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Sirolimus Mechanism Of Action

Sirolimus Mechanism Of Action

Sirolimus

Sirolimus (rapamycin) is a novel immunosuppressive agent that impairs cytokine-induced lymphocyte proliferation. The prolonged half-life of sirolimus means that once-daily dosing is sufficient. It is metabolized via the cytochrome P-450 system; thus, the potential for multiple drug interactions exists. Adverse effects of sirolimus include hyperlipidemia, anemia, thrombocytopenia, diarrhea, and interstitial pneumonitis. Short- and medium-term data suggest sirolimus may have a useful role as a CNI-sparing agent. There is growing evidence that sirolimus has important antineoplastic effects in vivo.

Sirolimus: a new promising immunosuppressive drug.

For about 30 years, maintenance immunosuppression in the field of organ transplantation has been limited by the availability of only three drugs: corticosteroids, azathioprine, and cyclosporin. For the last 10 years, however, new immunosuppressive agents such as tacrolimus and mycophenolate mofetil (MMF) have been developed and are now available for transplant patients. Sirolimus (rapamycin), the latest one, is still being developed. It seems a very promising immunosuppressive drug which could in future replace calcineurin inhibitors such as cyclosporin.

Mechanisms of action

T‐cell activation comprises two major phases. The first, which follows triggering of the T‐cell receptor, results in the transcriptional activation of cytokine genes, and leads from the quiescent T‐cell state (G0) to the competent state (G1). The second phase involves the response of the competent T cells, i.e. their secretion of growth‐promoting interleukins (IL) such as IL2 or IL4, in an autocrine or paracrine fashion. It also drives competent T‐cell entry into the proliferation cycle via progression from the G1 to the S phase, with subsequent clonal expansion and the acquisition of T‐cell effector functions.

Absence of nephrotoxic effects

Animal studies in Wistar rats and pigs have demonstrated that unlike treatment with calcineurin inhibitors, sirolimus treatment alters neither renal blood flow nor glomerular filtration rate. This absence of nephrotoxicity has been confirmed in humans. At the end of a 12‐week treatment with sirolimus at three different doses, psoriasis patients exhibited normal renal function, as did control group patients given a placebo only (Wyeth‐Ayerst, personal communication).

In addition, the results of two phase‐II randomized trials involving renal transplant recipients, in which sirolimus and cyclosporin were compared as base immunosuppressive therapy, showed that 2 years after transplantation, serum creatinine levels were always lower in sirolimus‐treated patients.

Use of sirolimus in human renal transplantation

because in vitro and animal studies have confirmed the synergistic immunosuppressive effect of cyclosporin and sirolimus these drugs were initially combined in human renal transplantation. two large phase‐iii and randomized studies showed that the cyclosporin–sirolimus combination reduced the number of acute rejection episodes significantly, more than either a placebo or azathioprine. nevertheless, despite this reduction, the apparent absence of intrinsic nephrotoxicity, and similar cyclosporin trough levels in the groups compared, sirolimus patients had worse renal function at 1 year than those treated with placebo or azathioprine (wyeth‐ayerth, personal communication).

Sirolimus as base immunosuppressive therapy

Because sirolimus has potent immunosuppressive properties and does not cause intrinsic nephrotoxicity, it has also been used as base immunosuppressive therapy together with steroids and either azathioprine or MMF. Two prospective phase‐II randomized European studies using therapeutic dose monitoring centred on the comparative effects of combining either cyclosporin or sirolimus with steroids and azathioprine.

Conclusions and prospects

For the last 4 years, sirolimus has proved a potent immunosuppressive drug in humans. It has been successfully used with and without cyclosporin, and might be a good alternative to calcineurin inhibitors. Its original mechanisms of action and toxicity profile make it a true immunosuppressive agent. Given these characteristics, other combinations need testing in randomized studies. Preliminary data in humans showed that tacrolimus could be an efficient and safe partner for sirolimus.

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