The Antithrombotic Efficacy of AT-1459, a Novel, Direct Thrombin Inhibitor, in Rat Models of Venous and Arterial Thrombosis

Summary

The antithrombotic efficacy of AT-1459, a novel, direct thrombin inhibitor (Ki = 4.9 nM) was evaluated in rat models of venous thrombosis combined with a bleeding time test and arterial thrombosis.

After drugs were given by i. v. bolus injection plus a continuous infusion, the ID₅₀ (a dose that exhibits 50% inhibition of thrombus formation over each vehicle group) values of AT-1459, argatroban, and dalteparin were 0.04 mg/kg plus 0.04 mg/kg/h, 0.1 mg/kg plus 0.4 mg/ kg/h, and 13.0 IU/kg plus 26.0 IU/kg/h, respectively, in the venous thrombosis study. The BT₂ (a dose that causes 2-fold prolongation of bleeding time over each vehicle group) values of AT-1459, argatroban, and dalteparin were 0.9 mg/kg plus 0.9 mg/kg/h, 1.0 mg/kg plus 0.6 mg/kg/h, and 345.5 IU/kg plus 691.0 IU/kg/h in the rat tail transection model. The ratios of BT₂/ID₅₀ of AT-1459, argatroban, and dalteparin were 22.5, 10.0, and 26.6, respectively.

In a rat model of arterial thrombosis induced by topical FeCl₂ application, intravenous administration of AT-1459, argatroban, and dalteparin improved the vessel patency significantly (P <0.01) at 0.6 mg/kg plus 0.6 mg/kg/h, 0.6 mg/kg plus 2.4 mg/kg/h, and 300 IU/kg plus 600 IU/kg/h, respectively.

The oral antithrombotic effect of AT-1459 lasted for 6 after administering 30 mg/kg and improved the vessel patency significantly 1 h after administering the same dose in venous and arterial thrombosis models, respectively, with a rapid onset of action. Warfarin also inhibited thrombus weight and improved the vessel patency significantly after oral administration of 0.3 mg/kg for three consecutive days in the same study. The antithrombotic and hemorrhagic effects of all drugs studied were correlated with plasma concentration or clotting times.

These results suggest that AT-1459 may be clinically useful as an orally available antithrombotic agent for the prevention of venous and arterial thrombosis.

Keywords

AT-1459 - antithrombotic effect - bleeding time - clotting times

^* Present address: Dr. Jae-hyung Cho, 3750 Medical Sciences Center, 1300 University Ave, University of Wisconsin, Madison, WI 53706, USA – E-mail: [e-mail]

• References

• 1 Agnelli G, Sonaglia F. Prevention of venous thromboembolism. Thromb Res 2000; 97: V49-V62.
• 2 Fuster V. Mechanisms of arterial thrombosis: foundation for therapy. Am Heart J 1998; 135: S361-6.
• 3 FitzGerald GA. The human pharmacology of thrombin inhibition. Coronary Artery Dis 1996; 7: 911-8.
• 4 Berry CN, Giardot C, Lecoffre C, Lunven C. Effects of the synthetic thrombin inhibitor argatroban on fibrin- or clot-incorporated thrombin: comparison with heparin and recombinant hirudin. Thromb Haemost 1994; 72: 381-6.
• 5 Lunven C, Gauffeny C, Lecoffre C, O’Brien DP, Roome NO, Berry CN. Inhibition by Argatroban, a specific thrombin inhibitor, of platelet activation by fibrin clot-associated thrombin. Thromb Haemost 1996; 75: 154-60.
• 6 Berry CN, Girard D, Lochot S, Lecoffre C. Antithrombotic actions of argatroban in rat models of venous, “mixed” and arterial thrombosis, and its effects on the tail transection bleeding time. Br J Pharmacol 1994; 113: 1209-14.
• 7 Berry CN, Girard D, Girardot C, Lochot S, Lunven C, Visconte C. Anti-thrombotic activity of argatroban in experimental thrombosis in the rabbit. Semin Thromb Hemost 1996; 22: 233-41.
• 8 Sakai M, Ohteki H, Narita Y, Naitoh K, Natsuaki M, Itoh T. Argatroban as a potential anticoagulant in cardiopulmonary bypass-studies in a dog model. Cardiovasc Surg 1999; 7: 187-94.
• 9 Jang IK, Brown DF, Giugliano RP, Anderson HV, Losordo D, Nicolau JC, Dutra OP, Bazzino O, Viamonte VM, Norbady R, Liprandi AS, Massey TJ, Dinsmore R, Schwarz Jr RP. A multi-center, randomized study of argatroban versus heparin as adjunct to tissue plasminogen activator (TPA) in acute myocardial infarction: myocardial infarction with novastan and TPA (MINT) study. J Am Coll Cardiol 1999; 33: 1879-85.
• 10 Berry CN, Visconte C, Lecoffre C, Lochot S, Girard D. Activity of a subcutaneously administered novel mixed micellar formulation of argatroban in rat and rabbit models of venous thrombosis. Thromb Haemost 2000; 84: 286-90.
• 11 Matsuo T, Koide M, Kario K. Development of argatroban, a direct thrombin inhibitor, and its clinical application. Semin Thromb Hemost 1997; 23: 517-22.
• 12 Koo B, Nam W, Park C. Substituted aromatic amidine derivative and medicinal composition comprising the same Patent Application WO 0055156-A1. 2000
• 13 Cho J, Seo H, Yun C, Koo B, Yoshida S, Koga T, Dan T, Kim H. In vitro an in vivo studies of AT-1362, a newly synthesized and orally active inhibitor of thrombin. Thromb Res 2000; 100: 97-107.
• 14 Kurz KD, Main BW, Sandusky GE. Rat model of arterial thrombosis induced by ferric chloride. Thromb Res 1990; 60: 269-80.
• 15 Eriksson BI, Carlsson S, Halvarsson M, Risberg B, Mattsson C. Antithrombotic effect of two low molecular weight thrombin inhibitors and a low-molecular weight heparin in a caval vein thrombosis model in the rat. Thromb Haemost 1997; 78: 1404-7.
• 16 Cziraky MJ, Spindler SA. Low-molecular-weight heparins for the treatment of deep-vein thrombosis. Clin Pharm 1993; 12: 892-9.
• 17 Dunn CJ, Sorkin EM. Dalteparin Sodium: A review of its pharmacology and clinical use in the prevention and treatment of thromboembolic disorders. Drugs 1996; 52: 276-305.
• 18 Hirsh J. Optimal therapeutic ranges for unfractionated heparin and low molecular weight heparins. In: Fuster V, Verstraete M. eds. Thrombosis in Cardiovascular disorders. Philadelphia: Saunders; 1992: 147-60.
• 19 Lockner D, Bratt G, Tönebohm E, Aberg W, Granqvist S. Intravenous and subcutaneous administration of Fragmin in deep venous thrombosis. Haemostasis 1986; 16 (Suppl. 02) 25-9.
• 20 Levine M, Gent M, Hirsh J, Leclerc J, Anderson D, Weitz J, Ginsberg J, Turpie AG, Demers C, Kovacs M. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996; 334: 677-81.
• 21 Theroux P, Fuster V. Acute coronary syndromes. Unstable angina and nonQ-wave myocardial infarction. Circulation 1998; 97: 1195-206.
• 22 Green D, Ts’ao C, Reynolds N, Kahn D, Kohl H, Cohen I. In vitro studies of a new synthetic thrombin inhibitor. Thromb Res 1985; 37: 145-53.
• 23 Reilly TM, Knabb RM, Hassell SM, Bozarth JM, Forsythe MS, Mayo MC, Racanelli AL, Mousa SA. Effect of thrombin inhibitors on platelet functions: Comparative analysis of DuP714 and hirudin. Blood Coagul Fibrinolysis 1992; 3: 513-7.
• 24 Elg M, Börjesson I, Pehrsson S, Zachrisson H, Carlsson S, Gustafsson D. Feiba™ and Autoplex^®, superimposed on a high dose of melagatran, the active form of the oral direct thrombin inhibitor H376/95 reversed bleeding times and blood loss. Haemostasis 2000; 30: 10.
• 25 Hogg PJ, Jackson CM. Fibrin monomer protects thrombin from inactivation by heparin-antithrombin III: implications for heparin efficacy. Proc Natl Acad Sci USA 1989; 86: 3619-23.
• 26 Weitz JI, Hudoba M, Massel D, Maraganore J, Hirsh J. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990; 86: 385-91.
• 27 Andersen K, Dellborg M, Emanuelsson H, Grip L, Swedberg K. Thrombin inhibition with inogatran for unstable angina pectoris: Evidence for reactivated ischaemia after cessation of short-term treatment. Coron Artery Dis 1996; 7: 673-81.
• 28 Hirsh J, Fuster V. Guide to anticoagulant therapy Part 2: Oral Anticoagulants. Circulation 1994; 89: 1469-80.
• 29 Pineo GF, Hull RD. Prevention and treatment of venous thromboembolism. Drugs 1996; 52: 71-92.
• 30 Berry CN, Lunven C, Girardot C, Lechaire I, Girard D, Charles M-C, Ferrari P, O’Brien DP. Ecarin clotting time: a predictive coagulation assay for the antithrombotic activity of argatroban in the rat. Thromb Haemost 1998; 79: 228-33.