Successful Attenuation of Venous Thrombus Growth in Rabbits after the Administration of a Novel Oral Thrombin Inhibitor

Venous and arterial thromboembolism are a major cause for morbidity and mortality. The list of established drugs for the prevention of thrombus formation and embolisation includes heparins, hirudin and derivatives, aspirin, ADP and glycoprotein IIb/IIIa receptor antagonists, as well as vitamin K antagonists. Several limitations exist for these drugs that have stimulated the search for new and better anticoagulants. A series of selective clotting factor Xa inhibitors and direct factor IIa (thrombin) inhibitors are on the horizon, two of which are getting close to broad clinical application. Additional therapeutics that are still under preclinical and clinical investigation include inhibitors of the tissue factor pathway/factor VII complex, clotting factor VIII and XIII inhibitors and modulators of the protein C pathway or of endogenous fibrinolysis, as well as novel antiplatelet drugs. This review is focused on the current status of development of novel antithrombotics and their clinical potential. Even though only a few of a broad array of antithrombotic agents have reached clinical testing, some hold the potential for significant improvement in efficacy and safety of anticoagulant therapy.

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Inhibition of thrombin: relevance to anti-thrombosis strategy

Shen¹

2006

Front Biosci

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Thromboembolism is a common cause of death and disability. Heparin or warfarin, the current standard management for thromboembolism may cause serious bleeding complications. Thrombin is the key enzyme of coagulation. Hirudin, the most potent natural thrombin-specific inhibitor, was first isolated from leech salivary fluid. Synthetic thrombin-specific inhibitors are rationally designed based on the knowledge on the structures of the activate site of thrombin. Thrombin-specific inhibitors are the current best choice for the treatment of heparin-induced thrombocytopenia (HIT). Recombinant hirudins (such as desirudin) were also approved for the prevention of thrombosis after hip or knee surgery. Bivalirudin (hirulog-1 or Angiomax), in adjunct to aspirin, was approved for prevention of thrombosis in patients with unstable angina following angioplasty. Argatroban has been used for the treatment of HIT, peripheral and cerebral thrombotic diseases. The benefit of using thrombin-specific inhibitors alone in acute myocardial infarction or unstable angina remains uncertain. Some of thrombin-specific inhibitors which are small molecules are orally active. The major concern for the use of thrombin-specific inhibitors is bleeding complication. The efficacy, safety, stability and oral bioavailability may be considerably improved through structural optimization. A growing line of evidence suggests that statins, the most commonly prescribed cholesterol lowering drug, may inhibit thrombin generation. Statins do not cause bleeding and have an outstanding safety profile. The findings suggest that further development of thrombin-specific inhibitors and exploration of the potential applications of non-specific thrombin inhibitors, including statins, may improve the prevention and management of thromboembotic events.

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Successful Attenuation of Venous Thrombus Growth in Rabbits after the Administration of a Novel Oral Thrombin Inhibitor

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References 34 publications

Chapter 8. Anticoagulants: Inhibitors of thrombin and factor Xa

Chapter 8. Anticoagulants: Inhibitors of thrombin and factor Xa

New antithrombotic drugs on the horizon

Inhibition of thrombin: relevance to anti-thrombosis strategy

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