Document Detail


Potent arterial antithrombotic effect of direct factor-Xa inhibition with ZK-807834 administered to coronary artery disease patients.
MedLine Citation:
PMID:  17334518     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
It was the objective of this study to evaluate the anti-thrombotic potency of direct factor-Xa inhibition with ZK-807834 in stable coronary patients, using an ex-vivo model of arterial thrombus formation. Tissue factor pathway is important in atherothrombosis. Direct factor-Xa blockade may more potently reduce thrombosis and prevent coronary events. Badimon Perfusion Chamber 5-minute quantitative studies have shown 40-55% arterial thrombus reduction with abciximab, 23% with clopidogrel, but none with heparin. Coronary patients (n = 18, 59 +/- 9 years, 55% males) were blindly randomized to four groups receiving 24-hour infusion of a low, medium or high dose of direct factor- Xa inhibitor ZK-807834, or placebo. Arterial thrombus formation was measured in Badimon Chamber at baseline, end-of-infusion [EoI], and four hours and eight hours after EoI, and factor-X activity, prothrombin time [PT] ratio and plasma drug levels were measured simultaneously. For the low-, medium- and high-dose ZK-807834 groups, mean percent-reduction in thrombus size from baseline to EoI were 29%, 34% and 68%, respectively (p < 0.001), and at 8-h post EoI were 11%, 19% and 27%, respectively (p < 0.01). Mean PT-ratio prolongation showed a strong linear relationship (Pearson's r = 0.93) with ZK-807834 plasma concentration. Mean percent-reduction in factor-X activity from baseline was 13%, 42% and 58%, respectively. Placebo had no effect on thrombus size or factor-X activity. In conclusion, direct factor-Xa inhibition with ZK-807834 markedly reduces ex-vivo arterial thrombus formation and factor-X activity in a dose-dependent manner. Plasma levels of ZK-807834 show a strong linear correlation with PT ratio. This direct factor-Xa inhibitor may reduce the need for additional potent glycoprotein IIbIIIa inhibition.
Authors:
M Urooj Zafar; Michael E Farkouh; Julio Osende; Daichi Shimbo; Stella Palencia; Julia Crook; Robert Leadley; Valentin Fuster; James H Chesebro
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Publication Detail:
Type:  Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Thrombosis and haemostasis     Volume:  97     ISSN:  0340-6245     ISO Abbreviation:  Thromb. Haemost.     Publication Date:  2007 Mar 
Date Detail:
Created Date:  2007-03-05     Completed Date:  2007-05-04     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  7608063     Medline TA:  Thromb Haemost     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  487-92     Citation Subset:  IM    
Affiliation:
Zena and Michael A. Wiener, Cardiovascular Institute, New York, NY 10029, USA.
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MeSH Terms
Descriptor/Qualifier:
Amidines / administration & dosage,  pharmacokinetics,  therapeutic use*
Animals
Aorta / drug effects*,  pathology
Blood Coagulation / drug effects*
Coronary Artery Disease / blood,  complications,  drug therapy*
Dose-Response Relationship, Drug
Double-Blind Method
Factor Xa / antagonists & inhibitors*
Female
Fibrinolytic Agents / administration & dosage,  pharmacokinetics,  therapeutic use*
Humans
Infusions, Intravenous
Injections, Intravenous
Male
Middle Aged
Perfusion
Prothrombin Time
Pyridines / administration & dosage,  pharmacokinetics,  therapeutic use*
Swine
Thrombosis / blood,  etiology,  pathology,  prevention & control*
Time Factors
Treatment Outcome
Chemical
Reg. No./Substance:
0/Amidines; 0/Fibrinolytic Agents; 0/Pyridines; 0/ZK 807834; EC 3.4.21.6/Factor Xa

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


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