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American Journal of Therapeutics May 1996Dolasetron, a 5-hydroxytryptamine(3) receptor antagonist, is under investigation for prevention of nausea and vomiting due to chemotherapy. The keto-reduced metabolite...
Dolasetron, a 5-hydroxytryptamine(3) receptor antagonist, is under investigation for prevention of nausea and vomiting due to chemotherapy. The keto-reduced metabolite of dolasetron has been identified in human plasma and is likely responsible for the antiemetic activity. This study evaluated single and multiple dose pharmacokinetics of the reduced metabolite following oral administration of dolasetron mesylate in healthy male subjects. Five groups (six active/two placebo each) of subjects received either oral doses of dolasetron mesylate ranging from 25 to 200 mg or placebo on day 1 and every 12 h on days 2 through 9. Because plasma dolasetron concentrations were low and sporadic, pharmacokinetics of the parent compound could not be determined. The reduced metabolite appeared rapidly in the plasma and reached a maximal plasma concentration in about 1 h. The maximal plasma concentrations and areas under plasma concentration--time curves were proportional to the dose. The mean apparent oral clearance ranged from 9.89 to 23.10 ml min(minus sign1) kg(minus sign1). The half-life ranged from 5.20 to 10.80 h. Mean renal clearance and fraction of dose excreted in urine were 0.97 to 3.97 ml min(minus sign1) kg(minus sign1) and 7.47 to 31.9%, respectively. The pharmacokinetics of reduced metabolite appears to be dose independent after single and multiple dosing.
PubMed: 11862273
DOI: 10.1097/00045391-199605000-00006 -
Clinical Pharmacology and Therapeutics Nov 1996Dolasetron mesylate is a selective 5-HT3 receptor antagonist under investigation as an antiemetic in children. Published studies indicate that its antiemetic activity...
BACKGROUND
Dolasetron mesylate is a selective 5-HT3 receptor antagonist under investigation as an antiemetic in children. Published studies indicate that its antiemetic activity results from the active metabolite (MDL 74,156), which is produced within 10 minutes of administration of dolasetron mesylate.
METHODS
The pharmacokinetics of MDL 74,156 and the safety and tolerability of dolasetron mesylate were studied after a single oral or intravenous dose of 1.2 mg.kg-1 dolasetron mesylate to healthy children from 2 to 12 years of age. Oral dolasetron was administered to 12 children 1 to 2 hours before anesthesia. Intravenous dolasteron was administered to 18 children at induction of anesthesia. Serial blood samples were collected for 24 hours after dosing to measure the plasma concentration of MDL 74,156. Indexes of liver and kidney function were determined, and electrocardiograms and adverse events were recorded.
Topics: Administration, Oral; Anesthesia; Antiemetics; Child; Child, Preschool; Electrocardiography; Female; Humans; Indoles; Injections, Intravenous; Male; Quinolizines; Serotonin Antagonists
PubMed: 8941021
DOI: 10.1016/S0009-9236(96)90144-7 -
Future Oncology (London, England) Oct 2006Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents,... (Review)
Review
Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles and patient risk factors (female gender, younger age, alcohol consumption, history of motion sickness) are the major risk factors for CINV. The use of 5-hydroxytryptamine (5-HT)3 receptor antagonists plus dexamethasone has significantly improved the control of acute CINV, but delayed nausea and vomiting remains a clinical problem. A new agent, palonosetron, has recently been approved for the prevention of acute CINV in patients receiving either moderately or highly emetogenic chemotherapy and for the prevention of delayed CINV in patients receiving moderately emetogenic chemotherapy. Palonosetron is a 5-HT3 receptor antagonist with a longer half-life and a higher binding affinity than first-generation 5-HT3 receptor antagonists. In a single dosing study, palonosetron was highly effective in controlling CINV compared with a single dose of dolasetron or ondansetron in patients receiving moderately emetogenic chemotherapy. Palonosetron in combination with dexamethasone demonstrated control of CINV in patients receiving highly emetogenic chemotherapy. Palonosetron appeared to be as effective in subsequent courses of chemotherapy compared with the initial course of chemotherapy. There were no clinically relevant differences seen among palonosetron, ondansetron or dolasetron in laboratory, electrocardiographic or vital-sign changes, and adverse reactions reported in the clinical trials were the most common reactions reported for the 5-HT3 receptor antagonist class. Recent studies using palonosetron-based anti-emetic combinations in moderately and highly emetogenic chemotherapy, as well as in the clinical setting of multiple-day chemotherapy, have been reported. Future studies may consider the use of palonosetron with current and other new agents and in other clinical settings, such as bone marrow transplantation and radiation therapy.
Topics: Age Factors; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dexamethasone; Humans; Isoquinolines; Nausea; Palonosetron; Quinuclidines; Risk Factors; Serotonin 5-HT3 Receptor Antagonists; Serotonin Antagonists; Sex Factors
PubMed: 17026451
DOI: 10.2217/14796694.2.5.591 -
European Journal of Anaesthesiology Oct 2003In a randomized, placebo-controlled, double-blind trial, we compared the efficacy of oral dolasetron and ondansetron in preventing postoperative nausea and vomiting in... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
BACKGROUND AND OBJECTIVE
In a randomized, placebo-controlled, double-blind trial, we compared the efficacy of oral dolasetron and ondansetron in preventing postoperative nausea and vomiting in children after various surgical operations.
METHODS
Children were assigned randomly to one of three groups (each contained 50 children) to receive dolasetron 1.8 mg kg(-1) or ondansetron 0.15 mg kg(-1) orally, or a placebo. All children received methylene blue capsules (10 mg) orally as an indicator before the induction of anaesthesia. Postoperatively, contamination of the mouth and the endotracheal tube by methylene blue was recorded, and postoperative nausea and vomiting was recorded for 0-1, 1-24 and 0-24 h. Metoclopramide (0.1 mg kg(-1)) intravenously was used as the rescue antiemetic.
RESULTS
In the 0-1 h period after operation, there were no differences between the groups. In the 1-24 h period, dolasetron was significantly better than placebo (nausea 8 versus 24%; vomiting 4 versus 20%; total nausea and vomiting scores 16 versus 48%). Over the 0-24 h period, both dolasetron and ondansetron were significantly better than placebo (nausea 16 versus 26 versus 40%), vomiting (8 versus 16 versus 30%), and total nausea and vomiting scores (32 versus 48 versus 78%). There were no significant differences between dolasetron and ondansetron. There was no important methylene blue contamination, and little use of rescue metoclopramide. There were no important adverse events.
CONCLUSIONS
Prophylactic oral dolasetron and ondansetron were effective in reducing postoperative nausea and vomiting in children.
Topics: Acetaminophen; Administration, Oral; Analgesics, Non-Narcotic; Anesthesia Recovery Period; Antiemetics; Chi-Square Distribution; Child; Double-Blind Method; Female; Humans; Indoles; Male; Ondansetron; Pain Measurement; Postoperative Nausea and Vomiting; Quinolizines; Surgical Procedures, Operative; Time Factors; Treatment Outcome
PubMed: 14580054
DOI: 10.1017/s0265021503001340 -
Medical and Pediatric Oncology Aug 1999Nausea and vomiting are among the most unpleasant adverse side effects of cancer therapy. (Clinical Trial)
Clinical Trial Comparative Study
Open-label comparison of the antiemetic efficacy of single intravenous doses of dolasetron mesylate in pediatric cancer patients receiving moderately to highly emetogenic chemotherapy.
BACKGROUND
Nausea and vomiting are among the most unpleasant adverse side effects of cancer therapy.
PROCEDURE
An open-label dose-escalation study was conducted to assess the appropriate intravenous dose of dolasetron for pediatric patients undergoing chemotherapy. Patients received dolasetron in single intravenous doses of 0.6 (n = 10), 1.2 (n = 12), 1.8 (n = 12), or 2.4 (n = 12) mg/kg 30 min before receiving emetogenic chemotherapy. Pharmacokinetic parameters were evaluated at each dose level and efficacy was evaluated over the first 24 hr following the administration of dolasetron.
RESULTS
A complete response was achieved in 10% of patients given 0.6 mg/kg, 25% of patients given 1. 2 mg/kg, 67% of patients given 1.8 mg/kg, and 33% of patients given 2.4 mg/kg. Peak plasma concentrations (Cmax) were observed between 0. 33 and 0.75 hr following dolasetron infusion. Cmax and area under plasma concentration-time (AUC) increased with larger doses of dolasetron, while terminal disposition half-life (t1/2) and apparent clearance (Clapp) were not significantly changed with respect to dose. For 1.8-mg/kg dolasetron, the t1/2 was 4.98 hr and the maximum plasma concentration (tmax) 0.47 hr. Adverse events were mild to moderate. No serious events occurred. Conclusions. This study suggests that a single intravenous dose of 1.8 mg/kg is the optimum single intravenous dose for controlling chemotherapy-induced emesis in pediatric patients.
Topics: Adolescent; Antiemetics; Antineoplastic Agents; Area Under Curve; Child; Child, Preschool; Female; Humans; Indoles; Infusions, Intravenous; Male; Nausea; Neoplasms; Quinolizines; Serotonin Antagonists; Vomiting
PubMed: 10398184
DOI: 10.1002/(sici)1096-911x(199908)33:2<99::aid-mpo7>3.0.co;2-p -
Journal of Pediatric Hematology/oncology 1999The safety, antiemetic efficacy, and pharmacokinetics of single oral doses of dolasetron, a new highly selective 5-HT3 receptor antagonist, were evaluated in children...
Safety, tolerability, antiemetic efficacy, and pharmacokinetics of oral dolasetron mesylate in pediatric cancer patients receiving moderately to highly emetogenic chemotherapy.
PURPOSE
The safety, antiemetic efficacy, and pharmacokinetics of single oral doses of dolasetron, a new highly selective 5-HT3 receptor antagonist, were evaluated in children with cancer undergoing treatment with moderately to highly emetogenic chemotherapy.
PATIENTS AND METHODS
A total of 32 children, ages 3 to 18 years, were enrolled in a nonrandomized, multicenter, open-label, dose-escalation study. Three oral dose levels (0.6, 1.2, or 1.8 mg/kg) were studied. Safety, efficacy, and pharmacokinetic parameters were assessed over 24 hours at each dosage level.
RESULTS
The most effective dose was 1.8 mg/kg; 60% of the patients achieved a complete or major response (< or =2 emetic episodes in 24 hours). A complete response was achieved in 3 of 9 patients (33%) who received 0.6 mg/kg, 4 of 13 (31%) patients who received 1.2 mg/kg, and 5 of 10 (50%) patients who received 1.8 mg/kg of dolasetron. Overall, dolasetron was well tolerated. Adverse events were mild and similar to those reported in adults. Peak plasma concentrations (Cmax) of dolasetron's active reduced metabolite, MDL 74,156, were dose proportional and occurred, on the average, within 1 hour of oral administration. The half-life (t1/2) in plasma was approximately 6 hours for all dose levels, and the mean clearance (CLapp) was unrelated to dose.
CONCLUSIONS
Oral dolasetron is safe and effective in reducing chemotherapy-induced nausea and vomiting, particularly at the 1.8-mg/kg dose level. These results support further evaluation of oral dolasetron in larger randomized clinical trials in the pediatric cancer population.
Topics: Administration, Oral; Adolescent; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Female; Humans; Indoles; Male; Nausea; Quinolizines; Serotonin Antagonists; Treatment Outcome; Vomiting
PubMed: 10445889
DOI: 10.1097/00043426-199907000-00007 -
Acta Anaesthesiologica Scandinavica Aug 1997Intravenous dolasetron mesilate has shown efficacy in the prevention of postoperative nausea and vomiting (PONV) when administered as a single dose prior to emergence... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
BACKGROUND
Intravenous dolasetron mesilate has shown efficacy in the prevention of postoperative nausea and vomiting (PONV) when administered as a single dose prior to emergence from anesthesia. This trial compared intravenous dolasetron and ondansetron for the prevention of PONV when administered at induction of anesthesia.
METHODS
This double-blind, placebo-controlled, multicenter trial randomized patients to one of four single IV treatments placebo, 25 or 50 mg dolasetron, or 4 mg ondansetron. Efficacy was measured by complete response (0 emetic episodes and no rescue medication), nausea severity and patient satisfaction as measured on a visual analog scale (VAS), investigator's rating, of nausea severity, and total response (complete response with no nausea [< or = 5 mm VAS]).
RESULTS
514 patients at 24 sites were evaluated for efficacy. The 50 mg dolasetron and 4 mg ondansetron doses were statistically equivalent, and superior to placebo, for all efficacy measures. Complete response rates were 49%, 51%, 71% and 64% for placebo, 25 and 50 mg dolasetron, and ondansetron, respectively. Dolasetron 50 mg was statistically superior to 25 mg dolasetron for complete response, total response, VAS maximum nausea, time to first emetic episode, and patient satisfaction. The majority of adverse events were of mild-to-moderate intensity. Headache was the most frequently reported treatment-related adverse event with a 3%-5% incidence across treatments.
CONCLUSION
When given at induction of anesthesia, 50 mg intravenous dolasetron is equivalent to 4 mg ondansetron and superior to 25 mg dolasetron and placebo for the prevention of PONV. All treatments were safely administered and well tolerated.
Topics: Adult; Aged; Antiemetics; Double-Blind Method; Female; Humans; Indoles; Injections, Intravenous; Male; Middle Aged; Nausea; Ondansetron; Postoperative Complications; Quinolizines; Serotonin Antagonists; Vomiting
PubMed: 9265937
DOI: 10.1111/j.1399-6576.1997.tb04809.x -
Current Medical Research and Opinion Jun 2004Comparative studies examining the use of oral serotonin type 3 (5-HT(3)) receptor antagonists for the management of acute chemotherapy-induced nausea and vomiting (CINV)... (Clinical Trial)
Clinical Trial Comparative Study
OBJECTIVE
Comparative studies examining the use of oral serotonin type 3 (5-HT(3)) receptor antagonists for the management of acute chemotherapy-induced nausea and vomiting (CINV) are limited. Therefore, we performed an experiential open-label pilot study at Stony Brook Hospital to allow clinicians to make informed formulary decisions at our institution and to stimulate further study. Specifically, the objective of this study was to compare the effectiveness of oral granisetron versus oral dolasetron for prophylaxis of acute CINV.
RESEARCH DESIGN AND METHODS
The study was conducted during the period of 1 February 2001 to 31 March 2001. Patients (n = 26) with lymphoma or malignancies of the lungs, larynx, or uterus undergoing moderately high and highly emetogenic chemotherapy were studied. Patients admitted during February (n = 13) were administered a single oral dose of 100 mg of dolasetron; those admitted in March (n = 13) received a single oral dose of 2mg of granisetron. All patients were administered intravenous dexamethasone 20 mg before the initiation of chemotherapy.
MAIN OUTCOME MEASURES
Patients were monitored for at least 24 h by clinicians. The data recorded for each patient included age, sex, the number of episodes of nausea and emesis, the intensity of nausea (when applicable), and the number of doses of rescue antiemetic medication administered (when applicable).
RESULTS
Overall, granisetron provided significantly greater control of acute CINV than dolasetron. More patients treated with granisetron experienced total control of nausea and vomiting (69.2 vs 23.1%, p < 0.05). Fewer granisetron-treated patients experienced emesis (7.7 vs 53.8%, p < 0.05) and nausea (30.8 vs 76.9%, p < 0.05). Of those patients who experienced nausea, intensity was significantly less with granisetron than with dolasetron (p < 0.05). Consequently, a significantly greater proportion of patients treated with dolasetron required a rescue antiemetic and significantly more doses of rescue antiemetics (both p < 0.01).
CONCLUSIONS
These data suggest that oral granisetron may demonstrate improved CINV outcomes compared with oral dolasetron in patients undergoing moderately high and highly emetogenic chemotherapy.
Topics: Antiemetics; Drug-Related Side Effects and Adverse Reactions; Female; Granisetron; Humans; Indoles; Male; Middle Aged; Nausea; Neoplasms; Quinolizines; United States; Vomiting
PubMed: 15200746
DOI: 10.1185/030079904125003728 -
Pharmacotherapy 1996To evaluate the safety, tolerability, and pharmacokinetics of single, escalating doses of oral dolasetron mesylate, a new 5-HT3 receptor antagonist. (Clinical Trial)
Clinical Trial Randomized Controlled Trial
STUDY OBJECTIVES
To evaluate the safety, tolerability, and pharmacokinetics of single, escalating doses of oral dolasetron mesylate, a new 5-HT3 receptor antagonist.
DESIGN
Double-blind, placebo-controlled, dose-escalating phase I study.
SETTING
A clinical research center.
PATIENTS
One hundred twenty healthy male volunteers.
INTERVENTIONS
Subjects received either placebo or oral dolasetron mesylate 50, 100, 150, 200, 250, 300, or 400 mg.
MEASUREMENTS AND MAIN RESULTS
Compared with placebo, subjects receiving dolasetron mesylate reported a greater frequency of headache, light-headedness, dizziness, increased appetite, and nausea. There were no clinically significant changes in mean laboratory values from before to after treatment. Adverse events were transient, mild or moderate, and similar to those after single intravenous doses of the drug. No clinically significant electrocardiographic changes occurred, but lengthening of the QRS complex duration and dose-dependent lengthening of PR and QTc intervals were observed 1-2 hours after dosing. These effects were asymptomatic and were mainly associated with higher doses (< or = 300 mg).
CONCLUSION
Dolasetron mesylate is well tolerated when administered in single oral doses up to 400 mg to healthy volunteers. Clinical trials are under way to evaluate the agent's efficacy in preventing chemotherapy-induced and postoperative nausea and vomiting with doses up to 200 mg.
Topics: Administration, Oral; Adolescent; Adult; Antiemetics; Double-Blind Method; Electrocardiography; Humans; Indoles; Male; Middle Aged; Nausea; Quinolizines; Serotonin Antagonists; Vomiting
PubMed: 8820468
DOI: No ID Found -
Paediatric Anaesthesia Jul 2003Children undergoing strabismus surgery have a high incidence of postoperative vomiting (POV). The purpose of this study was to assess the efficacy and safety of... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
BACKGROUND
Children undergoing strabismus surgery have a high incidence of postoperative vomiting (POV). The purpose of this study was to assess the efficacy and safety of dolasetron for the prevention of emesis comparing a single 0.35 mg.kg-1 or 12.5 mg dose with placebo.
METHODS
Children aged 2-12 years with an ASA status of 1 or 2 undergoing strabismus surgery were randomized in a double-blind manner to one of three treatment groups. Patients were excluded with a history of previous postoperative vomiting or motion sickness, allergy to serotonin receptor antagonists or previous antiemetic administration within 24 h prior to enrollment. General anaesthesia was induced with sevoflurane and N2O/O2 and maintained with isoflurane and N2O/O2. The study medication was administered 15 min prior to the end of surgery. Patients experiencing two or more episodes of vomiting were rescued in the postanaesthesia care unit (PACU) with metoclopramide 0.15 mg.kg-1. A total of 118 patients were enrolled with documentation of the number and severity of vomiting episodes, time to awakening, PACU length of stay and postoperative agitation.
RESULTS
Patients with an acute complete response (ACR), defined as no emetic episodes and no rescue medication within 24 h of study drug administration were 62% (weight dose), 64% (fixed dose) and 33% (placebo, P < 0.05).
CONCLUSIONS
There was no statistical difference between the 0.35 mg.kg-1 dose and the fixed 12.5 mg dose of dolasetron with both reducing the incidence of POV.
Topics: Acetaminophen; Analgesics, Non-Narcotic; Anesthesia, General; Antiemetics; Child; Child, Preschool; Double-Blind Method; Female; Humans; Indoles; Male; Ophthalmologic Surgical Procedures; Postoperative Nausea and Vomiting; Quinolizines; Strabismus
PubMed: 12846709
DOI: 10.1046/j.1460-9592.2003.01076.x