Significant prolongation of animal survival by combined therapy of FR167653 and cyclosporine A in rat renal allografts.
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 FR 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.
Azuma
Haruhito
H
Department of Urology, Osaka Medical College, Takatsuki, Osaka, Japan.
Wada
Takashi
T
Gotoh
Rieko
R
Furuichi
Kengo
K
Sakai
Norihiko
N
Yazawa
Koji
K
Yokoyama
Hitoshi
H
Katsuoka
Yoji
Y
Takahara
Shiro
S
D000818:Animals; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors; D016572:Cyclosporine / Q000494:pharmacology*; D004357:Drug Synergism; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D016030:Kidney Transplantation; D011720:Pyrazoles / Q000009:adverse effects / Q000494:pharmacology*; D011725:Pyridines / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016019:Survival Analysis; D014184:Transplantation, Homologous
D015815:Cell Adhesion Molecules; C104334:FR 167653; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D011720:Pyrazoles; D011725:Pyridines; D016572:Cyclosporine