Ramosetron for the treatment of irritable bowel syndrome with diarrhea: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Ramosetron is a potent and selective serotonin type 3 receptor antagonist. This meta-analysis aimed to analyze the efficacy and safety of ramosetron for irritable bowel syndrome with diarrhea (IBS-D). METHODS: Pubmed, MEDLINE, EMBASE and the Cochrane Library were searched for randomized controlled trials investigating the efficacy and safety of ramosetron for IBS-D. Risk of bias was assessed as described in the Cochrane handbook. A random effects model was used to calculate the effects of ramosetron vs placebo on symptomatic improvements, including relief of overall IBS symptoms, relief of abdominal discomfort/pain, improvement in abnormal bowel habits, and improvement in stool consistency, expressed as pooled relative risks (RRs) with 95% confidence interval (CI). Adverse events data were also summarized with RRs. RESULTS: Four randomized controlled trials involving 1623 participants were included. Compared with placebo, ramosetron could lead to relief of overall IBS symptoms (RR 1.70; 95%CI 1.48, 1.95), relief of abdominal discomfort/pain (RR 1.41; 95%CI, 1.24, 1.59), improvement in abnormal bowel habits (RR 1.72; 95%CI, 1.50, 1.98) and improvement in stool consistency (RR 1.71; 95%CI 1.40, 2.08). Ramosetron could lead to relief of overall IBS symptoms in both male and female patients (RR; 95%CI: 1.94; 1.58, 2.38 and 1.49; 1.25, 1.79). The RR (95%CI) for reported adverse events of ramosetron vs placebo was 1.10 (0.97, 1.26) across all studies. No serious adverse events (e.g., ischemic colitis) were reported. The incidences of hard stool and constipation were higher in ramosetron group compared with placebo group (RR; 95%CI: 4.74; 3.00, 7.51 and 2.53; 1.57, 4.10, respectively). CONCLUSIONS: Ramosetron had beneficial effects to both male and female IBS-D patients. Treatment with ramosetron could cause more hard stool and constipation, without severe adverse events.

Prophylactic Effects of Ephedrine, Ondansetron and Ringer on Hemodynamic Changes during Cesarean Section under Spinal Anesthesia - a randomized clinical trial.

BACKGROUND: Hemodynamic change during spinal anaesthesia for cesarean section is prevalent. OBJECTIVE: Comparing the prophylactic effects of ephedrine, ondansetron and ringer on hemodynamic changes in patients undergoing cesarean section with spinal anaesthesia. MATERIAL AND METHODS: This randomized clinical trial was carried out on pregnant women undergoing elective cesarean sec-tion referred to teaching hospitals of Mashhad, Iran. Patients allocated to three groups of intravenous ondansetron (O) (4 mg, 5 min),intramuscular ephedrine (E) (25 mg, 25 min) and ringer (R) (500 ml, 20 min) prior to spinal anaesthesia. Anaesthesia inducted with 10-15 mg of bupivacaine. Vital signs were recorded every 3 minutes for 18 minutes including systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), pulse rate (PR), pulse oximetry (SpO2). RESULTS: Ninety patients with a mean age of 29.4 ± 5.4 years were studied in three groups of O (n = 30), E (n = 30), R (n = 30). Results showed a statistically significant difference in the incidence rate of hypotension 12 minutes after spinal anaesthesia in the three groups, but no statistically significant difference was found in the rest of minutes among the three groups. Dur-ing follow-up minutes, bradycardia was observed in only one patient (1.1%) of Group O and no cases of this sign were observed in other minutes and other groups. CONCLUSION: Intramuscular administration of ephedrine 25 minutes prior to the spinal anaesthesia leads to better prevention of systolic blood pressure changes compared with intravenous ondansetron and ringer, while administration of ondansetron and ringer had the same effects on reducing hemodynamic changes.

Ramosetron Reduces Symptoms of Irritable Bowel Syndrome With Diarrhea and Improves Quality of Life in Women.

BACKGROUND & AIMS: Previous studies have indicated that serotonin-3-receptor antagonists might have a sex-specific effect in patients with irritable bowel syndrome with diarrhea (IBS-D). Alosetron has been approved for the treatment of only women, and ramosetron has been approved for the treatment for only men. We performed a randomized, placebo-controlled, phase 3 study to determine whether ramosetron reduces symptoms of IBS-D in women. METHODS: We performed a prospective study of 576 female outpatients with IBS-D (according to the Rome III criteria), from February 2013 through February 2014, at 70 academic Gastroenterology Departments in Japan. After a 1-week baseline period, subjects received either 2.5 µg ramosetron (n = 292) or placebo (n = 284) once daily for 12 weeks. Primary end points were the monthly rates of response for relief from overall IBS symptoms and increased stool consistency at the last evaluation point. Quality of life (QOL) also was quantified. RESULTS: A significantly higher proportion of patients given ramosetron reported global improvement (50.7%; 95% confidence interval [CI], 44.8-56.6) than patients given placebo (32.0%; 95% CI, 26.7-37.8)--a difference of 18.6% (95% CI, 10.7-26.5; P < .001). The relative risk was 1.58 (95% CI, 1.29-1.94) and the number needed to treat was 6 (95% CI, 4-10). A significantly higher proportion of patients in the ramosetron group reported increased stool consistency (40.8%; 95% CI, 35.1%-46.6%) than in the placebo group (24.3%; 95% CI, 19.4%-29.7%)--a difference of 16.5% (95% CI, 8.9%-24.0%; P < .001). Patients receiving ramosetron had significant reductions in abdominal pain and discomfort (P = .001) and greater improvement in QOL (P = .002) compared with placebo. Ramosetron induced constipation in 11.0% of patients. CONCLUSIONS: In a randomized, placebo-controlled study of 576 women with IBS-D, 2.5 µg ramosetron per day reduced symptoms and increased stool consistency and QOL. Clinicaltrials.gov no: NCT01870895.

Comparative safety and effectiveness of serotonin receptor antagonists in patients undergoing chemotherapy: a systematic review and network meta-analysis.

BACKGROUND: Although serotonin (5-HT3) receptor antagonists are effective in reducing nausea and vomiting, they may be associated with increased cardiac risk. Our objective was to examine the comparative safety and effectiveness of 5-HT3 receptor antagonists (e.g., dolasetron, granisetron, ondansetron, palonosetron, tropisetron) alone or combined with steroids for patients undergoing chemotherapy. METHODS: We searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception until December 2015 for studies comparing 5-HT3 receptor antagonists with each other or placebo in chemotherapy patients. The search results were screened, data were abstracted, and risk of bias was appraised by pairs of reviewers, independently. Random-effects meta-analyses and network meta-analyses (NMAs) were conducted. RESULTS: After screening 9226 citations and 970 full-text articles, we included 299 studies (n = 58,412 patients). None of the included studies reported harms for active treatment versus placebo. For NMAs on the risk of arrhythmia (primary outcome; three randomized controlled trials [RCTs], 627 adults) and mortality (secondary outcome; eight RCTs, 4823 adults), no statistically significant differences were observed between agents. A NMA on the risk of QTc prolongation showed a significantly greater risk for dolasetron + dexamethasone versus ondansetron + dexamethasone (four RCTs, 3358 children and adults, odds ratio 2.94, 95% confidence interval 2.13-4.17). For NMAs on the number of patients without nausea (44 RCTs, 11,664 adults, 12 treatments), number of patients without vomiting (63 RCTs, 15,460 adults, 12 treatments), and number of patients without chemotherapy-induced nausea or vomiting (27 RCTs, 10,924 adults, nine treatments), all agents were significantly superior to placebo. For a NMA on severe vomiting (10 RCTs, 917 adults), all treatments decreased the risk, but only ondansetron and ramosetron were significantly superior to placebo. According to a rank-heat plot with the surface under the cumulative ranking curve results, palonosetron + steroid was ranked the safest and most effective agent overall. CONCLUSIONS: Most 5-HT3 receptor antagonists were relatively safe when compared with each other, yet none of the studies compared active treatment with placebo for harms. However, dolasetron + dexamethasone may prolong the QTc compared to ondansetron + dexamethasone. All agents were effective for reducing risk of nausea, vomiting, and chemotherapy-induced nausea or vomiting. TRIAL REGISTRATION: This study was registered at PROSPERO: ( CRD42013003564 ).

Combination of 5-HT3 Antagonist and Dexamethasone Is Superior to 5-HT3 Antagonist Alone for PONV Prophylaxis After Laparoscopic Surgeries: A Meta-analysis.

INTRODUCTION: 5-Hydroxytryptamine type 3 (5-HT3) receptor antagonists are the most commonly used drugs for postoperative nausea vomiting (PONV) prophylaxis. Dexamethasone is another antiemetic with proven efficacy in reducing PONV. The aim of this study was to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) to compare the combination of dexamethasone and 5-HT3 antagonist versus a 5-HT3 antagonist alone as prophylaxis of PONV in laparoscopic surgical patients. METHODS: PubMed, PubMed Central, and CENTRAL databases were searched to identify those randomized trials that compared a 5-HT3 antagonist with the 5-HT3 antagonist and dexamethasone combination for PONV prophylaxis after laparoscopic surgeries. RESULTS: Data from 17 RCTs that evaluated 1402 patients were included. Results from our meta-analysis show that the combination of dexamethasone and a 5-HT3 receptor antagonist is more effective in preventing PONV than the 5-HT3 antagonist alone (odds ratio 0.38, 95% confidence interval [CI] 0.27-0.54; number needed to treat = 6.6), with no statistical heterogeneity (I = 0) among studies. The need for rescue antiemetic is also decreased in patients receiving the combination (odds ratio 0.21, 99% CI 0.10-0.46; number needed to treat = 6), although data are insufficient to detect any significant difference in incidence of adverse effects. In addition, patients in the combination group complained of less pain after 24 hours (Weighted Mean Difference -0.67, 99% CI -1.27 to -0.08). CONCLUSION: Combination of a 5-HT3 receptor antagonist and dexamethasone is significantly more effective than 5-HT3 antagonist alone in preventing PONV after laparoscopic surgeries, with possible improvement in postoperative analgesia.

Ondansetron and pregnancy: possible congenital heart defects.

Two cohort studies, including more than 2500 pregnant women exposed to ondansetron in early pregnancy, have raised concerns over an increased risk of congenital heart defects.

Theoretical evaluation of antiemetic effects of 5-HT3 receptor antagonists for prevention of vomiting induced by cisplatin.

5-HT(3) receptor antagonists are widely used as antiemetic agents in clinical setting, of which palonosetron, with a long elimination half life (t(1/2)), has recently become available. It is important to evaluate the concentration of serotonin when investigating the antiemetic effects of 5-HT(3) receptor antagonists, as those effects are not based solely on the t(1/2) value. We theoretically evaluated the antiemetic effects of three 5-HT(3) receptor antagonists (granisetron, azasetron, palonosetron) on cisplatin-induced nausea and vomiting by estimating the time course of the 5-HT(3) receptor occupancy of serotonin. We estimated the 5-HT(3) receptor occupancy of serotonin in the small intestine, based on the time course of plasma concentration of each 5-HT(3) receptor antagonist and the time course of concentration of serotonin near the 5-HT(3) receptor in the small intestine after administration of cisplatin. The antiemetic effect of each 5-HT(3) receptor antagonist was evaluated based on the normal level of 5-HT(3) receptor occupancy of serotonin. Our results suggest that an adequate antiemetic effect will be provided when a dose of 75 mg/m(2) of cisplatin is given to patients along with any single administration of granisetron, azasetron, or palonosetron at a usual dose. On the other hand, the 5-HT(3) receptor occupancy of serotonin was found to be significantly lower than normal for several days after administration of palonosetron, as compared to granisetron and azasetron, indicating that constipation may be induced. Our results show that granisetron, azasetron, and palonosetron each have an adequate antiemetic effect after administration of 75 mg/m(2) of cisplatin.

Safety and compliance of long-term low-dose ondansetron in alcohol use disorder treatment.

BACKGROUND: The increasing prevalence of alcohol use disorder (AUD) and the parallel surge in alcohol-associated liver disease (ALD) emphasize the urgent need for comprehensive alcohol management strategies. Low-dose ondansetron (AD04, a 5-HT3 antagonist) was shown recently to be a promising treatment for AUD with a specific genotypic profile (5-marker). The liver safety of AD04 has never been evaluated in subjects with AUD. The aim of the present study was to assess the liver safety profile of AD04 compared with placebo in subjects with AUD. METHODS: Liver biochemical parameters were assessed in subjects with AUD with a 5-marker genetic profile who participated in a Phase 3 randomized controlled trial and received either twice-daily, low-dose AD04 (ondansetron 0.33 mg twice daily) or matching placebo, combined with brief psychosocial counseling. ALT, AST, GGT, Serum Bilirubin, MCV, and Prothrombin were evaluated at weeks 0, 12, and 24. Adverse cardiac events, general well-being, and study completion were also assessed. RESULTS: Low-dose AD04 did not significantly change biochemical markers of liver injury, such as ALT, AST, and Serum Bilirubin. While patients with AUD displayed elevated GGT levels, typically associated with increased alcohol consumption, this parameter remained unaffected by low-dose AD04. Notably, no significant adverse effects were observed due to oral low-dose AD04 treatment. CONCLUSIONS: Low-dose AD04 has the potential to be a safe treatment option for subjects with AUD and ALD, indicating the need for an RCT for this specific cohort. Such a trial would pave the way for the design of a precision treatment for combined AUD with ALD.

Does pharmacogenomics account for variability in control of acute chemotherapy-induced nausea and vomiting with 5-hydroxytryptamine type 3 receptor antagonists?

Chemotherapy-induced nausea and vomiting is one of the most concerning adverse drug effects from cytotoxic chemotherapy. Despite appropriate use of antiemetic guidelines, 20-30 % of patients experience breakthrough nausea and vomiting secondary to chemotherapy. To assess the variability of 5-hydroxytryptamine type 3 receptor antagonist efficacy caused by genetic variation, a review of the available literature was conducted. From the literature, three sources of pharmacogenomic variability were identified: polymorphisms associated with 5-hydroxytryptamine type 3 receptor subunits, drug metabolism via cytochromes P450, and drug transport in the body. Testing for receptor subunit polymorphisms is not applicable to a clinical setting at this time; however, cytochrome P450 2D6 testing is FDA-approved and widely accessible. Cytochrome P450 2D6 ultrarapid metabolizers and poor metabolizers displayed altered antiemetic efficacy when compared with intermediate metabolizers and extensive metabolizers. We postulate that testing for cytochrome P450 2D6 phenotypes may be the most accessible way to provide individualized antiemetic therapy in the future.

The efficacy of triplet antiemetic therapy with 0.75 mg of palonosetron for chemotherapy-induced nausea and vomiting in lung cancer patients receiving highly emetogenic chemotherapy.

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) are some of the most problematic symptoms for cancer patients. Triplet therapy consisting of a 5HT3 receptor antagonist, aprepitant, and dexamethasone is a guideline-recommended antiemetic prophylaxis for highly emetogenic chemotherapy (HEC). The efficacy and safety of triplet therapy using a 0.75-mg dose of palonosetron have not yet been investigated. We performed a prospective phase II study using triplet antiemetic therapy with 0.75 mg of palonosetron. METHODS: Chemotherapy-naïve lung cancer patients scheduled to receive HEC were enrolled. The eligible patients were pretreated with antiemetic therapy consisting of the intravenous administration of 0.75 mg of palonosetron, and 9.9 mg of dexamethasone and the oral administration of 125 mg of aprepitant on day 1, followed by the oral administration of 80 mg of aprepitant on days 2-3 and the oral administration of 8 mg of dexamethasone on days 2-4. The primary endpoint was the complete response rate (the CR rate; no vomiting and no rescue medication) during the overall phase (0-120 h). RESULTS: The efficacy analysis was performed in 63 patients. The CR rates during the overall, acute and delayed phases were 81.0, 96.8, and 81.0%, respectively. The no nausea and no significant nausea rate during the overall phase were 54.0 and 66.7%, respectively. The most common adverse event was grade 1 or 2 constipation. CONCLUSIONS: Triplet antiemetic therapy using a 0.75-mg dose of palonosetron shows a promising antiemetic effect in preventing CINV in lung cancer patients receiving HEC.

Aprepitant plus palonosetron and dexamethasone for prevention of chemotherapy-induced nausea and vomiting in patients receiving multiple-day cisplatin chemotherapy.

BACKGROUND: Chemotherapy-induced nausea and vomiting remain among the most feared adverse effects for cancer patients. AIM: The aim of this study was to evaluate the efficacy and safety of a combination of aprepitant, palonosetron and dexamethasone as antiemetic prophylaxis in patients receiving multiple-day cisplatin-based chemotherapy. METHODS: Forty-one solid cancer patients received aprepitant, palonosetron and dexamethasone during a 3-day cisplatin-based chemotherapy. Primary end-point was complete response in the overall phase (day 1 until 5 days after the end of chemotherapy). RESULTS: Aprepitant in combination with palonosetron and dexamethasone was safe, with hiccups (31.7%), fatigue (17.1%), headache (14.6%) and constipation (12.2%) the most common treatment-related adverse events, mostly mild. Complete response was seen in 58.5% of patients in the overall phase. In 23 patients receiving aprepitant in combination with palonosetron and dexamethasone more than one cycle (range: 2-5 cycles), the cumulative emetic protection rate after five cycles was 0.82. CONCLUSION: This study shows aprepitant in combination with palonosetron and dexamethasone is safe and effectively controls chemotherapy-induced nausea and vomiting in patients undergoing 3-day cisplatin-based chemotherapy, moreover, the efficacy is maintained during multiple cycles.

Comparative efficacy and safety of palonosetron with the first 5-HT3 receptor antagonists for the chemotherapy-induced nausea and vomiting: a meta-analysis.

A number of studies have reported the difference between the 5-HT3 receptor antagonists and palonosetron in preventing the chemotherapy-induced nausea and vomiting (CINV). Through analysing the efficacy and safety in palonosetron-treated patients, it can provide evidence for palonosetron administration. We identified randomised controlled clinical trials comparing palonosetron with the first-generation 5-HT3 receptor antagonists in the prevention of CINV in cancer patients. Nine studies investigated the outcomes in a total of 3463 cases. Compared with the first-generation 5-HT3 receptor antagonists, the cumulative incidences of emesis were significantly reduced in the patients treated with palonosetron (0.25 mg i.v.) on the first day [relative risk (RR) = 1.11, 95% confidence interval (CI): 1.05-1.17], from 2 to 5 days (RR = 1.26, 95% CI: 1.16-1.36) and the overall five days (RR = 1.23, 95% CI: 1.13-1.34). Regarding the drug safety, there was no significant difference between palonosetron-treated group and the first-generation 5-HT3 receptor antagonists-treated group. Results from the analysis suggest that palonosetron is highly effective in preventing nausea and vomiting in the days after administration of moderately or highly emetogenic chemotherapy agents.

Potential Roles of 5-HT3 Receptor Antagonists in Reducing Chemotherapy-induced Peripheral Neuropathy (CIPN).

5-HT3 receptor antagonists corresponding to ondansetron, granisetron, tropisetron, and palonosetron are clinically accustomed to treating nausea and emesis in chemotherapy patients. However, current and previous studies reveal novel potentials of those ligands in other diseases involving the nervous system, such as addiction, pruritus, and neurological disorders, such as anxiety, psychosis, nociception, and cognitive function. This review gathers existing studies to support the role of 5-HT3 receptors in CIPN modulation. It has been reported that chemotherapy drugs increase the 5-HT content that binds with the 5-HT3 receptor, which later induces pain. As also shown in pre-clinical and clinical studies that various neuropathic pains could be blocked by the 5-HT3 receptor antagonists, we proposed that 5-HT3 receptor antagonists via 5- HT3 receptors may also inhibit neuropathic pain induced by chemotherapy. Our review suggests that future studies focus more on the 5-HT3 receptor antagonists and their modulation in CIPN to reduce the gap in the current pharmacotherapy for cancer-related pain.

A phase III open-label study to assess safety and efficacy of palonosetron for preventing chemotherapy-induced nausea and vomiting (CINV) in repeated cycles of emetogenic chemotherapy.

PURPOSE: Prevention of chemotherapy-induced nausea and vomiting (CINV) is of great importance for the completion of multiple cycles of cancer chemotherapy. Palonosetron is a second-generation 5-HT(3) receptor antagonist with proven efficacy for both acute and delayed CINV. This study was designed to assess the safety and efficacy of 0.75 mg palonosetron in repeated cycles of highly emetogenic chemotherapy or anthracycline-cyclophosphamide combination (AC/EC). METHODS: We gave 0.75 mg palonosetron to 538 patients 30 min prior to ≥ 50 mg/m(2) cisplatin or AC/EC on day 1. Prophylactic dexamethasone was administered on days 1-3. The primary endpoint was the incidence rate of adverse events (AEs). The secondary endpoint was complete response rate (CR, defined as no emesis and no rescue medication) throughout the study period. RESULTS: Treatment-related AEs were seen in 44% (237 of 538 patients). Serious AEs were seen in 4% (23 of 538 patients), all considered unrelated or unlikely to be related to palonosetron. Only one patient discontinued the study due to a treatment-related AE. No trend toward worsening of AEs was observed in subsequent cycles of chemotherapy. Complete response rates were maintained throughout repeated cycles. CONCLUSION: The extraordinary safety profile and maintenance of efficacy of 0.75 mg palonosetron combined with dexamethasone were demonstrated throughout repeated chemotherapy cycles.

Electrocardiographic findings of palonosetron in cancer patients.

PURPOSE: Nausea and vomiting are among the major problems occurring during and after the chemotherapy treatments of cancer patients. The recently developed 5-HT(3) antagonists have proved much more effective than former agents. Several studies have shown that these agents cause certain ECG changes. We aimed to evaluate the ECG changes caused by palonosetron, one of the new 5-HT(3) antagonists. METHODS: Our study includes a total of 50 patients diagnosed with solid-organ tumors receiving chemotherapy. The patients were applied 12-lead ECG before palonosetron infusion. Afterwards, subsequent ECGs were applied on the 30th, 60th, and 90th minutes following the infusion of palonosetron. Arterial blood pressure was measured before and after the infusion. PR, QRS, QT, QTmax, QTmin, QTd, Pmax, Pmin, Pd, QTc, QTcmax, QTcmin, and QTcd values were evaluated for each ECG. RESULTS: We did not detect significant correlations between the systolic and diastolic blood pressures before and after (30 min) palonosetron infusion (p > 0.05). However, there was a statistically significant decrease in heart rate (p = 0.000). The evaluation of ECG findings revealed that there was a significant prolongation in PR distance, as shown by the comparisons of 0 min with 30, 60, and 90 min. On the other hand, there was no significant difference in QRS, QT, QTmax, QTmin, QTd, Pmax, Pmin, Pd, QTc, QTcmax, QTcmin, and QTcd values (p > 0.05). CONCLUSION: In this study, we revealed that palonosetron did not cause any severe rhythmic disorders or symptomatic ECG changes. We concluded that it could be safe to administer palonosetron antiemetically.

Ondansetron-induced muscular contractures in malignant hyperthermia-susceptible individuals.

BACKGROUND: The 5-HT(3)-receptor antagonist ondansetron, commonly used to treat nausea and vomiting, was suspected of triggering malignant hyperthermia (MH) when a 5-year-old boy died after receiving a therapeutic dose of ondansetron. To evaluate a possible influence of ondansetron on the onset of MH, we investigated its effect on muscle specimens of MH-susceptible (MHS) and MH-nonsusceptible (MHN) individuals in vitro. METHODS: Muscle bundles of 6 MHS and 10 MHN patients were incubated in a tissue bath with ondansetron at increasing concentrations (0.1 to 300 µg/mL). Changes in resting tension and twitch height were monitored continuously. Data are reported as median and interquartile range; Mann-Whitney U test for differences between the groups (P < 0.05). RESULTS: Weight, length, initial resting tension, and twitch height of the muscle bundles did not significantly differ between the investigated groups. An increasing twitch amplitude after ondansetron application was observed in both groups. However, contractures developed only in MHS but not in MHN muscle at ondansetron concentrations of 50 µg/mL (MHS 2.5 [2.1 to 4.0] vs. MHN 0 [0 to 0] mN) and 100 µg/mL (18.0 [11.8 to 22.8] vs 0 [0 to 0] mN). At 300 µg/mL ondansetron, a muscular response was also observed in MHN (23.3 [20.1 to 40.1] vs 1.8 [0.3 to 4.9] mN). CONCLUSIONS: Ondansetron induced contractures in skeletal muscle bundles in vitro. The effect was significantly higher in MHS than in MHN muscle. Because the necessary concentration of ondansetron exceeded the therapeutic plasma levels by a minimum of 500 times, a trigger potency in vivo seems unlikely.

Evaluation of the acute effect of palonosetron on transmural dispersion of myocardial repolarization.

BACKGROUND: 5-hydroxytryptamine receptor type-3 (5-HT3) antagonists are widely used for prophylaxis of chemotherapy-induced nausea and vomiting (CINV) and regarded to have a high safety profile. However, several electrocardiographic changes and cardiac arrhythmias have been reported due to administration of 5-HT3 antagonists. Only prolongation of QT interval has been investigated as an index of potential for life-threatening arrhythmias in adult patients using 5-HT3 antagonists. Recently, increase in transmural dispersion of repolarization (TDR) has been proposed as a more reliable determinant of arrhythmogenic potential. AIM: To assess the effects of palonosetron, a second-generation 5-HT3 antagonist, on the T-wave peak to T-wave end (TpTe) interval which has been proposed as a reliable index of spatial TDR. PATIENTS AND METHODS: A total of 50 consecutive cancer patients (aged: 57 +/- 12 years) who were scheduled to receive emetogenic chemotherapy were included to the study. Baseline12-lead electrocardiography (ECG) recordings were obtained. Then, all patients received 8 mg intravenous dexamethasone followed by a single dose of 0.25 mg intravenous palonosetron administered over 30 seconds. A second ECG was performed 30 minutes after the administration of palonosetron. Indices of cardiac repolarization and TDR before and after the administration of palonosetron were compared. RESULTS: In comparison with baseline there was no statistically significant change in any of the heart rate-corrected parameters, including QT(c) (lead V5), QT(maxc), QT(minc), QT(cd), TpTe (V5), TpTe(max), TpTe(min), TpTe(d) and TpTe/QT (V5). CONCLUSIONS: Palonosetron does not have any significant effect on QT(c) and TpTe intervals. It might be the drug of choice for prophylaxis of CINV in cancer patients receiving chemotherapy with known cardiotoxic potential or who have pre-existing cardiac disease that predispose them to drug-induced arrhythmias.

[Treatment of nausea and vomiting with 5HT3 receptor antagonists, steroids, antihistamines, anticholinergics, somatostatinantagonists, benzodiazepines and cannabinoids in palliative care patients : a systematic review]. / Behandlung von übelkeit und erbrechen mit 5HT3-antagonisten, steroiden, antihistaminika, anticholinergika, somatostatinanaloga, benzodiazepinen und cannabinoiden bei palliativpatienten : ein systematisches review.

BACKGROUND: Various recommendations exist for the treatment of nausea and vomiting in palliative care but only few studies and even less systematic reviews look into antiemetic therapy for patients receiving palliative care. OBJECTIVES: This systematic review aims to analyze the current evidence for antiemetic treatment with 5HT3 receptor antagonists, steroids, antihistamines, anticholinergics, somatostatin analogs, benzodiazepines and cannabinoids in palliative care patients with far advanced cancer not receiving chemotherapy or radiotherapy, acquired immune deficiency syndrome (AIDS), chronic obstructive pulmonary disease (COPD), progressive heart failure, amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). Results regarding evidence of treatment with prokinetic and neuroleptic agents will be published separately. METHODS: The electronic databases PubMed and EmBase were systematically searched for studies (published 1966-2011) dealing with antiemetic therapy in palliative care and electronic retrieval was completed by manual searching. Studies with patients undergoing chemotherapy or radiotherapy, pediatric studies and studies published in languages other than English or German were excluded. Studies addressing therapy with 5HT3 receptor antagonists, steroids, antihistamines, anticholinergics, somatostatin analogs, benzodiazepines or cannabinoids were identified and selected for this systematic review. RESULTS: In the general search 75 relevant studies were found. Of those 36 addressed 5HT3 receptor antagonists, steroids, antihistamines, anticholinergics, somatostatin analogs, benzodiazepines and cannabinoids, 13 considered 5HT3 receptor antagonists, 10 somatostatin antagonists, 9 steroids, 5 cannabinoids, 4 anticholinergics, 1 antihistamines and none benzodiazepines. Furthermore six systematic reviews exist. Evidence for any drug used as an antiemetic is low. Concerning 5HT3 receptor antagonists data are insufficient for recommendations on the treatment of patients with AIDS and MS due to the small size of included patient groups. For patients with cancer contradictory results were published: the larger studies showed a positive effect of 5HT3 receptor antagonists and better efficacy, as compared to metoclopramide, dexamethasone and neuroleptics. Heterogeneous results were found for steroids, with a positive trend for patients with cancer. Data are insufficient for antihistamines. Studies prove effectiveness of butylscopolammonium in the treatment of nausea and vomiting caused by malignant gastrointestinal obstruction, whereas octreotide is superior to butylscopolammonium. Regarding benzodiazepines for symptom control of nausea and vomiting in palliative care patients no studies were detected. Cannabinoids were found to relieve nausea and vomiting in patients with cancer and AIDS but with notable side effects. Furthermore, the studies compared cannabinoids to less recent antiemetic drugs but not, for example to 5HT3 receptor antagonists. Regarding symptom control of nausea and vomiting in patients with COPD, progressive heart failure and ALS no studies were undertaken in patients receiving palliative care. CONCLUSIONS: In palliative care patients with nausea and vomiting 5HT3 receptor antagonists can be used if treatment with other antiemetics, such as metoclopramide and neuroleptics is not sufficient. There is a trend that steroids in combination with other antiemetics improve symptom relief. Cannabinoids rather have a status as a second line antiemetic. In cases of nausea and vomiting caused by malignant gastrointestinal obstruction octreotide showed the best and butylscopolammonium bromide the second best results. Concerning antihistamines and benzodiazepines insufficient data was found. Recommendations in the literature are mainly based on studies in patients with cancer. The overall strength of evidence is low. More well designed studies in palliative care patients are needed in order to provide evidence-based therapy. The English full text version of this article will be available in SpringerLink as of November 2012 (under "Supplemental").

A systematic review and meta-analysis of intravenous palonosetron in the prevention of chemotherapy-induced nausea and vomiting in adults.

OBJECTIVES: We performed a systematic review and meta-analysis to compare treatment effectiveness and adverse effects in cancer patients receiving chemotherapy with palonosetron to prevent chemotherapy-induced nausea and vomiting (CINV). METHODS: We identified randomized controlled clinical trials (RCT) comparing palonosetron with first-generation 5-HT3RA in the prevention of CINV in cancer patients. Meta-analyses were performed on homogeneous studies. Fixed or random-effects models were used to combine data. RESULTS: Eight eligible trials were identified, reporting outcomes on 3,592 patients. Meta-analyses showed statistically significant differences in favor of palonosetron compared with first-generation 5-HT3RA in prevention of acute CINV (p = .0003), delayed CINV (p < .00001), and overall phase of CINV (p < .00001). Subgroup analyses showed statistically significant differences in favor of both 0.25 mg and 0.75 mg of palonosetron in prevention of all phases of CINV. There were no statistically significant differences between 0.25 and 0.75 mg of palonosetron. Compared with the first-generation 5-HT3RA, 0.75 mg of palonosetron showed a statistically significant difference in the occurrence of constipation (p = .04). INTERPRETATION: The use of palonosetron should be considered an integral part of adjuvant therapy for prevention of the acute, delayed, and overall phases of CINV. The 0.25 mg intravenous palonosetron dose is as effective as the 0.75 mg intravenous palonosetron dose. However, 0.75 mg intravenous palonosetron causes constipation more frequently than the first-generation 5-HT3RA.

Ondansetron-induced dystonia, hypoglycemia, and seizures in a child.

OBJECTIVE: To document ondansetron-induced dystonia, hypoglycemia, and seizures in a child. CASE SUMMARY: A 4-year-old boy was admitted with dystonia following an intravenous dose of ondansetron 2 mg (0.13 mg/kg) that he had received for vomiting that day. In the emergency department, he developed generalized tonicclonic seizures lasting for a few minutes. He was administered lorazepam 1.5 mg (0.1 mg/kg) to control the seizures. His blood glucose level was 10 mg/dL; the hypoglycemia responded promptly to intravenous dextrose 10% (7 mL/kg). Serum electrolytes, renal profile, capillary blood gas, and results of a computed tomography scan of the brain were normal. Subsequent blood glucose values were within normal range. On follow-up after 7 days, the child was healthy with no recurrences of the symptoms. A provisional diagnosis of ondansetron-induced acute dystonia with seizures and hypoglycemia was made. DISCUSSION: Ondansetron is an antiemetic known for its safety profile. There have been a few case reports of extrapyramidal adverse effects and seizures from this drug but none of ondansetron-associated hypoglycemia. 5-Hydroxytryptamine (5-HT(3)) receptors are involved in arginine vasopressin-mediated release of adrenocorticotropin hormone and cortisol in response to stress. Blunting of this stress response by ondansetron, a 5-HT(3) receptor antagonist, could have caused the hypoglycemia in this patient. According to the Naranjo scale, ondansetron was probably the cause of the dystonia and seizures, and possibly the cause of the hypoglycemia. Other potential explanations for hypoglycemia were considered but were thought to be less likely. CONCLUSIONS: Dystonia and seizures have been associated with ondansetron in a few case reports. In addition, clinicians need to consider hypoglycemia as a possible adverse effect of ondansetron.