QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.103.059873v1 309/1/235    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lorrain, J. Articles by Herbert, J.-M. Search for Related Content PubMed PubMed Citation Articles by Lorrain, J. Articles by Herbert, J.-M.

CARDIOVASCULAR

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

Cardiovascular/Thrombosis Department, Sanofi-Synthélabo Recherche, Chilly-Mazarin and Toulouse, France (J.L., I.L., J.-P.H., S.E.O., P.S.); and Toxicology Department, Sanofi-Synthélabo Recherche, Porcheville, France (C.G., R.M., N.R.)

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.

Address correspondence to: Dr. Janine Lorrain, Cardiovascular/Thrombosis Department, Sanofi-Synthélabo Recherche, 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin Cedex, France. E-mail: janine.lorrain{at}sanofi-synthelabo.com

This article has been cited by other articles:

				M. R. Lassen, O. Dahl, P. Mismetti, D. Zielske, and A. G.G. Turpie SR123781A: A New Once-Daily Synthetic Oligosaccharide Anticoagulant for Thromboprophylaxis After Total Hip Replacement Surgery: The DRIVE (Dose Ranging Study in Elective Total Hip Replacement Surgery) Study J. Am. Coll. Cardiol., April 15, 2008; 51(15): 1498 - 1504. [Abstract] [Full Text] [PDF]