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Cancer Management and Research 2012Chemotherapy-induced nausea and vomiting and postoperative nausea and vomiting are one of the most frequent but also very concerning consequences for patients undergoing...
Chemotherapy-induced nausea and vomiting and postoperative nausea and vomiting are one of the most frequent but also very concerning consequences for patients undergoing chemotherapy or surgical procedures under general anesthesia. There are a variety of mechanisms involved in the activation of nausea and vomiting. Serotonin, a ubiquitous central and peripheral neurotransmitter, is thought to be the predominant mediator of the perception of nausea and triggering of the vomiting response in both the brain and the periphery via the 5-hydroxytryptamine type 3 (5-HT(3)) receptor pathways. 5-HT(3) receptor antagonists disrupt this pathway, largely at the level of the vagal afferent pathways, to decrease nausea and vomiting. This review will focus on dolasetron, an older but sill commonly used 5-HT(3) receptor antagonist and its multimodal mechanism of action, safety and tolerability, patient considerations, and a review of the current literature on its use to combat both chemotherapy-induced and postoperative nausea and vomiting in these two important patient populations.
PubMed: 22427733
DOI: 10.2147/cmar.s15545 -
Clinical Therapeutics Feb 2012The serotonin type 3 receptor antagonists (5-HT(3) antagonists) ondansetron, granisetron, tropisetron, and dolasetron are potential prophylactic agents for patients with... (Meta-Analysis)
Meta-Analysis
A network meta-analysis on the efficacy of serotonin type 3 receptor antagonists used in adults during the first 24 hours for postoperative nausea and vomiting prophylaxis.
BACKGROUND
The serotonin type 3 receptor antagonists (5-HT(3) antagonists) ondansetron, granisetron, tropisetron, and dolasetron are potential prophylactic agents for patients with mild to moderate risk of postoperative nausea and vomiting (PONV). A few trials have been conducted to compare the efficacy among 2 to 3 of these 4 agents. However, the comparative efficacy of all four 5-HT(3) antagonists has not yet been quantitatively investigated.
OBJECTIVE
The goal of this study was to investigate whether the 5-HT(3) antagonists--ondansetron, granisetron, tropisetron, and dolasetron-differ in efficacy when used for the prevention of PONV.
METHODS
PubMed and the Cochrane Library were searched for randomized controlled, double-blind studies measuring efficacy in terms of PONV prophylaxis. A Bayesian meta-analysis was conducted using published studies of 5-HT(3) antagonists for PONV prophylaxis. The odds of patients with no PONV and postoperative vomiting (POV) within each study arm 24 hours after surgery were the primary indices of drug efficacy. Data were extracted and analyzed via indirect comparisons using random effects Bayesian models in WinBUGS version 1.4.3.
RESULTS
A total of 85 studies were identified, representing 15,269 patients. The results indicate that granisetron was significantly better than ondansetron (odds ratio [OR] = 1.53 [95% credible interval (CI), 1.15-2.00]) and dolasetron (OR = 1.67 [95% CI, 1.12-2.38]) in preventing PONV. Four antiemetic drugs had comparable efficacy in terms of preventing POV: granisetron showed similar efficacy compared with ondansetron (OR = 1.49 [95% CI, 0.90-2.43]), tropisetron (OR = 1.69 [95% CI, 0.92-3.13]), and dolasetron (OR = 1.32 [95% CI, 0.71-2.38]). Ondansetron exhibited comparable efficacy compared with tropisetron (OR = 1.14 [95% CI, 0.66-1.96]) and dolasetron (OR = 0.88 [95% CI, 0.51-1.47]). Tropisetron and dolasetron were also similar in efficacy (OR = 0.78 [95% CI, 0.40-1.45]). All 5-HT(3) antagonists were statistically significantly better at preventing PONV or POV than placebo.
CONCLUSIONS
With respect to PONV prophylaxis, granisetron was significantly better than ondansetron and dolasetron; ondansetron, tropisetron, and dolasetron exhibited similar efficacy. With respect to POV prophylaxis, ondansetron, granisetron, tropisetron, and dolasetron seemed to have comparable efficacy.
Topics: Adult; Humans; Postoperative Nausea and Vomiting; Randomized Controlled Trials as Topic; Serotonin 5-HT3 Receptor Antagonists; Time Factors
PubMed: 22296947
DOI: 10.1016/j.clinthera.2012.01.007 -
Drug Metabolism and Pharmacokinetics 2012Human hepatocytes are a physiologically relevant tool useful in evaluating liver-related pharmacokinetics, including non-cytochrome P-450 (CYP) metabolism, due to their... (Comparative Study)
Comparative Study
Human hepatocytes are a physiologically relevant tool useful in evaluating liver-related pharmacokinetics, including non-cytochrome P-450 (CYP) metabolism, due to their broad spectrum of metabolic enzyme activity. To verify the usefulness of human hepatocytes in evaluating non-CYP metabolism for drug discovery, we compared intrinsic clearance values (CL(int)) in freshly isolated and cryopreserved hepatocytes using 14 compounds primarily metabolized by non-CYP enzymes, including UDP-glucuronosyltransferase, carbonyl/aldo-keto reductase, aldehyde oxidase, flavin-containing monooxygenase, and monoamineoxidase. Cryopreservation resulted in a >20% reduction (maximum: 50%) in CL(int) in 7/14 compounds (statistically significant for 5 compounds) on comparing CL(int) values in freshly isolated and cryopreserved hepatocytes from the same donors (n = 4). However, the number of compounds with >20% CL(int) reduction decreased to 3 on comparing average of CL(int) values including un-matched donors (dolasetron: -27%, naltorexone: -32%, and phthalazine: -48%; statistically significant for phthalazine, n = 6-11). These findings suggest that fresh hepatocytes are useful in evaluating intact non-CYP enzyme activities. However, we must note that the reduction in CL(int) by cryopreservation could be rendered negligible if high-activity lots are selected for assay. We therefore recommend using cryopreserved hepatocytes for large-scale screening for non-CYP metabolism in drug discovery research considering the advantages in usability with cryopreserved hepatocytes.
Topics: Alcohol Oxidoreductases; Aldehyde Oxidase; Aldehyde Reductase; Aldo-Keto Reductases; Cell Survival; Cryopreservation; Drug Evaluation, Preclinical; Enzymes; Hepatocytes; Humans; Metabolic Clearance Rate; Pharmaceutical Preparations; Substrate Specificity
PubMed: 22027494
DOI: 10.2133/dmpk.dmpk-11-rg-097 -
Journal of Anesthesia Dec 2011Breast cancer surgery performed under general anesthesia is associated with a high incidence of postoperative nausea and vomiting (PONV). A number of approaches are... (Review)
Review
Breast cancer surgery performed under general anesthesia is associated with a high incidence of postoperative nausea and vomiting (PONV). A number of approaches are available for the management of PONV after breast cancer surgery. First, the risk factors related to patient characteristics, surgical procedure, anesthetic technique, and postoperative care can be reduced. More specifically, the use of propofol-based anesthesia can reduce the incidence of PONV. Secondly, a wide range of prophylactic antiemetics, including butyrophenones (droperidol), benzamides (metoclopramide), glucocorticoids (dexamethasone), clonidine, a small dose of propofol, and serotonin receptor (SR) antagonists (ondansetron, granisetron, tropisetron, dolasetron, ramosetron, and palonosetron), are available for preventing PONV. Thirdly, antiemetic therapy combined with granisetron and droperidol or dexamethasone, and a multimodal management strategy which includes a package consisting of dexamethasone, total intravenous anesthesia with propofol, and ondansetron are highly effective in preventing PONV. Unfortunately, the use of glucocorticoids and SR antagonists for preventing PONV is not permitted in Japan according to national health insurance guidelines. Fourth, electro-acupoint stimulation at the P6 point (Nei-Guwan) as a non-pharmacologic therapy is as effective as ondansetron for preventing PONV. Knowledge of the risk factors for PONV, antiemetics, and a non-pharmacologic approach are needed for the management of PONV in women undergoing breast cancer surgery.
Topics: Anesthesia, General; Antiemetics; Breast Neoplasms; Female; Humans; Postoperative Nausea and Vomiting; Propofol; Risk Factors
PubMed: 21964679
DOI: 10.1007/s00540-011-1241-1 -
Canadian Journal of Anaesthesia =... Sep 2011
PubMed: 21792705
DOI: 10.1007/s12630-011-9531-5 -
Journal of Clinical Anesthesia Jun 2011To investigate whether a common single nucleotide polymorphism (SNP), rs10494366, is associated with significant prolongation of the QTc interval following...
STUDY OBJECTIVE
To investigate whether a common single nucleotide polymorphism (SNP), rs10494366, is associated with significant prolongation of the QTc interval following administration of 5-HT(3)-receptor antagonists in the perioperative setting.
DESIGN
Post-hoc analysis of deoxyribonucleic acid (DNA) samples and electrocardiographic (ECG) data from an established perioperative genomics database.
SETTING
University teaching hospital.
MEASUREMENTS
DNA samples of 132 ASA physical status 1, 2, and 3 patients were obtained from an established genomic database of surgical patients who had received either granisetron or dolasetron as part of their general anesthesia plan. ECG recordings were collected on all subjects before administration of antiemetic medication, then 10 minutes after drug injection. DNA analysis was performed using TaqMan real-time PCR genotyping assay. Results from the TaqMan real-time PCR assay were used to calculate relative frequencies of the T (major) and G (minor) alleles, in addition to calculating the genotype frequencies. QTc intervals were calculated according to Bazett's formula.
RESULTS
Relative frequencies for T and G alleles were 0.63 and 0.37, respectively. The relative frequencies of the pertinent genotypes were TT 39.4%, TG 46.9%, and GG 13.7%. No significant difference was noted in QTc interval pre-antiemetic or post-antiemetic drug administration for the homozygous carriers of the minor allele GG (P = 0.059), but a significant difference was seen in the pre-drug and post-drug QTc intervals in the heterozygous and homozygous carriers of the major allele TG and TT (P = 0.003 and P = 0.017, respectively). Compared with homozygous carriers of the minor allele, absolute risk increase for QTc interval prolongation after antiemetic administration was 0.08 and 0.15 in heterozygous and homozygous carriers of the major allele, respectively.
CONCLUSION
Homozygous and heterozygous carrier status for the major SNP, rs10494366 allele (T), in intron 1 of the human NOSA1P gene may be associated with an increased risk of QTc interval prolongation following administration of 5-HT(3)-receptor antagonists in the perioperative setting, when compared with homozygotes for the minor (G) allele.
Topics: Adaptor Proteins, Signal Transducing; Adult; Alleles; Databases, Genetic; Electrocardiography; Female; Genotype; Granisetron; Hospitals, University; Humans; Indoles; Long QT Syndrome; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Quinolizines; Retrospective Studies; Serotonin 5-HT3 Receptor Antagonists
PubMed: 21663814
DOI: 10.1016/j.jclinane.2010.11.003 -
European Journal of Anaesthesiology Jun 2011
PubMed: 21540659
DOI: 10.1097/EJA.0b013e328347b41c -
Asian Pacific Journal of Cancer... 2011Nausea and vomiting are recognized as two separate and distinct conditions with a wide spectrum of etiologies either directly associated with cancer itself or its...
INTRODUCTION
Nausea and vomiting are recognized as two separate and distinct conditions with a wide spectrum of etiologies either directly associated with cancer itself or its treatment. According to the new ranking of chemotherapy side effects, nausea is the number one or the most disturbing side effects while vomiting is the third and sometimes the fifth. The introduction of 5-HT3-recptor antagonists in the early of 1990s has revolutionized the treatment of nausea and vomiting, these agents remaining the mainstay of antiemetic therapy today. Ethnic variation (due to genetic polymorphisms) may lead to diversity in antiemetic treatment pharmacokinetic and pharmacodynamic properties, in terms of distribution, elimination, disposition and clinical effects. The aim of the present study was to clarify genetic polymorphism effects in the three main races in Malaysia i.e., Malay, Chinese and Indian, on the clinical antiemetic effects of granisetron.
METHODS
In this longitudinal prospective observational study, 158 breast cancer patients treated with chemotherapy were monitored for nausea and vomiting in the first 24 hours after chemotherapy administration. The patients were then followed up again after 3 to 5 days of chemotherapy.
RESULTS
Genetic polymorphisms in the three races in Malaysia have significant effect on granisetron clinical antiemetic action because each is characterized by variant CYP3A4 enzymatic action.
CONCLUSION
According to the result, different type of 5-HT3 receptor antagonists, such as tropisetron and dolasetron which are predominantly metabolized by CYP2D6, should be used especially for Chinese breast cancer patients.
Topics: Adult; Aged; Antiemetics; Antineoplastic Agents; Breast Neoplasms; Cytochrome P-450 CYP3A; Female; Follow-Up Studies; Granisetron; Humans; Longitudinal Studies; Malaysia; Middle Aged; Nausea; Neoplasm Staging; Polymorphism, Genetic; Prospective Studies; Serotonin 5-HT3 Receptor Antagonists; Vomiting
PubMed: 21517255
DOI: No ID Found -
Anesthesia and Analgesia May 2011
PubMed: 21451086
DOI: 10.1213/ANE.0b013e31821a9648 -
European Journal of Pain (London,... May 2011The purpose of the study was to evaluate the efficacy and safety of dolasetron for symptomatic relief of pain associated with fibromyalgia (FM). (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
The purpose of the study was to evaluate the efficacy and safety of dolasetron for symptomatic relief of pain associated with fibromyalgia (FM).
METHODS
This prospective, double-blind, placebo-controlled trial randomly assigned 60 patients with FM to receive placebo (n = 31) or dolasetron (n = 29) 12.5mg/d via the intravenous route on 4 days at baseline (M0), 1 month (M1), 2 months (M2) and 3 months (M3) with follow-up to month 12. The primary outcome variable was the reduction in pain intensity measured by visual analogue scale (VAS) between M0 and M3. The secondary outcome variables were patient global impression of change (PGIC), the FM impact questionnaire, assessment of quality of life (SF-36), the hospital anxiety and depression scale, the manual tender point count, and functional symptoms associated with FM.
RESULTS
Reduction in pain intensity at M3 was significantly greater in dolasetron-treated patients (p = 0.04, -21.3 on a 0-100 scale) compared with placebo controls (-5.9). More patients in the dolasetron group had ≥ 30% and ≥ 50% improvement in pain (42.5% and 28% respectively in the dolasetron group versus 25% and 16% in the placebo group). The PGIC was significantly greater in the dolasetron group at M3 (p = 0.02). The other secondary outcomes failed to reach statistical significance. The most common adverse events were constipation, nausea, dizziness and headache, with no significant differences between the two groups.
CONCLUSION
Intermittent IV dolasetron was safe and efficacious for the reduction of pain intensity associated with FM at 3 months.
Topics: Adolescent; Adult; Aged; Chronic Disease; Double-Blind Method; Fibromyalgia; Follow-Up Studies; Humans; Indoles; Injections, Intravenous; Middle Aged; Pain; Placebos; Prospective Studies; Quality of Life; Quinolizines; Serotonin 5-HT3 Receptor Antagonists; Treatment Outcome; Young Adult
PubMed: 21036635
DOI: 10.1016/j.ejpain.2010.09.013