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- Impact of 5-HT3 receptor antagonists on chemotherapy-induced nausea and vomiting: a retrospective cohort study. [Comparative Study, Journal Article, Research Support, Non-U.S. Gov't]
- BMC Health Serv Res 2012.:215.
1st generation 5-hydroxytryptamine receptor antagonists (5-HT3 RAs), and palonosetron, a 2nd generation 5-HT3 RA, are indicated for the prevention of chemotherapy (CT)-induced nausea and vomiting (CINV) associated with moderately (MEC) and highly emetogenic CT agents (HEC). This study explores the impact of step therapy policies requiring use of an older 5-HT3 RA before palonosetron on risk of CINV associated with hospital or emergency department (ED) admissions.Patients who received cyclophosphamide post breast cancer (BC) surgery or who were diagnosed with lung cancer on carboplatin (LC-carboplatin) or cisplatin (LC-cisplatin) were selected from PharMetrics' (IMS LifeLink) claims dataset (2005-2008). Patients were followed for 6 months from initial CT administration for CINV events identified through ICD-9-CM codes. Patients were grouped into those initiated with older, generic 5-HT3 RAs (ondansetron, granisetron, and dolasetron) and those initiated and maintained on palonosetron throughout study follow-up. CINV events and CINV days were analyzed using multivariate regressions controlling for demographic and clinical variables.Eligible patients numbered 3,606 in BC, 4,497 in LC-carboplatin and 1,154 in LC-cisplatin cohorts, with 52%, 40%, and 34% in the palonosetron group, respectively. There was no significant difference between the two 5-HT3 RA groups in age or Charlson Comorbidity Index among the two MEC cohorts (BC and LC-carboplatin). Among the LC-cisplatin cohort, palonosetron users were older with more males than the older 5-HT3 RA group (age: 60.1 vs. 61.3; males, 66.9% vs. 56.9%). Compared to the older 5-HT3 RAs, the palonosetron groups incurred 22%-51% fewer 5-HT3 RA pharmacy claims, had fewer patients with CINV events (3.5% vs. 5.5% in BC, 9.5% vs. 12.8% in LC-carboplatin, 16.4% vs. 21.7% in LC-cisplatin), and had lower risk for CINV events (odds ratios 0.62, 0.71, or 0.71, respectively; p<0.05). The BC and LC-carboplatin palonosetron groups experienced 50% and 30% fewer CINV days than the generic 5-HT3 RA group (p<0.05).Patients with breast or lung cancer initiated and maintained on palonosetron were at significantly lower risk for potentially costly CINV versus those on older 5-HT3 RAs. Further studies on impact of step therapy policy are warranted in order to minimize the clinical and economic burden of CINV.
- Optimization of sample pretreatment methods for simultaneous determination of dolasetron and hydrodolasetron in human plasma by HPLC-ESI-MS. [Comparative Study, Journal Article, Research Support, Non-U.S. Gov't]
- J Chromatogr Sci 2012 Oct; 50(9):785-91.
A high-performance liquid chromatographic method coupled with electrospray mass spectrometry was developed for the simultaneous determination of dolasetron and its major metabolite, hydrodolasetron, in human plasma. A new sample pretreatment method, i.e., salt induced phase separation extraction (SIPSE), was proposed and compared with four other methods, i.e., albumin precipitation, liquid-liquid extraction, hydrophobic solvent-induced phase separation extraction and subzero-temperature induced phase separation extraction. Among these methods, SIPSE showed the highest extraction efficiency and the lowest matrix interferences. The extraction recoveries obtained from the SIPSE method were all more than 96% for dolasetron, hydrodolasetron and ondansetron (internal standard). The SIPSE method is also very fast and easy because protein precipitation, analyte extraction and sample cleanup are combined into one simple process by mixing acetonitrile with plasma and partitioning with 2 mol/L sodium carbonate aqueous solution. The correlation coefficients of the calibration curves were all more than 0.997, in the range of 7.9-4750.0 ng/mL and 4.8-2855.1 ng/mL for dolasetron and hydrodolasetron, respectively. The limits of quantification were 7.9 and 4.8 ng/mL for dolasetron and hydrodolasetron, respectively. The intra-day and inter-day repeatability were all less than 10%. The method was successfully applied to the pharmacokinetic study of dolasetron.
- Reappraisal of the role of dolasetron in prevention and treatment of nausea and vomiting associated with surgery or chemotherapy. [Journal Article]
- Cancer Manag Res 2012.:67-73.
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.
- 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. [Journal Article, Meta-Analysis]
- Clin Ther 2012 Feb; 34(2):282-94.
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.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.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.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.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.
- A practical and direct comparison of intrinsic metabolic clearance of several non-CYP enzyme substrates in freshly isolated and cryopreserved hepatocytes. [Comparative Study, Journal Article]
- Drug Metab Pharmacokinet 2012; 27(2):181-91.
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.
- Management of postoperative nausea and vomiting in women scheduled for breast cancer surgery. [Journal Article, Review]
- J Anesth 2011 Dec; 25(6):917-22.
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.
- Retraction note to: Dolasetron, but not metoclopramide prevents nausea and vomiting in patients undergoing laparoscopic cholecystectomy. [Retraction of Publication]
- Can J Anaesth 2011 Sep; 58(9):885, 885-6.
- 5 HT(3)-receptor antagonists and cardiac repolarization time in patients expressing a novel genetic target associated with baseline QTc interval abnormalities. [Journal Article, Research Support, Non-U.S. Gov't]
- J Clin Anesth 2011 Jun; 23(4):297-302.
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.Post-hoc analysis of deoxyribonucleic acid (DNA) samples and electrocardiographic (ECG) data from an established perioperative genomics database.University teaching hospital.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.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.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.
- Genetic polymorphisms in the three malaysian races effect granisetron clinical antiemetic actions in breast cancer patients receiving chemotherapy. [Journal Article]
- Asian Pac J Cancer Prev 2011; 12(1):185-91.
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.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.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.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.