title: 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.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109-0632, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Sudo
authors.forename: B R
authors.initials: BR
authors.lastname: Lucchesi
mesh_terms: D000818:Animals; D016255:Anistreplase / Q000494:pharmacology; D000991:Antithrombins / Q000494:pharmacology*; D001760:Bleeding Time; D001775:Blood Circulation / Q000187:drug effects; D001783:Blood Flow Velocity / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects; D004285:Dogs; D006493:Heparin / Q000494:pharmacology*; D007601:Jugular Veins / Q000187:drug effects; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology*; D010314:Partial Thromboplastin Time; D015912:Thrombolytic Therapy; D013927:Thrombosis / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control
chemical_list: D000991:Antithrombins; D009842:Oligopeptides; D016255:Anistreplase; D006493:Heparin; C064289:efegatran