Abstract
Hiccups can significantly reduce the quality of life of patients and can occur as a drug side effect. Previous reports have revealed sex-specific differences in the incidence of drug-induced hiccups. However, the pathogenesis of drug-induced hiccups remains unknown, and there is limited evidence on its treatment or prevention. This study examined molecular initiating events (MIEs), which are the starting point of adverse events, to investigate the drug-induced pathways of hiccups. We extracted drugs suspected to cause hiccups using the FDA Adverse Event Reporting System, a large database on adverse drug reactions. Information on drugs suspected to be associated with hiccups was extracted from the overall population and sex-specific subgroups were divided. In each data table, the predicted activity values of nuclear receptors and stress response pathways for each drug were calculated using the Toxicity Predictor, a machine-learning model. Transforming growth factor-beta and antioxidant response elements were considered an independent factor for hiccups in the male and female subgroups, respectively. This report first examined one of the mechanisms of drug-induced hiccups and identified MIEs associated with drug-induced hiccups. The use of an adverse event database and the machine-learning model, Toxicity Predictor, may be useful for generating hypotheses for other adverse effects with unknown mechanisms.