The side effect profile of sirolimus: A phase I study in quiescent cyclosporine-prednisone-treated renal transplant patients
The side effect profile of sirolimus: A phase I study in quiescent cyclosporine-prednisone-treated renal transplant patients
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DOI：
10.1038/ki.1996.28
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发表时间：
1996-01-01
影响因子：
19.6
通讯作者：
Kahan, BD
中科院分区：
文献类型：
--
作者：
Murgia, MG;Jordan, S;Kahan, BD
在一项双盲随机研究中，对接受双药环孢素（CsA）/皮质类固醇方案的静止期肾移植患者给予14天剂量递增的西罗莫司（雷帕霉素，RAPA）。口服西罗莫司或安慰剂每日两次分次给药，持续13天，并在研究第14天早晨给予末次给药。此外，将西罗莫司和安慰剂治疗组的患者与人口统计学匹配的同时接受治疗的对照队列（30例接受相同浓度对照CsA/皮质类固醇方案的患者）进行比较。研究队列分为4个西罗莫司剂量水平组：安慰剂（0 mg/m2/天，N = 10）、低剂量（1 - 3 mg/m2/天，N = 9）、中剂量（5 - 6 mg/m2/天，N = 9）和高剂量（7 - 13 mg/m2/天，N = 12）。西罗莫司的主要副作用是血小板（PLT）和白色血细胞（WBC）计数的可逆性降低。与安慰剂组患者相比，西罗莫司治疗组患者的胆固醇值在统计学上显著增加，但与对照组患者相比，胆固醇值无统计学意义。西罗莫司剂量组（包括安慰剂）之间的CsA稳态平均浓度无统计学显著差异。西罗莫司治疗前后的收缩压和舒张压值、肾小球滤过率（GFR）、血清肌酐值（S-Cr）和血清谷草转氨酶（SGOT）、血清谷丙转氨酶（SGPT）或甘油三酯水平之间未观察到差异。由于西罗莫司的主要副作用与CsA的主要肾毒性特性不同，因此该药物组合可显示有效的免疫抑制而不加重毒性。
A 14-day ascending dose course of sirolimus (rapamycin, RAPA) was administered to quiescent renal transplant patients receiving a double-drug cyclosporine (CsA)/corticosteroid regimen in a double-blinded randomized study. Oral sirolimus or placebo was delivered twice daily in divided doses for 13 days and a final dose was administered on the morning of study day 14. In addition, patients in the sirolimus- and placebo-treated groups were compared with a demographically matched, concurrently treated control cohort of 30 patients who received the same concentration-controlled CsA/corticosteroid regimen. The study cohort was partitioned into four sirolimus dose level groups: placebo (0 mg/m(2)/day, N = 10), low dose (1 to 3 mg/m(2)/day, N = 9), medium dose (5 to 6 mg/m(2)/day, N = 9), and high dose (7 to 13 mg/m(2)/day, N = 12). The primary side effect of sirolimus was a reversible decrease in platelet (PLT) and white blood cell (WBC) counts. Cholesterol values increased statistically significantly in the sirolimus-treated patients when compared with those of the placebo patients, but not when compared with those of the control group patients. There were no statistically significant differences in the steady-state average concentrations of CsA among sirolimus dose groups (including placebo). No differences were observed between the pre- and post-sirolimus treatment values of systolic and diastolic blood pressure values, glomerular filtration rates (GFR), serum creatinine values (S-Cr), and serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT) or triglyceride levels. Because the principal side effects of sirolimus are distinct from the principal nephrotoxic properties of CsA, this drug combination may display potent immunosuppression without exacerbated toxicity.