title: Antithrombotic effects of TAK-029, a novel GPIIb/IIIa antagonist, in guinea pigs: comparative studies with ticlopidine, clopidogrel, aspirin, prostaglandin E1 and argatroban.
abstract: The antithrombotic and bleeding time (BT)-prolonging effects of TAK-029, a novel glycoprotein IIb/IIIa antagonist, were characterized and compared with those of conventional antithrombotic agents in guinea pigs. TAK-029 potently inhibited the binding of fibrinogen and von Willebrand factor to purified human GPIIb/IIIa with IC50 values of 0.67 +/- 0.03 and 0.33 +/- 0.04 nM; it also inhibited human platelet aggregation induced by various aggregating agents with IC50 values of 29 to 38 nM. The in vitro antiplatelet effect of TAK-029 was potent in humans, guinea pigs and monkeys. When TAK-029 was given p.o. to guinea pigs, severe prolonging of BT (>1800 sec) was not observed with plasma concentrations of TAK-029 that inhibited ex vivo platelet aggregation by < 100%. The p.o. administration of TAK-029, ticlopidine and clopidogrel prolonged BT to the same extent, in parallel with their inhibition of ex vivo platelet aggregation. TAK-029 inhibited ex vivo platelet adhesion and thrombus formation in an arteriovenous shunt model more strongly than ticlopidine, clopidogrel and aspirin at doses causing similar prolongations of BT. In a balloon catheter-induced carotid thrombosis model, i.v. administration of TAK-029 significantly inhibited thrombus formation without prolonging BT. At doses that caused an incomplete antithrombotic effect, PGE1-alpha-cyclodextrin and argatroban produced hypotension and prolongation of BT, respectively. TAK-029 may be effective in patients suffering from arterial thrombotic diseases, which are refractory to these conventional antithrombotic agents.
authors.affiliation: Pharmaceutical Research Laboratories, Takeda Chemical Industries Ltd., Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kawamura
authors.forename: Y
authors.initials: Y
authors.lastname: Imura
authors.forename: N
authors.initials: N
authors.lastname: Moriya
authors.forename: S
authors.initials: S
authors.lastname: Kita
authors.forename: H
authors.initials: H
authors.lastname: Fukushi
authors.forename: H
authors.initials: H
authors.lastname: Sugihara
authors.forename: K
authors.initials: K
authors.lastname: Nishikawa
authors.forename: Z
authors.initials: Z
authors.lastname: Terashita
mesh_terms: D000527:Alprostadil / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives; D001241:Aspirin / Q000494:pharmacology*; D000077144:Clopidogrel; D004285:Dogs; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D010875:Pipecolic Acids / Q000494:pharmacology*; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011719:Pyrazines / Q000494:pharmacology*; D013449:Sulfonamides; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D005343:Fibrinolytic Agents; D006146:Guanidines; D010875:Pipecolic Acids; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011719:Pyrazines; D013449:Sulfonamides; D001120:Arginine; D000077144:Clopidogrel; D000527:Alprostadil; C031942:argatroban; D013988:Ticlopidine; D001241:Aspirin; C099142:TAK 029