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Ed's profile was raised even higher with a series of specials and appearances on the national music video channel MuchMusic.
The series was taken off the air in Alberta and other parts of the country after the show aired a comedy sequence in which Ed is shown supposedly having sex with a Playboy playmate, even though the program was being broadcast in a late night time slot.
In addition to its record-breaking run in Canada, the show briefly ran on G4 in the United States as part of their "Midnight Spank" late night television programming block.
The show was also carried on the Ripe TV on-demand service.
The show was retired with its final episode airing on CITY-TV on August 31, 2008.
In Australia the show is seen on Fuel TV, where it is known as "Ed the Sock".
After the shows cancellation, both Ed the Sock, Liana Kerzner, and Ron Sparks would later return together on a different show produced by CHCH-TV Hamilton called "This Movie Sucks!
", where the three pick on bad movies.
Sirolimus
Sirolimus, also known as rapamycin, is a macrolide compound that is used to coat coronary stents, prevent organ transplant rejection and treat a rare lung disease called lymphangioleiomyomatosis.
It has immunosuppressant functions in humans and is especially useful in preventing the rejection of kidney transplants.
It inhibits activation of T cells and B cells by reducing their sensitivity to interleukin-2 (IL-2) through mTOR inhibition.
It is produced by the bacterium "Streptomyces hygroscopicus" and was isolated for the first time in 1972 by Surendra Nath Sehgal and colleagues from samples of "Streptomyces hygroscopicus" found on Easter Island.
The compound was originally named rapamycin after the native name of the island, Rapa Nui.
Sirolimus was initially developed as an antifungal agent.
However, this use was abandoned when it was discovered to have potent immunosuppressive and antiproliferative properties due to its ability to inhibit mTOR.
It was approved by the US Food and Drug Administration in September 1999 and is marketed under the trade name Rapamune by Pfizer (formerly by Wyeth).
Sirolimus is indicated for the prevention of organ transplant rejection and for the treatment of lymphangioleiomyomatosis (LAM).
The chief advantage sirolimus has over calcineurin inhibitors is its low toxicity toward kidneys.
Transplant patients maintained on calcineurin inhibitors long-term tend to develop impaired kidney function or even kidney failure; this can be avoided by using sirolimus instead.
It is particularly advantageous in patients with kidney transplants for hemolytic-uremic syndrome, as this disease is likely to recur in the transplanted kidney if a calcineurin-inhibitor is used.
However, on 7 October 2008, the FDA approved safety labeling revisions for sirolimus to warn of the risk for decreased renal function associated with its use.
In 2009, the FDA notified healthcare professionals that a clinical trial conducted by Wyeth showed an increased mortality in stable liver transplant patients after switching from a calcineurin inhibitor-based immunosuppressive regimen to sirolimus.
Sirolimus can also be used alone, or in conjunction with a calcineurin inhibitor (such as tacrolimus), and/or mycophenolate mofetil, to provide steroid-free immunosuppression regimens.
Impaired wound healing and thrombocytopenia are a possible side effects of sirolimus; therefore, some transplant centers prefer not to use it immediately after the transplant operation, but instead administer it only after a period of weeks or months.
Its optimal role in immunosuppression has not yet been determined, and it remains the subject of a number of ongoing clinical trials.
On 28 May 2015, the FDA approved sirolimus to treat lymphangioleiomyomatosis (LAM), a rare, progressive lung disease that primarily affects women of childbearing age.
This made sirolimus the first drug approved to treat this disease.
LAM involves lung tissue infiltration with smooth muscle-like cells with mutations of the tuberous sclerosis complex gene (TSC2).
Loss of TSC2 gene function activates the mTOR signaling pathway, resulting in the release of lymphangiogenic growth factors.
Sirolimus blocks this pathway.
The safety and efficacy of sirolimus treatment of LAM were investigated in clinical trials that compared sirolimus treatment with a placebo group in 89 patients for 12 months.
The patients were observed for 12 months after the treatment had ended.
The most commonly reported side effects of sirolimus treatment of LAM were mouth and lip ulcers, diarrhea, abdominal pain, nausea, sore throat, acne, chest pain, leg swelling, upper respiratory tract infection, headache, dizziness, muscle pain and elevated cholesterol.
Serious side effects including hypersensitivity and swelling (edema) have been observed in renal transplant patients.
While sirolimus was considered for treatment of LAM, it received orphan product designation status because LAM is a rare condition.
Development for the product was partially supported by the FDA Orphan Products Grants Program, which provides grants for clinical studies on safety and/or effectiveness of products for use in rare diseases or conditions.
The safety of LAM treatment by sirolimus in patients younger than 18 years old has not been tested.
The antiproliferative effect of sirolimus has also been used in conjunction with coronary stents to prevent restenosis in coronary arteries following balloon angioplasty.
The sirolimus is formulated in a polymer coating that affords controlled release through the healing period following coronary intervention.
Several large clinical studies have demonstrated lower restenosis rates in patients treated with sirolimus-eluting stents when compared to bare-metal stents, resulting in fewer repeat procedures.
A sirolimus-eluting coronary stent was marketed by Cordis, a division of Johnson & Johnson, under the tradename Cypher.
However, this kind of stent may also increase the risk of vascular thrombosis.
Sirolimus is contraindicated in individuals with a known hypersensitivity to the drug.
The most common adverse reactions (≥30% occurrence, leading to a 5% treatment discontinuation rate) observed with sirolimus in clinical studies of organ rejection prophylaxis in individuals with kidney transplants include: peripheral edema, hypercholesterolemia, abdominal pain, headache, nausea, diarrhea, pain, constipation, hypertriglyceridemia, hypertension, increased creatinine, fever, urinary tract infection, anemia, arthralgia, and thrombocytopenia.
The most common adverse reactions (≥20% occurrence, leading to an 11% treatment discontinuation rate) observed with sirolimus in clinical studies for the treatment of lymphangioleiomyomatosis are: peripheral edema, hypercholesterolemia, abdominal pain, headache, nausea, diarrhea, chest pain, stomatitis, nasopharyngitis, acne, upper respiratory tract infection, dizziness, and myalgia.
The following adverse effects occurred in 3–20% of individuals taking sirolimus for organ rejection prophylaxis following a kidney transplant:
While sirolimus inhibition of mTORC1 appears to mediate the drug's benefits, it also inhibits mTORC2, which results in diabetes-like symptoms.
This includes decreased glucose tolerance and insensitivity to insulin.
Sirolimus treatment may additionally increase the risk of type 2 diabetes.
In mouse studies, these symptoms can be avoided through the use of alternate dosing regimens or analogs such as everolimus or temsirolimus.
Lung toxicity is a serious complication associated with sirolimus therapy, especially in the case of lung transplants.
The mechanism of the interstitial pneumonitis caused by sirolimus and other macrolide MTOR inhibitors is unclear, and may have nothing to do with the mTOR pathway.
The interstitial pneumonitis is not dose-dependent, but is more common in patients with underlying lung disease.
There have been warnings about the use of sirolimus in transplants, where it may increase mortality due to an increased risk of infections.
According to the FDA prescribing information, sirolimus may increase an individual's risk for contracting skin cancers from exposure to sunlight or UV radiation, and risk of developing lymphoma.
In studies, the skin cancer risk under sirolimus was lower than under other immunosuppressants such as azathioprine and calcineurin inhibitors, and lower than under placebo.
Individuals taking sirolimus are at increased risk of experiencing impaired or delayed wound healing, particularly if they have a high body mass index (i.e., a BMI of ≥30 kg/m).
Sirolimus is metabolized by the CYP3A4 enzyme and is a substrate of the P-glycoprotein (P-gp) efflux pump; hence, inhibitors of either protein may increase sirolimus concentrations in blood plasma, whereas inducers of CYP3A4 and P-gp may decrease sirolimus concentrations in blood plasma.
Unlike the similarly named tacrolimus, sirolimus is not a calcineurin inhibitor, but it has a similar suppressive effect on the immune system.
Sirolimus inhibits IL-2 and other cytokine receptor-dependent signal transduction mechanisms, via action on mTOR, and thereby blocks activation of T and B cells.
Ciclosporin and tacrolimus inhibit the secretion of IL-2, by inhibiting calcineurin.
The mode of action of sirolimus is to bind the cytosolic protein FK-binding protein 12 (FKBP12) in a manner similar to tacrolimus.
Unlike the tacrolimus-FKBP12 complex, which inhibits calcineurin (PP2B), the sirolimus-FKBP12 complex inhibits the mTOR (mammalian Target Of Rapamycin, rapamycin being another name for sirolimus) pathway by directly binding to mTOR Complex 1 (mTORC1).
mTOR has also been called FRAP (FKBP-rapamycin-associated protein), RAFT (rapamycin and FKBP target), RAPT1, or SEP.
The earlier names FRAP and RAFT were coined to reflect the fact that sirolimus must bind FKBP12 first, and only the FKBP12-sirolimus complex can bind mTOR.
However, mTOR is now the widely accepted name, since Tor was first discovered via genetic and molecular studies of sirolimus-resistant mutants of "Saccharomyces cerevisiae" that identified FKBP12, Tor1, and Tor2 as the targets of sirolimus and provided robust support that the FKBP12-sirolimus complex binds to and inhibits Tor1 and Tor2.
Sirolimus is metabolized by the CYP3A4 enzyme and is a substrate of the P-glycoprotein (P-gp) efflux pump.
It has an elimination half-life of 57–63 hours.
The absorption of sirolimus into the blood stream from the intestine varies widely between patients, with some patients having up to eight times more exposure than others for the same dose.
Drug levels are, therefore, taken to make sure patients get the right dose for their condition.
This is determined by taking a blood sample before the next dose, which gives the trough level.
However, good correlation is noted between trough concentration levels and drug exposure, known as area under the concentration-time curve, for both sirolimus (SRL) and tacrolimus (TAC) (SRL: r2 = 0.83; TAC: r2 = 0.82), so only one level need be taken to know its pharmacokinetic (PK) profile.
PK profiles of SRL and of TAC are unaltered by simultaneous administration.
Dose-corrected drug exposure of TAC correlates with SRL (r2 = 0.8), so patients have similar bioavailability of both.
Sirolimus is a natural product and macrocyclic lactone.
The biosynthesis of the rapamycin core is accomplished by a type I polyketide synthase (PKS) in conjunction with a nonribosomal peptide synthetase (NRPS).
The domains responsible for the biosynthesis of the linear polyketide of rapamycin are organized into three multienzymes, RapA, RapB, and RapC, which contain a total of 14 modules (figure 1).
The three multienzymes are organized such that the first four modules of polyketide chain elongation are in RapA, the following six modules for continued elongation are in RapB, and the final four modules to complete the biosynthesis of the linear polyketide are in RapC.
Then, the linear polyketide is modified by the NRPS, RapP, which attaches L-pipecolate to the terminal end of the polyketide, and then cyclizes the molecule, yielding the unbound product, prerapamycin.
The core macrocycle, prerapamycin (figure 2), is then modified (figure 3) by an additional five enzymes, which lead to the final product, rapamycin.
First, the core macrocycle is modified by RapI, SAM-dependent O-methyltransferase (MTase), which O-methylates at C39.
Next, a carbonyl is installed at C9 by RapJ, a cytochrome P-450 monooxygenases (P-450).
Then, RapM, another MTase, O-methylates at C16.
Finally, RapN, another P-450, installs a hydroxyl at C27 immediately followed by O-methylation by Rap Q, a distinct MTase, at C27 to yield rapamycin.
The biosynthetic genes responsible for rapamycin synthesis have been identified.
As expected, three extremely large open reading frames (ORF's) designated as "rapA", "rapB", and "rapC" encode for three extremely large and complex multienzymes, RapA, RapB, and RapC, respectively.
The gene "rapL" has been established to code for a NAD+-dependent lysine cycloamidase, which converts L-lysine to L-pipecolic acid (figure 4) for incorporation at the end of the polyketide.
The gene "rapP", which is embedded between the PKS genes and translationally coupled to "rapC", encodes for an additional enzyme, an NPRS responsible for incorporating L-pipecolic acid, chain termination and cyclization of prerapamycin.
In addition, genes "rapI", "rapJ", "rapM", "rapN", "rapO", and "rapQ" have been identified as coding for tailoring enzymes that modify the macrocyclic core to give rapamycin (figure 3).
Finally, "rapG" and "rapH" have been identified to code for enzymes that have a positive regulatory role in the preparation of rapamycin through the control of rapamycin PKS gene expression.
Biosynthesis of this 31-membered macrocycle begins as the loading domain is primed with the starter unit, 4,5-dihydroxocyclohex-1-ene-carboxylic acid, which is derived from the shikimate pathway.
Note that the cyclohexane ring of the starting unit is reduced during the transfer to module 1.
The starting unit is then modified by a series of Claisen condensations with malonyl or methylmalonyl substrates, which are attached to an acyl carrier protein (ACP) and extend the polyketide by two carbons each.
After each successive condensation, the growing polyketide is further modified according to enzymatic domains that are present to reduce and dehydrate it, thereby introducing the diversity of functionalities observed in rapamycin (figure 1).
Once the linear polyketide is complete, L-pipecolic acid, which is synthesized by a lysine cycloamidase from an L-lysine, is added to the terminal end of the polyketide by an NRPS.
Then, the NSPS cyclizes the polyketide, giving prerapamycin, the first enzyme-free product.
The macrocyclic core is then customized by a series of post-PKS enzymes through methylations by MTases and oxidations by P-450s to yield rapamycin.
The antiproliferative effects of sirolimus may have a role in treating cancer.
When dosed appropriately, sirolimus can enhance the immune response to tumor targeting or otherwise promote tumor regression in clinical trials.