Document Detail


CU-2010--a novel small molecule protease inhibitor with antifibrinolytic and anticoagulant properties.
MedLine Citation:
PMID:  19104179     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: In cardiac surgery, the contact of blood with the artificial surfaces of the cardiopulmonary bypass results in activation of coagulation, fibrinolysis, and platelets, which is recognized as reason for increased bleeding tendency. Antifibrinolytics like tranexamic acid or the broad-spectrum protease inhibitor aprotinin attenuate this response. The marketing of aprotinin has been suspended after a recent clinical trial suggested increased risks associated with aprotinin. Moreover, aprotinin is a protein of animal origin and has antigenic properties. As a result, alternative antifibrinolytic compounds are desirable. METHODS: This in vitro study compared the antifibrinolytic efficacy of the synthetic small molecule CU-2010 with aprotinin and tranexamic acid. Antifibrinolytic activity in plasma and whole blood of ten healthy volunteers was examined with a turbidometric method and with tissue factor-activated thromboelastometry (ROTEM; Pentapharm, Munich, Germany). In addition, anticoagulant effects were assessed through measurement of plasma and whole blood clotting times and thrombin generation. RESULTS: With its high affinity for plasmin (Ki, 2 nM), CU-2010 inhibited fibrinolysis comparable to aprotinin (Ki, 4 nM) and was ten times more potent than tranexamic acid. CU-2010 also inhibited plasma kallikrein (Ki < 1 nM) and factors Xa (Ki, 45 nM) and XIa (Ki, 18nM), which was reflected in prolongation of coagulation times and an attenuation of thrombin generation. CONCLUSION: These findings suggest that CU-2010 has similar antifibrinolytic potency compared to aprotinin, is more potent than tranexamic acid, and possesses some anticoagulant effects.
Authors:
Wulf Dietrich; Silke Nicklisch; Andreas Koster; Michael Spannagl; Helmut Giersiefen; Andreas van de Locht
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Anesthesiology     Volume:  110     ISSN:  1528-1175     ISO Abbreviation:  Anesthesiology     Publication Date:  2009 Jan 
Date Detail:
Created Date:  2008-12-23     Completed Date:  2009-01-22     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  1300217     Medline TA:  Anesthesiology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  123-30     Citation Subset:  AIM; IM    
Affiliation:
Institute for Research in Cardiac Anesthesia, and Department of Hemostasiology, Ludwig Maximilian University, Munich, Germany. wulf.dietrich@tonline.de
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MeSH Terms
Descriptor/Qualifier:
Animals
Anticoagulants / chemical synthesis,  pharmacology*
Antifibrinolytic Agents / chemical synthesis,  pharmacology*
Aprotinin / pharmacology
Blood Coagulation / drug effects,  physiology
Cattle
Dose-Response Relationship, Drug
Humans
Protease Inhibitors / chemical synthesis,  pharmacology*
Serine Proteinase Inhibitors / chemical synthesis,  pharmacology
Chemical
Reg. No./Substance:
0/Anticoagulants; 0/Antifibrinolytic Agents; 0/Protease Inhibitors; 0/Serine Proteinase Inhibitors; 9087-70-1/Aprotinin

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


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