Antithrombotic effects of a synthetic inhibitor of activated factor X, JTV-803, in animals

Hayashi, Mikio; Matsuo, Akira; Nakamoto, Hiromitsu; Aisaka, Kazuo

doi:10.1016/s0014-2999(00)00942-0

Cited by 14 publications

(11 citation statements)

References 26 publications

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“…These direct inhibitors are synthetic and low molecular weight compounds and include DX-9065a [Hara et al, 1994], YM-60828 ], DDR *Correspondence to: Yoshiyuki Iwatsuki, Cardiovascular Diseases Research, Pharmacology Laboratories, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. E-mail: iwatsuki.yoshiyuki@yamanouchi.co.jp RPR120844 [Bostwick et al, 1999], SK549 [Wong, et al, 2000], FXV673 [Chu et al, 2001], and JTV-803 [Hayashi et al, 2001]. These small molecular weight compounds have two advantages over ATIII-dependent inhibitors such as fondaparinux or low molecular weight heparin.…”

Section: Introductionmentioning

confidence: 99%

Antithrombotic effects of YM466, a synthesized direct inhibitor of factor Xa, in an arterio‐venous shunt thrombosis model in squirrel monkeys

Iwatsuki¹,

Kaku²,

Moritani³

et al. 2003

Drug Development Research

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The antithrombotic effects of YM466, a synthetic direct inhibitor of human factor Xa (FXa), were evaluated in an arterio-venous shunt thrombosis model in squirrel monkeys. YM466 significantly inhibited thrombus formation after continuous IV zx infusion at doses of 3-30 mg/kg/h. Although prothrombin time (PT) was significantly prolonged at doses of 10 and 30 mg/kg/h, this effect was small (1.2-and 1.4-fold of the control, respectively). Furthermore, YM466 had no effect on template bleeding time and activated partial thromboplastin time at any dose. Plasma anti-FXa activity increased in a dosedependent manner correlating with the antithrombotic effect of YM466. Thrombin-antithrombin III complex levels decreased to less than normal levels at 30 mg/kg/h of YM466. Mean plasma concentrations of YM466 measured by LC/MS/MS were 2.5, 10.5, 27.4, and 75.5 ng/ml at doses of 1, 3, 10, and 30 mg/kg/ h, respectively. These results suggest that YM466 is a safe antithrombotic agent with low bleeding risk, and that plasma anti-FXa activity may be a suitable parameter for monitoring its antithrombotic effect. Drug Dev.

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Section: Introductionmentioning

confidence: 99%

Antithrombotic effects of YM466, a synthesized direct inhibitor of factor Xa, in an arterio‐venous shunt thrombosis model in squirrel monkeys

Iwatsuki¹,

Kaku²,

Moritani³

et al. 2003

Drug Development Research

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“…The clinical relevance of our in vivo rat model can be discussed. It is a classical model of in vivo thrombosis, sensitive to the antithrombotic effects of aspirin [17] and polyphenols [10,11], among other antiplatelet and/or anticoagulant drugs [18][19][20][21][22][23][24][25][26][27][28]. It may be as relevant to actual clinical effects of these drugs as other in vitro models used, or the in vivo measure of prostaglandin metabolites in man [6].…”

Section: Discussionmentioning

confidence: 99%

Interactions between aspirin and COX‐2 inhibitors or NSAIDs in a rat thrombosis model

Umar

Boisseau²,

Yusup

et al. 2004

Fundamemntal Clinical Pharma

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Recent in vitro studies, clinical trials and epidemiological studies have suggested possible interactions between aspirin and other cyclo-oxygenase (COX) inhibitors, such as ibuprofen of the COX-2 inhibitors celecoxib and rofecoxib. The objective of this study was to test the effects of aspirin (1, 2.5 and 5 mg/kg), and ibuprofen (4 and 15 mg/kg), diclofenac (2.5 mg/kg), flurbiprofen (2 mg/kg), celecoxib (7.5 mg/kg), and rofecoxib (1 mg/kg), alone or combined on a rat model of arterial thrombosis. Drugs were given orally daily for 7 days, before insertion of an arterio-venous shunt thrombosis system, left in place for 15 min. Main parameter was thrombus weight. Five to 12 rats were used per experiment, and 35 controls overall. Aspirin inhibited thrombus formation in a dose-dependent manner. All NSAIDS given alone also inhibited thrombus formation to approximately the same level as aspirin 1 mg/kg/day. Ibuprofen, celecoxib and rofecoxib inhibited the effects of aspirin, but not diclofenac or flurbiprofen. The interactions with aspirin do not seem to affect all NSAIDs to equal levels. The clinical impact of this needs to be confirmed in adequately powered clinical trials or pharmaco-epidemiological studies.

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“…In an animal model of experimental venous or arterial thrombosis, intravenous infusion of JTV-803 doses equal or higher than 0.3 mg/kg/h or oral administration at the dose of 10 mg/kg inhibited thrombus formation and prolonged the occlusion time. The dose of 10 mg/kg/h prolonged the aPTT and the dose of 30 mg/kg/h prolonged bleeding time showing that JTV-803 has a wide therapeutic window in animal experimental systems [115]. In addition, JTV-803 has been shown to be effective in animal models of experimental disseminated intravascular coagulation and haemodialysis [116,117].…”

Section: Ym-75466mentioning

confidence: 99%

Heterogeneity of Synthetic Factor Xa Inhibitors

Gerotziafas

Samama²

2005

CPD

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Heparins and vitamin K antagonists are the landmarks of antithrombotic treatment. Both of them were discovered by serendipity; they are multi-targeted drugs and share several limitations. New molecules have been designed in order to be both more selective concerning their biological target and more homogeneous in their biochemical structure aiming at an improved benefit/risk ratio in the treatment of thrombotic disease. In this article, we will review the pharmacological characteristics of the new synthetic direct or antithrombin dependent inhibitors of FXa in the light of the modern concept of blood coagulation process. We will also present the most recent data from the clinical trials with synthetic inhibitors of FXa. Among them, the synthetic pentasaccharide fondaparinux is the first synthetic and specific FXa inhibitor, which has been approved by health authorities in Europe and in the USA for the prophylaxis of venous thromboembolism in major orthopaedic surgery and is being approved for the treatment of pulmonary embolism and DVT as a single daily subcutaneous injection. The phase II dose-finding trial of the "meta-pentasaccharide" idraparinux administered subcutaneously once weekly in the secondary prevention of VTE has been completed. DX-9065a is the first direct synthetic inhibitor which has been studied in patients with coronary disease. Razaxaban, BAY59-7939, ZK-807834 and JTV-803 are orally active direct FXa inhibitors, which have been studied in phase II trials. Several other synthetic direct inhibitors of FXa (such as FXV673, YM60828, KFA-1411) are in a pre-clinical stage of research. From a clinical point of view, the results of recent trials with the synthetic specific FXa inhibitors clearly show that the inhibition of FXa is a critical point in the antithrombotic strategy.

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Antithrombotic effects of a synthetic inhibitor of activated factor X, JTV-803, in animals

Cited by 14 publications

References 26 publications

Antithrombotic effects of YM466, a synthesized direct inhibitor of factor Xa, in an arterio‐venous shunt thrombosis model in squirrel monkeys

Antithrombotic effects of YM466, a synthesized direct inhibitor of factor Xa, in an arterio‐venous shunt thrombosis model in squirrel monkeys

Interactions between aspirin and COX‐2 inhibitors or NSAIDs in a rat thrombosis model

Heterogeneity of Synthetic Factor Xa Inhibitors

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