Kahan B D
University of Texas Medical School at Houston, Houston, Texas 77030, USA.
Transplant Proc. 2008 Dec;40(10 Suppl):S17-20. doi: 10.1016/j.transproceed.2008.10.019.
Over the course of 15 years the use of sirolimus, a macrocyclic lactone, has evolved from an adjunct to calcineurin inhibitors (CNI) to the foundation of therapy due to the drug's unique properties: First, it displays synergistic pharmacodynamic interactions with CNI. Even among high immunologic risk patients, this regimen attenuates the risk of acute allograft rejection episodes when used in combination with cyclosporine or tacrolimus. Indeed >80% reduction in CNI exposure de novo yields better long-term renal function than full cyclosporine (CsA) doses, a useful tradeoff, despite the augmented occurrence of lymphoceles and impaired wound healing. Second, by inhibiting mammalian target of rapamycin (mTOR), it exerts profound anti-neoplastic effects reducing the incidence and mediating the regression of tumors displaying PTEN-deletions and/or Akt-activations in transplant and non-transplant patients. Third, it is relatively non-nephrotoxic although it may exacerbate that property of CNI agents. Fourth, it allows prompt withdrawal of steroid therapy. Fifth, it displays reduced rates of cytomegalovirus, and BK virus infections. The major adverse reactions can generally be controlled with countermeasure therapy. Myelosuppressive effects, which tend to be transient (unless sirolimus is combined with mycophenolic acid), are readily amenable to treatment with granulocyte colony stimulating factor for leukopenia, interleukin 11 for thrombocytopenia and erythropoietin for anemia. Combinations of statins and fibrates represent effective countermeasure therapy for hypercholesterolemia and hypertriglyceridemia, respectively. Idiosyncratic reactions include hypoxemic pulmonary toxicity, refractory edema and diarrhea. Thus, sirolimus represents the vanguard of a new class of maintenance agents for immunosuppression.
在15年的时间里，大环内酯类药物西罗莫司的使用已从钙调神经磷酸酶抑制剂（CNI）的辅助药物演变为治疗基础，这归因于该药物的独特特性：其一，它与CNI表现出协同药效学相互作用。即使在高免疫风险患者中，该方案与环孢素或他克莫司联合使用时，也能降低急性移植排斥反应的风险。事实上，与全剂量环孢素（CsA）相比，从头减少>80%的CNI暴露可产生更好的长期肾功能，这是一个有益的权衡，尽管淋巴囊肿的发生率增加且伤口愈合受损。其二，通过抑制哺乳动物雷帕霉素靶蛋白（mTOR），它发挥着深远的抗肿瘤作用，降低了移植和非移植患者中显示PTEN缺失和/或Akt激活的肿瘤的发生率并介导其消退。其三，它相对无肾毒性，尽管可能会加剧CNI药物的这一特性。其四，它允许迅速停用类固醇治疗。其五，它显示出较低的巨细胞病毒和BK病毒感染率。主要不良反应通常可用对策疗法控制。骨髓抑制作用往往是短暂的（除非西罗莫司与霉酚酸联合使用），对于白细胞减少症，用粒细胞集落刺激因子治疗很容易见效，对于血小板减少症，用白细胞介素11治疗，对于贫血，用促红细胞生成素治疗。他汀类药物和贝特类药物的组合分别是治疗高胆固醇血症和高甘油三酯血症的有效对策疗法。特异反应包括低氧性肺毒性、难治性水肿和腹泻。因此，西罗莫司代表了一类新型免疫抑制维持药物的前沿。
