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Gerri E Schwartz - One of the best experts on this subject based on the ideXlab platform.
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lack of sexual dysfunction with the selective noradrenaline reuptake inhibitor Reboxetine during treatment for major depressive disorder
International Clinical Psychopharmacology, 2003Co-Authors: Anita H Clayton, Mark T. Brown, James M Ferguson, John Zajecka, Jacqueline K Filipiakreisner, Gerri E SchwartzAbstract:Sexual side-effects due to antidepressant treatment are an important consideration when selecting a treatment regimen and can influence patient compliance. Sexual function during treatment with the selective noradrenaline reuptake inhibitor Reboxetine, the selective serotonin reuptake inhibitor (SSRI) fluoxetine and placebo has been assessed in a multicentre, randomized, 8-week, double-blind study of 450 patients diagnosed with major depressive disorder. Sexual function was measured by the Rush Sexual Inventory completed by male and female patients and administered at baseline, week 4 and week 8. The results indicate that Reboxetine was similar to placebo and superior to fluoxetine in its effect on overall sexual function. There was a greater degree of sexual satisfaction in the Reboxetine group compared to fluoxetine (P=0.02). The percentage of female patients able to achieve orgasm increased during the study period for women who received Reboxetine and placebo, but decreased for those who received fluoxetine. These results suggest that Reboxetine may be of particular benefit for patients at risk for sexual dysfunction with SSRIs.
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The antidepressant efficacy of Reboxetine in patients with severe depression.
Journal of clinical psychopharmacology, 2003Co-Authors: Stuart A. Montgomery, James M Ferguson, Gerri E SchwartzAbstract:We examined the effectiveness of Reboxetine, a norepinephrine reuptake inhibitor (NRI), compared with placebo for the treatment of patients with severe major depression (defined as a score on the 17-item Hamilton Rating Scale for Depression [HAM-D] >/=25). Data were obtained from four prospective, double-blind, randomized, placebo-controlled clinical trials of the efficacy of Reboxetine (8 to 10 mg/d) over 4 to 8 weeks in patients with major depression. In three of the trials, Reboxetine produced a significantly greater reduction than placebo in mean HAM-D scores from baseline to the last clinical assessment (p 50% between baseline and the last follow-up observation) treated with Reboxetine than placebo in three trials. The overall mean responder rate with Reboxetine was 63% (range: 56-74%) compared with 36% (range: 20-52%) with placebo. These results demonstrate that Reboxetine is significantly more effective than placebo in a subgroup of patients with severe depression.
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Reboxetine versus paroxetine versus placebo effects on cognitive functioning in depressed patients
International Clinical Psychopharmacology, 2003Co-Authors: James M Ferguson, Keith Wesnes, Gerri E SchwartzAbstract:Impaired cognitive functioning is often associated with major depressive disorder (MDD). Moreover, a number of agents used to treat MDD are known to have negative effects on cognitive functioning. We report an assessment of the effects of the selective norepinephrine reuptake inhibitor Reboxetine, the selective serotonin reuptake inhibitor paroxetine, and placebo on a variety of measures of cognitive functioning in patients with MDD. Cognitive functioning in 74 adult patients (aged 18-65 years) with a confirmed diagnosis of MDD (DSM-IV) was assessed as part of two identical, randomized, double-blind, placebo- and active-treatment-controlled, fixed/flexible dose comparisons of 8 weeks of treatment with Reboxetine (8-10 mg/day), paroxetine (20-40 mg/day) and placebo. Cognitive function was assessed at baseline, day 14 and day 56 using a selection of tasks from the Cognitive Drug Research computerized assessment system, including Simple Reaction Time, Digit Vigilance, Choice Reaction Time, Numeric Working Memory, Word Recognition and Critical Flicker Frequency. The results in the 74 patients (Reboxetine n = 25, paroxetine n = 23, placebo n = 26) showed that Reboxetine significantly improved the ability to sustain attention at day 56 compared with baseline (P = 0.023). In addition, patients who received Reboxetine experienced significant improvements in their speed of cognitive functioning when tested at day 56 compared to baseline (P = 0.024). No significant changes or trends in this direction were seen among patients who received either placebo or paroxetine. The results of the present study provide objective data to support the possibility that Reboxetine favourably affects cognitive processes in depressed patients.
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effects of Reboxetine on hamilton depression rating scale factors from randomized placebo controlled trials in major depression
International Clinical Psychopharmacology, 2002Co-Authors: James M Ferguson, J Mendels, Gerri E SchwartzAbstract:Reboxetine is the first selective norepinephrine reuptake inhibitor (NRI) approved for the treatment of major depressive disorder (MDD). Although Reboxetine has demonstrated efficacy for the treatment of depression, its effects on specific depressive symptoms have not been reported. We evaluated the effects of Reboxetine on four Hamilton Depression Rating Scale (HAM-D) factors: psychomotor retardation, anxiety, cognitive disturbance and insomnia. Data were obtained from four short-term (4-8-week), randomized, placebo-controlled trials of Reboxetine for the treatment of MDD. For each study, mean changes in HAM-D symptom factor scores from randomization to the study endpoint were compared between Reboxetine and placebo. In addition, data from all four studies were pooled to determine the proportions of patients who either improved or worsened with treatment were compared between placebo (n = 353) and Reboxetine (n = 350) treatment groups. Compared to placebo, Reboxetine significantly improved psychomotor retardation in all four trials. Cognitive disturbance and anxiety were improved in three of four trials, and insomnia was improved in one trial with a positive trend in the second trial. Reboxetine, a selective NRI, improves symptoms of psychomotor retardation, anxiety and cognitive disturbance during treatment of MDD.
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Effects of Reboxetine on anxiety, agitation, and insomnia: results of a pooled evaluation of randomized clinical trials.
Journal of clinical psychopharmacology, 2002Co-Authors: Stephen M. Stahl, J Mendels, Gerri E SchwartzAbstract:Several recent clinical trials have established that Reboxetine, a new selective norepinephrine reuptake inhibitor (selective NRI), is effective and safe for the treatment of major depression. However, the effects of Reboxetine on specific symptoms of anxiety, agitation, and insomnia have not been reported. Data were obtained from nine short-term, double-blind, randomized clinical trials in patients with major depression. After initial titration, patients received Reboxetine 8 to 10 mg per day. The effects on specific HAM-D symptoms of agitation, anxiety, and insomnia were compared between Reboxetine- and placebo-treated patients. In addition, the incidence of treatment-emergent agitation, anxiety, and insomnia side effects with Reboxetine were examined. Compared with placebo, the proportion of patients with improvement on the HAM-D agitation item and the HAM-D anxiety and insomnia factors from baseline was significantly greater with Reboxetine at most assessment intervals. In general, the incidence of agitation- or anxiety-related side effects was comparable with Reboxetine and placebo. Although Reboxetine was associated with a significant (p < 0.05) increase in treatment-emergent insomnia reported as an adverse effect during the first week of treatment, very few reports of insomnia were made at subsequent evaluations. The incidence of treatment-emergent agitation or anxiety was comparable between treatment groups.
Italo Poggesi - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics of single-dose Reboxetine in volunteers with renal insufficiency.
Journal of clinical pharmacology, 2000Co-Authors: François Coulomb, Italo Poggesi, Joseph C. Fleishaker, M. Gabriella Jannuzzo, Francis Ducret, Jean‐paul Laneury, Francesco Fiorentini, Georges Houin, Patrick DucheneAbstract:Reboxetine is a new selective norepinephrine reuptake inhibitor (selective NRI) for the short- and long-term treatment of depression that is effective and well tolerated at a dose of 8 to 10 mg/day. This study assessed the pharmacokinetics of Reboxetine in volunteers with renal impairment. A single 4 mg dose of Reboxetine was administered to a total of 18 volunteers with mild (n = 6), moderate (n = 6), or severe (n = 6) renal impairment (creatinine clearance: 56-64, 26-51, and 9-19 ml/min, respectively), and Reboxetine concentrations were measured in plasma by HPLC. Mean AUC∞ increased by 43% (mild vs. severe; p< 0.01) as renal function declined, while renal clearance and total urinary excretion of unchanged Reboxetine decreased by 67% and 62%, respectively (mild vs. severe; p < 0.01 for both parameters). t max and t 1/2 were not significantly different between groups. In comparison with historical data from young healthy volunteers, AUC∞ and t 1/2 are at least doubled in volunteers with renal impairment, while CL r is halved. This pharmacokinetic study has shown that increasing renal dysfunction leads to increasing systemic exposure to Reboxetine, particularly in severe renal insufficiency, although Reboxetine was well tolerated by all volunteers. Thus, a reduction of the starting dose of Reboxetine to 2 mg twice daily would be prudent in patients with renal dysfunction.
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Hemodynamic effects of Reboxetine in healthy male volunteers.
Clinical pharmacology and therapeutics, 1999Co-Authors: Thierry Denolle, C. Pellizzoni, M. Gabriella Jannuzzo, Italo PoggesiAbstract:Background Reboxetine [(R,S)-2[(R,S)-α-(2-ethoxyphenoxy)benzyl]morpholine methanesulfonate] is a racemic compound that consists of equal proportions of R,R- and S,S-enantiomers. This study investigated the hemodynamic effects of Reboxetine and the R,R-enantiomer compared with placebo in volunteers. The pharmacokinetics of Reboxetine and its enantiomers were also investigated in the study. Methods Nine healthy, male volunteers received single doses of 4 mg Reboxetine, 2 mg R,R-enantiomer, and placebo at weekly intervals. Reboxetine and the R,R-enantiomer were well tolerated in all volunteers. Results The heart rates of patients in the supine and standing positions were increased after Reboxetine administration compared with the R,R-enantiomer (P < .05, except supine heart rate at 6 hours) and placebo (P < .05). Supine systolic and diastolic blood pressure was also increased by 3 ± 4 and 1 ± 4 mm Hg, respectively, after Reboxetine compared with R,R-enantiomer (−2 ± 4 and −4 ± 3 mm Hg) and placebo (−4 ± 4 and −4 ± 4 mm Hg) administration. The systolic and diastolic blood pressure measurements for subjects while standing did not differ significantly among treatments. There was no significant difference between the maximum plasma concentration, mean time to maximum plasma concentration, plasma half-life, or area under the plasma concentration–time curve (AUC) of the R,R-enantiomer after Reboxetine or R,R-enantiomer administration. The ratio of the mean AUC values for the R,R- and S,S-enantiomers was 2.1. Conclusion These findings suggest that the S,S-enantiomer is responsible for the hemodynamic effects of Reboxetine in humans. Increases in supine blood pressure after Reboxetine administration may be interpreted as regression to the mean value and not caused by any treatment effect. Clinical Pharmacology & Therapeutics (1999) 66, 282–287; doi:
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Absolute bioavailability of Reboxetine enantiomers and effect of gender on pharmacokinetics.
Biopharmaceutics & drug disposition, 1999Co-Authors: Joseph C. Fleishaker, C. Pellizzoni, Massimiliano Mucci, Italo PoggesiAbstract:The absolute bioavailability of Reboxetine enantiomers was assessed in six male and six female volunteers. In a two-way crossover study, subjects received 1.0 mg Reboxetine orally and 0.3 mg Reboxetine as an intravenous bolus. The R,R(−) and S,S(+) enantiomers in serial plasma and urine samples were determined by a validated LC-MS-MS method. There were no significant differences between treatments for clearance or dose-corrected AUC0–∞ values. The absolute bioavailability was 0.919 and 1.02 for R,R(−) Reboxetine and S,S(+) Reboxetine, respectively. A secondary objective of the study was to assess gender effects on pharmacokinetics of the enantiomers. Significant differences in volume of distribution between genders were observed, but differences in weight-corrected volumes were not significant. Weight-corrected systemic clearance and oral clearance tended to be lower in males, but this difference reached statistical significance only for weight-corrected oral clearance of R,R(−) Reboxetine. Cmax after oral administration was 40 and 48% higher in women than men for R,R(−) Reboxetine and S,S(+) Reboxetine, respectively. These results indicate that Reboxetine enantiomers are well absorbed after oral administration and that little first-pass metabolism occurs. There are no clinically significant effects of gender on the pharmacokinetics of Reboxetine enantiomers. Copyright © 1999 John Wiley & Sons, Ltd.
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Pharmacokinetics of Reboxetine enantiomers in the dog
Chirality, 1997Co-Authors: E Frigerio, A. Benecchi, G. Brianceschi, C. Pellizzoni, M. Strolin Benedetti, Italo Poggesi, Philippe DostertAbstract:Reboxetine, (RS)-2-[(RS)-alpha-(2-ethoxyphenoxy)benzyl]morpholine methanesulphonate, is a racemic compound and consists of a mixture of the (R,R)- and (S,S)-enantiomers. The pharmacokinetics of Reboxetine enantiomers were determined in a crossover study in three male beagle dogs. Each animal received the following oral treatments, separated by 1-week washout period: 10 mg/kg Reboxetine, 5 mg/kg (R,R)- and 5 mg/kg (S,S)-. Plasma and urinary levels of the Reboxetine enantiomers were monitored up to 48 h post-dosing using an enantiospecific HPLC method with fluorimetric detection (LOQ: 1.1 ng/ml in plasma and 5 ng/ml in urine for each enantiomer). After Reboxetine administration mean tmax was about 1 h for both enantiomers. Cmax and AUC were about 1.5 times higher for the (R,R)- than for the (S,S)-enantiomer, mean values +/- SD being 704 +/- 330 and 427 +/- 175 ng/ml for Cmax and 2,876 +/- 1,354 and 1,998 +/- 848 ng.h/ml for AUC, respectively. No differences between the (R,R)- and (S,S)-enantiomers were observed in t1/2 (3.9 h). Total recovery of the two enantiomers in urine was similar, the Ae (0-48 h) being 1.3 +/- 0.7 and 1.1 +/- 0.7% of the enantiomer dose for the (R,R)- and the (S,S)-enantiomers, respectively. No marked differences in the main plasma pharmacokinetic parameters were found for either enantiomer on administration of the single enantiomers or Reboxetine. No chiral inversion was observed after administration of the separate enantiomers, as already observed in humans.
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Review of the pharmacokinetics and metabolism of Reboxetine, a selective noradrenaline reuptake inhibitor.
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 1997Co-Authors: Philippe Dostert, M S Benedetti, Italo PoggesiAbstract:The pharmacokinetics and metabolism of Reboxetine, a selective noradrenaline reuptake inhibitor, in humans and animal models are reviewed here. Reboxetine has potent antidepressant activity, low affinity for alpha-adrenergic and muscarinic receptors and low toxicity in animals. It is a mixture of (R,R) and (S,S) enantiomer, the latter being more potent but no qualitative differences in pharmacodynamic properties are observed between the two. Humans rapidly absorb Reboxetine (tmax about 2 h) with a terminal half-life of elimination (t1/2) of 13 h, allowing twice-daily administration. Animal models also rapidly absorb Reboxetine (tmax 0.5-2 h) but t1/2 was 1-2 h. Food does not affect bioavailability. There were no major inter-species differences in the metabolic profile of Reboxetine. Elimination is principally renal in humans and monkeys. Reboxetine has linear pharmacokinetics in young, healthy males for single doses of 1-5 mg and in elderly, female depressed patients (up to 4 mg b.i.d.). Multiple dosing, gender or liver insufficiency had no significant effects on the pharmacokinetics. Elderly (particularly frail elderly) patients and patients with severe renal impairment may need dose reduction. Reboxetine shows no clinically relevant interaction with lorazepam and has no inhibitory effects on the major enzymes involved in drug metabolism. It may be possible to use Reboxetine in combination with monoamine oxidase inhibitors as it has no inhibitory effect on this enzyme; in addition, it may protect patients against tyramine-induced reactions. In conclusion, Reboxetine seems to be an antidepressant with negligible interference with the pharmacokinetics of other drugs thus fewer drug-drug interactions are expected.
Joseph C. Fleishaker - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics of Reboxetine in healthy volunteers with different ethnic descents.
Psychopharmacology, 2001Co-Authors: Pamela E. Hendershot, Joseph C. Fleishaker, Keh-ming Lin, Inocencia Nuccio, Russell E. PolandAbstract:Rationale: Ethnicity can affect the pharmacokinetics and pharmacodynamics of psychopharmacologic drugs. Objectives: Reboxetine disposition differences among Asians, blacks, and Caucasians were examined. Methods: Healthy subjects (12 Asians, 12 blacks, 12 Caucasians) received a single oral dose of one 4-mg Reboxetine tablet in an open label, parallel study design. Plasma concentrations of Reboxetine enantiomers [R,R(–) Reboxetine and predominantly active S,S(+) Reboxetine] were quantified using HPLC-MS-MS. Plasma unbound fractions of Reboxetine enantiomers were evaluated by equilibrium dialysis. Ethnic group effects on pharmacokinetic parameters were assessed by ANOVA. Results: Mean S,S(+) Reboxetine CLPO for blacks was significantly greater, compared to Asians and Caucasians (154±82 ml/min, 101±19 ml/min and 101±18 ml/min, respectively). Mean S,S(+) Reboxetine free fractions (fu) were significantly greater for Asians and blacks, compared to Caucasians (3.04±1.28%, 2.89±0.69%, and 1.99±0.58%, respectively). S,S(+) Reboxetine unbound clearance (CLu) was significantly less for Asians, compared to blacks and Caucasians (3742±1468 ml/min, 5187±2027 ml/min, and 5294±1163 ml/min, respectively). S,S(+) Reboxetine mean unbound AUC (AUCu) in these groups were 20.2±7.1 ng.h/ml, 14.6±5.1 ng.h/ml, and 13.2±3.2 ng.h/ml, respectively. AUCu was significantly greater for Asians. CLu and AUCu did not differ significantly between blacks and Caucasians. Ethnic effects of R,R(–) Reboxetine were similar to those observed for S,S(+) Reboxetine. Conclusions: The AUCu difference between Asian and black and Caucasian subjects was modest. Tolerability differences among groups were not observed. No dosage adjustment is necessary for Asians or blacks.
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Lack of effect of Reboxetine on cardiac repolarization.
Clinical pharmacology and therapeutics, 2001Co-Authors: Joseph C. Fleishaker, Beth D. Herman, Steven F. Francom, Dean W. Knuth, Nkechi E. AzieAbstract:Objective The effect of Reboxetine on electrocardiographic parameters, particularly the QTc interval, was assessed in 20 healthy subjects (15 male, 5 female). Methods In a 5-way crossover study, subjects received placebo, 2 mg, 4 mg, or 6 mg Reboxetine, or 6 mg Reboxetine and 200 mg ketoconazole twice daily for 7 days. Plasma samples, vital signs, and 12-lead electrocardiograms (ECGs) were obtained during one dosing interval of days 1, 4, and 7. Additional ECGs were recorded immediately after an exercise paradigm, so that the RR versus QT relationship might be used in calculating QTc. Plasma concentrations of R,R (−)Reboxetine and the more active S,S (+)Reboxetine were measured by HPLC-dual mass spectrometry. Results No statistically significant differences among treatments in mean dose-corrected pharmacokinetic parameters were observed, except that the dose-corrected area under the concentration-time curve from time zero to 12 hours and the peak plasma concentration were significantly increased on days 4 and 7 in the presence of ketoconazole. As expected, heart rate increased from baseline (approximately 8–11 beats/min) at ≥8 mg Reboxetine daily. No statistically significant prolongation of QTc (Fridericia correction) occurred after any of the treatments. No relationships between ΔQTc and plasma concentrations of Reboxetine enantiomers were apparent. Similar results were obtained with Bazett's correction and two linear corrections that relied on exercise data generated before drug administration. Conclusions Reboxetine, at systemic exposures approximately twice the recommended dose, did not significantly affect cardiac repolarization in healthy subjects. Use of QT versus RR relationship in the drug-free state to correct QT for heart rate in the drug-treated state may provide an acceptable alternative to classic correction equations. Clinical Pharmacology & Therapeutics (2001) 70, 261–269; doi: 10.1067/mcp.2001.117705
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Clinical Pharmacokinetics of Reboxetine, a Selective Norepinephrine Reuptake Inhibitor for the Treatment of Patients with Depression
Clinical Pharmacokinetics, 2000Co-Authors: Joseph C. FleishakerAbstract:Reboxetine is a novel selective norepinephrine inhibitor that has been evaluated in the treatment of patients with depression. Reboxetine is a racemic mixture, and the ( S,S )-(+)-enantiomer appears to be the more potent inhibitor. However, the ratio of the areas under the concentration-time curves of the ( S,S )-(+)- and ( R,R )-(−)-enantiomers in vivo is approximately 0.5. There is no evidence for chiral inversion. Differences in the clearances of the 2 enantiomers may be explained by differences in protein binding. The pharmacokinetics of Reboxetine are linear following both single and multiple oral doses up to a dosage of 12 mg/day. The plasma concentration-time profile following oral administration is best described by a 1-compartment model, and the mean half-life (approximately 12 hours) is consistent with the recommendation to administer the drug twice daily. Reboxetine is well absorbed after oral administration. The absolute bioavailability is 94.5%, and maximal concentrations are generally achieved within 2 to 4 hours. Food affects the rate, but not the extent, of absorption. The distribution of Reboxetine appears to be limited to a fraction of the total body water due to its extensive (>97%) binding to plasma proteins. The primary route of Reboxetine elimination appears to be through hepatic metabolism. Less than 10% of the dose is cleared renally. Anumber of metabolites formed through hepatic oxidation have been identified, but Reboxetine is the major circulating species in plasma. In vitro studies show that Reboxetine is predominantly metabolised by cytochrome P450 (CYP) 3A4; CYP2D6 is not involved. Reboxetine plasma concentrations are increased in elderly individuals and in those with hepatic or renal dysfunction, probably because of reduced metabolic clearance. In these populations, Reboxetine should be used with caution, and a dosage reduction is indicated. Ketoconazole decreases the clearance of Reboxetine, so that the dosage of Reboxetine may need to be reduced when potent inhibitors of CYP3A4 are coadministered. Quinidine does not affect the in vivo clearance of Reboxetine, confirming the lack of involvement of CYP2D6. There is no pharmacokinetic interaction between Reboxetine and lorazepam or fluoxetine. Reboxetine at therapeutic concentrations has no effect on the in vitro activity of CYP1A2, 2C9, 2D6, 2E1 or 3A4. The lack of effect of Reboxetine on CYP2D6 and CYP3A4 was confirmed by the lack of effect on the metabolism of dextromethorphan and alprazolam in healthy volunteers. Thus, Reboxetine is not likely to affect the clearance of other drugs metabolised by CYP isozymes.
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Pharmacokinetics of single-dose Reboxetine in volunteers with renal insufficiency.
Journal of clinical pharmacology, 2000Co-Authors: François Coulomb, Italo Poggesi, Joseph C. Fleishaker, M. Gabriella Jannuzzo, Francis Ducret, Jean‐paul Laneury, Francesco Fiorentini, Georges Houin, Patrick DucheneAbstract:Reboxetine is a new selective norepinephrine reuptake inhibitor (selective NRI) for the short- and long-term treatment of depression that is effective and well tolerated at a dose of 8 to 10 mg/day. This study assessed the pharmacokinetics of Reboxetine in volunteers with renal impairment. A single 4 mg dose of Reboxetine was administered to a total of 18 volunteers with mild (n = 6), moderate (n = 6), or severe (n = 6) renal impairment (creatinine clearance: 56-64, 26-51, and 9-19 ml/min, respectively), and Reboxetine concentrations were measured in plasma by HPLC. Mean AUC∞ increased by 43% (mild vs. severe; p< 0.01) as renal function declined, while renal clearance and total urinary excretion of unchanged Reboxetine decreased by 67% and 62%, respectively (mild vs. severe; p < 0.01 for both parameters). t max and t 1/2 were not significantly different between groups. In comparison with historical data from young healthy volunteers, AUC∞ and t 1/2 are at least doubled in volunteers with renal impairment, while CL r is halved. This pharmacokinetic study has shown that increasing renal dysfunction leads to increasing systemic exposure to Reboxetine, particularly in severe renal insufficiency, although Reboxetine was well tolerated by all volunteers. Thus, a reduction of the starting dose of Reboxetine to 2 mg twice daily would be prudent in patients with renal dysfunction.
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Ketoconazole inhibits the clearance of the enantiomers of the antidepressant Reboxetine in humans.
Clinical pharmacology and therapeutics, 1999Co-Authors: Beth D. Herman, Joseph C. Fleishaker, Mark T. BrownAbstract:Background Ketoconazole is a potent inhibitor of the cytochrome P450 3A4 enzyme. Reboxetine, a selective norepinephrine reuptake inhibitor, is metabolized by cytochrome P450 3A4. The potential interaction of Reboxetine with this representative from the azole derivative class was examined. Methods Eleven healthy volunteers received (1) 4 mg Reboxetine orally on the second day of a 5-day regimen of 200 mg ketoconazole once daily and (2) 4 mg Reboxetine orally in a crossover design. Plasma concentrations of Reboxetine enantiomers [R,R (–)–Reboxetine and the more active S,S (+)-Reboxetine] were measured by high-performance liquid chromatography–tandem mass spectrometry. Effects of ketoconazole on enantiomer pharmacokinetics were assessed by ANOVA. Results Ketoconazole increased R,R (–)–Reboxetine and S,S (+)-Reboxetine mean area under the plasma concentration–time curves (AUC) by 58% and 43%, respectively (P .1). Mean terminal half-life after administration of ketoconazole (21.5 hours and 18.9 hours) was significantly longer than after Reboxetine alone (14.8 hours and 14.4 hours; P < .005). The AUC ratio for R,R (–)–Reboxetine to S,S (+)-Reboxetine was reduced by ketoconazole administration (2.76 after ketoconazole versus 2.39; P < .003). Conclusion Ketoconazole decreases clearance of both Reboxetine enantiomers. Although the adverse effect profile for Reboxetine was not altered by ketoconazole, the results of this study suggest that caution should be used and that a reduction in Reboxetine dose should be considered when the two are coadministered. Clinical Pharmacology & Therapeutics (1999) 66, 374–379; doi: 10.1053/cp.1999.v66.a101207
Siegfried Kasper - One of the best experts on this subject based on the ideXlab platform.
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a meta analysis of clinical trials comparing Reboxetine a norepinephrine reuptake inhibitor with selective serotonin reuptake inhibitors for the treatment of major depressive disorder
European Neuropsychopharmacology, 2008Co-Authors: George I Papakostas, Siegfried Kasper, Craig J Nelson, Hansjurgen MollerAbstract:The goal of the present work was to conduct a meta-analysis comparing Reboxetine and the selective serotonin reuptake inhibitors (SSRIs) for major depressive disorder (MDD). Medline/ Pubmed was searched for double-blind, randomized trials comparing these two agents for MDD. The makers of Reboxetine (Pfizer Inc.) were also contacted to provide missing data and/or unpublished studies. 9 trials (n=2641) were combined using a random effects model. Response rates were comparable between the SSRI (63.9%) and Reboxetine (59.2%)-treated groups (p=0.118). There was no significant difference in the degree of improvement in psychosocial functioning, as measured by the social adaptation self-evaluation scale, between the two groups. Overall discontinuation rates (25.1% versus 32.0%; p=0.015), and the rate of discontinuation due to intolerance (8.5% versus 12.6%; p=0.007) favored SSRI treatment. The rate of discontinuation due to lack of efficacy did not differ significantly between the two groups. SSRI-treated patients were more likely to experience nausea, hypersomnia, and fatigue. Reboxetine-treated patients were more likely to experience constipation, difficulty urinating, and insomnia. These results suggest that the NRI Reboxetine and the SSRIs differ with respect to their side-effect profile and overall tolerability but not their efficacy in treating MDD.
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Reboxetine: the first selective noradrenaline re-uptake inhibitor.
Expert opinion on pharmacotherapy, 2000Co-Authors: Siegfried Kasper, N El Giamal, E. HilgerAbstract:Several treatment approaches are available for treatment of depression. However, Reboxetine is the first selective noradrenaline re-uptake inhibitor. Whereas formerly only noradrenaline re-uptake inhibitors with a mixed mechanism of action were available. These included action not only at noradrenergic, but also at serotonergic and other neurotransmitter-sites. Thus, Reboxetine represents the first of a new class of antidepressant agents with specificity for the noradrenergic system. Reboxetine has been shown to be an effective first-line treatment for patients with all grades of depression, to be effective in the prevention of relapse and recurrence and to offer significant benefits in terms of relieving the impaired social functioning associated with depressive disorders. Reboxetine was significantly superior to the serotonergic compound fluoxetine in improvement of social functioning in both the general depressed population and in those patients who achieved symptomatic remission, indicating a superior quality of remission. Altogether Reboxetine was well tolerated during the acute and long-term treatment phase; side-effects such as increased sweating, constipation and dry mouth were the most prominent to be reported. The availability of Reboxetine represents a significant addition to the currently available pharmacologic armamentarium for the treatment of depression.
Marcio Versiani - One of the best experts on this subject based on the ideXlab platform.
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Reboxetine a selective norepinephrine reuptake inhibitor is an effective and well tolerated treatment for panic disorder
The Journal of Clinical Psychiatry, 2002Co-Authors: Marcio Versiani, Giovanni B Cassano, Giulio Perugi, Alessandra Benedetti, Luigia Mastalli, Antonio Egidio Nardi, M SavinoAbstract:Background: Tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) as well as benzodiazepines have been shown to be effective for the treatment of panic disorder. The introduction of SSRIs has enabled a greater understanding of the role of serotonin in the etiology of panic disorder; however, the role of norepinephrine has been more challenging to ascertain. The aim of this study was to determine the efficacy and tolerability of Reboxetine, a novel selective norepinephrine reuptake inhibitor, in patients with panic disorder with and without agoraphobia. Method: Eighty-two patients (aged 18-65 years) with DSM-III-R panic disorder, with or without agoraphobia, were randomly assigned to receive 6 to 8 mg/day of Reboxetine (42 patients) or placebo (40 patients) for 8 weeks in this placebo-controlled, parallel-group, double-blind clinical trial. Results: Of the 82 patients enrolled in the trial, 75 were considered in the analysis (37 patients in the Reboxetine group and 38 patients in the placebo group). At last assessment, there was a significant reduction in the mean number of panic attacks (range, 9.3-1.2) and phobic symptoms (range, 8.1-3.2) in the Reboxetine group compared with the placebo group (ranges, 8.5-5.8 and 7.7-5.2, respectively; p <.05). Improvement in Hamilton Rating Scale for Depression, Hopkins Symptom Checklist-90, and Sheehan Disability Scale scores were also greater in the Reboxetine group compared with the placebo group. Adverse events reported more frequently with Reboxetine than placebo included dry mouth (36% vs. 16%), constipation (27% vs. 22%), and insomnia (26% vs. 22%), Conclusion: Reboxetine was effective and well tolerated in the treatment of panic disorder.
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the selective noradrenaline re uptake inhibitor Reboxetine has an early onset of antidepressant action
International Journal of Psychiatry in Clinical Practice, 2000Co-Authors: Marcio VersianiAbstract:INTRODUCTION: Most antidepressants take several weeks to demonstrate a therapeutic effect. We examined the time to onset of action of Reboxetine, a unique selective noradrenaline re-uptake inhibitor (selective NRI). METHODS: In a multinational, multicentre, double-blind, parallel-group study, 56 inpatients with major depression were randomized to receive placebo or Reboxetine titrated to 10 mg/day for 6 weeks. Efficacy was principally assessed by the Hamilton Depression Rating Scale. RESULTS: Reboxetine was associated with a significantly greater reduction in mean HAM-D total score from baseline to last assessment when compared with placebo. The effect of Reboxetine separated from placebo at day 10 (P=0.006), indicated an early onset. In accordance with this observation, individual HAM-D item scores early showed significant improvements among patients treated with Reboxetine when compared with those who received placebo: mood improved by day 10 (P=0.004), insomnia and interest in work and daily activities...
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Reboxetine a unique selective nri prevents relapse and recurrence in long term treatment of major depressive disorder
The Journal of Clinical Psychiatry, 1999Co-Authors: Marcio Versiani, Lembit Mehilane, Peter Gaszner, Rene ArnaudcastiglioniAbstract:BACKGROUND The long-term efficacy and tolerability of the antidepressant Reboxetine, a unique selective norepinephrine reuptake inhibitor (selective NRI), were assessed in an international study. METHOD Two hundred eighty-three patients with recurrent DSM-III-R major depression who responded to 6 weeks of Reboxetine treatment (> or =50% decrease in Hamilton Rating Scale for Depression [HAM-D] total score) were randomly assigned to receive Reboxetine or placebo for 46 weeks in a double-blind phase. Relapse (> or =50% increase in HAM-D total score and/or a HAM-D total score > or =18) rate was the principal assessment criterion and included patients who experienced relapse or recurrence. Only patients who remained relapse-free at the end of the first 6-month treatment period were included in the relapse rate assessment at the end of the second 6-month treatment period. RESULTS Reboxetine was associated with a markedly lower relapse rate than placebo (22% vs. 56%; p<.001) and a greater cumulative probability of a maintained response (p = .0001) during long-term treatment. Patients in remission (HAM-D total score < or =10) at the time of random assignment were less likely to relapse (16% Reboxetine, 48% placebo; p<.001). The proportion of patients who were relapse-free and therefore remained in the study was significantly (p< or =.001) higher among those on Reboxetine treatment than on placebo at the end of the first (61% vs. 40%) and second (88% vs. 59%) 6 months of treatment. Additional efficacy measures supported these findings. The incidence of adverse events with Reboxetine was low and comparable with that for placebo. Discontinuation due to adverse events occurred infrequently. CONCLUSION Reboxetine treatment over 1 year is more effective than placebo in the prevention of relapse in patients with recurrent depression. The low relapse rates at the end of the second 6 months of treatment further suggest that Reboxetine effectively prevents recurrence of depressive symptoms following episode resolution. Reboxetine is well tolerated in long-term treatment of depression, a finding that bodes well for long-term patient compliance.
