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Azuma J.,Health Science University | Azuma J.,Osaka University | Ohno M.,Osaka University | Ohno M.,Health Science University | And 9 more authors.
European Journal of Clinical Pharmacology | Year: 2013

Objective: This study is a pharmacogenetic clinical trial designed to clarify whether the N-acetyltransferase 2 gene (NAT2) genotype-guided dosing of isoniazid improves the tolerability and efficacy of the 6-month four-drug standard regimen for newly diagnosed pulmonary tuberculosis. Methods: In a multicenter, parallel, randomized, and controlled trial with a PROBE design, patients were assigned to either conventional standard treatment (STD-treatment: approx. 5 mg/kg of isoniazid for all) or NAT2 genotype-guided treatment (PGx-treatment: approx. 7.5 mg/kg for patients homozygous for NAT2*4: rapid acetylators; 5 mg/kg, patients heterozygous for NAT2*4: intermediate acetylators; 2.5 mg/kg, patients without NAT2*4: slow acetylators). The primary outcome included incidences of 1) isoniazid-related liver injury (INH-DILI) during the first 8 weeks of therapy, and 2) early treatment failure as indicated by a persistent positive culture or no improvement in chest radiographs at the8th week. Results: One hundred and seventy-two Japanese patients (slow acetylators, 9.3 %; rapid acetylators, 53.5 %) were enrolled in this trial. In the intention-to-treat (ITT) analysis, INH-DILI occurred in 78 % of the slow acetylators in the STD-treatment, while none of the slow acetylators in the PGx-treatment experienced either INH-DILI or early treatment failure. Among the rapid acetylators, early treatment failure was observed with a significantly lower incidence rate in the PGx-treatment than in the STD-treatment (15.0 % vs. 38 %). Thus, the NAT2 genotype-guided regimen resulted in much lower incidences of unfavorable events, INH-DILI or early treatment failure, than the conventional standard regimen. Conclusion: Our results clearly indicate a great potential of the NAT2 genotype-guided dosing stratification of isoniazid in chemotherapy for tuberculosis. © 2012 The Author(s). Source


Furukawa Y.,Nara Womens University | Furukawa Y.,Japan National Cardiovascular Center Research Institute | Kokubo Y.,Japan National Cardiovascular Center Research Institute | Okamura T.,Japan National Cardiovascular Center Research Institute | And 7 more authors.
Stroke | Year: 2010

Background and Purpose:Body mass index is most commonly used as the obesity index. Recently, waist circumference (WC) has been shown to be associated with the risk of cardiovascular disease (CVD). However, no studies have observed an association between WC and CVD in Japan. We examined the relationships of WC and body mass index with CVD in a Japanese urban population. Methods-We studied 5474 Japanese individuals (aged 30 to 79 years without CVD at baseline) who completed a baseline survey and received follow-up through December 2005. WC was measured at the umbilical level of participants in the standing position to the nearest 1 cm. The Cox proportional hazard ratios for CVD according to the quartiles of WC were calculated after adjustment for age, smoking, and drinking status. Results-During a mean follow-up of 11.7 years, 207 strokes and 133 myocardial infarctions were documented. In women, compared with the lowest quartile (WC <70 cm), the hazard ratio (95% CIs) after adjusting for age, smoking, and drinking in the highest quartile (WC ≥84 cm) were 1.85 (1.03 to 3.31) for CVD and 2.64 (1.16 to 6.03) for stroke. However, no such relationships of WC with CVD or stroke risk were observed in men. After further adjustment of hypertension, diabetes, and hypercholesterolemia, all of the mentioned relationships were not statistically significant. No associations of body mass index with CVD or strokes were observed. Conclusions:s:WC may be a better predictor for CVD or stroke in Japanese women. © 2010 American Heart Association, Inc. Source


Kudoh S.,Japan Anti Tuberculosis Association | Kudoh S.,Nippon Medical School | Keicho N.,National Health Research Institute
Clinics in Chest Medicine | Year: 2012

Diffuse panbronchiolitis (DPB) is characterized by chronic airway infection with diffuse bilateral micronodular pulmonary lesions. DPB is mainly distributed in east Asian people. Studies on causes of the disease point to a genetic predisposition unique to Asians. The advent of low-dose, long-term macrolide therapy has changed disease prognosis. The mechanism of action is attributed to anti-inflammatory actions of 14-membered and 15-membered ring macrolides. Recently, the success of macrolide therapy in DPB has extended its application to the treatment of other chronic airway inflammatory diseases. © 2012 Elsevier Inc. Source


Higashiyama A.,Hyogo College of Medicine | Wakabayashi I.,Hyogo College of Medicine | Ono Y.,National Cerebral and Cardiovascular Center | Watanabe M.,National Cerebral and Cardiovascular Center | And 4 more authors.
Stroke | Year: 2011

Background And Purpose- Light-to-moderate alcohol consumption is associated with reduced risk for cardiovascular disease, whereas high serum γ-glutamyltransferase (GGT) level is associated with cardiovascular disease. However, whether light-to-moderate alcohol drinking is still related to reduced risk of cardiovascular disease irrespective of GGT level is uncertain. Methods- We performed a 12.5-year cohort study of 2336 men (excluding exdrinkers) who were free from cardiovascular disease. They were classified into 4 groups according to alcohol consumption: never, and current light, moderate, or heavy drinker. The multivariate-adjusted hazard ratios of alcohol consumption for incidence of coronary artery disease, total stroke, and ischemic stroke compared with those of never drinkers were assessed with stratification by GGT median (32 IU/L). Results- In participants with GGT >32 IU/L, the hazard ratios of all current drinkers for total and ischemic stroke were higher than those of never drinkers. However, in all current drinkers with GGT ≤32 IU/L, the multivariate-adjusted hazard ratios for total and ischemic stroke were lower than in never drinkers. Conclusions- In men with above GGT median, alcohol drinking even with light-to-moderate consumption could be a risk factor for ischemic stroke. © 2011 American Heart Association, Inc. Source


Higashiyama A.,Hyogo College of Medicine | Okamura T.,Keio University | Watanabe M.,National Cerebral and Cardiovascular Center | Kokubo Y.,National Cerebral and Cardiovascular Center | And 3 more authors.
Hypertension Research | Year: 2013

The relationship between alcohol consumption and the risk for cardiovascular disease (CVD) is U-shaped, whereas alcohol drinking is linearly associated with blood pressure, and the CVD risk also increases linearly according to blood pressure level. Accordingly, we investigated the net effect of alcohol consumption and hypertension on CVD and its subtypes in this study. A 13-year prospective study of 2336 Japanese men who were free from CVD was performed; ex-drinkers were excluded. The participants were divided into eight groups classified by the combination of the presence of hypertension (systolic/diastolic blood pressure ≥140/90 mm Hg) and alcohol consumption (never-, current-(light, moderate and heavy) drinkers). Multivariate-adjusted hazard ratios (HRs) for the incidence of CVD, coronary artery disease (CAD) and stroke due to the combination of hypertension and alcohol consumption were calculated and compared with non-hypertensive never-drinkers. The HRs for CVD and its subtypes were higher in hypertensives than those in non-hypertensives; in hypertensives without medication for hypertension, the relationship between alcohol consumption and the risks for CVD and CAD was U-shaped, with the highest and most significant increase in never-drinkers. The risk for total stroke was the highest in heavy-drinkers, which was significant. In non-hypertensives, there was no evident increase or decrease in the HRs for CVD and its subtypes in drinkers. Accordingly, controlling blood pressure is important to prevent CVD. In hypertensives, heavy drinking should be avoided to prevent CVD, although light-to-moderate drinking could be protective for CAD. Furthermore, in non-hypertensives, drinkers may need to continuously monitor their blood pressure. © 2013 The Japanese Society of Hypertension All rights reserved. Source

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