Intravenous and endobronchial administration of G4120, a cyclic Arg-Gly-Asp-containing platelet GPIIb/IIIa receptor-blocking pentapeptide, enhances and sustains coronary arterial thrombolysis with rt-PA in a canine preparation.

Abstract

Arg-Gly-Asp-containing pentapeptide, has a high affinity (dissociation constant of 4 nM) for the platelet glycoprotein (GP) Ilb/IIIa receptor. The effects of its intravenous or endobronchial administration on thrombolysis, reocclusion, and bleeding time prolongation induced with 0.45 mg/kg bolus injections of recombinant tissue-type plasminogen activator in combination with intravenous heparin (4,000-unit bolus and 1,000 units each hour) were studied in a canine model consisting of an erythrocyte-rich blood clot in the left anterior descending coronary artery. Coronary patency was monitored for 3 hours both by ultrasonic flow probe and by repeat coronary angiography. Four groups of six to 10 dogs were studied with intravenous infusions of 0, 0.1, 0.2, or 0.3 mg/kg G4120 over 60 minutes. G4120 at a dose of 0.3 mg/kg reduced the time to reflow from a mean control value of 45 to 8 minutes (p=0.036) and delayed reocclusion (p=0.001). Four groups of five or six dogs were studied with endobronchial instillation of G4120 in a randomized, blinded study design using 0,0.13,0.25, or 0.5 mg/kg G4120. Endobronchial G4120 at a dose of 0.5 mg/kg reduced the time to reflow from a mean control value of 52 to 7 minutes (p=0.039) and abolished cyclic reocclusion and reflow (p=0.008). G4120 induced a dose-related transient prolongation of the template bleeding time and inhibition of ADP-induced platelet aggregation. G4120, a synthetic low-molecular-weight GPIIb/IIIa inhibitor that may be produced by chemical synthesis, may be of clinical value as a conjunctive agent for thrombolysis in patients with ischemic coronary syndromes. (Arteriosclerosis and Thrombosis 1993;13:738-747) KEY WORDS • acute myocardial infarction • thrombolytic therapy • arterial reocclusion • template bleeding time • glycoprotein Ilb/IIIa receptor I t is well established that thrombolytic therapy improves the outcome of acute myocardial infarction and that the conjunctive use of anticoagulants and /or antiplatelet agents increases the efficacy of coronary arterial thrombolysis. 12 The efficacy of heparin and aspirin in enhancing and sustaining coronary arterial recanalization in humans is, however, limited,

Enhancement of Tissue-type Plasminogen Activator-induced Thrombolysis and Prevention of Reocclusion by Combination with a Humanized Anti-glycoprotein IIb/IIIa Monoclonal Antibody, YM337, in a Rhesus Monkey Model of Coronary Thrombosis

“…YM337 accelerated tPA-induced thrombolysis and prevented acute reocclusion after successful thrombolysis. Similar results have been reported for many studies on the effectiveness of c7E3 and other GPIIb/IIIa antagonists (20)(21)(22)(23)(24). The efficacy of aspirin after thrombolytic therapy in the prevention of reinfarction has been confirmed clinically (25).…”

Conjunctive Use of Platelet Glycoprotein IIb/IIIa Antagonists and Thrombolytic Therapy for Acute Myocardial Infarction

“…These studies showed the combination of 7E3 F[ab']z or c7E3 and t-PA to restore coronary perfusion rapidly and to nearly abolish the occurrence of reocclusion. Similar findings were observed using short, synthetic peptide, reversible inhibitors of the IIb/IIIa receptor (35,36).…”

Toward a New Frontier in Myocardial Reperfusion Therapy

“…[57][58][59][60][61][62][63][64][65][66][67][68][69][70][71] Cumulatively, these studies have shown that the dose of fibrinolytic therapy can be substantially reduced to Ϸ50% or even 25% of the dose required in control experiments 57,58 and that fibrinolysis occurs much more rapidly and more completely and is much more stable, as reflected by the absence of cyclic flow variations or reocclusion once flow is restored. Nicolini and associates 65 showed that a low dose of a GP IIb/IIIa inhibitor combined with a low dose of a direct thrombin inhibitor (hirudin) also markedly facilitated coronary fibrinolysis in the canine electrolytic model.…”