EFFECTS OF TAK-029, A NOVEL GPIIB IIIA ANTAGONIST, ON ARTERIAL THROMBOSIS IN GUINEA-PIGS, DOGS AND MONKEYS/

The antithrombotic and bleeding time (BT) prolonging effects of TAK-02 9, a novel GPIIb/IIIa antagonist, were examined in three arterial thro mbosis models. In guinea pigs, TAK-029 at 30 mu g/kg (i.v.) inhibited ADP-induced ex vivo platelet aggregation completely and prolonged BT t o 4.5 times the control value 5 min after administration, and it preve nted thrombotic occlusion in 2 out of 5 animals in a photochemically-i nduced basilar thrombosis model. TAK-029 at 100 mu g/kg (i.v.) prolong ed BT more than 9 times 5 min after administration, and it prevented t hrombus formation for over 60 min. In dogs, TAK-029 at 30 mu g/kg (i.v .) inhibited ADP-induced ex vivo platelet aggregation by 87% 5 min aft er administration, and it prevented thrombotic occlusion in injured an d stenosed coronary arteries for 22 min without prolonging the BT. TAK -029 at 100 mu g/kg (i.v.) inhibited platelet aggregation completely a nd prolonged BT 3.6 times 5 min after administration, and it prevented thrombus formation for over 45 min. In monkeys, TAK-029 at 10 mu g/kg (i.v.) inhibited ADP-induced ex vivo platelet aggregation by 84% and prolonged BT 4.6 times 5 min after the administration, and it prevente d thrombotic occlusion in injured and stenosed carotid arteries for 24 min. TAK-029 at 30 mu g/kg (i.v.) completely inhibited platelet aggre gation and thrombus formation for over 60 min, and it prolonged BT mor e than 7.3 times 60 min after administration. In conclusion, TAK-029 e xerted potent antithrombotic effects with BT prolongation in three dif ferent arterial thrombosis models. TAK-029 may be effective for the tr eatment of various arterial thrombotic diseases. (C) 1997 Elsevier Sci ence Ltd.