Oral antiplatelet, antithrombotic efficacy of DMP 728, a novel platelet GPIIb/IIIa antagonist.

Abstract

BACKGROUND:

Currently used antiplatelet drugs, including aspirin and ticlopidine, are effective against certain but not all of the many endogenous platelet activators. Because of their limited efficacy, a significant number of serious thromboembolic complications still occur, highlighting the need for a more effective therapy. DMP 728 has been characterized as a potent and specific platelet glycoprotein IIb/IIIa complex (GPIIb/IIIa) antagonist. The goals of the present study were to determine the oral antiplatelet and antithrombotic efficacies of DMP 728 in various arterial thrombosis models in dogs.

METHODS AND RESULTS:

In conscious and anesthetized mongrel dogs, DMP 728 at 0.02 to 1.0 mg/kg PO in gelatin capsules produced dose-dependent antiplatelet effects in inhibiting ex vivo platelet aggregation induced by ADP and prolonging template bleeding time. DMP 728 effects on bleeding time prolongation could be reversed more rapidly than those on platelet aggregation inhibition. A maximal antiplatelet effect for DMP 728 was demonstrated at 1.0 mg/kg PO. DMP 728 demonstrated dose-dependent oral antiplatelet effects with an absolute oral bioavailability of 8% to 12% in dogs. Additionally, the antithrombotic efficacy of DMP 728 was examined after intravenous and oral administration at different doses in various models of arterial thrombosis. In the coronary artery Folts' model in dogs, DMP 728 demonstrated maximal antithrombotic efficacy at 0.01 mg/kg IV and < 0.6 mg/kg PO. Additionally, DMP 728 at 0.1 and 1.0 mg/kg IV or PO demonstrated 60% to 100% prevention of primary thrombosis (P < .01) in an electrolytically induced carotid artery thrombosis model in dogs.

CONCLUSIONS:

These data suggest that DMP 728, a low-molecular-weight GPIIb/IIIa receptor antagonist, may have therapeutic potential as an oral antithrombotic agent in coronary and carotid artery thromboembolic disorders.

• Authors: S A Mousa, W F DeGrado, D X Mu, R P Kapil, B R Lucchesi, T M Reilly
• Journal: Circulation (Circulation) Vol. 93 Issue 3 Pg. 537-43 (Feb 01 1996) ISSN: 0009-7322 [Print] United States
• PMID: 8565173 (Publication Type: Journal Article)

Chemical References

• Capsules
• Fibrinolytic Agents
• Mesylates
• Peptides, Cyclic
• Platelet Aggregation Inhibitors
• Platelet Glycoprotein GPIIb-IIIa Complex
• DMP 728
• Adenosine Diphosphate

Topics

• Adenosine Diphosphate (pharmacology)
• Administration, Oral
• Anesthesia, General
• Animals
• Bleeding Time
• Capsules
• Coronary Thrombosis (prevention & control)
• Dogs
• Female
• Fibrinolytic Agents (administration & dosage, pharmacokinetics, therapeutic use)
• In Vitro Techniques
• Male
• Mesylates (administration & dosage, pharmacokinetics, therapeutic use)
• Peptides, Cyclic (administration & dosage, pharmacokinetics, therapeutic use)
• Platelet Aggregation (drug effects)
• Platelet Aggregation Inhibitors (administration & dosage, pharmacokinetics, therapeutic use)
• Platelet Glycoprotein GPIIb-IIIa Complex (antagonists & inhibitors)