Low-dose versus standard-dose olanzapine with triple antiemetic therapy for prevention of highly emetogenic chemotherapy-induced nausea and vomiting in patients with solid tumours: a single-centre, open-label, non-inferiority, randomised, controlled, phase 3 trial.

BACKGROUND: Olanzapine is an effective antiemetic agent but it results in substantial daytime somnolence when administered at the standard dose. Our aim was to compare the efficacy of low-dose versus standard-dose olanzapine after highly emetogenic chemotherapy in patients with solid tumours. METHODS: This was a single-centre, open-label, non-inferiority, randomised, controlled, phase 3 trial done in a tertiary care referral centre in India (Tata Memorial Centre, Homi Bhabha National Institute, Mumbai). Patients aged 13-75 years with an Eastern Cooperative Oncology Group performance status of 0-2, who were receiving doxorubicin-cyclophosphamide or high-dose cisplatin for a solid tumour were eligible. Patients were randomly assigned (1:1), with block randomisation (block sizes of 2 or 4) and stratified by sex, age (≥55 or <55 years), and chemotherapy regimen, to receive low-dose (2·5 mg) oral olanzapine or standard-dose (10·0 mg) oral olanzapine daily for 4 days, in combination with a triple antiemetic regimen. Study staff were masked to treatment allocation but patients were aware of their group assignment. The primary endpoint was complete control, defined as no emetic episodes, no rescue medications, and no or mild nausea in the overall phase (0-120 hours), assessed in the modified intention-to-treat (mITT) population (ie, all eligible patients who received protocol-specified treatment, excluding those who had eligibility violations and who withdrew consent after randomisation). Daytime somnolence was the safety endpoint of interest. Non-inferiority was shown if the upper limit of the one-sided 95% CI for the difference in the complete control proportions between the treatment groups excluded the non-inferiority margin of 10%. This study is registered with the Clinical Trial Registry India, CTRI/2021/01/030233, is closed to accrual, and this is the final data analysis. RESULTS: Between Feb 9, 2021, and May 30, 2023, 356 patients were pre-screened for eligibility, of whom 275 patients were enrolled and randomly assigned (134 to the 2·5 mg olanzapine group and 141 to the 10·0 mg olanzapine group). 267 patients (132 in the 2·5 mg group and 135 in the 10·0 mg group) were included in the mITT population, of whom 252 (94%) were female, 15 (6%) were male, and 242 (91%) had breast cancer. 59 (45%) of 132 patients in the 2·5 mg olanzapine group had complete control in the overall phase versus 59 (44%) of 135 in the 10·0 mg olanzapine group (difference -1·0% [one-sided 95% CI -100·0 to 9·0]; p=0·87). In the overall phase, there were significantly fewer patients in the 2·5 mg olanzapine group than in the 10·0 mg olanzapine group with daytime somnolence of any grade (86 [65%] of 132 vs 121 [90%] of 135; p<0·0001) and of severe grade on day 1 (six]5%] vs 54 [40%]; p<0·0001). INTERPRETATION: Our findings suggest that olanzapine 2·5 mg is non-inferior to 10·0 mg in antiemetic efficacy and results in reduced occurrence of daytime somnolence among patients receiving highly emetic chemotherapy and should be considered as a new standard of care. FUNDING: Progressive Ladies Welfare Association.

The antiemetic actions of GIP receptor agonism.

Nausea and vomiting are primitive aspects of mammalian physiology and behavior that ensure survival. Unfortunately, both are ubiquitously present side effects of drug treatments for many chronic diseases with negative consequences on pharmacotherapy tolerance, quality of life, and prognosis. One of the most critical clinical examples is the profound emesis and nausea that occur in patients undergoing chemotherapy, which continue to be among the most distressing side effects, even with the use of modern antiemetic medications. Similarly, antiobesity/diabetes medications that target the glucagon-like peptide-1 system, despite their remarkable metabolic success, also cause nausea and vomiting in a significant number of patients. These side effects hinder the ability to administer higher dosages for optimal glycemic and weight management and represent the major reasons for treatment discontinuation. Our inability to effectively control these side effects highlights the need to anatomically, molecularly, and functionally characterize novel neural substrates that drive and inhibit nausea and emesis. Here, we discuss clinical and preclinical evidence that highlights the glucose-dependent insulinotropic peptide receptor system as a novel therapeutic central target for the management of nausea and emesis.

Dexamethasone and Surgical-Site Infection.

BACKGROUND: The glucocorticoid dexamethasone prevents nausea and vomiting after surgery, but there is concern that it may increase the risk of surgical-site infection. METHODS: In this pragmatic, international, noninferiority trial, we randomly assigned 8880 adult patients who were undergoing nonurgent, noncardiac surgery of at least 2 hours' duration, with a skin incision length longer than 5 cm and a postoperative overnight hospital stay, to receive 8 mg of intravenous dexamethasone or matching placebo while under anesthesia. Randomization was stratified according to diabetes status and trial center. The primary outcome was surgical-site infection within 30 days after surgery. The prespecified noninferiority margin was 2.0 percentage points. RESULTS: A total of 8725 participants were included in the modified intention-to-treat population (4372 in the dexamethasone group and 4353 in the placebo group), of whom 13.2% (576 in the dexamethasone group and 572 in the placebo group) had diabetes mellitus. Of the 8678 patients included in the primary analysis, surgical-site infection occurred in 8.1% (354 of 4350 patients) assigned to dexamethasone and in 9.1% (394 of 4328) assigned to placebo (risk difference adjusted for diabetes status, -0.9 percentage points; 95.6% confidence interval [CI], -2.1 to 0.3; P<0.001 for noninferiority). The results for superficial, deep, and organ-space surgical-site infections and in patients with diabetes were similar to those of the primary analysis. Postoperative nausea and vomiting in the first 24 hours after surgery occurred in 42.2% of patients in the dexamethasone group and in 53.9% in the placebo group (risk ratio, 0.78; 95% CI, 0.75 to 0.82). Hyperglycemic events in patients without diabetes occurred in 22 of 3787 (0.6%) in the dexamethasone group and in 6 of 3776 (0.2%) in the placebo group. CONCLUSIONS: Dexamethasone was noninferior to placebo with respect to the incidence of surgical-site infection within 30 days after nonurgent, noncardiac surgery. (Funded by the Australian National Health and Medical Research Council and others; PADDI Australian New Zealand Clinical Trials Registry number, ACTRN12614001226695.).

A multicenter phase II trial of the triplet antiemetic therapy with palonosetron, aprepitant, and olanzapine for a cisplatin-containing regimen. - PATROL-I.

Dexamethasone is one of the key antiemetic agents and is widely used even now. However, dexamethasone has been associated with several adverse reactions even after short-term administration. Therefore, developing a steroid-free antiemetic regimen is an important issue to consider. Thus, the purpose of this study was to investigate the efficacy and safety of palonosetron, aprepitant, and olanzapine in a multi-institutional phase II study. Chemotherapy-naive patients scheduled to receive cisplatin were enrolled and evaluated for the occurrence of chemotherapy-induced nausea and vomiting during 120 h after chemotherapy. The primary endpoint of the study was total control (TC) in the overall phase. The key secondary endpoint was complete response (CR), which was assessed in the acute, delayed, and overall phase, respectively. Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events. Eighty-five patients were enrolled from 8 centers in Japan, of which 83 were evaluable for analyses. The percentage of patients who achieved TC during the overall phase was 31.3%. CR was achieved in 61.4%, 84.3%, and 65.1% of patients during the overall, acute, and delayed phases, respectively. The most frequently reported adverse event was anorexia. The primary endpoint was below the threshold and we could not find benefit in the dexamethasone-free regimen, but CR during the overall phase was similar to that of the conventional three-drug regimen. This antiemetic regimen without dexamethasone might be an option for patients for whom corticosteroids should not be an active application.

Safety and tolerability of intravenous aprepitant and fosaprepitant in children with cancer: A retrospective, single-center review.

NK-1 receptor antagonists (NK1-RA) are key agents for chemotherapy-induced nausea and vomiting (CINV) prevention in patients receiving highly emetogenic chemotherapy. Current pediatric practice guidelines recommend the use of intravenous fosaprepitant or oral aprepitant. However, there are reports of hypersensitivity reactions with fosaprepitant due to polysorbate 80. Intravenous aprepitant does not contain polysorbate 80, but its use in pediatric patients has not been described. In this retrospective, single-center study, 106 pediatric patients received either fosaprepitant or intravenous aprepitant as part of their antiemetic regimen. Intravenous aprepitant was well tolerated and did not lead to any instances of hypersensitivity reactions requiring discontinuation.

The effect of intravenous ondansetron on QT interval in the emergency department.

OBJECTIVE: Ondansetron, a 5HT3 receptor antagonist, is commonly used in emergency departments to treat nausea and vomiting. In 2011, the Food and Drug Administration (FDA) issued a warning that this medicine may cause QT prolongation, potentially leading to deadly arrhythmias. The objective of this study was to characterize the QT interval prolongation associated with ondansetron use in the Emergency Department. METHODS: This was a prospective, observational cohort study of adult patients who presented to the emergency department during a one-year period and were treated with intravenous ondansetron. We investigated the QT prolongation associated with dosages. ECGs were obtained before the medication and 5, 15, and 30 minutes after IV drug administration. Every QT measurement was recorded and compared to the zero point. The severity of drug-induced QT prolongation was determined according to the recommendations of the International Conference on Compliance (ICH). QTc prolongation was categorized as 'negligible' (<5 ms), 'significant' (>20 ms), 'potential concern' (>30 ms), or 'definitely worrying' (>60 ms). RESULTS: Of the 435 patients enrolled in the study, 60% (261 patients) were female and the mean age was 39 (±18). The QT prolongation peaked at the fifth minute and remained consistent at the fifteenth and thirty-first minutes. The maximum prolongation of the mean QT duration occured at the fifth minute (7.9 ± 18.1 ms). No patient revealed any problems with cardiac conduction. The prolonged QT interval was not related to the dose of ondansetron, but QT measurements were higher in the 30th minute in patients treated with 8 mg of ondansetron. The effect of ondansetron administration on QT prolongation was found to be above the 'negligible' but below the 'significant' value, according to the ICH recommendations. DISCUSSION: In this study, QT prolongation due to ondansetron administration was below the 'important' value according to the recommendations of the ICH. No cases of cardiac arrhythmia were reported in any of the partients. Thus, routine ECG monitoring in patients given ondansetron due to the risk of QTc prolongation does not seem cost-effective when evaluated together with additional factors such as its negative impact on emergency patient flow, waste of personnel and time, and increase in healthcare costs. In the absence of a known risk of cardiac arrhythmia, IV administration of 4 mg and 8 mg of ondansetron doses no risk of QT prolongation in the emergency population.

Droperidol administration among emergency department patients with abdominal pain, nausea, and vomiting.

STUDY OBJECTIVE: The primary objective of this study was to examine the common usage patterns of droperidol in the relatively unrestricted environment of an urban, academic medical center. We focused specifically on the most common use of droperidol in our department: patients with a chief complaint of abdominal pain, nausea, and/or vomiting. METHODS: For this retrospective, observational, single-center study, we extracted records of all administrations of droperidol from August 2019 to August 2020. Patients with a chief complaint of abdominal pain, nausea, or vomiting, or any combination thereof, were included in data analysis. RESULTS: Between April 2019 to August 2020, 830 discrete patient visits involving droperidol administration were identified, comprising 706 patients. The average age was 39 years old with a range of 15 to 80. Seven patients (0.08%) were younger than 18, and 35 (4%) were older than 65. Five hundred sixty-five patients (68%) were female. Droperidol doses ranged from 0.625 mg to 5 mg intravenous (IV), with a median dose of 0.625 mg (interquartile range 0.625-1.25 mg), with 590 patients (71%) receiving a dose of 0.625 mg. Only 19 patients (2.3%) had a documented adverse event. Seven had akathisia or restlessness, 7 had anxiety or agitation, 3 had dystonia or stiffness, 1 had fatigue, and 1 had dizziness. For the entire cohort, there were no cardiac dysrhythmias, syncope, seizures, other major adverse events, or fatalities recorded. CONCLUSION: At one institution, droperidol is being used commonly for the chief complaints of abdominal pain, nausea, and/or vomiting. The preferred dosing is nearly universally below the 2.5 mg IV dose for which the FDA warning applies. Similar to previous studies, identification of adverse events was rare, and no major adverse outcomes such as dysrhythmia or death were identified.

Ginger for treating nausea and vomiting: an overview of systematic reviews and meta-analyses.

Ginger may be a potential remedy for nausea and vomiting. This review aimed to assess the reporting and methodological quality, and integrate the evidence in this field. A total of fifteen meta-analyses were analysed and met the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2009 guidelines, providing a relatively complete statement. However, methodological quality, assessed using the Assessment of Multiple Systematic Reviews-2 checklist, was deemed critically low to low. Our review's findings support ginger's effectiveness in managing chemotherapy-induced nausea and vomiting in cancer patients. It also reduces postoperative nausea and vomiting severity, decreasing the need for rescue antiemetics. Furthermore, ginger shows promise in alleviating pregnancy-related nausea and vomiting symptoms. The pooled evidence suggests ginger as a safe botanical option for managing nausea and vomiting, but it is important to improve the scientific quality of published meta-analyses in the future.

Associations between ondansetron and the incidence of postoperative nausea and vomiting and food intake in Japanese female undergoing laparoscopic gynecological surgery: a retrospective study.

PURPOSE: Prevention of postoperative nausea and vomiting (PONV) is important to achieve DREAM (drinking, eating, mobilization). Ondansetron inhibits PONV, but its effects on postoperative food intake have not been investigated. This study aimed to examine associations between ondansetron and PONV incidence, and postoperative food intake. METHODS: This retrospective study included adult patients (n = 632) who underwent laparoscopic gynecological surgery at Kyushu University Hospital between January 2017 and June 2023. Outcomes were PONV on the day of surgery, PONV up to the day after surgery, and food intake, which was assessed for breakfast and lunch on the day after surgery. Odds ratios (ORs) for PONV incidence and postoperative no-food intake were calculated between those with and without ondansetron during surgery. Multivariable-adjusted analysis was performed using possible confounding factors for PONV. Synergistic effects of combining ondansetron with dexamethasone or total intravenous anesthesia (TIVA) were assessed. RESULTS: Multivariable-adjusted ORs for PONV on the day of surgery and up to the day after surgery were 0.56 (95% confidence interval, 0.32-0.99, p = 0.04) and 0.52 (0.30-0.93, p = 0.03), respectively, in the ondansetron group (n = 84) compared with the non-ondansetron group (n = 548). In contrast, multivariable-adjusted ORs for no-food intake of breakfast and lunch the day after surgery in the ondansetron group compared with the non-ondansetron group were not significant. Analysis of synergistic effects on PONV showed no significant interaction between ondansetron and dexamethasone or ondansetron and TIVA combinations. CONCLUSION: Ondansetron administration during surgery was significantly associated with decreased PONV risk but was not associated with food intake the day after surgery.

Impact of body weight-based dosing of palonosetron and ondansetron on postoperative nausea and vomiting following laparoscopic sleeve gastrectomy: a randomized, double-blind study.

BACKGROUND: Postoperative nausea and vomiting (PONV) is a frequent adverse effect following laparoscopic sleeve gastrectomy. Palonosetron with a standard dosing (75 µg) schedule has been questioned due to its low efficiency in obese patients. This study aimed to investigate the effectiveness and safety of the body weight-based dosing of palonosetron in managing PONV following laparoscopic sleeve gastrectomy. METHODS: A single-center, prospective, double-blinded randomized study was conducted between August 2021 and December 2021. Patients who underwent laparoscopic sleeve gastrectomy were prospectively recruited in the study. One hundred patients were randomly divided into palonosetron (Group P) and ondansetron (Group O). The demographic and clinical variables were recorded. The primary outcome of the study was the incidence of PONV between the two groups during the hospitalization. The secondary outcomes were the number of rescue anti-emetic and analgesic medications and the Functional Living Index-Emesis scores. RESULTS: There were 50 patients in each group (Group P and Group O). There were significant differences in the scores of POVN, nausea, and vomiting favoring Group P. In Group P, the rate of patients using rescue anti-emetics was significantly lower. The incidence of complete response and proportion of patients with higher Functional Living Index-Emesis scores were significantly higher in patients using palonosetron. CONCLUSIONS: The use of palonosetron significantly reduced the incidence of PONV following laparoscopic sleeve gastrectomy. There was a significant improvement in the scores of Functional Living Index-Emesis in patients using palonosetron.

Association Between Intraoperative Dexamethasone and Postoperative Mortality in Patients Undergoing Oncologic Surgery: A Multicentric Cohort Study.

OBJECTIVE: We examined the effects of dexamethasone on postoperative mortality, recurrence-free survival, and side effects in patients undergoing oncologic operations. BACKGROUND: Dexamethasone prevents nausea and vomiting after anesthesia and may affect cancer proliferation. METHODS: A total of 30,561 adult patients undergoing solid cancer resection between 2005 and 2020 were included. Multivariable logistic regression was applied to investigate the effect of dexamethasone on 1-year mortality and recurrence-free survival. Effect modification by the cancer's potential for immunogenicity, defined as a recommendation for checkpoint inhibitor therapy based on the National Comprehensive Cancer Network guidelines, was investigated through interaction term analysis. Key safety endpoints were dexamethasone-associated risk of hyperglycemia >180 mg/dL within 24 hours and surgical site infections within 30 days after surgery. RESULTS: Dexamethasone was administered to 38.2% (11,666/30,561) of patients (6.5±2.3 mg). Overall, 3.2% (n=980/30,561) died and 15.4% (n=4718/30,561) experienced cancer recurrence within 1 year of the operation. Dexamethasone was associated with a -0.6% (95% confidence interval: -1.1, -0.2, P =0.007) 1-year mortality risk reduction [adjusted odds ratio (OR adj ): 0.79 (0.67, 0.94), P =0.009; hazard ratio=0.82 (0.69, 0.96), P =0.016] and higher odds of recurrence-free survival [OR adj : 1.28 (1.18, 1.39), P <0.001]. This effect was only present in patients with solid cancers who were defined as not to respond to checkpoint inhibitor therapy [OR adj : 0.70 (0.57, 0.87), P =0.001 vs OR adj : 1.13 (0.85, 1.50), P =0.40]. A high (>0.09 mg/kg) dose of dexamethasone increased the risk of postoperative hyperglycemia [OR adj : 1.55 (1.32, 1.82), P <0.001], but not for surgical site infections [OR adj : 0.84 (0.42, 1.71), P =0.63]. CONCLUSIONS: Dexamethasone is associated with decreased 1-year mortality and cancer recurrence in patients undergoing surgical resection of cancers that are not candidates for immune modulators. Dexamethasone increased the risk of postoperative hyperglycemia, however, no increase in surgical site infections was identified.

Effectiveness of Palonosetron, 1-Day Dexamethasone, and Aprepitant in Patients Undergoing Carboplatin-Based Chemotherapy.

INTRODUCTION: Dexamethasone (DEX)-sparing strategy with 5-hydroxytryptamine-3 receptor antagonist (5HT3RA) and aprepitant (APR), as triplet antiemetic prophylaxis, is associated with poor control of delayed chemotherapy-induced nausea and vomiting (CINV) in patients receiving carboplatin (CBDCA)-based chemotherapy. This study aimed to evaluate whether using palonosetron (PALO) as a 5HT3RA provides superior control with CINV than first-generation (1st) 5HT3RA in triplet antiemetic prophylaxis with a DEX-sparing strategy. METHODS: Pooled patient-level data from a nationwide, multicenter, and prospective observational study were analyzed to compare the incidence of CINV between patients administered PALO and 1st 5HT3RA in combination with 1-day DEX and APR. RESULTS: No significant differences were observed in the incidence of CINV, pattern of CINV, or severity of nausea by type of 5HT3RA in triplet antiemetic prophylaxis with DEX-sparing strategy. In both groups, the incidence of nausea gradually increased from day 3, peaked on day 4 or 5, and then declined slowly. The visual analog scale scores in the delayed phase remained high throughout the 7-day observation period. CONCLUSION: Careful patient selection and symptom monitoring are needed when implementing the DEX-sparing strategy in triplet antiemetic prophylaxis for patients undergoing CBDCA-based chemotherapy. Furthermore, additional strategies may be needed to achieve better control of delayed CINV.

Antiemetic Administration and Its Association with Race: A Retrospective Cohort Study.

BACKGROUND: Anesthesiologists' contribution to perioperative healthcare disparities remains unclear because patient and surgeon preferences can influence care choices. Postoperative nausea and vomiting is a patient- centered outcome measure and a main driver of unplanned admissions. Antiemetic administration is under the sole domain of anesthesiologists. In a U.S. sample, Medicaid insured versus commercially insured patients and those with lower versus higher median income had reduced antiemetic administration, but not all risk factors were controlled for. This study examined whether a patient's race is associated with perioperative antiemetic administration and hypothesized that Black versus White race is associated with reduced receipt of antiemetics. METHODS: An analysis was performed of 2004 to 2018 Multicenter Perioperative Outcomes Group data. The primary outcome of interest was administration of either ondansetron or dexamethasone; secondary outcomes were administration of each drug individually or both drugs together. The confounder-adjusted analysis included relevant patient demographics (Apfel postoperative nausea and vomiting risk factors: sex, smoking history, postoperative nausea and vomiting or motion sickness history, and postoperative opioid use; as well as age) and included institutions as random effects. RESULTS: The Multicenter Perioperative Outcomes Group data contained 5.1 million anesthetic cases from 39 institutions located in the United States and The Netherlands. Multivariable regression demonstrates that Black patients were less likely to receive antiemetic administration with either ondansetron or dexamethasone than White patients (290,208 of 496,456 [58.5%] vs. 2.24 million of 3.49 million [64.1%]; adjusted odds ratio, 0.82; 95% CI, 0.81 to 0.82; P < 0.001). Black as compared to White patients were less likely to receive any dexamethasone (140,642 of 496,456 [28.3%] vs. 1.29 million of 3.49 million [37.0%]; adjusted odds ratio, 0.78; 95% CI, 0.77 to 0.78; P < 0.001), any ondansetron (262,086 of 496,456 [52.8%] vs. 1.96 million of 3.49 million [56.1%]; adjusted odds ratio, 0.84; 95% CI, 0.84 to 0.85; P < 0.001), and dexamethasone and ondansetron together (112,520 of 496,456 [22.7%] vs. 1.0 million of 3.49 million [28.9%]; adjusted odds ratio, 0.78; 95% CI, 0.77 to 0.79; P < 0.001). CONCLUSIONS: In a perioperative registry data set, Black versus White patient race was associated with less antiemetic administration, after controlling for all accepted postoperative nausea and vomiting risk factors.

Treatment of breakthrough and prevention of refractory chemotherapy-induced nausea and vomiting in pediatric cancer patients: Clinical practice guideline update.

This clinical practice guideline update provides recommendations for treating breakthrough chemotherapy-induced nausea and vomiting (CINV) and preventing refractory CINV in pediatric patients. Two systematic reviews of randomized controlled trials in adult and pediatric patients informed the recommendations. In patients with breakthrough CINV, escalation of antiemetic agents to those recommended for chemotherapy of the next higher level of emetogenic risk is strongly recommended. A similar recommendation to escalate therapy is made to prevent refractory CINV in patients who did not experience complete breakthrough CINV control and are receiving minimally or low emetogenic chemotherapy. A strong recommendation to use antiemetic agents that controlled breakthrough CINV for the prevention of refractory CINV is also made.

Serotonin type-3 receptor antagonists selectively kill melanoma cells through classical apoptosis, microtubule depolymerisation, ERK activation, and NF-κB downregulation.

Malignant melanoma is a highly metastatic tumour, resistant to treatment. Serotonin type-3 (5-HT3) receptor antagonists, such as tropisetron and ondansetron, are well-tolerated antiemetic drugs commonly used to prevent nausea caused by chemotherapy or radiotherapy. We investigated the anticancer effects of these drugs on melanoma cancer cell lines WM-266-4 and B16F10 with or without paclitaxel. We constructed IC50 curves and performed Chou-Talalay analysis, using data obtained with the MTT assay. Flow cytometry and fluorescent microscopy were used to examine characteristics of the cell cycle, cell death and cytoskeleton changes. Protein levels and activation were analysed by western blotting and molecular docking studies carried out. Data were analysed by one way ANOVA and post hoc testing. Ondansetron and tropisetron showed selective concentration-dependent cytotoxicity in melanoma cell lines WM-266-4 and B16F10. The effect in combination with paclitaxel was synergistic. The drugs did not cause cell cycle arrest but did promote characteristics of classical apoptosis, including accumulation of subG1 DNA, cleaved caspase-3, mitochondrial membrane permeability and phosphatidylserine exposure. As well, the cytosolic calcium level in the melanoma cells was enhanced, phosphorylated ERK1/2 induced and NF-κB inhibited. Finally, the formation of microtubules was shown to be impaired in melanoma cells treated with ondansetron or tropisetron. Docking studies were used to predict that these drugs could bind to the colchicine binding site on the tubulin molecule. Antiemetic drugs, already given in combination with chemotherapy, may enhance the cytotoxic effect of chemotherapy, following successful delivery to the tumour site.

Gastroparesis Worsens Indomethacin-Induced Gastric Antral Ulcers by Bile Reflux via Activation of 5-HT3 and Dopamine D2 Receptors in Mice.

BACKGROUND/AIMS: We examined the contributions of gastric emptying and duodenogastric bile reflux in the formation of gastric antral ulcers induced by NSAIDs in mice. METHODS: We used the murine re-fed indomethacin (IND) experimental ulcer model. Outcome measures included the appearance of gastric lesions 24 h after IND treatment and the assessment of gastric contents and the concentration of bile acids 1.5 h after re-feeding. The effects of atropine, dopamine, SR57227 (5-HT3 receptor agonist), apomorphine, ondansetron, haloperidol, and dietary taurocholate and cholestyramine were also examined. RESULTS: IND (10 mg/kg, s.c.) induced severe lesions only in the gastric antrum in the re-fed model. The antral lesion index and the amount of food intake during the 2-h refeeding period were positively correlated. Atropine and dopamine delayed gastric emptying, increased bile reflux, and worsened IND-induced antral lesions. SR57227 and apomorphine worsened antral lesions with increased bile reflux. These effects were prevented by the anti-emetic drugs ondansetron and haloperidol, respectively. The anti-emetic drugs markedly decreased the severity of antral lesions and the increase of bile reflux induced by atropine or dopamine without affecting delayed gastric emptying. Antral lesions induced by IND were increased by dietary taurocholate but decreased by the addition of the bile acid sequestrant cholestyramine. CONCLUSIONS: These results suggest that gastroparesis induced by atropine or dopamine worsens NSAID-induced gastric antral ulcers by increasing duodenogastric bile reflux via activation of 5-HT3 and dopamine D2 receptors.

Investigating the Association Between a Risk-Directed Prophylaxis Protocol and Postoperative Nausea and Vomiting: Validation in a Low-Income Setting.

BACKGROUND: The efficacy of postoperative nausea and vomiting (PONV) prevention protocols in low-income countries is not well known. Different surgical procedures, available medications, and co-occurring diseases imply that existing protocols may need validation in these settings. We assessed the association of a risk-directed PONV prevention protocol on the incidence of PONV and short-term surgical outcomes in a teaching hospital in Rwanda. METHODS: We compared the incidence of PONV during the first 48 hours postoperatively before (April 1, 2019-June 30, 2019; preintervention) and immediately after (July 1, 2019-September 30, 2019; postintervention) implementing an Apfel score-based PONV prevention strategy in 116 adult patients undergoing elective open abdominal surgery at Kigali University Teaching Hospital in Rwanda. Secondary outcomes included time to first oral intake, hospital length of stay, and rate of wound dehiscence. Interrupted time series analyses were performed to assess the associated temporal slopes of the outcome before and immediately after implementation of the risk-directed PONV prevention protocol. RESULTS: Compared to just before the intervention, there was no change in the odds of PONV at the beginning of the postintervention period (odds ratio [OR], 0.23; 95% confidence interval [CI], 0.05-1.01). There was a decreasing trend in the odds of nausea (OR, 0.60; 95% CI, 0.36-0.97) per month. However, there was no difference in the incidence of nausea immediately after implementation of the protocol (OR, 0.96; 95% CI, 0.25-3.72) or in the slope between preintervention and postintervention periods (OR, 1.48; 95% CI, 0.60-3.65). In contrast, there was no change in the odds of vomiting during the preintervention period (OR, 1.01; 95% CI, 0.61-1.67) per month. The odds of vomiting decreased at the beginning of the postintervention period compared to just before (OR, 0.10; 95% CI, 0.02-0.47; P = .004). Finally, there was a significant decrease in the average time to first oral intake (estimated 14 hours less; 95% CI, -25 to -3) when the protocol was first implemented, after adjusting for confounders; however, there was no difference in the slope of the average time to first oral intake between the 2 periods ( P = .44). CONCLUSIONS: A risk-directed PONV prophylaxis protocol was associated with reduced vomiting and time to first oral intake after implementation. There was no substantial difference in the slopes of vomiting incidence and time to first oral intake before and after implementation.

QT prolongation, torsades des pointes, and cardiac arrest after 4 mg of IV ondansetron.

Ondansetron is a commonly used antiemetic in the emergency department despite a 2011 FDA warning regarding dose-related QTc prolongation and torsades des pointes (TdP). Cases of TdP from small ondansetron doses administered in the emergency department are lacking. A 41-year-old-woman with alcohol use disorder on no medications or supplements presented to an emergency department with one day of nausea, vomiting, and epigastric pain. Examination revealed a pulse of 77 beats/min and epigastric tenderness. The patient received 4 mg IV ondansetron, 30 mg IV ketorolac, and was placed on cardiac monitoring. ECG obtained one minute after ondansetron demonstrated premature ventricular contractions with QTc = 653 ms. Thirteen minutes after receiving ondansetron she suffered TdP and cardiac arrest. She received immediate CPR and IV epinephrine with successful defibrillation at one minute. She then received IV magnesium. Post-arrest ECGs demonstrated persistent QTc prolongation immediately and at three hours post-arrest. Laboratory studies, drawn prior to arrest, demonstrated hypokalemia (3.2 mEq/L), hypomagnesemia (1.3 mg/dL), and elevated lipase (4918 IU/L). She received no additional QT-prolonging agents. Transthoracic echocardiogram and troponins were normal; ECG intervals completely normalized within 12 h and she was discharged neurologically intact. The patient returned 18 months later with recurrent pancreatitis and similar electrolyte abnormalities; QT-prolonging drugs were avoided at that time and her course was uncomplicated. QT prolongation with subsequent torsades des pointes and cardiac arrest may occur in high-risk patients receiving small doses of ondansetron. Further studies are warranted to determine the safest antiemetic for use in the emergency department.

Multi-institutional survey of antiemetic therapy in lung cancer patients treated with carboplatin in Hokushin region.

OBJECTIVE: Appropriate monitoring and management of chemotherapy-induced nausea and vomiting (CINV) with prophylactic antiemetics is important for cancer patients. This study was performed to validate the clinical practice of antiemetic use with carboplatin-based chemotherapy in lung cancer patients in the Hokushin region (Toyama, Ishikawa, Fukui, and Nagano prefectures), Japan. METHODS: We surveyed retrospective data of newly diagnosed and registered lung cancer patients initially treated with carboplatin-based chemotherapy in 21 principal hospitals in the Hokushin region linked with health insurance claims data between 2016 and 2017. RESULTS: A total of 1082 lung cancer patients (861 [79.6%] men, 221 [20.4%] women; median age 69.4 years [range, 33-89 years]). All patients received antiemetic therapy, with 613 (56.7%) and 469 patients (43.3%) receiving 5-hydroxytryptamine-3 receptor antagonist/dexamethasone double regimen and 5-hydroxytryptamine-3 receptor antagonist/dexamethasone/neurokinin-1 receptor antagonist triple regimen, respectively. However, the rates of double regimen and use of palonosetron were higher in Toyama and Fukui prefectures. Thirty-nine patients (3.6%) changed from double to triple regimen, while 41 patients (3.8%) changed from triple to double regimen after the second cycle, but six of these returned to triple antiemetics in subsequent cycles. CONCLUSION: Adherence to antiemetic guidelines in clinical practice was high in Hokushin region. However, rates of double and triple antiemetic regimens differed between the four prefectures. Simultaneous analysis of nationwide registry and insurance data was valuable for evaluating and comparing the differences in the status of antiemesis and management.

Comparison of postoperative nausea and vomiting between Remimazolam and Propofol in Patients undergoing oral and maxillofacial surgery: a prospective Randomized Controlled Trial.

BACKGROUND: Remimazolam is a recently approved, ultra-short-acting benzodiazepine. However, few studies have investigated remimazolam in relation to postoperative nausea and vomiting (PONV). This study aimed to compare the effects of remimazolam and propofol on PONV in patients undergoing oral and maxillofacial surgery. METHODS: Patients (n = 206) aged 19-65 years who were scheduled for oral and maxillofacial surgery were randomized into two groups, the remimazolam (R) and propofol group (P). In the R group (n = 94), remimazolam was used to induce anesthesia at 12 mg/kg/h and to maintain anesthesia at 1-2 mg/kg/h. In the P group (n = 95), anesthesia was induced and maintained with propofol (target effect-site concentration: 3-5 µg/ml). In both groups, remifentanil was administered at a target effect-site concentration of 2.5-4 ng/ml. The primary outcome was the overall incidence of PONV during the first 24 h after surgery. Secondary outcomes included the severity of nausea, use of rescue antiemetics, severity of postoperative pain, use of rescue analgesia, and quality of recovery. RESULTS: The incidence of PONV during the first 24 h after surgery was 11.7% and 10.5% in the R group and P group, respectively, and there was no significant difference in the severity of nausea (P > 0.05). Ten patients in the R group and ten patients in the P group required rescue antiemetics during the first 24 h after surgery (P = 0.98). No inter-group differences were observed in terms of postoperative pain score, use of rescue analgesia, and quality of recovery (P > 0.05). CONCLUSIONS: In this study, remimazolam did not increase the incidence and severity of PONV compared with propofol. TRIAL REGISTRATION: KCT0006965, Clinical Research Information Service (CRIS), Republic of Korea. Registration date: 26/01/2022.