キシ　セイジ   Seiji Kishi   岸　誠司    所属   川崎医科大学  医学部 臨床医学　腎臓・高血圧内科学    職種   特任准教授
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Diphenhydramine may be a preventive medicine against cisplatin-induced kidney toxicity.
掲載誌名	正式名：Kidney international 略　 称：Kidney Int ISSNコード：15231755/00852538
掲載区分	国外
巻・号・頁	99(4),pp.885-899
著者・共著者	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
発行年月	2021/04
概要	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
PMID	33307103