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

Abstract

The antithrombotic effect of the glycoprotein IIb/IIIa receptor antagonist, CRL42796, was examined in canine models of carotid and coronary artery thrombosis. In the carotid artery thrombosis model, occlusion occurred in all control vessels (time to thrombosis 47.6±8.9 min). After treatment with low dose CRL42796 (15 μg kg−1 loading dose +0.31 μg kg−1 min−1 i.v.), two of five vessels occluded. Time to thrombosis increased significantly to 155.2±23.1 min. When the drug infusion was increased (0.69 μg kg−1 min−1), each of five vessels remained patent. Ex vivo platelet aggregation in response to arachidonic acid (AA) and ADP was examined in platelet rich plasma (PRP) prepared from citrate or heparin anticoagulated blood. CRL42796 reduced platelet reactivity at low and high doses in PRP from citrate anticoagulated blood. However, in PRP from heparin anticoagulated blood, only the higher infusion dose produced a significant reduction in ex vivo platelet responses. A combination of oral aspirin (4.6 mg kg−1 −41, −17 h) and the low infusion dose of CRL42796 did not produce an additional benefit beyond that provided by CRL42796 alone. Coronary artery thrombosis was inhibited in four of five vessels treated with the lower infusion dose of CRL42796 and in five of five vessels treated with the higher infusion. Time to thrombosis increased with both doses (Control, 90.8±10.4 min; low dose, 165.8±14.2 min; high dose, >180.0±0 min). The results indicate that CRL42796 is an effective in vivo antithrombotic agent against experimentally‐induced carotid and coronary artery thrombosis. British Journal of Pharmacology (2002) 136, 927–937. doi:

1‐Methylnicotinamide (MNA), a primary metabolite of nicotinamide, exerts anti‐thrombotic activity mediated by a cyclooxygenase‐2/prostacyclin pathway

“…Thus, our present findings that MNA with its PGI 2 releasing properties, while ineffective in venous thrombosis, displays the ability to limit platelet‐dependent thrombosis is fully consistent with the nature of these experimental models and highlights the specificity of MNA and PGI 2 ‐triggered mechanisms towards arterial, platelet‐dependent, thrombosis. It would be still worthwhile to examine MNA activity in a different animal model of platelet‐dependent thrombosis, sensitive to agents that modulate the COX pathways (Hennan et al , 2002) to confirm our conclusion.…”

Glycoprotein IIb/IIIa Receptor Antagonist (2 S)-2-[(2-Naphthyl-sulfonyl)amino]-3-{[2-({4-(4-piperidinyl)-2-[2-(4-piperidinyl)ethyl] butanoyl}amino)acetyl]amino}propanoic Acid Dihydrochloride (CRL42796), in Combination with Aspirin and/or Enoxaparin, Prevents Coronary Artery Rethrombosis after Successful Thrombolytic Treatment by Recombinant Tissue Plasminogen Activator

“…Several oral GPIIb/IIIa antagonists (xemilofiban, sibrafiban, lamifiban, and roxifiban) were examined experimentally as well as clinically but have not been approved for clinical use due to limited oral bioavailability and the potential to induce serious bleeding. The nonpeptide GPIIb/IIIa receptor antagonist CRL42796 was reported to prevent primary thrombosis when administered intravenously (Hennan et al, 2002) or after oral dosing (Hennan et al, 2003). The minimal effective intravenous dosing regimen for preventing arterial thrombosis required a loading dose of 15 g/kg and a continuous infusion ranging between 0.31 and 0.69 g/kg/min.…”

Effect of thrombolysis on myocardial injury: recombinant tissue plasminogen activator vs. alfimeprase

“…The present study used the adjunctive agent CRL-42796, a GPIIb/IIIa platelet receptor antagonist (13,14). The platelet receptor antagonist was administered as a continuous intravenous infusion commencing before the administration of the respective lytic agents.…”