Inhibition of monoamine oxidase by moclobemide: effects on monoamine metabolism and secretion of anterior pituitary hormones and cortisol in healthy volunteers.

1. Single oral doses (100, 200 and 300 mg) of moclobemide, a reversible inhibitor of monoamine oxidase (MAO) with predominant effects on the A-type of the enzyme, were administered to eight young, healthy male volunteers in a double-blind, random-order, placebo-controlled study. The investigation was thereafter continued in an open fashion by administering a single 10 mg dose of the MAO-B inhibitor deprenyl to the same subjects. 2. Deamination of catecholamines was powerfully and dose-dependently inhibited by moclobemide, as evidenced by up to 40% decreases in the urinary excretion of deaminated catecholamine metabolites, corresponding increases in the excretion of non-deaminated, methylated metabolites, and up to 79% average decreases in the plasma concentration of 3,4-dihydroxyphenylglycol (DHPG), a deaminated metabolite of noradrenaline (NA), and up to 75% average decreases in the plasma concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC), a deaminated metabolite of dopamine. The urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA) was only slightly reduced. In contrast, deprenyl, in a dose which almost totally inhibited MAO-B activity in blood platelets, did not appreciably affect the plasma concentrations of DHPG or DOPAC. 3. Due to the rapid, reversible, dose-dependent and MAO-A specific effect of moclobemide on plasma concentrations of DHPG, it is suggested that DHPG in plasma may be a useful indicator of the magnitude and duration of MAO-A inhibition in man. 4. Sympatho-adrenal function at rest was not significantly altered by moclobemide, as judged by unchanged plasma catecholamine concentrations and stable blood pressure and heart rate recordings. 5. Monoamine oxidase type B activity in blood platelets was slightly (less than 30%) and transiently inhibited after moclobemide. 6. The secretion of prolactin was dose-dependently stimulated by moclobemide, whereas the plasma concentrations of growth hormone (hGH) and cortisol remained unchanged.     

Initial monoamine oxidase-A inhibition by moclobemide does not predict the therapeutic response in patients with major depression

It is generally accepted that the clinical efficacy of monoamine oxidase inhibitors (MAOI) is related to inhibition of this enzyme. In order to evaluate the predictive ability of monoamine oxidase-A inhibition for therapeutic efficacy, the start of treatment effects of moclobemide, a selective, reversible monoamine oxidase-A inhibitor, on plasma concentrations of monoamines and monoamine metabolites were determined. The plasma levels of 3,4-dihydroxy-phenylglycol (DHPG, deaminated metabolite of noradrenaline), 5-hydroxyindoleacetic acid (5-HIAA, deaminated metabolite of serotonin), 3,4-dihydroxyphenylacetic acid and homovanillic acid (DOPAC and HVA, deaminated metabolites of dopamine),l-dihydroxyphenylalanine (l-dopa) and noradrenaline were investigated and related to treatment outcome. This was a randomized double blind parallel group study in 47 patients with criteria of major depression according to DSM III R. Moclobemide 300 mg/day, 450 mg/day or 600 mg/day was administered continuously for 6 wecks. Plasma concentrations of monoamine metabolites and monoamines were determined just before treatment by moclobemide, 4 h after the first dose, 24 h after the first dose, before the first dose on day 7, and 4 h after the first dose on day 7. Each moclobemide dose improved depression as measured by MADRS (Montgomery-Asberg Depression Rating scale) but there was no difference between the three doses. Moclobemide dose-dependently reduced plasma concentration of DHPG,l-dopa and HVA. No dose-dependent treatment effect was observed for plasma 5-HIAA, noradrenaline and DOPAC. The clinical outcome as defined by the final MADRS score was not related to any start of treatment changes in plasma monoamine metabolites reflecting inhibition of MAO-A. It is concluded that monoamine oxidase-A inhibition at the beginning of the treatment does not predict clinical outcome.     

Initial monoamine oxidase-A inhibition by moclobemide does not predict the therapeutic response in patients with major depression A double blind,randomized study

It is generally accepted that the clinical efficacy of monoamine oxidase inhibitors (MAOI) is related to inhibition of this enzyme. In order to evaluate the predictive ability of monoamine oxidase-A inhibition for therapeutic efficacy, the start of treatment effects of moclobemide, a selective, reversible monoamine oxidase-A inhibitor, on plasma concentrations of monoamines and monoamine metabolites were determined. The plasma levels of 3,4-dihydroxyphenylglycol (DHPG, deaminated metabolite of noradrenaline), 5-hydroxyindoleacetic acid (5-HIAA, deaminated metabolite of serotonin), 3,4-dihydroxyphenylacetic acid and homovanillic acid (DOPAC and HVA, deaminated metabolites of dopamine), L-dihydroxyphenylalanine (L-dopa) and noradrenaline were investigated and related to treatment outcome. This was a randomized double blind parallel group study in 47 patients with criteria of major depression according to DSM III R. Moclobemide 300 mg/day, 450 mg/day or 600 mg/day was administered continuously for 6 weeks. Plasma concentrations of monoamine metabolites and monoamines were determined just before treatment by moclobemide, 4 h after the first dose, 24 h after the first dose, before the first dose on day 7, and 4 h after the first dose on day 7. Each moclobemide dose improved depression as measured by MADRS (Montgomery-Asberg Depression Rating scale) but there was no difference between the three doses. Moclobemide dose-dependently reduced plasma concentration of DHPG, L-dopa and HVA. No dose-dependent treatment effect was observed for plasma 5-HIAA, noradrenaline and DOPAC. The clinical outcome as defined by the final MADRS score was not related to any start of treatment changes in plasma monoamine metabolites reflecting inhibition of MAO-A. It is concluded that monoamine oxidase-A inhibition at the beginning of the treatment does not predict clinical outcome. Received: 29 February 1996/Final version: 30 May 1996     

Pharmacokinetics of oral moclobemide in healthy human subjects and effects on MAO-activity in platelets and excretion of urine monoamine metabolites

The plasma concentrations of the MAO-inhibitor moclobemide (Ro 11-1163) were determined in six healthy male subjects after oral (tablets) administration. Effects on MAO activity in platelets and excretion of monoamine metabolites in urine were investigated. The design of the study was a double-blind cross-over study with single oral doses of placebo, 50, 100 and 200 mg of moclobemide. The elimination profile of the drug showed that the half life of the unchanged drug ranged between 1 and 2 h except in one subject with a half-life of about 4 h. The mean bioavailability calculated using flow model concepts was F = 0.43 after 50 mg, F = 0.47 after 100 mg and F = 0.59 after 200 mg. The outlier with a t 1/2 of 4 h was found to have a bioavailability of more than 0.80 after all 3 doses. The slightly increasing bioavailability with higher doses was interpreted as evidence of saturable hepatic first-pass elimination of the drug. MAO activity in platelets was measured before and 2, 6 and 24 h after drug administration. No inhibition of platelet MAO was obtained at any point in time or dose level, as to be expected since moclobemide preferentially inhibits MAO A. Urine excretion of the monoamine metabolites homovanillic acid (HVA), dihydroxyphenylacetic acid (DOP-AC), 3-methoxy-4-hydroxy-phenylglycol (MOPEG) and 5-hydroxyindoleacetic acid (5-HIAA) was followed during 48 h after placebo, 50 and 200 mg of moclobemide. Time but not dose contributed significantly to the variability in excretion of the monoamine metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)     

Participation of type A monoamine oxidase in the activated deamination of brain monoamines shortly after reperfusion in rats

Changes in monoamine levels during and after ischemia and effects of RS-8359, a type A monoamine oxidase (MAO-A) inhibitor, were studied in the cerebral cortex, hippocampus, and striatum of rats killed by microwave irradiation. The patterns of the changes in norepinephrine (NE), dopamine (DA), and serotonin (5HT) levels were similar during ischemia: All these monoamines decreased in all three regions. After reperfusion, however, the three monoamines showed different patterns of changes: NE, except in the striatum, decreased further; DA increased over the controls; 5HT remained suppressed in all three regions. With regard to the metabolites of the monoamines, the changes during and after reperfusion were almost similar in all regions: O-methylated metabolites, normetanephrine and 3-methoxytyramine, markedly increased during ischemia; After reperfusion, the elevated levels of normetanephrine and 3-methoxytyramine returned to normal, while deaminated metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid, homovanillic acid (HVA), and 3-methoxy-4-hydroxy-phenylethyleneglycol clearly increased. RS-8359 pretreatment (30 mg/kg, p.o.) at an hour prior to ischemia elevated the levels of NE in the cortex and hippocampus during ischemia and inhibited the increases in DOPAC and HVA levels and the decrease in 3MT levels at 30 min after reperfusion. These results suggest that deamination of NE, DA, and 5HT is activated by the increases in the substrates for MAO in all three regions, except the noradrenergic system in the striatum, and that MAO-A participates in the activated deamination after reperfusion.     

Effects of monoamine oxidase inhibitors on levels of catechols and homovanillic acid in striatum and plasma

Levels of homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC) and dihydroxyphenylglycol (DHPG) in plasma and the striatium were measured after inhibition of monoamine oxidase type A (MAO-A) by clorgyline (4 mg/kg i.p.), MAO-B by (-)deprenyl (1 mg/kg i.p.), both MAO-A and MAO-B by nialamide (75 mg/kg i.p.) or peripheral neuronal MAO by debrisoquin (40 mg/kg i.p.). Levels of HVA in plasma decreased by about 60% after single doses of nialamide or clorgyline, by about 80% after repeated doses of nialamide, by about 40% after a single dose of debrisoquin and by about 50% after repeated doses of debrisoquin. The administration of clorgyline, nialamide or debrisoquin significantly decreased concentrations of DOPAC and DHPG in plasma, whereas (-)deprenyl did not affect levels of DHPG or HVA. None of the MAO inhibitors produced more than about 80% depression of levels of any of the deaminated metabolites. The results suggest that most of the HVA in plasma is derived from deamination of DA by MAO-A in peripheral neurons; that DOPAC in plasma is derived from cells outside the central nervous system; that DHPG in plasma is derived virtually exclusively from the metabolism of norepinephrine in sympathetic nerve endings and that residual levels of HVA after treatment with debrisoquin provide an improved but limited indication of central dopaminergic activity.     

The effects of moclobemide on the pharmacokinetics of the 5-HT1B/1D agonist rizatriptan in healthy volunteers

AIMS: The new 5-HT1B/1D agonist rizatriptan (MK-0462) has recently been registered for the treatment of migraine. Its primary route of metabolism is via monoamine oxidase-A (MAO-A). Antidepressants such as the MAO-A inhibitor moclobemide may be used in patients with chronic headache syndromes. Hence, this study aimed to investigate the interactions between rizatriptan and moclobemide. METHODS: In a double-blind, randomized, placebo-controlled, two-period cross-over study 12 healthy, young volunteers (six males, six females) were treated with moclobemide (150 mg twice daily) or placebo for 4 days. On the fourth day, a single dose of rizatriptan (10 mg) was administered, and subsequently blood and urine samples were collected for assay of rizatripan and N-monodesmethyl rizatriptan. Plasma concentrates of 3,4-dihydroxyphenylglycol (DHPG), a marker of MAO-A inhibition, were also assessed. Supine and standing blood pressure were measured regularly. RESULTS: Both treatments were well tolerated. During moclobemide, the increase in supine diastolic blood pressure following rizatriptan administration was augmented. Inhibition of MAO by moclobemide was inferred from a persistent decrease in DHPG level (43% on average). When rizatriptan was coadministered with moclobemide, the area under the plasma drug concentration-time profiles for rizatriptan and its N-monodesmethyl metabolite increased 2.2-fold (90% CI, 1.93-2.47) and 5.3-fold (90% CI, 4.81-5.91), respectively, when compared with placebo. Peak plasma drug concentrations for rizatriptan and its n-monodesmethyl metabolite increased 1.4-fold (90% CI, 1.11-1.80) and 2.6-fold (90% CI, 2.23-3.14), respectively, and half-lives of both were prolonged. CONCLUSIONS: Moclobemide inhibited the metabolism of rizatriptan and its active N-monodesmethyl metabolite through inhibition of MAO-A. Thus, moclobemide may considerably potentiate rizatriptan action. Concurrent administration of moclobemide and rizatriptan is not recommended.     

Plasma moclobemide and metabolites: lack of correlation with clinical response and biogenic amines

The concentration of the reversible monoamine oxidase type-A (MAO-A) inhibitor moclobemide (Ro 11-1163) was determined by high pressure liquid chromatography (HPLC) in the plasma of 16 depressives treated with moclobemide. Moreover, the inhibitory potency of organic extracts of the plasma on a standard MAO-A preparation from human placenta was measured spectrophotometrically. The inhibitory potency significantly correlated with the HPLC results. However, it overestimated the concentration of moclobemide by one order of magnitude possibly due to the presence of yet unknown metabolites more active than moclobemide itself. These have already been suggested in view of the higher inhibitory potency of moclobemide ex vivo than in vitro. This new methodological approach might represent a comfortable alternative to HPLC procedures in pharmacokinetic studies on reversible MAO inhibitors. Plasma biogenic amines and their metabolites might be indicative of the biologic activity of moclobemide. Plasma homovanillic acid (HVA) decreased and norepinephrine (NE) increased under moclobemide, although insignificantly. There was no significant correlation between the plasma concentration of moclobemide as estimated by either method and the therapeutic response and the change of plasma HVA and NE.     

Deamination of norepinephrine, dopamine, and serotonin by type A monoamine oxidase in discrete regions of the rat brain and inhibition by RS-8359

Levels of monoamines and their metabolites were determined in the cortex, hippocampus, and striatum of rats killed by microwave irradiation. Moclobemide (20 mg/kg, p.o.) and clorgyline (10 mg/kg, p.o.), type A monoamine oxidase (MAO-A) inhibitors, increased the levels of normetanephrine (NM) and 3-methoxytyramine (3MT) and decreased those of 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5HIAA) in almost all three regions. Deprenyl (10 mg/kg, p.o.), a type B monoamine oxidase inhibitor, however, little affected monoamine and metabolite levels in all regions. The maximum effects of RS-8359 (10 mg/kg, p.o.) were obtained at 2 to 6 hr after administration, when the levels of norepinephrine (NE), NM, 3MT, and serotonin (5HT) in all regions and dopamine (DA) in the striatum increased, while DOPAC and HVA levels decreased. The levels of monoamines and metabolites had returned to normal by 20 hr after administration. Dose-dependency of the effects of RS-8359 on monoamine metabolites was observed at doses up to 30 mg/kg (p.o.) at 1 and 6 hr after administration. In conclusion, NE, DA, and 5HT are exclusively or preferentially deaminated by MAO-A in the cortex, hippocampus, and striatum of rats, and RS-8359 exhibits a reversible MAO-A inhibitory action in all three regions tested in vivo.     

Effects of harmine on dopamine output and metabolism in rat striatum: role of monoamine oxidase-A inhibition

In vivo microdialysis was used to investigate the effects of acute injections of harmine on extracellular concentrations of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxindoleacetic acid (5-HIAA) in the striatum of awake rats. Administration of harmine in doses of 0.5, 2.5, and 10 mg/kg (i.p.) elicited a dose-dependent increase of the dopamine efflux to 152, 173, and 243% and a decrease in DOPAC to 52, 36, and 10%, and HVA to 67, 45, and 20% throughout, respectively; 5-HIAA concentrations were decreased to 81, 74, and 72% only. In contrast to D-amphetamine, which also increases dopamine release and decreases its metabolites, the stimulatory action of harmine on dopamine release in the striatum was totally abolished in the presence of tetrodotoxin (1 microM). Similar to monoamine oxidase (MAO)-A inhibitors, harmine potentiated the stimulatory effect of D-amphetamine (10 microM), infused by reverse microdialysis in the striatum, on dopamine release. Pre-treatment with the benzodiazepine receptor antagonist flumazenil (5 mg/kg, i.p.) did not modulate the effect of harmine on striatal dopamine release and metabolism. Administration of the reversible MAO-A inhibitor, moclobemide (20 mg/kg, i.p.), induced an increase in dopamine to 256% and a decrease in DOPAC, HVA, and 5-HIAA to 30, 24, and 62%, respectively, reproducing a pattern similar to that of harmine. Taken together, these results indicate that harmine affects the brain dopamine system probably by acting as a MAO-A inhibitor and not as an inverse agonist for the benzodiazepine receptors.     

Tofisopam and midazolam: differences in clinical effects and in changes of CSF monoamine metabolites.

The effect of two repeated oral doses of 100 mg tofisopam 15 mg midazolam and placebo on the concentrations of monoamine metabolites (MHPG, 5-HIAA, HVA) in lumbar CSF were studied in general surgical patients operated on under spinal analgesia (n = 12 in each group). Midazolam, but not tofisopam, improved the quality of sleep the night before surgery. Both active agents reduced preoperative anxiety of the patients, but tofisopam was without subjective sedative action. In the placebo group, in contrast to the active drug groups, there was a slight positive correlation between the MHPG concentration and degree of anxiety before surgery. The only significant difference in the monoamine metabolites in lumbar CSF was found in the concentrations of HVA between tofisopam and placebo treated patients. The lower HVA concentrations suggest that the curious 3,4-benzodiazepine derivative, tofisopam, modifies central dopaminergic activity.     

Acute effects of beclamide on brain regional monoamine concentrations, their metabolites and radioligand binding studies.

The effects of beclamide on regional brain monoamine levels and radioligand binding have been studied in rats. One hour oral pre-treatment with beclamide (400 mg kg-1) increased rat striatal dopamine turnover by increasing the levels of its major metabolites (DOPAC and HVA) three-fold. Simultaneously the drug reduced the concentration of striatal dopamine by a similar factor, and the concentrations of 5-hydroxytryptamine, (5-HT), 5-hydroxyindoleacetic acid, (5-HIAA) and 3-methoxytyramine in the striatum were reduced below the detection limits of the assay. In the frontal cortex, beclamide depleted the dopamine, 5-HT and 5-HIAA content whilst having no significant effect on the noradrenaline level. The concentrations of bioamines and their metabolites in the hypothalamus were unaffected by such acute beclamide treatment. In radioligand binding studies beclamide lacked affinity and failed to displace radioligands from alpha 2, beta, 5-HT, 5-HT2 and dopamine D2 sites in selective loci of the rat brain.     

Dose-dependent effects of deprenyl on CSF monoamine metabolites in patients with Alzheimer's disease

Deprenyl, a monoamine oxidase (MAO) inhibitor with selective effects on MAO type-B at low doses, was administered to 13 patients with dementia of the Alzheimer type (DAT), a disorder reported to be associated with increased brain MAO-B activity. Cerebrospinal fluid was obtained for measurement of three monoamine metabolites, homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), by high pressure liquid chromatography with electrochemical detection. Deprenyl treatment (10 mg/day) for 3–4 weeks was associated with small but statistically significant reductions in HVA (21%) and 5-HIAA (15%) compared to baseline values. Subsequent administration of deprenyl at the higher dose of 40 mg/day for 3–4 more weeks led to greater reductions in HVA (40%) and MHPG (43%) than 5-HIAA (20%). These dose-dependent reductions are consistent with in vitro biochemical and anatomical data from primate brain suggesting that at low doses of deprenyl, MAO-B inhibition might be expected to selectively affect dopamine and serotonin-containing neurons, while at higher doses (which lead to MAO-A as well as MAO-B inhibition), noradrenergic neurons may become relatively more affected by the drug.     

The neuropharmacological profile of N-methyl-N-propargyl-2-aminotetralin: a potent monoamine oxidase inhibitor

Summary N-methyl-N-propargyl-2-aminotetralin (N-0425), a semi rigid analogue of deprenyl was found to be a potent inhibitor of monoamine oxidase type-A and-B. The MAO inhibitory potency was determined in in-vitro, ex-vivo and in-vivo experiments for racemic N-0425 and for both enantiomers, and compared with deprenyl. Racemic N-0425 and (–)N-0425 were found to inactivate both MAO-A and-B to about the same extent in rat brain homogenates, whereas (+)N-0425 was 10 times more potent in inhibiting MAO-B than MAO-A under in-vitro conditions. The latter compound was almost 3 times less active than (–)deprenyl with respect to inactivation of MAO-B. In ex-vivo experiments it was shown that (±)- and (+)N-0425 inhibited rat striatal MAO-B activity almost completely 2 h after a dose of 0.01 mmol/kg ip, whereas both compounds produced a much less rapid inactivation of type-A MAO, which was about 65% after 23 h. No potentiation of the tyramine induced increase in systolic blood pressure was found in normotensive rats following doses up to 0.01 mmol/kg ip of racemic N-0425, but a potentiation was observed after a higher dose of 0.04 mmol/kg. Levels of dopamine and noradrenaline were both increased in rat frontal cortex after the administration of N-0425, which can be interpreted as a reflection of MAO inactivation. Since we were able to select a dose of (±)N-0425 which potently inhibits MAO, without producing a concomittant potentiation of the tyramine effect on blood pressure in normotensive rats, it is reasonable to suggest that this compound, like deprenyl, could be useful in the treatment of Parkinson's disease.Abbreviations used MAO monoamine oxidase - l-DOPA 3,4-dihydroxyphenylalamine - DA dopamine - DOPAC 3,4-dihydroxyphenylacetic acid - HVA homovanillic acid - 3-MT 3-methoxytyramine - NA noradrenaline - NM normetanephrine - 5-HT 5-hydroxytryptamine - 5-HIAA 5-hydroxyindoleacetic acid - PEA -phenylethylamine - N-0425 N-methyl-N-propargyl-2-aminotetralin Some of these results have been presented in a preliminary form at the 5th International Catecholamine Symposium, Göteborg, Sweden, June 12–16, 1983. This work was partly supported by a grant from Nelson Research, Irvine, California, USA     

Effects of pentylenetetrazol and trimethadione on feline brain monoamine metabolism

The effects of pentylenetetrazol on behavioral excitation and brain monoamine metabolism were compared by monitoring the EEG and assaying feline cerebrospinal fluid (CSF) for monoamine metabolites. After a non-convulsant dose of pentylenetetrazol, neither the concentrations of the 5-hydroxytryptamine (5-HT) metabolite, 5-hydroxyindoleacetic acid (5-HIAA), nor the dopamine(DA) metabolite, homovanillic acid (HVA), were altered in CSF if the rectal temperature of the cat was maintained. After a convulsant dose there was an increase in 5-HIAA and HVA levels. The norepinephrine (NE) metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), was also increased, but returned to control within 3 hr, while 5-HIAA and HVA levels were elevated for 24 hr. Trimethadione produced a transient decrease in HVA levels. When the convulsions, but not EEG excitation, are prevented by trimethadione pretreatment, brain monoamine metabolism is increased. Plasma tryptophan levels decreased after convulsant doses of pentylenetetrazol. Pentylenetetrazol was not detectable in plasma or CSF 24 hr after injection, while CSF 5-HIAA and HVA levels were still increased. These data show that pentylenetetrazol directly increases brain NE, DA and 5-HT metabolism while causing EEG excitatory changes, an effect which may precede convulsions.     

Rhesus monkey cerebrospinal fluid amine metabolite changes following treatment with the reversible monoamine oxidase type-A inhibitor cimoxatone

The effects of cimoxatone, a reversible inhibitor of monoamine oxidase type A (MAO-A), on the deaminated metabolites of norepinephrine, dopamine, and serotonin were examined in continuously collected rhesus monkey cerebrospinal fluid (CSF). Cimoxatone, 0.5–8 mg/kg given PO, produced dose-proportionate reductions of 24-h mean CSF 3-methoxy, 4-hydroxy phenylglycol (MHPG) concentrations of 21%–52%. Homovanillic acid (HVA) concentrations also decreased 27%–55%, while CSF 5-hydroxyindoleacetic acid (5-HIAA) decreases were somewhat smaller (7%–32% from baseline). All three metabolite concentrations reached a nadir approximately 6–10 h after drug administration, and required over 40 h to gradually return towards baseline following drug discontinuation. HVA concentration reductions in particular persisted during the entire 24-h period following treatment and were the slowest to return to baseline values. CSF concentrations of cimoxatone and its MAO-inhibiting O-demethyl metabolite showed a parallel time course peaking 6–10 h after treatment and persisting for up to 24 h in the case of cimoxatone and over 48 h for its metabolite. Single simultaneous time point determinations revealed 10-to 20-fold lower concentrations of cimoxatone and its metabolite in CSF compared to plasma 2 h after treatment. MAO-B activity in platelet-rich plasma was not inhibited by 8 mg/kg cimoxatone, indicating that this drug maintains MAO-A selectivity in vivo. As cimoxatone's preferential effects on catecholamine metabolites were similar to those previously observed with the irreversible MAO-A inhibiting antidepressant, clorgyline, our results are consistent with limited clinical trials data suggesting that cimoxatone may also prove to be an effective antidepressant.     

Effects of acute and repeated administration of amiflamine on monoamine oxidase inhibition in the rat

The inhibitory effect on monoamine oxidase (MAO) of the reversible MAO-A inhibitor (+)-4-dimethylamino-2,alpha-dimethylphenethylamine [amiflamine, FLA 336(+)] was evaluated in the rat after acute and repeated (twice daily for two weeks) oral treatment. MAO activity was measured ex vivo in slices from the hypothalamus and the duodenum for both MAO-A and MAO-B. Amiflamine selectively inhibited the A form of MAO after repeated as well as after acute treatment (ED50 approximately 7 mumoles/kg both acute and repeated). In the brain slices this inhibition corresponded to a decrease in the concentration of 5-hydroxyindoleacetic acid (5-HIAA) and to an increase in the concentration of 5-HT in the hypothalamus, the hippocampus and the striatum. The concentration of 3,4-dihydroxyphenylacetic acid (DOPAC) was decreased in the striatum to the same extent as the decrease in the 5-HIAA concentrations. The effect on the homovanillic acid (HVA) concentration was somewhat weaker as was the increase in the concentration of dopamine. No essential difference was found after acute and chronic treatment on the amine and metabolite levels. The MAO activity returned to normal 24 hours after final dosing. A large difference between the neuronal and the extraneuronal protection against the phenelzine-induced irreversible MAO inhibition in the hypothalamus was found after both acute and repeated treatment. The ED50 of the protection within the serotonergic neurons was 1.3 mumoles/kg p.o. (acute) and 0.75 mumoles/kg p.o. (repeated). Amiflamine was 3 times less potent within noradrenergic neurons than within serotonergic neurons. A brain to plasma ratio of about 20:1 was found for amiflamine and its metabolites. The plasma and the brain concentrations of the N-demethylated metabolite [FLA 788(+)] exceeded that of amiflamine after a single dose, whereas the N,N-demethylated [FLA 668(+)] was found in low concentrations. The effect on MAO-A correlated significantly with the plasma and the brain concentration of FLA 788(+).     

Effect of theophylline on monoamine metabolism in the rat brain

The effect of theophylline on brain monoamine metabolism was studied in rats. Single doses of theophylline caused a striking and dose-related increase in the levels of 3-methoxy-4-hydroxyphenylethylene glycol sulfate (MOPEG-SO₄) and 5-hydroxyindoleacetic acid (5-HIAA) in the brain. The level of brain homovanillic acid was only slightly affected. No appreciable change occurred, however, in the levels of brain norepinephrine, serotonin and dopamine. The increased level of brain MOPEG-SO₄ or 5-HIAA after theophylline does not appear to result from its interference with the transport system for the acids in the brain since the rate of decline of the acid levels following pargyline was not affected. Under the conditions of brain monoamine oxidase inhibition, theophylline enhanced the increase in brain normetanephrine level without causing any change in 3-methoxytyramine level. The enhancement of brain normetanephrine level by theophylline became more pronounced when rats were pretreated with imipramine in addition to pargyline.These results suggest that, in the brain, theophylline may cause a release of serotonin leading to its increased turnover. The results also confirm the previous conclusion that the methylxanthine causes a release of norepinephrine and a concomitant increase in its turnover in the brain.     

Rat brain monoamine metabolism and hypobaric hypoxia: a new approach

A chromatographic method with electrochemical detection was used to measure noradrenaline (NA), dopamine (DA), and serotonin (5-HT), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-methoxytyramine (3-MT) and 5-hydroxyindoleacetic acid (5-HIAA) in several brain areas (hypothalamus, hippocampus, striatum and rest of the brain) of rats exposed to a 7000 m simulated altitude for 3 hr. This new direct approach, not using a pharmacological tool, provides further information on the hypobaric hypoxia effects on the main DA and 5-HT metabolic steps. In the hypothalamus, a decreased NA level with increased DA and DOPAC contents was considered as the result of dopamine-beta-hydroxylase activity impairment. The decrease of both 5-HIAA and DOPAC in all brain areas provides further evidence of the hypoxia-induced decrement in MAO activity. Furthermore, in the striatum, it was shown that catechol-O-methyl transferase, up to now considered unaffected by hypoxia, may also be altered by oxygen deficiency.     

Mode of action and characteristics of monoamine oxidase-A inhibition by moclobemide

The mode of interaction of the reversible monoamine oxidase-A (MAO-A) inhibitor moclobemide with the enzyme was investigated. The inhibition of rat brain or human placenta MAO-A by moclobemide showed an initial competitive phase, with a relatively low affinity (K_I=0.2–0.4 mM). However, the potency of the inhibitor was increased with incubation time. The time-dependent component of the association of moclobemide with MAO-A followed pseudo-first order kinetics. In contrast to mechanism-based inhibitors, no indication for adduct or product formation was detected after incubation of moclobemide with the enzyme. Even though some aspects of the moclobemide interaction with MAO-A are still not completely elucidated, this compound seems to have the characteristics of a slow-binding inhibitor.