Reversible inhibitor of monoamine oxidase A

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. 

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. 

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. 

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. 

Of the monoamine oxidase inhibitors, phenelzine (Nardil) is the most likely to cause weight gain (Zimmermann et al. 2003). Treatment with moclobemide (Manerix), a reversible inhibitor of monoamine oxidase A, is not accompanied by any consistent increase in body weight (Silverstone 1993). 

Some of the newer and more recently developed drugs with MAO inhibitory activity (see Table 32.1 , (below)) interact to a lesser extent than the older MAOIs. This is because they are largely selective. One group of these selective inhibitors targets MAO-A, and are relatively rapidly reversible inhibition of this enzyme is responsible for the antidepressant effect. These selective MAO-A inhibitors (moclobemide, toloxatone) have been given the acronym RIMAs (Reversible Inhibitors of Monoamine oxidase A). They leave MAO-B largely uninhibited so that there is still a metabolic pathway available for the breakdown of amines, such as... 

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. 

Two drugs belonging to the selective and reversible class of MAOls, moclobemide and brofaromine, have been studied for use in the treatment of social phobia. Both agents are selective inhibitors of monoamine oxidase-A,... 

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... 

Inhibitors of monoamine oxidase A (thy-meretics). Moclobemide is the only representative of this group. It produces a reversible inhibition of MAOa, which is responsible for inactivation of the amines norepinephrine, dopamine, and serotonin (A). Enzyme inhibition results in an increased concentration of these neurotransmitters in the synaptic cleft. Moclobemide is less effective as an antidepressant than as a psychomotor stimulant. It is indicated only in depressions with extreme psychomotor slowing and is contraindicated in patients at risk of suicide. 

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. 

Antidepressants are considered to have additive effects, therefore combined use is not recommended. Inhibitors of serotonin reuptake by CNS neurons may interact with other drugs or circumstances which cause serotonin release. The enhancement of the serotonergic effects may produce a life-threatening serotonin syndrome. Drugs which can increase the serotonin level when taken in combination with SSRIs include TCAs, MAOIs, reversible inhibitors of monoamine oxidase, carbamazepine, lithium, or serotoneric substances. These drugs should not be coadministered with SSRIs and they may increase the risks of developing a serotonin syndrome. 

Reversible inhibitors of monoamine oxidase type A (RIMAs)... 

Selective serotonin reuptake inhibitors (SSRIs) are regarded as first-line treatment in social phobia. Fluvoxamine, paroxetine, and sertraline have been shown to be effective in double-blind placebo-controlled studies. - The irreversible monoamine oxidase inhibitor (MAOI) phenelzine shows robust results in terms of efficacy and has demonstrated (at least anecdotally), its efficacy in improving some of the cognitive aspects associated with SAD. However, phenelzine is usually less well tolerated than alternative treatments due to its associated dietary restrictions and adverse side-effect profile, including sedation and postural hypotension. Results with the reversible inhibitor of monoamine oxidase type A (RiMA) mociobemide are inconsistent. 

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