研究者詳細 - 小山　敏広

論文 - 小山　敏広

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International trends in biliary tract cancer-related mortality, 2000-2022: An observational study of the World Health Organization mortality database. 国際誌

Quynh Thi Vu, Yoshito Nishimura, Ko Harada, Hiroki Ito, Tsukasa Higashionna, Akinari Maruo, Keisaku Harada, Tatsuaki Takeda, Hirofumi Hamano, Yoshito Zamami, Hideharu Hagiya, Toshihiro Koyama

Hepatology (Baltimore, Md.) 2024年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND AIMS: Biliary tract cancers (BTCs), including intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma (eCCA), gallbladder cancer (GBC), and ampullary cancer, exhibit poor prognosis. This study examined temporal trends in mortality due to BTCs and their major subtypes at international, regional, and national levels. APPROACH RESULTS: This observational study used the World Health Organization mortality database. Locally weighted regression (LOESS) was used to produce a smoothed curve of long-term international and regional BTC and major subtype-related mortality rates in 2000-2022 based on available data from countries. Trends in age-standardised mortality rates (ASRs) during 2013-2022 for individual countries were examined using joinpoint regression analysis. Internationally, LOESS-smoothed ASRs per 100,000 population due to BTCs were 2.8 (95% confidence interval: 2.5-3.1) in 2000, and 2.7 (2.3-3.1) in 2022. LOESS-smoothed BTC-related ASRs were the highest in the Western Pacific region at 4.2 (1.8-6.6) in 2022, compared with those in the European and American regions at 2.6 (2.3-2.9) and 2.2 (1.8-2.6), respectively. Among major subtypes, LOESS-smoothed ASRs due to iCCA increased by 120.0%, those due to GBC decreased by 45.5%, and those due to eCCA remained stable between 2000 and 2022. Disparities in BTC and major subtype-related ASR trends were observed between countries during 2013-2022, with iCCA-associated ASRs showing increasing trends in many countries. CONCLUSIONS: Although internationally estimated BTC-associated ASRs showed a stable trend over the last two decades, a large increase in estimated iCCA-associated ASRs necessitates developing effective screening for high-risk individuals and disease management strategies.

DOI： 10.1097/HEP.0000000000001200

International Trends in Adverse Drug Event-Related Mortality from 2001 to 2019: An Analysis of the World Health Organization Mortality Database from 54 Countries. 査読

Koyama T, Iinuma S, Yamamoto M, Niimura T, Osaki Y, Nishimura S, Harada K, Zamami Y, Hideharu Hagiya

Drug safety 2023年12月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）

<h4>Background and objective</h4>Adverse drug events (ADEs) are becoming a significant public health issue. However, reports on ADE-related mortality are limited to national-level evaluations. Therefore, we aimed to reveal overall trends in ADE-related mortality across the 21st century on an international level.<h4>Methods</h4>This observational study analysed long-term trends in ADE-related mortality rates from 2001 to 2019 using the World Health Organization Mortality Database. The rates were analysed according to sex, age and region. North America, Latin America and the Caribbean, Western Europe, Eastern Europe and Western Pacific regions were assessed. Fifty-four countries were included with four-character International Statistical Classification of Disease and Related Health Problems, Tenth Revision codes in the database, population data in the World Population Prospects 2019 report, mortality data in more than half of the study period, and high-quality or medium-quality death registration data. A locally weighted regression curve was used to show international trends in age-standardised rates.<h4>Results</h4>The global ADE-related mortality rate per 100,000 population increased from 2.05 (95% confidence interval 0.92-3.18) in 2001 to 6.86 (95% confidence interval 5.76-7.95) in 2019. Mortality rates were higher among men than among women, especially in those aged 20-50 years. The population aged ≥ 75 years had higher ADE-related mortality rates than the younger population. North America had the highest mortality rate among the five regions. The global ADE-related mortality rate increased by approximately 3.3-fold from 2001 to 2019.<h4>Conclusions</h4>The burden of ADEs has increased internationally with rising mortality rates. Establishing pharmacovigilance systems can facilitate efforts to reduce ADE-related mortality rates globally.

DOI： 10.1007/s40264-023-01387-0

Trends in Head and Neck Cancer Mortality from 1999 to 2019 in Japan: An Observational Analysis. 査読国際誌

Tsukasa Higashionna, Keisaku Harada, Akinari Maruo, Takahiro Niimura, Elizabeth Tan, Quynh Thi Vu, Takayoshi Kawabata, Soichiro Ushio, Hirofumi Hamano, Makoto Kajizono, Yoshito Zamami, Keisuke Ishizawa, Ko Harada, Shiro Hinotsu, Mitsunobu R Kano, Hideharu Hagiya, Toshihiro Koyama

Cancers 15 ( 15 ) 2023年7月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Globally, the numbers of head and neck cancer (HNC) cases and related deaths have recently increased. In Japan, few studies have examined crude or age-adjusted HNC mortality rates. Therefore, this study aimed to determine the trends in crude and age-adjusted mortality rates for HNC per million individuals in Japan from 1999 to 2019. Data on HNC-associated deaths were extracted from the national death certificate database using the International Classification of Diseases, Tenth Revision (n = 156,742). HNC mortality trends were analysed using joinpoint regression models to estimate annual percentage change (APC) and average APC (AAPC). Among men, no significant change was observed in the age-adjusted death rate trend from 1999 to 2014; however, a marked decrease was observed from 2014 to 2019. No changing point was observed in women. Age-adjusted mortality rates continuously decreased over the 21-year period, with an AAPC of -0.7% in men and -0.6% in women. In conclusion, the overall trend in age-adjusted rates of HNC-associated deaths decreased, particularly among men, in the past 5 years. These results will contribute to the formulation of medical policies to develop targeted screening and prevention programmes for HNC in Japan and determine the direction of treatment strategies.

DOI： 10.3390/cancers15153786

Global trends of seasonal influenza-associated mortality in 2001-2018: A longitudinal epidemiological study. 査読国際誌

Hideharu Hagiya, Yuka Osaki, Michio Yamamoto, Takahiro Niimura, Ko Harada, Tsukasa Higashionna, Hirofumi Hamano, Yoshito Zamami, Shiro Hinotsu, Toshihiro Koyama

The Journal of infection 87 ( 3 ) e54-e57 2023年6月

Association between immune checkpoint inhibitor-induced myocarditis and concomitant use of thiazide diuretics. 査読国際誌

Satoru Mitsuboshi, Hirofumi Hamano, Takahiro Niimura, Aya F Ozaki, Pranav M Patel, Tsung-Jen Lin, Yuta Tanaka, Ikuya Kimura, Naohiro Iwata, Shoya Shiromizu, Masayuki Chuma, Toshihiro Koyama, Yoshihiro Yamanishi, Yasunari Kanda, Keisuke Ishizawa, Yoshito Zamami

International journal of cancer 153 ( 8 ) 1472 - 1476 2023年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Although an association has been reported between diuretics and myocarditis, it is unclear whether the risk of immune checkpoint inhibitor (ICI)-induced myocarditis is affected by concomitant diuretics. Thus, the aim of this work was to evaluate the impact of concomitant diuretics on ICI-induced myocarditis. This cross-sectional study used disproportionality analysis and a pharmacovigilance database to assess the risk of myocarditis with various diuretics in patients receiving ICIs via the analysis of data entered into the VigiBase database through December 2022. Multiple logistic regression analysis was performed to identify risk factors for myocarditis in patients who received ICIs. A total of 90 611 patients who received ICIs, including 975 cases of myocarditis, were included as the eligible dataset. A disproportionality in myocarditis was observed for loop diuretic use (reporting odds ratio 1.47, 95% confidence interval [CI] 1.02-2.04, P = .03) and thiazide use (reporting odds ratio 1.76, 95% CI 1.20-2.50, P < .01) in patients who received ICIs. The results of the multiple logistic regression analysis showed that the use of thiazides (odds ratio 1.67, 95% CI 1.15-2.34, P < .01) was associated with an increased risk of myocarditis in patients who received ICIs. Our findings may help to predict the risk of myocarditis in patients receiving ICIs.

DOI： 10.1002/ijc.34616

Cardiovascular Toxicities Associated with Anaplastic Lymphoma Kinase Inhibitors: A Disproportionality Analysis of the WHO Pharmacovigilance Database (VigiBase). 査読国際誌

Takahiro Niimura, Koji Miyata, Hirofumi Hamano, Yuuki Nounin, Hiroto Unten, Masaki Yoshino, Satoru Mitsuboshi, Fuka Aizawa, Kenta Yagi, Toshihiro Koyama, Mitsuhiro Goda, Yasunari Kanda, Yuki Izawa-Ishizawa, Yoshito Zamami, Keisuke Ishizawa

Drug safety 46 ( 6 ) 545 - 552 2023年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: Recently, cases of cardiovascular toxicities, such as pericarditis, caused by anaplastic lymphoma kinase (ALK) inhibitors have been reported; however, whether these adverse events are common among all ALK inhibitors remains unclear. AIMS: This study aimed to clarify the cardiovascular toxicity profile of ALK inhibitors using an adverse event spontaneous report database. METHODS: We analyzed data from VigiBase, the WHO global database of individual safety reports, from its inception in 1968 to December 2021. We calculated the reporting odds ratio to evaluate the association between ALK inhibitors (crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib) and 21 cardiovascular adverse events. Time to onset of pericarditis from ALK inhibitor administration was analyzed. RESULTS: Of the 27,994,584 reports, 19,911 involved treatment with ALK inhibitors. Among the 21 cardiovascular toxicities, only pericarditis signals were detected with all five ALK inhibitors (crizotinib [reporting odds ratios (ROR), 4.7; 95% CI 3.63-6.15], ceritinib [ROR, 12.9; 95% CI 9.37-17.79], alectinib [ROR, 4.8; 95% CI 3.15-7.42], brigatinib [ROR, 3.5; 95% CI 1.33-9.46], and lorlatinib [ROR, 6.4; 95% CI 3.60-11.22]). For torsade de pointes/QT prolongation, signals were detected with crizotinib (ROR, 5.0; 95% CI 3.72-6.77) and ceritinib (ROR, 4.2; 95% CI 2.17-8.05), whereas for hypertension, they were identified only with brigatinib (ROR, 3.9; 95% CI 2.88-5.20), and for heart failure, they were detected with alectinib (ROR, 2.2; 95% CI 1.60-2.90), crizotinib (ROR, 2.1; 95% CI 1.72-2.48), and lorlatinib (ROR, 2.0; 95% CI 1.27-3.23). Regarding time-to-onset analysis from drug administration to adverse event reporting, for pericarditis, it ranged from 52.5 days for alectinib to 166.5 days for crizotinib. CONCLUSIONS: Systematic evaluation of ALK inhibitor-associated adverse events revealed differences in the cardiotoxicity profiles among ALK inhibitors. Understanding the differences in the cardiovascular toxicity profile of each ALK inhibitor will contribute to safe drug therapy when switching between ALK inhibitors.

DOI： 10.1007/s40264-023-01300-9

Characterization of Immune Checkpoint Inhibitor-Induced Myasthenia Gravis Using the United States Food and Drug Administration Adverse Event Reporting System. 査読国際誌

Takahiro Niimura, Yoshito Zamami, Koji Miyata, Takahisa Mikami, Mizuho Asada, Keijo Fukushima, Masaki Yoshino, Satoru Mitsuboshi, Naoto Okada, Hirofumi Hamano, Takumi Sakurada, Rie Matsuoka-Ando, Fuka Aizawa, Kenta Yagi, Mitsuhiro Goda, Masayuki Chuma, Toshihiro Koyama, Yuki Izawa-Ishizawa, Hiroaki Yanagawa, Hiromichi Fujino, Yoshihiro Yamanishi, Keisuke Ishizawa

Journal of clinical pharmacology 63 ( 4 ) 473 - 479 2022年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Myasthenia gravis (MG) is a rare but fatal adverse event of immune checkpoint inhibitors (ICI). We assessed whether patient characteristics differed between those with immune checkpoint inhibitor-related MG and those with idiopathic MG. Reports from the United States Food and Drug Administration Adverse Event Reporting System were analyzed. Multivariate analyses were conducted to evaluate the associations between age, sex, and ICI treatment and the reporting rate of MG. Among 5,464,099 cases between 2011 to 2019, 53,447 were treated with ICIs. MG was reported more often in ICI user. Multiple logistic regression analyses showed that the reporting rate of ICI-related MG did not differ significantly between male and female; however, it was higher in older people than in younger people (adjusted odds ratio, 2.4 [95% confidence interval: 1.84-3.13]). We also investigated useful signs for the early detection of myositis and myocarditis, which are fatal when overlapping with ICI-related MG. Patients with elevated serum creatine kinase or troponin levels were more likely to have concurrent myositis and myocarditis. Unlike idiopathic MG, there was no sex difference in the development of ICI-related MG, which may be more common in older people. Considering the physiological muscle weakness that occurs in the elderly, it may be necessary to monitor ICI-related MG more closely in older people. This article is protected by copyright. All rights reserved.

DOI： 10.1002/jcph.2187

Trends in places and causes of death among centenarians in Japan from 2006 to 2016. 査読

Toshihiro Koyama, Tsukasa Higashionna, Akinori Maruo, Soichiro Ushio, Yoshito Zamami, Ko Harada, Hideharu Hagiya

Geriatrics & gerontology international 22 ( 8 ) 675 - 680 2022年6月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）

AIM: Amid the global aging, an establishment of healthcare policies for the aged population is a common issue to be addressed. However, few studies on centenarians have reported place and cause of death (PoD and CoD, respectively) as indicators of end-of-life care quality. This study aimed to analyze trends in PoD and CoD among centenarians in Japan. METHODS: Data from death certificates from Japanese vital statistics were analyzed; 205 513 deaths occurred among centenarians (aged ≥100 years) in Japan during the period from 2006 to 2016. PoD prevalence was calculated for each CoD. Trends in PoD prevalence were analyzed using the Joinpoint regression model. Changing points, annual percentage changes, and average annual percentage changes (AAPCs) were calculated to examine trends. RESULTS: The number of deaths more than doubled from 10 340 in 2006 to 26 427 in 2016. PoDs were composed of hospitals (52.7%), nursing homes (31.4%), own homes (13.6%) and others (2.2%). Dementia and old age increased rapidly as CoD. Proportions of hospital and home deaths decreased, with AAPCs of -2.3% (95% confidence interval [CI], -2.6 to -1.9) and -2.3% (95% CI, -3.2 to -1.4), respectively. Conversely, the proportion of deaths in nursing homes rapidly increased, with an AAPC of 6.8% (95% CI, 6.0-7.7). CONCLUSIONS: The results revealed changes in PoD among centenarians in Japan. Understanding these transitions is indispensable for health policy in aging societies. Geriatr Gerontol Int 2022; ••: ••-••.

DOI： 10.1111/ggi.14416

Identification of prophylactic drugs for oxaliplatin-induced peripheral neuropathy using big data. 査読国際誌

Yoshito Zamami, Takahiro Niimura, Takehiro Kawashiri, Mitsuhiro Goda, Yutaro Naito, Keijo Fukushima, Soichiro Ushio, Fuka Aizawa, Hirofumi Hamano, Naoto Okada, Kenta Yagi, Koji Miyata, Kenshi Takechi, Masayuki Chuma, Toshihiro Koyama, Daisuke Kobayashi, Takao Shimazoe, Hiromichi Fujino, Yuki Izawa-Ishizawa, Keisuke Ishizawa

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 148 112744 - 112744 2022年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Drug repositioning is a cost-effective method to identify novel disease indications for approved drugs; it requires a shorter developmental period than conventional drug discovery methods. We aimed to identify prophylactic drugs for oxaliplatin-induced peripheral neuropathy by drug repositioning using data from large-scale medical information and life science information databases. METHODS: Herein, we analyzed the reported data between 2007 and 2017 retrieved from the FDA's database of spontaneous adverse event reports (FAERS) and the LINCS database provided by the National Institute of Health. The efficacy of the drug candidates for oxaliplatin-induced peripheral neuropathy obtained from the database analysis was examined using a rat model of peripheral neuropathy. Additionally, we compared the incidence of peripheral neuropathy in patients who received oxaliplatin at the Tokushima University Hospital, Japan. The effects of statins on the animal model were examined in six-week-old male Sprague-Dawley rats and seven or eight-week-old male BALB/C mice. Retrospective medical chart review included clinical data from Tokushima University Hospital from April 2009 to March 2018. RESULTS: Simvastatin, indicated for dyslipidemia, significantly reduced the severity of peripheral neuropathy and oxaliplatin-induced hyperalgesia. In the nerve tissue of model rats, the mRNA expression of Gstm1 increased with statin administration. A retrospective medical chart review using clinical data revealed that the incidence of peripheral neuropathy decreased with statin use. CONCLUSION AND RELEVANCE: Thus, drug repositioning using data from large-scale basic and clinical databases enables the discovery of new indications for approved drugs with a high probability of success.

DOI： 10.1016/j.biopha.2022.112744

Trends in hepatitis C virus-associated mortality rates in Japan, 1998–2017 査読国際誌

Hideharu Hagiya, Toshihiro Koyama, Matsuo Deguchi, Yusuke Minato, Satomi Miura, Tomoko Funahashi, Yusuke Teratani, Yoshito Zamami, Kazuaki Shinomiya, Yoshihisa Kitamura, Toshiaki Sendo, Shiro Hinotsu, Mitsunobu Kano

Journal of Gastroenterology and Hepatology 36 ( 9 ) 2486 - 2492 2021年5月

Effectiveness of Sensing Gloves-Applied Virtual Reality Education System on Hand Hygiene Practice: A Randomised Controlled Trial. 国際誌

Mahiro Izumi, Hideharu Hagiya, Yuki Otsuka, Yoshiaki Soejima, Shinnosuke Fukushima, Mitsunobu Shibata, Satoshi Hirota, Toshihiro Koyama, Fumio Otsuka, Akio Gofuku

American journal of infection control 2024年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: We developed a virtual reality (VR) education system and evaluated its clinical utility for promoting hand hygiene practices. METHODS: This prospective, two-week, randomised controlled study conducted at Okayama University Hospital, Japan, from November 2023 to January 2024, involved 22 participants (18 medical students and four residents). A fully immersive 360° VR system (VIVE Pro Eye) using a head-mounted display and sensing gloves was used to develop three healthcare tasks in a virtual patient room-Environmental Cleaning, Gauze Exchange, and Urine Collection. After monitoring all participants' baseline usage data of portable hand-rubbing alcohol in the first week, we randomly assigned them into 1:1 groups (VR training and video lecture groups). The primary outcome was differences in hand-rubbed alcohol use before and after intervention. RESULTS: Before the intervention, alcohol use did not significantly differ between both groups. After the intervention, a significant increase in alcohol use was observed in the VR training group (median: 8.2 g vs. 16.2 g; p=0.019) but not in the video lecture group. CONCLUSION: Our immersive 360° VR education system enhanced hand hygiene practices. Infection prevention and control practitioners and digital technology experts must collaborate to advance the development of superior educational devices and content.

DOI： 10.1016/j.ajic.2024.08.003

Burden of depressive disorders in Vietnam from 1990 to 2019: A secondary analysis of the Global Burden of Disease Study 2019. 査読国際誌

Quynh Thi Vu, Ko Harada, Yoshito Nishimura, Hideharu Hagiya, Elizabeth Tan, Odifentse Mapula E Lehasa, Yoshito Zamami, Toshihiro Koyama

Journal of psychiatric research 172 420 - 426 2024年4月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Depressive disorders are among the leading causes of disability globally. However, information on the burden of depressive disorders in Vietnam is limited. We aimed to analyse the burden of depressive disorders in Vietnam from 1990 to 2019. Using data from the Global Burden of Disease Study 2019, prevalence and disability-adjusted life-years (DALYs) were used as indicators to analyse the burden of depressive disorders by age and sex. In 2019 in Vietnam, depressive disorders comprised 2629.1 thousand (95% uncertainty interval (UI): 2233.3-3155.9) estimated cases and 380.6 thousand (95% UI: 258.9-533.8) estimated DALYs. The crude prevalence rate of depressive disorders was higher among females than among males. The DALYs of depressive disorder accounted for a higher percentage of the total all-cause DALYs in the 10-64-year age group than in other age groups. Major depressive disorder was the largest contributor to the burden of depressive disorders. From 1990 to 2019, the crude prevalence and DALY rates per 100 000 population due to depressive disorders increased significantly, whereas age-standardised rates of prevalence and DALYs decreased significantly; the respective average annual percent changes were 0.88% (95% confidence interval: 0.87 to 0.89), 0.68% (0.66 to 0.70), -0.20% (-0.21 to -0.19), and -0.27% (-0.28 to -0.25). Although the age-standardised prevalence rate was lower than that seen globally, depressive disorders were considerable mental health issues in Vietnam. This study will help governments and policymakers to establish appropriate strategies to reduce the burden of these disorders by identifying the priority areas and individuals.

DOI： 10.1016/j.jpsychires.2024.02.041

Trends in the Incidence of Disseminated Cryptococcosis in Japan: A Nationwide Observational study, 2015–2021 (in press) 査読

Akazawa H, Hagiya H, Koyama T, Otsuka F

Mycopathologia 2024年1月

本邦の小児肥満有病率の10年間の推移 Joinpoint regressionを用いた小児肥満トレンド解析

藤原進太郎, 原田洸, 萩谷英大, 小山敏広, 長谷川高誠, 塚原宏一, 大塚文男

日本内分泌学会雑誌 99 ( 4 ) 1052 - 1052 2024年1月

Changes in the place of death before and during the COVID-19 pandemic in Japan. 査読国際誌

Masashi Shibata, Yuki Otsuka, Hideharu Hagiya, Toshihiro Koyama, Hideyuki Kashiwagi, Fumio Otsuka

PloS one 19 ( 2 ) e0299700 2024年

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: In the global aging, the coronavirus disease 2019 (COVID-19) pandemic may have affected the place of death (PoD) in Japan, where hospital deaths have dominated for decades. We analyzed the PoD trends before and during the COVID-19 pandemic in Japan. METHODS: This nationwide observational study used vital statistics based on death certificates from Japan between 1951 and 2021. The proportion of PoD; deaths at home, hospitals, and nursing homes; and annual percentage change (APC) were estimated using joinpoint regression analysis. Analyses were stratified by age groups and causes of death. RESULTS: After 2019, home deaths exhibited upward trends, while hospital death turned into downward trends. By age, no significant trend change was seen in the 0-19 age group, while hospital deaths decreased in the 20-64 age group in 2019. The trend change in home death in the ≥65 age group significantly increased since 2019 with an APC of 12.3% (95% confidence interval [CI]: 9.0 to 15.7), while their hospital death trends decreased by -4.0% (95% CI: -4.9 to -3.1) in 2019-2021. By cause of death, home death due to cancer and the old age increased since 2019 with an APC of 29.3% (95% CI: 25.4 to 33.2) and 8.8% (95% CI: 5.5 to 12.2), respectively. CONCLUSION: PoD has shifted from hospital to home during the COVID-19 pandemic in Japan. The majority of whom were older population with cancer or old age.

DOI： 10.1371/journal.pone.0299700

Trends in childhood obesity in Japan: A nationwide observational study from 2012 to 2021. (in press) 査読

Shintaro Fujiwara, Ko Harada, Hideharu Hagiya, Toshihiro Koyama, Kosei Hasegawa, Hirokazu Tsukahara, Fumio Otsuka

Clinical Obesity 2023年12月

Epidemiological Characteristics and Trends in the Incidence of Leptospirosis in Japan: A Nationwide, Observational Study from 2006 to 2021. 査読国際誌

Hideharu Hagiya, Toshihiro Koyama, Fumio Otsuka

The American journal of tropical medicine and hygiene 109 ( 3 ) 589 - 594 2023年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

During this age of climate change, the incidence of tropical diseases may change. This study compared the epidemiological characteristics and trends of leptospirosis in Japan between the endemic region, Okinawa, and the rest of the country. Infectious Diseases Weekly Reports were used to determine the numbers and crude incidence rates of leptospirosis. Data were stratified by sex, age, the estimated location of the infection, the notified regions, and the reporting month. A joinpoint regression analysis was performed to estimate the annual percentage change (APC). During the 16-year study period (2006-2021), 543 leptospirosis cases were reported, with male dominance (86.2%). Approximately half of these cases were reported from Okinawa (47.1%). The patients were relatively younger in Okinawa (20-29 years, 23.4%; 30-39 years, 20.7%) than outside Okinawa. The frequency of imported cases was significantly higher outside Okinawa (0.4% versus 14.3%). The incidences of leptospirosis in and outside Okinawa were apparently higher during the summer and typhoon seasons. The annual crude incidence ratios were 20-200 times higher in Okinawa than in the rest of the country. The average APCs for the entire study period in Okinawa and the rest of Japan were 1.6% (95% CI: -5.9 to 9.6) and -1.8% (95% CI: -7.8 to 4.6), respectively, without any particular trends. Collectively, the patient profile of leptospirosis differed between Okinawa (younger men) and outside Okinawa (middle- or older-aged men with a history of traveling abroad). The disease remains a neglected tropical disease; continuous surveillance with close monitoring is required.

DOI： 10.4269/ajtmh.23-0131

Trends in the Incidence of Japanese Spotted Fever in Japan: A Nationwide, Two-Decade Observational Study from 2001-2020. 査読国際誌

Yuki Otsuka, Hideharu Hagiya, Shinnosuke Fukushima, Ko Harada, Toshihiro Koyama, Fumio Otsuka

The American journal of tropical medicine and hygiene 2023年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

The worldwide spread of tick-borne diseases (TBDs) has become a public health concern. Therefore, this study aimed to clarify trends in the incidence of Japanese spotted fever (JSF), one of Japan's most prevalent TBDs. Weekly infectious disease reports were used to calculate the annual incidence rates (AIRs) of JSF. Data were stratified by age and sex, and joinpoint regression analysis was performed to estimate the annual percentage change (APC). AIR and APC were geographically compared among the 47 prefectures. A total of 3,453 JSF cases were observed from 2001 to 2020. The AIR per 100,000 population was 0.03 in 2001, which increased approximately 10-fold to 0.33 in 2020. The average APC (AAPC) during the study period was 12.3% (95% CI: 10.7-13.9). By age group, the incidence of JSF increased more rapidly among the older population: 11.5% (95% CI: 10.1-12.9) in those aged ≥ 65 years and 8.9% (95% CI: 6.4-11.5) in those aged < 50 years. Although the AIR over the past two decades was higher in climatically warm regions located in southwestern Japan and on the Pacific coast, increases in the AAPC were notable in colder regions located in eastern Japan. The incidence of JSF continues to increase in Japan, especially among older populations and in eastern prefectures, where the disease has not been previously diagnosed.

DOI： 10.4269/ajtmh.22-0487

Significance of UGT1A6, UGT1A9, and UGT2B7 genetic variants and their mRNA expression in the clinical outcome of renal cell carcinoma. 査読国際誌

Jun Matsumoto, Anzu Nishimoto, Shogo Watari, Hideo Ueki, Shoya Shiromizu, Naohiro Iwata, Tatsuaki Takeda, Soichiro Ushio, Makoto Kajizono, Masachika Fujiyoshi, Toshihiro Koyama, Motoo Araki, Koichiro Wada, Yoshito Zamami, Yasutomo Nasu, Noritaka Ariyoshi

Molecular and cellular biochemistry 478 ( 8 ) 1779 - 1790 2022年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

UDP-glucuronosyltransferase (UGT) metabolizes a number of endogenous and exogenous substrates. Renal cells express high amounts of UGT; however, the significance of UGT in patients with renal cell carcinoma (RCC) remains unknown. In this study, we profile the mRNA expression of UGT subtypes (UGT1A6, UGT1A9, and UGT2B7) and their genetic variants in the kidney tissue of 125 Japanese patients with RCC (Okayama University Hospital, Japan). In addition, we elucidate the association between the UGT variants and UGT mRNA expression levels and clinical outcomes in these patients. The three representative genetic variants, namely, UGT1A6 541A > G, UGT1A9 i399C > T, and UGT2B7-161C > T, were genotyped, and their mRNA expression levels in each tissue were determined. We found that the mRNA expression of the three UGTs (UGT1A6, UGT1A9, and UGT2B7) are significantly downregulated in RCC tissues. Moreover, in patients with RCC, the UGT2B7-161C > T variant and high UGT2B7 mRNA expression are significantly correlated with preferable cancer-specific survival (CSS) and overall survival (OS), respectively. As such, the UGT2B7-161C > T variant and UGT2B7 mRNA expression level were identified as significant independent prognostic factors of CSS and CSS/OS, respectively. Taken together, these findings indicate that UGT2B7 has a role in RCC progression and may, therefore, represent a potential prognostic biomarker for patients with RCC.

DOI： 10.1007/s11010-022-04637-4

Trends in the incidence of syphilis in the middle-aged and older adults in Japan: A nationwide observational study, 2009-2019. 査読

Misa Takahashi, Hideharu Hagiya, Toshihiro Koyama, Fumio Otsuka

Geriatrics & gerontology international 2022年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIM: Sexually transmitted infections remain a neglected area of research in geriatrics. However, in the global aging societies, sexual health among the middle-aged and older adults is an emerging public concern. High-income countries are facing a resurgence of syphilis cases among young generations, but little is known about its prevalence in older populations. We aimed to investigate the national trend of syphilis cases in Japan. METHODS: This nationwide observational study used the publicly-available database (2009-2019) to calculate crude and age-adjusted incidence rates of syphilis per 100 000 population by age, sex and clinical stage. We collected data from patients aged ≥50 years and performed joinpoint regression analysis to estimate long-term trends and average annual percentage changes (AAPCs). RESULTS: The total number of patients with syphilis increased about 8-fold from 165 in 2009 to 1280 in 2019. AAPCs of crude incidence rates significantly increased in every age category; 33.2% in 50-59 years, 23.8% in 60-69 years and 20.9% in ≥70 years. Age-adjusted incidence rates have surged at AAPCs of 28.7% in men and 23.1% in women, reaching 4.09 in men and 0.71 in women in 2019. By clinical stage, marked increases were observed in primary (AAPCs, 42.3% in men and 41.6% in women) and secondary syphilis (AAPCs, 24.9% in men and 24.2% in women). CONCLUSIONS: An up-toward trend of syphilis among people aged ≥50 years was observed. The importance of sexual health among older people should be highlighted in this aging Japanese society. Geriatr Gerontol Int 2022; ••: ••-••.

DOI： 10.1111/ggi.14500

Impact of the cervical cancer awareness months on public interest in Japan: A Google Trends analysis, 2012-2021. 査読国際誌

Hideharu Hagiya, Toshihiro Koyama, Fumio Otsuka

Scientific reports 12 ( 1 ) 15391 - 15391 2022年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

The immunization and screening rates for human papillomavirus in Japan are lower than those in other countries. We aimed to evaluate the impact of cervical cancer awareness months on public attention using Google Trends analysis. Between 2012 and 2021, we analyzed the trends in relative search volumes (RSVs) for "Shikyuu-keigan" (cervical cancer in English) in Japan, during the cervical cancer awareness month (CCAM) in January and cervical cancer prevention awareness enhancement month (CCPAEM) in November. We performed a joinpoint regression analysis to identify a statistically significant trend change point. Additionally, we compared the mean RSVs of each awareness month with the rest of the year. Significant trend change points were observed, but none were found in CCAM and CCPAEM periods. Comparison of mean RSVs among CCAM, CCPAEM, and the rest of the months did not suggest any significant increases in RSVs during these awareness periods. In conclusion, CAM and CCPAEM did not raise public interest in cervical cancer in Japan. Although the results are based on internet users, the findings might suggest a need to develop a more effective and attractive approach to achieve the 90-70-90 targets of cervical cancer prevention by 2030.

DOI： 10.1038/s41598-022-19798-x

Correlation between national surveillance and search engine query data on respiratory syncytial virus infections in Japan. 査読国際誌

Kazuhiro Uda, Hideharu Hagiya, Takashi Yorifuji, Toshihiro Koyama, Mitsuru Tsuge, Masato Yashiro, Hirokazu Tsukahara

BMC public health 22 ( 1 ) 1517 - 1517 2022年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: The respiratory syncytial virus (RSV) disease burden is significant, especially in infants and children with an underlying disease. Prophylaxis with palivizumab is recommended for these high-risk groups. Early recognition of a RSV epidemic is important for timely administration of palivizumab. We herein aimed to assess the correlation between national surveillance and Google Trends data pertaining to RSV infections in Japan. METHODS: The present, retrospective survey was performed between January 1, 2018 and November 14, 2021 and evaluated the correlation between national surveillance data and Google Trends data. Joinpoint regression was used to identify the points at which changes in trends occurred. RESULTS: A strong correlation was observed every study year (2018 [r = 0.87, p < 0.01], 2019 [r = 0.83, p < 0.01], 2020 [r = 0.83, p < 0.01], and 2021 [r = 0.96, p < 0.01]). The change-points in the Google Trends data indicating the start of the RSV epidemic were observed earlier than by sentinel surveillance in 2018 and 2021 and simultaneously with sentinel surveillance in 2019. No epidemic surge was observed in either the Google Trends or the surveillance data from 2020. CONCLUSIONS: Our data suggested that Google Trends has the potential to enable the early identification of RSV epidemics. In countries without a national surveillance system, Google Trends may serve as an alternative early warning system.

DOI： 10.1186/s12889-022-13899-y

Trends in sarcoidosis mortality rate in Japan from 2001 to 2020: A population-based study. 査読国際誌

Ko Harada, Hideharu Hagiya, Toshihiro Koyama, Fumio Otsuka

Respiratory medicine 196 106828 - 106828 2022年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: The sarcoidosis mortality rate has increased over the years, which contributes to the health care burden. Although epidemiological studies of sarcoidosis mortality in aging societies are essential, none have been published since 1989 in Japan. METHODS: We aimed to investigate the trends in crude and age-adjusted sarcoidosis-associated mortality rates per 1,000,000 population in Japan from 2001 to 2020 using national death certificate data among older adults aged over 50 years. The data were analysed using the joinpoint regression models to estimate long-term trends and average annual percentage changes (AAPCs). RESULTS: A total of 3094 sarcoidosis-associated deaths were recorded from 2001 to 2020 in Japan; women constituted 65.3% of these, with a female:male ratio of 1.89. Nearly 80% of deaths were over the age of 65 years, of which 32% were over the age of 80 years. The trend in crude mortality of those aged ≥80 years markedly increased from 0.81 to 9.68 per 1,000,000 population in men and from 2.38 to 12.87 in women, respectively. The overall age-adjusted sarcoidosis mortality rate increased 2.46-fold during the study period, with an AAPC of 5.1%. CONCLUSIONS: This study revealed that sarcoidosis-associated deaths in Japan have significantly increased over the past two decades, especially among the older population with a female predominance. Given the rising mortality rate and susceptibility of the older population, sarcoidosis will require more attention from health care providers in terms of a multidisciplinary approach to address the specific needs of the older population.

DOI： 10.1016/j.rmed.2022.106828

Trends in the amyloidosis mortality rate in Japan: A nationwide observational study from 1998 to 2019. 査読

Ko Harada, Hideharu Hagiya, Toshihiro Koyama, Fumio Otsuka

Geriatrics & gerontology international 22 ( 3 ) 246 - 250 2022年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIM: Despite the increasing attention that has been paid to amyloidosis in recent years, there have been few reports on amyloidosis mortality and its trends worldwide. This study aimed to evaluate the trends in crude and age-adjusted amyloidosis-associated mortality rates in Japan from 1998 to 2019. METHODS: We used national Vital Statistics data among older adults aged over 50 years. The data were analyzed using the joinpoint regression program to estimate the long-term trends and average annual percentage changes (AAPCs). RESULTS: A total of 9158 amyloidosis-associated deaths were recorded from 1998 to 2019, of which 56.1% were in men. The crude mortality rate per 1 000 000 older adults aged over 80 years increased from 9.65 to 54.3 among men and from 7.02 to 22.1 among women during the study period. Overall, the AAPCs of age-adjusted amyloidosis-associated mortality rates increased significantly over the study period (1.8%, 95% confidence interval [CI], 1.0-2.7%). While the annual percentage change (APC) of age-adjusted mortality rates in women showed no significant change over the study period, the APC in men markedly increased in the 2013-2019 period (8.2%, 95% CI: 6.0-10.4%). CONCLUSIONS: This study revealed an increasing trend in mortality associated with amyloidosis, and in particular a marked increase in mortality among men over the past 6 years. Considering its high mortality rate and susceptibility to the effects of an increasing population of older adults, amyloidosis deserves more attention from healthcare providers to improve the understanding of diagnosis, clinical treatment, and healthcare planning. Geriatr Gerontol Int 2022; 22: 246-250.

DOI： 10.1111/ggi.14348

Impact of the world hand hygiene and global handwashing days on public awareness between 2016 and 2020: Google trends analysis. 査読国際誌

Yoshito Nishimura, Hideharu Hagiya, Koichi Keitoku, Toshihiro Koyama, Fumio Otsuka

American journal of infection control 50 ( 2 ) 141 - 147 2021年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Scientific evidence suggest that hand hygiene as one of the most effective measures to control infection. To promote good hand hygiene practices, the World Health Organization introduced May 5 as World Hand Hygiene Day (WHHD), and international stakeholders established Global Handwashing Day (GHD) on October 15. However, its contributions to raising public awareness of hand hygiene is unclear. METHODS: This study evaluates the impact of the WHHD and GHD on the public awareness of hand hygiene in Japan, the United Kingdom, the United States, and worldwide from 2016 to 2020, using the relative search volume of "Hand hygiene" in Google Trends as a surrogate. To identify a statistically significant timepoint of a trend change, we performed Joinpoint regression analysis. RESULTS: Upticks of the relative search volumes as well as joinpoints were noted worldwide around the WHHD and GHD from 2016 to 2019, but no joinpoints were identified around the WHHD and GHD in 2020. No such changes were observed in Japan, the United Kingdom, and the United States during these periods. CONCLUSIONS: While the WHHD was originally established to raise awareness of hand hygiene in healthcare facilities, our result suggests that the WHHD and GHD may not have effectively disseminated the importance of hand hygiene to the general public at a country level. Additional policy measures to advocate hand hygiene to the public are necessary to communicate its benefits.

DOI： 10.1016/j.ajic.2021.08.033

Impact of the World Antimicrobial Awareness Week on public interest between 2015 and 2020: A Google Trends analysis. 査読国際誌

Koichi Keitoku, Yoshito Nishimura, Hideharu Hagiya, Toshihiro Koyama, Fumio Otsuka

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 111 12 - 20 2021年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: To evaluate the impact of the World Antimicrobial Awareness Week (WAAW) on public awareness of antimicrobial resistance using Google Trends analysis. METHODS: The impact of WAAW on public awareness of 'antimicrobial resistance' (AMR), 'antibacterial', and 'antibiotics' in Japan, the UK, the United States, and worldwide from 2015 to 2020 was analyzed, using the relative search volume (RSV) of Google Trends as a surrogate. A joinpoint regression analysis was performed to identify a statistically significant time point of a change in trend. RESULTS: No joinpoints around WAAW were identified in Japan, the United Kingdom, or the United States from 2015 to 2020 with RSVs of 'AMR', whereas increasing RSVs were noted worldwide in 2017 and 2020. Further, there were decreasing RSVs of 'antibiotics' in the first half of 2020, which could be due to the COVID-19 pandemic. The study results suggest that WAAW did little to improve public awareness of AMR in the selected countries despite its contribution worldwide. CONCLUSIONS: This study implies that we need to develop a more effective method to improve public awareness to fight against AMR.

DOI： 10.1016/j.ijid.2021.08.018

Impact of the World Inflammatory Bowel Disease Day and Crohn’s & Colitis Awareness Week on Population Interest between 2016 and 2020: Google Trends Analysis 査読

Krixie Silangcruz, Yoshito Nishimura, Torrey Czech, Nobuhiko Kimura, Hideharu Hagiya, Toshihiro Koyama, Fumio Otsuka

JMIR Infodemiology 1 ( 1 ) 2021年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：{JMIR} Publications Inc.

<jats:sec>
<jats:title>Background</jats:title>
<jats:p>More than 6 million people are affected by inflammatory bowel disease (IBD) globally. The World IBD Day (WID, May 19) and Crohn’s and Colitis Awareness Week (CCAW, December 1-7) occur yearly as national health observances to raise public awareness of IBD, but their effects are unclear.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Objective</jats:title>
<jats:p>The aim of this study was to analyze the relationship between WID or CCAW and the public health awareness on IBD represented by the Google search engine query data.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Methods</jats:title>
<jats:p>This study evaluates the impact of WID and CCAW on the public awareness of IBD in the United States and worldwide from 2016 to 2020 by using the relative search volume of “IBD,” “ulcerative colitis,” and “Crohn’s disease” in Google Trends. To identify significant time points of trend changes (joinpoints), we performed joinpoint regression analysis.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Results</jats:title>
<jats:p>No joinpoints were noted around the time of WID or CCAW during the study period in the search results of the United States. Worldwide, joinpoints were noted around WID in 2020 with the search for “IBD” and around CCAW in 2017 and 2019 with the search for “ulcerative colitis.” However, the extents of trend changes were modest without statistically significant increases.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Conclusions</jats:title>
<jats:p>These results posed a question that WID and CCAW might not have worked as expected to raise public awareness of IBD. Additional studies are needed to precisely estimate the impact of health observances to raise the awareness of IBD.</jats:p>
</jats:sec>

DOI： 10.1101/2021.08.01.21261456

Relevance of CYP3A5 expression on the clinical outcome of patients with renal cell carcinoma. 査読国際誌

Jun Matsumoto, Yumi Kotera, Shogo Watari, Koichi Takeuchi, Hideo Ueki, Toshihiro Koyama, Koichiro Wada, Masachika Fujiyoshi, Yasutomo Nasu, Noritaka Ariyoshi

Anticancer Research 41 ( 5 ) 2511 - 2521 2021年5月

Population-Based Observational Study of Adverse Drug Event-Related Mortality in the Super-Aged Society of Japan 査読国際誌

Tomoko Funahashi, Toshihiro Koyama, Hideharu Hagiya, Ko Harada, Syunya Iinuma, Soichiro Ushio, Yoshito Zamami, Takahiro Niimura, Kazuaki Shinomiya, Keisuke Ishizawa, Toshiaki Sendo, Shiro Hinotsu, Mitsunobu R. Kano

Drug Safety 44 ( 5 ) 531 - 539 2021年4月

Trends in the incidence and mortality of legionellosis in Japan: a nationwide observational study, 1999-2017. 査読国際誌

Shinnosuke Fukushima, Hideharu Hagiya, Yuki Otsuka, Toshihiro Koyama, Fumio Otsuka

Scientific reports 11 ( 1 ) 7246 - 7246 2021年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

This study examined temporal trend, seasonality, and geographical variations of legionellosis incidence and mortality in Japan. This nationwide observational study used the Japanese Vital Statistics and Infectious Diseases Weekly Report (1999-2017) data to calculate legionellosis crude and age-adjusted incidence and mortality rates per 100,000 population by age and sex. Incidence was compared among the 4 seasons and regional incidence among 47 prefectures. Of 13,613 (11,194 men) people with legionellosis in Japan, 725 (569 men) were fatal. Increasing incidence trend occurred from 0.0004 (1999) to 1.37 (2017) per 100,000 population. People aged ≥ 70 years accounted for 43.1% overall; men's age-adjusted incidence rate was consistently approximately five times higher than for women. Significantly higher incidence occurred in summer than in winter (p = 0.013). Geographically, highest incidence (≥ 2.0 per 100,000 population) occurred in Hokuriku District, with increasing trends in Hokkaido and middle-part of Japan. Estimated fatality rates decreased consistently at 5.9% (95% confidence interval: - 8.1, - 3.5) annually, from 1999 to 2017, with no trend change point. Increasing legionellosis incidence occurred in Japan during 1999-2017, with declining estimated fatality rates. In this aging society and warming world, disease clinical burden may further deteriorate in future due to increasing incidence trends.

DOI： 10.1038/s41598-021-86431-8

日本人高齢者における転倒関連死死亡統計データを用いた20年間のトレンド解析査読

萩谷英大, 小山敏広, 樂木宏実, 狩野光伸

日本老年医学会雑誌 57 ( Suppl. ) 68 - 68 2020年7月

Trends in the nontuberculous mycobacterial disease mortality rate in Japan: A nationwide observational study, 1997-2016. 査読国際誌

Ko Harada, Hideharu Hagiya, Tomoko Funahashi, Toshihiro Koyama, Mitsunobu R Kano, Fumio Otsuka

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 73 ( 2 ) e321-e326 2020年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: The incidence of nontuberculous mycobacterial (NTM) infections has been increasing worldwide, becoming a significant healthcare burden especially among elderly people. This study aimed to evaluate the trends in NTM-associated mortality in Japan. METHODS: This study used vital statistics data and data on all NTM-associated deaths (N=18,814) among individuals aged ≥40 years in Japan from 1997 to 2016. We calculated the crude and age-adjusted mortality rates by age and sex and used joinpoint regression to analyze trends and estimate the average annual percentage change (AAPC). We compared crude NTM- and tuberculosis (TB)-associated mortality rates by sex. RESULTS: The overall crude annual mortality rate increased from 0.63/100,000/year in 1997 to 1.93/100,000/year in 2016 and was the highest among individuals aged 80-84 years. The AAPC of the crude mortality rates among males of all ages and females aged 40-59 years were stable but increased among females aged 60-79 years (3.5%, 95% confidence interval [CI]: 2.8-4.3%) and ≥80 years (4.3%, 95% CI: 3.7-4.9%). Among males, the age-adjusted mortality rates did not show a significant trend, while among females, the rates increased over the study period (AAPC: 4.6%, 95% CI: 2.7-6.6%). In females, the crude NTM-associated mortality rate exceeded the TB mortality rate in 2014, 2015, and 2016. CONCLUSIONS: NTM mortality increased in Japan between 1997 and 2016, especially among the elderly female population. Given the increasing NTM-associated mortality and susceptible aging population, public health authorities in Japan should pay greater attention to NTM infections.

DOI： 10.1093/cid/ciaa810

Antibiotic prescriptions for Japanese outpatients with acute respiratory tract infections (2013-2015): A retrospective Observational Study. 査読国際誌

Toshihiro Koyama, Hideharu Hagiya, Yusuke Teratani, Yasuhisa Tatebe, Ayako Ohshima, Mayu Adachi, Tomoko Funahashi, Yoshito Zamami, Hiroyoshi Y Tanaka, Ken Tasaka, Kazuaki Shinomiya, Yoshihisa Kitamura, Toshiaki Sendo, Shiro Hinotsu, Mitsunobu R Kano

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 26 ( 7 ) 660 - 666 2020年3月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: Appropriate antibiotic prescriptions for outpatients with acute respiratory tract infections (ARTIs) are urgently needed in Japan. However, the empirical proof of this need is under-documented. Therefore, we aimed to determine antibiotic prescription rates, and the proportions of antibiotic classes prescribed for Japanese patients with ARTIs. METHODS: We analysed health insurance claims data over 2013-2015 among Japanese patients aged <75 years and determined the following indicators: 1) visit rates for patients with ARTIs and antibiotic prescription rates per 1000 person-years, and 2) proportion of visits by antibiotic-prescribed patients with ARTIs. We defined broad-spectrum antibiotics using the WHO Anatomical Therapeutic Chemical classification 4 level codes. RESULTS: Among 8.65 million visits due to ARTIs at 6859 hospitals and 62,024 physicians' offices, the visit rate and antibiotic prescription rate per 1000 person-years were 990.6 (99% confidence interval [CI], 989.4-991.7) and 532.4 (99% CI, 531.6-533.3), respectively. The visit rates for patients aged 0-17, 18-59, and 60-74 years were 2410.0 (99% CI, 2407.2-2412.9), 683.6 (99% CI, 682.7-684.6), and 682.1 (99% CI, 678.2-686.0), and antibiotic prescription rates were 1093.3 (99% CI, 1091.4-1095.2), 434.1 (99% CI, 433.4-434.9), and 353.4 (99% CI, 350.7-356.1), respectively. The overall proportion of antibiotic prescriptions for ARTI visits was 52.7% and 91.3% of the antibiotics prescribed were broad-spectrum. CONCLUSIONS: Both the visit rates and antibiotic prescription rates for ARTIs were high in this Japanese cohort. The proportion of antibiotic prescriptions exceeded that recommended in the clinical guidelines. Thus, there might be a scope for reducing the current antibiotic prescription rate in Japan.

DOI： 10.1016/j.jiac.2020.02.001

日本における副作用に起因した死亡率の傾向に関する全国規模の観察研究

船橋智子, 小山敏広, 萩谷英大, 原田洸, 寺谷祐亮, 座間味義人, 建部泰尚, 三上奈緒子, 大島礼子, 四宮一昭, 北村佳久, 千堂年昭, 樋之津史郎, 狩野光伸

日本薬学会年会要旨集 140年会 28X - am11 2020年3月

Trends in place of death in a super-aged society: A population-based study, 1998–2017. 査読国際誌

Toshihiro Koyama, Hideharu Hagiya, Tomoko Funahashi, Yoshito Zamami, Miyu Yamagishi, Hiroshi Onoue, Yusuke Teratani, Naoko Mikami, Kazuaki Shinomiya, Yoshihisa Kitamura, Toshiaki Sendo, Shiro Hinotsu, Mitsunobu R Kano

Journal of Palliative Medicine 23 ( 7 ) 950 - 956 2020年1月

A nationwide trend analysis in the incidence and mortality of Creutzfeldt–Jakob disease in Japan between 2005 and 2014 査読国際誌

Nishimura, Y., Harada, K., Koyama, T., Hagiya, H., Otsuka, F.

Scientific Reports 10 ( 1 ) 15509 - 15509 2020年

記述言語：英語掲載種別：研究論文（学術雑誌）

In the era of hyper-ageing, Creutzfeldt-Jakob disease (CJD) can become more prevalent as an important cause of dementia. This study aimed to evaluate the trends in crude and age-adjusted CJD-associated mortality and incidence rates in Japan using national vital statistics data on CJD-associated deaths among individuals aged over 50 years, as well as the government-funded nationwide CJD surveillance data (pertaining to the years 2005-2014) in Japan. The data were analysed using the Joinpoint Regression Program to estimate the long-term trends and average annual percentage changes (AAPCs). Overall, the AAPCs of age-adjusted CJD-associated mortality rates rose significantly over the study period (3.2%; 95% confidence interval [CI] 1.4-5.1%). The AAPC of the age-adjusted incidence rates also increased (overall 6.4%; 95% CI 4.7-8.1%). The CJD-associated increases in the mortality and incidence rates were especially prominent among adults over the age of 70 years. Given this trend in aging of population, the disease burden of CJD will continue to increase in severity. Our findings thus recommend that policymakers be aware of the importance of CJD and focus on preparing to address the increasing prevalence of dementia.

DOI： 10.1038/s41598-020-72519-0

Place of death trends among patients with dementia in Japan: a population-based observational study. 査読国際誌

Toshihiro Koyama, Misato Sasaki, Hideharu Hagiya, Yoshito Zamami, Tomoko Funahashi, Ayako Ohshima, Yasuhisa Tatebe, Naoko Mikami, Kazuaki Shinomiya, Yoshihisa Kitamura, Toshiaki Sendo, Shiro Hinotsu, Mitsunobu R Kano

Scientific reports 9 ( 1 ) 20235 - 20235 2019年12月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Dementia is a major public health concern in ageing societies. Although the population of Japan is among the most aged worldwide, long-term trends in the place of death (PoD) among patients with dementia is unknown. In this Japanese nationwide observational study, we analysed trends in PoD using the data of patients with dementia who were aged ≥65 years and died during 1999-2016. Trends in the crude death rates and PoD frequencies were analysed using the Joinpoint regression model. Changes in these trends were assessed using the Joinpoint regression analysis in which significant change points, the annual percentage change (APC) and average APCs (AAPC) in hospitals, homes, or nursing homes were estimated. During 1999-2016, the number of deaths among patients with dementia increased from 3,235 to 23,757 (total: 182,000). A trend analysis revealed increased mortality rates, with an AAPC of 8.2% among men and 9.3% among women. Most patients with dementia died in the hospital, although the prevalence of hospital deaths decreased (AAPC: -1.0%). Moreover, the prevalence of nursing home deaths increased (AAPC: 5.6%), whereas the prevalence of home deaths decreased (AAPC: -5.8%). These findings support a reconsideration of the end-of-life care provided to patients with dementia.

DOI： 10.1038/s41598-019-56388-w

Fall-related mortality trends in older Japanese adults aged ≥65 years: a nationwide observational study。査読国際誌

BMJ Open 9 ( 12 ) e033462 2019年12月

Oral Anticoagulants usage in Japanese Patients aged 18 – 74 years with Non-Valvular Atrial Fibrillation: a retrospective analysis based on insurance claims data 査読国際誌

Family Practice 36 ( 6 ) 685 - 692 2019年11月

Factors Associated With Immune Checkpoint Inhibitor–Related Myocarditis 査読国際誌

JAMA Oncology 5 ( 11 ) 1635 - 1637 2019年8月

Pattern of antibiotic prescriptions for outpatients with acute respiratory tract infections in Japan, 2013-15: A retrospective observational study 査読

Yusuke Teratani, Hideharu Hagiya, Toshihiro Koyama, Mayu Adachi, Ayako Ohshima, Yoshito Zamami, Hiroyoshi Y. Tanaka, Yasuhisa Tatebe, Ken Tasaka, Naoko Mikami, Kazuaki Shinomiya, Yoshihisa Kitamura, Mitsunobu R. Kano, Shiro Hinotsu, Toshiaki Sendo

Family Practice 36 ( 4 ) 402 - 409 2019年8月

担当区分：責任著者掲載種別：研究論文（学術雑誌）

© 2018 The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. Background: In this age of antimicrobial resistance, unnecessary use of antibiotics to treat non-bacterial acute respiratory tract infections (ARTIs) and inappropriate use of antibiotics in treating bacterial ARTIs are public health concerns. Purpose: Our aim is to identify the pattern of oral antibiotic prescriptions for outpatients with ARTIs in Japan. Methods: We analysed health insurance claims data of patients (aged ≤74 years) from 2013 to 2015, to determine the pattern of antibiotic prescriptions for outpatient ARTIs and calculated the proportion of each antibiotic. Results: Data on 4.6 million antibiotic prescriptions among 1559394 outpatients with ARTIs were analysed. The most commonly prescribed classes of antibiotics included cephalosporins (41.9%), macrolides (32.8%) and fluoroquinolones (14.7%). The proportion of first-, second- and third-generation cephalosporins was 1.0%, 1.7% and 97.3%, respectively. Fluoroquinolones accounted for a quarter of the prescriptions for ARTIs in patients aged >20 years. In contrast, penicillins accounted for just 8.0% of the total number of antibiotic prescriptions for ARTIs. Conclusions: According to clinical guidelines, penicillins are first-line antibiotics against ARTIs. However, third-generation cephalosporins, macrolides and fluoroquinolones are more frequently prescribed in Japan. Although we could not assess the extent to which appropriate antibiotics are selected, our results support the necessity of improving antibiotic choices in the treatment of ARTIs.

DOI： 10.1093/fampra/cmy094

その他リンク： http://orcid.org/0000-0002-7755-1754

Hypoglycemia associated with pivalate-conjugated antibiotics in young children: A retrospective study using a medical and pharmacy claims database in Japan (in press) 査読国際誌

Journal of Infection and Chemotherapy 26 ( 1 ) 86 - 91 2019年8月

Association between rapid antigen detection tests and antibiotics for acute pharyngitis in Japan: A retrospective observational study. 査読国際誌

Yusuke Teratani, Hideharu Hagiya, Toshihiro Koyama, Ayako Ohshima, Yoshito Zamami, Yasuhisa Tatebe, Ken Tasaka, Kazuaki Shinomiya, Yoshihisa Kitamura, Toshiaki Sendo, Shiro Hinotsu, Mitsunobu R Kano

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 25 ( 4 ) 267 - 272 2019年4月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

The application and clinical impact of rapid antigen detection test (RADT) in the treatment of acute pharyngitis is unknown in Japan. We aimed to examine the proportions of RADT usage to identify Group A β-hemolytic Streptococcus (GAS) in outpatients with acute pharyngitis and evaluate the association between RADT and antibiotic treatment. We analyzed health insurance claims data from 2013 to 2015. Logistic regression models were used to analyze associated factors with RADT, overall antibiotic prescription, or penicillin use. We analyzed 1.27 million outpatient visits with acute pharyngitis, in which antibiotics were prescribed in 59.3% of visits. Of the total visits, 5.6% of patients received RADT, and 10.8% of the antibiotics were penicillin. Penicillin selection rates were higher in cases with RADT (25.4%) than those without RADT (9.7%). Compared to large-scale facilities, antibiotic prescription rates were higher in physicians' offices. For factor analysis, age (3-15 years), diagnosis code (streptococcal pharyngitis), size of the medical facility (large-scale hospitals), and physician's specialty (pediatrics) were associated with RADT use. Penicillin selection rate increased with RADT implementation (25.4% vs. 9.7%: adjusted odds ratio 1.55; 95% CI, 1.50-1.60). At 63% of the facilities, the RADT implementation rate was <5% of acute pharyngitis visits prescribed antibiotics. In conclusion, the proportion of RADT usage for outpatients with acute pharyngitis was low in Japan. With appropriate indication and evaluation, we expect that more utilization of RADT can help promote antimicrobial stewardship for outpatients with acute pharyngitis by prompting penicillin therapy. Further investigation with detailed clinical data are warranted.

DOI： 10.1016/j.jiac.2018.12.005

その他リンク： http://orcid.org/0000-0002-7755-1754

Search for Therapeutic Agents for Cardiac Arrest Using a Drug Discovery Tool and Large-Scale Medical Information Database. 査読国際誌

Yoshito Zamami, Takahiro Niimura, Toshihiro Koyama, Yuta Shigemi, Yuki Izawa-Ishizawa, Mizuki Morita, Ayako Ohshima, Keisaku Harada, Toru Imai, Hiromi Hagiwara, Naoto Okada, Mitsuhiro Goda, Kenshi Takechi, Masayuki Chuma, Yutaka Kondo, Koichiro Tsuchiya, Shiro Hinotsu, Mitsunobu R Kano, Keisuke Ishizawa

Frontiers in pharmacology 10 1257 - 1257 2019年

記述言語：英語掲載種別：研究論文（学術雑誌）

The survival rate of cardiac arrest patients is less than 10%; therefore, development of a therapeutic strategy that improves their prognosis is necessary. Herein, we searched data collected from medical facilities throughout Japan for drugs that improve the survival rate of cardiac arrest patients. Candidate drugs, which could improve the prognosis of cardiac arrest patients, were extracted using "TargetMine," a drug discovery tool. We investigated whether the candidate drugs were among the drugs administered within 1 month after cardiac arrest in data of cardiac arrest cases obtained from the Japan Medical Data Center. Logistic regression analysis was performed, with the explanatory variables being the presence or absence of the administration of those candidate drugs that were administered to ≥10 patients and the objective variable being the "survival discharge." Adjusted odds ratios for survival discharge were calculated using propensity scores for drugs that significantly improved the proportion of survival discharge; the influence of covariates, such as patient background, medical history, and treatment factors, was excluded by the inverse probability-of-treatment weighted method. Using the search strategy, we extracted 165 drugs with vasodilator activity as candidate drugs. Drugs not approved in Japan, oral medicines, and external medicines were excluded. Then, we investigated whether the candidate drugs were administered to the 2,227 cardiac arrest patients included in this study. The results of the logistic regression analysis showed that three (isosorbide dinitrate, nitroglycerin, and nicardipine) of seven drugs that were administered to ≥10 patients showed significant association with improvement in the proportion of survival discharge. Further analyses using propensity scores revealed that the adjusted odds ratios for survival discharge for patients administered isosorbide dinitrate, nitroglycerin, and nicardipine were 3.35, 5.44, and 4.58, respectively. Thus, it can be suggested that isosorbide dinitrate, nitroglycerin, and nicardipine could be novel therapeutic agents for improving the prognosis of cardiac arrest patients.

DOI： 10.3389/fphar.2019.01257

Trends in Polypharmacy in Japan: A Nationwide Retrospective Study. 査読国際誌

Onoue H, Koyama T, Zamami Y, Hagiya H, Tatebe Y, Mikami N, Shinomiya K, Kitamura Y, Hinotsu S, Sendo T, Ouchi Y, Kano MR

Journal of the American Geriatrics Society 66 ( 12 ) 2267 - 2273 2018年12月

Relationship between the administration of nicardipine hydrochloride and the development of delirium in patients on mechanical ventilation. 査読

PHARMAZIE 73 ( 12 ) 740 - 743 2018年12月

Antibiotic-associated adverse drug events at a Japanese academic hospital. 査読国際誌

Journal of Infection and Chemotherapy 25 ( 5 ) 392 - 395 2018年11月

Trends in incidence and mortality of tuberculosis in Japan: A population-based study, 1997–2016 査読国際誌

Epidemiology and Infection 147 e38 2018年9月

Trends in the medication reviews of community pharmacies in Japan: a nationwide retrospective study. 査読国際誌

Toshihiro Koyama, Hiroshi Onoue, Ayako Ohshima, Yuri Tanaka, Yasuhisa Tatebe, Yoshito Zamami, Kazuaki Shinomiya, Yoshihisa Kitamura

International journal of clinical pharmacy 40 ( 1 ) 101 - 108 2018年2月

担当区分：筆頭著者,　責任著者記述言語：英語

Background The trends in medication reviews made by community pharmacies in Japan are currently unknown. Objective We aimed to comprehensively describe the national trends in medication reviews in Japan's community pharmacies in the backdrop of the country's ageing population. Setting Community pharmacies in Japan. Methods We analysed national health insurance claims data for 2010-2015. These data were provided by the Ministry of Health, Labour and Welfare as part of the Survey of Medical Care Activities in Public Health Insurance. Main outcome measures The national trends in community pharmacy visits involving medicine dispensing and medication reviews that involve consultations with a physician. Results Among the 365 million pharmacy visits for 2010-2015, we identified 373,429 medication reviews accompanied by consultations with a physician. The pharmacy visit rate per 1000 population increased from 427.2 in 2010 to 483.7 in 2015. Medication reviews also increased from 407 per million pharmacy visits in 2010 to 1445 in 2015. Among the 373,429 medication reviews during the study period, the prescription was changed through collaboration with a physician 338,982 times (90.4%). The proportion of medication review acceptance increased from 80.6% in 2010 to 94.8% in 2015. The prescription change rate was higher among older patients than among younger ones. Conclusions Medication reviews by community pharmacists involving consultations with a physician increased in Japan from 2010 to 2015, as did prescription changes following these reviews.

DOI： 10.1007/s11096-017-0559-7

Administration of Kampo medicine through a tube at an advanced critical care center. 査読

Takahiro Niimura, Yoshito Zamami, Toru Imai, Tsuyoshi Ito, Hidenori Sagara, Hichiya Hiroyuki, Satoru Esumi, Kenshi Takechi, Masaki Imanishi, Toshihiro Koyama, Manabu Amano, Naomi Kurata, Yoshihisa Kitamura, Hironori Nakura, Toshiaki Sendo, Keisuke Ishizawa

The journal of medical investigation : JMI 65 ( 1.2 ) 32 - 36 2018年

記述言語：英語掲載種別：研究論文（学術雑誌）

n emergency and critical care medical centers, tube administration is employed for patients who have difficulty swallowing oral drugs owing to decreased consciousness or mechanical ventilation. However, tube clogging due to drug injection is a concern. We compared the crushing method with the simple suspension method for the passage of amlodipine, an antihypertensive drug, in combination with rikkunshito, which has been used to treat upper gastrointestinal disorders such as functional dyspepsia and gastroesophageal reflux in emergency and critical care medical centers, to ascertain the effect of Kampo products on the passage of other drugs during tube administration. When the crushing method was employed, poorly water-soluble solid products were formed, while a uniformly dispersed suspension was obtained using the simple suspension method. In addition, the passage rate of amlodipine through the tube was 64% and 93% in the crushing and simple suspension methods, respectively, thereby indicating that the simple suspension method provided more favorable than the crushing method. The results of this study suggested that the passage rate of amlodipine for patients who received Kampo products concurrently was higher when the simple suspension method was used, and an appropriate drug amount might well be able to administered to patients using this method. J. Med. Invest. 65:32-36, February, 2018.

DOI： 10.2152/jmi.65.32

Evaluation of the Benefits of De-Escalation for Patients with Sepsis in the Emergency Intensive Care Unit. 査読国際誌

Takahiro Niimura, Yoshito Zamami, Toru Imai, Kanako Nagao, Masafumi Kayano, Hidenori Sagara, Mitsuhiro Goda, Naoto Okada, Masayuki Chuma, Kenshi Takechi, Masaki Imanishi, Toshihiro Koyama, Tadashi Koga, Hironori Nakura, Toshiaki Sendo, Keisuke Ishizawa

Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques 21 ( 1 ) 54 - 59 2018年

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: Although the 2016 Japanese guidelines for the management of sepsis recommend de-escalation of treatment after identification of the causative pathogen, adherence to this practice remain unknown. The objective of this study was to evaluate the benefits of de-escalating treatment for sepsis patients at an advanced critical care and emergency medical centre. METHODS: Based on electronic patient information, 85 patients who were transported to the centre by ambulance, and diagnosed with sepsis between January 2008 and September 2013 were enrolled and evaluated. Patients were divided into two groups with and without de-escalation, and comparisons were conducted for several variables, including length of hospital stay, and length of antibiotic administration. Two types of subgroup analysis were conducted between patients with septic shock or positive blood cultures. Statistical analysis was conducted using chi-square and Mann-Whitney U tests. RESULTS: The length of hospital stay after diagnosis was significantly shorter for the de-escalation group than for the non-de-escalation group. In the subgroup analysis, de-escalation for blood culture-positive patients was beneficial in terms of the length of hospital stay and length of antibiotic administration. CONCLUSIONS: The findings of this study suggest that sepsis treatment de-escalation is beneficial for treatment efficacy and appropriate use of antibiotics. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

DOI： 10.29173/jpps29737

Hydrocortisone administration was associated with improved survival in Japanese patients with cardiac arrest. 査読国際誌

Takahiro Niimura, Yoshito Zamami, Toshihiro Koyama, Yuki Izawa-Ishizawa, Masashi Miyake, Tadashi Koga, Keisaku Harada, Ayako Ohshima, Toru Imai, Yutaka Kondo, Masaki Imanishi, Kenshi Takechi, Keijo Fukushima, Yuya Horinouchi, Yasumasa Ikeda, Hiromichi Fujino, Koichiro Tsuchiya, Toshiaki Tamaki, Shiro Hinotsu, Mitsunobu R Kano, Keisuke Ishizawa

Scientific reports 7 ( 1 ) 17919 - 17919 2017年12月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

There are few reports on hydrocortisone administration after cardiac arrest, and those that have been published included few subjects. This study aimed to evaluate the effect of hydrocortisone administration on the outcomes of patients who experienced cardiac arrest. We investigated the survival discharge rates and the length of hospital stay from cardiac arrest to discharge, stratified by use of hydrocortisone, using a Japanese health-insurance claims dataset that covers approximately 2% of the Japanese population. The study included the data of 2233 subjects who experienced either in-hospital or out-of-hospital cardiac arrest between January 2005 and May 2014. These patients were divided into two groups, based on the administration of hydrocortisone. We adjusted the baseline characteristics, medical treatment, and drug administration data of the two groups using propensity scores obtained via the inverse probability of treatment weighted method. The hydrocortisone group had a significantly higher survival discharge rate (13/61 [21.1%] vs. 240/2172 [11.0%], adjusted odds ratio: 4.2, 95% CI: 1.60-10.98, p = 0.004). In addition, the administration of hydrocortisone was independent predictor of survival to discharge (hazard ratio: 4.6, p < 0.001). The results demonstrate a correlation between hydrocortisone administration and the high rates of survival to discharge.

DOI： 10.1038/s41598-017-17686-3

その他リンク： http://orcid.org/0000-0002-7755-1754

Patterns of CT use in Japan, 2014: A nationwide cross-sectional study 査読

Toshihiro Koyama, Yoshito Zamami, Ayako Ohshima, Yusuke Teratani, Kazuaki Shinomiya, Yoshihisa Kitamura

EUROPEAN JOURNAL OF RADIOLOGY 97 96 - 100 2017年12月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER IRELAND LTD

Objectives: To describe CT usage in Japan by age, gender, and region and to clarify the relationship between aging and CT examination rate.
Materials and methods: We conducted a cross-sectional study using openly accessible data from the National Database, which includes all Japanese health insurance claim data from 2014. These data are anonymized and publicly available as spreadsheets. Therefore, this study did not require institutional review board approval. We calculated the rate of CT examinations per 1000 population by age, sex, and region with 99% confidence intervals. Pearson correlation coefficients were calculated between CT rate and aging in each region.
Results: We analyzed 28.1 million CT scans, and the rate per 1000 population was 221.5 (99% CI, 221.4-221.6). By age, the corresponding rate for age 0-9 years was 28.9, that for age 10-9 years was 48.6, that for 20-29 years was 52.2, that for 30-39 years was 69.0, that for 40-49 years was 105.9, that for 50-59 years was 177.6, that for 60-69 years was 303.3, that for 70-79 years was 532.5 and that for= 80 years was 801.5. The rate for male individuals was 233.6 and that for females was 210.0. The CT examination rate was 171.7 and 296.0 in the lowest-and highest-frequency regions, respectively. The average correlation coefficient between the aging rate in each region and the CT examination rate was 0.58 (0.35-0.74, p = 0.00002).
Conclusion: In Japan, the CT examination rate per 1000 population was high (third highest in the world). Age may be a factor that increases CT use. Furthermore, because variation in CT examination rates by age, gender, and region were observed, it is necessary to standardize CT utilization.

DOI： 10.1016/j.ejrad.2017.10.023

Drug Repositioning Research Utilizing a Large-scale Medical Claims Database to Improve Survival Rates after Cardiopulmonary Arrest 査読

Yoshito Zamami, Takahiro Niimura, Kenshi Takechi, Masaki Imanishi, Toshihiro Koyama, Keisuke Ishizawa

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN 137 ( 12 ) 1439 - 1442 2017年12月

記述言語：日本語出版者・発行元：PHARMACEUTICAL SOC JAPAN

Approximately 100000 people suffer cardiopulmonary arrest in Japan every year, and the aging of society means that this number is expected to increase. Worldwide, approximately 100 million develop cardiac arrest annually, making it an international issue. Although survival has improved thanks to advances in cardiopulmonary resuscitation, there is a high rate of postresuscitation encephalopathy after the return of spontaneous circulation, and the proportion of patients who can return to normal life is extremely low. Treatment for postresuscitation encephalopathy is long term, and if sequelae persist then nursing care is required, causing immeasurable economic burdens as a result of ballooning medical costs. As at present there is no drug treatment to improve postresuscitation encephalopathy as a complication of cardiopulmonary arrest, the development of novel drug treatments is desirable. In recent years, new efficacy for existing drugs used in the clinical setting has been discovered, and drug repositioning has been proposed as a strategy for developing those drugs as therapeutic agents for different diseases. This review describes a large-scale database study carried out following a discovery strategy for drug repositioning with the objective of improving survival rates after cardiopulmonary arrest and discusses future repositioning prospects.

DOI： 10.1248/yakushi.17-00139-3

Meta-analysis of the efficacies of amiodarone and nifekalant in shock-resistant ventricular fibrillation and pulseless ventricular tachycardia 査読

Shiho Sato, Yoshito Zamami, Toru Imai, Satoshi Tanaka, Toshihiro Koyama, Takahiro Niimura, Masayuki Chuma, Tadashi Koga, Kenshi Takechi, Yasuko Kurata, Yutaka Kondo, Yuki Izawa-Ishizawa, Toshiaki Sendo, Hironori Nakura, Keisuke Ishizawa

SCIENTIFIC REPORTS 7 ( 1 ) 12683 2017年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Amiodarone (AMD) and nifekalant (NIF) are used in the treatment of ventricular fibrillation or tachycardia; however, only few studies have been conducted on their efficacies. Therefore, a meta-analysis was conducted. Relevant sources were identified from PubMed, Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi. The outcomes were short-term and long-term survival in patients with shock-resistant ventricular fibrillation/pulseless ventricular tachycardia. Thirty-three studies were analysed. The results showed that, compared to the control treatment, AMD did not improve short-term survival (odds ratio (OR): 1.25, 95% confidence interval (CI): 0.91-1.71) or long-term survival (OR: 1.00, 95% CI: 0.63-1.57). However, compared to the control treatment, NIF significantly improved short-term survival (OR: 3.23, 95% CI: 2.21-4.72) and long-term survival (OR: 1.88, 95% CI: 1.36-2.59). No significant difference was observed in short-term survival (OR: 0.85, 95% CI: 0.63-1.15) or long-term survival (OR: 1.25, 95% CI: 0.67-2.31) between AMD- and NIF-treated patients. The results suggest that NIF is beneficial for short-term and long-term survival in shock-resistant ventricular fibrillation/pulseless ventricular tachycardia; however, the efficacy of AMD in either outcome is not clear.

DOI： 10.1038/s41598-017-13073-0

Emotional Intelligence and its Effect on Pharmacists and Pharmacy Students with Autistic-like Traits 査読

Yuji Higuchi, Masatoshi Inagaki, Toshihiro Koyama, Yoshihisa Kitamura, Toshiaki Sendo, Maiko Fujimori, Hitomi Kataoka, Chinatsu Hayashibara, Yosuke Uchitomi, Norihito Yamada

AMERICAN JOURNAL OF PHARMACEUTICAL EDUCATION 81 ( 4 ) 74 2017年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER ASSOC COLL PHARMACY

Objective. To measure whether Emotional intelligence (EI) would minimize the negative association between autistic-like traits (ALT) and empathic behavior and enhance the positive association between ALT and psychological distress.Methods. Our sample population included 823 hospital pharmacists belonging to a district society, and 378 pharmacy students. Analyses were performed to examine relationships between scores on the Emotional Intelligence Scale (EQS), Autism-Spectrum Quotient (AQ), Jefferson Scale of Empathy (JSE), and General Health Questionnaire-12 (GHQ).Results. Complete answers were obtained from 373 pharmacists, and 341 students. EQS partially intervened the associations between AQ and JSE and between AQ and GHQ.Conclusion. EI partially intervened the relationships between ALT and empathy, and between ALT and mental health, both of which are necessary for optimal pharmaceutical practice.

DOI： 10.5688/ajpe81474

A cross-sectional study of psychological distress, burnout, and the associated risk factors in hospital pharmacists in Japan 査読

Yuji Higuchi, Masatoshi Inagaki, Toshihiro Koyama, Yoshihisa Kitamura, Toshiaki Sendo, Maiko Fujimori, Yosuke Uchitomi, Norihito Yamada

BMC PUBLIC HEALTH 16 534 2016年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BMC

Background: Opportunities for face-to-face communication with patients is increasing in modern hospital pharmacist practice. This may impose new burdens on hospital pharmacists. We performed a cross-sectional study to examine the prevalence of psychological distress, burnout, and compassion fatigue among hospital pharmacists. We also investigated possible relevant factors, such as sex, years of experience, hospital size, interpersonal work hours, and personality traits related to communication.Methods: We mailed self-administered questionnaires to all pharmacists (n = 823) belonging to the prefectural society of hospital pharmacists in Japan. The questionnaires were the General Health Questionnaire (GHQ-12), Burnout (BO) and Compassion Fatigue and Secondary Traumatic Stress (CF/STS) subscales of the Professional Quality of Life Scale, the Autism Spectrum Quotient (AQ), and the Adult ADHD (attention deficit hyperactivity disorder) Self-Report Scale (ASRS). We examined associations between personality traits (AQ, ASRS) and psychological burden (GHQ-12, BO, CF/STS) using rank ANCOVA or multivariate logistic regression analyses.Results: Complete responses were obtained from 380 pharmacists (46.2 % response rate). A substantial number of participants obtained scores that were higher than the cutoff points of the GHQ-12 (54.7 %), BO (49.2 %), and CF/STS (29.2 %). The GHQ-12 scores were negatively affected by years of experience (p < 0.001), and positively affected by AQ (p < 0.001) and ASRS (p < 0.001) scores. The BO scores was positively affected by AQ (p < 0.001) and ASRS (p = 0.001) scores, while the CF/STS (p = 0.023) score was negatively affected by years of experience, and positively affected by AQ (p < 0.001) and ASRS (p < 0.001) scores.Conclusions: There is a high prevalence of psychological distress and work-related burnout/CF among hospital pharmacists. Additionally, two common personality traits, such as autistic-like traits and ADHD-like symptoms, which might be related to communication style, could increase the risk of psychological distress and burnout/CF. Early risk assessment and preventive interventions that are specialized for these characteristics could protect individuals with these specific traits from burnout.

DOI： 10.1186/s12889-016-3208-5

Pharmaceutical Education Focused on Pharmacotherapy in Emergency Medical Care 査読

Yoshito Zamami, Toshihiro Koyama, Toru Imai, Akane Takemoto, Hidenori Sagara, Toshiaki Sendo, Hironori Nakura

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN 136 ( 7 ) 987 - 991 2016年7月

記述言語：日本語出版者・発行元：PHARMACEUTICAL SOC JAPAN

Pharmacists are expected to be active members of the healthcare team in emergency medicine, because many pharmaceuticals are administered to patients with life-threatening conditions. However, adequate education for pharmacists and pharmacy students is not provided. The "Emergency Pharmaceutical Sciences" course was introduced for the first time in Japan by the Department of Pharmacy, Okayama University, to offer advanced education in emergency medicine and research related to critical care. We offer an emergency pharmaceutical training program with high-performance simulators and have succeeded in improving the clinical skills and confidence of pharmacy students. In this review, we introduce our activities intended to mold pharmacy students into emergency pharmacists who can contribute to emergency medicine.

DOI： 10.1248/yakushi.15-00286-4

Possibility of Pharmacist in Emergency Medical Care: To Bring Up a Familiar Pharmacist for Emergency Care by Fusing Clinical Pharmacist Activity and University Education Foreword 査読

Yoshito Zamami, Toshihiro Koyama, Hironori Nakura, Shuichi Enomoto

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN 136 ( 7 ) 965 - 965 2016年7月

Vascular responses to compound 48/80 in rat mesenteric vascular beds 査読

Honghua Jin, Zhen Li, Shingo Takatori, Toshihiro Koyama, Xin Jin, Yoshito Zamami, Hiromu Kawasaki, Pengyuan Sun

CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 94 ( 6 ) 620 - 626 2016年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：CANADIAN SCIENCE PUBLISHING, NRC RESEARCH PRESS

A further investigation was performed on the vascular effect of endogenous histamine using the histamine releaser, compound 48/80, in rat mesenteric vascular beds with active tone. In preparations with intact endothelium, low concentrations of compound 48/80 (1.53 x 10(-5)-3 x 1.53 x 10(-5) mg/mL) perfusion for 1 min only induced a small vasodilation. High concentrations of compound 48/80 (1.53 x 10(-4)-3 x 1.53 x 10(-2) mg/mL) induced a biphasic vascular responses, an initial vasoconstriction followed a subsequent long-lasting vasodilation. The vasodilation induced by low concentrations of compound 48/80 and the vasoconstriction induced by high concentration of compound 48/80 was inhibited by olopatadine. However, cimetidine did not affect the responses induced by compound 48/80. Endothelium removal enlarged the compound 48/80-induced phase-2 vasoconstriction, while it attenuated the phase-3 vasodilation. Additionally, indomethacin and seratrodast significantly inhibited vasoconstriction but it did not affect the long-lasting vasodilation induced by high concentrations of compound 48/80. Ruthenium red inhibited the vasodilation induced by low concentrations and high concentrations of compound 48/80. These results suggest that the vasoconstriction induce by high concentrations of compound 48/80 is mediated by endogenous histamine released from mast cells. It is also suggested that thromboxane A(2) released from mast cells is related to the vasoconstriction.

DOI： 10.1139/cjpp-2015-0442

Evaluation of pharmaceutical lifesaving skills training oriented pharmaceutical intervention. 査読国際誌

Zamami Y, Imai T, Imanishi M, Takechi K, Shiraishi N, Koyama T, Sagara H, Shiino Y, Sendo T, Ishizawa K

Journal of pharmaceutical health care and sciences 2 ( 1 ) 21 - 21 2016年

Risk factor of acute renal failure induced by edaravone in patients with cerebrovascular disorder 査読

座間味義人, 相良英憲, 萱野由佳, 小山敏広, 白石奈緒子, 江角悟, 川豊世武, 千堂年昭, 氏家良人, 名倉弘哲

日本臨床救急医学会雑誌 Vol.19 ( No.3 ) 461 - 465 2016年

記述言語：日本語掲載種別：研究論文（学術雑誌）

エダラボンを用いた治療は患者の神経学的予後を改善する一方，急性腎障害発現のリスクがあると報告されている．本研究はエダラボン投与による急性腎障害発現を予防するために，エダラボン投与時の患者背景から危険因子を解析することを目的とした．岡山大学病院においてエダラボンが投与された患者を対象に，患者基本情報およびエダラボン投与情報，血液検査結果を電子カルテより遡及的に調査した．調査データから単変量解析を実施し，抽出した因子を用いて二項ロジスティック回帰分析を行った結果，感染症の併発が，エダラボンによる急性腎障害発現の有意な危険因子(予測因子)であることが示唆された．したがって，感染症の所見がある患者にエダラボンを投与する際は，急性腎障害発現に留意する必要がある．

DOI： 10.11240/jsem.19.461

Exploring autistic-like traits relating to empathic attitude and psychological distress in hospital pharmacists 査読

Yuji Higuchi, Yosuke Uchitomi, Maiko Fujimori, Toshihiro Koyama, Hitomi Kataoka, Yoshihisa Kitamura, Toshiaki Sendo, Masatoshi Inagaki

INTERNATIONAL JOURNAL OF CLINICAL PHARMACY 37 ( 6 ) 1258 - 1266 2015年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER

Background Pharmacists are expected to play a key role in modern cancer care. Research suggests that an empathic approach and attitude in medical staff improves the quality of patient care. An empathic attitude and psychological distress are thought to be associated with autistic-like traits, but little is known about such traits. Objective In this study, we aimed to clarify the associations among autistic-like traits, empathic attitude in a medical context, and psychological health in hospital pharmacists. Setting Eligibility criteria for inclusion were certified pharmacists working at hospitals for patient care who returned their questionnaires. Method Eight hundred and twenty-three hospital pharmacists completed a number of self-administered questionnaires anonymously by mail. Main outcome measures Scores were obtained on the Autism-Spectrum Quotient, the Jefferson Scale of Empathy, the General Health Questionnaire-12, and subscales of the Interpersonal Reactivity Index (Perspective Taking, IRI-Empathic Concern, IRIPersonal Distress). We performed correlation and mediation analyses to confirm that the empathy and general health questionnaires were associated with autism-spectrum quotient scores, and with each IRI subscale. Results Complete responses were obtained from 379 pharmacists comprising 151 males (39.8 %) with a mean age of 37.7 +/- A 10.8 years (missing data, n = 13) and a median of 11 years after qualification as a pharmacist. Autism-Spectrum Quotient scores were inversely correlated with empathy (r = -0.22, p < 0.001) and positively correlated with general health scores (r = 0.40, p < 0.001). In the models with mediation, the inverse correlation between autism-spectrum quotient and empathy scores was mediated indirectly by IRI-Perspective Taking and IRI-Empathic Concern, and the positive correlation between autism-spectrum quotient and general health was mediated indirectly by IRI-Personal Distress. There were also direct effects, with significant effects of autism-spectrum quotient on empathy and general health scores. Conclusion Our findings suggest that autistic-like traits affect both empathic attitude in a medical context and the psychological health of pharmacists. We recommend that to improve empathy in those with high levels of autistic-like traits, we may need to develop specialized interventions, such as improving communication skills training.

DOI： 10.1007/s11096-015-0204-2

The Effectiveness of Team-based Learning (TBL) as a New Teaching Approach for Pharmaceutical Care Education 査読

Manabu Suno, Toshiko Yoshida, Toshihiro Koyama, Yoshito Zamami, Tomoko Miyoshi, Takaaki Mizushima, Mitsune Tanimotoa

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN 133 ( 10 ) 1127 - 1134 2013年10月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：PHARMACEUTICAL SOC JAPAN

The concept of Team-Based Learning (TBL) was developed in the late 1970s by Larry Michaelsen, who wanted students to enjoy the benefits of small group learning within large classes in the business school environment. In contrast to problem-based learning (PBL), which is student centered, TBL is typically instructor centered. Recently, TBL is being used as a teaching method in over 60 health science professional schools in the US and other countries. In the present study, the impact of adopting TBL in teaching pharmaceutical care practices to students was evaluated. Students were required to answer a set of multiple-choice questions individually in individual readiness assessment test (IRAT) before the TBL sessions to assess their level of preparation. The same set of questions was then reattempted by the group readiness assessment test (GRAT) during TBL. Comparing the scores obtained in the GRAT and IRAT before the first TBL session, the scores from the GRAT were always higher than those of the IRAT, indicating that TBL has encouraged active learning. In addition, students were surveyed about their level of satisfaction with TBL and written comments about TBL were solicited. The results of the questionnaire showed that 87.3 +/- 9.3% of the students were satisfied. Moreover, no student commented that TBL was in any way inferior to the PBL. Implementation of a TBL approach was successfully integrated into the pharmaceutical care education course. In order to further improve the usefulness of TBL in teaching pharmaceutical care, a hybrid teaching approach that also comprises PBL and a lecture-based course is desirable.

DOI： 10.1248/yakushi.12-00254

The mechanisms of electroconvulsive stimuli in BrdU-positive cells of the dentate gyrus in ACTH-treated rats 査読

Keiko Kuwatsuka, Hiromi Hayashi, Yuka Onoue, Ikuko Miyazaki, Toshihiro Koyama, Masato Asanuma, Yoshihisa Kitamura, Toshiaki Sendo

Journal of Pharmacological Sciences 122 ( 1 ) 34 - 41 2013年

記述言語：英語掲載種別：研究論文（学術雑誌）

In clinical studies, electroconvulsive stimuli have been associated with improvements in both depression and treatment-resistant depression. In a previous study, treatment with adrenocorticotropic hormone (ACTH) for 14 days decreased adult hippocampal cell proliferation. Furthermore, electroconvulsive stimuli significantly decreased the duration of immobility following repeated administration of ACTH for 14 days in rats. The present study was undertaken to further characterize the mechanism of treatment-resistant antidepressant effects of electroconvulsive stimuli by measuring cell proliferation, brain-derived neurotrophic factor (BDNF) levels, and phosphorylated and total cyclic adenosine monophosphate (cAMP) response element-binding protein (pCREB/CREB) levels in the hippocampus of ACTH-treated rats. Electroconvulsive stimuli increased cell proliferation in both saline-treated and ACTH-treated rats. Mature-BDNF protein levels showed a tendency to decrease in ACTH-treated rats. Electroconvulsive stimuli treatment increased mature-BDNF protein levels in the hippocampus of both saline-treated and ACTH-treated rats. Furthermore, electroconvulsive stimuli increased phospho-Ser133-CREB (pCREB) levels and the ratio of pCREB/CREB in both saline-treated and ACTH-treated rats. These findings suggest that the treatment-resistant antidepressant effects of electroconvulsive stimuli may be attributed, at least in part, to an enhancement of hippocampal cell proliferation. © The Japanese Pharmacological Society.

DOI： 10.1254/jphs.13015FP

Influence of doxorubicin and cyclophosphamide on psychological behavior in rats 査読

Kitamura Yoshihisa, Hattori Sayo, Miyake Ayaka, Koyama Toshihiro, Miyazaki Ikuko, Asanuma Masato, Sendo Toshiaki

JOURNAL OF PHARMACOLOGICAL SCIENCES 121 143P 2013年

Effect of the 5-HT1A receptor function on antidepressive effect and neurogenesis in ACTH treated rats 査読

Miyake Ayaka, Kitamura Yoshihisa, Hattori Sayo, Koyama Toshihiro, Miyazaki Ikuko, Asanuma Masato, Sendo Toshiaki

JOURNAL OF PHARMACOLOGICAL SCIENCES 121 144P 2013年

Adrenergic Stimulation-Released Histamine Taken-up in Adrenergic Nerves Induces Endothelium-Dependent Vasodilation in Rat Mesenteric Resistance Arteries 査読

Yuto Haruki, Shingo Takatori, Sayo Hattori, Yoshito Zamami, Toshihiro Koyama, Panot Tangsucharit, Hiromu Kawasaki

JOURNAL OF PHARMACOLOGICAL SCIENCES 118 ( 4 ) 537 - 542 2012年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAPANESE PHARMACOLOGICAL SOC

The present study investigated whether histamine was taken up by perivascular adrenergic nerves and released by periarterial nerve stimulation (PNS) to induce vascular responses. In rat mesenteric vascular beds treated with capsaicin to eliminate calcitonin gene related peptide (CGRP)ergic vasodilation and with active tone, PNS (1 - 4 Hz) induced only adrenergic nerve-mediated vasoconstriction. Histamine treatment for 20 min induced PNS-induced vasoconstriction followed by vasodilation without affecting CGRP-induced vasodilation. Chlorpheniramine, guanethidine, combination of histamine and desipramine, and endothelium-removal abolished PNS-induced vasodilation in histamine-treated preparations. These results suggest that histamine taken up by and released from adrenergic nerves by PNS causes endothelium-dependent vasodilation in rat mesenteric arteries.

DOI： 10.1254/jphs.12012SC

Involvement of perivascular nerves and transient receptor potential vanilloid 1 (TRPV1) in vascular responses to histamine in rat mesenteric resistance arteries 査読

Honghua Jin, Pengyuan Sun, Shingo Takatori, Toshihiro Koyama, Yoshito Zamami, Panot Tangsucharit, Yoshihisa Kitamura, Hiromu Kawasaki

EUROPEAN JOURNAL OF PHARMACOLOGY 680 ( 1-3 ) 73 - 80 2012年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCIENCE BV

A previous report showed that histamine in denuded mesenteric vascular beds produced a triphasic response; an initial small histamine H-2 receptor-mediated vasodilation, a transient histamine H-1 receptor-mediated vasoconstriction, and finally a long-lasting vasodilation. We further investigated the vascular effect of histamine in mesenteric preparations without an endothelium to clarify the possible involvement of perivascular nerves. Male Wistar rat mesenteric vascular beds without an endothelium were perfused with Krebs solution containing methoxamine to produce active tone and lafutidine to block histamine H-2 receptor-mediated vasodilation. Histamine (1-100 mu M) was perfused for 1 min and perfusion pressure was measured with a pressure transducer. Histamine caused a biphasic vascular response; initial vasoconstriction followed vasodilation. Tetrodotoxin (a neurotoxin, 1 mu M) and procaine (a local anesthetic, 100 mu M) significantly inhibited the vasoconstriction and vasodilation. Ruthenium red (a transient receptor potential vanilloid 1 (TRPV1) antagonist, 1 mu M) also significantly inhibited both phases of the response. Pretreatment with capsaicin (a depletor of calcitonin gene-related peptide (CGRP)-containing nerves, 5 mu M) significantly inhibited the vasodilation without affecting the initial vasoconstriction. Both indomethacin (a cyclooxygenase inhibitor, 0.5 mu M) and seratrodast (a thromboxane A(2) receptor antagonist, 0.1 mu M) abolished the histamine-induced vasoconstriction and subsequent vasodilation. These results suggest that histamine-induced vasoconstriction and long-lasting vasodilation are mediated by activation of TRPV1 on capsaicin-sensitive and capsaicin-insensitive nerves. They also suggest that perivascular nerves and prostanoids, probably thromboxane A(2), are responsible for the vascular response to histamine. (C) 2012 Elsevier B. V. All rights reserved.

DOI： 10.1016/j.ejphar.2012.01.018

Investigation on the Mechanisms for the Suppression of Cell Proliferation in the Dentate Gyrus of the Hippocampus in ACTH Treated Rats 査読

Hiromi Hayashi, Maho Doi, Yuka Onoue, Keiko Kuwatsuka, Ayaka Miyake, Toshihiro Koyama, Kazuaki Shinomiya, Ikuko Miyazaki, Masato Aasanuma, Yoshihisa Kitamura

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN 132 ( 2 ) 173 - 178 2012年2月

記述言語：日本語出版者・発行元：PHARMACEUTICAL SOC JAPAN

We previously reported that adrenocorticotropic hormone (ACTH) -treated rats serve as a valuable animal model for tricyclic antidepressant-resistant depressive conditions. The present study was undertaken to investigate the changes in neurogenesis in the hippocampus of ACTH-treated rats. Chronic treatment of ACTH decreased the number of bromodeoxyuridine-labeled cells in the dentate gyrus, and the coadministration of imipramine and lithium, and electroconvulsive stimuli recovered these reductions. Furthermore, chronic ACTH treatment also decreased the expression of brain-derived neurotrophic factor, and the coadministration of imipramine and lithium, and electroconvulsive stimuli recovered these reductions. These results suggest that antidepressant-resistant depression is caused by the suppression of neurogenesis, and the coadministration of imipramine and lithium, and electroconvulsive stimuli exert an antidepressant-like effect by recovering proliferative signals and neurogenesis.

DOI： 10.1248/yakushi.132.173

Effect of Pharmacist Management on Serum Hemoglobin Levels with Renal Anemia in Hemodialysis Outpatients 査読

Junko Ohnishi, Akiyo Miyake, Keiko Kuwatsuka, Yuka Onoue, Miyoshi Lee, Toshihiro Koyama, Toshiaki Sendo, Hiromu Kawasaki, Yoshihisa Kitamura

BIOLOGICAL & PHARMACEUTICAL BULLETIN 34 ( 10 ) 1609 - 1612 2011年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PHARMACEUTICAL SOC JAPAN

The initiation of a pharmacist-implemented management program to ensure appropriate use of erythropoietin-stimulating agents at Mizushima Kyodo Hospital is described. In the present study, we examined the influence of having pharmacists actively manage hemoglobin levels on therapeutic outcome in a retrospective study of 84 outpatients receiving hemodialysis. We compiled in-hospital guidelines for the use of erythropoietin and iron for outpatients with renal anemia. Pharmacists made recommendations, particularly about changes in the dose of erythropoietin and administration of iron preparations, to physicians. Clinical test results were monitored for 12 months (between November 2007 and October 2008) with and without the participation of pharmacists (continuous 6 months). The counseling by pharmacists significantly decreased hemoglobin levels in the high group (>12 g/dl) and significantly increased them in low group (<10 g/dl). Furthermore, it increased hemoglobin levels in the optimal group, suggesting the management of our hospital guidelines. On the other hand, low levels of hemoglobin indicated low levels of albumin. It is suggested that no improvement in hemoglobin levels may indicate low levels of albumin. These findings suggest that the active participation of pharmacists in the management of renal anemia in hemodialysis patients had a great therapeutic impact.

DOI： 10.1248/bpb.34.1609

Histamine H-3 receptor-mediated modulation of perivascular nerve transmission in rat mesenteric arteries 査読

Pengyuan Sun, Shingo Takatori, Xin Jin, Toshihiro Koyama, Panot Tangsucharit, Simin Li, Yoshito Zamami, Yoshihisa Kitamura, Hiromu Kawasaki

EUROPEAN JOURNAL OF PHARMACOLOGY 655 ( 1-3 ) 67 - 73 2011年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCIENCE BV

The rat mesenteric artery has been shown to be innervated by adrenergic vasoconstrictor nerves and calcitonin gene-related peptide (CGRP)-containing (CGRPergic) vasodilator nerves. The present study was designed to investigate the involvement of histamine H-3 receptors in the neurotransmission of perivascular adrenergic and CGRPergic nerves. The mesenteric vascular beds without an endothelium isolated from male Wistar rats were perfused with Krebs solution and perfusion pressure was measured. In preparations with resting tension, the selective H-3 receptor agonist (R)-alpha-methylhistamine (alpha-methylhistamine; 10-100 nM) significantly reduced periarterial nerve stimulation (2-8 Hz)-induced vasoconstriction and noradrenaline release in the perfusate without an effect on the vasoconstriction induced by exogenously injected noradrenaline (0.5, 1.0 nmol). In preparations with active tone produced by methoxamine (2 mu M) and in the presence of guanethidine (5 mu M), the periarterial nerve stimulation (1, 2 Hz)-induced vasodilator response was inhibited by a-methylhistamine (0.1-1 mu M) perfusion without affecting vasodilation induced by exogenously injected CGRP (5 pmol). Clobenpropit (histamine H-3 receptor antagonist, 1 mu M) canceled the alpha-methylhistamine-induced decrease in the periarterial nerve stimulation-induced vasoconstriction and noradrenaline release and periarterial nerve stimulation-induced vasodilation. These results suggest that the stimulation of H-3 receptors located in rat perivascular nerves inhibits presynaptically the neurotransmission of not only adrenergic nerves, but also CGRP nerves, by decreasing neurotransmitters. (C) 2011 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ejphar.2011.01.020

Chronic Treatment with Imipramine and Lithium Increases Cell Proliferation in the Hippocampus in Adrenocorticotropic Hormone-Treated Rats 査読

Yoshihisa Kitamura, Maho Doi, Keiko Kuwatsuka, Yuka Onoue, Ikuko Miyazaki, Kazuaki Shinomiya, Toshihiro Koyama, Toshiaki Sendo, Hiromu Kawasaki, Masato Asanuma, Yutaka Gomita

BIOLOGICAL & PHARMACEUTICAL BULLETIN 34 ( 1 ) 77 - 81 2011年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PHARMACEUTICAL SOC JAPAN

Adult hippocampal neurogenesis is reported to change in animal models of depression and antidepressants. We have used the mitotic marker 5-bromo-2'-deoxyyridine to address the effects of imipramine and lithium on cell proliferation and survival following chronic treatment with adrenocorticotropic hormone (ACTH) in the subgranular zone of the hippocampal dentate gyrus. ACTH treatment for 14d decreased adult hippocampal cell proliferation and survival. Coadministration of imipramine and lithium for 14d blocked the loss of cell proliferation but not cell survival resulting from the chronic treatment with ACTH. The coadministration of imipramine and lithium may have treatment-resistant antidepressive properties, which may be attributed, in part, to a normalization of hippocampal cell proliferation.

DOI： 10.1248/bpb.34.77

Paracrine control of mesenteric perivascular axo-axonal interaction. 査読

H Kawasaki, S Takatori, 座間味義人, T Koyama, M Goda, K Hirai, P Tangsucharit, X Jin, N Hobara, Y Kitamura

Acta Physiologica Vol.203 ( No.1 ) 3 - 11 2010年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Immunohistochemical study of rat mesenteric arteries showed dense innervation of adrenergic nerves, calcitonin gene-related peptide (CGRP)-containing nerves (CGRPergic nerves), nitric oxide-containing nerves (nitrergic nerves). Double-immunostaining revealed that most CGRPergic or nitrergic nerves were in close contact with adrenergic nerves. CGRPergic and transient receptor potential vanilloid-1 (TRPV1)-immunopositive nerves appeared in the same neurone. In rat perfused mesenteric vascular beds without endothelium and with active tone, perfusion of nicotine, or bolus injection of capsaicin and acetylcholine and periarterial nerve stimulation (PNS) lowered pH levels of out flowed perfusate concomitant with vasodilation. Cold-storage denervation of preparations abolished pH lowering induced by nicotine and PNS. Guanethidine inhibited PNS- and nicotine-, but not acetylcholine- and capsaicin-, induced pH lowering. Pharmacological analysis showed that protons were released not only from adrenergic nerves but also from CGRPergic nerves. A study using a fluorescent pH indicator demonstrated that nicotine, acetylcholine and capsaicin applied outside small mesenteric artery lowered perivascular pH levels, which were not observed in Ca(2+) free medium. Exogenously injected hydrochloric acid in denuded preparations induced pH lowering and vasodilation, which was inhibited by denervation, TRPV1 antagonists and capsaicin without affecting pH lowering. These results suggest that excitement of adrenergic nerves releases protons to activate TRPV1 in CGRPergic nerves and thereby induce vasodilation. It is also suggested that CGRPergic nerves release protons with exocytosis to facilitate neurotransmission via a positive feedback mechanism.

DOI： 10.1111/j.1748-1716.2010.02197.x

Endothelial Modulation of Agonist-induced Vasoconstriction in Mesenteric Microcirculation 査読

Xin Jin, Yukiko Otonashi-Satoh, Yoshito Zamami, Toshihiro Koyama, Pengyuan Sun, Yoshihisa Kitamura, Hiromu Kawasaki

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN 130 ( 5 ) 723 - 728 2010年5月

記述言語：英語出版者・発行元：PHARMACEUTICAL SOC JAPAN

It is widely accepted that vascular endothelium regulates vasoconstriction via release of endothelium-derived relaxing factors (EDRF). The mesenteric circulation, which is the largest vascular bed, influences regulation of systemic blood pressure. However, the role of EDRF in the modulation of vascular tone in peripheral mesenteric circulation has not been extensively studied. Therefore, our recent studies investigated the role of the vascular endothelium in the regulation of methoxamine (alpha(1)-adrenoceptor agonist)-induced vasoconstriction and their age-related changes in rat mesenteric vascular beds. In mesenteric vascular beds with intact endothelium isolated from 8 week-old rats, the initial maximum vasoconstriction induced by continuous perfusion of methoxamine was time-dependently decreased during 3 hour-perfusion. Neither nitric oxide synthase inhibitor nor cyclooxygenase inhibitor altered this time-dependent reduction of methoxamine-induced vasoconstriction. Endothelium removal, K+-channel inhibitors and gap junction inhibitor significantly inhibited the time-dependent reduction of methoxamine-induced vasoconstriction. In the preparations with intact endothelium from 16 week-old rats, the time-dependent reduction of methoxamine-induced vasoconstriction disappeared. Furthermore, endothelium removal and treatment with cyclooxygenase inhibitor, thromboxane A(2) receptor antagonist or superoxide dismutase mimetic significantly reduced the methoxamine-induced vasoconstriction in the preparations from 16 week-old rats. These findings suggest that vascular endothelium acts to depress methoxamine-induced vasoconstriction by releasing endothelium-derived hyperpolarizing factor (EDHF), and dysfunction in this endothelial modulation develops with ageing.

DOI： 10.1248/yakushi.130.723

Altered function of nitrergic nerves inhibiting sympathetic neurotransmission in mesenteric vascular beds of renovascular hypertensive rats 査読

Toshihiro Koyama, Yukako Hatanaka, Xin Jin, Ayako Yokomizo, Hidetoshi Fujiwara, Mitsuhiro Goda, Narumi Hobara, Yoshito Zamami, Yoshihisa Kitamura, Hiromu Kawasaki

HYPERTENSION RESEARCH 33 ( 5 ) 485 - 491 2010年5月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Neuronal nitric oxide (NO) has been shown to modulate perivascular adrenergic neurotransmission by inhibiting noradrenaline release from terminals in rat mesenteric arteries. This study was conducted to investigate changes in the inhibitory function of NO-containing nerves (nitrergic nerves) in mesenteric vascular beds of 2-kidney, 1-clip renovascular hypertensive rats (2K1C-RHR). Rat mesenteric vascular beds without endothelium were perfused with Krebs solution and the perfusion pressure was measured. In preparations from sham-operated rats (control) and 2K1C-RHRs, vasoconstriction induced by periarterial nerve stimulation (PNS; 2-8 Hz), but not vasoconstriction induced by exogenously injected noradrenaline (0.5, 1.0 nmol), was markedly facilitated in the presence of a nonselective NO synthase (NOS) inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME) (100 mu M). The facilitatory effect of L-NAME in preparations from 2K1C-RHR was smaller than that in control preparations. L-NAME augmented PNS-evoked noradrenaline release, which was smaller in 2K1C-RHRs than in controls. The expression of neuronal NO synthase (nNOS) measured by western blotting in mesenteric arteries from 2K1C-RHRs was significantly decreased compared with control arteries. Immunohistochemical staining of mesenteric arteries showed dense innervation of nNOS-immunopositive nerves that was significantly smaller in arteries from 2K1C-RHR than that in control arteries. Mesenteric arteries were densely innervated by tyrosine hydroxylase-immunopositive nerves, which coalesced with nNOS-immunopositive nerves. These results suggest that the inhibitory function of nitrergic nerves in adrenergic neurotransmission is significantly decreased in 2K1C-RHRs. This functional alteration based on the decrease in nNOS expression and nitrergic innervation leads to enhanced adrenergic neurotransmission and contributes to the initiation and development of renovascular hypertension. Hypertension Research (2010) 33, 485-491; doi: 10.1038/hr.2010.48; published online 9 April 2010

DOI： 10.1038/hr.2010.48

R-(-)-alpha-Methylhistamine, a Histamine H-3 Receptor Agonist, Induces Endothelium-Dependent Vasodilation in Rat Mesenteric Resistance Arteries 査読

Pengyuan Sun, Xin Jin, Toshihiro Koyama, Simin Li, Yoshihisa Kitamura, Hiromu Kawasaki

BIOLOGICAL & PHARMACEUTICAL BULLETIN 33 ( 1 ) 58 - 63 2010年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PHARMACEUTICAL SOC JAPAN

A novel histamine receptor subtype, histamine H-3 receptor, mediates inhibition of peripheral autonomic neurotransmission. The present study was designed to examine vascular effects of histamine H-3 receptor by using a selective histamine H-3 receptor agonist, R-(-)-alpha methylhistamine (alpha-methylhistamine), in rat mesenteric resistance arteries. The isolated mesenteric vascular beds were perfused with Krebs solution and perfusion pressure was measured. Active tone was produced by perfusion of Krebs solution containing 7 mu M methoxamine. In preparations with intact endothelium, perfusion of alpha-methylhistamine (1-100 mu M) for 1 min produced a concentration-dependent vasodilation. The maximum vasodilation at the highest concentration was approximately 45%. This vasodilation was abolished by endothelium removal and attenuated by histamine H-3 receptor antagonists, thioperamide and clobenpropit, but not by chlorpheniramine (histamine H-1 receptor antagonist) and cimetidine (histamine H-2 receptor antagonist). N-omega-nitro-L-arginine methyl ester (L-NAME, nitric oxide (NO) synthase inhibitor), indomethacin (cyclooxygenase inhibitor) and tetraethylammonium (nonselective K+-channel blocker) and high KCl (30 mM) significantly inhibited alpha-methylhistamine-induced endothelium-dependent vasodilation. These findings suggest that alpha-methylhistamine induces endothelium-dependent vasodilation mainly via endothelium histamine H-3 receptors. It is also suggested that activation of histamine H-3 receptors in the endothelium releases mainly NO and partially prostaglandin I-2 and endothelium-derived hyperpolarizing factors to induce endothelium-dependent vasodilation.

DOI： 10.1248/bpb.33.58

Chronic hyperinsulinemia induces hypertension resulted from abnormal innervation of perivascular nerves in rat mesenteric resistance arteries 査読

Yoshito Zamami, Shingo Takatori, Nana Yabumae, Miho Hosoda, Toshihiro Koyama, Xin Jin, Narumi Hobara, Kenji Sasaki, Hiromu Kawasaki

JOURNAL OF PHARMACOLOGICAL SCIENCES 112 76P - 76P 2010年

Age-Related Disappearance of the Inhibitory Effect of Vascular Endothelium on Agonist-Induced Vasoconstriction in Rat Mesenteric Vascular Beds 査読

Xin Jin, Yukiko Satoh-Otonashi, Yoshito Zamami, Narumi Hobara, Toshihiro Koyama, Pengyuan Sun, Simin Li, Yoshihisa Kitamura, Hiromu Kawasaki

JOURNAL OF PHARMACOLOGICAL SCIENCES 111 ( 4 ) 372 - 380 2009年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAPANESE PHARMACOLOGICAL SOC

We previously reported that endothelium-derived hyperpolarizing factor (EDHF)mediated response time-dependently suppressed methoxamine-induced vasoconstriction in mesenteric vascular beds isolated from 8-week-old rats. We investigated age-related changes in endothelial regulation of methoxamine-induced vasoconstriction. Mesenteric vascular beds isolated from young (8-week-old) to adult (16-week-old) rats were perfused, and changes in perfusion pressure induced by continuous perfusion of methoxamine or high KCl (60 mM) were measured over 180 min. In young preparations with intact endothelium, methoxamine-induced vasoconstriction time-dependently decreased to 20% of the initial levels, while time-dependent reduction was not observed in adult preparations. High KCl-induced vasoconstriction in young and adult preparations did not show time-dependent reduction. Endothelium removal abolished time-dependent reduction of methoxamine-induced vasoconstriction in young preparations and significantly attenuated vasoconstriction in adult preparations. Indomethacin, seratrodast, or tempol but not catalase significantly reduced methoxamine-induced vasoconstriction in adult preparations with endothelium. A23187 (Ca(2+)-ionophore)-, but not acetylcholine-, induced endothelium-dependent vasodilation in the presence of N(G)-L-nitro arginine methyl ether in adult preparations was significantly smaller than that in young preparations. These findings suggest that the inhibitory effect of mesenteric vascular endothelium on methoxamine-induced vasoconstriction disappears with aging by reducing EDHF and increasing endothelium-derived contracting factors and reactive oxygen species.

DOI： 10.1254/jphs.09183FP

Proton Acts as a Neurotransmitter for Nicotine-Induced Adrenergic and Calcitonin Gene-Related Peptide-Containing Nerve-Mediated Vasodilation in the Rat Mesenteric Artery 査読

Hiromu Kawasaki, Shinji Eguchi, Satoko Miyashita, Shu Chan, Kazuhiro Hirai, Narumi Hobara, Ayako Yokomizo, Hidetoshi Fujiwara, Yoshito Zamami, Toshihiro Koyama, Xin Jin, Yoshihisa Kitamura

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 330 ( 3 ) 745 - 755 2009年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS

Nicotine stimulates presynaptic nicotinic acetylcholine receptors in perivascular adrenergic nerves and releases unknown transmitter(s) that activate transient receptor potential vanilloid-1 (TRPV1) located on calcitonin gene-related peptide (CGRP)-containing (CGRPergic) nerves, resulting in vasodilation. The present study investigated a potential transmitter transmitting between perivascular adrenergic nerves and CGRPergic nerves. Rat mesenteric vascular beds without endothelium were contracted by perfusion with Krebs' solution containing methoxamine, and the perfusion pressure and pH levels of the perfusate were measured. Nicotine perfusion for 1 min induced concentration-dependent vasodilation and lowered pH levels, which were abolished by cold-storage denervation of preparations, guanethidine (adrenergic neuron blocker), and mecamylamine (nicotinic alpha(3)beta(4)-acetylcholine receptor antagonist). Capsazepine (TRPV1 antagonist) blunted nicotine-induced vasodilation, but had no effect on the reduction of pH. Injection of hydrochloric acid (HCl) and perfusion of Krebs' solution at low pH (6.0-7.2) induced vasodilation. HCl-induced vasodilation was inhibited by cold-storage denervation, capsazepine, capsaicin (CGRP depletor), and CGRP(8 37) (CGRP receptor antagonist). Perfusion of adrenergic transmitter metabolites (normetanephrine and 3-methoxydopamine), but not of other metabolites, induced vasodilation, which was not inhibited by capsaicin treatment. Immunohistochemical staining of mesenteric arteries showed dense innervation of CGRP-and TRPV1-immunopositive nerves, with both immunostainings appearing in the same neuron. Mesenteric arteries were densely innervated by neuropeptide Y-immunopositive nerves, which coalesced with CGRP-immunopositive nerves. Scanning and immunoscanning electron microscopic images showed coalescence sites of different perivascular fibers before they intruded into smooth muscles. These results indicate that nicotine initially stimulates adrenergic nerves via nicotinic alpha(3)beta(4)-receptors to release protons and thereby induces CGRPergic nerve-mediated vasodilation via TRPV1.

DOI： 10.1124/jpet.108.149435

腎血管性高血圧における血管周囲神経の機能変化査読

小山敏広, 畑中由香子, 合田光寛, 座間味義人, 芳原成美, 川崎博己

薬学雑誌 129 ( 2 ) 185 - 189 2009年2月

Functional Alteration of Nervous System in Renovascular Hypertension 査読

Toshihiro Koyama, Yukako Hatanaka, Mitsuhiro Goda, Yoshito Zamami, Narumi Hobara, Hiromu Kawasaki

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN 129 ( 2 ) 185 - 189 2009年2月

担当区分：筆頭著者記述言語：日本語出版者・発行元：PHARMACEUTICAL SOC JAPAN

The role of nitric oxide (NO)-containing nerves in adrenergic neurotransmission in hypertension was studied in mesenteric resistance arteries without endothelium in 2-kidney-1-clip renal hypertensive rats (2K-1C RHR) and sham-operated normotensive rats (Sham-R). Mesenteric vascular beds isolated from 2K-1C RHR and Sham-R were perfused with Krebs solution and changes in perfusion pressure were measured with a pressure transducer. Perfusion of a NO synthase inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME), markedly augmented vasoconstrictor responses to periarterial nerve stimulation (PNS) without affecting vasoconstriction induced by exogenously injected noradrenaline. L-NAME significantly increased the neurogenic release of NA evoked by PNS in both 2K-1C RHR and Sham-R preparations. The facilitatory effect Of L-NAME based on the inhibition of NO production in 2K-1C RHR was less than that in Sham-R. These results Suggest that the function of NO-containing nerves, which presynaptically inhibit adrenergic neurotransmission, is decreased in the renovascular hypertensive model rat.

DOI： 10.1248/yakushi.129.185

Young Pharmacological Researchers Develop the Way to Drug Discovery Based on Interpretation of Diseases and Medicinal Assessment: The Way to Create New Drugs by Fields Interchange Foreword 査読

Toshihiro Koyama, Sokichi Honda

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN 129 ( 2 ) 183 - 183 2009年2月

Changes in neuronal regulation of vascular tone and its pathophysiological role in diabetic state 査読

Yoshito Zamami, Shingo Takatori, Yukiko Iwatani, Xin Jin, Toshihiro Koyama, Yoshihisa Kitamura, Hiromu Kawasaki

JOURNAL OF PHARMACOLOGICAL SCIENCES 109 25P - 25P 2009年

Royal jelly ameliorates insulin resistance in fructose-drinking rats. 査読

Yoshito Zamami, Shingo Takatori, Mitsuhiro Goda, Toshihiro Koyama, Yukiko Iwatani, Xin Jin, Shima Takai-Doi, Hiromu Kawasaki

Biological & pharmaceutical bulletin 31 ( 11 ) 2103 - 7 2008年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Royal jelly (RJ) is known to contain excellent nutrition and a variety of biological activities. The present study was designed to investigate the effects of RJ on insulin resistance (hyperinsulinemia) in fructose-drinking rats (FDR; insulin resistance animal model). Male Wistar rats (6 weeks old) received 15% fructose solution in drinking water for 8 weeks. FDR showed significant increases in plasma levels of insulin and triglyceride, Homeostasis Model Assessment ratio (HOMA-R, an index of insulin resistance), and systolic blood pressure, but not blood glucose levels, when compared with control rats. RJ (100, 300 mg/kg, p.o.) treatment for 8 weeks significantly decreased the plasma levels of insulin and triglyceride, HOMA-R, without affecting blood glucose or total cholesterol levels and tended to lower systolic blood pressure. In isolated and perfused mesenteric vascular beds of FDR, RJ treatment resulted in a significant reduction in sympathetic nerve-mediated vasoconstrictor response to periarterial nerve stimulation (PNS) and tended to increase the calcitonin gene-related peptide (CGRP) nerve-mediated vasodilator response to PNS, compared with those in untreated FDR. However, RJ treatment did not significantly affect norepinephrine-induced vasoconstriction or CGRP-induced vasodilation. These results suggest that RJ could be an effective functional food to prevent insulin resistance associated with the development of hypertension.

DOI： 10.1248/bpb.31.2103

A ketolide antibiotic, telithromycin, inhibits vascular adrenergic neurotransmission in the rat mesenteric vascular bed 査読

Y. Hatanaka, Y. Zamami, T. Koyama, N. Hobara, X. Jin, Y. Kitamura, H. Kawasaki

British Journal of Pharmacology 155 ( 6 ) 826 - 836 2008年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Background and purpose: A ketolide antibiotic, telithromycin, has side effects including temporary loss of consciousness in clinical use, but the underlying mechanisms remain unclear. This study investigated the effects of telithromycin on perivascular nerve function in rat mesenteric arteries, in comparison with those of macrolide (erythromycin and clarithromycin) and new quinolone antibiotics (levofloxacin and gatifloxacin). Experimental approach: In vitro, vascular responses and release of noradrenaline induced by periarterial nerve stimulation (PNS) of rat perfused mesenteric vascular beds were measured in the presence of each antibiotic. In vivo blood pressure measurement was performed in Wistar rats. Key results: In mesenteric preparations with resting tone, telithromycin (10 nM-10 μM) markedly inhibited PNS (4-12 Hz)-induced adrenergic nerve- and exogenous noradrenaline-mediated vasoconstriction, whereas the other antibiotics slightly inhibited PNS-induced responses without affecting noradrenaline-induced responses. Telithromycin significantly reduced PNS (12 Hz)-evoked noradrenaline release in the perfusate. In pre-constricted preparations with or without endothelium, telithromycin (0.1 nM-10 μM) caused a concentration-dependent vasodilation. Telithromycin (10 nM) inhibited calcium-induced vasoconstriction in high KCl and calcium-free medium. None of the antibiotics used affected PNS (0.5-2 Hz)-induced calcitonin gene-related peptide (CGRP) nerve- and exogenous CGRP-mediated vasodilation. Intravenous injection of telithromycin significantly lowered blood pressure in anaesthetized rats. Conclusions and implications: These results suggest that telithromycin causes not only strong inhibition of perivascular adrenergic neurotransmission but also a vasodilator action in mesenteric vascular beds and hypotension. It is thus possible that telithromycin increases visceral blood flow, consequently reducing cerebral blood flow and resulting in a temporary loss of consciousness. © 2008 Macmillan Publishers Limited All rights reserved.

DOI： 10.1038/bjp.2008.313

A ketolide antibiotic, telithromycin, inhibits vascular adrenergic neurotransmission in the rat mesenteric vascular bed 査読

Y. Hatanaka, Y. Zamami, T. Koyama, N. Hobara, X. Jin, Y. Kitamura, H. Kawasaki

BRITISH JOURNAL OF PHARMACOLOGY 155 ( 6 ) 826 - 836 2008年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-BLACKWELL

Background and purpose: A ketolide antibiotic, telithromycin, has side effects including temporary loss of consciousness in clinical use, but the underlying mechanisms remain unclear. This study investigated the effects of telithromycin on perivascular nerve function in rat mesenteric arteries, in comparison with those of macrolide (erythromycin and clarithromycin) and new quinolone antibiotics (levofloxacin and gatifloxacin).
Experimental approach: In vitro, vascular responses and release of noradrenaline induced by periarterial nerve stimulation (PNS) of rat perfused mesenteric vascular beds were measured in the presence of each antibiotic. In vivo blood pressure measurement was performed in Wistar rats.
Key results: In mesenteric preparations with resting tone, telithromycin (10 nM-10 mu M) markedly inhibited PNS (4 -12 Hz)-induced adrenergic nerve- and exogenous noradrenaline-mediated vasoconstriction, whereas the other antibiotics slightly inhibited PNS-induced responses without affecting noradrenaline-induced responses. Telithromycin significantly reduced PNS (12Hz)-evoked noradrenaline release in the perfusate. In pre-constricted preparations with or without endothelium, telithromycin (0.1 nM-10 mu M) caused a concentration-dependent vasodilation. Telithromycin (10 nM) inhibited calcium-induced vasoconstriction in high KCl and calcium-free medium. None of the antibiotics used affected PNS (0.5-2 Hz)-induced calcitonin gene-related peptide (CGRP) nerve- and exogenous CGRP-mediated vasodilation. Intravenous injection of telithromycin significantly lowered blood pressure in anaesthetized rats.
Conclusions and implications: These results suggest that telithromycin causes not only strong inhibition of perivascular adrenergic neurotransmission but also a vasodilator action in mesenteric vascular beds and hypotension. It is thus possible that telithromycin increases visceral blood flow, consequently reducing cerebral blood flow and resulting in a temporary loss of consciousness.

DOI： 10.1038/bjp.2008.313

Characterization of the inhibitory effect of vascular endothelium on agonist-induced vasoconstriction in rat mesenteric resistance arteries 査読

Xin Jin, Yukiko Satoh-Otonashi, Yoshito Zamami, Toshihiro Koyama, Pengyuan Sun, Yoshihisa Kitamura, Hiromu Kawasaki

JOURNAL OF PHARMACOLOGICAL SCIENCES 108 ( 1 ) 95 - 103 2008年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAPANESE PHARMACOLOGICAL SOC

Vascular endothelium regulates vascular tone by releasing endothelium-derived vasoactive substances. We performed this study to characterize the Inhibitory effect of the endothelium on vasoconstrictor stimuli in rat mesenteric vascular beds. Changes in perfusion pressure induced by continuous perfusion of Krebs solution containing methoxamine (alpha(1)-adrenoceptor agonist) or high KCl were measured over 180 min. In preparations with intact endothelium, methoxamine-Induced vasoconstriction was time-dependently decreased to cause 60%-80% reduction of the initial vasoconstriction level, while no reduction was observed in high-KCl-induced vasoconstriction. Endothelium removal significantly blunted the time-dependent reduction of methoxamine-induced vasoconstriction without affecting high-KCl-induced vasoconstriction. Neither a nitric oxide synthase inhibitor (L-NAME) nor indomethacin (cyclooxygenase inhibitor) altered the time-dependent reduction of vasoconstriction. High KCl, K+-channel inhibitors tetraethylammonium and apamin plus charybdotoxin, and 18 alpha-glycyrrhetinic acid (18 alpha-GA, a gap-junction inhibitor) significantly inhibited the time-dependent reduction of methoxamine-induced vasoconstriction. In preconstricted preparations, bolus injection of acetylcholine and Ca2+-ionophore A23187 (A23187) evoked a sharp vasodilation, which was inhibited by endothelium removal, high KCl and tetraethylammonium, but not indomethacin, L-NAME, or 18 alpha-GA. However, 18 alpha-GA plus L-NAME inhibited vasodilation induced by A23187, but not acetylcholine. These findings suggest that endothelium-derived hyperpolarizing factor (EDHF) via gap junctions mainly counteracts vasoconstriction induced by methoxamine in mesenteric resistance arteries.

DOI： 10.1254/jphs.08115FP

若手薬理研究者が展開する病態解明と薬効評価による創薬へのアプローチ領域を超えた交流から広がる創薬への道腎血管性高血圧ラット腸間膜動脈における血管周囲一酸化窒素含有神経の機能変化

小山敏広, 畑中由香子, 合田光寛, 芳原成美, 高山房子, 川崎博己

日本薬学会年会要旨集 128年会 ( 1 ) 249 - 249 2008年3月

腎性高血圧ラット腸間膜動脈における血管周囲一酸化窒素含有神経機能変化

小山敏広, 庄司知世, 畑中由香子, 合田光寛, 芳原成美, 高山房子, 川崎博己

日本薬理学雑誌 131 ( 3 ) 25p - 25p 2008年3月

[Effect of propolis on insulin resistance in fructose-drinking rats]. 査読

Yoshito Zamami, Shingo Takatori, Toshihiro Koyama, Mitsuhiro Goda, Yukiko Iwatani, Shima Doi, Hiromu Kawasaki

Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan 127 ( 12 ) 2065 - 73 2007年12月

記述言語：日本語掲載種別：研究論文（学術雑誌）

Propolis, a honeybee product, contains a variety of biologically active substances. The present study was designed to investigate the effects of propolis on insulin resistance induced by fructose-drinking rats (FDR; type 2 diabetic animal model). Male Wistar rats (6 weeks old) received 15% fructose solution in drinking water for 8 weeks. FDR showed significant increases in plasma levels of insulin, Homeostasis Model Assessment ratio (HOMA-R, an index of insulin resistance), body weight, and systolic blood pressure but not blood glucose levels, when compared with control rats. Brazilian propolis extract (100 and 300 mg/kg, p.o.) treatment for 8 weeks significantly decreased the plasma level of insulin, HOMA-R, and body weight, increased plasma triglyceride levels without affecting blood glucose and total cholesterol levels, and tended to decrease systolic blood pressure. In isolated and perfused mesenteric vascular beds of FDR, propolis treatment resulted in a significant reduction of sympathetic nerve-mediated vasoconstrictor response to periarterial nerve stimulation (PNS; 8 Hz) and tended to increase the calcitonin gene-related peptide (CGRP) nerve-mediated vasodilator response to PNS, compared with those in untreated FDR. However, propolis treatment did not significantly affect norepinephrine-induced vasoconstriction and CGRP-induced vasodilation. These results suggest that propolis could be an effective functional food to prevent the development of insulin resistance.

DOI： 10.1248/yakushi.127.2065

高血圧モデルラットの腸間膜動脈における一酸化窒素含有神経の血管緊張度調節における機能変化

小山敏広, 庄司知世, 畑中由香子, 合田光寛, 芳原成美, 高山房子, 川崎博己

日本薬理学雑誌 129 ( 2 ) 32P - 32P 2007年2月

2-Kidney,1-Clip(2K-1C)高血圧ラット腸間膜動脈における一酸化窒素(NO)含有神経による血管緊張度調節機能の減弱

小山敏広, 庄司知世, 畑中由香子, 合田光寛, 芳原成美, 高山房子, 川崎博己

血管 30 ( 1 ) 28 - 28 2007年1月

ワルファリンを用いた抗凝固療法中の血液凝固能における季節変化の影響

小山敏広, 森英樹, 高山房子, 川崎博己, 柴田和彦, 五味田裕, 出石文男

日本薬学会年会要旨集 126年会 ( 2 ) 192 - 192 2006年3月

Histamine-induced vasodilation and vasoconstriction in the mesenteric resistance artery of the rat 査読

H Jin, T Koyama, Y Hatanaka, S Akiyama, F Takayama, H Kawasaki

EUROPEAN JOURNAL OF PHARMACOLOGY 529 ( 1-3 ) 136 - 144 2006年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCIENCE BV

The present study was designed to examine the vascular response to histamine in rat perfused mesenteric vascular beds with active tone. In preparations with intact endothelium, perfusion of histamine (1 nM-100 mu M) produced a concentration-dependent vasodilation. Histamine-induced vasodilation was attenuated by L-NAME (nitric oxide (NO) synthase inhibitor, 100 mu M) and olopatadine (histamine H, receptor antagonist, 1 mu M) but not by laftitidine (histamine H-2 receptor antagonist, 1 mu M). Cold-storage denervation (4 degrees C for 72 h) of the preparation with intact endothelium attenuated the histamine-induced vasodilation. In preparations without endothelium, histamine at low concentrations (1-100 nM) produced only a small and rapid vasodilation, whereas histamine at concentrations higher than 1 mu M produced triphasic vascular responses: initial sharp vasodilation followed by transient vasoconstriction and subsequent gradual vasodilation. Lafutidine abolished only the histamine-induced initial vasodilation. Olopatadine abolished the histamine-induced second vasoconstriction and third vasodilation. Cold-storage denervation of the denuded preparation abolished the histamine-induced second vasoconstriction and third vasodilation. These findings suggest that histamine induced endothelium-dependent vasodilation via endothelium histamine H-1 receptors and endothelium-independent vasodilation via smooth muscle histamine H-2 receptors. It is also suggested that the histamine-induced endothelium-independent vasoconstriction and vasodilation are mediated by histamine H-1 receptors and perivascular nerves. (c) 2005 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ejphar.2005.10.060

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