THE ANTITHROMBOTIC AND ANTICOAGULANT EFFECTS OF A SYNTHETIC TRIPEPTIDE AND RECOMBINANT HIRUDIN IN VARIOUS ANIMAL-MODELS

The pharmacologic activities of two thrombin inhibitors (D-MePhe-Pro-A rg-H, recombinant-hirudin) were compared in two animal models. The ant ithrombotic effect was investigated in vivo in rabbits using a modifie d Wessler stasis thrombosis model. During these experiments, blood was drawn for ex vivo testing to determine the coagulation profile and to determine plasma concentrations using pre-constructed calibration cur ves. A dose-dependent antithrombotic effect was observed for both agen ts. On an equigravimetric basis (100 mug/kg i.v.), r-hirudin showed a stronger antithrombotic effect than the tripeptide, which correlated w ell with the ex vivo anticoagulant effect. No adverse reactions were o bserved during this study. In a rabbit ear bleeding model, a dose and time dependent hemorrhagic effect was observed for both agents. Only s light bleeding effects were observed at 1.0 mg/kg dosages. These studi es show that the tripeptide D-MePhe-Pro-Arg-H and r-hirudin are specif ic thrombin inhibitors with potent antithrombotic effects and a high t herapeutic (antithrombotic/hemorrhagic) index. Furthermore, the result s of these two animal models and ex vivo analyses can be used to deter mine the therapeutic index of thrombin inhibitors.