Takashi Musha

Eisai Japan, Edo, Tōkyō, Japan

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Publications (4)33.99 Total impact

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    ABSTRACT: Background: In Japan, the safety and efficacy of thrombolytic therapy using tissue-type plasminogen activator for acute pulmonary embolism (PE) in the real world remain unclear. Methods and results: A total of 1,254 patients with acute PE covered by the post-marketing surveillance of thrombolytic therapy using monteplase were divided into 3 groups: cardiopulmonary arrest (CPA)/collapse group (n=85); massive group, patients with unstable hemodynamics without CPA/collapse (n=217); and submassive group, patients with stable hemodynamics and right ventricular dysfunction (RVD) (n=465). In the efficacy analysis of 767 cases, the response rate to monteplase was 94.6% according to pulmonary circulation assessment and 93.3% according to clinical efficacy judged by symptoms and signs. Overall survival rates at 30 days after monteplase administration were 89.2% overall, 41.2% for the CPA/collapse group, 93.0% for the massive group, and 96.3% for the submassive group. When the safety of monteplase was analyzed in 1,241 cases, severe bleeding complications occurred in 100 patients (8.1%). Intracranial hemorrhage (ICH) occurred in 21 patients (1.7%), but no significant independent predictors were found in multivariate analysis. Conclusions: Thrombolytic therapy is highly effective in Japanese acute PE patients and offers acceptable safety, but attention is needed regarding severe bleeding complications, including ICH.
    No preview · Article · Jul 2012 · Circulation Journal
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    ABSTRACT: Thrombin is a powerful agonist for a variety of cellular responses including platelet aggregation and vascular smooth muscle cell (SMC) proliferation. These actions are mediated by a thrombin receptor known as protease-activated receptor-1 (PAR-1). Recently we discovered that 1-(3-tert-butyl-4-methoxy-5-morpholinophenyl)-2-(5,6-diethoxy-7-fluoro-1-imino-1,3-dihydro-2H-isoindol-2-yl)ethanone hydrobromide (E5555, atopaxar) is a potent and selective thrombin receptor antagonist. This study characterized the pharmacological effects of E5555 on SMC proliferation in vitro and in a rat model of intimal thickening after balloon injury in vivo. E5555 selectively inhibited rat aortic SMC proliferation induced by thrombin and thrombin receptor-activating peptide (TRAP) with half maximal inhibitory concentration (IC(50)) values of 0.16 and 0.038 μM, respectively. E5555 did not inhibit rat SMC proliferation induced by basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) at concentrations up to 1μM. In addition, E5555 inhibited human aortic SMC proliferation induced by thrombin at concentrations of 0.3 and 3units/ml with IC(50) values of 0.028 and 0.079 μM, respectively, whereas it did not affect bFGF-induced proliferation at concentrations up to 1μM. Repeated oral administration of 30 mg/kg E5555 (once daily for 16 days) significantly reduced neointimal formation in the balloon-injured rat arterial model. These results suggested that a PAR-1 antagonist could be effective for treating restenosis following vascular intervention in addition to preventing thrombus formation. E5555 could thus have therapeutic potential for restenosis and chronic atherothrombotic disease.
    No preview · Article · May 2011 · European journal of pharmacology
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    Preview · Article · Mar 2004 · Journal of the American College of Cardiology
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    ABSTRACT: An antibody was raised in rabbits against SFFLRNPSEDTFEQF peptide, which is an NH2-terminal peptide of the thrombin-cleaved rat thrombin receptor. In vitro, the antibody inhibited rat smooth muscle cell proliferation but had no effect on rat platelet aggregation or clotting time. These data indicate that the antibody is a specific blocker of the thrombin receptor-signaling pathway in rat smooth muscle cells but does not work as a blocker in rat platelets, suggesting the existence of a second thrombin receptor in the platelets. Using an in vivo balloon catheter-induced injury model in rats, we examined the effect of the anti-rat thrombin receptor IgG on intimal smooth muscle cell accumulation 2 weeks after angioplasty. Analysis of the ratio of intimal to medial cross-sectional areas showed that injection of immune IgG resulted in 43.7% and 53.1% reduction (P<0.01) of neointimal smooth muscle cell accumulation compared with saline and nonimmune IgG treatment, respectively. Moreover, the injection of immune IgG caused a significant decrease of thrombin receptor mRNA expression and also 40.5% and 43.0% decreases (P<0.01) of the proliferating cell nuclear antigen (PCNA) index in the intima compared with the PCNA index after saline and nonimmune IgG treatment, respectively. The suppression of the PCNA index was also observed in the immune IgG-treated group at an early stage after angioplasty. These results suggest that thrombin receptor activation is involved in the proliferation and accumulation of neointimal smooth muscle cells induced by balloon injury.
    No preview · Article · Jun 1998 · Circulation Research