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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

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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

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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

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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

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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

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Pharmaceutical Society of Japan  

Although myocarditis is listed as a serious adverse reaction in the package inserts of mesalazine and some other anti-ulcerative colitis (UC) drugs currently in use, and regulatory authorities have issued related warnings, the detailed characteristics of anti-UC drug-induced myocarditis remain unknown. We aimed to investigate the association between UC drugs and myocarditis development as an adverse event and its characteristics using data from a spontaneous adverse drug reaction reporting database. We searched for adverse event signals of five drugs, mesalazine, sulfasalazine, azathioprine, mercaptopurine, and budesonide, listed in the treatment guidelines for UC, using VigiBase. The information component was calculated, and a signal was considered present when the lower limit of the 95% confidence interval of the information component exceeded zero. The total number of VigiBase and myocarditis (as a target adverse event) reports was 38459016 and 71571, respectively. No trend was identified based on age or sex. Analysis of the five UC drugs for severity in VigiBase showed that most patients recovered, with a low reported mortality rate. However, the time to onset of adverse drug reactions varied among the drugs. Mesalazine signals were detected regardless of age or sex. This finding suggests that myocarditis, an adverse event, may be a potential complication regardless of patient characteristics. Our results also indicate that UC itself may induce myocarditis. Our findings warrant multifaceted investigations, including basic and clinical studies, on the characteristics of each drug regarding the development of myocarditis as an adverse event.

DOI： 10.1248/bpb.b24-00766

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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

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Background/Objectives: The risk of fractures associated with immune checkpoint inhibitors (ICIs) is increasing; however, the relationship between fracture risk and potential factors, such as osteoporosis and hyperthyroidism, remains unclear. Methods: Using VigiBase, the World Health Organization's global pharmacovigilance database, we investigated the signals for osteoporosis, hyperthyroidism, and fractures associated with ICIs (nivolumab, pembrolizumab, atezolizumab, durvalumab, ipilimumab, and tremelimumab) by calculating information components (ICs) and their 95% confidence intervals (CIs). Furthermore, we estimated the association between the occurrence of fractures in patients receiving ICIs and osteoporosis or hyperthyroidism. Results: Signals of hyperthyroidism (IC = 4.66, 95% CI: 4.58-4.73), but not osteoporosis (IC = -1.79, 95% CI: -2.22 to -1.36) or fractures (IC = -0.21, 95% CI: -0.36 to -0.06), were detected in patients using ICIs. Osteoporosis (odds ratio: 118.00, 95% CI: 61.00-230.00) was associated with an increased reporting frequency of fractures related to ICIs, whereas hyperthyroidism (odds ratio: 0.60, 95% CI: 0.19-1.87) was not associated with such an increase. Conclusions: The VigiBase analysis indicates that the use of ICIs does not increase the reporting frequency of osteoporosis or fractures. Additionally, hyperthyroidism did not increase the reporting frequency of fractures associated with ICIs.

DOI： 10.3390/ph18030333

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：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

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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

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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

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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

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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

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：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

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Other Link： https://link.springer.com/article/10.1007/s00228-024-03767-6/fulltext.html

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BACKGROUND: Despite the global use of trastuzumab biosimilars, concerns remain regarding their efficacy and safety. In particular, when used concurrently with pertuzumab, trastuzumab biosimilars lack extensive real-world data and safety information. Additionally, as cancer drug expenditures continue to rise worldwide, cost savings from biosimilars have become increasingly important. OBJECTIVE: This study aims to assess the safety, efficacy, and cost effectiveness of trastuzumab originators and their biosimilars in real-world clinical settings, focusing on a large patient population. METHODS: The analysis included 31,661 patients with HER2-positive breast cancer from the Medical Data Vision Co., Ltd. database in Japan. Additionally, adverse event reports for the trastuzumab originator and its biosimilars were obtained for 58,799 patients from the World Health Organization's VigiBase, the global adverse event reporting database. RESULTS: No significant differences were observed in heart failure hospitalizations, liver dysfunction, or infusion reaction rates in both the Medical Data Vision Co., Ltd. database and the World Health Organization's VigiBase. In the Medical Data Vision Co., Ltd. database, the addition of pertuzumab did not significantly influence the incidence of adverse events, and the use of biosimilars significantly reduced medical costs, with no significant difference in breast cancer recurrence rates. CONCLUSIONS: By analyzing two large and diverse datasets from multiple perspectives, we obtained reliable results that the trastuzumab originator and its biosimilars have similar safety profiles. The concurrent use of pertuzumab was also found to be safe. The use of biosimilars can lead to cost savings. These findings provide crucial insights for the evaluation and adoption of biosimilars in clinical practice.

DOI： 10.1007/s40259-024-00686-x

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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

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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

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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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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

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J-GLOBAL

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Language：Japanese   Publisher：(一社)日本臨床腫瘍薬学会  

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Language：Japanese   Publisher：(一社)日本臨床腫瘍薬学会  

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Language：Japanese   Publisher：日本ジェネリック医薬品・バイオシミラー学会  

J-GLOBAL

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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

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Language：Japanese   Publisher：(公社)日本薬学会  

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Other Link： 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

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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

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Language：Japanese   Publisher：(一社)日本臨床薬理学会  

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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

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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

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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

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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

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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

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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

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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

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Authorship：Corresponding author   Language：English  

DOI： 10.1002/ijc.34767

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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

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<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

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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

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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

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DOI： 10.1016/j.jinf.2023.06.011

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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

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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

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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

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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

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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

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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

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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

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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

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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.

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This study was undertaken to identify baseline conditions and triggering factors for skeletal-related events (SRE) in multiple myeloma (MM) patients treated with denosumab. During the median follow-up of 17 months, SRE occurred in 6 out of 52 newly diagnosed patients and in 5 out of 23 relapsed/refractory patients. Bone fractures occurred by falling down due to orthostatic hypotension and/or muscle weakness in three out of four cases with amyloid light-chain (AL) amyloidosis. A loss of balance and falling down appear to be triggering factors for SRE, especially in frail MM patients with AL amyloidosis, indicating the importance of retaining physical functions to prevent SRE.

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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

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DOI： 10.1254/jpssuppl.95.0_1-ss-48

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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

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【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

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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

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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

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

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DOI： 10.1111/cts.13045

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DOI： 10.50993/jsptsuppl.42.0_2-p-h-7

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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

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Language：Japanese   Publisher：一般社団法人 日本臨床薬理学会  

DOI： 10.50993/jsptsuppl.42.0_3-p-r-2

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Language：Japanese   Publisher：日本腎臓病薬物療法学会  

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Other Link： 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=http%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

Language：Japanese   Publisher：(一社)日本臨床救急医学会  

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<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

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<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

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<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

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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

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Language：English   Publishing type：Research paper, summary (international conference)  

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