Tu Y, Stepkowski S M, Chou T C, Kahan B D
Department of Surgery, University of Texas Medical School at Houston 77030.
Transplantation. 1995 Jan 27;59(2):177-83.
The effects of cyclosporine (CsA), sirolimus (RAPA), and/or brequinar (BQR) were examined in a vascularized heterotopic heart transplant model in mice. Untreated C3H (H-2k) recipients reject C57 BL/10 (H-2b) heart allografts at a mean survival time (MST) of 7.7 +/- 1.4 days. A 7-d intravenous (i.v.) infusion by osmotic pump of CsA at doses of 5.0, 10.0, or 20.0 mg/kg extended heart allograft survival to 9.8 +/- 1.3 d (NS), 15.0 +/- 5.1 d (P < 0.01) or 15.0 +/- 1.9 d (P < 0.01), respectively. RAPA delivered i.v. for 7 d at a dose of 0.1 mg/kg produced an MST of 13.0 +/- 7.5 d; 0.2 mg/kg, 20.0 +/- 10.9 d; and 0.4 mg/kg, 15.8 +/- 4.1 d (all P < 0.01). A 7-d alternate-day (q.o.d.) course of oral gavage with BQR (0.5, 1.0, or 2.0 mg/kg) produced survivals of 12.0 +/- 2.4 d, 17.6 +/- 3.4 d, and 20.0 +/- 4.1 d, respectively (all P < 0.01). The combination of 2.5 mg/kg CsA with 0.05 mg/kg RAPA extended graft survival to 18.2 +/- 2.9 d (P < 0.01), and 5.0 mg/kg CsA with 0.1 mg/kg RAPA prolonged survival to 23.0 +/- 9.0 d (P < 0.01). These combinations represent synergistic interactions based upon combination index (CI) values of 0.1-0.6. Although 7-d courses of 0.5 mg/kg CsA (7.3 +/- 1.0 d; NS), 0.01 mg/kg RAPA (7.6 +/- 0.9 d; NS), or 0.125 mg/kg BQR (7.6 +/- 0.9 d; NS) were individually ineffective, the triple-drug combination prolonged the MST to 64.6 +/- 32.7 d (P < 0.005; CI = 0.001), with 2/5 grafts beating for more than 100 d. Similar results were produced by 14-day therapy in the BALB/c (H-2d) to C3H combination.
在小鼠血管化异位心脏移植模型中研究了环孢素（CsA）、西罗莫司（RAPA）和/或布喹那（BQR）的作用。未经治疗的C3H（H-2k）受体平均在7.7±1.4天内排斥C57 BL/10（H-2b）心脏同种异体移植物。通过渗透泵以5.0、10.0或20.0 mg/kg的剂量进行7天静脉内（i.v.）输注CsA，可将心脏同种异体移植物的存活时间分别延长至9.8±1.3天（无统计学意义）、15.0±5.1天（P<0.01）或15.0±1.9天（P<0.01）。以0.1 mg/kg的剂量静脉内给予RAPA 7天，产生的平均存活时间为13.0±7.5天；0.2 mg/kg时为20.0±10.9天；0.4 mg/kg时为15.8±4.1天（均P<0.01）。以BQR（0.5、1.0或2.0 mg/kg）进行7天隔日（q.o.d.）口服灌胃疗程，分别产生的存活时间为12.0±2.4天、17.6±3.4天和20.0±4.1天（均P<0.01）。2.5 mg/kg CsA与0.05 mg/kg RAPA的组合将移植物存活时间延长至18.2±2.9天（P<0.01），5.0 mg/kg CsA与0.1 mg/kg RAPA的组合将存活时间延长至23.0±9.0天（P<0.01）。根据组合指数（CI）值为0.1 - 0.6，这些组合代表协同相互作用。尽管0.5 mg/kg CsA（7.3±1.0天；无统计学意义）、0.01 mg/kg RAPA（7.6±0.9天；无统计学意义）或0.125 mg/kg BQR（7.6±0.9天；无统计学意义）的7天疗程单独无效，但三联药物组合将平均存活时间延长至64.6±32.7天（P<0.005；CI = 0.001），2/5的移植物跳动超过100天。在BALB/c（H-2d）至C3H组合中进行14天治疗也产生了类似的结果。
