QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Résumé Extracto Full Text PDF Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Articles Ahead of Print [Order Reprint] Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nutescu, E. A Articles by Wittkowsky, A. K Search for Related Content PubMed PubMed Citation Articles by Nutescu, E. A Articles by Wittkowsky, A. K

CARDIOLOGY

Direct Thrombin Inhibitors for Anticoagulation

Clinical Assistant Professor; Director, Antithrombosis Service, College of Pharmacy, The University of Illinois at Chicago, Chicago, IL

Ann K Wittkowsky, PharmD

Clinical Professor, School of Pharmacy, University of Washington, Seattle, WA; Director, Anticoagulation Services, University of Washington Medical Center

Reprints: Edith A Nutescu PharmD, College of Pharmacy, The University of Illinois at Chicago, 833 S. Wood St., M/C 886, Rm. 164, Chicago, IL 60612-7230, fax 312/996-0379, enutescu{at}uic.edu

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.

Key Words: anticoagulants, direct thrombin inhibitors, thrombosis

Published Online, December 5, 2003. www.theannals.com, DOI 10.1345/aph.1D066

THIS ARTICLE IS APPROVED FOR CONTINUING EDUCATION CREDIT
ACPE UNIVERSAL PROGRAM NUMBER: 407-000-04-003-H01

This article has been cited by other articles:

				M. P. Gulseth Ximelagatran: An orally active direct thrombin inhibitor Am. J. Health Syst. Pharm., July 15, 2005; 62(14): 1451 - 1467. [Abstract] [Full Text] [PDF]

				S. T. Haines and E. A. Nutescu Current and emerging treatment options for venous thrombosis: A case discussion Am. J. Health Syst. Pharm., March 15, 2005; 62(6): 593 - 605. [Full Text] [PDF]

				J. M. Hoffman, N. D. Shah, L. C. Vermeulen, R. J. Hunkler, and K. M. Hontz Projecting future drug expenditures--2005 Am. J. Health Syst. Pharm., January 15, 2005; 62(2): 149 - 167. [Abstract] [Full Text] [PDF]

				W. E Dager, T. G Vondracek, B. A McIntosh, and E. A Nutescu Ximelagatran: An Oral Direct Thrombin Inhibitor Ann. Pharmacother., November 1, 2004; 38(11): 1881 - 1897. [Abstract] [Full Text] [PDF]

				E. A. Nutescu and J. L. Bauman Shifting Paradigms in Oral Anticoagulation Management Journal of Cardiovascular Pharmacology and Therapeutics, July 1, 2004; 9(3): 149 - 150. [PDF]