Cardiotoxic Antiemetics Metoclopramide and Domperidone Block Cardiac Voltage-Gated Na+ Channels.

BACKGROUND: Metoclopramide and domperidone are prokinetic and antiemetic substances often used in clinical practice. Although domperidone has a more favorable side effect profile and is considered the first-line agent, severe cardiac side effects were reported during the administration of both substances. Cardiac Na channels are common targets of therapeutics inducing cardiotoxicity. Therefore, the aim of this study was to investigate whether the differential cardiotoxicities of metoclopramide and domperidone correlate with the block of Na channels. METHODS: Effects of metoclopramide and domperidone on the human α-subunit Nav1.5 expressed in human embryonic kidney 293 cells and on Na currents in neonatal rat cardiomyocytes were investigated by means of whole-cell patch clamp recordings. RESULTS: Tonic block of resting Nav1.5 channels was more potent for domperidone (IC50 85 ± 25 µM; 95% confidence interval [CI], 36-134) compared with metoclopramide (IC50 458 ± 28 µM; 95% CI, 403-513). Both agents induced use-dependent block at 10 and 1 Hz, stabilized fast and slow inactivation, and delayed recovery from inactivation. However, metoclopramide induced considerably smaller effects compared with domperidone. Na currents in rat cardiomyocytes displayed tonic and use-dependent block by both substances, and in this system, domperidone (IC50 312 ± 15 µM; 95% CI, 22-602) and metoclopramide (IC50 250 ± 30 µM; 95% CI, 191-309) induced a similar degree of tonic block. CONCLUSIONS: Our data demonstrate that the clinically relevant cardiotoxicity of domperidone and metoclopramide corresponds to a rather potent and local anesthetic-like inhibition of cardiac Na channels including Nav1.5. These data suggest that Nav1.5 might be a hitherto unrecognized molecular mechanism of some cardiovascular side effects, for example, malignant arrhythmias of prokinetic and antiemetic agents.

Social violence among Thai gender role conforming and non-conforming secondary school students: Types, prevalence and correlates.

BACKGROUND: Gender role non-conforming behaviors are a significant risk factor for school-related violence. The objective of this study is to describe the types, prevalence and correlates of social violence among Thai secondary school students, with a focus on gender role non-conformity. METHODS: This article uses secondary data from a national study of 2070 secondary school students aged 13-20 years representing Bangkok and all four regions of Thailand. Students were asked about their gender/sexual identity, self-perception of their masculinity or femininity, and experiences of social violence. Correlates of social violence were examined using multivariable logistic regression models. RESULTS: Prevalence of social violence victimization was high (57%). Most students considered themselves to be as masculine or as feminine as other members of their sex (82.6%), while 9.1% thought that they were less masculine/less feminine, and 8.3% thought they were more masculine/more feminine. Students who considered themselves less masculine or less feminine than others of their sex (AOR = 1.59, 95% CI: 1.13, 2.25) were more likely to experience social violence, compared to students who considered themselves equally masculine/feminine. Students who self-identified as lesbian, gay, bisexual or transgender (LGBT) (AOR = 1.37, 95% CI: 1.01, 1.86) were also more likely to experience social violence, compared to students who did not identify as LGBT. However, students who considered themselves more masculine or feminine than other students of their sex (AOR = 0.62, 95% CI: 0.44, 0.88) were less likely to experience social violence. DISCUSSION: Students who identified as LGBT, or considered themselves to be less masculine or less feminine than other students of their sex, had higher odds of social violence victimization. Anti-bullying campaigns need to emphasize that perpetrating social violence is not tolerated, and gender-based violence needs to be included in comprehensive sexuality education curricula.

An apple a day won't keep the doctor away: presentation, treatment, and outcome in pediatric apple aspirations.

INTRODUCTION: Foreign body (FB) aspiration is a frequent and preventable source of morbidity and mortality, especially in children under 4 years of age. Few comprehensive studies exist on presentation and outcome of apple aspirations in children. METHODS: In a retrospective analysis of bronchoscopy records of a tertiary medical care center from January 2007 to August 2019, we identified pediatric cases of suspected apple aspirations. RESULTS: A total of 11 suspected apple aspirations were identified (observation time 12.7 years, n = 5858 bronchoscopies, n = 226 interventions due to suspected FB aspirations in total). The mean age of patients was 24 months (standard error mean, 7 months; range, 8-83 months), and 6 out of 11 cases (55%) were male. Bronchoscopy confirmed apple aspiration in n = 6/11 cases (55%). In n = 2/11 cases (18%), a bite of the apple was located in the esophagus causing significant tracheal narrowing, and in n = 3/11 cases (27%), no FB was found. In all cases of airway FB identification, extraction was successful. Hypersalivation was associated with esophageal FB location, whereas persistent cough, stridor, or dyspnea were associated with airway FB location. Outcomes ranged from complete reconstitution 1 day after bronchoscopy in most cases to hypoxemia with severe brain damage in one patient. DISCUSSION: This analysis shows that apple aspirations are not entirely uncommon in children and may lead to disastrous complications. Typical signs of airway location are persistent cough, stridor or dyspnea, whereas hypersalivation may point toward an esophageal location. In each case of suspected apple aspiration, timely bronchoscopy with possible FB extraction should be performed by an experienced team.