PubMed · 14132848
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R T MCCARTHY. 1964. VOMITING.. https://doi.org/10.1111/j.1744-6198.1964.tb00259.x
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Torsades de pointes (TdP) is a potentially fatal form of ventricular arrhythmia that occurs under conditions where cardiac repolarization is delayed (as indicated by prolonged QT intervals from electrocardiographic recordings). A likely mechanism for QT prolongation and TdP is blockade of the rapid component of the cardiac delayed rectifier K(+) current (I(Kr)), which is encoded by HERG (human ether-a-go-go-related gene). The gastroprokinetic agent cisapride is a potent blocker of HERG currents and serious cardiac arrhythmias and deaths from TdP and ventricular fibrillation have been reported in patients taking cisapride. The aim of the present study was to compare the effects of the gastroprokinetic agents domperidone and metoclopramide on HERG channels transiently expressed in human embryonic kidney (HEK 293) cells using the whole-cell configuration of the patch-clamp technique. Both domperidone and metoclopramide concentration-dependently blocked HERG currents, and the following values were calculated for IC(50) (the concentrations causing half-maximal inhibition) and n (the Hill coefficient): 57.0 nmol/l and 0.99 for domperidone, 5.4 micromol/l and 0.95 for metoclopramide. The observation that the extent of block of HERG currents by domperidone increased at more positive membrane potentials whereas block of HERG currents by metoclopramide displayed a smaller degree of voltage dependency seems to indicate that domperidone and metoclopramide have distinct binding sites on HERG channels. In conclusion, the potency for block of HERG currents is about 100-fold lower for metoclopramide when compared to domperidone.
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BACKGROUND: Postoperative vomiting (POV) after pediatric strabismus surgery remains a major problem. OBJECTIVE: To evaluate the efficacy and safety of a single dose of ramosetron, a new serotonin antagonist, for preventing POV in children undergoing strabismus surgery. METHOD: In a prospective, randomized, double-masked, placebo-controlled study, 80 children (38 boys and 42 girls), aged 4 to 10 years, scheduled for strabismus surgery, received intravenously either placebo or ramosetron at 1 of 3 different doses (3 microg/kg, 6 microg/kg, or 12 microg/kg) (n = 20 each) at the end of the surgical procedure. A standard general anesthetic technique was used. MAIN OUTCOME MEASURES: Emetic episodes were recorded and safety assessments performed during the first and second 24-hour periods (ie, 0-24 and 24-48 hours) after receiving anesthesia. RESULTS: The rate of patients who were emesis-free (defined as no retching and no vomiting), during the 0- to 24-hour period after anesthesia was 35% with 3 microg/kg of ramosetron (P = .37), 90% with 6 microg/kg of ramosetron (P = .001), and 90% with 12 microg/kg of ramosetron (P = .001) compared with placebo (25%). The corresponding rate during the 24- to 48-hour period after anesthesia was 40% (P = .371), 90% (P = .001), and 90% (P = .001), respectively, compared with placebo (30%). No clinically important adverse events were observed in any group. CONCLUSIONS: A 6-microg/kg dose of ramosetron is sufficient, but a 3-microg/kg dose is insufficient for preventing POV during the 0- to 48-hour period after anesthesia in children undergoing strabismus surgery. Increasing the dose to 12 microg/kg of ramosetron provides no demonstrable additional benefit.