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: M Kawamura, Y Imura, N Moriya, S Kita, H Fukushi, H Sugihara, K Nishikawa, Z Terashita
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 277 Issue 1 Pg. 502-10 (Apr 1996) ISSN: 0022-3565 [Print] United States
• PMID: 8613960 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Fibrinolytic Agents
• Guanidines
• Pipecolic Acids
• Platelet Aggregation Inhibitors
• Platelet Glycoprotein GPIIb-IIIa Complex
• Pyrazines
• Sulfonamides
• Arginine
• Clopidogrel
• Alprostadil
• argatroban
• Ticlopidine
• Aspirin
• TAK 029

Topics

• Alprostadil (pharmacology)
• Animals
• Arginine (analogs & derivatives)
• Aspirin (pharmacology)
• Clopidogrel
• Dogs
• Fibrinolytic Agents (pharmacology)
• Guanidines (pharmacology)
• Guinea Pigs
• Humans
• Macaca fascicularis
• Male
• Pipecolic Acids (pharmacology)
• Platelet Adhesiveness (drug effects)
• Platelet Aggregation (drug effects)
• Platelet Aggregation Inhibitors (pharmacology)
• Platelet Glycoprotein GPIIb-IIIa Complex (antagonists & inhibitors)
• Pyrazines (pharmacology)
• Sulfonamides
• Ticlopidine (analogs & derivatives, pharmacology)