Effects of SanOrg123781A, a Synthetic Hexadecasaccharide, in a Mouse Model of Electrically Induced Carotid Artery Injury: Synergism with the Antiplatelet Agent Clopidogrel

• Published in: The Journal of pharmacology and experimental therapeutics 2004-04, Vol.309 (1), p.235-240
• Main Authors: Lorrain, Janine, Lechaire, Irène, Gauffeny, Christiane, Masson, Régis, Roome, Nigel, Herault, Jean-Pascal, O'Connor, Stephen Eric, Schaeffer, Paul, Herbert, Jean-Marc
• Format: Article
• Language: English
• Subjects: Animals; Carotid Artery Injuries - drug therapy; Carotid Artery Thrombosis - drug therapy; Drug Synergism; Electric Injuries; Male; Mice; Mice, Inbred BALB C; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - pharmacology; Platelet Aggregation Inhibitors - therapeutic use; Polysaccharides - pharmacology; Polysaccharides - therapeutic use; Thrombosis - metabolism; Ticlopidine - analogs & derivatives; Ticlopidine - pharmacology; Ticlopidine - therapeutic use
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.103.059873

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.