title: Significant prolongation of animal survival by combined therapy of FR167653 and cyclosporine A in rat renal allografts.
abstract: 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.
authors.affiliation: Department of Urology, Osaka Medical College, Takatsuki, Osaka, Japan.
authors.forename: Haruhito
authors.initials: H
authors.lastname: Azuma
authors.forename: Takashi
authors.initials: T
authors.lastname: Wada
authors.forename: Rieko
authors.initials: R
authors.lastname: Gotoh
authors.forename: Kengo
authors.initials: K
authors.lastname: Furuichi
authors.forename: Norihiko
authors.initials: N
authors.lastname: Sakai
authors.forename: Koji
authors.initials: K
authors.lastname: Yazawa
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yokoyama
authors.forename: Yoji
authors.initials: Y
authors.lastname: Katsuoka
authors.forename: Shiro
authors.initials: S
authors.lastname: Takahara
mesh_terms: 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
chemical_list: D015815:Cell Adhesion Molecules; C104334:FR 167653; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D011720:Pyrazoles; D011725:Pyridines; D016572:Cyclosporine