This study investigates the effect of the
glycoprotein IIb/IIIa receptor antagonist
CRL42796 in a canine model of
carotid artery thrombosis. Both carotid arteries developed occlusive
thrombosis in each of the five control animals (time to occlusion: right carotid artery, 92.6 minutes; left carotid artery, 89.0 minutes). A single oral dose of
CRL42796 (3 mg/kg) prevented occlusive
thrombosis in 4 of 6 vessels and increased time to
thrombosis, albeit not significantly (right carotid artery, 134.1 minutes; left carotid artery, 145.0 minutes). When the initial dose of
CRL42796 was followed by a second oral dose (3 mg/kg) 2 hours later, 10 of 10 carotid arteries remained patent throughout the period of electrolytic injury.
CRL42796 reduced
thrombus weight in both treatment protocols. Ex vivo platelet aggregation with
arachidonic acid (AA) or
adenosine diphosphate (
ADP) was reduced at 120, 240, and 360 minutes after two doses of
CRL42796. A single oral dose reduced
ADP-induced responses at 240 and 360 minutes, but significant effects were not observed with AA. Bleeding time increased 360 minutes after two oral doses of
CRL42796, but not at 120 minutes. Bleeding time was unchanged with the single dose of
CRL42796. The results demonstrate that
oral administration of
CRL42796 prevents
carotid artery thrombosis in response to deep vessel wall injury and may have potential value to be characterized in extended preclinical and clinical study.