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BMC Medicine Dec 2016Although serotonin (5-HT) receptor antagonists are effective in reducing nausea and vomiting, they may be associated with increased cardiac risk. Our objective was to... (Comparative Study)
Comparative Study Meta-Analysis Review
BACKGROUND
Although serotonin (5-HT) 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-HT 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-HT 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-HT 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 ).
Topics: Adult; Antiemetics; Antineoplastic Agents; Drug Therapy, Combination; Glucocorticoids; Humans; Nausea; Network Meta-Analysis; Serotonin 5-HT3 Receptor Antagonists; Vomiting
PubMed: 28007031
DOI: 10.1186/s12916-016-0761-9 -
Journal of Pharmaceutical Analysis Dec 2016A simple and straightforward method for the determination of dolasetron mesylate (DM) in aqueous solution was developed based on the fluorescence quenching of...
A simple and straightforward method for the determination of dolasetron mesylate (DM) in aqueous solution was developed based on the fluorescence quenching of 3-Mercaptopropionic acid (MPA) capped CdS quantum dots (QDs). The structure, morphology, and optical properties of synthesized QDs were characterized by using UV-Vis absorption spectroscopy, fluorescence spectroscopy, transmission electron microscopy (TEM) and dynamic light scattering (DLS) measurements. Under the optimum conditions, the MPA-CdS QDs fluorescence probe offered good sensitivity and selectivity for detecting DM. The probe provided a highly specific selectivity and a linear detection of DM in the range of 2-40 µg/mL with detection limit (LOD) 1.512 µg/mL. The common excipients did not interfere in the proposed method. The fluorescence quenching mechanism of CdS QDs is also discussed. The developed sensor was applied to the quantification of DM in urine and human serum sample with satisfactory results.
PubMed: 29404011
DOI: 10.1016/j.jpha.2016.07.002 -
European Radiology Apr 2017Evaluate patients' intraoperative experience of percutaneous vertebroplasty (PV) performed without general anaesthesia in order to assess the feasibility of local...
OBJECTIVE
Evaluate patients' intraoperative experience of percutaneous vertebroplasty (PV) performed without general anaesthesia in order to assess the feasibility of local anaesthesia and simple analgesic medication as pain control protocol.
METHODS
Ninety-five patients who underwent single-site PV were consecutively included in the study between 2011 and 2013. Each procedure was achieved under local anaesthesia and perfusion of paracetamol, tramadol and dolasetron, with combined CT and fluoroscopy guidance. Numeric pain scale (NPS) was collected before, during and after intervention. After intervention, patients were asked to evaluate their experience as "very bad", "bad", "fair", "good" or "very good", independently of the pain.
RESULTS
Indications for vertebroplasty were osteopenic fractures (78 %), aggressive angiomas (13 %) and somatic tumours (9 %). In 76 % of cases, patients' experience was described as "very good" (44 %) or "good" (32 %), whereas 19 % described it as "fair" and 5 % as "very bad". Mean operative NPS was 5.5. After intervention, NPS was significantly lower with a decrease of 4.5 points. No differences were found according to the localization, type of lesion, age or sex either in terms of experience or NPS.
CONCLUSION
Percutaneous vertebroplasty is feasible under local anaesthesia alone, with a very good or good experience in 76 % of the patients.
KEY POINTS
• Vertebroplasty is a first-line therapy for consolidation and pain control of vertebral lesions. • This procedure is commonly performed under general anaesthesia or conscious sedation. • We perform vertebroplasty under local anaesthesia and simple analgesic protocol with acceptable experience. • Percutaneous vertebroplasty can safely be proposed in a fragile population.
Topics: Adult; Aged; Aged, 80 and over; Anesthesia, Local; Bone Cements; Feasibility Studies; Female; Fluoroscopy; Humans; Male; Middle Aged; Patient Satisfaction; Prospective Studies; Radiography, Interventional; Spinal Diseases; Treatment Outcome; Vertebroplasty
PubMed: 27553927
DOI: 10.1007/s00330-016-4521-1 -
European Journal of Pharmacology Oct 20165-hydroxytryptamine 3 receptor (5-HT3 receptor) antagonists are administered for prevention and therapy of nausea and vomiting. Although regarded as safe therapeutics,...
5-hydroxytryptamine 3 receptor (5-HT3 receptor) antagonists are administered for prevention and therapy of nausea and vomiting. Although regarded as safe therapeutics, they can also provoke arrhythmias by prolonging the QRS interval. However, the mechanisms mediating this cardiotoxicity are poorly understood. Here we investigated effects of 5-HT3 receptor antagonists on the cardiac Na(+) channel Nav1.5. We explored the interaction of dolasetron, tropisetron, granisetron and ondansetron on the human α-subunit Nav1.5 heterologously expressed in HEK293 cells. Sodium currents were explored by means of whole-cell patch clamp recordings. All four substances inhibited the Nav1.5 in a concentration and state-dependent manner. Dolasetron displayed the lowest blocking efficacy, and tropisetron was the most potent blocker with a half maximum blocking concentration of 18µM for tonic block of inactivated channels. Tropisetron was also the most potent use-dependent inhibitor, and it also induced a strong open -channel block. Both tonic and use-dependent block by tropisetron were abbreviated on the local-anesthetic insensitive mutant Nav1.5-F1760A. Co-administration of tropisetron and the local anesthetic bupivacaine or the hypnotic propofol augmented inhibition of Nav1.5. Our data demonstrate that 5-HT3 receptor antagonists induce a local-anesthetic like inhibition of Nav1.5, and that they display different blocking efficacies. Reports on a relevant cardiotoxicity of dolasetron as opposed to other 5-HT3 receptor antagonists do not seem to correlate with a block of Nav1.5. As inhibition of Nav1.5 was enhanced by propofol and bupivacaine however, it is possible that a combined administration of Na(+) channel blockers and 5-HT3 receptor antagonists can provoke arrhythmias.
Topics: Anesthetics, Local; Drug Synergism; HEK293 Cells; Humans; Mutation; Myocardium; NAV1.5 Voltage-Gated Sodium Channel; Neurons; Receptors, Serotonin, 5-HT3; Serotonin 5-HT3 Receptor Antagonists; Sodium; Sodium Channel Blockers
PubMed: 27401036
DOI: 10.1016/j.ejphar.2016.07.020 -
Cancer Management and Research 2016[This corrects the article on p. 67 in vol. 4, PMID: 22427733.].
[This corrects the article on p. 67 in vol. 4, PMID: 22427733.].
PubMed: 27390532
DOI: 10.2147/CMAR.S115369 -
Journal of Clinical Pharmacology Jan 2017The revised ICH E14 document allows the use of exposure-response analysis to exclude a small QT effect of a drug. If plasma concentrations exceeding clinically relevant...
The revised ICH E14 document allows the use of exposure-response analysis to exclude a small QT effect of a drug. If plasma concentrations exceeding clinically relevant levels is achieved, a positive control is not required. In cases when this cannot be achieved, there may be a need for metrics to protect against false-negative results. The objectives of this study were to create bias in electrocardiogram laboratory QT-interval measurements and define a metric that can be used to detect bias severe enough to cause false-negative results using exposure-response analysis. Data from the IQ-CSRC study, which evaluated the QT effect of 5 QT-prolonging drugs, were used. Negative bias using 3 deterministic and 2 random methods was introduced into the reported QTc values and compared with fully automated data from the underlying electrocardiogram algorithm (COMPAS). The slope estimate of the Bland-Altman plot was used as a bias metric. With the deterministic bias methods, negative bias, measured between electrocardiogram laboratory values and COMPAS, had to be larger than approximately -20 milliseconds over a QTcF range of 100 milliseconds to cause failures to predict the QT effect of ondansetron, quinine, dolasetron, moxifloxacin, and dofetilide. With the random methods, the rate of false-negatives was ≤5% with bias severity < -10 milliseconds for all 5 drugs when plasma levels exceeded those of interest. Severe and therefore detectable bias has to be introduced into reported QTc values to cause false-negative predictions with exposure-response analysis.
Topics: Cardiotoxins; Dose-Response Relationship, Drug; Electrocardiography; Heart Conduction System; Heart Rate; Humans; Long QT Syndrome
PubMed: 27271102
DOI: 10.1002/jcph.779 -
Expert Review of Clinical Pharmacology Sep 2016Chemotherapy-induced nausea and vomiting are adverse effects responsible for worsening quality of life in cancer patients. To assess the efficacy, safety and... (Comparative Study)
Comparative Study Meta-Analysis Review
Efficacy, safety and effectiveness of ondansetron compared to other serotonin-3 receptor antagonists (5-HT3RAs) used to control chemotherapy-induced nausea and vomiting: systematic review and meta-analysis.
INTRODUCTION
Chemotherapy-induced nausea and vomiting are adverse effects responsible for worsening quality of life in cancer patients. To assess the efficacy, safety and effectiveness of serotonin receptor antagonist in cancer patients undergoing chemotherapy, comparing ondansetron with granisetron, dolasetron, tropisetron and palonosetron.
AREAS COVERED
Systematic review and meta-analysis. The data were collected using CINAHL; CENTRAL; MEDLINE/PubMed; and LILACS databases; grey literature; and manual search. The methodological quality was assessed using the modified Jadad scale; Cochrane Collaboration's tool for assessing risk of bias in randomized clinical trials and the Newcastle-Ottawa Scale for observational studies. The search was completed in November, 2015. 26 studies were included in the meta-analysis. Ondansetron exhibited similar efficacy than granisetron and tropisetron, as well as greater efficacy than dolasetron for acute vomiting. Palonosetron exhibited greater efficacy than ondansetron for delayed nausea and acute and delayed vomiting. The comparison of granisetron with ondansetron in the cohort studies showed no difference. Expert commentary: In this review, palonosetron had increased efficiency compared with ondansetron, except in the subgroup analysis and acute nausea. Few cohort studies have been published addressing this topic.
Topics: Antiemetics; Antineoplastic Agents; Humans; Nausea; Neoplasms; Ondansetron; Quality of Life; Randomized Controlled Trials as Topic; Serotonin 5-HT3 Receptor Agonists; Vomiting
PubMed: 27180992
DOI: 10.1080/17512433.2016.1190271 -
The Oncologist Apr 2016Standard prophylaxis for chemotherapy-induced nausea and vomiting (CINV) with highly emetogenic and anthracycline-cyclophosphamide-based chemotherapy includes a...
BACKGROUND
Standard prophylaxis for chemotherapy-induced nausea and vomiting (CINV) with highly emetogenic and anthracycline-cyclophosphamide-based chemotherapy includes a 5-hydroxytryptamine-3 receptor antagonist, a neurokinin-1 receptor antagonist (NK1RA), and corticosteroid therapy. NEPA is a fixed combination of netupitant and palonosetron. The primary objective of this analysis was to document the safety profile, including cardiac safety, of NEPA + dexamethasone in comparison with current therapies across all phase II/III trials.
MATERIALS AND METHODS
This pooled analysis was based on data from 3,280 patients in 4 randomized, double-blind clinical trials. Patients were categorized into 1 of 3 pooled groups on the basis of actual treatment received: NEPA + dexamethasone, palonosetron + dexamethasone, and aprepitant + ondansetron/palonosetron + dexamethasone. Safety was assessed by number and frequency of adverse events (AEs) and changes from baseline electrocardiogram measures.
RESULTS
Most patients were female and younger than 65 years of age. Demographic characteristics varied among studies and pooled groups. Frequencies of treatment-emergent AEs (TEAEs) and treatment-related AEs (TRAEs) were similar across groups. TEAEs were mostly mild and consistent with expected chemotherapy and disease-related AEs (hematologic events, hair loss, general weakness). TRAEs in ≥2% of patients were headache and constipation. Frequencies of cardiac TEAEs were similar across groups, with QT prolongation (1.6%), tachycardia (1.1%), and dyspnea (0.9%) the most common. Serious cardiac TEAEs were rare.
CONCLUSION
NEPA was well-tolerated, with an AE profile as expected for the regimen. Sample size, demographic characteristics, study design, chemotherapy, and antiemetic regimen differences across the four studies may have contributed to differences in frequencies of neutropenia and alopecia. Adding an NK1RA to a CINV prophylaxis regimen can improve outcomes without additional toxicity.
IMPLICATIONS FOR PRACTICE
Supportive care for cancer should ideally be efficacious, convenient, and well-tolerated. There have been concerns about cardiac safety with current antiemetic prophylactic agents, namely dolasetron and ondansetron. This pooled safety analysis demonstrates that the new oral fixed combination therapy NEPA can be safely added to an antiemetic regimen without increased toxicity.
Topics: Adult; Aged; Antiemetics; Biomarkers, Pharmacological; Dexamethasone; Drug Combinations; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Isoquinolines; Male; Middle Aged; Nausea; Neoplasms; Neurokinin-1 Receptor Antagonists; Pyridines; Quinuclidines; Randomized Controlled Trials as Topic; Serotonin 5-HT3 Receptor Antagonists; Vomiting
PubMed: 27000465
DOI: 10.1634/theoncologist.2015-0301 -
Journal of Pharmacological and... 2016Early clinical Phase I ECG investigations designed to replace the currently applied thorough QT (TQT) study are reviewed to examine how they could complement and verify...
INTRODUCTION
Early clinical Phase I ECG investigations designed to replace the currently applied thorough QT (TQT) study are reviewed to examine how they could complement and verify the conclusions of nonclinical investigations and, in particular, the Comprehensive in vitro Proarrhythmia Assay (CiPA).
TOPICS
The IQ-CSRC trial is a prospective ascending multiple-dose first in human (FIH) type investigation performed as a possible replacement for the thorough QT study (TQT). Designed in accordance with the results of a simulation study by the FDA QT Interdisciplinary Review Team (IRT), it succeeded in correctly categorizing 5/5 established QTc-prolonging agents free of notable heart rate effects (dofetilide, dolasetron, moxifloxacin, ondansetron, and quinine) and the QTc-negative drug, levocetirizine.
DISCUSSION
The positive results obtained with the IQ-CSRC study require additional confirmation with threshold QTc-positive and negative drugs and established QTc prolongers producing both increases and decreases in heart rate. In the future, similar studies should also adopt and validate innovative proarrhythmic metrics, in addition to, or instead of, the traditional proarrhythmic surrogate of QTc, to assess the proarrhythmic safety of candidate drugs.
Topics: Arrhythmias, Cardiac; Clinical Trials, Phase I as Topic; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Electrocardiography; Heart Rate; Humans; Long QT Syndrome; Prospective Studies; Research Design; United States; United States Food and Drug Administration
PubMed: 26903171
DOI: 10.1016/j.vascn.2016.02.181 -
Drug Metabolism Reviews 2015Carbonyl reductase 1 (CBR1), an enzyme belonging to the short-chain dehydrogenases/reductases family, has been detected in all human tissues. CBR1 catalyzes the... (Review)
Review
Carbonyl reductase 1 (CBR1), an enzyme belonging to the short-chain dehydrogenases/reductases family, has been detected in all human tissues. CBR1 catalyzes the reduction of many xenobiotics, including important drugs (e.g. anthracyclines, nabumetone, bupropion, dolasetron) and harmful carbonyls and quinones. Moreover, it participates in the metabolism of a number of endogenous compounds and it may play a role in certain pathologies. Plant polyphenols are not only present in many human food sources, but are also a component of many popular dietary supplements and herbal medicines. Many studies reviewed herein have demonstrated the potency of certain flavonoids, stilbenes and curcuminoids in the inhibition of the activity of CBR1. Interactions of these polyphenols with transcriptional factors, which regulate CBR1 expression, have also been reported in several studies. As CBR1 plays an important role in drug metabolism as well as in the protection of the organism against potentially harmful carbonyls, the modulation of its expression/activity may have significant pharmacological and/or toxicological consequences. Some polyphenols (e.g. luteolin, apigenin and curcumin) have been shown to be very potent CBR1 inhibitors. The inhibition of CBR1 seems useful regarding the increased efficacy of anthracycline therapy, but it may cause the worse detoxification of reactive carbonyls. Nevertheless, all known information about the interactions of polyphenols with CBR1 have only been based on the results of in vitro studies. With respect to the high importance of CBR1 and the frequent consumption of polyphenols, in vivo studies would be very helpful for the evaluation of risks/benefits of polyphenol interactions with CBR1.
Topics: Alcohol Oxidoreductases; Animals; Bupropion; Butanones; Butyrophenones; Daunorubicin; Doxorubicin; Gene Expression Regulation, Enzymologic; Haloperidol; Humans; Indoles; Nabumetone; Neoplasms; Phenylpropionates; Polyphenols; Quinolizines; Substrate Specificity; Xenobiotics
PubMed: 26415702
DOI: 10.3109/03602532.2015.1089885