Prevention of rethrombosis after coronary thrombolysis in a chronic canine model. I. Adjunctive therapy with monoclonal antibody 7E3 F(ab')2 fragment.
We examined the efficacy of the monoclonal antibody (MoAb) 7E3 F(ab')2 fragment, an inhibitor of the platelet glycoprotein (GP)IIb/IIIa receptor, to prevent coronary artery rethrombosis after successful thrombolysis with rt-PA. The circumflex coronary artery of anesthetized dogs was instrumented with a flow probe, an electrode, and a stenosis. After recovery from the surgical procedure, the animals were reanesthetized on post-operative day 9, and vessel wall injury was induced with current applied to the intimal surface of the circumflex coronary artery. The resulting occlusive thrombus was aged for 30 min, and recombinant tissue plasminogen activator (rt-PA) was administered. The animals were allocated to receive either placebo or a single dose of 7E3 [0.8 mg/kg intravenous (i.v.) bolus] as the sole adjunctive agent. Ex vivo platelet function and coronary artery blood flow velocity were recorded on each of 5 consecutive days. Reocclusion and mortality were reduced significantly in animals treated with 7E3 as compared with the placebo-treated group. Significant inhibition of ex vivo platelet aggregation persisted for 48 h after a single injection of 7E3. The MoAb 7E3 F(ab')2 fragment is effective as the sole adjunctive agent with rt-PA for prevention of rethrombosis. The present study is unique in that it examined the efficacy of GPIIb/IIIa inhibition in an experimental model for an extended time, demonstrating the duration of antiplatelet therapy required to prevent rethrombosis after thrombolysis.
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Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48108-0626.
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Bates
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Nedelman
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Lucchesi
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D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects; D002908:Chronic Disease; D003326:Coronary Circulation / Q000502:physiology; D003328:Coronary Thrombosis / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D003331:Coronary Vessels / Q000473:pathology / Q000503:physiopathology; D004285:Dogs; D004562:Electrocardiography; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D007140:Immunoglobulin Fab Fragments / Q000627:therapeutic use*; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology; D010974:Platelet Aggregation / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D012008:Recurrence; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D005343:Fibrinolytic Agents; D007140:Immunoglobulin Fab Fragments; D010980:Platelet Membrane Glycoproteins; D010959:Tissue Plasminogen Activator