piperidines and brofaromine

Placebo-controlled trials have evaluated the efficacy of several medications in the treatment of social anxiety disorder but information regarding their relative efficacy is lacking. We compared the efficacy of medications systematically studied for the treatment of social anxiety disorder using meta-analytic techniques. The methodology included a database search of articles published between January 1980 and June 2001 and manual searches of bibliographies in published manuscripts. Trials were included if they reported outcome data on the Liebowitz Social Anxiety Scale (LSAS) or a categorical measure of responder status. Data were extracted independently by two authors. The Q statistic was used to assess homogeneity across trials. All analyses were conducted using intent-to-treat data. There was substantial heterogeneity across trials. The medications with largest effect sizes were phenelzine [effect size, 1.02; 95% Confidence Interval (CI), 0.52-1.52], clonazepam (effect size, 0.97; 95% CI, 0.49-1.45), gabapentin (effect size, 0.78; 95% CI, 0.29-1.27), brofaromine (effect size, 0.66; 95% CI, 0.38-0.94), and the selective serotonin reuptake inhibitors (SSRIs; effect size, 0.65; 95% CI, 0.50-0.81). There were no statistically significant differences between medications or medication groups. However, formal methods of interim monitoring adapted for meta-analyses suggested strongest evidence of efficacy for SSRIs and brofaromine. Several medications are efficacious for the treatment of social anxiety disorder. The stability of the SSRI effect size estimate in conjunction with other evidence for safety and tolerability and their ability to treat comorbid conditions supports the use of SSRIs as the first-line treatment. Direct comparisons of SSRIs vs. other promising medications deserve consideration.

Topics: Acetates; Amines; Anti-Anxiety Agents; Antidepressive Agents; Antimanic Agents; Anxiety Disorders; Calcium Channel Blockers; Clonazepam; Cyclohexanecarboxylic Acids; Excitatory Amino Acid Antagonists; Female; GABA Modulators; Gabapentin; gamma-Aminobutyric Acid; Humans; Male; Monoamine Oxidase Inhibitors; Phenelzine; Phobic Disorders; Piperidines; Selective Serotonin Reuptake Inhibitors; Treatment Outcome

This article reviews evidence for the utility of antidepressant medications in the treatment of social phobia. Monoamine oxidase inhibitors (MAOIs) were the first antidepressants shown to be effective for social phobia, but dietary restrictions and a relatively high rate of adverse effects often relegate MAOIs to use after other treatments have been found ineffective. Reversible inhibitors of monoamine oxidase (RIMAs) hold promise as safer alternatives to MAOIs, but RIMAs may be less effective and are currently unavailable in the United States. Selective serotonin reuptake inhibitors (SSRIs), of which paroxetine has been the best studied in social phobia to date, have recently emerged as a first-line treatment for the generalized subtype of social phobia. The SSRIs are well tolerated and consistently have been shown to be efficacious in controlled trials.

Topics: Antidepressive Agents; Controlled Clinical Trials as Topic; Drug Approval; Humans; Moclobemide; Monoamine Oxidase Inhibitors; Paroxetine; Phenelzine; Phobic Disorders; Piperidines; Selective Serotonin Reuptake Inhibitors; Treatment Outcome; United States

The reversible inhibitors of monoamine oxidase type A (RIMAs) are a newer group of antidepressants that have had much less impact on clinical psychopharmacology than another contemporary class of medications, the selective serotonin reuptake-inhibitors (SSRIs). The RIMAs agents are distinguished from the older monoamine oxidase inhibitors (MAOIs) by their selectivity and reversibility. As a result, dietary restrictions are not required during RIMA therapy, and hypertensive crises are quite rare. In this article, we describe a series of meta-analyses of studies of the two most widely researched RIMAs, moclobemide (MOC; Aurorex) and brofaromine (BRO). Our findings confirm that both BRO and MOC are as effective as the tricyclic antidepressants, and they are better tolerated. However, BRO is not being studied at present for reasons unrelated to efficacy or side effects. MOC, which is available throughout much of the world (but not the United States), is significantly more effective than placebo and, at the least, comparable to the SSRIs in both efficacy and tolerability. For MOC, higher dosages may enhance efficacy for more severe depressions. We also found evidence that supports clinical impressions that MOC is somewhat less effective, albeit better tolerated, than older MAOIs, such as phenelzine or tranylcypromine. Little evidence has yet emerged to suggest that the RIMAs share older MAOIs' utility for treatment of depressions characterized by prominent reverse neurovegetative features. Based on available evidence, the RIMAs appear to have a limited, but useful, role in the differential therapeutics of the depressive disorders.

Topics: Benzamides; Controlled Clinical Trials as Topic; Depression; Humans; Moclobemide; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Piperidines; Treatment Outcome

In this Research Review, several recent clinical trials in panic disorder and social phobia are reviewed. First, two social phobia studies which used the monoamine oxidase type A inhibitors brofaromine and moclobemide are considered. Then, three panic disorder studies which used clonazepam, clomipramine or paroxetine, and citalopram are examined. These studies serve to strengthen the empirical research base regarding which treatments are useful in these disorders.

Topics: Antidepressive Agents, Tricyclic; Benzamides; Benzodiazepines; Citalopram; Clinical Trials as Topic; Clomipramine; Clonazepam; Dose-Response Relationship, Drug; Female; Humans; Male; Moclobemide; Monoamine Oxidase Inhibitors; Panic Disorder; Paroxetine; Piperidines; Recurrence; Selective Serotonin Reuptake Inhibitors; Social Behavior Disorders

The antidepressant activity of monoamine oxidase inhibitors has been well established for 30 years. Nevertheless, this group of compounds was handled with great care, mainly because of the interaction potential with tyramine-containing foodstuff. With the discovery of reversible and selective inhibitors of monoamine oxidase type A a renaissance of these compounds has begun. In this paper one of these new substances--brofaromine--will be described in detail. Biochemical and pharmacological aspects will be reviewed, showing that brofaromine is a selective and reversible inhibitor of monoamine oxidase type A with additional serotonin reuptake inhibiting properties. Both mechanisms of action may synergize in the antidepressant effect of the compound. The main results of clinical trials in depression and other indication areas will also be covered. Special attention will be put on the side effect profile.

Topics: Animals; Brain Chemistry; Depressive Disorder; Humans; Monoamine Oxidase Inhibitors; Piperidines

The concept of reversible type A monoamine oxidase (MAO-A) inhibitors as effective antidepressant drugs with a minimal side effect profile has been vindicated in practice. Despite this, the pharmacological basis for their actions is unclear. Studies with the irreversible inhibitor clorgyline have shown that chronic but not acute treatment of rats leads to a significant enhancement of noradrenaline release from peripheral sympathetic nerves and cerebral cortex together with a more effective inhibition of MAO-A, as shown by reduction in levels of deaminated metabolites in cortical microdialysis fluid. Reversible inhibitors, however, do not have a cumulative effect on MAO inhibition and may have different effects on noradrenaline release. Reversible inhibitors did not produce the acute reduction in sympathetic nerve activity seen with clorgyline, which may be one factor in explaining their milder side effect profile. Other aspects of the pharmacology of reversible and irreversible selective inhibitors of MAO-A are reviewed.

Topics: Animals; Benzamides; Clorgyline; Dopamine; Moclobemide; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Norepinephrine; Piperidines; Rats; Serotonin; Sympathetic Nervous System; Tyramine

Social phobia, though the third most common psychiatric disorder in the United States, has received little systematic attention until recently. Chronic and disabling symptoms usually precede other disorders in individuals with comorbidity, including alcohol abuse. Though about 80% of individuals do not seek treatment, controlled trials have demonstrated efficacy for several medications, of which phenelzine (an irreversible monoamine oxidase inhibitor [MAOI]) is the best studied. The benzodiazepines, clonazepam and alprazolam, also hold promise. New reversible MAOIs such as moclobemide and brofaromine are under investigation; fluoxetine and other serotonin selective reuptake inhibitors need further controlled study. The benefits of group cognitive-behavioral therapy also appear substantial. Issues for future investigation include long-term outcome, differential therapeutics, diagnostic subtyping, and combination treatments.

Topics: Benzamides; Benzodiazepines; Clinical Trials as Topic; Cognitive Behavioral Therapy; Combined Modality Therapy; Comorbidity; Fluoxetine; Humans; Moclobemide; Monoamine Oxidase Inhibitors; Phenelzine; Phobic Disorders; Piperidines; Selective Serotonin Reuptake Inhibitors; Treatment Outcome

1. Recently, a new generation of monoamine oxidase (MAO) inhibitors has been developed which selectively and reversibly inhibit MAO-A activity. 2. One of these compounds, called brofaromine, has been administered in subjects suffering from endogenous depression, revealing antidepressive efficacy in a majority of them without inducing serious adverse events. 3. The results obtained so far suggest that brofaromine might be effective in endogenous depressed patients who failed to respond to tricyclic antidepressants.

Topics: Antidepressive Agents; Depressive Disorder; Humans; Monoamine Oxidase Inhibitors; Piperidines

Brofaromine is a tight-binding, reversible inhibitor of monoamine oxidase-A (MAO-A), with concomitant serotonin (5-HT) uptake-inhibiting properties. In psychopharmacologic investigations, the compound shows the properties expected of an MAO inhibitor, antagonizing the effects of reserpine, tetrabenazine, and 5-hydroxytryptophan in rats and mice, and suppressing rapid eye movement sleep in cats. Brofaromine showed antidepressant-like activity in a rat social conflict test. In radioligand binding assays, brofaromine exhibited weak or no interaction with alpha 1- and alpha 2-noradrenergic, 5-HT1, 5-HT2, 5-HT3, cholinergic, histamine H1 and H2, mu-opiate, GABAA, benzodiazepine, adenosine, neurotensin, and substance P receptors. Comparison of in vitro and in vivo potencies to inhibit 5-HT uptake with those of reference drugs, and direct evidence in patients and volunteers suggest that 5-HT uptake inhibition plays a role in the clinical profile of brofaromine.

Topics: Animals; Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Piperidines; Selective Serotonin Reuptake Inhibitors

Monoamine oxidase (MAO) inhibitors (MAOIs) provide effective alternative therapy for those patients with major depression who do not respond to tricyclic antidepressants or such related compounds as the selective serotonin reuptake inhibitors. This article reviews studies on the efficacy of both the classical MAOIs and the new, selective monoamine oxidase-A (MAO-A) inhibitor brofaromine in patients with resistant major depression. Brofaromine appears to be as effective as the older MAOIs in these patients, but is better tolerated and safer to use. Brofaromine was also found to be better tolerated than lithium when added to treatment with the tetracyclic antidepressant maprotiline. More studies on the benefits of the new MAO-A inhibitors in resistant depression are indicated, not only with brofaromine but also with moclobemide, which to date has not been studied in this indication. Studies to determine their place in the overall treatment strategy of major depression are also needed.

Topics: Antidepressive Agents; Depressive Disorder; Drug Resistance; Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Piperidines

1. The reasons for developing second-generation MAOI are outlined. The expected advantage of reversibility as a safety valve with respect to tyramine potentiation is discussed. 2. Earlier data from in vitro and some ex vivo experiments had suggested an irreversible interaction of brofaromine with MAO-A, whereas the short duration of action, the absence of cumulation of effect and the displaceability by endogenously released substrates indicated reversibility. This apparent conflict could be solved by the demonstration that brofaromine behaves as a tight-binding reversible inhibitor. 3. In in vivo binding experiments with [3H]brofaromine given i.v., clorgyline, brofaromine and moclobemide were shown to dose-dependently displace the radioligand from MAO-A in the rat brain when administered after it. In corresponding experiments in the rat intestine in which the radioligand was administered p.o., similar results were obtained. Moreover, tyramine given orally in pressor doses after the radioligand also displaced it, confirming the idea that reversibility could act as a safety valve. 4. The evidence from animal and human experiments is presented that brofaromine is safer than classical MAO inhibitors with respect to tyramine potentiation. 5. Based on computer simulations, it is suggested that reduced liability of the new MAO reversible inhibitors to cause tyramine potentiation may potentially be linked to a reduced therapeutic efficacy. 6. The evidence is discussed that 5-HT uptake inhibition by brofaromine is relevant in its therapeutic effect in humans and may synergize with MAO-A inhibition, thus enhancing the impact of the latter on serotonergic transmission.

Topics: Animals; Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Piperidines; Selective Serotonin Reuptake Inhibitors; Tyramine

During recent years the MAO inhibitors have come to assume increasing importance in clinical practice. Attempts have been made to improve the tolerability of these substances by evolving a new generation of MAO inhibitors. Brofaromine, a newly developed MAO inhibitor of the second generation, is a selective, reversible, and short-acting MAO-A inhibitor. Under this drug, the dangerous "cheese effect" can be expected to occur only under extreme conditions, if at all. Clinical trials performed to date, including double-blind trials versus tranylcypromine and imipramine, have shown that brofaromine displays good antidepressive efficacy and good tolerability.

Topics: Animals; Humans; Monoamine Oxidase Inhibitors; Piperidines

Acceptance into clinical practice of monoamine oxidase (MAO) antidepressants requires unequivocal evidence that novel, non-hepatotoxic and reversible MAO-A inhibitors carry little or no risk of inducing severe hypertensive crises (cheese effect). This study summarizes the most relevant preclinical aspects which differentiate the novel reversible MAO-A inhibitors moclobemide and brofaromine, from previous irreversible MAO inhibitors of the old generation, particularly phenelzine and tranylcypromine. Moclobemide and brofaromine bear no chemical relation to irreversible inhibitors such as hydrazine derivatives (phenelzine) or aminocyclopropyl derivatives (tranylcypromine). Experiments in rats show that moclobemide and brofaromine increase the level of serotonin (5-hydroxytryptamine) and decrease that of 3,4-dihydroxyphenylacetic acid for only 16-24 hours. In vitro, moclobemide and brofaromine behave as mechanism-based, enzyme-activated inhibitors since their intrinsic inhibitory activity increases with the duration of their interaction with the enzyme in tissue homogenates. In contrast to irreversible monoamine oxidase inhibitors, which are much more potent in vitro than in vivo, moclobemide has the characteristic to be virtually equipotent in vitro and in vivo. MAO-A inhibition induced by moclobemide in the rat in vivo was rapidly reversed by simply incubating liver homogenates at 37 degrees C in the absence of the inhibitor, indicating a rapid metabolic inactivation of moclobemide in vitro. This reversibility is a distinctive feature of moclobemide, when compared with brofaromine or irreversible MAO inhibitors. Hepatotoxicity is not an inherent property of MAO inhibitors indeed, moclobemide or brofaromine, due to their chemical structures, cannot be converted into isopropyl hydrazine, the hepatotoxic metabolite of iproniazid suspected to induce liver necrosis. Results from preclinical and clinical investigations demonstrate that moclobemide and brofaromine, in contrast to tranylcypromine and phenelzine, very weakly potentiate the pressor effects of orally administered tyramine. In conclusion, the reversible MAO-A inhibitors moclobemide and brofaromine, due to their well-documented safety characteristics, to their lack of anticholinergic-effects and to their good tolerability, will provide innovative tools for clarifying the role of MAO-A inhibitors in the treatment of endogenous and atypical depressive states.

Topics: Animals; Benzamides; Brain Chemistry; Humans; Moclobemide; Monoamine Oxidase Inhibitors; Piperidines

During the last years the MAO-inhibitors reached a progressive importance in clinical practice. It was attempted to solve problems of tolerability by a new generation of MAO-inhibitors. Brofaromine is a MAO-inhibitor of the second generation, a selective, reversible and short acting MAO-A-inhibitor, promising that the dangerous "cheese effect" will occur only under extreme conditions. The clinical trials performed hitherto, among other double-blind test versus tranylcypromine and imipramine, demonstrate a good antidepressive efficacy and a good tolerability.

Topics: Antidepressive Agents; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Humans; Piperidines

In this paper an overview of the present state of monoamine oxidase inhibitors (MAOIs) is presented. The irreversible inhibitors are firstly considered. They have been divided into four chemical types: substituted hydrazine, cyclopropylamine, propargylamine and allylamine derivatives. Moreover, a tetrahydropyridine derivative (MPTP), recently described as an irreversible inhibitor of MAO-B, has been included among the irreversible MAOIs. The reversible inhibitors such as tetrahydro-beta-carbolines and salsolinol, phenylalkylamines: amphetamine, amiflamine and 2,3-dichloro-alpha-methyl-benzylamine. Among the short acting or reversible inhibitors the 4-(2-benzofuranyl) piperidine series and the morpholinoethylamino derivatives are discussed. Finally the oxazolidinone series is presented separately, as in this series reversible or irreversible inhibitors of the A or B form of MAO have been obtained.

Topics: Animals; Benzamides; Humans; Hydrazines; Isoquinolines; Monoamine Oxidase Inhibitors; Oxazoles; Oxazolidinones; Parkinson Disease; Phenethylamines; Piperidines; Selegiline; Structure-Activity Relationship

The new pharmacological developments in antidepressants are reviewed with particular reference to MAOIs. Combining an MAOI with amitriptyline reduces the risk of a tyramine-induced rise of blood pressure but does not eliminate the risk which is comparable to that of one of the new reversible MAO-A inhibitors (CGP 11305A).

Topics: Amitriptyline; Drug Interactions; Humans; Hypertension; Monoamine Oxidase Inhibitors; Piperidines; Tyramine

1. This study examines the relation between baseline clinical characteristics in patients with posttraumatic stress disorder (PTSD) and response to treatment with a reversible monoamine oxidase A inhibitor (RIMA), brofaromine. 2. Data from two comparable, double-blind, placebo-controlled studies of brofaromine in patients with PTSD were combined. Bivariate analyses of variables of interest and outcome were performed. 3. Treatment response was significantly associated with lower baseline scores on the full scale Clinician-Administered PTSD Scale (CAPS) and on CAPS subscales B (re-experiencing) and C (avoidance/numbing), as well as to drug treatment with brofaromine. Placebo response was related to a history of past sexual trauma. 4. Brofaromine may have therapeutic benefit in treating PTSD, with lower baseline levels of reexperiencing and avoidance/numbing and overall less severe PTSD most predictive of outcome.

Topics: Adult; Age of Onset; Analysis of Variance; Disasters; Double-Blind Method; Female; Humans; Male; Monoamine Oxidase Inhibitors; Piperidines; Placebos; Predictive Value of Tests; Prognosis; Psychological Tests; Sex Offenses; Stress Disorders, Post-Traumatic; Treatment Outcome; United States; Warfare

The effects of trazodone on subjective and objective sleep parameters were compared to those of placebo in a double-blind design in seven patients who developed insomnia during treatment with the selective and reversible MAO-A inhibitor, brofaromine. Trazodone significantly increased deep sleep and altered the architecture of sleep in these patients. Subjectively, patients reported a better and deeper sleep. No negative interactions between brofaromine and trazodone were observed and side-effects were minimal. A low dose of trazodone may be a safe and effective agent in the treatment of MAO-I induced insomnia.

Topics: Dose-Response Relationship, Drug; Double-Blind Method; Electroencephalography; Follow-Up Studies; Humans; Monoamine Oxidase Inhibitors; Piperidines; Selective Serotonin Reuptake Inhibitors; Sleep Initiation and Maintenance Disorders; Sleep, REM; Trazodone; Wakefulness

Brofaromine is a selective and reversible inhibitor of monoamine oxidase A. The efficacy and safety of this compound as compared with tricyclic antidepressants, classical monoamine oxidase inhibitors and placebo has been demonstrated in several clinical trials. The present 6-week, double-blind, randomized trial compared brofaromine with imipramine in in-patients with major depression. Brofaromine was as effective as imipramine in the treatment of major depression, but exhibited a different side-effect profile, in particular lacking the anticholinergic and certain cardiovascular side-effects of the tricyclic imipramine, but more likely to induce sleep disturbances. In this study, in-patients were examined, since the majority of controlled clinical trials on depressed patients conducted so far have focused on the evaluation of out-patients. If one assumes that a different degree of severity of depression exists between these two patient groups, then the results of those trials conducted on out-patients cannot readily be transferred to in-patients.

Topics: Adolescent; Adult; Aged; Antidepressive Agents, Tricyclic; Depressive Disorder; Dose-Response Relationship, Drug; Double-Blind Method; Female; Hospitalization; Humans; Imipramine; Male; Middle Aged; Monoamine Oxidase Inhibitors; Piperidines; Sleep Wake Disorders

The timing of clinical drug effects in depression can be estimated by a variety of methodological approaches, which might account for the heterogeneity of findings. We compared the patients' own ratings of the onset of antidepressant effect with onset estimations that were based on the intraindividual courses of depression as measured by the Hamilton Depression Rating Scale and a self-rating scale, the von Zerssen Adjective Mood Scale. The data of two control-group studies on brofaromine vs. imipramine were reanalyzed, the first, comprising 224 non-elderly and the second 195 elderly patients. In both studies the patients rated a significantly earlier onset of activity (means: days 12 and 16) than any other method. The means of the scale-based ratings varied between days 20 and 31 and showed a marked dependence on the response criteria selected: strict response criteria produced later onset estimations than less strict ones. Whereas the patient's own ratings indicated a significantly later onset of activity in the elderly patients, none of the scale-based measures supported this difference. The discussion focuses on the importance of methodological aspects.

Topics: Adult; Aged; Antidepressive Agents; Antidepressive Agents, Tricyclic; Depressive Disorder; Double-Blind Method; Female; Humans; Imipramine; Male; Middle Aged; Monoamine Oxidase Inhibitors; Piperidines; Psychiatric Status Rating Scales

The comparison of two different modes of data processing and two different approaches to statistical testing both applied to the same set of EEG recordings was the main objective of this pharmacological study. Brofaromine (CGP 11,305 A), a new selective and reversible monoamine oxidase type A inhibitor was used as an example for investigating a potentially antidepressant drug in clinical development. The two modes of pharmaco-EEG (PEEG) data processing differed mainly in the sampling frequency and definition of spectral parameters. Patterns of significant changes were noted in terms of descriptive data analysis using either a nonparametric Wilcoxon signed-rank test or an ANOVA of transformed data, as suggested by Conover and Iman. These data clearly demonstrate that slight discrepancies in the results may simply arise from differences in data processing and statistical approach applied. In spite of these discrepancies, the pattern of brofaromine-induced PEEG changes was very similar regardless of the mode of data handling used.

Topics: Adult; Electroencephalography; Female; Humans; Male; Monoamine Oxidase Inhibitors; Piperidines

Differences between responders and non-responders to drug therapy were investigated in social phobia. Two previously published studies were pooled to obtain data of 30 patients who were treated for 12 weeks with brofaromine or fluvoxamine. Four criterion variables were used to divide patients in responders and non-responders. Depending on the criterion variable up to 72% of the patients were regarded as responders. Non-responders differed from responders in that they had a higher heart rate and a higher blood pressure. They were also characterized by higher scores on several psychometric scales, indicative of illness severity.

Topics: Adult; Arousal; Blood Pressure; Double-Blind Method; Female; Fluvoxamine; Heart Rate; Humans; Male; Middle Aged; Monoamine Oxidase Inhibitors; Personality Inventory; Phobic Disorders; Piperidines; Prognosis; Selective Serotonin Reuptake Inhibitors; Treatment Outcome

Previous studies have shown that both selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) are effective in the treatment of panic disorders (PD). In this study, the SSRI fluvoxamine (Fluv) was compared with the MAO-A-I brofaromine (Brof). Thirty patients with the diagnosis of PD with or without agoraphobia were treated with either Fluv or Brof (150 mg daily) in a double-blind design. After 12 weeks of treatment, 93% of the Brof group and 87% of the Fluv group considered themselves much or very much improved. Taking a reduction in the Hamilton Rating Scale for Anxiety score of 50% or more, 33% of the Fluv patients and 47% of the Brof patients were responders to treatment. After an increase in anxiety in the 1st week, which was more severe in Fluv-treated patients than for Brof, a clinically relevant decrease in anxiety symptoms and reduction in panic attacks and avoidance behavior was observed. There was no significant difference between the treatment groups. The most prominent side effects were middle-sleep disturbance (Brof), tiredness (Fluv), and nausea after taking the medication (Brof and Fluv). During a double-blind follow-up period of another 12 weeks, a further improvement was found in both treatment groups without significant differences between the two groups. The selective and reversible MAO-A-I brofaromine and the SSRI fluvoxamine are equally effective in the treatment of PD. Both compounds lead to a reduction in the number of panic attacks and a subsequent reduction in agoraphobic avoidance.

Topics: Adult; Anti-Anxiety Agents; Double-Blind Method; Female; Fluvoxamine; Headache; Humans; Male; Middle Aged; Monoamine Oxidase Inhibitors; Nausea; Panic Disorder; Piperidines; Selective Serotonin Reuptake Inhibitors

The pharmacokinetics of brofaromine, a selective inhibitor of monoamine oxidase A, was evaluated in 12 frail elderly patients (66-92 y) and 12 healthy volunteers (20-35 y).. Quantitative liver function tests were performed to show whether brofaromine elimination in the elderly could be predicted from noninvasive assessment of CYP1A2 activity (caffeine clearance) or liver plasma flow (sorbitol clearance).. In the elderly the AUC of brofaromine was significantly increased (e.g. for the 75 mg dose 43.2 vs 19.9 mumol*h.l-1, clearance was reduced (5.0 vs. 11.8 l.h-1), the volume of distribution was smaller (130 vs. 230 l), and the half-life was slightly increased (19.0 vs. 14.2 h). No significant correlation was observed between hepatic plasma flow and brofaromine clearance (r = 0.41, P = 0.05), whereas CYP1A2 activity and brofaromine clearance were tightly correlated (r = 0.94, P < 0.0001).. Caffeine clearance, a simple, noninvasive test of CYP1A2 activity, is predictive of brofaromine clearance.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Aging; Caffeine; Chromatography, Gas; Cross-Over Studies; Cytochrome P-450 CYP1A2; Female; Frail Elderly; Half-Life; Humans; Liver Function Tests; Male; Monoamine Oxidase Inhibitors; Piperidines; Regression Analysis; Sorbitol

Little is known about biological predictors of treatment response in panic disorder (PD). In the present study heart rate, blood pressure, plasma cortisol and plasma MHPG were investigated at baseline in a sample of 44 PD patients as possible predictors for nonresponse to treatment. We used a strict definition of nonresponse to find patients who did not respond at all after 12 weeks of treatment with brofaromine or fluvoxamine. Patients were considered nonresponders when they fulfilled two criteria: they did not show a 50% reduction of agoraphobic avoidance and they still experienced panic attacks at endpoint. The variables that differed significantly between the groups were used to predict nonresponse to drug therapy. Using this strict definition of nonresponse, 15 patients (32.6%) were considered nonresponders. These patients were characterised by a higher plasma MHPG concentration and a higher heart rate at baseline. These variables were subsequently used to predict nonresponse.

Topics: Adult; Biomarkers; Blood Pressure; Double-Blind Method; Female; Fluvoxamine; Heart Rate; Humans; Hydrocortisone; Male; Methoxyhydroxyphenylglycol; Middle Aged; Monoamine Oxidase Inhibitors; Panic Disorder; Piperidines; Selective Serotonin Reuptake Inhibitors; Treatment Failure

To compare the reliability of instruments used in clinical trials involving cognitively impaired older adults when the instruments are administered in-home rather than in-clinic and to compare withdrawal rates is these two groups.. This study was part of a larger n-of-1 clinical trial to investigate the efficacy and safety of a MAO/A inhibitor (Brofaromine) in patients with Alzheimer's disease. Participants were initially assessed at the clinic (baseline) and then randomly allocated to in-home or in-clinic assessments for the remainder of the trial. The baseline and second assessment (performed before initiation of the treatment) were used for the reliability analysis. Withdrawal rates were examined over the course of the 6-month trial.. Assessments took place at a geriatric clinic in an urban university teaching hospital and at residences of some of the patients.. Forty-six Alzheimer's disease patients participated in the study, of which, 22 were randomized to in-home assessments and 24 to in-clinic assessments.. Test-retest reliability was measured for all five instruments used in the study and was based on the first two assessments. Sample size requirements, based on within-group variance, were calculated. Withdrawal rates were obtained for the total duration of the trial.. Test-retest reliability of the instruments, as determined by intraclass correlations, was good in both groups but favored in-clinic for all but one instrument (range: 0.47-0.90 for in-home vs 0.57-0.92 for in-clinic). Sample size requirements based on reliability assessment data were found to be larger for some instruments when administered in-home. Only four in-home patients withdrew before completion of the study, compared with eight in-clinic patients.. The results suggest the in-home assessments in cognitively impaired older adults may result in lower withdrawal rates but may necessitate larger sample sizes to offset larger test-retest variability.

Topics: Aged; Alzheimer Disease; Clinical Trials as Topic; Female; Geriatric Assessment; Home Care Services; Humans; Male; Monoamine Oxidase Inhibitors; Outpatient Clinics, Hospital; Patient Dropouts; Piperidines; Reproducibility of Results; Selection Bias; Survival Analysis

There is a rather limited database of controlled clinical trials on the comparative effects of antidepressants in elderly and non-elderly depressed patients. A common finding is reduced efficacy and an increased incidence of side effects. To further examine the question of efficacy and safety of antidepressant drugs in elderly versus non-elderly patients, the differential effects of a new selective type A monoamine oxidase inhibitor brofaromine, and the classical tricyclic imipramine were investigated using the data of two recently published trials. We found no major difference between non-elderly and elderly depressed patients as concerns efficacy, total incidence of adverse findings or safety parameters such as laboratory values and heart rate. These results are discussed in the light of some methodological questions and previous reports.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aging; Antidepressive Agents, Tricyclic; Depressive Disorder; Double-Blind Method; Female; Humans; Imipramine; Male; Middle Aged; Monoamine Oxidase Inhibitors; Piperidines; Psychiatric Status Rating Scales

Factors that predict nonresponse to drug therapy (brofaromine or fluvoxamine) were investigated in a sample of 44 panic disorder patients. We used a strict definition of nonresponse to find patients who did not respond at all after 12 weeks of treatment. Using this definition, 15 patients (32.6%) were considered nonresponders. Nonresponders had a higher score on the Blood-Injury subscore of the Fear Questionnaire (FQ) and more often had high scores on several FQ subscores, indicative of comorbid phobic symptoms. These variables were subsequently used to predict nonresponse.

Topics: Adult; Agoraphobia; Double-Blind Method; Female; Fluvoxamine; Humans; Male; Middle Aged; Monoamine Oxidase Inhibitors; Panic; Panic Disorder; Personality Inventory; Phobic Disorders; Piperidines; Prognosis; Treatment Outcome

Patients with social phobia often describe personality traits characterized by avoidant social behavior and more general depressive-anxious features. There is only sparse knowledge about the effects of drug treatment on these traits.. Fifty-seven patients with social phobia completed a 12-week double-blind, placebo-controlled trial with the reversible and selective monoamine oxidase A inhibitor brofaromine 150 mg/day. The Clinical Global Impressions-Improvement scale, Liebowitz Social Anxiety Scale, a questionnaire with 140 items regarding personality traits, and ratings on the presence or absence of diagnostic criteria for the DSM-III-R avoidant and dependent personality disorders were used for assessments at baseline and endpoint. Comparisons were made with a group of 58 healthy controls.. Before treatment, there were no significant differences between the brofaromine and placebo groups in their ratings on situationally bound social anxiety or on personality traits that differed significantly from those of the controls. At endpoint, a marked normalization was noted in the brofaromine group. The changes that had occurred differed significantly from those in the placebo group. The normalization of traits seemed more marked than the normalization of anxiety in more specific social phobic situations. The number of brofaromine patients who fulfilled the criteria for avoidant personality disorder had diminished from 15 (60%) to 5 (20%).. The results support the conclusion that the maladaptive personality traits characteristic of social phobia are at least as responsive to the monoamine oxidase inhibitor brofaromine as are the more circumscribed social anxiety responses.

Topics: Adult; Comorbidity; Double-Blind Method; Female; Humans; Male; Middle Aged; Monoamine Oxidase Inhibitors; Mood Disorders; Personality Disorders; Phobic Disorders; Piperidines; Placebos; Self Concept; Treatment Outcome

Most findings of antidepressant treatment prediction have not been replicated, and this applies to biological predictors as well as sociodemographic and early course predictors. One exception might be early psychopathological improvement. To reevaluate this question, we examined the results of two large-scale controlled clinical trials comparing the selective and reversible inhibitor of monoamine oxidase type A (MAO-A) brofaromine with the standard tricyclic compound imipramine. One trial was carried out in a normal-aged patient group; the other, in elderly patients. Above all, we were interested in determining whether early treatment course would prove predictive of later outcome. The main finding was that the initial antidepressant effect (measured after 1 and 2 weeks) predicted longer term outcome. Although this association was not as strong in the elderly patient group, its predictive value did possess a certain clinical relevance.

Topics: Adult; Affect; Aged; Antidepressive Agents, Tricyclic; Depressive Disorder; Double-Blind Method; Female; Geriatric Assessment; Humans; Imipramine; Male; Middle Aged; Monoamine Oxidase Inhibitors; Personality Inventory; Piperidines; Prognosis; Treatment Outcome

Seventy-seven patients with a primary diagnosis of social phobia (DSM-III-R) were randomized to treatment with the reversible and selective monoamine oxidase type A inhibitor brofaromine (n = 37) or placebo (n = 40) for 12 weeks in a double-blind trial. A fixed dose of 150 mg/day or a matching placebo was given after a 2-week dose titration phase. Patients with additional diagnoses of simple phobia, generalized anxiety disorder, dysthymia or major depressive disorder currently in remission were accepted. Patients with other Axis I mental disorders were excluded. In the brofaromine group, 78% of the patients scored much or very much improved on the Clinical Global Impression scale compared with 23% in the placebo group. The anxiety and avoidance scores on the Liebowitz Social Anxiety Scale (LSAS) were significantly reduced in favor of brofaromine. The clinical effects were not significantly correlated with the plasma concentration of brofaromine. After 12 weeks the brofaromine group scored significantly lower than the placebo group on a core depression part of the Montgomery-Asberg Depression Rating Scale. After 12 weeks of treatment the brofaromine group had significantly higher total scores on the LSAS than an age- and gender-matched group of healthy controls. The brofaromine group improved further during 9-month follow-up treatment period, whereas 60% of the placebo responders who continued long-term treatment relapsed. The most common side effects in the brofaromine group were sleep disturbances, dry mouth and nausea.

Topics: Adult; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Monoamine Oxidase Inhibitors; Personality Inventory; Phobic Disorders; Piperidines; Selective Serotonin Reuptake Inhibitors; Treatment Outcome

A large multi-center, double-blind, parallel trial to assess the efficacy of brofaromine in the treatment of post traumatic stress disorder (PTSD) failed to show a significant difference between the brofaromine and placebo treatment groups. The placebo response rate in this study was higher than that in previously published double-blind, placebo-controlled studies of PTSD.

Topics: Adult; Aged; Double-Blind Method; Female; Humans; Male; Middle Aged; Monoamine Oxidase Inhibitors; Piperidines; Stress Disorders, Post-Traumatic

In a 6-week double-blind study, 220 patients with major depression (mostly outpatients) were randomly assigned to receive a fixed dose of brofaromine 150 mg daily (n = 111) or placebo (n = 109) after a 1-week single-blind placebo washout. Except for the HAM-D sleep items, brofaromine was superior to placebo on measures of depression as determined by the four methods of assessing drug efficacy: (1) psychiatric symptom rating (HAM-D 17-item less the three sleep items); (2) self-rating scale (Beck Depression Inventory); (3) Clinical Global Assessment of Efficacy; and (4) drop-out rate due to lack of efficacy. Most commonly reported adverse events with brofaromine were: headache, nausea, dizziness and sleep disturbance. Brofaromine was found to be an effective antidepressant, superior to placebo with a good tolerability profile.

Topics: Adolescent; Adult; Depressive Disorder; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Monoamine Oxidase Inhibitors; Personality Inventory; Piperidines

Results from two separate studies were combined to compare the acute and subchronic effects of two monoamine oxidase-A (MAO-A) inhibitors, moclobemide and brofaromine, on actual driving performance and sleep. Both studies were conducted according to a double-blind, crossover design involving 18 patients receiving moclobemide and 16 patients receiving brofaromine. Patients were administered either moclobemide 200 mg b.i.d., mianserin 10 mg. t.i.d., and placebo (study 1), or brofaromine 50 and 75 mg b.i.d., doxepin 25 mg t.i.d., and placebo (study 2) for 8 consecutive days. A standardized driving test was conducted on day 1 and day 8 of treatment. Daily logs of estimated sleep duration and quality were obtained. Neither moclobemide nor brofaromine impaired driving performance. Some indication, although statistically not significant, was found that moclobemide improved driving performance on day 1. Brofaromine 75 mg significantly improved driving performance on day 8 of treatment. No significant difference between the effects of both drugs was found in a cross-study comparison. Moclobemide did not affect any sleep parameter, whereas brofaromine shortened sleep duration and decreased sleep quality. On day 1, mianserin and doxepin impaired driving. Impairment dissipated after 8 days of treatment with doxepine but not during treatment with mianserin. Sleep duration was prolonged during treatment with both drugs, whereas sleep quality remained unaffected. It is concluded that both MAO-A inhibitors are safe drugs with respect to driving.

Topics: Adult; Automobile Driving; Benzamides; Cross-Over Studies; Double-Blind Method; Doxepin; Female; Humans; Male; Mianserin; Middle Aged; Moclobemide; Monoamine Oxidase Inhibitors; Multivariate Analysis; Piperidines; Psychomotor Performance; Sleep

In a controlled, double-blind, comparative four-week trial on reactive or neurotic major depressed inpatients, the efficacy and safety of the new selective and reversible inhibitor of monoamine oxidase type A, brofaromine, was evaluated in three dose steps (50 mg/day [N = 13], 100 mg/day [N = 12], and 150 mg/day [N = 11]) versus 20 mg tranylcypromine/day (N = 11). In the four groups a pronounced reduction of the depressive symptomatology (measured by the Hamilton Depression Scale, the Zung Self-Rating Scale of Depression, and by a global evaluation of efficacy) was found, but it was not possible to show any differential effect. The safety parameters in all groups were comparable. The results of the trial are compared with other trials of monoamine oxidase inhibitors in this patient group and the possible reasons for the lack of a clear dose-response relationship are discussed.

Topics: Adolescent; Adult; Aged; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Middle Aged; Monoamine Oxidase Inhibitors; Piperidines; Psychiatric Status Rating Scales; Tranylcypromine

The predictive value of eight domains or sets of variables including sociodemographic aspects, premorbid history, symptomatology, personality, social and diagnostic data are evaluated in depressed outpatients with a Hamilton Rating Scale for Depression (HRSD) score of at least 14. Patients were treated using a three-phase sequential treatment strategy. Of the 119 patients, 88 completed the trial. The HRSD-score at the end of phases I, II or III was used as an outcome measure. Patients with an initially high HRSD-score and an obsessive-compulsive personality had a greater chance of recovery, while patients with somatization and a passive-aggressive personality had less of a chance of recovery. Variables involving psychiatric history, premorbid history or symptomatology of the depression, were not significantly related to outcome. The endogenous/non-endogenous distinction was not a predictor of response.

Topics: Adult; Antidepressive Agents; Cross-Over Studies; Depressive Disorder; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Lithium; Male; Maprotiline; Middle Aged; Monoamine Oxidase Inhibitors; Personality Assessment; Personality Inventory; Piperidines; Treatment Outcome

In a controlled clinical inpatient trial (n = 93) comparing the efficacy and safety of brofaromine versus tranylcypromine for 6 weeks in treatment-resistant major depressed patients, the two drugs were found to be of comparable afficacy and tolerability. The response rate (a 50% reduction) on the Hamilton Scale for Depression (HAMD) in both groups was about 73%. The most common side effects in the brofaromine group were sleep disorders, hypotension, tremor and dryness of mouth; and in the tranylcypromine group sleep disorders, fatigue, hypotension, tremor and vertigo. Methodological and practical clinical implications of the results are discussed.

Topics: Adult; Aged; Depressive Disorder; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Monoamine Oxidase Inhibitors; Personality Inventory; Piperidines; Tranylcypromine

Depressed outpatients (n = 51) resistant to treatment with maprotiline were treated in a blind, randomized, single-centre study, for 6 weeks with either the reversible and selective monoamine oxidase A-inhibitor (MAO-A-I), brofaromine or lithium addition to maprotiline. The Hamilton Rating Scale for Depression was scored by an independent rater before and after the 6 week treatment period. No significant differences in efficacy were found between the two treatment regimes. In the patients who completed the trial, brofaromine was well tolerated with the exception of insomnia. Anticholinergic effects as well as thyroid dysfunctions (17 out of 20) were more frequent in the maprotiline/lithium group.

Topics: Adolescent; Adult; Aged; Depressive Disorder; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Lithium; Male; Maprotiline; Middle Aged; Monoamine Oxidase Inhibitors; Personality Inventory; Piperidines; Prospective Studies; Recurrence

Topics: Adult; Agoraphobia; Humans; Male; Monoamine Oxidase Inhibitors; Panic Disorder; Phobic Disorders; Piperidines

1. Brofaromine or placebo were administered to female bulimia nervosa patients over a period of eight weeks. Plasma and urinary trace amines, their acidic metabolites and the acidic metabolites of the catecholamines and serotonin were assessed prior to treatment and at four and eight weeks after commencement of treatment. 2. The levels of both plasma and urinary homovanillic and vanilmandelic acids declined significantly during the first four weeks of treatment with brofaromine and then partially recovered to pre-drug levels by the eighth week. 5-Hydroxyindoleacetic acid levels were not affected by drug treatment at the times assessments were made. Urinary tryptamine increased significantly during the first four weeks of brofaromine treatment then partially recovered towards pre-drug levels by the eighth week. No effect from placebo treatment was observed.

Topics: Biogenic Amines; Bulimia; Double-Blind Method; Female; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Piperidines; Tryptamines; Vanilmandelic Acid

Brofaromine, a selective and reversible inhibitor of monoamine oxidase-A (MAO-A) was given to 19 women while 17 received placebo for 8 weeks. All met DSM III-R criteria for bulimia nervosa, a psychiatric disorder in which uncontrolled overeating episodes are accompanied by purging activities and extreme concerns about body shape and weight. The following indices were measured: plasma and urinary phenylacetic acid (PAA), homovanillic acid (HVA), vanillylmandellic acid (VMA); plasma tryptamine (T), beta phenylethylamine (PE), and 5-hydroxyindoleacetic acid (5-HIAA) and urinary 6-sulphatoxymelatonin (aMT6s). PE levels remained the same but T showed a trend toward elevation over time. Twenty-four hour levels of urinary aMT6s in BN patients were higher at week 4 when compared to baseline and week 8. There was a significant reduction in plasma VMA and HVA over time during treatment with brofaromine and both plasma HVA and VMA were significantly lower for the brofaromine group compared to placebo at week 4. Plasma 5-HIAA was significantly higher for the brofaromine group after 8 weeks when compared to placebo. Urinary VMA decreased significantly from baseline to week 4 with a partial elevation at 8 weeks. Urinary VMA was also significantly lower in patients on brofaromine at week 4. This study verifies that brofaromine complies with predicted MAO-A inhibiting patterns in a clinical population.

Topics: Adolescent; Adult; Biogenic Amines; Bulimia; Female; Homovanillic Acid; Humans; Hydrogen-Ion Concentration; Hydroxyindoleacetic Acid; Melatonin; Monoamine Oxidase Inhibitors; Piperidines; Tryptamines; Vanilmandelic Acid

There is considerable evidence that antidepressants, particularly serotonin uptake inhibitors, are effective in the treatment of panic disorder (PD). Monoamine oxidase inhibitors (MAOI) may also have beneficial effects in PD. In this study 30 patients with PD with or without agoraphobia (DSM-III-R) were treated with the selective and reversible MAO-A inhibitor brofaromine (150 mg daily) in a 12-week double-blind placebo controlled design. A clinical relevant improvement was found in more than 70% of the patients treated with brofaromine, whereas no significant improvement was observed on placebo. After an increase in anxiety in the first week, a clinically relevant improvement in anxiety symptoms was found, followed by a subsequent reduction in agoraphobic avoidance in patients treated with brofaromine. A similar improvement was observed on distress scores related to panic attacks, although there was no significant reduction in the number of panic attacks. The most prominent side-effects were middle sleep disturbance and nausea. No increase in blood pressure was observed. During a follow-up period of another 12 weeks a further improvement was found in patients treated with brofaromine.

Topics: Adult; Agoraphobia; Double-Blind Method; Fear; Female; Follow-Up Studies; Humans; Male; Middle Aged; Monoamine Oxidase Inhibitors; Panic Disorder; Piperidines; Psychiatric Status Rating Scales

In an 8-week controlled double-blind clinical trial with a total of 189 elderly patients brofaromine showed comparable efficacy to imipramine (Hamilton Depression Scale, von Zerssen self-rating scale, global evaluation). The numbers of adverse events were the same in both groups, but the spectrum differed distinctly. In the global evaluation of tolerability, there was an advantage for brofaromine. Mean daily doses were 85 mg/day in the brofaromine group and 87 mg/day in the imipramine group. Long-term efficacy and tolerability also proved to be good in the open follow-up of the patients treated with brofaromine.

Topics: Aged; Antidepressive Agents; Depressive Disorder; Double-Blind Method; Female; Follow-Up Studies; Humans; Imipramine; Male; Middle Aged; Monoamine Oxidase Inhibitors; Piperidines; Psychiatric Status Rating Scales

Pharmacologic and cognitive behavioral therapies have been advocated in the treatment of bulimia nervosa (BN). Brofaromine, a selective and reversible inhibitor of monoamine oxidase-A was selected for a double-blind, placebo-controlled evaluation because of previous demonstrated monoamine oxidase inhibitor efficacy in BN and because of its safer adverse reaction profile. Thirty-six female patients who met DSM-III-R criteria for BN were randomly assigned to the drug group (N = 19) or to the placebo group (N = 17) for an 8-week outpatient trial. Brofaromine produced a significant effect in decreasing episodes of vomiting throughout the trial, although comparable reductions in episodes of binge eating were found in both groups. Also, there were no advantages of drug over placebo on improvements in attitudinal measures and shape or on self-report ratings of depression and anxiety. However, a significant proportion of the subjects on brofaromine lost weight when compared with the placebo group. Methodologic issues including subjective assessment measures, placebo response rates, and the elucidation of responder subgroups are discussed.

Topics: Adolescent; Adult; Affect; Attitude; Body Image; Body Weight; Bulimia; Double-Blind Method; Feeding Behavior; Female; Humans; Monoamine Oxidase Inhibitors; Piperidines; Psychiatric Status Rating Scales; Vomiting

Brofaromine is a new, reversible, and selective type-A monoamine oxidase inhibitor (MAOI) that also has serotonin reuptake inhibitory properties. Its dual pharmacologic effects offer promise in the treatment of a wide spectrum of depressed patients while producing less severe anticholinergic side effects in comparison with standard drugs. A multicenter, double-blind, placebo-controlled study including 220 patients was undertaken to evaluate the efficacy and safety of brofaromine in major depression. This study of a fixed-dose design and 6 weeks' duration found that brofaromine was significantly better than placebo on the Overall Evaluation of Efficacy, Beck self-rating scale, HAM-D Bech subscale, HAM-D total 14 items (minus the three sleep items), HAM-D depressed mood item and retardation factor, and worse than placebo on the insomnia items of HAM-D. Significantly more patients on placebo than on brofaromine did not complete the trial due to lack of efficacy. In comparative controlled studies (n = 899), brofaromine was found to be at least as efficacious as tricyclic antidepressants (imipramine) and standard MAOIs (tranylcypromine and phenelzine). Reductions of at least 50% in the HAM-D total score were seen in 58-66% of patients treated with either brofaromine or imipramine (n = 609). Brofaromine also was found to be of comparable efficacy to tranylcypromine in two clinical trials (n = 132), one of which included patients considered to have a treatment-resistant depression (n = 39). In another double-blind study that compared brofaromine (150 mg/day) to phenelzine (45 mg/day) (n = 158), there was no difference between brofaromine and phenelzine.

Topics: Adolescent; Adult; Aged; Antidepressive Agents; Canada; Depressive Disorder; Double-Blind Method; Female; Humans; Imipramine; Male; Middle Aged; Monoamine Oxidase Inhibitors; Phenelzine; Piperidines; Psychiatric Status Rating Scales; Tranylcypromine

Monoamine oxidase (MAO) inhibitors are known to be effective in panic disorder, but a high incidence of adverse reactions have limited their use. The new, selective, and reversible MAO-A inhibitors exemplified by brofaromine and moclobemide do not require dietary restrictions, have fewer drug interactions, and are better tolerated. This paper reports a randomized, double-blind, 8-week trial in which the efficacy and safety of brofaromine was compared to clomipramine in patients with panic disorder with or without agoraphobia. Both treatments achieved a significant and comparable reduction in the number of panic attacks, and were equally effective in all the parameters measured. Side effects were typical of the drug class. Further trials are required to evaluate this promising new treatment.

Topics: Agoraphobia; Clomipramine; Double-Blind Method; Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Panic Disorder; Piperidines; Psychiatric Status Rating Scales

Topics: Adult; Aged; Depressive Disorder; Female; Humans; Male; Middle Aged; Monoamine Oxidase Inhibitors; Piperidines; Regression Analysis; Sleep Wake Disorders

In a double-blind study the selective monoamine oxidase-A inhibitor brofaromine was compared with the classical MAOI tranylcypromine in 39 patients with major depression resistant to treatment with tricyclic antidepressants. Concerning efficacy no significant differences were found. Ten out of 22 patients responded to brofaromine and 5 out of 17 patients to tranylcypromine. Adverse effects favoured brofaromine. Although orthostatic hypotension occurred in both groups, severe decrease in blood pressure and dizziness occurred significantly more with tranylcypromine. Both MAOIs caused a decrease in stage 4 and REM sleep and an increase in REM latency. In most patients receiving tranylcypromine REM sleep was completely abolished.

Topics: Adult; Depressive Disorder; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hypotension, Orthostatic; Male; Middle Aged; Monoamine Oxidase Inhibitors; Piperidines; Psychiatric Status Rating Scales; Sleep, REM; Tranylcypromine

The effect of food on the bioavailability of brofaromine hydrochloride was investigated in a randomized cross-over study. Eight healthy male volunteers were given single peroral doses of 75 mg brofaromine hydrochloride after overnight fasting or a fat- and protein-rich breakfast. Mean (+/- SD) areas under the plasma concentration-time curves (AUC) were 9.66 (2.35) mumol l-1 h when given to the fasted volunteers and 11.82 (3.78) mumol l-1 h (p = 0.0413) when given after a substantial breakfast. Mean (+/- SD) maximum plasma concentrations (Cmax) were 0.71 (0.13) mumol l-1 when given to the fasted volunteers and 0.85 (0.22) mumol l-1 (p > 0.05) when given after breakfast. Thus, both the average AUC and Cmax were increased by approximately 20 per cent when brofaromine hydrochloride was given with food. The times when Cmax was reached (tmax) as well as the elimination half-lives were not influenced by concomitant intake of food. The tolerability was the same whether brofaromine was given before or after food in healthy volunteers. The slight effect of food on the bioavailability of brofaromine should be of little therapeutic consequence because of the observed wide inter-subject variability of the plasma levels.

Topics: Adult; Biological Availability; Chromatography, Gas; Food; Half-Life; Humans; Male; Middle Aged; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Piperidines

In an 8-week controlled double-blind clinical trial with a total of 216 patients Brofaromine was found to be superior to Imipramine with regard to efficacy (Hamilton Depression Scale, von Zerssen self-rating scale, global evaluation) and tolerability (adverse experiences, global evaluation). Mean daily dosages were 93.1 mg/day in the Brofaromine group and 92 mg/day in the Imipramine Group. No tyramine reduced diet had to be observed. Long-term efficacy and tolerability also proved to be good in an open follow-up in the Brofaromine group.

Topics: Adult; Depressive Disorder; Double-Blind Method; Female; Follow-Up Studies; Humans; Imipramine; Long-Term Care; Male; Middle Aged; Monoamine Oxidase Inhibitors; Personality Inventory; Piperidines

Topics: Depressive Disorder; Humans; Monoamine Oxidase Inhibitors; Piperidines; Psychiatric Status Rating Scales; Single-Blind Method

There is circumstantial evidence that antidepressants, particularly monoamine oxidase inhibitors (MAOIs) and beta-blockers, may have some beneficial effects in social phobia. In this study 30 patients with social phobia (DSM-IIIR) were treated with the selective and reversible MAO-A inhibitor brofaromine, using a 12-week double-blind placebo controlled design. A clinical relevant improvement was seen in 80% of the patients treated with brofaromine (150 mg daily). A significant improvement was found on measures of social anxiety, phobic avoidance, general (or anticipatory) anxiety and interpersonal sensitivity in patients on brofaromine, but not on placebo. Biochemical measurements revealed a decrease in turnover of noradrenaline, serotonin and dopamine as assessed by the plasma metabolite levels, and an increase in nocturnal release of melatonin. Most prominent side-effect was middle sleep disturbance. No changes in blood pressure were observed. During a follow-up period of 12 weeks a further improvement was found in patients treated with brofaromine.

Topics: Adult; Blood Pressure; Double-Blind Method; Female; Humans; Hydrocortisone; Male; Melatonin; Methoxyhydroxyphenylglycol; Monoamine Oxidase Inhibitors; Phobic Disorders; Piperidines; Psychiatric Status Rating Scales

The centrally active cholinesterase inhibitor physostigmine induces a behavioral syndrome which is thought to represent a model of spontaneous depression. In the present acute trial in 6 healthy volunteers, this model depression was accompanied by clearcut cardiovascular, metabolic and neuroendocrine phenomena of stress. The extent of the changes from baseline, however, scarcely correlated between the behavioral and physiologic phenomena. The behavioral and physiological phenomena could not be antagonized by brofaromine, a putative antidepressant reversibly and selectively inhibiting monoamine oxidase A (MAO-A), contrasting to the complete inhibition by the central cholinolytic scopolamine. This is further evidence that antidepressant efficacy depends on long-term adaptive changes secondary to the enhancement of aminergic neurotransmission rather than this enhancement itself.

Topics: Adult; Blood Glucose; Depression; Double-Blind Method; Humans; Hydrocortisone; Male; Monoamine Oxidase Inhibitors; Parasympathetic Nervous System; Physostigmine; Piperidines; Scopolamine; Sympathetic Nervous System; Synaptic Transmission

N = 53 inpatients with major depressive disorder have been treated with the reversible, selective MAO-A-inhibitors moclobemide (double-blind versus maprotiline) and brofaromine (open study), respectively. Clinically, significant improvement of depression and an activating profile of action could be observed, typical side effects were sleep disturbances, agitation and weight loss. The neurobiochemical data showed an increase of noradrenaline plasma concentrations under treatment with moclobemide. Visual reaction times improved with antidepressant treatment. MAO-A inhibitors proved to be effective antidepressants in the treatment of hospitalized patients with predominantly endogenous depressions.

Topics: Benzamides; Catecholamines; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Middle Aged; Moclobemide; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Piperidines; Psychiatric Status Rating Scales

Brofaromine (CGP 11 305 A), a new reversible and selective MAO-A inhibitor, was studied in two multicentre, (Trial A and Trial B) double-blind, dose-finding trials in a total of 124 depressed in-patients. Doses of 25, 50 and 75 mg bid were compared, to determine which was the most effective. The duration of the trials was four weeks. The comparative drugs were nomifensine (100 mg/day) and tranylcypromine (20 mg/day). The majority of patients in the Trial A was classified as "endogenous" depression. Diagnosis of depression was based on DSM-III or ICD-9 criteria. Conversely, most of the patients in Trial B were "non-endogenous" depressives. In "endogenous" depression, a statistically significant linear dose-response relationship was found in all the efficacy variables assessed. The most effective dose was 150 mg/day. This dose gave a mean drop of 25.3 +/- 11.9 (S.D.) points in the total Hamilton Depression Rating Scale (HAMD) scores and provided successful treatment in 83% of the patients treated, success being defined as a drop of at least 50% in the initial HAMD score at the end of the trial period. In "non-endogenous" depression, no statistical difference was found between the four treatment groups in any of the efficacy variables assessed. Response rate in all brofaromine groups averaged 59% (tranylcypromine group 60%). Tolerability was good in 90% or more of the brofaromine patients in both trials, regardless of the dose administered. The side effects reported most frequently were sleep disturbances, nausea, and headaches.

Topics: Adult; Aged; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Middle Aged; Monoamine Oxidase Inhibitors; Nomifensine; Piperidines; Psychiatric Status Rating Scales; Random Allocation; Tranylcypromine

During the last years the MAO-inhibitors reached a progressive importance in clinical practice. It was attempted to solve problems of tolerability by a new generation of MAO-inhibitors. Brofaromine is a MAO-inhibitor of the second generation, a selective, reversible and short acting MAO-A-inhibitor, promising that the dangerous "cheese effect" will occur only under extreme conditions. The clinical trials performed hitherto, among other double-blind test versus tranylcypromine and imipramine, demonstrate a good antidepressive efficacy and a good tolerability.

Topics: Antidepressive Agents; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Humans; Piperidines

The pressor effect of orally administered tyramine (TYR) has been evaluated in 124 tests of 49 healthy unmedicated volunteers, in 99 tests of 29 subjects treated with the reversible selective monoamine oxidase (MAO) A inhibitor brofaromine (BROF), and in 73 tests of 12 subjects treated with tranylcypromine (TCP). In unmedicated subjects, pressor doses of TYR to raise systolic blood pressure (BP) by 30 mm Hg (PD30) ranged between 200 and 800 mg of TYR. There was no correlation of PD30 with sex, age, or weight. In repeated tests, the intraindividual coefficient of variation of the PD30 (+/- SD) was 10 +/- 9%. During treatment for 8 to 16 days with the two MAO inhibitors (MAOIs) BROF and TCP, seven-fold and 56-fold increases of TYR pressor sensitivity were estimated. A significant correlation was found between the individual PD30 before and during MAO inhibition with BROF. Cheese with a pressor content equal to the PD30 of TYR raised the systolic BP in only three of 10 volunteers during BROF inconsistently by not more than 20 mm. Therefore, the probability of "cheese reactions" during treatment with this reversible MAOI seems to be small. For complete normalization of oral pressor responsiveness, delays of 8 and 30 days after the last doses of BROF and TCP, respectively, are needed. The total incidence of systolic BP elevations by more than 60 mm Hg was 13% in a total of 296 oral tests given to 49 subjects. This incidence of easily controllable hypertensive reactions is outweighed by the importance of the test as predictor of clinical risks for drugs with TYR potentiating effects.

Topics: Adolescent; Adult; Antidotes; Blood Pressure; Dose-Response Relationship, Drug; Female; Heart Rate; Humans; Male; Monoamine Oxidase Inhibitors; Phentolamine; Piperidines; Tranylcypromine; Tyramine

Pyrrolylethanoneamines 1-12, 18-23 and related amino alcohols 13-15, 24-27 were synthesized and tested against monoamine oxidases A and B (MAO-A and MAO-B) enzymes. In general, aminoketones 1-12, 18-23 were found to be potent and selective MAO-A inhibitors. In particular, 18 was more potent and selective against the MAO-A isoenzyme than reference drugs. Interestingly, amino alcohol 25 selectively inhibited MAO-B enzyme and could be a lead compound for designing more potent and selective MAO-B inhibitors.

Topics: Drug Design; Kinetics; Models, Molecular; Molecular Structure; Monoamine Oxidase Inhibitors; Oxazolidinones; Piperazines; Piperidines; Pyrrolidines; Structure-Activity Relationship

Chronic administration of several irreversible monoamine oxidase (MAO) inhibitors induces a down-regulation of tryptamine and 5-hydroxytryptamine(2) receptors in rat brain, but there is a paucity of information available on the effects of reversible MAO-A inhibitors on these receptors.. Acute and chronic experiments were conducted in rats and the effects of the irreversible monoamine oxidase inhibitor, phenelzine and the reversible MAO type-A inhibitors, moclobemide and brofaromine, on tryptamine and 5-hydroxytryptamine(2) receptors were analysed using radioligand binding techniques. In addition, activities of MAO-A and -B were determined radiochemically and brain and/or urine levels of tryptamine, 5-hydroxytryptamine, 3-methoxy-4-hydroxyphenylglycol (MHPG), beta-phenylethylamine, brofaromine and moclobemide were determined by chromatographic procedures.. After 30 days of administration, moclobemide and brofaromine selectively inhibited brain MAO-A activity and phenelzine inhibited MAO-A and -B to equal extents. All three drugs caused a significant down-regulation of tryptamine receptors, whereas only phenelzine significantly down-regulated 5-hydroxytryptamine(2) receptors. In a comparison of phenelzine and brofaromine, both caused marked elevations of urinary tryptamine and decreases of urinary MHPG levels, while only phenelzine increased beta-phenylethylamine levels. After 14 days of administration, phenelzine, but not moclobemide or brofaromine, significantly increased levels of tryptamine in brain; all three drugs significantly increased 5-HT levels.. 24-h urine samples were not collected for moclobemide-treated animals and brain levels of tryptamine were not measured after 30-day administration.. These studies revealed marked neurochemical differences among phenelzine, moclobemide and brofaromine which could contribute to their actions in the clinical setting.

Topics: Animals; Brain; Down-Regulation; Long-Term Care; Male; Moclobemide; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Phenelzine; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin

1. Brofaromine (CGP 11,305 A) belongs to a new generation of monoamine oxidase (MAO) inhibitors. These compounds induce short, reversible and selective inhibition of brain MAO of type A. 2. The aim of this work is to study monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) activities of several rat brain regions after increasing doses of brofaromine. 3. Brofaromine inhibits MAO-A activities in a dose dependent manner in all brain regions examined. 4. The largest reduction was found in hippocampal formation, striatum and prefrontal cortex respectively. ID50 is 2 times lower in hippocampus than in remaining brain. 5. Brofaromine does not inhibit MAO-B activities in the different regions examined. 6. Brofaromine is a very selective inhibitor of rat brain MAO-A with a preferential action on telencephalic monoaminergic nerve terminals.

Topics: Animals; Brain; Cerebellum; Corpus Striatum; Hippocampus; Hypothalamus; Isoenzymes; Kinetics; Male; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Organ Specificity; Piperidines; Prefrontal Cortex; Rats; Rats, Wistar

Kava-kava, a psychoactive beverage, induces relaxation, improves social interaction, promotes sleep and plays an important role in the sociocultural life in the islands of the South Pacific. On the other hand, standardized extracts of kava-kava roots are used for the therapy of anxiety, tension and restlessness. Kava pyrones, the major constituents of kava kava, are generally considered to be responsible for the pharmacological activity in humans and animals. To obtain more information on the mechanisms by which kava-kava exerts psychotropic properties we investigated the in vitro effects of kava-kava extract and pure synthetic kava pyrones on human platelet MAO-B, in comparison to amitriptyline, imipramine and brofaromine. Kava-kava extract was found to be a reversible inhibitor of MAO-B in intact platelets (IC50 24 microM) and disrupted platelet homogenates (IC50 1.2 microM). Structural differences of kava pyrones resulted in a different potency of MAO-B inhibition. The order of potency was desmethoxyyangonin > (+/-)-methysticin > yangonin > (+/-)-dihydromethysticin > (+/-)- dihydrokavain > (+/-)-kavain. The two most potent kava pyrones, desmethoxyyangonin and (+/-)-methysticin displayed a competetive inhibition pattern with mean Ki 0.28 microM and 1.14 microM respectively. The inhibition of MAO-B by kava pyrone-enriched extracts might be an important mechanism for their psychotropic activity.

Topics: Amitriptyline; Anti-Anxiety Agents; Blood Platelets; Humans; Imipramine; Kava; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Piperidines; Plant Extracts; Plants, Medicinal; Pyrones

Brofaromine (4-5(-methoxy-7-bromobenzofuranyl)-2-piperidine-HCl) is a potent and selective inhibitor of monoamine oxidase (MAO) A. Two methods for its synthesis and a preliminary positron emission tomography (PET) evaluation in monkey brain are described. The first method, at low carrier concentration of CO2, consisted of direct O-methylation of (4-(5-hydroxy-7-bromobenzofuranyl)-2-piperidine). The total radiochemical yield achieved ranged from 30 to 50% (from end of bombardment [EOB] and decay corrected) with an overall synthesis time of 45 min. The second approach, with high carrier amounts of CO2 arising from inherent target problems, was accomplished in a three-step route involving protection of secondary amino functionality, O-methylation and deprotection. The total radiochemical yield was 10% (from EOB and decay corrected) with a total synthesis time of 70 min. For both methods methylation was achieved using the classical methylating agent [11C]CH3I, and radiochemical purity was higher than 98%. PET evaluation of the radioligand in a Rhesus monkey showed a high uptake of radioactivity in the brain. Using the irreversible MAO-A inhibitor clorgyline and reversible MAO-A inhibitors moclobemide and brofaromine, three blockade experiments were designed to determine the extent of specific binding of [11C]brofaromine to MAO-A. No apparent decrease in accumulation of radioactivity in the monkey brain was observed when compared to a baseline scan.

Topics: Animals; Benzamides; Brain; Carbon Radioisotopes; Clorgyline; Female; Hydrocarbons, Iodinated; Indicators and Reagents; Isoenzymes; Isotope Labeling; Macaca mulatta; Moclobemide; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Piperidines; Tomography, Emission-Computed

Topics: Analysis of Variance; Animals; Antidepressive Agents; Clomipramine; Clorgyline; Fluvoxamine; Frontal Lobe; Hydroxyindoleacetic Acid; Imipramine; Microdialysis; Monoamine Oxidase Inhibitors; Piperidines; Pyrimidines; Raphe Nuclei; Rats; Serotonin; Stereotaxic Techniques; Tranylcypromine; Tryptophan

We have used intracerebral microdialysis to examine the reversibility of the action of brofaromine, a selective inhibitor of monoamine oxidase-A (MAO, E.C. 1.4.3.4.), on 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) output in rat frontal cortex. Brofaromine significantly increased the 5-HT output to about 200% of basal values 4 h after the s.c. administration of 10 and 30 mg/kg (but not 3 mg/kg) and reduced the concentration of 5-HIAA in the dialysate dose-dependently (61%, 53% and 41% of basal value with doses of 3, 10 and 30 mg/kg, respectively). At this time, cortical 5-HT concentration was increased and cortical 5-HIAA concentration was decreased in a dose-dependent manner. Treatment of rats with 10 mg/kg brofaromine plus 2.5 mg/kg of the irreversible MAO-B inhibitor L-deprenyl increased the concentration of 5-HT in the dialysate more than did brofaromine alone (503% vs 206% of the basal value, 4h after administration). Similarly, clorgyline (5 mg/kg) plus L-deprenyl (2.5 mg/kg) increased the concentration of 5-HT in the dialysate to 461% of the control value. This indicates that the concurrent inhibition of both types of MAO increases 5-HT output more than the selective blockade of either enzyme subtype. We have used this characteristic to examine, in vivo, the reversibility of the interaction of brofaromine with MAO-A. The output of 5-HT and 5-HIAA was examined 19-21 h after treatment with L-deprenyl plus clorgyline or L-deprenyl plus brofaromine.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Brain; Dose-Response Relationship, Drug; Frontal Lobe; Hydroxyindoleacetic Acid; Male; Microdialysis; Monoamine Oxidase Inhibitors; Piperidines; Rats; Rats, Wistar; Serotonin; Time Factors

The clinically tested reversible inhibitors of monoamine oxidase A (RIMAs) include brofaromine, moclobemide and toloxatone. Moclobemide has shown unequivocal antidepressant activity against serious depressive illness in 4 placebo-controlled double-blind trials. It has been compared with amitriptyline, imipramine, clomipramine, desipramine, maprotiline, fluoxetine, fluvoxamine, tranylcypromine, toloxatone, mianserin and amineptine in the treatment of depressive disorders. Meta-analysis showed convincing evidence of moclobemide efficacy, comparable with the most potent antidepressants available. The efficacy of moclobemide has been demonstrated in psychotic and non-psychotic depression, in depression with and without melancholia, in endogenous depression (both unipolar and bipolar), in retarded depression and in agitated depression. The efficacy of moclobemide, allied to the unusually benign side effect profile, has led to exploration of its use in other disorders. Two small studies have given encouraging results in the treatment of attention-deficit hyperactivity disorder. Large placebo-controlled studies have shown the activity of moclobemide in the depression that accompanies dementia (such as senile dementia of Alzheimer type). The results also suggested that, in this patient population, cognitive ability improved in parallel. Social phobia has also been shown to improve on treatment with either moclobemide or brofaromine. Clinical trials are in progress on the effect of moclobemide in chronic fatigue syndrome. Moreover, there are encouraging results with the use of brofaromine and moclobemide in panic disorder. Other disorders in which treatment with RIMA is of interest include agoraphobia, bulimia, borderline personality disorder, post-traumatic stress disorder, compulsive hair pulling (trichotillomania), dysmorphophobia, kleptomania as well as various anxiety syndromes.

Topics: Alzheimer Disease; Antidepressive Agents, Tricyclic; Attention Deficit Disorder with Hyperactivity; Benzamides; Humans; Moclobemide; Monoamine Oxidase Inhibitors; Oxazoles; Oxazolidinones; Panic Disorder; Phobic Disorders; Piperidines

The present study compared the extent and duration of MAO inhibition by the selective and reversible MAO-A inhibitor brofaromine with the selective and irreversible MAO-A inhibitor clorgyline using amine pressor tests and excretion of urinary amine metabolites (MHPG, tryptamine). The pharmacological characterization of clorgyline as an irreversible and brofaromine as a reversible MAO-A inhibitor in clinically effective doses was confirmed in humans.

Topics: Administration, Oral; Adult; Blood Pressure; Clorgyline; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Synergism; Female; Humans; Hypertension; Infusions, Intravenous; Male; Methoxyhydroxyphenylglycol; Monoamine Oxidase; Norepinephrine; Piperidines; Reference Values; Tryptamines; Tyramine

Women with bulimia nervosa undergoing treatment with the reversible monoamine oxidase type A inhibitor, brofaromine, were rated for mood and eating behaviour and their plasma and urine were assessed for phenylacetic acid (unconjugated and total) and unconjugated phenylethylamine prior to and after four weeks of drug treatment. Changes in plasma unconjugated phenylacetic acid concentrations were significantly and negatively correlated with the corresponding changes in Hamilton Depression scores but not with eating behavior measures. There were no significant correlations between changes in phenylethylamine levels and changes in rating scores. Patients diagnosed as suffering concurrently from severe depression (Hamilton Depression score of 17 or higher) had lower plasma and urinary phenylacetic acid levels than did those whose depression was not severe (Hamilton score less than 17). Phenylethylamine concentrations were not different between the severely and mildly depressed subgroups. The results confirm earlier studies on the relationship between phenylacetic acid and depression while showing that a similar relationship does not pertain to phenylacetic acid and eating behavior in bulimia nervosa.

Topics: Adult; Bulimia; Depressive Disorder; Female; Humans; Monoamine Oxidase Inhibitors; Phenylacetates; Piperidines; Placebos; Psychiatric Status Rating Scales; Severity of Illness Index; Single-Blind Method

The effects of brofaromine, a reversible inhibitor of MAO-A, on the extracellular content of serotonin (5-hydroxytryptamine, 5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) have been studied in two regions of the rat brain (midbrain raphe nuclei and frontal cortex). In both areas, locally infused brofaromine induced dose-dependent increases of 5-HT which were more marked in the raphe nuclei. Brofaromine increased extracellular 5-HT more markedly than clorgyline, suggesting that other factors (i.e. inhibition of 5-HT uptake) may be involved in its local effects. Systemic (3 mg/kg, s.c.) brofaromine did not modify extracellular 5-HT in any brain area examined. In contrast, the concurrent administration of brofaromine and deprenyl led to significant changes in the concentration of 5-HT and 5-HIAA in the brain extracellular space. The results are discussed in relation to the role of MAO-A in the control of 5-HT output.

Topics: Animals; Dose-Response Relationship, Drug; Extracellular Space; Frontal Lobe; Injections, Subcutaneous; Microdialysis; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Piperidines; Raphe Nuclei; Rats; Serotonin

Topics: Acute Disease; Cyproheptadine; Depressive Disorder; Drug Interactions; Female; Fluoxetine; Humans; Middle Aged; Monoamine Oxidase Inhibitors; Paranoid Disorders; Piperidines; Recurrence

The metabolic fate of brofaromine (CGP 11 305 A), a new, reversible, selective MAO-A inhibitor, has been assessed in poor (PM) and extensive (EM) metabolizers of debrisoquine. Compared to EM, PM had significantly longer t1/2 (136%) and larger AUC(0-infinity) (110%) of the parent compound brofaromine and a lower Cmax (69%) and AUC (0-72 h) (40%) of its O-desmethyl metabolite. The mean metabolite/substrate ratio (based on urine excretion) was about 6-times greater in EM than in PM. Treatment with quinidine converted all EM into phenocopies of PM. All pharmacokinetic parameters of brofaromine and O-desmethyl-brofaromine in EM treated with quinidine were similar to those of untreated PM, including the metabolite/substrate ratio. Quinidine treatment of PM did not alter the pharmacokinetics of brofaromine or of its metabolite, nor the metabolite/substrate ratio. The results indicate a role for the debrisoquine type of oxidation polymorphism in the O-demethylation and pharmacokinetics of brofaromine.

Topics: Adult; Cytochrome P-450 CYP2D6; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Female; Humans; Male; Mixed Function Oxygenases; Monoamine Oxidase Inhibitors; Phenotype; Piperidines; Quinidine

Severe side effects such as hepatotoxicity and potentiation of the sympathomimetic action of tyramine ("the cheese effect") caused the withdrawal of nonselective irreversible monoamine oxidase (MAO) inhibitors from use in psychiatric therapy. The development of selective irreversible inhibitors for MAO type A did not eliminate cardiovascular side effects such as "the cheese effect" or, conversely, the hypotensive effect of these drugs. To overcome at least "the cheese effect," selective reversible MAO-A inhibitor antidepressants such as moclobemide and brofaromine have been developed. Being reversibly bound to MAO, these drugs may be displaced from their binding site in the intestine by ingested, indirectly sympathomimetic amines such as tyramine, thus avoiding the initiation of the hypertensive crises. Using a rat renal nerve preparation, we have demonstrated that acute administration of either moclobemide or brofaromine (10 mg/kg) does not cause a decrease in blood pressure or a significant reduction in sympathetic renal nerve activity. These data contrast with those obtained with clorgyline or desipramine. The results indicate that moclobemide and brofaromine may be devoid of a hypotensive effect, including orthostatic hypotension.

Topics: Animals; Antidepressive Agents; Benzamides; Blood Pressure; Clorgyline; Desipramine; Heart Rate; Kidney; Moclobemide; Monoamine Oxidase Inhibitors; Piperidines; Rats; Rats, Sprague-Dawley; Sympathetic Nervous System

The effects of the administration of selective and non-selective inhibitors of monoamine oxidase (MAO) on the concentrations of three trace acid metabolites [phenylacetic acid (PAA); m-hydroxyphenylacetic acid (mHPAA); and p-hydroxyphenylacetic acid (pHPAA)] and of an acid metabolite of dopamine [3,4-dihydroxyphenylacetic acid (DOPAC)] in the rat striatum were determined. Administration of brofaromine (1-100 mg/kg, s.c.) a type AMAO inhibitor, dose-dependently decreased DOPAC and mHPAA levels. pHPAA levels were decreased by 100 mg/kg brofaromine, but PAA levels were unaffected. Doses of deprenyl of less than 100 mg/kg, i.p., had no effect on any of the acids, while 100 mg/kg decreased DOPAC, mHPAA and pHPAA but not PAA levels. Clorgyline, pargyline and tranylcypromine treatment decreased the levels of DOPAC, mHPAA and pHPAA but not PAA. Administration of alpha-monofluoromethyldopa, an inhibitor of aromatic amino acid decarboxylase, decreased the levels of all four acids. It was concluded that deamination of the respective parent amine by type A MAO is primarily responsible for the synthesis of DOPAC and mHPAA, but that another pathway contributes to pHPAA synthesis. It appears that either PAA arises predominantly independently from the actions of MAO or that is removal via transport or further metabolism regulates its concentration.

Topics: 3,4-Dihydroxyphenylacetic Acid; Amines; Animals; Corpus Striatum; Dopamine; Male; Methyldopa; Monoamine Oxidase Inhibitors; Phenylacetates; Piperidines; Rats; Rats, Wistar; Selegiline

The effects of reversible inhibitors of monoamine oxidase-A (moclobemide, Ro 41-1049, both 20 mg/kg, i.p., and brofaromine, 10 mg/kg, i.p.) on the outflow of dopamine (DA) and its metabolites (3,4-dihydroxyphenylacetic acid and homovanillic acid) as well as of 5-hydroxyindoleacetic acid was investigated by trans-striatal microdialysis in rats. These drugs markedly increased the level of DA in the dialysis fluid by 100% of basal values and concomitantly reduced the output of 3,4-dihydroxy-phenylacetic acid and homovanillic acid by 90%. The presence of tetrodotoxin in the perfusion fluid decreased the basal DA outflow and virtually abolished the rise in DA efflux after moclobemide administration. On the other hand, tetrodotoxin did not counteract the DA outflow induced by Ro 4-1284 (1 mg/kg, i.p.), a tetrabenazine derivative which rapidly releases DA from vesicles and causes a massive increase in the concentration of extravesicular amine. The injection of Ro 4-1284 30 min after moclobemide, brofaromine or Ro 41-1049 induced a 6-fold increase in DA outflow, which was accompanied by a transient increase in 3,4-dihydroxyphenylacetic acid levels. This latter effect was more marked for moclobemide than for the other two reversible inhibitors tested and was not observed in rats given the irreversible inhibitor clorgyline (5 mg/kg, i.p.). These results support the view that a large increase in the concentration of endogenous substrates in the cytosol might displace reversible monoamine oxidase-A inhibitors from the enzyme active sites. Therefore, the microdialysis technique seems to be a reliable in vivo method for assessing the degree of reversibility of monoamine oxidase inhibitors.

Topics: 2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-hexahydro-3-isobutyl-9,10-dimethoxy-; Animals; Benzamides; Biogenic Monoamines; Caudate Nucleus; Cytosol; Dopamine; Male; Moclobemide; Monoamine Oxidase Inhibitors; Piperidines; Rats; Serotonin; Tetrodotoxin

Topics: Administration, Oral; Adult; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP2D6; Cytochrome P-450 Enzyme System; Debrisoquin; Female; Humans; Male; Mixed Function Oxygenases; Monoamine Oxidase Inhibitors; Piperidines

We have examined the effects of two monoamine oxidase (MAO) inhibitors with different mechanisms of action--phenelzine and brofaromine--on peripheral serotonergic (5-hydroxytryptamine [5-HT]) measures, sensitive to the inhibition of MAO-A (intra- and extracellular 5-HT and related metabolites in blood). Both drugs increased the concentration of 5-HT in platelet-free plasma (254%, p less than 0.001) in patients with depressive illness (DSM-III-R) after 6 weeks of daily treatment. Platelet 5-HT was also increased significantly in both drug treatment groups but more marked in the patient group treated with phenelzine. The acid/amine ratio at 6 weeks was 30% of pretreatment values (p less than 0.000) and individual variability correlated significantly with the Hamilton Rating Scale for Depression. Plasma 5-HT increased more markedly in responders than in nonresponders and a significant inverse relationship surfaced between plasma 5-HT and the Hamilton Rating Scale for Depression. The results support other reports of comparable antidepressant efficacy for brofaromine and phenelzine, both inhibitors of MAO-A in humans. The consistent relationship we found between the biochemical and clinical changes again suggests and supports a key role of 5-HT in the antidepressant effect of these MAO inhibitors.

Topics: Adult; Ambulatory Care; Depressive Disorder; Female; Humans; Hydroxyindoleacetic Acid; Male; Middle Aged; Monoamine Oxidase Inhibitors; Phenelzine; Piperidines; Serotonin; Treatment Outcome

The reversibility of the interaction of inhibitors with monoamine oxidase (MAO) is thought to provide a safety valve with respect to tyramine potentiation. We sought experimental evidence for this concept by studying the binding of orally administered [3H]brofaromine to the A-form of MAO in the rat ileum. Specific binding, defined by pretreatment with 10 mg/kg clorgyline p.o., amounted to 70-90% of total binding between 30 min and 6 h after administration of the radioligand. Brofaromine and clorgyline dose dependently displaced [3H]brofaromine with ED50 values of about 0.2 mg/kg when administered orally after the radioligand; so did orally administered tyramine in doses relevant for tyramine potentiation in the rat. It was also found that tyramine was relatively more effective in partially MAO-inhibited rats. The data suggest that the concept of reversibility functioning as a safety valve with respect to the potentially hazardous effects of tyramine ingestion is realistic.

Topics: Administration, Oral; Animals; Binding Sites; Binding, Competitive; Clorgyline; Drug Synergism; Ileum; Intestinal Mucosa; Kinetics; Male; Monoamine Oxidase Inhibitors; Piperidines; Rats; Tyramine

The acute effect of two different reversible inhibitors of monoamine oxidase-A on nociceptive thresholds was evaluated in the rat by the tail-flick and hot-plate tests. CGP 11305-A, a monoamine oxidase-A inhibitor that also blocks serotonin reuptake, elicited an increase of latency in the tail-flick and the hot-plate test. Ineffective doses of CGP 11305-A increased nociceptive thresholds when administered in combination with other serotoninergic agents, i.e. chlorimipramine or 5-hydroxytryptophan, at doses that were ineffective alone. CGP 22364-A, a pure inhibitor of monoamine oxidase-A, increased latency only in the hot-plate test. Both compounds decreased spontaneous locomotor activity at the doses effective in the hot-plate test, suggesting that the responses observed in this test are not related to a pure effect on nociceptive thresholds. The data suggest that the increase in serotonin availability induced by monoamine oxidase-A inhibition alone is not sufficient to affect nociceptive thresholds.

Topics: Animals; Male; Monoamine Oxidase Inhibitors; Pain; Piperidines; Rats; Rats, Inbred Strains; Sensory Thresholds; Serotonin

MAO-B activity was compared in healthy volunteers following oral treatment with clinically effective doses of the selective MAO-A inhibitors brofaromine (100 mg q.d. for 14 days), moclobemide (150 mg t.i.d. for 14 days) and clorgyline (5 mg t.i.d. for 10 days). Brofaromine and clorgyline did not alter platelet MAO activity. Following moclobemide treatment, MAO-B activity was reduced by 32% (p less than 0.05). It recovered during the 5 subsequent days after discontinuation of treatment. These results confirm earlier findings. The explanation for this finding may be that metabolites of moclobemide are active inhibitors of MAO-B.

Topics: Adult; Benzamides; Blood Platelets; Clorgyline; Female; Humans; Male; Moclobemide; Monoamine Oxidase Inhibitors; Piperidines

The therapeutic efficacy of brofaromine--a new reversible and short acting MAO-A inhibitor--was evaluated in 14 inpatients with a panic disorder. In an open trial, the patients were treated with placebo during the first week and with 150 mg brofaromine per day during the following four weeks. In all patients a distinct improvement in both anxiety and depressive symptoms was observed under the active drug. Treatment outcome was the same in patients with and without a concomitant major depressive episode. No side-effects of any note were reported. Our findings suggest that the MAO-A inhibitor brofaromine is an effective drug in the treatment of anxiety disorders.

Topics: Adult; Agoraphobia; Female; Humans; Male; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Panic Disorder; Piperidines; Psychiatric Status Rating Scales

Topics: Animals; Brain Chemistry; Humans; Monoamine Oxidase Inhibitors; Piperidines; Rats; Serotonin

Topics: Benzamides; Depressive Disorder; Humans; Moclobemide; Monoamine Oxidase Inhibitors; Piperidines

The effects of brofaromine, clorgyline (reversible and irreversible type A MAO inhibitors, respectively) and tranylcypromine (non-selective MAO inhibitor) on rat striatal levels of phenylethylamine, tryptamine, m-tyramine and p-tyramine were determined. Brofaromine and clorgyline increased m- and p-tyramine levels, but not phenylethylamine levels. Brofaromine given at a dose of 100 mg/kg did increase tryptamine levels. Tranylcypromine increased the levels of all four amines greatly. The effects of chronic treatment with brofaromine on amine levels were not different from those following acute treatment. By contrast, chronic treatment with clorgyline caused greater increases in striatal m- and p-tyramine levels than did acute clorgyline. These data show that changes in the rat striatal levels of m-tyramine and p-tyramine may be used as in vivo indicators of the selectivity and reversiblity of inhibition of type A MAO, while tryptamine levels reflect non-selective inhibition of both types of MAO.

Topics: Animals; Biogenic Amines; Clorgyline; Corpus Striatum; Dose-Response Relationship, Drug; Drug Administration Schedule; Kinetics; Male; Monoamine Oxidase Inhibitors; Phenethylamines; Piperidines; Rats; Rats, Inbred Strains; Tranylcypromine; Tryptamines; Tyramine

The tolerability and antidepressive effect of brofaromine, a selective MAO-A inhibitor was tested in 14 depressive patients. None of the patients showed blood pressure or pulse frequency changes after ingesting tyramine-enriched meals. Four instances of agitation were observed as side effects. In two of these cases, the appearance of paranoid thinking and suicidal tendencies led to premature termination of the study. In 3 cases sleep disturbances, in particular difficulties in falling asleep, were observed. In the test of antidepressive effectiveness (measured on the HAMD-scale) significant improvement was observed from day 14 onwards.

Topics: Adult; Aged; Blood Pressure; Depressive Disorder; Female; Humans; Male; Middle Aged; Monoamine Oxidase Inhibitors; Piperidines; Psychiatric Status Rating Scales; Pulse

The inhibition of rat liver mitochondrial monoamine oxidase-A (MAO-A) by brofaromine was time-dependent at low enzyme and inhibitor concentrations. The apparent sensitivity to inhibition decreased when the concentration of the mitochondrial preparation was increased. After preincubation of the enzyme with brofaromine repeated washing of the preparation, by sedimentation and resuspension, resulted in a gradual recovery of activity. This occurred more slowly than was the case when the reversible inhibitor amphetamine was used. After incubation with radioactively-labeled brofaromine the loss of radioactivity also occurred slowly. After incubation with radioactively-labeled pargyline polyacrylamide-gel electrophoresis in the presence of sodium dodecyl sulphage (SDS-PAGE) showed the radioactivity to be associated with a peptide of approximate Mr 50,000, corresponding to the subunit of MAO. Pretreatment with unlabeled pargyline depressed this labeling by pargyline, indicating the latter compound to bind to the active-site of the enzyme. Labeling experiments with radioactive brofaromine indicated that there was a high degree of non-specific binding but that no significant radioactivity remained associated with the enzyme on SDS-PAGE. Chromatographic techniques and determination of H2O2 liberation indicated that, in liver there was no appreciable metabolism of brofaromine under the conditions used in the inhibition experiments. These data indicate brofaromine to be a tight-binding, but reversible inhibitor of MAO.

Topics: Animals; Chromatography, Thin Layer; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Kinetics; Mitochondria, Liver; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Myocardium; Pargyline; Piperidines; Rats; Serum Albumin, Bovine; Temperature

Topics: Depressive Disorder; Drug Therapy, Combination; Humans; Lithium; Maprotiline; Monoamine Oxidase Inhibitors; Pilot Projects; Piperidines; Psychiatric Status Rating Scales

In an open clinical trial 13 depressives significantly improved under the reversible and selective type-A monoamine oxidase (MAO) inhibitor brofaromine. The inhibitory potency of deproteinated plasma on a crude MAO preparation from human placenta was measured as a parameter for plasma brofaromine. There were no significant differences in plasma MAO inhibitory potency between responders (improvement greater than 50%; n = 5) and non-responders. MAO inhibitory potency significantly (p less than 0.05) increased parallel to the increase of the dosage from 50 mg b.i.d. to t.i.d. confirming the validity of this technique. The biologic assay, however, overestimated brofaromine by a factor of two in acute kinetic experiments with healthy volunteers as compared to a chromatographic technique, although both methods significantly correlated (r = 0.928).

Topics: Adult; Aged; Chromatography, Liquid; Depressive Disorder; Female; Humans; In Vitro Techniques; Male; Middle Aged; Mitochondria; Monoamine Oxidase Inhibitors; Piperidines; Placenta; Pregnancy

Previous work has shown that 5-hydroxytryptamine (5-HT) receptor agonists such as 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) reduce 5-HT neurotransmission and induce feeding in rats. The effects of 8-OH-DPAT appear to be mediated in part in the dorsal raphe nucleus by serotonergic somatodendritic autoreceptors which normally regulate impulse flow in 5-HT dorsal raphe neurons. The present experiments sought to examine whether suppression of dorsal raphe serotonergic neural activity induced by exogenously applied, or endogenously released 5-HT would increase feeding. Free-feeding rats were microinjected in the dorsal raphe with 5-HT, the 5-HT releasing compound d-fenfluramine, the 5-HT re-uptake inhibitor zimelidine, or the type-A monoamine oxidase inhibitor brofaromine. Dose dependent increases in food intake over a 1 h period were found following treatment with 5-HT and the three indirectly acting compounds. Thus, increased serotonergic activity within the dorsal raphe increases feeding, presumably by inhibiting the activity of dorsal raphe 5-HT neurons. In addition the effects of 5-HT were blocked by pretreatment with haloperidol, indicating the involvement of a dopaminergic mechanism in mediating the effects of feeding of a suppression in dorsal raphe 5-HT neural activity. The results are discussed in terms of the general role which serotonergic neurons arising from the dorsal raphe may play in behavioural inhibition.

Topics: Animals; Feeding Behavior; Fenfluramine; Male; Microinjections; Monoamine Oxidase Inhibitors; Piperidines; Raphe Nuclei; Rats; Receptors, Serotonin; Serotonin; Zimeldine

The binding of [3H]prazosin to alpha 1-adrenoreceptors, as well as of [3H]SCH 23390 (R(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-o l) to dopamine D1 receptors, and [3H]spiperone to D2 receptors was studied following repeated administration of the monoamine oxidase inhibitors (MAOI) brofaromine, moclobemide and deprenyl to rats. Scatchard analysis showed no change in the density (Bmax) and affinity (Kd) of [3H]prazosin sites, yet the ability of phenylephrine (an alpha 1-adrenoceptor agonist) to compete for [3H]antagonist binding sites was enhanced in the cerebral cortex after repeated brofaromine administration, as well as in the hippocampus of rats pretreated with moclobemide and deprenyl. The density and the binding affinity of dopaminergic D1 and D2 receptors were not affected by repeated treatment with all the MAOI used. The results seem to indicate that a small increase in the alpha 1-adrenoceptor agonist affinity occurs after repeated administration of MAOI.

Topics: Animals; Benzamides; Brain; Male; Moclobemide; Phenethylamines; Piperidines; Prazosin; Rats; Rats, Inbred Strains; Receptors, Adrenergic, alpha; Receptors, Dopamine; Selegiline

Short duration of action, displaceability by endogenously released monoamines, and absence of cumulation of effect of the selective inhibitor of monoamine oxidase type A (MAO-A), brofaromine (CGP 11305 A), indicate reversibility of its interaction with the enzyme in vivo. However, its in vitro interaction with the enzyme showed features commonly associated with irreversible inhibition. To clarify this issue, the in vivo binding of [3H]brofaromine to MAO-A in areas of the rat brain, and in rat heart and liver was investigated. Specific binding, defined by pretreatment with the irreversible inhibitor, clorgyline, was between 15 and 75% of total binding depending ont eh tissue and the time elapsed after injection of radioactivity. In brain and heart tissue, unlabelled brofaromine, another reversible inhibitor of MAO-A, moclobemide and clorgyline were able to displace [3H]brofaromine when administered after the labelled compound with ED50s of 1-3 mg/kg p.o., 3 mg/kg p.o. and 0.3-1 mg/kg s.c., respectively. In the liver, brofaromine and moclobemide and the inhibitor of drug-metabolizing enzymes, proadifen (SK&F 525 A), were able to significantly inhibit [3H]brofaromine binding. Clorgyline was only marginally effective, suggesting that, in this organ, [3H]brofaromine binds predominantly to such enzymes. In conclusion, the binding of [3H]brofaromine to MAO-A in rat brain and heart in vivo was found to be displaceable by other MAO inhibitors and is therefore reversible. In the liver, the compound bound predominantly to other sites, probably microsomal drug-metabolizing enzymes.

Topics: Animals; Benzamides; Binding, Competitive; Biogenic Monoamines; Clorgyline; In Vitro Techniques; Male; Microsomes, Liver; Moclobemide; Monoamine Oxidase; Piperidines; Proadifen; Propylamines; Rats; Rats, Inbred Strains; Tissue Distribution

In an open clinical trial, 13 depressives were treated with the reversible and selective type-A monoamine oxidase (MAO)-inhibitor brofaromine (CGP 11 305 A), the inhibitory potency of deproteinated plasma on a crude MAO preparation from human placenta was measured as a parameter for plasma brofaromine and possibly active metabolites of brofaromine. Patients significantly (p less than 0.01) improved under brofaromine. There were, however, no significant differences in plasma MAO-inhibitory potency between responders (improvement greater than 50%; n = 5) and nonresponders and no correlations with the change from baseline of the total Hamilton Depression Score (HAMD) or with changes of sleep (change from baseline of the HAMD sleep items). MAO-inhibitory potency significantly (p less than 0.05) increased parallel to the increase of the dosage from 50 mg b.i.d. to t.i.d., confirming the validity of this technique. The biological assay applied is a simple and reliable alternative when estimating the plasma concentrations of brofaromine and, possibly, other reversible MAO inhibitors.

Topics: Adult; Aged; Depressive Disorder; Female; Humans; Male; Middle Aged; Mitochondria; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Piperidines; Placenta; Psychiatric Status Rating Scales

Subcutaneous injection of 1 mg/kg 5-hydroxytryptamine (5-HT) reduced the intake of a 10% sucrose solution in rats. A single injection of the monoamine oxidase inhibitor (MAOI) clorgyline enhanced the anorectic effect of 5-HT. Such an effect persists 2, 24, 48, 72 and 96 h after injection. The clorgyline treatment almost completely inhibited type A MAO activity in the liver at 2 h post-injection. By 120 h, the time at which potentiation of 5-HT induced anorexia disappeared, MAO-A activity had returned to 80% of control values. These results demonstrate that the clorgyline effect is long-lasting and irreversible. Brofaromine (5 mg/kg) and cimoxatone (20 mg/kg) also enhanced the anorectic effect of 5-HT injected 2 h later. The potentiating effects of brofaromine and cimoxatone were not observed when 5-HT was administered 24 h later. These results indicate that brofaromine and cimoxatone are short-acting, reversible inhibitors of MAO-A activity in vivo. Moclobemide (30 mg/kg) failed to enhance the anorectic action of 5-HT injected 2 and 24 h later. The potentiation of 5-HT induced anorexia may be a useful behavioural test for investigating the degree of reversibility, and time course of action of MAOIs.

Topics: Animals; Benzamides; Clorgyline; Drug Synergism; Feeding Behavior; Male; Moclobemide; Monoamine Oxidase Inhibitors; Oxazoles; Oxazolidinones; Piperidines; Rats; Rats, Inbred Strains; Serotonin

Healthy ambulatory subjects took 6 different MAO inhibitors (MAOIs) orally for 2 to 4 weeks. The new reversible MAO-A inhibitors brofaromine and moclobemide were compared with the irreversible MAOIs clorgyline, selegiline, phenelzine and tranylcypromine. Pressor responsiveness to oral tyramine was assessed before, during and after treatment. In unmedicated subjects, doses of tyramine to raise systolic blood pressure by at least 30 mmHg (PD30) ranged between 200 and 800 mg. During treatment with MAOIs, the PD30 decreased. The ratio of median effective doses (ED50) of tyramine (pre- vs post-treatment) was: selegiline 5, moclobemide 7, brofaromine 10, clorgyline 10, phenelzine 13 and tranylcypromine 55. Pressor responsiveness normalized within 8 days after stopping the reversible MAOIs and 30 days after tranylcypromine. The increased sensitivity after phenelzine persisted for longer than 8 weeks and after clorgyline for longer than 15 weeks. The results suggest that the two reversible MAO-A inhibitors moclobemide and brofaromine carry a much reduced liability to tyramine-related hypertensive reactions.

Topics: Administration, Oral; Adult; Benzamides; Blood Pressure; Female; Humans; Hypertension; Male; Moclobemide; Monoamine Oxidase Inhibitors; Piperidines; Risk Factors; Tyramine

The rat studies presented in this manuscript show that the new non-hydrazine compounds moclobemide, brofaromine and toloxatone have a profile typical of monoamine oxidase-A (MAO-A) inhibitors. These inhibitors are short-acting (16-24 h), reversible, non-hepatotoxic and have only low liability to potentiate tyramine pressor effects (cheese-effect). The present results in rats and the clinical trials provide evidence that moclobemide is an orally active MAO-A inhibitor which, due to its remarkably low tyramine potentiating pressor effects and to its lack of anticholinergic activity, has a very attractive pharmacological profile. In contrast to moclobemide, tranylcypromine is an irreversible and mixed MAO-A and MAO-B inhibitor with long-lasting effects. This hydrazine derivative is not devoid of hepatotoxic effects and markedly potentiates tyramine pressor effects. Moclobemide, being a particularly safe MAO-A inhibitor, seems to be an effective new compound for the therapy of exogenous and endogenous depressive states.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Antidepressive Agents; Benzamides; Blood Pressure; Heart Rate; Moclobemide; Monoamine Oxidase Inhibitors; Oxazoles; Oxazolidinones; Piperidines; Rats; Serotonin; Structure-Activity Relationship; Tranylcypromine

A sensitive gas chromatographic assay for the simultaneous determination of brofaromine [4-(7-bromo-5-methoxy-2-benzofuranyl)piperidine hydrochloride], a new monoamine oxidase-A inhibitor, and its major metabolite was developed and validated. After addition of 4-(5-bromo-2-benzofuranyl)piperidine as internal standard, the compounds were isolated from biological fluids by liquid-liquid extraction at basic pH. After derivatization with heptafluorobutyric anhydride the compounds were chromatographed using a packed column (OV-17) and an electron-capture detector. The limit of quantitation was ca. 0.03 nmol per sample (10 ng) for both compounds. analysis of spiked samples demonstrated the good accuracy and precision of the method, which is suitable for use in pharmacokinetic and bioavailability studies. The method was applied to samples from an experiment in a healthy volunteer treated with a single oral dose of 75 mg of brofaromine hydrochloride. Plasma profiles before and after enzymic hydrolysis showed that about one-third of the total brofaromine in plasma and practically all of the major metabolite (O-desmethylbrofaromine) were present in the conjugated form.

Topics: Chemical Phenomena; Chemistry; Chromatography, Gas; Electrochemistry; Humans; Kinetics; Monoamine Oxidase Inhibitors; Piperidines

Healthy ambulatory subjects were treated p.o. for 2 to 4 weeks with 6 different MAO inhibitors (MAOI). MAOI drugs were given to (n) subjects. Brofaromine (Brof): 100-150 mg/d (39); moclobemide (Mocl): 450 mg/d (8); clorgyline (Clor): 5, 10, 15 mg/d (5); selegiline (Sel): 5, 20 mg/d (7); phenelzine (Phen): 30, 45, 60 mg/d (6); tranylcypromine (TCP): 20 mg/d (12). Pressor responsiveness to oral tyramine (TYR) was assessed before, during, and after treatment. In unmedicated subjects (Cont), doses of TYR to raise systolic blood pressure by at least 30 mm Hg (PD30), ranged between 200 and 800 mg. During treatment with MAOIs, the PD30 decreased. The median effective doses (ED 50) of TYR were: Cont (n = 55): 437 mg; Sel, 20 mg/d: 96 mg; Mocl 450 mg/d: 63 mg; Brof: 100-150 mg/d: 44 mg; Phen, 60 mg/d: 33 mg; Clor, 10 mg/d: 43 mg; CP: 8 mg. Pressor responsiveness to oral TYR normalized within 3 d (Mocl), 8 d (Brof), and 30 d (TCP). After Phen, in 2 subjects the potentiation persisted for 2 and 4 weeks, in 4 volunteers for 8 and more weeks. After Clor, only one of 4 subjects reached 83% of his early pressor sensitivity within 15 weeks. The results suggest that the two reversible MAO-A inhibitors Mocl and Brof may lessen the liability to TYR-related hypertensive reactions.

Topics: Adult; Benzamides; Blood Pressure; Drug Synergism; Female; Humans; Male; Moclobemide; Monoamine Oxidase Inhibitors; Piperidines; Time Factors; Tyramine

The inhibition of the binding of [3H]cyanoimipramine in the rat brain in vivo, with and without pretreatment with proadifen (SK & F 525 A) to prevent its metabolism, has recently been shown to reflect inhibition of 5-HT uptake. This method has been suggested to be more sensitive than other more indirect methods. We have used this method to study the reversible MAO-A inhibitor, brofaromine, which has been shown previously to inhibit 5-HT uptake into synaptosomal preparations in vitro and ex vivo at doses about 30 times higher than those that inhibited MAO-A, and a number of 5-HT uptake inhibitors. The effects of orally administered clomipramine, imipramine, citalopram, CGP 6085 A, fluoxetine and brofaromine on [3H]cyanoimipramine binding were similar to those obtained in the synaptosome ex vivo model in the absence of proadifen; ifoxetine seemed to be more potent in inhibiting [3H]cyanoimipramine binding. The effects of clomipramine, imipramine, citalopram and ifoxetine were moderately to markedly enhanced by proadifen, indicating a first-pass effect. The effect of brofaromine on [3H]cyanoimipramine binding showed a time course similar to that on MAO-A, and was not altered upon repeated treatment. The inactivity of another MAO-A inhibitor, moclobemide, suggest that the effect of brofaromine was due to true inhibition of 5-HT uptake and not to displacement of [3H]cyanoimipramine by elevated synaptic 5-HT. The possible role of inhibition of 5-HT uptake in the antidepressant effect of brofaromine is discussed.

Topics: Animals; Brain; Imipramine; In Vitro Techniques; Male; Monoamine Oxidase Inhibitors; Piperidines; Proadifen; Rats; Rats, Inbred Strains; Serotonin; Serotonin Antagonists

The two monoamine oxidase (MAO) inhibitors phenelzine and brofaromine given for 2 to 3 weeks were compared in six volunteers. Blood pressure sensitivity to intravenous tyramine increased 2.6-fold during phenelzine (60 mg/day) and 4.8-fold during brofaromine, whereas sensitivity to oral tyramine increased more during phenelzine (15.7-fold vs 8.5-fold). After withdrawal of phenelzine, pressor sensitivity to oral tyramine returned to control values within 2 and for more than 8 weeks. Relative bioavailability of conjugated tyramine was elevated sixfold by brofaromine and 11.6-fold by phenelzine. Urinary elimination of tryptamine increased during phenelzine and brofaromine to 12.7-fold and threefold, respectively. 3-Methoxy-4-hydroxyphenylglycol (MHPG) and 3-methoxy-4-hydroxymandelic acid (VMA) excretion decreased during brofaromine significantly by 72% and 49%, respectively. The nonsignificant decrease of MHPG excretion and the increase of intravenous tyramine pressor sensitivity caused by phenelzine are significantly related. The data suggest that the selective reversible MAO-A inhibitor brofaromine has a larger therapeutic safety than phenelzine.

Topics: Adult; Biological Availability; Blood Pressure; Heart Rate; Humans; Male; Methoxyhydroxyphenylglycol; Monoamine Oxidase Inhibitors; Phenelzine; Piperidines; Tryptamines; Tyramine; Vanilmandelic Acid

The effects of monoamine oxidase inhibitors (MAOIs) that selectively inhibit the MAO-A or MAO-B forms of MAO were studied in rats performing under a differential-reinforcement-of-low-rate 72-s (DRL 72-s) schedule of reinforcement. Clorgyline and CGP11'305A, irreversible and reversible MAO-A inhibitors, respectively, increased the reinforcement rate, decreased the response rate, and enhanced temporal discrimination. The irreversible MAO-B inhibitor (-)-deprenyl did not produce similar effects. Pargyline did not increase the reinforcement rate at low doses that selectively inhibit MAO-B, but did increase the reinforcement rate at doses that inhibit MAO-A by more than 90%. The present results are in accord with clinical data demonstrating that MAO-A inhibitors are effective therapeutic agents in treating depression while MAO-B inhibitors are of questionable antidepressant efficacy. The present findings provide further evidence that the DRL 72-s schedule may be useful both as a screen for identifying new antidepressants and for investigating the neurochemical effects of antidepressant drugs that are responsible for their therapeutic effects.

Topics: Animals; Antidepressive Agents; Clorgyline; Conditioning, Operant; Dose-Response Relationship, Drug; Male; Monoamine Oxidase Inhibitors; Pargyline; Piperidines; Rats; Rats, Inbred Strains; Reinforcement Schedule; Selegiline

Topics: Animals; Benzamides; Brain; Clorgyline; Humans; In Vitro Techniques; Male; Moclobemide; Monoamine Oxidase Inhibitors; Phenelzine; Picolinic Acids; Piperidines; Rats; Selegiline

Intraperitoneal injection of cimoxatone, moclobemide, amiflamine CGP 11305 A (all 5 mg/kg) increased pressor responses to intravenous tyramine (100 micrograms) in conscious, freely moving rats. Area under mean arterial pressure curve increased by 7.01, 4.28, 5.3 and 3.46 fold respectively. Clorgyline (2 mg/kg) increased area under pressor response curve by 10.4 fold. Tyramine responses returned to normal 24 hours after reversible inhibitors but were still potentiated 24 hours after clorgyline.

Topics: Animals; Benzamides; Blood Pressure; Clorgyline; Drug Synergism; Male; Moclobemide; Monoamine Oxidase Inhibitors; Oxazoles; Oxazolidinones; Phenethylamines; Piperidines; Rats; Rats, Inbred Strains; Tyramine

Topics: Chromatography, High Pressure Liquid; Humans; Monoamine Oxidase Inhibitors; Piperidines

1. Plasma melatonin was used to determine the influence of two monoamine oxidase inhibitor drugs in 11 normal subjects. 2. Acute oral administration of the selective reversible MAO-A inhibitor brofaromine but not of the - in low doses - selective MAO-B inhibitor pargyline increased daytime melatonin with large variations in onset, degree and duration. 3. Further investigation of this selective action on melatonin might help to better understand the action of the therapeutically effective antidepressive therapy with selective MAO-A inhibitors.

Topics: Administration, Oral; Adult; Circadian Rhythm; Dose-Response Relationship, Drug; Humans; Melatonin; Monoamine Oxidase Inhibitors; Pargyline; Piperidines

The effects of brofaremine (CGP 11 305A), a short-acting, reversible and selective inhibitor of MAO-A, on sleep, nocturnal penile tumescence (NPT) and hormonal secretion during the night were studied during a long-term trial. Three healthy males underwent sleep-EEG and NPT recordings during consecutive nights (1) under placebo, (2) under stepwise increasing dosages of brofaremine and (3) under placebo after withdrawal. Hormone profiles were sampled during selected nights to analyze the plasma concentration of cortisol, HGH, prolactin, testosterone, LH and FSH. REM sleep was suppressed markedly under 150 mg brofaremine, while stages 1 and 2 increased. In comparison to the effect of irreversible MAOIs the REM suppression was shorter and did not persist after withdrawal. A decrease of the plasma concentration of the drug coincided with a return of sleep variables to baseline values. A REM rebound occurred after withdrawal of brofaremine. REM sleep and NPT showed a dissociation; NPT variables did not follow the decrease of REM sleep. The effects of REM parameters are correlated with the dosage and the plasma concentration of the substance. Intraindividually, a decrease in secretion of HGH was observed throughout the trial. No marked changes were found in the other endocrinological variables.

Topics: Adult; Electroencephalography; Hormones; Humans; Male; Monoamine Oxidase Inhibitors; Penile Erection; Piperidines; Sleep; Sleep, REM

In an open clinical trial the authors treated 18 hospitalized patients suffering from endogenous depression with brofaromine (CGP 11305A), a competitive, selective, and short-acting inhibitor of type A monoamine oxidase (MAO). Four patients were defined as good responders, as they had a final HAMD score of between 0 and 7 points. Four patients were judged as improved, with final HAMD scores of between 8 and 15 points, while the remaining eight patients failed to respond (final HAMD score greater than or equal to 16 points). The major observations were a beneficial influence on drive in most patients, while paranoid symptoms worsened markedly, rendering the substance contraindicated in psychotic depression. Brofaromine appears to be safe and well tolerated and largely free of side effects. As objectified by the tyramine pressor test, dietary restrictions during brofaromine treatment require less stringency than is the case with conventional MAO inhibitors. The specificity of brofaromine to inhibit deamination is limited to MAO-A, since no reduction in platelet MAO activity was measurable. Sleep EEG recordings in a subset of patients reveals that the amount of rapid eye movement (REM) sleep is significantly reduced during brofaromine treatment.

Topics: Adult; Aged; Blood Platelets; Depressive Disorder; Dexamethasone; Electroencephalography; Female; Humans; Male; Middle Aged; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Personality Assessment; Piperidines; Serotonin; Sleep, REM; Tyramine

The inhibition of monoamine oxidase (MAO) in rat liver and brain by the short-acting MAO-A inhibitors moclobemide (Ro 11-1163 = p-chloro-N-[2-morpholinoethyl]benzamide) and brofaremine and by the short-acting MAO-B inhibitors Ro 16-6491 (N-[2-aminoethyl]-p-chloro-benzamide) and almoxatone, administered p.o. at roughly equieffective doses 2 h before decapitation, was investigated for its reversibility under various in vitro conditions. MAO A activity in liver homogenates, inhibited by moclobemide (300 mumol/kg) to approx. 15% of control, time dependently recovered during 0.5 to 2 h of incubation at 37 degrees C, irrespective of whether the homogenates were prepared and incubated in distilled water or Krebs-Ringer buffer (KRB). Dialysis of such homogenates for 4 h in distilled water at 37 degrees C (but not at 13 degrees C) led to a complete return of the MAO activity. In liver homogenates from rats pretreated with brofaremine (30 mumol/kg), dialysis for 4 h at 37 degrees C against distilled water caused only little recovery of the MAO activity. Likewise, MAO-B inhibited by Ro 16-6491 (30 mumol/kg) to approx. 4% of control returned to almost control activity after 4 h of dialysis at 37 degrees C, while inhibition induced by almoxatone (30 mumol/kg) was little or not reversed at all. In brain homogenates prepared in, and dialysed against, distilled water or KRB at 37 degrees C (but not at 13 degrees C), MAO-A inhibited by moclobemide (100-300 mumol/kg) to approx. 15% of control, partially (KRB) or almost completely (dist. water) returned to control activity after 4 h of dialysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzamides; Brain; Brain Chemistry; Dialysis; In Vitro Techniques; Liver; Male; Moclobemide; Monoamine Oxidase Inhibitors; Piperidines; Rats; Tyramine

Topics: Adult; Humans; Male; Penile Erection; Piperidines; Sleep, REM

The aim of this study was to assess a) the validity of an ex vivo approach for the estimation of the in vivo MAO A inhibitory properties of the new short-acting MAO A inhibitors, amiflamine, brofaremine, cimoxatone and moclobemide, by studying the effect of dilution of brain and liver homogenates from pretreated rats on the degree of enzyme inhibition; b) the displaceability of the inhibitors from the enzyme by substrate in brain and liver homogenates from pretreated rats; c) idem, in the in vivo situation in the brain, by increasing the availability of the substrate by releasing it from its endogenous stores by tetrabenazine. The following results were obtained: The ex vivo approach was found to be valid for moclobemide in brain and liver and for cimoxatone in brain tissue; a slight underestimation of the MAO A inhibitory effect of the latter in the liver is likely. Definite underestimation occurred with amiflamine in both tissues. Kinetic investigations using homogenates from pretreated rats showed amiflamine to be a competitive inhibitor; cimoxatone was competitive in the liver but showed a more complex pattern in the brain. Moclobemide was noncompetitive in both tissues, as has been shown previously for brofaremine. Moclobemide prevented the deamination of dopamine and serotonin released from their striatal stores by tetrabenazine nearly as efficiently as clorgyline at an otherwise equieffective dose; cimoxatone was somewhat less effective relative to the reference compound, as was brofaremine, which was however given at a more effective dose. Amiflamine was much less effective than clorgyline at protecting dopamine, but equieffective with respect to serotonin.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Benzamides; Brain; Clorgyline; Dopamine; Female; Homovanillic Acid; Kinetics; Liver; Moclobemide; Monoamine Oxidase Inhibitors; Oxazoles; Oxazolidinones; Phenethylamines; Piperidines; Rats; Rats, Inbred Strains; Serotonin

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Biogenic Amines; Brain; Brain Chemistry; Female; Hemodynamics; Hydroxyindoleacetic Acid; Liver; Male; Methoxyhydroxyphenylglycol; Monoamine Oxidase Inhibitors; Piperidines; Rats; Rats, Inbred Strains; Serotonin Antagonists; Synaptosomes; Tranylcypromine

CGP 11305 A [4-(5-methoxy-7-bromo-benzofuranyl-2)piperidine HCl), a reversible, selective inhibitor of MAO A, increased the levels of rat brain noradrenaline, dopamine, and serotonin dose-dependently and to approximately the same extent. Concomitantly, it lowered the levels of their metabolites, MHPG-SO4, HVA, DOPAC, and 5-HIAA. When compared with the irreversible MAO A inhibitor clorgyline, the effects of CGP 11305 A were of much shorter duration. Moreover, the increases of noradrenaline and serotonin and the decreases of their metabolites MHPG-SO4 and 5-HIAA were smaller after CGP 11305 A than after clorgyline in equieffective doses for MAO A inhibition. CGP 11305 A decreased the synthesis of catecholamines and serotonin less markedly than clorgyline. This is probably due to the reversibility of the interaction of the compound with MAO A. In contrast to CGP 11305 A, clorgyline increased the level of dopamine less than those of noradrenaline and serotonin. This is explained by assuming that dopamine synthesis is particularly sensitive to end product inhibition. CGP 11305 A also exhibited some inhibitory properties on the uptake of serotonin and, to a lesser degree, of noradrenaline in vitro and in vivo. Compared with MAO inhibition, however, uptake inhibition required 30-100 times higher doses.

Topics: Animals; Biogenic Amines; Brain; Brain Chemistry; Clorgyline; Dopamine; Female; Hydroxyindoleacetic Acid; In Vitro Techniques; Monoamine Oxidase Inhibitors; Myocardium; Norepinephrine; Piperidines; Rats; Serotonin; Tryptophan

The aim of this study was to resolve the apparent discrepancy between the short duration of action of the MAO inhibitory effect of CGP 11305 A in vivo and its irreversible interaction with the enzyme in vitro. When rats were treated with CGP 11305 A 2 h prior to clorgyline administration and MAO activity was determined 46 h thereafter, MAO A in brains and livers was protected from inhibition by clorgyline provided the dose relation was adequate. However, if clorgyline doses were equal to or higher than those of CGP 11305 A, there was only partial or no protection despite the fact that the doses of CGP 11305 A blocked MAO A nearly completely at the moment of clorgyline administration. Using a different approach, it was found that dopamine and serotonin released from their stores in rat striatum by tetrabenazine could displace CGP 11305 A from the MAO A active site in vivo, in contrast to clorgyline. These results suggest that the interaction of CGP 11305 A with MAO in vivo is reversible and competitive.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Brain; Clorgyline; Dopamine; Female; Homovanillic Acid; Hydroxyindoleacetic Acid; Liver; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Piperidines; Rats; Serotonin; Tetrabenazine

To assess the effect of the new, selective, reversible MAO A inhibitor, CGP 11305 A (4-(5-methoxy-7-bromo-benzofuranyl-2-)piperidine HCl), on MAO A and B activity in man, the daily excretion of total normetanephrine (NMN), metanephrine (MN), 3-methoxytyramine (3-MT) and beta-phenylethylamine (PEA) was measured in the urine of healthy volunteers treated with weekly increasing doses from 40 to 150 mg/d. A similar study was carried out with tranylcypromine in weekly increasing doses from 10 to 25 mg/d. Both compounds increased the excretion of NMN; with CGP 11305 A, a plateau was obtained at 50 mg/d, and tranylcypromine 20 mg was more effective than 10 mg, and was also more active than the highest dose of CGP 11305 A. Increases in MN and 3-MT produced by the latter compound were comparable to that in NMN, whereas tranylcypromine had a biphasic effect on MN excretion, and caused only a small increase in 3-MT excretion. CGP 11305 A up to 150 mg/d did not alter total tyramine excretion, whereas tranylcypromine at 20 mg caused a definite increase. Tranylcypromine led to 4-6 fold increases in PEA output at 20 and 25 mg/d, but not at 10 mg. No such effect could be demonstrated for CGP 11305 A up to 150 mg/d. These results suggest that in man MAO A was inhibited by CGP 11305 A in daily dose of 40 mg or more, whereas it did not affect MAO B at up to 150 mg.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Amphetamine; Epinephrine; Female; Humans; Male; Metanephrine; Monoamine Oxidase Inhibitors; Normetanephrine; Phenethylamines; Piperidines; Tranylcypromine; Tyramine

CGP 11305 A (4-(5-methoxy-7-bromo-benzofuranyl)2-piperidine-HCl) inhibited serotonin (5-HT) deamination in brains and livers of pretreated rats. The ED50S were 1 and 0.7 mg/kg p.o., respectively. Phenylethylamine (PEA) deamination was only marginally affected up to doses of 100 mg/kg p.o. The duration of action of the compound was less than 48 h, and its effects did not cumulate after repeated oral treatment. Kinetic studies in mitochondrial preparations from both tissues of the rat showed that with both 5-HT and PEA as substrates the inhibition was of the competitive type when the enzyme preparation and the inhibitor were not preincubated prior to assay. These properties suggested a reversible interaction of the compound with the enzyme. However, in 'ex vivo' studies, the inhibitory activity of CGP 11305 A was not lost by dilution or dialysis of homogenates from pretreated animals and the inhibitor could not be displaced by 5-HT. Similar results were obtained when CGP 11305 A was preincubated with mitochondria or homogenates from rat liver in vitro, indicating an irreversible interaction. The apparent contradiction between the short duration of the MAO inhibitory effect of CGP 11305 A in vivo and the seemingly irreversible interaction with the enzyme under ex vivo and in vitro conditions has not yet been resolved, although a number of possible mechanisms have been considered. The short duration of action and the lack of cumulative effects of this powerful and selective monoamine oxidase-A inhibitor in vivo might, however, result in it being a valuable antidepressant.

Topics: Animals; Brain; Dialysis; Female; Kinetics; Mitochondria, Liver; Monoamine Oxidase Inhibitors; Piperidines; Rats; Time Factors

Topics: Adult; Biogenic Amines; Blood Pressure; Female; Hemodynamics; Humans; Kinetics; Male; Monoamine Oxidase Inhibitors; Piperidines; Time Factors; Tranylcypromine