In Vitro and In Vivo Studies of AT-1362, a Newly Synthesized and Orally Active Inhibitor of Thrombin

Cho, Jaehyung; Seo, Hyoung sik; Yun, Chi Ho; Koo, Bon Am; Yoshida, Shoshin; Koga, Takaki; Dan, Takashi; Kim, Hak yeop

doi:10.1016/s0049-3848(00)00298-x

Cited by 9 publications

(1 citation statement)

References 30 publications

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“…Our venous thrombosis model combined with a bleeding time test was produced by using a method described in our previous study (13). The inferior vena cava was carefully isolated and all branches from the vena cava were ligated.…”

Section: Venous Thrombosis Model Combined With Bleeding Time Testmentioning

confidence: 99%

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

Cho¹,

Yun

Seo

et al. 2001

Thromb Haemost

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SummaryThe 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.

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Section: Venous Thrombosis Model Combined With Bleeding Time Testmentioning

confidence: 99%

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

Cho¹,

Yun

Seo

et al. 2001

Thromb Haemost

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A New Rat Pain Model of Thrombus-Induced Ischemia

Lee

2012

Methods in Molecular Biology

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Pathophysiology of peripheral ischemic pain has not been fully demonstrated since the proper animal model has not been established. We designed this study to develop a new thrombus-induced ischemic pain (TIIP) animal model mimicking human peripheral ischemic pain by using ferrous chloride (FeCl(2)) in rats. Histological examination and Evans blue experiment revealed that the application of FeCl(2) onto the femoral artery produced an excessive thrombosis and ischemic condition in ipsilateral hind paw. Furthermore, ischemia-sensitive markers, such as hypoxia inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) were upregulated in the ipsilateral plantar muscles of FeCl(2)-applied rats. The mechanical allodynia was induced in bilateral hind paws from 1 day after FeCl(2) application and sustained for 30 days. However, thermal threshold of bilateral hind paws did not change in this animal model. In conclusion, we have developed a novel animal model of TIIP, which is characterized by the development of bilateral mechanical allodynia, but not thermal hyperalgesia. Thus, we suggest that this TIIP model can be useful in investigating the pathophysiological mechanisms that underlie human peripheral ischemic pain.

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The anticoagulant fraction from the leaves ofDiospyros kaki L. has an antithrombotic activity

2005

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The leaves of Persimmon (Diospyros kaki L.) has long been used for tea in Korea since it was thought to be effective against hypertension. An anticoagulant fraction was purified through gel filtration G-100, hydrophobic, gel filtration G-150, and FPLC, Phenyl superpose column chromatographies. The purified fraction was homogenous and its Mr was estimated 10,000 Da by gel filtration and SDS-PAGE. The purified fraction was sensitive to treatment of subtilisin B, but not to heat and its activity was not changed after periodate oxidation, indicating that the activity was not due to carbohydrates. It delayed thrombin time (TT), activated partial thromboplastin time (APTT), and prothrombin time (PT) using human plasma. TT was more sensitive than APTT and PT, suggesting that the anticoagulant activity may be caused by a degradation or a defect of fibrin or thrombin. It did not cause the hydrolysis of fibrin after incubation. However, it inhibited thrombin-catalyzed fibrin formation with a competitive inhibition pattern. These results indicate that it may be an antithrombotic agent and that it is bound to fibrinogen binding sites of thrombin.

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In Vitro and In Vivo Studies of AT-1362, a Newly Synthesized and Orally Active Inhibitor of Thrombin

Cited by 9 publications

References 30 publications

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

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

A New Rat Pain Model of Thrombus-Induced Ischemia

The anticoagulant fraction from the leaves ofDiospyros kaki L. has an antithrombotic activity

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