Prolongation of canine liver allograft survival by a novel immunosuppressant, FTY720 - Effect of monotherapy and combined treatment with conventionaldrugs

Background. The immunosuppressive effect and other properties of a novel im munosuppressant, FTY720, have been studied mostly in the experimental trans plantation of various extrahepatic organs. In this experiment, we evaluated the antirejection potency and adverse effects of this agent on liver graft s using a canine liver transplantation model. Methods. Forty-eight orthotopic liver transplantations were performed by th e standard technique under a veno-venous bypass, Liver recipients were divi ded into two studies: a single-dose study with FTY720 at various doses and a combined dose study with conventional immunosuppressants (cyclosporine or tacrolimus) alone and combined with FTY720, Survival, biochemical and hema tological tests, blood levels of immunosuppressants, and postmortem histolo gy were determined. Results, The median survival of untreated control animals was 9 days, where as treatment with FTY720 at a dose of 0.1 mg/kg/day prolonged graft surviva l to 49.5 days. FTY720 at 1 mg/kg/day showed a slight but insignificant pro longation to 16 days, but when the dose was increased to 5 mg/kg/day, the g raft was rejected at 10 days. The combination of FTY720, 0.1 mg/kg/day, wit h a subtherapeutic dose of cyclosporine, 5 mg/kg/day, prolonged median anim al survival from 40 days with cyclosporine alone to 74 days. A combination of FTY720 (0.1 mg/kg/day) with tacrolimus (0.5 mg/kg/day) compromised anima l survival, reducing survival from 83.5 days with tacrolimus alone to 30.5 days due to infectious complication and emaciation by overimmunosuppression . No evident drug-induced side effects were observed. Conclusions. FTY720 has a potent immunosuppressive effect when used alone a t 0.1 mg/kg/day in canine liver transplantation. FTY720 is a promising cand idate for future clinical application in orthotopic liver transplantation.