Background
Cisplatin is a prominent chemotherapeutic agent. Counteracting its benefits, roughly 25% of the patients suffer severe nephrotoxicity, and no preventive drugs are currently available. The FDA Adverse Events Reporting System (FAERS) database, containing numerous reports of drug-associated adverse events, is a pivotal pharmacovigilance tool. This database has recently been found useful for drug repositioning, recognizing approved drugs as potential candidates to treat ailments like hypertension. Utilizing both the FAERS database and experimental methods offers a pipeline for the discovery of "novel efficacies" of existing drugs.
Purpose
This study sought to assess the potential of diphenhydramine (DPH), an antihistamine, as a novel preventive treatment for cisplatin-induced nephrotoxicity (CIN) using in-silico and in-vitro/in-vivo experimental methods.
Methods and Results
Using the FAERS, 1,534 drugs were evaluated with cisplatin, and DPH was identified as a potential agent for preventing CIN. In in-vitro assays, DPH reduced cisplatin-induced death in kidney cells. Cisplatin-treated mice exhibited kidney injury, marked by altered plasma creatinine levels (0.43 vs 0.15 mg/dL) and increased oxidative stress and inflammation. DPH administration attenuated the kidney damage and inflammation in H1RKO mice. Notably, no differences in renal OCT2 expression or cisplatin content were observed between WT and H1RKO mice, implying that DPH's protection against CIN involves both H1R-dependent and H1R-independent mechanisms. Furthermore, DPH treatment significantly reduced the cisplatin concentration in the kidneys without diminishing its anti-tumor effects. While cisplatin-treated mice exhibited elevated plasma creatinine levels, those treated with both cisplatin and DPH showed markedly improved renal function. In a study of 1,467 patients, propensity-matched analysis showed DPH users had reduced acute kidney injury incidence (6.1%) compared to that of non-users (22.4%).
Conclusion
DPH has shown potential efficacy in preventing CIN, suggesting the feasibility of its repositioning, especially since it is already being used in chemotherapy regimens. A subsequent prospective study is warranted to further explore DPH's prophylactic capacities against CIN.