Diphenhydramine may be a preventive medicine against cisplatin-induced kidney toxicity
Diphenhydramine may be a preventive medicine against cisplatin-induced kidney toxicity
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DOI：
10.1016/j.kint.2020.10.041
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发表时间：
2021-03-18
影响因子：
19.6
通讯作者：
Tsuchiya, Koichiro
中科院分区：
文献类型：
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作者：
Hamano, Hirofumi;Ikeda, Yasumasa;Tsuchiya, Koichiro
顺铂被广泛用作治疗实体瘤的抗肿瘤药物。不幸的是，它导致肾毒性作为一个关键的副作用，限制了其使用，因为目前没有预防药物对顺铂诱导的肾毒性。在这里，基于对美国食品和药物管理局不良事件报告系统的重新定位分析，我们发现以前开发的药物苯海拉明可能为顺铂诱导的肾毒性提供新的治疗方法。为了证实这一点，在体外和体内实验中评价了苯海拉明的实际功效。苯海拉明抑制顺铂诱导的肾小管上皮细胞死亡。给予顺铂的小鼠发生肾损伤，伴有显著功能障碍（平均血浆肌酐：0.43 vs 0.15 mg/dl），并显示氧化应激增强、细胞凋亡增加、炎性细胞因子升高和MAPK活化。然而，这些症状中的大多数通过苯海拉明治疗得到抑制。此外，在苯海拉明处理的小鼠中，肾脏中顺铂的浓度显著降低（平均铂含量：70.0 vs 53.4 mg/g肾干重）。重要的是，苯海拉明在任何体外或体内实验中均不影响或干扰顺铂的抗肿瘤作用。在来自1467例患者的回顾性数据库的98例1：1匹配患者的选定队列中，显示在顺铂治疗前使用苯海拉明的恶性癌症患者与未使用苯海拉明的患者相比表现出显著更少的急性肾损伤（分别为6.1%和22.4%）。因此，苯海拉明作为一种新型预防药物对顺铂诱导的肾毒性有效。
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 cisplatininduced 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 mg/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.