RESUMEN
OBJECTIVE: To investigate the safety, pharmacokinetics (PK), binding activity and immunogenicity of CR002, a human monoclonal antibody (mAb) directed against platelet-derived growth factor-D (PDGF-D), administered as a single intravenous (i.v.) infusion over a range of doses. SUBJECTS: 40 healthy male subjects received increasing doses of CR002 at 0.3, 1, 3, 10, 30 mg/kg or placebo. METHOD: This was a randomized, double-blind, placebo-controlled, dose-escalation Phase I study. The trial had a duration of 90 days, with dosing on Day 1 and follow-up visits on Days 2, 4, 7, 14, 21, 30, 45 and 90. Serum was collected for PK, binding activity and immunogenicity analysis at screening and up to Day 90. Safety was recorded throughout the study by performing laboratory tests, recording vital signs and electrocardiograms (ECGs), by monitoring the occurrence of adverse events (AEs). The use of concomitant medications was also recorded. RESULTS: All 40 subjects received CR002 or placebo, and completed the trial. No dose-limiting toxicities (DLTs) occurred, the maximum tolerated dose (MTD) was not reached and was estimated as > 30 mg/kg. There were no deaths during this study and no SAEs or other significant AEs reported. The most frequent drug-related treatment-emergent AE (TEAE) was headache in 4 of 30 subjects (13.3%) in the CR002 group vs. 0 of 10 subjects in the placebo group. CR002 exhibited linear PK parameters, had a long half-life (t1/2 in the range 15.5 â 48.1 days) and a volume of distribution at steady state in the range 4.7 â 6.5. Free PDGF-D in the serum bound to CR002 in a reversible manner, as shown in the lowest dose cohort. However, levels of total circulating PDGF-D remained constant throughout the study. There were no anti-CR002 antibodies detected in subjects dosed with CR002. CONCLUSIONS: CR002 was safe and well-tolerated at all doses tested as a single i.v. administration. The MTD was estimated to be above 30 mg/kg, the highest dose tested. CR002 had a long half-life, low clearance and a limited tissue distribution. Although total levels of PDGF-D at all dose levels remained relatively constant, there was no detectable circulating free PDGF-D after CR002 administration. At the lowest CR002 dose tested (0.3 mg/kg), PDGF-D was detectable again by Day 21 and the levels increased near to pre-infusion levels by Day 90. In this study, CR002 was not immunogenic during the 90-day study period.
Asunto(s)
Anticuerpos Monoclonales/farmacocinética , Linfocinas/antagonistas & inhibidores , Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales Humanizados , Método Doble Ciego , Humanos , Infusiones Intravenosas , Linfocinas/inmunología , Linfocinas/metabolismo , Masculino , Factor de Crecimiento Derivado de Plaquetas/inmunología , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Unión ProteicaRESUMEN
BACKGROUND: Integrated gastric and oesophageal acidity can be calculated from measurements of gastric and oesophageal pH and used to quantify gastric and oesophageal acidity over time. Rabeprazole is a new proton pump inhibitor that is effective in treating gastro-oesophageal reflux disease (GERD). AIM: To use measurement of integrated gastric and oesophageal acidity to determine the onset, duration and overall effect of rabeprazole in subjects with GERD. METHODS: Subjects with GERD were required to have oesophageal pH less-than-or-equal 4 for at least 10% of a 24-h recording. Effects of 20 mg rabeprazole on 24-h gastric and oesophageal pH were measured on days 1 and 7 of dosing. Integrated gastric and oesophageal acidity were calculated from time-weighted average hydrogen ion concentrations at each second of the 24-h record. RESULTS: At steady-state, 20 mg rabeprazole inhibited gastric acidity by 89% and oesophageal acidity by 95%. The first dose of rabeprazole inhibited gastric and oesophageal acidity by at least 70% of the steady-state effect. Oesophageal acidity could be divided into monophasic and biphasic patterns, and rabeprazole had different effects on oesophageal and gastric acidity in these two GERD subpopulations. The onset of action of the first dose of rabeprazole on gastric acidity was 4 h and on oesophageal acidity was 4 h in monophasic subjects and 7 h in biphasic subjects. Integrated acidity was more sensitive than time pH less-than-or-equal 4 in measuring the inhibitory actions of rabeprazole. CONCLUSIONS: Integrated gastric and oesophageal acidity are quantitative measurements that provide useful and novel information regarding the pathophysiology of GERD as well as the impact of antisecretory agents such as rabeprazole.
Asunto(s)
Antiulcerosos/farmacología , Bencimidazoles/farmacología , Esofagitis Péptica/fisiopatología , Ácido Gástrico/metabolismo , Reflujo Gastroesofágico/fisiopatología , 2-Piridinilmetilsulfinilbencimidazoles , Adulto , Antiulcerosos/uso terapéutico , Bencimidazoles/uso terapéutico , Esofagitis Péptica/tratamiento farmacológico , Femenino , Determinación de la Acidez Gástrica , Reflujo Gastroesofágico/tratamiento farmacológico , Humanos , Concentración de Iones de Hidrógeno/efectos de los fármacos , Masculino , Persona de Mediana Edad , Omeprazol/análogos & derivados , Rabeprazol , Resultado del TratamientoRESUMEN
Rabeprazole's favourable pharmacodynamic profile is a result of its rapid onset and its 24-h control of gastric parietal secretion. These qualities, and its antimicrobial properties, make it particularly effective in the treatment of Helicobacter pylori (H. pylori), which is a short course of treatment compared to other conditions treated with proton pump inhibitors. Recently completed trials in combination with amoxicillin, clarithromycin and metronidazole for 7 days achieved high eradication of H. pylori. An additional study assessing the efficacy of combined rabeprazole and antibiotic treatments of 3, 7, and 10 days' duration vs. FDA-approved 10-day omeprazole triple therapy is under way to address the possibility of shorter duration therapies in the USA.
Asunto(s)
Antiulcerosos/uso terapéutico , Bencimidazoles/uso terapéutico , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori/efectos de los fármacos , Omeprazol/análogos & derivados , 2-Piridinilmetilsulfinilbencimidazoles , Ensayos Clínicos como Asunto , Quimioterapia Combinada , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/microbiología , Humanos , Lansoprazol , Omeprazol/uso terapéutico , Pantoprazol , Úlcera Péptica/tratamiento farmacológico , Úlcera Péptica/etiología , Inhibidores de la Bomba de Protones , Rabeprazol , Sulfóxidos/uso terapéuticoRESUMEN
OBJECTIVES: To evaluate the efficacy and tolerability of rabeprazole 10 mg and 20 mg versus placebo for the prevention of endoscopically demonstrable relapse in patients previously diagnosed with erosive or ulcerative gastro-oesophageal reflux disease (GORD) who had no oesophageal erosions or ulcerations at study entry. The study also assessed the effectiveness of rabeprazole in preventing GORD symptom recurrence and reductions in quality of life. DESIGN/METHODS: The trial used a multicentre, randomized, double-blind, parallel-group design and enrolled 288 male and female outpatients of > or =18 years of age. Patients were assigned to treatment with either rabeprazole 10 mg or 20 mg once daily in the morning (QAM) or placebo and followed for 52 weeks. RESULTS: Both rabeprazole doses were significantly more effective than placebo in preventing endoscopically demonstrable GORD relapse (P<0.001 versus placebo). The cumulative relapse rate for rabeprazole 10 mg at week 52 was 23%; for rabeprazole 20 mg, 14%; and for placebo, 71%. Both rabeprazole doses were also significantly superior to placebo in preventing relapse of heartburn frequency (P<0.001 for all comparisons between rabeprazole and placebo), with no significant differences between the two doses. Rabeprazole was also significantly more effective than placebo in preventing relapse of day-and night-time heartburn severity, maintaining overall patient well-being, and reducing antacid use. Both rabeprazole doses were well tolerated; most treatment-emergent adverse events were mild or moderate. There were no clinically significant changes in clinical laboratory values, thyroid function tests, vital signs, or electrocardiograms. CONCLUSION: Once-daily treatment with rabeprazole 10 mg or 20 mg is effective and well tolerated in preventing relapse of erosive or ulcerative GORD and associated symptoms and maintaining quality of life.
Asunto(s)
Bencimidazoles/administración & dosificación , Inhibidores Enzimáticos/administración & dosificación , Esofagitis/tratamiento farmacológico , Reflujo Gastroesofágico/tratamiento farmacológico , 2-Piridinilmetilsulfinilbencimidazoles , Adulto , Anciano , Análisis de Varianza , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esofagitis/patología , Esofagitis/prevención & control , Esofagoscopía , Femenino , Estudios de Seguimiento , Reflujo Gastroesofágico/patología , Reflujo Gastroesofágico/prevención & control , Humanos , Masculino , Persona de Mediana Edad , Omeprazol/análogos & derivados , Probabilidad , Rabeprazol , Prevención Secundaria , Estadísticas no Paramétricas , Resultado del TratamientoRESUMEN
In a multicentre, randomized, double-blind, placebo-controlled dose-ranging study, 1030 patients undergoing outpatient surgery with general anaesthesia received i.v. dolasetron mesylate (12.5, 25, 50, or 100 mg) or placebo. The principal outcome measure was the proportion of patients who were free of emesis or rescue medication for the 24-h period after the study drug was given; the subsidiary outcome measure was survival time without rescue medication. Effects on nausea were quantified using a visual analogue scale. Compared with placebo, a complete response was significantly higher when all four dolasetron doses were combined (49% vs. 58%, P =0.025). In females, dolasetron, 12.5-mg, dolasetron provided maximum clinical benefit (effectiveness compared with adverse events), with no additional benefit in complete response rates or nausea visual analogue scale scores at higher doses. No significant differences were observed in complete response for any dolasetron dose in males compared with placebo. The majority of adverse events reported were mild or moderate. Dolasetron provided well-tolerated, safe, and effective prophylaxis for post-operative nausea and vomiting with maximum effectiveness observed at a dose of 12.5 mg.
Asunto(s)
Procedimientos Quirúrgicos Ambulatorios , Anestesia General , Antieméticos/uso terapéutico , Indoles/uso terapéutico , Náusea y Vómito Posoperatorios/prevención & control , Quinolizinas/uso terapéutico , Adulto , Procedimientos Quirúrgicos Ambulatorios/efectos adversos , Análisis de Varianza , Anestesia General/efectos adversos , Antieméticos/administración & dosificación , Antieméticos/efectos adversos , Distribución de Chi-Cuadrado , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Indoles/administración & dosificación , Indoles/efectos adversos , Inyecciones Intravenosas , Modelos Logísticos , Masculino , Placebos , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Quinolizinas/administración & dosificación , Quinolizinas/efectos adversos , Inducción de Remisión , Seguridad , Factores Sexuales , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Dolasetron mesylate (MDL 73,147, Anzemet, Hoechst Marion Roussel, Kansas City, MO) is a 5-HT ( 3 ) receptor antagonist undergoing clinical evaluation as an antiemetic agent. Dolasetron is rapidly metabolized to form hydrodolasetron (MDL 74,156). The pharmacokinetics of hydrodolasetron were studied after administration of a single intravenous infusion of 0.6 mg/kg (group I) or 1.8 mg/kg (group II) in 21 cancer patients participating in a randomized, double-blind, parallel-group, multicenter trial of the drug in patients receiving their first course of high-dose (>/=75 mg/m ( 2 ) ) cisplatin-containing chemotherapy. The intent of this study was to obtain preliminary data on the pharmacokinetics of the active metabolite, hydrodolasetron, in cancer patients. The reduced metabolite, hydrodolasetron, was formed rapidly with peak plasma concentrations (group I, mean = 128.6 ng/mL; group II, mean = 505.3 ng/mL) occurring at or shortly after the end of the infusion. Plasma concentrations of hydrodolasetron remained quantifiable for up to 24 hours. Increases in peak plasma concentrations and AUC of hydrodolasetron were proportional to dose, suggesting linear pharmacokinetics over this dose range. Apparent clearance, apparent volume of distribution, elimination rate, and terminal elimination half-life of the reduced metabolite were similar at both doses. The results support a pharmacokinetic basis for the prolonged duration of antiemetic efficacy after a single intravenous dose.
Asunto(s)
Antieméticos/farmacocinética , Antineoplásicos/efectos adversos , Cisplatino/efectos adversos , Indoles/farmacocinética , Neoplasias/metabolismo , Quinolizinas/farmacocinética , Antagonistas de la Serotonina/farmacocinética , Anciano , Antieméticos/administración & dosificación , Método Doble Ciego , Femenino , Humanos , Indoles/administración & dosificación , Indoles/sangre , Masculino , Persona de Mediana Edad , Quinolizinas/administración & dosificación , Quinolizinas/sangre , Antagonistas de la Serotonina/administración & dosificación , Factores de TiempoRESUMEN
In this first part of a two-part investigation, the intravenous dose proportionality of dolasetron mesylate, a 5-HT3 receptor antagonist, and the absolute bioavailability of oral dolasetron mesylate were investigated. In an open-label, randomized, four-way crossover design, 24 healthy men between the ages of 19 and 45 years received the following doses: 50, 100, or 200 mg dolasetron mesylate administered by 10-min intravenous infusion or 200 mg dolasetron mesylate solution administered orally. Serial blood and urine samples were collected for 48 h after dosing. Following intravenous administration, dolasetron was rapidly eliminated from plasma, with a mean elimination half-life (t1/2) of less than 10 min. Dolasetron was rarely detected in plasma after oral administration of the 200 mg dose. Hydrodolasetron, the active primary metabolite of dolasetron, appeared rapidly in plasma following both oral and intravenous administration of dolasetron mesylate, with a mean time to maximum concentration (t(max)) of less than 1 h. The mean t1/2 of hydrodolasetron ranged from 6.6-8.8 h. The plasma area under the concentration-time curve (AUC0-infinity)) for both dolasetron and hydrodolasetron increased proportionally with dose over the intravenous dose range of 50-200 mg dolasetron mesylate. Approximately 29-33%) and 22% of the dose was excreted in urine as hydrodolasetron following intravenous and oral administration of dolasetron, respectively. For dolasetron as well as hydrodolasetron, mean systemic clearance (C1), volume of distribution (Vd), and t1/2 were similar at each dolasetron dose. The mean 'apparent' bioavailability of dolasetron calculated using plasma concentrations of hydrodolasetron was 76%. The R(+) enantiomer of hydrodolasetron represented the majority of drug in plasma (> 75%) and urine (> 86%). Dolasetron was well tolerated following both oral and intravenous administration.
Asunto(s)
Indoles/farmacocinética , Quinolizinas/farmacocinética , Antagonistas de la Serotonina/farmacocinética , Administración Oral , Adulto , Análisis de Varianza , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Semivida , Humanos , Indoles/administración & dosificación , Indoles/sangre , Indoles/orina , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Quinolizinas/administración & dosificación , Quinolizinas/sangre , Quinolizinas/orina , Antagonistas de la Serotonina/administración & dosificación , Antagonistas de la Serotonina/sangre , Antagonistas de la Serotonina/orina , EstereoisomerismoRESUMEN
The single- and multiple-dose pharmacokinetics and dose-proportionality of oral dolasetron and its active metabolites over the therapeutic dose range was investigated in 18 healthy men. In an open-label, randomized, complete three-way crossover design, each subject received three separate doses: 50, 100, and 200 mg doses of dolasetron mesylate solution given orally. Each dose was administered on the morning of Days 1 and 3-7 during each of the three treatment periods. Serial blood and urine samples were collected for 48 h after the first and last doses. Blood was analysed for dolasetron and hydrodolasetron concentrations; urine was analysed for dolasetron, the R(+) and S(-)-enantiomers of hydrodolasetron, and the 5'-hydroxy and 6'-hydroxy metabolites of hydrodolasetron. Dolasetron was rarely detected in plasma. Hydrodolasetron was formed rapidly, with a time to maximum concentration (t(max)) of less than 1 h. Steady-state conditions for hydrodolasetron were reached 2-3 days after starting once-daily dosing. Although statistical significance was found for hydrodolasetron AUC(0->infinity) and C(max) between dose groups after both single and multiple doses of dolasetron, the differences were small and unlikely to be of clinical significance. About 17-22% of the dose was excreted in urine as hydrodolasetron, with the majority (> 83%) as the R(+) enantiomer.
Asunto(s)
Indoles/sangre , Indoles/metabolismo , Indoles/farmacocinética , Quinolizinas/sangre , Quinolizinas/metabolismo , Quinolizinas/farmacocinética , Antagonistas de la Serotonina/metabolismo , Antagonistas de la Serotonina/farmacocinética , Administración Oral , Adulto , Análisis de Varianza , Área Bajo la Curva , Presión Sanguínea/efectos de los fármacos , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Electrocardiografía , Semivida , Humanos , Indoles/administración & dosificación , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Quinolizinas/administración & dosificación , Antagonistas de la Serotonina/administración & dosificación , EstereoisomerismoRESUMEN
Dolasetron mesilate is a selective 5-HT3 receptor antagonist that prevents chemotherapy-induced and postoperative nausea and vomiting. For the majority of patients in intravenous dolasetron trials for chemotherapy-induced nausea and vomiting, dosing has been based on body weight (mg/kg). The approved weight-based dose is 1.8 mg/kg based on results of controlled clinical trials. However, trials of dolasetron evaluating oral doses for prevention of chemotherapy-induced emesis, and intravenous doses for prevention and treatment of postoperative emesis have used a fixed milligram dose. To identify an appropriate intravenous fixed milligram dose for the prevention of chemotherapy-induced nausea and vomiting, this analysis was performed to derive efficacy results for fixed milligram doses from pooled results obtained with dosing based on body weight. Intravenous dolasetron doses for 1,598 patients treated on a mg/kg basis (0.3, 0.6, 1.2, 1.8, 2.4, 3.0 and 5.0 mg/kg) in 14 clinical trials were converted to fixed milligram doses based on weight. Fixed-dose groups were established at doses of 50, 75, 100, 125, 150, and 200 mg. Doses less than or equal to the midpoint between two dose groups were included in the lower dose group. Pooled results showed that the 100 mg intravenous dolasetron dose group (who received actual doses of 88-112 mg) produced the highest rate (53%) of complete response (0 emetic episodes and no rescue medication in the 24-h period following initiation of chemotherapy).
Asunto(s)
Antieméticos/administración & dosificación , Antineoplásicos/efectos adversos , Cisplatino/efectos adversos , Indoles/administración & dosificación , Náusea/prevención & control , Quinolizinas/administración & dosificación , Vómitos/prevención & control , Adolescente , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Neoplasias/tratamiento farmacológico , Vómitos/inducido químicamenteRESUMEN
STUDY OBJECTIVE: To examine the safety and effectiveness of a range of single oral doses of dolasetron mesylate for the prevention of postoperative nausea and vomiting. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: 32 hospitals. PATIENTS: 789 female ASA physical status I, II, and III patients, ages 18 to 60 years, weighing between 45 and 100 kg, scheduled for major gynecologic surgery (including abdominal hysterectomy, gynecologic laparotomy, or vaginal hysterectomy) with general anesthesia. INTERVENTIONS: 25, 50, 100, or 200 mg oral doses of dolasetron mesylate or placebo were administered 1 to 2 hours before induction of anesthesia. Efficacy was assessed for 24 hours postrecovery by measuring complete response (no emetic episodes, no rescue medication), total response (complete response with no nausea), time to first emetic episode or rescue, and patient visual analog scale evaluations of nausea severity and satisfaction with antiemetic therapy. MEASUREMENTS AND MAIN RESULTS: Complete response rates for the 50, 100, and 200 mg dose groups were statistically greater than placebo (p < or = 0.018). Likewise, total response rates were statistically greater in the 50, 100, and 200 mg dose groups than in the placebo group (p = 0.012). Percentage of patients with no nausea and patient satisfaction scores were significantly higher for each dolasetron dose group than placebo (p < or = 0.047 and p < or = 0.004, respectively). Efficacy peaked at the 50 mg dose. The incidence of adverse events was similar in the placebo (30.1%) and dolasetron groups (29.4%). Headache was the most frequent treatment-related adverse event, with 2% to 5% incidence across groups. Incidence of adverse events did not increase with increasing dolasetron doses. Dose-related decreases in blood pressure at acute time points were not clinically significant. CONCLUSION: Single oral doses of dolasetron, administered 1 to 2 hours before induction of anesthesia, are safe and effective for preventing postoperative nausea and vomiting in this patient sample. Maximal antiemetic response was seen with the 50 mg oral dolasetron dose.
Asunto(s)
Antieméticos/uso terapéutico , Indoles/uso terapéutico , Náusea/prevención & control , Complicaciones Posoperatorias/prevención & control , Quinolizinas/uso terapéutico , Vómitos/prevención & control , Adolescente , Adulto , Anestesia General , Antieméticos/efectos adversos , Presión Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Procedimientos Quirúrgicos Ginecológicos , Humanos , Indoles/efectos adversos , Persona de Mediana Edad , Quinolizinas/efectos adversosRESUMEN
Anzemet (dolasetron mesylate) is being developed for the prevention of chemotherapy-induced emesis and postoperative nausea and vomiting. Twenty-four healthy male subjects were orally dosed with dolasetron mesylate, 200 mg, after either an overnight fast or a high-fat breakfast. The ratio of the mean area under the plasma concentration-time curve of the reduced active metabolite (MDL 74,156) to infinity (AUC(0-infinity)) values in fed compared to fasting subjects was 86.3% with a 90% confidence interval for the ratio within (80, 125)%, indicating bioequivalence. The ratio of the mean MDL 74,156 maximum plasma concentration (Cmax) values was 70.6% in fed versus fasted subjects. The time to Cmax was statistically significantly longer after the high-fat breakfast (mean values, 1.11 h fasting and 1.80 h fed), probably due to delayed gastric emptying. It may be concluded that, although the rate of absorption was somewhat delayed, the extent of absorption did not change significantly when dolasetron mesylate was given with food.
Asunto(s)
Interacciones Alimento-Droga , Indoles/farmacocinética , Quinolizinas/farmacocinética , Antagonistas de la Serotonina/farmacocinética , Adulto , Área Bajo la Curva , Disponibilidad Biológica , Cromatografía Liquida , Estudios Cruzados , Ayuno/metabolismo , Semivida , Humanos , Espectrometría de Masas , ComprimidosRESUMEN
OBJECTIVE: To evaluate the safety, tolerance, and pharmacokinetics of dolasetron mesylate and its active metabolite hydrodolasetron when dolasetron mesylate was administered intravenously at increasing infusion rates. DESIGN: A double-blind, placebo-controlled, parallel-group study. METHODS: Forty-nine healthy nonsmoking male volunteers were randomly assigned to receive intravenous doses of dolasetron mesylate 100 mg or placebo. Three groups of 16 subjects each (12 dolasetron mesylate, 4 placebo) received escalating infusion rates (50, 100, then 200 mg/min). Physical examinations, vital signs, laboratory tests, and adverse events were recorded before and after administration of the study drug. Serial blood samples and 12-lead electrocardiogram measurements were obtained for 24 hours after the infusion. Plasma samples were analyzed for dolasetron and hydrodolasetron. RESULTS: Dolasetron mesylate was well tolerated, with no apparent differences in vital signs or adverse event profiles among the different rates of infusion. In general, the pharmacokinetics of dolasetron and hydrodolasetron were superimposable among the three infusion rate groups. Plasma dolasetron concentrations declined rapidly in all three infusion rate groups, with mean elimination half-life (t1/2) of less than 10 minutes. The reduced metabolite hydrodolasetron, which accounts for most pharmacologic activity, formed rapidly, with maximum concentrations occurring between 0.4 and 0.5 hours and disappeared with a mean t1/2 of 8-9 hours. The correlation coefficients of least-squares regression analysis between the pharmacokinetic parameters and the infusion rate of dolasetron were less than 0.083 and the slopes were not significantly different from 0, suggesting that none of the hydrodolasetron pharmacokinetic parameters were affected by rate of infusion. CONCLUSIONS: The intravenous administration of dolasetron 100 mg over 0.5-2 minutes did not significantly alter the pharmacokinetic profiles of either dolasetron or hydrodolasetron. In addition, the safety profile of dolasetron did not change with increasing rate of infusion. Therefore, the rate of infusion of dolasetron mesylate appears to have no pharmacokinetic or clinical implications when assessed over a 0.5-2-minute time period.
Asunto(s)
Antieméticos/farmacocinética , Indoles/farmacocinética , Quinolizinas/farmacocinética , Antagonistas de la Serotonina/farmacocinética , Adolescente , Adulto , Antieméticos/administración & dosificación , Antieméticos/efectos adversos , Método Doble Ciego , Humanos , Indoles/administración & dosificación , Indoles/efectos adversos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Quinolizinas/administración & dosificación , Quinolizinas/efectos adversos , Antagonistas de la Serotonina/administración & dosificación , Antagonistas de la Serotonina/efectos adversosRESUMEN
UNLABELLED: This study was conducted to determine the efficacy and safety of four intravenous (I.V.) doses of dolasetron, an investigational 5-HT3 receptor antagonist, for the treatment of postoperative nausea and/or vomiting (PONV) after outpatient surgery under general anesthesia. This multicenter, randomized, double-blind trial compared the antiemetic efficacy of 12.5, 25, 50, or 100 mg I.V. dolasetron with placebo over 24 h using complete response (no emetic episodes and no rescue medication), time to first emetic episode or rescue medication, and patient nausea and satisfaction with antiemetic therapy as rated by visual analog scale (VAS). Of 1557 patients enrolled, 620 patients were eligible for treatment. Complete response rates for all dolasetron doses--12.5 mg (35%), 25 mg (28%), 50 mg (29%), and 100 mg (29%)--were significantly more effective than placebo (11%, P < 0.05). There was a significant gender interaction for complete response (P < 0.01). Of the patients in the 25-mg and 100-mg dose groups, 12% and 13%, respectively, experienced no nausea (VAS score < 5 mm) versus 5% in the placebo group (P < 0.05). There were no clinically relevant changes in vital signs or laboratory values and no trends with dose for adverse events. Dolasetron is effective for treating PONV and has an adverse event profile similar to that of placebo. The 12.5-mg dose was as effective as larger doses for complete response. IMPLICATIONS: Nausea and vomiting are common problems for postsurgical patients. In this study of 620 patients undergoing surgery, a 12.5-mg dose of intravenous dolasetron, a new serotonin-receptor blocker, was significantly more effective than placebo in treating established postoperative nausea and vomiting. Dolasetron 12.5 mg was as safe as placebo.
Asunto(s)
Antieméticos/administración & dosificación , Indoles/administración & dosificación , Náusea/tratamiento farmacológico , Complicaciones Posoperatorias/tratamiento farmacológico , Quinolizinas/administración & dosificación , Vómitos/tratamiento farmacológico , Adulto , Procedimientos Quirúrgicos Ambulatorios , Anestesia General , Antieméticos/efectos adversos , Método Doble Ciego , Femenino , Humanos , Indoles/efectos adversos , Inyecciones Intravenosas , Modelos Logísticos , Masculino , Satisfacción del Paciente , Quinolizinas/efectos adversosRESUMEN
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.
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Antieméticos/uso terapéutico , Indoles/uso terapéutico , Náusea/prevención & control , Ondansetrón/uso terapéutico , Complicaciones Posoperatorias/prevención & control , Quinolizinas/uso terapéutico , Antagonistas de la Serotonina/uso terapéutico , Vómitos/prevención & control , Adulto , Anciano , Método Doble Ciego , Femenino , Humanos , Indoles/administración & dosificación , Indoles/efectos adversos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Ondansetrón/administración & dosificación , Ondansetrón/efectos adversos , Quinolizinas/administración & dosificación , Quinolizinas/efectos adversosRESUMEN
STUDY OBJECTIVE: To evaluate a range of doses of intravenous (i.v.) dolasetron mesilate, in preventing postoperative nausea and vomiting (PONV). DESIGN: Double-blind, placebo-controlled, randomized, multicenter trial. SETTING: Ten hospitals and/or surgical centers. PATIENTS: 281 women undergoing gynecologic surgery with general anesthesia. INTERVENTIONS: Patients received one of four single, i.v. doses of dolasetron mesilate (12.5 mg, 25 mg, 50 mg, and 100 mg) or placebo administered following cessation of anesthesia. MEASUREMENTS AND MAIN RESULTS: Patients were monitored for 24 hours following study drug administration. The antiemetic efficacy of each dolasetron mesilate dose was evaluated by recording the number and timing of emetic episodes, and the effects on nausea were assessed by use of visual analog scales (VAS). Safety was assessed by adverse event reports, clinical laboratory tests, electrocardiographic (ECG) measurements, and monitoring vital signs. Complete responses (patients with no emetic episodes and no escape antiemetic medication requirements in 24 hours) were achieved by 54% in the 12.5-mg, 67% in the 25-mg, and 59% in both the 50-mg and 100-mg dolasetron mesilate dose groups, and by 43% in the placebo group. Nausea VAS assessments demonstrated that dolasetron-treated patients were significantly (p = 0.048) more likely to report no nausea (VAS score < 5 mm) than those in the placebo group. Adverse events reported generally were mild in intensity, and there were no clinically significant changes in laboratory tests, vital signs, or ECG parameters. CONCLUSIONS: Dolasetron was effective and well tolerated for the prevention of PONV in female patients undergoing gynecologic surgery with general anesthesia.
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Antieméticos/uso terapéutico , Indoles/uso terapéutico , Náusea/prevención & control , Complicaciones Posoperatorias/prevención & control , Quinolizinas/uso terapéutico , Antagonistas de la Serotonina/uso terapéutico , Vómitos/prevención & control , Adolescente , Adulto , Análisis de Varianza , Método Doble Ciego , Femenino , Enfermedades de los Genitales Femeninos/cirugía , Humanos , Indoles/efectos adversos , Inyecciones Intravenosas , Persona de Mediana Edad , Náusea/etiología , Quinolizinas/efectos adversos , Antagonistas de la Serotonina/efectos adversos , Resultado del Tratamiento , Vómitos/etiologíaRESUMEN
BACKGROUND: This double blind parallel group study assessed the acute antiemetic efficacy of four oral doses of dolasetron mesylate in cancer patients receiving their first course of intravenous chemotherapy with doxorubicin and/or cyclophosphamide. METHODS: Patients were randomized to receive 25, 50, 100, or 200 mg of dolasetron mesylate 30 minutes prior to chemotherapy and were monitored for nausea and emetic episodes for the next 24 hours. RESULTS: Three hundred and nineteen cancer patients at 32 sites completed the study. Most patients were female (81%); of this group, 69% had breast carcinoma. A highly statistically significant linear trend demonstrating improved response with higher doses was detected for complete response (no emetic episodes and no rescue medication) (P < 0.001), for complete plus major response (0-2 emetic episodes and no rescue medication) (P < 0.001), and for patient visual analog scale assessments of nausea (P = 0.001) and general satisfaction with antiemetic therapy (P = 0.001). No serious adverse events were noted. The most frequent adverse event was mild, self-limiting headache, which has been reported with other drugs in this class. CONCLUSIONS: Single oral doses of dolasetron mesylate were found to be effective in preventing acute emesis in cancer patients receiving moderately emetogenic chemotherapy.
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Antieméticos/administración & dosificación , Antineoplásicos/efectos adversos , Indoles/administración & dosificación , Náusea/prevención & control , Quinolizinas/administración & dosificación , Administración Oral , Antieméticos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/efectos adversos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Doxorrubicina/efectos adversos , Femenino , Humanos , Indoles/efectos adversos , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Quinolizinas/efectos adversosRESUMEN
PURPOSE: To compare the efficacy, safety, and tolerability of dolasetron mesilate with placebo for the treatment of postoperative nausea and vomiting (PONV). METHODS: In a randomized, multicentre, double-blind, placebo-controlled study 337 adult patients undergoing surgery with general anaesthesia received one of four single, doses of dolasetron mesilate iv (12.5, 25, 50, or 100 mg) or placebo. Study medication was administered postoperatively when the patient reported nausea lasting 10 min or when one emetic episode occurred within two hours of the patient's arrival in the recovery room. Efficacy was assessed by the investigators over the 24-hr study period by recording the number and timing of emetic episodes, the severity of nausea, the timing of administration of escape antiemetic medications, and patients' and investigators' satisfaction with antiemetic therapy. RESULTS: The study sample was predominately women, and the surgical procedures were primarily gynaecological. All dolasetron mesilate doses produced higher complete response rates than placebo (P < 0.05). Only approximately one-third of dolasetron patients required escape antiemetic medication compared with more than 50% of patients in the placebo group. Both patient and physician satisfaction with dolasetron treatment was high. The most common adverse event was mild or moderate headache for both placebo-treated patients and dolasetron-treated patients. Clinical laboratory results were unremarkable. CONCLUSION: Single doses of dolasetron mesilate iv, given after the first episode of PONV, were both effective and safe in this adult patient population.
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Antieméticos/administración & dosificación , Indoles/administración & dosificación , Náusea/prevención & control , Complicaciones Posoperatorias/prevención & control , Quinolizinas/administración & dosificación , Antagonistas de la Serotonina/administración & dosificación , Vómitos/prevención & control , Adolescente , Adulto , Anciano , Método Doble Ciego , Femenino , Humanos , Indoles/efectos adversos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Quinolizinas/efectos adversosRESUMEN
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.
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Procedimientos Quirúrgicos Ambulatorios , Antieméticos/administración & dosificación , Genitales Femeninos/cirugía , Indoles/administración & dosificación , Laparoscopía , Náusea/prevención & control , Complicaciones Posoperatorias/prevención & control , Quinolizinas/administración & dosificación , Vómitos/prevención & control , Adulto , Antieméticos/efectos adversos , Método Doble Ciego , Femenino , Humanos , Indoles/efectos adversos , Inyecciones Intravenosas , Náusea/etiología , Satisfacción del Paciente , Quinolizinas/efectos adversos , Vómitos/etiologíaRESUMEN
PURPOSE: This double-blind, dose-response study was conducted to assess the safety and efficacy of four oral doses of dolasetron mesylate for preventing acute emesis in cancer patients receiving their first course of moderately emetogenic platinum-containing chemotherapy. PATIENTS AND METHODS: Patients were randomized to receive a single oral dose of 25, 50, 100, or 200 mg dolasetron 30 minutes before receiving IV carboplatin (275-400 mg/m2)- or cisplatin (20-50 mg/m2)-containing chemotherapy, then monitored for nausea and vomiting for 24 hours. RESULTS: Three hundred seven cancer patients from 32 sites completed the study. There was a statistically significant dose response across the four doses for complete response (no emetic episodes or rescue medication): 44.7%, 71.3%, 73.2%, and 82.5% for the 25, 50, 100, or 200 mg doses of dolasetron, respectively. Patients' nausea severity and patient satisfaction visual analogue scale scores also showed a statistically significant trend with dose. All doses of dolasetron were well tolerated. The most common adverse events were headache (17.6%) and dizziness (2.0%). DISCUSSION: This study demonstrates the safety and antiemetic efficacy of oral dolasetron mesylate in patients receiving moderately emetogenic platinum-containing chemotherapy with the highest antiemetic activity observed at 200 mg.
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Antieméticos/uso terapéutico , Indoles/uso terapéutico , Quinolizinas/uso terapéutico , Vómitos/prevención & control , Administración Oral , Anciano , Antineoplásicos/administración & dosificación , Carboplatino/administración & dosificación , Cisplatino/administración & dosificación , Demografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Vómitos/inducido químicamenteRESUMEN
This study compared the antiemetic efficacy and safety of two different intravenous (i.v.) dolasetron dosing regimens in patients receiving their first course of high-dose (> or = 80 mg/m2) cisplatin. Of 30 patients enrolled, 14 received a single i.v. dolasetron dose (0.6 mg/kg) before cisplatin and 16 received a multiple i.v. dose regimen (0.6 mg/kg x 3) given before and after cisplatin. Complete plus major responses were achieved by 71% (10/14) of patients who received single-dose dolasetron and by 50% (8/16) of those who received the multiple-dose regimen. Forty-three percent (6/14) of patients who received the single dose had a complete response compared with 25% (4/16) who received multiple doses. Multiple doses resulted in less nausea at 24 hr following cisplatin; however, differences were not statistically significant. Both regimens were well tolerated, with mild headache (33%) and diarrhea (13%) the most common adverse events. This study demonstrated that a single 0.6-mg/kg dose of dolasetron given before chemotherapy provides equivalent antiemetic efficacy to three 0.6-mg/kg doses given before and after high-dose cisplatin chemotherapy; thus, there was no additional antiemetic benefit by using the multiple-dose regimen.