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

Jae-hyung Cho; Chi-ho Yun; Hyoung-sik Seo; Takaki Koga; Takashi Dan; Bon-am Koo; Hak-yeop Kim

doi:10.1055/s-0037-1616756

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2001; 86(06): 1512-1520
DOI: 10.1055/s-0037-1616756

Review Article

Schattauer GmbH

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

Jae-hyung Cho^*

¹C&C Research Laboratories, Taean-ub, Hwasung-goon, Kyunggi-do, Republic of Korea; Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd., Gotemba, Shizuoka, Japan

,

Chi-ho Yun

¹C&C Research Laboratories, Taean-ub, Hwasung-goon, Kyunggi-do, Republic of Korea; Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd., Gotemba, Shizuoka, Japan

,

Hyoung-sik Seo

¹C&C Research Laboratories, Taean-ub, Hwasung-goon, Kyunggi-do, Republic of Korea; Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd., Gotemba, Shizuoka, Japan

,

Takaki Koga

¹C&C Research Laboratories, Taean-ub, Hwasung-goon, Kyunggi-do, Republic of Korea; Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd., Gotemba, Shizuoka, Japan

,

Takashi Dan

¹C&C Research Laboratories, Taean-ub, Hwasung-goon, Kyunggi-do, Republic of Korea; Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd., Gotemba, Shizuoka, Japan

,

Bon-am Koo

¹C&C Research Laboratories, Taean-ub, Hwasung-goon, Kyunggi-do, Republic of Korea; Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd., Gotemba, Shizuoka, Japan

,

Hak-yeop Kim

¹C&C Research Laboratories, Taean-ub, Hwasung-goon, Kyunggi-do, Republic of Korea; Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd., Gotemba, Shizuoka, Japan

› Author Affiliations

Abstract

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

Full Text

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