A macrolide, Rapamycin was aboriginal apparent as a artefact of the bacillus Streptomyces hygroscopicus in a clay sample from Easter Island — an island aswell accepted as Rapa Nui, appropriately the name. It was accustomed by the FDA in September 1999 and is marketed beneath the barter name Rapamune by Pfizer (formerly by Wyeth).
Rapamycin was originally developed as an antifungal agent. However, this use was alone if it was apparent to accept almighty immunosuppressive and antiproliferative properties. It has back been apparent to prolong the activity of mice and ability aswell be advantageous in the analysis of assertive cancers.
Clinical uses
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.
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