From the Thrombosis Research Department, Searle, Skokie, Ill.
Correspondence to Leo G. Frederick, Senior Research Investigator, Searle, 4901 Searle Pkwy, Skokie, IL 60077.
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.
Methods and 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 µA
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
Conclusions—Xemilofiban
© 1998 American Heart Association, Inc.
Basic Science Reports
Protective Effect of Oral Xemilofiban in Arterial Thrombosis in Dogs
Increased Activity in Combination With Aspirin
2.5
mg/kg, HD ASA, or xemilofiban 1.25 mg/kg plus HD ASA compared with
placebo. Xemilofiban 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
2.5 mg/kg but not with xemilofiban 1.25 mg/kg plus HD ASA. 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 2.5 mg/kg but
not xemilofiban 1.25 mg/kg plus HD ASA significantly increased BT.
Key Words: platelet aggregation inhibitors • glycoproteins • thrombosis
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