Document Detail

Studies on the different modes of action of the anticoagulant protease inhibitors DX-9065a and Argatroban. I. Effects on thrombin generation.
MedLine Citation:
PMID:  12496240     Owner:  NLM     Status:  MEDLINE    
The present study began with mathematical modeling of how inhibitors of both factor Xa (fXa) and thrombin affect extrinsic pathway-triggered blood coagulation. Numerical simulation demonstrated a stronger inhibition of thrombin generation by a thrombin inhibitor than a fXa inhibitor, but both prolonged clot time to a similar extent when they were given an equal dissociation constant (30 nm) for interaction with their respective target enzymes. These differences were then tested by comparison with the real inhibitors DX-9065a and argatroban, specific competitive inhibitors of fXa and thrombin, respectively, with similar K(i) values. Comparisons were made in extrinsically triggered human citrated plasma, for which endogenous thrombin potential and clot formation were simultaneously measured with a Wallac multilabel counter equipped with both fluorometric and photometric detectors and a fluorogenic reporter substrate. The results demonstrated stronger inhibition of endogenous thrombin potential by argatroban than by DX-9065a, especially when coagulation was initiated at higher tissue factor concentrations, while argatroban appeared to be slightly less potent in its ability to prolong clot time. This study demonstrates differential inhibition of thrombin generation by fXa and thrombin inhibitors and has implications for the pharmacological regulation of blood coagulation by the anticoagulant protease inhibitors.
Hajime Nagashima
Publication Detail:
Type:  Journal Article     Date:  2002-10-22
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  277     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2002 Dec 
Date Detail:
Created Date:  2002-12-23     Completed Date:  2003-02-27     Revised Date:  2004-12-08    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  50439-44     Citation Subset:  IM    
New Product Research Laboratories II, Daiichi Pharmaceutical Co., Ltd., Tokyo 104-8369, Japan.
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MeSH Terms
Anticoagulants / pharmacology*
Binding, Competitive
Blood Coagulation / drug effects*
Models, Theoretical
Naphthalenes / pharmacology*
Pipecolic Acids / pharmacology*
Platelet Aggregation Inhibitors / pharmacology*
Propionic Acids / pharmacology*
Serine Proteinase Inhibitors / pharmacology*
Thrombin / metabolism*
Reg. No./Substance:
0/Anticoagulants; 0/Naphthalenes; 0/Pipecolic Acids; 0/Platelet Aggregation Inhibitors; 0/Propionic Acids; 0/Serine Proteinase Inhibitors; 155204-81-2/DX 9065a; 74863-84-6/argatroban; EC

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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