The preclinical and clinical pharmacology of Novastan (argatroban): A small-molecule, direct thrombin inhibitor

Because of the unsatisfactory options available for safe and effective antithrombotic therapy, recent, intense research and development efforts have been focused on direct thrombin inhibitors, also known as site-directed thrombin inhibitors. The intravenous agent Novastan (argatroban) is a small-molecule, reversible, direct thrombin inhibitor that is selective for the catalytic site of the thrombin molecule. Argatroban's molecular properties (small molecule; fast, selective, and reversible inhibition of the thrombin catalytic site; and similar in vitro potency for inhibiting both clot-bound and soluble thrombin) offer the potential for significant antithrombotic efficacy with minimal systemic anticoagulant effects. Its clinical pharmacologic properties offer the potential for minimal risk of bleeding, very rapid achievement of therapeutic antithrombotic efficacy, predictable dose-response, and rapid restoration of the hemostatic systems to normal upon termination of intravenous infusion. Argatroban is currently approved for clinical use in Japan for the treatment of peripheral arterial occlusive disease. It is in advanced clinical development in North America, South America, and Western Europe for several clinical indications, including (1) adjunctive therapy to thrombolytic agents in the treatment of acute myocardial infarction and (2) antithrombotic therapy for patients with heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and thrombosis syndrome.