Edith A Nutescu1, Ann K Wittkowsky. 1. Antithrombosis Service, College of Pharmacy, The University of Illinois at Chicago, Chicago, IL 60612, USA. enutescu@uic.edu
Abstract
OBJECTIVE: To review the progress in developing direct thrombin inhibitors (DTIs) for anticoagulation within the context of existing anticoagulation therapies. DATA SOURCES: Searches of MEDLINE (1993-June 2003) were conducted. STUDY SELECTION AND DATA EXTRACTION: We examined English-language articles, human studies, and relevant animal studies, and obtained additional citations from the references of these articles. DATA SYNTHESIS: Because of its pivotal role in hemostasis, thrombin is a key therapeutic target in the treatment and prevention of thromboembolic disorders. Conventional anticoagulant therapies, such as warfarin, unfractionated heparin, and low-molecular-weight heparin, exert their pharmacologic action by indirect thrombin inhibition. Although these agents are effective, each has limitations, prompting a search for more effective, specific, better-tolerated, and convenient anticoagulants. The efficacy and safety of factor Xa inhibitors are being investigated. Furthermore, the development of DTIs such as recombinant hirudin (lepirudin), bivalirudin, and argatroban continues. Challenges in the development of DTIs include establishing a binding affinity for thrombin that is not associated with excessive bleeding, attaining high thrombin specificity, achieving inhibition of both unbound and clot-bound thrombin, and producing an effective, fixed-dose oral anticoagulant to improve the practicality of anticoagulation therapy. Ximelagatran, an oral DTI designed to meet these standards, is currently in Phase III clinical trials. CONCLUSIONS: Significant progress has been made in developing DTIs. The recent emergence of orally administered DTIs may simplify the prevention and treatment of thrombosis.
OBJECTIVE: To review the progress in developing direct thrombin inhibitors (DTIs) for anticoagulation within the context of existing anticoagulation therapies. DATA SOURCES: Searches of MEDLINE (1993-June 2003) were conducted. STUDY SELECTION AND DATA EXTRACTION: We examined English-language articles, human studies, and relevant animal studies, and obtained additional citations from the references of these articles. DATA SYNTHESIS: Because of its pivotal role in hemostasis, thrombin is a key therapeutic target in the treatment and prevention of thromboembolic disorders. Conventional anticoagulant therapies, such as warfarin, unfractionated heparin, and low-molecular-weight heparin, exert their pharmacologic action by indirect thrombin inhibition. Although these agents are effective, each has limitations, prompting a search for more effective, specific, better-tolerated, and convenient anticoagulants. The efficacy and safety of factor Xa inhibitors are being investigated. Furthermore, the development of DTIs such as recombinant hirudin (lepirudin), bivalirudin, and argatroban continues. Challenges in the development of DTIs include establishing a binding affinity for thrombin that is not associated with excessive bleeding, attaining high thrombin specificity, achieving inhibition of both unbound and clot-bound thrombin, and producing an effective, fixed-dose oral anticoagulant to improve the practicality of anticoagulation therapy. Ximelagatran, an oral DTI designed to meet these standards, is currently in Phase III clinical trials. CONCLUSIONS: Significant progress has been made in developing DTIs. The recent emergence of orally administered DTIs may simplify the prevention and treatment of thrombosis.