Selective Monoamine oxidase-A Inhibitor Research Articles

Carotid baroreceptor stimulation prevents oxidative stress by inhibiting MAO-A and prevents cardiac remodeling in obese rats.

Sympathetic nervous system overactivation and abnormal lipid metabolism are featured in obesity and may lead to cardiac remodeling. The effects of carotid baroreceptor stimulation (CBS) on cardiac remodeling in obese rats and the underlying mechanisms were explored. An obesity model was induced by 16-week high-fat diet feeding. A CBS device was implanted at the 8th week. Body weight and blood pressure measurements, electrocardiography, echocardiography, and glucose and insulin tolerance tests were conducted before sampling. Plasma analysis and histological and biological analyses of left ventricle were also performed. Neonatal rat cardiomyocytes cocultured with 3T3-L1 in transwell chambers were used to investigate the mechanisms. CBS alleviated several manifestations of obesity, including increased body weight, high blood pressure, hyperlipidemia, and enhanced sympathetic activity. In obese hearts, norepinephrine levels decreased, and the monoamine oxidase A (MAO-A) and reactive oxygen species level increased; these changes, as well as cardiac fibrosis, lipid metabolic disorders, and heart dysfunction, were inhibited by CBS. Neonatal rat cardiomyocytes incubated with norepinephrine showed MAO-A upregulation, increased reactive oxygen species levels, lipid metabolic disorders, and inflammatory response, which were inhibited by clorgyline, a selective MAO-A inhibitor. CBS effectively suppresses sympathetic nervous system activity and oxidative stress mediated by MAO-A and prevents cardiac remodeling in obese rats.

Administration of moclobemide facilitates fear extinction and attenuates anxiety-like behaviors by regulating synaptic-associated proteins in a rat model of post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a long-lasting mental disorder and accompanied by worse fear extinction. Enhanced fear memory or poor fear extinction are typical features of PTSD. Dysfunction of the serotonergic neurotransmitter system is involved in numerous mental and behavioral disorders. Monoamine oxidase A (MAOA) is important in the metabolism of serotonin and play an important role in behavious. The aim of this study was to explore the change of MAOA and effect of MAOA on fear memory in PTSD. We used single prolonged stress (SPS) to create animal model of PTSD. A startle/fear box and elevated plus maze were used to observe fear memory and anxiety level, respectively. We examined the expression of MAOA and synaptic marker protein, as well as the immunological activity of MAOA in the infralimbic cortex (IL) area, which is a critical brain region involved in emotions, especially fear regulation. We found increased anxiety-like behavior, dysfunction in fear extinction, and increased MAOA in SPS rats. After treatment with moclobemide (a selective inhibitor of MAOA), SPS rats showed significantly improved fear memory and decreased anxiety-like behavior, which indicated that moclobemide could reverse fear extinction deficit and attenuate abnormally increased levels of anxiety caused by SPS in short term. On the contrary, decreased PSD-95 and SYN1 expression in the IL region were also reversed by moclobemide. These results suggest that increased MAOA play a negative role in fear extinction and levels of anxiety in PTSD, which may be involved in change in PSD-95 and SYN1.

Selective inhibition of monoamine oxidase A by chelerythrine, an isoquinoline alkaloid

Chelerythrine, an isoquinoline alkaloid isolated from the herbaceous perennial Chelidonium majus, was found to potently and selectively inhibit an isoform of recombinant human monoamine oxidase-A (MAO-A) with an IC50 value of 0.55 µM. Chelerythrine was a reversible competitive MAO-A inhibitor (Ki = 0.22 µM) with a potency much greater than toloxatone (IC50 = 1.10 µM), a marketed drug. Other isoquinoline alkaloids tested did not effectively inhibit MAO-A or MAO-B. A structural comparison with corynoline suggested the 1- and/or 2-methoxy groups of chelerythrine increase its inhibitory activity against MAO-A. Molecular docking simulations revealed that the binding affinity of chelerythrine for MAO-A (−9.7 kcal/mol) was greater than that for MAO-B (−4.6 kcal/mol). Docking simulation implied that Cys323 and Tyr444 of MAO-A are key residues for hydrogen-bond interaction with chelerythrine. Our findings suggest chelerythrine is one of the most reversible selective and potent natural inhibitor of MAO-A, and that it be regarded a potential lead compound for the design of novel reversible MAO-A inhibitors.

The monoamine oxidase-A inhibitor clorgyline promotes a mesenchymal-to-epithelial transition in the MDA-MB-231 breast cancer cell line

Monoamine oxidase-A (MAO-A) dysfunction has been historically associated with depression. Recently, depression as well as altered MAO-A expression have both been associated with a poor prognosis in cancers, although the mechanism involved remains ambiguous. For example, MAO-A mRNA is repressed across cancers, yet MAO-A protein and levels of serotonin, a substrate of MAO-A implicated in depression, are paradoxically increased in malignancies, including breast cancer.The effect of clorgyline (CLG), a selective inhibitor of MAO-A, on malignant behaviour, expression of transitional markers, and biochemical correlates was examined in two human breast carcinoma cell lines, i.e. the epithelial, oestrogen receptor (ER)-positive MCF-7 cell line and the post-EMT (mesenchymal), ER-negative MDA-MB-231 cell line.CLG exerted little effect on malignant behaviour in MCF-7 cells, but inhibited proliferation and anchorage-independent growth, and increased invasiveness and active migration of MDA-MB-231 cells. CLG induced the expression of the mesenchymal marker vimentin in MCF-7 cells, but not in MDA-MB-231 cells. In contrast, CLG induced the epithelial protein marker E-cadherin in both cell lines, with a more robust effect in MDA-MB-231 cells (where a nuclear E-cadherin signal was also detected). This effect appears to be independent of any canonical Snai1-mediated regulation of E-cadherin mRNA expression. CLG interfered with the β-catenin/[phospho]GSK-3β complex as well as the E-cadherin/β-catenin complex in both cell lines cells, but, again, the effect was more robust in MDA-MB-231 cells. Parallel studies revealed a general lack of effect of CLG on the ER-negative, epithelial Au565 breast cancer cell line. Thus, any effect of CLG on metastatic behaviours appears to rely on the cell's EMT status rather than on the cell's ER status.These data suggest that inactivation of MAO-A triggers a mesenchymal-to-epithelial transition in MDA-MB-231 cells via a non-canonical mechanism. This potentially implicates an MAO-A-sensitive step in advanced breast cancer and should be borne in mind when considering pharmacological treatment options for co-morbid depression in breast cancer patients.

Coupling of a High‐resolution Monoamine Oxidase‐A Inhibitor Assay and HPLC–SPE–NMR for Advanced Bioactivity Profiling of Plant Extracts

Depression is a mental disease causing large personal and socio-economic problems, and new improved drugs are therefore needed. Selective monoamine oxidase A (MAO-A) inhibitors are potential anti-depressants, but discovering new MAO-A inhibitors from natural sources by bioassay-guided approaches are a lengthy and time-consuming process. New analytical technologies that allow simultaneously chemical and biological screening of extracts are therefore urgently needed. In the present study we describe coupling of a photometric microplate-based high-resolution MAO-A inhibitor assay with a hyphenated system consisting of high-performance liquid chromatography, solid-phase extraction and tube transfer nuclear magnetic resonance (HPLC-SPE-ttNMR). The standard compound clorgyline, and an extract of black pepper (Piper nigrum L.), representing a complex plant matrix, were used for proof-of-concept. The work with clorgyline showed that the microplate-based high-resolution assay produced MAO-A inhibition profiles that easily allowed detection of submicrogram amounts of this selective MAO-A inhibitor. Furthermore, the HPLC-SPE-ttNMR/high-resolution MAO-A inhibition assay platform allowed identification of piperine and two piperine analogues as the main MAO-A inhibitors in the black pepper petroleum ether extract. The HPLC-SPE-ttNMR/high-resolution MAO-A inhibition assay platform is a powerful tool for fast and efficient identification of new MAO-A inhibitors from complex extracts, and promise future advancement in the search for new anti-depressants from natural sources.

Monoamine oxidase A inhibitor occupancy during treatment of major depressive episodes with moclobemide or St. John’s wort: an [11C]-harmine PET study

Monoamine oxidase A (MAO-A) inhibitor antidepressants raise levels of multiple monoamines, whereas the selective serotonin reuptake inhibitors (SSRIs) only raise extracellular serotonin. Despite this advantage of MAO-A inhibitors, there is much less frequent development of MAO inhibitors compared with SSRIs. We sought to measure brain MAO-A occupancy after 6 weeks of treatment in depressed patients with a clinically effective dose of a selective MAO-A inhibitor and measure MAO-A occupancy after repeated administration of St. John's wort, an herb purported to have MAO-A inhibitor properties. Participants underwent 2 [(11)C]-harmine positron emission tomography scans. Healthy controls completed a test-retest condition, and depressed patients were scanned before and after repeated administration of moclobemide or St. John's wort for 6 weeks at the assigned dose. We measured MAO-A VT, an index of MAO-A density, in the prefrontal, anterior cingulate and anterior temporal cortices, putamen, thalamus, midbrain and hippocampus. We included 23 participants (10 controls and 13 patients with major depressive disorder [MDD]) in our study. Monoamine oxidase A VT decreased significantly throughout all regions after moclobemide treatment in patients with MDD compared with controls (repeated-measures analysis of variance, F1,15 = 71.08-130.06, p < 0.001 for all regions, mean occupancy 74% [standard deviation 6%]). Treatment with St. John's wort did not significantly alter MAO-A VT. The occupancy estimates are limited by the sample size of each treatment group; hence, our estimate for the overall moclobemide occupancy of 74% has a 95% confidence interval of 70%-78%, and we can estimate with 95% certainty that the occupancy of St. John's wort is less than 5%. For new MAO-A inhibitors, about 74% occupancy at steady-state dosing is desirable. Consistent with this, St. John's wort should not be classified as an MAO-A inhibitor. The magnitude of MAO-A blockade during moclobemide treatment exceeds the elevation of MAO-A binding during illness by at least 30%, suggesting that the treatment effect should exceed the disease effect when designing selective antidepressants for this target.

Moclobemide exerts anti-inflammatory effect in lipopolysaccharide-activated primary mixed glial cell culture

An increasing body of evidence indicates that glial activation and neuroinflammation play an important role in the pathogenesis of psychiatric and neurodegenerative diseases. Activated glial cells secrete various cytokines that influence neurotransmission, hypothalamus-pituitary-adrenal axis activity, neuronal plasticity and neurogenesis. It has been suggested that alterations in cytokine networks are involved in the mechanism of action of antidepressant drugs. Until now, only a few studies demonstrated that some tricyclic antidepressants and selective serotonin reuptake inhibitors reduced production of pro-inflammatory cytokines in brain glia cells. We have investigated for the first time whether the antidepressant, moclobemide (a reversible selective inhibitor of monoamine oxidase-A) has an influence on pro-inflammatory cytokines [interleukin (IL)-1β and tumor necrosis factor (TNF)-α] and anti-inflammatory cytokine (IL-10) in primary rat mixed glial cell cultures stimulated by lipopolysaccharide (LPS). Our results showed that moclobemide used in a wide range of concentrations diminished LPS-stimulated IL-1β and TNF-α mRNAs expression in cellular extracts and remarkably reduced the levels of both pro-inflammatory cytokines in culture medium. In opposite to this, the drug had no influence on IL-10 mRNA and slightly reduced IL-10 concentration. Moreover, moclobemide decreased LPS-stimulated translocation of NFκB p65 subunit into cellular nuclei. These results suggest that moclobemide exerts anti-inflammatory effect in the central nervous system because it affects the balance between pro- and anti-inflammatory cytokines (IL-1β, TNF-α/IL-10) in primary mixed glial cell cultures.

P.2.c.012 Testosterone gel replacement improves sexual function in hypogonadal depressed men taking antidepressants

In a meta-analysis of the selective serotonin reuptake inhibitor fluoxetine (n = 440) and the reversible and selective monoamine oxidase-A inhibitor moclobemide (n = 437) we investigated the time course of improvement over 6 weeks for these two classes of anti-depressants. Two different methods of approach were applied: (1) repeated measurement analysis of variance in combination with regression analysis, and (2) a survival-analytical approach that allowed us to determine onset of improvement for the individual patient, to distinguish between early and late improvers, to assess the predictive value of early improvement, and to adequately process premature withdrawals. The two antidepressants of large biochemical and pharmacological differences yielded virtually identical response- and drop-out rates, and exhibited no difference with respect to the time course of improvement. Onset of improvement occurred in more than half of the patients within the first 2 weeks of treatment, and early improvement was highly predictive of later outcome. In particular, there was no indication for a delayed onset of action of antidepressants. We suggest that future studies should be standardised with respect to washout period and sufficiently dense assessments during the first 2 weeks of trial. Thus, patient samples can be subdivided reproducibly into early-, late-, partial- and non-remitters. This, in turn, may help to identify “true” drug responders, and to discover why in some patients recovery becomes “stuck”. Data already held by the pharmaceutical companies should be reanalysed in this respect.

Sulfur-Substituted α-Alkyl Phenethylamines as Selective and Reversible MAO-A Inhibitors: Biological Activities, CoMFA Analysis, and Active Site Modeling

A series of phenethylamine derivatives with various ring substituents and with or without N-methyl and/or C-alpha methyl or ethyl groups was synthesized and assayed for their ability reversibly to inhibit monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). Several compounds showed potent and selective MAO-A inhibitory activity (IC(50) in the submicromolar range) but none showed appreciable activity toward MAO-B. A three-dimensional quantitative structure-activity relationship study for MAO-A inhibition was performed on the series using comparative molecular field analysis (CoMFA). The resulting model gave a cross-validated q(2) of 0.72 and showed that in this series of compounds steric properties of the substituents were more important than electrostatic effects. Molecular modeling based on the recently published crystal structure of inhibitor-bound MAO-A provided detailed evidence for specific interactions of the ligands with the enzyme, supported by previous references and consistent with results from the CoMFA. On the basis of these results, structural determinants for selectivity of substituted amphetamines for MAO-A are discussed.

Frequency of sexual dysfunction in depressed adults and impact on quality of life

The protective effect of moclobemide, a reversible and highly selective inhibitor of monoamine oxidase-A, against hypoxia-induced lethality was investigated in the present experiment. Moclobemide showed an apparent protective potency against hypoxia and significantly prolonged the latencies for convulsions and death in a dose-dependent manner. Hypothermia is known to protect animals from hypoxia. Moclobemide also decreased body temperature in mice; however, the hypothermic effect was unrelated to the antihypoxic effect. These results suggest that the protective effect of moclobemide in hypoxia is not due to a decrease in body temperature.

Further characteristics of a new genetic mouse model of depression: Differential responsiveness of mice prone or resistant to helplessness in several behavioural tests

1.1. The efficacies of different classes of antidepressants were investigated using the forced swimming test with mice at different ages.2.2. Imipramine (4–32 mg/kg), desipramine (2–16 mg/kg) and bupropion (32, 64 mg/kg) showed activity in all age groups.3.3. The selective serotonin reuptake inhibitors (SSRIs) citalopram (16 and 32 mg) and paroxetine (4 and 8 mg) were inactive in the oldest (40 weeks) group of mice, despite showing activity at the same doses in mice ranging in age from 4–24 weeks old.4.4. Both SSRIs showed anti-immobility effects at low doses, (paroxetine: 1 and 2 mg/kg; citalopram: 4 and 8 mg/kg) in the 40-week old mice. These effects were not evident in the three younger groups of mice.5.5. Moclobemide, a reversible selective inhibitor of monoamine oxidase-A, showed activity only at a high dose (128 mg/kg) and only in 12-week old animals.6.6. Since SSRIs have been reported to have relatively selective effects on 5-HT1B receptors, the present results suggest that further studies comparing the effectiveness of SSRIs and other antidepressants in elderly patients should be done. Studies of the effects of aging on the density and/or affinity of 5-HT1a and 5-HT1B/1D receptors are also warranted.

5-HT 1A receptor antagonists neither potentiate nor inhibit the effects of fluoxetine and befloxatone in the forced swim test in rats

Recent clinical data suggest that coadministration of pindolol with an antidepressant, particularly the 5-hydroxytryptamine (5-HT) reuptake inhibitor fluoxetine, can shorten the time to onset of clinical activity and increase the proportion of responders. We have examined the interaction of antidepressants with 5-HT 1A receptors using the forced swim test in rats using both (±)-pindolol and the selective 5-HT 1A receptor antagonist WAY 100,635 ( N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]- N-(pyridinyl) cyclohexanecarboxamide trihydrochloride) in combination with either fluoxetine or the selective monoamine oxidase-A inhibitor befloxatone. 8-Hydroxy-dipropylaminotetralin (8-OH-DPAT; 0.125–1 mg/kg s.c.), used as a reference for 5-HT 1A agonist activity, reduced immobility in the forced swim test and this effect was significantly antagonised by WAY 100,635. WAY 100,635 alone (0.01–0.1 mg/kg s.c.) was without effect, although a higher dose, 0.3 mg/kg s.c., had a nonsignificant tendency to increase immobility. In contrast, (±)-pindolol (1–16 mg/kg s.c.) significantly reduced immobility, but to a lesser extent than 8-OH-DPAT. As expected, the antidepressants fluoxetine (10–80 mg/kg p.o.) and befloxatone (0.03–1 mg/kg p.o.) dose-dependently reduced immobility time. When the antidepressants were combined with WAY 100,635 (0.1 mg/kg), WAY 100,635 either had no effect or, at relatively high doses, significantly reduced their activity in this test. Combination of the antidepressants with (±)-pindolol (2 or 4 mg/kg s.c.) failed to reveal a significant interaction. These results demonstrate that the anti-immobility effects of fluoxetine and befloxatone are neither facilitated nor antagonised by doses of WAY 100,635 that completely reverse the effects of 8-OH-DPAT. Furthermore, there was no evidence that coadministration of the antidepressants with (±)-pindolol was able to facilitate their antidepressant-like effects. Thus, whereas direct agonist activity at 5-HT 1A receptors can modulate immobility in the forced swim test, this receptor subtype does not appear to play a major role in the antidepressant-like effects of fluoxetine or befloxatone under the conditions used in this study.

Regional action of brofaromine on rat brain MAO-A and MAO-B

1. 1. Brofaromine (CGP 11305 A) belongs to a new generation of monoamine oxidase (MAO) inhibitors. These compounds induce short, reversible and selective inhibition of brain MAO of type A. 2. 2. The aim of this work is to study monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) activities of several rat brain regions after increasing doses of brofaromine. 3. 3. Brofaromine inhibits MAO-A activities in a dose dependent manner in all brain regions examined. 4. 4. The largest reduction was found in hippocampal formation, striatum and prefrontal cortex respectively. ID 50 is 2 times lower in hippocampus than in remaining brain. 5. 5. Brofaromine does not inhibit MAO-B activities in the different regions examined. 6. 6. Brofaromine is a very selective inhibitor of rat brain MAO-A with a preferential action on telencephalic monoaminergic nerve terminals.

Inhibition of monoamine oxidase-B by condensed pyridazines and pyrimidines: effects of lipophilicity and structure-activity relationships.

A number of condensed pyridazines and pyrimidines were synthesized and tested for their monoamine oxidase-A (MAO-A) and MAO-B inhibitory activity. Their lipophilicity was examined by measuring partition coefficients and RP-HPLC capacity factors, revealing some peculiar electronic and conformational effects. Further insights were obtained by X-ray crystallography and a thermodynamic study of RP-HPLC retention. Structure-activity relations highlighted the main factors determining both selectivity and inhibitory potency. Thus, while most of the condensed pyridazines were reversible inhibitors of MAO-B with little or no MAO-A effects, the pyrimidine derivatives proved to be reversible and selective MAO-A inhibitors. Substituents on the diazine nucleus modulated enzyme inhibition. A QSAR analysis of X-substituted 3-X-phenyl-5H-indeno[1,2-c]pyridazin-5-ones showed lipophilicity to increase MAO-B and not MAO-A inhibitory activity.

Onset of improvement under fluoxetine and moclobemide

In a meta-analysis of the selective serotonin reuptake inhibitor fluoxetine (n = 440) and the reversible and selective monoamine oxidase-A inhibitor moclobemide (n = 437) we investigated the time course of improvement over 6 weeks for these two classes of anti-depressants. Two different methods of approach were applied: (1) repeated measurement analysis of variance in combination with regression analysis, and (2) a survival-analytical approach that allowed us to determine onset of improvement for the individual patient, to distinguish between early and late improvers, to assess the predictive value of early improvement, and to adequately process premature withdrawals. The two antidepressants of large biochemical and pharmacological differences yielded virtually identical response- and drop-out rates, and exhibited no difference with respect to the time course of improvement. Onset of improvement occurred in more than half of the patients within the first 2 weeks of treatment, and early improvement was highly predictive of later outcome. In particular, there was no indication for a delayed onset of action of antidepressants. We suggest that future studies should be standardised with respect to washout period and sufficiently dense assessments during the first 2 weeks of trial. Thus, patient samples can be subdivided reproducibly into early-, late-, partial- and non-remitters. This, in turn, may help to identify "true" drug responders, and to discover why in some patients recovery becomes "stuck". Data already held by the pharmaceutical companies should be reanalysed in this respect.

Evaluation of efficacies of different classes of antidepressants in the forced swimming test in mice at different ages

1. 1. The efficacies of different classes of antidepressants were investigated using the forced swimming test with mice at different ages. 2. 2. Imipramine (4–32 mg/kg), desipramine (2–16 mg/kg) and bupropion (32, 64 mg/kg) showed activity in all age groups. 3. 3. The selective serotonin reuptake inhibitors (SSRIs) citalopram (16 and 32 mg) and paroxetine (4 and 8 mg) were inactive in the oldest (40 weeks) group of mice, despite showing activity at the same doses in mice ranging in age from 4–24 weeks old. 4. 4. Both SSRIs showed anti-immobility effects at low doses, (paroxetine: 1 and 2 mg/kg; citalopram: 4 and 8 mg/kg) in the 40-week old mice. These effects were not evident in the three younger groups of mice. 5. 5. Moclobemide, a reversible selective inhibitor of monoamine oxidase-A, showed activity only at a high dose (128 mg/kg) and only in 12-week old animals. 6. 6. Since SSRIs have been reported to have relatively selective effects on 5-HT 1B receptors, the present results suggest that further studies comparing the effectiveness of SSRIs and other antidepressants in elderly patients should be done. Studies of the effects of aging on the density and/or affinity of 5-HT 1a and 5-HT 1B/1D receptors are also warranted.

Design and Synthesis of Novel and Potent Monoamine Oxidase Inhibitors

Reversible and selective monoamine oxidase-A inhibitors (RIMA's) like moclobemide (Aurorix®) have rehabilitated the use of MAO inhibitors as drugs of choice in depression. Starting from the structure of moclobemide, we tried to identify novel types of MAO inhibitors by bioisosteric replacement of the amide group. 2-Aminomethyl-5-phenylpyrroles retained some in vitro activity and served as a starting point for the construction of restricted rotation analogues. 3,4-Dihydro-6-phenylpyrrolo[1,2-a]pyrazines were the most interesting members of a family of 6-, 7-, and 8-phenyl-substituted pyrrolo[1,2-a]pyrazines and were subsequently optimized. A 'lipophilic linker' between phenyl and pyrrole ring proved exceedingly useful to improve affinity and led to the benzo[g]pyrazino[1,2-a]indole ring system. Synthetic procedures starting from substituted 1-tetralones allowed the synthesis of substituted derivatives of this ring system. Once the optimal substitution pattern had been identified, facile synthesis of derivatives was achieved from aromatic triflates by Stille or Suzuki coupling. In this series selective and reversible monoamine oxidase-A inhibitors as well as mixed MAO-A and B inhibitors were identified. Affinity of this compounds for MAO was in the nanomolar or even sub-nanomolar range (for monoamine oxidase-A). In conclusion, benzo[g]pyrazino[1,2-a]indoles have been identified as a new class of reversible and highly potent monoamine oxidase inhibitors.

The protective effect of moclobemide against hypoxia-induced lethality in mice is not due to a decrease in body temperature

The protective effect of moclobemide, a reversible and highly selective inhibitor of monoamine oxidase-A, against hypoxia-induced lethality was investigated in the present experiment. Moclobemide showed an apparent protective potency against hypoxia and significantly prolonged the latencies for convulsions and death in a dose-dependent manner. Hypothermia is known to protect animals from hypoxia. Moclobemide also decreased body temperature in mice; however, the hypothermic effect was unrelated to the antihypoxic effect. These results suggest that the protective effect of moclobemide in hypoxia is not due to a decrease in body temperature.

Pressor Effect of Oral Tyramine During Treatment with Befloxatone, a New Reversible Monoamine Oxidase‐A Inhibitor, in Healthy Subjects

The interaction between tyramine and befloxatone, a new selective, reversible monoamine oxidase-A (MAO-A) inhibitor, was studied in a single-blind, parallel-group study in 30 healthy male volunteers whose fasting tyramine 30 dose (Tyr30) was 400 or 600 mg. Each subject completed a placebo run-in period followed by a befloxatone period. Befloxatone was given in repeated doses according to one of three regimens: befloxatone 20 mg once daily at the end of a meal rich in tyramine or befloxatone 10 or 20 mg twice daily 2 hours before a meal rich in tyramine. Subjects were given increasing daily doses of tyramine mixed with the meal, until a systolic blood pressure increase of at least 30 mm Hg was achieved (Tyr30). The mean Tyr30 decreased from 1220 mg (range, 600-1800 mg) during placebo to 290 mg (range, 150-500 mg) during befloxatone 20 mg once daily, 250 mg (range, 100-300) during befloxatone 10 mg twice daily, and 155 mg (range, 100-250 mg) during befloxatone 20 mg twice daily; corresponding to a potentiation factor of 5.2-, 6.5-, and 7.9-fold, respectively. The extent and the duration of the systolic blood pressure increase did not significantly differ between the placebo and the befloxatone regimens, except for a longer duration with the 20-mg twice daily regimen. These results are similar to those reported with the therapeutic dosage of other selective MAO-A inhibitors. They suggest that there would be little risk of hypertensive crisis in patients treated in clinical studies with befloxatone, and thus dietary restrictions appear to be unnecessary when the drug is given in a regimen of up to 20-mg once daily after meals.

The clinical relevance of treatment with antidepressants.

Oince the discovery in the late 1950's of imipramine (Tofranil®), the first tricyclic antidepressant (TCA), and iproniazid, the first monoamine oxidase inhibitor (MAOI), many other TCAs and MAOIs, now being considered the classical antidepressants, have become available. Their effectiveness has been shown in numerous studies, although according to nowadays standards well designed studies (placebo-controlled, defined diagnostic groups, the use of standardized rating scales) with these compounds are relatively scarce. From the early 1980's the so called modern antidepressants have been introduced: the selective serotonin re-uptake inhibitors (SSRIs), the reversible selective monoamine oxidase-A inhibitors (RIMAs) and a variety of other compounds. All these drugs have been registered after their effectiveness had been shown in well designed, placebo-controlled studies. In defining the efficacy of antidepressants, registration authorities consider two aspects important: statistical evidence and clinical relevance.