lactoferrin molecule can reversibly bind two ions of iron, zinc, copper or other metals.[16] The binding sites are localized in each of the two protein globules. There, each ion is bonded with six ligands: four from the polypeptide chain (two tyrosine residues, one histidine residue and one aspartic acid residue) and two from carbonate or bicarbonate ions.
Lactoferrin forms reddish complex with iron; its affinity for iron is 300 times higher than that of transferrin.[17] The affinity increases in weakly acidic medium. This facilitates the transfer of iron from transferrin to lactoferrin during inflammations, when the pH of tissues decreases due to accumulation of lactic and other acids.[18] The saturated iron concentration in lactoferrin in human milk is estimated as 10 to 30% (100% corresponds to all lactoferrin molecules containing 2 iron atoms). It is demonstrated that lactoferrin is involved not only in the transport of iron, zinc and copper, but also in the regulation of their intake.[19] Presence of loose ions of zinc and copper does not affect the iron binding ability of lactoferrin, and might even increase it.
## Polymeric forms
Both in blood plasma and in secretory fluids lactoferrin can exist in different polymeric forms ranging from monomers to tetramers. Lactoferrin tends to polymerize both in vitro and in vivo, especially at high concentrations.[18] Several authors found that the dominant form of lactoferrin in physiological conditions is a tetramer, with the monomer:tetramer ratio of 1:4 at the protein concentrations of 10−5 M.[20][21][22]
It is suggested that the oligomer state of lactoferrin is determined by its concentration and that polymerization of lactoferrin is strongly affected by the presence of Ca2+ ions. In particular, monomers were dominant at concentrations below 10−10−10−11 M in the presence of Ca2+, but they converted into tetramers at lactoferrin concentrations above 10−9−10−10 M.[20][23] Titer of lactoferrin in the blood corresponds to this particular "transition concentration" and thus lactoferrin in the blood should be presented both as a monomer and tetramer. Many functional properties of lactoferrin depend on its oligomeric state. In particular, monomeric, but not tetrameric lactoferrin can strongly bind to DNA.
# Function
Lactoferrin belongs to the innate immune system. Apart from its main biological function, namely binding and transport of iron ions, lactoferrin also has antibacterial, antiviral, antiparasitic, catalytic, anti-cancer, and anti-allergic functions and properties.[24]
## Enzymatic activity of lactoferrin
Lactoferrin hydrolyzes RNA and exhibits the properties of pyrimidine-specific secretory ribonucleases. In particular, by destroying the RNA genome, milk RNase inhibits reverse transcription of retroviruses that cause breast cancer in mice.[25] Parsi women in West India have the milk RNase level markedly lower than in other groups, and their breast cancer rate is three times higher than average.[26] Thus, ribonucleases of milk, and lactoferrin in particular, might play an important role in pathogenesis of diseases caused by various retroviruses.
## Lactoferrin receptor
The lactoferrin receptor plays an important role in the internalization of lactoferrin; it also facilitates absorption of iron ions by lactoferrin. It was shown that gene expression increases with age in the duodenum and decreases in the jejunum.[27]
The moonlighting glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been demonstrated to function as a receptor for lactoferrin.[28]
## Bone activity
Ribonuclease-enriched lactoferrin has been used to examine how lactoferrin affects bone. Lactoferrin has shown to have positive effects on bone turnover. It has aided in decreasing bone resorption and increasing bone formation. This was indicated by a decrease in the levels of two bone resorption markers (deoxypyridinoline and N-telopeptide) and an increase in the levels two bone formation markers (osteocalcin and alkaline phosphatase).[29] It has reduced osteoclast formation, which signifies a decrease in pro-inflammatory responses and an increase in anti-inflammatory responses [30] which indicates a reduction in bone resorption as well.
## Interaction with nucleic acids
One of the important properties of lactoferrin is its ability to bind with nucleic acids. The fraction of protein extracted from milk, contains 3.3% RNA,[20]
but, the protein preferably binds to double-stranded DNA rather than single-stranded DNA. The ability of lactoferrin to bind DNA is used for its isolation and purification using affinity chromatography with columns containing immobilized DNA-containing sorbents, such as agarose with the immobilized single-stranded DNA.[31]
# Clinical significance
## Antibacterial activity
Lactoferrin's primary role is to sequester free iron, and in doing so remove essential substrate required for bacterial growth.[33] Antibacterial action of lactoferrin is also explained by the presence of specific receptors on the cell surface of microorganisms. Lactoferrin binds to lipopolysaccharide of bacterial walls, and the oxidized iron part of the lactoferrin oxidizes bacteria via formation of peroxides. This affects the membrane permeability and results in the cell breakdown (lysis).[33]
Although lactoferrin also has other antibacterial mechanisms not related to iron, such as stimulation of phagocytosis,[34] the interaction with the outer bacterial membrane described above is the most dominant and most studied.[35] Lactoferrin not only disrupts the membrane, but even penetrates into the cell. Its binding to the bacteria wall is associated with the specific peptide lactoferricin, which is located at the N-lobe of lactoferrin and is produced by in vitro cleavage of lactoferrin with another protein, trypsin.[36][37] A mechanism of the antimicrobial action of lactoferrin has been reported as lactoferrin targets H+-ATPase and interferes with proton translocation in the cell membrane, resulting in a lethal effect in vitro.[38]
Lactoferrin prevents the attachment of H. pylori in the stomach, which in turn, aids in reducing digestive system disorders. Bovine lactoferrin has more activity against H. pylori than human lactoferrin.[39]
## Antiviral activity
Lactoferrin in sufficient strength example;- 2 grams oral capsule daily acts, mostly in vivo, on a wide range of human and animal viruses based on DNA and RNA genomes,[40] including the herpes simplex virus 1 and 2,[41][42] cytomegalovirus,[43] HIV,[42][44] hepatitis C virus,[45][46] hantaviruses, rotaviruses, poliovirus type 1,[47] human respiratory syncytial virus, murine leukemia viruses[37] and Mayaro virus.[48]
The most studied mechanism of antiviral activity of lactoferrin is its diversion of virus particles from the target cells. Many viruses tend to bind to the lipoproteins of the cell membranes and then penetrate into the cell.[46] Lactoferrin binds to the same lipoproteins thereby repelling the virus particles. Iron-free apolactoferrin is more efficient in this function than hololactoferrin; and lactoferricin, which is responsible for antimicrobial properties of lactoferrin, shows almost no antiviral activity.[40]
Beside interacting with the cell membrane, lactoferrin also directly binds to viral particles, such as the hepatitis viruses.[46] This mechanism is also confirmed by the antiviral activity of lactoferrin against rotaviruses,[37] which act on different cell types.
Lactoferrin also suppresses virus replication after the virus penetrated into the cell.[37][44] Such an indirect antiviral effect is achieved by affecting natural killer cells, granulocytes and macrophages – cells, which play a crucial role in the early stages of viral infections, such as severe acute respiratory syndrome (SARS).[49]
## Antifungal activity
Lactoferrin and lactoferricin inhibit in vitro growth of Trichophyton mentagrophytes, which are responsible for several skin diseases such as ringworm.[50] Lactoferrin also acts against the Candida albicans – a diploid fungus (a form of yeast) that causes opportunistic oral and genital infections in humans.[51][52] Fluconazole has long been used against Candida albicans, which resulted in emergence of strains resistant to this drug. However, a combination of lactoferrin with fluconazole can act against fluconazole-resistant strains of Candida albicans as well as other types of Candida: C. glabrata, C. krusei, C. parapsilosis and C. tropicalis.[51] Antifungal activity is observed for sequential incubation of Candida with lactoferrin and then with fluconazole, but not vice versa. The antifungal activity of lactoferricin exceeds that of lactoferrin. In particular, synthetic peptide 1–11 lactoferricin shows much greater activity against Candida albicans than native lactoferricin.[51]
Administration of lactoferrin through drinking water to mice with weakened immune systems and symptoms of aphthous ulcer reduced the number of Candida albicans strains in the mouth and the size of the damaged areas in the tongue.[53] Oral administration of lactoferrin to animals also reduced the number of pathogenic organisms in the tissues close to the gastrointestinal tract. Candida albicans could also be completely eradicated with a mixture containing lactoferrin, lysozyme and itraconazole in HIV-positive patients who were resistant to other antifungal drugs.[54] Such antifungal action when other drugs deem inefficient is characteristic of lactoferrin and is especially valuable for HIV-infected patients.[55] Contrary to the antiviral and antibacterial actions of lactoferrin, very little is known about the mechanism of its antifungal action. Lactoferrin seems to bind the plasma membrane of C. albicans inducing an apoptotic-like process.[52][56]
## Anticarcinogenic activity
The anticancer activity of bovine lactoferrin (bLF) has been demonstrated in experimental lung, bladder, tongue, colon, and liver carcinogeneses on rats, possibly by suppression of phase I enzymes, such as cytochrome P450 1A2 (CYP1A2).[57] Also, in another experiment done on hamsters, bovine lactoferrin decreased the incidence of oral cancer by 50%.[58] Currently, bLF is used as an ingredient in yogurt, chewing gums, infant formulas, and cosmetics.[58]
## Cystic fibrosis
The human lung and saliva contain a wide range of antimicrobial compound including lactoperoxidase system, producing hypothiocyanite and lactoferrin, with hypothiocyanite missing in cystic fibrosis patients.[59] Lactoferrin, a component of innate immunity, prevents bacterial biofilm development.[60][61] The loss of microbicidal activity and increased formation of biofilm due to decreased lactoferrin activity is observed in patients with cystic fibrosis.[62] In cystic fibrosis, antibiotic susceptibility may be modified by lactoferrin[63] These findings demonstrate the important role of lactoferrin in human host defense and especially in lung.[64] Lactoferrin with hypothiocyanite has been granted orphan drug status by the EMEA[65] and the FDA.[66]
## Necrotizing enterocolitis
A 2017 Cochrane review with low quality suggests that oral lactoferrin with or without probiotic decreases late onset of sepsis and necrotizing enterocolitis (stage II or III) in preterm infants with no adverse effects.[67]
## In diagnosis
Lactoferrin levels in tear fluid have been shown to decrease in dry eye diseases such as Sjögren's syndrome.[68] A rapid, portable test utilizing microfluidic technology has been developed to enable measurement of lactoferrin levels in human tear fluid at the point-of-care with the aim of improving diagnosis of Sjögren's syndrome and other forms of dry eye disease.[69]
# Nanotechnology
Lactotransferrin has been used in the synthesis of fluorescent gold quantum clusters, which has potential applications in nanotechnology.[70] | https://www.wikidoc.org/index.php/Lactoferrin | |
cfad309527b785485e94217c53c94012c10d4c62 | wikidoc | Lactucarium | Lactucarium
Lactucarium is the milky fluid secreted by several species of lettuce, especially Lactuca virosa, usually from the base of the stems. Lactucarium is known as lettuce opium because of its sedative and analgesic properties. It has been reported to promote a mild sensation of euphoria, but Lactuca virosa is poisonous, and at least one fatality has occurred during an attempt to use it for intoxication. Because it is a latex, Lactucarium physically resembles opium, in that is excreted as a white fluid and can be reduced to a thick smokeable solid.
# History
"Lettuce Opium" was used by the Ancient Egyptians, and was introduced as a drug in the United States as early as 1799. The drug was prescribed and studied extensively in Poland during the nineteenth century, and was viewed as an alternative to opium, weaker but lacking side-effects, and in some cases preferable. However, early efforts to isolate an active alkaloid were unsuccessful. It is described and standardized in the 1898 United States Pharmacopoeia and 1911 British Pharmaceutical Codex for use in lozenges, tinctures, and syrups as a sedative for irritable cough or as a mild hypnotic (sleeping aid) for insomnia. The standard definition of lactucarium in these codices required its production from Lactuca virosa, but it was recognized that smaller quantities of lactucarium could be produced in a similar way from Lactuca sativa and Lactuca canadensis var. elongata, and even that lettuce-opium obtained from Lactuca scariola or Lactuca altissima was of superior quality.
In the twentieth century, two major studies found commercial lactucarium to be without effect. In 1944, Fulton concluded, "Modern medicine considers its sleep producing qualities a superstition, its therapeutic action doubtful or nil." Another study of the time identified active bitter principles lactucin and lactucopicrin, but noted that these compounds from the fresh latex were unstable and did not remain in commercial preparations of lactucarium. Accordingly, lettuce opium fell from favor, until publications of the hippie movement began to promote it in the mid-1970s as a legal drug producing euphoria, sometimes compounded with catnip or damiana.
The seeds of lettuce have also been used to relieve pain. Lettuce seed was listed between belladonna and snow in order of anaesthetic potency in Avicenna's The Canon of Medicine, which served as an authoritative medical textbook from soon after 1000 A.D. until the seventeenth century.
# Contemporary use
Although lactucarium has faded from general use as a pain reliever, it remains available, sometimes promoted as a legal psychotropic.
The seed of ordinary lettuce, Lactuca sativa, is still used in Avicenna's native Iran as a folk medicine, and a crude extract of the seeds was shown to have analgesic and antiinflammatory effects in standard formalin and carrageenan tests of laboratory rats. It was not toxic to the rats at a dose of 6 grams per kilogram
# Mechanism
The active ingredients of lactucarium are believed to be lactucin and its derivatives lactucopicrin and 11β13-dihydrolactucin, which have been found to have analgesic activity equal or greater to that of ibuprofen in standard hot-plate and tail-flick tests of sensitivity to pain in laboratory mice. Lactucin and lactucropicrin were also found to have sedative activity in measurements of spontaneous movements of the mice. Some effects have also been credited to a trace of hyoscyamine in Lactuca virosa, but the alkaloid was undetectable in standard lactucarium.
# Formulations
Lactucarium was used unmodified in lozenges, 30-60 milligrams (0.5 to 1 grain, sometimes mixed with borax. However, it was found to be more efficient to formulate the drug in a cough syrup (Syrupus Lactucarii, U.S.P.) containing net 5% lactucarium, 22% glycerin, 5% alcohol, and 5% orange-flower water in syrup. | Lactucarium
Lactucarium is the milky fluid secreted by several species of lettuce, especially Lactuca virosa, usually from the base of the stems. Lactucarium is known as lettuce opium because of its sedative and analgesic properties. It has been reported to promote a mild sensation of euphoria, but Lactuca virosa is poisonous[1], and at least one fatality has occurred during an attempt to use it for intoxication.[2][3] Because it is a latex, Lactucarium physically resembles opium, in that is excreted as a white fluid and can be reduced to a thick smokeable solid.
Template:Infobox Botanical product
# History
"Lettuce Opium" was used by the Ancient Egyptians, and was introduced as a drug in the United States as early as 1799.[citation needed] The drug was prescribed and studied extensively in Poland during the nineteenth century, and was viewed as an alternative to opium, weaker but lacking side-effects, and in some cases preferable. However, early efforts to isolate an active alkaloid were unsuccessful.[4] It is described and standardized in the 1898 United States Pharmacopoeia[5] and 1911 British Pharmaceutical Codex[6] for use in lozenges, tinctures, and syrups as a sedative for irritable cough or as a mild hypnotic (sleeping aid) for insomnia. The standard definition of lactucarium in these codices required its production from Lactuca virosa, but it was recognized that smaller quantities of lactucarium could be produced in a similar way from Lactuca sativa and Lactuca canadensis var. elongata, and even that lettuce-opium obtained from Lactuca scariola or Lactuca altissima was of superior quality.[7]
In the twentieth century, two major studies found commercial lactucarium to be without effect. In 1944, Fulton concluded, "Modern medicine considers its sleep producing qualities a superstition, its therapeutic action doubtful or nil." Another study of the time identified active bitter principles lactucin and lactucopicrin, but noted that these compounds from the fresh latex were unstable and did not remain in commercial preparations of lactucarium. Accordingly, lettuce opium fell from favor, until publications of the hippie movement began to promote it in the mid-1970s as a legal drug producing euphoria, sometimes compounded with catnip or damiana.[8]
The seeds of lettuce have also been used to relieve pain. Lettuce seed was listed between belladonna and snow in order of anaesthetic potency in Avicenna's The Canon of Medicine, which served as an authoritative medical textbook from soon after 1000 A.D. until the seventeenth century.[9]
# Contemporary use
Although lactucarium has faded from general use as a pain reliever, it remains available, sometimes promoted as a legal psychotropic.
The seed of ordinary lettuce, Lactuca sativa, is still used in Avicenna's native Iran as a folk medicine, and a crude extract of the seeds was shown to have analgesic and antiinflammatory effects in standard formalin and carrageenan tests of laboratory rats. It was not toxic to the rats at a dose of 6 grams per kilogram[10]
# Mechanism
The active ingredients of lactucarium are believed to be lactucin and its derivatives lactucopicrin and 11β13-dihydrolactucin, which have been found to have analgesic activity equal or greater to that of ibuprofen in standard hot-plate and tail-flick tests of sensitivity to pain in laboratory mice. Lactucin and lactucropicrin were also found to have sedative activity in measurements of spontaneous movements of the mice.[11] Some effects have also been credited to a trace of hyoscyamine in Lactuca virosa, but the alkaloid was undetectable in standard lactucarium.[6]
# Formulations
Lactucarium was used unmodified in lozenges, 30-60 milligrams (0.5 to 1 grain, sometimes mixed with borax. However, it was found to be more efficient to formulate the drug in a cough syrup (Syrupus Lactucarii, U.S.P.) containing net 5% lactucarium, 22% glycerin, 5% alcohol, and 5% orange-flower water in syrup.[6] | https://www.wikidoc.org/index.php/Lactucarium | |
1e2002dd087b5e11ec651521fd5510efe7530f09 | wikidoc | Lamotrigine | Lamotrigine
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# Black Box Warning
# Overview
Lamotrigine is an antipileptic drug that is FDA approved for the {{{indicationType}}} of partial seizures, primary generalized tonic-clonic seizures, generalized seizures of Lennox-Gastaut syndrome, epilepsy-monotherapy in patients ≥16 years of age, maintenance treatment of bipolar I disorder. There is a Black Box Warning for this drug as shown here. Common adverse reactions include dizziness, headache, diplopia, ataxia, nausea, blurred vision, rhinitis, rash, vomiting, infection, fever, accidental injury, pharyngitis, tremor, insomnia, somnolence, back pain, fatigue, abdominal pain, and xerostomia..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Adjunctive Therapy: LAMICTAL is indicated as adjunctive therapy for the following seizure types in patients ≥2 years of age:
- partial seizures
- primary generalized tonic-clonic seizures
- generalized seizures of Lennox-Gastaut syndrome
- Monotherapy: LAMICTAL is indicated for conversion to monotherapy in adults (≥16 years of age) with partial seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (AED).
- Safety and effectiveness of LAMICTAL have not been established (1) as initial monotherapy; (2) for conversion to monotherapy from AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate; or (3) for simultaneous conversion to monotherapy from 2 or more concomitant AEDs.
- LAMICTAL is indicated for the maintenance treatment of Bipolar I Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in adults (≥18 years of age) treated for acute mood episodes with standard therapy. The effectiveness of LAMICTAL in the acute treatment of mood episodes has not been established.
- The effectiveness of LAMICTAL as maintenance treatment was established in 2 placebo-controlled trials in patients with Bipolar I Disorder as defined by DSM-IV . The physician who elects to prescribe LAMICTAL for periods extending beyond 16 weeks should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lamotrigine in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Lamotrigine, initiated at 25 mg per day and titrated up to 250 mg/day.
- Dosing Information
Lamotrigine was initially started at 0.2 mg/kg twice daily and gradually increased to a maximum of 5 mg/kg.
- Dosing Information
- Lamotrigine 100 mg daily.
- Dosing Information
- Initial dosing of lamotrigine was 25 mg/day titrated every 2 weeks until the maintenance dose of 150 to 200 mg/day was reached.
- Dosing Information
- Lamotrigine 25 mg/day with increments of 25 mg/week to a dose of 100 mg/day at week 4.
- Dosing Information
- Lamotrigine 400 mg/day.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Adjunctive Therapy: LAMICTAL is indicated as adjunctive therapy for the following seizure types in patients ≥2 years of age:
- partial seizures
- primary generalized tonic-clonic seizures
- generalized seizures of Lennox-Gastaut syndrome
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lamotrigine in pediatric patients.
### Non–Guideline-Supported Use
- Dosing Information
- Patients were titrated on lamotrigine with a mean final dose of 132 +/- 31 mg/day.
- Dosing Information
- In neonates who were taking enzyme-inducing agents, doses up to 10 mg/kg/day were prescribed. In infants between 1 and 12 months of age, who were taking enzyme-inducing agents, final doses ranged between 10 to 20 mg/kg/day. Infants between 1 and 12 months of age, taking valproate and enzyme inducers, were dosed between 5 to 10 mg/kg/day. In infants between 1 and 12 months of age, taking valproate alone, 5 mg/kg/day was the final dose.
- Dosing Information
Lamotrigine starting daily dose was 0.2 to 2.5 mg/kg titrated over 2 to 4 weeks to an initial maintenance dose of 0.75 to 10 mg/kg.
# Contraindications
- LAMICTAL is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.
# Warnings
### Precautions
- Serious Skin Rashes
- Pediatric Population: The incidence of serious rash associated with hospitalization and discontinuation of LAMICTAL in a prospectively followed cohort of pediatric patients (2 to 16 years of age) with epilepsy receiving adjunctive therapy was approximately 0.8% (16 of 1,983). When 14 of these cases were reviewed by 3 expert dermatologists, there was considerable disagreement as to their proper classification. To illustrate, one dermatologist considered none of the cases to be Stevens-Johnson syndrome; another assigned 7 of the 14 to this diagnosis. There was 1 rash-related death in this 1,983-patient cohort. Additionally, there have been rare cases of toxic epidermal necrolysis with and without permanent sequelae and/or death in US and foreign postmarketing experience.
- There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in pediatric patients. In pediatric patients who used valproate concomitantly, 1.2% (6 of 482) experienced a serious rash compared with 0.6% (6 of 952) patients not taking valproate.
- Adult Population: Serious rash associated with hospitalization and discontinuation of LAMICTAL occurred in 0.3% (11 of 3,348) of adult patients who received LAMICTAL in premarketing clinical trials of epilepsy. In the bipolar and other mood disorders clinical trials, the rate of serious rash was 0.08% (1 of 1,233) of adult patients who received LAMICTAL as initial monotherapy and 0.13% (2 of 1,538) of adult patients who received LAMICTAL as adjunctive therapy. No fatalities occurred among these individuals. However, in worldwide postmarketing experience, rare cases of rash-related death have been reported, but their numbers are too few to permit a precise estimate of the rate.
- Among the rashes leading to hospitalization were Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, and those associated with multiorgan hypersensitivity.
- There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in adults. Specifically, of 584 patients administered LAMICTAL with valproate in epilepsy clinical trials, 6 (1%) were hospitalized in association with rash; in contrast, 4 (0.16%) of 2,398 clinical trial patients and volunteers administered LAMICTAL in the absence of valproate were hospitalized.
- Patients With History of Allergy or Rash to Other Antiepileptic Drugs: The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of LAMICTAL is exceeded and in patients with a history of allergy or rash to other AEDs.
- Multiorgan Hypersensitivity Reactions and Organ Failure
- Multiorgan hypersensitivity reactions, also known as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have occurred with LAMICTAL. Some have been fatal or life threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved.
- Fatalities associated with acute multiorgan failure and various degrees of hepatic failure have been reported in 2 of 3,796 adult patients and 4 of 2,435 pediatric patients who received LAMICTAL in epilepsy clinical trials. Rare fatalities from multiorgan failure have also been reported in postmarketing use.
- Isolated liver failure without rash or involvement of other organs has also been reported with LAMICTAL.
- It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though a rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. LAMICTAL should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
- Prior to initiation of treatment with LAMICTAL, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a physician immediately.
- Blood Dyscrasias
- There have been reports of blood dyscrasias that may or may not be associated with multiorgan hypersensitivity (also known as DRESS). These have included neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia.
- Suicidal Behavior and Ideation
- AEDs, including LAMICTAL, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
- Pooled analyses of 199 placebo-controlled clinical trials (monotherapy and adjunctive therapy) of 11 different AEDs showed that patients randomized to 1 of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately 1 case of suicidal thinking or behavior for every 530 patients treated. There were 4 suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number of events is too small to allow any conclusion about drug effect on suicide.
- The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
- The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanism of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.
- Table 7 shows absolute and relative risk by indication for all evaluated AEDs.
- The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
- Anyone considering prescribing LAMICTAL or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
- Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
- Use in Patients With Bipolar Disorder
- Acute Treatment of Mood Episodes: Safety and effectiveness of LAMICTAL in the acute treatment of mood episodes have not been established.
- Children and Adolescents (less than 18 years of age): Safety and effectiveness of LAMICTAL in patients below the age of 18 years with mood disorders have not been established.
- Clinical Worsening and Suicide Risk Associated With Bipolar Disorder: Patients with bipolar disorder may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviors (suicidality) whether or not they are taking medications for bipolar disorder. Patients should be closely monitored for clinical worsening (including development of new symptoms) and suicidality, especially at the beginning of a course of treatment or at the time of dose changes.
- In addition, patients with a history of suicidal behavior or thoughts, those patients exhibiting a significant degree of suicidal ideation prior to commencement of treatment, and young adults are at an increased risk of suicidal thoughts or suicide attempts and should receive careful monitoring during treatment.
- Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who experience clinical worsening (including development of new symptoms) and/or the emergence of suicidal ideation/behavior especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
- Prescriptions for LAMICTAL should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose. Overdoses have been reported for LAMICTAL, some of which have been fatal.
- Aseptic Meningitis
- Therapy with LAMICTAL increases the risk of developing aseptic meningitis. Because of the potential for serious outcomes of untreated meningitis due to other causes, patients should also be evaluated for other causes of meningitis and treated as appropriate.
- Postmarketing cases of aseptic meningitis have been reported in pediatric and adult patients taking LAMICTAL for various indications. Symptoms upon presentation have included headache, fever, nausea, vomiting, and nuchal rigidity. Rash, photophobia, myalgia, chills, altered consciousness, and somnolence were also noted in some cases. Symptoms have been reported to occur within 1 day to one and a half months following the initiation of treatment. In most cases, symptoms were reported to resolve after discontinuation of LAMICTAL. Re-exposure resulted in a rapid return of symptoms (from within 30 minutes to 1 day following re-initiation of treatment) that were frequently more severe. Some of the patients treated with LAMICTAL who developed aseptic meningitis had underlying diagnoses of systemic lupus erythematosus or other autoimmune diseases.
- Cerebrospinal fluid (CSF) analyzed at the time of clinical presentation in reported cases was characterized by a mild to moderate pleocytosis, normal glucose levels, and mild to moderate increase in protein. CSF white blood cell count differentials showed a predominance of neutrophils in a majority of the cases, although a predominance of lymphocytes was reported in approximately one third of the cases. Some patients also had new onset of signs and symptoms of involvement of other organs (predominantly hepatic and renal involvement), which may suggest that in these cases the aseptic meningitis observed was part of a hypersensitivity reaction.
- Potential Medication Errors
- Medication errors involving LAMICTAL have occurred. In particular, the names LAMICTAL or lamotrigine can be confused with the names of other commonly used medications. Medication errors may also occur between the different formulations of LAMICTAL. To reduce the potential of medication errors, write and say LAMICTAL clearly. Depictions of the LAMICTAL Tablets, Chewable Dispersible Tablets, and Orally Disintegrating Tablets can be found in the Medication Guide that accompanies the product to highlight the distinctive markings, colors, and shapes that serve to identify the different presentations of the drug and thus may help reduce the risk of medication errors. To avoid the medication error of using the wrong drug or formulation, patients should be strongly advised to visually inspect their tablets to verify that they are LAMICTAL, as well as the correct formulation of LAMICTAL, each time they fill their prescription.
- Concomitant Use With Oral Contraceptives
- Some estrogen-containing oral contraceptives have been shown to decrease serum concentrations of lamotrigine. Dosage adjustments will be necessary in most patients who start or stop estrogen-containing oral contraceptives while taking LAMICTAL. During the week of inactive hormone preparation (“pill-free” week) of oral contraceptive therapy, plasma lamotrigine levels are expected to rise, as much as doubling at the end of the week. Adverse reactions consistent with elevated levels of lamotrigine, such as dizziness, ataxia, and diplopia, could occur.
- Withdrawal Seizures
- As with other AEDs, LAMICTAL should not be abruptly discontinued. In patients with epilepsy there is a possibility of increasing seizure frequency. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of LAMICTAL; however, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Unless safety concerns require a more rapid withdrawal, the dose of LAMICTAL should be tapered over a period of at least 2 weeks (approximately 50% reduction per week) .
- Status Epilepticus
- Valid estimates of the incidence of treatment-emergent status epilepticus among patients treated with LAMICTAL are difficult to obtain because reporters participating in clinical trials did not all employ identical rules for identifying cases. At a minimum, 7 of 2,343 adult patients had episodes that could unequivocally be described as status epilepticus. In addition, a number of reports of variably defined episodes of seizure exacerbation (e.g., seizure clusters, seizure flurries) were made.
- Sudden Unexplained Death in Epilepsy (SUDEP)
- During the premarketing development of LAMICTAL, 20 sudden and unexplained deaths were recorded among a cohort of 4,700 patients with epilepsy (5,747 patient-years of exposure).
- Some of these could represent seizure-related deaths in which the seizure was not observed, e.g., at night. This represents an incidence of 0.0035 deaths per patient-year. Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving LAMICTAL (ranging from 0.0005 for the general population of patients with epilepsy, to 0.004 for a recently studied clinical trial population similar to that in the clinical development program for LAMICTAL, to 0.005 for patients with refractory epilepsy). Consequently, whether these figures are reassuring or suggest concern depends on the comparability of the populations reported upon to the cohort receiving LAMICTAL and the accuracy of the estimates provided. Probably most reassuring is the similarity of estimated SUDEP rates in patients receiving LAMICTAL and those receiving other AEDs, chemically unrelated to each other, that underwent clinical testing in similar populations. Importantly, that drug is chemically unrelated to LAMICTAL. This evidence suggests, although it certainly does not prove, that the high SUDEP rates reflect population rates, not a drug effect.
- Addition of LAMICTAL to a Multidrug Regimen That Includes Valproate
- Because valproate reduces the clearance of lamotrigine, the dosage of lamotrigine in the presence of valproate is less than half of that required in its absence.
- Binding in the Eye and Other Melanin-Containing Tissues
- Because lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over time. This raises the possibility that lamotrigine may cause toxicity in these tissues after extended use. Although ophthalmological testing was performed in 1 controlled clinical trial, the testing was inadequate to exclude subtle effects or injury occurring after long-term exposure. Moreover, the capacity of available tests to detect potentially adverse consequences, if any, of lamotrigine’s binding to melanin is unknown.
- Accordingly, although there are no specific recommendations for periodic ophthalmological monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects.
- Laboratory Tests
- The value of monitoring plasma concentrations of lamotrigine in patients treated with LAMICTAL has not been established. Because of the possible pharmacokinetic interactions between lamotrigine and other drugs including AEDs (see Table 15), monitoring of the plasma levels of lamotrigine and concomitant drugs may be indicated, particularly during dosage adjustments. In general, clinical judgment should be exercised regarding monitoring of plasma levels of lamotrigine and other drugs and whether or not dosage adjustments are necessary.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- LAMICTAL has been evaluated for safety in patients with epilepsy and in patients with Bipolar I Disorder. Adverse reactions reported for each of these patient populations are provided below. Excluded are adverse reactions considered too general to be informative and those not reasonably attributable to the use of the drug.
- Epilepsy: Most Common Adverse Reactions in All Clinical Studies: Adjunctive Therapy in Adults With Epilepsy: The most commonly observed (≥5% for LAMICTAL and more common on drug than placebo) adverse reactions seen in association with LAMICTAL during adjunctive therapy in adults and not seen at an equivalent frequency among placebo-treated patients were: dizziness, ataxia, somnolence, headache, diplopia, blurred vision, nausea, vomiting, and rash. Dizziness, diplopia, ataxia, blurred vision, nausea, and vomiting were dose-related. Dizziness, diplopia, ataxia, and blurred vision occurred more commonly in patients receiving carbamazepine with LAMICTAL than in patients receiving other AEDs with LAMICTAL. Clinical data suggest a higher incidence of rash, including serious rash, in patients receiving concomitant valproate than in patients not receiving valproate.
- Approximately 11% of the 3,378 adult patients who received LAMICTAL as adjunctive therapy in premarketing clinical trials discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were rash (3.0%), dizziness (2.8%), and headache (2.5%).
- In a dose-response study in adults, the rate of discontinuation of LAMICTAL for dizziness, ataxia, diplopia, blurred vision, nausea, and vomiting was dose-related.
- Monotherapy in Adults With Epilepsy: The most commonly observed (≥5% for LAMICTAL and more common on drug than placebo) adverse reactions seen in association with the use of LAMICTAL during the monotherapy phase of the controlled trial in adults not seen at an equivalent rate in the control group were vomiting, coordination abnormality, dyspepsia, nausea, dizziness, rhinitis, anxiety, insomnia, infection, pain, weight decrease, chest pain, and dysmenorrhea. The most commonly observed (≥5% for LAMICTAL and more common on drug than placebo) adverse reactions associated with the use of LAMICTAL during the conversion to monotherapy (add-on) period, not seen at an equivalent frequency among low-dose valproate-treated patients, were dizziness, headache, nausea, asthenia, coordination abnormality, vomiting, rash, somnolence, diplopia, ataxia, accidental injury, tremor, blurred vision, insomnia, nystagmus, diarrhea, lymphadenopathy, pruritus, and sinusitis.
- Approximately 10% of the 420 adult patients who received LAMICTAL as monotherapy in premarketing clinical trials discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were rash (4.5%), headache (3.1%), and asthenia (2.4%).
- Adjunctive Therapy in Pediatric Patients With Epilepsy: The most commonly observed (≥5% for LAMICTAL and more common on drug than placebo) adverse reactions seen in association with the use of LAMICTAL as adjunctive treatment in pediatric patients 2 to 16 years of age and not seen at an equivalent rate in the control group were infection, vomiting, rash, fever, somnolence, accidental injury, dizziness, diarrhea, abdominal pain, nausea, ataxia, tremor, asthenia, bronchitis, flu syndrome, and diplopia.
- In 339 patients 2 to 16 years of age with partial seizures or generalized seizures of Lennox-Gastaut syndrome, 4.2% of patients on LAMICTAL and 2.9% of patients on placebo discontinued due to adverse reactions. The most commonly reported adverse reaction that led to discontinuation of LAMICTAL was rash.
- Approximately 11.5% of the 1,081 pediatric patients 2 to 16 years of age who received LAMICTAL as adjunctive therapy in premarketing clinical trials discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were rash (4.4%), reaction aggravated (1.7%), and ataxia (0.6%).
- Controlled Adjunctive Clinical Studies in Adults With Epilepsy: Table 8 lists treatment-emergent adverse reactions that occurred in at least 2% of adult patients with epilepsy treated with LAMICTAL in placebo-controlled trials and were numerically more common in the patients treated with LAMICTAL. In these studies, either LAMICTAL or placebo was added to the patient’s current AED therapy. Adverse reactions were usually mild to moderate in intensity.
- Patients in these adjunctive studies were receiving 1 to 3 of the following concomitant AEDs (carbamazepine, phenytoin, phenobarbital, or primidone) in addition to LAMICTAL or placebo. Patients may have reported multiple adverse reactions during the study or at discontinuation; thus, patients may be included in more than one category.
- In a randomized, parallel study comparing placebo and 300 and 500 mg/day of LAMICTAL, some of the more common drug-related adverse reactions were dose-related (see Table 9).
- aSignificantly greater than placebo group (P<0.05).
- bSignificantly greater than group receiving LAMICTAL 300 mg (P<0.05).
- The overall adverse reaction profile for LAMICTAL was similar between females and males, and was independent of age. Because the largest non-Caucasian racial subgroup was only 6% of patients exposed to LAMICTAL in placebo-controlled trials, there are insufficient data to support a statement regarding the distribution of adverse reaction reports by race. Generally, females receiving either LAMICTAL as adjunctive therapy or placebo were more likely to report adverse reactions than males. The only adverse reaction for which the reports on LAMICTAL were greater than 10% more frequent in females than males (without a corresponding difference by gender on placebo) was dizziness (difference = 16.5%). There was little difference between females and males in the rates of discontinuation of LAMICTAL for individual adverse reactions.
- Controlled Monotherapy Trial in Adults With Partial Seizures: Table 10 lists treatment-emergent adverse reactions that occurred in at least 5% of patients with epilepsy treated with monotherapy with LAMICTAL in a double-blind trial following discontinuation of either concomitant carbamazepine or phenytoin not seen at an equivalent frequency in the control group.
- Patients in these studies were converted to LAMICTAL or valproate monotherapy from adjunctive therapy with carbamazepine or phenytoin. Patients may have reported multiple adverse reactions during the study; thus, patients may be included in more than one category.
- bUp to 500 mg/day.
- c1,000 mg/day.
- Adverse reactions that occurred with a frequency of less than 5% and greater than 2% of patients receiving LAMICTAL and numerically more frequent than placebo were:
Asthenia, fever.
Anorexia, dry mouth, rectal hemorrhage, peptic ulcer.
Peripheral edema.
Amnesia, ataxia, depression, hypesthesia, libido increase, decreased reflexes, increased reflexes, nystagmus, irritability, suicidal ideation.
Epistaxis, bronchitis, dyspnea.
Contact dermatitis, dry skin, sweating.
Vision abnormality.
- Incidence in Controlled Adjunctive Trials in Pediatric Patients With Epilepsy: Table 11 lists adverse reactions that occurred in at least 2% of 339 pediatric patients with partial seizures or generalized seizures of Lennox-Gastaut syndrome, who received LAMICTAL up to 15 mg/kg/day or a maximum of 750 mg/day. Reported adverse reactions were classified using COSTART terminology.
- Bipolar Disorder: The most commonly observed (≥5%) treatment-emergent adverse reactions seen in association with the use of LAMICTAL as monotherapy (100 to 400 mg/day) in adult patients (≥18 years of age) with Bipolar Disorder in the 2 double-blind, placebo-controlled trials of 18 months’ duration, and numerically more frequent than in placebo-treated patients are included in Table 12. Adverse reactions that occurred in at least 5% of patients and were numerically more common during the dose-escalation phase of LAMICTAL in these trials (when patients may have been receiving concomitant medications) compared with the monotherapy phase were: headache (25%), rash (11%), dizziness (10%), diarrhea (8%), dream abnormality (6%), and pruritus (6%).
- During the monotherapy phase of the double-blind, placebo-controlled trials of 18 months’ duration, 13% of 227 patients who received LAMICTAL (100 to 400 mg/day), 16% of 190 patients who received placebo, and 23% of 166 patients who received lithium discontinued therapy because of an adverse reaction. The adverse reactions which most commonly led to discontinuation of LAMICTAL were rash (3%) and mania/hypomania/mixed mood adverse reactions (2%). Approximately 16% of 2,401 patients who received LAMICTAL (50 to 500 mg/day) for Bipolar Disorder in premarketing trials discontinued therapy because of an adverse reaction, most commonly due to rash (5%) and mania/hypomania/mixed mood adverse reactions (2%).
- The overall adverse reaction profile for LAMICTAL was similar between females and males, between elderly and nonelderly patients, and among racial groups.
- aPatients in these studies were converted to LAMICTAL (100 to 400 mg/day) or placebo monotherapy from add-on therapy with other psychotropic medications. Patients may have reported multiple adverse reactions during the study; thus, patients may be included in more than one category.
- bIn the overall bipolar and other mood disorders clinical trials, the rate of serious rash was 0.08% (1 of 1,233) of adult patients who received LAMICTAL as initial monotherapy and 0.13% (2 of 1,538) of adult patients who received LAMICTAL as adjunctive therapy.
- These adverse reactions were usually mild to moderate in intensity. Other reactions that occurred in 5% or more patients but equally or more frequently in the placebo group included: dizziness, mania, headache, infection, influenza, pain, accidental injury, diarrhea, and dyspepsia.
- Adverse reactions that occurred with a frequency of less than 5% and greater than 1% of patients receiving LAMICTAL and numerically more frequent than placebo were:
Fever, neck pain.
Migraine.
Flatulence.
Weight gain, edema.
Arthralgia, myalgia.
Amnesia, depression, agitation, emotional lability, dyspraxia, abnormal thoughts, dream abnormality, hypoesthesia.
Sinusitis.
Urinary frequency.
- Adverse Reactions Following Abrupt Discontinuation: In the 2 maintenance trials, there was no increase in the incidence, severity, or type of adverse reactions in Bipolar Disorder patients after abruptly terminating therapy with LAMICTAL. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of LAMICTAL. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients.
- Mania/Hypomania/Mixed Episodes: During the double-blind, placebo-controlled clinical trials in Bipolar I Disorder in which patients were converted to monotherapy with LAMICTAL (100 to 400 mg/day) from other psychotropic medications and followed for up to 18 months, the rates of manic or hypomanic or mixed mood episodes reported as adverse reactions were 5% for patients treated with LAMICTAL (n = 227), 4% for patients treated with lithium (n = 166), and 7% for patients treated with placebo (n = 190). In all bipolar controlled trials combined, adverse reactions of mania (including hypomania and mixed mood episodes) were reported in 5% of patients treated with LAMICTAL (n = 956), 3% of patients treated with lithium (n = 280), and 4% of patients treated with placebo (n = 803).
- Other Adverse Reactions Observed in All Clinical Trials
- LAMICTAL has been administered to 6,694 individuals for whom complete adverse reaction data was captured during all clinical trials, only some of which were placebo controlled. During these trials, all adverse reactions were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse reactions, similar types of adverse reactions were grouped into a smaller number of standardized categories using modified COSTART dictionary terminology. The frequencies presented represent the proportion of the 6,694 individuals exposed to LAMICTAL who experienced an event of the type cited on at least one occasion while receiving LAMICTAL. All reported adverse reactions are included except those already listed in the previous tables or elsewhere in the labeling, those too general to be informative, and those not reasonably associated with the use of the drug.
- Adverse reactions are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse reactions are defined as those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients; rare adverse reactions are those occurring in fewer than 1/1,000 patients.
Infrequent: Allergic reaction, chills, and malaise.
Infrequent: Flushing, hot flashes, hypertension, palpitations, postural hypotension, syncope, tachycardia, and vasodilation.
Infrequent: Acne, alopecia, hirsutism, maculopapular rash, skin discoloration, and urticaria. Rare: Angioedema, erythema, exfoliative dermatitis, fungal dermatitis, herpes zoster, leukoderma, multiforme erythema, petechial rash, pustular rash, Stevens-Johnson syndrome, and vesiculobullous rash.
Infrequent: Dysphagia, eructation, gastritis, gingivitis, increased appetite, increased salivation, liver function tests abnormal, and mouth ulceration. Rare: Gastrointestinal hemorrhage, glossitis, gum hemorrhage, gum hyperplasia, hematemesis, hemorrhagic colitis, hepatitis, melena, stomach ulcer, stomatitis, and tongue edema.
Rare: Goiter and hypothyroidism.
Infrequent: Ecchymosis and leukopenia. Rare: Anemia, eosinophilia, fibrin decrease, fibrinogen decrease, iron deficiency anemia, leukocytosis, lymphocytosis, macrocytic anemia, petechia, and thrombocytopenia.
Infrequent: Aspartate transaminase increased. Rare: Alcohol intolerance, alkaline phosphatase increase, alanine transaminase increase, bilirubinemia, general edema, gamma glutamyl transpeptidase increase, and hyperglycemia.
Infrequent: Arthritis, leg cramps, myasthenia, and twitching. Rare: Bursitis, muscle atrophy, pathological fracture, and tendinous contracture.
Frequent: Confusion and paresthesia. Infrequent: Akathisia, apathy, aphasia, central nervous system (CNS) depression, depersonalization, dysarthria, dyskinesia, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, libido decreased, memory decrease, mind racing, movement disorder, myoclonus, panic attack, paranoid reaction, personality disorder, psychosis, sleep disorder, stupor, and suicidal ideation. Rare: Choreoathetosis, delirium, delusions, dysphoria, dystonia, extrapyramidal syndrome, faintness, grand mal convulsions, hemiplegia, hyperalgesia, hyperesthesia, hypokinesia, hypotonia, manic depression reaction, muscle spasm, neuralgia, neurosis, paralysis, and peripheral neuritis.
Infrequent: Yawn. Rare: Hiccup and hyperventilation.
Frequent: Amblyopia. Infrequent: Abnormality of accommodation, conjunctivitis, dry eyes, ear pain, photophobia, taste perversion, and tinnitus. Rare: Deafness, lacrimation disorder, oscillopsia, parosmia, ptosis, strabismus, taste loss, uveitis, and visual field defect.
Infrequent: Abnormal ejaculation, hematuria, impotence, menorrhagia, polyuria, and urinary incontinence. Rare: Acute kidney failure, anorgasmia, breast abscess, breast neoplasm, creatinine increase, cystitis, dysuria, epididymitis, female lactation, kidney failure, kidney pain, nocturia, urinary retention, and urinary urgency.
## Postmarketing Experience
- The following adverse events (not listed above in clinical trials or other sections of the prescribing information) have been identified during postapproval use of LAMICTAL. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Agranulocytosis, hemolytic anemia, lymphadenopathy not associated with hypersensitivity disorder.
Esophagitis.
Pancreatitis.
Lupus-like reaction, vasculitis.
Apnea.
Rhabdomyolysis has been observed in patients experiencing hypersensitivity reactions.
Exacerbation of Parkinsonian symptoms in patients with pre-existing Parkinson’s disease, tics.
Progressive immunosuppression.
# Drug Interactions
- Significant drug interactions with lamotrigine are summarized in Table 13. Additional details of these drug interaction studies are provided in the Clinical Pharmacology section.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- No evidence of teratogenicity was found in mice, rats, or rabbits when lamotrigine was orally administered to pregnant animals during the period of organogenesis at doses up to 1.2, 0.5, and 1.1 times, respectively, on a mg/m2 basis, the highest usual human maintenance dose (i.e., 500 mg/day). However, maternal toxicity and secondary fetal toxicity producing reduced fetal weight and/or delayed ossification were seen in mice and rats, but not in rabbits at these doses. Teratology studies were also conducted using bolus intravenous administration of the isethionate salt of lamotrigine in rats and rabbits. In rat dams administered an intravenous dose at 0.6 times the highest usual human maintenance dose, the incidence of intrauterine death without signs of teratogenicity was increased.
- A behavioral teratology study was conducted in rats dosed during the period of organogenesis. At day 21 postpartum, offspring of dams receiving 5 mg/kg/day or higher displayed a significantly longer latent period for open field exploration and a lower frequency of rearing. In a swimming maze test performed on days 39 to 44 postpartum, time to completion was increased in offspring of dams receiving 25 mg/kg/day. These doses represent 0.1 and 0.5 times the clinical dose on a mg/m2 basis, respectively.
- Lamotrigine did not affect fertility, teratogenesis, or postnatal development when rats were dosed prior to and during mating, and throughout gestation and lactation at doses equivalent to 0.4 times the highest usual human maintenance dose on a mg/m2 basis.
- When pregnant rats were orally dosed at 0.1, 0.14, or 0.3 times the highest human maintenance dose (on a mg/m2 basis) during the latter part of gestation (days 15 to 20), maternal toxicity and fetal death were seen. In dams, food consumption and weight gain were reduced, and the gestation period was slightly prolonged (22.6 vs. 22.0 days in the control group). Stillborn pups were found in all 3 drug-treated groups with the highest number in the high-dose group. Postnatal death was also seen, but only in the 2 highest doses, and occurred between days 1 and 20. Some of these deaths appear to be drug-related and not secondary to the maternal toxicity. A no-observed-effect level (NOEL) could not be determined for this study.
- Although lamotrigine was not found to be teratogenic in the above studies, lamotrigine decreases fetal folate concentrations in rats, an effect known to be associated with teratogenesis in animals and humans. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Non-Teratogenic Effects: As with other AEDs, physiological changes during pregnancy may affect lamotrigine concentrations and/or therapeutic effect. There have been reports of decreased lamotrigine concentrations during pregnancy and restoration of pre-partum concentrations after delivery. Dosage adjustments may be necessary to maintain clinical response.
- Pregnancy Exposure Registry: To provide information regarding the effects of in utero exposure to LAMICTAL, physicians are advised to recommend that pregnant patients taking LAMICTAL enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website /.
- Physicians are also encouraged to register patients in the Lamotrigine Pregnancy Registry; enrollment in this registry must be done prior to any prenatal diagnostic tests and before fetal outcome is known. Physicians can obtain information by calling the Lamotrigine Pregnancy Registry at 1-800-336-2176 (toll-free).
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lamotrigine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Lamotrigine during labor and delivery.
### Nursing Mothers
- Lamotrigine is present in milk from lactating women taking LAMICTAL. Data from multiple small studies indicate that lamotrigine plasma levels in human milk-fed infants have been reported to be as high as 50% of the maternal serum levels. Neonates and young infants are at risk for high serum levels because maternal serum and milk levels can rise to high levels postpartum if lamotrigine dosage has been increased during pregnancy but not later reduced to the pre-pregnancy dosage. Lamotrigine exposure is further increased due to the immaturity of the infant glucuronidation capacity needed for drug clearance. Events including apnea, drowsiness, and poor sucking have been reported in infants who have been human milk-fed by mothers using lamotrigine; whether or not these events were caused by lamotrigine is unknown. Human milk-fed infants should be closely monitored for adverse events resulting from lamotrigine. Measurement of infant serum levels should be performed to rule out toxicity if concerns arise. Human milk-feeding should be discontinued in infants with lamotrigine toxicity. Caution should be exercised when LAMICTAL is administered to a nursing woman.
### Pediatric Use
- LAMICTAL is indicated for adjunctive therapy in patients ≥2 years of age for partial seizures, the generalized seizures of Lennox-Gastaut syndrome, and primary generalized tonic-clonic seizures.
- Safety and efficacy of LAMICTAL, used as adjunctive treatment for partial seizures, were not demonstrated in a small randomized, double-blind, placebo-controlled, withdrawal study in very young pediatric patients (1 to 24 months of age). LAMICTAL was associated with an increased risk for infectious adverse reactions (LAMICTAL 37%, placebo 5%), and respiratory adverse reactions (LAMICTAL 26%, placebo 5%). Infectious adverse reactions included bronchiolitis, bronchitis, ear infection, eye infection, otitis externa, pharyngitis, urinary tract infection, and viral infection. Respiratory adverse reactions included nasal congestion, cough, and apnea.
- Safety and effectiveness in patients below the age of 18 years with Bipolar Disorder have not been established.
### Geriatic Use
- Clinical studies of LAMICTAL for epilepsy and in Bipolar Disorder did not include sufficient numbers of subjects 65 years of age and over to determine whether they respond differently from younger subjects or exhibit a different safety profile than that of younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Lamotrigine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Lamotrigine with respect to specific racial populations.
### Renal Impairment
- Lamotrigine is metabolized mainly by glucuronic acid conjugation, with the majority of the metabolites being recovered in the urine. In a small study comparing a single dose of lamotrigine in patients with varying degrees of renal impairment with healthy volunteers, the plasma half-life of lamotrigine was significantly longer in the patients with renal impairment.
- Initial doses of LAMICTAL should be based on patients’ AED regimens; reduced maintenance doses may be effective for patients with significant renal impairment. Few patients with severe renal impairment have been evaluated during chronic treatment with LAMICTAL. Because there is inadequate experience in this population, LAMICTAL should be used with caution in these patients.
### Hepatic Impairment
- Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment, the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Lamotrigine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Lamotrigine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Lamotrigine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Lamotrigine in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Overdoses involving quantities up to 15 g have been reported for LAMICTAL, some of which have been fatal. Overdose has resulted in ataxia, nystagmus, seizures (including tonic-clonic seizures), decreased level of consciousness, coma, and intraventricular conduction delay.
### Management
- There are no specific antidotes for lamotrigine. Following a suspected overdose, hospitalization of the patient is advised. General supportive care is indicated, including frequent monitoring of vital signs and close observation of the patient. If indicated, emesis should be induced; usual precautions should be taken to protect the airway. It should be kept in mind that lamotrigine is rapidly absorbed. It is uncertain whether hemodialysis is an effective means of removing lamotrigine from the blood. In 6 renal failure patients, about 20% of the amount of lamotrigine in the body was removed by hemodialysis during a 4-hour session. A Poison Control Center should be contacted for information on the management of overdosage of LAMICTAL.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Lamotrigine in the drug label.
# Pharmacology
## Mechanism of Action
- The precise mechanism(s) by which lamotrigine exerts its anticonvulsant action are unknown. In animal models designed to detect anticonvulsant activity, lamotrigine was effective in preventing seizure spread in the maximum electroshock (MES) and pentylenetetrazol (scMet) tests, and prevented seizures in the visually and electrically evoked after-discharge (EEAD) tests for antiepileptic activity. Lamotrigine also displayed inhibitory properties in the kindling model in rats both during kindling development and in the fully kindled state. The relevance of these models to human epilepsy, however, is not known.
- One proposed mechanism of action of lamotrigine, the relevance of which remains to be established in humans, involves an effect on sodium channels. In vitro pharmacological studies suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids (e.g., glutamate and aspartate).
- Although the relevance for human use is unknown, the following data characterize the performance of lamotrigine in receptor binding assays. Lamotrigine had a weak inhibitory effect on the serotonin 5-HT3 receptor (IC50 = 18 µM). It does not exhibit high affinity binding (IC50>100 µM) to the following neurotransmitter receptors: adenosine A1 and A2; adrenergic α1, α2, and β; dopamine D1 and D2; γ-aminobutyric acid (GABA) A and B; histamine H1; kappa opioid; muscarinic acetylcholine; and serotonin 5-HT2. Studies have failed to detect an effect of lamotrigine on dihydropyridine-sensitive calcium channels. It had weak effects at sigma opioid receptors (IC50 = 145 µM). Lamotrigine did not inhibit the uptake of norepinephrine, dopamine, or serotonin (IC50>200 µM) when tested in rat synaptosomes and/or human platelets in vitro.
- Effect of Lamotrigine on N-Methyl d-Aspartate-Receptor Mediated Activity: Lamotrigine did not inhibit N-methyl d-aspartate (NMDA)-induced depolarizations in rat cortical slices or NMDA-induced cyclic GMP formation in immature rat cerebellum, nor did lamotrigine displace compounds that are either competitive or noncompetitive ligands at this glutamate receptor complex (CNQX, CGS, TCHP). The IC50 for lamotrigine effects on NMDA-induced currents (in the presence of 3 µM of glycine) in cultured hippocampal neurons exceeded 100 µM.
- The mechanisms by which lamotrigine exerts its therapeutic action in Bipolar Disorder have not been established.
## Structure
- LAMICTAL (lamotrigine), an AED of the phenyltriazine class, is chemically unrelated to existing AEDs. Its chemical name is 3,5-diamino-6-(2,3-dichlorophenyl)-as-triazine, its molecular formula is C9H7N5Cl2, and its molecular weight is 256.09. Lamotrigine is a white to pale cream-colored powder and has a pKa of 5.7. Lamotrigine is very slightly soluble in water (0.17 mg/mL at 25°C) and slightly soluble in 0.1 M HCl (4.1 mg/mL at 25°C). The structural formula is:
- LAMICTAL Tablets are supplied for oral administration as 25 mg (white), 100 mg (peach), 150 mg (cream), and 200 mg (blue) tablets. Each tablet contains the labeled amount of lamotrigine and the following inactive ingredients: lactose; magnesium stearate; microcrystalline cellulose; povidone; sodium starch glycolate; FD&C Yellow No. 6 Lake (100-mg tablet only); ferric oxide, yellow (150-mg tablet only); and FD&C Blue No. 2 Lake (200-mg tablet only).
- LAMICTAL Chewable Dispersible Tablets are supplied for oral administration. The tablets contain 2 mg (white), 5 mg (white), or 25 mg (white) of lamotrigine and the following inactive ingredients: blackcurrant flavor, calcium carbonate, low-substituted hydroxypropylcellulose, magnesium aluminum silicate, magnesium stearate, povidone, saccharin sodium, and sodium starch glycolate.
- LAMICTAL ODT Orally Disintegrating Tablets are supplied for oral administration. The tablets contain 25 mg (white to off-white), 50 mg (white to off-white), 100 mg (white to off-white), or 200 mg (white to off-white) of lamotrigine and the following inactive ingredients: artificial cherry flavor, crospovidone, ethylcellulose, magnesium stearate, mannitol, polyethylene, and sucralose.
- LAMICTAL ODT Orally Disintegrating Tablets are formulated using technologies (Microcaps® and AdvaTab®) designed to mask the bitter taste of lamotrigine and achieve a rapid dissolution profile. Tablet characteristics including flavor, mouth-feel, after-taste, and ease of use were rated as favorable in a study of 108 healthy volunteers.
## Pharmacodynamics
- Folate Metabolism: In vitro, lamotrigine inhibited dihydrofolate reductase, the enzyme that catalyzes the reduction of dihydrofolate to tetrahydrofolate. Inhibition of this enzyme may interfere with the biosynthesis of nucleic acids and proteins. When oral daily doses of lamotrigine were given to pregnant rats during organogenesis, fetal, placental, and maternal folate concentrations were reduced. Significantly reduced concentrations of folate are associated with teratogenesis. Folate concentrations were also reduced in male rats given repeated oral doses of lamotrigine. Reduced concentrations were partially returned to normal when supplemented with folinic acid.
- Accumulation in Kidneys: Lamotrigine accumulated in the kidney of the male rat, causing chronic progressive nephrosis, necrosis, and mineralization. These findings are attributed to α-2 microglobulin, a species- and sex-specific protein that has not been detected in humans or other animal species.
- Melanin Binding: Lamotrigine binds to melanin-containing tissues, e.g., in the eye and pigmented skin. It has been found in the uveal tract up to 52 weeks after a single dose in rodents.
- Cardiovascular: In dogs, lamotrigine is extensively metabolized to a 2-N-methyl metabolite. This metabolite causes dose-dependent prolongations of the PR interval, widening of the QRS complex, and, at higher doses, complete AV conduction block. Similar cardiovascular effects are not anticipated in humans because only trace amounts of the 2-N-methyl metabolite (<0.6% of lamotrigine dose) have been found in human urine. However, it is conceivable that plasma concentrations of this metabolite could be increased in patients with a reduced capacity to glucuronidate lamotrigine (e.g., in patients with liver disease).
## Pharmacokinetics
- The pharmacokinetics of lamotrigine have been studied in patients with epilepsy, healthy young and elderly volunteers, and volunteers with chronic renal failure. Lamotrigine pharmacokinetic parameters for adult and pediatric patients and healthy normal volunteers are summarized in Tables 14 and 16.
- aThe majority of parameter means determined in each study had coefficients of variation between 20% and 40% for half-life and Cl/F and between 30% and 70% for Tmax. The overall mean values were calculated from individual study means that were weighted based on the number of volunteers/patients in each study. The numbers in parentheses below each parameter mean represent the range of individual volunteer/patient values across studies.
- bCarbamazepine, phenobarbital, phenytoin, and primidone have been shown to increase the apparent clearance of lamotrigine. Estrogen-containing oral contraceptives and other drugs such as rifampin that induce lamotrigine glucuronidation have also been shown to increase the apparent clearance of lamotrigine.
- Absorption: Lamotrigine is rapidly and completely absorbed after oral administration with negligible first-pass metabolism (absolute bioavailability is 98%). The bioavailability is not affected by food. Peak plasma concentrations occur anywhere from 1.4 to 4.8 hours following drug administration. The lamotrigine chewable/dispersible tablets were found to be equivalent, whether they were administered as dispersed in water, chewed and swallowed, or swallowed as whole, to the lamotrigine compressed tablets in terms of rate and extent of absorption. In terms of rate and extent of absorption, lamotrigine orally disintegrating tablets whether disintegrated in the mouth or swallowed whole with water were equivalent to the lamotrigine compressed tablets swallowed with water.
- Dose Proportionality: In healthy volunteers not receiving any other medications and given single doses, the plasma concentrations of lamotrigine increased in direct proportion to the dose administered over the range of 50 to 400 mg. In 2 small studies (n = 7 and 8) of patients with epilepsy who were maintained on other AEDs, there also was a linear relationship between dose and lamotrigine plasma concentrations at steady state following doses of 50 to 350 mg twice daily.
- Distribution: Estimates of the mean apparent volume of distribution (Vd/F) of lamotrigine following oral administration ranged from 0.9 to 1.3 L/kg. Vd/F is independent of dose and is similar following single and multiple doses in both patients with epilepsy and in healthy volunteers.
- Protein Binding: Data from in vitro studies indicate that lamotrigine is approximately 55% bound to human plasma proteins at plasma lamotrigine concentrations from 1 to 10 mcg/mL (10 mcg/mL is 4 to 6 times the trough plasma concentration observed in the controlled efficacy trials). Because lamotrigine is not highly bound to plasma proteins, clinically significant interactions with other drugs through competition for protein binding sites are unlikely. The binding of lamotrigine to plasma proteins did not change in the presence of therapeutic concentrations of phenytoin, phenobarbital, or valproate. Lamotrigine did not displace other AEDs (carbamazepine, phenytoin, phenobarbital) from protein-binding sites.
- Metabolism: Lamotrigine is metabolized predominantly by glucuronic acid conjugation; the major metabolite is an inactive 2-N-glucuronide conjugate. After oral administration of 240 mg of 14C-lamotrigine (15 μCi) to 6 healthy volunteers, 94% was recovered in the urine and 2% was recovered in the feces. The radioactivity in the urine consisted of unchanged lamotrigine (10%), the 2-N-glucuronide (76%), a 5-N-glucuronide (10%), a 2-N-methyl metabolite (0.14%), and other unidentified minor metabolites (4%).
- Enzyme Induction: The effects of lamotrigine on the induction of specific families of mixed-function oxidase isozymes have not been systematically evaluated.
- Following multiple administrations (150 mg twice daily) to normal volunteers taking no other medications, lamotrigine induced its own metabolism, resulting in a 25% decrease in t½ and a 37% increase in Cl/F at steady state compared with values obtained in the same volunteers following a single dose. Evidence gathered from other sources suggests that self-induction by lamotrigine may not occur when lamotrigine is given as adjunctive therapy in patients receiving enzyme-inducing drugs such as carbamazepine, phenytoin, phenobarbital, primidone, or drugs such as rifampin that induce lamotrigine glucuronidation.
- Elimination: The elimination half-life and apparent clearance of lamotrigine following administration of LAMICTAL to adult patients with epilepsy and healthy volunteers is summarized in Table 14. Half-life and apparent oral clearance vary depending on concomitant AEDs.
- Drug Interactions: The apparent clearance of lamotrigine is affected by the coadministration of certain medications.
- The net effects of drug interactions with LAMICTAL are summarized in Tables 13 and 15, followed by details of the drug interaction studies below.
- aFrom adjunctive clinical trials and volunteer studies.
- bNet effects were estimated by comparing the mean clearance values obtained in adjunctive clinical trials and volunteer studies.
- cThe effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated in clinical trials, although the effect may be similar to that seen with the ethinylestradiol/levonorgestrel combinations.
- dModest decrease in levonorgestrel.
- eNot administered, but an active metabolite of carbamazepine.
- fSlight decrease, not expected to be clinically relevant.
- gNot administered, but an active metabolite of oxcarbazepine.
- hSlight increase, not expected to be clinically relevant.
- ↔ = No significant effect.
- ? = Conflicting data.
- Estrogen-Containing Oral Contraceptives: In 16 female volunteers, an oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel increased the apparent clearance of lamotrigine (300 mg/day) by approximately 2-fold with mean decreases in AUC of 52% and in Cmax of 39%. In this study, trough serum lamotrigine concentrations gradually increased and were approximately 2-fold higher on average at the end of the week of the inactive hormone preparation compared with trough lamotrigine concentrations at the end of the active hormone cycle.
- Gradual transient increases in lamotrigine plasma levels (approximate 2-fold increase) occurred during the week of inactive hormone preparation (“pill-free” week) for women not also taking a drug that increased the clearance of lamotrigine (carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation. The increase in lamotrigine plasma levels will be greater if the dose of LAMICTAL is increased in the few days before or during the “pill-free” week. Increases in lamotrigine plasma levels could result in dose-dependent adverse reactions.
- In the same study, coadministration of LAMICTAL (300 mg/day) in 16 female volunteers did not affect the pharmacokinetics of the ethinylestradiol component of the oral contraceptive preparation. There were mean decreases in the AUC and Cmax of the levonorgestrel component of 19% and 12%, respectively. Measurement of serum progesterone indicated that there was no hormonal evidence of ovulation in any of the 16 volunteers, although measurement of serum FSH, LH, and estradiol indicated that there was some loss of suppression of the hypothalamic-pituitary-ovarian axis.
- The effects of doses of LAMICTAL other than 300 mg/day have not been systematically evaluated in controlled clinical trials.
- The clinical significance of the observed hormonal changes on ovulatory activity is unknown. However, the possibility of decreased contraceptive efficacy in some patients cannot be excluded. Therefore, patients should be instructed to promptly report changes in their menstrual pattern (e.g., break-through bleeding).
- Dosage adjustments may be necessary for women receiving estrogen-containing oral contraceptive preparations .
- Other Hormonal Contraceptives or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of LAMICTAL in the presence of progestogens alone will likely not be needed.
- Bupropion: The pharmacokinetics of a 100-mg single dose of LAMICTAL in healthy volunteers (n = 12) were not changed by coadministration of bupropion sustained-release formulation (150 mg twice daily) starting 11 days before LAMICTAL.
- Carbamazepine: LAMICTAL has no appreciable effect on steady-state carbamazepine plasma concentration. Limited clinical data suggest there is a higher incidence of dizziness, diplopia, ataxia, and blurred vision in patients receiving carbamazepine with lamotrigine than in patients receiving other AEDs with lamotrigine . The mechanism of this interaction is unclear. The effect of lamotrigine on plasma concentrations of carbamazepine-epoxide is unclear. In a small subset of patients (n = 7) studied in a placebo-controlled trial, lamotrigine had no effect on carbamazepine-epoxide plasma concentrations, but in a small, uncontrolled study (n = 9), carbamazepine-epoxide levels increased.
- The addition of carbamazepine decreases lamotrigine steady-state concentrations by approximately 40%.
- Felbamate: In a study of 21 healthy volunteers, coadministration of felbamate (1,200 mg twice daily) with lamotrigine (100 mg twice daily for 10 days) appeared to have no clinically relevant effects on the pharmacokinetics of lamotrigine.
- Folate Inhibitors: Lamotrigine is a weak inhibitor of dihydrofolate reductase. Prescribers should be aware of this action when prescribing other medications that inhibit folate metabolism.
- Gabapentin: Based on a retrospective analysis of plasma levels in 34 patients who received lamotrigine both with and without gabapentin, gabapentin does not appear to change the apparent clearance of lamotrigine.
- Levetiracetam: Potential drug interactions between levetiracetam and lamotrigine were assessed by evaluating serum concentrations of both agents during placebo-controlled clinical trials. These data indicate that lamotrigine does not influence the pharmacokinetics of levetiracetam and that levetiracetam does not influence the pharmacokinetics of lamotrigine.
- Lithium: The pharmacokinetics of lithium were not altered in healthy subjects (n = 20) by coadministration of lamotrigine (100 mg/day) for 6 days.
- Olanzapine: The AUC and Cmax of olanzapine were similar following the addition of olanzapine (15 mg once daily) to lamotrigine (200 mg once daily) in healthy male volunteers (n = 16) compared with the AUC and Cmax in healthy male volunteers receiving olanzapine alone (n = 16).
- In the same study, the AUC and Cmax of lamotrigine were reduced on average by 24% and 20%, respectively, following the addition of olanzapine to lamotrigine in healthy male volunteers compared with those receiving lamotrigine alone. This reduction in lamotrigine plasma concentrations is not expected to be clinically relevant.
- Oxcarbazepine: The AUC and Cmax of oxcarbazepine and its active 10-monohydroxy oxcarbazepine metabolite were not significantly different following the addition of oxcarbazepine (600 mg twice daily) to lamotrigine (200 mg once daily) in healthy male volunteers (n = 13) compared with healthy male volunteers receiving oxcarbazepine alone (n = 13).
- In the same study, the AUC and Cmax of lamotrigine were similar following the addition of oxcarbazepine (600 mg twice daily) to LAMICTAL in healthy male volunteers compared with those receiving LAMICTAL alone. Limited clinical data suggest a higher incidence of headache, dizziness, nausea, and somnolence with coadministration of lamotrigine and oxcarbazepine compared with lamotrigine alone or oxcarbazepine alone.
- Phenobarbital, Primidone: The addition of phenobarbital or primidone decreases lamotrigine steady-state concentrations by approximately 40%.
- Phenytoin: Lamotrigine has no appreciable effect on steady-state phenytoin plasma concentrations in patients with epilepsy. The addition of phenytoin decreases lamotrigine steady-state concentrations by approximately 40%.
- Pregabalin: Steady-state trough plasma concentrations of lamotrigine were not affected by concomitant pregabalin (200 mg 3 times daily) administration. There are no pharmacokinetic interactions between lamotrigine and pregabalin.
- Rifampin: In 10 male volunteers, rifampin (600 mg/day for 5 days) significantly increased the apparent clearance of a single 25-mg dose of lamotrigine by approximately 2-fold (AUC decreased by approximately 40%).
- Topiramate: Topiramate resulted in no change in plasma concentrations of lamotrigine. Administration of lamotrigine resulted in a 15% increase in topiramate concentrations.
- Valproate: When lamotrigine was administered to healthy volunteers (n = 18) receiving valproate, the trough steady-state valproate plasma concentrations decreased by an average of 25% over a 3-week period, and then stabilized. However, adding lamotrigine to the existing therapy did not cause a change in valproate plasma concentrations in either adult or pediatric patients in controlled clinical trials.
- The addition of valproate increased lamotrigine steady-state concentrations in normal volunteers by slightly more than 2-fold. In one study, maximal inhibition of lamotrigine clearance was reached at valproate doses between 250 and 500 mg/day and did not increase as the valproate dose was further increased.
- Zonisamide: In a study of 18 patients with epilepsy, coadministration of zonisamide (200 to 400 mg/day) with lamotrigine (150 to 500 mg/day for 35 days) had no significant effect on the pharmacokinetics of lamotrigine.
- Known Inducers or Inhibitors of Glucuronidation: Drugs other than those listed above have not been systematically evaluated in combination with lamotrigine. Since lamotrigine is metabolized predominately by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine may require adjustment based on clinical response.
- Other: Results of in vitro experiments suggest that clearance of lamotrigine is unlikely to be reduced by concomitant administration of amitriptyline, clonazepam, clozapine, fluoxetine, haloperidol, lorazepam, phenelzine, risperidone, sertraline, or trazodone.
- Results of in vitro experiments suggest that lamotrigine does not reduce the clearance of drugs eliminated predominantly by CYP2D6.
- Special Populations:Patients With Renal Impairment: Twelve volunteers with chronic renal failure (mean creatinine clearance: 13 mL/min, range: 6 to 23) and another 6 individuals undergoing hemodialysis were each given a single 100-mg dose of lamotrigine. The mean plasma half-lives determined in the study were 42.9 hours (chronic renal failure), 13.0 hours (during hemodialysis), and 57.4 hours (between hemodialysis) compared with 26.2 hours in healthy volunteers. On average, approximately 20% (range: 5.6 to 35.1) of the amount of lamotrigine present in the body was eliminated by hemodialysis during a 4-hour session .
- Hepatic Disease: The pharmacokinetics of lamotrigine following a single 100-mg dose of lamotrigine were evaluated in 24 subjects with mild, moderate, and severe hepatic impairment (Child-Pugh Classification system) and compared with 12 subjects without hepatic impairment. The patients with severe hepatic impairment were without ascites (n = 2) or with ascites (n = 5). The mean apparent clearances of lamotrigine in patients with mild (n = 12), moderate (n = 5), severe without ascites (n = 2), and severe with ascites (n = 5) liver impairment were 0.30 ± 0.09, 0.24 ± 0.1, 0.21 ± 0.04, and 0.15 ± 0.09 mL/min/kg, respectively, as compared with 0.37 ± 0.1 mL/min/kg in the healthy controls. Mean half-lives of lamotrigine in patients with mild, moderate, severe without ascites, and severe with ascites hepatic impairment were 46 ± 20, 72 ± 44, 67 ± 11, and 100 ± 48 hours, respectively, as compared with 33 ± 7 hours in healthy controls.
- Age: Pediatric Patients: The pharmacokinetics of lamotrigine following a single 2-mg/kg dose were evaluated in 2 studies of pediatric patients (n = 29 for patients 10 months to 5.9 years of age and n = 26 for patients 5 to 11 years of age). Forty-three patients received concomitant therapy with other AEDs and 12 patients received lamotrigine as monotherapy. Lamotrigine pharmacokinetic parameters for pediatric patients are summarized in Table 16.
- Population pharmacokinetic analyses involving patients 2 to 18 years of age demonstrated that lamotrigine clearance was influenced predominantly by total body weight and concurrent AED therapy. The oral clearance of lamotrigine was higher, on a body weight basis, in pediatric patients than in adults. Weight-normalized lamotrigine clearance was higher in those subjects weighing less than 30 kg, compared with those weighing greater than 30 kg. Accordingly, patients weighing less than 30 kg may need an increase of as much as 50% in maintenance doses, based on clinical response, as compared with subjects weighing more than 30 kg being administered the same AEDs. These analyses also revealed that, after accounting for body weight, lamotrigine clearance was not significantly influenced by age. Thus, the same weight-adjusted doses should be administered to children irrespective of differences in age. Concomitant AEDs which influence lamotrigine clearance in adults were found to have similar effects in children.
- aCarbamazepine, phenobarbital, phenytoin, and primidone have been shown to increase the apparent clearance of lamotrigine. Estrogen-containing oral contraceptives and rifampin have also been shown to increase the apparent clearance of lamotrigine .
- bTwo subjects were included in the calculation for mean Tmax.
- cParameter not estimated.
- Elderly: The pharmacokinetics of lamotrigine following a single 150-mg dose of LAMICTAL were evaluated in 12 elderly volunteers between the ages of 65 and 76 years (mean creatinine clearance = 61 mL/min, range: 33 to 108 mL/min). The mean half-life of lamotrigine in these subjects was 31.2 hours (range: 24.5 to 43.4 hours), and the mean clearance was 0.40 mL/min/kg (range: 0.26 to 0.48 mL/min/kg).
- Gender: The clearance of lamotrigine is not affected by gender. However, during dose escalation of LAMICTAL in one clinical trial in patients with epilepsy on a stable dose of valproate (n = 77), mean trough lamotrigine concentrations, unadjusted for weight, were 24% to 45% higher (0.3 to 1.7 mcg/mL) in females than in males.
- Race: The apparent oral clearance of lamotrigine was 25% lower in non-Caucasians than Caucasians.
## Nonclinical Toxicology
- No evidence of carcinogenicity was seen in 1 mouse study or 2 rat studies following oral administration of lamotrigine for up to 2 years at maximum tolerated doses (30 mg/kg/day for mice and 10 to 15 mg/kg/day for rats, doses that are equivalent to 90 mg/m2 and 60 to 90 mg/m2, respectively). Steady-state plasma concentrations ranged from 1 to 4 mcg/mL in the mouse study and 1 to 10 mcg/mL in the rat study. Plasma concentrations associated with the recommended human doses of 300 to 500 mg/day are generally in the range of 2 to 5 mcg/mL, but concentrations as high as 19 mcg/mL have been recorded.
- Lamotrigine was not mutagenic in the presence or absence of metabolic activation when tested in 2 gene mutation assays (the Ames test and the in vitro mammalian mouse lymphoma assay). In 2 cytogenetic assays (the in vitro human lymphocyte assay and the in vivo rat bone marrow assay), lamotrigine did not increase the incidence of structural or numerical chromosomal abnormalities.
- No evidence of impairment of fertility was detected in rats given oral doses of lamotrigine up to 2.4 times the highest usual human maintenance dose of 8.33 mg/kg/day or 0.4 times the human dose on a mg/m2 basis. The effect of lamotrigine on human fertility is unknown.
# Clinical Studies
- Monotherapy With LAMICTAL in Adults With Partial Seizures Already Receiving Treatment With Carbamazepine, Phenytoin, Phenobarbital, or Primidone as the Single Antiepileptic Drug: The effectiveness of monotherapy with LAMICTAL was established in a multicenter, double-blind clinical trial enrolling 156 adult outpatients with partial seizures. The patients experienced at least 4 simple partial, complex partial, and/or secondarily generalized seizures during each of 2 consecutive 4-week periods while receiving carbamazepine or phenytoin monotherapy during baseline. LAMICTAL (target dose of 500 mg/day) or valproate (1,000 mg/day) was added to either carbamazepine or phenytoin monotherapy over a 4-week period. Patients were then converted to monotherapy with LAMICTAL or valproate during the next 4 weeks, then continued on monotherapy for an additional 12-week period.
- Study endpoints were completion of all weeks of study treatment or meeting an escape criterion. Criteria for escape relative to baseline were: (1) doubling of average monthly seizure count, (2) doubling of highest consecutive 2-day seizure frequency, (3) emergence of a new seizure type (defined as a seizure that did not occur during the 8-week baseline) that is more severe than seizure types that occur during study treatment, or (4) clinically significant prolongation of generalized tonic-clonic seizures. The primary efficacy variable was the proportion of patients in each treatment group who met escape criteria.
- The percentages of patients who met escape criteria were 42% (32/76) in the group receiving LAMICTAL and 69% (55/80) in the valproate group. The difference in the percentage of patients meeting escape criteria was statistically significant (P = 0.0012) in favor of LAMICTAL. No differences in efficacy based on age, sex, or race were detected.
- Patients in the control group were intentionally treated with a relatively low dose of valproate; as such, the sole objective of this study was to demonstrate the effectiveness and safety of monotherapy with LAMICTAL, and cannot be interpreted to imply the superiority of LAMICTAL to an adequate dose of valproate.
- Adjunctive Therapy With LAMICTAL in Adults With Partial Seizures: The effectiveness of LAMICTAL as adjunctive therapy (added to other AEDs) was established in 3 multicenter, placebo-controlled, double-blind clinical trials in 355 adults with refractory partial seizures. The patients had a history of at least 4 partial seizures per month in spite of receiving one or more AEDs at therapeutic concentrations and, in 2 of the studies, were observed on their established AED regimen during baselines that varied between 8 to 12 weeks. In the third, patients were not observed in a prospective baseline. In patients continuing to have at least 4 seizures per month during the baseline, LAMICTAL or placebo was then added to the existing therapy. In all 3 studies, change from baseline in seizure frequency was the primary measure of effectiveness. The results given below are for all partial seizures in the intent-to-treat population (all patients who received at least one dose of treatment) in each study, unless otherwise indicated. The median seizure frequency at baseline was 3 per week while the mean at baseline was 6.6 per week for all patients enrolled in efficacy studies.
- One study (n = 216) was a double-blind, placebo-controlled, parallel trial consisting of a 24-week treatment period. Patients could not be on more than 2 other anticonvulsants and valproate was not allowed. Patients were randomized to receive placebo, a target dose of 300 mg/day of LAMICTAL, or a target dose of 500 mg/day of LAMICTAL. The median reductions in the frequency of all partial seizures relative to baseline were 8% in patients receiving placebo, 20% in patients receiving 300 mg/day of LAMICTAL, and 36% in patients receiving 500 mg/day of LAMICTAL. The seizure frequency reduction was statistically significant in the 500-mg/day group compared with the placebo group, but not in the 300-mg/day group.
- A second study (n = 98) was a double-blind, placebo-controlled, randomized, crossover trial consisting of two 14-week treatment periods (the last 2 weeks of which consisted of dose tapering) separated by a 4-week washout period. Patients could not be on more than 2 other anticonvulsants and valproate was not allowed. The target dose of LAMICTAL was 400 mg/day. When the first 12 weeks of the treatment periods were analyzed, the median change in seizure frequency was a 25% reduction on LAMICTAL compared with placebo (P<0.001).
- The third study (n = 41) was a double-blind, placebo-controlled, crossover trial consisting of two 12-week treatment periods separated by a 4-week washout period. Patients could not be on more than 2 other anticonvulsants. Thirteen patients were on concomitant valproate; these patients received 150 mg/day of LAMICTAL. The 28 other patients had a target dose of 300 mg/day of LAMICTAL. The median change in seizure frequency was a 26% reduction on LAMICTAL compared with placebo (P<0.01).
- No differences in efficacy based on age, sex, or race, as measured by change in seizure frequency, were detected.
- Adjunctive Therapy With LAMICTAL in Pediatric Patients With Partial Seizures: The effectiveness of LAMICTAL as adjunctive therapy in pediatric patients with partial seizures was established in a multicenter, double-blind, placebo-controlled trial in 199 patients 2 to 16 years of age (n = 98 on LAMICTAL, n = 101 on placebo). Following an 8-week baseline phase, patients were randomized to 18 weeks of treatment with LAMICTAL or placebo added to their current AED regimen of up to 2 drugs. Patients were dosed based on body weight and valproate use. Target doses were designed to approximate 5 mg/kg/day for patients taking valproate (maximum dose: 250 mg/day) and 15 mg/kg/day for the patients not taking valproate (maximum dose: 750 mg/day). The primary efficacy endpoint was percentage change from baseline in all partial seizures. For the intent-to-treat population, the median reduction of all partial seizures was 36% in patients treated with LAMICTAL and 7% on placebo, a difference that was statistically significant (P<0.01).
- Adjunctive Therapy With LAMICTAL in Pediatric and Adult Patients With Lennox-Gastaut Syndrome: The effectiveness of LAMICTAL as adjunctive therapy in patients with Lennox-Gastaut syndrome was established in a multicenter, double-blind, placebo-controlled trial in 169 patients 3 to 25 years of age (n = 79 on LAMICTAL, n = 90 on placebo). Following a 4-week single-blind, placebo phase, patients were randomized to 16 weeks of treatment with LAMICTAL or placebo added to their current AED regimen of up to 3 drugs. Patients were dosed on a fixed-dose regimen based on body weight and valproate use. Target doses were designed to approximate 5 mg/kg/day for patients taking valproate (maximum dose: 200 mg/day) and 15 mg/kg/day for patients not taking valproate (maximum dose: 400 mg/day). The primary efficacy endpoint was percentage change from baseline in major motor seizures (atonic, tonic, major myoclonic, and tonic-clonic seizures). For the intent-to-treat population, the median reduction of major motor seizures was 32% in patients treated with LAMICTAL and 9% on placebo, a difference that was statistically significant (P<0.05). Drop attacks were significantly reduced by LAMICTAL (34%) compared with placebo (9%), as were tonic-clonic seizures (36% reduction versus 10% increase for LAMICTAL and placebo, respectively).
- Adjunctive Therapy With LAMICTAL in Pediatric and Adult Patients With Primary Generalized Tonic-Clonic Seizures: The effectiveness of LAMICTAL as adjunctive therapy in patients with primary generalized tonic-clonic seizures was established in a multicenter, double-blind, placebo-controlled trial in 117 pediatric and adult patients ≥2 years (n = 58 on LAMICTAL, n = 59 on placebo). Patients with at least 3 primary generalized tonic-clonic seizures during an 8-week baseline phase were randomized to 19 to 24 weeks of treatment with LAMICTAL or placebo added to their current AED regimen of up to 2 drugs. Patients were dosed on a fixed-dose regimen, with target doses ranging from 3 mg/kg/day to 12 mg/kg/day for pediatric patients and from 200 mg/day to 400 mg/day for adult patients based on concomitant AED.
- The primary efficacy endpoint was percentage change from baseline in primary generalized tonic-clonic seizures. For the intent-to-treat population, the median percent reduction of primary generalized tonic-clonic seizures was 66% in patients treated with LAMICTAL and 34% on placebo, a difference that was statistically significant (P = 0.006).
- The effectiveness of LAMICTAL in the maintenance treatment of Bipolar I Disorder was established in 2 multicenter, double-blind, placebo-controlled studies in adult patients who met DSM-IV criteria for Bipolar I Disorder. Study 1 enrolled patients with a current or recent (within 60 days) depressive episode as defined by DSM-IV and Study 2 included patients with a current or recent (within 60 days) episode of mania or hypomania as defined by DSM-IV. Both studies included a cohort of patients (30% of 404 patients in Study 1 and 28% of 171 patients in Study 2) with rapid cycling Bipolar Disorder (4 to 6 episodes per year).
- In both studies, patients were titrated to a target dose of 200 mg of LAMICTAL, as add-on therapy or as monotherapy, with gradual withdrawal of any psychotropic medications during an 8- to 16-week open-label period. Overall 81% of 1,305 patients participating in the open-label period were receiving 1 or more other psychotropic medications, including benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), atypical antipsychotics (including olanzapine), valproate, or lithium, during titration of LAMICTAL. Patients with a CGI-severity score of 3 or less maintained for at least 4 continuous weeks, including at least the final week on monotherapy with LAMICTAL, were randomized to a placebo-controlled, double-blind treatment period for up to 18 months. The primary endpoint was TIME (time to intervention for a mood episode or one that was emerging, time to discontinuation for either an adverse event that was judged to be related to Bipolar Disorder, or for lack of efficacy). The mood episode could be depression, mania, hypomania, or a mixed episode.
- In Study 1, patients received double-blind monotherapy with LAMICTAL 50 mg/day (n = 50), LAMICTAL 200 mg/day (n = 124), LAMICTAL 400 mg/day (n = 47), or placebo (n = 121). LAMICTAL (200- and 400-mg/day treatment groups combined) was superior to placebo in delaying the time to occurrence of a mood episode. Separate analyses of the 200- and 400-mg/day dose groups revealed no added benefit from the higher dose.
- In Study 2, patients received double-blind monotherapy with LAMICTAL (100 to 400 mg/day, n = 59), or placebo (n = 70). LAMICTAL was superior to placebo in delaying time to occurrence of a mood episode. The mean dose of LAMICTAL was about 211 mg/day.
- Although these studies were not designed to separately evaluate time to the occurrence of depression or mania, a combined analysis for the 2 studies revealed a statistically significant benefit for LAMICTAL over placebo in delaying the time to occurrence of both depression and mania, although the finding was more robust for depression.
# How Supplied
- 25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25”, bottles of 100 (NDC 0173-0633-02).
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) in a dry place.
- 100 mg, peach, scored, shield-shaped tablets debossed with “LAMICTAL” and “100”, bottles of 100 (NDC 0173-0642-55).
- 150 mg, cream, scored, shield-shaped tablets debossed with “LAMICTAL” and “150”, bottles of 60 (NDC 0173-0643-60).
- 200 mg, blue, scored, shield-shaped tablets debossed with “LAMICTAL” and “200”, bottles of 60 (NDC 0173-0644-60).
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) in a dry place and protect from light.
- 25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25”, blisterpack of 35 tablets (NDC 0173-0633-10).
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) in a dry place.
- 25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25” and 100 mg, peach, scored, shield-shaped tablets debossed with “LAMICTAL” and “100”, blisterpack of 98 tablets (84/25-mg tablets and 14/100-mg tablets) (NDC 0173-0817-28).
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) in a dry place and protect from light.
- 25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25” and 100 mg, peach, scored, shield-shaped tablets debossed with “LAMICTAL” and “100”, blisterpack of 49 tablets (42/25-mg tablets and 7/100-mg tablets) (NDC 0173-0594-02).
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) in a dry place and protect from light.
- 2 mg, white to off-white, round tablets debossed with “LTG” over “2”, bottles of 30 (NDC 0173-0699-00). ORDER DIRECTLY FROM GlaxoSmithKline 1-800-334-4153.
- 5 mg, white to off-white, caplet-shaped tablets debossed with “GX CL2”, bottles of 100 (NDC 0173-0526-00).
- 25 mg, white, super elliptical-shaped tablets debossed with “GX CL5”, bottles of 100 (NDC 0173-0527-00).
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) in a dry place.
- 25 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with “LMT” on one side and “25” on the other, Maintenance Packs of 30 (NDC 0173-0772-02).
- 50 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with “LMT” on one side and “50” on the other, Maintenance Packs of 30 (NDC 0173-0774-02).
- 100 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with “LAMICTAL” on one side and “100” on the other, Maintenance Packs of 30 (NDC 0173-0776-02).
- 200 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with “LAMICTAL” on one side and “200” on the other, Maintenance Packs of 30 (NDC 0173-0777-02).
- Store between 20°C to 25°C (68°F to 77°F); with excursions permitted between 15°C and 30°C (59°F and 86°F).
- 25 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with “LMT” on one side and “25” on the other, and 50 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with “LMT” on one side and “50” on the other, blisterpack of 28 tablets (21/25-mg tablets and 7/50-mg tablets) (NDC 0173-0779-00).
- 50 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with “LMT” on one side and “50” on the other, and 100 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with “LAMICTAL” on one side and “100” on the other, blisterpack of 56 tablets (42/50-mg tablets and 14/100-mg tablets) (NDC 0173-0780-00).
- 25 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with “LMT” on one side and “25” on the other, 50 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with “LMT” on one side and “50” on the other, and 100 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with “LAMICTAL” on one side and “100” on the other, blisterpack of 35 (14/25-mg tablets, 14/50-mg tablets, and 7/100-mg tablets) (NDC 0173-0778-00).
- Store between 20°C to 25°C (68°F to 77°F); with excursions permitted between 15°C and 30°C (59°F and 86°F).
- Blisterpacks: If the product is dispensed in a blisterpack, the patient should be advised to examine the blisterpack before use and not use if blisters are torn, broken, or missing.
## Storage
There is limited information regarding Lamotrigine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Rash
- Prior to initiation of treatment with LAMICTAL, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a physician immediately.
- Multiorgan Hypersensitivity Reactions, Blood Dyscrasias, and Organ Failure
- Patients should be instructed that multiorgan hypersensitivity reactions and acute multiorgan failure may occur with LAMICTAL. Isolated organ failure or isolated blood dyscrasias without evidence of multiorgan hypersensitivity may also occur. Patients should contact their physician immediately if they experience any signs or symptoms of these conditions.
- Suicidal Thinking and Behavior
- Patients, their caregivers, and families should be counseled that AEDs, including LAMICTAL, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
- Worsening of Seizures
- Patients should be advised to notify their physician if worsening of seizure control occurs.
- Central Nervous System Adverse Effects
- Patients should be advised that LAMICTAL may cause dizziness, somnolence, and other symptoms and signs of CNS depression. Accordingly, they should be advised neither to drive a car nor to operate other complex machinery until they have gained sufficient experience on LAMICTAL to gauge whether or not it adversely affects their mental and/or motor performance.
- Pregnancy and Nursing
- Patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy. Patients should be advised to notify their physicians if they intend to breastfeed or are breastfeeding an infant.
- Patients should also be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334].
- Patients who intend to breastfeed should be informed that LAMICTAL is present in breast milk and that they should monitor their child for potential adverse effects of this drug. Benefits and risks of continuing breastfeeding should be discussed with the patient.
- Oral Contraceptive Use
- Women should be advised to notify their physician if they plan to start or stop use of oral contraceptives or other female hormonal preparations. Starting estrogen-containing oral contraceptives may significantly decrease lamotrigine plasma levels and stopping estrogen-containing oral contraceptives (including the “pill-free” week) may significantly increase lamotrigine plasma levels. Women should also be advised to promptly notify their physician if they experience adverse reactions or changes in menstrual pattern (e.g., break-through bleeding) while receiving LAMICTAL in combination with these medications.
- Discontinuing LAMICTAL
- Patients should be advised to notify their physician if they stop taking LAMICTAL for any reason and not to resume LAMICTAL without consulting their physician.
- Aseptic Meningitis
- Patients should be advised that LAMICTAL may cause aseptic meningitis. Patients should be advised to notify their physician immediately if they develop signs and symptoms of meningitis such as headache, fever, nausea, vomiting, stiff neck, rash, abnormal sensitivity to light, myalgia, chills, confusion, or drowsiness while taking LAMICTAL.
- Potential Medication Errors
- Medication errors involving LAMICTAL have occurred. In particular the names LAMICTAL or lamotrigine can be confused with the names of other commonly used medications. Medication errors may also occur between the different formulations of LAMICTAL. To reduce the potential of medication errors, write and say LAMICTAL clearly. Depictions of the LAMICTAL Tablets, Chewable Dispersible Tablets, and Orally Disintegrating Tablets can be found in the Medication Guide that accompanies the product to highlight the distinctive markings, colors, and shapes that serve to identify the different presentations of the drug and thus may help reduce the risk of medication errors. To avoid a medication error of using the wrong drug or formulation, patients should be strongly advised to visually inspect their tablets to verify that they are LAMICTAL, as well as the correct formulation of LAMICTAL, each time they fill their prescription.
# Precautions with Alcohol
- Alcohol-Lamotrigine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- LAMICTAL®
# Look-Alike Drug Names
- LaMICtal® — LamISIL®
- lamoTRIgine® — lamiVUDine®
- lamoTRIgine® — levothyroxine®
# Drug Shortage Status
# Price | Lamotrigine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Black Box Warning
# Overview
Lamotrigine is an antipileptic drug that is FDA approved for the {{{indicationType}}} of partial seizures, primary generalized tonic-clonic seizures, generalized seizures of Lennox-Gastaut syndrome, epilepsy-monotherapy in patients ≥16 years of age, maintenance treatment of bipolar I disorder. There is a Black Box Warning for this drug as shown here. Common adverse reactions include dizziness, headache, diplopia, ataxia, nausea, blurred vision, rhinitis, rash, vomiting, infection, fever, accidental injury, pharyngitis, tremor, insomnia, somnolence, back pain, fatigue, abdominal pain, and xerostomia..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Adjunctive Therapy: LAMICTAL is indicated as adjunctive therapy for the following seizure types in patients ≥2 years of age:
- partial seizures
- primary generalized tonic-clonic seizures
- generalized seizures of Lennox-Gastaut syndrome
- Monotherapy: LAMICTAL is indicated for conversion to monotherapy in adults (≥16 years of age) with partial seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (AED).
- Safety and effectiveness of LAMICTAL have not been established (1) as initial monotherapy; (2) for conversion to monotherapy from AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate; or (3) for simultaneous conversion to monotherapy from 2 or more concomitant AEDs.
- LAMICTAL is indicated for the maintenance treatment of Bipolar I Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in adults (≥18 years of age) treated for acute mood episodes with standard therapy. The effectiveness of LAMICTAL in the acute treatment of mood episodes has not been established.
- The effectiveness of LAMICTAL as maintenance treatment was established in 2 placebo-controlled trials in patients with Bipolar I Disorder as defined by DSM-IV [see Clinical Studies (14.2)]. The physician who elects to prescribe LAMICTAL for periods extending beyond 16 weeks should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lamotrigine in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Lamotrigine, initiated at 25 mg per day and titrated up to 250 mg/day.
- Dosing Information
Lamotrigine was initially started at 0.2 mg/kg twice daily and gradually increased to a maximum of 5 mg/kg.
- Dosing Information
- Lamotrigine 100 mg daily.
- Dosing Information
- Initial dosing of lamotrigine was 25 mg/day titrated every 2 weeks until the maintenance dose of 150 to 200 mg/day was reached.
- Dosing Information
- Lamotrigine 25 mg/day with increments of 25 mg/week to a dose of 100 mg/day at week 4.
- Dosing Information
- Lamotrigine 400 mg/day.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Adjunctive Therapy: LAMICTAL is indicated as adjunctive therapy for the following seizure types in patients ≥2 years of age:
- partial seizures
- primary generalized tonic-clonic seizures
- generalized seizures of Lennox-Gastaut syndrome
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lamotrigine in pediatric patients.
### Non–Guideline-Supported Use
- Dosing Information
- Patients were titrated on lamotrigine with a mean final dose of 132 +/- 31 mg/day.
- Dosing Information
- In neonates who were taking enzyme-inducing agents, doses up to 10 mg/kg/day were prescribed. In infants between 1 and 12 months of age, who were taking enzyme-inducing agents, final doses ranged between 10 to 20 mg/kg/day. Infants between 1 and 12 months of age, taking valproate and enzyme inducers, were dosed between 5 to 10 mg/kg/day. In infants between 1 and 12 months of age, taking valproate alone, 5 mg/kg/day was the final dose.
- Dosing Information
Lamotrigine starting daily dose was 0.2 to 2.5 mg/kg titrated over 2 to 4 weeks to an initial maintenance dose of 0.75 to 10 mg/kg.
# Contraindications
- LAMICTAL is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.
# Warnings
### Precautions
- Serious Skin Rashes
- Pediatric Population: The incidence of serious rash associated with hospitalization and discontinuation of LAMICTAL in a prospectively followed cohort of pediatric patients (2 to 16 years of age) with epilepsy receiving adjunctive therapy was approximately 0.8% (16 of 1,983). When 14 of these cases were reviewed by 3 expert dermatologists, there was considerable disagreement as to their proper classification. To illustrate, one dermatologist considered none of the cases to be Stevens-Johnson syndrome; another assigned 7 of the 14 to this diagnosis. There was 1 rash-related death in this 1,983-patient cohort. Additionally, there have been rare cases of toxic epidermal necrolysis with and without permanent sequelae and/or death in US and foreign postmarketing experience.
- There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in pediatric patients. In pediatric patients who used valproate concomitantly, 1.2% (6 of 482) experienced a serious rash compared with 0.6% (6 of 952) patients not taking valproate.
- Adult Population: Serious rash associated with hospitalization and discontinuation of LAMICTAL occurred in 0.3% (11 of 3,348) of adult patients who received LAMICTAL in premarketing clinical trials of epilepsy. In the bipolar and other mood disorders clinical trials, the rate of serious rash was 0.08% (1 of 1,233) of adult patients who received LAMICTAL as initial monotherapy and 0.13% (2 of 1,538) of adult patients who received LAMICTAL as adjunctive therapy. No fatalities occurred among these individuals. However, in worldwide postmarketing experience, rare cases of rash-related death have been reported, but their numbers are too few to permit a precise estimate of the rate.
- Among the rashes leading to hospitalization were Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, and those associated with multiorgan hypersensitivity.
- There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in adults. Specifically, of 584 patients administered LAMICTAL with valproate in epilepsy clinical trials, 6 (1%) were hospitalized in association with rash; in contrast, 4 (0.16%) of 2,398 clinical trial patients and volunteers administered LAMICTAL in the absence of valproate were hospitalized.
- Patients With History of Allergy or Rash to Other Antiepileptic Drugs: The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of LAMICTAL is exceeded and in patients with a history of allergy or rash to other AEDs.
- Multiorgan Hypersensitivity Reactions and Organ Failure
- Multiorgan hypersensitivity reactions, also known as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have occurred with LAMICTAL. Some have been fatal or life threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved.
- Fatalities associated with acute multiorgan failure and various degrees of hepatic failure have been reported in 2 of 3,796 adult patients and 4 of 2,435 pediatric patients who received LAMICTAL in epilepsy clinical trials. Rare fatalities from multiorgan failure have also been reported in postmarketing use.
- Isolated liver failure without rash or involvement of other organs has also been reported with LAMICTAL.
- It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though a rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. LAMICTAL should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
- Prior to initiation of treatment with LAMICTAL, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a physician immediately.
- Blood Dyscrasias
- There have been reports of blood dyscrasias that may or may not be associated with multiorgan hypersensitivity (also known as DRESS). These have included neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia.
- Suicidal Behavior and Ideation
- AEDs, including LAMICTAL, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
- Pooled analyses of 199 placebo-controlled clinical trials (monotherapy and adjunctive therapy) of 11 different AEDs showed that patients randomized to 1 of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately 1 case of suicidal thinking or behavior for every 530 patients treated. There were 4 suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number of events is too small to allow any conclusion about drug effect on suicide.
- The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
- The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanism of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.
- Table 7 shows absolute and relative risk by indication for all evaluated AEDs.
- The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
- Anyone considering prescribing LAMICTAL or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
- Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
- Use in Patients With Bipolar Disorder
- Acute Treatment of Mood Episodes: Safety and effectiveness of LAMICTAL in the acute treatment of mood episodes have not been established.
- Children and Adolescents (less than 18 years of age): Safety and effectiveness of LAMICTAL in patients below the age of 18 years with mood disorders have not been established.
- Clinical Worsening and Suicide Risk Associated With Bipolar Disorder: Patients with bipolar disorder may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviors (suicidality) whether or not they are taking medications for bipolar disorder. Patients should be closely monitored for clinical worsening (including development of new symptoms) and suicidality, especially at the beginning of a course of treatment or at the time of dose changes.
- In addition, patients with a history of suicidal behavior or thoughts, those patients exhibiting a significant degree of suicidal ideation prior to commencement of treatment, and young adults are at an increased risk of suicidal thoughts or suicide attempts and should receive careful monitoring during treatment.
- Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who experience clinical worsening (including development of new symptoms) and/or the emergence of suicidal ideation/behavior especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
- Prescriptions for LAMICTAL should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose. Overdoses have been reported for LAMICTAL, some of which have been fatal.
- Aseptic Meningitis
- Therapy with LAMICTAL increases the risk of developing aseptic meningitis. Because of the potential for serious outcomes of untreated meningitis due to other causes, patients should also be evaluated for other causes of meningitis and treated as appropriate.
- Postmarketing cases of aseptic meningitis have been reported in pediatric and adult patients taking LAMICTAL for various indications. Symptoms upon presentation have included headache, fever, nausea, vomiting, and nuchal rigidity. Rash, photophobia, myalgia, chills, altered consciousness, and somnolence were also noted in some cases. Symptoms have been reported to occur within 1 day to one and a half months following the initiation of treatment. In most cases, symptoms were reported to resolve after discontinuation of LAMICTAL. Re-exposure resulted in a rapid return of symptoms (from within 30 minutes to 1 day following re-initiation of treatment) that were frequently more severe. Some of the patients treated with LAMICTAL who developed aseptic meningitis had underlying diagnoses of systemic lupus erythematosus or other autoimmune diseases.
- Cerebrospinal fluid (CSF) analyzed at the time of clinical presentation in reported cases was characterized by a mild to moderate pleocytosis, normal glucose levels, and mild to moderate increase in protein. CSF white blood cell count differentials showed a predominance of neutrophils in a majority of the cases, although a predominance of lymphocytes was reported in approximately one third of the cases. Some patients also had new onset of signs and symptoms of involvement of other organs (predominantly hepatic and renal involvement), which may suggest that in these cases the aseptic meningitis observed was part of a hypersensitivity reaction.
- Potential Medication Errors
- Medication errors involving LAMICTAL have occurred. In particular, the names LAMICTAL or lamotrigine can be confused with the names of other commonly used medications. Medication errors may also occur between the different formulations of LAMICTAL. To reduce the potential of medication errors, write and say LAMICTAL clearly. Depictions of the LAMICTAL Tablets, Chewable Dispersible Tablets, and Orally Disintegrating Tablets can be found in the Medication Guide that accompanies the product to highlight the distinctive markings, colors, and shapes that serve to identify the different presentations of the drug and thus may help reduce the risk of medication errors. To avoid the medication error of using the wrong drug or formulation, patients should be strongly advised to visually inspect their tablets to verify that they are LAMICTAL, as well as the correct formulation of LAMICTAL, each time they fill their prescription.
- Concomitant Use With Oral Contraceptives
- Some estrogen-containing oral contraceptives have been shown to decrease serum concentrations of lamotrigine. Dosage adjustments will be necessary in most patients who start or stop estrogen-containing oral contraceptives while taking LAMICTAL. During the week of inactive hormone preparation (“pill-free” week) of oral contraceptive therapy, plasma lamotrigine levels are expected to rise, as much as doubling at the end of the week. Adverse reactions consistent with elevated levels of lamotrigine, such as dizziness, ataxia, and diplopia, could occur.
- Withdrawal Seizures
- As with other AEDs, LAMICTAL should not be abruptly discontinued. In patients with epilepsy there is a possibility of increasing seizure frequency. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of LAMICTAL; however, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Unless safety concerns require a more rapid withdrawal, the dose of LAMICTAL should be tapered over a period of at least 2 weeks (approximately 50% reduction per week) .
- Status Epilepticus
- Valid estimates of the incidence of treatment-emergent status epilepticus among patients treated with LAMICTAL are difficult to obtain because reporters participating in clinical trials did not all employ identical rules for identifying cases. At a minimum, 7 of 2,343 adult patients had episodes that could unequivocally be described as status epilepticus. In addition, a number of reports of variably defined episodes of seizure exacerbation (e.g., seizure clusters, seizure flurries) were made.
- Sudden Unexplained Death in Epilepsy (SUDEP)
- During the premarketing development of LAMICTAL, 20 sudden and unexplained deaths were recorded among a cohort of 4,700 patients with epilepsy (5,747 patient-years of exposure).
- Some of these could represent seizure-related deaths in which the seizure was not observed, e.g., at night. This represents an incidence of 0.0035 deaths per patient-year. Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving LAMICTAL (ranging from 0.0005 for the general population of patients with epilepsy, to 0.004 for a recently studied clinical trial population similar to that in the clinical development program for LAMICTAL, to 0.005 for patients with refractory epilepsy). Consequently, whether these figures are reassuring or suggest concern depends on the comparability of the populations reported upon to the cohort receiving LAMICTAL and the accuracy of the estimates provided. Probably most reassuring is the similarity of estimated SUDEP rates in patients receiving LAMICTAL and those receiving other AEDs, chemically unrelated to each other, that underwent clinical testing in similar populations. Importantly, that drug is chemically unrelated to LAMICTAL. This evidence suggests, although it certainly does not prove, that the high SUDEP rates reflect population rates, not a drug effect.
- Addition of LAMICTAL to a Multidrug Regimen That Includes Valproate
- Because valproate reduces the clearance of lamotrigine, the dosage of lamotrigine in the presence of valproate is less than half of that required in its absence.
- Binding in the Eye and Other Melanin-Containing Tissues
- Because lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over time. This raises the possibility that lamotrigine may cause toxicity in these tissues after extended use. Although ophthalmological testing was performed in 1 controlled clinical trial, the testing was inadequate to exclude subtle effects or injury occurring after long-term exposure. Moreover, the capacity of available tests to detect potentially adverse consequences, if any, of lamotrigine’s binding to melanin is unknown.
- Accordingly, although there are no specific recommendations for periodic ophthalmological monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects.
- Laboratory Tests
- The value of monitoring plasma concentrations of lamotrigine in patients treated with LAMICTAL has not been established. Because of the possible pharmacokinetic interactions between lamotrigine and other drugs including AEDs (see Table 15), monitoring of the plasma levels of lamotrigine and concomitant drugs may be indicated, particularly during dosage adjustments. In general, clinical judgment should be exercised regarding monitoring of plasma levels of lamotrigine and other drugs and whether or not dosage adjustments are necessary.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- LAMICTAL has been evaluated for safety in patients with epilepsy and in patients with Bipolar I Disorder. Adverse reactions reported for each of these patient populations are provided below. Excluded are adverse reactions considered too general to be informative and those not reasonably attributable to the use of the drug.
- Epilepsy: Most Common Adverse Reactions in All Clinical Studies: Adjunctive Therapy in Adults With Epilepsy: The most commonly observed (≥5% for LAMICTAL and more common on drug than placebo) adverse reactions seen in association with LAMICTAL during adjunctive therapy in adults and not seen at an equivalent frequency among placebo-treated patients were: dizziness, ataxia, somnolence, headache, diplopia, blurred vision, nausea, vomiting, and rash. Dizziness, diplopia, ataxia, blurred vision, nausea, and vomiting were dose-related. Dizziness, diplopia, ataxia, and blurred vision occurred more commonly in patients receiving carbamazepine with LAMICTAL than in patients receiving other AEDs with LAMICTAL. Clinical data suggest a higher incidence of rash, including serious rash, in patients receiving concomitant valproate than in patients not receiving valproate.
- Approximately 11% of the 3,378 adult patients who received LAMICTAL as adjunctive therapy in premarketing clinical trials discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were rash (3.0%), dizziness (2.8%), and headache (2.5%).
- In a dose-response study in adults, the rate of discontinuation of LAMICTAL for dizziness, ataxia, diplopia, blurred vision, nausea, and vomiting was dose-related.
- Monotherapy in Adults With Epilepsy: The most commonly observed (≥5% for LAMICTAL and more common on drug than placebo) adverse reactions seen in association with the use of LAMICTAL during the monotherapy phase of the controlled trial in adults not seen at an equivalent rate in the control group were vomiting, coordination abnormality, dyspepsia, nausea, dizziness, rhinitis, anxiety, insomnia, infection, pain, weight decrease, chest pain, and dysmenorrhea. The most commonly observed (≥5% for LAMICTAL and more common on drug than placebo) adverse reactions associated with the use of LAMICTAL during the conversion to monotherapy (add-on) period, not seen at an equivalent frequency among low-dose valproate-treated patients, were dizziness, headache, nausea, asthenia, coordination abnormality, vomiting, rash, somnolence, diplopia, ataxia, accidental injury, tremor, blurred vision, insomnia, nystagmus, diarrhea, lymphadenopathy, pruritus, and sinusitis.
- Approximately 10% of the 420 adult patients who received LAMICTAL as monotherapy in premarketing clinical trials discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were rash (4.5%), headache (3.1%), and asthenia (2.4%).
- Adjunctive Therapy in Pediatric Patients With Epilepsy: The most commonly observed (≥5% for LAMICTAL and more common on drug than placebo) adverse reactions seen in association with the use of LAMICTAL as adjunctive treatment in pediatric patients 2 to 16 years of age and not seen at an equivalent rate in the control group were infection, vomiting, rash, fever, somnolence, accidental injury, dizziness, diarrhea, abdominal pain, nausea, ataxia, tremor, asthenia, bronchitis, flu syndrome, and diplopia.
- In 339 patients 2 to 16 years of age with partial seizures or generalized seizures of Lennox-Gastaut syndrome, 4.2% of patients on LAMICTAL and 2.9% of patients on placebo discontinued due to adverse reactions. The most commonly reported adverse reaction that led to discontinuation of LAMICTAL was rash.
- Approximately 11.5% of the 1,081 pediatric patients 2 to 16 years of age who received LAMICTAL as adjunctive therapy in premarketing clinical trials discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were rash (4.4%), reaction aggravated (1.7%), and ataxia (0.6%).
- Controlled Adjunctive Clinical Studies in Adults With Epilepsy: Table 8 lists treatment-emergent adverse reactions that occurred in at least 2% of adult patients with epilepsy treated with LAMICTAL in placebo-controlled trials and were numerically more common in the patients treated with LAMICTAL. In these studies, either LAMICTAL or placebo was added to the patient’s current AED therapy. Adverse reactions were usually mild to moderate in intensity.
- Patients in these adjunctive studies were receiving 1 to 3 of the following concomitant AEDs (carbamazepine, phenytoin, phenobarbital, or primidone) in addition to LAMICTAL or placebo. Patients may have reported multiple adverse reactions during the study or at discontinuation; thus, patients may be included in more than one category.
- In a randomized, parallel study comparing placebo and 300 and 500 mg/day of LAMICTAL, some of the more common drug-related adverse reactions were dose-related (see Table 9).
- aSignificantly greater than placebo group (P<0.05).
- bSignificantly greater than group receiving LAMICTAL 300 mg (P<0.05).
- The overall adverse reaction profile for LAMICTAL was similar between females and males, and was independent of age. Because the largest non-Caucasian racial subgroup was only 6% of patients exposed to LAMICTAL in placebo-controlled trials, there are insufficient data to support a statement regarding the distribution of adverse reaction reports by race. Generally, females receiving either LAMICTAL as adjunctive therapy or placebo were more likely to report adverse reactions than males. The only adverse reaction for which the reports on LAMICTAL were greater than 10% more frequent in females than males (without a corresponding difference by gender on placebo) was dizziness (difference = 16.5%). There was little difference between females and males in the rates of discontinuation of LAMICTAL for individual adverse reactions.
- Controlled Monotherapy Trial in Adults With Partial Seizures: Table 10 lists treatment-emergent adverse reactions that occurred in at least 5% of patients with epilepsy treated with monotherapy with LAMICTAL in a double-blind trial following discontinuation of either concomitant carbamazepine or phenytoin not seen at an equivalent frequency in the control group.
- Patients in these studies were converted to LAMICTAL or valproate monotherapy from adjunctive therapy with carbamazepine or phenytoin. Patients may have reported multiple adverse reactions during the study; thus, patients may be included in more than one category.
- bUp to 500 mg/day.
- c1,000 mg/day.
- Adverse reactions that occurred with a frequency of less than 5% and greater than 2% of patients receiving LAMICTAL and numerically more frequent than placebo were:
Asthenia, fever.
Anorexia, dry mouth, rectal hemorrhage, peptic ulcer.
Peripheral edema.
Amnesia, ataxia, depression, hypesthesia, libido increase, decreased reflexes, increased reflexes, nystagmus, irritability, suicidal ideation.
Epistaxis, bronchitis, dyspnea.
Contact dermatitis, dry skin, sweating.
Vision abnormality.
- Incidence in Controlled Adjunctive Trials in Pediatric Patients With Epilepsy: Table 11 lists adverse reactions that occurred in at least 2% of 339 pediatric patients with partial seizures or generalized seizures of Lennox-Gastaut syndrome, who received LAMICTAL up to 15 mg/kg/day or a maximum of 750 mg/day. Reported adverse reactions were classified using COSTART terminology.
- Bipolar Disorder: The most commonly observed (≥5%) treatment-emergent adverse reactions seen in association with the use of LAMICTAL as monotherapy (100 to 400 mg/day) in adult patients (≥18 years of age) with Bipolar Disorder in the 2 double-blind, placebo-controlled trials of 18 months’ duration, and numerically more frequent than in placebo-treated patients are included in Table 12. Adverse reactions that occurred in at least 5% of patients and were numerically more common during the dose-escalation phase of LAMICTAL in these trials (when patients may have been receiving concomitant medications) compared with the monotherapy phase were: headache (25%), rash (11%), dizziness (10%), diarrhea (8%), dream abnormality (6%), and pruritus (6%).
- During the monotherapy phase of the double-blind, placebo-controlled trials of 18 months’ duration, 13% of 227 patients who received LAMICTAL (100 to 400 mg/day), 16% of 190 patients who received placebo, and 23% of 166 patients who received lithium discontinued therapy because of an adverse reaction. The adverse reactions which most commonly led to discontinuation of LAMICTAL were rash (3%) and mania/hypomania/mixed mood adverse reactions (2%). Approximately 16% of 2,401 patients who received LAMICTAL (50 to 500 mg/day) for Bipolar Disorder in premarketing trials discontinued therapy because of an adverse reaction, most commonly due to rash (5%) and mania/hypomania/mixed mood adverse reactions (2%).
- The overall adverse reaction profile for LAMICTAL was similar between females and males, between elderly and nonelderly patients, and among racial groups.
- aPatients in these studies were converted to LAMICTAL (100 to 400 mg/day) or placebo monotherapy from add-on therapy with other psychotropic medications. Patients may have reported multiple adverse reactions during the study; thus, patients may be included in more than one category.
- bIn the overall bipolar and other mood disorders clinical trials, the rate of serious rash was 0.08% (1 of 1,233) of adult patients who received LAMICTAL as initial monotherapy and 0.13% (2 of 1,538) of adult patients who received LAMICTAL as adjunctive therapy.
- These adverse reactions were usually mild to moderate in intensity. Other reactions that occurred in 5% or more patients but equally or more frequently in the placebo group included: dizziness, mania, headache, infection, influenza, pain, accidental injury, diarrhea, and dyspepsia.
- Adverse reactions that occurred with a frequency of less than 5% and greater than 1% of patients receiving LAMICTAL and numerically more frequent than placebo were:
Fever, neck pain.
Migraine.
Flatulence.
Weight gain, edema.
Arthralgia, myalgia.
Amnesia, depression, agitation, emotional lability, dyspraxia, abnormal thoughts, dream abnormality, hypoesthesia.
Sinusitis.
Urinary frequency.
- Adverse Reactions Following Abrupt Discontinuation: In the 2 maintenance trials, there was no increase in the incidence, severity, or type of adverse reactions in Bipolar Disorder patients after abruptly terminating therapy with LAMICTAL. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of LAMICTAL. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients.
- Mania/Hypomania/Mixed Episodes: During the double-blind, placebo-controlled clinical trials in Bipolar I Disorder in which patients were converted to monotherapy with LAMICTAL (100 to 400 mg/day) from other psychotropic medications and followed for up to 18 months, the rates of manic or hypomanic or mixed mood episodes reported as adverse reactions were 5% for patients treated with LAMICTAL (n = 227), 4% for patients treated with lithium (n = 166), and 7% for patients treated with placebo (n = 190). In all bipolar controlled trials combined, adverse reactions of mania (including hypomania and mixed mood episodes) were reported in 5% of patients treated with LAMICTAL (n = 956), 3% of patients treated with lithium (n = 280), and 4% of patients treated with placebo (n = 803).
- Other Adverse Reactions Observed in All Clinical Trials
- LAMICTAL has been administered to 6,694 individuals for whom complete adverse reaction data was captured during all clinical trials, only some of which were placebo controlled. During these trials, all adverse reactions were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse reactions, similar types of adverse reactions were grouped into a smaller number of standardized categories using modified COSTART dictionary terminology. The frequencies presented represent the proportion of the 6,694 individuals exposed to LAMICTAL who experienced an event of the type cited on at least one occasion while receiving LAMICTAL. All reported adverse reactions are included except those already listed in the previous tables or elsewhere in the labeling, those too general to be informative, and those not reasonably associated with the use of the drug.
- Adverse reactions are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse reactions are defined as those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients; rare adverse reactions are those occurring in fewer than 1/1,000 patients.
Infrequent: Allergic reaction, chills, and malaise.
Infrequent: Flushing, hot flashes, hypertension, palpitations, postural hypotension, syncope, tachycardia, and vasodilation.
Infrequent: Acne, alopecia, hirsutism, maculopapular rash, skin discoloration, and urticaria. Rare: Angioedema, erythema, exfoliative dermatitis, fungal dermatitis, herpes zoster, leukoderma, multiforme erythema, petechial rash, pustular rash, Stevens-Johnson syndrome, and vesiculobullous rash.
Infrequent: Dysphagia, eructation, gastritis, gingivitis, increased appetite, increased salivation, liver function tests abnormal, and mouth ulceration. Rare: Gastrointestinal hemorrhage, glossitis, gum hemorrhage, gum hyperplasia, hematemesis, hemorrhagic colitis, hepatitis, melena, stomach ulcer, stomatitis, and tongue edema.
Rare: Goiter and hypothyroidism.
Infrequent: Ecchymosis and leukopenia. Rare: Anemia, eosinophilia, fibrin decrease, fibrinogen decrease, iron deficiency anemia, leukocytosis, lymphocytosis, macrocytic anemia, petechia, and thrombocytopenia.
Infrequent: Aspartate transaminase increased. Rare: Alcohol intolerance, alkaline phosphatase increase, alanine transaminase increase, bilirubinemia, general edema, gamma glutamyl transpeptidase increase, and hyperglycemia.
Infrequent: Arthritis, leg cramps, myasthenia, and twitching. Rare: Bursitis, muscle atrophy, pathological fracture, and tendinous contracture.
Frequent: Confusion and paresthesia. Infrequent: Akathisia, apathy, aphasia, central nervous system (CNS) depression, depersonalization, dysarthria, dyskinesia, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, libido decreased, memory decrease, mind racing, movement disorder, myoclonus, panic attack, paranoid reaction, personality disorder, psychosis, sleep disorder, stupor, and suicidal ideation. Rare: Choreoathetosis, delirium, delusions, dysphoria, dystonia, extrapyramidal syndrome, faintness, grand mal convulsions, hemiplegia, hyperalgesia, hyperesthesia, hypokinesia, hypotonia, manic depression reaction, muscle spasm, neuralgia, neurosis, paralysis, and peripheral neuritis.
Infrequent: Yawn. Rare: Hiccup and hyperventilation.
Frequent: Amblyopia. Infrequent: Abnormality of accommodation, conjunctivitis, dry eyes, ear pain, photophobia, taste perversion, and tinnitus. Rare: Deafness, lacrimation disorder, oscillopsia, parosmia, ptosis, strabismus, taste loss, uveitis, and visual field defect.
Infrequent: Abnormal ejaculation, hematuria, impotence, menorrhagia, polyuria, and urinary incontinence. Rare: Acute kidney failure, anorgasmia, breast abscess, breast neoplasm, creatinine increase, cystitis, dysuria, epididymitis, female lactation, kidney failure, kidney pain, nocturia, urinary retention, and urinary urgency.
## Postmarketing Experience
- The following adverse events (not listed above in clinical trials or other sections of the prescribing information) have been identified during postapproval use of LAMICTAL. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Agranulocytosis, hemolytic anemia, lymphadenopathy not associated with hypersensitivity disorder.
Esophagitis.
Pancreatitis.
Lupus-like reaction, vasculitis.
Apnea.
Rhabdomyolysis has been observed in patients experiencing hypersensitivity reactions.
Exacerbation of Parkinsonian symptoms in patients with pre-existing Parkinson’s disease, tics.
Progressive immunosuppression.
# Drug Interactions
- Significant drug interactions with lamotrigine are summarized in Table 13. Additional details of these drug interaction studies are provided in the Clinical Pharmacology section.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- No evidence of teratogenicity was found in mice, rats, or rabbits when lamotrigine was orally administered to pregnant animals during the period of organogenesis at doses up to 1.2, 0.5, and 1.1 times, respectively, on a mg/m2 basis, the highest usual human maintenance dose (i.e., 500 mg/day). However, maternal toxicity and secondary fetal toxicity producing reduced fetal weight and/or delayed ossification were seen in mice and rats, but not in rabbits at these doses. Teratology studies were also conducted using bolus intravenous administration of the isethionate salt of lamotrigine in rats and rabbits. In rat dams administered an intravenous dose at 0.6 times the highest usual human maintenance dose, the incidence of intrauterine death without signs of teratogenicity was increased.
- A behavioral teratology study was conducted in rats dosed during the period of organogenesis. At day 21 postpartum, offspring of dams receiving 5 mg/kg/day or higher displayed a significantly longer latent period for open field exploration and a lower frequency of rearing. In a swimming maze test performed on days 39 to 44 postpartum, time to completion was increased in offspring of dams receiving 25 mg/kg/day. These doses represent 0.1 and 0.5 times the clinical dose on a mg/m2 basis, respectively.
- Lamotrigine did not affect fertility, teratogenesis, or postnatal development when rats were dosed prior to and during mating, and throughout gestation and lactation at doses equivalent to 0.4 times the highest usual human maintenance dose on a mg/m2 basis.
- When pregnant rats were orally dosed at 0.1, 0.14, or 0.3 times the highest human maintenance dose (on a mg/m2 basis) during the latter part of gestation (days 15 to 20), maternal toxicity and fetal death were seen. In dams, food consumption and weight gain were reduced, and the gestation period was slightly prolonged (22.6 vs. 22.0 days in the control group). Stillborn pups were found in all 3 drug-treated groups with the highest number in the high-dose group. Postnatal death was also seen, but only in the 2 highest doses, and occurred between days 1 and 20. Some of these deaths appear to be drug-related and not secondary to the maternal toxicity. A no-observed-effect level (NOEL) could not be determined for this study.
- Although lamotrigine was not found to be teratogenic in the above studies, lamotrigine decreases fetal folate concentrations in rats, an effect known to be associated with teratogenesis in animals and humans. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Non-Teratogenic Effects: As with other AEDs, physiological changes during pregnancy may affect lamotrigine concentrations and/or therapeutic effect. There have been reports of decreased lamotrigine concentrations during pregnancy and restoration of pre-partum concentrations after delivery. Dosage adjustments may be necessary to maintain clinical response.
- Pregnancy Exposure Registry: To provide information regarding the effects of in utero exposure to LAMICTAL, physicians are advised to recommend that pregnant patients taking LAMICTAL enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.
- Physicians are also encouraged to register patients in the Lamotrigine Pregnancy Registry; enrollment in this registry must be done prior to any prenatal diagnostic tests and before fetal outcome is known. Physicians can obtain information by calling the Lamotrigine Pregnancy Registry at 1-800-336-2176 (toll-free).
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lamotrigine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Lamotrigine during labor and delivery.
### Nursing Mothers
- Lamotrigine is present in milk from lactating women taking LAMICTAL. Data from multiple small studies indicate that lamotrigine plasma levels in human milk-fed infants have been reported to be as high as 50% of the maternal serum levels. Neonates and young infants are at risk for high serum levels because maternal serum and milk levels can rise to high levels postpartum if lamotrigine dosage has been increased during pregnancy but not later reduced to the pre-pregnancy dosage. Lamotrigine exposure is further increased due to the immaturity of the infant glucuronidation capacity needed for drug clearance. Events including apnea, drowsiness, and poor sucking have been reported in infants who have been human milk-fed by mothers using lamotrigine; whether or not these events were caused by lamotrigine is unknown. Human milk-fed infants should be closely monitored for adverse events resulting from lamotrigine. Measurement of infant serum levels should be performed to rule out toxicity if concerns arise. Human milk-feeding should be discontinued in infants with lamotrigine toxicity. Caution should be exercised when LAMICTAL is administered to a nursing woman.
### Pediatric Use
- LAMICTAL is indicated for adjunctive therapy in patients ≥2 years of age for partial seizures, the generalized seizures of Lennox-Gastaut syndrome, and primary generalized tonic-clonic seizures.
- Safety and efficacy of LAMICTAL, used as adjunctive treatment for partial seizures, were not demonstrated in a small randomized, double-blind, placebo-controlled, withdrawal study in very young pediatric patients (1 to 24 months of age). LAMICTAL was associated with an increased risk for infectious adverse reactions (LAMICTAL 37%, placebo 5%), and respiratory adverse reactions (LAMICTAL 26%, placebo 5%). Infectious adverse reactions included bronchiolitis, bronchitis, ear infection, eye infection, otitis externa, pharyngitis, urinary tract infection, and viral infection. Respiratory adverse reactions included nasal congestion, cough, and apnea.
- Safety and effectiveness in patients below the age of 18 years with Bipolar Disorder have not been established.
### Geriatic Use
- Clinical studies of LAMICTAL for epilepsy and in Bipolar Disorder did not include sufficient numbers of subjects 65 years of age and over to determine whether they respond differently from younger subjects or exhibit a different safety profile than that of younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Lamotrigine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Lamotrigine with respect to specific racial populations.
### Renal Impairment
- Lamotrigine is metabolized mainly by glucuronic acid conjugation, with the majority of the metabolites being recovered in the urine. In a small study comparing a single dose of lamotrigine in patients with varying degrees of renal impairment with healthy volunteers, the plasma half-life of lamotrigine was significantly longer in the patients with renal impairment.
- Initial doses of LAMICTAL should be based on patients’ AED regimens; reduced maintenance doses may be effective for patients with significant renal impairment. Few patients with severe renal impairment have been evaluated during chronic treatment with LAMICTAL. Because there is inadequate experience in this population, LAMICTAL should be used with caution in these patients.
### Hepatic Impairment
- Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment, the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Lamotrigine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Lamotrigine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Lamotrigine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Lamotrigine in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Overdoses involving quantities up to 15 g have been reported for LAMICTAL, some of which have been fatal. Overdose has resulted in ataxia, nystagmus, seizures (including tonic-clonic seizures), decreased level of consciousness, coma, and intraventricular conduction delay.
### Management
- There are no specific antidotes for lamotrigine. Following a suspected overdose, hospitalization of the patient is advised. General supportive care is indicated, including frequent monitoring of vital signs and close observation of the patient. If indicated, emesis should be induced; usual precautions should be taken to protect the airway. It should be kept in mind that lamotrigine is rapidly absorbed. It is uncertain whether hemodialysis is an effective means of removing lamotrigine from the blood. In 6 renal failure patients, about 20% of the amount of lamotrigine in the body was removed by hemodialysis during a 4-hour session. A Poison Control Center should be contacted for information on the management of overdosage of LAMICTAL.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Lamotrigine in the drug label.
# Pharmacology
## Mechanism of Action
- The precise mechanism(s) by which lamotrigine exerts its anticonvulsant action are unknown. In animal models designed to detect anticonvulsant activity, lamotrigine was effective in preventing seizure spread in the maximum electroshock (MES) and pentylenetetrazol (scMet) tests, and prevented seizures in the visually and electrically evoked after-discharge (EEAD) tests for antiepileptic activity. Lamotrigine also displayed inhibitory properties in the kindling model in rats both during kindling development and in the fully kindled state. The relevance of these models to human epilepsy, however, is not known.
- One proposed mechanism of action of lamotrigine, the relevance of which remains to be established in humans, involves an effect on sodium channels. In vitro pharmacological studies suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids (e.g., glutamate and aspartate).
- Although the relevance for human use is unknown, the following data characterize the performance of lamotrigine in receptor binding assays. Lamotrigine had a weak inhibitory effect on the serotonin 5-HT3 receptor (IC50 = 18 µM). It does not exhibit high affinity binding (IC50>100 µM) to the following neurotransmitter receptors: adenosine A1 and A2; adrenergic α1, α2, and β; dopamine D1 and D2; γ-aminobutyric acid (GABA) A and B; histamine H1; kappa opioid; muscarinic acetylcholine; and serotonin 5-HT2. Studies have failed to detect an effect of lamotrigine on dihydropyridine-sensitive calcium channels. It had weak effects at sigma opioid receptors (IC50 = 145 µM). Lamotrigine did not inhibit the uptake of norepinephrine, dopamine, or serotonin (IC50>200 µM) when tested in rat synaptosomes and/or human platelets in vitro.
- Effect of Lamotrigine on N-Methyl d-Aspartate-Receptor Mediated Activity: Lamotrigine did not inhibit N-methyl d-aspartate (NMDA)-induced depolarizations in rat cortical slices or NMDA-induced cyclic GMP formation in immature rat cerebellum, nor did lamotrigine displace compounds that are either competitive or noncompetitive ligands at this glutamate receptor complex (CNQX, CGS, TCHP). The IC50 for lamotrigine effects on NMDA-induced currents (in the presence of 3 µM of glycine) in cultured hippocampal neurons exceeded 100 µM.
- The mechanisms by which lamotrigine exerts its therapeutic action in Bipolar Disorder have not been established.
## Structure
- LAMICTAL (lamotrigine), an AED of the phenyltriazine class, is chemically unrelated to existing AEDs. Its chemical name is 3,5-diamino-6-(2,3-dichlorophenyl)-as-triazine, its molecular formula is C9H7N5Cl2, and its molecular weight is 256.09. Lamotrigine is a white to pale cream-colored powder and has a pKa of 5.7. Lamotrigine is very slightly soluble in water (0.17 mg/mL at 25°C) and slightly soluble in 0.1 M HCl (4.1 mg/mL at 25°C). The structural formula is:
- LAMICTAL Tablets are supplied for oral administration as 25 mg (white), 100 mg (peach), 150 mg (cream), and 200 mg (blue) tablets. Each tablet contains the labeled amount of lamotrigine and the following inactive ingredients: lactose; magnesium stearate; microcrystalline cellulose; povidone; sodium starch glycolate; FD&C Yellow No. 6 Lake (100-mg tablet only); ferric oxide, yellow (150-mg tablet only); and FD&C Blue No. 2 Lake (200-mg tablet only).
- LAMICTAL Chewable Dispersible Tablets are supplied for oral administration. The tablets contain 2 mg (white), 5 mg (white), or 25 mg (white) of lamotrigine and the following inactive ingredients: blackcurrant flavor, calcium carbonate, low-substituted hydroxypropylcellulose, magnesium aluminum silicate, magnesium stearate, povidone, saccharin sodium, and sodium starch glycolate.
- LAMICTAL ODT Orally Disintegrating Tablets are supplied for oral administration. The tablets contain 25 mg (white to off-white), 50 mg (white to off-white), 100 mg (white to off-white), or 200 mg (white to off-white) of lamotrigine and the following inactive ingredients: artificial cherry flavor, crospovidone, ethylcellulose, magnesium stearate, mannitol, polyethylene, and sucralose.
- LAMICTAL ODT Orally Disintegrating Tablets are formulated using technologies (Microcaps® and AdvaTab®) designed to mask the bitter taste of lamotrigine and achieve a rapid dissolution profile. Tablet characteristics including flavor, mouth-feel, after-taste, and ease of use were rated as favorable in a study of 108 healthy volunteers.
## Pharmacodynamics
- Folate Metabolism: In vitro, lamotrigine inhibited dihydrofolate reductase, the enzyme that catalyzes the reduction of dihydrofolate to tetrahydrofolate. Inhibition of this enzyme may interfere with the biosynthesis of nucleic acids and proteins. When oral daily doses of lamotrigine were given to pregnant rats during organogenesis, fetal, placental, and maternal folate concentrations were reduced. Significantly reduced concentrations of folate are associated with teratogenesis. Folate concentrations were also reduced in male rats given repeated oral doses of lamotrigine. Reduced concentrations were partially returned to normal when supplemented with folinic acid.
- Accumulation in Kidneys: Lamotrigine accumulated in the kidney of the male rat, causing chronic progressive nephrosis, necrosis, and mineralization. These findings are attributed to α-2 microglobulin, a species- and sex-specific protein that has not been detected in humans or other animal species.
- Melanin Binding: Lamotrigine binds to melanin-containing tissues, e.g., in the eye and pigmented skin. It has been found in the uveal tract up to 52 weeks after a single dose in rodents.
- Cardiovascular: In dogs, lamotrigine is extensively metabolized to a 2-N-methyl metabolite. This metabolite causes dose-dependent prolongations of the PR interval, widening of the QRS complex, and, at higher doses, complete AV conduction block. Similar cardiovascular effects are not anticipated in humans because only trace amounts of the 2-N-methyl metabolite (<0.6% of lamotrigine dose) have been found in human urine. However, it is conceivable that plasma concentrations of this metabolite could be increased in patients with a reduced capacity to glucuronidate lamotrigine (e.g., in patients with liver disease).
## Pharmacokinetics
- The pharmacokinetics of lamotrigine have been studied in patients with epilepsy, healthy young and elderly volunteers, and volunteers with chronic renal failure. Lamotrigine pharmacokinetic parameters for adult and pediatric patients and healthy normal volunteers are summarized in Tables 14 and 16.
- aThe majority of parameter means determined in each study had coefficients of variation between 20% and 40% for half-life and Cl/F and between 30% and 70% for Tmax. The overall mean values were calculated from individual study means that were weighted based on the number of volunteers/patients in each study. The numbers in parentheses below each parameter mean represent the range of individual volunteer/patient values across studies.
- bCarbamazepine, phenobarbital, phenytoin, and primidone have been shown to increase the apparent clearance of lamotrigine. Estrogen-containing oral contraceptives and other drugs such as rifampin that induce lamotrigine glucuronidation have also been shown to increase the apparent clearance of lamotrigine.
- Absorption: Lamotrigine is rapidly and completely absorbed after oral administration with negligible first-pass metabolism (absolute bioavailability is 98%). The bioavailability is not affected by food. Peak plasma concentrations occur anywhere from 1.4 to 4.8 hours following drug administration. The lamotrigine chewable/dispersible tablets were found to be equivalent, whether they were administered as dispersed in water, chewed and swallowed, or swallowed as whole, to the lamotrigine compressed tablets in terms of rate and extent of absorption. In terms of rate and extent of absorption, lamotrigine orally disintegrating tablets whether disintegrated in the mouth or swallowed whole with water were equivalent to the lamotrigine compressed tablets swallowed with water.
- Dose Proportionality: In healthy volunteers not receiving any other medications and given single doses, the plasma concentrations of lamotrigine increased in direct proportion to the dose administered over the range of 50 to 400 mg. In 2 small studies (n = 7 and 8) of patients with epilepsy who were maintained on other AEDs, there also was a linear relationship between dose and lamotrigine plasma concentrations at steady state following doses of 50 to 350 mg twice daily.
- Distribution: Estimates of the mean apparent volume of distribution (Vd/F) of lamotrigine following oral administration ranged from 0.9 to 1.3 L/kg. Vd/F is independent of dose and is similar following single and multiple doses in both patients with epilepsy and in healthy volunteers.
- Protein Binding: Data from in vitro studies indicate that lamotrigine is approximately 55% bound to human plasma proteins at plasma lamotrigine concentrations from 1 to 10 mcg/mL (10 mcg/mL is 4 to 6 times the trough plasma concentration observed in the controlled efficacy trials). Because lamotrigine is not highly bound to plasma proteins, clinically significant interactions with other drugs through competition for protein binding sites are unlikely. The binding of lamotrigine to plasma proteins did not change in the presence of therapeutic concentrations of phenytoin, phenobarbital, or valproate. Lamotrigine did not displace other AEDs (carbamazepine, phenytoin, phenobarbital) from protein-binding sites.
- Metabolism: Lamotrigine is metabolized predominantly by glucuronic acid conjugation; the major metabolite is an inactive 2-N-glucuronide conjugate. After oral administration of 240 mg of 14C-lamotrigine (15 μCi) to 6 healthy volunteers, 94% was recovered in the urine and 2% was recovered in the feces. The radioactivity in the urine consisted of unchanged lamotrigine (10%), the 2-N-glucuronide (76%), a 5-N-glucuronide (10%), a 2-N-methyl metabolite (0.14%), and other unidentified minor metabolites (4%).
- Enzyme Induction: The effects of lamotrigine on the induction of specific families of mixed-function oxidase isozymes have not been systematically evaluated.
- Following multiple administrations (150 mg twice daily) to normal volunteers taking no other medications, lamotrigine induced its own metabolism, resulting in a 25% decrease in t½ and a 37% increase in Cl/F at steady state compared with values obtained in the same volunteers following a single dose. Evidence gathered from other sources suggests that self-induction by lamotrigine may not occur when lamotrigine is given as adjunctive therapy in patients receiving enzyme-inducing drugs such as carbamazepine, phenytoin, phenobarbital, primidone, or drugs such as rifampin that induce lamotrigine glucuronidation.
- Elimination: The elimination half-life and apparent clearance of lamotrigine following administration of LAMICTAL to adult patients with epilepsy and healthy volunteers is summarized in Table 14. Half-life and apparent oral clearance vary depending on concomitant AEDs.
- Drug Interactions: The apparent clearance of lamotrigine is affected by the coadministration of certain medications.
- The net effects of drug interactions with LAMICTAL are summarized in Tables 13 and 15, followed by details of the drug interaction studies below.
- aFrom adjunctive clinical trials and volunteer studies.
- bNet effects were estimated by comparing the mean clearance values obtained in adjunctive clinical trials and volunteer studies.
- cThe effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated in clinical trials, although the effect may be similar to that seen with the ethinylestradiol/levonorgestrel combinations.
- dModest decrease in levonorgestrel.
- eNot administered, but an active metabolite of carbamazepine.
- fSlight decrease, not expected to be clinically relevant.
- gNot administered, but an active metabolite of oxcarbazepine.
- hSlight increase, not expected to be clinically relevant.
- ↔ = No significant effect.
- ? = Conflicting data.
- Estrogen-Containing Oral Contraceptives: In 16 female volunteers, an oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel increased the apparent clearance of lamotrigine (300 mg/day) by approximately 2-fold with mean decreases in AUC of 52% and in Cmax of 39%. In this study, trough serum lamotrigine concentrations gradually increased and were approximately 2-fold higher on average at the end of the week of the inactive hormone preparation compared with trough lamotrigine concentrations at the end of the active hormone cycle.
- Gradual transient increases in lamotrigine plasma levels (approximate 2-fold increase) occurred during the week of inactive hormone preparation (“pill-free” week) for women not also taking a drug that increased the clearance of lamotrigine (carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation. The increase in lamotrigine plasma levels will be greater if the dose of LAMICTAL is increased in the few days before or during the “pill-free” week. Increases in lamotrigine plasma levels could result in dose-dependent adverse reactions.
- In the same study, coadministration of LAMICTAL (300 mg/day) in 16 female volunteers did not affect the pharmacokinetics of the ethinylestradiol component of the oral contraceptive preparation. There were mean decreases in the AUC and Cmax of the levonorgestrel component of 19% and 12%, respectively. Measurement of serum progesterone indicated that there was no hormonal evidence of ovulation in any of the 16 volunteers, although measurement of serum FSH, LH, and estradiol indicated that there was some loss of suppression of the hypothalamic-pituitary-ovarian axis.
- The effects of doses of LAMICTAL other than 300 mg/day have not been systematically evaluated in controlled clinical trials.
- The clinical significance of the observed hormonal changes on ovulatory activity is unknown. However, the possibility of decreased contraceptive efficacy in some patients cannot be excluded. Therefore, patients should be instructed to promptly report changes in their menstrual pattern (e.g., break-through bleeding).
- Dosage adjustments may be necessary for women receiving estrogen-containing oral contraceptive preparations [see Dosage and Administration (2.1)].
- Other Hormonal Contraceptives or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of LAMICTAL in the presence of progestogens alone will likely not be needed.
- Bupropion: The pharmacokinetics of a 100-mg single dose of LAMICTAL in healthy volunteers (n = 12) were not changed by coadministration of bupropion sustained-release formulation (150 mg twice daily) starting 11 days before LAMICTAL.
- Carbamazepine: LAMICTAL has no appreciable effect on steady-state carbamazepine plasma concentration. Limited clinical data suggest there is a higher incidence of dizziness, diplopia, ataxia, and blurred vision in patients receiving carbamazepine with lamotrigine than in patients receiving other AEDs with lamotrigine [see Adverse Reactions (6.1)]. The mechanism of this interaction is unclear. The effect of lamotrigine on plasma concentrations of carbamazepine-epoxide is unclear. In a small subset of patients (n = 7) studied in a placebo-controlled trial, lamotrigine had no effect on carbamazepine-epoxide plasma concentrations, but in a small, uncontrolled study (n = 9), carbamazepine-epoxide levels increased.
- The addition of carbamazepine decreases lamotrigine steady-state concentrations by approximately 40%.
- Felbamate: In a study of 21 healthy volunteers, coadministration of felbamate (1,200 mg twice daily) with lamotrigine (100 mg twice daily for 10 days) appeared to have no clinically relevant effects on the pharmacokinetics of lamotrigine.
- Folate Inhibitors: Lamotrigine is a weak inhibitor of dihydrofolate reductase. Prescribers should be aware of this action when prescribing other medications that inhibit folate metabolism.
- Gabapentin: Based on a retrospective analysis of plasma levels in 34 patients who received lamotrigine both with and without gabapentin, gabapentin does not appear to change the apparent clearance of lamotrigine.
- Levetiracetam: Potential drug interactions between levetiracetam and lamotrigine were assessed by evaluating serum concentrations of both agents during placebo-controlled clinical trials. These data indicate that lamotrigine does not influence the pharmacokinetics of levetiracetam and that levetiracetam does not influence the pharmacokinetics of lamotrigine.
- Lithium: The pharmacokinetics of lithium were not altered in healthy subjects (n = 20) by coadministration of lamotrigine (100 mg/day) for 6 days.
- Olanzapine: The AUC and Cmax of olanzapine were similar following the addition of olanzapine (15 mg once daily) to lamotrigine (200 mg once daily) in healthy male volunteers (n = 16) compared with the AUC and Cmax in healthy male volunteers receiving olanzapine alone (n = 16).
- In the same study, the AUC and Cmax of lamotrigine were reduced on average by 24% and 20%, respectively, following the addition of olanzapine to lamotrigine in healthy male volunteers compared with those receiving lamotrigine alone. This reduction in lamotrigine plasma concentrations is not expected to be clinically relevant.
- Oxcarbazepine: The AUC and Cmax of oxcarbazepine and its active 10-monohydroxy oxcarbazepine metabolite were not significantly different following the addition of oxcarbazepine (600 mg twice daily) to lamotrigine (200 mg once daily) in healthy male volunteers (n = 13) compared with healthy male volunteers receiving oxcarbazepine alone (n = 13).
- In the same study, the AUC and Cmax of lamotrigine were similar following the addition of oxcarbazepine (600 mg twice daily) to LAMICTAL in healthy male volunteers compared with those receiving LAMICTAL alone. Limited clinical data suggest a higher incidence of headache, dizziness, nausea, and somnolence with coadministration of lamotrigine and oxcarbazepine compared with lamotrigine alone or oxcarbazepine alone.
- Phenobarbital, Primidone: The addition of phenobarbital or primidone decreases lamotrigine steady-state concentrations by approximately 40%.
- Phenytoin: Lamotrigine has no appreciable effect on steady-state phenytoin plasma concentrations in patients with epilepsy. The addition of phenytoin decreases lamotrigine steady-state concentrations by approximately 40%.
- Pregabalin: Steady-state trough plasma concentrations of lamotrigine were not affected by concomitant pregabalin (200 mg 3 times daily) administration. There are no pharmacokinetic interactions between lamotrigine and pregabalin.
- Rifampin: In 10 male volunteers, rifampin (600 mg/day for 5 days) significantly increased the apparent clearance of a single 25-mg dose of lamotrigine by approximately 2-fold (AUC decreased by approximately 40%).
- Topiramate: Topiramate resulted in no change in plasma concentrations of lamotrigine. Administration of lamotrigine resulted in a 15% increase in topiramate concentrations.
- Valproate: When lamotrigine was administered to healthy volunteers (n = 18) receiving valproate, the trough steady-state valproate plasma concentrations decreased by an average of 25% over a 3-week period, and then stabilized. However, adding lamotrigine to the existing therapy did not cause a change in valproate plasma concentrations in either adult or pediatric patients in controlled clinical trials.
- The addition of valproate increased lamotrigine steady-state concentrations in normal volunteers by slightly more than 2-fold. In one study, maximal inhibition of lamotrigine clearance was reached at valproate doses between 250 and 500 mg/day and did not increase as the valproate dose was further increased.
- Zonisamide: In a study of 18 patients with epilepsy, coadministration of zonisamide (200 to 400 mg/day) with lamotrigine (150 to 500 mg/day for 35 days) had no significant effect on the pharmacokinetics of lamotrigine.
- Known Inducers or Inhibitors of Glucuronidation: Drugs other than those listed above have not been systematically evaluated in combination with lamotrigine. Since lamotrigine is metabolized predominately by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine may require adjustment based on clinical response.
- Other: Results of in vitro experiments suggest that clearance of lamotrigine is unlikely to be reduced by concomitant administration of amitriptyline, clonazepam, clozapine, fluoxetine, haloperidol, lorazepam, phenelzine, risperidone, sertraline, or trazodone.
- Results of in vitro experiments suggest that lamotrigine does not reduce the clearance of drugs eliminated predominantly by CYP2D6.
- Special Populations:Patients With Renal Impairment: Twelve volunteers with chronic renal failure (mean creatinine clearance: 13 mL/min, range: 6 to 23) and another 6 individuals undergoing hemodialysis were each given a single 100-mg dose of lamotrigine. The mean plasma half-lives determined in the study were 42.9 hours (chronic renal failure), 13.0 hours (during hemodialysis), and 57.4 hours (between hemodialysis) compared with 26.2 hours in healthy volunteers. On average, approximately 20% (range: 5.6 to 35.1) of the amount of lamotrigine present in the body was eliminated by hemodialysis during a 4-hour session [see Dosage and Administration (2.1)].
- Hepatic Disease: The pharmacokinetics of lamotrigine following a single 100-mg dose of lamotrigine were evaluated in 24 subjects with mild, moderate, and severe hepatic impairment (Child-Pugh Classification system) and compared with 12 subjects without hepatic impairment. The patients with severe hepatic impairment were without ascites (n = 2) or with ascites (n = 5). The mean apparent clearances of lamotrigine in patients with mild (n = 12), moderate (n = 5), severe without ascites (n = 2), and severe with ascites (n = 5) liver impairment were 0.30 ± 0.09, 0.24 ± 0.1, 0.21 ± 0.04, and 0.15 ± 0.09 mL/min/kg, respectively, as compared with 0.37 ± 0.1 mL/min/kg in the healthy controls. Mean half-lives of lamotrigine in patients with mild, moderate, severe without ascites, and severe with ascites hepatic impairment were 46 ± 20, 72 ± 44, 67 ± 11, and 100 ± 48 hours, respectively, as compared with 33 ± 7 hours in healthy controls.
- Age: Pediatric Patients: The pharmacokinetics of lamotrigine following a single 2-mg/kg dose were evaluated in 2 studies of pediatric patients (n = 29 for patients 10 months to 5.9 years of age and n = 26 for patients 5 to 11 years of age). Forty-three patients received concomitant therapy with other AEDs and 12 patients received lamotrigine as monotherapy. Lamotrigine pharmacokinetic parameters for pediatric patients are summarized in Table 16.
- Population pharmacokinetic analyses involving patients 2 to 18 years of age demonstrated that lamotrigine clearance was influenced predominantly by total body weight and concurrent AED therapy. The oral clearance of lamotrigine was higher, on a body weight basis, in pediatric patients than in adults. Weight-normalized lamotrigine clearance was higher in those subjects weighing less than 30 kg, compared with those weighing greater than 30 kg. Accordingly, patients weighing less than 30 kg may need an increase of as much as 50% in maintenance doses, based on clinical response, as compared with subjects weighing more than 30 kg being administered the same AEDs. These analyses also revealed that, after accounting for body weight, lamotrigine clearance was not significantly influenced by age. Thus, the same weight-adjusted doses should be administered to children irrespective of differences in age. Concomitant AEDs which influence lamotrigine clearance in adults were found to have similar effects in children.
- aCarbamazepine, phenobarbital, phenytoin, and primidone have been shown to increase the apparent clearance of lamotrigine. Estrogen-containing oral contraceptives and rifampin have also been shown to increase the apparent clearance of lamotrigine [see Drug Interactions (7)].
- bTwo subjects were included in the calculation for mean Tmax.
- cParameter not estimated.
- Elderly: The pharmacokinetics of lamotrigine following a single 150-mg dose of LAMICTAL were evaluated in 12 elderly volunteers between the ages of 65 and 76 years (mean creatinine clearance = 61 mL/min, range: 33 to 108 mL/min). The mean half-life of lamotrigine in these subjects was 31.2 hours (range: 24.5 to 43.4 hours), and the mean clearance was 0.40 mL/min/kg (range: 0.26 to 0.48 mL/min/kg).
- Gender: The clearance of lamotrigine is not affected by gender. However, during dose escalation of LAMICTAL in one clinical trial in patients with epilepsy on a stable dose of valproate (n = 77), mean trough lamotrigine concentrations, unadjusted for weight, were 24% to 45% higher (0.3 to 1.7 mcg/mL) in females than in males.
- Race: The apparent oral clearance of lamotrigine was 25% lower in non-Caucasians than Caucasians.
## Nonclinical Toxicology
- No evidence of carcinogenicity was seen in 1 mouse study or 2 rat studies following oral administration of lamotrigine for up to 2 years at maximum tolerated doses (30 mg/kg/day for mice and 10 to 15 mg/kg/day for rats, doses that are equivalent to 90 mg/m2 and 60 to 90 mg/m2, respectively). Steady-state plasma concentrations ranged from 1 to 4 mcg/mL in the mouse study and 1 to 10 mcg/mL in the rat study. Plasma concentrations associated with the recommended human doses of 300 to 500 mg/day are generally in the range of 2 to 5 mcg/mL, but concentrations as high as 19 mcg/mL have been recorded.
- Lamotrigine was not mutagenic in the presence or absence of metabolic activation when tested in 2 gene mutation assays (the Ames test and the in vitro mammalian mouse lymphoma assay). In 2 cytogenetic assays (the in vitro human lymphocyte assay and the in vivo rat bone marrow assay), lamotrigine did not increase the incidence of structural or numerical chromosomal abnormalities.
- No evidence of impairment of fertility was detected in rats given oral doses of lamotrigine up to 2.4 times the highest usual human maintenance dose of 8.33 mg/kg/day or 0.4 times the human dose on a mg/m2 basis. The effect of lamotrigine on human fertility is unknown.
# Clinical Studies
- Monotherapy With LAMICTAL in Adults With Partial Seizures Already Receiving Treatment With Carbamazepine, Phenytoin, Phenobarbital, or Primidone as the Single Antiepileptic Drug: The effectiveness of monotherapy with LAMICTAL was established in a multicenter, double-blind clinical trial enrolling 156 adult outpatients with partial seizures. The patients experienced at least 4 simple partial, complex partial, and/or secondarily generalized seizures during each of 2 consecutive 4-week periods while receiving carbamazepine or phenytoin monotherapy during baseline. LAMICTAL (target dose of 500 mg/day) or valproate (1,000 mg/day) was added to either carbamazepine or phenytoin monotherapy over a 4-week period. Patients were then converted to monotherapy with LAMICTAL or valproate during the next 4 weeks, then continued on monotherapy for an additional 12-week period.
- Study endpoints were completion of all weeks of study treatment or meeting an escape criterion. Criteria for escape relative to baseline were: (1) doubling of average monthly seizure count, (2) doubling of highest consecutive 2-day seizure frequency, (3) emergence of a new seizure type (defined as a seizure that did not occur during the 8-week baseline) that is more severe than seizure types that occur during study treatment, or (4) clinically significant prolongation of generalized tonic-clonic seizures. The primary efficacy variable was the proportion of patients in each treatment group who met escape criteria.
- The percentages of patients who met escape criteria were 42% (32/76) in the group receiving LAMICTAL and 69% (55/80) in the valproate group. The difference in the percentage of patients meeting escape criteria was statistically significant (P = 0.0012) in favor of LAMICTAL. No differences in efficacy based on age, sex, or race were detected.
- Patients in the control group were intentionally treated with a relatively low dose of valproate; as such, the sole objective of this study was to demonstrate the effectiveness and safety of monotherapy with LAMICTAL, and cannot be interpreted to imply the superiority of LAMICTAL to an adequate dose of valproate.
- Adjunctive Therapy With LAMICTAL in Adults With Partial Seizures: The effectiveness of LAMICTAL as adjunctive therapy (added to other AEDs) was established in 3 multicenter, placebo-controlled, double-blind clinical trials in 355 adults with refractory partial seizures. The patients had a history of at least 4 partial seizures per month in spite of receiving one or more AEDs at therapeutic concentrations and, in 2 of the studies, were observed on their established AED regimen during baselines that varied between 8 to 12 weeks. In the third, patients were not observed in a prospective baseline. In patients continuing to have at least 4 seizures per month during the baseline, LAMICTAL or placebo was then added to the existing therapy. In all 3 studies, change from baseline in seizure frequency was the primary measure of effectiveness. The results given below are for all partial seizures in the intent-to-treat population (all patients who received at least one dose of treatment) in each study, unless otherwise indicated. The median seizure frequency at baseline was 3 per week while the mean at baseline was 6.6 per week for all patients enrolled in efficacy studies.
- One study (n = 216) was a double-blind, placebo-controlled, parallel trial consisting of a 24-week treatment period. Patients could not be on more than 2 other anticonvulsants and valproate was not allowed. Patients were randomized to receive placebo, a target dose of 300 mg/day of LAMICTAL, or a target dose of 500 mg/day of LAMICTAL. The median reductions in the frequency of all partial seizures relative to baseline were 8% in patients receiving placebo, 20% in patients receiving 300 mg/day of LAMICTAL, and 36% in patients receiving 500 mg/day of LAMICTAL. The seizure frequency reduction was statistically significant in the 500-mg/day group compared with the placebo group, but not in the 300-mg/day group.
- A second study (n = 98) was a double-blind, placebo-controlled, randomized, crossover trial consisting of two 14-week treatment periods (the last 2 weeks of which consisted of dose tapering) separated by a 4-week washout period. Patients could not be on more than 2 other anticonvulsants and valproate was not allowed. The target dose of LAMICTAL was 400 mg/day. When the first 12 weeks of the treatment periods were analyzed, the median change in seizure frequency was a 25% reduction on LAMICTAL compared with placebo (P<0.001).
- The third study (n = 41) was a double-blind, placebo-controlled, crossover trial consisting of two 12-week treatment periods separated by a 4-week washout period. Patients could not be on more than 2 other anticonvulsants. Thirteen patients were on concomitant valproate; these patients received 150 mg/day of LAMICTAL. The 28 other patients had a target dose of 300 mg/day of LAMICTAL. The median change in seizure frequency was a 26% reduction on LAMICTAL compared with placebo (P<0.01).
- No differences in efficacy based on age, sex, or race, as measured by change in seizure frequency, were detected.
- Adjunctive Therapy With LAMICTAL in Pediatric Patients With Partial Seizures: The effectiveness of LAMICTAL as adjunctive therapy in pediatric patients with partial seizures was established in a multicenter, double-blind, placebo-controlled trial in 199 patients 2 to 16 years of age (n = 98 on LAMICTAL, n = 101 on placebo). Following an 8-week baseline phase, patients were randomized to 18 weeks of treatment with LAMICTAL or placebo added to their current AED regimen of up to 2 drugs. Patients were dosed based on body weight and valproate use. Target doses were designed to approximate 5 mg/kg/day for patients taking valproate (maximum dose: 250 mg/day) and 15 mg/kg/day for the patients not taking valproate (maximum dose: 750 mg/day). The primary efficacy endpoint was percentage change from baseline in all partial seizures. For the intent-to-treat population, the median reduction of all partial seizures was 36% in patients treated with LAMICTAL and 7% on placebo, a difference that was statistically significant (P<0.01).
- Adjunctive Therapy With LAMICTAL in Pediatric and Adult Patients With Lennox-Gastaut Syndrome: The effectiveness of LAMICTAL as adjunctive therapy in patients with Lennox-Gastaut syndrome was established in a multicenter, double-blind, placebo-controlled trial in 169 patients 3 to 25 years of age (n = 79 on LAMICTAL, n = 90 on placebo). Following a 4-week single-blind, placebo phase, patients were randomized to 16 weeks of treatment with LAMICTAL or placebo added to their current AED regimen of up to 3 drugs. Patients were dosed on a fixed-dose regimen based on body weight and valproate use. Target doses were designed to approximate 5 mg/kg/day for patients taking valproate (maximum dose: 200 mg/day) and 15 mg/kg/day for patients not taking valproate (maximum dose: 400 mg/day). The primary efficacy endpoint was percentage change from baseline in major motor seizures (atonic, tonic, major myoclonic, and tonic-clonic seizures). For the intent-to-treat population, the median reduction of major motor seizures was 32% in patients treated with LAMICTAL and 9% on placebo, a difference that was statistically significant (P<0.05). Drop attacks were significantly reduced by LAMICTAL (34%) compared with placebo (9%), as were tonic-clonic seizures (36% reduction versus 10% increase for LAMICTAL and placebo, respectively).
- Adjunctive Therapy With LAMICTAL in Pediatric and Adult Patients With Primary Generalized Tonic-Clonic Seizures: The effectiveness of LAMICTAL as adjunctive therapy in patients with primary generalized tonic-clonic seizures was established in a multicenter, double-blind, placebo-controlled trial in 117 pediatric and adult patients ≥2 years (n = 58 on LAMICTAL, n = 59 on placebo). Patients with at least 3 primary generalized tonic-clonic seizures during an 8-week baseline phase were randomized to 19 to 24 weeks of treatment with LAMICTAL or placebo added to their current AED regimen of up to 2 drugs. Patients were dosed on a fixed-dose regimen, with target doses ranging from 3 mg/kg/day to 12 mg/kg/day for pediatric patients and from 200 mg/day to 400 mg/day for adult patients based on concomitant AED.
- The primary efficacy endpoint was percentage change from baseline in primary generalized tonic-clonic seizures. For the intent-to-treat population, the median percent reduction of primary generalized tonic-clonic seizures was 66% in patients treated with LAMICTAL and 34% on placebo, a difference that was statistically significant (P = 0.006).
- The effectiveness of LAMICTAL in the maintenance treatment of Bipolar I Disorder was established in 2 multicenter, double-blind, placebo-controlled studies in adult patients who met DSM-IV criteria for Bipolar I Disorder. Study 1 enrolled patients with a current or recent (within 60 days) depressive episode as defined by DSM-IV and Study 2 included patients with a current or recent (within 60 days) episode of mania or hypomania as defined by DSM-IV. Both studies included a cohort of patients (30% of 404 patients in Study 1 and 28% of 171 patients in Study 2) with rapid cycling Bipolar Disorder (4 to 6 episodes per year).
- In both studies, patients were titrated to a target dose of 200 mg of LAMICTAL, as add-on therapy or as monotherapy, with gradual withdrawal of any psychotropic medications during an 8- to 16-week open-label period. Overall 81% of 1,305 patients participating in the open-label period were receiving 1 or more other psychotropic medications, including benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), atypical antipsychotics (including olanzapine), valproate, or lithium, during titration of LAMICTAL. Patients with a CGI-severity score of 3 or less maintained for at least 4 continuous weeks, including at least the final week on monotherapy with LAMICTAL, were randomized to a placebo-controlled, double-blind treatment period for up to 18 months. The primary endpoint was TIME (time to intervention for a mood episode or one that was emerging, time to discontinuation for either an adverse event that was judged to be related to Bipolar Disorder, or for lack of efficacy). The mood episode could be depression, mania, hypomania, or a mixed episode.
- In Study 1, patients received double-blind monotherapy with LAMICTAL 50 mg/day (n = 50), LAMICTAL 200 mg/day (n = 124), LAMICTAL 400 mg/day (n = 47), or placebo (n = 121). LAMICTAL (200- and 400-mg/day treatment groups combined) was superior to placebo in delaying the time to occurrence of a mood episode. Separate analyses of the 200- and 400-mg/day dose groups revealed no added benefit from the higher dose.
- In Study 2, patients received double-blind monotherapy with LAMICTAL (100 to 400 mg/day, n = 59), or placebo (n = 70). LAMICTAL was superior to placebo in delaying time to occurrence of a mood episode. The mean dose of LAMICTAL was about 211 mg/day.
- Although these studies were not designed to separately evaluate time to the occurrence of depression or mania, a combined analysis for the 2 studies revealed a statistically significant benefit for LAMICTAL over placebo in delaying the time to occurrence of both depression and mania, although the finding was more robust for depression.
# How Supplied
- 25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25”, bottles of 100 (NDC 0173-0633-02).
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature] in a dry place.
- 100 mg, peach, scored, shield-shaped tablets debossed with “LAMICTAL” and “100”, bottles of 100 (NDC 0173-0642-55).
- 150 mg, cream, scored, shield-shaped tablets debossed with “LAMICTAL” and “150”, bottles of 60 (NDC 0173-0643-60).
- 200 mg, blue, scored, shield-shaped tablets debossed with “LAMICTAL” and “200”, bottles of 60 (NDC 0173-0644-60).
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature] in a dry place and protect from light.
- 25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25”, blisterpack of 35 tablets (NDC 0173-0633-10).
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature] in a dry place.
- 25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25” and 100 mg, peach, scored, shield-shaped tablets debossed with “LAMICTAL” and “100”, blisterpack of 98 tablets (84/25-mg tablets and 14/100-mg tablets) (NDC 0173-0817-28).
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature] in a dry place and protect from light.
- 25 mg, white, scored, shield-shaped tablets debossed with “LAMICTAL” and “25” and 100 mg, peach, scored, shield-shaped tablets debossed with “LAMICTAL” and “100”, blisterpack of 49 tablets (42/25-mg tablets and 7/100-mg tablets) (NDC 0173-0594-02).
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature] in a dry place and protect from light.
- 2 mg, white to off-white, round tablets debossed with “LTG” over “2”, bottles of 30 (NDC 0173-0699-00). ORDER DIRECTLY FROM GlaxoSmithKline 1-800-334-4153.
- 5 mg, white to off-white, caplet-shaped tablets debossed with “GX CL2”, bottles of 100 (NDC 0173-0526-00).
- 25 mg, white, super elliptical-shaped tablets debossed with “GX CL5”, bottles of 100 (NDC 0173-0527-00).
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature] in a dry place.
- 25 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with “LMT” on one side and “25” on the other, Maintenance Packs of 30 (NDC 0173-0772-02).
- 50 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with “LMT” on one side and “50” on the other, Maintenance Packs of 30 (NDC 0173-0774-02).
- 100 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with “LAMICTAL” on one side and “100” on the other, Maintenance Packs of 30 (NDC 0173-0776-02).
- 200 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with “LAMICTAL” on one side and “200” on the other, Maintenance Packs of 30 (NDC 0173-0777-02).
- Store between 20°C to 25°C (68°F to 77°F); with excursions permitted between 15°C and 30°C (59°F and 86°F).
- 25 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with “LMT” on one side and “25” on the other, and 50 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with “LMT” on one side and “50” on the other, blisterpack of 28 tablets (21/25-mg tablets and 7/50-mg tablets) (NDC 0173-0779-00).
- 50 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with “LMT” on one side and “50” on the other, and 100 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with “LAMICTAL” on one side and “100” on the other, blisterpack of 56 tablets (42/50-mg tablets and 14/100-mg tablets) (NDC 0173-0780-00).
- 25 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with “LMT” on one side and “25” on the other, 50 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with “LMT” on one side and “50” on the other, and 100 mg, white to off-white, round, flat-faced, radius edge, tablets debossed with “LAMICTAL” on one side and “100” on the other, blisterpack of 35 (14/25-mg tablets, 14/50-mg tablets, and 7/100-mg tablets) (NDC 0173-0778-00).
- Store between 20°C to 25°C (68°F to 77°F); with excursions permitted between 15°C and 30°C (59°F and 86°F).
- Blisterpacks: If the product is dispensed in a blisterpack, the patient should be advised to examine the blisterpack before use and not use if blisters are torn, broken, or missing.
## Storage
There is limited information regarding Lamotrigine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Rash
- Prior to initiation of treatment with LAMICTAL, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a physician immediately.
- Multiorgan Hypersensitivity Reactions, Blood Dyscrasias, and Organ Failure
- Patients should be instructed that multiorgan hypersensitivity reactions and acute multiorgan failure may occur with LAMICTAL. Isolated organ failure or isolated blood dyscrasias without evidence of multiorgan hypersensitivity may also occur. Patients should contact their physician immediately if they experience any signs or symptoms of these conditions.
- Suicidal Thinking and Behavior
- Patients, their caregivers, and families should be counseled that AEDs, including LAMICTAL, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
- Worsening of Seizures
- Patients should be advised to notify their physician if worsening of seizure control occurs.
- Central Nervous System Adverse Effects
- Patients should be advised that LAMICTAL may cause dizziness, somnolence, and other symptoms and signs of CNS depression. Accordingly, they should be advised neither to drive a car nor to operate other complex machinery until they have gained sufficient experience on LAMICTAL to gauge whether or not it adversely affects their mental and/or motor performance.
- Pregnancy and Nursing
- Patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy. Patients should be advised to notify their physicians if they intend to breastfeed or are breastfeeding an infant.
- Patients should also be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334].
- Patients who intend to breastfeed should be informed that LAMICTAL is present in breast milk and that they should monitor their child for potential adverse effects of this drug. Benefits and risks of continuing breastfeeding should be discussed with the patient.
- Oral Contraceptive Use
- Women should be advised to notify their physician if they plan to start or stop use of oral contraceptives or other female hormonal preparations. Starting estrogen-containing oral contraceptives may significantly decrease lamotrigine plasma levels and stopping estrogen-containing oral contraceptives (including the “pill-free” week) may significantly increase lamotrigine plasma levels. Women should also be advised to promptly notify their physician if they experience adverse reactions or changes in menstrual pattern (e.g., break-through bleeding) while receiving LAMICTAL in combination with these medications.
- Discontinuing LAMICTAL
- Patients should be advised to notify their physician if they stop taking LAMICTAL for any reason and not to resume LAMICTAL without consulting their physician.
- Aseptic Meningitis
- Patients should be advised that LAMICTAL may cause aseptic meningitis. Patients should be advised to notify their physician immediately if they develop signs and symptoms of meningitis such as headache, fever, nausea, vomiting, stiff neck, rash, abnormal sensitivity to light, myalgia, chills, confusion, or drowsiness while taking LAMICTAL.
- Potential Medication Errors
- Medication errors involving LAMICTAL have occurred. In particular the names LAMICTAL or lamotrigine can be confused with the names of other commonly used medications. Medication errors may also occur between the different formulations of LAMICTAL. To reduce the potential of medication errors, write and say LAMICTAL clearly. Depictions of the LAMICTAL Tablets, Chewable Dispersible Tablets, and Orally Disintegrating Tablets can be found in the Medication Guide that accompanies the product to highlight the distinctive markings, colors, and shapes that serve to identify the different presentations of the drug and thus may help reduce the risk of medication errors. To avoid a medication error of using the wrong drug or formulation, patients should be strongly advised to visually inspect their tablets to verify that they are LAMICTAL, as well as the correct formulation of LAMICTAL, each time they fill their prescription.
# Precautions with Alcohol
- Alcohol-Lamotrigine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- LAMICTAL®[1]
# Look-Alike Drug Names
- LaMICtal® — LamISIL®[2]
- lamoTRIgine® — lamiVUDine®[2]
- lamoTRIgine® — levothyroxine®[2]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Lamictal | |
c40e9f3d37e8e73c77fb5ab9ea392b176b024963 | wikidoc | Laminectomy | Laminectomy
# Overview
Laminectomy is a surgical procedure for treating spinal stenosis by relieving pressure on the spinal cord. The lamina of the vertebra is removed or trimmed to widen the spinal canal and create more space for the spinal nerves.
The first laminectomy was performed in 1887 by Dr. Victor Alexander Haden Horsley, a professor of surgery at the University College London. He was lauded for his breakthrough procedure.
A common type of laminectomy is performed to permit the removal or reshaping of a spinal disc as part of a lumbar discectomy. This is a treatment for a herniated disc, bulging or degenerated disc. | Laminectomy
Template:Interventions infobox
# Overview
Laminectomy is a surgical procedure for treating spinal stenosis by relieving pressure on the spinal cord. The lamina of the vertebra is removed or trimmed to widen the spinal canal and create more space for the spinal nerves.
The first laminectomy was performed in 1887 by Dr. Victor Alexander Haden Horsley, a professor of surgery at the University College London. He was lauded for his breakthrough procedure.
A common type of laminectomy is performed to permit the removal or reshaping of a spinal disc as part of a lumbar discectomy. This is a treatment for a herniated disc, bulging or degenerated disc.
# External links
- Laminectomy - Information for Patients
- Laminectomy - Better Health Channel
Template:Neurosurgical procedures
de:Laminektomie
nl:Laminectomie
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Laminectomy |
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