TY - JOUR T1 - Effects of SanOrg123781A, a Synthetic Hexadecasaccharide, in a Mouse Model of Electrically Induced Carotid Artery Injury: Synergism with the Antiplatelet Agent Clopidogrel JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 235 LP - 240 DO - 10.1124/jpet.103.059873 VL - 309 IS - 1 AU - Janine Lorrain AU - Irène Lechaire AU - Christiane Gauffeny AU - Régis Masson AU - Nigel Roome AU - Jean-Pascal Herault AU - Stephen Eric O'Connor AU - Paul Schaeffer AU - Jean-Marc Herbert Y1 - 2004/04/01 UR - http://jpet.aspetjournals.org/content/309/1/235.abstract N2 - SanOrg123781A is a synthetic hexadecasaccharide that displays antithrombin-dependent inhibition of factor Xa and thrombin and potent antithrombotic effects. The antithrombotic activity of SanOrg123781A has been studied in a new mouse model of arterial thrombosis, where thrombus formation was induced by the application of an electrical current to the adventitial surface of a carotid artery. In this model, antiplatelet agents such as the ADP-receptor antagonist clopidogrel (30 mg/kg, p.o. 2 h before stimulation) and the GpIIb/IIIa antagonist SR121566A [3-{N-[4-{4-[amino(imino)methyl]phenyl}-1,3-thiazol-2-yl]-N-[1-(carboxymethyl)piperidin-4-yl]amino}propionic acid, trihydrochloride] (0.3 mg/kg, i.v. 5 min before stimulation) strongly prolonged the time to occlusion (TTO) (761 and 473% increases, respectively), whereas aspirin was devoid of antithrombotic activity. Standard heparin (2 mg/kg, i.v.), the low molecular weight heparin enoxaparin (20 mg/kg, i.v.), and the synthetic, antithrombin-dependent inhibitor of factor Xa fondaparinux (10 mg/kg, i.v.) were also active in this model (742, 707, and 602% TTO increases, respectively). Interestingly, SanOrg123781A was active at much lower doses than the other oligosaccharides (554% increase in TTO at 0.3 mg/kg, i.v. 5 min before stimulation). Low doses of SanOrg123781A administered in combination with low doses of clopidogrel led to a marked increase in TTO, which was statistically more important than the additive effects of the two compounds given alone. These results indicate that SanOrg123781A exerts a potent antithrombotic activity in a mouse model of arterial thrombosis when compared with reference compounds and show that the combination of SanOrg123781A with clopidogrel leads to a marked synergistic antithrombotic effect. The American Society for Pharmacology and Experimental Therapeutics ER -