Interspecies comparison of the antiplatelet, antithrombotic, and hemorrhagic effects of SR 121566A, a novel nonpeptide GP IIb/IIIa antagonist.
We report the results from an interspecies comparison of the antiplatelet, antithrombotic, and hemorrhagic actions of SR 121566A, a novel nonpeptide antiplatelet agent with high affinity and specificity for the GP IIb/IIIa complex. SR 121566A exhibited in vitro antiplatelet activity against adenosine diphosphate (ADP)-induced aggregation with a rank order of potency [humans = baboons = dogs] > marmosets > guinea pigs > rabbits. These in vitro findings were predictive for the ex vivo antiplatelet potency after i.v. administration of SR 121566A to dogs, guinea pigs, and rabbits [median effective dose (ED50) values, 0.02, 0.05, and 0.15 mg/kg]. The antiplatelet actions of SR 121566A translated into an acute antithrombotic effect in an arteriovenous shunt model after i.v. administration in dogs, guinea pigs, rabbits, and marmosets (ED50, 0.08, 0.10, 0.50, and 0.007 mg/kg). Hemorrhagic effects of SR 121566A were observed in guinea pigs and rabbits at doses that represented 2-3 times the antithrombotic ED50, whereas in marmosets, no bleeding was observed at the antithrombotic ED90. These results demonstrate that SR 121566A exhibits favorable actions in terms of antithrombotic potency and hemostatic safety in different animal species, suggesting that, in humans, SR 121566A will be a good candidate as an antithrombotic compound.
Bernat
A
A
Haemobiology Research Department, Sanofi Recherche, Toulouse, France.
Hoffmann
P
P
Savi
P
P
Lalé
A
A
Herbert
J M
JM
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001166:Arteriovenous Shunt, Surgical; D001596:Benzylamines; D004285:Dogs; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006168:Guinea Pigs; D006470:Hemorrhage / Q000209:etiology / Q000517:prevention & control*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D010215:Papio; D010880:Piperidines; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011817:Rabbits; D051381:Rats; D013045:Species Specificity; D013844:Thiazoles
D001596:Benzylamines; D005343:Fibrinolytic Agents; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C106774:SR 121566; D013844:Thiazoles; D000244:Adenosine Diphosphate