THE RELATIONSHIP OF BLOOD CONCENTRATIONS OF RAPAMYCIN AND CYCLOSPORINE TO SUPPRESSION OF ALLOGRAFT REJECTION IN A RABBIT HETEROTOPIC HEART TRANSPLANT MODEL1
THE RELATIONSHIP OF BLOOD CONCENTRATIONS OF RAPAMYCIN AND CYCLOSPORINE TO SUPPRESSION OF ALLOGRAFT REJECTION IN A RABBIT HETEROTOPIC HEART TRANSPLANT MODEL1
复制标题
兔异位心脏移植模型中雷帕霉素和环孢素血药浓度与抑制同种异体移植排斥反应的关系1
DOI：
10.1097/00007890-199302000-00021
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发表时间：
1993
期刊：
影响因子：
6.2
通讯作者：
J. Thliveris
中科院分区：
文献类型：
--
作者：
J. Fryer;R. Yatscoff;E. Pascoe;J. Thliveris
对50只新西兰大白兔进行了异位心脏移植。随机分成5组，分别静脉注射雷帕霉素(RAPA)或环孢素A(RAPA)(0.05、0.1、0.5和1.0 mg/kg/d)，CsA(5.0、10.0和15.0 mg/kg/d)。药物载体和生理盐水对照组也包括在内。在整个研究过程中，RAPA组和CsA组每周监测谷状血药浓度。在研究开始和结束时进行肾和肝功能的生化评估。接受RAPA的动物表现出很好的同种异体移植物存活率；最低剂量组(0.05 mg/kg/天)只有两只动物排斥他们的移植物。相比之下，CsA治疗组没有发生排斥反应。排斥移植的动物继续服用药物，直到移植后60天达到研究终点，以监测药物引起的副作用。在某些情况下，由于传染病和其他并发症，动物在此之前被宰杀。在RAPA治疗组中，肾脏或肝脏功能没有明显变化，而在接受最高剂量CsA(15.0 mg/kg/天)的动物组中，肌酐清除量显著下降。两种药物的剂量与谷浓度之间存在相关性。RAPA的全血浓度在10-60μg/L范围内效果最好，毒性最小。兔的全血浓度为10μg/L时，排斥反应。CsA的治疗范围更广(50-300μg/L)。结果表明，在所测试的动物模型中，RAPA在预防同种异体移植排斥反应方面与CsA一样有效。与CsA一样，对RAPA低谷血药浓度的治疗性监测可能有助于指导剂量调整，以最大限度地提高免疫抑制效果，同时将药物副作用降至最低。
Heterotopic heart transplants were performed on 50 New Zealand white rabbits. Groups of 5 rabbits were randomly assigned to receive, through an intravenous route, rapamycin (RAPA) or cyclosporine at the following doses: RAPA (0.05, 0.1, 0.5, and 1.0 mg/kg/day); CsA (5.0, 10.0, and 15.0 mg/kg/day). Drug vehicle and saline controls were also included. Trough blood concentrations were monitored in both RAPA- and CsA-treated groups on a weekly basis throughout the study. Biochemical assessment of renal and liver function was performed at the beginning and end of the study. Animals receiving RAPA exhibited excellent allograft survival; only two animals in the lowest dosage group (0.05 mg/kg/day) rejected their grafts. In contrast, no rejection occurred in the CsA-treated groups. Animals that rejected their grafts were maintained on the drug until the endpoint of the study was reached at 60 days posttransplant to monitor drug induced side-effects. In some instances animals were sacrificed prior to this time due to infectious and other complications. No significant changes in renal or liver function were noted in the RAPA-treated group, while in the group of animals receiving the highest dose of CsA (15.0 mg/kg/day) a significant decrease in creatinine clearance was noted. A correlation was shown to exist between dose and the trough concentrations of both drugs. The whole-blood concentrations of RAPA that resulted in maximal efficacy with minimal toxicity was in the range of 10–60 μg/L. Rabbits having trough whole-blood concentrations of <10 μg/L rejected their grafts. A much wider therapeutic range for CsA (50–300 μg/L) was noted. The results suggest that RAPA is as efficacious as CsA in prevention of allograft rejection in the animal model tested. The therapeutic monitoring of trough blood concentrations of RAPA, as with CsA, may be useful in guiding dosage adjustments to maximize the immunosuppressive efficacy while minimizing drug-induced side-effects.