Antiplatelet and antithrombotic efficacy of SR 121787, a nonpeptide orally active GP IIb/IIIa antagonist, in rabbits: comparison with clopidogrel and aspirin.
Previous reports indicate that rabbits are not an appropriate species for testing glycoprotein (GP) IIb/IIIa antagonists because tested compounds caused only a weak inhibitory action on aggregation of rabbit platelets. SR 121566 is a novel low-molecular-weight antiplatelet agent with high affinity and specificity for the GP IIb/IIIa complex. In this study, SR 121566 exhibited a potent dose-dependent inhibition of adenosine diphosphate (ADP)-induced aggregation of rabbit platelets in vitro [median inhibitory concentration (IC50), 0.8 +/- 0.04 microM], whereas the GP IIb/IIIa antagonists SC 52012A and GR 144053F were devoid of antiplatelet activity. After oral administration of SR 121787, the prodrug of SR 121566, rabbit platelet aggregation ex vivo was inhibited in a dose-dependent manner [median effective dose (ED50) for ADP- arachidonic acid (AA)- and collagen-induced aggregation 2 h after gavage, 2.3 +/- 0.3, 6.1 +/- 0.9, and 2.5 +/- 0.4 mg/kg], a 58% inhibition of ADP-induced platelet aggregation being still observed 6 h after single oral treatment with 20 mg/kg. In an arteriovenous-shunt model, oral administration of SR 121787 resulted in a dose-dependent inhibition of thrombus growth (ED50, 10.4 +/- 0.8 mg/kg). Clopidogrel revealed a maximal inhibitory efficacy of 40% at 20 mg/kg p.o., and aspirin, at 100 mg/kg p.o., was without effect in this model. SR 121787 at oral doses < or = 10 mg/kg, did not cause an increase in blood loss after incision of the rabbit ear. In conclusion, SR 121787 is the first GP IIb/IIIa antagonist with oral antiplatelet and antithrombotic activity in rabbits.
Hoffmann
P
P
Sanofi Recherche, Haemobiology Research Department, Toulouse, France.
Bernat
A
A
Savi
P
P
Herbert
J M
JM
D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001596:Benzylamines; D000077144:Clopidogrel; D006439:Hemodynamics / Q000187:drug effects; D006487:Hemostasis / Q000187:drug effects*; D008297:Male; 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; D013844:Thiazoles; D013927:Thrombosis / Q000517:prevention & control; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology
D001596:Benzylamines; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C106774:SR 121566; D013844:Thiazoles; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin