2. Academic Validation
  3. Diphenhydramine may be a preventive medicine against cisplatin-induced kidney toxicity

Diphenhydramine may be a preventive medicine against cisplatin-induced kidney toxicity

  • Kidney Int. 2021 Apr;99(4):885-899. doi: 10.1016/j.kint.2020.10.041.
Hirofumi Hamano 1,  Yasumasa Ikeda 2,  Mitsuhiro Goda 1,  Keijo Fukushima 3,  Seiji Kishi 4,  Masayuki Chuma 5,  Michiko Yamashita 6,  Takahiro Niimura 7,  Kenshi Takechi 5,  Masaki Imanishi 8,  Yoshito Zamami 9,  Yuya Horinouchi 8,  Yuki Izawa-Ishizawa 10,  Licht Miyamoto 11,  Keisuke Ishizawa 9,  Hiromichi Fujino 3,  Toshiaki Tamaki 12,  Ken-Ichi Aihara 13,  Koichiro Tsuchiya 11
Affiliations

Affiliations

  • 1 Department of Pharmacy, Tokushima University Hospital, Tokushima, Japan.
  • 2 Department of Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan. Electronic address: yasuike@tokushima-u.ac.jp.
  • 3 Department of Pharmacology for Life Sciences, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
  • 4 Department of Nephrology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan; Department of General Medicine, Kawasaki Medical School, Kurashiki, Japan.
  • 5 Clinical Trial Center for Developmental Therapeutics, Tokushima University Hospital, Tokushima, Japan.
  • 6 Department of Pathological Science and Technology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
  • 7 Department of Clinical Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
  • 8 Department of Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
  • 9 Department of Pharmacy, Tokushima University Hospital, Tokushima, Japan; Department of Clinical Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
  • 10 AWA Support Center, Tokushima University, Tokushima, Japan.
  • 11 Department of Medical Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
  • 12 Department of Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan; Anan Medical Center, Anan, Japan.
  • 13 Department of Community Medicine for Diabetes and Metabolic Disorders, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
PMID: 33307103 DOI: 10.1016/j.kint.2020.10.041
Abstract

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.

Keywords

cisplatin; diphenhydramine; nephrotoxicity.

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