Gruber S A, Hrushesky W J, Cipolle R J, Erdmann G R, Burke B A, Skjei K L, Mueller R P, Fryd D S, Matas A J, Simmons R L
Department of Surgery, University of Minnesota, Minneapolis 55455.
Transplantation. 1989 Dec;48(6):936-43. doi: 10.1097/00007890-198912000-00008.
We compared the efficacy of continuous intraarterial versus intravenous 6-mercaptopurine (6-MP) infusion in a mongrel canine renal allograft model with regard to overall survival, incidence of systemic and renal toxicity, and systemic drug exposure. Arterial anastomoses were done end-to-end, and infusion catheters were placed in the iliac artery or vena cava and connected to a subcutaneously placed programmable pump. A dose of 0.5 mg/kg/day 6-MP did not prolong survival over heparin-treated or untreated controls (MST = 7 days for both groups) when administered either locally or systemically. However, 0.75 mg/kg/day 6-MP i.a. (MST = 20 days) significantly prolonged survival over both untreated (P = 0.007) and heparin-treated controls (P = 0.02), with all dogs eventually dying of rejection. In contrast, 0.75 mg/kg/day i.v. (MST = 7 days) failed to prolong survival over controls (P greater than 0.1) and produced death from systemic toxicity in 3 of 7 animals. Six of 7 dogs receiving 2.0 mg/kg/day 6-MP i.a. (MST = 12 days) developed azotemia secondary to drug-induced nephrotoxicity. Identical renal histologic changes occurred in the same time frame in autotransplants treated similarly. Of 7 animals receiving 2.0 mg/kg/day i.v. (MST = 12 days), 5 died from early, severe systemic drug toxicity and 2 from early rejection. During 6-MP infusion at 0.5 mg/kg/day, systemic exposure was significantly less in the locally treated than in the systemically treated dogs when Cr concentrations were normal or moderately elevated (P less than 0.0005 and P = 0.01, respectively) but not when renal function became severely impaired (P = 0.34). In contrast to i.v. infusion, i.a. 6-MP delivery dissociated immunosuppressive efficacy from systemic toxicity, supporting previous work demonstrating high first-pass renal elimination of 6-MP. We conclude that tightly controlled local delivery of an immunosuppressive agent can effectively prolong graft survival with reduced systemic toxicity in a large animal model employing a pump/catheter system applicable to man.
我们在杂种犬同种异体肾移植模型中比较了持续动脉内输注与静脉输注6-巯基嘌呤（6-MP）在总体生存期、全身和肾脏毒性发生率以及全身药物暴露方面的疗效。动脉吻合采用端端吻合，输注导管置于髂动脉或腔静脉，并连接至皮下放置的可编程泵。当局部或全身给予0.5mg/kg/天的6-MP剂量时，与肝素治疗或未治疗的对照组相比，生存期并未延长（两组的中位生存期均为7天）。然而，0.75mg/kg/天的动脉内6-MP（中位生存期=20天）与未治疗的对照组（P=0.007）和肝素治疗的对照组（P=0.02）相比，显著延长了生存期，所有犬最终均死于排斥反应。相比之下，0.75mg/kg/天的静脉输注（中位生存期=7天）未能延长生存期超过对照组（P>0.1），并且7只动物中有3只因全身毒性死亡。接受2.0mg/kg/天动脉内6-MP的7只犬中有6只（中位生存期=12天）因药物诱导的肾毒性继发氮质血症。在相似处理的自体移植中，相同的肾脏组织学变化在相同时间框架内出现。接受2.0mg/kg/天静脉输注的7只动物（中位生存期=12天）中，5只因早期严重的全身药物毒性死亡，2只因早期排斥反应死亡。在以0.5mg/kg/天的剂量输注6-MP期间，当肌酐浓度正常或中度升高时，局部治疗的犬的全身暴露显著低于全身治疗的犬（分别为P<0.0005和P=0.01），但当肾功能严重受损时则不然（P=0.34）。与静脉输注相比，动脉内给予6-MP使免疫抑制疗效与全身毒性分离，支持了先前关于6-MP经肾脏首过消除率高的研究。我们得出结论，在采用适用于人类的泵/导管系统的大型动物模型中，严格控制免疫抑制剂的局部给药可有效延长移植物生存期并降低全身毒性。
