AN EVALUATION OF LEFLUNOMIDE IN THE CANINE RENAL TRANSPLANTATION MODEL1
AN EVALUATION OF LEFLUNOMIDE IN THE CANINE RENAL TRANSPLANTATION MODEL1
复制标题
来氟米特在犬肾移植模型中的评价1
作者：
L. McChesney;F. Xiao;H. Sankary;P. Foster;Shobha Sharma;M. Haklin;James W. Williams
Leflunomide is an isoxazole with newly discovered immunosuppressive properties. Its mechanism of action operates later in the cell cycle than cyclosporine and appears to interfere with lymphocyte IL-2 responsiveness. With the encouraging results from in vitro and small-animal studies, we subjected leflunomide to the rigorous canine renal transplantation model in a dose response protocol. Thirty-eight female mongrel dogs underwent renal transplantation and bilateral nephrectomy. Immunosuppression was stratified from controls with no immunosuppression to monotherapy with leflunomide at 2, 4, 8, and 16 mg/kg/day given orally and in a combination therapy with cyclosporine. To evaluate its toxicity while maintaining a low constant blood level, eight dogs were treated by continuous intravenous infusion at doses of 2, 4, 6, and 8 mg/kg/day. The mean survival time for nonimmuno suppressed controls (n=2) was 9 days, leflunomide 2 mg/kg/day (n=2) was 9 days, leflunomide 4 mg/kg/day (n=4) was 16 days, leflunomide 8 mg/kg/day (n=5) was 28 days, leflunomide 16 mg/kg/day (n=7) was 21 days. Cyclosporine alone at 10 mg/kg/day (n=4) resulted in a mean survival time of 13 days. The mean survival time with the combination of cyclosporine 10 mg/kg/day with leflunomide 4 mg/kg/day (n=6) was 68 days. The mean survival time for continuous intravenous leflunomide 2 mg/kg/day (n=2) was 10 days; for leflunomide 4 mg/kg/day, 20 days; for leflunomide 6 mg/kg/day, 14 days; and leflunomide 8 mg/kg/day, 21 days. The mean serum trough levels of leflunomide ranged from 10 μUg/ml at the 2 mg dose to 55 μUg/ml for the 16 mg dose, levels that have been well tolerated in man. Leflunomide at 16 mg/kg/day reliably prevented acute al-lograft rejection, but the dogs died of inanition with normal renal function. Leflunomide at a nontoxic dose of 4 mg/kg/day extended survival to 16 days, but all dogs died of rejection. A combination of inadequate doses of leflunomide (4 mg/kg/day) and cyclosporine (10 mg/kg/day) resulted in all animals having normal renal function and weight for 30 days. Even at a high dose of 16 mg/kg/day, no viral or bacterial infections were noted. These observations in a canine system add to the growing enthusiasm for the evaluation of leflunomide in human transplantation.
