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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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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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.

DOI： 10.1016/j.euf.2022.07.003

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

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

DOI： 10.1016/j.ejphar.2022.175083

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

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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.

DOI： 10.1002/jha2.402

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

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

DOI： 10.1111/cts.13282

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

DOI： 10.1007/s10639-022-11032-5

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Language：Japanese   Publisher：徳島医学会  

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

DOI： 10.1093/oncolo/oyab077

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

DOI： 10.1093/cid/ciac128

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER  

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

DOI： 10.1016/j.biopha.2022.112744

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

In April 2018, the Clinical Trials Act pertaining to investigator-initiated clinical trials was passed in Japan. The purpose of this study was to investigate activity in investigator-initiated clinical studies before and after enforcement of the new Clinical Trials Act. This was done by analysing the records of the Ethics Committee of Tokushima University Hospital, which reviews studies based on the Japanese government's Ethical Guidelines for Medical and Health Research Involving Human Subjects prior to the Clinical Trials Act, and records of the Certified Review Board established at Tokushima University under the Clinical Trials Act in 2018. The number of new applications to these two review boards during fiscal years 2015-2017 (pre-Act) and fiscal years 2018 and 2019 (post-Act) were used as an indicator of activity in investigator-initiated clinical studies. The number of new applications to the Ethics Committee was 303, 261, 316, 303, and 249 in 2015, 2016, 2017, 2018, and 2019, respectively. The data show that the total number of new interventional studies decreased from 50.3 in average in 2015-2017 (pre-Act) to 42 in 2018 and 40 in 2019 (post-Act), respectively. These results suggest that fewer interventional studies were started following enforcement of the new Clinical Trials Act. To confirm this trend and identify contributing factors, further studies are required. In addition, possible way, such as broader contribution of clinical research coordinators, to promote clinical studies in the new Clinical Trials Act era should be examined.

DOI： 10.1248/bpb.b21-00753

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

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

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

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

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

DOI： 10.1016/j.clinthera.2021.09.007

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

BACKGROUND: Cisplatin is widely used as an antitumor drug for the treatment of solid tumors. However, its use has been limited owing to nephrotoxicity, a major side effect. The mechanism of cisplatin-induced nephrotoxicity (CIN) has long been investigated in order to develop preventive/therapeutic drugs. Ferroptosis is a newly identified form of non-apoptotic regulated cell death induced by iron-mediated lipid peroxidation and is involved in the pathophysiology of various diseases. In this study, we examined the role of ferroptosis in CIN. METHODS: We evaluated the role of ferroptosis in CIN by in vivo experiments in a mouse model. RESULTS: Cisplatin increased the protein expressions of transferrin receptor-1 and ferritin, and iron content in the kidney of mice. In addition, treatment with cisplatin augmented renal ferrous iron and hydroxyl radical levels with co-localization. Mice administered cisplatin demonstrated kidney injury, with renal dysfunction and increased inflammatory cytokine expression; these changes were ameliorated by Ferrostatin-1 (Fer-1), an inhibitor of ferroptosis. The expression of the ferroptosis markers, COX2 and 4-hydroxynonenal (4-HNE), increased with cisplatin administration, and decreased with the administration of Fer-1. By contrast, cisplatin-induced apoptosis and necroptosis were inhibited by treatment with Fer-1. Moreover, deferoxamine, an iron chelator, also inhibited CIN, with a decrease in the expression of COX-2 and 4-HNE. CONCLUSION: Ferroptosis is involved in the pathogenesis of CIN and might be used as a new preventive target for CIN.

DOI： 10.1016/j.jtemb.2021.126798

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DOI： 10.1016/j.kint.2021.01.009

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

DOI： 10.1016/j.kint.2020.10.041

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DOI： 10.1016/j.kint.2021.01.009

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

DOI： 10.1002/cam4.3587

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

DOI： 10.1248/bpb.b20-00609

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

DOI： 10.1248/bpb.b21-00165

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

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

DOI： 10.3389/fphar.2021.655605

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

DOI： 10.3389/fphar.2021.752174

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

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

DOI： 10.1016/j.toxlet.2019.10.016

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

DOI： 10.1007/s00125-020-05153-0

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Language：Japanese   Publisher：Japanese Pharmacological Society  

<p>OBJECTIVE: Cisplatin (CDDP) is known to frequently cause nausea and vomiting, renal injury as a side effect. There are many kinds of 5-HT3 receptor antagonists, which are one of the basic antiemetic drugs for nausea and vomiting by cancer chemotherapy, such as the first generation ondansetron, granisetron, the second generation palonosetron. It is suggested that ondansetron may be a risk factor for the onset of CDDP-induced acute kidney injury (AKI). Therefore, in this study, the effect of various 5-HT3 receptor antagonists on CDDP-induced renal injury was examined.</p><p>METHODS: C57BL/6 mice were intraperitoneally administered with CDDP. Renal function was evaluated by serum creatinine and blood urea nitrogen. Histological damage in the cortex of HE‐stained kidney sections was scored. Various 5-HT3 receptor antagonists were administered 30 minutes before administration of CDDP.</p><p>RESULTS: CDDP-induced renal injury got significantly worse by pre-administration of ondansetron, but not by pretreatment of palonosetron compared with cisplatin alone group. </p><p>CONCLUSIONS: These results suggest that the second generation 5-HT3 receptor antagonist may have less effect on CDDP‐induced AKI than the first generation.</p>

DOI： 10.1254/jpssuppl.92.0_1-P-102

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

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

DOI： 10.1007/s00228-019-02756-4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：FEDERATION AMER SOC EXP BIOL  

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

DOI： 10.1096/fj.201802724RR

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DOI： 10.1111/bjh.15837

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

DOI： 10.1002/cam4.1920

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

DOI： 10.1007/s00520-018-4367-y

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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A history of hypertension is a known risk factor for delirium in patients in intensive care units, but the effect of antihypertensive agents on delirium development is unclear. Nicardipine, a calcium channel blocker, is widely used in ICU as a treatment agent for hypertensive emergency. This study investigated the relationship between the administration of nicardipine hydrochloride and delirium development in patients under mechanical ventilation. We conducted a medical chart review of 103 patients, who were divided into two groups according to the use of nicardipine hydrochloride. The prevalence of delirium was compared with respect to factors such as age, sex, laboratory data, and medical history, by multivariate analysis. 21 patients (20.4 %) were treated with nicardipine hydrochloride in 103 patients. The treatment and non-treatment groups differed significantly in age (72 vs. 65 years) and history of high blood pressure (57% vs. 11%). Multivariate analysis revealed that patients in the treatment group developed delirium significantly less often than those in the non-treatment group (19% vs. 48%). These results suggested that treatment of high blood pressure with nicardipine hydrochloride is a possible method for preventing the development of delirium.

DOI： 10.1691/ph.2018.8711

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

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

DOI： 10.1038/s41598-018-29008-2

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

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

DOI： 10.1093/ndt/gfx252

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Language：English   Publisher：ELSEVIER SCIENCE INC  

DOI： 10.1016/j.freeradbiomed.2017.10.323

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

Renal anemia is a major complication in chronic kidney disease (CKD). Iron supplementation, as well as erythropoiesis-stimulating agents, are widely used for treatment of renal anemia. However, excess iron causes oxidative stress via the Fenton reaction, and iron supplementation might damage remnant renal function including erythropoietin (EPO) production in CKD. EPO gene expression was suppressed in mice following direct iron treatment. Hypoxia-inducible factor 2 alpha (HIF-2 alpha), a positive regulator of the EPO gene, was also diminished in the kidney of mice following iron treatment. Anemia-induced increase in renal EPO and HIF-2 alpha expression was inhibited by iron treatment. In in vitro experiments using EPO-producing HepG2 cells, iron stimulation reduced the expression of the EPO gene, as well as HIF-2 alpha. Moreover, iron treatment augmented oxidative stress, and iron-induced reduction of EPO and HIF-2 alpha expression was restored by tempol, an antioxidant compound. HIF-2 alpha interaction with the Epo promoter was inhibited by iron treatment, and was restored by tempol. These findings suggested that iron supplementation reduced EPO gene expression via an oxidative stress-HIF-2 alpha-dependent signaling pathway.

DOI： 10.1038/labinvest.2017.11

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

Increased proteinuria causes tubulointerstitial injury due to inflammation in chronic kidney disease (CKD). Iron restriction exhibits protective effects against renal dysfunction; however, its effects against protein overload-induced tubulointerstitial damage remain unclear. Here, we investigated dietary iron restriction effect on tubulointerstitial damage in mice with protein-overload tubulointerstitial injury. Renal tubulointerstitial injury in animal model was induced by intraperitoneal injection of an overdose of bovine serum albumin (BSA). We divided mice into three groups: normal saline + normal diet (ND), BSA + ND, and BSA + iron-restricted diet (IRD). BSA overload induced renal tubulointerstitial injury in the ND mice, which was ameliorated in the IRD mice. Inflammatory cytokines and extracellular matrix mRNA expression was upregulated in BSA + ND mice kidneys and was inhibited by IRD. BSA-induced increase in renal superoxide production, NADPH oxidase activity, and p22(phox) expression was diminished in the IRD mice. IRD suppression increased BSA-induced renal macrophage infiltration. Moreover, BSA mice exhibited nucleotide-binding oligomerisation domain-like receptor pyrin domain-containing protein (NLRP) inflammasome activation, which was inhibited by IRD. Ferrous iron increased in kidneys with BSA overload and was inhibited by IRD. Thus, iron restriction inhibited oxidative stress and inflammatory changes, contributing to the protective effect against BSA overload-induced tubulointerstitial injury.

DOI： 10.1038/s41598-017-11089-0

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An automatic ultrasonic-testing apparatus has been developed for integral-type crankshafts used in four-stroke engines for marine and power-plant industries. The apparatus adopts a unique phased-array technique applicable to fillets and comprises a scanning mechanism that enables its probe to rotatably follow the surfaces of eccentric shafts, while maintaining stable scanning pitch and coupling. The defect detectability has turned out to be f0.5 mm flat-bottom hole (FBH) at depths down to 50 mm.

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Authorship：Lead author   Language：English   Publisher：JAPANESE PHARMACOLOGICAL SOC  

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Language：English   Publisher：JAPANESE PHARMACOLOGICAL SOC  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER GMBH, URBAN & FISCHER VERLAG  

Skeletal muscle wasting or sarcopenia is a critical health problem. Skeletal muscle atrophy is induced by an excess of iron, which is an essential trace metal for all living organisms. Excessive amounts of iron catalyze the formation of highly toxic hydroxyl radicals via the Fenton reaction. However, the molecular mechanism of iron-induced skeletal muscle atrophy has remained unclear. In this study, 8-weeks-old C57BL6/J mice were divided into 2 groups: vehicle-treated group and the iron-injected group (10 mg iron day(-1) mouse(-1)) during 2 weeks. Mice in the iron-injected group showed an increase in the iron content of the skeletal muscle and serum and ferritin levels in the muscle, along with reduced skeletal muscle mass. The skeletal muscle showed elevated mRNA expression of the muscle atrophy-related E3 ubiquitin ligases, atrogin-1 and muscle ring finger-1(MuRF1), on days 7 and 14 of iron treatment. Moreover, iron-treated mice showed reduced phosphorylation of Akt and forkhead box 03 (FOXO3a) in skeletal muscles. Inhibition of FOXO3a using siRNA in vitro in C2C12 myotube cells inhibited iron-induced upregulation of atrogin-1 and MuRF1 and reversed the reduction in myotube diameters. Iron-load caused oxidative stress, and an oxidative stress inhibitor abrogated iron-induced muscle atrophy by reactivating the Akt-FOXO3a pathway. Iron-induced skeletal muscle atrophy is suggested to involve the E3 ubiquitin ligase mediated by the reduction of Akt-FOXO3a signaling by oxidative stress. (C) 2016 Elsevier GmbH. All rights reserved.

DOI： 10.1016/j.jtemb.2016.01.011

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Low serum bilirubin levels are associated with the risk of cardiovascular diseases including peripheral artery disease. Bilirubin is known to exert its property such as antioxidant effect or the enhancement of flow-mediated vasodilation, however, bilirubin action on angiogenesis remains unclear. To investigate the molecular mechanism of bilirubin on angiogenic effect, we first employed C57BL/6J mice with unilateral hindlimb ischemia surgery and divided the mice into two groups (vehicle-treated group and bilirubin-treated group). The analysis of laser speckle blood flow demonstrated the enhancement of blood flow recovery in response to ischemia of mice with bilirubin treatment. The density of capillaries was significantly higher in ischemic-adductor muscles of bilirubin-treated mice. The phosphorylated levels of endothelial nitric oxide synthase (eNOS) and Akt were increased in ischemic skeletal muscles of mice with bilirubin treatment compared with vehicle treatment. In in vitro experiments by using human aortic endothelial cells, bilirubin augmented eNOS and Akt phosphorylation, cell proliferation, cell migration and tube formation. These bilirubin actions on endothelial cell activation were inhibited by LY294002, a phosphatidylinositol 3-kinase inhibitor. In conclusion, bilirubin promotes angiogenesis through endothelial cells activation via Akt-eNOS-dependent manner.

DOI： 10.1038/hr.2015.74

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

While gene knockout technology can reveal the roles of proteins in cellular functions, including in mast cells, fetal death due to gene manipulation frequently interrupts experimental analysis. We generated mast cells from mouse fetal liver (FLMC), and compared the fundamental functions of FLMC with those of bone marrow-derived mouse mast cells (BMMC). Under electron microscopy, numerous small and electron-dense granules were observed in FLMC. In FLMC, the expression levels of a subunit of the FcεRI receptor and degranulation by IgE cross-linking were comparable with BMMC. By flow cytometry we observed surface expression of c-Kit prior to that of FcεRI on FLMC, although on BMMC the expression of c-Kit came after FcεRI. The surface expression levels of Sca-1 and c-Kit, a marker of putative mast cell precursors, were slightly different between bone marrow cells and fetal liver cells, suggesting that differentiation stage or cell type are not necessarily equivalent between both lineages. Moreover, this indicates that phenotypically similar mast cells may not have undergone an identical process of differentiation. By comprehensive analysis using the next generation sequencer, the same frequency of gene expression was observed for 98.6% of all transcripts in both cell types. These results indicate that FLMC could represent a new and useful tool for exploring mast cell differentiation, and may help to elucidate the roles of individual proteins in the function of mast cells where gene manipulation can induce embryonic lethality in the mid to late stages of pregnancy. © 2013 Fukuishi et al.

DOI： 10.1371/journal.pone.0060837

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

The spatial contact of immune cells is predominant machinery for the modulation of local inflammatory sites as much as humoral regulation is for inflammation. In this study, we investigated the role of mast cells in the regulation of invariant natural killer T cells (iNKTs) functions. Co-cultivation of bone-marrow derived mouse mast cells (BMMCs) with purified and stimulated mouse iNKTs caused marked suppression of interleukin (IL)-4 but not interferon (IFN)-gamma production in iNKTs. Suppression was accompanied by down-regulation of IL-4 mRNA expression. The Notch intracellular cytoplasmic domain in iNKTs was also completely diminished by co-cultivation with BMMCs. Suppressed IL-4 production was recovered when iNKTs were separately co-cultured with BMMCs using the transwell system. Furthermore, co-culture of iNKTs with activated BMMCs elicited partial suppression of IL-4 production. These findings suggest that mast cells modulate the function of iNKTs via the inhibition of Notch signaling.

DOI： 10.1248/jhs.57.197

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Language：Japanese   Publisher：(一社)日本医薬品情報学会  

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Language：Japanese   Publisher：日本心脈管作動物質学会  

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Language：Japanese   Publisher：徳島医学会  

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Language：Japanese   Publisher：Japanese Pharmacological Society  

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

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

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

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

DOI： 10.1254/jpssuppl.95.0_1-ss-48

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Language：Japanese   Publisher：Japanese Pharmacological Society  

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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Language：Japanese   Publisher：Japanese Pharmacological Society  

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

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

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

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

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

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

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

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

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

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

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

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

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

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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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Nausea, vomiting, and renal injury are the common adverse effects associated with cisplatin. Cisplatin is excreted via the multidrug and toxin release (MATE) transporter, and the involvement of the MATE transporter in cisplatin-induced kidney injury has been reported. The MATE transporter is also involved in the excretion of ondansetron, but the effects of 5-HT3 receptor antagonists used clinically for cisplatin-induced renal injury have not been elucidated. Therefore, the aim of this study was to investigate the effects of 5-HT3 receptor antagonists in a mouse model of cisplatin-induced kidney injury and to validate the results using medical big data analysis of more than 1.4 million reports and a survey of 3000 hospital medical records. The concomitant use of a first-generation 5-HT3 receptor antagonist (ondansetron, granisetron, or ramosetron) significantly increased cisplatin accumulation in the kidneys and worsened renal damage. Conversely, the concomitant use of palonosetron had no effect on renal function compared with the use of cisplatin alone. Furthermore, an analysis of data from the US Food and Drug Administration Adverse Event Reporting System and retrospective medical records revealed that the combination treatment of cisplatin and a first-generation 5-HT3 receptor antagonist significantly increased the number of reported renal adverse events compared with the combination treatment of cisplatin and a second-generation 5-HT3 receptor antagonist. These results suggest that compared with the first-generation antagonists, second-generation 5-HT3 receptor antagonists do not worsen cisplatin-induced acute kidney injury. The findings should be validated in a prospective controlled trial before implementation in clinical practice.Study HighlightsWHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?The involvement of the multidrug and toxin release (MATE) transporter in cisplatin-induced kidney injury has been reported. The MATE transporter is involved in the excretion of not only cisplatin but also ondansetron, a 5-HT3 receptor antagonist used as an antiemetic; however, the effects of 5-HT3 receptor antagonists used clinically for cisplatin-induced renal injury have not been elucidated.WHAT QUESTION DID THIS STUDY ADDRESS?The aim of this study was to investigate the effects of 5-HT3 receptor antagonists in a mouse model of cisplatin-induced kidney injury and to validate the results using medical big data analysis of more than 1.4 million reports and a survey of 3000 hospital medical records.WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?The results suggest that compared with the first-generation antagonists, second-generation 5-HT3 receptor antagonists do not worsen cisplatin-induced acute kidney injury.HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?Promoting the use of second-generation 5-HT3 receptor antagonists is expected to reduce the number of patients who develop cisplatin-induced renal damage.

DOI： 10.1111/cts.13045

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Aortic dissection (or dissecting aortic aneurysm) is a condition in which the aortic wall is separated into two layers at the medial level to form a pseudocavity. The intima crack, called the "entry", allows blood to tear through the medial layer and flow in. The location of the "entry" and the extent of the dissection can cause a variety of serious complications, including rupture, cardiac tamponade, and obstruction of branched vessels. According to the Guideline on Diagnosis and Treatment of Aortic Aneurysm and Aortic Dissection 2020, it is estimated that 61.4% of the onset of dissection die before arrival at the hospital, and 93% will die within 24 hours after the onset. It has been suggested that the morbidity rate has been increasing in recent years. Since many of them have a fatal prognosis, it is an important issue to prevent the onset itself. However, no effective therapeutic agent or preventive strategy has been established so far. The first reason is that it is extremely difficult to design clinical studies because aortic dissection traced the rapid onset and progression. The second is that the pathophysiology and preventive drug search are not sufficiently conducted even at the basic research level. Epidemiologically, the results of the International Registry of Aortic Dissection (IRAD) revealed that aging, hypertension, atherosclerosis, and hereditary connective tissue diseases are risk factors. The aortic aneurysm also shows similar pathological conditions caused by these risk factors. However, one of the major differences between aneurysm and dissection is the presence of aortic intima rupture. Therefore, we attempted to establish a mouse model developing dissection at a high rate by adding the endothelial dysfunction to a pharmacologically induced aortic aneurysm model mouse. Furthermore, we evaluated the efficacy of pitavastatin and several nutrients using our novel model mice and verified its usefulness as a model animal.

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【目的】

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

【方法】

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

【結果】

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

【考察】

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

【結論】

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

DOI： 10.50993/jsptsuppl.42.0_2-p-h-7

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

DOI： 10.50993/jsptsuppl.42.0_3-p-r-2

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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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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：FEDERATION AMER SOC EXP BIOL  

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Web of Science

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Language：Japanese   Publisher：(一社)日本腎臓学会  

J-GLOBAL

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Language：Japanese   Publisher：日本心脈管作動物質学会  

J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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Language：Japanese   Publisher：徳島医学会  

J-GLOBAL

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J-GLOBAL

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

J-GLOBAL

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

J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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Language：Japanese   Publisher：徳島県立図書館  

CiNii Article

CiNii Books

J-GLOBAL

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Language：Japanese   Publisher：(公社)日本薬理学会  

J-GLOBAL

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

J-GLOBAL

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

J-GLOBAL

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Author：Myself 

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