西罗莫司/环孢素联合方案用于肾移植的免疫抑制作用及安全性
Immunosuppressive effects and safety of a sirolimus/cyclosporine combination regimen for renal transplantation.
作者信息
Kahan B D, Podbielski J, Napoli K L, Katz S M, Meier-Kriesche H U, Van Buren C T
机构信息
Department of Surgery, The University of Texas Medical School at Houston, 77030, USA.
出版信息
Transplantation. 1998 Oct 27;66(8):1040-6. doi: 10.1097/00007890-199810270-00013.
BACKGROUND
Sirolimus, a novel immunosuppressant that inhibits cytokine-driven cell proliferation and maturation, prolongs allograft survival in animal models. After a phase I trial in stable renal transplant recipients documented that cyclosporine and sirolimus have few overlapping toxicities, we conducted an open-label, single-center, phase I/II dose-escalation trial to examine the safety and efficacy of this drug combination.
METHODS
Forty mismatched living-donor renal transplant recipients were sequentially assigned to receive escalating initial doses of sirolimus (0.5-7.0 mg/m2/day), in addition to courses of prednisone and a concentration-controlled regimen of cyclosporine. We conducted surveillance for drug-induced side effects among sirolimus-treated patients and compared their incidence of acute rejection episodes as well as mean laboratory values with those of a historical cohort of 65 consecutive, immediately precedent, demographically similar recipients treated with the same concentration-controlled regimen of cyclosporine and tapering doses of prednisone.
RESULTS
The addition of sirolimus reduced the overall incidence of acute allograft rejection episodes to 7.5% from 32% in the immediately precedent cyclosporine/prednisone-treated patients. At 18- to 47-month follow-up periods, both treatment groups displayed similar rates of patient and graft survival, as well as morbid complications. Although sirolimus-treated patients displayed comparatively lower platelet and white blood cell counts and higher levels of serum cholesterol and triglycerides, sirolimus did not augment the nephrotoxic or hypertensive proclivities of cyclosporine. The degree of change in the laboratory values was more directly associated with whole blood trough drug concentrations than with doses of sirolimus.
CONCLUSIONS
Sirolimus potentiates the immunosuppressive effects of a cyclosporine-based regimen by reducing the rate of acute rejection episodes.
背景
西罗莫司是一种新型免疫抑制剂，可抑制细胞因子驱动的细胞增殖和成熟，在动物模型中可延长同种异体移植物存活时间。在一项针对稳定肾移植受者的I期试验证明环孢素和西罗莫司几乎没有重叠毒性后，我们开展了一项开放标签、单中心、I/II期剂量递增试验，以研究这种药物组合的安全性和有效性。
方法
40例配型不合的活体供肾肾移植受者被依次分配接受递增初始剂量的西罗莫司（0.5 - 7.0 mg/m²/天），同时接受泼尼松疗程以及环孢素浓度控制方案。我们对接受西罗莫司治疗的患者进行药物诱导副作用监测，并将他们的急性排斥反应发生率以及平均实验室值与65例连续的、紧接在前的、人口统计学特征相似且接受相同环孢素浓度控制方案和逐渐减量泼尼松治疗的历史队列患者进行比较。
结果
添加西罗莫司后，急性同种异体移植排斥反应的总体发生率从紧接在前的接受环孢素/泼尼松治疗患者的32%降至7.5%。在18至47个月的随访期内，两个治疗组的患者和移植物存活率以及发病并发症发生率相似。尽管接受西罗莫司治疗的患者血小板和白细胞计数相对较低，血清胆固醇和甘油三酯水平较高，但西罗莫司并未增加环孢素的肾毒性或高血压倾向。实验室值的变化程度与全血谷浓度的相关性比与西罗莫司剂量的相关性更直接。
结论
西罗莫司通过降低急性排斥反应发生率增强了基于环孢素方案的免疫抑制作用。
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