The aim of this study was to evaluate the antithrombotic potential of
T-686 ((3E,4E)-3-benzylidene-4-(3,4,5-trimethoxy-benzylidene)-pyrr olidine-2,5-dione), a novel inhibitor of
plasminogen activator inhibitor-1 (PAI-1), in rat
thrombosis models.
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
hypercoagulability. The antithrombotic effect was enhanced by repeated administration of
T-686.
Warfarin (0.1 mg/kg per day for 3 days) also prevented
thrombus formation. The antithrombotic action by
warfarin was accompanied by prolongation of coagulation time, while no effect on coagulation time was observed in T-686-treated rats.
T-686 lowered the activity of
PAI-1 in plasma. In the arterio-venous shunt model, pretreatment 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 affect bleeding time
at 10-100 times the antithrombotic dose, while
warfarin dose dependently prolonged bleeding time at and around the antithrombotic dose. These results suggest that
T-686 prevents
thrombus formation in rats without impairment of hemostasis.