From heparins to factor Xa inhibitors and beyond

被引:48
作者
Alban, S [1 ]
机构
[1] Univ Kiel, Inst Pharmaceut, D-24118 Kiel, Germany
关键词
antithrombotic; drug development; factor Xa inhibitor; fondaparinux; heparin; low molecular weight heparin;
D O I
10.1111/j.0960-135X.2005.01452.x
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Despite some disadvantages, unfractionated heparin (UFH) and oral anticoagulants have been the only anticoagulants for prophylaxis and therapy of thromboembolic disorders for several decades. Based on the increasing knowledge of the structure and pharmacology of heparin, low molecular weight heparins (LMWH) have been developed in the 1980s. Compared to UFH, their advantages are mainly based on their reduced nonspecific binding to proteins and cells resulting in improved pharmacokinetics. In 1991, LMWH were declared as the most efficient prophylaxis in high-risk patients. Although the use of LMWH is increasing and they are today also applied for therapy and in other indications like acute coronary syndrome, they are considered not optimal concerning efficacy and safety. With the approval of fondaparinux for the prevention of venous thromboembolic disease in high-risk orthopedic patients, there might be a paradigm shift in the field of anticoagulants. Fondaparinux, a synthetic, chemically defined pentasaccharide, is the first selective inhibitor of factor Xa. By its highly specific binding to antithrombin, it selectively inhibits factor Xa and consequently prevents thrombin generation. In contrast to UFH and LMWH it does not bind to any other cells and other proteins than antithrombin. This leads to a,favourable linear pharmacokinetic profile, allowing once-daily subcutaneous application of a fixed dose without monitoring in thromboembolism prophylaxis. In addition to the evaluation of fondaparinux for further indications, chemical modifications of this pentasaccharide such as the long-acting idraparinux are currently under investigation.
引用
收藏
页码:12 / 20
页数:9
相关论文
共 48 条
[11]  
Béguin S, 1999, HAEMOSTASIS, V29, P170
[12]   Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers [J].
Bijsterveld, NR ;
Moons, AH ;
Boekholdt, SM ;
van Aken, BE ;
Fennema, H ;
Peters, RJG ;
Meijers, JCM ;
Büller, HR ;
Levi, M .
CIRCULATION, 2002, 106 (20) :2550-2554
[13]  
BJORK I, 1989, HEPARIN CHEM BIOL PR, P229
[14]  
Buller HR, 2004, J THROMB HAEMOST, V2, P47
[15]   STRUCTURE-ACTIVITY RELATIONSHIP IN HEPARIN - A SYNTHETIC PENTASACCHARIDE WITH HIGH-AFFINITY FOR ANTI-THROMBIN-III AND ELICITING HIGH ANTI-FACTOR-XA ACTIVITY [J].
CHOAY, J ;
PETITOU, M ;
LORMEAU, JC ;
SINAY, P ;
CASU, B ;
GATTI, G .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1983, 116 (02) :492-499
[16]   Improved cancer mortality with low-molecular-weight heparin treatment: A review of the evidence [J].
Cosgrove, RH ;
Zacharski, LR ;
Racine, E ;
Andersen, JC .
SEMINARS IN THROMBOSIS AND HEMOSTASIS, 2002, 28 (01) :79-87
[17]   Anticoagulant and antiprotease effects of a novel heparinlike compound from shrimp (Penaeus brasiliensis) and its neutralization by heparinase I [J].
Demir, M ;
Iqbal, O ;
Dietrich, CP ;
Hoppensteadt, DA ;
Ahmad, S ;
Daud, AN ;
Fareed, J .
CLINICAL AND APPLIED THROMBOSIS-HEMOSTASIS, 2001, 7 (01) :44-52
[18]   Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. [J].
Eriksson, BI ;
Bauer, KA ;
Lassen, MR ;
Turpie, AGG .
NEW ENGLAND JOURNAL OF MEDICINE, 2001, 345 (18) :1298-1304
[19]  
GALLUS A S, 1976, Seminars in Thrombosis and Hemostasis, V2, P232
[20]  
Garon Jack E, 2003, Clin Leadersh Manag Rev, V17, P47