Nonpeptide glycoprotein IIb/IIIa inhibitors: 14: oral antithrombotic efficacy of L-738,167 in a conscious canine model of coronary artery electrolytic injury.

Abstract

BACKGROUND:

A conscious dog model of left circumflex coronary artery electrolytic injury was used to assess the oral antithrombotic efficacy of L-738,167, a potent nonpeptide antagonist of platelet GP IIb/IIIa. L-738,167 was administered either as a single oral pretreatment dose 2 hours before initiation of vessel injury or as two oral doses administered 24 hours apart, 12 hours before and after initiation of vessel injury.

METHODS AND RESULTS:

In untreated controls, electrolytic coronary injury (50 microA, 3 hours) resulted in thrombotic occlusion and myocardial ischemia in 15 of 16 dogs, with 4 developing lethal arrhythmias. Significant reductions in thrombus mass and complete prevention of myocardial ischemia and infarction were achieved with a single 100- to 300-microg/kg dose of L-738,167 pretreatment and with two 100-microg/kg doses administered 12 hours before and after initiation of vessel injury. Delays and/or reductions in incidence of ischemia, thrombus mass, and infarct sizes also were achieved with 10- to 30-microg/kg pretreatment and with two 30-microg/kg doses administered 12 hours before and after initiation of vessel injury. None of the L-738,167-treated animals developed lethal arrhythmias. A single oral 100-microg/kg dose of L-738,167 achieved >90% inhibitions of ADP (extent)- and collagen (rate)-induced ex vivo platelet aggregation and fivefold to sixfold or greater elevations in bleeding time; a single oral 30-microg/kg dose of L-738,167 achieved sustained 40% to 70% inhibitions of ADP- and collagen-induced ex vivo platelet aggregation and modest twofold to threefold elevations in bleeding time. At 12 to 24 hours after single oral 30- and 100-microg/kg doses of L-738,167, a substantially greater L-738,167 concentration was associated with platelets than free in plasma.

CONCLUSIONS:

These findings are indicative of potent and sustained oral antithrombotic efficacy and suggest that L-738,167 possesses potential for the oral management of chronic thrombotic occlusive disorders.

• Authors: J J Cook, J D Glass, G R Sitko, M A Holahan, R F Stupienski 3rd, A A Wallace, G L Stump, E L Hand, B C Askew, G D Hartman, R J Gould, J J Lynch Jr
• Journal: Circulation (Circulation) Vol. 96 Issue 3 Pg. 949-58 (Aug 05 1997) ISSN: 0009-7322 [Print] United States
• PMID: 9264506 (Publication Type: Journal Article)

Chemical References

• Azepines
• Fibrinolytic Agents
• L 738167
• Platelet Glycoprotein GPIIb-IIIa Complex
• Sulfonamides

Topics

• Administration, Oral
• Animals
• Azepines (administration & dosage, pharmacology)
• Bleeding Time
• Blood Platelets (drug effects)
• Coronary Disease (blood)
• Coronary Thrombosis (prevention & control)
• Dogs
• Drug Administration Schedule
• Female
• Fibrinolytic Agents (administration & dosage, pharmacology)
• Male
• Platelet Function Tests
• Platelet Glycoprotein GPIIb-IIIa Complex (antagonists & inhibitors)
• Sulfonamides (administration & dosage, pharmacology)