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 1 pharmacokinetic study of oral NEPA, the fixed combination of netupitant and palonosetron, in Chinese healthy volunteers.

PURPOSE: Oral NEPA, the only fixed-combination antiemetic, is composed of the neurokinin-1 receptor antagonist netupitant (300 mg) and the 5-hydroxytryptamine-3 receptor antagonist palonosetron (0.50 mg). This study was conducted to evaluate the pharmacokinetic profile of netupitant and its main metabolites M1 and M3, and palonosetron in Chinese subjects. Oral NEPA tolerability and safety were also analyzed. METHODS: This was a single-center, single-dose phase 1 study in healthy, adult Chinese volunteers. Eligible subjects received oral NEPA, and blood samples were collected on day 1 predose and at various time points up until day 10 postdose. Pharmacokinetic parameters were analyzed using noncompartmental methods. For safety assessments, adverse events (AEs) were monitored during the study. RESULTS: In total 18 Chinese healthy volunteers received oral NEPA. Netupitant mean maximum plasma concentration (Cmax) [± standard deviation] of 698 ± 217 ng/mL was reached at 3-6 h, with a mean total exposure (AUC0-inf) of 22,000 ± 4410 h·ng/mL. For palonosetron, a mean Cmax of 1.8 ± 0.252 ng/mL was reached at 2-6 h postadministration, with a mean AUC0-inf of 81.0 ± 14.0 h·ng/mL. The most common treatment-related AEs in > 2 subjects were constipation (n = 9) and tiredness (n = 3). No severe AEs were observed, and no subject withdrew due to AEs. CONCLUSION: Following single-dose administration of oral NEPA in Chinese subjects, the pharmacokinetic profiles of the NEPA components were mostly similar to those reported previously in Caucasians. NEPA was well tolerated with a safety profile in line with that observed in pivotal trials in Caucasians.

Nephrotoxicity Evaluation on Cisplatin Combined with 5-HT3 Receptor Antagonists: A Retrospective Study.

OBJECTIVE: 5-HT3 receptor antagonist (ondansetron) has been reported to have nephrotoxic effect when combined with cisplatin in mice; however, little evidence exists in explaining its nephrotoxic effects on patients. The aim of this present study was to investigate whether 5-HT3 receptor antagonist could enhance or aggravate the incidence of cisplatin-induced nephrotoxicity in patients. METHODS: We retrospectively reviewed 600 tumor patients which were treated with cisplatin (⩾60 mg/m2) as a first-time chemotherapy and combined with 5-HT3 receptor antagonist (i.e., ondansetron, tropisetron, or ramosetron, each kind of 5-HT3 receptor antagonist contains 200 cases) between January 2010 and December 2015. Cisplatin dosing, the baseline creatinine clearance, and other independent risk factors such as patient's age, sex, PS score, and weight associated with nephrotoxicity were evaluated in a multivariable model. RESULTS: The incidence of Grade ⩾ 2 serum creatinine elevation in cisplatin + ondansetron group was significantly higher than cisplatin + tropisetron group (P = 0.04), but no significant difference was found between cisplatin + ondansetron group and cisplatin + ramosetron group (P = 0.3). It was also found that cisplatin dosage and tumor type were independent risk factors in the development of nephrotoxicity. CONCLUSION: Higher cisplatin dosage and regular use of ondansetron combined with cisplatin are more likely to increase the incidence of nephrotoxicity; tropisetron showed the relatively mild effect on kidney function, suggesting that tropisetron is a preferable alternative in the process of cisplatin chemotherapy.

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.

Effects of Palonosetron on Perioperative Cardiovascular Complications in Patients Undergoing Noncardiac Surgery With General Anesthesia: A Retrospective Cohort Study.

We retrospectively investigated whether palonosetron administered during the induction of general anesthesia is associated with an increased risk of perioperative cardiovascular complications in a single tertiary center cohort consisting of 4,517 palonosetron-exposed patients and 4,517 propensity score-matched patients without palonosetron exposure. The primary endpoint was a composite of perioperative cardiovascular complications, including intraoperative cardiac arrhythmia, intraoperative cardiac death, and myocardial injury within the first postoperative week, and there was no significant difference between the groups (odds ratio [OR] = 1.04; 95% confidence interval [CI] = 0.92-1.19). As secondary endpoints, intraoperative cardioversion, cardiac compression, use of cardiovascular drugs, postoperative hospital stay, and in-hospital mortality showed no differences between the groups. However, the palonosetron group showed decreased intraoperative hypotension (OR = 0.88; 95% CI = 0.79-0.97) and length of postoperative intensive care unit (ICU) stay (4.26 ± 9.86 vs. 6.14 ± 16.75; P = 0.026). Palonosetron did not increase the rate of perioperative cardiovascular complications, and can therefore be used safely during anesthetic induction.

Interventions to decrease the risk of adverse cardiac events for patients receiving chemotherapy and serotonin (5-HT3) receptor antagonists: a systematic review.

BACKGROUND: Patients may experience nausea and vomiting when undergoing chemotherapy or surgery requiring anesthesia. Serotonin 5-hydroxytryptamine 3 (5-HT3) receptor antagonists are effective antiemetics, yet may cause adverse cardiac events, such as arrhythmia. We aimed to identify interventions that mitigate the cardiac risk of 5-HT3 receptor antagonists. METHODS: Electronic databases, trial registries, and references were searched. Studies on patients undergoing chemotherapy or surgery examining interventions to monitor cardiac risk of 5-HT3 receptor antagonists were included. Search results were screened and data from relevant studies were abstracted in duplicate. Risk of bias of included studies was assessed using the Cochrane Effective Practice and Organisation of Care (EPOC) group's risk-of-bias tool. Due to a dearth of included studies, meta-analysis was not conducted. RESULTS: Two randomized clinical trials (RCT) and 1 non-randomized clinical trial (NRCT) were included after screening 7,637 titles and abstracts and 1,554 full-text articles. Intravenous administration of different dolasetron doses was examined in the NRCT, while dolasetron versus ondansetron and palonosetron versus ondansetron were examined in the RCT. Electrocardiogram (ECG) was the only intervention examined to mitigate cardiac harm. No differences in ECG evaluations were observed between dolasetron or palonosetron versus ondansetron after 15 minutes, 24 hours, and 1 week post-administration in the 2 RCTs. Four deaths were observed in one RCT, which were deemed unrelated to palonosetron or ondansetron administration. Minor increases in PR and QT intervals were observed in the NRCT for dolasetron dosages greater than 1.2 mg/kg 1-2 hours post-administration, but were deemed not clinically relevant. CONCLUSIONS: ECG monitoring of chemotherapy patients administered with 5-HT3 receptor antagonists did not reveal clinically significant differences in arrhythmia between the medications at the examined time periods. The usefulness of ECG to monitor chemotherapy patients administered with 5-HT3 receptor antagonists remains unclear, as all patients received ECG monitoring. TRIAL REGISTRATION: PROSPERO registry number: CRD42013003565.

Analgesic interaction between ondansetron and acetaminophen after tonsillectomy in children: the Paratron randomized, controlled trial.

BACKGROUND: The mechanism of action of acetaminophen remains unclear. One hypothesis involves an interaction with the serotoninergic system. Antagonists to serotonin (5-HT)3 receptors (setrons) have antiemetic properties. Therefore, co-administration of acetaminophen and a setron could lead to a decrease or a loss of acetaminophen analgesic effects. The aim of this study was to demonstrate such an interaction. METHODS: Paratron is a prospective, randomized, controlled, double-blind, parallel group trial. All children aged 2-7 years (n = 69) scheduled for a tonsillectomy ± adenoidectomy received intraoperative acetaminophen with ondansetron or droperidol. Pain scores [Children's Hospital of Eastern Ontario Pain Scale (CHEOPS)], morphine consumption and the incidence of post-operative nausea and vomiting (PONV) were measured for 24 h following surgery. RESULTS: Pain scores were not different at all times between the groups but median morphine consumption (µg) in recovery was 322.5 [interquartile range (IQR) 0.0-500.0] and 0 (IQR 0-0) in the ondansetron (n = 35) and droperidol (n = 34) groups, respectively (p = 0.004). The percentages of patients who received morphine titration were 57.1% and 20.6% in the ondansetron and droperidol groups, respectively (p = 0.008). No significant difference was found for PONV. CONCLUSIONS: An interaction between acetaminophen and ondansetron is suggested, with children receiving three times more morphine during pain titration in the recovery room. More studies are necessary to evaluate whether this finding is clinically relevant enough to preclude the simultaneous perioperative administration of both drugs in the future.

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.

5-Hydroxytryptamine3 receptor antagonists and cardiac side effects.

INTRODUCTION: 5-Hydroxytryptamine3-receptor antagonists (5-HT3-RA) are the most widely used antiemetics in oncology, and although tolerability is high, QTC prolongation has been observed in some patients. AREAS COVERED: The purpose of this article is to outline the risk of cardiac adverse events (AEs) from 5-HT3-RAs, with focus on the three most commonly used, ondansetron, granisetron and palonosetron. EXPERT OPINION: Most of the studies analyze electrocardiogram (ECG) changes after 5-HT3-RA administrations in healthy, young adults, or in noncancer patients to treat postoperative nausea and vomiting (PONV). Only a few studies have addressed ECG changes in cancer patients treated for chemotherapy-induced nausea and vomiting (CINV). Investigations in cancer patients are essential, because these patients are older and have a higher incidence of comorbidity, than those usually included in clinical trials. Furthermore, polypharmacy is frequent and drug-drug interactions between chemotherapy and other QTc-prolonging drugs may influence the pharmacokinetics and pharmacodynamics of the 5-HT3-RAs. During the next 10 - 15 years a huge increase in the number of cancer patients is expected, primarily in the group of 65-plus-year old. Therefore it will be crucial to address the incidence of cardiac AEs in cancer patients with known heart disease receiving chemotherapy and a 5-HT3 RA for the prophylaxis of CINV.

Olanzapine for the prevention of chemotherapy-induced nausea and vomiting in patients receiving highly or moderately emetogenic chemotherapy: a randomized, double-blind, placebo-controlled study.

CONTEXT: Chemotherapy-induced nausea and vomiting (CINV) can severely impair patients' quality of life (QOL). Psychotropics, especially olanzapine, have a strong antiemetic effect. OBJECTIVES: To determine whether olanzapine could reduce the frequency of CINV and improve patients' QOL during chemotherapy. METHODS: This was a randomized, double-blind, placebo-controlled trial. Forty-four patients scheduled to receive highly or moderately emetogenic chemotherapy were enrolled. All patients received a 5-hydroxytryptamine3 receptor antagonist, steroid, and neurokinin-1 receptor antagonist. Patients were randomly assigned to take 5 mg/day of oral olanzapine (OL group, n = 22) or placebo (control group, n = 22) daily from the day before chemotherapy (Day 0) to Day 5. The primary endpoint was the rate of patients who achieved total control (no vomiting, no use of rescue medications, and maximum nausea of <5/100mm on a visual analogue scale). The secondary endpoint was Functional Living Index-Emesis questionnaire score on Days 0 and 6. RESULTS: The rate of patients achieving total control was significantly higher in the OL group (86% and 64% in acute and delayed phases, respectively) than in the control group (55% and 23%, P = 0.045, P = 0.014, respectively). Furthermore, the OL group experienced a better QOL than the control group, as reported on the Functional Living Index-Emesis questionnaire (P = 0.0004). CONCLUSION: The addition of 5mg/day of oral olanzapine to standard therapy can reduce the frequency of CINV and improve QOL of patients receiving highly or moderately emetogenic chemotherapy.

Interventions to decrease the risk of adverse cardiac events for post-surgery or chemotherapy patients taking serotonin (5-HT3) receptor antagonists: protocol for a systematic review and network meta-analysis.

BACKGROUND: Patients undergoing surgery or chemotherapy often experience nausea and vomiting. To increase their quality of life and treatment satisfaction, antiemetic medication, such as serotonin receptor antagonists, is often prescribed for patients experiencing these symptoms. However, early warning signs suggest that serotonin receptor antagonists can cause harm, including arrhythmia. Our objective is to identify the most effective interventions that mitigate the risk of adverse cardiac events associated with serotonin receptor antagonists in patients undergoing surgery and chemotherapy through a systematic review and network meta-analysis. METHODS/DESIGN: We will search electronic databases (for example, MEDLINE, Embase) from inception onwards, as well as dissertations and governmental reports, to identify interventions (for example, telemetry, electrocardiography, electrolyte monitoring) that decrease the cardiac risk associated with serotonin receptor antagonists among surgery and chemotherapy patients. Eligible comparators include placebo or supportive care; eligible study designs are experimental studies (randomized controlled trials (RCTs), quasi-RCTs, non-RCTs), non-experimental studies (interrupted time series, controlled before-and-after studies), and cohort studies. Outcomes of interest include arrhythmia, sudden cardiac death, QT prolongation, PR prolongation, and all-cause mortality. We will include unpublished studies and studies published in languages other than English.Draft inclusion and exclusion criteria will be established and pilot tested amongst the team. Subsequently, two team members will screen the results in duplicate and resolve conflicts through discussion. The same process will be followed to screen full-text articles, data abstraction, and appraise quality or risk of bias. To determine validity of results, experimental and quasi-experimental studies will be assessed using the Cochrane Effective Practice and Organisation of Care (EPOC) Risk of Bias tool, while cohort studies will be appraised using the Newcastle-Ottawa Scale. We anticipate sufficient data and homogeneity to conduct random effects meta-analysis and network or mixed treatment comparisons meta-analysis, if appropriate. DISCUSSION: Our results will provide information regarding the utility of different strategies that can be used to mitigate cardiac risk amongst patients taking serotonin antagonist receptors. Such results are likely to be of use to clinicians prescribing these agents, as well as policy makers responsible for making decisions about antiemetic medications. TRIAL REGISTRATION: PROSPERO registry number: CRD42013003565.

Safety of serotonin (5-HT3) receptor antagonists in patients undergoing surgery and chemotherapy: protocol for a systematic review and network meta-analysis.

BACKGROUND: Serotonin (5-HT3) receptor antagonists are a class of antiemetic medications often used to prevent nausea and vomiting among patients undergoing chemotherapy, radiotherapy or surgery. However, recent studies suggest that these agents might be associated with increased cardiac harm. To examine this further, we are proposing to conduct a systematic review and network meta-analysis on the comparative safety of 5-HT3 receptor antagonists among patients undergoing chemotherapy or surgery. METHODS/DESIGN: Studies reporting one or more safety outcomes of interest for 5-HT3 receptor antagonists compared with each other, placebo, and/or other anti-emetic agents (for example, benzamides, phenothiazines, butyrophenones, antihistamines, and anticholinergics) among children and adult patients undergoing surgery or chemotherapy will be included. Our primary outcome of interest is arrhythmia. Our secondary outcomes include cardiac death, QT prolongation, PR prolongation, all-cause mortality, nausea, and vomiting. We will include experimental studies, quasi-experimental studies (namely controlled before-after and interrupted time series), and observational studies (namely cohort studies). We will not limit inclusion by publication status, time period, duration of follow-up or language of dissemination.Electronic databases (for example, MEDLINE, EMBASE) will be searched from inception onwards. These main searches will be supplemented by searching for difficult to locate and unpublished studies, such as dissertations, and governmental reports. The eligibility criteria will be pilot-tested and subsequently used to screen the literature search results by two reviewers in duplicate. A similar process will be followed for full-text screening, data abstraction, and risk of bias/methodological quality appraisal. The Cochrane Risk of Bias tool will be used to appraise experimental and quasi-experimental studies, and cohort studies will be assessed using the Newcastle Ottawa Scale. If the data allows, random effects meta-analysis and a network (that is, mixed treatment comparisons) meta-analysis will be conducted. All analyses will be conducted separately for different study designs, patient populations (for example, children and adults), and reason for administering 5-HT3 receptor antagonists (for example, post-surgery and chemotherapy). DISCUSSION: Our results will help inform patients, clinicians, and health policy-makers about the potential safety concerns, as well as the comparative safety, of using these antiemetic agents. TRIAL REGISTRATION: PROSPERO registry number:CRD42013003564.

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.

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.

An update on palonosetron hydrochloride for the treatment of radio/chemotherapy-induced nausea and vomiting.

INTRODUCTION: Nausea and vomiting are well recognized in different clinical situations, suggesting that no single mechanism is likely to be responsible for their production. Chemotherapy-induced nausea and vomiting (CINV) can have a negative impact on quality of life and this may lead to a refusal of curative therapy or to a decline in palliative benefits offered by cytotoxic treatment. Palonosetron is a new agent in the class of 5-HT3 receptor antagonists (5-HT3RAs), and differs from the other agents by its higher receptor-binding affinity and longer half-life. These pharmacological properties have resulted in improved antiemetic activity in clinical trials, particularly in the treatment of delayed CINV following moderate emetogenic chemotherapy (MEC). AREA COVERED: A systematic review of the medical literature was completed to inform this update. MEDLINE, the Cochrane Collaboration Library and meeting materials from ASCO and MASCC were all searched. EXPERT OPINION: Palonosetron was the only serotonin receptor antagonist approved for prevention of delayed CINV caused by MEC and its use was incorporated in guideline recommendations. To date, several treatment settings such as multiple day chemotherapy require further studies to improve emesis related to therapy.

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.

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.

5-HT3 receptor antagonists ameliorate 5-fluorouracil-induced intestinal mucositis by suppression of apoptosis in murine intestinal crypt cells.

BACKGROUND AND PURPOSE: Chemotherapeutic agents, including 5-fluorouracil (5-FU), frequently cause intestinal mucositis resulting in severe diarrhoea and morphological mucosal damage. 5-HT3 receptor antagonists are clinically effective in the treatment of nausea and emesis during cancer chemotherapy. Therefore we here have examined the effects of 5-HT3 receptor antagonists on 5-FU-induced intestinal mucositis in mice. EXPERIMENTAL APPROACH: Intestinal mucositis was induced in male C57BL/6 mice by daily administration of 5-FU (50 mg·kg⁻¹) for 5 days. Effects of 5-HT3 receptor antagonists, ramosetron (0.01-0.1 mg·kg⁻¹) and ondansetron (5 mg·kg⁻¹), on the accompanying histology, cytokine production and apoptosis were assessed. KEY RESULTS: Continuous administration of 5-FU to mice caused severe intestinal mucositis, which was histologically characterized by the shortening of villi and destruction of intestinal crypts, accompanied by body weight loss and diarrhoea. Daily ramosetron administration dose-dependently reduced the severity of intestinal mucositis, body weight loss and diarrhoea. Similar beneficial effects were observed with ondansetron. The number of apoptotic, caspase-3- and caspase-8-activated cells increased 24 h after the first 5-FU administration, and these responses were reduced by ramosetron. The up-regulation of TNF-α, IL-1ß and IL-6 following 5-FU treatment was also attenuated by ramosetron. CONCLUSIONS AND IMPLICATIONS: 5-HT3 receptor antagonists ameliorated 5-FU-induced intestinal mucositis in mice, and this action could result from suppression of apoptotic responses in the intestinal crypt cells via inhibition of cytokine expression. Thus, 5-HT3 receptor antagonists may be useful for preventing not only nausea and emesis but also intestinal mucositis during 5-FU chemotherapy.

[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").