title: Prevention of carotid artery thrombosis after oral administration of the glycoprotein IIb/IIIa antagonist CRL42796.
abstract: This study investigates the effect of the glycoprotein IIb/IIIa receptor antagonist CRL42796 in a canine model of carotid artery thrombosis. Both carotid arteries developed occlusive thrombosis in each of the five control animals (time to occlusion: right carotid artery, 92.6 minutes; left carotid artery, 89.0 minutes). A single oral dose of CRL42796 (3 mg/kg) prevented occlusive thrombosis in 4 of 6 vessels and increased time to thrombosis, albeit not significantly (right carotid artery, 134.1 minutes; left carotid artery, 145.0 minutes). When the initial dose of CRL42796 was followed by a second oral dose (3 mg/kg) 2 hours later, 10 of 10 carotid arteries remained patent throughout the period of electrolytic injury. CRL42796 reduced thrombus weight in both treatment protocols. Ex vivo platelet aggregation with arachidonic acid (AA) or adenosine diphosphate (ADP) was reduced at 120, 240, and 360 minutes after two doses of CRL42796. A single oral dose reduced ADP-induced responses at 240 and 360 minutes, but significant effects were not observed with AA. Bleeding time increased 360 minutes after two oral doses of CRL42796, but not at 120 minutes. Bleeding time was unchanged with the single dose of CRL42796. The results demonstrate that oral administration of CRL42796 prevents carotid artery thrombosis in response to deep vessel wall injury and may have potential value to be characterized in extended preclinical and clinical study.
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0632, USA.
authors.forename: James K
authors.initials: JK
authors.lastname: Hennan
authors.forename: David E
authors.initials: DE
authors.lastname: Willens
authors.forename: Edward M
authors.initials: EM
authors.lastname: Driscoll
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Hong
authors.forename: Thierry
authors.initials: T
authors.lastname: Giboulot
authors.forename: Benedict R
authors.initials: BR
authors.lastname: Lucchesi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001760:Bleeding Time; D020212:Carotid Artery Injuries / Q000150:complications; D002341:Carotid Artery Thrombosis / Q000097:blood / Q000503:physiopathology / Q000517:prevention & control*; D004151:Dipeptides / Q000008:administration & dosage / Q000627:therapeutic use*; D004285:Dogs; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D012039:Regional Blood Flow / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: C472490:CRL 42796; D004151:Dipeptides; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D013449:Sulfonamides