研究者詳細 - 座間味　義人

論文 - 座間味　義人

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Incidence of Myocarditis Caused by Drugs Used for Ulcerative Colitis as Examined Using VigiBase, a Spontaneous Adverse Drug Reaction Reporting Database

Yumi Kawai, Yasuko Kurata, Hirofumi Hamano, Takahiro Niimura, Mitsuhiro Goda, Yoshito Zamami, Keisuke Ishizawa, Hideki Nawa

Biological and Pharmaceutical Bulletin 48 ( 4 ) 383 - 389 2025年4月

Incidence and survival outcomes of myocarditis and pericardial diseases associated with immune checkpoint inhibitor therapy. 国際誌

Aya F Ozaki, Michael Sayer, Hirofumi Hamano, Misako Nagasaka, Benjamin J Lee, Jean Doh, Ali Naqvi, Nareh Nowrouzi, Yoshito Zamami, Pranav M Patel

Cardio-oncology (London, England) 11 ( 1 ) 26 - 26 2025年3月

記述言語：英語

INTRODUCTION: Immune checkpoint inhibitor(ICI) induced cardiac immune related adverse events are challenging to study; Leveraging large data bases like TriNetX global health network may provide needed insights. METHODS: We performed a retrospective cohort study including patients diagnosed neoplasm and 18 and older when receiving ICI therapy from 1/1/2011 to 12/31/2022. Queried ICD 9/10 codes identified patients experiencing myocarditis, pericarditis, pericardial effusion, and cardiac tamponade within 1 year of ICI initiation. Survival analyses compared one-year overall survival (OS) of patients experiencing cardiac irAEs against propensity score matched populations not experiencing them. RESULTS: In 88,928 identified ICI patients, the incidence of myocarditis(0.48%), pericarditis(0.22%), and cardiac tamponade(0.47%) were less than 1% while pericardial effusion occurred in 4.71% of patients. Hazard ratios (HRs) were significantly higher in all cardiac irAE groups: myocarditis (HR:1.26, 95% CI:1.04-1.54, p = 0.02), pericarditis (HR:1.36, 95% CI:1.02-1.82, p = 0.04), pericardial effusion (HR:1.49, 95% CI:1.39-1.59, p < 0.0001), cardiac tamponade (HR:2.15, 95% CI:1.79-2.57, p < 0.0001), and overall pericardial disease (HR:1.46, 95% CI:1.37-1.56, p < 0.0001). There was no significant difference in OS between myocarditis and pericarditis or overall pericardial diseases. DISCUSSION/CONCLUSION: Utilizing a uniquely large cohort of ICI patients, this study further shows the rarity of cardiac inflammatory irAEs and highlights their significant impact on patient survival.

DOI： 10.1186/s40959-025-00300-1

Evaluation of Interstitial Lung Disease Complications Caused by Biologic Agents Using a Spontaneous Adverse Drug Reaction Reporting Database 国際誌

Ayu Minagi, Hideki Nawa, Mitsuhiro Goda, Takahiro Niimura, Koji Miyata, Hirofumi Hamano, Yoshito Zamami, Keisuke Ishizawa

Pharmacology Research & Perspectives 13 ( 2 ) e70063 2025年2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

ABSTRACT

Interstitial lung disease (ILD) is a clinically relevant adverse event associated with biologic agent use. However, the current incidence of ILD remains unclear as large‐scale risk assessments of biologic agents have not been conducted. The aim of this study was to clarify the association between biologic agent use and ILD development in clinical practice by detecting adverse event signals using a spontaneous adverse drug reaction database. The VigiBase database is used for spontaneous adverse event reporting. The analysis focused on nine biologics used to treat psoriasis, rheumatoid arthritis, and Crohn's disease. The safety of each biologic agent was evaluated using the information component signal detection method. There were 32,520,983 reports in VigiBase, of which 68,489 (0.21%) were for ILD. Signals were mainly detected for tumor necrosis factor‐α inhibitors when the information component for ILD caused by biologic agents was calculated. Comorbidity analysis in patients who developed ILD and analysis of the time from the start of treatment with each drug to ILD onset showed differences for each biologic agent. ILD is a serious adverse effect of biologic agents, and there are several cases in which a causal relationship with ILD development cannot be ruled out. The occurrence of interstitial ILD should be noted when using biologics, particularly TNF‐α inhibitors.

DOI： 10.1002/prp2.70063

Photoinitiators Induce Histamine Production in Human Mast Cells.

Taro Miura, Yoichi Kawasaki, Hirofumi Hamano, Yoshito Zamami, Toshiaki Sendo

Acta medica Okayama 79 ( 1 ) 51 - 58 2025年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Photoinitiators are used in the manufacture of many daily products, and may produce harmful effects due to their cytotoxicity. They have also been detected in human serum. Here, we investigated the histamine-producing effects in HMC-1 cells and the inflammatory cytokine release effects in RAW264 cells for four photoinitiators: 1-hydroxycyclohexyl phenyl ketone; 2-isopropylthioxanthone; methyl 2-benzoylbenzoate; and 2-methyl-4´-(methylthio)-2-morpholinopropiophenone. All four promoted histamine production in HMC-1 cells; however, they did not significantly affect the release of inflammatory cytokines in RAW264 cells. These findings suggest that these four photoinitiators induce inflammatory cytokine-independent histamine production, potentially contributing to histamine-mediated chronic inflammation in vitro.

DOI： 10.18926/AMO/68362

Authors' Reply to Noguchi et al. Comment on: "Differences in the Adverse Event Profiles of Sodium-Glucose Cotransporter 2 Inhibitors Used in Patients with Diabetes and Heart Failure: An Analysis Using the Japanese Adverse Drug Event Report Database". 国際誌

Toshiaki Sakamoto, Hirotaka Miyamoto, Junya Hashizume, Hayato Akamatsu, Tomoaki Akagi, Yukinobu Kodama, Hirofumi Hamano, Yoshito Zamami, Kaname Ohyama

Clinical drug investigation 45 ( 1 ) 47 - 49 2024年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND AND OBJECTIVES: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have recently become a standard treatment for heart failure and renal failure. The number of patients using these drugs is expected to increase further. However, no adverse drug event profiles have been published for the use of SGLT2i in patients without diabetes. To analyze and clarify the differences in adverse event profiles associated with the use of SGLT2i in patients with diabetes or heart failure using the Japanese Adverse Drug Event Report (JADER) database, a Japanese reporting system for adverse events. METHODS: The JADER database, containing reports submitted between April 2004 and January 2024, was used. Our study focused on patients with diabetes or heart failure, analyzing adverse events associated with empagliflozin and dapagliflozin. The reporting odds ratio (ROR) and 95% confidence interval (CI) were calculated for signal detection. RESULTS: We identified risks of adverse drug events such as ketoacidosis, urinary tract infection, dehydration, and acidosis in both patient groups. However, the risks of cerebral infarction and ischemic heart disease were identified only in patients with diabetes, while risks of renal dysfunction, hypoglycemia, and sepsis were identified only in those with heart failure. CONCLUSION: Adverse events should be managed appropriately for patients using SGLT2i, as the adverse event profiles differ between those with diabetes and those with heart failure. Understanding these differences is crucial for improving patient safety and optimizing treatment outcomes.

DOI： 10.1007/s40261-024-01414-7

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

ためになる薬の話薬物相互作用(がん悪液質治療薬の相互作用)

川上英治, 奥田浩人, 濱野裕章, 座間味義人

岡山医学会雑誌 136 ( 3 ) 135 - 138 2024年12月

Evaluating the impact of loperamide on irinotecan-induced adverse events: a disproportionality analysis of data from the World Health Organization pharmacovigilance database (VigiBase) 国際誌

Tomoaki Akagi, Hirofumi Hamano, Hirotaka Miyamoto, Tatsuaki Takeda, Yoshito Zamami, Kaname Ohyama

European Journal of Clinical Pharmacology 81 ( 1 ) 129 - 137 2024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：Springer Science and Business Media LLC

PURPOSE: SN-38, the active metabolite of irinotecan, may cause adverse events necessitating treatment discontinuation and management. Diarrhea, which is treated with loperamide, is one such event. However, loperamide may delay SN-38 elimination, causing more adverse events. Therefore, understanding the adverse events caused by symptomatic drugs is crucial for safe drug therapy. This study aimed to assess the association between loperamide and irinotecan-induced adverse events. METHODS: We analyzed data up to December 2022 from VigiBase, the World Health Organization's adverse event database. The study used reporting odds ratios (RORs) to evaluate the associations between concomitant medications and irinotecan-induced adverse events. Fisher's exact probability test was used to analyze the adverse events. Logistic regression analysis was performed to identify associated adverse event signals. RESULTS: Of the 32,520,983 cases analyzed, 57,454 involved the use of irinotecan. Among these, 1589 (2.8%) patients were co-treated with loperamide. Signals for neutropenia (ROR 1.37, 95% confidence interval (CI) 1.20-1.57, p < 0.001), anemia (ROR 1.81, 95% CI 1.43-2.30, p < 0.001), and alopecia (ROR 1.89, 95% CI 1.30-2.74, p < 0.01) were detected with concomitant loperamide. Multivariate logistic regression analysis confirmed that concomitant loperamide use was associated with signals for neutropenia, anemia, and alopecia. CONCLUSION: Our results suggest that loperamide increases the risk of irinotecan-induced adverse events and enhances irinotecan toxicity. The study methodology may be useful for predicting adverse event risk when choosing symptomatic therapy drugs during irinotecan use.

DOI： 10.1007/s00228-024-03767-6

その他リンク： https://link.springer.com/article/10.1007/s00228-024-03767-6/fulltext.html

Differences in the Adverse Event Profiles of Sodium-Glucose Cotransporter 2 Inhibitors used in Patients with Diabetes Mellitus and Heart Failure: An Analysis Using the Japanese Adverse Drug Event Report Database. 国際誌

Toshiaki Sakamoto, Hirotaka Miyamoto, Junya Hashizume, Hayato Akamatsu, Tomoaki Akagi, Yukinobu Kodama, Hirofumi Hamano, Yoshito Zamami, Kaname Ohyama

Clinical drug investigation 44 ( 10 ) 761 - 771 2024年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND AND OBJECTIVES: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have recently become a standard treatment for heart failure and renal failure. The number of patients using these drugs is expected to increase further. However, no adverse drug event profiles have been published for the use of SGLT2i in patients without diabetes. To analyze and clarify the differences in adverse event profiles associated with the use of SGLT2i in patients with diabetes or heart failure using the Japanese Adverse Drug Event Report (JADER) database, a Japanese reporting system for adverse events. METHODS: The JADER database, containing reports submitted between April 2004 and January 2024, was used. Our study focused on patients with diabetes or heart failure, analyzing adverse events associated with empagliflozin and dapagliflozin. The reporting odds ratio (ROR) and 95% confidence interval (CI) were calculated for signal detection. RESULTS: We identified risks of adverse drug events such as ketoacidosis, urinary tract infection, dehydration, and acidosis in both patient groups. However, the risks of cerebral infarction and ischemic heart disease were identified only in patients with diabetes, while risks of renal dysfunction, hypoglycemia, and sepsis were identified only in those with heart failure. CONCLUSION: Adverse events should be managed appropriately for patients using SGLT2i, as the adverse event profiles differ between those with diabetes and those with heart failure. Understanding these differences is crucial for improving patient safety and optimizing treatment outcomes.

DOI： 10.1007/s40261-024-01394-8

Assessing the effects of interprofessional education by hospital pharmacists on pharmaceutical students using a self-evaluation scale. 国際誌

Fuka Aizawa, Hirofumi Hamano, Naoto Okada, Kenta Yagi, Mitsuhiro Goda, Hideki Nawa, Yuya Horinouchi, Toshimi Nakamura, Harumasa Hakuno, Kazuaki Shinomiya, Yoshito Zamami, Masahiko Azuma, Masashi Akaike, Keisuke Ishizawa

Journal of pharmaceutical health care and sciences 10 ( 1 ) 61 - 61 2024年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Understanding the roles and competencies of professions outside of one's specialty is essential for providing efficient healthcare. However, it is difficult for medical professionals to understand the roles and competencies of other related professions while performing their duties. This study examined the impact of clinical practice-based interprofessional education (IPE) on pharmacy students, who are future medical professionals. METHODS: Sixty-eight pharmaceutical students undergoing clinical practice were divided into non-IPE or IPE groups, with the IPE group attending an educational program with medical students conducted by doctors, pharmacists, and teachers during the clinical practice period. The effect was evaluated through a group survey using self-administered questionnaires focusing on contributing to multidisciplinary team medicine based on the Readiness for Interprofessional Learning Scale. The survey included specific behavioral objectives (SBOs), the Readiness for Interpersonal Learning Scale (RIPLS), and Kikuchi's Scale of Social Skills (KiSS-18). RESULTS: Regardless of group, SBOs [non-IPE: 3.2, 95% CI (2.6-3.8), p < 0.001; IPE: 3.7, 95% CI (2.5-4.9), p < 0.001] and social skills [non-IPE: 4.0, 95% CI (2.5-6.1), p < 0.001; IPE: 6.7 95% CI (3.0-10.4), p < 0.001] showed improvement after the clinical practice. In RIPLS Factor 3, pharmacy students with IPE awareness scored significantly higher by 1.5 points [95% CI (0.2-2.8), p = 0.025] post-practice than those without IPE awareness. CONCLUSIONS: This study suggests that IPE for students during clinical practice could enhance their expertise in multidisciplinary medicine and facilitate the development of seamless team care in the future. TRIAL REGISTRATION: This study was retrospectively registered and conducted in compliance with the "Ethical Guidelines for Medical Research Involving Human Subjects" and was approved by The Ethics Committee of Tokushima University Hospital (approval number: 3544).

DOI： 10.1186/s40780-024-00382-6

Statins ameliorate oxaliplatin- and paclitaxel-induced peripheral neuropathy via glutathione-S-transferase. 国際誌

Fuka Aizawa, Haruna Kajimoto, Ami Okabayashi, Daishi Moriyama, Kenta Yagi, Shimon Takahashi, Yuhei Sonoda, Takahiro Shibata, Mitsuhiro Goda, Takahiro Niimura, Yuki Izawa-Ishizawa, Hirofumi Hamano, Kei Kawada, Yoshito Zamami, Keisuke Ishizawa

Neurochemistry international 180 105863 - 105863 2024年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Some therapeutic agents have been found to have effects beyond their primary indications. Peripheral neuropathy, a common side effect of chemotherapy, remains inadequately treated. Identifying additional properties of existing medications could thus uncover novel therapeutic avenues. Previous studies have identified an additional effect of simvastatin in reducing neuropathy; however, the mechanism underlying this effect remains unclear. We investigated the novel effects of statins on chemotherapy-induced peripheral neuropathy in mice. Mice treated with oxaliplatin or paclitaxel did not show exacerbation or improvement in cold sensations upon acetone testing with statin administration. However, concurrent oral statin treatment mitigated the nociceptive response to mechanical stimuli induced by each anti-tumor agent. Co-administration of a glutathione-S-transferase inhibitor, which modulates redox reactions, abolished the ameliorative effect of statins on mechanical nociceptive behavior. Additionally, the glutathione-S-transferase inhibitor did not affect normal sensory perception or impair the anti-tumor effect of chemotherapy agents. A search for GST-associated molecules and pathways using artificial intelligence revealed that GST regulates inflammatory cytokines as a regulatory or causative gene. Our findings suggest that statins have class effects that ameliorate cytotoxic anti-cancer drug-induced mechanical allodynia via GST pathway activation.

DOI： 10.1016/j.neuint.2024.105863

Unveiling the association between fluoroquinolones and aortic diseases using real-world database analysis and pharmacological experiments. 査読国際誌

Koji Miyata, Yuki Izawa-Ishizawa, Kaito Tsujinaka, Honoka Nishi, Syuto Itokazu, Tatsumi Miyata, Masateru Kondo, Toshihiko Yoshioka, Takahiro Niimura, Fuka Aizawa, Kenta Yagi, Maki Sato, Mizusa Hyodo, Hirofumi Hamano, Kei Kawada, Masayuki Chuma, Yoshito Zamami, Koichi Tsuneyama, Mitsuhiro Goda, Keisuke Ishizawa

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 179 117418 - 117418 2024年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Fluoroquinolones, which are widely used antibiotics, have been linked to aortic disease, which prompted an FDA warning in 2018. Recent reports have challenged the perception that fluoroquinolones pose a significant risk for vascular diseases. This study aimed to investigate whether fluoroquinolones increase the risk of aortic diseases by focusing on the onset of aortic dissection. Levofloxacin (LVFX), a fluoroquinolone, was studied in vitro using cultured vascular cells and in vivo using a mouse model prone to aortic dissection. Risk of adverse drug events was analyzed using VigiBase, a global safety database, and a retrospective cohort analysis was conducted using the JMDC Claims database. LVFX resulted in endothelial cell injury and increased matrix metalloproteinases in vitro. However, in vivo studies showed no significant effect on elastin degradation or aortic dissection incidence. The effect of LVFX on endothelial injury was altered during the onset of dissection, exacerbating injury before onset but inhibiting it afterward. Safety database analysis showed no significant risk signals for aortic dissection associated with fluoroquinolones, which was supported by findings in the receipt database. Inconsistencies were observed in the in vitro and in vivo actions of fluoroquinolones and differences in their effects on aortic dissection and aneurysms. Despite cytotoxicity, the risk of aortic dissection was not significantly increased in clinical scenarios. Based on our findings, concerns regarding aortic diseases do not justify discontinuation of fluoroquinolone use. Further studies are needed to elucidate the conflicting actions of fluoroquinolones, taking into account background pathophysiology such as infection and inflammation.

DOI： 10.1016/j.biopha.2024.117418

Ameliorating effect of chotosan and its active component, Uncaria hook, on lipopolysaccharide-induced anxiety-like behavior in mice 査読国際誌

Yasumasa Okawa, Soichiro Ushio, Yasuhisa Izushi, Yoshihisa Kitamura, Yoshito Zamami, Toshiaki Sendo

Frontiers in Pharmacology 15 1471602 - 1471602 2024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：Frontiers Media SA

Introduction

In this study, we aimed to examine the effects of chotosan, a traditional Japanese botanical drug, and its active component, Uncaria hook, on anxiety-like behaviors induced by systemic inflammation in mice.

Methods

To induce systemic inflammation, the mice were treated with lipopolysaccharide (LPS), a bacterial endotoxin. Prior to LPS treatment, the mice were administered chotosan or Uncaria hook orally each day for 14 days. Anxiety-like behavior of the mice was evaluated using the light–dark test 24 h after LPS treatment.

Results

Repeated administration of chotosan prevented anxiety-like behavior in both normal and LPS-treated mice. Similarly, administration of Uncaria hook suppressed LPS-induced anxiety-like behavior in mice. Furthermore, treatment with tandospirone, a 5-HT_1A receptor agonist, alleviated anxiety-like behavior in mice, whereas treatment with DOI, a 5-HT_2A receptor agonist, enhanced anxiety-like behavior in mice. LPS treatment significantly increased serotonin (5-HT)_2A receptor mRNA expression in the frontal cortex, whereas 5-HT_1A receptor mRNA expression remained unchanged in the hippocampus. Notably, chotosan significantly suppressed the mRNA expression of 5-HT_2A receptor.

Discussion

These findings indicate that chotosan exerts anxiolytic-like effects in the context of inflammation-induced anxiety, potentially mediated by the inhibition of 5-HT_2A receptor hyperfunction in LPS-treated mice. Consequently, we postulate that chotosan may be effective in managing inflammation-induced anxiety-like behaviors.

DOI： 10.3389/fphar.2024.1471602

ためになる薬の話薬物相互作用(60-慢性疼痛治療薬の薬物相互作用)

高橋徹多, 東恩納司, 濱野裕章, 座間味義人

岡山医学会雑誌 136 ( 2 ) 80 - 82 2024年8月

mRNAワクチン

田中雄太, 座間味義人

岡山医学会雑誌 136 ( 2 ) 83 - 84 2024年8月

ためになる薬の話薬物相互作用(60-慢性疼痛治療薬の薬物相互作用)

高橋徹多, 東恩納司, 濱野裕章, 座間味義人

岡山医学会雑誌 136 ( 2 ) 80 - 82 2024年8月

A network-based trans-omics approach for predicting synergistic drug combinations. 査読国際誌

Midori Iida, Yurika Kuniki, Kenta Yagi, Mitsuhiro Goda, Satoko Namba, Jun-Ichi Takeshita, Ryusuke Sawada, Michio Iwata, Yoshito Zamami, Keisuke Ishizawa, Yoshihiro Yamanishi

Communications medicine 4 ( 1 ) 154 - 154 2024年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Combination therapy can offer greater efficacy on medical treatments. However, the discovery of synergistic drug combinations is challenging. We propose a novel computational method, SyndrumNET, to predict synergistic drug combinations by network propagation with trans-omics analyses. METHODS: The prediction is based on the topological relationship, network-based proximity, and transcriptional correlation between diseases and drugs. SyndrumNET was applied to analyzing six diseases including asthma, diabetes, hypertension, colorectal cancer, acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). RESULTS: Here we show that SyndrumNET outperforms the previous methods in terms of high accuracy. We perform in vitro cell survival assays to validate our prediction for CML. Of the top 17 predicted drug pairs, 14 drug pairs successfully exhibits synergistic anticancer effects. Our mode-of-action analysis also reveals that the drug synergy of the top predicted combination of capsaicin and mitoxantrone is due to the complementary regulation of 12 pathways, including the Rap1 signaling pathway. CONCLUSIONS: The proposed method is expected to be useful for discovering synergistic drug combinations for various complex diseases.

DOI： 10.1038/s43856-024-00571-2

レセプトデータを用いたダサチニブの有効性・安全性に胃酸分泌抑制薬が及ぼす影響の評価

亀沖真希, 牛尾聡一郎, 佐田光, 建部泰尚, 濱野裕章, 座間味義人

The Journal of Toxicological Sciences 49 ( Suppl. ) S128 - S129 2024年7月

COVID-19ワクチン接種後の小児の心筋炎リスクに関する大規模研究

東さくら, 濱野裕章, 座間味義人

The Journal of Toxicological Sciences 49 ( Suppl. ) S125 - S125 2024年7月

大規模データベースを用いたチロシンキナーゼ阻害剤による心臓毒性リスクの評価

井川祐輔, 江角悟, 武田達明, 濱野裕章, 鍛治園誠, 西原茂樹, 村川公央, 座間味義人

The Journal of Toxicological Sciences 49 ( Suppl. ) S90 - S90 2024年7月

免疫チェックポイント阻害薬誘発心筋炎の発症予測モデルの構築

山元黎奈, 濱野裕章, 中込昂希, 座間味義人, 上原孝

The Journal of Toxicological Sciences 49 ( Suppl. ) S126 - S127 2024年7月

Effect of Lipopolysaccharide on the Duration of Zolpidem-Induced Loss of Righting Reflex in Mice. 査読

Yudai Wada, Soichiro Ushio, Yoshihisa Kitamura, Yoshito Zamami, Toshiaki Sendo

Acta medica Okayama 78 ( 3 ) 227 - 235 2024年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Zolpidem, a non-benzodiazepine hypnotic, is primarily used to treat insomnia. In a previous study, pior treatment with non-benzodiazepine receptor agonists was associated with inflammation. The present study aimed to clarify the association between the effects of zolpidem and inflammation in mice treated with lipopolysaccharide (LPS), a known model of inflammation. We assessed the zolpidem-induced loss of righting reflex (LORR) duration 24 h after LPS treatment in mice. Additionally, the expressions of γ-aminobutyric acid (GABA)A receptor subunit and K+-Cl- cotransporter isoform 2 (KCC2) mRNA in the hippocampus and frontal cortex were examined in LPS-treated mice. Pretreatment with LPS was associated with significantly prolonged duration of zolpidem-induced LORR compared to control mice. This effect was significantly attenuated by administering bicuculline, a GABAA receptor antagonist, or flumazenil, a benzodiazepine receptor antagonist, in LPS-treated mice. Compared to controls, LPS-treated mice showed no significant change in the expression of GABAA receptor subunits in the hippocampus or frontal cortex. Bumetanide, an Na+-K+-2Cl- cotransporter isoform 1 blocker, attenuated the extended duration of zolpidem-induced LORR observed in LPS-treated mice. LPS significantly decreased Kcc2 mRNA expression in the hippocampus and the frontal cortex. These findings suggest that inflammation increases zolpidem-induced LORR, possibly through a reduction in KCC2 expression.

DOI： 10.18926/AMO/67197

医薬品供給問題が採用医薬品に与える影響に関する調査後発医薬品の使用促進および代替薬の確保の点から

槇田崇志, 佐田光, 田中雄太, 濱野裕章, 西原茂樹, 村川公央, 座間味義人

ジェネリック研究 ( 第18回学術大会要旨集 ) 65 - 65 2024年5月

薬剤師による探索的アプローチの実際～CQからRQへの変換と試験の組み立て方～小児がん治療における探求的アプローチ

岩田直大, 蔵田靖子, 田中雄太, 濱野裕章, 鍛治園誠, 座間味義人

日本臨床腫瘍薬学会雑誌 36 72 - 72 2024年5月

薬剤師による探索的アプローチの実際～CQからRQへの変換と試験の組み立て方～小児がん治療における探求的アプローチ

岩田直大, 蔵田靖子, 田中雄太, 濱野裕章, 鍛治園誠, 座間味義人

日本臨床腫瘍薬学会雑誌 36 72 - 72 2024年5月

副作用報告データベースを用いたベバシズマブのバイオシミラーの安全性に関する検討

槇田崇志, 藤井緑, 濱野裕章, 座間味義人

日本医薬品情報学会総会・学術大会講演要旨集 26回 132 - 132 2024年5月

医薬品供給問題が採用医薬品に与える影響に関する調査後発医薬品の使用促進および代替薬の確保の点から

槇田崇志, 佐田光, 田中雄太, 濱野裕章, 西原茂樹, 村川公央, 座間味義人

ジェネリック研究 ( 第18回学術大会要旨集 ) 65 - 65 2024年5月

薬剤師による探索的アプローチの実際～CQからRQへの変換と試験の組み立て方～医療データ解析を起点とした臨床研究の実践

新村貴博, 八木健太, 相澤風花, 石澤有紀, 濱野裕章, 合田光寛, 座間味義人, 石澤啓介

日本臨床腫瘍薬学会雑誌 36 70 - 70 2024年5月

Adverse events of nivolumab plus ipilimumab versus nivolumab plus cabozantinib: a real-world pharmacovigilance study. 査読国際誌

Yurie Oka, Jun Matsumoto, Tatsuaki Takeda, Naohiro Iwata, Takahiro Niimura, Aya Fukuma Ozaki, Kensuke Bekku, Hirofumi Hamano, Motoo Araki, Keisuke Ishizawa, Yoshito Zamami, Noritaka Ariyoshi

International journal of clinical pharmacy 46 ( 3 ) 745 - 750 2024年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: No head-to-head clinical trials have compared the differences in adverse events (AEs) between nivolumab plus ipilimumab (NIVO-IPI) and nivolumab plus cabozantinib (NIVO-CABO) in the treatment of metastatic renal cell carcinoma (mRCC). AIM: We analysed the two largest real-world databases, the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and the World Health Organization's VigiBase, to elucidate the differences in AEs between NIVO-IPI and NIVO-CABO. METHOD: In total, 40,376 and 38,022 records were extracted from FAERS and VigiBase, and 193 AEs were analysed. The reporting odds ratios (ROR) with 95% confidence interval were calculated using a disproportionality analysis (NIVO-CABO/NIVO-IPI). RESULTS: The reported numbers of immune-related AEs, including myocarditis, colitis, and hepatitis, were significantly higher with NIVO-IPI (ROR = 0.18 for FAERS and 0.13 for VigiBase). Contrarily, the reported numbers of other AEs, including gastrointestinal disorders (ROR = 2.68 and 2.92) and skin and subcutaneous tissue disorders (ROR = 2.94 and 3.55), considered to be potentiated by the combination of NIVO and CABO, were higher with NIVO-CABO. CONCLUSION: Our findings contribute to the selection and clinical management of NIVO-IPI and NIVO-CABO, which minimizes the risk of AEs for individual patients with mRCC by considering distinctive differences in the AE profiles.

DOI： 10.1007/s11096-024-01713-1

ためになる薬の話薬物相互作用肺癌希少フラクションの分子標的治療薬

奥田浩人, 黒田智, 濱野裕章, 座間味義人

岡山医学会雑誌 136 ( 1 ) 29 - 32 2024年4月

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

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

ためになる薬の話薬物相互作用肺癌希少フラクションの分子標的治療薬

奥田浩人, 黒田智, 濱野裕章, 座間味義人

岡山医学会雑誌 136 ( 1 ) 29 - 32 2024年4月

抗がん剤心毒性の統合的な理解～基礎から臨床まで～大規模医療情報データベースを用いた薬剤性心毒性の予防法の開発

濱野裕章, 座間味義人, 牛尾聡一郎, 新村貴博, 合田光寛, 石澤有紀, 石澤啓介

薬学雑誌 144 ( 3 ) 257 - 264 2024年3月

記述言語：日本語出版者・発行元：(公社)日本薬学会

著者らの研究グループでは、薬剤性心毒性への対策を確立することを目標に、大規模な医療情報を活用した研究を行い、医療情報解析によって多数のリスク因子を特定し、それら因子を抑える薬剤について探索している。今回、これまでの研究成果を以下の項目に分けて紹介した。1)医療ビッグデータ解析によって抽出した免疫チェックポイント阻害薬(ICI)関連心筋炎のリスク因子(年齢、性別、薬物相互作用)。2)医療ビッグデータ解析およびオミクスデータベース解析によって抽出したドキソルビシン誘発心毒性における予防候補薬の評価。

その他リンク： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J01459&link_issn=&doc_id=20240426250003&doc_link_id=%2Fcs7yakug%2F2024%2F014403%2F004%2F0257-0264%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcs7yakug%2F2024%2F014403%2F004%2F0257-0264%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

A comparison between the adverse event profiles of patients receiving palbociclib and abemaciclib: analysis of two real-world databases. 査読国際誌

Tatsuaki Takeda, Shiho Sugimoto, Jun Matsumoto, Naohiro Iwata, Akihiko Nakamoto, Aya Fukuma Ozaki, Hirofumi Hamano, Noritaka Ariyoshi, Yoshito Zamami

International journal of clinical pharmacy 46 ( 2 ) 536 - 541 2024年1月

担当区分：最終著者記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Palbociclib and abemaciclib are cyclin-dependent kinase (CDK) 4/6 inhibitors currently used to treat breast cancer. Although their therapeutic efficacies are considered comparable, differences in adverse event (AE) profiles of the two drugs remain unclear. AIM: We analysed two real-world databases, the World Health Organization's VigiBase and the Food and Drug Administration Adverse Event Reporting System (FAERS), to identify differences in AE profiles of palbociclib and abemaciclib. METHOD: Data of patients with breast cancer receiving palbociclib or abemaciclib recorded until December 2022 were extracted from the VigiBase and FAERS databases. In total, 200 types of AEs were analysed. The reporting odds ratios were calculated using a disproportionality analysis. RESULTS: Cytopenia was frequently reported in patients receiving palbociclib, whereas interstitial lung disease and diarrhoea were frequently reported in those receiving abemaciclib. Moreover, psychiatric and nervous system disorders were more common in the palbociclib group, whereas renal and urinary disorders were more common in the abemaciclib group. CONCLUSION: This study is the first to show comprehensively the disparities in the AE profiles of palbociclib and abemaciclib. The findings highlight the importance of considering these differences when selecting a suitable CDK4/6 inhibitor to ensure safe and favourable outcomes for patients with breast cancer.

DOI： 10.1007/s11096-023-01687-6

ステロイドはバンコマイシン関連腎障害を予防するビッグデータ解析・基礎研究・臨床研究の統合による検討

中馬真幸, 合田光寛, 座間味義人, 濱野裕章, 武智研志, 石田俊介, 坂東貴司, 新村貴博, 近藤正輝, 石澤有紀, 田崎嘉一, 石澤啓介

日本臨床薬理学会学術総会抄録集 44回 2 - 2 2024年1月

レセプトデータを用いたダサチニブと胃酸分泌抑制薬の薬物相互作用に関する検討

亀沖真希, 牛尾聡一郎, 佐田光, 建部泰尚, 濱野裕章, 座間味義人

日本臨床薬理学会学術総会抄録集 44回 2 - I3 2024年1月

レセプトデータを用いたダサチニブと胃酸分泌抑制薬の薬物相互作用に関する検討

亀沖真希, 牛尾聡一郎, 佐田光, 建部泰尚, 濱野裕章, 座間味義人

日本臨床薬理学会学術総会抄録集 44回 2 - I3 2024年1月

ステロイドはバンコマイシン関連腎障害を予防するビッグデータ解析・基礎研究・臨床研究の統合による検討

中馬真幸, 合田光寛, 座間味義人, 濱野裕章, 武智研志, 石田俊介, 坂東貴司, 新村貴博, 近藤正輝, 石澤有紀, 田崎嘉一, 石澤啓介

日本臨床薬理学会学術総会抄録集 44回 2 - 2 2024年1月

Lysyl oxidase-like 4 promotes the invasiveness of triple-negative breast cancer cells by orchestrating the invasive machinery formed by annexin A2 and S100A11 on the cell surface. 査読国際誌

Tetta Takahashi, Nahoko Tomonobu, Rie Kinoshita, Ken-Ichi Yamamoto, Hitoshi Murata, Ni Luh Gede Yoni Komalasari, Youyi Chen, Fan Jiang, Yuma Gohara, Toshiki Ochi, I Made Winarsa Ruma, I Wayan Sumardika, Jin Zhou, Tomoko Honjo, Yoshihiko Sakaguchi, Akira Yamauchi, Futoshi Kuribayashi, Eisaku Kondo, Yusuke Inoue, Junichiro Futami, Shinichi Toyooka, Yoshito Zamami, Masakiyo Sakaguchi

Frontiers in oncology 14 1371342 - 1371342 2024年

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Our earlier research revealed that the secreted lysyl oxidase-like 4 (LOXL4) that is highly elevated in triple-negative breast cancer (TNBC) acts as a catalyst to lock annexin A2 on the cell membrane surface, which accelerates invasive outgrowth of the cancer through the binding of integrin-β1 on the cell surface. However, whether this machinery is subject to the LOXL4-mediated intrusive regulation remains uncertain. METHODS: Cell invasion was assessed using a transwell-based assay, protein-protein interactions by an immunoprecipitation-Western blotting technique and immunocytochemistry, and plasmin activity in the cell membrane by gelatin zymography. RESULTS: We revealed that cell surface annexin A2 acts as a receptor of plasminogen via interaction with S100A10, a key cell surface annexin A2-binding factor, and S100A11. We found that the cell surface annexin A2/S100A11 complex leads to mature active plasmin from bound plasminogen, which actively stimulates gelatin digestion, followed by increased invasion. CONCLUSION: We have refined our understanding of the role of LOXL4 in TNBC cell invasion: namely, LOXL4 mediates the upregulation of annexin A2 at the cell surface, the upregulated annexin 2 binds S100A11 and S100A10, and the resulting annexin A2/S100A11 complex acts as a receptor of plasminogen, readily converting it into active-form plasmin and thereby enhancing invasion.

DOI： 10.3389/fonc.2024.1371342

[Development of Preventive Methods for Drug-induced Cardiotoxicity Using a Large-scale Medical Information Database]. 査読

Hirofumi Hamano, Yoshito Zamami, Soichiro Ushio, Takahiro Niimura, Mitsuhiro Goda, Yuki Izawa-Ishizawa, Keisuke Ishizawa

Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan 144 ( 3 ) 257 - 264 2024年

記述言語：日本語掲載種別：研究論文（学術雑誌）

Cancer therapies have evolved considerably thereby substantially improving the survival of patients with cancer. However, cardiotoxicity, such as myocarditis and heart failure, induced by anticancer drugs, including immune checkpoint inhibitor(ICI)s and doxorubicin, present serious challenges. Numerous observations have indicated increased risks of cardiotoxicity- and cancer-related mortality in patients with drug-induced cardiotoxicity. Therefore, the prevention and management of drug-induced cardiotoxicity should be prioritized to enable sustainable long-term treatment while preserving patients' quality of life. Recently, medical research has been primarily focused on elucidation of therapeutic benefits and adverse events using medical big data, including worldwide databases of adverse events. The aim of the present study was to establish prevention strategies for drug-induced cardiotoxicity and advance data analytics. A data-driven approach was adopted to comprehensively analyze patient data and drug-induced cardiotoxicity. These data analytics revealed numerous risk factors, leading to the development of drugs that mitigate these factors. Furthermore, many unknown adverse events with molecularly targeted drugs were brought to light. Consequently, the importance of managing adverse events, guided by insights from data science, is predicted to increase. In this symposium review, we introduce our research exemplifying pharmaceutical studies utilizing medical big data. In particular, we discuss in detail the risk factors associated with myocarditis induced by immune checkpoint inhibitors along with prophylactic agents to mitigate doxorubicin-induced cardiotoxicity.

DOI： 10.1248/yakushi.23-00164-2

The Association between PDE5 Inhibitors and Aneurysm/Arterial Dissection:A Pharmacovigilance Study Using WHO Safety Database. 査読

Koji Miyata, Yuki Izawa-Ishizawa, Takahiro Niimura, Hirofumi Hamano, Fuka Aizawa, Kenta Yagi, Kei Kawada, Yoshito Zamami, Mitsuhiro Goda, Keisuke Ishizawa

The journal of medical investigation : JMI 71 ( 1.2 ) 134 - 140 2024年

記述言語：英語掲載種別：研究論文（学術雑誌）

Aneurysm and arterial dissection have been reported as adverse drug events, associated with angiogenesis inhibitors and fluoroquinolones. Specifically, several cases of severe arterial disease following cGMP-specific phosphodiesterase type 5 (PDE5) inhibitors usage have recently been reported. It is necessary to ascertain the risks of serious adverse events caused by PDE5 inhibitors. We aimed to evaluate the association of aneurysm and artery dissection with PDE5 inhibitors using VigiBase, which is a World Health Organization database of spontaneously reported adverse events, for explorative hypothesis-generating analysis. We performed disproportionality analysis using a dataset from inception in 1967 to December 2022 and calculated reporting odds ratios (ROR) between PDE5 inhibitors and arterial diseases. We extracted 195,839 reports on PDE5 inhibitors with 254 reports of arterial disease as adverse events from VigiBase. Disproportionality analysis showed disproportional signals for PDE5 inhibitors (ROR, 2.30;95% confidence intervals, 2.04-2.61);disproportional signals were detected in analyses restricting the lesion site to the aorta or cerebral arteries. From stratified analysis, disproportional signals were noted in females, as well as males, generally recognized as a risk factor for artery diseases. This real-world data analysis suggests that PDE5 inhibitors may play a role in the development of lethal arterial disease. J. Med. Invest. 71 : 134-140, February, 2024.

DOI： 10.2152/jmi.71.134

Letermovir at a Prophylactic Dose for Cytomegalovirus Infection in Children Undergoing Allogeneic Hematopoietic Stem Cell Transplantation: A Single-Center Retrospective Study in Japan.

Yasuhisa Tatebe, Yohei Manabe, Yuta Tanaka, Takahiro Shiwaku, Motoharu Ochi, Kosuke Tamefusa, Hisashi Ishida, Kaori Fujiwara, Kana Washio, Hirofumi Hamano, Kiminaka Murakawa, Yoshito Zamami

Biological & pharmaceutical bulletin 47 ( 9 ) 1575 - 1582 2024年

記述言語：英語掲載種別：研究論文（学術雑誌）

Cytomegalovirus (CMV) infection is a major complication of hematopoietic stem cell transplantation (HSCT). Previous studies in adults demonstrated that letermovir prophylaxis for 100 d after HSCT reduces the occurrence of CMV infection; however, studies in children are limited. In this study, we aimed to examine the incidence of CMV infection in children who underwent allogeneic HSCT with prophylactic letermovir therapy. A single-center retrospective study was conducted among patients aged ≤17 who underwent allogeneic HSCT. We compared the cumulative incidence of CMV infection, mainly monitored by pp65-antigenemia, after HSCT between patients with and without letermovir prophylaxis (10-12 or 5-6 mg/kg/d when co-administered with cyclosporine) using Gray's test. We analyzed 79 patients with a median follow-up period of 126 d. The median age of these patients was 8.3 years (Interquartile range, 3.7-12.4). Prophylactic letermovir was used in 25 patients. Twenty-five patients developed CMV infection, and the cumulative incidence was 38.9% (95% confidence intervals, 25.0-52.5). The cumulative incidence of CMV infection was not significantly different between the letermovir and no-letermovir groups (33.1 vs. 36.6%, p = 0.228). Meanwhile, the cumulative incidence of CMV infection up to 100 d following HSCT was significantly lower in the letermovir group than in the no-letermovir group (8.0 vs. 32.8%, p = 0.026). Most patients experienced no noticeable adverse effects associated with letermovir; however, one patient discontinued letermovir because of nausea and anorexia. In conclusion, the results of this study suggest that letermovir prophylaxis against CMV infection may be effective in children without severe adverse effects.

DOI： 10.1248/bpb.b24-00217

Cardiovascular toxicity risk assessment of tyrosine kinase inhibitors: a pharmacovigilance study using the VigiBase database. 国際誌

Yusuke Igawa, Hirofumi Hamano, Satoru Esumi, Tatsuaki Takeda, Makoto Kajizono, Ryo Kikuoka, Ikuya Kimura, Yoshito Zamami

Frontiers in pharmacology 15 1472008 - 1472008 2024年

記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: Advances in the early detection and treatment of cancer have significantly improved the prognosis of patients with cancer. Tyrosine kinase inhibitors (TKIs) are effective targeted treatments for various malignancies that act by inhibiting kinase activity. Although these drugs share a common mechanism of action, they differ in their targeted kinases, pharmacokinetics, and side effects. TKIs can cause cardiovascular side effects, which adversely affect the prognosis of cancer survivors. This study aimed to assess the risk of cardiac toxicity associated with TKIs using the World Health Organization Global Database, VigiBase. METHODS: We conducted a cross-sectional analysis of data from VigiBase, a comprehensive global database of suspected drug reactions. The dataset included reports up to December 2022. We identified patients treated with Food and Drug Administration-approved TKIs and analyzed their age and sex data. The primary outcome was cardiovascular impairment, defined by 21 preferred terms in the Medical Dictionary for Regulatory Activities Terminology version 25.1. Disproportionality analysis using the reported odds ratio was performed to detect adverse cardiovascular signals. Statistical analyses were conducted using R 3.3.2, with a P-value <0.05 considered significant. RESULTS: Of the 32, 520, 983 reports in VigiBase, 23, 181, 539 were eligible for the analysis. Significant cardiovascular signals were identified for 17 TKIs, including erlotinib, gefitinib, and imatinib. Stratified analyses revealed potential sex- and age-related differences in the risk of adverse events. Heatmaps indicated significant signals for drugs such as lapatinib in males and gefitinib in younger patients. DISCUSSION: Our findings indicate that some TKIs, particularly those classified as VEGFR, BCR-ABL, and BTK, pose similar risks of cardiotoxicity, while others, including EGFR, HER2, and ALK TKIs, exhibit varied risk profiles. These results underscore the importance of individualized risk assessment and management of TKI-treated patients. In conclusion, this study provides valuable insights into the cardiotoxic risk of TKIs, which is essential for developing tailored treatment plans.

DOI： 10.3389/fphar.2024.1472008

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

Toshihiro Koyama, Shunya Iinuma, Michio Yamamoto, Takahiro Niimura, Yuka Osaki, Sayoko Nishimura, Ko Harada, Yoshito Zamami, Hideharu Hagiya

Drug safety 47 ( 3 ) 237 - 249 2023年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND AND OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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

Concomitant Use of Multiple Nephrotoxins including Renal Hypoperfusion Medications Causes Vancomycin-Associated Nephrotoxicity: Combined Retrospective Analyses of Two Real-World Databases. 査読

Takashi Bando, Masayuki Chuma, Hirofumi Hamano, Takahiro Niimura, Naoto Okada, Masateru Kondo, Yuki Izumi, Shunsuke Ishida, Toshihiko Yoshioka, Mizuho Asada, Yoshito Zamami, Kenshi Takechi, Mitsuhiro Goda, Koji Miyata, Kenta Yagi, Yuki Izawa-Ishizaka, Momoyo Azuma, Hiroaki Yanagawa, Yoshikazu Tasaki, Keisuke Ishizawa

Acta medica Okayama 77 ( 6 ) 595 - 605 2023年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

There is a growing concern about the relationship between vancomycin-associated nephrotoxicity (VAN) and concomitant use of nephrotoxins. We examined this relationship by combined retrospective analyses of two real-world databases. Initially, the FDA Adverse Event Reporting System (FAERS) was analyzed for the effects of concomitant use of one or more nephrotoxins on VAN and the types of combinations of nephrotoxins that exacerbate VAN. Next, electronic medical records (EMRs) of patients who received vancomycin (VCM) at Tokushima University Hospital between January 2006 and March 2019 were examined to confirm the FAERS analysis. An elevated reporting odds ratio (ROR) was observed with increases in the number of nephrotoxins administered (VCM + one nephrotoxin, adjusted ROR (95% confidence interval [CI]) 1.67 [1.51-1.85]; VCM + ≥2 nephrotoxins, adjusted ROR [95% CI] 1.54 [1.37-1.73]) in FAERS. EMRs analysis showed that the number of nephrotoxins was associated with higher incidences of VAN [odds ratio: 1.99; 95% CI: 1.42-2.78]. Overall, concomitant use of nephrotoxins was associated with an increased incidence of VAN, especially when at least one of those nephrotoxins was a renal hypoperfusion medication (furosemide, non-steroidal anti-inflammatory drugs, and vasopressors). The concomitant use of multiple nephrotoxins, especially including renal hypoperfusion medication, should be avoided to prevent VAN.

DOI： 10.18926/AMO/66151

ためになる薬の話薬物相互作用(58-タクロリムスの薬物相互作用)

木村郁哉, 濱野裕章, 鍛治園誠, 座間味義人

岡山医学会雑誌 135 ( 3 ) 167 - 171 2023年12月

ためになる薬の話薬物相互作用(58-タクロリムスの薬物相互作用)

木村郁哉, 濱野裕章, 鍛治園誠, 座間味義人

岡山医学会雑誌 135 ( 3 ) 167 - 171 2023年12月

Influence of vasopressin receptor antagonists on triple-whammy acute kidney injury: A VigiBase analysis. 査読国際誌

Satoru Mitsuboshi, Kenji Hayakawa, Hirofumi Hamano, Ayako Oshima, Tatsuaki Takeda, Kiminaka Murakawa, Hideki Mori, Yoshito Zamami

British journal of clinical pharmacology 90 ( 3 ) 900 - 904 2023年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Although diuretics play an important role in triple-whammy acute kidney injury (AKI), it is unclear whether the type of diuretic influences the risk of triple-whammy AKI. The aim of this study was to evaluate whether vasopressin receptor antagonists affect triple-whammy AKI. This cross-sectional study used disproportionality analysis of VigiBase data to assess the risk of AKI with various diuretics. Although multiple logistic regression analysis showed that aldosterone antagonists (odds ratio [OR] 2.19, 95% CI 2.01-2.37), loop diuretics (OR 4.40, 95% CI 4.07-4.76) and thiazide diuretics (OR 1.98, 95% CI 1.83-2.15) increased the risk of AKI in patients who received non-steroidal anti-inflammatory drugs (NSAIDs) and renin-angiotensin system inhibitors (RASi), vasopressin receptor antagonists did not increase the risk of AKI in those patients. Vasopressin receptor antagonists might not influence the development of triple-whammy AKI.

DOI： 10.1111/bcp.15974

Effect of pre-treatment of EGFR-TKIs on immune checkpoint inhibitor-associated interstitial lung disease in lung cancer patients: Analysis using a Japanese claims database. 査読国際誌

Naoto Okada, Hirofumi Hamano, Kenta Yagi, Takahiro Niimura, Fuka Aizawa, Mitsuhiro Goda, Yoshito Zamami, Takashi Kitahara, Keisuke Ishizawa

International journal of clinical pharmacology and therapeutics 62 ( 2 ) 69 - 76 2023年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Immune checkpoint inhibitors (ICI) and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) are key drugs for the treatment of EGFR mutation-positive lung cancer. While previous studies reported that the concomitant use of these drugs increases the risk of interstitial lung disease (ILD), the impact of sequential treatment on ILD risk is unknown. This study aimed to analyze the impact of EGFR-TKI pre-treatment on the risk of developing ILD after subsequent ICI administration. MATERIALS AND METHODS: We conducted a retrospective study using a Japanese health insurance claims database. ILD-naive lung cancer patients who had first ICI administration during the screening period from July 2014 to February 2019 were selected. Patients who had ILD within 1 year of receiving the first ICI dose were included in the ILD group. Multivariate logistic regression analysis was conducted to evaluate the effect of pre-treatment with EGFR-TKI on the development of ICI-associated ILD. RESULTS: A total of 353 patients were included, of which 61 were included in the ILD group. The median time to onset of ILD after ICI administration was 3 months. Multivariate logistic regression analysis revealed that pre-treatment with EGFR-TKI was not associated with ICI-associated ILD (odds ratio: 0.26, 95% confidence interval: 0.033 - 2.01). CONCLUSION: Although further analyses are required to confirm our findings, this study indicated that pre-treatment with EGFR-TKI might not increase the ILD risk after ICI treatment.

DOI： 10.5414/CP204491

Reply to: Comments on Association between immune checkpoint inhibitor-induced myocarditis and concomitant use of thiazide diuretics. 査読国際誌

Satoru Mitsuboshi, Hirofumi Hamano, Yoshito Zamami

International journal of cancer 154 ( 3 ) 586 - 587 2023年10月

Angiogenesis inhibitor-specific hypertension increases the risk of developing aortic dissection. 査読国際誌

Kaito Tsujinaka, Yuki Izawa-Ishizawa, Koji Miyata, Toshihiko Yoshioka, Kohei Oomine, Honoka Nishi, Masateru Kondo, Syuto Itokazu, Tatsumi Miyata, Takahiro Niimura, Maki Sato, Fuka Aizawa, Kenta Yagi, Masayuki Chuma, Yoshito Zamami, Mitsuhiro Goda, Keisuke Ishizawa

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 167 115504 - 115504 2023年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Aortic dissection is an adverse event of angiogenesis inhibitors; however, the association between the drugs and aortic dissection is unclear. Therefore, we investigated if and how angiogenesis inhibitors increase the onset of aortic dissection using pharmacologically-induced aortic dissection-prone model (LAB) mice, cultured endothelial cells, and real-world databases, which is a novel integrated research approach. Disproportionality analysis was performed and calculated using the reporting odds ratio as a risk signal using a worldwide database of spontaneous adverse events to estimate the risk of adverse events. Angiogenesis inhibitors, but not other hypertension-inducing drugs, showed significant risk signals for aortic aneurysms and dissection. A retrospective cohort analysis using JMDC, a medical receipt database in Japan, showed that the history of atherosclerosis and dyslipidemia, but not hypertension, were significantly associated with the onset of aortic dissection during angiogenesis inhibitor medication administration. For in vivo studies, sunitinib (100 mg/kg/day) was administered to LAB mice. Sunitinib increased systolic blood pressure (182 mmHg vs. 288 mmHg with sunitinib; p＜0.01) and the incidence of aortic dissection (40% vs. 59% with sunitinib; p = 0.34) in mice. In vivo and in vitro studies revealed that sunitinib increased endothelin-1 expression and induced endothelial cell damage evaluated by intracellular- and vascular cell adhesion molecule-1 expressions. The increased risk of developing aortic dissection with angiogenesis inhibitors is associated with the development of drug-specific hypertension via endothelial cell damage and endothelin-1 expression. Our findings are invaluable in establishing safer anticancer therapies and strategies to prevent the development of vascular toxicity in high-risk patients.

DOI： 10.1016/j.biopha.2023.115504

Valproic acid treatment attenuates cisplatin-induced kidney injury by suppressing proximal tubular cell damage. 国際誌

Toshihiko Yoshioka, Mitsuhiro Goda, Masaya Kanda, Sayuri Itobayashi, Yugo Sugimoto, Yuki Izawa-Ishizawa, Kenta Yagi, Fuka Aizawa, Koji Miyata, Takahiro Niimura, Hirofumi Hamano, Takumi Sakurada, Yoshito Zamami, Keisuke Ishizawa

Clinical and translational science 16 ( 11 ) 2369 - 2381 2023年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Cisplatin treatment is effective against several types of carcinomas. However, it frequently leads to kidney injury, which warrants effective prevention methods. Sodium valproic acid is a prophylactic drug candidate with a high potential for clinical application against cisplatin-induced kidney injury. Therefore, in this study, we aimed to elucidate the mechanism underlying the prophylactic effect of valproic acid on cisplatin-induced kidney injury in a mouse model and HK2 and PODO cells with cisplatin-induced toxicity. In the mouse model of cisplatin-induced kidney injury, various renal function parameters and tubular damage scores were worsened by cisplatin, but they were significantly improved upon combination with valproic acid. No difference was observed in cisplatin accumulation between the cisplatin-treated and valproic acid-treated groups in whole blood and the kidneys. The mRNA expression levels of proximal tubular damage markers, apoptosis markers, and inflammatory cytokines significantly increased in the cisplatin group 72 h after cisplatin administration but significantly decreased upon combination with valproic acid. In HK2 cells, a human proximal tubular cell line, the cisplatin-induced decrease in cell viability was significantly suppressed by co-treatment with valproic acid. Valproic acid may inhibit cisplatin-induced kidney injury by suppressing apoptosis, inflammatory responses, and glomerular damage throughout the kidney by suppressing proximal tubular cell damage. However, prospective controlled trials need to evaluate these findings before their practical application.

DOI： 10.1111/cts.13638

Evaluation of cardiovascular toxicity of the atezolizumab and bevacizumab combination

Takahiro Niimura, Mitsuhiro Goda, Koji Miyata, Jun Matsumoto, Toshihiko Yoshioka, Hirofumi Hamano, Fuka Aizawa, Kenta Yagi, Yuki Izawa-Ishizawa, Yoshito Zamami, Keisuke Ishizawa

Frontiers in Drug Safety and Regulation 2023年8月

掲載種別：研究論文（学術雑誌）

<jats:p><jats:bold>Introduction:</jats:bold> The combination of atezolizumab, an immune checkpoint inhibitor (ICI), and bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, is the first choice for systemic therapy in hepatocellular carcinoma. Immune-related cardiovascular toxicity—myocarditis and pericarditis—are known to occur during ICI treatment. By contrast, VEGF inhibitors (VEGFIs) cause cardiovascular complications such as hypertension and heart failure. Thus, different cardiovascular toxicities have been recognized for ICIs and VEGFIs, but the impact of their combination remains unclear. Here, we aimed to investigate the cardiovascular toxicity profile of atezolizumab in combination with bevacizumab using the World Health Organization adverse event reporting database—VigiBase.</jats:p><jats:p><jats:bold>Methods:</jats:bold> We analyzed data included in VigiBase till December 2022. To evaluate the frequency of reports related to atezolizumab, bevacizumab, and their combinations for 21 adverse events, we calculated the reporting odds ratio and information component. Analyses of the fatality of various cardiovascular toxicities associated with the use of each drug were performed.</jats:p><jats:p><jats:bold>Results:</jats:bold> The database included 84,951, 10,595, and 2,092 reports of treatment with bevacizumab, atezolizumab, and their combination, respectively. The disproportionality signal of hypertension, arterial embolism and thrombosis, supraventricular tachyarrhythmias, heart failure, myocarditis, hemorrhage-related clinical events, venous embolism and thrombosis, cardiomyopathy, respiratory failure with combination regimen of atezolizumab and bevacizumab was detected. Signals of these adverse events were also detected treatment with either atezolizumab or bevacizumab alone. Venous embolism and thrombosis exhibited the highest fatality rate in the two drug combination (12.82%) relative to those of atezolizumab (6.19%) and bevacizumab (4.54%).</jats:p><jats:p><jats:bold>Discussion:</jats:bold> Cardiovascular toxicity, owing to the combination of atezolizumab and bevacizumab, was similar to that of each single agent, and no new safety concerns were observed. Caution should be exercised when combining the two drugs since the fatality rate of thromboembolism increases with combination treatment.</jats:p>

DOI： 10.3389/fdsfr.2023.1213771

ためになる薬の話薬物相互作用腎不全の薬物相互作用

濱野裕章, 鍛治園誠, 西原茂樹, 村川公央, 座間味義人

岡山医学会雑誌 135 ( 2 ) 89 - 91 2023年8月

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

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

Structural characterization of the optical isomers esomeprazole and omeprazole using the JADER and FAERS databases. 査読国際誌

Mami Neishi, Hirofumi Hamano, Takahiro Niimura, Masaya Denda, Kenta Yagi, Koji Miyata, Tsung-Jen Lin, Tsukasa Higashionna, Mitsuhiro Goda, Yoshito Zamami, Keisuke Ishizawa, Hideki Nawa

Toxicology and applied pharmacology 475 116632 - 116632 2023年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: It is unclear whether the s (-) form of esomeprazole (EPZ) has an improved safety profile when compared with its racemic form omeprazole (OPZ). We assessed the potential complications of these optical isomers when combined with cilostazol, clopidogrel, and prasugrel, which are frequently used concomitant medications. METHODS: Using two adverse event spontaneous reporting databases, Japanese Adverse Drug Event Report (JADER) and FDA Adverse Event Reporting System (FAERS), adverse event names for hemorrhage, venous/arterial embolization, and thrombus were obtained from the Medical Dictionary for Regulatory Activities. Reported odds ratios were calculated using a 2 × 2 contingency table, and a signal was considered present if the lower limit of the 95% confidence interval was >1. RESULTS: In combination with cilostazol, a hemorrhagic signal for OPZ in JADER and arterial emboli and thrombus signals for EPZ were detected in both databases. In combination with clopidogrel, OPZ showed arterial emboli and thrombus signals in JADER and venous/arterial emboli and thrombus signals in FAERS, while EPZ displayed arterial emboli and thrombus signals in FAERS. In contrast, when in combination with prasugrel, there were no adverse event signals in either database. CONCLUSION: This study has confirmed using big data, that EPZ, the optical isomer and racemic form of omeprazole, has the beneficial characteristics of being less sensitive to CYP, as was intended by its design.

DOI： 10.1016/j.taap.2023.116632

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

担当区分：最終著者記述言語：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

A polo-like kinase inhibitor identified by computational repositioning attenuates pulmonary fibrosis. 査読国際誌

Takeshi Imakura, Seidai Sato, Kazuya Koyama, Hirohisa Ogawa, Takahiro Niimura, Kojin Murakami, Yuya Yamashita, Keiko Haji, Nobuhito Naito, Kozo Kagawa, Hiroshi Kawano, Yoshito Zamami, Keisuke Ishizawa, Yasuhiko Nishioka

Respiratory research 24 ( 1 ) 148 - 148 2023年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease with few effective therapeutic options. Recently, drug repositioning, which involves identifying novel therapeutic potentials for existing drugs, has been popularized as a new approach for the development of novel therapeutic reagents. However, this approach has not yet been fully utilized in the field of pulmonary fibrosis. METHODS: The present study identified novel therapeutic options for pulmonary fibrosis using a systematic computational approach for drug repositioning based on integration of public gene expression signatures of drug and diseases (in silico screening approach). RESULTS: Among the top compounds predicted to be therapeutic for IPF by the in silico approach, we selected BI2536, a polo-like kinase (PLK) 1/2 inhibitor, as a candidate for treating pulmonary fibrosis using an in silico analysis. However, BI2536 accelerated mortality and weight loss rate in an experimental mouse model of pulmonary fibrosis. Because immunofluorescence staining revealed that PLK1 expression was dominant in myofibroblasts while PLK2 expression was dominant in lung epithelial cells, we next focused on the anti-fibrotic effect of the selective PLK1 inhibitor GSK461364. Consequently, GSK461364 attenuated pulmonary fibrosis with acceptable mortality and weight loss in mice. CONCLUSIONS: These findings suggest that targeting PLK1 may be a novel therapeutic approach for pulmonary fibrosis by inhibiting lung fibroblast proliferation without affecting lung epithelial cells. In addition, while in silico screening is useful, it is essential to fully determine the biological activities of candidates by wet-lab validation studies.

DOI： 10.1186/s12931-023-02446-x

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

ドキソルビシン誘発心筋障害の予防薬探索

西内栞, 合田光寛, 新村貴博, 生田賢治, 八木健太, 相澤風花, 濱野裕章, 座間味義人, 石澤啓介, 西内栞, 石澤有紀

四国医学雑誌 79 ( 1-2 ) 139 - 139 2023年6月

ドキソルビシン誘発心筋障害の予防薬探索

西内栞, 合田光寛, 新村貴博, 生田賢治, 八木健太, 相澤風花, 濱野裕章, 座間味義人, 石澤啓介, 西内栞, 石澤有紀

四国医学雑誌 79 ( 1-2 ) 139 - 139 2023年6月

ためになる薬の話薬物相互作用(56-抗不整脈薬の薬物相互作用)

村尾卓哉, 江角悟, 濱野裕章, 村川公央, 座間味義人

岡山医学会雑誌 135 ( 1 ) 39 - 42 2023年4月

Proton Pump Inhibitors and Rhabdomyolysis: Analysis of Two Different Cross-Sectional Databases. 査読国際誌

Satoru Mitsuboshi, Hirofumi Hamano, Yurika Kuniki, Takahiro Niimura, Masayuki Chuma, Soichiro Ushio, Tsung-Jen Lin, Jun Matsumoto, Tatsuaki Takeda, Makoto Kajizono, Yoshito Zamami, Keisuke Ishizawa

The Annals of pharmacotherapy 57 ( 11 ) 10600280231156270 - 10600280231156270 2023年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: It is unclear whether use of a proton pump inhibitors (PPIs) increases the risk of rhabdomyolysis. OBJECTIVE: To clarify whether use of PPIs increases the risk of rhabdomyolysis. METHODS: This cross-sectional study analyzed data entered into the Medical Data Vision (MDV) database in Japan and into the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). The MDV data were analyzed to evaluate the association between use of PPIs and rhabdomyolysis. Then, the FAERS data were analyzed to evaluate whether the risk of rhabdomyolysis was increased further when a statin or fibrate was used concomitantly with a PPI. In both analyses, histamine-2 receptor antagonist was set as a comparator because it is used to treat gastric disease. In the MDV analysis, Fisher's exact test and multiple logistic regression analysis were performed. In the FAERS analysis, a disproportionality analysis using Fisher's exact test and multiple logistic regression analysis were performed. RESULTS: Multiple logistic regression analysis of both databases showed a significant association between use of PPIs and an increased risk of rhabdomyolysis (odds ratio [OR] = 1.74-1.95, P ≤ 0.01). However, use of a histamine-2 receptor antagonist was not significantly associated with increased risk of rhabdomyolysis. In the sub-analysis of the FAERS data, use of a PPI did not increase the risk of rhabdomyolysis in patients receiving a statin. CONCLUSION AND RELEVANCE: The data in 2 separate databases consistently suggest that PPIs may increase the risk of rhabdomyolysis. The evidence for this association should be assessed in further drug safety studies.

DOI： 10.1177/10600280231156270

Effects of vonoprazan and proton pump inhibitors on the efficacy of bevacizumab: a multicentre retrospective study. 査読国際誌

Kenta Yagi, Akinori Maruo, Shunsuke Ishida, Fuka Aizawa, Soichiro Ushio, Satoshi Sakaguchi, Makoto Kajizono, Takahiro Niimura, Mitsuhiro Goda, Hirofumi Hamano, Yuki Izawa-Ishizawa, Yoshito Zamami, Keisuke Ishizawa

Clinical and experimental medicine 23 ( 6 ) 2799 - 2804 2023年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Gastric acid secretion inhibitors such as proton pump inhibitors (PPIs) and vonoprazan may change the duration of treatment with bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, for cancer. However, there are no data on this prolongation effect. Here, we aimed to determine whether the use of PPIs or vonoprazan in patients with cancer receiving bevacizumab affected the duration of bevacizumab treatment. This observational study was conducted at two national university hospitals in Japan and involved 222 patients using oral PPIs (N = 190) or vonoprazan (N = 32) at the start of bevacizumab treatment between January 2015 and December 2018. Patients who received only one course of bevacizumab were excluded. The primary endpoint was the duration of bevacizumab treatment. The duration of bevacizumab treatment varied significantly between the PPI and vonoprazan groups. For cancer types other than colorectal cancer (breast, lung, brain, and ovarian cancers), the median duration of treatment was 217 days (p < 0.05) and was longer in the vonoprazan group than in the PPI group. However, for colorectal cancer, the median duration of bevacizumab treatment was 147 days longer in the PPI group than in the vonoprazan group. Selection of appropriate gastric acid secretion inhibitors may improve the therapeutic efficacy of anti-VEGF drugs, including bevacizumab. Oestrogen is a key regulator of this effect and may be responsible for the varying association between PPI or vonoprazan administration and the difference in bevacizumab treatment duration between colon cancer and other cancer types.

DOI： 10.1007/s10238-023-01008-1

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

Differential effects of proton pump inhibitors and vonoprazan on vascular endothelial growth factor expression in cancer cells. 査読国際誌

Rie Ando-Matsuoka, Kenta Yagi, Mayu Takaoka, Yuko Sakajiri, Tomokazu Shibata, Ryusuke Sawada, Akinori Maruo, Koji Miyata, Fuka Aizawa, Hirofumi Hamano, Takahiro Niimura, Yuki Izawa-Ishizawa, Mitsuhiro Goda, Satoshi Sakaguchi, Yoshito Zamami, Yoshihiro Yamanishi, Keisuke Ishizawa

Drug development research 84 ( 1 ) 75 - 83 2022年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Proton pump inhibitors (PPIs) are potent inhibitors of gastric acid secretion, used as first-line agents in treating peptic ulcers. However, we have previously reported that PPIs may diminish the therapeutic effect of anti-vascular endothelial growth factor (VEGF) drugs in patients with cancer. In this study, we explored the effects of vonoprazan, a novel gastric acid secretion inhibitor used for the treatment of peptic ulcers, on the secretion of VEGF in cancer cells and attempted to propose it as an alternative PPI for cancer chemotherapy. The effects of PPI and vonoprazan on VEGF expression in cancer cells were compared by real-time reverse transcription-polymerase chain reaction and ELISA. The interaction of vonoprazan and PPIs with transcriptional regulators by docking simulation analysis. In various cancer cell lines, including the human colorectal cancer cell line (LS174T), PPI increased VEGF messenger RNA expression and VEGF protein secretion, while this effect was not observed with vonoprazan. Molecular docking simulation analysis showed that vonoprazan had a lower binding affinity for estrogen receptor alpha (ER-α), one of the transcriptional regulators of VEGF, compared to PPI. Although the PPI-induced increase in VEGF expression was counteracted by pharmacological ER-α inhibition, the effect of vonoprazan on VEGF expression was unchanged. Vonoprazan does not affect VEGF expression in cancer cells, which suggests that vonoprazan might be an alternative to PPIs, with no interference with the therapeutic effects of anti-VEGF cancer chemotherapy.

DOI： 10.1002/ddr.22013

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

大規模医療情報解析を活用したシスプラチン誘発急性腎障害に対する予防薬の探索

神田将哉, 合田光寛, 吉岡俊彦, 座間味義人, 石澤啓介, 小川敦, 石田俊介, 相澤風花, 新村貴博, 八木健太, 石澤有紀

四国医学雑誌 78 ( 5-6 ) 249 - 250 2022年12月

医療ビッグデータ解析と基礎研究を融合した研究手法によるハイブリッド創薬

合田光寛, 相澤風花, 八木健太, 新村貴博, 櫻田巧, 小川敦, 石澤有紀, 座間味義人, 石澤啓介

日本臨床薬理学会学術総会抄録集 43回 3 - 4 2022年12月

Polypharmacy in Older Adults with Alzheimer's Disease. 国際誌

Satoru Esumi, Soichiro Ushio, Yoshito Zamami

Medicina (Kaunas, Lithuania) 58 ( 10 ) 2022年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

The number of patients with Alzheimer's disease is increasing annually. Most of these patients are older adults with comorbid physical illnesses, which means that they are often treated with a combination of medications for the disease they have and those for Alzheimer's disease. Thus, older adults with Alzheimer's disease are potentially at risk for polypharmacy. In addition, the drug interactions between Alzheimer's disease medications and those for the treatment of physical illnesses may reduce their efficacy and increase side effects. This article reviews polypharmacy and drug interactions in elderly patients with Alzheimer's disease, with a focus on psychotropic drugs.

DOI： 10.3390/medicina58101445

Non-recovery of vancomycin-associated nephrotoxicity is related to worsening survival outcomes-combined retrospective analyses of two real-world databases. 国際誌

Masayuki Chuma, Hirofumi Hamano, Takashi Bando, Masateru Kondo, Naoto Okada, Yuki Izumi, Shunsuke Ishida, Toshihiko Yoshioka, Mizuho Asada, Takahiro Niimura, Yoshito Zamami, Kenshi Takechi, Mitsuhiro Goda, Koji Miyata, Kenta Yagi, Sachiko Kasamo, Yuki Izawa-Ishizawa, Momoyo Azuma, Hiroaki Yanagawa, Yoshikazu Tasaki, Keisuke Ishizawa

Basic & clinical pharmacology & toxicology 131 ( 6 ) 525 - 535 2022年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

There has been growing concern in worsening survival and renal outcomes following vancomycin-associated nephrotoxicity (VAN) onset, but the factors associated with these phenomena remain unclear. To examine these factors, we performed a retrospective study combining the analysis of two real-world databases. Initially, the FDA Adverse Event Reporting System (FAERS) was used to evaluate the relationship between VAN and mortality using odds ratios (ORs) and 95% confidence intervals (CIs). Next, electronic medical records (EMRs) were examined in a more robust cohort for evaluation of the association between renal outcomes and worsening survival using Cox proportional hazards regression models. FAERS analysis revealed a significant correlation between VAN occurrence and increased mortality (OR: 1.30; 95% CI: 1.17-1.46). EMR analysis showed that non-recovery of VAN was associated with increased hospital mortality (hazard ratio [HR]: 4.05; 95% CI: 2.42-6.77) and one-year mortality (HR: 3.03, 95% CI: 1.98-4.64). The HR for VAN recovery was lower for patients with acute kidney injury (AKI) stage ≥ 2 (HR: 0.09; 95% CI: 0.02-0.40). Thus, worsening survival outcomes were associated with non-recovery of VAN, whereby AKI stage ≥ 2 was a significant risk factor. Progression to severe VAN should be prevented for better survival outcomes.

DOI： 10.1111/bcpt.13799

Low‐dose acyclovir for prophylaxis of varicella‐zoster virus reactivation after hematopoietic stem cell transplantation in children 国際誌

Yasuhisa Tatebe, Soichiro Ushio, Satoru Esumi, Hikaru Sada, Motoharu Ochi, Kosuke Tamefusa, Hisashi Ishida, Kaori Fujiwara, Kiichiro Kanamitsu, Kana Washio, Risa Katsube, Kiminaka Murakawa, Yoshito Zamami

Pediatric Blood & Cancer 69 ( 12 ) e29979 2022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：Wiley

BACKGROUND: Varicella-zoster virus (VZV) reactivation is a serious complication of hematopoietic stem cell transplantation (HSCT). Although low-dose acyclovir can prevent VZV reactivation after HSCT in adults, the efficacy of a dose of acyclovir lower than the recommended dose, such as 60-80 mg/kg/day in children, is unclear. In this study, we aimed to evaluate the incidence of VZV reactivation after HSCT during and after low-dose acyclovir administration for preventing VZV reactivation in children. METHODS: This single-center retrospective study included children aged ≤15 years who received oral acyclovir (at 15 mg/kg/day) to prevent VZV reactivation after HSCT. We examined the cumulative incidence of VZV reactivation after HSCT, during and after prophylactic acyclovir administration. RESULTS: Fifty-three eligible patients were included in this study, of whom 37 underwent allogeneic HSCT. The median duration of prophylactic acyclovir therapy was 264 days (range: 69-1140 days). VZV reactivation occurred in 13 patients (24.5%, 95% confidence interval [CI]: 14.9-37.6). The cumulative incidence of VZV reactivation 1 and 2 years after HSCT was 6.26% (95% CI: 1.60-15.5) and 20.9% (95% CI: 10.3-34.0), respectively. While only one patient developed VZV reactivation during the administration of prophylactic acyclovir, the cumulative incidence of VZV reactivation increased to 24.2% (95% CI: 12.5-38.0) 1 year after the cessation of acyclovir. CONCLUSION: Low-dose acyclovir (15 mg/kg/day) could be effective for preventing VZV reactivation after HSCT in children because VZV reactivation seldom occurs during the administration of 15 mg/kg/day acyclovir.

DOI： 10.1002/pbc.29979

その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/pbc.29979

Evaluation of the potential complication of interstitial lung disease associated with antifibrotic drugs using data from databases reporting spontaneous adverse effects. 国際誌

Hideki Nawa, Hirofumi Hamano, Takahiro Niimura, Koji Miyata, Kenta Yagi, Mitsuhiro Goda, Yoshito Zamami, Keisuke Ishizawa

Clinical and translational science 15 ( 12 ) 2982 - 2988 2022年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Interstitial lung disease (ILD), as an adverse effect of certain drugs, leads to inflammation and damage in the walls of the alveoli, making it difficult for the alveoli to take up oxygen. Interstitial pneumonia with no identifiable cause is called idiopathic interstitial pneumonia (IIP), and, among the major IIPs, idiopathic pulmonary fibrosis (IPF) is diagnosed in about half of patients. Current treatment options are limited, among which the antifibrotic drugs nintedanib (Ofev) and pirfenidone (Pirespa) are the first-line drugs. In this study, we investigated the incidence of ILD possibly caused by antifibrotic agents using data from the Japanese Adverse Drug Event Report (JADER) database, a database of spontaneous adverse event reports published by the Pharmaceuticals and Medical Devices Agency (PMDA), and the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), published by the FDA. We used the FAERS and JADER to detect the signals of adverse events on the basis of reporting odds ratios. The relationship between indications and adverse events was clarified by separating indications and adverse events using the spontaneous adverse event reporting database with novel drug involvement. Regarding the involvement of nintedanib and pirfenidone in the development of ILD, JADER and FAERS showed signals for both nintedanib and pirfenidone as suspect drugs, and no signals for nintedanib or pirfenidone as concomitant drug interactions were detected. We highlight this because there are only a few effective drugs for IPF, and effective and safe drug therapies should be implemented by taking into consideration drug-induced ILD.

DOI： 10.1111/cts.13419

【薬にまつわる疑問に答える】薬にまつわる疑問その他透析患者に対する処方のコツを教えてください

有木沙織, 牛尾聡一郎, 村川公央, 座間味義人

JOHNS 38 ( 9 ) 1168 - 1171 2022年9月

Adverse Events of Axitinib plus Pembrolizumab Versus Lenvatinib plus Pembrolizumab: A Pharmacovigilance Study in Food and Drug Administration Adverse Event Reporting System. 国際誌

Jun Matsumoto, Naohiro Iwata, Shogo Watari, Soichiro Ushio, Shoya Shiromizu, Tatsuaki Takeda, Hirofumi Hamano, Makoto Kajizono, Motoo Araki, Yasutomo Nasu, Noritaka Ariyoshi, Yoshito Zamami

European urology focus 9 ( 1 ) 141 - 144 2022年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

No head-to-head postmarket surveillance study has compared the differences in adverse events (AEs) between two combination therapies, axitinib (AXI) + pembrolizumab (PEMBRO) and lenvatinib (LEN) + PEMBRO, against metastatic renal cell carcinoma. This study aims to highlight the comprehensive differences in AEs between these two therapies based on the real-world big data from the Food and Drug Administration Adverse Event Reporting System (FAERS) database. In total, 28 937 records were extracted from the FAERS database, and 139 AEs grouped into the System Organ Class according to the Medical Dictionary for Regulatory Activities were analysed. Logistic regression analyses were performed, and the reporting odds ratio with a 95% confidence interval was determined. We found that the incidences of cardiac and hepatobiliary disorders for AXI + PEMBRO, and blood and lymphatic system, metabolism and nutrition, and vascular disorders for LEN + PEMBRO, all of which were associated with serious AEs, were higher than those for LEN + PEMBRO and AXI + PEMBRO, respectively. The differences in the AEs between AXI + PEMBRO and LEN + PEMBRO were not derived merely from those between AXI and LEN monotherapies. Furthermore, remarkable AE potentiation was observed for AXI + PEMBRO. As FAERS is a spontaneous reporting system comprising partially limited information, analysing more detailed relationships between AEs and patient or treatment characteristics was challenging in this study. The present study is the first to show the overall real-world postmarketing differences in AEs between AXI + PEMBRO and LEN + PEMBRO. Our novel findings will substantially improve clinical practice; we recommend comparing patients' conditions associated with the above AEs when selecting between these two therapies. PATIENT SUMMARY: Herein, we highlight the differences in adverse events (AEs) between axitinib + pembrolizumab and lenvatinib + pembrolizumab therapies using data from the real-world Food and Drug Administration Adverse Event Reporting System database aimed at patients with metastatic renal cell carcinoma. We identified AEs that needed attention in each combination. We recommend the differences in AEs to be considered when selecting these two therapies.

DOI： 10.1016/j.euf.2022.07.003

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

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

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

遺伝子発現および大規模医療情報データベースを活用したシスプラチン関連腎障害に対する予防薬の探索

合田光寛, 神田将哉, 吉岡俊彦, 吉田愛美, 糸林小友理, 新村貴博, 櫻田巧, 小川敦, 岡田直人, 相澤風花, 八木健太, 濱野裕章, 石澤有紀, 座間味義人, 石澤啓介

血管 45 ( 1 ) 62 - 62 2022年6月

遺伝子発現および大規模医療情報データベースを活用したシスプラチン関連腎障害に対する予防薬の探索

合田光寛, 神田将哉, 吉岡俊彦, 吉田愛美, 糸林小友理, 新村貴博, 櫻田巧, 小川敦, 岡田直人, 相澤風花, 八木健太, 濱野裕章, 石澤有紀, 座間味義人, 石澤啓介

血管 45 ( 1 ) 62 - 62 2022年6月

Investigation of drugs for the prevention of doxorubicin-induced cardiac events using big data analysis. 国際誌

Shiori Nishiuchi, Kenta Yagi, Hiroumi Saito, Yoshito Zamami, Takahiro Niimura, Koji Miyata, Yoshika Sakamoto, Kimiko Fukunaga, Shunsuke Ishida, Hirofumi Hamano, Fuka Aizawa, Mitsuhiro Goda, Masayuki Chuma, Yuki Izawa-Ishizawa, Hideki Nawa, Hiroaki Yanagawa, Yasunari Kanda, Keisuke Ishizawa

European journal of pharmacology 928 175083 - 175083 2022年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIM: Doxorubicin, an anthracycline anti-tumour agent, is an essential chemotherapeutic drug; however, the adverse events associated with doxorubicin usage, including cardiotoxicity, prevent patients from continuing treatment. Here, we used databases to explore existing approved drugs with potential preventative effects against doxorubicin-induced cardiac events and examined their efficacy and mechanisms. METHODS: The Gene Expression Omnibus (GEO), Library of Integrated Network-based Cellular Signatures (LINCS), and Food and Drug Administration Adverse Events Reporting System (FAERS) databases were used to extract candidate prophylactic drugs. Mouse models of doxorubicin-induced cardiac events were generated by intraperitoneal administration of 20 mg/kg of doxorubicin on Day 1 and oral administration of prophylactic candidate drugs for 6 consecutive days beginning the day before doxorubicin administration. On Day 6, mouse hearts were extracted and examined for mRNA expression of apoptosis-related genes. RESULTS: GEO analysis showed that doxorubicin administration upregulated 490 genes and downregulated 862 genes, and LINCS data identified sirolimus, verapamil, minoxidil, prednisolone, guanabenz, and mosapride as drugs capable of counteracting these genetic alterations. Examination of the effects of these drugs on cardiac toxicity using FAERS identified sirolimus and mosapride as new prophylactic drug candidates. In model mice, mosapride and sirolimus suppressed the Bax/Bcl-2 mRNA ratio, which is elevated in doxorubicin-induced cardiotoxicity. These drugs also suppressed the expression of inflammatory cytokines Il1b and Il6 and markers associated with myocardial fibrosis, including Lgal3 and Timp1. CONCLUSION: These findings suggest that doxorubicin-induced cardiac events are suppressed by the administration of mosapride and sirolimus.

DOI： 10.1016/j.ejphar.2022.175083

副作用対策は今後も進歩するのか?マンネリ化させない研究のデザイン力医療ビッグデータ解析と基礎研究を融合した研究手法による抗がん剤誘発副作用に対する予防法の探索

合田光寛, 神田将哉, 吉岡俊彦, 新村貴博, 櫻田巧, 小川敦, 岡田直人, 相澤風花, 八木健太, 濱野裕章, 石澤有紀, 座間味義人, 石澤啓介

日本臨床腫瘍薬学会雑誌 25 241 - 241 2022年5月

副作用対策は今後も進歩するのか?マンネリ化させない研究のデザイン力医療ビッグデータ解析と基礎研究を融合した研究手法による抗がん剤誘発副作用に対する予防法の探索

合田光寛, 神田将哉, 吉岡俊彦, 新村貴博, 櫻田巧, 小川敦, 岡田直人, 相澤風花, 八木健太, 濱野裕章, 石澤有紀, 座間味義人, 石澤啓介

日本臨床腫瘍薬学会雑誌 25 241 - 241 2022年5月

フェンタニルクエン酸塩経皮吸収型製剤0.5mgの使用実態と安全性の評価

鍛治園誠, 佐藤晶子, 高下典子, 太田佳男, 片山英樹, 座間味義人

日本臨床腫瘍薬学会雑誌 25 186 - 186 2022年5月

Discovery of preventive drugs for cisplatin-induced acute kidney injury using big data analysis. 国際誌

Masaya Kanda, Mitsuhiro Goda, Akiko Maegawa, Toshihiko Yoshioka, Ami Yoshida, Koji Miyata, Fuka Aizawa, Takahiro Niimura, Hirofumi Hamano, Naoto Okada, Takumi Sakurada, Masayuki Chuma, Kenta Yagi, Yuki Izawa-Ishizawa, Hiroaki Yanagawa, Yoshito Zamami, Keisuke Ishizawa

Clinical and translational science 15 ( 7 ) 1664 - 1675 2022年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Cisplatin is effective against many types of carcinoma. However, a high rate of renal damage is a clinical problem. Thus, there is a need to establish a method to prevent it. Although various compounds have been reported to be effective against cisplatin-induced renal injury, there are no examples of their clinical application. Therefore, we attempted to search for prophylactic agents with a high potential for clinical application. We used Cascade Eye to identify genes that are altered during cisplatin-induced renal injury, Library of Integrated Network-based Cellular Signatures (LINCS) to identify drugs that inhibit changes in gene expression, and a large database of spontaneous adverse drug reaction reports to identify drugs that could prevent cisplatin-induced kidney injury in clinical practice. In total, 10 candidate drugs were identified. Using the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), we identified drugs that reduce cisplatin-induced kidney injury. Fenofibrate was selected as a candidate drug to prevent cisplatin-induced kidney injury based on the FAERS analysis. A model was used to evaluate the efficacy of fenofibrate against cisplatin-induced renal injury. Studies using HK2 cells and mouse models showed that fenofibrate significantly inhibited cisplatin-induced renal injury but did not inhibit the antitumor effect of cisplatin. Fenofibrate is a candidate prophylactic drug with high clinical applicability for cisplatin-induced renal injury. Analysis of data from multiple big databases will improve the search for novel prophylactic drugs with high clinical applicability. For the practical application of these findings, evaluation in prospective controlled trials is necessary.

DOI： 10.1111/cts.13282

A web-based survey of educational opportunities of medical professionals based on changes in conference design during the COVID-19 pandemic. 国際誌

Kenta Yagi, Yasutaka Sato, Satoshi Sakaguchi, Mitsuhiro Goda, Hirofumi Hamano, Fuka Aizawa, Mayuko Shimizu, Arisa Inoue-Hamano, Toshihide Nishimori, Masato Tagi, Marina Kanno, Rie Matsuoka-Ando, Toshihiko Yoshioka, Yoshiko Matstubara, Yuki Izawa-Ishizawa, Rieko Shimizu, Akinori Maruo, Yurika Kuniki, Yoshika Sakamoto, Sayuri Itobayashi, Yoshito Zamami, Hiroaki Yanagawa, Keisuke Ishizawa

Education and information technologies 27 ( 7 ) 1 - 16 2022年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Owing to the coronavirus disease 2019 (COVID-19) pandemic, understanding how to hold future online academic conferences effectively is imperative. We assessed the impact of COVID-19 on academic conferences, including facilities and settings for attendance, participation status, cost burden, and preferences for future styles of holding conferences, through a web-based questionnaire survey of 2,739 Japanese medical professionals, from December 2020 to February 2021. Of the participants, 28% preferred web conferences, 60% preferred a mix of web and on-site conferences, and 12% preferred on-site conferences. Additionally, 27% of the presenters stopped presenting new findings at web conferences. The proportion of participants who audio-recorded or filmed the sessions, despite prohibition, was six times higher at web than face-to-face conferences. Since the COVID-19 outbreak, the percentage of participants attending general presentations decreased from 91 to 51%. While web conferencing offers advantages, these are offset by a decrease in presentations pertaining to novel findings and data. Supplementary Information: The online version contains supplementary material available at 10.1007/s10639-022-11032-5.

DOI： 10.1007/s10639-022-11032-5

Drug interaction (53. Interaction of traditional Japanese herbal medicines in chemotherapy)

Naohiro Iwata, Satoru Esumi, Yoshito Zamami

Okayama Igakkai Zasshi (Journal of Okayama Medical Association) 134 ( 1 ) 43 - 47 2022年4月

Identification of prophylactic drugs for oxaliplatin-induced peripheral neuropathy using big data. 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

Prevention of Pemetrexed-Induced Rash Using Low-Dose Corticosteroids: A Phase II Study. 国際誌

Takumi Sakurada, Hiroshi Nokihara, Tadashi Koga, Yoshito Zamami, Mitsuhiro Goda, Kenta Yagi, Hirofumi Hamano, Fuka Aizawa, Hirokazu Ogino, Seidai Sato, Yasushi Kirino, Hisatsugu Goto, Yasuhiko Nishioka, Keisuke Ishizawa

The oncologist 27 ( 7 ) e554-e560 2022年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Rash eruptions are a common side-effect of pemetrexed, for which the administration of 8 mg/day of dexamethasone for 3 days from the day preceding pemetrexed administration is recommended. This study aimed to prospectively assess the effectiveness of prophylactic administration of low-dose dexamethasone for pemetrexed-induced rashes. METHODS: This single-arm, phase II study recruited patients with non-squamous non-small cell lung cancer and malignant pleural mesothelioma scheduled to receive chemotherapy including pemetrexed. Patients received 2 mg of dexamethasone daily from days 2 to 6 after chemotherapy with pemetrexed. The primary endpoint was the 3-week incidence of rash eruptions. RESULTS: Twenty-five patients were enrolled between September 2017 and May 2019. The incidence of rash after 3 weeks was 16.7%. Rashes erupted mainly on the upper half of the body, such as the chest and neck, and were of grades 1 and 2 in 2 patients each. No rashes of grade 3 or higher were observed, and there were no adverse events associated with additional corticosteroids. CONCLUSION: Prophylactic administration of low-dose dexamethasone for 5 days from the day after pemetrexed administration resulted in a milder incidence and severity of rash. These findings may provide a standard preventative strategy for pemetrexed-induced rashes. (Trial identifier: UMIN000025666).

DOI： 10.1093/oncolo/oyab077

Association between statin use and daptomycin-related musculoskeletal adverse events: A mixed approach combining a meta-analysis and a disproportionality analysis. 国際誌

Masayuki Chuma, Aki Nakamoto, Takashi Bando, Takahiro Niimura, Yutaka Kondo, Hirofumi Hamano, Naoto Okada, Mizuho Asada, Yoshito Zamami, Kenshi Takechi, Mitsuhiro Goda, Koji Miyata, Kenta Yagi, Toshihiko Yoshioka, Yuki Izawa-Ishizawa, Hiroaki Yanagawa, Yoshikazu Tasaki, Keisuke Ishizawa

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 75 ( 8 ) 1416 - 1422 2022年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: There is a growing concern about the association between the combined use of daptomycin (DAP) and statins and the occurrence of musculoskeletal adverse events (MAEs), but this remains controversial. This study aimed to clarify the association between statin use and DAP-related MAEs. METHODS: We used a mixed approach that combines two methodologies. First, we conducted a meta-analysis to examine the effects of statin use on DAP-related MAEs. Second, we conducted a disproportionality analysis using the FDA Adverse Events Reporting System (FAERS) to further confirm the results of the meta-analysis and to examine the effect of each type of statin on DAP-related MAEs in a large population. RESULTS: In the meta-analysis, statin use significantly increased the incidence of DAP-related rhabdomyolysis (odds ratio [OR]: 3.83, 95% confidence interval [CI]: 1.43-10.26) but not DAP-related myopathy (OR: 1.72, 95% CI: 0.95-3.12). In the disproportionality analysis using the FAERS, the use of statin significantly increased the reporting OR (ROR) for DAP-related myopathy (ROR: 5.69, 95% CI: 4.31-7.51) and rhabdomyolysis (ROR: 5.77, 95% CI: 4.33-7.68). Atorvastatin, rosuvastatin, and simvastatin all increased the incidence of DAP-related myopathy and rhabdomyolysis. CONCLUSION: The mixed approach combining a meta-analysis and disproportionality analysis showed that statin use was associated with the occurrence of DAP-related rhabdomyolysis. The appropriate use of statins and DAP should be performed with careful consideration of its safety.

DOI： 10.1093/cid/ciac128

各種プロトンポンプ阻害剤のがん細胞におけるVEGF発現に与える影響

安藤里英, 八木健太, 岡本尚大, 高岡麻佑, 相澤風花, 濱野裕章, 石澤有紀, 合田光寛, 座間味義人, 石澤啓介

日本薬学会年会要旨集 142年会 28H - pm04S 2022年3月

自発的副作用報告データベースを用いた、抗線維化薬と間質性肺疾患との関連性についての検討

大西明日香, 名和秀起, 濱野裕章, 新村貴博, 宮田晃志, 八木健太, 合田光寛, 座間味義人, 石澤啓介

日本薬学会年会要旨集 142年会 28PO1 - 46 2022年3月

有害事象自発報告データベースに基づく光学異性体が薬剤間相互作用に与える影響についての検討

根石茉実, 濱野裕章, 新村貴博, 宮田晃志, 八木健太, 合田光寛, 座間味義人, 石澤啓介, 名和秀起

日本薬学会年会要旨集 142年会 28PO1 - 45S 2022年3月

医療ビックデータを活用した免疫チェックポイント阻害剤関連肺炎のリスク因子に関する検討

朝田瑞穂, 見神尊修, 新村貴博, 座間味義人, 中馬真幸, 合田光寛, 石澤啓介, 植沢芳広

日本薬学会年会要旨集 142年会 26PO1 - 14 2022年3月

医療ビックデータを活用した免疫チェックポイント阻害剤関連肺炎のリスク因子に関する検討

朝田瑞穂, 見神尊修, 新村貴博, 座間味義人, 中馬真幸, 合田光寛, 石澤啓介, 植沢芳広

日本薬学会年会要旨集 142年会 26PO1 - 14 2022年3月

Atenolol and mortality events in patients with chronic kidney disease: Analysis of data from the Japanese Adverse Drug Event Report database. 国際誌

Satoru Mitsuboshi, Takahiro Niimura, Fuka Aizawa, Mitsuhiro Goda, Yoshito Zamami, Keisuke Ishizawa

Basic & clinical pharmacology & toxicology 130 ( 4 ) 553 - 556 2022年2月

杜仲葉エキスによる大動脈解離発症抑制効果の検討

宮田晃志, 石澤有紀, 近藤正輝, 辻中海斗, 大峯航平, 西穂香, 相澤風花, 濱野裕章, 八木健太, 座間味義人, 合田光寛, 石澤啓介

日本薬理学会年会要旨集 95 1-SS-37 2022年

記述言語：日本語出版者・発行元：公益社団法人日本薬理学会

Aortic dissection is a severe aortic disease, in which the aortic wall is separated into two layers at the medial level, resulting in two lumens being created, a true and a false lumen. Most cases have a sudden onset resulting in death. Therefore, it is required to establish a preventive strategy. Eucommia ulmoides leaf (EUL) extract contains various flavonoids such as quercetin, chlorogenic acid, geniposidic acid, and so on, and it is suggested to have a protective effect against cardiovascular diseases. In this study, we investigated the preventive effect of EUL on the onset of aortic dissection.

We generated pharmacologically-induced aortic dissection model mice (LAB model). In C57Bl / 6J mice, three agents are administered; (1) nitric oxide synthase inhibitor (L-NAME) that causes vascular endothelial damage, (2) angiotensin II (Ang II) that causes hypertention, and (3) lysyl oxidase inhibitor (BAPN) that causes medial fragility. EUL extract was orally administered daily throughout the experiment.

Hypertension, caused by Ang II+BAPN loading was significantly suppressed by EUL. In the LAB model, macrophage infiltration into the aortic wall was increased, but it was suppressed by EUL administration. As a result, EUL showed the preventive effects against the onset of aortic aneurysm, dissection, and death from rupture.

DOI： 10.1254/jpssuppl.95.0_1-ss-37

慢性骨髄性白血病に対するBcr-Abl阻害剤とALDH阻害剤併用による抗腫瘍効果

國木悠理香, 八木健太, 吉田莉奈, 岡本尚大, 安藤里英, 山川裕介, 濱野裕章, 新村貴博, 相澤風花, 石澤有紀, 合田光寛, 座間味義人, 石澤啓介

日本薬理学会年会要旨集 95 1-SS-66 2022年

記述言語：日本語出版者・発行元：公益社団法人日本薬理学会

【Introduction】Chronic myelogenous leukemia (CML) has become a disease with five-year-survival rate of more than 90% according to appearance of Bcr-Abl inhibitor. Stopping treatment with Bcr-Abl inhibitors leads to relapse in many patients. This is due to the fact that Bcr-Abl inhibitors are not effective against cancer stem cells, and suggests that a different drug is necessary to eradicate cancer stem cells. ALDH is overexpressed in cancer stem cells and promotes their survival. We have shown in past studies that Bcr-Abl inhibitors do not inhibit ALDH expression. In this study, we examine the effect of ALDH inhibitors on CML.

【Methods】We examined the effects of an ALDH inhibitor using K562 cells, which are CML cell line. We verified the effect of an ALDH inhibitor against CML using a WST-8 assay. We then measured ALDH protein expression using flow cytometry.

【Results】ALDH inhibitors reduced cell survival in a concentration-dependent manner, and when combined with a Bcr-Abl inhibitor, cell viability was synergistically decreased. ALDH protein expression was decreased in cells treated with ALDH inhibitor alone or Bcr-Abl inhibitor alone according to flow cytometry. In cells treated with ALDH inhibitor and Bcr-Abl inhibitor, ALDH protein expression was more strongly repressed.

【Conclusion】The results of this study suggest that ALDH inhibitor use might be effective in CML treatment.

DOI： 10.1254/jpssuppl.95.0_1-ss-66

リアルワールドデータに基づく抗がん剤支持療法の開発；スタチン系薬剤による末梢神経障害治療および予防効果の検証

相澤風花, 梶本春奈, 森山大嗣, 岡林亜美, 合田光寛, 濱野裕章, 八木健太, 石澤有紀, 座間味義人, 石澤啓介

日本薬理学会年会要旨集 95 1-O-024 2022年

記述言語：日本語出版者・発行元：公益社団法人日本薬理学会

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the adverse events associated with the anticancer drugs, however, almost available analgesic drugs lack efficacy against CIPN. Previously our results using medical database, FAERS, suggested that HMG-CoA reductase inhibitors (statins) have the potential to ameliorate oxaliplatin-induced peripheral neuropathy (OIPN). In this study, we elucidated the effect and mechanism of statins to OIPN model mice and PC12 cell. Three statins (simvastatin, atorvastatin, and rosuvastatin) could not show the therapeutic and preventive effects against oxaliplatin-induced cold allodynia. On the other hand, repeated orally administration of each statins ameliorate development of oxaliplatin-induced mechanical allodynia and significantly suppressed already established allodynia induced by oxaliplatin. A gene-related database revealed that the expression of glutathione S-transferase (GST) family members is regulated by statins. Decreased survival rate of PC12 cells by treatment of oxaliplatin was canceled cotreatment of each statin for 24 hours. Furthermore, cell protective effect of statin was disappeared transfection of gstmu1 siRNA into PC12 cells. These our results suggest that statins might be one of the novel supportive care, which have neuroprotective effect to OIPN.

DOI： 10.1254/jpssuppl.95.0_1-o-024

シスプラチン誘発急性腎障害に対するバルプロ酸ナトリウムの影響

吉岡俊彦, 合田光寛, 神田将哉, 吉田愛美, 糸林小友理, 杉本祐悟, 石澤有紀, 八木健太, 相澤風花, 濱野裕章, 岡田直人, 座間味義人, 石澤啓介

日本薬理学会年会要旨集 95 1-SS-48 2022年

記述言語：日本語出版者・発行元：公益社団法人日本薬理学会

OBJECTIVE: Cisplatin-induced acute kidney injury (AKI) is well known, and the nephrotoxicity of cisplatin restricts its clinical application. Currently, there are no drugs are recommended for the prevention of cisplatin-induced AKI. Forced hydration and diuresis may partially prevent nephrotoxicity of cisplatin, but it is still difficult to entirely prevent kidney injury. Thus, establishment of a new preventive method against cisplatin-induced AKI is required. Therefore, in this study, the purpose of this study was to clarify the efficacy of sodium valproate in cisplatin-induced AKI.

METHODS: In order to establish cisplatin‐induced AKI animal model, C57BL/6 mice were administered with either cisplatin (15 mg/kg, i.p.) or saline (control). The degree of renal damage was assessed by various renal function parameters and pathological evaluation. The effect of sodium valproate on cisplatin-induced cytotoxicity was evaluated using HK2 cells, MKN-1 cells and LLC cells.

RESULTS: Cisplatin treatment worsened various renal function parameters and tubular damage scores, which were significantly improved by co-treatment with sodium valproate. The decrease in cell viability of HK2 cells by cisplatin was significantly improved by co-treatment with sodium valproate. On the other hand, sodium valproate had no adverse effect on the reduction of cell viability of various cancer cells by cisplatin.

CONCLUSIONS: The results of this study indicated that sodium valproate could act as a potential preventive drug for cisplatin-induced AKI.

DOI： 10.1254/jpssuppl.95.0_1-ss-48

大規模医療情報データベースを用いたスニチニブ誘発心不全に対する予防薬の探索

阪本淑華, 友近七海, 濱野裕章, 合田光寛, 新村貴博, 相澤風花, 八木健太, 仲村明人, 西内栞, 石澤有紀, 座間味義人, 石澤啓介

日本薬理学会年会要旨集 95 1-SS-35 2022年

記述言語：日本語出版者・発行元：公益社団法人日本薬理学会

BACKGROUND: Several studies have reported that patients treated with sunitinib, a tyrosine kinase inhibitor, have developed left ventricular dysfunction and heart failure, but there is currently no treatment for heart failure with sunitinib. The purpose of the present study is to identify candidate drugs for the treatment of sunitinib-induced heart failure using a large medical database. METHOD: We analyzed the FDA Adverse Event Reporting System (FAERS) and the WHO global adverse event reporting database (VigiBase) to find candidate drugs for prevention of sunitinib-induced heart failure. The effects of the candidate drugs on cell viability and cell morphology were evaluated using the WST-8 assay and immunostaining in H9c2 cells derived from rat cardiac rhabdomeres. RESULTS: FAERS and VigiBase searches revealed significantly higher reporting odds ratio (ROR) of heart failure in patients treated with sunitinib than in those not treated with sunitinib. The ROR was reduced by concomitant use of Vitamin D (FAERS: ROR 0.50, 95% CI 0.26-0.96; VigiBase: ROR 0.37, 95% CI 0.10-0.95). In vitro, Vitamin D significantly improved the viability and maintained the cell morphology in H9c2 cells exposed to sunitinib. CONCLUSION: The findings suggest the potential value of Vitamin D in preventing sunitinib-induced heart failure.

DOI： 10.1254/jpssuppl.95.0_1-ss-35

免疫チェックポイント阻害剤関連心筋炎の新規病態モデル開発

新村貴博, 運天拡人, 濱野裕章, 内田和志, 友近七海, 宮田晃志, 合田光寛, 八木健太, 相澤風花, 石澤有紀, 座間味義人, 石澤啓介

日本薬理学会年会要旨集 96 YIA05-2 2022年

記述言語：日本語出版者・発行元：公益社団法人日本薬理学会

Immune Checkpoint Inhibitors (ICI) show anti-tumor activity against various types of cancer, but they also disrupt the balance of the immune system and cause autoimmune-like adverse events. ICI-related myocarditis, in particular, has a fatality rate of over 40%, making the development of preventive and therapeutic agents an urgent priority. In present study, we developed a simple and reproducible experimental model for ICI-associated myocarditis.

Myocardial myosin peptide (50 µg) was administered subcutaneously to male, 8-week-old BALB/c wild-type and PD-1KO mice at day 0 and 7. Three weeks after the initial myosin administration, the development of myocarditis was evaluated. HE staining and Masson trichrome staining showed inflammatory cell infiltration and fibrosis in myocardial tissue in myosin peptide-treated PD-1 KO mice. Next, the involvement of CD4⁺ and CD8⁺ cells was examined by immunostaining, and the infiltration of CD4⁺ and CD8⁺ cells was confirmed in the hearts of myosin-treated PD-1KO mice. Finally, the results of real-time PCR showed that myosin administration tended to increase gene expression of inflammatory cytokines and fibrosis markers in the hearts of PD-1KO mice.

It is expected that this model will be used to develop new prophylactic and therapeutic agents for ICI-associated myocarditis.

DOI： 10.1254/jpssuppl.96.0_yia05-2

ホスホジエステラーゼ5阻害剤に関連した致死的な血管毒性

宮田晃志, 石澤有紀, 濱野裕章, 新村貴博, 相澤風花, 八木健太, 座間味義人, 合田光寛, 石澤啓介

日本臨床薬理学会学術総会抄録集 43 1-C-P-011 2022年

記述言語：日本語出版者・発行元：一般社団法人日本臨床薬理学会

【目的】大動脈をはじめとした各種動脈における瘤・解離疾患は、死亡率の高い血管疾患の一つである。動脈瘤・解離の危険因子として高齢者、男性、喫煙、高血圧、動脈硬化、結合組織病などが知られているが、加えて、フルオロキノロン系抗菌薬や血管新生阻害剤などを用いた薬物治療の有害事象として、動脈瘤・解離のリスクが高まる可能性が示唆されている。近年、勃起障害などに使用されるcGMP特異的ホスホジエステラーゼ (PDE5) 阻害剤使用後に動脈瘤・解離を発症した患者の症例が複数報告されている。動脈瘤モデルマウスを用いた動物実験においても大動脈瘤を悪化させるという結果が得られており、PDE5阻害剤は動脈瘤・解離に関与する可能性が示唆される。本研究では、世界保健機関 (WHO) のグローバルファーマコビジランスデータベースであるVigiBaseを用いたファーマコビジランス手法により、PDE5阻害剤のヒトに対する動脈瘤・解離リスクを明らかにすることを目的として研究を行った。【方法】WHOの個別症例安全性報告データベースであるVigiBaseを使用し2021年12月までのデータを不均衡分析により解析した。PDE5阻害剤としてシルデナフィル、タダラフィル、バルデナフィル、ウデナフィル、アバナフィルに関して解析した。副作用発現の有無や薬剤使用の有無から報告オッズ比 (ROR) を算出し、RORの95%信頼区間の下限値が1を超えるものを、副作用シグナルが検出された、とみなした。【結果・考察】VigiBaseにある27,994,584件の報告のうち249件でPDE５阻害剤使用との関連が疑われる動脈瘤・解離が報告されていた。不均衡分析の結果ではPDE５阻害剤投与例において副作用シグナルが検出され、個別の薬剤としてはシルデナフィル、タダラフィルでシグナルを認めた。またPDE5阻害剤使用症例に関して、適応症ごと、または瘤・解離病変が形成された各動脈の部位ごとに実施した不均衡分析においても、それぞれシグナルが検出された。年齢・性別で層別化した解析でも同様にシグナルが検出された。これらの結果はPDE5阻害剤の使用と動脈瘤・解離の関連を示しており、PDE5阻害剤の使用が動脈瘤・解離発症のリスクを上昇させる可能性を示している。【結論】本研究によりPDE5阻害剤は動脈瘤・解離のリスクを高める可能性があり、PDE5阻害剤の使用と動脈瘤・解離発症の因果関係を証明するために、母集団解析を含むさらなる研究が必要であることが示された。

DOI： 10.50993/jsptsuppl.43.0_1-c-p-011

バンコマイシン関連腎障害発症後の腎障害遷延は、生命予後を悪化させる― 2種類のリアルワールドデータを用いた融合解析 ―

中馬真幸, 濱野裕章, 坂東貴司, 新村貴博, 岡田直人, 笠茂紗千子, 八木健太, 合田光寛, 座間味義人, 楊河宏章, 石澤啓介, 田崎嘉一

日本臨床薬理学会学術総会抄録集 43 3-C-O08-3 2022年

記述言語：日本語出版者・発行元：一般社団法人日本臨床薬理学会

【目的】バンコマイシン(VCM)関連腎障害(VAN; VCM-associated nephrotoxicity)は、投与症例の約10～40%に発症する重篤な有害事象である。近年、発症後の腎障害遷延や生命予後の悪化が問題となっているが、転帰に関連する因子は明らかになっていない。今回、VAN発症後の腎障害遷延や生命予後に関連する因子について検討した。

【方法】2つのリアルワールドデータを用いて解析した。まず、世界最大規模の副作用自発報告が集積されているFAERS (FDA Adverse Event Reporting System)を用いてVAN発症と死亡の関係を検討した(1. FAERS解析)。次に、詳細な情報を得られる診療情報データ(EMR: Electronic Medical Records)を用いて、VAN発症後の腎機能遷延および生命予後の悪化に関連する因子を検討した(2. EMR解析)。

(1.FAERS解析) 2004年第1期～2020年第1期に、注射用VCMが投与された10,414例の報告を解析した。VAN発症と死亡の関係は、ロジスティック回帰分析により検討した。

(2. EMR解析) 2006年1月～2019年3月に徳島大学病院において、VCMが初回投与された482例を解析した。VAN発症後の腎障害遷延および生命予後に対する観察期間は、それぞれ7日、1年間とした。VAN発症後の転帰に関連する因子は、Cox比例ハザード分析により検討した。

【結果・考察】FAERS解析におけるVAN発症例の死亡率 (23.3%, 613/2634)は、非発症例 (17.2%, 1338/7780)よりも有意に高かった [調整オッズ比: 1.43, 95%信頼区間(CI): 1.28-1.59]。FAERS解析にてVAN発症後の死亡率上昇が示唆されたため、VAN発症後の予後悪化に関連する因子をEMR解析にて検討した。全482例中、VAN発症は72例(14.9%)、院内死亡は74例(15.4%)に認められた。1年の観察期間における生存は234例 (48.5%)、死亡は136例 (28.2%)、打ち切りは112例 (23.2%)であった。VAN発症後の腎障害遷延は、院内死亡[ハザード比 (HR):4.05, 95%CI: 2.42-6.77]および1年死亡(HR: 3.03, 95% CI: 1.98-4.64]に有意に関連していた。腎障害の改善率は、AKIステージ≧2に進展したVAN発症例で有意に低かった (HR: 0.09; 95% CI: 0.02-0.40)。VAN発症後の生命予後悪化には腎障害の遷延が関連しており、そのリスク因子はAKIステージ≧2への進展であることが示された。

【結論】VCM投与症例の生命予後改善には、VANの発症と重症化を予防することが重要である。

DOI： 10.50993/jsptsuppl.43.0_3-c-o08-3

臨床試験実施可能性調査における被験者候補の効率的な絞り込み手法の検討

岡崎理紗, 奥田浩人, 濱野裕章, 難波志穂子, 神川邦久, 宇野秀樹, 牛尾聡一郎, 黒田智, 座間味義人, 狩野光伸, 森田瑞樹

日本臨床薬理学会学術総会抄録集 43 3-C-P-095 2022年

記述言語：日本語出版者・発行元：一般社団法人日本臨床薬理学会

【背景】臨床試験は新薬・新医療機器等の開発のみならず診療の最適化においても必要であり、文部科学省と厚生労働省は継続して臨床試験の活性化に取り組んできた。臨床試験の成功率を上げるために、臨床試験の受託前に、被験者となりうる患者の数（候補患者数）の見積もり調査が実施される。このような調査を行っているにも関わらず、調査に十分なリソースが割けないなどの理由から見積もりの精度が低くなり、臨床試験開始後に想定通り被験者が集まらないケースがある。このことが、臨床試験全体の遅れや中止による医薬品開発費の増大や科研費等の浪費につながっている。そこで、電子カルテのデータを用いた機械的な絞り込みを行うことによって被験者の候補者数の見積もりを効率化することで、被験者が想定通り集まらない事態を回避できるのではないかと考え、検討を行った。【目的】本研究では、電子カルテのデータを用いた機械的な患者絞り込みによって、候補患者数の見積もりが効率化されるか検討することを目的とした。【方法】一型糖尿病および潰瘍性大腸炎の臨床試験を対象とし、適格基準を満たす患者を以下の2つの方法で抽出した。(1)電子カルテのデータを用いた機械的な絞り込みを実施する。(2)臨床研究コーディネーター(CRC)によるカルテ調査を実施する。本研究では、(2)の方法で抽出された患者群を正解データとし、(1)の機械的な絞り込みの精度を求めた。【結果・考察】一型糖尿病では感度が37.5%となり、本来被験者候補とすべき症例をすべて網羅することができなかった。一方、潰瘍性大腸炎では感度が100%となり、被験者候補とすべき症例を漏れることなく抽出し、加えてカルテ調査をすべき症例数を約1/10に絞り込むことに成功した。このことから、CRCによるカルテ調査の前に機械的な絞り込みを実施するという運用を想定すると、被験者候補の抽出に要する時間を約1/10に短縮できる計算となった。【結論】潰瘍性大腸炎では、電子カルテのデータを用いた機械的な絞り込みが成功し、候補患者数の見積もりの効率化につながる結果が得られた。一方で、一型糖尿病に対する適応は困難であった。今後本研究手法の適合性を高めるために、成否に影響を与える疾患、臨床試験または適格基準の特徴について更なる調査と分析が必要である。

DOI： 10.50993/jsptsuppl.43.0_3-c-p-095

臨床薬理学集中講座受講者による臨床薬理共同研究推進体制の構築に向けた取り組み

武智研志, 座間味義人, 肥田典子, 鈴木啓介

日本臨床薬理学会学術総会抄録集 43 2-C-S28-5 2022年

記述言語：日本語出版者・発行元：一般社団法人日本臨床薬理学会

近年、医療の中で薬物療法とそれを支える臨床薬理学の重要性が高まっており、薬物の人体における作用と動態を研究し、合理的薬物治療を確立するための科学である臨床薬理学を担う人材の育成が益々求められています。臨床薬理学集中講座は、若手の医師及び薬剤師等が臨床薬理学を体系的・集中的に研鑽する場となり、臨床試験を通じたエビデンスの創造・発信のできる医療従事者・研究者の育成を目指して2016年より開講し、今年度は第6回がWebにて開催されました。受講生は、臨床薬理学について本講座で体系的に学び、受講後その知識を活かせる臨床研究の場が必要と考えられます。そこで本セミナーは、臨床研究を共同で立ち上げ、スタートできるようにすることを一つの狙いとし、本講座参加者メンバーにより、共同研究をこれまでに2本計画してきました。今回は、研究実施準備中のポリファーマシーに関する共同研究と現在実施中である、抗がん剤誘発末梢神経障害の予防に関するドラッグリポジショニングの多施設共同研究の進捗や今後の展望などをご紹介し、昨年度までのフォローアップセミナーにて抽出されてきた課題を振り返りながら、参加者の皆さんと臨床薬理学を通じた実践的な活動や、今後の臨床研究について討論できたらと思います。また、昨年度から引き続き新型コロナウィルス感染症が終息していないことから、多施設共同研究の実施が容易ではない状況が続いています。しかし、本共同研究では、Webツールなどを積極的に取り入れながら、可能な限り多施共同研究の進展を図るべき工夫も行っており、本共同研究で行ったツールや工夫などを紹介し、臨床研究を共同研究として進める場合の実践的な知恵や工夫を共有できる場にできたらと思います。本セミナーにて、臨床薬理学を軸とした臨床研究の開始や参加者の臨床研究をブラッシュアップいただける場になるように、より多くの方々の参加やご意見を頂ければと思います。

DOI： 10.50993/jsptsuppl.43.0_2-c-s28-5

パルボシクリブの用量調節による服用継続日数への影響

岩田直大, 牛尾聡一郎, 正岡康幸, 濱野裕章, 鍛治園誠, 座間味義人

日本臨床薬理学会学術総会抄録集 43 1-C-P-019 2022年

記述言語：日本語出版者・発行元：一般社団法人日本臨床薬理学会

【目的】パルボシクリブはサイクリン依存性キナーゼ4および6を特異的に阻害する経口分子標的薬であり、ホルモン受容体陽性/ヒト上皮増殖因子受容体2陰性の進行・再発乳がん患者に使用されている。パルボシクリブは1日1回125mgを3週間連続して内服し、その後1週間休薬する。有害事象の発生状況によっては1日1回100mgや75mgへ用量の調節を行うこととなっており、好中球減少をはじめ高頻度に有害事象が発生し、休薬や減量を余儀なくされる場合も多い。しかしながら、これまでパルボシクリブの用量調節と治療継続に関する報告はない。そこで本研究では、岡山大学病院においてパルボシクリブが投与された乳がん患者を対象として、パルボシクリブの用量調節と治療継続への影響について検討を行った。【方法】2018年1月から2022年6月までの期間に、岡山大学病院においてパルボシクリブが処方された乳がん患者38名を対象とした。調査項目は患者背景（年齢、身長、体重、体表面積）、投与量、投与期間、副作用歴、投与開始前の血液検査値、有害事象、投与中止理由とした。パルボシクリブを投与開始してから中止するまでの日数はKaplan-Meier法を用いて、log-rank testを行った。【結果・考察】対象患者38名のうちパルボシクリブ125mgで継続した患者は12名、125mg投与後に減量した患者は26名であった。治療期間の中央値は、125mg継続群で212日（35-791日）、減量群で502日（77-1733日）であり、減量群において有意に治療期間の延長がみられた（p=0.00248）。投与中止の原因として、減量群のうちパルボシクリブ服用継続中の患者を除き15名中12名がprogressive disease (PD)であった。パルボシクリブは125mgから投与開始しするが、Grade 3の有害事象が出現する場合は、休薬し、回復後は同一投与量で投与を再開する。しかし、回復に日数を要するなどの場合は減量を考慮することとなっている。今回、パルボシクリブの投与量を125mgで継続するよりも、減量した患者の方が服用継続日数が高かった。また投与中止した原因の多くがPDであった。本調査は、症例数が40例未満であり、今後症例数を増やしたさらなる検討が必要である。【結論】パルボシクリブは投与量を125mgで継続するよりも、有害事象の発生に応じた適切な用量調節を行うことで治療期間が継続する可能性がある。

DOI： 10.50993/jsptsuppl.43.0_1-c-p-019

臨床薬理共同研究推進体制の構築に向けた取り組み

座間味義人, 武智研志, 鈴木啓介, 肥田典子

日本臨床薬理学会学術総会抄録集 42回 1 - 2 2021年12月

Renin-angiotensin-aldosterone system inhibitors prevent the onset of oxaliplatin-induced peripheral neuropathy: A retrospective multicenter study and in vitro evaluation.

Mami Uchida, Soichiro Ushio, Takahiro Niimura, Kenshi Takechi, Hitoshi Kawazoe, Noriaki Hidaka, Akihiro Tanaka, Hiroaki Araki, Yoshito Zamami, Keisuke Ishizawa, Yoshihisa Kitamura, Toshiaki Sendou, Hiromu Kawasaki, Hiroyuki Namba, Kazuhiko Shibata, Mamoru Tanaka, Shingo Takatori

Biological & pharmaceutical bulletin 45 ( 2 ) 226 - 234 2021年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Oxaliplatin (OXA) is used in chemotherapy for various cancer types and is associated with acute and chronic neurotoxicity. However, a preventive strategy for OXA-induced peripheral neuropathy (OIPN) and its underlying mechanism remain unclear. We examined the effects of renin-angiotensin-aldosterone system inhibitors (RAASIs) on OIPN by performing a retrospective multicenter study and an in vitro assay. We retrospectively evaluated electronic medical records of 976 patients who underwent one or more courses of OXA-containing regimens at Ehime, Okayama, and Tokushima University Hospitals. The primary endpoint was the incidence of OIPN during or after OXA administration. The effects of RAASIs and OXA on the neurite length in PC12 cells were determined. The combined administration of an OXA-containing regimen and RAASI significantly inhibited the cumulative incidence grade-2 or higher OIPN (log-rank test; P=0.0001). RAASIs markedly suppressed the development of both acute and chronic OIPN (multivariate analysis; P=0.017 and P=0.011). In an in vitro assay, 10 µM OXA suppressed the neurite length; treatment with 1 μM aliskiren, spironolactone, 10 μM candesartan, and enalapril significantly restored neurite length to the control level. Moreover, 1 μM SCH772984 (a selective inhibitor of extracellular signal-regulated kinase, ERK1/2) and 500 μM SQ22536 (a cell-permeable adenylate cyclase [AC] inhibitor) markedly abolished neuroprotective effects of candesartan and enalapril. These results indicate that RAASIs possess preventive or therapeutic effects in acute and chronic OIPN, candesartan and enalapril may directly increase in the activity of ERK1/2 and AC in PC12 cells.

DOI： 10.1248/bpb.b21-00852

Risk of Hematologic Events With Coadministration of Methotrexate and the Breast Cancer Resistance Protein Inhibitor Febuxostat. 国際誌

Satoru Mitsuboshi, Takahiro Niimura, Masaya Kanda, Shunsuke Ishida, Yoshito Zamami, Keisuke Ishizawa

The Annals of pharmacotherapy 56 ( 8 ) 10600280211055794 - 10600280211055794 2021年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: The breast cancer resistance protein (BCRP) is a key drug transporter found in the liver, kidney, central nervous system, and gastrointestinal tract. Due to the wide expression of BCRP, interactions of other drugs with methotrexate (MTX) may differ in oral and intravenous MTX users, and understanding of these interactions may be useful in preventing severe adverse events. Febuxostat, a urate-lowering drug, inhibits BCRP. OBJECTIVE: The objective of this study was to clarify the differences in the drug-drug interaction profiles of oral and intravenous methotrexate, associated with BCRP. METHODS: We analyzed the Japanese Adverse Drug Event Report database and compared the frequency of hematologic events in patients taking oral and intravenous MTX, with or without the concomitant use of febuxostat or allopurinol. Hematologic events were defined as pancytopenia and neutropenia. Multiple logistic regression analysis was then used to identify the risk factors for hematologic events in oral and intravenous MTX users. RESULTS: We identified 8 453 oral and 810 intravenous MTX users with 546 and 126 cases of hematologic events, respectively. Compared with those not using febuxostat, a disproportionate number of hematologic events was observed in intravenous MTX users concomitantly using febuxostat (P < 0.01). The multivariate logistic analysis of intravenous MTX users showed that hematologic events were significantly associated with febuxostat use (P < 0.01) and age ≥ 60 years (P < 0.01). CONCLUSION AND RELEVANCE: Our findings suggest that patients being treated with intravenous MTX who concomitantly use febuxostat may be at an increased risk of hematologic events, presumably due to BCRP-mediated drug-drug interaction.

DOI： 10.1177/10600280211055794

Impact of Area Under the Concentration-Time Curve on the Prevalence of Vancomycin-Induced Nephrotoxicity in Combination With Tazobactam/Piperacillin or Cefepime: A Single-Institution Retrospective Study. 国際誌

Naoto Okada, Yuki Izumi, Aki Nakamoto, Masayuki Chuma, Mitsuhiro Goda, Kenta Yagi, Fuka Aizawa, Hirofumi Hamano, Yoshito Zamami, Momoyo Azuma, Keisuke Ishizawa

Clinical therapeutics 43 ( 11 ) 1910 - 1920 2021年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: Risk for vancomycin-induced nephrotoxicity (VIN) is reportedly reduced by AUC-guided vancomycin dosing. However, it remains unknown whether the increased VIN risk in combination treatment with vancomycin and tazobactam/piperacillin, which is a VIN risk factor, can be diminished by AUC-guided vancomycin dosing (vancomycin-AUC). The aim of this study was to assess whether the evaluation of vancomycin-AUC + tazobactam/piperacillin (VT) combination therapy could prevent VIN. METHODS: The data from patients who received VT or vancomycin + cefepime (VC; the control group) at Tokushima University Hospital (Kuramoto, Japan) between April 2010 and March 2020 were analyzed in this retrospective study. The between-group difference in the prevalence of VIN onset, stratified by AUC, was investigated. The AUC of vancomycin was calculated using the Bayesian method with the blood concentration of vancomycin. The risk factors and probability of VIN onset from the vancomycin exposure-toxicity curve were evaluated using the logistic model. FINDINGS: The prevalences of VIN were 29.5% (18/61) and 7.1% (3/42) in the VT and VC groups, respectively. Multivariate logistic regression analysis of data from all patients revealed concurrent use of tazobactam/piperacillin (odds ratio [OR] = 4.59; P = 0.039) and AUC increase (OR = 1.01; P < 0.01) as risk factors for VIN, but only concurrent use of tazobactam/piperacillin was identified as a risk factor in patients with an AUC of <600 μg · h/mL, the guideline-recommended value (OR = 9.52; P = 0.041). Moreover, the vancomycin exposure-toxicity curve showed that in the guideline-recommended AUC range, VIN probability was consistently higher and the slope of VIN probability was greater in the VT group than in the VC group. IMPLICATIONS: VIN risk was higher with VT than with VC, even when the AUC was controlled to the guideline-recommended range. These results strongly suggest that VIN prevention may be difficult with AUC-guided vancomycin dosing in patients receiving VT.

DOI： 10.1016/j.clinthera.2021.09.007

薬学生を対象とした病院実務実習における栄養管理教育の効果

林明希, 合田光寛, 座間味義人, 八木健太, 中馬真幸, 濱野裕章, 岡田直人, 桐野靖, 中村敏己, 石澤啓介

学会誌JSPEN 3 ( Suppl.1 ) 844 - 844 2021年10月

薬学生を対象とした病院実務実習における栄養管理教育の効果

林明希, 合田光寛, 座間味義人, 八木健太, 中馬真幸, 濱野裕章, 岡田直人, 桐野靖, 中村敏己, 石澤啓介

学会誌JSPEN 3 ( Suppl.1 ) 844 - 844 2021年10月

腎臓病薬物療法研究を加速する、データベース研究ことはじめリアルワールドデータを操り新たなエビデンスを創出するレセプトデータを中心に

岡田直人, 座間味義人, 石澤啓介

日本腎臓病薬物療法学会誌 10 ( 特別号 ) S99 - S99 2021年10月

Fluoropyridmidine use and hypertriglyceridemia among Japanese patients: analysis of adverse event database. 国際誌

Satoru Mitsuboshi, Takahiro Niimura, Masaki Yoshino, Yoshika Sakamoto, Yoshito Zamami, Keisuke Ishizawa

International journal of clinical pharmacy 44 ( 1 ) 260 - 263 2021年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Background The association between fluoropyrimidines except for capecitabine and the risk of hypertriglyceridemia is unclear. Objective To investigate hypertriglyceridemia in patients receiving fluoropyrimidines. Method This observational study used anonymized patient data recorded in the open-access Japanese Adverse Drug Event Report database. All fluoropyrimidine and taxane users were investigated. Results We identified 29,451 fluoropyrimidine users and 21,266 taxane users. Disproportionality for both hypertriglyceridemia and an increase in serum triglyceride levels was observed in fluoropyrimidine users compared with in taxane users (reporting odds ratio, 6.74; 95% confidence interval [CI] 2.05-22.17; P < .001). Multivariate logistic analysis showed that both hypertriglyceridemia and an increase in serum triglyceride levels among fluoropyrimidines users were significantly associated with doxifluridine use (odds ratio [OR] 42.50; 95% CI 5.34-338.00; P < .001), tegafur use (OR 9.56; 95% CI 2.08-43.90; P < .001), capecitabine use (OR 12.30; 95% CI 2.67-56.80; P < .001), and breast cancer (OR 5.61; 95% CI 1.07-29.50; P = .042). Conclusion This study suggests that the use of tegafur and doxifluridine is associated with an increased risk of hypertriglyceridemia similar to that with the use of capecitabine; in particular, fluoropyrimidine users with breast cancer may have a high risk of hypertriglyceridemia.

DOI： 10.1007/s11096-021-01324-0

Examination of the antiepileptic effects of valacyclovir using kindling mice- search for novel antiepileptic agents by drug repositioning using a large medical information database. 国際誌

Shimon Takahashi, Kenshi Takechi, Natsumi Jozukuri, Takahiro Niimura, Masayuki Chuma, Mitsuhiro Goda, Yoshito Zamami, Yuki Izawa-Ishizawa, Masaki Imanishi, Yuya Horinouchi, Yasumasa Ikeda, Koichiro Tsuchiya, Hiroaki Yanagawa, Keisuke Ishizawa

European journal of pharmacology 902 174099 - 174099 2021年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Despite the availability of more than 20 clinical antiepileptic drugs, approximately 30% of patients with epilepsy do not respond to antiepileptic drug treatment. Therefore, it is important to develop antiepileptic products that function via novel mechanisms. In the present study, we evaluated data from one of the largest global databases to identify drugs with antiepileptic effects, and subsequently attempted to understand the effect of the combination of antiepileptic drugs and valacyclovir in epileptic seizures using a kindling model. To induce kindling in mice, pentylenetetrazol at a dose of 40 mg/kg was administered once every 48 h. Valacyclovir was orally administered 30 min before antiepileptic drug injection in kindled mice, and behavioral seizures were monitored for 20 min following pentylenetetrazol administration. Additionally, c-Fos expression in the hippocampal dentate gyrus was measured in kindled mice. Valacyclovir showed inhibitory effects on pentylenetetrazol-induced kindled seizures. In addition, simultaneous use of levetiracetam and valacyclovir caused more potent inhibition of seizure activity, and neither valproic acid nor diazepam augmented the anti-seizure effect in kindled mice. Furthermore, kindled mice showed increased c-Fos levels in the dentate gyrus. The increase in c-Fos expression was significantly inhibited by the simultaneous use of levetiracetam and valacyclovir. The findings of the present study indicate that a combination of levetiracetam and valacyclovir had possible anticonvulsive effects on pentylenetetrazol-induced kindled epileptic seizures. These results suggest that valacyclovir may have an antiseizure effect in patients with epilepsy.

DOI： 10.1016/j.ejphar.2021.174099

医療ビッグデータを活用したドラッグリポジショニングによるオキサリプラチン誘発末梢神経障害の予防薬開発

座間味義人, 新村貴博, 川尻雄大, 合田光寛, 濱野裕章, 八木健太, 相澤風花, 小林大介, 島添隆雄, 石澤有紀, 楊河宏章, 石澤啓介

臨床薬理の進歩 ( 42 ) 72 - 84 2021年6月

血管新生阻害剤における大動脈解離発症の関連要因解明

辻中海斗, 石澤有紀, 新村貴博, 吉岡俊彦, 合田光寛, 近藤正輝, 大峯航平, 西穂果, 宮田晃志, 濱野裕章, 相澤風花, 八木健太, 座間味義人, 石澤啓介

血管 44 ( 1 ) 38 - 38 2021年6月

血管新生阻害剤における大動脈解離発症の関連要因解明

辻中海斗, 石澤有紀, 新村貴博, 吉岡俊彦, 合田光寛, 近藤正輝, 大峯航平, 西穂果, 宮田晃志, 濱野裕章, 相澤風花, 八木健太, 座間味義人, 石澤啓介

血管 44 ( 1 ) 38 - 38 2021年6月

Effects of 5-HT₃ receptor antagonists on cisplatin-induced kidney injury. 国際誌

Mitsuhiro Goda, Masaya Kanda, Toshihiko Yoshioka, Ami Yoshida, Yoichi Murai, Yoshito Zamami, Fuka Aizawa, Takahiro Niimura, Hirofumi Hamano, Naoto Okada, Kenta Yagi, Masayuki Chuma, Yuki Izawa-Ishizawa, Keisuke Ishizawa

Clinical and translational science 14 ( 5 ) 1906 - 1916 2021年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Nausea, vomiting, and renal injury are the common adverse effects associated with cisplatin. Cisplatin is excreted via the multidrug and toxin release (MATE) transporter, and the involvement of the MATE transporter in cisplatin-induced kidney injury has been reported. The MATE transporter is also involved in the excretion of ondansetron, but the effects of 5-HT3 receptor antagonists used clinically for cisplatin-induced renal injury have not been elucidated. Therefore, the aim of this study was to investigate the effects of 5-HT3 receptor antagonists in a mouse model of cisplatin-induced kidney injury and to validate the results using medical big data analysis of more than 1.4 million reports and a survey of 3000 hospital medical records. The concomitant use of a first-generation 5-HT3 receptor antagonist (ondansetron, granisetron, or ramosetron) significantly increased cisplatin accumulation in the kidneys and worsened renal damage. Conversely, the concomitant use of palonosetron had no effect on renal function compared with the use of cisplatin alone. Furthermore, an analysis of data from the US Food and Drug Administration Adverse Event Reporting System and retrospective medical records revealed that the combination treatment of cisplatin and a first-generation 5-HT3 receptor antagonist significantly increased the number of reported renal adverse events compared with the combination treatment of cisplatin and a second-generation 5-HT3 receptor antagonist. These results suggest that compared with the first-generation antagonists, second-generation 5-HT3 receptor antagonists do not worsen cisplatin-induced acute kidney injury. The findings should be validated in a prospective controlled trial before implementation in clinical practice.

DOI： 10.1111/cts.13045

Evaluation of potential complication of interstitial lung disease with abemaciclib and palbociclib treatments. 国際誌

Hideki Nawa, Takahiro Niimura, Kenta Yagi, Mitsuhiro Goda, Yoshito Zamami, Keisuke Ishizawa

Cancer reports (Hoboken, N.J.) 5 ( 1 ) e1402 2021年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Various cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have demonstrated promising anti-tumor effects. The Japanese Ministry of Health, Labour and Welfare has issued a warning about interstitial lung diseases as an adverse effect of CDK4/6 inhibitors. However, a large-scale evaluation of potential complications has not been conducted to date, and the occurrence of these adverse effects is unclear. AIM: The aim of this study was to evaluate the clinical incidence of interstitial lung disease caused by two CDK4/6 inhibitors, abemaciclib and palbociclib, and assess the relationship between each drug and interstitial lung disease. METHODS AND RESULTS: We evaluated the relationship between the CDK4/6 inhibitors (abemaciclib and palbociclib) and interstitial lung disease in clinical practice using data from the Japanese Adverse Drug Event Report (JADER) database and FDA Adverse Event Reporting System (FAERS) to detect adverse event signals with reported odds ratios (RORs). Furthermore, we performed an adverse event-time analysis for each drug using data from the JADER database to examine the time of onset of the adverse events. The analysis of the reports in the JADER database showed that the lower limit of the 95% confidence interval (CI) of ROR for abemaciclib was >1 regardless of age, and a signal was detected. Interstitial lung disease associated with abemaciclib and palbociclib use has been reported, with an average onset period from treatment initiation [median (25th-75th quartile)] of 65.1 [56.0 days (25.3-98.3 days)] and 53.1 days [38.0 days (10.8-76.0 days)], respectively. The analysis of the reports in the FAERS showed that the lower limit of the 95% CI of the ROR for the two drugs was >1, and a signal was detected. CONCLUSION: Treatment with abemaciclib and palbociclib is associated with a potential complication of interstitial lung disease, regardless of age.

DOI： 10.1002/cnr2.1402

Population-Based Observational Study of Adverse Drug Event-Related Mortality in the Super-Aged Society of Japan. 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5月

記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: Adverse drug events (ADEs) are a major cause of mortality. OBJECTIVE: We examined long-term trends for ADE-related deaths in Japan. METHODS: This observational study was conducted using the Japanese Vital Statistics from 1999 to 2016. Data for all ADE-related deaths were extracted using International Classification of Diseases, Tenth Revision codes. We analysed ADE-related deaths by age and sex and calculated crude and age-standardised mortality rates (ASMR) per 100,000 people. We used Joinpoint regression analysis to identify significant changing points in mortality trends and to estimate annual percentage change (APC). RESULTS: In total, 16,417 ADE-related deaths were identified. The crude mortality rate for individuals aged ≥ 65 years was higher than that of young individuals. The ASMR per 100,000 people increased from 0.44 in 1999 to 0.64 in 2016. The crude mortality rate increased from 0.44 in 1999 to 1.01 in 2016. The APC of ASMR increased at a rate of 2.8% (95% confidence interval [CI] 1.4-4.2) throughout the study period. In addition, crude mortality increased at a rate of 5.7% (95% CI 4.2-7.3) annually from 1999 to 2016. The ADE-related mortality rate was higher for men than for women during the study period. CONCLUSIONS: The number of and trend in ADE-related deaths increased in Japan from 1999 to 2016, particularly in the older population.

DOI： 10.1007/s40264-020-01037-9

Trends in hepatitis C virus-associated mortality rates in Japan, 1998-2017. 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4月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND AND AIM: The current prevalence of hepatitis C virus infection and hepatitis C virus-associated mortality in Japan falls short of the World Health Organization goal of viral hepatitis elimination by 2030. We aimed to evaluate the trends in hepatitis C virus-associated mortality in Japan. METHODS: This nationwide observational study used the Japanese Vital Statistics from 1998 to 2017 and included all Japanese hepatitis C virus-associated deaths (84 936) of adults aged ≥ 40 years. We calculated the crude and age-standardized mortality rates per 100 000 persons by age and sex. Joinpoint regression analysis was used to identify significant changing points in trends and to estimate the annual percentage changes and the average annual percentage changes for the entire study period. RESULTS: The crude mortality rate per 100 000 persons (annual death number) increased from 5.5 (3548) in 1998 to 7.0 (4843) in 2005 and decreased to 4.0 (3095) in 2017. By 2017, the crude mortality rates per 100 000 persons among men and women had dropped to 3.6 and 4.3, respectively. The age-standardized mortality rate was higher in women than in men. The average annual percentage change was -3.8% (95% confidence interval: -5.0 to -2.5). The declining trend was more rapid in men (-4.5%, 95% confidence interval: -5.3 to -3.6) than in women (-2.7%, 95% confidence interval: -3.8 to -1.6). CONCLUSIONS: Trends in hepatitis C virus-associated mortality rates have declined in an accelerating manner in Japan, especially among men.

DOI： 10.1111/jgh.15517

薬剤誘発性大動脈解離易発症モデルマウスを用いた薬効評価

石澤有紀, 合田光寛, 相澤風花, 座間味義人, 濱野裕章, 八木健太, 池田康将, 石澤啓介, 玉置俊晃

四国医学雑誌 77 ( 1-2 ) 57 - 62 2021年4月

オキサリプラチン誘発末梢神経障害に対するHMG-CoA還元酵素阻害剤の影響

相澤風花, 座間味義人, 濱野裕章, 石澤啓介, 梶本春奈, 森山大嗣, 新村貴博, 合田光寛, 八木健太, 石澤有紀

四国医学雑誌 77 ( 1-2 ) 109 - 109 2021年4月

A comparison of the safety and effectiveness of prasugrel and clopidogrel in younger population undergoing percutaneous coronary intervention: A retrospective study using a Japanese claims database. 国際誌

Hiromi Hagiwara, Hidekatsu Fukuta, Hiroya Hashimoto, Takahiro Niimura, Yoshito Zamami, Keisuke Ishizawa, Takeshi Kamiya, Nobuyuki Ohte

Journal of cardiology 77 ( 3 ) 285 - 291 2021年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Prasugrel inhibits platelet aggregation more potently than clopidogrel. In the global phase III trial, prasugrel [loading dose/maintenance dose (LD/MD), 60/10 mg] reduced the incidence of ischemic events but involved a higher risk of hemorrhage than clopidogrel in patients with acute coronary syndromes who were scheduled to undergo percutaneous coronary intervention (PCI). In the Japanese phase III trial for similar patients wherein the prasugrel dose regimen was adjusted (LD/MD, 20/3.75 mg), the efficacy of prasugrel and clopidogrel were comparable to that in the global trial; however, the safety could not be determined due to limited power. Given the strict enrollment criteria, the results of the Japanese phase III trial may not be applicable to routine clinical practice. We compared the safety and effectiveness of prasugrel and clopidogrel in the real-world setting in Japanese patients. METHODS: With an analysis of a large claims database prepared during the post-marketing stages in Japan, we identified patients undergoing PCI and compared the incidence of bleeding and ischemic coronary events between patients who received prasugrel and those receiving clopidogrel. RESULTS: Between January 1, 2014 and December 31, 2018, we identified 1977 patients who were scheduled to undergo urgent PCI (urgent PCI cohort) and 1922 who were scheduled to undergo elective PCI (elective PCI cohort). After propensity-score matching, there were no significant differences in the baseline clinical characteristics of the prasugrel and clopidogrel groups in the urgent (n = 1080) and elective PCI (n = 1626) cohorts. In Cox proportional hazard analyses, there were no significant differences in the incidence of bleeding or ischemic coronary events during the median 8-month follow-up in both cohorts. CONCLUSIONS: The safety and effectiveness of prasugrel was comparable to that of clopidogrel in real-world Japanese patients scheduled to undergo PCI.

DOI： 10.1016/j.jjcc.2020.10.001

【抗菌薬供給トラブルもし入手困難になったら、そのときどうする】主要な抗菌薬が供給不足になったときに考慮する代替薬セファゾリン、セファレキシン

岡田直人, 座間味義人, 石澤啓介

薬局 72 ( 3 ) 422 - 426 2021年3月

記述言語：日本語出版者・発行元：(株)南山堂

＜Key Points＞◎セファゾリンやセファレキシンは黄色ブドウ球菌やレンサ球菌、大腸菌・クレブシエラ属・プロテウス属、ペプトストレプトコッカス属に抗菌活性を示す。◎セファゾリンは他のセファロスポリン系抗菌薬やバンコマイシンと比較してメチシリン感性黄色ブドウ球菌(MSSA)菌血症における治療失敗率が有意に低い。◎無菌検体からMSSAが検出された感染症の場合は、セファゾリンを優先的に使用できるようなスキームの構築が必要である。◎MSSAをターゲットにした手術部位感染の予防の場合は、施設のアンチバイオグラムを参考に、良好な抗菌活性を示す狭域スペクトルの抗菌薬を用いる。◎セファゾリンやセファレキシンの代替薬を考える場合、抗菌スペクトルの「大は小を兼ねる」理論は適さない場合があることに留意する。(著者抄録)

第5回病院薬剤師が実践するリバーストランスレーショナルリサーチの最前線〜臨床情報を突破口とした創薬・育薬研究〜大規模医療情報データベースを活用した抗がん剤副作用予防のためのリバーストランスレーショナルリサーチ

合田光寛, 座間味義人, 新村貴博, 萱野純史, 濱野裕章, 岡田直人, 相澤風花, 八木健太, 石澤有紀, 桐野靖, 中村敏己, 石澤啓介

日本薬学会年会要旨集 141年会 S21 - 3 2021年3月

COVID-19感染拡大に伴うオンライン型薬学実務実習の導入

相澤風花, 座間味義人, 濱野裕章, 岡田直人, 林明希, 八木健太, 合田光寛, 桐野靖, 中村敏己, 石澤啓介

日本薬学会年会要旨集 141年会 28P01 - 257 2021年3月

大規模医療情報データベースを活用したバンコマイシン関連腎障害に対する薬剤性腎障害原因薬剤の多剤併用における影響

坂東貴司, 中馬真幸, 新村貴博, 座間味義人, 石澤有紀, 合田光寛, 八木健太, 濱野裕章, 岡田直人, 泉侑希, 桐野靖, 中村敏己, 石澤啓介

日本薬学会年会要旨集 141年会 27V11 - pm01 2021年3月

次世代の若手研究者が切り開く薬学研究の発展と医療への貢献大規模医療情報データベースを用いたドキソルビシン誘発心筋症に対する予防薬の探索

阪本淑華, 座間味義人, 新村貴博, 相澤風花, 八木健太, 合田光寛, 石澤有紀, 石澤啓介

日本薬学会年会要旨集 141年会 GS04 - 6 2021年3月

大規模医療情報データベースを活用したバンコマイシン関連腎障害に対する薬剤性腎障害原因薬剤の多剤併用における影響

坂東貴司, 中馬真幸, 新村貴博, 座間味義人, 石澤有紀, 合田光寛, 八木健太, 濱野裕章, 岡田直人, 泉侑希, 桐野靖, 中村敏己, 石澤啓介

日本薬学会年会要旨集 141年会 27V11 - pm01 2021年3月

基礎研究と臨床研究の融合による薬剤性末梢神経障害に対する予防薬探索

新村貴博, 座間味義人, 川尻雄大, 合田光寛, 相澤風花, 八木健太, 石澤有紀, 石澤啓介

日本薬学会年会要旨集 141年会 27P02 - 198S 2021年3月

COVID-19感染拡大に伴うオンライン型薬学実務実習の導入

相澤風花, 座間味義人, 濱野裕章, 岡田直人, 林明希, 八木健太, 合田光寛, 桐野靖, 中村敏己, 石澤啓介

日本薬学会年会要旨集 141年会 28P01 - 257 2021年3月

第5回病院薬剤師が実践するリバーストランスレーショナルリサーチの最前線〜臨床情報を突破口とした創薬・育薬研究〜大規模医療情報データベースを活用した抗がん剤副作用予防のためのリバーストランスレーショナルリサーチ

合田光寛, 座間味義人, 新村貴博, 萱野純史, 濱野裕章, 岡田直人, 相澤風花, 八木健太, 石澤有紀, 桐野靖, 中村敏己, 石澤啓介

日本薬学会年会要旨集 141年会 S21 - 3 2021年3月

次世代の若手研究者が切り開く薬学研究の発展と医療への貢献レニン・アンジオテンシン・アルドステロン系阻害薬はオキサリプラチン誘発末梢神経障害の発症を抑制する

内田真美, 牛尾聡一郎, 新村貴博, 飛鷹範明, 田中亮裕, 北村佳久, 千堂年昭, 座間味義人, 石澤啓介, 武智研志, 柴田和彦, 難波弘行, 川崎博己, 高取真吾

日本薬学会年会要旨集 141年会 GS04 - 5 2021年3月

Concomitant Use of Acetaminophen and Aspirin Increases Risk of Kidney Injury: Analysis of the Japanese Adverse Drug Event Report Database. 国際誌

Satoru Mitsuboshi, Takahiro Niimura, Yoshito Zamami

Journal of clinical pharmacology 61 ( 2 ) 269 - 270 2021年2月

The Risk Factors Associated with Immune Checkpoint Inhibitor-Related Pneumonitis. 国際誌

Mizuho Asada, Takahisa Mikami, Takahiro Niimura, Yoshito Zamami, Yoshihiro Uesawa, Masayuki Chuma, Keisuke Ishizawa

Oncology 99 ( 4 ) 1 - 4 2021年1月

記述言語：英語

BACKGROUND: Pneumonitis is a serious adverse event in patients treated with immune checkpoint inhibitors (ICIs), with a mortality rate of up to 20%. The risk factors for ICI-related pneumonitis remain unclear due to the scarce data and infrequent event rate of 0-10% for all grades in patients using ICIs. OBJECTIVES: This study evaluated the risk factors for ICI-related pneumonitis using the United States Food and Drug Administration (US FDA) Adverse Event Reporting System (FAERS) database. METHOD: To investigate the association between pneumonitis and ICIs, the FAERS database, which contains spontaneous adverse event reports submitted to the US FDA, was utilized. Data between January 2014 and December 2019 were collected. Univariate logistic regression analysis with covariates, including age, sex, and ICI use, was performed to assess the risk of ICI-related pneumonitis. The relative risk of pneumonitis was estimated using by the odds ratio. RESULTS: We identified 4,248,808 reports, including 51,166 cases of those who received eight different ICIs. Nivolumab was the most common ICI (n = 27,273 of 51,166 [53.3%] patients). Reporting rates of pneumonitis were significantly high in ICI users (odds ratio 29.48; 95% confidence interval [CI], 27.49-31.62). Univariate logistic regression analysis showed that pneumonitis risk was significantly associated with age. Age ≤60 years old was associated with an increase in the reported frequency of pneumonitis. CONCLUSIONS: Our data suggest that the risk of ICI-related pneumonitis may increase in certain populations, including younger age (age <60 years) and ICIs users. These patients require careful monitoring.

DOI： 10.1159/000512633

Neuroimmunological adverse events associated with immune checkpoint inhibitor: a retrospective, pharmacovigilance study using FAERS database. 国際誌

Takahisa Mikami, Bobby Liaw, Mizuho Asada, Takahiro Niimura, Yoshito Zamami, Deborah Green-LaRoche, Lori Pai, Michael Levy, Suriya Jeyapalan

Journal of neuro-oncology 152 ( 1 ) 135 - 144 2021年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: To investigate the characteristics and risk factors for neurologic adverse events (AEs) induced by immune checkpoint inhibitors (ICIs). METHODS: An observational, retrospective, and pharmacovigilance study based on the FAERS database collected between January 2014 and December 2019 was conducted. ICI-related AEs were defined as adverse reactions in patients using anti-PD-1 (nivolumab and pembrolizumab), anti-PD-L1 (atezolizumab, avelumab, and durvalumab), and anti-CTLA-4 (ipilimumab and tremelimumab). Neurologic AEs previously reported to be associated with ICI were evaluated in the disproportionality analysis using the reporting odds ratio (ROR). RESULTS: Among 50,406 ICI-related reports, 3619 (7.2%) neurological case was found: 1985 with anti-PD-1, 372 with anti-PD-L1, 366 with anti-CTLA-4, and 896 with the combination of ICIs. In comparison to non-ICI drug use, ICI use demonstrated higher risk for neurologic complication, including hypophysitis/hypopituitarism, myasthenia gravis, encephalitis/myelitis, meningitis, Guillain-Barre syndrome, vasculitis, and neuropathy. The risk of neurologic AEs associated with ICI combination therapy was as high as or even higher than ICI monotherapy, most significantly in hypophysitis/hypopituitarism. The proportion of serious neurological events and death related to combination therapy has been decreasing in recent years. Older age, male and female sex, and metastasis were not significant risk factors for the incidence of neurologic ICI-related AEs. Patients at older age, with melanoma or non-small cell lung cancer, or on dual ICI therapy may be at higher risk of fatal neurologic AEs. CONCLUSION: ICI use is associated with a higher risk of neurological complications, with dual ICI therapy posing a higher risk, while older age, sex, or metastasis were not. Patients at older age, with certain cancer types, or on dual ICI therapy may be at higher risk of fatal neurologic AEs.

DOI： 10.1007/s11060-020-03687-2

Investigation of drugs affecting hypertension in bevacizumab-treated patients and examination of the impact on the therapeutic effect. 国際誌

Kenta Yagi, Marin Mitstui, Yoshito Zamami, Takahiro Niimura, Yuki Izawa-Ishizawa, Mitsuhiro Goda, Masayuki Chuma, Kimiko Fukunaga, Takahiro Shibata, Shunsuke Ishida, Takumi Sakurada, Naoto Okada, Hirofumi Hamano, Yuya Horinouchi, Yasumasa Ikeda, Hiroaki Yanagawa, Keisuke Ishizawa

Cancer medicine 10 ( 1 ) 164 - 172 2021年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: In patients treated with bevacizumab, hypertension may be a biomarker of therapeutic efficacy. However, it is not clear whether drugs that control blood pressure influence bevacizumab's efficacy. In this study, we investigated drugs that may affect hypertension in bevacizumab-treated patients and examined the impact on the therapeutic effect. PATIENTS AND METHODS: We analyzed 3,724,555 reports from the third quarter of 2010 to the second quarter of 2015. All data were obtained from the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) analysis. In this retrospective cohort study, we investigated a total of 58 patients diagnosed with colorectal cancer and treated for the first time with bevacizumab containing XELOX or mFOLFOX6 at The University of Tokushima Hospital between January 2010 and December 2015. The effect of the treatment was evaluated according to Response Evaluation Criteria in Solid Tumors version 1.0. Thereafter, the effect was confirmed using Gene Expression Omnibus (GEO) and cultured cells. RESULTS: There are few reports in FAERS of hypertension in patients treated with omeprazole on bevacizumab. Based on the chart review, patients who used proton pump inhibitors (PPI) had a lower response to treatment than those who did not (response rate: 25% vs 50%). Furthermore, experiments on GEO and cell lines suggested that induction of vascular endothelial growth factor (VEGF) gene expression by PPIs is the cause of the reduced therapeutic effect. CONCLUSION: PPIs prevent hypertension in bevacizumab-treated patients but may reduce bevacizumab's anti-tumoral effects by inducing VEGF expression.

DOI： 10.1002/cam4.3587

Advanced Life Support vs. Basic Life Support for Patients With Trauma in Prehospital Settings: A Systematic Review and Meta-Analysis. 国際誌

Yutaka Kondo, Tatsuma Fukuda, Ryo Uchimido, Masahiro Kashiura, Soichiro Kato, Hiroshi Sekiguchi, Yoshito Zamami, Toru Hifumi, Kei Hayashida

Frontiers in medicine 8 660367 - 660367 2021年

記述言語：英語

Background: Advanced Life Support (ALS) is regarded to be associated with improved survival in pre-hospital trauma care when compared to Basic Life Support (BLS) irrespective of lack of evidence. The aim of this study is to ascertain ALS improves survival for trauma in prehospital settings when compared to BLS. Methods: We searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials for published controlled trials (CTs), and observational studies that were published until Aug 2017. The population of interest were adults (>18 years old) trauma patients who were transported by ground transportation and required resuscitation in prehospital settings. We compared outcomes between the ALS and BLS groups. The primary outcome was in-hospital mortality and secondary outcomes were neurological outcome and time spent on scene. Results: We identified 2,502 studies from various databases and 10 studies were included in the analysis (two CTs, and eight observational studies). The outcomes were not statistically significant between the ALS and BLS groups (pooled OR 1.14; 95% CI 0.95 to 1.36 for mortality, pooled OR 1.12; 95% CI 0.88 to 1.42 for good neurological outcomes, pooled mean difference -0.96; 95% CI-6.64 to 4.72 for on-scene time) in CTs. In observational studies, ALS prolonged on-scene time and increased mortality (pooled OR 1.56; 95% CI: 1.31 to 1.86 for mortality, and pooled mean difference, 1.26; 95% CI: 0.07 to 2.45 for on-scene time). Conclusions: In prehospital settings, the present study showed no advantages of ALS on the outcomes in patients with trauma compared to BLS.

DOI： 10.3389/fmed.2021.660367

Assessment of Adherence to Post-exposure Prophylaxis with Oseltamivir in Healthcare Workers: A Retrospective Questionnaire-Based Study.

Naoto Okada, Noriko Fujiwara, Momoyo Azuma, Kaito Tsujinaka, Masayuki Chuma, Kenta Yagi, Hirofumi Hamano, Fuka Aizawa, Mitsuhiro Goda, Yasushi Kirino, Toshimi Nakamura, Yoshito Zamami, Ichiro Hashimoto, Keisuke Ishizawa

Biological & pharmaceutical bulletin 44 ( 6 ) 869 - 874 2021年

記述言語：英語掲載種別：研究論文（学術雑誌）

Post-exposure prophylaxis (PEP) for healthcare workers is one of the effective strategies for preventing nosocomial outbreaks of influenza. However, PEP adherence in healthcare workers is rarely analysed, and no strategies have been established to improve adherence to PEP for healthcare workers. We aimed to retrospectively analyse adherence to PEP and the factors associated with non-adherence in healthcare workers. A survey of 221 healthcare workers who were eligible for PEP at Tokushima University Hospital in the 2016/2017 season was conducted. Once-daily oseltamivir (75 mg for 10 d) was used as the PEP regimen. Of the 221 healthcare workers, 175 received PEP and were surveyed for adherence using a questionnaire. Of the 130 healthcare workers who responded to the questionnaire, 121 (93.1%) had been vaccinated. In this survey, 82 healthcare workers (63.1%) did not fully complete PEP. Multiple logistic regression analysis revealed that physicians (odds ratio: 4.62, 95% confidence interval [CI]: 2.08-10.25) and non-vaccination (odds ratio: 9.60, 95% CI: 1.12-82.25) were the factors for non-adherence to PEP. Of the 47 healthcare workers who responded to the item regarding reasons for non-adherence, 36 (76.6%) reported forgetting to take oseltamivir or discontinuing it due to a misguided self-decision that continuation of PEP was unnecessary, and 5 (10.6%) reported discontinuing treatment due to adverse effects. In conclusion, healthcare workers, particularly physicians, had low PEP adherence owing to forgetting or stopping to take oseltamivir due to a misguided self-decision. To obtain the maximum preventive effect of PEP, medication education should be provided to endorse PEP compliance.

DOI： 10.1248/bpb.b21-00165

Academic investigators' interest in promoting specified clinical trials : Questionnaire survey before and after implementation of the Clinical Trial Act.

Masayuki Chuma, Kenshi Takechi, Kenta Yagi, Satoshi Sakaguchi, Hiroshi Nokihara, Chikako Kane, Yasutaka Sato, Takahiro Niimura, Mitsuhiro Goda, Yoshito Zamami, Keisuke Ishizawa, Hiroaki Yanagawa

The journal of medical investigation : JMI 68 ( 1.2 ) 71 - 75 2021年

記述言語：英語掲載種別：研究論文（学術雑誌）

Background : Enforcement of the 2018 Clinical Trials Act (CTA) in Japan resulted in strict and complicated regulations surrounding intervention studies. Few Japan-specific measures have been developed to promote intervention studies in Japan despite concerns about CTA's negative influence on such studies. Therefore, this study examined the changes in academic investigators' interest in conducting clinical studies before and after enforcement of the CTA to determine measures to promote specified clinical trials. Methods : We conducted a questionnaire survey with investigators belonging to the Institute of Biomedical Sciences, Tokushima University Graduate School, before and after enforcement of the CTA. Results : Investigators had lesser interest in intervention studies in the post-questionnaire survey (post) group than in the pre-questionnaire survey (pre) group. Their desire for "project management" was significantly higher in the post-group than in the pre-group. Their desire for "support for preparing documents when conducting specified clinical trials" was significantly higher in the group interested in conducting specified clinical trials than that in the not-interested group. Conclusion : We revealed that investigators were highly interested in "project management" and "support for preparing documents when conducting specified clinical trials" after enforcement of the CTA. Measures for these desires may promote specified clinical trials. J. Med. Invest. 68 : 71-75, February, 2021.

DOI： 10.2152/jmi.68.71

Evaluation of Potential Complications of Interstitial Lung Disease Associated With Antiandrogens Using Data From Databases Reporting Spontaneous Adverse Effects. 国際誌

Hideki Nawa, Takahiro Niimura, Hirofumi Hamano, Kenta Yagi, Mitsuhiro Goda, Yoshito Zamami, Keisuke Ishizawa

Frontiers in pharmacology 12 655605 - 655605 2021年

記述言語：英語掲載種別：研究論文（学術雑誌）

From 2002 to 2018, the number of patients with prostate cancer significantly increased from 679,023 to 1276,106 worldwide. Total prostatectomy (including robot-assisted prostatectomy), radiation therapy, and pharmacological treatment are commonly used to treat prostate cancer. The Chief of the Pharmaceutical Safety Division, that is, the Federation of Pharmaceutical Manufacturers' Associations of Japan (FPMAJ), recently called for the revision of package inserts for ethical drugs. However, the pathogenesis of interstitial lung disease (ILD), a serious drug-induced adverse effect, remains unclear. Moreover, there have been no large-scale evaluations of potential complications associated with currently used antiandrogens, which are commonly employed to treat prostate cancer. Hence, ILD, as an adverse event, remains poorly understood. Therefore, we conducted a survey of reports in the Japanese Adverse Drug Event Report (JADER) database to investigate the potential association between the reporting of ILD and antiandrogen drug use in clinical practice. The occurrence of ILD was investigated by evaluating the relationship between antiandrogen drug use and ILD. Adverse event signals were detected with reporting odds ratios (RORs), using data from the JADER and FDA Adverse Event Reporting System (FAERS) databases, for the analysis of post-marketing adverse event reports. The JADER was used to examine the time profile of adverse event occurrence for each drug, whereas the FAERS was used to screen cases of unknown adverse events and analyze their trends of occurrence. The analysis of data from both databases revealed the 95% confidence interval lower limits of ROR for bicalutamide and flutamide to be > 1, and adverse event signals were detected following the use of either drug. While caution should be exercised for drugs that are new to the market, we conclude that drugs with similar therapeutic effects that have been in use for a long period should also be re-examined for potential adverse events.

DOI： 10.3389/fphar.2021.655605

Effects of Palonosetron on Nausea and Vomiting Induced by Multiple-Day Chemotherapy: A Retrospective Study.

Hirofumi Hamano, Chisato Mitsuhashi, Yoshiko Suzuki, Yoshito Zamami, Kaito Tsujinaka, Naoto Okada, Takahiro Niimura, Tatsuya Hayama, Toru Imai, Shunsuke Ishida, Kumiko Sakamoto, Mitsuhiro Goda, Kenshi Takechi, Kenta Yagi, Masayuki Chuma, Yuya Horinouchi, Kazuaki Shinomiya, Yasumasa Ikeda, Yasushi Kirino, Toshimi Nakamura, Hiroaki Yanagawa, Yasuhiro Hamada, Keisuke Ishizawa

Biological & pharmaceutical bulletin 44 ( 4 ) 478 - 484 2021年

記述言語：英語掲載種別：研究論文（学術雑誌）

Patients who undergo multiple-day chemotherapy sessions experience hard-to-treat nausea and vomiting. Currently, there is no effective standard treatment for this condition. This study compared the preventive effect of first-generation 5-hydroxytryptamine 3 receptor antagonists (5-HT3 RAs) and second-generation 5-HT3 RAs palonosetron in multiple-day chemotherapy-induced nausea and vomiting. The design of this study was a retrospective case-control study of patients who received a five-day cisplatin-based chemotherapy and were treated with aprepitant, dexamethasone, granisetron, and ramosetron or palonosetron. The patients were divided into two groups: patients given granisetron and ramosetron (the first-generation group), and those given palonosetron (palonosetron group). The percentage of patients with a complete response or total control was assessed. They were divided into three phases: 0-216 h (overall phase), 0-120 h (remedial phase), and 120-216 h (after phase). The remedial phase was further divided into 0-24 h (early phase) and 24-120 h (later phase). Moreover, the nutritional status of each patient was assessed by noting the patients' total calorie-intake per day and total parenteral nutrition. First-generation 5-HT3 RAs and palonosetron were used for treatment in 18 and 28 patients, respectively. The complete response rate and caloric oral intake of the later phase were higher in the palonosetron group than in the first-generation group. We conclude that palonosetron treatment was more effective than first-generation 5-HT3 RAs in controlling multiple-day chemotherapy-induced nausea and vomiting.

DOI： 10.1248/bpb.b20-00609

Drug-Repositioning Approaches Based on Medical and Life Science Databases. 国際誌

Yoshito Zamami, Hirofumi Hamano, Takahiro Niimura, Fuka Aizawa, Kenta Yagi, Mitsuhiro Goda, Yuki Izawa-Ishizawa, Keisuke Ishizawa

Frontiers in pharmacology 12 752174 - 752174 2021年

記述言語：英語掲載種別：研究論文（学術雑誌）

Drug repositioning is a drug discovery strategy in which an existing drug is utilized as a therapeutic agent for a different disease. As information regarding the safety, pharmacokinetics, and formulation of existing drugs is already available, the cost and time required for drug development is reduced. Conventional drug repositioning has been dominated by a method involving the search for candidate drugs that act on the target molecules of an organism in a diseased state through basic research. However, recently, information hosted on medical information and life science databases have been used in translational research to bridge the gap between basic research in drug repositioning and clinical application. Here, we review an example of drug repositioning wherein candidate drugs were found and their mechanisms of action against a novel therapeutic target were identified via a basic research method that combines the findings retrieved from various medical and life science databases.

DOI： 10.3389/fphar.2021.752174

ラモトリギンの皮膚障害リスクに影響する因子の探索

宮田晃志, 坂東寛, 合田光寛, 中馬真幸, 新田侑生, 田崎嘉一, 吉岡俊彦, 小川淳, 座間味義人, 濱野裕章, 石澤有紀, 石澤啓介

日本臨床薬理学会学術総会抄録集 42 3-P-R-2 2021年

記述言語：日本語出版者・発行元：一般社団法人日本臨床薬理学会

【目的】てんかんおよび双極性障害の維持療法に適応を有するラモトリギンは、副作用として重篤な皮膚障害が現れることがあり、死亡に至った例も報告されたことから2015年に安全性速報で注意喚起がなされた。ラモトリギン誘発皮膚障害は、血中濃度の急激な上昇が関与しており、代謝経路に関与するUDP-グルクロン酸転移酵素（UGT）阻害作用を示すバルプロ酸との併用でリスクが高いことが知られている。しかし、UGT阻害作用を示す薬剤はバルプロ酸の他にも睡眠薬、鎮痛薬、免疫抑制薬など多数存在するにも関わらず、それらの薬剤併用によるラモトリギン誘発皮膚障害への影響は不明である。本研究では、医療ビッグデータ解析を用いてUGT阻害作用を示す薬剤がラモトリギン誘発皮膚障害の報告オッズ比に与える影響を検討した。さらに、徳島大学病院の病院診療情報を用いて、併用薬によるラモトリギンの皮膚障害リスクの変化を検討した。【方法】大規模副作用症例報告データベース（FAERS：FDA Adverse Event Reporting System）を用いて、ラモトリギンとの併用により皮膚障害報告数を上昇させる薬剤を探索した。さらに徳島大学病院診療録より、ラモトリギン服用を開始した患者を対象とし、ラモトリギンの投与量、併用薬、皮膚障害の有無などを調査した。【結果】FAERS解析から、UGT阻害作用を示す医薬品のうち、ラモトリギンとの併用により皮膚障害リスクの上昇が示唆される薬剤として、バルプロ酸（ROR: 2.98, 95%CI: 2.63-3.37）、フルニトラゼパム（ROR: 5.93, 95%CI: 4.33-8.14）およびニトラゼパム（ROR: 2.09, 95%CI: 1.24-3.51）が抽出された。徳島大学病院診療情報を用いた後方視的観察研究の結果、ラモトリギン服用が開始された患者の内、20％程度で皮膚障害が認められ、フルニトラゼパム併用患者では皮膚障害発生頻度が上昇する傾向が認められた。【考察】フルニトラゼパムおよびニトラゼパムは、UGT阻害作用を示す薬剤であることから、ラモトリギンの血中濃度に影響し、ラモトリギンの皮膚障害リスクを上昇させている可能性がある。また、睡眠薬であることから精神科領域で併用する可能性があり、睡眠薬の選択や併用時の副作用モニタリングに注意を要すると考えられる。

DOI： 10.50993/jsptsuppl.42.0_3-p-r-2

シスプラチン起因性腎障害の予防薬の同定

池田康将, 濱野裕章, 合田光寛, 福島圭穰, 岸誠司, 中馬真幸, 座間味義人, 宮本理人, 石澤啓介, 藤野裕道, 粟飯原賢一, 土屋浩一郎, 玉置俊晃

日本薬理学会年会要旨集 94 2-O-D3-1 2021年

記述言語：日本語出版者・発行元：公益社団法人日本薬理学会

Background: Cisplatin is widely used as an anti-tumor drug for the treatment of solid tumors. Unfortunately, it causes nephrotoxicity as a critical side effect, limiting its use, given that no preventive drug against cisplatin-induced nephrotoxicity (CIN) is currently available. In the present study, we searched and identified candidate drugs for preventing CIN

Methods: We used a database of medical big data for the screening of candidate drugs for the prevention of CIN. Based on the results of the analysis of medical big data, we evaluated the actual efficacy of DPH via in vitro and in vivo experiments in culture cells and a mouse model.

Results: We identified that a previously developed drug, diphenhydramine (DPH), may provide a novel treatment for CIN by the analysis of medical big data. DPH inhibited cisplatin-induced cell death in renal proximal tubular cells. Mice administered cisplatin developed kidney injury with renal dysfunction, augmented oxidative stress, increased apoptosis, and elevated inflammatory cytokines; however, most of these symptoms were suppressed by treatment with DPH. Additionally, the renal concentration of cisplatin was attenuated in DPH-treated mice. Importantly, DPH did not i interfere with its anti-tumor effect in any of the in vitro or in vivo experiments. Moreover, a retrospective clinical study showed that patients with malignant cancer who had used DPH before cisplatin treatment exhibited less acute kidney injury.

Conclusion: DPH may be a preventive medicine against CIN.

DOI： 10.1254/jpssuppl.94.0_2-o-d3-1

シスプラチン誘発急性腎障害に対する各種5-HT₃受容体拮抗薬併用の影響

神田将哉, 合田光寛, 吉岡俊彦, 吉田愛美, 新村貴博, 座間味義人, 石澤由紀, 八木健太, 濱野裕章, 岡田直人, 石澤啓介

日本薬理学会年会要旨集 94 1-Y-E2-1 2021年

記述言語：日本語出版者・発行元：公益社団法人日本薬理学会

OBJECTIVE: Although cisplatin has been used as a key drug for standard anticancer treatment, it is known that nausea and vomiting, renal injury occur frequently as a side effect.

Cisplatin is also known to be excreted via the multidrug and toxin release (MATE) transporter, and the involvement of the MATE transporter in cisplatin-induced kidney injury has been reported. On the other hand, the MATE transporter is also involved in the excretion of ondansetron, a 5-HT₃ receptor antagonist used as an antiemetic, but the effects of various 5-HT₃receptor antagonists currently used clinically on cisplatin-induced renal injury has not been elucidated. Therefore, in this study, the effect of various 5-HT₃ receptor antagonists on cisplatin-induced renal injury was examined.

METHOD: In order to establish cisplatin‐induced AKI, C57BL/6 mice were intraperitoneally administered with cisplatin or saline. Various 5-HT₃ receptor antagonists were administered 30 minutes before administration of cisplatin. Renal function was evaluated by serum creatinine and BUN. Histological damage in the cortex of HE‐stained kidney sections was scored. The changes in the number of reported renal injuries due to the combination of cisplatin and various 5-HT₃ receptor antagonists was analyzed by FAERS.

RESULT : The concomitant use of ondansetron significantly increased cisplatin accumulation in the kidney and significantly worsened renal damage. On the other hand, there was no worsening of renal function in the palonosetron combination group compared to the cisplatin alone group.

FAERS analysis revealed that the combination of cisplatin and first-generation 5-HT₃ receptor antagonists resulted in a significant increase in the number of reported renal injuries.

CONCLUSION : These results suggest that the second generation 5-HT₃ receptor antagonist may have less effect on cisplatin‐induced AKI than the first generation.

DOI： 10.1254/jpssuppl.94.0_1-y-e2-1

ドキソルビシン誘発心筋症に対する予防薬探索を目的としたドラッグリポジショニング研究

西内栞, 斎藤広海, 新村貴博, 座間味義人, 合田光寛, 八木健太, 相澤風花, 濱野裕章, 石澤有紀, 石澤啓介

日本臨床薬理学会学術総会抄録集 42 2-P-H-7 2021年

記述言語：日本語出版者・発行元：一般社団法人日本臨床薬理学会

【目的】

Doxorubicin (Dox)は累積投与量に依存して重篤な心筋症を発現することが知られている。Doxに関連した心筋症は、生命予後を著しく悪化させることが報告されているが、現在までに有効な対策は確立されておらず、予防薬の開発が喫緊の課題である。そこで、本研究では、大規模医療情報データベースを用いたドラッグリポジショニング研究によってDox誘発心筋症に対する予防薬を探索した。

【方法】

はじめに、遺伝子発現データベース(GEO) より得られたマイクロアレイデータの解析を行い、Dox投与後の心筋組織における発現変動遺伝子を抽出した。次に、創薬ツール(LINCS)を用いて、Doxによる遺伝子発現変動を打ち消す既存承認薬を探索した。さらに、有害事象自発報告データベース(FAERS)を解析し、LINCS解析によって抽出した薬剤がDox誘発心筋症の報告数に及ぼす影響を検討した。FAERS解析においても有効性が示唆された薬剤に関して、C57BL6マウスを用いてDox誘発心筋症モデルを作製し、心筋組織の炎症およびアポトーシス関連タンパク質のmRNA発現変化を評価した。

【結果】

マイクロアレイデータ解析より見出された発現変動遺伝子を用いて、LINCS解析を行った結果、既存承認薬6剤が候補薬として抽出された。FAERS解析によりこれらのうち3剤でDox誘発心筋症の報告オッズ比が減少する傾向が認められた。in vivoの検討において、Doxの投与によって上昇した心筋組織のIL-1b, IL-6およびBax/Bcl-2 mRNA発現比が予防薬候補の併用によって減少する傾向が認められた。

【考察】

異なる2種類のビッグデータ解析により抽出された3種類の既存承認薬は、臨床においてもDox誘発心筋症のリスクを軽減する薬剤となることが示唆される。Dox誘発心筋症モデルマウスを用いた検討結果から、抽出された予防薬候補は、Doxによる心筋組織の炎症反応を抑制することでアポトーシスを抑制する可能性が考えられる。

【結論】

本研究の結果から、創薬ツールおよび大規模医療情報データベース解析により見出された既存承認薬がDox誘発心筋症に対する新規予防薬となる可能性が示唆された。

DOI： 10.50993/jsptsuppl.42.0_2-p-h-7

Diphenhydramine may be a preventive medicine against cisplatin-induced kidney toxicity. 国際誌

Hirofumi Hamano, Yasumasa Ikeda, Mitsuhiro Goda, Keijo Fukushima, Seiji Kishi, Masayuki Chuma, Michiko Yamashita, Takahiro Niimura, Kenshi Takechi, Masaki Imanishi, Yoshito Zamami, Yuya Horinouchi, Yuki Izawa-Ishizawa, Licht Miyamoto, Keisuke Ishizawa, Hiromichi Fujino, Toshiaki Tamaki, Ken-Ichi Aihara, Koichiro Tsuchiya

Kidney international 99 ( 4 ) 885 - 899 2020年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Cisplatin is widely used as an anti-tumor drug for the treatment of solid tumors. Unfortunately, it causes kidney toxicity as a critical side effect, limiting its use, given that no preventive drug against cisplatin-induced kidney toxicity is currently available. Here, based on a repositioning analysis of the Food and Drug Administration Adverse Events Reporting System, we found that a previously developed drug, diphenhydramine, may provide a novel treatment for cisplatin-induced kidney toxicity. To confirm this, the actual efficacy of diphenhydramine was evaluated in in vitro and in vivo experiments. Diphenhydramine inhibited cisplatin-induced cell death in kidney proximal tubular cells. Mice administered cisplatin developed kidney injury with significant dysfunction (mean plasma creatinine: 0.43 vs 0.15 mg/dl) and showed augmented oxidative stress, increased apoptosis, elevated inflammatory cytokines, and MAPKs activation. However, most of these symptoms were suppressed by treatment with diphenhydramine. Furthermore, the concentration of cisplatin in the kidney was significantly attenuated in diphenhydramine-treated mice (mean platinum content: 70.0 vs 53.4 μg/g dry kidney weight). Importantly, diphenhydramine did not influence or interfere with the anti-tumor effect of cisplatin in any of the in vitro or in vivo experiments. In a selected cohort of 98 1:1 matched patients from a retrospective database of 1467 patients showed that patients with malignant cancer who had used diphenhydramine before cisplatin treatment exhibited significantly less acute kidney injury compared to ones who did not (6.1 % vs 22.4 %, respectively). Thus, diphenhydramine demonstrated efficacy as a novel preventive medicine against cisplatin-induced kidney toxicity.

DOI： 10.1016/j.kint.2020.10.041

Differences in risk factors for anticoagulant-related nephropathy between warfarin and direct oral anticoagulants: Analysis of the Japanese adverse drug event report database. 国際誌

Satoru Mitsuboshi, Takahiro Niimura, Yoshito Zamami, Keisuke Ishizawa

British journal of clinical pharmacology 87 ( 7 ) 2977 - 2981 2020年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Limited information is available on anticoagulant-related nephropathy (ARN). We therefore reviewed the Japanese Adverse Drug Event Report database to investigate kidney injury (KI) in patients administered warfarin or direct oral anticoagulants (DOACs) and sought to clarify the risk factors for ARN. KI risk in warfarin users was associated with male sex (odds ratio [OR], 1.70; 95% confidence interval [CI], 1.35-2.13; P < .01) and age ≥80 years (OR, 1.35; 95% CI, 1.07-1.72; P = .01). KI risk in DOAC users was associated with body weight ≥80 kg (OR, 1.60; 95% CI, 1.01-2.53; P = .04) and use of dabigatran (OR, 1.61; 95% CI, 1.09-2.37; P < .01). Our findings suggest that risk factors for ARN differ between warfarin and DOACs and that these risk factors may be associated with bleeding risk. Therefore, the risk of ARN may be decreased by better managing bleeding risk in patients taking anticoagulants.

DOI： 10.1111/bcp.14688

臨床現場の疑問に応える(答える)腎臓病薬物療法研究臨床現場で勤務する薬剤師の視点を生かしたトランスレーショナルリサーチ

中馬真幸, 座間味義人, 合田光寛, 八木健太, 石澤有紀, 濱野裕章, 岡田直人, 近藤正輝, 楊河宏章, 石澤啓介

日本腎臓病薬物療法学会誌 9 ( 特別号 ) S81 - S81 2020年11月

腎とポリファーマシー対策 CKD・AKI患者におけるポリファーマシー

岡田直人, 中馬真幸, 合田光寛, 八木健太, 座間味義人, 石澤啓介

日本腎臓病薬物療法学会誌 9 ( 特別号 ) S80 - S80 2020年11月

感染と腎機能慢性期(寝たきりの人、筋力の落ちている人)への抗菌薬の使用方法正確な腎機能評価に基づいた抗菌薬の投与設計

岡田直人, 中馬真幸, 合田光寛, 八木健太, 座間味義人, 石澤啓介

日本腎臓病薬物療法学会誌 9 ( 特別号 ) S63 - S63 2020年11月

入院栄養管理において薬剤師に期待される業務の多職種アンケート調査

濱野裕章, 三橋知里, 座間味義人, 岡田直人, 武智研志, 中馬真幸, 石田俊介, 坂本久美子, 合田光寛, 八木健太, 桐野靖, 中村敏己, 石澤啓介

日本病院薬剤師会雑誌 56 ( 10 ) 1181 - 1186 2020年10月

記述言語：日本語出版者・発行元：(一社)日本病院薬剤師会

医療の進歩と近年のチーム医療推進に伴い、薬剤師は多職種と患者治療を目的として情報を共有し、適切な業務役割の分担を行う必要性が生まれた。薬剤師が参入しているチーム医療の1つに栄養サポートチーム(nutrition support team:以下、NST)があるが、適切な薬剤師の業務体制をつくるためには多職種の視点を取り入れる必要がある。本調査では栄養療法において多職種が期待する薬剤師の役割を明確化することを目的として多職種にアンケート調査を実施した。回答者の約7割はNSTの構成員に薬剤師が必要だと答えており、内容として配合変化および投与経路の指摘、栄養のプランニングや患者・家族・医療スタッフへの情報提供、脂肪乳剤の推奨といった栄養管理に対して、なかでも配合変化の回避に関して強く希望していた。結論として、栄養療法において多職種がもつ薬剤師への期待に我々薬剤師は応えていかなければならない。(著者抄録)

研究者から見た特定臨床研究推進に寄与する因子臨床研究法施行前後のアンケート調査

八木健太, 中馬真幸, 武智研志, 坂口暁, 軒原浩, 加根千賀子, 佐藤康敬, 新村貴博, 合田光寛, 座間味義人, 石澤啓介, 楊河宏章

臨床薬理 51 ( Suppl. ) S270 - S270 2020年10月

多施設・多職種連携による医薬品適正使用ならびに医療費削減の推進大規模医療情報データベースを活用した有害事象軽減のための多施設共同研究

座間味義人, 川尻雄大, 牛尾聡一郎, 武智研志, 新村貴博, 合田光寛, 八木健太, 中馬真幸, 石澤有紀, 楊河宏章, 石澤啓介

臨床薬理 51 ( Suppl. ) S191 - S191 2020年10月

データ駆動型薬理学・臨床薬理学研究有害事象自発報告データベースを活用した抗がん剤副作用に対する予防法の探索

石澤啓介, 合田光寛, 中馬真幸, 八木健太, 石澤有紀, 座間味義人

臨床薬理 51 ( Suppl. ) S140 - S140 2020年10月

臨床薬理共同研究推進体制の構築に向けた事例紹介

座間味義人, 鈴木啓介, 武智研志, 肥田典子

臨床薬理 51 ( Suppl. ) S111 - S111 2020年10月

シスプラチン誘発性腎障害を予防する既存薬物の同定と検証

濱野裕章, 池田康将, 合田光寛, 福島圭穣, 岸誠司, 武智研志, 中馬真幸, 座間味義人, 堀之内裕也, 藤野裕道, 石澤啓介, 玉置俊晃

臨床薬理 51 ( Suppl. ) S261 - S261 2020年10月

データ駆動型薬理学・臨床薬理学研究有害事象自発報告データベースを活用した抗がん剤副作用に対する予防法の探索

石澤啓介, 合田光寛, 中馬真幸, 八木健太, 石澤有紀, 座間味義人

臨床薬理 51 ( Suppl. ) S140 - S140 2020年10月

腫瘍循環器学(Cardio-Oncology)研究〜基礎-臨床間の双方向性研究を展開するためにビッグデータ解析と基礎研究を融合した新たな研究手法による腫瘍循環器学へのアプローチ

石澤有紀, 座間味義人, 新村貴博, 合田光寛, 八木健太, 中馬真幸, 今西正樹, 石澤啓介

日本癌学会総会記事 79回 S8 - 2 2020年10月

研究者から見た特定臨床研究推進に寄与する因子臨床研究法施行前後のアンケート調査

八木健太, 中馬真幸, 武智研志, 坂口暁, 軒原浩, 加根千賀子, 佐藤康敬, 新村貴博, 合田光寛, 座間味義人, 石澤啓介, 楊河宏章

臨床薬理 51 ( Suppl. ) S270 - S270 2020年10月

多施設・多職種連携による医薬品適正使用ならびに医療費削減の推進大規模医療情報データベースを活用した有害事象軽減のための多施設共同研究

座間味義人, 川尻雄大, 牛尾聡一郎, 武智研志, 新村貴博, 合田光寛, 八木健太, 中馬真幸, 石澤有紀, 楊河宏章, 石澤啓介

臨床薬理 51 ( Suppl. ) S191 - S191 2020年10月

入院栄養管理において薬剤師に期待される業務の多職種アンケート調査

濱野裕章, 三橋知里, 座間味義人, 岡田直人, 武智研志, 中馬真幸, 石田俊介, 坂本久美子, 合田光寛, 八木健太, 桐野靖, 中村敏己, 石澤啓介

日本病院薬剤師会雑誌 56 ( 10 ) 1181 - 1186 2020年10月

記述言語：日本語出版者・発行元：(一社)日本病院薬剤師会

医療の進歩と近年のチーム医療推進に伴い、薬剤師は多職種と患者治療を目的として情報を共有し、適切な業務役割の分担を行う必要性が生まれた。薬剤師が参入しているチーム医療の1つに栄養サポートチーム(nutrition support team:以下、NST)があるが、適切な薬剤師の業務体制をつくるためには多職種の視点を取り入れる必要がある。本調査では栄養療法において多職種が期待する薬剤師の役割を明確化することを目的として多職種にアンケート調査を実施した。回答者の約7割はNSTの構成員に薬剤師が必要だと答えており、内容として配合変化および投与経路の指摘、栄養のプランニングや患者・家族・医療スタッフへの情報提供、脂肪乳剤の推奨といった栄養管理に対して、なかでも配合変化の回避に関して強く希望していた。結論として、栄養療法において多職種がもつ薬剤師への期待に我々薬剤師は応えていかなければならない。(著者抄録)

その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J04451&link_issn=&doc_id=20201005220012&doc_link_id=%2Fdg4hppha%2F2020%2F005610%2F012%2F1181-1186%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg4hppha%2F2020%2F005610%2F012%2F1181-1186%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Preventive Effects of Quercetin against the Onset of Atherosclerosis-Related Acute Aortic Syndromes in Mice. 国際誌

Masateru Kondo, Yuki Izawa-Ishizawa, Mitsuhiro Goda, Mayuko Hosooka, Yuu Kagimoto, Naoko Saito, Rie Matsuoka, Yoshito Zamami, Masayuki Chuma, Kenta Yagi, Kenshi Takechi, Koichi Tsuneyama, Keisuke Ishizawa

International journal of molecular sciences 21 ( 19 ) 2020年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Atherosclerosis-related acute aortic syndromes, such as aortic aneurysms or aortic dissection are life-threatening diseases. Since they develop suddenly and progress rapidly, the establishment of preventive strategies is urgently needed. Quercetin, a flavonoid abundant in various vegetables and fruits, is suggested to reduce the risk of cardiovascular disease. Therefore, in this study, the preventive effect of quercetin was evaluated using a mouse model of aortic aneurysm and dissection. The model was established by administering angiotensin II (Ang II) and β-aminopropionitrile (BAPN), a lysyl oxidase inhibitor, to mice to induce hypertension and degeneration of the elastic lamina, which would eventually result in the onset of an aortic aneurysm. Ang II, BAPN, and a nitric oxide synthase inhibitor was administered to induce aortic dissection via endothelial dysfunction. Quercetin (60 mg/kg/day) was administered 2 weeks before inducing aortic diseases by the end of the experiments (8 weeks in the aneurysm model, 6 weeks in the dissection model). It was found to reduce the incidence of aneurysm (from 72 to 45%), dissection (from 17 to 10%), and rupture (from 33 to 15%) in mice. Elastin degradation was ameliorated in the quercetin-treated mice compared to that in the mice without quercetin treatment (degradation score 2.9 ± 0.3 vs 2.2 ± 0.2). Furthermore, quercetin suppressed the expression of vascular cell adhesion molecule-1, macrophage infiltration, and pro-matrix metalloproteinase-9 activity. Our results suggest that quercetin might prevent the onset of atherosclerosis-related acute aortic syndromes through its anti-inflammatory and endothelial cell-protective effects.

DOI： 10.3390/ijms21197226

Risk factors of immune checkpoint inhibitor-related interstitial lung disease in patients with lung cancer: a single-institution retrospective study. 国際誌

Naoto Okada, Rie Matsuoka, Takumi Sakurada, Mitsuhiro Goda, Masayuki Chuma, Kenta Yagi, Yoshito Zamami, Yasuhiko Nishioka, Keisuke Ishizawa

Scientific reports 10 ( 1 ) 13773 - 13773 2020年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Immune checkpoint inhibitors (ICIs) elicit antitumour effects by activating the host immunity and cause immune-related adverse events (irAEs). ICI-related interstitial lung disease (ICI-ILD) is a fatal irAE that is difficult to treat; moreover, its incidence is relatively higher in patients with lung cancer. Therefore, early ICI-ILD detection and intervention are important for patient safety. However, a risk assessment method for ICI-ILD has not been established and the prediction of ICI-ILD occurrence is difficult. The aim of our study was to identify the risk factors associated with ICI-ILD. To this end, we retrospectively analysed 102 patients with lung cancer who first received ICI and completed the treatment between April 2016 and December 2019 at Tokushima University Hospital. Nineteen patients had all grades of ICI-ILD and 10 had grade ≥ 3 ICI-ILD. The 30-day mortality rate of patients with grade ≥ 3 ICI-ILD was the highest among all patients (P < 0.01). The multivariate logistic analysis indicated that the performance status ≥ 2 alone and both performance status ≥ 2 and ≥ 50 pack-year were independent risk factors of ICI-ILD of grade ≥ 3 and all grades, respectively. Overall, our study provides insights to predict ICI-ILD occurrence.

DOI： 10.1038/s41598-020-70743-2

Successful Vancomycin Dose Adjustment in a Sepsis patient with Bacterial Meningitis Using Cystatin C.

Masayuki Chuma, Masateru Kondo, Yoshito Zamami, Kenshi Takechi, Mitsuhiro Goda, Naoto Okada, Akitomo Shibata, Mizuho Asada, Jun Oto, Hiroaki Yanagawa, Keisuke Ishizawa

Acta medica Okayama 74 ( 4 ) 365 - 370 2020年8月

記述言語：英語

Cystatin C-guided vancomycin (VCM) dosing is useful in critically ill patients. Its usefulness in septic patients with bacterial meningitis remains unknown, as there are no published reports. In this study, we sought to clarify its benefit. Cystatin C was used to guide VCM dosing in a septic bacterial meningitis patient with normal kidney function, according to therapeutic drug monitoring (TDM). Using cystatin C, the Bayesian method-based TDM made optimal VCM dosing possible, and decreased the predicted error (4.85 mg/L) compared to serum creatinine (16.83 mg/L). We concluded TDM of VCM using cystatin C can be considered in sepsis patients with bacterial meningitis with normal kidney function.

DOI： 10.18926/AMO/60376

Deletion of H-ferritin in macrophages alleviates obesity and diabetes induced by high-fat diet in mice. 査読国際誌

Yasumasa Ikeda, Hiroaki Watanabe, Tetsuya Shiuchi, Hirofumi Hamano, Yuya Horinouchi, Masaki Imanishi, Mitsuhiro Goda, Yoshito Zamami, Kenshi Takechi, Yuki Izawa-Ishizawa, Licht Miyamoto, Keisuke Ishizawa, Ken-Ichi Aihara, Koichiro Tsuchiya, Toshiaki Tamaki

Diabetologia 63 ( 8 ) 1588 - 1602 2020年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIMS/HYPOTHESIS: Iron accumulation affects obesity and diabetes, both of which are ameliorated by iron reduction. Ferritin, an iron-storage protein, plays a crucial role in iron metabolism. H-ferritin exerts its cytoprotective action by reducing toxicity via its ferroxidase activity. We investigated the role of macrophage H-ferritin in obesity and diabetes. METHODS: Conditional macrophage-specific H-ferritin (Fth, also known as Fth1) knockout (LysM-Cre Fth KO) mice were used and divided into four groups: wild-type (WT) and LysM-Cre Fth KO mice with normal diet (ND), and WT and LysM-Cre Fth KO mice with high-fat diet (HFD). These mice were analysed for characteristics of obesity and diabetes, tissue iron content, inflammation, oxidative stress, insulin sensitivity and metabolic measurements. RAW264.7 macrophage cells were used for in vitro experiments. RESULTS: Iron concentration reduced, and mRNA expression of ferroportin increased, in macrophages from LysM-Cre Fth KO mice. HFD-induced obesity was lower in LysM-Cre Fth KO mice than in WT mice at 12 weeks (body weight: KO 34.6 ± 5.6 g vs WT 40.1 ± 5.2 g). mRNA expression of inflammatory cytokines and infiltrated macrophages and oxidative stress increased in the adipose tissue of HFD-fed WT mice, but was not elevated in HFD-fed LysM-Cre Fth KO mice. However, WT mice fed an HFD had elevated iron concentration in adipose tissue and spleen, which was not observed in LysM-Cre Fth KO mice fed an HFD (adipose tissue [μmol Fe/g protein]: KO 1496 ± 479 vs WT 2316 ± 866; spleen [μmol Fe/g protein]: KO 218 ± 54 vs WT 334 ± 83). Moreover, HFD administration impaired both glucose tolerance and insulin sensitivity in WT mice, which was ameliorated in LysM-Cre Fth KO mice. In addition, energy expenditure, mRNA expression of thermogenic genes, and body temperature were higher in KO mice with HFD than WT mice with HFD. In vitro experiments showed that iron content was reduced, and lipopolysaccharide-induced Tnf-α (also known as Tnf) mRNA upregulation was inhibited in a macrophage cell line transfected with Fth siRNA. CONCLUSIONS/INTERPRETATION: Deletion of macrophage H-ferritin suppresses the inflammatory response by reducing intracellular iron levels, resulting in the prevention of HFD-induced obesity and diabetes. The findings from this study highlight macrophage iron levels as a potential therapeutic target for obesity and diabetes.

DOI： 10.1007/s00125-020-05153-0

救急認定薬剤師に今後期待すること救急認定薬剤師に対する研究のすすめ共に歩もう! エビデンス創出へ!!

中馬真幸, 武智研志, 座間味義人, 合田光寛, 石田俊介, 濱野裕章, 近藤正輝, 坂東貴司, 石澤啓介, 楊河宏章

日本臨床救急医学会雑誌 23 ( 3 ) 351 - 351 2020年8月

血液凝固因子製剤の在庫適正化に向けた取り組みによる薬剤廃棄額の削減効果

岡田直人, 神農麻里奈, 中村信元, 三木浩和, 渡辺浩良, 合田光寛, 中馬真幸, 武智研志, 座間味義人, 桐野靖, 中村敏己, 寺岡和彦, 安倍正博, 石澤啓介

日本病院薬剤師会雑誌 56 ( 7 ) 803 - 808 2020年7月

記述言語：日本語出版者・発行元：(一社)日本病院薬剤師会

血友病治療に用いる血液凝固因子製剤(coagulation factor:以下、CF)は高価である一方で、在庫流動性が低いという製剤的性質を有するが、これまで適切な在庫管理法の報告はない。徳島大学病院は2017年4月から、診療科と連携したCFの在庫適正化の取り組みを開始した。取り組み開始前である2015年4月〜2017年3月の期間と、取り組み開始後である2017年4月〜2019年3月の期間における血友病患者数、CF調剤薬剤数に差はなかったが、取り組み開始後のCF廃棄額は取り組み開始前と比較して78.4%減少した。また、取り組み開始前後におけるCF購入額に対するCF廃棄額の割合は2.3%から0.3%に減少し、全注射剤廃棄額に対するCF廃棄額の割合は37.7%から10.7%に減少した。以上の結果から、診療科と連携したCFの在庫適正化により、薬剤廃棄額の削減効果が得られることが示された。(著者抄録)

循環器疾患治療薬の相互作用とポリファーマシー高齢者の薬物療法管理ツールを活用した薬剤業務の効率化

泉侑希, 石田俊介, 長谷川結美, 武智研志, 合田光寛, 座間味義人, 桐野靖, 中村敏己, 寺岡和彦, 八木秀介, 佐田政隆, 石澤啓介

日本循環器学会学術集会抄録集 84回チーム医療シンポジウム3 - 5 2020年7月

【薬物動態・薬物相互作用・薬物アレルギーから最適化スペシャル・ポピュレーションの抗菌薬投与設計】(第3章)特殊病態の患者敗血症患者

中馬真幸, 岡田直人, 武智研志, 合田光寛, 近藤正輝, 座間味義人, 楊河宏章, 石澤啓介

薬事 62 ( 10 ) 2048 - 2055 2020年7月

記述言語：日本語出版者・発行元：(株)じほう

＜Key Points＞・2016年に敗血症の定義が変更になった。従来より臓器障害を意識した投与設計が必要である。・敗血症により、さまざまな薬物動態の変動が生じる。薬物動態の変動に関連する病態の適切な把握を行い、投与設計に反映する必要がある。・具体的な用法・用量に関するエビデンスに乏しいため、個別の症例への対応が求められる場面も多い。最新のエビデンスを把握しておく必要があるとともに、抗菌薬適正使用支援チーム(AST)に関与する薬剤師が積極的にエビデンスの創出を推進する必要がある。(著者抄録)

血液凝固因子製剤の在庫適正化に向けた取り組みによる薬剤廃棄額の削減効果

岡田直人, 神農麻里奈, 中村信元, 三木浩和, 渡辺浩良, 合田光寛, 中馬真幸, 武智研志, 座間味義人, 桐野靖, 中村敏己, 寺岡和彦, 安倍正博, 石澤啓介

日本病院薬剤師会雑誌 56 ( 7 ) 803 - 808 2020年7月

記述言語：日本語出版者・発行元：(一社)日本病院薬剤師会

血友病治療に用いる血液凝固因子製剤(coagulation factor:以下、CF)は高価である一方で、在庫流動性が低いという製剤的性質を有するが、これまで適切な在庫管理法の報告はない。徳島大学病院は2017年4月から、診療科と連携したCFの在庫適正化の取り組みを開始した。取り組み開始前である2015年4月〜2017年3月の期間と、取り組み開始後である2017年4月〜2019年3月の期間における血友病患者数、CF調剤薬剤数に差はなかったが、取り組み開始後のCF廃棄額は取り組み開始前と比較して78.4%減少した。また、取り組み開始前後におけるCF購入額に対するCF廃棄額の割合は2.3%から0.3%に減少し、全注射剤廃棄額に対するCF廃棄額の割合は37.7%から10.7%に減少した。以上の結果から、診療科と連携したCFの在庫適正化により、薬剤廃棄額の削減効果が得られることが示された。(著者抄録)

その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J04451&link_issn=&doc_id=20200710240010&doc_link_id=%2Fdg4hppha%2F2020%2F005607%2F010%2F0803-0808%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg4hppha%2F2020%2F005607%2F010%2F0803-0808%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

循環器疾患治療薬の相互作用とポリファーマシー高齢者の薬物療法管理ツールを活用した薬剤業務の効率化

泉侑希, 石田俊介, 長谷川結美, 武智研志, 合田光寛, 座間味義人, 桐野靖, 中村敏己, 寺岡和彦, 八木秀介, 佐田政隆, 石澤啓介

日本循環器学会学術集会抄録集 84回チーム医療シンポジウム3 - 5 2020年7月

特殊病態・母集団における体内動態からみた抗菌薬投与設計の最適化敗血症における抗菌薬投与設計の最適化に向けて

中馬真幸, 武智研志, 座間味義人, 合田光寛, 岡田直人, 近藤正輝, 石澤啓介, 楊河宏章

日本化学療法学会雑誌 68 ( 3 ) 419 - 419 2020年5月

特殊病態・母集団における体内動態からみた抗菌薬投与設計の最適化敗血症における抗菌薬投与設計の最適化に向けて

中馬真幸, 武智研志, 座間味義人, 合田光寛, 岡田直人, 近藤正輝, 石澤啓介, 楊河宏章

感染症学雑誌 94 ( 3 ) 380 - 380 2020年5月

Fibroblast-specific ERK5 deficiency changes tumor vasculature and exacerbates tumor progression in a mouse model. 査読国際誌

Masaki Imanishi, Yusuke Yamakawa, Keijo Fukushima, Raiki Ikuto, Akiko Maegawa, Yuki Izawa-Ishizawa, Yuya Horinouchi, Masateru Kondo, Masatoshi Kishuku, Mitsuhiro Goda, Yoshito Zamami, Kenshi Takechi, Masayuki Chuma, Yasumasa Ikeda, Koichiro Tsuchiya, Hiromichi Fujino, Koichi Tsuneyama, Keisuke Ishizawa

Naunyn-Schmiedeberg's archives of pharmacology 393 ( 7 ) 1239 - 1250 2020年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

The roles of cancer-associated fibroblasts (CAFs) have been studied in the tumor progression, and CAFs are expected to become the new targets for cancer pharmacotherapies. CAFs contribute to tumor cell survival and proliferation, tumor angiogenesis, immune suppression, tumor inflammation, tumor cell invasion and metastasis, and extracellular matrix remodeling. However, detailed mechanisms of how CAFs function in the living system remain unclear. CAFs include α-smooth muscle actin, expressing activated fibroblasts similar to myofibroblasts, and are highly capable of producing collagen. Several reports have demonstrated the contributions of extracellular-signal-regulated kinase 5 (ERK5) in fibroblasts to the fibrotic processes; however, the roles of CAF-derived ERK5 remain unclear. To investigate the roles of CAF-derived ERK5 in the tumor progression, we created mice lacking the ERK5 gene specifically in fibroblasts. Colon-26 mouse colon cancer cells were implanted into the mice subcutaneously, and the histological analyses of the tumor tissue were performed after 2 weeks. Immunofluorescence analyses showed that recipient-derived fibroblasts existed within the tumor tissue. The present study demonstrated that fibroblast-specific ERK5 deficiency exacerbated tumor progression and it was accompanied with thicker tumor vessel formation and the increase in the number of activated fibroblasts. We combined the results of The Cancer Genome Atlas (TCGA) database analysis with our animal studies, and indicated that regulating ERK5 activity in CAFs or CAF invasion into the tumor tissue can be important strategies for the development of new targets in cancer pharmacotherapies.

DOI： 10.1007/s00210-020-01859-5

薬物療法にかかわる副作用マネジメントのエビデンス確立に向けて薬剤師が実践する向精神薬の副作用対策に向けた臨床研究についてエビデンスをもった効率的な副作用マネジメントを目指して

武智研志, 石田俊介, 坂東寛, 中馬真幸, 座間味義人, 合田光寛, 石澤啓介, 楊河宏章

日本病院薬剤師会雑誌 56 ( 4 ) 373 - 376 2020年4月

シスプラチン誘発性腎障害を予防する既存薬物の同定

濱野裕章, 合田光寛, 座間味義人, 石澤啓介, 池田康将, 堀ノ内裕也, 福島圭穣, 藤野裕道, 岸誠司, 武智研志, 中馬真幸, 宮本理人, 土屋浩一郎, 玉置俊晃

四国医学雑誌 76 ( 1-2 ) 116 - 117 2020年4月

シスプラチン誘発腎障害に対する新規予防薬の探索とその有効性の検証

前川晃子, 吉田愛美, 村井陽一, 新村貴博, 座間味義人, 石澤啓介, 合田光寛, 神田将哉, 濱野裕章, 岡田直人, 石澤有紀, 中馬真幸, 武智研志, 堀ノ内裕也, 池田康将

四国医学雑誌 76 ( 1-2 ) 116 - 116 2020年4月

血管平滑筋細胞石灰化シグナルにおけるRhoキナーゼ-サイクロフィリンA経路の関与

津田達也, 橋本一郎, 堀ノ内裕也, 池田康将, 石澤有紀, 合田光寛, 座間味義人, 石澤啓介

四国医学雑誌 76 ( 1-2 ) 119 - 119 2020年4月

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

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

Rho-associated protein kinase and cyclophilin a are involved in inorganic phosphate-induced calcification signaling in vascular smooth muscle cells. 査読

Tatsuya Tsuda, Masaki Imanishi, Mizuho Oogoshi, Mitsuhiro Goda, Yoshitaka Kihira, Yuya Horinouchi, Yoshito Zamami, Keisuke Ishizawa, Yasumasa Ikeda, Ichiro Hashimoto, Toshiaki Tamaki, Yuki Izawa-Ishizawa

Journal of pharmacological sciences 142 ( 3 ) 109 - 115 2020年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Arterial calcification, a risk factor of cardiovascular events, develops with differentiation of vascular smooth muscle cells (VSMCs) into osteoblast-like cells. Cyclophilin A (CypA) is a peptidyl-prolyl isomerase involved in cardiovascular diseases such as atherosclerosis and aortic aneurysms, and rho-associated protein kinase (ROCK) is involved in the pathogenesis of vascular calcification. CypA is secreted in a ROCK activity-dependent manner and works as a mitogen via autocrine or paracrine mechanisms in VSMCs. We examined the involvement of the ROCK-CypA axis in VSMC calcification induced by inorganic phosphate (Pi), a potent cell mineralization initiator. We found that Pi stimulated ROCK activity, CypA secretion, extracellular signal-regulated protein kinase (ERK) 1/2 phosphorylation, and runt-related transcription factor 2 expression, resulting in calcium accumulation in rat aortic smooth muscle cells (RASMCs). The ROCK inhibitor Y-27632 significantly suppressed Pi-induced CypA secretion, ERK1/2 phosphorylation, and calcium accumulation. Recombinant CypA was found to be associated with increased calcium accumulation in RASMCs. Based on these results, we suggest that autocrine CypA is mediated by ROCK activity and is involved in Pi-induced ERK1/2 phosphorylation following calcification signaling in RASMCs.

DOI： 10.1016/j.jphs.2019.12.005

第4回病院薬剤師が実践するリバーストランスレーショナルリサーチの最前線〜臨床薬剤師の視点から新たな薬物療法を提案する〜医療ビッグデータ解析と基礎研究を融合したオキサリプラチン誘発末梢神経障害に対する予防薬探索

合田光寛, 座間味義人, 新村貴博, 川尻雄大, 武智研志, 中馬真幸, 萱野純史, 濱野裕章, 岡田直人, 小林大介, 島添隆雄, 石澤有紀, 石澤啓介

日本薬学会年会要旨集 140年会 S37 - 3 2020年3月

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2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Background:
Globally, the number of deaths is estimated to increase to 74 million per year by 2030. Place of death (PoD) is increasingly being recognized as an important aspect of end-of-life care. However, recent trends in PoD in Japan, one of the super-aged societies, are unknown.
Objective:
To analyze trends in PoD in Japan over two decades.
Design:
Population-based retrospective observational study.
Setting:
All deaths reported in Japan, 1998-2017. PoD was defined as hospital, nursing home, or own home.
Results:
All Japanese decedents (∼22.6 million) over the past 20 years were analyzed. The proportion of hospital deaths was consistently high (>80%), with a significant decreasing trend from the mid-2000s. Although the proportion of deaths at home decreased in the first half of the study period, they later increased. There was a low proportion of deaths in nursing homes compared to other places of death; however, the proportion increased continually throughout the study period, particularly among women. In 2015, more women died in nursing homes than at home. Although the proportion of hospital deaths declined in the second half of the study period, their overall number continued to increase, reflecting an increase in total deaths in Japan.
Conclusions:
This study highlighted rapid changes in trends in PoD in Japan, and the need to consider affordable end-of-life care in Japan as well as other countries with aging populations. The findings from this long-term epidemiological study provide important insights on this issue.

DOI： 10.1089/jpm.2019.0445

Proton pump inhibitors block iron absorption through direct regulation of hepcidin via the aryl hydrocarbon receptor-mediated pathway. 査読国際誌

Hirofumi Hamano, Takahiro Niimura, Yuya Horinouchi, Yoshito Zamami, Kenshi Takechi, Mitsuhiro Goda, Masaki Imanishi, Masayuki Chuma, Yuki Izawa-Ishizawa, Licht Miyamoto, Keijo Fukushima, Hiromichi Fujino, Koichiro Tsuchiya, Keisuke Ishizawa, Toshiaki Tamaki, Yasumasa Ikeda

Toxicology letters 318 86 - 91 2020年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Proton pump inhibitors (PPIs) have been used worldwide to treat gastrointestinal disorders. A recent study showed that long-term use of PPIs caused iron deficiency; however, it is unclear whether PPIs affect iron metabolism directly. We investigated the effect of PPIs on the peptide hepcidin, an important iron regulatory hormone. First, we used the FDA Adverse Event Reporting System database and analyzed the influence of PPIs. We found that PPIs, as well as H2 blockers, increased the odds ratio of iron-deficient anemia. Next, HepG2 cells were used to examine the action of PPIs and H2 blockers on hepcidin. PPIs augmented hepcidin expression, while H2 blockers did not. In fact, the PPI omeprazole increased hepcidin secretion, and omeprazole-induced hepcidin upregulation was inhibited by gene silencing or the pharmacological inhibition of the aryl hydrocarbon receptor. In mouse experiments, omeprazole also increased hepatic hepcidin mRNA expression and blood hepcidin levels. In mice treated with omeprazole, protein levels of duodenal and splenic ferroportin decreased. Taken together, PPIs directly affect iron metabolism by suppressing iron absorption through the inhibition of duodenal ferroportin via hepcidin upregulation. These findings provide a new insight into the molecular mechanism of PPI-induced iron deficiency.

DOI： 10.1016/j.toxlet.2019.10.016

Comparison of Hemorrhagic Risk between Prasugrel and Clopidogrel: a Retrospective Study using Adverse Drug Event Reporting Databases. 査読国際誌

Hiromi Hagiwara, Hidekatsu Fukuta, Takahiro Niimura, Yoshito Zamami, Keisuke Ishizawa, Kazunori Kimura, Takeshi Kamiya, Nobuyuki Ohte

International journal of medical sciences 17 ( 6 ) 728 - 733 2020年

記述言語：英語掲載種別：研究論文（学術雑誌）

Background: Prasugrel inhibits platelet aggregation more potently and exerts therapeutic action faster than clopidogrel. In the global phase III trial conducted in Western and South American countries that excluded Asian countries, prasugrel reduced ischemic events but increased hemorrhagic risk compared with clopidogrel in patients with acute coronary syndrome scheduled for percutaneous coronary intervention. In the Japanese phase III trial for similar patients, the efficacy of prasugrel compared with clopidogrel was comparable to the global trial, but the safety could not be confirmed because of an insufficient number of patients. Furthermore, given the strict enrollment criteria, the results of these trials may not be applicable to routine clinical practice. Accordingly, we compared the hemorrhagic risk of prasugrel and clopidogrel in real-world settings by analyzing adverse drug event reports in post-marketing stages provided by the Japanese regulatory authorities and the U.S. Food and Drug Administration (FDA). Methods: We analyzed a total of 3,970 reports for prasugrel (n = 518) or clopidogrel (n = 3,452) between 2014 and 2017 in the Japanese Adverse Drug Event Report (JADER) and a total of 91,914 reports for either prasugrel (n = 5,992) or clopidogrel (n = 85,922) between 2009 and 2019 in the FDA Adverse Event Reporting System (FAERS). Results: In JADER and FAERS, prasugrel was more frequently and significantly associated with hemorrhagic event reports than clopidogrel. After adjustment for known confounders including age, sex, and concomitant medications (aspirin, anticoagulants, and proton pump inhibitors), the hemorrhagic risk of prasugrel compared with clopidogrel remained significant (adjusted reporting odds ratios [95% CI] for total, intracranial, and gastrointestinal hemorrhagic events = 2.42 [1.97-2.96], 2.45 [1.85-3.24], and 2.27 [1.73-2.97] in JADER, and 2.21 [2.09-2.34], 1.21 [1.09-1.33], and 1.41 [1.29-1.54] in FAERS). Conclusions: The hemorrhagic risk was found to be greater with prasugrel than clopidogrel in real-world patients, including Japanese patients.

DOI： 10.7150/ijms.43168

シスプラチン腎障害における鉄依存性細胞死の検討

池田康将, 濱野裕章, 堀ノ内祐也, 合田光寛, 座間味義人, 宮本理人, 石澤啓介, 土屋浩一郎

日本薬理学会年会要旨集 93 2 - O-060 2020年

記述言語：日本語出版者・発行元：公益社団法人日本薬理学会

<p>Background: Ferroptosis has been identified as iron-dependent regulated cell death, and it participates with a various disorder including kidney disease. Cisplatin, a classical anti-cancer drug, causes nephrotoxicity, which is inhibited by iron chelator. In the present study, we examined the involvement of ferroptosis on cisplatin-induced nephrotoxicity.</p><p>Methods: We used male mice with cisplatin-induced nephrotoxicity that were pretreated with vehicle or a ferroptosis inhibitor. Mice were sacrificed at 48 hours later. </p><p>Results: Cisplatin administration actually augmented ferrous iron and hydroxyl radical production in the kidney. Cisplatin-induced COX-2 expression, as well as lipid peroxide, was increased by cisplatin-treated kidney. An inhibitor of ferroptosis also suppressed cisplatin-induced increased of COX-2 expression and lipid peroxide. Mice with cisplatin administration developed kidney injury with renal dysfunction, and showed augmented oxidative stress, increased apoptosis, and elevated inflammatory cytokines. However, most of these symptoms were suppressed by a ferroptosis inhibitor.</p><p>Conclusion: Ferroptosis is suggested to involve cisplatin-induced nephrotoxicity.</p>

DOI： 10.1254/jpssuppl.93.0_2-O-060

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

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

Hideharu Hagiya, Toshihiro Koyama, Yoshito Zamami, Yasuhisa Tatebe, Tomoko Funahashi, Kazuaki Shinomiya, Yoshihisa Kitamura, Shiro Hinotsu, Toshiaki Sendo, Hiromi Rakugi, Mitsunobu R Kano

BMJ open 9 ( 12 ) e033462 2019年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: Fall-related mortality among older adults is a major public health issue, especially for ageing societies. This study aimed to investigate current trends in fall-related mortality in Japan using nationwide population-based data covering 1997-2016. DESIGN: We analysed fall-related deaths among older persons aged ≥65 years using the data provided by the Japanese Ministry of Health, Labour and Welfare. RESULTS: The crude and age-standardised mortality rates were calculated per 100 000 persons by stratifying by age (65-74, 75-84 and ≥85 years) and sex. To identify trend changes, a joinpoint regression model was applied by estimating change points and annual percentage change (APC). The total number of fall-related deaths in Japan increased from 5872 in 1997 to 8030 in 2016, of which 78.8% involved persons aged ≥65 years. The younger population (65-74 years) showed continuous and faster-decreasing trends for both men and women. Average APC among men aged ≥75 years did not decrease. Among middle-aged and older women (75-84 and ≥85 years) decreasing trends were observed. Furthermore, the age-adjusted mortality rate of men was approximately twice that of women, and it showed a faster decrease for women. CONCLUSIONS: Although Japanese healthcare has shown improvement in preventing fall-related deaths over the last two decades, the crude mortality for those aged over 85 years remains high, indicating difficulty in reducing fall-related deaths in the super-aged population. Further investigations to uncover causal factors for falls in older populations are required.

DOI： 10.1136/bmjopen-2019-033462

Effect of serum concentration and concomitant drugs on vancomycin-induced acute kidney injury in haematologic patients: a single-centre retrospective study. 査読国際誌

Naoto Okada, Masayuki Chuma, Momoyo Azuma, Shingen Nakamura, Hirokazu Miki, Hirofumi Hamano, Mitsuhiro Goda, Kenshi Takechi, Yoshito Zamami, Masahiro Abe, Keisuke Ishizawa

European journal of clinical pharmacology 75 ( 12 ) 1695 - 1704 2019年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: Appropriate use of vancomycin (VCM) is important in preventing acute kidney injury (AKI). Because of the high frequency of VCM use for febrile neutropenia and concomitant use of other nephrotoxic drugs, haematologic patients have a different nephrotoxic background compared with patients with other diseases. Therefore, it is unclear whether the risk factors of VCM-induced AKI identified in other patient groups are also applicable to haematologic patients. Herein, we performed a single-centre retrospective analysis to identify the factors associated with VCM-induced AKI in haematologic patients. METHODS: We retrospectively analysed 150 haematologic patients to whom VCM was administered between April 2010 and March 2018 at Tokushima University Hospital. VCM-induced AKI was defined according to Kidney Disease Improving Global Outcomes (KDIGO) criteria. Multivariate logistic regression analyses were performed to identify risk factors for VCM-induced AKI. RESULTS: Seventeen patients had VCM-induced AKI. Multivariate analysis revealed that the risk factors of VCM-induced AKI were an initial VCM trough concentration of > 15 mg/L and concomitant use of tazobactam/piperacillin (TAZ/PIPC) and liposomal amphotericin B (L-AMB). Patients with an initial VCM trough concentration of < 10 mg/L showed significantly lower efficacy in febrile neutropenia. Interestingly, concomitant L-AMB use increased the incidence of VCM-induced AKI in a VCM concentration-dependent manner, whereas concomitant TAZ/PIPC increased the incidence in a VCM concentration-independent manner. CONCLUSIONS: The optimal initial VCM trough concentration was 10-15 mg/L in haematologic patients, considering safety and effectiveness. There were differences in the effect of VCM-induced AKI between nephrotoxic drugs.

DOI： 10.1007/s00228-019-02756-4

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

Ayako Ohshima, Toshihiro Koyama, Aiko Ogawa, Yoshito Zamami, Hiroyoshi Y Tanaka, Yoshihisa Kitamura, Toshiaki Sendo, Shiro Hinotsu, Michael W Miller, Mitsunobu R Kano

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

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Oral anticoagulants use has increased rapidly, internationally. Here we look at risks and benefits, based on Japanese data, of therapy with low risk non-valvular atrial fibrillation patients. OBJECTIVES: Using a health insurance claims data set we assessed: (i) oral anticoagulants usage in Japan, and (ii) efficacy and safety of dabigatran compared with warfarin, in Japanese patients with non-valvular atrial fibrillation, aged 18-74 years. METHODS: We identified 4380 non-valvular atrial fibrillation patients treated with anticoagulants between 1 January 2005, and 28 February 2014, and estimated the adjusted hazard ratio for stroke or systemic embolism, and any hemorrhagic event (Cox proportional hazards regression model with stabilized inverse probability treatment weighting). RESULTS: The data included 101 989 anticoagulant prescriptions for 4380 patients, of which direct oral anticoagulants increased to 40.0% of the total by the end of the study. After applying exclusion criteria, 1536 new non-valvular atrial fibrillation patients were identified, including 1071 treated with warfarin and 465 with dabigatran. Mean ages were 56.11 ± 9.70 years for warfarin, and 55.80 ± 9.65 years for dabigatran. The adjusted hazard ratio (95% confidence interval), comparing dabigatran with warfarin, was 0.48 (0.25-0.91) for stroke or systemic embolism, and 0.91 (0.60-1.39) for any hemorrhage including intracranial and gastrointestinal. CONCLUSIONS: Number of patients prescribed direct oral anticoagulants steadily increased, and incidence of all-cause bleeding related to dabigatran was similar to warfarin, in our study population of younger non-valvular atrial fibrillation patients. Dabigatran, compared with warfarin, generally reduced risk of all-cause stroke and systemic embolism.

DOI： 10.1093/fampra/cmz016

臨床薬理共同研究推進体制の構築に関する取り組み査読

武智研志, 座間味義人, 肥田典子, 鈴木啓介

臨床薬理 50 ( Suppl. ) S228 - S228 2019年11月

認定薬剤師の科学力を考える基礎研究と医療ビッグデータ解析を融合させたドラッグ・リボジショニングへの試み査読

堀ノ内裕也, 池田康将, 福島圭穣, 今西正樹, 濱野裕章, 石澤有紀, 座間味義人, 武智研志, 藤野裕道, 石澤啓介, 土屋浩一郎, 玉置俊晃

臨床薬理 50 ( Suppl. ) S176 - S176 2019年11月

Prophylactic administration of granulocyte colony-stimulating factor in epirubicin and cyclophosphamide chemotherapy for Japanese breast cancer patients: a retrospective study. 査読国際誌

Takumi Sakurada, Sanako Bando, Yoshito Zamami, Kenshi Takechi, Masayuki Chuma, Mitsuhiro Goda, Yasushi Kirino, Toshimi Nakamura, Kazuhiko Teraoka, Masami Morimoto, Akira Tangoku, Keisuke Ishizawa

Cancer chemotherapy and pharmacology 84 ( 5 ) 1107 - 1114 2019年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: Epirubicin and cyclophosphamide (EC) therapy, a major chemotherapy for patients with early-stage breast cancer, has a low risk (< 10%) of febrile neutropenia (FN). However, data used in reports on the incidence rate of FN were derived primarily from non-Asian populations. In this study, we investigated the FN incidence rate using EC therapy among Japanese patients with breast cancer and evaluated the significance of prophylactic administration of granulocyte colony-stimulating factor (G-CSF). METHODS: We evaluated medical records of patients with early-stage breast cancer who had been treated with EC therapy as neoadjuvant or adjuvant therapy between November 2014 and July 2018. RESULTS: The incidence rate of FN was 23.9%. In patients who received G-CSF as primary prophylaxis, FN expression was completely suppressed. The incidence rate of severe leucopenia/neutropenia, emergency hospitalization, and the use of antimicrobial agents were low in patients receiving primary prophylaxis with G-CSF compared with those not receiving G-CSF (27.3% vs. 64.8%, 9.1% vs. 27.3%, and 27.3% vs. 71.6%, respectively). Furthermore, in all patients who received primary prophylaxis with G-CSF, a relative dose intensity > 85% using EC therapy was maintained. CONCLUSION: The incidence of FN in EC therapy among Japanese patients was higher than expected, EC therapy appears to be a high-risk chemotherapy for FN, and prophylactic administration of G-CSF is recommended. Maintaining high therapeutic intensity is associated with a positive prognosis for patients with early breast cancer, and prophylactic administration of G-CSF is likely to be beneficial in treatment involving EC therapy.

DOI： 10.1007/s00280-019-03948-6

臨床薬理共同研究推進体制の構築に関する取り組み

武智研志, 座間味義人, 肥田典子, 鈴木啓介

臨床薬理 50 ( Suppl. ) S228 - S228 2019年11月

ドラッグリポジショニング手法を用いたバンコマイシン関連腎障害の予防薬探索とその有用性の検討査読

中馬真幸, 合田光寛, 谷友歩, 座間味義人, 武智研志, 石澤有紀, 濱野裕章, 石田俊介, 新村貴博, 近藤正輝, 坂東貴司, 岡田直人, 福島圭穣, 藤野裕道, 土屋浩一郎, 堀ノ内裕也, 池田康将, 楊河宏章, 石澤啓介

日本腎臓病薬物療法学会誌 8 ( 特別号 ) S138 - S138 2019年10月

【医師・看護師のギモンに"的確"かつ"迅速"に答える!病棟・カンファレンスでそのまま使える想定問答集151】(第9章)感染症 (Q109)イトラコナゾール剤形変更時の注意点イトラコナゾールをカプセルから内用液へと切り替える際の注意点を教えてください

岡田直人, 座間味義人, 石澤啓介

薬事 61 ( 14 ) 2690 - 2691 2019年10月

【医師・看護師のギモンに"的確"かつ"迅速"に答える!病棟・カンファレンスでそのまま使える想定問答集151】(第9章)感染症 (Q108)腸ろう患者へのボリコナゾール投与経腸栄養剤を腸ろうから24時間持続投与している患者に対し、ボリコナゾールの経胃投与は可能ですか?

岡田直人, 座間味義人, 石澤啓介

薬事 61 ( 14 ) 2688 - 2689 2019年10月

【医師・看護師のギモンに"的確"かつ"迅速"に答える!病棟・カンファレンスでそのまま使える想定問答集151】(第9章)感染症 (Q107)感染性心内膜炎に対する予防投与感染性心内膜炎の予防では、どのような患者にどのような抗菌薬が使用されますか?

岡田直人, 座間味義人, 石澤啓介

薬事 61 ( 14 ) 2685 - 2687 2019年10月

医療ビッグデータを活用した救急薬学研究査読

中馬真幸, 座間味義人, 合田光寛, 武智研志, 石澤有紀, 新村貴博, 濱野裕章, 近藤正輝, 楊河宏章, 石澤啓介

日本救急医学会雑誌 30 ( 9 ) 506 - 507 2019年9月

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

Yoshito Zamami, Takahiro Niimura, Naoto Okada, Toshihiro Koyama, Keijo Fukushima, Yuki Izawa-Ishizawa, Keisuke Ishizawa

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

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

Iron accumulation causes impaired myogenesis correlated with MAPK signaling pathway inhibition by oxidative stress. 査読国際誌

Yasumasa Ikeda, Akiho Satoh, Yuya Horinouchi, Hirofumi Hamano, Hiroaki Watanabe, Mizuki Imao, Masaki Imanishi, Yoshito Zamami, Kenshi Takechi, Yuki Izawa-Ishizawa, Licht Miyamoto, Tasuku Hirayama, Hideko Nagasawa, Keisuke Ishizawa, Ken-Ichi Aihara, Koichiro Tsuchiya, Toshiaki Tamaki

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 33 ( 8 ) 9551 - 9564 2019年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Skeletal muscle atrophy is caused by disruption in the homeostatic balance of muscle degeneration and regeneration under various pathophysiological conditions. We have previously reported that iron accumulation induces skeletal muscle atrophy via a ubiquitin ligase-dependent pathway. However, the potential effect of iron accumulation on muscle regeneration remains unclear. To examine the effect of iron accumulation on myogenesis, we used a mouse model with cardiotoxin (CTX)-induced muscle regeneration in vivo and C2C12 mouse myoblast cells in vitro. In mice with iron overload, the skeletal muscles exhibited increased oxidative stress and decreased expression of satellite cell markers. Following CTX-induced muscle injury, these mice also displayed delayed muscle regeneration with a decrease in the size of regenerating myofibers, reduced expression of myoblast differentiation markers, and decreased phosphorylation of MAPK signaling pathways. In vitro, iron overload also suppressed the differentiation of C2C12 myoblast cells but the suppression could be reversed by superoxide scavenging using tempol. Excess iron inhibits myogenesis via oxidative stress, leading to an imbalance in skeletal muscle homeostasis.-Ikeda, Y., Satoh, A., Horinouchi, Y., Hamano, H., Watanabe, H., Imao, M., Imanishi, M., Zamami, Y., Takechi, K., Izawa-Ishizawa, Y., Miyamoto, L., Hirayama, T., Nagasawa, H., Ishizawa, K., Aihara, K.-I., Tsuchiya, K., Tamaki, T. Iron accumulation causes impaired myogenesis correlated with MAPK signaling pathway inhibition by oxidative stress.

DOI： 10.1096/fj.201802724RR

Pattern of antibiotic prescriptions for outpatients with acute respiratory tract infections in Japan, 2013-15: a retrospective observational study. 査読国際誌

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7月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

Nerve growth factor (NGF) has an anti-tumor effects through perivascular innervation of neovessels in HT1080 fibrosarcoma and HepG2 hepatitis tumor in nude mice. 査読

Hiromu Kawasaki, Mitsuhiro Goda, Satoko Fukuhara, Narumi Hashikawa-Hobara, Yoshito Zamami, Shingo Takatori

Journal of pharmacological sciences 140 ( 1 ) 1 - 7 2019年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

This study investigated whether NGF prevents tumor growth by promoting neuronal regulation of tumor blood flow. HT1080 fibrosarcoma cells or HepG2 hepatitis cells were subcutaneously implanted into nude mice. On Day 21 after the implantation of tumor cells, human NGF (40 or 80 ng/h for 14 days) was administered using a micro-osmotic pump. Growth rates of both tumors were significantly inhibited by the treatment of NGF, and the survival rate was also extended. Significant suppression of HT1080 tumor growth lasted after withdrawing NGF. NGF markedly increased the density of α-smooth muscle actin (α-SMA)-immunoreactive (ir) cells without changing neovessel density in HT1080 tumor tissues. Double immunostaining demonstrated protein gene product (PGP) 9.5-ir nerves around α-SMA-ir cells were found in HT1080 tumor tissue treated with NGF. The blood flow in HepG2 tumors treated with saline was significantly higher than in the non-tumor control area, but the tumor blood flow was markedly reduced by NGF treatment. In in vitro studies, NGF significantly accelerated migration of aortic smooth muscle cells but not endothelial cells, whereas NGF had no cytotoxic action on both cells. NGF inhibits tumor growth via indirect action, probably through innervation and maturation of tumor neovasculature, which regulates blood flow into tumor tissues.

DOI： 10.1016/j.jphs.2019.02.011

Factors Affecting the Absorption of Midazolam to the Extracorporeal Membrane Oxygenation Circuit. 査読

Atsuyoshi Iida, Hiromichi Naito, Takashi Yorifuji, Yoshito Zamami, Akane Yamada, Tadashi Koga, Toru Imai, Toshiaki Sendo, Atsunori Nakao, Shingo Ichiba

Acta medica Okayama 73 ( 2 ) 101 - 107 2019年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Sedatives are administered during extracorporeal membrane oxygenation (ECMO) therapy to ensure patient safety, reduce the metabolic rate and correct the oxygen supply-demand balance. However, the concentrations of sedatives can be decreased due to absorption into the circuit. This study examined factors affecting the absorption of a commonly used sedative, midazolam (MDZ). Using multiple ex vivo simulation models, three factors that may influence MDZ levels in the ECMO circuit were examined: polyvinyl chloride (PVC) tubing in the circuit, use of a membrane oxygenator in the circuit, and heparin coating of the circuit. We also assessed changes in drug concentration when MDZ was re-injected in a circuit. The MDZ level decreased to approximately 60% of the initial concentration in simulated circuits within the first 30 minutes. The strongest factor in this phenomenon was contact with the PVC tubing. Membrane oxygenator use tended to increase MDZ loss, whereas heparin circuit coating had no influence on MDZ absorption. Similar results were obtained when a second dose of MDZ was injected to the second-use circuits.

DOI： 10.18926/AMO/56645

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

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

Irinotecan-induced neutropenia is reduced by oral alkalization drugs: analysis using retrospective chart reviews and the spontaneous reporting database. 査読国際誌

Hirofumi Hamano, Marin Mitsui, Yoshito Zamami, Kenshi Takechi, Takahiro Nimura, Naoto Okada, Keijo Fukushima, Masaki Imanishi, Masayuki Chuma, Yuya Horinouchi, Yuki Izawa-Ishizawa, Yasushi Kirino, Toshimi Nakamura, Kazuhiko Teraoka, Yasumasa Ikeda, Hiromichi Fujino, Hiroaki Yanagawa, Toshiaki Tamaki, Keisuke Ishizawa

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 27 ( 3 ) 849 - 856 2019年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: SN-38, an active metabolite of irinotecan, is reabsorbed by the intestinal tract during excretion, causing diarrhoea and neutropenia. In addition, the association between blood levels of SN-38 and neutropenia has been reported previously, and the rapid excretion of SN-38 from the intestinal tract is considered to prevent neutropenia. Oral alkalization drugs are used as prophylactic agents for suppressing SN-38 reabsorption. The relationship between oral alkalization drugs and neutropenia, however, has not been well studied. The aim of this study was to investigate the relationship between oral alkalization drugs and neutropenia in irinotecan-treated patients. METHODS AND RESULTS: Patients with cervical or ovarian cancer were administered irinotecan and investigated by medical chart reviews to determine whether oral alkalization drugs were effective at ameliorating irinotecan-induced neutropenia. The drug combination in the oral alkalization drugs-ursodeoxycholic acid, magnesium oxide, and sodium hydrogen carbonate-significantly improved neutrophil counts and reduced dose intensity compared with those of non-users. In the large-scale Japanese Adverse Drug Event Report database, the reporting odds ratio of irinotecan-induced neutropenia was significantly lower when irinotecan had been given in combination with oral alkalization drugs. CONCLUSIONS: These data indicate that oral alkalization drugs may reduce the frequency of neutropenia caused by irinotecan administration, making it possible to increase the dose safely.

DOI： 10.1007/s00520-018-4367-y

抗菌薬の使い方 PK/PD理論やTDMに基づく用法・用量設定を中心に

中馬真幸, 座間味義人, 武智研志, 今西正樹, 岡田直人, 合田光寛, 近藤正輝, 石澤啓介, 楊河宏章

日本化学療法学会雑誌 67 ( 2 ) 216 - 216 2019年3月

抗菌薬TDMガイドライン2019 再改訂のポイント持続的腎代替療法

中馬真幸, 武智研志, 座間味義人, 合田光寛, 岡田直人, 近藤正輝, 石澤啓介, 楊河宏章

日本化学療法学会雑誌 67 ( Suppl.A ) 137 - 137 2019年3月

Xanthine Oxidase Inhibition by Febuxostat in Macrophages Suppresses Angiotensin II-Induced Aortic Fibrosis. 査読国際誌

Masateru Kondo, Masaki Imanishi, Keijo Fukushima, Raiki Ikuto, Yoichi Murai, Yuya Horinouchi, Yuki Izawa-Ishizawa, Mitsuhiro Goda, Yoshito Zamami, Kenshi Takechi, Masayuki Chuma, Yasumasa Ikeda, Hiromichi Fujino, Koichiro Tsuchiya, Keisuke Ishizawa

American journal of hypertension 32 ( 3 ) 249 - 256 2019年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Several reports from basic researches and clinical studies have suggested that xanthine oxidase (XO) inhibitors have suppressive effects on cardiovascular diseases. However, the roles of a XO inhibitor, febuxostat (FEB), in the pathogenesis of vascular remodeling and hypertension independent of the serum uric acid level remain unclear. METHODS: To induce vascular remodeling in mice, angiotensin II (Ang II) was infused for 2 weeks with a subcutaneously implanted osmotic minipump. FEB was administered every day during Ang II infusion. Aortic fibrosis was assessed by elastica van Gieson staining. Mouse macrophage RAW264.7 cells (RAW) and mouse embryonic fibroblasts were used for in vitro studies. RESULTS: FEB suppressed Ang II-induced blood pressure elevation and aortic fibrosis. Immunostaining showed that Ang II-induced macrophage infiltration in the aorta tended to be suppressed by FEB, and XO was mainly colocalized in macrophages, not in fibroblasts. Transforming growth factor-β1 (TGF-β1) mRNA expression was induced in the aorta in the Ang II alone group, but not in the Ang II + FEB group. Ang II induced α-smooth muscle actin-positive fibroblasts in the aortic wall, but FEB suppressed them. XO expression and activity were induced by Ang II stimulation alone but not by Ang II + FEB in RAW. FEB suppressed Ang II-induced TGF-β1 mRNA expression in RAW. CONCLUSIONS: Our results suggested that FEB ameliorates Ang II-induced aortic fibrosis via suppressing macrophage-derived TGF-β1 expression.

DOI： 10.1093/ajh/hpy157

ASチームが知っておきたい薬物動態侵襲時の薬物動態

中馬真幸, 武智研志, 座間味義人, 合田光寛, 岡田直人, 近藤正輝, 石澤啓介, 楊河宏章

日本環境感染学会総会プログラム・抄録集 34回 [シンポ - 2] 2019年2月

集中治療患者における臓器系統別評価方法の習得臓器系統別評価3/5 感染・炎症・免疫管理敗血症に対する抗菌薬治療を中心に

中馬真幸, 近藤正輝, 武智研志, 座間味義人, 合田光寛, 岡田直人, 石澤啓介, 楊河宏章

日本病院薬剤師会雑誌 55 ( 2 ) 163 - 166 2019年2月

マクロファージフェリチン欠損は肥満・糖尿病における脂肪炎症を抑制する査読

堀ノ内裕也, 池田康将, 渡邉大晃, 濱野裕章, 石澤有紀, 今西正樹, 座間味義人, 武智研志, 宮本理人, 石澤啓介, 土屋浩一郎, 玉置俊晃

血管 42 ( 1 ) 44 - 44 2019年1月

Development of a novel aortic dissection mouse model and evaluation of drug efficacy using in-vivo assays and database analyses. 査読国際誌

Yuki Izawa-Ishizawa, Masaki Imanishi, Yoshito Zamami, Hiroki Toya, Tomoko Nagao, Marin Morishita, Koichi Tsuneyama, Yuya Horinouchi, Yoshitaka Kihira, Kenshi Takechi, Yasumasa Ikeda, Koichiro Tsuchiya, Masanori Yoshizumi, Toshiaki Tamaki, Keisuke Ishizawa

Journal of hypertension 37 ( 1 ) 73 - 83 2019年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: Aortic dissection is a life-threatening disease. At present, the only therapeutic strategies available are surgery and antihypertensive drugs. Moreover, the molecular mechanisms underlying the onset of aortic dissection are still unclear. We established a novel aortic dissection model in mice using pharmacologically induced endothelial dysfunction. We then used the Japanese Adverse Drug Event Report database to investigate the role of pitavastatin in preventing the onset of aortic dissection. METHODS AND RESULTS: To induce endothelial dysfunction, Nω-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, was administered to C57BL/6 mice. Three weeks later, angiotensin II (Ang II) and β-aminopropionitrile (BAPN), a lysyl oxidase inhibitor, were administered with osmotic mini-pumps. False lumen formation was used as the pathological determinant of aortic dissection. The incidences of aortic dissection and death from aneurysmal rupture were significantly higher in the Nω-nitro-L-arginine methyl ester, Ang II, and BAPN (LAB) group than they were in the Ang II and BAPN (AB) group.Pitavastatin was administered orally to LAB mice. It significantly lowered the incidences of dissection and rupture. It also decreased inflammation and medial degradation, both of which were exacerbated in the LAB group. The Japanese Adverse Drug Event Report database analysis indicated that there were 113 cases of aortic dissection out of 95 090 patients (0.12%) not receiving statins but only six cases out of 16 668 patients receiving statins (0.04%) (odds ratio: 0.30; P = 0.0043). CONCLUSION: Our results suggest that endothelial dysfunction is associated with the onset of aortic dissection and pitavastatin can help prevent this condition.

DOI： 10.1097/HJH.0000000000001898

Pharmacovigilance evaluation of the relationship between impaired glucose metabolism and BCR-ABL inhibitor use by using an adverse drug event reporting database. 査読国際誌

Naoto Okada, Takahiro Niimura, Yoshito Zamami, Hirofumi Hamano, Shunsuke Ishida, Mitsuhiro Goda, Kenshi Takechi, Masayuki Chuma, Masaki Imanishi, Keisuke Ishizawa

Cancer medicine 8 ( 1 ) 174 - 181 2019年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Breakpoint cluster region-Abelson murine leukemia (BCR-ABL) inhibitors markedly improve the prognosis of chronic myeloid leukemia. However, high treatment adherence is necessary for successful treatment with BCR-ABL inhibitors. Therefore, an adequate understanding of the adverse event profiles of BCR-ABL inhibitors is essential. Although many adverse events are observed in trials, an accurate identification of adverse events based only on clinical trial results is difficult because of strict entry criteria or limited follow-up durations. In particular, BCR-ABL inhibitor-induced impaired glucose metabolism remains controversial. Pharmacovigilance evaluations using spontaneous reporting systems are useful for analyzing drug-related adverse events in clinical settings. Therefore, we conducted signal detection analyses for BCR-ABL inhibitor-induced impaired glucose metabolism by using the FDA Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) database. Signals for an increased reporting rate of impaired glucose metabolism were detected only for nilotinib use, whereas these signals were not detected for other BCR-ABL inhibitors. Subgroup analyses showed a clearly increased nilotinib-associated reporting rate of impaired glucose metabolism in male and younger patients. Although FAERS- and JADER-based signal detection analyses cannot determine causality perfectly, our study suggests the effects on glucose metabolism are different between BCR-ABL inhibitors and provides useful information for the selection of appropriate BCR-ABL inhibitors.

DOI： 10.1002/cam4.1920

Association Between Immune-Related Adverse Events and Clinical Efficacy in Patients with Melanoma Treated With Nivolumab: A Multicenter Retrospective Study. 査読国際誌

Naoto Okada, Hitoshi Kawazoe, Kenshi Takechi, Yoshihiro Matsudate, Ryo Utsunomiya, Yoshito Zamami, Mitsuhiro Goda, Masaki Imanishi, Masayuki Chuma, Noriaki Hidaka, Koji Sayama, Yoshiaki Kubo, Akihiro Tanaka, Keisuke Ishizawa

Clinical therapeutics 41 ( 1 ) 59 - 67 2019年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: Nivolumab, an anti-programmed death 1 antibody, produces antitumor effects by activating host immunity, which also causes immune-related adverse events (irAEs). The aim of this study was to analyze the association between antitumor effect and irAEs induced by nivolumab in patients with melanoma. METHODS: Fifteen patients with melanoma who had received nivolumab at Tokushima University Hospital or Ehime University Hospital between January 2015 and December 2016 were enrolled in this study. Patients who had and did not have irAEs during nivolumab treatment were classified into an irAEs-positive group (n = 8) and an irAEs-negative group (n = 7), respectively. We compared the disease control rate (DCR) and overall survival (OS) between the 2 groups. Data on blood cell counts were also analyzed. FINDINGS: After a median of 4 cycles of nivolumab treatment, irAEs occurred. The DCRs were 75% and 14% in the irAEs-positive and irAEs-negative groups, respectively (p < 0.05). OS in the irAEs-positive group was higher than that in the irAEs-negative group (p < 0.05). Multivariable Cox proportional hazards regression analysis revealed that irAE occurrence affected OS with nivolumab treatment. Moreover, the increase in baseline peripheral lymphocyte count at the time of onset of irAEs was significantly greater in the irAEs-positive group than in the irAEs-negative group after 4 cycles of nivolumab treatment (p < 0.05). IMPLICATIONS: Our study indicated that clinical response with nivolumab treatment improves with irAE occurrence in patients with melanoma. Moreover, the early increase in peripheral lymphocyte count may act as a biomarker for predicting the occurrence of irAEs induced by nivolumab.

DOI： 10.1016/j.clinthera.2018.11.004

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

シスプラチン誘発腎障害に対する新規予防薬の有効性の検証

合田光寛, 濱野裕章, 生田賢治, 岡田直人, 武智研志, 堀ノ内裕也, 池田康将, 石澤啓介, 斉家和仁, 神田将哉, 村井陽一, 吉田愛美, 新村貴博, 石澤有紀, 座間味義人, 中馬真幸

日本薬理学会年会要旨集 92 ( 0 ) 3 - P-076 2019年

記述言語：日本語出版者・発行元：公益社団法人日本薬理学会

<p>OBJECTIVE: Cisplatin (CDDP)-induced acute kidney injury (AKI) is highly expressed. Forced hydration and diuresis may partially prevent nephrotoxicity, but it is still difficult to completely prevent kidney injury, so establishment of a new preventive method is required. Therefore, in this study, we elected to candidates for preventive drugs of CDDP-induced AKI using big data analysis, and to verify the effectiveness of the drugs.</p><p>METHODS: Using FAERS (FDA Adverse Event Reporting System), existing drugs that may reduce CDDP-induced AKI were extracted. C57BL/6 mice were intraperitoneally administered with CDDP. Renal function was evaluated by serum creatinine and blood urea nitrogen. Histological damage in the cortex of kidney sections was scored. The effect of preventive drugs for CDDP-induced nephropathy was evaluated.</p><p>Results: The drug X was extracted a candidate drug suggesting the protective effect of CDDP-induced AKI by FAERS analysis. It was revealed that administration of the drug X significantly suppressed CDDP-induced AKI.</p><p>Conclusions: From the results of this study, it was suggested that existing pharmaceutical products elected by FAERS could be a preventive drug for CDDP-induced AKI.</p>

DOI： 10.1254/jpssuppl.92.0_3-P-076

大規模医療情報データベースを活用した抗がん剤誘発副作用に対する予防薬の探索

座間味義人, 石澤有紀, 池田康将, 小林大介, 島添隆雄, 石澤啓介, 川尻雄大, 新村貴博, 合田光寛, 岡田直人, 濱野裕章, 武智研志, 中馬真幸, 堀ノ内裕也

日本薬理学会年会要旨集 92 2 - AS1-3 2019年

記述言語：日本語出版者・発行元：公益社団法人日本薬理学会

<p>Treatment outcomes of cancer patients have improved with progress in oncology medication therapy, but side effects caused by anticancer agents are becoming widespread. Side effects caused by anticancer drugs not only significantly lower the patient's QOL but also often lead to dose reduction or discontinuation of the anticancer drugs. Addressing these side effects is important for improving patient prognosis. Therefore, improvement of the quality of cancer therapy through the development of preventive drugs against anticancer drug-induced side effects is an urgent goal. In recent years, clinical research has been carried out in Japan using large-scale medical information sources such as disease/side effect databases, in order to accurately evaluate the effects of drug used in clinical practice. Research utilizing such a large-scale medical information database can cover various patient parameters and a wide range of observation areas. Therefore, this approach is suitable for conducting clinical research on rare diseases and low-frequency side effects. In this symposium, we will introduce research conducted using drug discovery tools and cell/animal experiments based on a large-scale medical information database to search for preventive agents against anticancer drug-induced side effects, as well as consider future prospects for this approach.</p>

DOI： 10.1254/jpssuppl.92.0_2-AS1-3

慢性腎不全関連骨格筋萎縮における鉄代謝異常

堀ノ内裕也, 池田康将, 濱野裕章, 今西正樹, 福島圭穣, 合田光寛, 武智研志, 宮本理人, 石澤有紀, 座間味義人, 藤野裕道, 石澤啓介, 土屋浩一郎, 玉置俊晃

日本薬理学会年会要旨集 92 3-P-078 2019年

記述言語：日本語出版者・発行元：公益社団法人日本薬理学会

Introduction and aims: Skeletal muscle atrophy is often observed in chronic renal failure (CRF) patients. However, the molecular mechanism of skeletal muscle atrophy in CRF has remained unclear. Iron is an essential trace metal for all living organisms. On the other hand, excessive iron catalyzes the formation of highly toxic hydroxyl radicals via the Fenton reaction. The purpose of this study was to determine whether iron is involved in CRF-related skeletal muscle atrophy.

Methods: In this study, we divided 8-weeks-old C57BL/6J mice into two groups: vehicle-treated group (control mice) and adenine-injected group (CRF mice).

Results: Iron content was elevated in the skeletal muscle in CRF mice. Although the expression of divalent metal transporter 1 did not change, the expression of transferrin receptor and ferroportin were downregulated in the skeletal muscle in CRF mice. The expression of ferritin heavy chain and ferritin light chain were upregulated in the skeletal muscle in CRF mice. CRF mice showed increased oxidative stress in the skeletal muscles.

Conclusions: These results suggest that iron accumulation mediated oxidative stress has the potential to accelerate skeletal muscle atrophy in CRF.

DOI： 10.1254/jpssuppl.92.0_3-p-078

シスプラチン誘発腎障害に対する各種5-HT₃受容体拮抗薬の影響

村井陽一, 合田光寛, 斉家和仁, 神田将哉, 吉田愛美, 新村貴博, 石澤有紀, 座間味義人, 中馬真幸, 濱野裕章, 岡田直人, 武智研志, 堀之内裕也, 池田康将, 石澤啓介

日本薬理学会年会要旨集 92 1-P-102 2019年

記述言語：日本語出版者・発行元：公益社団法人日本薬理学会

OBJECTIVE: Cisplatin (CDDP) is known to frequently cause nausea and vomiting, renal injury as a side effect. There are many kinds of 5-HT3 receptor antagonists, which are one of the basic antiemetic drugs for nausea and vomiting by cancer chemotherapy, such as the first generation ondansetron, granisetron, the second generation palonosetron. It is suggested that ondansetron may be a risk factor for the onset of CDDP-induced acute kidney injury (AKI). Therefore, in this study, the effect of various 5-HT3 receptor antagonists on CDDP-induced renal injury was examined.

METHODS: C57BL/6 mice were intraperitoneally administered with CDDP. Renal function was evaluated by serum creatinine and blood urea nitrogen. Histological damage in the cortex of HE‐stained kidney sections was scored. Various 5-HT3 receptor antagonists were administered 30 minutes before administration of CDDP.

RESULTS: CDDP-induced renal injury got significantly worse by pre-administration of ondansetron, but not by pretreatment of palonosetron compared with cisplatin alone group.

CONCLUSIONS: These results suggest that the second generation 5-HT3 receptor antagonist may have less effect on CDDP‐induced AKI than the first generation.

DOI： 10.1254/jpssuppl.92.0_1-p-102

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

Hiroshi Onoue, Toshihiro Koyama, Yoshito Zamami, Hideharu Hagiya, Yasuhisa Tatebe, Naoko Mikami, Kazuaki Shinomiya, Yoshihisa Kitamura, Shiro Hinotsu, Toshiaki Sendo, Yasuyoshi Ouchi, Mitsunobu R Kano

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

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: To describe and examine trends in polypharmacy according to age in Japan from 2010 to 2016. DESIGN: Retrospective observational study. SETTING: Outpatient settings. PARTICIPANTS: Japanese individuals aged 20 and older. MEASUREMENTS: We analyzed pharmacy claims data that the Japanese Ministry of Health, Labor, and Welfare provided in the Survey of Medical Care Activities in Public Health Insurance from 2010 to 2016. The use of 5 or more oral prescription medications per month was defined as polypharmacy and of 10 or more as excessive polypharmacy. Regression analysis was used to estimate trends in polypharmacy with annual percentage changes. Using number of medications (polypharmacy vs excessive polypharmacy), trends in polypharmacy and crude and age-adjusted rates of polypharmacy per 1,000 persons were calculated according to year and age group (20-34, 35-49, 50-64, 65-79, ≥ 80). RESULTS: We analyzed 240 million pharmacy claims data. The age-adjusted monthly prevalence rate of polypharmacy increased from 85.2 to 93.8 per 1,000 persons per month and of excessive polypharmacy from 13.6 to 14.0 per 1,000 persons per month from 2010 to 2016 in the entire study population. The highest rate of polypharmacy (per 1,000 persons) was observed in 2016 in those aged 80 and older (326.8), followed by those aged 65 to 79 (167.3). The polypharmacy rate increased by 6.3% (95% confidence interval (CI)=4.0-8.7) per year from 2010 to 2012, then decreased by 0.7% (95% CI=-1.3-0.0) per year from 2012 to 2016. The rate of excessive polypharmacy increased by 4.5% (95% CI=1.1-8.0) per year from 2010 to 2013 and then decreased by 3.7% (95% CI=-6.7 to -0.6) per year from 2013 to 2016. CONCLUSION: The overall trend of polypharmacy in Japan increased during the study period, although the increase ceased in 2013 and then declined from 2013 to 2016. Policy changes in Japan might be responsible for some of the changes. J Am Geriatr Soc 66:2267-2273, 2018.

DOI： 10.1111/jgs.15569

Development and pharmacist-mediated use of tools for monitoring atypical antipsychotic-induced side effects related to blood glucose levels. 査読国際誌

Shunsuke Ishida, Kenshi Takechi, Hiroshi Bando, Masaki Imanishi, Yoshito Zamami, Masayuki Chuma, Hiroaki Yanagawa, Yasushi Kirino, Toshimi Nakamura, Kazuhiko Teraoka, Keisuke Ishizawa

Pharmacoepidemiology and drug safety 27 ( 12 ) 1379 - 1384 2018年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: Drug side effects often lead to serious outcomes. Administration of second-generation antipsychotics has resulted in diabetic ketoacidosis and diabetic coma leading to death. Therefore, pharmacists are required to collect information on clinical test values, determine the appropriate test timing, and coordinate with doctors for further clinical laboratory orders, all of which are labor-intensive and time-intensive tasks. In this study, we developed a side effect-monitoring tool and aimed to clarify the influence and efficiency of monitoring side effects by using the tool in patients taking atypical antipsychotics in whom it is necessary to check clinical test values such as blood sugar levels. METHODS: We extracted clinical test values for patients treated with second-generation antipsychotics from electronic medical records. The test values are automatically displayed in the side effect grade classification specified by CTCAE ver. 4.0. A database was constructed using scripts to provide alerts for the timing of clinical testing. The pharmacist used this tool to confirm clinical test values for patients taking medication and requested the physician to inspect orders based on the appropriate test timings. RESULTS: The management tool reduced the pharmacists' effort in collecting information on patients' prescription status and test values. It enabled patients to undergo tests at the appropriate time according to the progression of glucose metabolism and allowed for easy monitoring of side effects. CONCLUSIONS: The results suggested that regardless of pharmacists' experience or skill, the introduction of this tool enables centralization of side effect monitoring and can contribute to proper drug use.

DOI： 10.1002/pds.4656

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

H Hagiya, T Koyama, 座間味義人, Y Minato, Y Tatebe, N Mikami, Y Teratani, A Ohshima, K Shinomiya, Y Kitamura, T Sendo, S Hinotsu, K Tomono, R M Kano

Epidemiology and infection 147 e38 2018年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Japan is still a medium-burden tuberculosis (TB) country. We aimed to examine trends in newly notified active TB incidence and TB-related mortality in the last two decades in Japan. This is a population-based study using Japanese Vital Statistics and Japan Tuberculosis Surveillance from 1997 to 2016. We determined active TB incidence and mortality rates (per 100 000 population) by sex, age and disease categories. Joinpoint regression was applied to calculate the annual percentage change (APC) in age-adjusted mortality rates and to identify the years showing significant trend changes. Crude and age-adjusted incidence rates reduced from 33.9 to 13.9 and 37.3 to 11.3 per 100 000 population, respectively. Also, crude and age-adjusted mortality rates reduced from 2.2 to 1.5 and 2.8 to 1.0 per 100 000 population, respectively. Average APC in the incidence and mortality rates showed significant decline both in men (-6.2% and -5.4%, respectively) and women (-5.7% and -4.6%, respectively). Age-specific analysis demonstrated decreases in incidence and mortality rates for every age category, except for the incidence trend in the younger population. Although trends in active TB incidence and mortality rates in Japan have favourably decreased, the rate of decline is far from achieving TB elimination by 2035.

DOI： 10.1017/S095026881800290X

Trends in Polypharmacy in Japan: A Nationwide Retrospective Study. 査読

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10月

Development and pharmacist-mediated use of tools for monitoring atypical antipsychotic-induced side effects related to blood glucose levels. 査読

Ishida S, Takechi K, Bando H, Imanishi M, Zamami Y, Chuma M, Yanagawa H, Kirino Y, Nakamura T, Teraoka K, Ishizawa K

Pharmacoepidemiology and drug safety 27 ( 12 ) 1379 - 1384 2018年9月

Renoprotective effects of a factor Xa inhibitor: fusion of basic research and a database analysis. 査読国際誌

Yuya Horinouchi, Yasumasa Ikeda, Keijo Fukushima, Masaki Imanishi, Hirofumi Hamano, Yuki Izawa-Ishizawa, Yoshito Zamami, Kenshi Takechi, Licht Miyamoto, Hiromichi Fujino, Keisuke Ishizawa, Koichiro Tsuchiya, Toshiaki Tamaki

Scientific reports 8 ( 1 ) 10858 - 10858 2018年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Renal tubulointerstitial injury, an inflammation-associated condition, is a major cause of chronic kidney disease (CKD). Levels of activated factor X (FXa), a blood coagulation factor, are increased in various inflammatory diseases. Therefore, we investigated the protective effects of an FXa inhibitor against renal tubulointerstitial injury using unilateral ureteral obstruction (UUO) mice (a renal tubulointerstitial fibrosis model) and the Food and Drug Administration Adverse Events Reporting System (FAERS) database. The renal expression levels of FX and the FXa receptors protease-activated receptor (PAR)-1 and PAR-2 were significantly higher in UUO mice than in sham-operated mice. UUO-induced tubulointerstitial fibrosis and extracellular matrix expression were suppressed in UUO mice treated with the FXa inhibitor edoxaban. Additionally, edoxaban attenuated UUO-induced macrophage infiltration and inflammatory molecule upregulation. In an analysis of the FAERS database, there were significantly fewer reports of tubulointerstitial nephritis for patients treated with FXa inhibitors than for patients not treated with inhibitors. These results suggest that FXa inhibitors exert protective effects against CKD by inhibiting tubulointerstitial fibrosis.

DOI： 10.1038/s41598-018-29008-2

The uremic toxin indoxyl sulfate interferes with iron metabolism by regulating hepcidin in chronic kidney disease. 査読国際誌

Hirofumi Hamano, Yasumasa Ikeda, Hiroaki Watanabe, Yuya Horinouchi, Yuki Izawa-Ishizawa, Masaki Imanishi, Yoshito Zamami, Kenshi Takechi, Licht Miyamoto, Keisuke Ishizawa, Koichiro Tsuchiya, Toshiaki Tamaki

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 33 ( 4 ) 586 - 597 2018年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Background: Hepcidin secreted by hepatocytes is a key regulator of iron metabolism throughout the body. Hepcidin concentrations are increased in chronic kidney disease (CKD), contributing to abnormalities in iron metabolism. Levels of indoxyl sulfate (IS), a uremic toxin, are also elevated in CKD. However, the effect of IS accumulation on iron metabolism remains unclear. Methods: We used HepG2 cells to determine the mechanism by which IS regulates hepcidin concentrations. We also used a mouse model of adenine-induced CKD. The CKD mice were divided into two groups: one was treated using AST-120 and the other received no treatment. We examined control mice, CKD mice, CKD mice treated using AST-120 and mice treated with IS via drinking water. Results: In the in vitro experiments using HepG2 cells, IS increased hepcidin expression in a dose-dependent manner. Silencing of the aryl hydrocarbon receptor (AhR) inhibited IS-induced hepcidin expression. Furthermore, IS induced oxidative stress and antioxidant drugs diminished IS-induced hepcidin expression. Adenine-induced CKD mice demonstrated an increase in hepcidin concentrations; this increase was reduced by AST-120, an oral adsorbent of the uremic toxin. CKD mice showed renal anemia, decreased plasma iron concentration, increased plasma ferritin and increased iron content in the spleen. Ferroportin was decreased in the duodenum and increased in the spleen. These changes were ameliorated by AST-120 treatment. Mice treated by direct IS administration showed hepatic hepcidin upregulation. Conclusions: IS affects iron metabolism in CKD by participating in hepcidin regulation via pathways that depend on AhR and oxidative stress.

DOI： 10.1093/ndt/gfx252

大規模医療情報データベース解析と基礎研究の融合による新規腎保護薬の探索査読

堀ノ内裕也, 池田康将, 石澤有紀, 玉置俊晃, 福島圭穣, 藤野裕道, 濱野裕章, 今西正樹, 座間味義人, 石澤啓介, 土屋浩一郎

四国医学雑誌 74 ( 1-2 ) 82 - 83 2018年4月

Potential Usefulness of Early Potassium Supplementation for Preventing Severe Hypokalemia Induced by Liposomal Amphotericin B in Hematologic Patients: A Retrospective Study. 査読国際誌

Naoto Okada, Momoyo Azuma, Masaki Imanishi, Yoshito Zamami, Yasushi Kirino, Toshimi Nakamura, Kazuhiko Teraoka, Masahiro Abe, Keisuke Ishizawa

Clinical therapeutics 40 ( 2 ) 252 - 260 2018年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: Liposomal amphotericin B (L-AMB) is an essential antifungal agent for patients with hematologic diseases; however, the drug causes severe hypokalemia at a high frequency. Meanwhile, there is little evidence regarding the risk factors for L-AMB-induced severe hypokalemia, and the prevention protocol has not been established. The goal of this study was to identify the risk factors related to severe hypokalemia induced by L-AMB in hematologic patients. METHODS: Seventy-eight hematologic patients with a first administration of L-AMB were enrolled in the study. Eleven patients who had serum potassium levels <3.0 mmol/L before L-AMB administration and 12 patients who received L-AMB administration within 3 days were excluded. Patients who had a serum potassium level <3.0 mmol/L during L-AMB administration were classified into a hypokalemia group (n = 26), and those who had a serum potassium level ≥3.0 mmol/L were classified into a non-hypokalemia group (n = 29). The patient characteristics were analyzed retrospectively. In addition, the usefulness of potassium supplementation was analyzed for those patients who received potassium formulations (non-hypokalemia group, n = 15; hypokalemia group, n = 24). FINDINGS: Twenty-six patients had hypolalemia after L-AMB administration. Hypokalemia with serum potassium levels <3.0 mmol/L was observed ~7 days after starting L-AMB administration. The patient characteristics, L-AMB dose, and L-AMB administration period did not differ between the 2 groups. In the patients who received potassium formulations, the period between starting L-AMB administration and starting potassium supplementation was significantly shorter in the non-hypokalemia group than in the hypokalemia group (median, 0 vs 4 days, respectively; P < 0.01); the potassium dose was not different between the 2 groups. A receiver-operating characteristic curve revealed that the cutoff time for the start of potassium supplementation to reduce the incidence of L-AMB-induced hypokalemia was 3 days. Multivariate logistic regression analysis revealed that beginning potassium supplementation within 2 days from the start of L-AMB administration was an independent factor reducing the risk of L-AMB-induced hypokalemia (odds ratio, 0.094 [95% CI, 0.019-0.47]). IMPLICATIONS: This study showed that starting administration of a potassium formulation within 2 days from the start of L-AMB administration was a risk reduction factor for L-AMB-induced hypokalemia. This finding indicates that early potassium supplementation should be incorporated into the regimen of hypokalemia management when L-AMB is used.

DOI： 10.1016/j.clinthera.2017.12.006

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

記述言語：英語掲載種別：研究論文（学術雑誌）

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

Niimura T, Zamami Y, Imai T, Nagao K, Kayano M, Sagara H, Goda M, Okada N, Chuma M, Takechi K, Imanishi M, Koyama T, Koga T, Nakura H, Sendo T, Ishizawa K

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）

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： 10.18433/jpps29737

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

Zamami Y, Kouno Y, Niimura T, Chuma M, Imai T, Mitsui M, Koyama T, Kayano M, Okada N, Hamano H, Goda M, Imanishi M, Takechi K, Horinouchi Y, Kondo Y, Yanagawa H, Kitamura Y, Sendo T, Ujike Y, Ishizawa K

Pharmazie 73 ( 12 ) 740 - 743 2018年

Development of a novel aortic dissection mouse model and evaluation of drug efficacy using in-vivo assays and database analyses. 査読

石澤有紀, 今西正樹, 座間味義人, 戸谷紘基, 長尾朋子, Marin Morishita, 常山幸一, 堀ノ内裕也, 木平孝高, 武智研志, 池田康将, 土屋浩一郎, 吉栖正典, 玉置俊晃, 石澤啓介

Journal of Hypertension 2018年

Nitrosonifedipine, a Photodegradation Product of Nifedipine, Suppresses Pharmacologically Induced Aortic Aneurysm Formation. 査読国際誌

Masaki Imanishi, Yuki Izawa-Ishizawa, Takumi Sakurada, Yusuke Kohara, Yuya Horinouchi, Eriko Sairyo, Yoshito Zamami, Kenshi Takechi, Masayuki Chuma, Keijo Fukushima, Yasumasa Ikeda, Hiromichi Fujino, Masanori Yoshizumi, Koichiro Tsuchiya, Toshiaki Tamaki, Keisuke Ishizawa

Pharmacology 102 ( 5-6 ) 287 - 299 2018年

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND/AIMS: We have reported that nitrosonifedipine (NO-NIF), a photodegradation product of nifedipine, has strong antioxidant and endothelial protective effects, and can suppress several cardiovascular diseases in animal models. The objective of the present study was to investigate the effects of NO-NIF on aortic aneurysm formation. METHODS: The mice were infused with β-aminopropionitrile for 2 weeks and angiotensin II for 6 weeks to induce aortic aneurysm formation. The oxidative stress was measured by dihydroethidium staining and nitrotyrosine staining. The expressions of inflammation-related genes were assessed by quantitative real-time PCR and immunohistochemical staining. To clarify the mechanisms of how NO-NIF suppresses vascular cell adhesion molecule (VCAM)-1, endothelial cells were used in in vitro system. RESULTS: NO-NIF suppressed pharmacologically induced the aortic aneurysm formation and aortic expansion without blood pressure changes. NO-NIF suppressed elastin degradation and matrix metalloproteinase-2 mRNA expression. NO-NIF suppressed the reactive oxygen species-cyclophilin A positive feedback loop. Upregulated mRNA expressions of inflammation-related genes and endothelial VCAM-1 were suppressed by NO-NIF co-treatment in aortae. CONCLUSION: NO-NIF has the potential to be a new, nifedipine-derived therapeutic drug for suppressing aortic aneurysm formation by directly improving aortic structure with its strong ability to reduce oxidative stress and inflammation.

DOI： 10.1159/000492577

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

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

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

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

European journal of radiology 97 96 - 100 2017年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

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

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 - 12683 2017年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

Dietary iron restriction alleviates renal tubulointerstitial injury induced by protein overload in mice. 査読国際誌

Yasumasa Ikeda, Yuya Horinouchi, Hirofumi Hamano, Tasuku Hirayama, Seiji Kishi, Yuki Izawa-Ishizawa, Masaki Imanishi, Yoshito Zamami, Kenshi Takechi, Licht Miyamoto, Keisuke Ishizawa, Ken-Ichi Aihara, Hideko Nagasawa, Koichiro Tsuchiya, Toshiaki Tamaki

Scientific reports 7 ( 1 ) 10621 - 10621 2017年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Increased proteinuria causes tubulointerstitial injury due to inflammation in chronic kidney disease (CKD). Iron restriction exhibits protective effects against renal dysfunction; however, its effects against protein overload-induced tubulointerstitial damage remain unclear. Here, we investigated dietary iron restriction effect on tubulointerstitial damage in mice with protein-overload tubulointerstitial injury. Renal tubulointerstitial injury in animal model was induced by intraperitoneal injection of an overdose of bovine serum albumin (BSA). We divided mice into three groups: normal saline + normal diet (ND), BSA + ND, and BSA + iron-restricted diet (IRD). BSA overload induced renal tubulointerstitial injury in the ND mice, which was ameliorated in the IRD mice. Inflammatory cytokines and extracellular matrix mRNA expression was upregulated in BSA + ND mice kidneys and was inhibited by IRD. BSA-induced increase in renal superoxide production, NADPH oxidase activity, and p22phox expression was diminished in the IRD mice. IRD suppression increased BSA-induced renal macrophage infiltration. Moreover, BSA mice exhibited nucleotide-binding oligomerisation domain-like receptor pyrin domain-containing protein (NLRP) inflammasome activation, which was inhibited by IRD. Ferrous iron increased in kidneys with BSA overload and was inhibited by IRD. Thus, iron restriction inhibited oxidative stress and inflammatory changes, contributing to the protective effect against BSA overload-induced tubulointerstitial injury.

DOI： 10.1038/s41598-017-11089-0

Evaluation of factors associated with the achievement of an optimal teicoplanin trough concentration . 査読国際誌

Kenshi Takechi, Hiroaki Yanagawa, Yoshito Zamami, Keisuke Ishizawa, Akihiro Tanaka, Hiroaki Araki

International journal of clinical pharmacology and therapeutics 55 ( 8 ) 672 - 677 2017年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: Because teicoplanin has a long serum half-life, a longer period of time is needed to achieve a steady-state concentration compared with vancomycin. The administration of an initial loading dose has been recommended to reach an effective teicoplanin serum concentration for the treatment of methicillin-resistant <italic>Staphylococcus aureus</italic> (MRSA). However, little is known regarding factors that affect teicoplanin concentration. This study aimed to retrospectively determine which factors are associated with achieving an optimal teicoplanin trough level. METHODS: We analyzed patients with MRSA infections who were treated with teicoplanin intravenously between January 2010 and July 2014. The effect of loading dose administration was evaluated in patients treated with 1,200 mg or 1,600 mg of teicoplanin, respectively. RESULTS: Approximately 32% (31/97) of patients achieved the trough concentration target (≥ 15 µg/mL) on the 3^rd or 4^th day. Multivariate analysis showed that loading doses and body surface area (BSA) were associated with trough concentration > 15 µg/mL on the 3^rd or 4^th day. Moreover, patients treated with the 2-day loading dose (1,600 mg group: 800 mg/day on 2 days) promptly achieved a trough concentration > 15 µg/mL on the 3^rd or 4^th day compared with those receiving a 1-day loading dose (1,200 mg group: 800 mg/day on only 1 day). The receiver operating characteristic curve showed that the optimal cut-off point of estimated glomerular filtration rate (eGFR) was 56 mL/min with 1-day loading dose to achieve a trough concentration target > 15 µg/mL. CONCLUSION: These results suggested that patients with decreased renal function (eGFR < 56 mL/min) can safely achieve an optimal trough level with the 1-day loading dose. In patients with normal renal function (eGFR ≥ 56 mL/min), administration of a 2-day loading dose may be needed to rapidly achieve a trough concentration ≥ 15 µg/mL. .

DOI： 10.5414/CP203009

HSP105 prevents depression-like behavior by increasing hippocampal brain-derived neurotrophic factor levels in mice. 査読国際誌

Naoya Hashikawa, Yuta Utaka, Takumi Ogawa, Ryo Tanoue, Yuna Morita, Sayumi Yamamoto, Satoru Yamaguchi, Masafumi Kayano, Yoshito Zamami, Narumi Hashikawa-Hobara

Science advances 3 ( 5 ) e1603014 - e1603014 2017年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Heat shock proteins (HSPs) are stress-induced chaperones that are involved in neurological disease. Although increasingly implicated in behavioral disorders, the mechanisms of HSP action, and the relevant functional pathways, are still unclear. We examined whether oral administration of geranylgeranylacetone (GGA), a known HSP inducer, produced an antidepressant effect in a social defeat stress model of depression in mice. We also investigated the possible molecular mechanisms involved, particularly focusing on hippocampal neurogenesis and neurotrophic factor expression. In stressed mice, hippocampal HSP105 expression decreased. However, administration of GGA increased HSP105 expression and improved depression-like behavior, induced hippocampal cell proliferation, and elevated brain-derived neurotrophic factor (BDNF) levels in mouse hippocampus. Co-treatment with GGA and the BDNF receptor inhibitor K252a suppressed the antidepressant effects of GGA. HSP105 knockdown decreased BDNF mRNA levels in HT22 hippocampal cell lines and hippocampal tissue and inhibited the GGA-mediated antidepressant effect. These observations suggest that GGA administration is a therapeutic candidate for depressive diseases by increasing hippocampal BDNF levels via HSP105 expression.

DOI： 10.1126/sciadv.1603014

Effects of endogenous nitric oxide on adrenergic nerve-mediated vasoconstriction and calcitonin gene-related peptide-containing nerve mediated vasodilation in pithed rats 査読

Kousuke Yamawaki, Yoshito Zamami, Hiromu Kawasaki, Shingo Takatori

EUROPEAN JOURNAL OF PHARMACOLOGY 802 69 - 75 2017年5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

Vascular adrenergic nerves mainly regulate the tone of blood vessels. Calcitonin gene-related peptide-containing (CGRPergic) vasodilator nerves also participate in the regulation of vascular tone. Furthermore, there are nitric oxide (NO)-containing (nitrergic) nerves, which include NO in blood vessels as vasodilator nerves, but it remains unclear whether nitrergic nerves participate in vascular regulation. The present study investigated the role of nitrergic nerves in vascular responses to spinal cord stimulation (SCS) and vasoactive agents in pithed rats. Wistar rats were anesthetized and pithed, and vasopressor responses to SCS and injections of norepinephrine were observed. To evaluate vasorelaxant responses, the BP was increased by a continuous infusion of methoxamine with hexamethonium to block autonomic outflow. After the elevated BP stabilized, SCS and injections of acetylcholine (ACh), sodium nitroprusside (SNP), and CGRP were intravenously administered. We then evaluated the effects of the NO synthase (NOS) inhibitor, N-omega-nitro-L-arginine methylester hydrochloride (L-NAME), on these vascular responses. Pressor responses to SCS and norepinephrine in pithed rats were enhanced by L-NAME, while the combined infusion of L-NAME and L-arginine had no effect on these responses. L-NAME infusion significantly increased the release of norepinephrine evoked by SCS. In pithed rats with artificially increased BP and L-NAME infusion, depressor response to ACh (except for 0.05 nmol/kg) was suppressed and SNP (only 2 nmol/kg) was enhanced. However, depressor responses to SCS and CGRP were similar to control responses. The present results suggest endogenous NO regulates vascular tone through endothelium function and inhibition of adrenergic neurotransmission, but not through CGRPergic nerves.

DOI： 10.1016/j.ejphar.2017.02.041

Effect of Nerve Growth Factor on Innervation of Perivascular Nerves in Neovasculatures of Mouse Cornea 査読

Akiko Matsuyama, Shingo Takatori, Yoko Sone, Eiko Ochi, Mitsuhiro Goda, Yoshito Zamami, Narumi Hashikawa-Hobara, Yoshihisa Kitamura, Hiromu Kawasaki

BIOLOGICAL & PHARMACEUTICAL BULLETIN 40 ( 4 ) 396 - 401 2017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：PHARMACEUTICAL SOC JAPAN

Angiogenesis, which is the generation of new vascular networks from existing blood vessels, occurs under normal and pathophysiological conditions. Perivascular nerves, which innervate mature vasculatures, maintain vascular tone and regulate tissue blood flow. However, little is known whether perivascular nerves innervate newborn blood vessels. Therefore, the aim of this study was to investigate the distribution and characterization of perivascular nerves in neovasculatures, which were generated by the mouse corneal micropocket method. Under anesthesia, a pellet containing basic fibroblast growth factor (bFGF) (100 ng/pellet) was implanted into a mouse cornea in one side of the eyeball. Nerve growth factor (NGF) was locally (2 or 20ng) applied with the pellet, or subcutaneously (40 ng/h for 7d) administered with an osmotic mini-pump. After the implantation, vascular endothelial cells, smooth muscle cells, and perivascular nerves in the cornea were immunohistochemically studied. Neovessels generated from existing limbal vessels were observed in pellet-implanted cornea. Immunostaining of neovasculatures showed the presence of CD31-like immunoreactive (LI) endothelial cells and a-smooth muscle actin-LI vascular smooth muscles. Perivascular nerves immunostained by protein gene product (PGP) 9.5, an axonal marker, were found in the existing limbal vessels, but they were not observed in neovasculatures. Local and subcutaneous treatment of NGF inhibits bFGF-derived angiogenesis and resulted in loop-shaped vessels that had many anastomoses, and produced innervation of PGP 9.5-LI perivascular nerves around bFGF-derived neovessels. These findings suggest that neovasculatures have no innervation of perivascular nerves, and that NGF facilitates innervations of perivascular nerves to regulate the blood flow in neovessels.

DOI： 10.1248/bpb.b16-00583

電気的除細動抵抗性心室細動/無脈性心室頻拍に対するニフェカラントの有効性評価メタ解析アミオダロンとの効果比較

佐藤志帆, 今井徹, 田中敏, 座間味義人, 名倉弘哲

日本薬学会年会要旨集 137年会 ( 4 ) 75 - 75 2017年3月

Pharmacological approach for drug repositioning against cardiorenal diseases. 査読

Yoshito Zamami, Masaki Imanishi, Kenshi Takechi, Keisuke Ishizawa

The journal of medical investigation : JMI 64 ( 3.4 ) 197 - 201 2017年

記述言語：英語掲載種別：研究論文（学術雑誌）

New applications of approved clinically used drugs are being discovered. Drug repositioning is a proposed strategy for developing these drugs as therapeutic agents for different diseases. Currently, approximately 2000 drugs are used in Japan. However, the compound targets and pathways involved in the pharmacological actions of 70-80% of these drugs have not been adequately clarified. Pharmacological examination of approved drugs is an important task in drug repositioning and vital for improving drug development efficiency. This review reports that angiotensin II type 1 receptor blockers show receptor-independent effects against reactive oxygen species generation in renal cells. Additionally, nitrosonifedipine has an antioxidative effect and protects endothelial cells against oxidative stress, and pioglitazone has multiple effects that improve dysfunctions in vascular control regulated by adrenergic and calcitonin gene-related peptide-containing nerves in animal models of diabetes. These data suggest that some approved drugs could be useful for treating cardiorenal diseases. Since cardiorenal diseases are likely to have chronic pathological conditions and require chronic drug administration, highly safe drugs are needed. Compared to newly developed drugs, drug repositioning of approved drugs with safety information is considered a particularly useful technique for searching new treatments for cardiorenal diseases. J. Med. Invest. 64: 197-201, August, 2017.

DOI： 10.2152/jmi.64.197

Psychiatric Patients with Antipsychotic Drug-Induced Hyperprolactinemia and Menstruation Disorders. 査読

Kenshi Takechi, Yurika Yoshioka, Hitoshi Kawazoe, Mamoru Tanaka, Shingo Takatori, Miwako Kobayashi, Ichiro Matsuoka, Hiroaki Yanagawa, Yoshito Zamami, Masaki Imanishi, Keisuke Ishizawa, Akihiro Tanaka, Hiroaki Araki

Biological & pharmaceutical bulletin 40 ( 10 ) 1775 - 1778 2017年

記述言語：英語掲載種別：研究論文（学術雑誌）

Treatment with antipsychotic drugs has been associated with hyperprolactinemia. The same antipsychotic drugs have also been associated with side effects such as menstruation disorders. The aim of this study was to evaluate the prevalence of hyperprolactinemia and menstruation disorders in women undergoing antipsychotic treatment. We performed a retrospective chart review study of psychiatric patients who underwent laboratory testing for serum prolactin (PRL) level between March 2011 and March 2015 in Ehime University Hospital. Patients presenting with and without menstruation disorders were evaluated to determine if they presented concomitant hyperprolactinemia. Patients with menstrual disorders had a significant increase in serum PRL level with a mean of approximately 90 ng/mL. Those with menstrual disorders presented increased PRL levels by 2-fold that of patients without menstrual disorder. However, there was no significant difference in the equivalent dose of chlorpromazine between these two groups. Additionally, about 70% of patients with menstrual disorders received risperidone treatment. The receiver operating characteristic curve showed that the optimal cutoff point of serum PRL level associated with the development of menstrual disorders was 60 ng/mL. Based on these results, we concluded that patients with menstrual disorders presented increased serum PRL, and that most of them underwent treatment with risperidone.

DOI： 10.1248/bpb.b17-00053

Nerve Growth Factor Facilitates the Innervation of Perivascular Nerves in Tumor-Derived Neovasculature in the Mouse Cornea 査読

Yoko Sone, Shingo Takatori, Eiko Ochi, Yoshito Zamami, Akiko Matsuyama, Satoko Fukuhara, Mitsuhiro Goda, Yoshihisa Kitamura, Hiromu Kawasaki

PHARMACOLOGY 99 ( 1-2 ) 57 - 66 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：KARGER

Background: Tumor neovascular vessels are not innervated by perivascular nerves. This study was an investigation of the effects of the nerve growth factor (NGF) on the distribution of perivascular nerves and neovessel formation in tumor tissues. Methods: A gel containing DU1 45 prostate carcinoma cells or HT1080 fibrosarcoma cells was implanted into mouse corneas. NGF was subcutaneously administered using an osmotic mini-pump. The distribution of perivascular nerves in mouse corneas and densities of CD31-immunopositive neovessels and smooth muscles (alpha-smooth muscle actin, alpha-SMA) in tumor tissues were quantified. Summary: Neovessels generated from corneal limber arteries in tumor tissues were observed 4-14 days after the implantation of tumor cells. The density of CD31-innmunopositive cells in endothelium increased after the implantation of DU145 or HT1080 cells, while that of alpha-SMA-immunopositive cells slightly increased. The NGF treatment significantly increased the density of alpha-SMA- but not that of CD31-innmunopositive cells (except for DU145 cells) and resulted in the innervation of perivascular nerves around tumor-derived neovessels, whereas no innervation was observed in the control group. Key Messages: These results suggest that NGF facilitates the innervation of perivascular nerves to regulate blood flow into tumor-derived neovessels. (C) 2016 S. Karger AG, Basel

DOI： 10.1159/000450582

Kamishoyosan and Shakuyakukanzoto promote recovery from paclitaxel-induced neurite retraction in PC12 cells. 査読国際誌

Ken Konaka, Kota Moriyama, Takumi Sakurada, Naoto Okada, Masaki Imanishi, Yoshito Zamami, Kazuyoshi Kawazoe, Shuji Fushitani, Keisuke Ishizawa

Journal of pharmaceutical health care and sciences 3 20 - 20 2017年

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: In chemotherapy, the full round of treatment must be completed as scheduled to achieve the strongest therapeutic effect. However, peripheral neuropathy, a severe side effect of the chemotherapeutic agent paclitaxel, can force the premature discontinuation of treatment. As some kampo practitioners have suggested that it may be possible to counteract such side effects, we analyzed the effects of Kamishoyosan, Shakuyakukanzoto, and Goshajinkigan in an in vitro model of paclitaxel-induced peripheral neuropathy. METHODS: Paclitaxel-treated PC12 cells were assessed for neurite length and performed Western blot analysis for growth-associated protein-43 (GAP-43) and light neurofilament protein (NF-L) levels in the presence of nerve growth factor (NGF); they were re-assessed, with additional testing for acetylcholinesterase levels, after application of one of the kampo. We also compared phosphorylation of extracellular signal-regulated kinase (Erk)1/2 and Akt via Western blot analysis. About effect of kampo to anticancer efficacy, we confirmed cell cytotoxicity in A549 cells using MTT assay. RESULTS: Addition of Kamishoyosan or Shakuyakukanzoto, but not Goshajinkigan, significantly improved neurite length and GAP-43 and NF-L levels from paclitaxel-treated PC12 cells, relative to those of only NGF-treated PC12 cells. The promoting effect of Kamishoyosan and Shakuyakukanzoto in neurite outgrowth is confirmed when NGF promoted neurite outgrowth, and it was inhibited partially when Erk1/2 and Akt were blocked by Erk1/2 inhibitor or Akt inhibitor alone. Furthermore, neurite outgrowth induced by TJ24 and TJ68 was inhibited more strongly when Erk1/2 inhibitor and Akt inhibitor were treated at the same time. NGF with Kamishoyosan or Shakuyakukanzoto promoted the proportion of phosphorylated Erk1/2 and phosphorylated Akt compare with NGF only. On the other hand, Kamishoyosan or Shakuyakukanzoto didn't influence cytotoxicity of paclitaxel in A549 cells. CONCLUSIONS: Kamishoyosan or Shakuyakukanzoto promotes neurite outgrowth with NGF via increasing the proportion of phosphorylated Erk1/2 and phosphorylated Akt in PC12 cells. The effect applies to recovery from paclitaxel-induced axonal involvement and might promote recovery from paclitaxel-induced neuropathy without influence of anticancer effect of paclitaxel.

DOI： 10.1186/s40780-017-0090-y

[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

記述言語：日本語掲載種別：研究論文（学術雑誌）

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

Drug-administering persons’ exposure to oral anticancer drugs to be administered through a tube 査読

Masahiro Murakami, Satoko Katsuragi, Masako Ohno, Makoto Shigematsu, Ayumi Kishi, Yoshito Zamami, Fusao Komada, Naomi Kurata, Manabu Amano

Asian Journal of Pharmaceutical and Clinical Research 9 ( No.3 ) 316 - 319 2016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：Innovare Academics Sciences Pvt. Ltd

Objective: The objective of this study was to quantitatively evaluate anticancer drug exposure of non-health care professionals who administer drugs through a tube employing a method devised by us. Methods: The subjects were 30 general volunteers aged 22-84 years. They wore gloves and administered Indian ink, simulating an anticancer drug, to a multipurpose adult human-type patient care simulator through a tube using 5 types of syringe, and the area stained with Indian ink was measured. Results: When comparing the number of pixels among the syringes regardless of age, Syringe B showed the lowest number (11.8±3.1 cm2), and there was a significant difference between Syringes B and E. Furthermore, we compared the total number of pixels in each age group regardless of the type of syringe. In the 20-year-old group, it was the lowest (10.9±2.3 cm2) showing significant differences in comparison with the other groups. When Syringe B was used, the number of pixels was markedly lower than on adopting the other syringes. Conclusion: It was clarified that the level of exposure to anticancer drugs markedly varies depending on the type of syringe and age. It was also clarified that the method to evaluate exposure to anticancer drugs using Indian ink devised by us is simple and useful.

DOI： 10.22159/ajpcr.2016.v9s3.13040

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9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Our high-performance patient simulator-based lifesaving skills training program not only increased the participants' understanding of the training content but also increased their confidence in their ability to perform pharmaceutical interventions. Therefore, the pharmaceutical lifesaving skills training program we developed will contribute to the education of emergency care pharmacists who can perform pharmaceutical interventions for emergency patients.

DOI： 10.1186/s40780-016-0054-7

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

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

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

脳梗塞患者における発症前後の薬物療法と副作用発現状況の調査

安尾哲郎, 座間味義人, 名倉弘哲

日本臨床救急医学会雑誌 19 ( 2 ) 425 - 425 2016年4月

Muscarinic acetylcholine receptor M1 and M3 subtypes mediate acetylcholine-induced endothelium-independent vasodilatation in rat mesenteric arteries 査読

Panot Tangsucharit, Shingo Takatori, Yoshito Zamami, Mitsuhiro Goda, Poungrat Pakdeechote, Hiromu Kawasaki, Fusako Takayama

JOURNAL OF PHARMACOLOGICAL SCIENCES 130 ( 1 ) 24 - 32 2016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：JAPANESE PHARMACOLOGICAL SOC

The present study investigated pharmacological characterizations of muscarinic acetylcholine receptor (AChR) subtypes involving ACh-induced endothelium-independent vasodilatation in rat mesenteric arteries. Changes in perfusion pressure to periarterial nerve stimulation and ACh were measured before and after the perfusion of Krebs solution containing muscarinic receptor antagonists. Distributions of muscarinic AChR subtypes in mesenteric arteries with an intact endothelium were studied using Western blotting. The expression level of M1 and M3 was significantly greater than that of M2. Endothelium removal significantly decreased expression levels of M2 and M3, but not M1. In perfused mesenteric vascular beds with intact endothelium and active tone, exogenous ACh (1, 10, and 100 nmol) produced concentration-dependent and long-lasting vasodilatations. In endothelium-denuded preparations, relaxation to ACh (1 nmol) disappeared, but ACh at 10 and 100 nmol caused long-lasting vasodilatations, which were markedly blocked by the treatment of pirenzepine (M1 antagonist) or 4-DAMP (M1 and M3 antagonist) plus hexamethonium (nicotinic AChR antagonist), but not methoctramine (M2 and M4 antagonist). These results suggest that muscarinic AChR subtypes, mainly M1, distribute throughout the rat mesenteric arteries, and that activation of M1 and/or M3 which may be located on CGRPergic nerves releases CGRP, causing an endothelium-independent vasodilatation. (C) 2015 Japanese Pharmacological Society. Production and hosting by Elsevier B.V.

DOI： 10.1016/j.jphs.2015.12.005

光に対して不安定な薬剤を経管投与する際の有用な投与法の開発査読

座間味義人, 江角悟, 相良英憲, 槙田崇志, 天野学, 安藤哲信, 名和秀起, 北村佳久, 千堂年昭, 名倉弘哲

医学と薬学 Vol.73 ( 4 ) 433 - 438 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

Time Course of Behavioral Alteration and mRNA Levels of Neurotrophic Factor Following Stress Exposure in Mouse 査読

Naoya Hashikawa, Takumi Ogawa, Yusuke Sakamoto, Mami Ogawa, Yumi Matsuo, Yoshito Zamami, Narumi Hashikawa-Hobara

CELLULAR AND MOLECULAR NEUROBIOLOGY 35 ( 6 ) 807 - 817 2015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：SPRINGER/PLENUM PUBLISHERS

Stress is known to affect neurotrophic factor expression, which induces depression-like behavior. However, whether there are time-dependent changes in neurotrophic factor mRNA expression following stress remains unclear. In the present study, we tested whether chronic stress exposure induces long-term changes in depression-related behavior, serum corticosterone, and hippocampal proliferation as well as neurotrophic factor family mRNA levels, such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and ciliary neurotrophic factor (CNTF), in the mouse hippocampus. The mRNA level of neurotrophic factors (BDNF, NGF, NT-3, and CNTF) was measured using the real-time PCR. The serum corticosterone level was evaluated by enzyme-linked immunosorbent assay, and, for each subject, the hippocampal proliferation was examined by 5-bromo-2-deoxyuridine immunostaining. Mice exhibited depression-like behavior in the forced-swim test (FST) and decreased BDNF mRNA and hippocampal proliferation in the middle of the stress exposure. After 15 days of stress exposure, we observed increased immobility in the FST, serum corticosterone levels, and BDNF mRNA levels and degenerated hippocampal proliferation, maintained for at least 2 weeks. Anhedonia-like behavior in the sucrose preference test and NGF mRNA levels were decreased following 15 days of stress. NGF mRNA levels were significantly higher 1 week after stress exposure. The current data demonstrate that chronic stress exposure induces prolonged BDNF and NGF mRNA changes and increases corticosterone levels and depression-like behavior in the FST, but does not alter other neurotrophic factors or performance in the sucrose preference test.

DOI： 10.1007/s10571-015-0174-x

Calcitonin gene-related peptide pre-administration acts as a novel antidepressant in stressed mice 査読

Narumi Hashikawa-Hobara, Takumi Ogawa, Yusuke Sakamoto, Yumi Matsuo, Mami Ogawa, Yoshito Zamami, Naoya Hashikawa

SCIENTIFIC REPORTS 5 12559 - 12559 2015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：NATURE PUBLISHING GROUP

Calcitonin gene-related peptide (CGRP) is a neuropeptide that has potent vasodilator properties and is involved in various behavioral disorders. The relationship between CGRP and depression-like behavior is unclear. In this study, we used chronically stressed mice to investigate whether CGRP is involved in depression-like behavior. Each mouse was exposed to restraint and water immersion stress for 15 days. After stress exposure, mice were assessed using behavioral tests: open field test, forced swim test and sucrose preference test. Serum corticosterone levels, hippocampal proliferation and mRNA expression of neurotrophins were measured. After stress exposure, mice exhibited depression-like behavior and decreased CGRP mRNA levels in the hippocampus. Although intracerebroventricular CGRP administration (0.5 nmol) did not alter depression-like behavior after 15-day stress exposure, a single CGRP administration into the brain, before the beginning of the 15-day stress exposure, normalized the behavioral dysfunctions and increased nerve growth factor (Ngf) mRNA levels in stressed mice. Furthermore, in the mouse E14 hippocampal cell line, CGRP treatment induced increased expression of Ngf mRNA. The NGF receptor inhibitor K252a inhibited CGRP's antidepressant-like effects in stressed mice. These results suggest that CGRP expression in the mouse hippocampus is associated with depression-like behavior and changes in Ngf mRNA levels.

DOI： 10.1038/srep12559

院内感染と薬剤管理トロンボモジュリン投与における出血発現の危険因子解析

名倉弘哲, 向井和也, 座間味義人, 平山敬浩, 氏家良人

日本臨床医学リスクマネジメント学会・学術集会プログラム・抄録集 13回 54 - 54 2015年5月

救急病棟における薬剤経管投与の実態調査と漢方製剤の経管投与方法の検討

座間味義人, 伊藤剛志, 名倉弘哲

日本臨床救急医学会雑誌 18 ( 2 ) 447 - 447 2015年4月

敗血症における重症度別de-escalationの有効性評価

萱野純史, 永尾香菜子, 平山敬浩, 座間味義人, 鵜川豊世武, 氏家良人, 名倉弘哲

日本臨床救急医学会雑誌 18 ( 2 ) 389 - 389 2015年4月

トロンボモジュリン投与における出血発現の危険因子解析敗血症性DIC患者に対する統計解析

三宅真史, 向井一也, 平山敬浩, 座間味義人, 鵜川豊世武, 氏家良人, 名倉弘哲

日本薬学会年会要旨集 135年会 ( 4 ) 193 - 193 2015年3月

救急・集中治療における敗血症性ショック患者に対する鎮静薬使用の検証

塩瀬麻衣, 江角純, 平山敬浩, 座間味義人, 鵜川豊世武, 氏家良人, 名倉弘哲

日本薬学会年会要旨集 135年会 ( 4 ) 193 - 193 2015年3月

岡山大学病院高度救命救急センターにおける敗血症患者へのde-escalationの有益性評価

萱野純史, 永尾香菜子, 平山敬浩, 座間味義人, 鵜川豊世武, 氏家良人, 名倉弘哲

日本薬学会年会要旨集 135年会 ( 4 ) 192 - 192 2015年3月

Quinolone Analogs 16: A Facile D-H Exchange for 3-H Proton of 2-Substituted 4-Quinolones in Acidic Media 査読

Yoshihisa Kurasawa, Kiminari Yoshida, Naoki Yamazaki, Kenji Sasaki, Yoshito Zamami, Zhao Min, Atsumi Togi, Hideyuki Ito, Eisuke Kaji, Haruhiko Fukaya

JOURNAL OF HETEROCYCLIC CHEMISTRY 51 ( 6 ) 1821 - 1829 2014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

The 4-quinolones having the urea or carbamate moiety at the 2-position showed the facile deuterium-hydrogen (D-H) exchange of the 3-H proton in deuteriotrifluoroacetic acid-deuteriodimethyl sulfoxide (3:1) at 60 degrees C, whereas the 4-quinolones possessing the carboxylate or carbohydrazide group at the 2-position and 2-substituted 4-methoxyquinolines represented no D-H exchange of the 3-H proton under the same condition. The aforementioned D-H exchange was found to require both the tautomerization of the 4-quinolone into 4-hydroxyquinoline in strongly acidic media and the nitrogen functional group at the 2-position.

DOI： 10.1002/jhet.1933

Quinolone analogs 13: Synthesis of novel 1,1′-(2-methylenepropane-1,3-diyl)di(4-quinolone-3-carboxylate) and related compounds 査読

Yoshihisa Kurasawa, Kiminari Yoshida, Naoki Yamazaki, Eisuke Kaji, Kenji Sasaki, Kenji Sasaki, Yoshito Zamami, Takatoshi Fujii, Min Zhao, Hideyuki Ito, Haruhiko Fukaya

Journal of Heterocyclic Chemistry 51 ( 6 ) 1720 - 1726 2014年11月

Quinolone Analogues 15: Synthesis and Antimalarial Activity of 4-Phenyl-1-(1-triazolylmethyl-4-quinolon-3-ylcarbonyl)semicarbazide and Related Compounds 査読

Yoshihisa Kurasawa, Kiminari Yoshida, Naoki Yamazaki, Kenji Sasaki, Yoshito Zamami, Zhao Min, Atsumi Togi, Hideyuki Ito, Eisuke Kaji, Haruhiko Fukaya

JOURNAL OF HETEROCYCLIC CHEMISTRY 51 ( No.S1 ) E249 - E254 2014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：WILEY-BLACKWELL

The 1-hydrazinocarbonylmethyl-4-quinolone-3-carboxylate (10) was converted into the 1-(4-amino-1,2,4-triazol-3-ylmethyl)-4-quinolone-3-carboxylic acid (13), whose reaction with arylcarbaldehydes gave the 1-(4-arylmethyleneamino-1,2,4-triazol-3-ylmethyl)-4-quinolone-3-carboxylic acids (5a, 5b, 5c, 5d, 5e, 5f, 5g). Compound 10 was also transformed into the 1-(4-amino-1,2,4-triazol-3-ylmethyl)-4-quinolone-3-carbohydrazide (15), whose reaction with phenyl isocyanate or phenyl isothiocyanate afforded the 4-phenyl-1-(1-triazolylmethyl-4-quinolon-3-ylcarbonyl)semicarbazide (6a) or 4-phenyl-1-(1-triazolylmethyl-4-quinolon-3-ylcarbonyl)thiosemicarbazide (6b), respectively. Compounds 6a, 6b showed the in vitro antimalarial activity to chloroquine-resistant Plasmodium falciparum, wherein their IC50 was 3.89 and 3.91 mu M, respectively.

DOI： 10.1002/jhet.1822

Quinolone Analogs 14: Synthesis of Antimalarial 1-Aryl-3-(4-quinolon-2-yl)-ureas and Related Compounds 査読

Yoshihisa Kurasawa, Kiminari Yoshida, Naoki Yamazaki, Kenji Sasaki, Yoshito Zamami, Zhao Min, Atsumi Togi, Hideyuki Ito, Eisuke Kaji, Haruhiko Fukaya

JOURNAL OF HETEROCYCLIC CHEMISTRY 51 ( No.S1 ) E241 - E248 2014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：WILEY-BLACKWELL

The 4-quinolone-2-carbohydrazide 6a was converted into 1-aryl-3-(4-quinolon-2-yl)ureas 5a, 5b, 5c, 5d, 5e, 1-aryl-3-(4-quinolon-2-yl)imidazolidine-2,4-diones 9a,9b, and N-(4-quinolon-2-yl)carbamates 10a,10b via 4-quinolone-2-carbonylazide 7a. The 4-methoxyquinoline-2-carbohydrazide 6b was also transformed into 1-aryl-3-(4-methoxyquinolin-2-yl)ureas 11a, 11b, 11c, 11d, 1-aryl-3-(4-methoxyquinolin-2-yl)imidazolidine-2,4-diones 12a,12b, and N-(4-methoxyquinolin-2-yl)carbamates 13a,13b via 4-methoxyquinoline-2-carbonylazide 7b. Some of the 1-aryl-3-(4-quinolon-2-yl)ureas 5a, 5b, 5c, 5d, 5e showed the in vitro antimalarial activity to chloroquine-resistant Plasmodium falciparum, wherein IC50 was 0.93 to 4.00 mu M.

DOI： 10.1002/jhet.1813

Decreased perivascular CGRP-containing nerves in Otsuka Long-Evans Tokushima Fatty rats with insulin resistance and hypertension 査読

Shingo Takatori, Hiroki Fujiwara, Yoshito Zamami, Narumi Hashikawa-Hobara, Hiromu Kawasaki

HYPERTENSION RESEARCH 37 ( 5 ) 398 - 404 2014年5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

We previously reported that chronic hyperinsulinemia induced by drinking fructose elicited an abnormal neuronal regulation of vascular tone, which contributed to the development of hypertension. This study was designed to elucidate the possible mechanisms underlying the dysfunctional neuronal regulation of vascular tone induced by chronic hyperinsulinemia by comparing isolated mesenteric vascular beds from Otsuka Long-Evans Tokushima Fatty (OLETF) rats with those of control Long-Evans Tokushima Otsuka rat (LETO) rats. Insulin, triglyceride and total cholesterol levels in plasma, blood glucose concentrations, a glucose-insulin index, systolic blood pressure and perivascular innervations were assessed using biochemical and immunohistochemical methods. Mesenteric vascular beds isolated from OLETF and LETO rats were perfused with a Krebs solution containing methoxamine, and changes in perfusion pressure in response to periarterial nerve stimulation (PNS) and the perfusion of vasoactive agents were measured. OLETF rats (8-25 weeks old) showed age-related increases in insulin, triglycerides, total cholesterol, blood glucose, the glucose-insulin index (homeostasis model assessment ratio (HOMA-IR)) and systolic blood pressure compared with LETO rats. In perfused mesenteric vascular beds, the PNS-induced adrenergic nerve-mediated vasoconstrictor responses in OLETF rats were significantly greater than those in LETO rats, whereas the PNS-induced calcitonin gene-related peptide (CGRP) nerve-mediated vasodilator responses in OLETF rats were significantly smaller than those in LETO rats. In immunohistochemical experiments, the density of CGRP-immunopositive nerves in the mesenteric arteries of OLETF rats decreased significantly with age. The present findings suggest that the abnormal innervation of perivascular nerves in mesenteric resistance arteries induced by chronic hyperinsulinemia disturbs the neuronal regulation of vascular tone and may cause hypertension in OLETF rats.

DOI： 10.1038/hr.2013.151

薬剤のリスクマネジメントデクスメデトミジンによる低血圧発現の危険因子および予防因子解析に関する研究

名倉弘哲, 塩見明日香, 座間味義人, 平山敬浩, 氏家良人

日本臨床医学リスクマネジメント学会・学術集会プログラム・抄録集 12回 62 - 62 2014年5月

高度救命救急センターにおけるデクスメデトミジンによるせん妄発症の危険因子解析

座間味義人, 藤原歩, 武本あかね, 飯田淳義, 鵜川豊世武, 市場晋吾, 名倉弘哲, 氏家良人

日本集中治療医学会雑誌 21 ( Suppl. ) [DP - 6] 2014年1月

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

Insulin Resistance-Induced Hypertension and a Role of Perivascular CGRPergic Nerves 査読

Shingo Takatori, Yoshito Zamami, Narumi Hashikawa-Hobara, Hiromu Kawasaki

CURRENT PROTEIN & PEPTIDE SCIENCE 14 ( 4 ) 275 - 281 2013年6月

記述言語：英語出版者・発行元：BENTHAM SCIENCE PUBL LTD

Insulin resistance is defined as a preliminary step of type 2 diabetes mellitus with decreased insulin action evoked by continuous postprandial hyperglycemia, which is provoked by high fat and calories dieting, a lack of physical activity and obesity. In the early phase of type 2 diabetes mellitus, patients have a hyperinsulinemia to compensate deficient insulin action by increased secretion from the pancreas to maintain euglycemia. Then, pancreatic cells progressively decrease secretion function, resulting in the development of diabetes mellitus with decreased serum insulin levels. Accumulating evidences show that insulin resistance is associated with hypertension. However, the mechanisms underlying hypertension associated with type 2 diabetes mellitus have still unknown. Therefore, to elucidate the mechanisms of insulin resistance-induced hypertension, we investigated that the effects of hyperinsulinemia or hyperglycemia on vascular responses mediated by perivascular nerves including sympathetic adrenergic nerves and calcitonin gene-related peptide (CGRP)-containing nerves (CGRPergic nerves). In this article, we show evidence that insulin resistance-induced hypertension could be resulted from increased density and function of sympathetic nerve, and decreased density and function of CGRPergic nerves. Furthermore, our findings provide a new insight into the research of therapeutic drugs for insulin resistance-induced hypertension.

DOI： 10.2174/13892037113149990047

岡山大学病院高度救急救命センターにおける抗MRSA薬TDMへの継続的関与の有用性

座間味義人, 名倉弘哲, 武本あかね, 森定淳, 木浪陽, 山内英雄, 寺戸通久, 鵜川豊世武, 市場晋吾, 氏家良人

日本臨床救急医学会雑誌 16 ( 3 ) 407 - 407 2013年6月

切除不能な進行・再発の直腸・結腸がん3次治療におけるセツキシマブとパニツムマブの費用対効果分析

永尾香菜子, 小林明日香, 座間味義人, 名和秀起, 野間和広, 五十嵐中, 千堂年昭, 名倉弘哲

日本薬学会年会要旨集 133年会 ( 3 ) 245 - 245 2013年3月

塩酸デクスメデトミジン投与患者におけるせん妄発症の危険因子解析

名倉弘哲, 藤原歩, 座間味義人, 鵜川豊世武, 氏家良人

日本臨床医学リスクマネジメント学会・学術集会プログラム・抄録集 11回 81 - 81 2013年3月

岡山大学病院高度救命救急センターにおける薬剤経管投与方法への薬剤師の介入症例

座間味義人, 名倉弘哲, 飯田淳義, 塚原紘平, 寺戸通久, 鵜川豊世武, 芝直基, 山内英雄, 市場晋吾, 氏家良人

日本集中治療医学会雑誌 20 ( Suppl. ) 413 - 413 2013年1月

岡山大学病院高度救命救急センターへの全国初となる救急薬学講座参入

名倉弘哲, 座間味義人, 寺戸通久, 芝直基, 平山敬浩, 森定淳, 山内英雄, 鵜川豊世武, 市場晋吾, 氏家良人

日本集中治療医学会雑誌 20 ( Suppl. ) 442 - 442 2013年1月

Do cholinergic nerves innervating rat mesenteric arteries regulate vascular tone? 査読

Panot Tangsucharit, Shingo Takatori, Pengyuan Sun, Yoshito Zamami, Mitsuhiro Goda, Poungrat Pakdeechote, Fusako Takayama, Hiromu Kawasaki

AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY 303 ( 11 ) R1147 - R1156 2012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：AMER PHYSIOLOGICAL SOC

Tangsucharit P, Takatori S, Sun P, Zamami Y, Goda M, Pakdeechote P, Takayama F, Kawasaki H. Do cholinergic nerves innervating rat mesenteric arteries regulate vascular tone? Am J Physiol Regul Integr Comp Physiol 303: R1147-R1156, 2012. First published October 10, 2012; doi:10.1152/ajpregu.00317.2012.-Vascular blood vessels have various types of cholinergic acetylcholine receptors (AChR), but the source of ACh has not been confirmed. Perivascular adrenergic nerves and nonadrenergic calcitonin gene-related peptide (CGRP)-containing (CGRPergic) nerves innervate rat mesenteric arteries and regulate vascular tone. However, function of cholinergic innervation remains unknown. The present study investigated cholinergic innervation by examining effects of cholinesterase inhibitor (neostigmine), a muscarinic AChR antagonist (atropine), and a nicotinic AChR antagonist (hexamethonium) on adrenergic nerve-mediated vasoconstriction and CGRPergic nerve-mediated vasodilation in rat mesenteric vascular beds without endothelium. In preparations treated with capsaicin (CGRP depletor) or in the presence of N-omega-nitro-L-arginine methyl ester (nonselective nitric oxide synthase inhibitor), perivascular nerve stimulation (PNS; 2-12 Hz) evoked a frequency-dependent vasoconstriction. In the same preparations, exogenous norepinephrine induced a concentration-dependent vasoconstriction. Atropine, hexamethonium, and neostigmine had no effect on vasoconstrictor responses to PNS and norepinephrine injections. In denuded preparations, these cholinergic agents did not affect the PNS (12 Hz)-evoked release of norepinephrine in perfusate. In preconstricted preparations without endothelium in the presence of guanethidine (adrenergic neuron blocker), PNS (1-4 Hz) induced a frequency-dependent vasodilation, which was not affected by atropine, hexamethonium, and neostigmine. In denuded preparations treated with capsaicin and guanethidine, PNS did not induce vascular responses, and atropine, neostigmine, and physostigmine had no effect on PNS. Immunohistochemistry study showed choline acetyltransferase-immunopositive fibers, which were resistant to capsaicin and 6-hydroxy-dopamine (adrenergic toxin). These results suggest that rat mesenteric arteries have cholinergic innervation, which is different from adrenergic and capsaicin-sensitive nerves and not associated with vascular tone regulation.

DOI： 10.1152/ajpregu.00317.2012

Quinolone Analogues 12: Synthesis and Tautomers of 2-Substituted 4-Quinolones and Related Compounds 査読

Yoshihisa Kurasawa, Kiminari Yoshida, Naoki Yamazaki, Kotoji Iwamoto, Yoshihiko Hamamoto, Eisuke Kaji, Kenji Sasaki, Yoshito Zamami

JOURNAL OF HETEROCYCLIC CHEMISTRY 49 ( 6 ) 1323 - 1331 2012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

The 4-quinolone-2-carboxylates 4a,b were converted into the 4-quinolone-2-carbohydrazides 5a,b, hydrazones 6,7,10, and related compounds 8,9,11. The 4-methoxyquinoline-2-carboxylate 12 was also transformed into the 4-methoxyquinoline-2-carbohydrazide 13, which was modified to the hydrazone 14 and related compound 15. The antimicrobial activities of compounds 6b and 14 are described together with the 4-oxo and 4-hydroxy tautomers of compounds 4-11 in deuteriodimethyl sulfoxide and deuteriotrifluoroacetic acid.

DOI： 10.1002/jhet.922

岡山大学薬学部救急薬学分野の発足全国初の救急薬学

名倉弘哲, 武本あかね, 座間味義人, 寺戸通久, 芝直基, 飯田淳義, 木浪陽, 山内英雄, 鵜川豊世武, 市場晋吾, 氏家良人

日本救急医学会雑誌 23 ( 10 ) 679 - 679 2012年10月

Pharmacist-Physical Assessment Lab(P-PAL)活動報告岡山大学大学院救急薬学分野との共催による卒後薬剤師教育について

立野朋志, 名倉弘哲, 座間味義人, 尾上洋, 堀淵浩二, 松永るみ

日本薬剤師会学術大会講演要旨集 45回 204 - 204 2012年10月

Adrenergic stimulation-released 5-HT stored in adrenergic nerves inhibits CGRPergic nerve-mediated vasodilatation in rat mesenteric resistance arteries 査読

Hirohito Fujii, Shingo Takatori, Yoshito Zamami, Narumi Hashikawa-Hobara, Natsuki Miyake, Panot Tangsucharit, Mitsunobu Mio, Hiromu Kawasaki

BRITISH JOURNAL OF PHARMACOLOGY 166 ( 7 ) 2084 - 2094 2012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：WILEY-BLACKWELL

BACKGROUND AND PURPOSE 5-HT is taken up by and stored in adrenergic nerves and periarterial nerve stimulation (PNS) releases 5-HT to cause vasoconstriction in rat mesenteric arteries. The present study investigated whether PNS-released 5-HT stored in adrenergic nerves affects the function of perivascular calcitonin gene-related peptide-containing (CGRPergic) nerves. EXPERIMENTAL APPROACH Rat mesenteric vascular beds without endothelium and with active tone were perfused with Krebs solution. Changes in perfusion pressure in response to PNS and CGRP injection were measured before (control) and after perfusion of Krebs solution containing 5-HT (10 mu M) for 20 min. Distributions of 5-HT- and TH-immunopositive fibres in mesenteric arteries were studied using immunohistochemical methods. KEY RESULTS PNS (14 Hz) frequency dependently caused adrenergic nerve-mediated vasoconstriction followed by CGRPergic nerve-mediated vasodilatation. 5-HT treatment inhibited PNS-induced vasodilatation without affecting exogenous CGRP-induced vasodilatation, while it augmented PNS-induced vasoconstriction. Guanethidine (adrenergic neuron blocker), methysergide (non-selective 5-HT receptor antagonist) and BRL15572 (selective 5-HT1D receptor antagonist) abolished inhibition of PNS-induced vasodilatation in 5-HT-treated preparations. Combined treatment with 5-HT and desipramine (catecholamine transporter inhibitor), but not fluoxetine (selective 5-HT reuptake inhibitor), did not inhibit PNS-induced vasodilatation. Exogenous 5-HT inhibited PNS-induced vasodilatation, which was antagonized by methysergide. In immunohistochemical experiments, 5-HT-immunopositive nerves, colocalized with adrenergic TH-immunopositive nerves, were observed only in 5-HT-treated mesenteric arteries, but not in control preparations or arteries co-treated with desipramine. CONCLUSIONS AND IMPLICATIONS These results suggest that 5-HT can be taken up by and released from adrenergic nerves in vitro by PNS to inhibit CGRPergic nerve transmission in rat mesenteric arteries.

DOI： 10.1111/j.1476-5381.2012.01935.x

Synthesis and antimalarial activity of calothrixins A and B, and their N-alkyl derivatives 査読

Kohji Matsumoto, Tominari Choshi, Mai Hourai, Yoshito Zamami, Kenji Sasaki, Takumi Abe, Minoru Ishikura, Noriyuki Hatae, Tatsunori Iwamura, Shigeo Tohyama, Junko Nobuhiro, Satoshi Hibino

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 22 ( 14 ) 4762 - 4764 2012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：PERGAMON-ELSEVIER SCIENCE LTD

We synthesized calothrixin B using our developed biomimetic method and derived N-alkyl-calothrixins A and B. The in vitro antimalarial activity of the calothrixin derivatives, including calothrixins A and B, against the Plasmodium falciparum FCR-3 strain was evaluated. All test compounds exhibited antimalarial activity over a concentration range of 6.4 x 10(-6)-1.2 x 10(-7) M. (C) 2012 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2012.05.064

Neurogenic Vascular Responses in Male Mouse Mesenteric Vascular Beds 査読

Hiroki Fujiwara, Narumi Hashikawa-Hobara, Yoshihiro Wake, Shingo Takatori, Mitsuhiro Goda, Hiroshi Higuchi, Yoshito Zamami, Panot Tangsucharit, Hiromu Kawasaki

JOURNAL OF PHARMACOLOGICAL SCIENCES 119 ( 3 ) 260 - 270 2012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：JAPANESE PHARMACOLOGICAL SOC

Rat mesenteric arteries were maintained by both adrenergic vasoconstrictor nerves and calcitonin gene related peptide (CGRP) vasodilator nerves. However, functions of these nerves in a pathophysiological state have not fully been analyzed. The use of disease models developed genetically in mice is expected to clarify neural function of perivascular nerves. Thus, we investigated basic mouse vascular responses. Mesenteric vascular beds isolated from male C57BL/6 mouse were perfused with Krebs solution and perfusion pressure was measured. Periarterial nerve stimulation (PNS, 8 - 24 Hz) induced frequency-dependent vasoconstriction, which increased flow rate dependently. PNS-induced vasoconstriction was abolished by tetrodotoxin (neurotoxin) and guanethidine (adrenergic neuron blocker) and blunted by prazosin (alpha(1)-adrenoceptor antagonist). Injection of norepinephrine caused vasoconstriction, which was abolished by prazosin. In preparations with active tone, PNS (1 - 8 Hz) induced frequency-dependent vasodilation, which was inhibited by tetrodotoxin, capsaicin (CGRP depletor), and CGRP8-37 (CGRP-receptor antagonist). Injections of CGRP, acetylcholine, and sodium nitroprusside induced vasodilations. Vasodilator response to CGRP was inhibited by CGRP8-37. Immunohistochemical study showed innervation of tyrosine hydroxylase- and CGRP-immunopositive fibers in mesenteric arteries and veins. These results suggest that male mouse mesenteric vascular beds are useful for studying neural regulation of mesenteric arteries, which are innervated by adrenergic and CGRPergic nerves regulating vascular tone.

DOI： 10.1254/jphs.12014FP

The Mechanism of Calcitonin Gene-Related Peptide-Containing Nerve Innervation 査読

Narumi Hashikawa-Hobara, Naoya Hashikawa, Yoshito Zamami, Shingo Takatori, Hiromu Kawasaki

JOURNAL OF PHARMACOLOGICAL SCIENCES 119 ( 2 ) 117 - 121 2012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：JAPANESE PHARMACOLOGICAL SOC

Calcitonin gene-related peptide (CGRP) is a major neurotransmitter and CGRP-containing primary sensory neurons play an important role in nociception and potent vasodilation. CGRP-containing nerves in mesenteric arteries are decreased in pathological animal models (hypertension, diabetes, and atherosclerosis). In apolipoprotein E knockout mice, which have atherosclerosis and peripheral sensory nerve defects, nerve growth factor (NGF)-mediated CGRP nerve facilitation was down-regulated, which may have been caused by the impairment of the Akt-NO-cGMP pathway. In addition, NGF-mediated CGRP neurite outgrowth was decreased in fructose-induced insulin-resistant rats. We recently discovered that renin angiotensin inhibitors improved CGR.P innervation in spontaneously hypertensive rats, indicating that rescuing CGRP nerve innervation might improve pathophysiological conditions. To find a novel reagent that facilitates CG.RP nerves, a new model, phenol-injured perivascular nerve model rats, was established. Adrenomedullin, hepatocyte growth factor, and angiotensin 11 type 2 receptor activation induced CGRP nerve distribution in phenol-injured rats. Furthermore, in insulin-resistant model rats, the down-regulation of CGRP nerves was likely due to the depression of phosphoinositide 3-kinase (PI3K)-dependent Akt activation. Administration of candesartan improves CGRPergic function via the PI3K Akt pathway in insulin-resistant rats. Thus, clarification of the mechanisms of CGRP nerve defects may constitute future therapeutic targets.

DOI： 10.1254/jphs.12R02CP

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

Candesartan Cilexetil Improves Angiotensin II Type 2 Receptor-Mediated Neurite Outgrowth via the PI3K-Akt Pathway in Fructose-Induced Insulin-Resistant Rats 査読

Narumi Hashikawa-Hobara, Naoya Hashikawa, Yusuke Inoue, Hitomi Sanda, Yoshito Zamami, Shingo Takatori, Hiromu Kawasaki

DIABETES 61 ( 4 ) 925 - 932 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：AMER DIABETES ASSOC

We have shown previously that stimulation of the angiotensin type 2 receptor (AT(2)R) results in nerve facilitation. In this study, we determined the capacity of candesartan to correct expression patterns characteristic of neuropathy and AT(2)R-mediated neurite outgrowth in the fructose-induced insulin-resistant rat, which is one of the human hyperinsulinemia models. Wistar rats received a 15% (w/v) fructose solution in their drinking water for 4 weeks (fructose-drinking rats [FDRs]), with or without candesartan (5 mg/kg/day). We evaluated physiological and behavioral parameters and performed immunohistochemical studies. We found that the FDR developed insulin resistance and downregulated both AT(2)R neuronal function and phosphorylated Akt expression in dorsal root ganglia (DRG) neurons. Candesartan improved neurite outgrowth in the FDR, which was associated with the restoration of AT(2)R and phosphorylated Akt expression. Furthermore, downregulation of phosphoinositide 3-kinase (PI3K) inhibited AT(2)R-mediated neurite outgrowth in control DRG cells. PI3K activation increased AT(2)R-mediated neurite outgrowth and phosphorylated Akt expression in FDR DRG cells. These results suggest that the decrease of AT(2)R-mediated neurite outgrowth in FDRs is likely to be the result of decreased PI3K-dependent Akt activation. Candesartan improved AT(2)R neuronal function and Akt phosphorylation, which were associated with sensory nerve defects and insulin sensitivity in the FDR. Diabetes 61:925 932, 2012

DOI： 10.2337/db11-1468

Anandamide Induces Endothelium-Dependent Vasoconstriction and CGRPergic Nerve-Mediated Vasodilatation in the Rat Mesenteric Vascular Bed 査読

Chihiro Tamaki, Hideki Nawa, Shingo Takatori, Sakiko Oda, Toshiaki Sendo, Yoshito Zamami, Hiromu Kawasaki

JOURNAL OF PHARMACOLOGICAL SCIENCES 118 ( 4 ) 496 - 505 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

An endogenous cannabinoid anandamide (N-arachidonoylethanolamide) has been shown to cause vasodilatation in vitro and a brief vasoconstriction followed by prolonged depressor response in vivo. This study investigated the vascular effects of anandamide and underlying mechanisms in rat mesenteric vascular beds. In preparations with an intact endothelium and active tone, anandamide at low concentrations (0.1 - 1 nM) caused a concentration-dependent decrease in perfusion pressure due to vasodilatation, but at high concentrations (10 nM - 1 mu M) elicited an initial and sharp increase in perfusion pressure due to vasoconstriction followed by long-lasting vasodilatation in a concentration-dependent manner. Treatment with SR141716A [cannabinoid-1 (CB1)-receptor antagonist] blunted both the vasoconstrictor and vasodilator responses. Also, removal of the endothelium and indomethacin (cyclooxygenase inhibitor), but not adrenergic denervation with 6-hydoxydopamine (adrenergic neurotoxin), markedly inhibited the vasoconstrictor response to anandamide, while these treatments did not affect vasodilatation. The vasodilatation, but not vasoconstriction, in response to anandamide was markedly attenuated by capsazepine [selective antagonist for transient receptor potential vanilloid-1 (TRPV1)], pretreatment with capsaicin [calcitonin gene related peptide (CGRP)ergic-nerve depletor], or cold-storage denervation. These results suggest that in rat mesenteric vascular beds, anandamide causes CB1-receptor and prostanoid-mediated endothelium-dependent vasoconstriction and perivascular capsaicin-sensitive CGRPergic nerve-mediated vasodilatation.

DOI： 10.1254/jphs.11236FP

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

Quinolone analogs 11: Synthesis of novel 4-quinolone-3-carbohydrazide derivatives with antimalarial activity 査読

Yoshihisa Kurasawa, Kiminari Yoshida, Naoki Yamazaki, Eisuke Kaji, Kenji Sasaki, Yoshito Zamami, Yasuhiro Sakai, Takatoshi Fujii, Hideyuki Ito

JOURNAL OF HETEROCYCLIC CHEMISTRY 49 ( 2 ) 288 - 292 2012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：WILEY-BLACKWELL

The reaction of the 6-substituted 1-methyl-4-quinolone-3-carboxylates 10a,b with hydrazine hydrate gave the 3-carbohydrazides 7a,b, respectively, whose reaction with 2-, 3-, and 4-pyridinecarbaldehydes afforded the 3-(N2-pyridylmethylene)carbohydrazides 8ac and 9ac. The Curtius rearrangement of compound 7b provided the N,N'-bis(4-quinolon-3-yl)urea 14 presumably via the 3-carboazide 11 and then 3-isocyanate 12. Compounds 7a, 8a, and 9a were found to possess antimalarial activity from the in vitro screening data. J. Heterocyclic Chem.,(2011).

DOI： 10.1002/jhet.774

Endothelium-Derived Relaxing Factor Mediated Vasodilation in Mouse Mesenteric Vascular Beds 査読

Hiroki Fujiwara, Yoshihiro Wake, Narumi Hashikawa-Hobara, Kento Makino, Shingo Takatori, Yoshito Zamami, Yoshihisa Kitamura, Hiromu Kawasaki

JOURNAL OF PHARMACOLOGICAL SCIENCES 118 ( 3 ) 373 - 381 2012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：JAPANESE PHARMACOLOGICAL SOC

The endothelium in rat mesenteric vascular beds has been demonstrated to regulate vascular tone by releasing mainly endothelium-derived hyperpolarizing factor (EDHF), which is involved in the activation of K+ channels and gap-junctions. However, it is unclear whether the endothelial system in mouse resistance arteries contributes to regulation of the vascular tone. The present study was designed to investigate the role of the endothelium using acetylcholine and A23187 (Ca2+ ionophore) in mesenteric vascular beds isolated from male C57BL/6 mice and perfused with Krebs solution to measure perfusion pressure. In preparations with active tone produced by methoxamine in the presence of guanethidine, injections of acetylcholine, A23187, and sodium nitroprusside (SNP) caused a concentration-dependent decrease in perfusion pressure due to vasodilation. The vasodilator responses to acetylcholine and A23187, but not SNP, were abolished by endothelium dysfunction and significantly inhibited by N-omega-nitro-L-arginine methyl ester (nitric oxide synthase inhibitor) and tetraethylammonium (K+-channel inhibitor) but not glibenclamide (ATP-sensitive K+-channel inhibitor). Indomethacin (cyclooxygenase inhibitor) significantly blunted only A23187-induced vasodilation, while 18 alpha-glycyrrhetinic acid (gap-junction inhibitor) attenuated only acetylcholine-induced vasodilation. These results suggest that the endothelium in mouse mesenteric arteries regulates vascular tone by prostanoids, EDHF, and partially by nitric oxide, different from the endothelium of rat mesenteric arteries.

DOI： 10.1254/jphs.11197FP

Long-term treatment with losartan augments vasodilator CGRPergic nerve activity in Spontaneously Hypertensive Rats 査読

Yoshito Zamami, Shingo Takatori, Narumi Hashikawa, Hiroko Ishikawa, Kenji Sasaki, Hiromu Kawasaki

JOURNAL OF PHARMACOLOGICAL SCIENCES 118 198P - 198P 2012年

Hyperinsulinemia induces hypertension associated with neurogenic vascular dysfunction resulting from abnormal perivascular innervations in rat mesenteric resistance arteries 査読

Yoshito Zamami, Shingo Takatori, Narumi Hobara, Nana Yabumae, Panot Tangsucharit, Xin Jin, Naoya Hashikawa, Yoshihisa Kitamura, Kenji Sasaki, Hiromu Kawasaki

HYPERTENSION RESEARCH 34 ( 11 ) 1190 - 1196 2011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：NATURE PUBLISHING GROUP

We previously reported that chronic hyperinsulinemia and insulin resistance induced by fructose-drinking loading elicited hypertension associated with abnormal neuronal regulation of vascular tone in an in vivo study using pithed rats. Therefore, to further clarify the detailed mechanisms of perivascular nervous system malfunction induced by chronic hyperinsulinemia, we investigated the neurogenic vascular responses and distribution of perivascular nerves using mesenteric vascular beds isolated from fructose-loaded rats with hyperinsulinemia. Male Wistar rats (6 weeks old) received 15% fructose solution as drinking fluid for 10 weeks (fructose-drinking rats, FDR), which resulted in significant increases in plasma levels of insulin, the glucose-insulin index, blood norepinephrine (NE) levels and systolic blood pressure, but not blood glucose levels, when compared with normal water-drinking rats (control rats). In perfused mesenteric vascular beds of FDR, enhanced adrenergic nerve-mediated vasoconstriction with no effect on NE-induced vasoconstriction and decreased calcitonin gene-related peptide (CGRP)-containing nerve-mediated vasodilation with no effect on CGRP-induced vasodilation were observed. Immunohistochemistry studies showed increased density of neuropeptide Y immunopositive adrenergic fibers and reduced density of CGRP immunopositive fibers in mesenteric arteries of FDR. Furthermore, FDR showed decreased CGRP content in dorsal root ganglia. These findings suggest that dysfunction of the neuronal vascular control system resulting from abnormal innervation of mesenteric perivascular nerves induced by the hyperinsulinemic state is responsible for the development of hypertension in FDR. Hypertension Research (2011) 34, 1190-1196; doi:10.1038/hr.2011.97; published online 28 July 2011

DOI： 10.1038/hr.2011.97

The Akt-Nitric Oxide-cGMP Pathway Contributes to Nerve Growth Factor-Mediated Neurite Outgrowth in Apolipoprotein E Knockout Mice 査読

Narumi Hashikawa-Hobara, Naoya Hashikawa, Chikao Yutani, Yoshito Zamami, Xin Jin, Shingo Takatori, Mitsunobu Mio, Hiromu Kawasaki

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 338 ( 2 ) 694 - 700 2011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：AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS

Apolipoprotein E (apo)-deficient [apoE(-/-)] mice have peripheral sensory nerve defects and a reduced and delayed response to noxious thermal stimuli. However, to date, no report has focused on the influence of apoE deficiency on calcitonin gene-related peptide (CGRP)-containing nerve fiber extensions. We have shown that the density of CGRP-containing nerve fibers decreases in mesenteric arteries of apoE(-/-) mice compared with wild-type mice. Here, we investigated whether apoE deficiency is involved in nerve growth factor (NGF)-induced CGRP-containing nerve regeneration using apoE(-/-) mice. NGF-mediated CGRP-like immunoreactivity (LI)-neurite outgrowth in apoE(-/-) cultured dorsal root ganglia (DRG) cells was significantly lower than that in wild-type cultures. However, the level of NGF receptor mRNA in apoE(-/-) DRG cells was similar to that in wild-type mice. To clarify the mechanism of the impaired ability of NGF-mediated neurite outgrowth, we focused on the Akt-nitric oxide (NO)-cGMP pathway. Expression of phosphorylated Akt was significantly reduced in apoE(-/-) DRG. The NO donor, sodium nitroprusside or S-nitroso-N-acetylpenicillamine, did not affect NGF-mediated neurite outgrowth in apoE(-/-) cultured DRG cells. However, 8-bromoguanosine 3',5'-cyclic monophosphate sodium salt n-hydrate, a cGMP analog, induced NGF-mediated nerve facilitation similar to wild-type NGF-mediated neurite outgrowth levels. Furthermore, in apoE(-/-) DRG, soluble guanylate cyclase expression was significantly lower than that in wild-type DRG. These results suggest that in apoE(-/-) mice the Akt-NO-cGMP pathway is impaired, which may be caused by NGF-mediated CGRP-LI-neurite outgrowth defects.

DOI： 10.1124/jpet.111.181487

New Molecular Mechanisms for Cardiovascular Disease: Contribution of Endothelium-Derived Hyperpolarizing Factor in the Regulation of Vasoconstriction in Peripheral Resistance Arteries 査読

Xin Jin, Yukiko Satoh-Otonashi, Yoshito Zamami, Shingo Takatori, Narumi Hashikawa-Hobara, Yoshihisa Kitamura, Hiromu Kawasaki

JOURNAL OF PHARMACOLOGICAL SCIENCES 116 ( 4 ) 332 - 336 2011年8月

記述言語：英語出版者・発行元：JAPANESE PHARMACOLOGICAL SOC

Endothelium regulates vascular tone via release of endothelium-derived relaxing factors (EDRF) including nitric oxide (NO), prostaglandin I(2) (PGI(2)), and endothelium-derived hyperpolarizing factor (EDHF). The mesenteric vascular bed produces vascular resistance to develop blood pressure and regulate tissue blood flow that plays an important role in maintenance of systemic blood pressure. There is now strong evidence that in these small resistance arteries, EDHF plays a major role in the response to vasoactive substances and regulation of vascular tone. Pharmacological analysis to investigate the role of the vascular endothelium in the regulation of alpha(1)-adrenoceptor agonist (methoxamine)-induced vasoconstriction in rat mesenteric vascular beds showed that vasoconstriction induced by continuous perfusion of methoxamine (7 mu M), but not high KCl (60 mM), time-dependently decreased to 20% of the initial constriction. The time-dependent reduction of methoxamine-induced vasoconstriction was inhibited by endothelium removal, inhibitor of EDHF (30 mM KCl, K(+)-channel blockers), and gap-junction inhibitor, but not NO synthase inhibitor and cyclooxygenase inhibitor and ageing. These results suggest that vascular endothelium counteracts to normalize excess vasoconstriction of the mesenteric resistance arteries by releasing EDHF, which is associated with activation of multiple K(+)-channels and gap junction involvement and markedly decreases with ageing.

DOI： 10.1254/jphs.10R30FM

Quercetin Diacylglycoside Analogues Showing Dual Inhibition of DNA Gyrase and Topoisomerase IV as Novel Antibacterial Agents 査読

Abugafar M. L. Hossion, Yoshito Zamami, Rafiya K. Kandahary, Tomofusa Tsuchiya, Wakano Ogawa, Akimasa Iwado, Kenji Sasaki

JOURNAL OF MEDICINAL CHEMISTRY 54 ( 11 ) 3686 - 3703 2011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：AMER CHEMICAL SOC

A structure-guided molecular design approach was used to optimize quercetin diacylglycoside analogues that inhibit bacterial DNA gyrase and topoisomerase IV and show potent antibacterial activity against a wide spectrum of relevant pathogens responsible for hospital- and community-acquired infections. In this paper, such novel 3,7-diacylquercetin, quercetin 6 ''-acylgalactoside, and quercetin 2 '',6 ''-diacylgalactoside analogues of lead compound 1 were prepared to assess their target specificities and preferences in bacteria. The significant enzymatic inhibition of both Escherichia coli DNA gyrase and Staphylococcus aureus topoIV suggest that these compounds are dual inhibitors. Most of the investigated compounds exhibited pronounced inhibition with MIC values ranging from 0.13 to 128 mu g/mL toward the growth of multidrug-resistant Gram-positive methicillin-resistant S. aureus, methicillin sensitive S. aureus, vancomycin-resistant enterococci (VRE), vancomycin intermediate S. aureus, and Streptococcus pneumoniae bacterial strains. Structure activity relationship studies revealed that the acyl moiety was absolutely essential for activity against Gram-positive organisms. The most active compound 5i was 512-fold more potent than vancomycin and 16-32-fold more potent than 1 against VRE strains. It also has realistic in situ intestinal absorption in rats and showed very low acute toxicity in mice. So far, this compound can be regarded as a leading antibacterial agent.

DOI： 10.1021/jm200010x

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

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

Role of Angiontensin Receptors on Remodeling Perivascular Nerves 査読

Narumi Hobara, Mitsuhiro Goda, Naoya Hashikawa, Xin Jin, Yoshito Zamami, Shingo Takatori, Hiromu Kawasaki

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN 130 ( 11 ) 1421 - 1425 2010年11月

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

The aim of this study was to investigate age-related changes in the density of calcitonin gene-related peptide (CGRP) -containing nerve fibers in spontaneously hypertensive rats (SHR) and the effects of long-term inhibition of the renin-angiotensin system on these changes. An age-related decrease in the density of CGRP-like immunoreactive (LI) -containing nerve fibers but not neuropeptide Y (NPY) -LI-containing sympathetic nerve fibers was found in the mesenteric artery of SHR but not Wistar-Kyoto rats (WKY). The density of NPY-LI-containing nerve fibers was significantly greater in SHR than in WKY. SHR were treated for 7 weeks with angiotensin-converting enzyme inhibitor (0.005% temocapril), angiotensin 11 type-1 (AT1) receptor antagonist (0.025% losartan), or vasodilator (0.01% hydralazine) in their drinking water. Each drug treatment significantly lowered the systolic blood pressure measured using the tail-cuff method. Long-term treatment of SHR with temocapril and losartan significantly increased the density of CGRP-LI-containing nerve fibers in mesenteric arteries. Furthermore, to clarify the effect of the angiontensin II type-2 (AT2) receptor in the restoration of perivascular nerve innervation, we used the phenol-injured rat model, in which the perivascular nerves are markedly reduced by the topical application of phenol. Activation of AT2R significantly restored CGRP-LI innervation in phenol-injured rats. These results suggest that selective stimulation of AT2 receptors facilitates reinnervation of mesenteric perivascular CGRP-containing nerves.

DOI： 10.1248/yakushi.130.1421

Design, synthesis, and biological evaluation of a novel series of quercetin diacylglucosides as potent anti-MRSA and anti-VRE agents 査読

Abugafar M. L. Hossion, Nao Otsuka, Rafiya K. Kandahary, Tomofusa Tsuchiya, Wakano Ogawa, Akimasa Iwado, Yoshito Zamami, Kenji Sasaki

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 20 ( 17 ) 5349 - 5352 2010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：PERGAMON-ELSEVIER SCIENCE LTD

A series of novel quercetin diacylglucosides were designed and first synthesized by Steglich esterification on the basis of MRSA strains inhibiting natural compound A. The in vitro inhibition of different multidrug resistant bacterial strains and Escherichia coli DNA gyrase B was investigated. In the series, compound 10h was up to 128-fold more potent against vancomycin-resistant enterococci and more effective than A, which represents a promising new candidate as a potent anti-MRSA and anti-VRE agent. (C) 2010 Published by Elsevier Ltd.

DOI： 10.1016/j.bmcl.2010.02.060

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

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

Ameliorative effect of Eucommia ulmoides Oliv. leaves extract (ELE) on insulin resistance and abnormal perivascular innervation in fructose-drinking rats 査読

Xin Jin, Keisuke Amitani, Yoshito Zamami, Shingo Takatori, Narumi Hobara, Naomi Kawamura, Tetsuya Hirata, Atsunori Wada, Yoshihisa Kitamura, Hiromu Kawasaki

JOURNAL OF ETHNOPHARMACOLOGY 128 ( 3 ) 672 - 678 2010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 IRELAND LTD

Aim of the study: Eucommia ulmoides Oliv, leaf is a traditional Chinese medicine that exhibits an antidiabetic action. This study was designed to investigate whether long-term administration of Eucommia ulmoides Oliv. leaves extract (ELE) ameliorates pre-diabetic state of insulin resistance and abnormal perivascular innervation in the hyperinsulinemic state.
Materials and methods: ELE at doses of 500 and 1000 mg/kg was administered orally once daily for 4 weeks in fructose-drinking rats (FDRs). Plasma levels of insulin, blood glucose levels, and perivascular innervation were assessed using biochemical and immunohistochemical methods.
Results: FDR showed significant increase in plasma levels of insulin, an index for insulin resistance (Homeostasis Model Assessment ratio-HOMA-IR) and systolic blood pressure (SBP), but not blood glucose levels, as compared with control rats. Immunohistochemical study showed significantly greater density of tyrosine hydroxylase (TH)-like immunoreactivity MO-containing nerves and significantly lower density of calcitonin gene-related peptide (CGRP)-LI-containing nerves in mesenteric arteries of FDR than those in control. A 4-week treatment with ELE (500 and 1000 mg/kg, p.o.) significantly decreased plasma levels of insulin and HOMA-IR without affecting blood glucose levels and significantly lowered SBP in FOR. ELE treatment in FDR resulted in significant increase in CGRP-LI never fiber density and significant decrease in TH-LI never fiber density in mesenteric arteries of FDR.
Conclusions: These results suggest that long-term ELE treatment effectively prevents insulin resistance development and ameliorates abnormal perivascular innervation in FOR. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.jep.2010.02.019

ラット腸間膜動脈におけるヒスタミン誘発血管弛緩反応に及ぼす塩酸レボカバスチンおよび塩酸オロパタジンの影響

小山敏広, 楢原由生未, 孫鵬遠, 李思敏, 金きょう, 座間味義人, 高取慎吾, 北村佳久, 川崎博巳

アレルギー・免疫 17 ( 4 ) 662 - 670 2010年3月

記述言語：日本語出版者・発行元：(株)医薬ジャーナル社

ヒスタミン誘発血管弛緩反応に対するヒスタミンH1受容体拮抗薬レボカバスチンとオロパタジンの効果についてラット腸間膜動脈灌流標本を用いて比較検討した。灌流圧を上昇させた標本において、ヒスタミン(10^-8-10^-4M)による濃度依存性の血管弛緩反応は、レボカバスチン(10μM)およびオロパタジン(10μM)によって抑制されたが、レボカバスチンの抑制率がオロパタジンの抑制率に比較して有意に大であった。H2およびH3受容体拮抗薬が共存するとオロパタジンの抑制作用はレボカバスチンの作用と同程度となった。これらの結果から、レボカバスチンはオロパタジンに比べて、強いH2、H3受容体への拮抗作用を有することが拮抗作用の要因と考えられる。(著者抄録)

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

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

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

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

Cardiovascular responses and drug evaluation using the pithed rat model 査読

Yoshito Zamami, Shingo Takatori, Hiromu Kawasaki

Folia Pharmacologica Japonica 133 ( 1 ) 22 - 26 2009年

PIOGLITAZONE OPPOSES NEUROGENIC VASCULAR DYSFUNCTION VIA ABNORMAL INNERVATION OF MESENTERIC PERIVASCULAR NERVES INDUCED BY HYPERINSULINEMIA 査読

Yoshito Zamami, Keisuke Amitani, Miho Hosoda, Xin Jin, Narumi Hobara, Shingo Takatori, Yoshihisa Kitamura, Kenji Sasaki, Hiromu Kawasaki

JOURNAL OF VASCULAR RESEARCH 46 130 - 130 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

Acute hyperglycemia and hyperinsulinemia enhance adrenergic vasoconstriction and decrease calcitonin gene-related peptide-containing nerve-mediated vasodilation in pithed rats 査読

Yoshito Zamami, Shingo Takatori, Kousuke Yamawaki, Satoko Miyashita, Mitsunobu Mio, Yoshihisa Kitamura, Hiromu Kawasaki

HYPERTENSION RESEARCH 31 ( 5 ) 1033 - 1044 2008年5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

Recent clinical studies have demonstrated that transient postprandial hyperglycemia and hyperinsulinemia may contribute to the development of hypertension. Therefore, we investigated the influence of acute hyperglycemia and/or hyperinsulinemia induced by glucose or insulin infusion on neuronal and humoral control of vascular tone in rats. Euglycemic male Wistar rats were pithed under anesthesia and arterial blood pressure was measured. Changes in vascular responses to spinal cord stimulation (SCS) and intravenous bolus injections of noradrenaline, angiotensin 11, calcitonin gene-related peptide (CGRP), acetylcholine and sodium nitroprusside (SNP) were studied by infusing various concentrations of glucose or insulin. Continuous glucose infusion, which increased both blood glucose and serum insulin levels, significantly augmented adrenergic nerve-mediated pressor responses to SCS without affecting pressor responses to injection of noradrenaline or angiotensin II. In pithed rats with artificially increased blood pressure and blockade of autonomic outflow, glucose infusion attenuated CGRPergic nerve-depressor responses to SCS without affecting depressor responses to injection of CGRP, acetylcholine or SNP. In pithed rats treated with octreotide, which increased blood glucose without increasing serum insulin levels, glucose infusion caused only significant augmentation of adrenergic nerve-mediated pressor responses. Combined infusion of insulin and glucose, which resulted in increased serum insulin levels with euglycemia, significantly augmented adrenergic nerve-mediated pressor responses and attenuated CGRPergic nerve-mediated depressor responses. The present results suggest that acute hyperglycemia and hyperinsulinemia increase adrenergic nerve-mediated vasoconstriction, which in turn blunts CGRPergic nerve function, and that the increase in plasma insulin concentration associated with hyperglycemia may be responsible for the alteration of neuronal vascular regulation.

DOI： 10.1291/hypres.31.1033

Pioglitazone opposes neurogenic vascular dysfunction associated with chronic hyperinsulinaemia 査読

S. Takatori, Y. Zamami, N. Yabumae, N. Hanafusa, M. Mio, T. Egawa, H. Kawasaki

BRITISH JOURNAL OF PHARMACOLOGY 153 ( 7 ) 1388 - 1398 2008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：NATURE PUBLISHING GROUP

Background and purpose: We previously demonstrated that chronic hyperinsulinaemia induced by drinking high levels of fructose augments adrenergic nerve-mediated vasoconstriction and suppresses vasodilatation mediated by calcitonin gene-related peptide ( CGRP)-containing (CGRPergic) vasodilator nerves. In this study, the effects of pioglitazone on vascular responses induced by stimulation of adrenergic nerves, CGRPergic nerves and vasoactive agents were investigated in pithed rats given 15% fructose solution to drink ( FDR).
Experimental approach: To assess the effect of pioglitazone on the altered vascular responsiveness in the hyperinsulinaemic state in vivo, changes in vascular responses to spinal cord stimulation ( SCS) and intravenous bolus injections of noradrenaline, angiotensin II and CGRP were evaluated in pithed control rats and FDR either untreated or treated with pioglitazone.
Key results: In the pithed FDR, vasoconstrictor responses to SCS and to injections of noradrenaline and angiotensin II were significantly greater than those of pithed control rats. In pithed FDR with artificially increased blood pressure and blockade of the autonomic ganglia, the vasodilator responses to SCS and CGRP injection were significantly smaller than those of pithed control rats. Oral administration of pioglitazone to FDR for two weeks markedly decreased plasma levels of insulin, triglycerides and blood glucose. In FDR pioglitazone diminished the augmented vasoconstrictor responses to SCS, noradrenaline and angiotensin II, and ameliorated the decrease in vasodilator responses to SCS.
Conclusions and implications: The present results suggest that pioglitazone improves not only insulin resistance, but also the dysfunctions in vascular control regulated by adrenergic and CGRPergic nerves in the hyperinsulinaemic state.

DOI： 10.1038/bjp.2008.8

Effect of postprandial hyperglycemia and hyperinsulinemia on vascular responsiveness 査読

Yoshito Zamami, Shingo Takatori, Yukiko Iwatani, Kousuke Yamawaki, Satoko Miyashita, Nana Yabumae, Fusako Takayama, Mitsunobu Mio, Hiromu Kawasaki

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN 128 ( 3 ) 419 - 424 2008年3月

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

Recent clinical studies demonstrated that transient postprandial hyperglycemia and hyperinsulinemia may contribute to the development of hypertension. Therefore, we investigated influence of acute hyperglycemia and/or hyperinsulinemia induced by glucose or insulin infusion on neuronal and humoral control of vascular tone in rats. Euglycemic male Wistar rats were pithed under anesthesia and arterial blood pressure was measured. Changes in vascular responses to spinal cord stimulation (SCS) and intravenous bolus injections of noradrenaline, angiotensin 11, calcitonin generelated peptide (CGRP), acetylcholine and sodium nitroprusside (SNP) were studied by infusing various concentration of glucose or insulin. Continuous glucose infusion, which increased both blood glucose and serum insulin levels, significantly augmented adrenergic nerve-mediated pressor responses to SCS without affecting injection of pressor responses to noradrenaline or angiotensin II. In pithed rats with artificially increased blood pressure and blockade of autonomic outflow, glucose infusion attenuated CGRPergic nerve-depressor responses to SCS without affecting depressor responses to injection of CGRP, acetylcholine or SNP. In pithed rats treated with octreotide, which increased blood glucose without increasing serum insulin levels, glucose infusion caused only significant augmentation of adrenergic nerve-mediated pressor responses. Combined infusion of insulin and glucose, which resulted in increased serum insulin levels with euglycemic, significantly augmented adrenergic nerve-mediated pressor responses and attenuated CGRPergic nerve-mediated depressor responses. The present results suggest that acute hyperglycemia and hyperinsulinemia increases adrenergic nerve-mediated vasoconstriction, which is partly associated with the blunted CGRPergic nerve function, and that plasma insulin concentration associated with hyperglycemia may be responsible for alteration of neuronal vascular regulation.

DOI： 10.1248/yakushi.128.419

Drug development using novel pharmacological evaluation 査読

Norifumi Shioda, Yoshito Zamami

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN 128 ( 3 ) 393 - 393 2008年3月

脊髄穿刺ラットの神経性血管反応に及ぼす一酸化窒素合成酵素阻害薬の影響

山脇康佑, 奥畑智, 座間味義人, 高山房子, 川崎博己

血管 30 ( 1 ) 28 - 28 2007年1月

Chronic hyperinsulinemia enhances adrenergic vasoconstriction and decreases calcitonin gene-related peptide-containing nerve-mediated vasodilation in pithed rats 査読

Shingo Takatori, Yoshito Zamami, Mitsunobu Mio, Yuji Kurosaki, Hiromu Kawasaki

HYPERTENSION RESEARCH 29 ( 5 ) 361 - 368 2006年5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 SOC HYPERTENSION CENT ACADEMIC SOC, PUBL OFFICE

The present study investigated the influence of chronic hyperinsulinemia on vascular responsiveness induced by adrenergic nerves and calcitonin gene-related peptide-containing (CGRPergic) nerves in pithed rats with insulin resistance. Male Wistar rats (6 weeks old) received 15% fructose solution in drinking fluid for 10 weeks (fructose-drinking rats: FDR), which resulted in significant increases in plasma levels of insulin, total cholesterol and triglyceride, and systolic blood pressure, as compared with control rats. Pithed FDR showed greater adrenergic nerve-mediated pressor response to spinal cord stimulation (SCS) at the lower thoracic vertebra (Th 9-12) and pressor response to exogenous noradrenaline than control rats. In pithed FDR with blood pressure artificially increased by continuous infusion of methoxamine and blockade of autonomic ganglia by hexamethonium, CGRPergic nerve-mediated depressor responses to SCS were significantly smaller than those in control rats, but depressor responses to other vasodilators such as acetylcholine, CGRP and sodium nitroprusside were similar to those in control rats. These results suggest that chronic hyperinsulinemia in FDR facilitates adrenergic nerve-mediated vasoconstriction, which is associated with attenuated CGRPergic nerve-mediated vasodilation.

DOI： 10.1291/hypres.29.361

簡易懸濁法を用いた経管栄養チューブによる薬剤投与方法の改善

座間味義人, 高山房子, 川崎博己, 石井雅人, 柴田和彦, 五味田裕

TDM研究 23 ( 2 ) 101 - 102 2006年4月

Effects of insulin on vascular responses to spinal cord stimulation and vasoactive agents in pithed rats 査読

S Takatori, M Mizote, Y Zamami, Y Kurosaki, H Kawasaki

BRITISH JOURNAL OF PHARMACOLOGY 140 ( 6 ) 1137 - 1145 2003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：NATURE PUBLISHING GROUP

1 Effects of insulin (2-600 pmol kg(-1) min(-1), i.v.) on vascular responses to spinal cord (lower thoracic vertebra, Th 9-12) stimulation (SCS) and to i.v. injection of noradrenaline (NA, 125-500 ng kg(-1)), angiotensin II (Ang II, 40-200 pmol kg(-1)), acetylcholine (ACh, 1 nmol kg(-1)), calcitonin gene-related peptide (CGRP, 0.1 nmol kg(-1)) and sodium nitroprusside (SNP, 5 mug kg(-1)) were examined in pithed rats.
2 In euglycemic pithed rats, low and medium doses of insulin dose-dependently potentiated vasopressor responses to SCS (2-8 Hz), NA, while higher doses of insulin had little effect on SCS- and NA-induced pressor responses. All doses of insulin significantly augmented pressor responses to Ang II.
3 In pithed rats with artificially increased blood pressure, SCS (2 and 4 Hz) induced a frequency-dependent depressor response, which was blocked by infusion of CGRP(8-37) (CGRP receptor antagonist, 60 nmol kg(-1) min(-1)).
4 In euglycemic pithed rats, low-doses of insulin significantly attenuated depressor responses to SCS and CGRP, but medium and high doses of insulin remained unaffected.
5 All doses of insulin significantly inhibited depressor response to ACh, while SNP-induced depressor response was not significantly affected by any doses of insulin.
6 These results suggest that insulin at low and medium concentrations increases adrenergic vasoconstriction, which is partly associated with inhibition of CGRPergic nerve function and endothelium function. It is also suggested that lack of insulin effect at higher concentrations may result from acute desensitization of insulin action, possibly via insulin receptors.

DOI： 10.1038/sj.bjp.0705539

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