SSR182289A enhances thrombolysis induced by fibrinolytic agents in rabbit models of venous and arterial thrombosis.
OBJECTIVE
The purpose of this work was to investigate whether thrombolysis induced by recombinant tissue plasminogen activator (rt-PA) or streptokinase (SK) was enhanced in different rabbit models of thrombolysis by SSR182289A, a novel synthetic direct thrombin inhibitor which has been shown to possess potent antithrombotic properties in several experimental animal models.


RESULTS
Human rt-PA alone (0.125 mg kg(-1) h(-1) for 2 h) induced a significant thrombolysis (18%, P < 0.05) of a venous-type thrombus in the rabbit jugular vein. Under these conditions, SSR182289A (3 mg kg(-1) i.v. bolus) inhibited 125I-fibrin accretion onto a preformed thrombus in the rabbit jugular vein by 72%, but was unable to induce thrombolysis on its own. However, coadministration of SSR182289A and rt-PA strongly enhanced rt-PA-induced thrombolysis (38.4%, P < 0.01). The effect of SSR182289A was further assessed in a model of thrombolysis of an electrical injury-induced, stable (occlusion duration > 2 h) thrombus formed in the rabbit femoral artery. Whereas local intra-arterial infusion of high doses of SSR182289A (3 mg kg(-1) h(-1) for 1 h) alone was able to restore flow, SK (12,000 U kg(-1) h(-1)) and a low dose of SSR182289A (0.3 mg kg(-1) h(-1)) were ineffective. However, intra-arterial coadministration of SSR182289A (0.3 mg kg(-1) h(-1)) and SK (12,000 U kg(-1) h(-1)) induced significant reflow (time to reflow was shortened by 34.7 +/- 7.5 min, P < 0.05). In the same model, systemic i.v. administration of high doses of SSR182289A (10 mg kg(-1) i.v. bolus) and rt-PA (1 mg kg(-1) h(-1)) alone did not induce any thrombolysis. However, the association of both compounds quickly (30 +/- 6 min) restored and maintained flow (duration > 2 h) in all animals.


CONCLUSIONS
The present results show that bolus i.v. injection of SSR182289A is able to potentiate thrombolysis induced by two fibrinolytic agents whether the thrombus is of venous or arterial origin, thus suggesting that SSR182289A may be of use as an adjunct to thrombolysis.
Visconte
C
C
Sanofi-Synthélabo Recherche, Cardiovascular-Thrombosis Department, Chilly Mazarin, France.
Sainte-Marie
M
M
Lorrain
J
J
Millet
L
L
O'Connor
S E
SE
Schaeffer
P
P
Herbert
J-M
JM
D000631:Aminopyridines / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005263:Femoral Artery; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007601:Jugular Veins; D008297:Male; D011817:Rabbits; D013300:Streptokinase / Q000494:pharmacology / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D015912:Thrombolytic Therapy / Q000379:methods*; D013927:Thrombosis / Q000188:drug therapy*; D010959:Tissue Plasminogen Activator / Q000494:pharmacology / Q000627:therapeutic use
D000631:Aminopyridines; D005343:Fibrinolytic Agents; C469682:N-(3-((((4-(5-amino-2-pyridinyl)-1-((4-difluoromethylene)-1-piperidinyl)carbonyl)butyl)amino)sulfonyl)(1,1'-biphenyl)-2-yl) acetamide; D013449:Sulfonamides; D013300:Streptokinase; D010959:Tissue Plasminogen Activator