Protective effect of oral xemilofiban in arterial thrombosis in dogs: increased activity in combination with aspirin.
BACKGROUND
Inhibition of platelet aggregation by preventing the binding of fibrinogen to glycoprotein (GP) IIb/IIIa on activated platelets results in antithrombotic activity. We report on the antithrombotic effect of xemilofiban (SC-54684A), an oral GP IIb/IIIa antagonist, administered alone or with aspirin (ASA) in an acute thrombosis model.


RESULTS
Conscious dogs were treated with xemilofiban (1.25, 2.5, 5.0, or 6 mg/kg, n=6); low-dose (LD, 81 mg) ASA, n=7; high-dose (HD, 162 mg) ASA, n=6; xemilofibran 1.25 mg/kg plus LD ASA, n=6; xemilofibran 1.25 mg/kg plus HD ASA, n=6; or placebo, n=7. Dogs were anesthetized 60 minutes later, and the effects of the treatments were evaluated after electrolytic injury (250 microA for 180 minutes) in the left circumflex coronary artery. Bleeding time (BT) was assessed in a separate study. Incidence of thrombosis was reduced (P<0.05) by xemilofiban > or =2.5 mg/kg, HD ASA, or xemilofiban 1.25 mg/kg plus HD ASA compared with placebo. Xemilofiban > or =2.5 mg/kg or xemilofiban 1.25 mg/kg plus HD ASA significantly increased time to occlusion, inhibited ex vivo platelet aggregation to collagen >90%, and prevented or decreased (P<0.05) cyclic flow variations (CFVs) compared with placebo. BT was increased (P<0.05) with xemilofiban > or =2.5 mg/kg but not with xemilofiban 1.25 mg/kg plus HD ASA.


CONCLUSIONS
Xemilofiban > or =2.5 mg/kg, HD ASA, or xemilofiban 1.25 mg/kg plus HD ASA significantly reduced the incidence of thrombosis. These doses of xemilofiban or xemilofiban 1.25 mg/kg plus HD ASA increased time to occlusion, inhibited ex vivo platelet aggregation by >90%, and prevented or reduced CFVs. Xemilofiban > or =2.5 mg/kg but not xemilofiban 1.25 mg/kg plus HD ASA significantly increased BT.
Frederick
L G
LG
Thrombosis Research Department, Searle, Skokie, Ill, USA.
Suleymanov
O D
OD
Szalony
J A
JA
Taite
B B
BB
Salyers
A K
AK
King
L W
LW
Feigen
L P
LP
Nicholson
N S
NS
D000284:Administration, Oral; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000517:prevention & control; D001241:Aspirin / Q000627:therapeutic use*; D001550:Benzamidines / Q000627:therapeutic use*; D001665:Binding Sites; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004558:Electric Stimulation; D005260:Female; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D013698:Templates, Genetic; D013927:Thrombosis / Q000188:drug therapy*
D001550:Benzamidines; D010975:Platelet Aggregation Inhibitors; C091295:xemilofiban; D001241:Aspirin