Virtual clinical QT exposure-response studies - A translational computational approach.

BACKGROUND AND PURPOSE: A recent paradigm shift in proarrhythmic risk assessment suggests that the integration of clinical, non-clinical, and computational evidence can be used to reach a comprehensive understanding of the proarrhythmic potential of drug candidates. While current computational methodologies focus on predicting the incidence of proarrhythmic events after drug administration, the objective of this study is to predict concentration-response relationships of QTc as a clinical endpoint. EXPERIMENTAL APPROACH: Full heart computational models reproducing human cardiac populations were created to predict the concentration-response relationship of changes in the QT interval as recommended for clinical trials. The concentration-response relationship of the QT-interval prolongation obtained from the computational cardiac population was compared against the relationship from clinical trial data for a set of well-characterized compounds: moxifloxacin, dofetilide, verapamil, and ondansetron. KEY RESULTS: Computationally derived concentration-response relationships of QT interval changes for three of the four drugs had slopes within the confidence interval of clinical trials (dofetilide, moxifloxacin and verapamil) when compared to placebo-corrected concentration-ΔQT and concentration-ΔQT regressions. Moxifloxacin showed a higher intercept, outside the confidence interval of the clinical data, demonstrating that in this example, the standard linear regression does not appropriately capture the concentration-response results at very low concentrations. The concentrations corresponding to a mean QTc prolongation of 10 ms were consistently lower in the computational model than in clinical data. The critical concentration varied within an approximate ratio of 0.5 (moxifloxacin and ondansetron) and 1 times (dofetilide, verapamil) the critical concentration observed in human clinical trials. Notably, no other in silico methodology can approximate the human critical concentration values for a QT interval prolongation of 10 ms. CONCLUSION AND IMPLICATIONS: Computational concentration-response modelling of a virtual population of high-resolution, 3-dimensional cardiac models can provide comparable information to clinical data and could be used to complement pre-clinical and clinical safety packages. It provides access to an unlimited exposure range to support trial design and can improve the understanding of pre-clinical-clinical translation.

Unveiling the antinociceptive mechanisms of Methyl-2-(4-chloro-phenyl)-5-benzoxazoleacetate: insights from nociceptive assays in mice.

OBJECTIVE: Methyl-2-(4-chloro- phenyl)-5-benzoxazoleacetate (MCBA), a synthetic benzoxazole derivative with established antipsoriatic efficacy, was investigated for potential antinociceptive effects. This study employs various nociceptive assays in mice to elucidate MCBA's antinociceptive mechanisms. MATERIALS AND METHODS: MCBA's antinociceptive potential was tested against various nociception models induced by formalin, glutamate, capsaicin, a transient receptor potential vanilloid 1 (TRPV1) receptor agonist, and phorbol 12-myristate 13-acetate, a protein kinase C (PKC) activator. It was then assessed using the hot plate test and examined within the acetic acid-induced writhing test. During the acetic acid-induced writhing test, MCBA was pre-challenged against selective receptor antagonists such as naloxone, caffeine, atropine, yohimbine, ondansetron, and haloperidol. It was also pre-challenged with ATP-sensitive potassium channel inhibitor (glibenclamide) to further elucidate its antinociceptive mechanism. RESULTS: The results showed that oral administration of MCBA led to a dose-dependent and significant inhibition (p < 0.05) of nociceptive effects across all evaluated models at doses of 60, 120, and 240 mg/kg. Moreover, the efficacy of MCBA's antinociceptive potential was significantly counteracted (p < 0.0001) by specific antagonists: (i) directed at adenosinergic, alpha-2 adrenergic, and cholinergic receptors using caffeine, yohimbine, and atropine, respectively; and (ii) targeting ATP-sensitive potassium channels, employing glibenclamide. Antagonists aimed at opioidergic and serotoninergic receptors (naloxone and ondansetron, respectively) had poor utility in inhibiting antinociceptive activity. Conversely, the dopaminergic receptor antagonist haloperidol potentiated locomotor abnormalities associated with MCBA treatment. CONCLUSIONS: MCBA-induced antinociception involves modulation of glutamatergic-, TRVP1 receptors- and PKC-signaling pathways. It impacts adenosinergic, alpha-2 adrenergic, and cholinergic receptors and opens ATP-sensitive potassium channels.

Antiemetic activity of abietic acid possibly through the 5HT3 and muscarinic receptors interaction pathways.

The present study was designed to evaluate the antiemetic activity of abietic acid (AA) using in vivo and in silico studies. To assess the effect, doses of 50 mg/kg b.w. copper sulfate (CuSO4⋅5H2O) were given orally to 2-day-old chicks. The test compound (AA) was given orally at two doses of 20 and 40 mg/kg b.w. On the other hand, aprepitant (16 mg/kg), domperidone (6 mg/kg), diphenhydramine (10 mg/kg), hyoscine (21 mg/kg), and ondansetron (5 mg/kg) were administered orally as positive controls (PCs). The vehicle was used as a control group. Combination therapies with the referral drugs were also given to three separate groups of animals to see the synergistic and antagonizing activity of the test compound. Molecular docking and visualization of ligand-receptor interaction were performed using different computational tools against various emesis-inducing receptors (D2, D3, 5HT3, H1, and M1-M5). Furthermore, the pharmacokinetics and toxicity properties of the selected ligands were predicted by using the SwissADME and Protox-II online servers. Findings indicated that AA dose-dependently enhances the latency of emetic retching and reduces the number of retching compared to the vehicle group. Among the different treatments, animals treated with AA (40 mg/kg) exhibited the highest latency (98 ± 2.44 s) and reduced the number of retching (11.66 ± 2.52 times) compared to the control groups. Additionally, the molecular docking study indicated that AA exhibits the highest binding affinity (- 10.2 kcal/mol) toward the M4 receptors and an elevated binding affinity toward the receptors 5HT3 (- 8.1 kcal/mol), M1 (- 7.7 kcal/mol), M2 (- 8.7 kcal/mol), and H1 (- 8.5 kcal/mol) than the referral ligands. Taken together, our study suggests that AA has potent antiemetic effects by interacting with the 5TH3 and muscarinic receptor interaction pathways. However, additional extensive pre-clinical and clinical studies are required to evaluate the efficacy and toxicity of AA.

The Effect of Granisetron, Ondansetron, and Meperidine in Preventing Postoperative Shivering: Controlled Clinical Trial.

BACKGROUND: Recently, use of HT35 receptor antagonists to prevent postoperative shivering has attracted a great deal of attention. This study was conducted with the aim of investigating the effectiveness of granisetron as an HT35 antagonist when compared with ondansetron and meperidine in preventing postoperative shivering. MATERIAL AND METHODS: In this triple blind random clinical trial study, 90 patients 18-50 years of age with ASA Class I and II undergoing general anesthesia were randomly assigned into one of the three drug groups: O (4-mg ondansetron), G (40 µg/kg of granisetron), and P (25 mg meperidine), immediately before induction of anesthesia. After anesthesia induction, at the end of the surgery, after the entrance and after leaving the recovery state, central temperature, peripheral temperature, heart rate, systolic blood pressure, diastolic blood pressure, and shivering were measured and documented. Two-tailed P < 0.05 was considered significant. RESULTS: In the meperidine, ondansetron, and granisetron groups, 4 (13.3%), 3 (10%), and 10 (33.3%) of patients experienced shivering during recovery, where the difference between the ondansetron and granisetron groups was significant (p-value=0.02). The variations in the mean arterial pressure during the investigation stages only in the ondansetron group were not significant (p>0.05). At the beginning of recovery, the reduction of peripheral temperature significantly was lower in the ondansetron group (p<0.05), while reduction of the central temperature was significantly (p<0.05) higher in the granisetron group. By the end of the recovery, the variations in the peripheral temperature across the three groups were consistent with the changes at the beginning of recovery, but variations of the central temperature across the three groups was not significantly diverse. CONCLUSION: Granisetron was not found to be much effective in preventing postoperative shivering. Ondansetron and meperidine were equally effective in preventing postoperative shivering. Ondansetron also causes less hemodynamic changes compared to other drugs, while granisetron is more effective in terms of preventing nausea and vomiting.

Cholecystokinin-Induced Duodenogastric Bile Reflux Increases the Severity of Indomethacin-Induced Gastric Antral Ulcers in Re-fed Mice.

BACKGROUND/AIMS: We examined the involvement of cholecystokinin (CCK) in the exacerbation of indomethacin (IND)-induced gastric antral ulcers by gastroparesis caused by atropine or dopamine in mice. METHODS: Male mice were fed for 2 h (re-feeding) following a 22-h fast. Indomethacin (IND; 10 mg/kg, s.c.) was administered after re-feeding; gastric lesions were examined 24 h after IND treatment. In another experiment, mice were fed for 2 h after a 22-h fast, after which the stomachs were removed 1.5 h after the end of the feeding period. Antral lesions, the amount of gastric contents, and the gastric luminal bile acids concentration were measured with or without the administration of the pro- and antimotility drugs CCK-octapeptide (CCK-8), atropine, dopamine, SR57227 (5-HT3 receptor agonist), apomorphine, lorglumide (CCK1 receptor antagonist), ondansetron, and haloperidol alone and in combination. RESULTS: IND produced severe lesions only in the gastric antrum in re-fed mice. CCK-8, atropine, dopamine, SR57227 and apomorphine administered just after re-feeding increased bile reflux and worsened IND-induced antral lesions. These effects were significantly prevented by pretreatment with lorglumide. Although atropine and dopamine also increased the amount of gastric content, lorglumide had no effect on the delayed gastric emptying provoked by atropine and dopamine. Both ondansetron and haloperidol significantly inhibited the increase of bile reflux and the exacerbation of antral lesions induced by atropine and dopamine, respectively, but did not affect the effects of CCK-8. CONCLUSIONS: These results suggest that CCK-CCK1 receptor signal increases bile reflux during gastroparesis induced by atropine and dopamine, exacerbating IND-induced antral ulcers.

Prevention of postoperative nausea and vomiting after orthognathic surgery: a scoping review.

INTRODUCTION: Postoperative nausea and vomiting (PONV) is one of the most common adverse events following orthognathic surgery. It's a distressing feeling for patients and continues to be the cause of postoperative complications such as bleeding, delayed healing, and wound infection. This scoping review aims to identify effective PONV prophylaxis strategies during orthognathic surgery that have emerged in the past 15 years. METHODS: We searched Pubmed, Cochrane Controlled Register of Trials, and Embase from 2008 to May 2023. Studies meeting the following criteria were eligible for inclusion: (1) recruited patients undergo any orthognathic surgery; (2) evaluated any pharmacologic or non-pharmacologic method to prevent PONV. Studies meeting the following criteria were excluded: (1) case series, review papers, or retrospective studies; (2) did not report our prespecified outcomes. RESULTS: Twenty-one studies were included in this review. Pharmacological methods for PONV prevention include ondansetron and dexamethasone (3 studies), peripheral nerve block technique (4 studies), dexmedetomidine (1 study), pregabalin (2 studies), nefopam (2 studies), remifentanil (1 study), propofol (2 studies), and penehyclidine (1 study). Non-pharmacologic methods include capsicum plaster (1 study), throat packs (2 studies) and gastric aspiration (2 studies). CONCLUSIONS: Based on current evidence, we conclude that prophylactic antiemetics like dexamethasone, ondansetron, and penehyclidine are the first defense against PONV. Multimodal analgesia with nerve block techniques and non-opioid analgesics should be considered due to their notable opioid-sparing and PONV preventive effect. For the non-pharmacological methods, throat packs are not recommended for routine use because of their poor effect and serious complications. More prospective RCTs are required to confirm whether gastric aspiration can prevent PONV effectively for patients undergoing orthognathic surgery.

Comparison of Nausea and Vomiting Incidence After Laparoscopic Cholecystectomy With Pretreatment With Haloperidol and Ondansetron: A Randomization Clinical Trial Study.

OBJECTIVE: Nausea and vomiting after surgery are the most common complications. Therefore, we performed this study to compare the effect of ondansetron and haloperidol on nausea and vomiting after laparoscopic cholecystectomy. PATIENTS AND METHODS: In this randomized clinical trial, 60 patients candidates for elective laparoscopic cholecystectomy were allocated to haloperidol (0.05 mg/kg, n = 30) and ondansetron (0.15 mg/kg, n = 30) groups. An Ocular Analog Scale was used to assess postoperative nausea and vomiting. Every 15 minutes in the recovery room, heart rate and blood pressure were measured up to 6 hours after surgery. In addition, patient satisfaction was assessed postoperatively. RESULTS: Haloperidol and ondansetron have the same effect on postoperative nausea and vomiting in the recovery room and ward. It was found that the trend of Visual Analog Scale variable changes in the recovery room was similar in the haloperidol and ondansetron group ( P = 0.58); it was also true for the ward ( P = 0.79). Comparing the length of stay in a recovery room in the 2 groups was not statistically significant ( P = 0.19). In addition, the 2 groups did not differ in satisfaction postoperatively ( P = 0.82). CONCLUSION: Haloperidol and ondansetron had an equal effect on reducing nausea and vomiting in the recovery room and ward after laparoscopic cholecystectomy. Patient satisfaction and length of stay in the recovery room did not differ between groups.

Mechanisms underlying the laxative effect of lactulose: A randomized placebo-controlled trial showing increased small bowel water and motility unaltered by the 5-HT3 receptor antagonist, ondansetron.

BACKGROUND: Lactulose is a laxative which accelerates transit and softens stool. Our aim was to investigate its mechanism of action and use this model of diarrhea to investigate the anti-diarrheal actions of ondansetron. METHODS: A double-blind, randomized, placebo-controlled crossover study of the effect of ondansetron 8 mg in 16 healthy volunteers. Serial MRI scans were performed fasted and 6 h after a meal. Participants then received lactulose 13.6 g twice daily and study drug for a further 36 h. On Day 3, they had further serial MRI scans for 4 h. Measurements included small bowel water content (SBWC), colonic volume, colonic gas, small bowel motility, whole gut transit, and ascending colon relaxation time (T1AC), a measure of colonic water content. KEY RESULTS: Lactulose increased area under the curve (AUC) of SBWC from 0 to 240 min, mean difference 14.2 L · min (95% CI 4.1, 24.3), p = 0.009, and substantially increased small bowel motility after 4 h (mean (95% CI) 523 (457-646) a.u. to 852 (771-1178) a.u., p = 0.007). There were no changes in T1AC after 36 h treatment. Ondansetron did not significantly alter SBWC, small bowel motility, transit, colonic volumes, colonic gas nor T1AC, with or without lactulose. CONCLUSION & INFERENCES: Lactulose increases SBWC and stimulates small bowel motility; however, unexpectedly it did not significantly alter colonic water content, suggesting its laxative effect is not osmotic but due to stimulation of motility. Ondansetron's lack of effect on intestinal water suggests its anti-diarrheal effect is not due to inhibition of secretion but more likely altered colonic motility.

5-HT3a receptor contributes to neuropathic pain by regulating central sensitization in a rat with brachial plexus avulsion.

PURPOSE: As a frequently occurring complication resulting from brachial plexus avulsion (BPA), neuropathic pain significantly impacts the quality of life of patients and places a substantial burden on their families. Recent reports have suggested that the 5-HT3a receptor may play a role in the development and regulation of neuropathic pain. The current study aimed to explore the involvement of the 5-HT3a receptor in neuropathic pain resulting from BPA in rats. METHODS: A rat model of neuropathic pain was induced through brachial plexus avulsion (BPA). The pain thresholds of the rats were measured after BPA. The spinal dorsal horn (SDH) of rats was collected at day 14 after surgery, and the expression and distribution of the 5-HT3a receptor were analyzed using immunohistochemistry and western blotting. The expression levels of various factors related to central sensitization were measured by western blot, including c-Fos, GFAP, IBA-1, IL-1ß and TNF-α. The effects of 5-HT3a receptor antagonists on hyperalgesia were assessed through behavioral tests after intrathecal administration of ondansetron. Additionally, at 120 min postinjection, the SDH of rats was acquired, and the change of expression levels of protiens related to central sensitization were measured by western blot. RESULTS: BPA induced mechanical and cold hypersensitivity in rats. The 5-HT3a receptor was increased and mainly distributed on neurons and microglia in the SDH after BPA, and the level of central sensitization and expression of inflammatory factors, such as c-Fos, GFAP, IBA-1, IL-1ß and TNF-α, were also increased markedly. Ondansetron, which is a selective 5-HT3a receptor antagonist, reversed the behavioral changes caused by BPA. The antagonist also decreased the expression of central sensitization markers and inflammatory factors. CONCLUSION: The results suggested that the 5-HT3a receptor is involved in neuropathic pain by regulating central nervous system sensitization in a rat brachial plexus avulsion model. Targeting the 5-HT3a receptor may be a promising approach for treating neuropathic pain after brachial plexus avulsion.

Review article: Efficacy of prophylactic ondansetron versus placebo or control in reducing vomiting in children undergoing ketamine procedural sedation in the emergency department: A systematic review and meta-analysis.

Ketamine is commonly used for procedural sedation anaesthesia in paediatric patients undergoing painful procedures in the ED. Ketamine's safety profile is excellent, but ketamine-associated vomiting (KAV) is common. Routine ondansetron prophylaxis could reduce KAV incidence. This literature review evaluated the efficacy of prophylactic ondansetron in reducing KAV incidence. A systematic literature review was performed on databases and trial registries on 14 January 2023 to identify randomised controlled trials. The primary outcome was reduction in KAV incidence, for any route of prophylactic ondansetron, in ED and up to 24 h post-discharge. ED length of stay, parental satisfaction and time to resumption of normal diet were secondary outcomes. Data analysis was performed using Revman 5.3. Meta-analysis was performed using random effects modelling. Risk of bias was assessed using the Cochrane Risk-of-Bias 2 tool. Evidence quality was assessed using Grading of Recommendation, Assessment Development and Evaluation methodology. Five trials with 920 participants met the eligibility criteria. Prophylactic ondansetron resulted in a reduction in KAV incidence overall odds ratio of 0.51 (95% confidence interval: 0.36-0.73). Intravenous and intramuscular prophylactic ondansetron showed benefit whereas the effect of oral administration was unclear. There was no difference between groups for secondary outcomes overall. The quality of evidence was deemed to be low overall because of high risk of bias and imprecision in outcome measures. This review found low to moderate certainty evidence that prophylactic ondansetron reduces KAV incidence. Methodologically rigorous research, with appropriately timed prophylactic ondansetron based on the route of administration, would further elucidate prophylactic oral ondansetron's efficacy.

Comparison of three different prophylactic treatments for postoperative nausea and vomiting after total joint arthroplasty under general anesthesia: a randomized clinical trial.

BACKGROUND: Postoperative nausea and vomiting (PONV) after total joint arthroplasty is common and associated with delayed recovery. This study was performed to evaluate the efficacy of three different prophylactic regimens for PONV after total joint arthroplasty under general anesthesia. METHODS: Patients undergoing primary total hip or knee arthroplasty were randomized to Group A (ondansetron), Group B (10 mg dexamethasone plus ondansetron and mosapride), or Group C (three doses of 10 mg dexamethasone plus ondansetron and mosapride). The primary outcome was the total incidence of PONV during postoperative 48 h. The secondary outcomes were complete response, rescue antiemetic treatment, opioid consumption, time until first defecation, postoperative appetite score, satisfaction score, length of hospital stay, blood glucose level, and complications. RESULTS: Patients in Group C experienced a lower incidence of total PONV (29.3%, p = 0.001) and a higher incidence of complete response (70.7%, p = 0.001) than did patients in Group A (51.9%, 48.2%, respectively). Patients in Group C also experienced a lower incidence of severe PONV (4.3%) than patients in Group A (25.9%, p<0.001) and B (20.4%, p<0.001). Moreover, less rescue antiemetic treatment (1.4 ± 0.5 mg Metoclopramide) and postoperative opioid consumption (1.8 ± 0.3 mg Oxycodone, 6.0 ± 1.0 mg Pethidine) was needed in Group C. Additionally, a shorter time until first defecation, shorter length of stay, and better postoperative appetite scores and satisfaction scores were detected in patients in Group C. A slight increase in the fasting blood glucose level was observed in Group C, and the complications were comparable among the groups. CONCLUSION: Combined use of ondansetron, mosapride and three doses of dexamethasone can provide better antiemetic effectiveness, postoperative appetite, bowel function recovery, and pain relief than a single dose or ondansetron only. TRIAL REGISTRATION INFORMATION: The protocol was registered at the Chinese Clinical Trial Registry (ChiCTR1800015896, April 27, 2018).

Ondansetron for the Prevention of Pruritus in Women Undergoing Cesarean Delivery With Intrathecal Opioid: A Systematic Review and Meta-Analysis.

BACKGROUND: Pruritus is a frequently reported and unpleasant side effect following intrathecal opioid use with frequency further increased among parturients. We have performed a systematic review to assess the overall efficacy of ondansetron for the prevention of pruritus in patients receiving intrathecal opioid as part of spinal anesthesia for cesarean delivery. METHODS: A literature search of MEDLINE, Embase, Cochrane, and Web of Science databases was conducted from date of inception to September 2022. Studies that included patients undergoing cesarean delivery with spinal anesthesia using intrathecal opioid were included. The primary outcome was the presence of pruritus, and the secondary outcome was time to onset of pruritus. Data from included studies were pooled for analysis using an appropriately determined random-effects model. Outcomes were presented using forest plots and 95% confidence intervals. Additional sensitivity and subgroup analysis were performed. Trial sequential analysis was conducted for the primary outcome. RESULTS: Twenty-three randomized controlled trials with a total of 2586 patients were included: 1219 received ondansetron, 1030 received a placebo, and a further 337 received a different study drug and were excluded from analysis. Opioids used in the included studies were morphine, fentanyl, and sufentanil. Patients who received ondansetron showed a significant reduction in the incidence of pruritus compared to the control group (RR, 0.81; 95% confidence interval [CI], 0.71-0.92; I 2 = 64%). There was no significant difference in pruritus onset between the groups (mean difference [MD], 17.54 minutes; 95% CI, -2.18 to 37.26; I 2 = 83%). The overall Grading of Recommendations Assessment, Development, and Evaluation (GRADE) assessment of quality of evidence was low. CONCLUSIONS: This systematic review has demonstrated a significant reduction in the incidence of pruritus following the use of ondansetron. This is in contrast to previously published meta-analyses. Studies included were of varying quality and some at high risk of bias with a high degree of statistical heterogeneity. Furthermore, high-quality and well-powered studies are required to confirm these findings.

Evaluation of palonosetron, fosaprepitant, and olanzapine as antiemetic prophylaxis for fludarabine and melphalan-based conditioning regimens prior to allogeneic hematopoietic stem cell transplants.

BACKGROUND: Limited data are available regarding efficacious antiemetic regimens to prevent chemotherapy-induced nausea and vomiting (CINV) for patients undergoing allogeneic hematopoietic stem cell transplant (HSCT). In patients aged 60 years or older, allogeneic HSCT is associated with improved survival, but tolerability of the transplant is a significant barrier. Fludarabine and melphalan (Flu-Mel) is a frequently utilized multi-day reduced intensity conditioning regimen for allogeneic HSCT. However, the optimal CINV prevention regimen is unknown. OBJECTIVE: The purpose of this study was to evaluate the efficacy of a novel CINV prophylaxis regimen prior to allogeneic HSCT with Flu-Mel compared to a historical control group. STUDY DESIGN: This was a retrospective, single-center, cohort review of 123 patients who received a Flu-Mel preparative regimen prior to allogeneic HSCT from January 1, 2019, to September 30, 2022. Fifty-nine patients received high dose ondansetron (HDO) for CINV prevention, while sixty-four patients received a combination of palonosetron, fosaprepitant, and olanzapine (PFO). The primary outcome was average number of rescue antiemetic doses administered per day. A key secondary outcome was time to first rescue antiemetic. RESULTS: The median number of antiemetic doses used per day was significantly lower in patients who received PFO compared to HDO (1.94 doses [0.31-3.60] vs 3.31 doses [1.61-4.92]; p = 0.002). In addition, use of PFO significantly prolonged the median time to first rescue antiemetic compared to HDO (41.3 h [24.3-122.7] vs 26.2 h [14.7-48.1]; p = 0.016). CONCLUSION: The combination of palonosetron, fosaprepitant, and olanzapine is an effective antiemetic regimen for patients receiving a Flu-Mel-based preparative regimen.

Comparative dose-response study on the infusion of norepinephrine combined with intravenous ondansetron versus placebo for preventing hypotension during spinal anesthesia for cesarean section: a randomised controlled trial.

BACKGROUND: Ondansetron has been reported to attenuate the incidence of spinal anaesthesia-induced hypotension (SAIH) and norepinephrine requirement during caesarean section. However, no quantitative study has evaluated the extent of this effect. This study aimed to determine the dose-response of prophylactic infusion of norepinephrine to prevent SAIH in parturients who received intravenous ondansetron or placebo before spinal anaesthesia for caesarean section. The median effective dose (ED 50 ) and 90% effective dose (ED 90 ) were compared to evaluate the effect of ondansetron versus placebo on the norepinephrine requirement. MATERIALS AND METHODS: One hundred fifty parturients undergoing caesarean section were randomized to receive either 0.1 mg/kg ondansetron (group O) or saline control (group C) 10 min before spinal anaesthesia. The parturients were randomly assigned to one of five different norepinephrine infusion groups: 0.02, 0.04, 0.06, 0.08 or 0.10 µg/kg/min. An effective infusion dose of norepinephrine was defined as non-occurrence of hypotension during the study period. The values for ED 50 and ED 90 of norepinephrine infusion were determined using probit regression. Differences between the two groups were evaluated by comparing the relative median potency with 95% CIs. RESULTS: The ED 50 values were 0.033 (95% CIs, 0.024-0.043) µg/kg/min in group C and 0.021 (95% CIs, 0.013-0.029) µg/kg/min in group O. The ED 90 values were 0.091 (95% CIs 0.068-0.147) µg/kg/min in group C and 0.059 (95% CIs 0.044-0.089) µg/kg/min in group O, respectively. The estimate of the relative median potency for norepinephrine in group C versus group O was 0.643 (95% CIs, 0.363-0.956). The incidence of side effects was comparable between groups. No significant difference in neonatal outcomes. CONCLUSION: Intravenous ondansetron 0.1 mg/kg before spinal anaesthesia significantly reduced the dose requirement of prophylactic norepinephrine infusion in parturients undergoing elective caesarean section. This finding is potentially useful for clinical practice and further research.

Ondansetron for Low Anterior Resection Syndrome (LARS): A Double-Blind, Placebo-Controlled, Cross-Over, Randomized Study.

OBJECTIVE: The aim of the study was to examine the efficacity and safety of ondansetron, a serotonin receptor antagonist, to treat patients with low anterior resection syndrome (LARS). BACKGROUND: LARS after rectal resection is common and debilitating. Current management strategies include behavioral and dietary modifications, physiotherapy, antidiarrheal drugs, enemas, and neuromodulation, but the results are not always satisfactory. METHODS: This is a randomized, multicentric, double-blinded, placebo-controlled, and cross-over study. Patients with LARS (LARS score >20) no longer than 2 years after rectal resection were randomized to receive either 4 weeks of ondansetron followed by 4 weeks of placebo (O-P group) or 4 weeks of placebo followed by 4 weeks of ondansetron (P-O group). The primary endpoint was LARS severity measured using the LARS score; secondary endpoints were incontinence (Vaizey score) and irritable bowel syndrome quality of life (IBS-QoL questionnaire). Patients' scores and questionnaires were completed at baseline and after each 4-week treatment period. RESULTS: Of 46 randomized patients, 38 were included in the analysis. From baseline to the end of the first period, in the O-P group, the mean (SD) LARS score decreased by 25% [from 36.6 (5.6) to 27.3 (11.5)] and the proportion of patients with major LARS (score >30) went from 15/17 (88%) to 7/17 (41%), ( P =0.001). In the P-O group, the mean (SD) LARS score decreased by 12% [from 37 (4.8) to 32.6 (9.1)], and the proportion of major LARS went from 19/21 (90%) to 16/21 (76%). After crossover, LARS scores deteriorated again in the O-P group receiving placebo, but further improved in the P-O group receiving ondansetron. Mean Vaizey scores and IBS QoL scores followed a similar pattern. CONCLUSIONS: Ondansetron is a safe and simple treatment that appears to improve both symptoms and QoL in LARS patients.

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.

Perioperative use of low dose haloperidol safely reduces episodes of postoperative nausea/vomiting and length of stay following elective minimally invasive bariatric surgery.

INTRODUCTION: While total intravenous anesthesia (TIVA) protocols include Dexamethasone and Ondansetron prophylaxis, bariatric patients continue to be considered at particularly high risk for postoperative nausea/vomiting (PONV). A multimodal approach for prophylaxis is recommended by the Bariatric Enhanced Recovery After Surgery (ERAS) Society however, there remains a lack of consensus on the optimal strategy to manage PONV in these patients. Haloperidol has been shown at low doses to have a therapeutic effect in treatment of refractory nausea and in PONV prophylaxis in other high risk surgical populations. We sought to investigate its efficacy as a prophylactic medication for PONV in the bariatric population and to identify which perioperative strategies were most effective at reducing episodes of PONV. METHODS: An institutional bariatric database was created by retrospectively reviewing patients undergoing elective minimally invasive bariatric procedures from 2018 to 2022. Demographic data reviewed included age, gender, preoperative body mass index (BMI), ethnicity, and primary language. Primary endpoints included patient reported episodes of PONV, total doses of Ondansetron administered, need for a second antiemetic (rescue medication), complication rate (most commonly readmission within 30 days), and length of stay. Fisher's exact test, Mann-Whitney test, and ANOVA were used to evaluate the effect of perioperative management on various endpoints. RESULTS: A total of 475 patients were analyzed with Haloperidol being utilized in 15.8% of all patients. Patients receiving Haloperidol were less likely to require Ondansetron outside of the immediate perioperative period (34.7% vs. 49.8%, p = 0.02), experienced less PONV (41.3% vs. 64.3%, p = 0.01) and also had a decreased median length of stay (27.3 vs. 35.8 h, p < 0.0001). CONCLUSIONS: Addition of low dose Haloperidol to Bariatric ERAS protocols decreases incidence of PONV and the need for additional antiemetic coverage resulting in a significantly shorter length of stay, increasing the likelihood of safe discharge on postoperative day 1.

Comparison of adding magnesium sulfate, dexmedetomidine and ondansetron to lidocaine for gargling before laryngoscopy and endotracheal intubation to prevent sore throat: a randomized clinical trial.

Postoperative sore throat is one well-recognized complication, occurring most frequently following tracheal intubation. Effective prevention of postoperative sore throat has been recognized as a top priority, bringing pleasant feelings and satisfaction to patients. This study aimed to assess the efficacy of magnesium sulfate, dexmedetomidine and ondansetron gargle with lidocaine administrated prior to laryngoscopy and tracheal intubation for postoperative sore throat prevention alongside hemodynamic management. This double-blind randomized clinical trial enrolled 105 general anesthesia-administered patients who had undergone laryngoscopy and endotracheal intubation, and they were equally randomized into three groups: magnesium sulfate, dexmedetomidine, and ondansetron groups. No significant intergroup difference was seen in oxygen saturation, non-invasive blood pressure, heart rate, duration of surgery, postoperative complications, analgesic consumption, and incidence of cough and hoarseness. The results showed statistically significant intergroup differences in pain scores and average pain intensity in the dexmedetomidine group was significantly lower than the other groups. Results suggest that dexmedetomidine gargle with lidocaine before general anesthesia induction could be recommended as an option depending on the patient's general condition and the anesthesiologist's discretion.