Renin-Angiotensin-Aldosterone System Inhibitors Prevent the Onset of Oxaliplatin-Induced Peripheral Neuropathy: A Retrospective Multicenter Study and <i>in Vitro</i> Evaluation
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- Uchida Mami
- Department of Clinical Pharmacy, College of Pharmaceutical Sciences, Matsuyama University
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- Ushio Soichiro
- Department of Pharmacy, Okayama University Hospital
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- Niimura Takahiro
- Department of Clinical Pharmacology and Therapeutics, Tokushima University Graduate School of Biomedical Sciences Department of Pharmacy, Tokushima University Hospital
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- Takechi Kenshi
- Department of Clinical Pharmacy, College of Pharmaceutical Sciences, Matsuyama University
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- Kawazoe Hitoshi
- Division of Pharmaceutical Care Sciences, Center for Social Pharmacy and Pharmaceutical Care Sciences, Keio University Faculty of Pharmacy
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- Hidaka Noriaki
- Division of Pharmacy, Ehime University Hospital
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- Tanaka Akihiro
- Division of Pharmacy, Ehime University Hospital
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- Araki Hiroaki
- Division of Pharmacy, Ehime University Hospital
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- Zamami Yoshito
- Department of Clinical Pharmacology and Therapeutics, Tokushima University Graduate School of Biomedical Sciences Division of Pharmacy, Ehime University Hospital
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- Ishizawa Keisuke
- Department of Clinical Pharmacology and Therapeutics, Tokushima University Graduate School of Biomedical Sciences Division of Pharmacy, Ehime University Hospital
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- Kitamura Yoshihisa
- Department of Pharmacotherapy, School of Pharmacy, Shujitsu University
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- Sendou Toshiaki
- Department of Pharmacy, Okayama University Hospital
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- Kawasaki Hiromu
- Department of Clinical Pharmacy, College of Pharmaceutical Sciences, Matsuyama University
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- Namba Hiroyuki
- Department of Clinical Pharmacy, College of Pharmaceutical Sciences, Matsuyama University
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- Shibata Kazuhiko
- Department of Clinical Pharmacy, College of Pharmaceutical Sciences, Matsuyama University
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- Tanaka Mamoru
- Division of Pharmaceutical Care Sciences, Center for Social Pharmacy and Pharmaceutical Care Sciences, Keio University Faculty of Pharmacy
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- Takatori Shingo
- Department of Clinical Pharmacy, College of Pharmaceutical Sciences, Matsuyama University
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<p>Oxaliplatin (OXA) is used in chemotherapy for various cancer types and is associated with acute and chronic neurotoxicity. However, a preventive strategy for OXA-induced peripheral neuropathy (OIPN) and its underlying mechanism remain unclear. We examined the effects of renin-angiotensin-aldosterone system inhibitors (RAASIs) on OIPN by performing a retrospective multicenter study and an in vitro assay. We retrospectively evaluated electronic medical records of 976 patients who underwent one or more courses of OXA-containing regimens at Ehime, Okayama, and Tokushima University Hospitals. The primary endpoint was the incidence of OIPN during or after OXA administration. The effects of RAASIs and OXA on the neurite length in PC12 cells were determined. The combined administration of an OXA-containing regimen and RAASI significantly inhibited the cumulative incidence grade-2 or higher OIPN (log-rank test; p = 0.0001). RAASIs markedly suppressed the development of both acute and chronic OIPN (multivariate analysis; p = 0.017 and p = 0.011). In an in vitro assay, 10 µM OXA suppressed the neurite length; treatment with 1 µM aliskiren, spironolactone, 10 µM candesartan, and enalapril significantly restored neurite length to the control level. Moreover, 1 µM SCH772984 (a selective inhibitor of extracellular signal-regulated kinase, ERK1/2) and 500 µM SQ22536 (a cell-permeable adenylate cyclase (AC) inhibitor) markedly abolished neurite-extending effects of candesartan and enalapril. These results indicate that RAASIs possess preventive or therapeutic effects in acute and chronic OIPN, candesartan and enalapril may increase in the activity of ERK1/2 and AC in PC12 cells.</p>
収録刊行物
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- Ｂｉｏｌｏｇｉｃａｌ ＆ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｂｕｌｌｅｔｉｎ
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Ｂｉｏｌｏｇｉｃａｌ ＆ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｂｕｌｌｅｔｉｎ 45 (2), 226-234, 2022-02-01
公益社団法人 日本薬学会
