研究者詳細 - 座間味　義人

論文 - 座間味　義人

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Trends in nontuberculous mycobacterial disease mortality based on 2000-2022 data from 83 countries. 国際誌

Ko Harada, Quynh Thi Vu, Yoshito Nishimura, Tatsuaki Takeda, Hirofumi Hamano, Yusuke Minato, Yoshito Zamami, Toshihiro Koyama, Hideharu Hagiya

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 158 107932 - 107932 2025年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: To examine the international trends for nontuberculous mycobacterial-associated mortality rates, as nontuberculous mycobacterial infections are becoming increasingly prevalent and pose a significant public health challenge, especially in older populations. METHODS: This retrospective observational study used data from the World Health Organization mortality database, which included patients with nontuberculous mycobacterial infection in 83 countries. We stratified the data by sex, age, and geographic region and calculated crude and age-standardized mortality rates to estimate long-term mortality trends. RESULTS: In total, 42,182 nontuberculous mycobacterial infection-associated deaths (58.1% in women) were reported in 83 countries between 2000 and 2022. The locally weighted regression model estimation for the nontuberculous mycobacterial infection-associated mortality rate more than doubled-from 0.36 deaths per 1000,000 individuals in 2000 to 0.77 deaths per 1000,000 individuals in 2022. Eighty-six percent of nontuberculous mycobacterial infection-associated deaths occurred in people aged ≥65 years. The mortality rate was the highest in the Western Pacific Region. CONCLUSION: This study highlights the impact of emerging nontuberculous mycobacterial diseases and the importance of targeted interventions for managing and reducing mortality, particularly in vulnerable older populations. Further studies are warranted to determine the factors contributing to geographical disparity and treatment options.

DOI： 10.1016/j.ijid.2025.107932

Comprehensive analysis of adverse event profile changes with pertuzumab addition to trastuzumab-based breast cancer therapy: Disproportionality analysis using VigiBase. 国際誌

Tatsuaki Takeda, Jun Matsumoto, Tomonori Sakai, Naohiro Iwata, Hirofumi Hamano, Toshihiro Koyama, Noritaka Ariyoshi, Yoshito Zamami

British journal of clinical pharmacology 91 ( 9 ) 2659 - 2671 2025年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIMS: Pertuzumab is used in combination with trastuzumab-based therapy for HER2-positive breast cancer. However, real-world safety information on pertuzumab remains limited. This study assessed the safety of adding pertuzumab to trastuzumab-based therapy for HER2-positive breast cancer using real-world data. METHODS: VigiBase, the World Health Organization's global database of adverse events (AEs), containing reports from November 1967 to December 2023, was used. Signals for pertuzumab-associated AEs in breast cancer cases were detected using the reporting odds ratio (ROR). RESULTS: Signals of trastuzumab plus pertuzumab relative to trastuzumab alone were detected in gastrointestinal disorders (ROR: 1.45, 95% confidence interval: 1.26-1.67), including diarrhoea (3.49, 2.83-4.30); infections and infestations (1.54, 1.24-1.91); and skin and subcutaneous tissue disorders (ROR: 1.63, 1.40-1.90), including pruritus (1.96, 1.51-2.55) and rash (1.63, 1.20-2.23). Further, signals of trastuzumab plus docetaxel plus pertuzumab relative to those of trastuzumab plus docetaxel were detected in gastrointestinal disorders (1.63, 1.38-1.93), including nausea (1.72, 1.24-2.39) and vomiting (1.48, 1.01-2.17), and in nervous system disorders (1.50, 1.20-1.87), including paraesthesia (2.60, 1.33-5.08) and peripheral sensory neuropathy (5.94, 1.79-19.71). The frequency of AEs causing or prolonging hospitalization was increased with trastuzumab plus pertuzumab compared to that with trastuzumab alone (1.18, 1.00-1.38). CONCLUSIONS: AE profiles after the addition of pertuzumab to trastuzumab-based therapy were comprehensively identified. The findings in this study highlight the importance of considering these AEs when selecting pertuzumab combination therapy to ensure the safety of patients with breast cancer.

DOI： 10.1002/bcp.70094

Cardiotoxicity Assessment of EGFR Tyrosine Kinase Inhibitors Using Human iPS Cell-Derived Cardiomyocytes and FDA Adverse Events Reporting System. 国際誌

Shota Yanagida, Hiroyuki Kawagishi, Mitsuo Saito, Hirofumi Hamano, Yoshito Zamami, Yasunari Kanda

Clinical and translational science 18 ( 8 ) e70325 2025年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Recent advances in the development of anti-cancer drugs have contributed to prolonged survival of cancer patients. In contrast, drug-induced cardiotoxicity, particularly cardiac contractile dysfunction, is of growing concern in cancer treatment. Therefore, it is important to understand the risks of anti-cancer drug-induced cardiac contractile dysfunction in drug development. We have previously developed image-based motion analysis using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to assess the effect of drugs on contractility. However, the utility and predictive potential of image-based motion analysis using hiPSC-CMs for anti-cancer drug-induced cardiac contractile dysfunction have not been well understood. Here we focused on epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) and investigated the correlation between the hiPSC-CMs data and clinical signals of adverse events related to cardiac contractile dysfunction. We examined the effects of the four EGFR-TKIs, osimertinib, gefitinib, afatinib, and erlotinib, on the contractility of hiPSC-CMs using image-based motion analysis. We found that osimertinib decreased contraction velocity and deformation distance in a dose- and time-dependent manner, whereas gefitinib, afatinib, and erlotinib had little effect on these parameters. Next, we examined the real-world data of the EGFR-TKIs using FDA Adverse Event Reporting System (FAERS; JAPIC AERS). Only osimertinib showed significant clinical signals of adverse events related to cardiac contractile dysfunction. These data suggest that hiPSC-CM data correlate with clinical signals in FAERS analysis for four EGFR-TKIs. Thus, image-based motion analysis using hiPSC-CMs can be a useful platform for predicting the risk of anti-cancer drug-induced cardiac contractile dysfunction in patients.

DOI： 10.1111/cts.70325

Global trends in mortality related to pulmonary embolism: an epidemiological analysis of data from the World Health Organization mortality database from 2001 to 2023. 国際誌

Hideharu Hagiya, Ko Harada, Yoshito Nishimura, Maki Yamamoto, Sayoko Nishimura, Michio Yamamoto, Takahiro Niimura, Yuka Osaki, Quynh Thi Vu, Mariko Fujii, Nanami Sako, Tatsuaki Takeda, Hirofumi Hamano, Yoshito Zamami, Toshihiro Koyama

EClinicalMedicine 86 103389 - 103389 2025年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Pulmonary embolism (PE) remains a major contributor to the global disease burden. However, disparities in international trends of PE-related mortality have not been comprehensively examined across geographic, economic, and healthcare system parameters. We employed multifaceted stratification to analyse long-term trends in PE-related mortality. METHODS: This epidemiological analysis used registration data from the World Health Organization Mortality Database. PE-related mortality was defined with the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes for acute PE (I26) and any forms of venous thromboembolism (I80, I822, I828, I829, O882, O222, O223, O229, O870, O871, and O879). Countries were deemed eligible for inclusion in the analysis if they provided mortality data for 5-year age intervals up to ≥85 years, from 2001 to 2023 (last update, February 2025). Countries with incomplete age- and sex-stratified demographic data were excluded. We used locally weighted regression (LOESS) to show global trends in crude and age-standardised mortality rates. Subgroup analyses by geographic region and income level were also performed. Additionally, joinpoint regression analysis was performed to estimate the average annual per cent change (AAPC) in the age-standardised mortality trends for each country during 2010-2023. FINDINGS: Data from 73 countries, encompassing 1,550,883 participants [57.8% (896,393) of whom were female], were eligible for the LOESS analysis, while those from 75 countries, including 915,518 participants (56.9% (520,587) of whom were female) were valid for the joinpoint analysis. The LOESS estimates of global age-standardised PE-related mortality rate (per 100,000) decreased from 3.49 (95% confidence interval [CI], 3.20-3.79) in 2001 to 2.42 (95% CI, 2.04-2.80) in 2023. The age-standardised mortality rates considerably reduced in European regions, such as Western Europe, from 5.24 (95% CI, 4.75-5.74) to 2.25 (95% CI, 1.62-2.87) in 2023; however, in Africa, they remained high from 4.23 (95% CI, 3.82-4.64) in 2001 to 3.90 (95% CI, 2.81-5.00) in 2023. High-income countries showed a continuous downward trend, from 3.68 (95% CI, 3.28-4.08) in 2001 to 2.20 (95% CI, 1.68-2.71) in 2023, whereas lower-to middle-income countries showed a rising trend, from 0.92 (95% CI, 0.04-1.81) in 2001 to 4.82 (95% CI, 3.12-6.52) in 2023. Higher increases in the age-standardised mortality rates were predominantly observed in lower-middle-income countries. INTERPRETATION: Globally, the PE-related mortality rate has declined over the last two decades, except in countries with certain geographical and economic conditions. Despite the potential limitation of misclassification and underreporting, our efforts corroborated that greater efforts are needed to reduce PE-related mortality, especially for populations in susceptible regions and lower-middle-income countries. A multi-layered approach will increase awareness of the disease and facilitate the development of healthcare policies that enhance its clinical management. FUNDING: The Japan Society for the Promotion of Science, the Pfizer Health Research Foundation, and the Ohyama Health Foundation Inc.

DOI： 10.1016/j.eclinm.2025.103389

Unravelling the cardioprotective effects of calcitriol in Sunitinib-induced toxicity: A comprehensive in silico and in vitro study. 国際誌

Yoshika Sakamoto, Takahiro Niimura, Mitsuhiro Goda, Nanami Tomochika, Wakana Murakawa, Fuka Aizawa, Kenta Yagi, Hirofumi Hamano, Yuki Izawa-Ishizawa, Yoshito Zamami, Keisuke Ishizawa

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 188 118137 - 118137 2025年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Sunitinib (SUN), a drug used to treat advanced renal cell carcinoma and other cancers, causes cardiotoxicity. This study aimed to identify a potential drug candidate to counteract SUN-induced cardiotoxicity. We analysed real-world data from adverse event report databases of existing clinically approved drugs to identify potential candidates. Through in silico analyses and in vitro experiments, the mechanisms of action were determined. The study identified calcitriol (CTL), an active form of vitamin D, as a promising candidate against SUN-induced cardiotoxicity. In H9c2 cells, SUN decreased cell viability significantly, whereas CTL mitigated this effect significantly. The SUN-treated group exhibited increased autophagy in H9c2 cells, which was reduced significantly in the CTL group. Bioinformatics analysis using Ingenuity Pathway Analysis revealed the mechanistic target of rapamycin (mTOR) as a common factor between autophagy and CTL. Notably, rapamycin, an mTOR inhibitor, nullified the effects of CTL on cell viability and autophagy. Furthermore, SUN treatment led to significant reductions in cardiomyocyte diameters and increases in their widths, changes that were inhibited by CTL. SUN also induced morphological changes in surviving H9c2 cells, causing them to adopt a rounded shape, whereas CTL improved their morphology to resemble the elongated shape of the control group. In conclusion, the findings of the present study suggest that CTL has the potential to prevent SUN-induced cardiomyocyte damage through autophagy, particularly via mTOR-mediated pathways. The findings indicate that CTL could serve as an effective prophylactic agent against SUN-induced cardiotoxicity, offering a promising avenue for further research and potential clinical applications.

DOI： 10.1016/j.biopha.2025.118137

Identifying New Candidate Predictors of Mortality in Japanese Patients with Severe Drug Eruptions. 国際誌

Shiho Sato, Tadao Ooka, Yoshito Zamami, Hirofumi Hamano, Fumikazu Hayashi, Eri Eguchi, Narumi Funakubo, Tetsuya Ohira

Drug safety 2025年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

UNLABELLED: BACKGROUND AND OBJECTIVES: SCORe of Toxic Epidermal Necrolysis (SCORTEN) and ABCD-10 have been developed as scoring systems for predicting mortality associated with Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). These scores were developed based on a small number of patients; hence, their generalizability requires further exploration. The present study used three algorithms, including a machine learning method, to construct a mortality prediction model for SJS/TEN and to identify new candidate predictors of mortality from severe drug eruptions. METHODS: Data from 5966 patients with SJS or TEN were extracted from the Japanese Adverse Drug Event Report Database. A mortality prediction model was then constructed using stepwise regression, L1 regularized-logistic regression, and random forests based on the patient characteristics (e.g., age, sex, primary disease, adverse events, drug classification, route of administration) and outcomes (death). RESULTS AND DISCUSSION: The mortality prediction models for SJS/TEN identified sex (men), primary disease (hyperlipidemia, diabetes mellitus, renal dysfunction, and malignant tumors), adverse events (renal dysfunction, liver dysfunction, respiratory dysfunction, bacteremia/sepsis, disseminated intravascular coagulation syndrome, shock, and multiple organ failure), number of concomitant drugs, and route of administration (injection) as common factors associated with mortality. CONCLUSIONS: Our findings showed that sex, hyperlipidemia as the primary disease, number of concomitant drugs, use of antipyretic analgesics, and route of administration may be considered as predictors of mortality in patients with SJS/TEN. The external validity of these factors needs to be examined in the future.

DOI： 10.1007/s40264-025-01572-3

Time dependent predictors of cardiac inflammatory adverse events in cancer patients receiving immune checkpoint inhibitors. 国際誌

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

Cardio-oncology (London, England) 11 ( 1 ) 40 - 40 2025年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Cardio-inflammatory immune related adverse events (irAEs) while receiving immune checkpoint inhibitor (ICI) therapy are particularly consequential due to their associations with poorer treatment outcomes. Evaluation of predictive factors of these serious irAEs with a time dependent approach allows better understanding of patients most at risk. OBJECTIVE: To identify different elements of patient data that are significant predictors of early and late-onset or delayed cardio-inflammatory irAEs through various predictive modeling strategies. METHODS: A cohort of patients receiving ICI therapy from January 1, 2010 to May 1, 2022 was identified from TriNetX meeting inclusion/exclusion criteria. Patient data collected included occurrence of early and later cardio-inflammatory irAEs, patient survival time, patient demographic information, ICI therapies, comorbidities, and medication histories. Predictive and statistical modeling approaches identified unique risk factors for early and later developing cardio-inflammatory irAEs. RESULTS: A cohort of 66,068 patients on ICI therapy were identified in the TriNetX platform; 193 (0.30%) experienced early cardio-inflammatory irAEs and 175 (0.26%) experienced later cardio-inflammatory irAEs. Significant predictors for early irAEs included: anti-PD-1 therapy at index, combination ICI therapy at index, and history of peripheral vascular disease. Significant predictors for later irAEs included: a history of myocarditis and/or pericarditis, cerebrovascular disease, and history of non-steroidal anti-inflammatory medication use. CONCLUSIONS: Cardio-inflammatory irAEs can be divided into clinically meaningful categories of early and late based on time since initiation of ICI therapy. Considering distinct risk factors for early-onset and late-onset events may allow for more effective patient monitoring and risk assessment.

DOI： 10.1186/s40959-025-00331-8

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

[Promotion of the appropriate use of antimicrobial agents by utilizing medical big data].

Masayuki Chuma, Mitsuhiro Goda, Hirofumi Hamano, Takahiro Niimura, Kenshi Takechi, Kenta Yagi, Yuki Izawa-Ishizawa, Yoshito Zamami, Keisuke Ishizawa, Yoshikazu Tasaki

Nihon yakurigaku zasshi. Folia pharmacologica Japonica 160 ( 3 ) 178 - 183 2025年

記述言語：日本語掲載種別：研究論文（学術雑誌）

The global surge in antimicrobial resistance (AMR) highlights the critical need for the development of innovative therapies and the appropriate use of antimicrobial agents. Our research focused on preventing, managing, and mitigating the adverse effects of treatments for infection with methicillin-resistant Staphylococcus aureus. In this review, we present our investigations utilizing medical big data. The first study aimed to elucidate the relationship between renal outcome and survival following the onset of vancomycin-associated nephrotoxicity (VAN). An initial analysis using the US Food and Drug Administration Adverse Events Reporting System (FAERS) database revealed elevated mortality rates among patients with VAN compared with those without VAN, forming the basis for further investigation. A subsequent, more rigorous, retrospective analysis using electronic medical records confirmed that poor survival outcomes were significantly associated with non-recovery from VAN, particularly when progression to acute kidney injury of stage ≥2 occurred. Therefore, preventing progression to severe VAN is critical for enhancing survival outcomes. The second study investigated the relationship between statin use and daptomycin-related musculoskeletal adverse events. By employing a mixed-method approach combining meta-analysis with disproportionality analysis of the FAERS data, a significant association between statin therapy and daptomycin-related rhabdomyolysis was identified. This highlights the importance of cautious statin and daptomycin use, with careful consideration of potential safety risks. Each medical big-data database possesses unique characteristics that require careful consideration during analysis. The accurate interpretation of medical big data, coupled with its integration with complementary methodologies, will produce more robust and reliable research outcomes across diverse fields.

DOI： 10.1254/fpj.24081

[An integrative drug discovery strategy using real-world data, in silico modeling, and network pharmacology].

Hirofumi Hamano, Yuta Tanaka, Yoshito Zamami

Nihon yakurigaku zasshi. Folia pharmacologica Japonica 160 ( 5 ) 352 - 359 2025年

記述言語：日本語掲載種別：研究論文（学術雑誌）

This study evaluated the utility of an integrated drug discovery strategy that combines three emerging data-driven approaches: real-world data analysis, in silico screening, and network pharmacology. First, transcriptomic data from public gene expression databases and adverse event reports were analyzed to address myocarditis induced by immune checkpoint inhibitors. The findings suggested a preventive effect of non-steroidal anti-inflammatory drugs, particularly those targeting the arachidonic acid metabolism pathway. Second, to identify therapeutic options for trastuzumab-resistant HER2-positive breast cancer, a cheminformatics approach was applied. A machine learning classification model and structure-based docking simulations enabled efficient in silico screening of approved drugs, identifying novel YES1 kinase inhibitors. Third, network-based analysis evaluated the topological distance between disease-associated gene modules and statin-induced gene modules in drug-induced peripheral neuropathy. This analysis indicated that certain statins may protect against drug-induced peripheral neuropathy through modulation of shared targets and neurodegenerative pathways. These findings demonstrate that integrating heterogeneous data modalities-from transcriptomics and chemical structure to protein-protein interaction networks and real-world clinical observations-can enable the discovery of repositioning candidates and risk-mitigating therapies. The study highlights the potential of multi-layered, data-driven strategies in constructing translational drug discovery frameworks aimed at both efficacy and safety.

DOI： 10.1254/fpj.25037

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

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