In this study, we used the large number of cases in the FDA adverse-event reporting system (FAERS) database to investigate risk factors for drug-induced hiccups and to explore the relationship between hiccups and gender. From 11,810,863 adverse drug reactions reported between the first quarter of 2004 and the first quarter of 2020, we extracted only those in which side effects occurred between the beginning and end of drug administration. Our sample included 1454 adverse reactions for hiccups, with 1159 involving males and 257 involving females (the gender in 38 reports was unknown). We performed univariate analyses of the presence or absence of hiccups for each drug and performed multivariate analysis by adding patient information. The multivariate analysis showed nicotine products to be key suspect drugs for both men and women. For males, the risk factors for hiccups included older age, lower body weight, nicotine, and 14 other drugs. For females, only nicotine and three other drugs were extracted as independent risk factors. Using FAERS, we were thus able to extract new suspect drugs for drug-induced hiccups. Furthermore, this is the first report of a gender-specific analysis of risk factors for hiccups that provides novel insights into drug-induced hiccups, and it suggests that the mechanism responsible is strongly related to gender. Thus, this study can contribute to elucidating the mechanism underlying this phenomenon.

β-Adrenergic receptor blockers (β-blockers) are used to treat hypertension, ischemic heart disease, chronic heart failure, and tachyarrhythmia. The main side effects of treatment include bradycardia, atrioventricular block, and hypotension. Bradycardia may result in pacemaker implantation as well as the discontinuation of β-blockers. Bradycardia is difficult to confirm at a single institution because it diagnosed only by symptoms when electrocardiogram (ECG) are not routinely performed. Previous studies reported an increase in bradycardia in heart failure patients treated with β-blockers; however, limited information is currently available for non-heart failure patients. Bradycardia induced by β-blockers has not yet been comprehensively examined. Therefore, the present study investigated data on the incidence and duration of bradyarrhythmia caused by β-blockers using the Japanese Adverse Drug Event Report database (JADER). Cases of adverse effects associated with this medication were extracted from JADER and Fisher’s exact test was performed to assess whether each β-blocker caused bradyarrhythmia. In addition, only data from patients who reported bradyarrhythmia after β-blocker treatment were extracted, and the Weibull distribution was used to analyze the time-to-onset of bradyarrhythmia. Thirteen β-blockers caused bradyarrhythmia and signals were observed for 12 drugs, except nadolol. Bradyarrhythmia induced by oral β-blockers was more likely to be of the early failure type, and developed within 2 months of treatment initiation with most β-blockers. A comprehensive analysis of bradyarrhythmia with β-blockers suggests that careful monitoring is needed, particularly early in the initiation of treatment.

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.

The Goto–Kakizaki (GK) rat is a non-obese and spontaneous model of mild Type 2 diabetes mellitus. In the present study, we compared the regulatory mechanisms of endogenous norepinephrine (NE) release from sympathetic nerves of caudal arteries of 12-week-old GK rats and age-matched normal Wistar rats. Electrical stimulation (ES) evoked significant NE release from caudal arteries of Wistar and GK rats. The amounts of NE released by ES were almost equal in Wistar and GK rats, although the NE content in caudal artery of GK rats was significantly lower than that of Wistar rats. We examined the effects of an α2-adrenoceptor agonist, clonidine (CLO), and an α2-adrenoceptor antagonist, yohimbine (YOH), on the release of endogenous NE evoked by ES. CLO significantly reduced NE release from caudal arteries of Wistar but not GK rats. On the other hand, YOH significantly increased NE release from both rats. Furthermore, we examined the effects of an A1-adenosine receptor agonist, 2-chloroadenosine (2CA), and an A1-adenosine receptor antagonist, 8-sulfophenyltheophylline (8SPT), on the release of endogenous NE evoked by ES. 2CA significantly reduced NE release from caudal arteries of Wistar but not GK rats. On the other hand, 8SPT did not affect NE release from both rats. These results suggest that the dysfunction of negative feedback regulation of NE release via presynaptic receptors on sympathetic nerves in GK rats may be involved in the autonomic nervous system dysfunction associated with diabetic autonomic neuropathy.