Reversible inhibitor of monoamine oxidase

Treatment of Major Depression. Dmgs commonly used for the treatment of depressive disorders can be classified heuristicaHy iato two main categories first-generation antidepressants with the tricycHc antidepressants (TCAs) and the irreversible, nonselective monoamine—oxidase (MAO) inhibitors, and second-generation antidepressants with the atypical antidepressants, the reversible inhibitors of monoamine—oxidase A (RIMAs), and the selective serotonin reuptake inhibitors (SSRIs). Table 4 fists the available antidepressants. 

Reversible Inhibitors of Monoamine Oxidase. Selective MAO-A inhibitors, which aie leveisible (so-called RIMAs), have also been developed, theiefoie substantially leduciag the potential foi food and dmg iateiactions. Indeed, the tyiamine-potentiating effects of these dmgs is much reduced compared with the irreversible MAO inhibitors. The RIMAs represent effective and safer alternatives to the older MAO inhibitors. The only marketed RIMAs ate toloxatone [29218-27-7] and moclobemide (55). The latter is used widely as an effective, weU-tolerated antidepressant. 

Da Prada, M, Kettler, R, Keller, HH, Burkard, WP, Muggli-Maniglio, D and Haefely, WE (1989) Neurochemical profile of moclobemide, a short-acting and reversible inhibitor of monoamine oxidase type A. /. Pharmacol. Exp. Ther. 248 400-414. 

The reversible inhibitors of monoamine oxidase (RIMAs) brofaramine and meclobemide have been studied with mixed results.48 Neither is approved for use in the United States, but they are available in Canada. 

Some evidence indicates that social phobia responds to SSRls, and case reports and studies with fluoxetine [B. Black et al. 1992 Van Ameringen et al. 1993), fluvoxamine [Mendels et al. 1995), paroxetine [Pitts et al. 1996 Ringold 1994), and sertraline [Katzelnick et al. 1995) have reported positive results. Although the full details of these studies have not been published, it seems that SSRls might well prove, in due course, to be effective treatments for social phobia. At the moment, the only treatment licensed for social phobia is moclobemide, which is a reversible inhibitor of monoamine oxidase-A [Nutt and Montgomery 1996 Versiani et al. 1992), and it is possible that it... 

Based on some intriguing case reports (Jenike et al. 1983), a trial with a monoamine oxidase inhibitor (MAOI) may be an option in OCD patients who have comorbid panic disorder. In a double-blind trial, both phenelzine and clomipramine were found to be effective in reducing symptoms in OCD, as reflected on two of four OC measures [Vallejo et al. 1992). None of the patients in this study had panic disorder. This study suggests that MAOIs may be helpful in some patients with OCD even in the absence of panic disorder. However, in an earlier comparison trial, clomipramine, but not the MAOI clorgiline, resulted in significant reduction in OC symptoms [Insel et al. 1983b). Additional studies are needed to evaluate the place of MAOIs (including the newer reversible inhibitors of monoamine oxidase A [RIMAs], such as moclobemide) in the pharmacotherapy of OCD. 

Reversible inhibitor of monoamine oxidase activity (RIMA). (Atypical agent. 

Another approach is to develop selective and reversible MAOIs. The goal again is to produce agents with a minimal risk of tyramine reactions and thus markedly diminish the need for the dietary restrictions that have plagued the use of nonselective and irreversible A, B inhibitors. Collaborative clinical trials of the reversible inhibitors of monoamine oxidase A (RIMAs) in Europe have included more than 2,000 patients, many hospitalized for more severe, endogenous depressive episodes (183). In comparison trials with the TCAs, the onset of effect with RIMAs was also more rapid in some cases. 

Lecrubies Y, Guelfi JD. Efficacy of reversible inhibitors of monoamine oxidase-A in various forms of depression. Acta Psychiatr Scand Supp1 1990 360 18-23. 

One Type B MAOl (i.e., selegiline) has a low propensity to cause hypertensive and hyperpyrexic reactions, but there is scant information on its use for PD. On the other hand, among the selective and reversible inhibitors of monoamine oxidase A (RIMAs) such as brofaromine, some may be as effective as phenelzine without posing the same risks. 

The harmala alkaloids harmaline (368 X = NH) and harmi.ne (369 X = NH) are active reversible inhibitors of monoamine oxidase (MAO). Benzo[ Jthiophene analogs of harmaline (368 X = S) and harmine (369 X = S), when tested in vitro as inhibitors of rat liver MAO, showed that (368 X = S) was 50 times more potent than harmaline, but (369 X = NH or S) were equivalent in potency. The replacement of the indolic nitrogen by sulfur greatly increased the lipid solubility of the molecule, which was reflected in the physiological disposition of the two analogs. 

Reversible inhibitors of monoamine oxidase A Clinical experience with RIMAs in those countries where these agents are approved for marketing or testing suggests potential utility as antipanic agents. Further research is required to determine the relative advantages and relative efficacy of these compounds as compared with available antipanic agents. 

The side effects and cardiotoxicity of the tricyclic antidepressants have been discussed in detail elsewhere in this volume and, while there is ample evidence of their therapeutic efficacy, it seems difficult to justify their use, particularly in a group of patients who are most vulnerable to their detrimental side effects. Of the newer antidepressants, the reversible inhibitors of monoamine oxidase type A such as moclobemide may also be of value in the elderly depressed patient, particularly in those patients who fail to respond to the amine uptake inhibitor type of antidepressant. 

Allen and Bevan (80) have applied the SMD technique to the study of reversible inhibitors of monoamine oxidase B, and this paper will be used as an example for discussion of the constant velocity SMD pulling method. They used the Gromacs suite of biomolecular simulation programs (18) with the united-atom Gromos 43al force field to parameterize the lipid bilayer, protein, and small-molecule inhibitors. The protein was inserted into their mixed bilayer composed of phosphatidyl choline (POPC) and phosphatidyl ethanolamine (POPE) lipids in a ratio known to be consistent for a mitochondrial membrane. Each inhibitor-bound system studied was preequilibrated in a periodic box of SPC water (20) with the simulations run using the NPT ensemble at 300 K and 1 atm pressure for 20 ns. Full atomic coordinates and velocities were saved in 200-ps increments giving five replicates for each inhibitor-bound system. A dummy atom was attached to an atom (the SMD atom shown in Fig. 7) of the inhibitor nearest to the... 

The drugs that can cause a serotonin syndrome when they are combined with SSRIs include monoamine oxidase inhibitors (including reversible inhibitors of monoamine oxidase types A and B), dextromethorphan,... 

Like moclobemide, toloxatone, a selective and reversible inhibitor of monoamine oxidase type A, is thought to be relatively safe in combination with sympathomimetics (SEDA-18, 16). However, sweating, tachycardia, and headache have been reported when terbutaline was added to toloxatone and phenylephrine (SEDA-18, 16). In healthy volunteers, doses up to 600 mg/day did not produce hypertensive reactions on challenge with oral tyramine (SEDA-17, 17). Two fatal cases of fulminant hepatitis have been reported (SEDA-16, 7). 

Tryon, Edward. Is the Universe a Vacuum Fluctuation Nature 246 (1973) 396-397. Undenfriend, S, B. Witkop, B. Redfield, andH. Weissbach. Studies with Reversible Inhibitors of Monoamine Oxidase Harmaline and Related Compounds. 

Within each class or subclass drugs are listed in order of frequency of prescription in the United Kingdom (1997 data). Abbreviations RIMA—reversible inhibitor of monoamine oxidase NaRI—noradrenaline reuptake inhibitor SNRI—serotonin and noradrenaline reuptake inhibitor NaSSA—noradrenaline and specific serotonergic antidepressant. 

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