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Mayo Clinic Proceedings Jan 2014To test the primary hypothesis that ondansetron or dolasetron extends the rate-corrected QT electrocardiographic interval (QTc) greater than 60 milliseconds or increases... (Comparative Study)
Comparative Study
OBJECTIVE
To test the primary hypothesis that ondansetron or dolasetron extends the rate-corrected QT electrocardiographic interval (QTc) greater than 60 milliseconds or increases the fraction of patients with QTc greater than 500 milliseconds in patients having noncardiac surgery, and the secondary hypothesis that QTc prolongation is worse in diabetic patients.
PATIENTS AND METHODS
We extracted data from the Cleveland Clinic's Perioperative Health Documentation System between March 25, 2006, and September 30, 2010, and additional perioperative medications from Cleveland Clinic pharmacy's Epic Cost of Goods Sold (COGS) system. We searched for patients who had a preoperative electrocardiogram within 1 month of surgery and postoperatively within 2 hours. We excluded patients given an antiemetic drug other than ondansetron or dolasetron perioperatively, and those given amiodarone.
RESULTS
A total of 1429 patients given serotonin-3 receptor (5HT3R) antagonists and 1022 controls met the enrollment criteria. Seventeen percent of patients given 5HT3R antagonists (n=242) and 22% of controls (n=220) had postoperative QTc exceeding 500 milliseconds. Mean ± SD presurgical and postsurgical QTc, respectively, were 438±37 milliseconds and 464±41 milliseconds for 5HT3R antagonist patients and 443±40 milliseconds and 469±47 milliseconds for control patients. Univariable mean ± SD perioperative increases in QTc were 26±39 and 26±48 milliseconds in the 2 groups. After adjusting for confounding variables, there were no differences in the mean increase in QTc in patients who were and were not given 5HT3R antagonists: -0.1 milliseconds (97.5% CI, -5.2 to 5.0 milliseconds; multivariable P=.97). The QTc was prolonged, but not significantly, in diabetic patients given 5HT3R antagonists (P=.16).
CONCLUSIONS
The average QTc prolongation from baseline was only 6%. Perioperative use of ondansetron or dolasetron was not associated with extended QT prolongation, and these results did not vary by diabetic status. Perioperative use of 5HT3R antagonists does not produce potentially dangerous perioperative electrocardiographic changes and does not seem to warrant a drug safety warning from the Food and Drug Administration.
Topics: Aged; Aged, 80 and over; Female; Heart Rate; Humans; Indoles; Long QT Syndrome; Male; Middle Aged; Ondansetron; Postoperative Complications; Postoperative Period; Preoperative Care; Quinolizines; Serotonin 5-HT3 Receptor Antagonists; Young Adult
PubMed: 24388024
DOI: 10.1016/j.mayocp.2013.10.008 -
Pharmacotherapy 1996To evaluate the safety, tolerability, and pharmacokinetics of increasing dose levels of oral dolasetron mesylate, a new 5-HT3 antagonist. (Clinical Trial)
Clinical Trial Randomized Controlled Trial
STUDY OBJECTIVES
To evaluate the safety, tolerability, and pharmacokinetics of increasing dose levels of oral dolasetron mesylate, a new 5-HT3 antagonist.
DESIGN
Double-blind, placebo-controlled, dose-ranging phase I study.
SETTING
A clinical research center.
PATIENTS
Forty healthy male volunteers.
INTERVENTIONS
Eight subjects at each dose level were randomized in a ratio of 3:1 to receive either dolasetron mesylate 25, 50, 100, 150, or 200 mg in a single oral dose on days 1 and 9, and twice/day on days 2-8, or placebo for 9 days.
MEASUREMENTS AND MAIN RESULTS
Dolasetron was well tolerated at all dose levels. The adverse event rates for dolasetron- and placebo-treated subjects who experienced at least one adverse event were 80% and 50%, respectively. Most frequently reported by subjects receiving dolasetron were headache, constipation, flatulence, and lightheadedness. They generally were mild, and none was severe. No dose-response relationship was apparent for any adverse event. There were no clinically significant changes in mean laboratory values or vital signs. Asymptomatic treatment-related electrocardiographic changes were consistent with the drug's electrophysiologic properties. These changes have been well characterized and have thus far been clinically unimportant. Pharmacokinetics of the reduced metabolite were dose independent, and multiple-dose exposure of this metabolite can be predicted from its single-dose values.
CONCLUSION
Oral dolasetron mesylate was well tolerated when administered in doses up to 200 mg/day for 9 days in healthy volunteers.
Topics: Administration, Oral; Adolescent; Adult; Antiemetics; Double-Blind Method; Electrocardiography; Humans; Indoles; Male; Middle Aged; Quinolizines; Serotonin Antagonists
PubMed: 8820469
DOI: No ID Found -
Internal Medicine Journal Aug 2005The need to control chemotherapy-induced emesis has stimulated research into anti-emetics. Emesis is not only unpleasant, but negatively impacts on global quality of... (Comparative Study)
Comparative Study Review
The need to control chemotherapy-induced emesis has stimulated research into anti-emetics. Emesis is not only unpleasant, but negatively impacts on global quality of life. The development of two new classes of drugs has been responsible for the major advances in anti-emesis. The 5 hydroxytryptamine3 (5HT3) antagonists in combination with dexamethasone significantly improved the control of acute post chemotherapy emesis, but delayed emesis which can last for several days was still problematic, yet its incidence was underestimated by clinicians. Both the control of acute and delayed emesis was improved when the neurokinin1 (NK1) receptor antagonists were added to 5HT3 antagonists and steroids. The complete control of delayed emesis was improved by 21% with little toxicity. The triple drug combination has become the standard of care for preventing the emesis associated with cytotoxic drugs of high emetic potential.
Topics: Administration, Oral; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Australia; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Granisetron; Humans; Indoles; Isoquinolines; Male; Neoplasms; Ondansetron; Palonosetron; Patient Satisfaction; Prognosis; Quality of Life; Quinolizines; Quinuclidines; Treatment Outcome; Tropisetron; Vomiting
PubMed: 16176471
DOI: 10.1111/j.1445-5004.2005.00879.x -
Anesthesia and Analgesia Oct 2001Dolasetron (12.5 mg IV) is effective in both preventing and treating postoperative nausea and vomiting (PONV) after ambulatory surgery. However, the optimal timing of... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
UNLABELLED
Dolasetron (12.5 mg IV) is effective in both preventing and treating postoperative nausea and vomiting (PONV) after ambulatory surgery. However, the optimal timing of dolasetron administration and its effect on the patient's quality of life after discharge have not been established. One-hundred-five healthy, consenting women undergoing gynecologic laparoscopic procedures with a standardized general anesthetic technique were enrolled in this randomized, double-blinded study. Group 1 received dolasetron 12.5 mg IV 10-15 min before the induction of anesthesia; Group 2 received dolasetron 12.5 mg IV at the end of the laparoscopy (79 +/- 48 min later than Group 1); and Group 3 received dolasetron 12.5 mg IV at the end of anesthesia (93 +/- 52 min later than Group 1). The incidence of PONV, complete responses (defined as no emetic episodes and no rescue medication within the 24-h period after anesthesia), recovery profiles, and patient satisfaction were recorded. In the postanesthesia care unit and during the 24-h follow-up period, the incidence of nausea and vomiting, as well as the need for rescue antiemetics, did not differ significantly among the three groups. The percentages of patients with complete responses to the study drug within the first postoperative 24 h were also similar in all three groups (55%, 59%, and 52% for Groups 1, 2, and 3, respectively). The early and intermediate recovery profiles, including resumption of a normal diet and patient satisfaction with the control of PONV, were not different among the three study groups. Dolasetron 12.5 mg IV administered before the induction of anesthesia is as effective as dolasetron given at the end of laparoscopy or at the end of anesthesia in preventing PONV after outpatient laparoscopy.
IMPLICATIONS
The timing of dolasetron administration appears to have little effect on its efficacy when administered as a prophylactic antiemetic in the ambulatory setting.
Topics: Adult; Ambulatory Surgical Procedures; Antiemetics; Double-Blind Method; Female; Gynecologic Surgical Procedures; Humans; Indoles; Laparoscopy; Middle Aged; Patient Satisfaction; Postoperative Nausea and Vomiting; Prospective Studies; Quinolizines; Time Factors
PubMed: 11574355
DOI: 10.1097/00000539-200110000-00021 -
Anesthesia and Analgesia Feb 1997The newer 5-hydroxytryptamine type 3 (5-HT3) antagonists are sometimes considered for routine prophylaxis of postoperative nausea and vomiting (PONV) in high-risk... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
The newer 5-hydroxytryptamine type 3 (5-HT3) antagonists are sometimes considered for routine prophylaxis of postoperative nausea and vomiting (PONV) in high-risk patients. This multicenter, randomized, double-blind, placebo-controlled study compared the efficacy and safety of three single intravenous (IV) doses of dolasetron mesylate salt (12.5, 25, or 50 mg) for the prevention of PONV in 635 females undergoing outpatient laparoscopic gynecologic surgery. Antiemetic efficacy was evaluated over a 24-h postoperative period by recording the number and timing of emetic episodes; effects on nausea were evaluated by a visual analog scale (VAS). The proportion of complete responders (no emetic episodes and no escape medication in 24 h) was significantly higher with each dolasetron mesylate dose (> 50% for each dose; P < or = 0.0003) than with placebo (30.6%). Fewer patients given dolasetron required or requested escape antiemetic medication compared with placebo (P < 0.0003). Dolasetron-treated patients had significantly (P < 0.0357) lower median postdose maximum nausea VAS scores compared with placebo-treated patients. Patient satisfaction with dolasetron was high and, overall, was significantly (P = 0.0131) greater than that with placebo. Dolasetron was an effective and well tolerated preventive treatment for PONV resulting from laparoscopic gynecologic surgery.
Topics: Adult; Ambulatory Surgical Procedures; Antiemetics; Double-Blind Method; Female; Genitalia, Female; Humans; Indoles; Injections, Intravenous; Laparoscopy; Nausea; Patient Satisfaction; Postoperative Complications; Quinolizines; Vomiting
PubMed: 9024022
DOI: 10.1097/00000539-199702000-00015 -
The Cochrane Database of Systematic... Jul 2017Drugs can prevent postoperative nausea and vomiting, but their relative efficacies and side effects have not been compared within one systematic review. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Drugs can prevent postoperative nausea and vomiting, but their relative efficacies and side effects have not been compared within one systematic review.
OBJECTIVES
The objective of this review was to assess the prevention of postoperative nausea and vomiting by drugs and the development of any side effects.
SEARCH METHODS
We searched The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 2, 2004), MEDLINE (January 1966 to May 2004), EMBASE (January 1985 to May 2004), CINAHL (1982 to May 2004), AMED (1985 to May 2004), SIGLE (to May 2004), ISI WOS (to May 2004), LILAC (to May 2004) and INGENTA bibliographies.
SELECTION CRITERIA
We included randomized controlled trials that compared a drug with placebo or another drug, or compared doses or timing of administration, that reported postoperative nausea or vomiting as an outcome.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed trial quality and extracted outcome data.
MAIN RESULTS
We included 737 studies involving 103,237 people. Compared to placebo, eight drugs prevented postoperative nausea and vomiting: droperidol, metoclopramide, ondansetron, tropisetron, dolasetron, dexamethasone, cyclizine and granisetron. Publication bias makes evidence for differences among these drugs unreliable. The relative risks (RR) versus placebo varied between 0.60 and 0.80, depending upon the drug and outcome. Evidence for side effects was sparse: droperidol was sedative (RR 1.32) and headache was more common after ondansetron (RR 1.16).
AUTHORS' CONCLUSIONS
Either nausea or vomiting is reported to affect, at most, 80 out of 100 people after surgery. If all 100 of these people are given one of the listed drugs, about 28 would benefit and 72 would not. Nausea and vomiting are usually less common and, therefore, drugs are less useful. For 100 people, of whom 30 would vomit or feel sick after surgery if given placebo, 10 people would benefit from a drug and 90 would not. Between one to five patients out of every 100 people may experience a mild side effect, such as sedation or headache, when given an antiemetic drug. Collaborative research should focus on determining whether antiemetic drugs cause more severe, probably rare, side effects. Further comparison of the antiemetic effect of one drug versus another is not a research priority.
Topics: Antiemetics; Humans; Postoperative Nausea and Vomiting; Randomized Controlled Trials as Topic
PubMed: 28715610
DOI: 10.1002/14651858.CD004125.pub3 -
American Health & Drug Benefits May 2014Individual studies have assessed the impact of standard prophylactic therapy with 5-hydroxytryptamine receptor antagonists (5-HT3RAs) for chemotherapy-induced nausea and... (Review)
Review
BACKGROUND
Individual studies have assessed the impact of standard prophylactic therapy with 5-hydroxytryptamine receptor antagonists (5-HT3RAs) for chemotherapy-induced nausea and vomiting (CINV) on cost and utilization, but no synthesis of the findings exists.
OBJECTIVE
To systematically review published literature on costs and utilization associated with CINV prophylaxis with palonosetron and other 5-HT3RAs.
METHODS
PubMed and the National Institute for Health Research Centre for Reviews and Dissemination databases, conferences of 4 organizations (ie, Academy of Managed Care Pharmacy, American Society of Clinical Oncology, International Society for Pharmacoeconomics and Outcomes Research, and Multinational Association of Supportive Care in Cancer), and the bibliographies of relevant articles were queried for the medical subject headings and key terms of "ondansetron," "granisetron," "palonosetron," "dolasetron mesylate," "costs," "cost analysis," and "economics." We included records published (full-length articles after 1997 and conference presentations after 2010) in English and with human patients, reporting data on cost and utilization (rescue medication, outpatient and inpatient services) associated with the use of 5-HT3RAs for the treatment or prevention of CINV.
RESULTS
Of the 434 identified studies, 32 are included in the current analysis: 7 studies report costs, 18 report utilization, and 7 studies report both. The costs are reported in US dollars (7 studies), in Euros (5 studies), and in Canadian dollars (2 studies). The studies vary in designs, patients, 5-HT3RA regimens, and the definition of outcomes. The US studies report higher drug costs for CINV prophylaxis with palonosetron compared with ondansetron, lower medical outpatient and inpatient costs for palonosetron versus other 5-HT3RAs, and higher acquisition costs for palonosetron versus ondansetron or other 5-HT3RAs. Fewer patients receiving palonosetron versus with ondansetron or other 5-HT3RAs required rescue medication or used outpatient or inpatient care. In Europe and in Canada, the total pharmacy costs and use of rescue medications reported are lower for patients receiving prophylaxis with palonosetron.
CONCLUSIONS
This analysis shows that prophylaxis with palonosetron for the treatment of CINV is associated with higher acquisition treatment costs, but also with lower use of rescue medications and outpatient and inpatient services compared with ondansetron or other 5-HT3RAs in the United States. Therefore, the use of palonosetron as a standard treatment may lead to reduced service utilization for CINV.
PubMed: 24991400
DOI: No ID Found -
Biopharmaceutics & Drug Disposition Mar 1993Dolasetron is a 5-hydroxytryptamine antagonist active at type III receptors; it is presently undergoing clinical evaluation for the reduction/prevention of cancer... (Clinical Trial)
Clinical Trial
Dolasetron is a 5-hydroxytryptamine antagonist active at type III receptors; it is presently undergoing clinical evaluation for the reduction/prevention of cancer chemotherapy-induced nausea and vomiting. A previous study demonstrated that following intravenous administration to healthy male subjects, dolasetron disappeared extremely rapidly from plasma, and less than 1 per cent of the dose appeared in the urine. A major plasma metabolite, reduced dolasetron, peaked rapidly in the plasma. In this study, dolasetron was administered orally to healthy male subjects at doses ranging from 50 to 400 mg (mesylate monohydrate). Plasma concentrations of dolasetron were low and sporadic, and there was little excreted in urine; this prevented dolasetron pharmacokinetic analysis. Reduced metabolite concentrations peaked rapidly, with a median value of 1.00 h. The median terminal disposition half-life was 7.80 h. Median values for fraction of dose excreted in urine and renal clearance were 22.2 per cent and 2.56 ml min-1 kg-1. Whereas areas under the plasma concentration-time curves were proportional to dose, renal clearance increased with dose (p < 0.05). However, given dose proportionality to AUC, this is probably of little therapeutic consequence. Since reduced dolasetron has significant anti-emetic activity in the ferret model, it appears that this metabolite may play a significant role in pharmacodynamic activity.
Topics: Absorption; Administration, Oral; Adolescent; Adult; Dose-Response Relationship, Drug; Humans; Indoles; Male; Metabolic Clearance Rate; Quinolizines; Serotonin Antagonists
PubMed: 8453023
DOI: 10.1002/bdd.2510140205 -
Journal of Clinical Oncology : Official... May 1994This dose-ranging trial of intravenous dolasetron mesylate (MDL73,147EF) was performed to determine its adverse and antiemetic effects in patients receiving cisplatin at... (Clinical Trial)
Clinical Trial
PURPOSE
This dose-ranging trial of intravenous dolasetron mesylate (MDL73,147EF) was performed to determine its adverse and antiemetic effects in patients receiving cisplatin at doses > or = 100 mg/m2.
PATIENTS AND METHODS
Eighty-nine patients treated with initial cisplatin received a single intravenous dose of dolasetron mesylate administered over 20 minutes beginning 30 minutes before chemotherapy. The following four dose levels were studied: 1.8, 2.4, 3.0, and 5.0 mg/kg. Emesis and adverse effects were measured for 24 hours after cisplatin.
RESULTS
All adverse effects were mild and transient including loose stools, headache, serum AST/ALT elevations, and asymptomatic prolongation of ECG intervals. Among the dose levels, no-emesis rates from 24% to 52% were observed, and the percentage of patients having zero, one, or two emetic episodes ranged from 48% to 82%. Complete control of vomiting increased as the dose was escalated to 2.4 mg/kg, but did not improve further with higher doses.
CONCLUSION
Dolasetron mesylate can be administered safely at doses up to 5.0 mg/kg, with comparable complete protection rates and increased adverse effects at doses greater than 2.4 mg/kg. Antiemetic activity was seen after cisplatin. Trials comparing single infusions of dolasetron mesylate and ondansetron are under way.
Topics: Adult; Aged; Antiemetics; Cisplatin; Drug Administration Schedule; Female; Humans; Indoles; Infusions, Intravenous; Male; Middle Aged; Nausea; Quinolizines; Serotonin Antagonists; Vomiting
PubMed: 8164028
DOI: 10.1200/JCO.1994.12.5.1045 -
Methods and Findings in Experimental... 2004Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from... (Review)
Review
Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Abetimus sodium, Ad5-FGF4, adeno-Interferon gamma, AE-941, AERx, alemtuzumab, alicaforsen sodium, almotriptan, alpharadin, anakinra, anatumomab mafenatox, ANG-453, anti-CTLA-4 Mab, AP-12009, aprepitant, aripiprazole, arsenic trioxide, astemizole, atlizumab, atomoxetine hydrochloride; Bevacizumab, BG-9928, BMS-188667, botulinum toxin type B, BufferGel; Caffeine, CDP-870, cetuximab, cilomilast, ciluprevir, clofarabine, continuous erythropoiesis receptor activator, CP-461; Darbepoetin alfa, deferasirox, desloratadine, desoxyepothilone B, diflomotecan, dolasetron, drotrecogin alfa (activated), duloxetine hydrochloride; ED-71, efalizumab, efaproxiral sodium, EKB-569, eletriptan, EMD-72000, enfuvirtide, erlotinib hydrochloride, escitalopram oxalate, etoricoxib; Fampridine, ferumoxytol, fondaparinux sodium; Gadofosveset sodium, gastrazole, gefitinib, gemtuzumab ozogamicin, gepirone hydrochloride glutamine; hLM609, HSPPC-96, human insulin; IDD-1, imatinib mesylate, indisulam, inhaled insulin, ixabepilone; Keratinocyte growth factor; Lapatinib, laquinimod, LDP-02, LE-SN38, levetiracetam, levosimendan, licofelone, liposomal doxorubicin, liposomal NDDP, lopinavir, lumiracoxib, LY-156735; Morphine hydrochloride, morphine-6-glucuronide, motexafin gadolinium, MS-27-275, MVA-5T4, MVA-Muc1-IL-2; Nemifitide ditriflutate, neridronic acid nitronaproxen, NSC-683864, NSC-703940, NVP-LAF-237; Oblimersen sodium, ocinaplon, oncomyc-NG, OPC-28326, ortataxel, ospemifene; Palonosetron hydrochloride, PEG-filgrastim peginterferon alfa-2(a), peginterferon alfa-2b, pegsunercept, pemetrexed disodium, pregabalin, prilocaine, pyridoxamine; RDP-58, recombinant glucagon-like peptide-1 (7-36) amide, recombinant human ApoA-I milano/phospholipid complex; SB-715992, soblidotin, sodium dichloroacetate, St. John's Wort extract; TAS-102, terfenadine, TG-1024, TG-5001, 4'-Thio-ara-C, tipranavir, topixantrone hydrochloride, trabectedin, transdermal selegiline, trimethoprim, troxacitabine, TT-232; Vatalanib succinate, vinflunine; Ximelagatran; Ziprasidone hydrochloride, Zoledronic acid monohydrate.
Topics: Clinical Trials as Topic; Databases, Factual; Humans; Statistics as Topic
PubMed: 14988742
DOI: No ID Found