MEDLINE Search on Reboxetine.

By, Ivan Goldberg, MD

Eur Neuropsychopharmacol 1997 Apr;7 Suppl 1:S37-S47
Efficacy and tolerability of reboxetine compared with imipramine in a double-blind study in patients suffering from major depressive offsodes.
Berzewski H, Van Moffaert M, Gagiano CA
German Reboxetine Study Group, Freie Universitat Berlin, Germany.

A 6-week, randomised, double-blind, multicentre study in 256 patients with a DSM-III-R diagnosis of major depression was carried out to compare the selective noradrenaline reuptake inhibitor (NARI), reboxetine, with the reference standard tricyclic antidepressant, imipramine. The efficacy of reboxetine, as measured by the extent of improvement of Hamilton Depression Rating Scale. Montgomery and Asberg Depression Rating Scale and the Clinical Global Impression Scale, was similar to that of imipramine. The improvement was observed in the overall population and in severely depressed and melancholic patients. Reboxetine tolerability compared favourably with that of imipramine. Frequency of discontinuation due to adverse events was lower in the reboxetine-treated group (10.0%) than in the imipramine-treated group (14.3%), and the cumulative risk of development (Kaplan-Meier analysis) of dry mouth, hypotension and/or related symptoms and tremor was significantly higher on imipramine than on reboxetine.

Eur Neuropsychopharmacol 1997 Apr;7 Suppl 1:S23-S35
Review of the pharmacokinetics and metabolism of reboxetine, a selective noradrenaline reuptake inhibitor.

Dostert P, Benedetti MS, Poggesi I

Pharmacia and Upjohn, Pharmacokinetics and Metabolism Department, Milan, Italy.

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.

Eur Neuropsychopharmacol 1997 Apr;7 Suppl 1:S17-S21
The effects of antidepressants on psychomotor function with particular reference to reboxetine.

Hindmarch I

University of Surrey, Department of Human Psychopharmacology, Milford Hospital, Godalming, UK. This review assesses the relative efficacy and side-effect profile of the currently available treatment options for major depression and the new selective noradrenergic agent, reboxetine. The effects of these treatments on psychomotor function are reviewed using: choice reaction time (CRT) and critical flicker fusion threshold (CFFT) measurements to compare and contrast the various antidepressants. Tricyclic antidepressant (TCA) agents are associated with an increased risk of accidents, especially in the elderly (primarily accidents related to driving or falls/fractures due to postural hypotension). In comparison, the newer noradrenergic agents such as reboxetine have demonstrated significant improvements in the incidence and severity of effects on psychomotor function. Such a lack of side-effects makes agents like reboxetine most useful for the treatment of depression in ambulant patients performing their usual activities of daily living.

Eur Neuropsychopharmacol 1997 Apr;7 Suppl 1:S3-S9
Is there a role for a pure noradrenergic drug in the treatment of depression?

Montgomery SA

Imperial College of Medicine at St Mary's, London, UK.

Depression is thought to result from a dysfunction in the noradrenergic or serotonergic systems. The noradrenergic system appears to be associated with increased drive, whereas the serotonergic system relates more to changes in mood and it is possible that the different symptoms of depression may benefit from drugs acting mainly on one or other of the neurotransmitter systems. A series of studies has shown that interruption of serotonin synthesis compromises the efficacy of serotonin but not noradrenaline reuptake inhibitors, and interruption of noradrenaline synthesis compromises the efficacy of noradrenaline but not serotonin reuptake inhibitors (SSRIs). This suggests that the two classes of drugs owe their activity to functional changes in different neurotransmitter systems. Reboxetine represents a new class of drugs-the selective noradrenaline reuptake inhibitors (NARIs). It acts specifically at noradrenergic sites unlike the non-selective tricyclic antidepressants (TCAs). NARIs have a role in the treatment of depression, either alone or as adjunctive therapy.

Biopharm Drug Dispos 1996 Oct;17(7):623-633
Pharmacokinetics of reboxetine in healthy volunteers. Single against repeated oral doses and lack of enzymatic alterations.

Pellizzoni C, Poggesi I, Jorgensen NP, Edwards DM, Paus E, Strolin Benedetti M

Pharmacia, Pharmacokinetics and Metabolism, Milan, Italy.

The pharmacokinetics of reboxetine have been investigated in 12 healthy male volunteers after a single 2 mg dose of reboxetine and at steady state, following the last administration of a multiple-dose regimen (2mg twice a day for 5 1/2 d). Reboxetine was analysed in plasma and urine samples collected up to 72 h post-dosing using an HPLC method with UV detection. The urinary excretion rate of 6-beta-hydroxycortisol, used as a marker for cytochrome P450IIIA activity, was also tested, and any possible alteration was correlated to reboxetine plasma levels. The dosing regimen was well tolerated by all subjects. Reboxetine pharmacokinetic parameters, calculated after the single dose using non-compartmental analysis, were in good agreement with those obtained in previous studies. Following the multiple-dosing regimen, no significant deviations from expectation based on linear superposition was observed. The accumulation ratio, based on repeated-dose/single-dose ratios of Cmax, AUC(0-12 h), and C(12 h) was approximately two. A slight rise was recorded for the average excretion rate of 6-beta-hydroxycortisol over 48 h by the end of treatment; however, the difference was not statistically significant and the mean excretion rates were within the normal reference range. Thus a significant induction of P450IIIA was not indicated.

Br J Clin Pharmacol 1996 Aug;42(2):239-241
The effects of reboxetine and amitriptyline, with and without alcohol on cognitive function and psychomotor performance.

Kerr JS, Powell J, Hindmarch I

HPRU, University of Surrey, Milford Hospital, Godalming, Surrey, UK.

Reboxetine is a novel antidepressant that has been shown to be effective in the treatment of major depressive disorders. The present experiment was designed to assess whether it affects the cognitive and psychomotor skills necessary for optimum function in everyday life. Ten healthy male volunteers received reboxetine 0.5 mg, 1 mg or 4 mg, amitriptyline 25 mg, or matched placebo with and without alcohol (0.6 mg kg-1) in a double-blind 10-way crossover study. A psychometric test battery was administered at baseline and at 1, 2.25, 3.5, 6 and 9 h post-dose. The results showed that reboxetine had little or no effect on performance at any dose, compared with placebo. Amitriptyline, however, with and without alcohol, lowered critical flicker fusion threshold compared with placebo and/or reboxetine at all test points (e.g. at 3.5 h: 28.51 vs 30.33 Hz; P < 0.05); increased reaction time (e.g. 619 vs 540 ms; P < 0.05); increased tracking error (e.g. 16.34 vs 8.54 RMS units; P < 0.05); and slowed short-term memory scanning (e.g. 742 vs 590 ms; P < 0.05). It is concluded that reboxetine at doses of 4 mg and below is free from disruptive effects on cognitive function and psychomotor performance, and that it does not act synergistically with alcohol, in contrast to amitriptyline.

Biopharm Drug Dispos 1995 Aug;16(6):443-460
Pharmacokinetics of reboxetine in healthy volunteers. Single oral doses, linearity and plasma protein binding.

Edwards DM, Pellizzoni C, Breuel HP, Berardi A, Castelli MG, Frigerio E, Poggesi I, Rocchetti M, Dubini A, Strolin Benedetti M

Pharmacia-Farmitalia Carlo Erba, Pharmacokinetics and Metabolism, Milan, Italy.

The pharmacokinetics of reboxetine, a new antidepressant agent, were found to be close to linear in a crossover study comparing administration of single 2, 3, 4, and 5 mg capsule doses in 15 healthy male volunteers, and in the same study the capsules were bioequivalent to the proposed therapeutic tablet formulation (4 mg). Kinetic analysis was based on HPLC assay of reboxetine in plasma and urine collected up to 72 h after each administration. Plasma levels indicated a rapid absorption (tmax approximately equal to 2 h) and an elimination half-life of about 13 h. Clearance and volume of distribution were modest (ratios to bioavailability: CL/F approximately equal to 29 mL min-1; Vz/F approximately equal to 32 L); urinary excretion was approximately 9% of dose, corresponding to a renal clearance of only 3 mL min-1 (a value consistent with the rate of glomerular filtration of unbound drug). In vitro, binding to plasma proteins, estimated from radioactivity levels following dialysis of 14C-labelled reboxetine, appeared to be dominated by alpha 1-acid glycoprotein without marked saturation up to plasma concentrations of over 500 ng mL-1 (2.8-3.1% unbound with human plasma from three additional volunteers; 1.8-2.0% for 2 gL-1 orosomucoid alpha 1-acid glycoprotein, and 46.4-47.4% for 40 g L-1 albumin), whilst the mean Cmax in the current study was much lower (164 ng mL-1 after a 5mg dose).

Br J Clin Pharmacol 1995 Mar;39(3):251-255
Effects of reboxetine and desipramine on the kinetics of the pupillary light reflex.

Theofilopoulos N, McDade G, Szabadi E, Bradshaw CM

Department of Psychiatry, University of Manchester.

1. The aim of the study was to examine the effects of single doses of two antidepressants (desipramine and reboxetine) on three kinetic parameters (latency, amplitude, 75% recovery time) of the pupillary light reflex response. 2. Six healthy male volunteers participated in three experimental sessions at biweekly intervals. Each session was associated with one of three treatment conditions (placebo, desipramine 100 mg, reboxetine 4 mg). Subjects were allocated to sessions and treatments double-blind according to a Latin Square design. 3. Pupil diameter was measured in the dark with binocular television pupillometry. Reflex responses were evoked by 12 light stimuli (5.3 x 10(-5)-3.5 mW cm-2; 500 ms), and the kinetic parameters of each response were recorded. 4. The amplitude and 75% recovery time were positively, and latency was negatively correlated with the logarithm of light stimulus intensity. In the presence of the antidepressants the latency was prolonged, the amplitude was reduced and the 75% recovery time was shortened. There was a positive linear relationship between reflex amplitude and recovery time under all three treatment conditions; this relationship was not significantly affected by the antidepressants. 5. The effects of the antidepressants on latency and amplitude are consistent with the blockade of muscarinic cholinoceptors in the iris, whereas the shortening of the recovery time appears to be secondary to the reduction in amplitude.

Cesk Psychiatr 1994 Feb;90(1):3-19
Antidepressives of the 3rd, 4th and 5th generation.
[Article in Czech]

Svestka J

Psychiatricka klinika Lekarske fakulty MU, Brno.

Antidepressants are classified into five generations. Preparations of the first generation affect various neurotransmitter systems and are therefore associated with many undesirable effects (e.g. tricyclic antidepressants, maprotiline). The second generation of antidepressants is already devoid of anticholinergic action and their adrenolytic and antihistaminic effects are weaker (e.g. mianserine, mirtazapine, trazodone). The antidepressant action of preparations of the third generation is mediated only by one of the three main neurotransmitter systems for depression (5-HT, noradrenaline, dopamine) and does not affect muscarine, histamine and adrenergic cerebral systems (e.g. SSRI, ipsapirone, viloxazine, reboxetine, bupropione). Recently antidepressants of the fourth generation were synthetized which influence only the serotonin, and noradrenaline or dopamine system (e.g. milnacipran, befloxatone). The fifth generation of antidepressants foresees the exclusive action on 5-HT, noradrenaline and dopamine systems of the CNS in varying ratios (e.g. venlafaxine, cericlamine).

Eur J Drug Metab Pharmacokinet 1991 Jul;16(3):231-239
Comparison of the disposition and of the metabolic pattern of Reboxetine, a new antidepressant, in the rat, dog, monkey and man.

Cocchiara G, Battaglia R, Pevarello P, Strolin Benedetti M

Farmitalia Carlo Erba R&D, Erbamont Group, Milan, Italy.

The purpose of this study was to compare the disposition and the metabolic pattern of Reboxetine in several species, including man. [14C]-Reboxetine was given orally to the rat, the dog, the monkey (5 mg/kg) and man (2 and 4 mg/kg). Radioactivity was eliminated both by the renal and faecal route in the rat and the dog, mainly in urine in the monkey and man. Reboxetine was extensively metabolized. A number of urinary metabolites were quantified by radio-HPLC and tentatively identified by comparison with the retention times of reference compounds. Suggested routes of metabolic transformation are: 2-O-dealkylation; hydroxylation of the ethoxyphenoxy ring; oxidation of the morpholine ring; morpholine ring-opening; and combinations of these. Metabolites were partially or completely conjugated with glucuronic acid and/or sulphuric acid.

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