Cosenza C A, Cramer D V, Eiras-Hreha G, Cajulis E, Wang H K, Makowka L
Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California 90048.
Transplantation. 1993 Sep;56(3):667-72. doi: 10.1097/00007890-199309000-00032.
Brequinar sodium (BQR) is a novel immunosuppressive drug that inhibits cell proliferation by virtue of its disruption of the de novo pyrimidine biosynthesis. The basis of the immunosuppressive activity of BQR is distinctively different from that of cyclosporine (CsA), and we have recently evaluated in vivo and in vitro the efficacy of the two drugs when used in combination. Subtherapeutic doses of BQR and CsA were tested for their ability to prolong heterotopic cardiac allograft survival in the MHC- and non-MHC-mismatched ACI-->LEW rat strain combination. The graft survival data derived from these experiments were analyzed using the median-effect analysis to establish the immunosuppressive interaction of both drugs. The administration of BQR 3 mg/kg three times weekly or CsA 2.5 mg/kg daily moderately prolonged cardiac allograft survival, with a mean survival of 10 +/- 0.5 and 16 +/- 5.3 days, respectively. The use of the two drugs in combination with the same dose schedule exerted a synergistic effect on graft survival, prolonging the graft function to a mean of 31 +/- 5.7 days. Sera from animals treated with the two drugs displayed, when compared with single treatment groups (BQR 3 mg/kg and CsA 2.5 mg/kg), significantly (P < 0.01) increased in vitro inhibition of lymphocyte proliferation following stimulation with PHA. Finally, a clear correlation between the mean survival time and BQR plasma levels of animals treated with BQR alone or in combination with CsA was seen. Those treatment groups with BQR levels below 2 micrograms/ml (1.5 and 3.0 mg/kg/3x/week) had a mean graft survival of less than 10 days). In contrast, recipients treated with a combination of low doses of BQR and CsA displayed higher drug plasma levels (> 2 micrograms/ml) and longer mean graft survival times. These observations suggest that BQR and CsA may be highly effective when used in combination to prevent organ allograft rejection for clinical transplantation.
布喹那钠（BQR）是一种新型免疫抑制药物，它通过破坏嘧啶的从头生物合成来抑制细胞增殖。BQR免疫抑制活性的基础与环孢素（CsA）明显不同，我们最近在体内和体外评估了这两种药物联合使用时的疗效。对低于治疗剂量的BQR和CsA进行了测试，以评估它们在MHC和非MHC不匹配的ACI→LEW大鼠品系组合中延长异位心脏同种异体移植存活时间的能力。使用中位效应分析对这些实验获得的移植物存活数据进行分析，以确定两种药物的免疫抑制相互作用。每周三次给予3mg/kg的BQR或每日给予2.5mg/kg的CsA可适度延长心脏同种异体移植的存活时间，平均存活时间分别为10±0.5天和16±5.3天。以相同的给药方案联合使用这两种药物对移植物存活产生协同作用，将移植物功能延长至平均31±5.7天。与单一治疗组（BQR 3mg/kg和CsA 2.5mg/kg）相比，用这两种药物治疗的动物血清在PHA刺激后对淋巴细胞增殖的体外抑制作用显著增强（P<0.01）。最后，观察到单独使用BQR或与CsA联合使用的动物的平均存活时间与BQR血浆水平之间存在明显相关性。那些BQR水平低于2μg/ml（1.5和3.0mg/kg/3次/周）的治疗组平均移植物存活时间少于10天。相反，用低剂量BQR和CsA联合治疗的受体显示出较高的药物血浆水平（>2μg/ml）和较长的平均移植物存活时间。这些观察结果表明，BQR和CsA联合使用时可能对预防临床移植中的器官同种异体排斥反应非常有效。
