Prevention of thrombosis and enhancement of thrombolysis in rabbits by SR 121787, a glycoprotein II/III antagonist.
SR 121566, a novel nonpeptide antiplatelet agent with high affinity and specificity for the GP IIb/IIIa complex, exhibits potent in vitro antiaggregating activity in rabbit platelets. This paper reports results from a study in rabbits about the efficacy and tolerability of SR 121787, the prodrug of SR 121566. After p.o. pretreatment with SR 121787, ADP-, arachidonic acid- and collagen-induced rabbit platelet aggregation was inhibited ex vivo in a dose-dependent manner (ED50 between 2.3 and 6.1 mg/kg). Collagen-induced thrombocytopenia was totally abolished by SR 121787 at 20 mg/kg p.o. In a carotid artery lesion model of arterial thrombosis, p.o. administration of SR 121787 resulted in a dose-dependent inhibition of thrombosis with a maximum effect of 68% (ED50 = 16.0 +/- 0.3 mg/kg). Recombinant tissue plasminogen activator-induced thrombolysis of a preformed thrombus in the jugular vein was potentiated by SR 121787 at doses between 1 and 6 mg/kg i.v. In an ear incision bleeding model, SR 121787 at doses up to 15 mg/kg p.o. did not cause an increase in blood loss. These results demonstrate that SR 121787 exerts oral antiplatelet, antithrombotic and thrombolysis-enhancing efficacy in rabbits. SR 121787 appears to be a promising compound for evaluation under clinical conditions in the therapy of acute coronary syndromes.
Sanofi Recherche, Haemobiology Research Department, Toulouse, France.
P
P
Hoffmann
A
A
Bernat
P
P
Savi
J M
JM
Herbert
D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D001596:Benzylamines; D001760:Bleeding Time; D020212:Carotid Artery Injuries; D003094:Collagen; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006487:Hemostasis / Q000187:drug effects; D066298:In Vitro Techniques; D007601:Jugular Veins / Q000293:injuries; D008297:Male; D010880:Piperidines / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011817:Rabbits; D013844:Thiazoles / Q000494:pharmacology*; D013921:Thrombocytopenia / Q000139:chemically induced / Q000517:prevention & control; D013927:Thrombosis / Q000517:prevention & control*
D001596:Benzylamines; D005343:Fibrinolytic Agents; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C108927:SR 121787; D013844:Thiazoles; D003094:Collagen; D001241:Aspirin