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More about Sirolimus

What is/are Sirolimus?

Sirolimus (INN/USAN), also known as rapamycin, is an immunosuppressant drug used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. It prevents activation of T cells and B cells by inhibiting their response to interleukin-2 (IL-2). Sirolimus is also used as a coronary stent coating.

A macrolide, sirolimus was discovered by Brazilian researchers as a product of the bacterium Streptomyces hygroscopicus in a soil sample from Easter Island — an island also known as Rapa Nui. It was approved by the FDA in September 1999 and is marketed under the trade name Rapamune by Pfizer (formerly by Wyeth).

Sirolimus was originally developed as an antifungal agent. However, this use was abandoned when it was discovered to have potent immunosuppressive and antiproliferative properties. It has since been shown to prolong the life of mice and might also be useful in the treatment of certain cancers.

Medical uses


Prevention of transplant rejection

The chief advantage sirolimus has over calcineurin inhibitors is its low toxicity towards kidneys. Transplant patients maintained on calcineurin inhibitors long-term tend to develop impaired kidney function or even chronic renal 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 October 7, 2008, the FDA approved safety labeling revisions for sirolimus to warn of the risk for decreased renal function associated with its use.

Sirolimus can also be used alone, or in conjunction with calcineurin inhibitors, 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 centres 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 is the subject of a number of ongoing clinical trials.

Sirolimus is absorbed into the blood stream from the intestine variably in each patient, 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. Fortunately, there is good correlation 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.

Coronary stent coating

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. It has been proposed, however, that such stents may increase the risk of vascular thrombosis.

Adverse effects

Lung toxicity

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.

Cancer risk

As with all immunosuppressive medications, in theory sirolimus may decrease the body's inherent anticancer activity and allow some cancers which would have been naturally destroyed to proliferate. Patients on immunosuppressive medications have a 10- to 100-fold increased risk of cancer compared to the general population. Historically, approximately 10% of solid organ recipients treated with calcineurin inhibitors develop skin tumours and lymphoma after 70 months. However, there is contradictory data regarding calcineurin inhibitors versus sirolimus via UV-induced carcinogenesis-associated processes such as DNA repair, p53 and MMP expression as a result from different biochemical mechanisms. People who currently have or have already been treated for cancer have a higher rate of tumor progression and recurrence than patients with an intact immune system[citation needed]. These general considerations counsel caution when exploring the potential of sirolimus to combat cancer. However, a plethora of studies indicate that when dosed appropriately, sirolimus can enhance the immune response to tumor targeting or otherwise promote tumor regression in clinical trials. Sirolimus seems to lower the cancer risk in some transplant patients.

Diabetes-like symptoms

Sirolimus inhibits a protein kinase complex known as mTORC1, and this appears to provide most of the beneficial effects of the drug (including life-lengthening in animal studies). Sirolimus also acts on a related complex known as mTORC2. Disruption of mTORC2 produces the diabetes-like symptoms of decreased glucose tolerance and insensitivity to insulin also associated with sirolimus.

Mechanism of action

Unlike the similarly named tacrolimus, sirolimus is not a calcineurin inhibitor, but it has a similar suppressive effect on the immune system. Sirolimus inhibits the response to interleukin-2 (IL-2), and thereby blocks activation of T and B cells. In contrast, tacrolimus inhibits the secretion of IL-2.

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 mammalian target of rapamycin (mTOR, rapamycin being an older name for sirolimus) pathway by directly binding the mTOR Complex1 (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.

This article uses material from the Wikipedia article Sirolimus, which is released under the Creative Commons Attribution-Share-Alike License 3.0.

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