Significant prolongation of animal survival by combined therapy of FR167653 and cyclosporine a in rat renal allografts

被引:5
作者
Azuma, H
Wada, T
Gotoh, R
Furuichi, K
Sakai, N
Yazawa, K
Yokoyama, H
Katsuoka, Y
Takahara, S
机构
[1] Osaka Univ, Grad Sch Med, Dept Urol, Suita, Osaka 5650871, Japan
[2] Osaka Med Coll, Dept Urol, Takatsuki, Osaka 569, Japan
[3] Kanazawa Univ, Sch Med, Dept Med, Kanazawa, Ishikawa 920, Japan
[4] Natl Cardiovasc Res Ctr, Dept Expt Surg & Bioengn, Suita, Osaka, Japan
关键词
D O I
10.1097/01.TP.0000090392.56694.06
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Background. Cyclosporine A (CsA) has improved short-term results in renal transplantation. However, its toxicities have been serious problems in clinical patients undergoing long-term administration. It is necessary to develop a nonnephrotoxic immunosuppressant that allows reducing doses of CsA. The authors tested the effect of a new pyrazolotriazin compound, FR167653 (FR), that inhibits the production of proinflammatory cytokines, using a rat renal acute-rejection model (Wistar-Lewis). Methods. The authors first examined the adverse reactions of Fit in naive rats. The effect of FR monotherapy was evaluated by treating allograft recipients at a dosage of 32 or 64 mg/kg/day intraperitoneally. The synergistic effect of FR and CsA at a minimum dose was examined by treating the recipients daily with 64 mg/kg of FR and 0.1, 0.5, or 1.0 mg/kg of CsA. Results. Long-term administration of FR caused no severe adverse reactions in naive rats at less than 96 mg/kg/day, and FR is a nonnephrotoxic but liver-toxic agent at higher doses. Monotherapy of FR (8.7+/-1.3 days) or CsA (8.7+/-1.7 days) did not influence graft survival (vs. 8.2+/-0.8 in controls, n=10). However, the combined treatment of FR and CsA significantly prolonged animal survival (>50% of animals survived a 42-day follow-up period; P<0.01 vs. all other groups, n=15/group), Immunologic analysis demonstrated the significantly decreased production of major inflammatory mediators and adhesion molecules in the allografts as compared with those of all other groups. Conclusions. A nonnephrotoxic agent, FR may be a promising candidate for a new combined immunosuppressive regimen that potentially reduces the amount of CsA.
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页码:1029 / 1036
页数:8
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