Cooperative antithrombotic effect from the simultaneous inhibition of thrombin and factor Xa.
Whereas heparin functions as an antithrombotic agent by promoting antithrombin III-based inhibition of thrombin and factor Xa, there is less appreciation for the combination behavior with small-molecule, direct inhibitors of these proteases. We conducted a study in a high-shear arterial environment to explore the potential for a cooperative antithrombotic effect with a thrombin inhibitor (argatroban), a factor Xa inhibitor (YM-60828), and a dual thrombin/factor Xa inhibitor (RWJ-445167). We employed a platelet-dependent vascular injury model in which rats were subjected to an acute electrical injury to the carotid artery. Antithrombotic efficacy was measured for thrombin inhibitor argatroban and factor Xa inhibitor YM-60828 administered alone or in combination. The results indicate that there is a cooperative antithrombotic effect in vivo when both thrombin and factor Xa are inhibited simultaneously. The dual thrombin/factor Xa inhibitor RWJ-445167 was found to have potent antithrombotic activity in this high-shear environment. A comparison of results for RWJ-445167 and argatroban showed additional efficacy with RWJ-445167, suggestive of drug synergy.
Giardino
Edward C
EC
Johnson & Johnson Pharmaceutical Research & Development, Welsh and McKean Roads, Spring House, PA 19477, USA.
Haertlein
Barbara J
BJ
de Garavilla
Lawrence
L
Costanzo
Michael J
MJ
Damiano
Bruce P
BP
Andrade-Gordon
Patricia
P
Maryanoff
Bruce E
BE
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives; D001777:Blood Coagulation / Q000187:drug effects; D004357:Drug Synergism; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D010875:Pipecolic Acids / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology*; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism
D065427:Factor Xa Inhibitors; D006146:Guanidines; D009281:Naphthalenes; D010875:Pipecolic Acids; D010880:Piperidines; C515002:RWJ 445167; D013449:Sulfonamides; C111032:YM 60828; D001120:Arginine; D013917:Thrombin; D015951:Factor Xa; C031942:argatroban