PubMed · 13772989
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J MOSBECH, H P OSTERGAARD KRISTENSEN. 1960-10-17. Chronic sialoadenitis caused by autoimmunization.. https://doi.org/10.1111/j.0954-6820.1960.tb06656.x
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PURPOSE: 5-Hydroxytryptamine-3 receptor antagonists (5-HT(3) antagonists) are effective for preventing acute chemotherapy-induced emesis but the benefits of continuing administration of these agents beyond 24 hours after chemotherapy (delayed emesis) remain unclear. The purpose of this study was to provide estimates of clinical efficacy and drug acquisition cost associated with administering 5-HT(3) antagonists beyond 24 hours, as monotherapy or as added to dexamethasone. METHODS: This analysis is based on the Cancer Care Ontario Practice Guidelines Initiative meta-analysis of the efficacy of 5-HT(3) antagonists. Results from the clinical trials covered in that meta-analysis were reanalyzed to provide estimates of absolute risk reductions (ARR) and numbers needed to treat (NNT) for 5-HT(3) antagonists, as monotherapy or as adjunct treatment. Numbers of 5-HT(3) antagonist unit doses per successfully treated patient were also calculated. RESULTS: Five studies (comprising 1,716 assessable patients) compared a 5-HT(3) antagonist with placebo; five studies (2,240 patients) compared a combination of a 5-HT(3) antagonist and dexamethasone with dexamethasone monotherapy. ARR for monotherapy was only 8.2% (95% CI, 3.0% to 13.4%). On average, 74 5-HT(3) antagonist doses must be administered to 12 patients (NNT, 12.2; 95% CI, 7.5 to 33.4) not receiving dexamethasone to protect one patient from delayed emesis. In those patients receiving dexamethasone as standard antiemetic treatment in the delayed phase, the addition of a 5-HT(3) antagonist did not significantly improve control of delayed emesis as compared with dexamethasone monotherapy (ARR, 2.6%; 95% CI, -0.6% to 5.8%). CONCLUSION: Neither clinical evidence nor considerations of cost effectiveness justify using 5-HT(3) antagonists beyond 24 hours after chemotherapy for prevention of delayed emesis.
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.