Methodological aspects in the studies on the mechanism of action of synthetic direct thrombin antagonists.
Requirements reported for an ideal anticoagulant [12] and for an ideal antithrombotic [18] show the necessity of many-sided methodological approach in order to detect the molecular mechanism of action of a novel synthetic antagonist of thrombin. The lack of a protocol internationally accepted, on the one hand, and with regard to a general proposal accepted [16], on the other hand, authors applied a complex methodological system involving also the study on the possible interactions at molecular level of some novel thrombin antagonists with the main components of their site of action. The surprising contradiction found between in vitro and in vivo efficacy of several antagonists could be attributed and explained by the significant differences in Ki and IC50 values determined in complex clotting assays containing plasma proteins and/or blood cells versus those measured in reaction mixtures consisting of a synthetic chromogenic substrate, the target enzyme, thrombin, and the antagonist compound in buffer solution.
Bagdy
D
D
Institute for Drug Research Ltd., Budapest, Hungary.
Barabás
E
E
Szabó
G
G
D000818:Animals; D000991:Antithrombins / Q000494:pharmacology*; D001780:Blood Coagulation Tests / Q000379:methods*; D002863:Chromogenic Compounds; D004151:Dipeptides; D016903:Drug Monitoring; D005340:Fibrinogen / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D011817:Rabbits; D013917:Thrombin / Q000037:antagonists & inhibitors
D000991:Antithrombins; D002863:Chromogenic Compounds; D004151:Dipeptides; D009842:Oligopeptides; C035202:H-D-Phe-Pro-arginal; C021129:S 2238; D005340:Fibrinogen; D013917:Thrombin