Faculty Profiles - ZAMAMI Yoshito

Papers - ZAMAMI Yoshito

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ドキソルビシン誘発心筋障害の予防薬探索

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

四国医学雑誌 79 ( 1-2 ) 139 - 139 2023.6

ドキソルビシン誘発心筋障害の予防薬探索

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

四国医学雑誌 79 ( 1-2 ) 139 - 139 2023.6

ためになる薬の話薬物相互作用(56-抗不整脈薬の薬物相互作用)

村尾卓哉, 江角悟, 濱野裕章, 村川公央, 座間味義人

岡山医学会雑誌 135 ( 1 ) 39 - 42 2023.4

Proton Pump Inhibitors and Rhabdomyolysis: Analysis of Two Different Cross-Sectional Databases. Reviewed International journal

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

The Annals of pharmacotherapy 57 ( 11 ) 10600280231156270 - 10600280231156270 2023.2

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

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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Effects of vonoprazan and proton pump inhibitors on the efficacy of bevacizumab: a multicentre retrospective study. Reviewed International journal

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

Clinical and experimental medicine 23 ( 6 ) 2799 - 2804 2023.2

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

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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Significance of UGT1A6, UGT1A9, and UGT2B7 genetic variants and their mRNA expression in the clinical outcome of renal cell carcinoma. Reviewed International journal

Jun Matsumoto, Anzu Nishimoto, Shogo Watari, Hideo Ueki, Shoya Shiromizu, Naohiro Iwata, Tatsuaki Takeda, Soichiro Ushio, Makoto Kajizono, Masachika Fujiyoshi, Toshihiro Koyama, Motoo Araki, Koichiro Wada, Yoshito Zamami, Yasutomo Nasu, Noritaka Ariyoshi

Molecular and cellular biochemistry 478 ( 8 ) 1779 - 1790 2022.12

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

UDP-glucuronosyltransferase (UGT) metabolizes a number of endogenous and exogenous substrates. Renal cells express high amounts of UGT; however, the significance of UGT in patients with renal cell carcinoma (RCC) remains unknown. In this study, we profile the mRNA expression of UGT subtypes (UGT1A6, UGT1A9, and UGT2B7) and their genetic variants in the kidney tissue of 125 Japanese patients with RCC (Okayama University Hospital, Japan). In addition, we elucidate the association between the UGT variants and UGT mRNA expression levels and clinical outcomes in these patients. The three representative genetic variants, namely, UGT1A6 541A > G, UGT1A9 i399C > T, and UGT2B7-161C > T, were genotyped, and their mRNA expression levels in each tissue were determined. We found that the mRNA expression of the three UGTs (UGT1A6, UGT1A9, and UGT2B7) are significantly downregulated in RCC tissues. Moreover, in patients with RCC, the UGT2B7-161C > T variant and high UGT2B7 mRNA expression are significantly correlated with preferable cancer-specific survival (CSS) and overall survival (OS), respectively. As such, the UGT2B7-161C > T variant and UGT2B7 mRNA expression level were identified as significant independent prognostic factors of CSS and CSS/OS, respectively. Taken together, these findings indicate that UGT2B7 has a role in RCC progression and may, therefore, represent a potential prognostic biomarker for patients with RCC.

DOI： 10.1007/s11010-022-04637-4

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Differential effects of proton pump inhibitors and vonoprazan on vascular endothelial growth factor expression in cancer cells. Reviewed International journal

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

Drug development research 84 ( 1 ) 75 - 83 2022.12

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

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

Takahiro Niimura, Yoshito Zamami, Koji Miyata, Takahisa Mikami, Mizuho Asada, Keijo Fukushima, Masaki Yoshino, Satoru Mitsuboshi, Naoto Okada, Hirofumi Hamano, Takumi Sakurada, Rie Matsuoka-Ando, Fuka Aizawa, Kenta Yagi, Mitsuhiro Goda, Masayuki Chuma, Toshihiro Koyama, Yuki Izawa-Ishizawa, Hiroaki Yanagawa, Hiromichi Fujino, Yoshihiro Yamanishi, Keisuke Ishizawa

Journal of clinical pharmacology 63 ( 4 ) 473 - 479 2022.12

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

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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大規模医療情報解析を活用したシスプラチン誘発急性腎障害に対する予防薬の探索

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

四国医学雑誌 78 ( 5-6 ) 249 - 250 2022.12

医療ビッグデータ解析と基礎研究を融合した研究手法によるハイブリッド創薬

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

日本臨床薬理学会学術総会抄録集 43回 3 - 4 2022.12

Polypharmacy in Older Adults with Alzheimer's Disease. International journal

Satoru Esumi, Soichiro Ushio, Yoshito Zamami

Medicina (Kaunas, Lithuania) 58 ( 10 ) 2022.10

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

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

DOI： 10.3390/medicina58101445

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

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

Basic & clinical pharmacology & toxicology 131 ( 6 ) 525 - 535 2022.9

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

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

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

Pediatric Blood & Cancer 69 ( 12 ) e29979 2022.9

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

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

DOI： 10.1002/pbc.29979

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/pbc.29979

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

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

Clinical and translational science 15 ( 12 ) 2982 - 2988 2022.9

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

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

有木沙織, 牛尾聡一郎, 村川公央, 座間味義人

JOHNS 38 ( 9 ) 1168 - 1171 2022.9

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

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

European urology focus 9 ( 1 ) 141 - 144 2022.7

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

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

Toshihiro Koyama, Tsukasa Higashionna, Akinori Maruo, Soichiro Ushio, Yoshito Zamami, Ko Harada, Hideharu Hagiya

Geriatrics & gerontology international 22 ( 8 ) 675 - 680 2022.6

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

AIM: Amid the global aging, an establishment of healthcare policies for the aged population is a common issue to be addressed. However, few studies on centenarians have reported place and cause of death (PoD and CoD, respectively) as indicators of end-of-life care quality. This study aimed to analyze trends in PoD and CoD among centenarians in Japan. METHODS: Data from death certificates from Japanese vital statistics were analyzed; 205 513 deaths occurred among centenarians (aged ≥100 years) in Japan during the period from 2006 to 2016. PoD prevalence was calculated for each CoD. Trends in PoD prevalence were analyzed using the Joinpoint regression model. Changing points, annual percentage changes, and average annual percentage changes (AAPCs) were calculated to examine trends. RESULTS: The number of deaths more than doubled from 10 340 in 2006 to 26 427 in 2016. PoDs were composed of hospitals (52.7%), nursing homes (31.4%), own homes (13.6%) and others (2.2%). Dementia and old age increased rapidly as CoD. Proportions of hospital and home deaths decreased, with AAPCs of -2.3% (95% confidence interval [CI], -2.6 to -1.9) and -2.3% (95% CI, -3.2 to -1.4), respectively. Conversely, the proportion of deaths in nursing homes rapidly increased, with an AAPC of 6.8% (95% CI, 6.0-7.7). CONCLUSIONS: The results revealed changes in PoD among centenarians in Japan. Understanding these transitions is indispensable for health policy in aging societies. Geriatr Gerontol Int 2022; ••: ••-••.

DOI： 10.1111/ggi.14416

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

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

血管 45 ( 1 ) 62 - 62 2022.6

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

血管 45 ( 1 ) 62 - 62 2022.6

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

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

European journal of pharmacology 928 175083 - 175083 2022.5

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

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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Papers - ZAMAMI Yoshito