The effect of some tricyclic antidepressants on the inhibition of mouse brain monoamine oxidase in-vivo by phenelzine
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Abstract:
Four tricyclic antidepressants, amitriptyline, imipramine, desipramine and iprindole have been shown to partially protect mouse brain monoamine oxidase in-vivo from the irreversible enzyme inhibition produced by subsequent injection of phenelzine. Levels of protection were similar when the enzyme was assayed with selective substrates (5-hydroxytryptamine and phenethylamine) for both the A and B forms of the enzyme. Although other explanations cannot at this stage be ruled out, these observations are consistent with the tricyclic antidepressants acting as reversible inhibitors of brain monoamine oxidase in-vivo.Keywords:
Tricyclic
Phenelzine
Desipramine
Monoamine oxidase A
Monoamine oxidase B
Moclobemide
Iproniazid
The mono-amine oxidase inhibitors, of which phenelzine (“Nardil”) is one example, were introduced for the treatment of depressive illness as a result of the observation that iproniazid, which is a mono-amine oxidase inhibitor, produced euphoria and increased mental alertness in some tuberculous patients to whom it was given. Trials of iproniazid in mental illness were carried out (Loomer et al. , 1957; Cesarman, 1959), but it was found to be very liable to give rise to side-effects, being particularly toxic to the liver. Other less toxic mono-amine oxidase inhibitors such as phenelzine, which is chemically related to iproniazid, were later developed.
Phenelzine
Iproniazid
Euphoriant
Monoamine oxidase inhibitor
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Moclobemide
Clorgyline
Harmaline
Monoamine oxidase A
Monoamine oxidase B
Nitrendipine
Tyramine
Methamphetamine
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In a double-blind, parallel group trial, 78 subjects with social phobia received moclobemide (a new reversible inhibitor of monoamine oxidase A) phenelzine, or placebo. After eight weeks, both active drugs-phenelzine somewhat more than moclobemide--were clinically and statistically significantly more effective than placebo, as assessed by rating scales. There was some further improvement between weeks 8 and 16, particularly in the moclobemide group; at week 16, 82% of the moclobemide and 91% of the phenelzine-treated patients were almost asymptomatic. Moclobemide was, however, much better tolerated than phenelzine. Patients withdrawn from active drugs had relapsed by week 24, providing additional support for the efficacy of the active drugs.
Moclobemide
Phenelzine
Monoamine oxidase inhibitor
Pharmacotherapy
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This study was conducted to establish the safety, tolerability, side effects, and pressor effects of tyramine on subjects treated with moclobemide, a short-acting reversible and preferential monoamine oxidase inhibitor, and to compare these responses with the responses of subjects treated with phenelzine. Twelve healthy male volunteers participated. An oral tyramine sensitivity test was performed on all subjects 24 hours before the start of a 28-day open-label treatment with phenelzine or moclobemide. A tyramine challenge was performed on day 28 on four subjects treated with phenelzine. The mean dose of oral tyramine required to increase systolic blood pressure by 30 mm Hg was 15 mg. The mean dose of tyramine that produced a clinical response (day 28) in subjects treated with moclobemide was 240 mg. No subject receiving moclobemide responded clinically on day 31 after receiving hourly doses of 20, 40, 80, 160, and 320 mg, respectively. These findings suggest that moclobemide may be used without stringent dietary precautions. Clinical Pharmacology and Therapeutics (1992) 52, 286–291; doi:10.1038/clpt.1992.143
Moclobemide
Phenelzine
Tyramine
Tolerability
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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.
Moclobemide
Tranylcypromine
Phenelzine
Monoamine oxidase A
Iproniazid
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Moclobemide
Monoamine oxidase A
Monoamine oxidase B
Monoamine oxidase inhibitor
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In phenobarbital-pretreated rats iproniazid produces distinct hepatotoxic symptoms, whereas moclobemide (Ro 11-1163) does not. Iproniazid's hepatotoxic effect is most impressive in histopathology where marked liver necrosis can be seen. Differences between the two compounds are also noted in the body weight development, mortalities and some haematological and blood chemistry parameters. The reversible and specific monoamine oxidase (MAO)-A inhibitor moclobemide, a benzamide, is therefore completely different from the classical irreversible MAO inhibitors of the hydrazine type and, as also confirmed in the clinical studies, does not have any hepatotoxic effect.
Moclobemide
Iproniazid
Hydrazine (antidepressant)
Benzamide
Monoamine oxidase inhibitor
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Moclobemide
Iproniazid
Monoamine oxidase inhibitor
Benzamide
Tyramine
Monoamine oxidase A
Neurochemical
Clorgyline
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Monoamine oxidase inhibitors (MAOIs) are being developed for major depressive disorder, Alzheimer's, and Parkinson's Disease. Newer MAOIs have minimal sensitivity to tyramine, but a key limitation for optimizing their development is that standards for in vivo monoamine oxidase-A (MAO-A) occupancy in humans are not well established. The objectives were to determine the dose-occupancy relationship of moclobemide and the occupancy of phenelzine at typical clinical dosing. Major depressive episode (MDE) subjects underwent [11C]harmine positron emission tomography scanning prior to and following 6 weeks of treatment with moclobemide or phenelzine. Mean brain MAO-A occupancies were 74.23±8.32% for moclobemide at 300–600mg daily (n = 11), 83.75±5.52% for moclobemide at 900–1200mg daily (n = 9), and 86.82±6.89% for phenelzine at 45–60mg daily (n = 4). The regional dose-occupancy relationship of moclobemide fit a hyperbolic function [F(x) = a(x/[b + x]); F(1,18) = 5.57 to 13.32, p = 0.002 to 0.03, mean 'a': 88.62±2.38%, mean 'b': 69.88±4.36 mg]. Multivariate analyses of variance showed significantly greater occupancy of phenelzine (45–60mg) and higher-dose moclobemide (900–1200mg) compared to lower-dose moclobemide [300–600mg; F(7,16) = 3.94, p = 0.01]. These findings suggest that for first-line MDE treatment, daily moclobemide doses of 300–600mg correspond to a MAO-A occupancy of 74%, whereas for treatment-resistant MDE, either phenelzine or higher doses of moclobemide correspond to a MAO-A occupancy of at least 84%. Therefore, novel MAO inhibitor development should aim for similar thresholds. The findings provide a rationale in treatment algorithm design to raise moclobemide doses to inhibit more MAO-A sites, but suggest switching from high-dose moclobemide to phenelzine is best justified by binding to additional targets.
Moclobemide
Phenelzine
Monoamine oxidase A
Tyramine
Monoamine oxidase inhibitor
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