The antithrombotic efficacy of AT-1459, a novel, direct thrombin inhibitor, in rat models of venous and arterial thrombosis.

Abstract

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.

• Authors: J H Cho, C H Yun, H S Seo, T Koga, T Dan, B A Koo, H Y Kim
• Journal: Thrombosis and haemostasis (Thromb Haemost) Vol. 86 Issue 6 Pg. 1512-20 (Dec 2001) ISSN: 0340-6245 [Print] Germany
• PMID: 11776321 (Publication Type: Comparative Study, Journal Article)

Chemical References

• 4-((1-(2-(2-(2-(6-amidino-1-ethylindol-2-yl)ethyl)pyrrolidinyl)-2-oxoethyl)-2-oxoazaperhydroepin-3-yl)amino)butanoic acid
• Amidines
• Azepines
• Fibrinolytic Agents
• Pipecolic Acids
• Sulfonamides
• Warfarin
• Arginine
• Thrombin
• argatroban
• Dalteparin

Topics

• Administration, Oral
• Amidines (chemistry, pharmacology, therapeutic use, toxicity)
• Animals
• Arginine (analogs & derivatives)
• Azepines (chemistry, pharmacology, therapeutic use, toxicity)
• Bleeding Time
• Carotid Artery Thrombosis (drug therapy, prevention & control)
• Dalteparin (therapeutic use)
• Drug Evaluation, Preclinical
• Fibrinolytic Agents (administration & dosage, chemistry, pharmacology, therapeutic use, toxicity)
• Hemorrhage (chemically induced)
• Humans
• Infusions, Intravenous
• Injections, Intravenous
• Male
• Molecular Structure
• Pipecolic Acids (therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Sulfonamides
• Thrombin (antagonists & inhibitors)
• Vena Cava, Inferior
• Venous Thrombosis (drug therapy, prevention & control)
• Warfarin (therapeutic use)