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-029, a novel GPIIb/IIIa antagonist, were examined in three arterial thrombosis models. In guinea pigs, TAK-029 at 30 micrograms/kg (i.v.) inhibited ADP-induced ex vivo platelet aggregation completely and prolonged BT to 4.5 times the control value 5 min after administration, and it prevented thrombotic occlusion in 2 out of 5 animals in a photochemically-induced basilar thrombosis model. TAK-029 at 100 micrograms/kg (i.v.) prolonged BT more than 9 times 5 min after administration, and it prevented thrombus formation for over 60 min. In dogs, TAK-029 at 30 micrograms/kg (i.v.) inhibited ADP-induced ex vivo platelet aggregation by 87% 5 min after administration, and it prevented thrombotic occlusion in injured and stenosed coronary arteries for 22 min without prolonging the BT. TAK-029 at 100 micrograms/ kg (i.v.) inhibited platelet aggregation completely and prolonged BT 3.6 times 5 min after administration, and it prevented thrombus formation for over 45 min. In monkeys, TAK-029 at 10 micrograms/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 prevented thrombotic occlusion in injured and stenosed carotid arteries for 24 min. TAK-029 at 30 micrograms/kg (i.v.) completely inhibited platelet aggregation and thrombus formation for over 60 min, and it prolonged BT more than 7.3 times 60 min after administration. In conclusion, TAK-029 exerted potent antithrombotic effects with BT prolongation in three different arterial thrombosis models. TAK-029 may be effective for the treatment of various arterial thrombotic diseases.
Kawamura
M
M
Pharmaceutical Research Laboratories II, Takeda Chemical Industries Ltd, Osaka, Japan. Kawamura_masaki@takeda.co.jp
Tsuji
N
N
Moriya
N
N
Terashita
Z
Z
D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000473:pathology; D001760:Bleeding Time; D002341:Carotid Artery Thrombosis / Q000188:drug therapy / Q000473:pathology; D003328:Coronary Thrombosis / Q000188:drug therapy / Q000473:pathology; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D006146:Guanidines / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D006168:Guinea Pigs; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000187:drug effects*; D011719:Pyrazines / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D013927:Thrombosis / Q000188:drug therapy* / Q000473:pathology
D006146:Guanidines; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011719:Pyrazines; C099142:TAK 029