Effects of SanOrg123781A, a synthetic hexadecasaccharide, in a mouse model of electrically induced carotid artery injury: synergism with the antiplatelet agent clopidogrel.
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.
Lorrain
Janine
J
Cardiovascular/Thrombosis Department, Sanofi-Synthélabo Recherche, 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin Cedex, France. janine.lorrain@sanofi-synthelabo.com
Lechaire
Irène
I
Gauffeny
Christiane
C
Masson
Régis
R
Roome
Nigel
N
Herault
Jean-Pascal
JP
O'Connor
Stephen Eric
SE
Schaeffer
Paul
P
Herbert
Jean-Marc
JM
D000818:Animals; D020212:Carotid Artery Injuries / Q000188:drug therapy*; D002341:Carotid Artery Thrombosis / Q000188:drug therapy*; D000077144:Clopidogrel; D004357:Drug Synergism; D004556:Electric Injuries; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011134:Polysaccharides / Q000494:pharmacology / Q000627:therapeutic use*; D013927:Thrombosis / Q000378:metabolism; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*
D010975:Platelet Aggregation Inhibitors; D011134:Polysaccharides; C464792:SanOrg 123781; D000077144:Clopidogrel; D013988:Ticlopidine