T-686, A NOVEL INHIBITOR OF PLASMINOGEN-ACTIVATOR INHIBITOR-1, INHIBITS THROMBOSIS WITHOUT IMPAIRMENT OF HEMOSTASIS IN RATS

The aim of this study was to evaluate the antithrombotic potential of T-686 4,5-trimethoxybenzylidene)-pyrrolidine-2,5-dione), a novel inhib itor of plasminogen activator inhibitor-1 (PAI-I), in rat thrombosis m odels. T-686 (0.1-100 mg/kg per day, p.o.) dose dependently decreased the weight of venous thrombi induced by a combination of stasis and hy percoagulability. The antithrombotic effect was enhanced by repeated a dministration of T-686. Warfarin (0.1 mg/kg per day for 3 days) also p revented thrombus formation. The antithrombotic action by warfarin was accompanied by prolongation of coagulation time, while no effect on c oagulation time was observed in T-686-treated rats. T-686 lowered the activity of PAI-1 in plasma. In the arterio-venous shunt model, pretre atment with T-686 (10 mg/kg per day) or ticlopidine (100 mg/kg per day ) for 8 days inhibited thrombus formation by 33% and 44%, respectively . T-686 had no effect on collagen-induced platelet aggregation ex vivo , while ticlopidine inhibited platelet aggregation. T-686 did not affe ct bleeding time at 10-100 times the antithrombotic dose, while warfar in dose dependently prolonged bleeding time at and around the antithro mbotic dose. These results suggest that T-686 prevents thrombus format ion in rats without impairment of hemostasis. (C) 1997 Elsevier Scienc e B.V.