論文 - 座間味　義人

基礎研究と臨床研究の融合による薬剤性末梢神経障害に対する予防薬探索

新村 貴博, 座間味 義人, 川尻 雄大, 合田 光寛, 相澤 風花, 八木 健太, 石澤 有紀, 石澤 啓介

日本薬学会年会要旨集   141年会   27P02 - 198S   2021年3月

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記述言語：日本語   出版者・発行元：(公社)日本薬学会  

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COVID-19感染拡大に伴うオンライン型薬学実務実習の導入

相澤 風花, 座間味 義人, 濱野 裕章, 岡田 直人, 林 明希, 八木 健太, 合田 光寛, 桐野 靖, 中村 敏己, 石澤 啓介

日本薬学会年会要旨集   141年会   28P01 - 257   2021年3月

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記述言語：日本語   出版者・発行元：(公社)日本薬学会  

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

合田 光寛, 座間味 義人, 新村 貴博, 萱野 純史, 濱野 裕章, 岡田 直人, 相澤 風花, 八木 健太, 石澤 有紀, 桐野 靖, 中村 敏己, 石澤 啓介

日本薬学会年会要旨集   141年会   S21 - 3   2021年3月

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記述言語：日本語   出版者・発行元：(公社)日本薬学会  

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

内田 真美, 牛尾 聡一郎, 新村 貴博, 飛鷹 範明, 田中 亮裕, 北村 佳久, 千堂 年昭, 座間味 義人, 石澤 啓介, 武智 研志, 柴田 和彦, 難波 弘行, 川崎 博己, 高取 真吾

日本薬学会年会要旨集   141年会   GS04 - 5   2021年3月

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記述言語：日本語   出版者・発行元：(公社)日本薬学会  

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

Satoru Mitsuboshi, Takahiro Niimura, Yoshito Zamami

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

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記述言語：英語  

DOI： 10.1002/jcph.1756

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

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

Oncology   99 ( 4 )   1 - 4   2021年1月

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記述言語：英語  

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

DOI： 10.1159/000512633

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

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

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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.1007/s11060-020-03687-2

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

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

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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.1002/cam4.3587

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

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

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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.1248/bpb.b20-00609

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

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

Frontiers in medicine   8   660367 - 660367   2021年

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記述言語：英語  

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

DOI： 10.3389/fmed.2021.660367

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

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

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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.1248/bpb.b21-00165

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

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

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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.2152/jmi.68.71

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

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

Frontiers in pharmacology   12   655605 - 655605   2021年

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.3389/fphar.2021.655605

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

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

Frontiers in pharmacology   12   752174 - 752174   2021年

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.3389/fphar.2021.752174

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ラモトリギンの皮膚障害リスクに影響する因子の探索

宮田 晃志, 坂東 寛, 合田 光寛, 中馬 真幸, 新田 侑生, 田崎 嘉一, 吉岡 俊彦, 小川 淳, 座間味 義人, 濱野 裕章, 石澤 有紀, 石澤 啓介

日本臨床薬理学会学術総会抄録集   42   3-P-R-2   2021年

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記述言語：日本語   出版者・発行元：一般社団法人 日本臨床薬理学会  

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

DOI： 10.50993/jsptsuppl.42.0_3-p-r-2

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シスプラチン起因性腎障害の予防薬の同定

池田 康将, 濱野 裕章, 合田 光寛, 福島 圭穰, 岸 誠司, 中馬 真幸, 座間味 義人, 宮本 理人, 石澤 啓介, 藤野 裕道, 粟飯原 賢一, 土屋 浩一郎, 玉置 俊晃

日本薬理学会年会要旨集   94   2-O-D3-1   2021年

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記述言語：日本語   出版者・発行元：公益社団法人 日本薬理学会  

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

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

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

Conclusion: DPH may be a preventive medicine against CIN.

DOI： 10.1254/jpssuppl.94.0_2-o-d3-1

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シスプラチン誘発急性腎障害に対する各種5-HT₃受容体拮抗薬併用の影響

神田 将哉, 合田 光寛, 吉岡 俊彦, 吉田 愛美, 新村 貴博, 座間味 義人, 石澤 由紀, 八木 健太, 濱野 裕章, 岡田 直人, 石澤 啓介

日本薬理学会年会要旨集   94   1-Y-E2-1   2021年

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記述言語：日本語   出版者・発行元：公益社団法人 日本薬理学会  

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

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

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

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

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

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

DOI： 10.1254/jpssuppl.94.0_1-y-e2-1

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

西内 栞, 斎藤 広海, 新村 貴博, 座間味 義人, 合田 光寛, 八木 健太, 相澤 風花, 濱野 裕章, 石澤 有紀, 石澤 啓介

日本臨床薬理学会学術総会抄録集   42   2-P-H-7   2021年

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記述言語：日本語   出版者・発行元：一般社団法人 日本臨床薬理学会  

【目的】

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

【方法】

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

【結果】

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

【考察】

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

【結論】

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

DOI： 10.50993/jsptsuppl.42.0_2-p-h-7

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

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

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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.1016/j.kint.2020.10.041

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

Satoru Mitsuboshi, Takahiro Niimura, Yoshito Zamami, Keisuke Ishizawa

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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.1111/bcp.14688

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