Antithrombotic effect of GYKI-14766 in a canine model of arterial and venous rethrombosis: a comparison with heparin.

Abstract

We compared the antithrombotic effects of the thrombin inhibitor, D-methyl-phenylalanyl-prolyl-arginal (GYKI-14766) with those of heparin in a canine model of arterial and venous rethrombosis. Thrombogenesis was induced by electrolytic injury to the endothelial surface of the carotid artery and jugular vein. Either heparin (300 U/kg, n = 7), GYKI-14766 (0.5 mg/kg/h, n = 7), or saline (n = 10) was administered intravenously (i.v.) immediately after the local administration of anisoylated plasminogen streptokinase activator complex (APSAC 0.1 U/kg). Supplemental doses of heparin (100 U/kg) were administered at 1-h intervals. Infusion of GYKI-14766 was maintained for 5 h throughout the experiment. Ex vivo platelet aggregation in response to ADP or arachidonic acid (AA) was not changed in any of the experimental groups. Both GYKI-14766 and heparin increased the activated partial thromboplastin time (aPTT) over their respective baseline values. Heparin, but not GYKI-14766, increased the bleeding time. After successful thrombolysis, arterial and venous rethrombosis occurred in all saline-treated dogs. GYKI-14766 prevented cyclic flow variations and reocclusion in the artery and the vein (p < 0.01). Heparin had only minimal effects on the artery and no effect on the vein. Arterial thrombus weights were reduced by GYKI-14766 [saline control = 24 +/- 4 mg, GYKI-14766 = 9 +/- 3 mg, (p < 0.05); heparin = 14 +/- 2 mg, p = NS]. The venous thrombus weights were reduced slightly by GYKI-14766 and were unchanged by heparin (saline = 25 +/- 5 mg, GYKI-14766 = 13 +/- 4 mg, heparin = 26 +/- 3 mg). The data suggest that GYKI-14766 is effective in preventing occlusive rethrombosis in both the arterial and venous circulation after thrombolysis without augmenting bleeding time. GYKI-14766 may represent an alternative to heparin as an adjunctive agent during thrombolytic therapy.

• Authors: Y Sudo, B R Lucchesi
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 27 Issue 4 Pg. 545-55 (Apr 1996) ISSN: 0160-2446 [Print] United States
• PMID: 8847872 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antithrombins
• Oligopeptides
• Anistreplase
• Heparin
• efegatran

Topics

• Animals
• Anistreplase (pharmacology)
• Antithrombins (pharmacology)
• Bleeding Time
• Blood Circulation (drug effects)
• Blood Flow Velocity (drug effects)
• Carotid Arteries (drug effects)
• Dogs
• Heparin (pharmacology)
• Jugular Veins (drug effects)
• Male
• Oligopeptides (pharmacology)
• Partial Thromboplastin Time
• Thrombolytic Therapy
• Thrombosis (drug therapy, physiopathology, prevention & control)