Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In rodents, SR 95191 [3-(2-morpholinoethylamino)-4-cyano-6-phenylpyridazine] has been shown to be active in animal models of depression. The profile of activity of SR 95191 suggests that the compound is a selective and short-acting type A monoamine oxidase (MAO) inhibitor (MAOI) in vivo. In the present study, the interaction of SR 95191 with MAO-A and MAO-B activity was further examined in vivo and in vitro. In brain, liver, and duodenum of pretreated rats, SR 95191 selectively inhibited MAO-A (ED50 = 3-5 mg/kg, p.o.), whereas MAO-B was only weakly inhibited for doses as high as 300 mg/kg, p.o. In vivo, SR 95191 (1-100 mg/kg, p.o.) antagonized, in a dose-dependent fashion, the irreversible inhibition of brain and liver MAO-A induced by phenelzine. Finally, dopamine and 5-hydroxytryptamine depleted from their striatal stores by tetrabenazine were able to displace SR 95191 from the active site of MAO-A. However, ex vivo, kinetic studies showed that the inhibitory effect of SR 95191 (1-10 mg/kg) towards MAO-A was noncompetitive and was unchanged after dilution or dialysis. In vitro, the inhibition of brain MAO-A, but not MAO-B, by SR 95191 was time dependent, with a 19-fold decrease in the IC50 values being observed over a 30-min incubation period (140 to 7.5 microM). At this time, the SR 95191-induced inhibition of MAO-A was not removed by repeated washings. When the reaction was started by adding the homogenate without prior preincubation with SR 95191, the inhibition of brain MAO-A was fully competitive (Ki = 68 microM).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Monoamine oxidase-inhibiting properties of SR 95191, a new pyridazine derivative, in the rat: evidence for selective and reversible inhibition of monoamine oxidase type A in vivo but not in vitro. 334 72

Utilizing a specific "low substrate concentration technique", intrasynaptosomal MAO-A and MAO-B activities within the rat brain noradrenaline system were studied. It was found that mainly MAO-A was localized intrasynaptosomally, whereas MAO-B contributed with less than 15% of the total intrasynaptosomal MAO activity, a phenomenon that was also observed within the central dopamine system. It is suggested that the intrasynaptosomal pool of MAO in the noradrenaline and the dopamine systems may reflect the density of innervation of the respective system throughout the brain. In addition, the effects of various selective monoamine oxidase (MAO) inhibitors on the noradrenergic intrasynaptosomal MAO activity as well as on the neuronal firing rate of noradrenaline containing cells in the locus coeruleus (LC) were investigated. Pretreatment with the MAO-A selective inhibitors clorgyline (10 mg/kg, i.p., 1 h) or (+)-FLA 336 (1 mg/kg, i.p., 1 h) caused a significant depression (40%) of mean spontaneous firing rate of LC neurones, randomly encountered throughout the LC. The MAO-B selective inhibitor pargyline (10 mg/kg, i.p., 1 h) was found to lack effect in this regard. However, pretreatment with (-)-deprenyl (10 mg/kg, i.p., 1 h), equally a selective MAO-B inhibitor, markedly suppressed the spontaneous firing rate of LC units. This inhibition by (-)-deprenyl was blocked by pretreatment with SK&F 525 A (50 mg/kg, i.p., 30 min), an inhibitor of microsomal drug metabolizing enzymes. Thus, the depression of LC units by (-)-deprenyl seems to be executed by a metabolite, e.g. l-amphetamine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Relation between brain monoamine oxidase (MAO) activity and the firing rate of locus coeruleus neurons. 376 38

Preliminary open trials performed by the authors and others with Moclobemide, a new MAO-A inhibitor, indicated that the drug has a satisfactory antidepressant activity. In the present double-blind study Moclobemide has been compared to placebo in a group of 34 unipolar psychotic or neurotic depressed patients. The mean daily dose of Moclobemide was 297 mg and treatment lasted from two to four weeks. Drug effectiveness was measured by improvements in the Hamilton Rating Scale for Depression (HRSD), Clinical Global Impression (CGI) and 100 mm Visual Analogue Scale (VAS). The results have shown that the active drug was markedly superior to placebo. The mean total score of HRSD was reduced from 41.7 to 16.5 in 18 pts. treated with Moclobemide and from 36.3 to 29.1 in 16 pts. who received placebo. Self-assessment with VAS showed a mean reduction from 82.7 mm to 42.2 mm and from 84.3 to 70.6 mm respectively. Moderate to marked improvement was observed by the CGI in 15 cases treated with Moclobemide and mild to moderate in 5 cases who received placebo. The treatment was well tolerated.
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PMID:A placebo-controlled study of the antidepressant activity of moclobemide, a new MAO-A inhibitor. 638 61

Several selective and reversible monoamine oxidase inhibitors (MAOIs) have recently become available. Preliminary studies suggest that these compounds have antidepressant effects and may offer significant safety and side effect advantages over classical MAOIs. Pilot studies with 1-deprenyl, a selective MAO-B inhibitor, indicate that it may be most effective for patients with nonendogenous depression and for those (endogenous or nonendogenous) who present with certain reverse vegetative signs. The drug appears ineffective in depressed patients with associated panic attacks and phobic symptoms. An alternative approach in the development of safer, effective MAOIs is the use of rapidly reversible MAO-A inhibitors, such as moclobemide, that carry less risk of a hypertensive reaction and yet appear to be effective antidepressants. As selective MAO-A and MAO-B inhibition may be effective in different depressive subtypes and may have different side effects, these drugs are valuable pharmacologic probes for studying the biochemical bases of depressive disorders.
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PMID:Studies of selective and reversible monoamine oxidase inhibitors. 642 30

A total of 56 patients attending a general practitioner for treatment of depression, most of whom met the criteria for major depression, were included in this double-blind, parallel group, 6-week study, in which the selective MAO-A inhibitor moclobemide (MOC; maximum dose 600 mg) was compared with the tricyclic antidepressant doxepin (DOX; maximum dose 250 mg). Thirty patients on MOC and 23 on DOX were assessed after treatment for at least 1 week and are included in the response evaluation. Improvement was assessed primarily with the Montgomery-Asberg Depression Rating Scale (MADRS). There were only 4 drop-outs in the MOC group and three in the DOX group after 1 week. Overall improvement measures showed a nonsignificant difference in favor of DOX. Two factors were found to have prognostic significance: (1) previous or present panic attacks (10 patients in the MOC group and--by chance--only one in the DOX group) were associated with significantly lower improvement within the MOC group. Since we had no a priori hypothesis about this effect, it could be a chance finding. (2) Improvement was negatively correlated with age; this was statistically significant in the total group as well as in the MOC group, with a nonsignificant trend in the same direction in the DOX group. Side effects differed little between the two groups; only dryness of mouth appeared with markedly higher frequency in the DOX group.
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PMID:A double-blind comparison of moclobemide and doxepin in depressed general practice patients. 757 58

There is no generally accepted definition of severe depression, but hospitalization, high scores on rating scales, and the presence of psychotic symptoms are widely considered to be indicators of severe cases. For the purpose of this analysis of the antidepressant efficacy of the reversible inhibitor of monoamine oxidase A moclobemide, all hospitalized cases were selected from the current database of comparative studies and compared with the standard tricyclics imipramine and clomipramine. The cases from comparisons of moclobemide and imipramine were analyzed together, because in accordance with the recommended range of doses, the dose ratio over all studies was approximately 3:1 (moclobemide: N = 238, mean dose, 453 mg/day; imipramine: N = 248, mean dose, 159 mg/day). The cases from comparisons of moclobemide and clomipramine could only be analyzed over all studies if dose was taken into account, because the dose ratio of approximately 3:1 was only given in one study (moclobemide: N = 62, mean dose, 466 mg/day; clomipramine: N = 66, mean dose, 154 mg/day), whereas the dose ratio over the other, earlier studies was approximately 2:1 (moclobemide: N = 58, mean dose, 258 mg/day; clomipramine, N = 59, mean dose, 124 mg/day). The efficacy as judged on the Hamilton Rating Scale for Depression (HAM-D) and Global Assessment of Efficacy was analyzed for subgroups of inpatients, according to different severity bands (17-item HAM-D baseline total score, cut-off, 28 points) and according to the presence or absence of mood-congruent psychotic features. The results of our analysis failed to reveal any difference in efficacy between moclobemide and imipramine in any subgroup of hospitalized depressives, including patients in the highest HAM-D severity band and psychotic patients.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Moclobemide and tricyclic antidepressants in severe depression: meta-analysis and prospective studies. 759 25

This article reviews efficacy studies of the reversible selective inhibitor of monoamine oxidase A (MAO-A) moclobemide, which has now received extensive evaluation. Placebo-controlled trials have shown it clearly to be effective. In comparisons with tricyclic and similar antidepressants and with serotonin reuptake inhibitors, it has been found of equal efficacy to these standard drugs. Because of previous suggestions that older MAO inhibitors are particularly effective in depressions characterized as atypical, the effects in subtypes are of particular interest. The evidence indicates that moclobemide is effective in typical severe depression with melancholia rather than being limited to less typical subtypes.
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PMID:Clinical efficacy of reversible and selective inhibitors of monoamine oxidase A in major depression. 771 91

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.
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PMID:Reversible and selective inhibitors of monoamine oxidase A in mental and other disorders. 771 94

1. The binding of [3H]-idazoxan in the presence of 10(-6) M (-)-adrenaline was used to quantitate I2 imidazoline-preferring receptors in the rat brain and liver after chronic treatment with various irreversible and reversible monoamine oxidase (MAO) inhibitors. 2. Chronic treatment (7-14 days) with the irreversible MAO inhibitors, phenelzine (1-20 mg kg-1, i.p.), isocarboxazid (10 mg kg-1, i.p.), clorgyline (3 mg kg-1, i.p.) and tranylcypromine (10 mg kg-1, i.p.) markedly decreased (21-71%) the density of I2 imidazoline-preferring receptors in the rat brain and liver. In contrast, chronic treatment (7 days) with the reversible MAO-A inhibitors, moclobemide (1 and 10 mg kg-1, i.p.) or chlordimeform (10 mg kg-1, i.p.) or with the reversible MAO-B inhibitor Ro 16-6491 (1 and 10 mg kg-1, i.p.) did not alter the density of I2 imidazoline-preferring receptors in the rat brain and liver; except for the higher dose of Ro 16-6491 which only decreased the density of these putative receptors in the liver (38%). 3. In vitro, phenelzine, clorgyline, 3-phenylpropargylamine, tranylcypromine and chlordimeform displaced the binding of [3H]-idazoxan to brain and liver I2 imidazoline-preferring receptors from two distinct binding sites. Phenelzine, 3-phenylpropargylamine and tranylcypromine displayed moderate affinity (KiH = 0.3-6 microM) for brain and liver I2 imidazoline-preferring receptors; whereas chlordimeform displayed high affinity (KiH = 6 nM) for these receptors in the two tissues studied, Clorgyline displayed very high affinity for rat brain (KiH = 40 pM) but not for rat liver I2 imidazoline-preferring receptors (KiH = 169 nM). 4. Preincubation of cortical or liver membranes with phenelzine (10-4 M for 30 min) did not alter the total density of I2 imidazoline-preferring receptors, indicating that this irreversible MAO inhibitor does not irreversibly bind to I2 imidazoline-preferring receptors. In contrast, preincubation with 10-6 Mclorgyline reduced by 40% the Bmax of [3H]-idazoxan to brain and liver I2 imidazoline-preferring receptors.5. Chronic treatment (7 days) with the inducers of cytochrome P-450 enzymes phenobarbitone (40 or 80 mg kg-1, i.p.), 3-methylcholanthrene (20 mg kg-1, i.p.) or 2-methylimidazole (40 mg kg-1, i.p.) did not alter the binding parameters of [3H]-idazoxan to brain and liver 12 imidazoline-preferring receptors.The compound SKF 525A, a potent inhibitor of cytochrome P-450 enzymes which forms a tight but reversible complex with the haemoprotein, completely displaced with moderate affinity (KiH = 2-10 microM)the specific binding of [3H]-idazoxan to brain and liver 12 imidazoline-preferring receptors. Preincubation of total liver homogenates with 3 x 10-4 M phenelzine in the presence of 10-3 M NADH, a treatment that irreversibly inactivates the haeme group of cytochrome P-450, did not reduce the density of liver I2 imidazoline-preferring receptors. These results discounted a possible interaction of [3H]-idazoxan with the haeme group of cytochrome P-450 enzymes.6. Together the results indicate that the down-regulation of I2 imidazoline-preferring receptors is associated with an irreversible inactivation of MAO (at least in the brain) that is not related either to the affinity of the MAO inhibitors for I2 imidazoline-preferring receptors or to an irreversible binding to these putative receptors. These findings indicate a novel effect of irreversible MAO inhibitors in the brain and suggest a new target for these compounds that could be of relevance in the treatment of depression, a disease in which an increased density of brain I2 imidazoline-preferring receptors has been reported.
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PMID:The effects of phenelzine and other monoamine oxidase inhibitor antidepressants on brain and liver I2 imidazoline-preferring receptors. 777 44

Moclobemide, p-chloro-N-[morpholinoethyl]benzamide, is a prototype of RIMA (reversible inhibitor of MAO-A) agents. The compound possesses antidepressant efficacy that is comparable to that of tricyclic and polycyclic antidepressants. In humans, moclobemide is rapidly absorbed after a single oral administration and maximum concentration in plasma is reached within an hour. It is moderately to markedly bound to plasma proteins. MAO-A inhibition rises to 80% within two hours; the duration of MAO inhibition is usually between eight and ten hours. The activity of MAO is completely reestablished within 24 hours of the last dose, so that a quick switch to another antidepressant can be safely undertaken if clinical circumstances demand. RIMAs are potent inhibitors of MAO-A in the brain; they increase the free cytosolic concentrations of norepinephrine, serotonin and dopamine in neuronal cells and in synaptic vesicles. Extracellular concentrations of these monoamines also increase. In the case of moclobemide, increase in the level of serotonin is the most pronounced. Moclobemide administration also leads to increased monoamine receptor stimulation, reversal of reserpine induced behavioral effects, selective depression of REM sleep, down regulation of beta-adrenoceptors and increases in plasma prolactin and growth hormone levels. It reduces scopolamine-induced performance decrement and alcohol induced performance deficit which suggest a neuroprotective role. Tyramine potentiation with moclobemide and most other RIMA agents is negligible.
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PMID:Biochemistry and pharmacology of reversible inhibitors of MAO-A agents: focus on moclobemide. 790 88


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