Medical therapies causing iatrogenic male infertility.

Primum non nocere. As physicians, our goal is to treat illnesses and alleviate suffering; however, in doing so, we can generate new problems in a game of medical whack-a-mole. For some patients, certain consequences or side effects are tolerable, while others may believe they have no alternative. For a male patient with infertility, a thorough history is imperative to elucidate whether the patient has been or is currently being exposed to medications that will harm libido, spermatogenesis, ejaculation, or the hypothalamic-pituitary-testosterone axis. This article will review the most common medications causing iatrogenic male infertility as well as options to minimize or even reverse their impact.

Potential drug-drug Interactions in hospitalized cancer patients: A report from the Middle-East.

INTRODUCTION: Patients suffering from solid tumors use a wide range of cytotoxic drugs. In this study, we aimed to detect, document, and descriptively analyze the potential drug-drug interactions in hospitalized solid tumor's patients in a Middle Eastern referral oncology-hematology University-affiliated hospital. MATERIALS AND METHODS: In this cross-sectional study, the medical record of solid tumor's patients who were admitted to the referral oncological center in Isfahan, Iran, during the six months period (2018) were considered. We included all patients who had received at least two chemotherapy or nonchemotherapy drugs simultaneously. The potential drug-drug interactions between chemotherapy and nonchemotherapy drugs were evaluated with Lexi-Interact ver.1.1 online software. RESULTS: During the study period, a total of 141 cancer patients were recruited, and their drug therapy regiment was thoroughly analyzed. We detected 227 drug-drug interactions with moderate or major severity out of included patients in which 96, 71, 32, and 28 interactions were in the category of C, D, B, and X, respectively. One hundred and fourteen patients (80.8%) encountered at least one potential drug-drug interactions during their hospitalization. Mechanistically, most of drug-drug interactions (56.4%) were pharmacodynamics. Interaction between granisetron and metoclopramide were the top 10 detected interaction (11.4%). The interaction between docetaxel and carboplatin was the most frequent drug-drug interactions between oncology drugs (2.6% of total drug-drug interactions). CONCLUSION: Potentially moderate or major drug-drug interactions frequently occur among solid tumor's cancer patients necessitate the establishment of a clinical pharmacy service for providing relevant pharmacotherapy consultations to prevent this potentially serious concern.

Comparison of weight-adjusted dose versus fixed dose ondansetron in preventing shivering following spinal anaesthesia for caesarean deliveries.

BACKGROUND: Spinal anaesthesia is an effective regional anaesthesia technique, which is preferred in almost 86% of caesarean sections in the United States and United Kingdom. Eighty percent of caesarean sections done at the Aga Khan University hospital are under spinal anaesthesia. Shivering is a common complication of spinal anaesthesia, it occurs in 40%-64% of patients after neuraxial anaesthesia. Shivering may cause maternal and fetal hypoxemia, maternal discomfort and a problem to the anaesthesiologists when it comes to monitoring the patient during caesarean sections. Ondansetron a 5-HT3 receptor antagonist is effective in treatment and prevention of post-spinal anesthesia shivering. In published studies, use of a fixed dose in patients with different weights, masked the dose effect ondansetron in preventing shivering, such that not adjusting the dose according to the weight of patients' resulted in a higher occurrence of shivering. No study has compared different doses of ondansetron in preventing shivering in parturient women who have had spinal anaesthesia for caesarean section. OBJECTIVES: To determine if a weight-adjusted dose is better than a fixed dose of ondansetron in preventing shivering following spinal anesthesia for caesarean delivery. METHOD: This was a randomized, double-blinded controlled trial of 124 women scheduled for elective caesarean surgery. The women were randomized into two equal groups. The intervention group received intravenous ondansetron weight adjusted dosing at 0.1mg/kg and the control group received a fixed dose of 4mg before spinal anesthesia. The occurrence and severity of shivering and other outcomes, such as headache, pruritus were assessed and recorded during the surgery and post-operative period. RESULTS: A total of 124 patients were included in the study. Social demographic data and baseline vital signs did not differ significantly between the groups. Shivering was observed in 14 patients (22.6%) in the control group that received 4mg ondansetron and 7 patients (11.3%) in the intervention group that had 0.1mg/kg of ondansetron, but there was no statistical difference between the groups (p- value 0.090). The severity of shivering was greater in the control group compared to intervention group where patients who developed grade two shivering were 8.1% to 0% respectively. (P value 0.047). There was no difference in the occurrence of pruritus between the two groups. No patient required treatment for very severe shivering. CONCLUSION: This study, found that ondansetron weight adjusted dose at 0.1mg/kg, reduced the severity of shivering when compared to a fixed dose ondansetron at 4mg.

What is new in the battle against postoperative nausea and vomiting?

The issue of postoperative nausea and vomiting (PONV) still poses a significant burden on our patients. Although rarely associated with a life-threatening condition, it is consistently considered as one of the most undesirable side effects of surgery and anesthesia. There are well-established risk factors for the development of PONV that include patient-related factors, anesthetic technique, use of volatile anesthetics, use of nitrous oxide, duration of anesthesia, opioid administration, and type of surgery. Because pharmacologic interventions for PONV are not without risks, practitioners must assess patient's risk status from low to high and consider the benefits of treatment. This review summarizes the current state of knowledge related to PONV and provides a practical approach toward risk assessment, prevention, and numerous treatment strategies.

A phase 2 study of fosaprepitant combined with high-dose dexamethasone for Japanese cancer patients receiving highly emetogenic chemotherapy.

PURPOSE: Combination therapy of fosaprepitant, dexamethasone (DEX) and a serotonin (5-HT3) receptor antagonist is a standard antiemetic prophylaxis for patients receiving highly emetogenic chemotherapy (HEC). However, the appropriate dose of DEX has not been established in Japan. This study determined the efficacy and safety of triplet antiemetic prophylaxis in Japanese patients receiving HEC when administered the same doses of DEX as those given in a previous international phase 3 study on this drug. METHODS: To assess the efficacy and safety of a sufficient dose of DEX (12 mg on day 1, 8 mg on day 2, 16 mg on days 3 and 4) in combination with intravenous fosaprepitant and granisetron, we prospectively examined patients receiving HEC including cisplatin (≥50 mg/m). The primary endpoint was to determine the percentage of patients who had achieved a complete response (CR), which was defined as no vomiting and no rescue therapy during the entire treatment course. RESULTS: Between February 2013 and January 2015, 44 patients were enrolled with a median age of 65 years (range, 30-75). There were 34 males (77.3%) in the study. Most of the patients had upper gastrointestinal cancers. The CR rate during the treatment course was 70% (95% confidence interval [CI]: 55%-83%) in the overall phase and 91% (95% CI: 78%-97%) in the acute phase and 70% (95% CI: 55%-83%) in the delayed phase. Appreciable severe toxicities related to the antiemetic therapy were not observed. CONCLUSIONS: These results suggest that a sufficient dose of DEX in combination with fosaprepitant and granisetron is optimal as an antiemetic prophylaxis for Japanese patients receiving HEC.

Delayed Serotonin Syndrome in the Setting of a Mixed Fluoxetine and Serotonin Antagonist Overdose.

BACKGROUND Serotonin syndrome is a condition characterized predominantly by neuromuscular symptoms and altered thermoregulation in response to serotonergic overtone. Treatment is focused on withdrawal of serotonergic agents, which leads to resolution in the majority of cases. In the setting of serotonergic overdose, the onset of serotonin syndrome is usually within 4 to 13 h. Here, we report a case of delayed-onset serotonin syndrome in a patient who ingested a mixture of longer-acting serotonin agonists with serotonin antagonists. CASE REPORT A 24-year-old male was transferred to our medical intensive care unit with hypotension and altered mental status after an overdose of fluoxetine, cyproheptadine, trazodone, olanzapine, risperidone, and bupropion. After approximately 72 h, the patient developed symptoms of fever, lower leg clonus, hyperreflexia, and agitation. He was diagnosed with delayed-onset serotonin syndrome, which responded well to re-administration of cyproheptadine, leading to resolution of symptoms by day 5 of his stay. CONCLUSIONS In this present case, our patient presented with the longest reported delay in the onset of serotonin syndrome after intentional ingestion. This was likely secondary to co-ingestion of long-acting serotonin agonists with protective shorter-acting serotonin antagonists (cyproheptadine and olanzapine). Clinicians should consider delayed-onset serotonin syndrome when patients ingest longer-acting serotonergic agents with serotonin antagonists.

In vitro and in vivo antithrombotic and cytotoxicity effects of ferulic acid.

We discovered recently in vitro and in vivo antithrombotic and cytotoxicity effects of ferulic acid. The cytotoxicity assays showed that ferulic acid (∼300 µg/mL) did not cause any significant toxicity on three cell lines, platelets, leukocytes, and erythrocytes. In vitro assays showed inhibitory effects of ferulic acid on thrombin (THR)- or collagen/epinephrine-stimulated platelet activation by inhibiting platelet aggregation, and decreasing clot retraction activity. The in vitro effect of ferulic acid on THR-stimulated platelet activation was proved by the decrease in the secretion of serotonin from the platelets. The anticoagulant effects of ferulic acid were confirmed by the prolongation of the intrinsic or/and extrinsic pathways and the delay of recalcification time in plasma coagulation. Ferulic acid had antithrombotic effect in acute thromboembolism model in vivo, and decreased the expression of αIIb ß3 /FIB and phosphorylation of AKT in THR-stimulated platelet activation in vivo, and their antithrombotic efficacies hold promise for therapeutic targeting in our ongoing studies.

The Effect of Ondansetron on Acute Opioid Tolerance in Patients Receiving Intrathecal Opioids Prior to Cesarean Delivery.

BACKGROUND: Multiple animal studies suggest that ondansetron ameliorates opioid-induced hyperalgesia and tolerance. In this study, we aimed to determine if the administration of ondansetron prior to spinal anesthesia would have an effect on intrathecal opioid-induced acute opioid tolerance, postoperative pain, and analgesic requirements in patients undergoing cesarean delivery with spinal anesthesia. METHODS: Eighty-six patients undergoing elective cesarean delivery were recruited and randomly allocated to receive either 8 mg intravenous ondansetron (n = 44) or placebo (n = 42) in a prospective, double-blind design. All patients received spinal anesthesia consisting of 15 mg bupivacaine, 20 µg of fentanyl, and 100 µg of preservative-free morphine. We used linear mixed-effects models to assess the difference in pain and opioid consumption in the first 24 hours after surgery between the 2 groups. RESULTS: No differences between the 2 groups were found in age, body mass index, American Society of Anesthesiologists physical status scores, duration of surgery, or sensory and motor block characteristics. There was no difference between the 2 groups in postoperative pain scores (P = 0.95) or opioid consumption (P = 0.68). CONCLUSIONS: In patients undergoing cesarean delivery under spinal anesthesia with intrathecal opioids, the administration of ondansetron prior to spinal anesthesia did not significantly affect postoperative pain scores or opioid consumption. Thus, the administration of ondansetron did not have an effect on acute opioid tolerance in our study.

Ziprasidone induces cytotoxicity and genotoxicity in human peripheral lymphocytes.

It has been stated that some antipsychotic drugs might cause genotoxic and carcinogenic effects. Ziprasidone (ZIP) is commonly used an antipsychotic drug. However, its genotoxicity and carcinogenicity data are very limited. The cytotoxicity and genotoxicity of ZIP on human peripheral blood lymphocytes were examined in vitro by sister chromatid exchange (SCE), chromosome aberration (CA) and micronucleus (MN) tests in this study. Lymphocyte cultures were treated with 50, 75 and 100 µg/ml of ZIP in the presence and absence of a metabolic activator (S9 mix). Dimethylsulfoxide was used as a solvent control. While the cells were treated with ZIP for 24 h and 48 h in cultures without S9 mix, the cultures with S9 mix were exposed to ZIP for 3 h. ZIP and its metabolites can exert cytotoxic activities due to significant decreases in mitotic index, proliferation index and nuclear division index in the presence and absence of S9 mix. Statistically significant increases in CAs, aberrant cells and MN values in the presence and absence of S9 mix were found in cultures treated with ZIP. While ZIP significantly increased the SCE values in the absence of S9 mix at all concentrations, increased SCE values in cultures with S9 mix were not found to significantly at all concentrations tested. Our results indicated that both ZIP and its metabolites have cytotoxic, cytostatic and genotoxic potential on lymphocyte cultures under the experimental conditions. Further studies are necessary to make a possible risk assessment in patients receiving therapy with this drug.

Meta-analysis of randomized controlled trials on the efficacy and safety of ondansetron in preventing postanesthesia shivering.

OBJECTIVES: Considerable controversy exists regarding the efficacy of ondansetron in preventing postanesthesia shivering (PAS). We performed a meta-analysis of randomized controlled trials to examine the controversy. MATERIALS AND METHODS: Randomized controlled trials assessing the effect of ondansetron on the prevention of PAS were identified from electronic databases (PubMed and EMBASE). The meta-analysis was performed with the fixed-effect model or random-effect model according to heterogeneity. RESULTS: Twelve trials randomized clinical trials met the inclusion criteria including 1205 subjects. Compared with placebo (saline), ondansetron was associated with a significant reduction of PAS (relative risk 0.33; 95% confidence interval, 0.21-0.51), Substantial heterogeneity was observed between trials (P = 0.0002; I2 = 71%). Trial sequential analysis showed that the cumulative Z-curve crossed the trial sequential monitoring boundary for benefit establishing sufficient and conclusive evidence. Meta-analysis with all five studies using a fixed-effects model suggested that ondansetron and meperidine have similar effects on the prevention of PAS (relative risk, 0.86; 95% confidence interval, 0.66-1.11), the heterogeneity was not significant (P = 0.34; I2 = 11%). No significant association of ondansetron with bradycardia was found both comparison with placebo and meperidine. CONCLUSIONS: Treat with ondansetron is safe, and may reduce PAS. This finding encourages the use of ondansetron to prevent PAS, but, more high quality randomized clinical trials are still warranted to confirm the effects of different doses of ondansetron on PAS.

Efficacy of palonosetron in postoperative nausea and vomiting (PONV)-a meta-analysis.

INTRODUCTION: Palonosetron is a second-generation 5-HT3 receptor antagonist with proposed higher efficacy and sustained action for prophylaxis of postoperative nausea and vomiting (PONV). METHODS: Randomized controlled trials involving adult population undergoing elective surgery under general anesthesia comparing palonosetron to placebo, ramosetron, granisetron, and ondansetron were included. Data were extracted for vomiting incidence (VI), complete response (no nausea/vomiting; Complete Response [CR]), and rescue antiemetic need. This was categorized as early phase (24 hours postoperative for ramosetron and 6 hours for rest) and delayed phase (48 hours for ramosetron and 24 hours for rest). VI and CR were used as markers of drug efficacy. Any adverse effects were evaluated. RESULTS: Twenty-two trials (4 with 3 groups) were included (comparing palonosetron to placebo in 5, ramosetron in 5, granisetron in 4, and ondansetron in 12 subgroups). Palonosetron demonstrated statistical superiority over placebo for VI and CR, both early/delayed PONV prevention. For delayed phase, palonosetron surpassed ramosetron in all 3 variables; however, none of the variables attained statistical significance during early phase. In early phase, palonosetron had better VI and CR than did granisetron; however, variables other than CR (better for palonosetron) failed to achieve statistical significance for delayed phase. All 3 outcomes were significantly better for palonosetron compared with ondansetron in delayed phase, but statistical superiority could only be demonstrated for VI in early phase. Being inconsistently documented across trials, nausea scores could not be evaluated. CONCLUSION: Palonosetron is as safe as and more effective than placebo, ramosetron, granisetron, and ondansetron in preventing delayed PONV. For early PONV, it has higher efficacy over placebo, granisetron, and ondansetron.

Effect of ramosetron on QTc interval: a randomised controlled trial in patients undergoing off-pump coronary artery bypass surgery.

BACKGROUND: Ramosetron is a relatively new 5-hydroxytryptamine three receptor antagonist with higher binding affinity and more prolonged duration of action compared to ondansetron. The present study was performed to evaluate the effects of ramosetron on QTc interval and possible cardiovascular adverse effects in patients undergoing cardiac surgery. METHOD: A total of 114 patients who underwent off-pump coronary artery bypass surgery were enrolled in this randomised placebo-controlled trial. Patients were allocated into two groups that received intravenous injection of 0.3 mg ramosetron or normal saline during induction of anaesthesia. QTc intervals were measured before the operation, intraoperatively (0, 1, 2, 3, 5, 10, 15, 30, 45, 60, 90, 120, and 240 min after injection of ramosetron or normal saline), at the end of the operation, and on postoperative day 1. RESULTS: There were no differences in mean QTc interval between groups at every time point. However, maximal change in QTc interval during surgery was higher in the ramosetron group than the placebo group (25.1 ± 22.0 vs. 17.5 ± 14.5 ms, 95 % CI 0.34-14.78, P = 0.040). Also, there were more patients with a QTc interval increase of > 60 ms in the ramosetron group (5 vs. 0, 95 % CI 1.6-18.0, P = 0.021). There were no significant differences in cardiovascular complications. CONCLUSIONS: Ramosetron administered during induction of anaesthesia may affect maximal change in QTc interval during off-pump coronary artery bypass surgery. Ramosetron should be used with caution in high risk patients for developing Torsades de Pointes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02139241. Registered November 12, 2013.

Randomized, double-blind, phase III trial of palonosetron versus granisetron in the triplet regimen for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy: TRIPLE study.

BACKGROUND: There has been no phase III study of comparing the efficacy of first- and second-generation 5-HT3 receptor antagonists in the triplet regimen with dexamethasone and aprepitant for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy (HEC). PATIENTS AND METHODS: Patients with a malignant solid tumor who would receive HEC containing 50 mg/m(2) or more cisplatin were randomly assigned to either palonosetron (0.75 mg) arm (Arm P) or granisetron (1 mg) arm (Arm G), on day 1, both arms with dexamethasone (12 mg on day 1 and 8 mg on days 2-4) and aprepitant (125 mg on day 1 and 80 mg on days 2-3). The primary end point was complete response (CR; no vomiting/retching and no rescue medication) at the 0-120 h period and secondary end points included complete control (CC; no vomiting/retching, no rescue medication, and no more than mild nausea) and total control (TC; no vomiting/retching, no rescue medication, and no nausea). RESULTS: Between July 2011 and June 2012, 842 patients were enrolled. Of 827 evaluable, 272 of 414 patients (65.7%) in Arm P had a CR at the 0-120 h period when compared with 244 of 413 (59.1%) in Arm G (P = 0.0539). Both arms had the same CR rate of 91.8% at the acute (0-24 h) period, while at the delayed (24-120 h) period, Arm P had a significantly higher CR rate than Arm G (67.2% versus 59.1%; P = 0.0142). In secondary end points, Arm P had significantly higher rates than Arm G at the 0-120 h period (CC rate: 63.8% versus 55.9%, P = 0.0234; TC rate: 47.6% versus 40.7%, P = 0.0369) and delayed periods (CC rate: 65.2% versus 55.9%, P = 0.0053; TC rate: 48.6% versus 41.4%, P = 0.0369). CONCLUSION: The present study did not show the superiority of palonosetron when compared with granisetron in the triplet regimen regarding the primary end point. CLINICAL TRIAL REGISTRY IDENTIFIER: UMIN000004863.

Ischemic Colitis as a Complication of Medication Use: An Analysis of the Federal Adverse Event Reporting System.

BACKGROUND: More than one decade ago, rising cases of ischemic colitis (IC) prompted the Federal Drug Administration to revoke alosetron's approval as treatment of irritable bowel syndrome (IBS). The aim of this study was to identify medical therapies associated with development of IC. METHODS: The Federal Adverse Event Reporting System was queried for the time between January 2004 and September 2015. We identified reports listing IC as treatment complication and extracted suspected causative and concomitantly administered drugs, indications for their use and outcomes. RESULTS: After eliminating duplicates, we found 2811 cases of IC (68.4 % women; 59.4 ± 0.4 years). Patients with IBS accounted for 3.9 % of the cases, mostly attributed to tegaserod or alosetron. Chemotherapeutic and immunosuppressive drugs, sex hormones, and anticoagulants were the most commonly suspected causes. Bisphosphonates, nonsteroidal anti-inflammatory drugs, antipsychotics, triptans, interferon therapy, and laxative use prior to colonoscopy were among the more commonly listed treatments. In 8 %, the adverse event contributed to the patient's death with male sex and older age predicting fatal outcomes. CONCLUSION: Beyond confirming known risks of IC, the results identified several potential culprits of ischemic colitis. This information may not only explain the development of this serious adverse event, but could also guide treatment decisions, cautioning healthcare providers when considering these agents in persons with known risk factors or other drugs that may increase their risk of IC.

Emerging Role of Olanzapine for Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting.

The prevention and treatment of chemotherapy-induced nausea and vomiting (CINV) continues to pose a challenge for clinicians. The development of 5-hydroxytryptamine (serotonin) antagonists and neurokinin-1 receptor antagonists (NK1 -RAs) have demonstrated significant improvements in acute and delayed CINV for highly and moderately emetogenic chemotherapy. Delayed and breakthrough CINV, however, continue to be difficult to manage despite available treatment agents. Randomized clinical trial data suggest that olanzapine, a second-generation thienobenzodiazepine, traditionally used in the treatment of manifestations of psychotic disorders, is an effective agent in these clinical settings. The short-term use of olanzapine has a favorable adverse event profile and was not associated with grade 3 or 4 toxicity in a phase III study. Olanzapine is recommended as an option within first-line prophylaxis for CINV in the National Comprehensive Cancer Network (NCCN) guidelines and is an option for treatment of refractory CINV in the Multinational Association of Supportive Care in Cancer/European Society for Medical Oncology and NCCN guidelines.

Antiemetic medication for prevention and treatment of chemotherapy-induced nausea and vomiting in childhood.

BACKGROUND: Nausea and vomiting remain a problem for children undergoing treatment for malignancies despite new antiemetic therapies. Optimising antiemetic regimens could improve quality of life by reducing nausea, vomiting, and associated clinical problems. This is an update of the original systematic review. OBJECTIVES: To assess the effectiveness and adverse events of pharmacological interventions in controlling anticipatory, acute, and delayed nausea and vomiting in children and young people (aged less than 18 years) about to receive or receiving chemotherapy. SEARCH METHODS: Searches included the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, LILACS, PsycINFO, conference proceedings of the American Society of Clinical Oncology, International Society of Paediatric Oncology, Multinational Association of Supportive Care in Cancer, and ISI Science and Technology Proceedings Index from incept to December 16, 2014, and trial registries from their earliest records to December 2014. We examined references of systematic reviews and contacted trialists for information on further studies. We also screened the reference lists of included studies. SELECTION CRITERIA: Two review authors independently screened abstracts in order to identify randomised controlled trials (RCTs) that compared a pharmacological antiemetic, cannabinoid, or benzodiazepine with placebo or any alternative active intervention in children and young people (less than 18 years) with a diagnosis of cancer who were to receive chemotherapy. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted outcome and quality data from each RCT. When appropriate, we undertook meta-analysis. MAIN RESULTS: We included 34 studies that examined a range of different antiemetics, used different doses and comparators, and reported a variety of outcomes. The quality and quantity of included studies limited the exploration of heterogeneity to narrative approaches only.The majority of quantitative data related to the complete control of acute vomiting (27 studies). Adverse events were reported in 29 studies and nausea outcomes in 16 studies.Two studies assessed the addition of dexamethasone to 5-HT3 antagonists for complete control of vomiting (pooled risk ratio (RR) 2.03; 95% confidence interval (CI) 1.35 to 3.04). Three studies compared granisetron 20 mcg/kg with 40 mcg/kg for complete control of vomiting (pooled RR 0.93; 95% CI 0.80 to 1.07). Three studies compared granisetron with ondansetron for complete control of acute nausea (pooled RR 1.05; 95% CI 0.94 to 1.17; 2 studies), acute vomiting (pooled RR 2.26; 95% CI 2.04 to 2.51; 3 studies), delayed nausea (pooled RR 1.13; 95% CI 0.93 to 1.38; 2 studies), and delayed vomiting (pooled RR 1.13; 95% CI 0.98 to 1.29; 2 studies). No other pooled analyses were possible.Narrative synthesis suggests that 5-HT3 antagonists are more effective than older antiemetic agents, even when these agents are combined with a steroid. Cannabinoids are probably effective but produce frequent side effects. AUTHORS' CONCLUSIONS: Our overall knowledge of the most effective antiemetics to prevent chemotherapy-induced nausea and vomiting in childhood is incomplete. Future research should be undertaken in consultation with children, young people, and families that have experienced chemotherapy and should make use of validated, age-appropriate measures. This review suggests that 5-HT3 antagonists are effective in patients who are to receive emetogenic chemotherapy, with granisetron or palonosetron possibly better than ondansetron. Adding dexamethasone improves control of vomiting, although the risk-benefit profile of adjunctive steroid remains uncertain.

Evaluation of weight-adjusted doses of palonosetron for prevention of postoperative nausea and vomiting in day care laparoscopic gynaecological surgery: A dose ranging, randomised controlled trial.

BACKGROUND: Palonosetron 75 mcg is being used for the prevention of postoperative nausea and vomiting. However, weight-adjusted doses in laparoscopic surgery are unevaluated. AIM: To determine the response to three doses of palonosetron (0.5, 1.0, or 1.5 mcg kg⁻¹) over 72 h in the postoperative period in women undergoing laparoscopic gynaecological procedures. DESIGN: A randomised dose-response study. SETTING: A tertiary care hospital and research institute in north India from July to December 2014. PATIENTS: American society of Anesthesiologists physical status I and II women, from 18 to 60 years old, undergoing laparoscopic gynaecological procedures on a day care basis. METHODS: Patients were randomised to receive palonosetron 0.5, 1 and 1.5 mcg kg⁻¹ intravenously before induction of anaesthesia. MAIN OUTCOMES MEASURES: The primary outcome was the proportion of patients with a complete response (i.e. who neither vomited nor required additional antiemetic drugs for nausea during the first 72 postoperative hours). The proportion of patients having nausea or emetic episodes and the requirement for rescue antiemetics and analgesics during the 72-h period were recorded as secondary outcomes. RESULTS: With palonosetron, there was a significant dose-dependent increase (37.5 vs. 67.5 vs. 75%, P < 0.001) in proportion of patients with a complete response during the 72 h. This was associated with a significant dose-dependent decrease in the proportion of patients with nausea (77.5 vs. 47.5 vs. 35%, P < 0.001) and vomiting (47.5 vs. 32.5 vs. 12.5%, P = 0.003). CONCLUSION: Following laparoscopic gynaecological surgery, intravenous palonosetron has a dose-dependent prophylactic effect against postoperative nausea and vomiting during the first 72 postoperative hours. TRIAL REGISTRATION: The trial was registered with Clinical trial registry of India(CTRI/2014/09/004987).

Alizapride and ondansetron for the prevention of postoperative nausea and vomiting in patients undergoing laparoscopic gynaecological surgery: A double-blind, randomised, placebo-controlled noninferiority study.

BACKGROUND: Postoperative nausea and vomiting (PONV) can be prevented. Alizapride is an established antiemetic that may be effective in this role. OBJECTIVE: Our primary objective was to test the hypothesis that alizapride is noninferior to ondansetron for the prophylaxis of PONV. DESIGN: A randomised, placebo-controlled, double-blinded noninferiority study. SETTING: University hospitals of Leuven, Belgium, from November 2008 to July 2011. PATIENTS: A total of 523 patients undergoing laparoscopic gynaecological surgery were included in the study. Reasons for exclusion were American Society of Anesthesiologists (ASA) greater than 2, hypersensitivity to the study medication, pregnancy, mental disorders, psychiatric illness or consumption of antiemetic drugs within 24 h before initiation of the study. INTERVENTION: Patients received either alizapride 100 mg, ondansetron 4 mg or placebo intravenously 30 min before the end of surgery. MAIN OUTCOME MEASURES: The main outcome measures included the incidences of postoperative nausea (PON) and postoperative vomiting (POV) during the stay in the postanaesthetic care unit (PACU), with noninferiority testing for alizapride versus ondansetron. The region of noninferiority was defined as a relative difference in incidence of 25%. Secondary outcome was the incidence of PONV in the PACU and after 24 h. RESULTS: In the alizapride group, 32% of the patients experienced PON during the PACU stay, compared with 28% in the ondansetron group [relative risk 1.13, 90% confidence interval (CI) 0.87 to 1.46], exceeding the predefined margin of noninferiority. With respect to the incidences of POV during the PACU stay, 12.8% of the patients randomised to receive alizapride experienced POV, compared with 7.7% of who received ondansetron (relative risk 1.67, 90% CI 1.00 to 2.87). The incidences of PON and POV in the placebo group during the PACU stay were 34.2 and 9.8%, respectively. The 24-h incidences of PONV were lower than expected in this high-risk group of patients and were similar at 39.3, 36.8 and 31.5% in the placebo, alizapride and ondansetron groups, respectively (χ², P = 0.36). Patients treated with ondansetron required significantly less rescue medication than placebo-treated patients (P = 0.035). Due to the lower than expected incidences of PONV in this study, the power to conclude any noninferiority of alizapride was reduced to only 41%. CONCLUSION: We found no evidence to support the noninferiority of alizapride 100 mg when compared with ondansetron 4 mg for the intraoperative prophylaxis of PONV. However, the lower than expected incidences of PONV reduced the power of this study to conclude noninferiority or confirm significant beneficial effects for either antiemetic for PON and POV during the PACU stay. TRIAL REGISTRATION: Eudra CT 2008-004789-20.

Effect of single doses of IV palonosetron, up to 2.25 mg, on the QTc interval duration: a double-blind, randomized, parallel group study in healthy volunteers.

PURPOSE: The use of serotonin type 3 (5-HT3) receptor antagonists (RAs) in the prevention of nausea and vomiting caused by emetogenic chemotherapy is part of a comprehensive management strategy for patients undergoing chemotherapy. Electrocardiographic effects have been reported in patients after intravenous administration of 5-HT3 RAs. The present study investigated the electrocardiogram (ECG) profile of the 5-HT3 RA palonosetron following International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) E14 Guidelines. METHODS: A total of 221 healthy subjects (101 females, 120 males) were randomized in this phase I, double-blind, double-dummy, parallel group study and assigned to one of five treatments: placebo, palonosetron (0.25, 0.75, or 2.25 mg), or moxifloxacin (400 mg). ECGs were recorded for 24 h pre-dosing until 48 h post-dose. The primary endpoint was the placebo time-matched and baseline-subtracted individual QTc interval prolongation (ΔΔQTcI). RESULTS: The QTc interval was not prolonged after administration of palonosetron (ΔΔQTcI upper confidence interval was <10 ms for all time points in all palonosetron treatment groups). Assay sensitivity was confirmed with the expected change in the QTc interval after administration of the positive control moxifloxacin. CONCLUSIONS: Palonosetron, even at supratherapeutic doses, has no effect on cardiac repolarization as measured by the QTc interval in a validated controlled clinical trial.