1. The antithrombotic effect of the
glycoprotein IIb/IIIa receptor antagonist,
CRL42796, was examined in canine models of carotid and coronary artery
thrombosis. 2. In the
carotid artery thrombosis model, occlusion occurred in all control vessels (time to
thrombosis 47.6+/-8.9 min).
After treatment with low dose
CRL42796 (15 microg kg(-1) loading dose +0.31 microg kg(-1) min(-1) i.v.), two of five vessels occluded. Time to
thrombosis increased significantly to 155.2+/-23.1 min. When the drug infusion was increased (0.69 microg kg(-1) min(-1)), each of five vessels remained patent. 3. Ex vivo platelet aggregation in response to
arachidonic acid (AA) and
ADP was examined in platelet rich plasma (PRP) prepared from
citrate or
heparin anticoagulated blood.
CRL42796 reduced platelet reactivity at low and high doses in PRP from
citrate anticoagulated blood. However, in PRP from
heparin anticoagulated blood, only the higher infusion dose produced a significant reduction in ex vivo platelet responses. 4. A combination of oral
aspirin (4.6 mg kg(-1) -41, -17 h) and the low infusion dose of
CRL42796 did not produce an additional benefit beyond that provided by
CRL42796 alone. 5. Coronary artery
thrombosis was inhibited in four of five vessels treated with the lower infusion dose of
CRL42796 and in five of five vessels treated with the higher infusion. Time to
thrombosis increased with both doses (Control, 90.8+/-10.4 min; low dose, 165.8+/-14.2 min; high dose, >180.0+/-0 min). 6. The results indicate that
CRL42796 is an effective in vivo
antithrombotic agent against experimentally-induced carotid and coronary artery
thrombosis.