Prevention of thrombosis and rethrombosis and enhancement of the thrombolytic actions of recombinant tissue‐type plasminogen activator in the canine heart by DMP728, a glycoprotein IIb/IIIa antagonist

Abstract

1 We studied DMP728, a non-peptide glycoprotein (GP) IIb/IIIa receptor antagonist, for prevention of coronary artery thrombosis or rethrombosis in a chronic canine model subjected to arterial injury. 2 In protocol I, DMP728 (1.0mg kg-', i.v., n = 8) or saline (n = 8) was administered and a 150 JA anodal current was applied to the intimal surface of the left circumflex coronary artery (LCX). Dogs were monitored for 6 h and again on each of 5 subsequent days. 3 Ex vivo platelet aggregation was inhibited but returned to baseline day after drug administration. Thrombus weight was reduced (saline, 20.7 ± 5.0 mg; DMP728 1.7 ± 0.4 mg; P < 0.05), as was infarct size [saline, 27.5 ± 4.3; DMP728, 1.6 ± 0.7 (per cent left ventricle); P<0.05]. All control animals died by day 3, while all but one of the treated dogs survived the entire protocol (P <0.05). 4 In protocol II, an LCX thrombus was induced and thrombolytic therapy was initiated 30 min later. DMP728 (1.0 mg kg-', i.v., n = 8) or saline (n = 8) was administered 5 min after recombinant tissue-type plasminogen activator infusion had begun. The incidence of reocclusion was reduced by DMP728 (saline, 4/8; DMP728, 1/8). One day after thrombolysis, 7/8 DMP728-treated animals were alive compared with 1/8 in the control group (P = 0.01). 5 DMP728 inhibited ex vivo platelet aggregation, prevented primary and secondary occlusive thrombus formation, reduced thrombus weight and infarct size and increased survival in a chronic canine model of coronary artery thrombus formation. DMP728 is an effective anti-platelet intervention when used as the singular adjunctive agent in association with thrombolytic therapy.

Prevention of experimental carotid and coronary artery thrombosis by the glycoprotein IIb/IIIa receptor antagonist CRL42796

“…Thus, CRL42796 displays a rapid‐on and rapid‐off pharmacological profile that may offer an improved safety factor in those clinical situations where increased bleeding might occur. Other GPIIb/IIIa receptor antagonists such as 7E3 (Bates et al ., 1992; Rote et al ., 1994c), DMP‐728 (Lucchesi et al ., 1994), and SM‐20302 (Huang et al ., 1999) result in extended maintenance of vessel patency despite the fact that ex vivo platelet aggregation responses return to baseline values. There are other factors to consider involving a time‐dependent decrease in the thrombogenicity of the injured vessel wall thus allowing preservation of blood flow in the presence of normal platelet function.…”

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).…”