A new immunosuppressant, FTY720, in canine kidney transplantation: effect of single-drug, induction and combination treatments

Abstract

A new immunosuppressant, FTY720, in canine kidney transplantation: effect of single-drug, induction and combination treatments Abstract Three different types of treatment were conducted to clarify the properties of a novel immunomodulator, FTY720, in canine kidney allograft models. Survival, biochemical and hematological tests, pharmacokinetics, and histopathology of grafts and extra-renal organs were analyzed. Accompanying a remarkable reduction in circulating lymphocytes, single-drug treatment of FTY720, ranging from 0.05 to 10 mg/kg, exhibited significant prolongation of graft survival without a dose-dependent effect. Short-course induction with FTY720 at 5 mg/kg per day exhibited similar anti-rejection effects as did single-drug treatment but no advantage in rescuing ongoing rejection. In combination with cyclosporine (CsA; 5 mg/kg) or tacrolimus (FK; 0.5 mg/kg), FTY720 had an additive effect. Trough blood concentrations of FTY720 were linearly correlated with dose. No animal showed critical adverse effects at any point. FTY720 holds promise as a candidate in a new category of drugs that can be combined with conventional agents for induction and maintenance immunosuppression in clinical organ transplantation.

Other Forms of Immunosuppression

“…279 Finally, FTY720 (0.1 mg/kg) synergizes with cyclosporine and FK506 in dog liver transplantation. 260 Synergy between FTY720 and rapamycin also was observed in cardiac transplantation in rats. 302…”

The role of the lysophospholipid sphingosine 1-phosphate in immune cell biology

“…Indeed, allograft survival was prolonged by FTY720 in grafts of skin [94], heart [85], and small bowels [35] in rats, pancreatic islet cells [17] and small bowels [91] in mice, liver [19] and kidney [78] in dogs, and kidney [71] in monkeys. FTY720 is effective in a concentration-dependent manner alone and has been shown to extend the survival time induced by classical immunosuppressive agents such as cyclosporine, FK506, rapamycin, and SDZ RAD (40-O-(2-hydroxyethyl)-rapamycin).…”

Tacrolimus in combination with FTY720 — an analysis of renal and blood parameters

“…Budde et al also demonstrated that side effects commonly related to CNI use, such as diabetes mellitus, nephrotoxicity, neurotoxicity, hepatotoxicity and myelosuppression, were not observed with FTY720 [16]. In animal models, the combination of FTY720 and FK506 resulted in increased graft survival in renal, cardiac and liver transplantation [17][18][19].…”