Hamano Hirofumi, Ikeda Yasumasa, Goda Mitsuhiro, Fukushima Keijo, Kishi Seiji, Chuma Masayuki, Yamashita Michiko, Niimura Takahiro, Takechi Kenshi, Imanishi Masaki, Zamami Yoshito, Horinouchi Yuya, Izawa-Ishizawa Yuki, Miyamoto Licht, Ishizawa Keisuke, Fujino Hiromichi, Tamaki Toshiaki, Aihara Ken-Ichi, Tsuchiya Koichiro
Department of Pharmacy, Tokushima University Hospital, Tokushima, Japan.
Department of Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
Kidney Int. 2021 Apr;99(4):885-899. doi: 10.1016/j.kint.2020.10.041. Epub 2020 Dec 9.
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.
顺铂作为一种用于治疗实体瘤的抗肿瘤药物被广泛使用。不幸的是，它会导致肾毒性这一关键副作用，鉴于目前尚无针对顺铂诱导的肾毒性的预防药物，这限制了其使用。在此，基于对美国食品药品监督管理局不良事件报告系统的重新定位分析，我们发现一种先前开发的药物苯海拉明可能为顺铂诱导的肾毒性提供一种新的治疗方法。为了证实这一点，在体外和体内实验中评估了苯海拉明的实际疗效。苯海拉明抑制了顺铂诱导的肾近端小管细胞死亡。给予顺铂的小鼠出现了肾功能显著受损的肾损伤（平均血浆肌酐：0.43 vs 0.15 mg/dl），并表现出氧化应激增强、细胞凋亡增加、炎性细胞因子升高和丝裂原活化蛋白激酶激活。然而，这些症状大多通过苯海拉明治疗得到了抑制。此外，在苯海拉明治疗的小鼠中，肾脏中顺铂的浓度显著降低（平均铂含量：70.0 vs 53.4 μg/g干肾重）。重要的是，在任何体外或体内实验中，苯海拉明均未影响或干扰顺铂的抗肿瘤作用。在一个从1467例患者的回顾性数据库中选取的98例1:1匹配患者的队列中显示，在顺铂治疗前使用过苯海拉明的恶性肿瘤患者与未使用过的患者相比，急性肾损伤明显更少（分别为6.1% vs 22.4%）。因此，苯海拉明作为一种针对顺铂诱导的肾毒性的新型预防药物显示出了疗效。
