tacrolimus and ozagrel

The study investigated the possibility of pharmacologically modulating hepatic allograft function from non-heart-beating donors (NHBDs) using male Lewis rats. The donors were divided into 4 groups: Group 1 in which the vehicle was administered, Group 2 in which FK506 (tacrolimus; a powerful immunosuppressive agent) was administered, Group 3 in which OKY046 (a specific thromboxane synthetase inhibitor) was administered and Group 4 in which FK506 and OKY046 were administered. The recipients received orthotopic liver transplantation. The survival rates differed significantly between the recipients that had received liver transplantation from Groups 1 and 4. The serum liver enzyme and inflammatory cytokine concentrations of the recipients which had received liver transplantation from Groups 2, 3 and 4 were significantly lower than those of the recipients that had received liver transplantation from Group 1. Although there was no significant difference, all parameters were better in the recipients that had received transplantation from Group 4 than those that had received transplantation from Groups 2 and 3. The action mechanisms of FK506 and OKY046 are completely different. Therefore, concomitant use of FK506 and OKY046 might have additive effects on liver transplantation from NHBDs. In conclusion, we demonstrated that pretreatment of NHBDs using FK506 and OKY046 ameliorated graft viability.

Topics: Animals; Enzyme Inhibitors; Graft Survival; Immunosuppressive Agents; Liver; Liver Transplantation; Male; Methacrylates; Rats; Rats, Inbred Lew; Reperfusion Injury; Tacrolimus; Thromboxane-A Synthase; Tissue Donors; Transplantation, Homologous

Juxtaglomerular (JG) hyperplasia and tubular damage along with a decrease in the urine creatinine level induced by FK506 in rat kidney have already been reported in previous paper by us. In this paper, we document the relationship of FK506 nephrotoxicity to the change in the production of thromboxane (Tx) A2 and the lipid peroxidation of the cellular membrane in the rat kidney in order to clarify its morphogenesis. The urinary excretion of TxB2 increased with FK506 administration even on day 1 (P < 0.02). Histologically, OKY-046 (thromboxane synthetase inhibitor) decreased tubular damage, although JG hyperplasia was not eradicated, while biochemically the excretion of TxB2 decreased significantly (P < 0.02), and both the decrease in the urine creatinine level and the increase in the N-acetyl-beta,D-glucosaminidase (NAG) index were relatively smaller. Although the FK506-induced morphological and biochemical changes could not be prevented by the continuous administration of superoxide dismutase (SOD) 30,000 U/kg daily, the malondialdehyde content in renal tissue removed 1 h after FK506 administration had increased. These data suggest that FK506 nephrotoxicity is related to the change in the production of TxA2 and lipid peroxidation of the cellular membrane. However, other mechanisms such as the involvement of sympathomimetic effects of FK506 and other vasoconstrictive factors cannot be ruled out.

Topics: Acetylglucosaminidase; Animals; Creatinine; Enzyme Inhibitors; Hyperplasia; Kidney; Kidney Tubules, Proximal; Methacrylates; Rats; Superoxide Dismutase; Tacrolimus; Thromboxane B2