-
Zhonghua Xue Ye Xue Za Zhi = Zhonghua... Feb 2016To investigate the effect of monoamine oxidase inhibitor phenelzine on proliferation, apoptosis and histone modulation in acute lymphoblastic leukemia cell line Molt-4...
OBJECTIVE
To investigate the effect of monoamine oxidase inhibitor phenelzine on proliferation, apoptosis and histone modulation in acute lymphoblastic leukemia cell line Molt-4 cells.
METHODS
The effect of Phenelzine on cell proliferation was detected by MTT. Apoptotic rate was measured by flow cytometry. The variation of apoptosis associated proteins Caspase-3, Bcl-2 and Bax, cyclin-dependent kinase inhibitor p21, tumor suppressor protein p15, and the expression level of histone methylation of H3K4, H3K9 and histone acetylation of H3, DNMT1 were detected by Western Blot.
RESULTS
① Molt-4 cell proliferation rates were (87.68±3.54)%, (67.84±3.24)%, (51.48±3.37)%, (28.72±2.56)% respectively after exposured to phenelzine at 5, 10, 15, 20 μmol/L for 24 h, P<0.05. ② After 10 μmol/L of phenelzine exposure for 24, 48, 72 h, cell proliferation rates were (67.84±3.24)%, (50.24±2.01)%, (40.31±2.25)%, P<0.05. ③ The apoptotic rates were (13.64±2.58)%, (31.24±3.42)%, (56.37±4.26)% after phenelzine treatment at 5, 10, 20 μmol/L for 24 h, which was concentration dependent. ④ Phenelzine could upregulate the expression of Bax, caspase-3, p21, and downregulate Bcl-2 expression. Phenelzine upregulated the methylation level of histone H3K4me1, H3K4me2 and histone acetylated H3, while it didn't change the level of histone H3K4me3, H3K9me1, H3K9me2. ⑤ Phenelzine inhibited DNMT1 expression and promoted p15 expression.
CONCLUSIONS
Phenelzine increased the methylation of histone H3K4me1, H3K4me2, acetylation of histone H3 and p21, and decreased the expression of DNMT1 and p15, and ultimately inhibited the proliferation and apoptosis of Molt-4 cells.
Topics: Acetylation; Apoptosis; Apoptosis Regulatory Proteins; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p15; Cyclin-Dependent Kinase Inhibitor p21; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases; Histones; Humans; Methylation; Phenelzine
PubMed: 27014985
DOI: 10.3760/cma.j.issn.0253-2727.2016.02.012 -
The Journal of Pain Apr 2016Changes in serotonin (5-hydroxytryptamine; 5-HT), noradrenaline (NA), and γ-aminobutyric acid (GABA) levels in the spinal cord are known to occur in response to...
UNLABELLED
Changes in serotonin (5-hydroxytryptamine; 5-HT), noradrenaline (NA), and γ-aminobutyric acid (GABA) levels in the spinal cord are known to occur in response to nociceptive stimuli, yet little research has examined possible underlying sex differences in these changes and how they might affect nociception. We have used pharmacological approaches in a well established model of tonic nociception, the formalin test, to explore the effects of altering neurotransmitter levels on nociceptive responses in male and female C57BL/6 mice. The monoamine oxidase (MAO) inhibitor phenelzine (PLZ), its metabolite phenylethylidenehydrazine (PEH), and a derivative compound of PLZ, N(2)-acetylphenelzine (N(2)-AcPLZ), were used to increase endogenous levels of: GABA, 5-HT, and NA (PLZ); GABA alone (PEH); or 5-HT and NA only (N(2)-AcPLZ). Although both sexes had a reduction in second phase nociceptive behaviors with PEH pretreatment, the analgesic effect of PLZ was only observed in male mice. High performance liquid chromatography analysis revealed male mice had greater spinal cord increases in 5-HT and NA levels compared with female mice. Female mice, in contrast, had greater increases in GABA levels with pretreatments. With N(2)-AcPLZ pretreatment, only male mice had a reduction in second phase nociceptive behaviors despite similar increases in 5-HT and NA levels in both sexes. These findings suggest that male mice may utilize serotonergic and noradrenergic pathways more efficiently for the attenuation of nociceptive behavior and female mice are more dependent on alternate mechanisms. To our knowledge, these findings are the first on the antinociceptive properties of altering 5-HT, NA, and GABA levels with the MAO inhibitor PLZ and its derivatives in a model of tonic pain processing. They also reveal significant underlying sex differences associated with these treatments.
PERSPECTIVE
The present study found that nociception in male and female mice may be regulated by different neurotransmitter systems. These results indicate that different pharmacological approaches may be needed to treat pain in both sexes.
Topics: Adrenergic alpha-2 Receptor Antagonists; Animals; Biphenyl Compounds; Castration; Estrous Cycle; Female; Fixatives; Formaldehyde; Idazoxan; Locomotion; Male; Mice; Mice, Inbred C57BL; Monoamine Oxidase Inhibitors; Neurotransmitter Agents; Nociception; Nociceptive Pain; Phenelzine; Piperazines; Pyridines; Serotonin Antagonists; Sex Characteristics
PubMed: 26748043
DOI: 10.1016/j.jpain.2015.12.013 -
PloS One 2015Social anxiety disorder is one of the most persistent and common anxiety disorders. Individually delivered psychological therapies are the most effective treatment...
BACKGROUND
Social anxiety disorder is one of the most persistent and common anxiety disorders. Individually delivered psychological therapies are the most effective treatment options for adults with social anxiety disorder, but they are associated with high intervention costs. Therefore, the objective of this study was to assess the relative cost effectiveness of a variety of psychological and pharmacological interventions for adults with social anxiety disorder.
METHODS
A decision-analytic model was constructed to compare costs and quality adjusted life years (QALYs) of 28 interventions for social anxiety disorder from the perspective of the British National Health Service and personal social services. Efficacy data were derived from a systematic review and network meta-analysis. Other model input parameters were based on published literature and national sources, supplemented by expert opinion.
RESULTS
Individual cognitive therapy was the most cost-effective intervention for adults with social anxiety disorder, followed by generic individual cognitive behavioural therapy (CBT), phenelzine and book-based self-help without support. Other drugs, group-based psychological interventions and other individually delivered psychological interventions were less cost-effective. Results were influenced by limited evidence suggesting superiority of psychological interventions over drugs in retaining long-term effects. The analysis did not take into account side effects of drugs.
CONCLUSION
Various forms of individually delivered CBT appear to be the most cost-effective options for the treatment of adults with social anxiety disorder. Consideration of side effects of drugs would only strengthen this conclusion, as it would improve even further the cost effectiveness of individually delivered CBT relative to phenelzine, which was the next most cost-effective option, due to the serious side effects associated with phenelzine. Further research needs to determine more accurately the long-term comparative benefits and harms of psychological and pharmacological interventions for social anxiety disorder and establish their relative cost effectiveness with greater certainty.
Topics: Adult; Anxiety Disorders; Cost-Benefit Analysis; Female; Humans; Male; Psychotherapy; Quality-Adjusted Life Years; Treatment Outcome
PubMed: 26506554
DOI: 10.1371/journal.pone.0140704 -
The International Journal of... Aug 2015Monoamine oxidase inhibitors (MAOIs) are being developed for major depressive disorder, Alzheimer's, and Parkinson's Disease. Newer MAOIs have minimal sensitivity to...
BACKGROUND
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.
METHODS
Major depressive episode (MDE) subjects underwent [(11)C]harmine positron emission tomography scanning prior to and following 6 weeks of treatment with moclobemide or phenelzine.
RESULTS
Mean brain MAO-A occupancies were 74.23±8.32% for moclobemide at 300-600 mg daily (n = 11), 83.75±5.52% for moclobemide at 900-1200 mg daily (n = 9), and 86.82±6.89% for phenelzine at 45-60 mg 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 (900-1200 mg) compared to lower-dose moclobemide [300-600 mg; F(7,16) = 3.94, p = 0.01].
CONCLUSIONS
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.
Topics: Adult; Brain; Carbon Isotopes; Dose-Response Relationship, Drug; Female; Harmine; Healthy Volunteers; Humans; Male; Middle Aged; Moclobemide; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Multivariate Analysis; Phenelzine; Positron-Emission Tomography; Protein Binding; Young Adult
PubMed: 26316187
DOI: 10.1093/ijnp/pyv078 -
The International Journal of... Jul 2015Cognitive dysfunction is often present in major depressive disorder (MDD). Several clinical trials have noted a pro-cognitive effect of antidepressants in MDD. The... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Cognitive dysfunction is often present in major depressive disorder (MDD). Several clinical trials have noted a pro-cognitive effect of antidepressants in MDD. The objective of the current systematic review and meta-analysis was to assess the pooled efficacy of antidepressants on various domains of cognition in MDD.
METHODS
Trials published prior to April 15, 2015, were identified through searching the Cochrane Central Register of Controlled Trials, PubMed, Embase, PsychINFO, Clinicaltrials.gov, and relevant review articles. Data from randomized clinical trials assessing the cognitive effects of antidepressants were pooled to determine standard mean differences (SMD) using a random-effects model.
RESULTS
Nine placebo-controlled randomized trials (2 550 participants) evaluating the cognitive effects of vortioxetine (n = 728), duloxetine (n = 714), paroxetine (n = 23), citalopram (n = 84), phenelzine (n = 28), nortryptiline (n = 32), and sertraline (n = 49) were identified. Antidepressants had a positive effect on psychomotor speed (SMD 0.16; 95% confidence interval [CI] 0.05-0.27; I(2) = 46%) and delayed recall (SMD 0.24; 95% CI 0.15-0.34; I(2) = 0%). The effect on cognitive control and executive function did not reach statistical significance. Of note, after removal of vortioxetine from the analysis, statistical significance was lost for psychomotor speed. Eight head-to-head randomized trials comparing the effects of selective serotonin reuptake inhibitors (SSRIs; n = 371), selective serotonin and norepinephrine reuptake inhibitors (SNRIs; n = 25), tricyclic antidepressants (TCAs; n = 138), and norepinephrine and dopamine reuptake inhibitors (NDRIs; n = 46) were identified. No statistically significant difference in cognitive effects was found when pooling results from head-to-head trials of SSRIs, SNRIs, TCAs, and NDRIs. Significant limitations were the heterogeneity of results, limited number of studies, and small sample sizes.
CONCLUSIONS
Available evidence suggests that antidepressants have a significant positive effect on psychomotor speed and delayed recall.
Topics: Antidepressive Agents; Cognition; Cognition Disorders; Depressive Disorder, Major; Humans; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 26209859
DOI: 10.1093/ijnp/pyv082 -
Pharmacotherapy Apr 2015Treatment-resistant depression (TRD) is a major health concern. More than 40% of patients treated for major depressive disorder with an appropriate antidepressant dose... (Review)
Review
Treatment-resistant depression (TRD) is a major health concern. More than 40% of patients treated for major depressive disorder with an appropriate antidepressant dose for an adequate duration fail to respond. Further, approximately half of adults with major depressive disorder fail to achieve sustained remission despite various medication trials. The utilization of monoamine oxidase inhibitors (MAOIs) for the treatment of depression in clinical practice today is low due to their widely known adverse effects, some of which may be life threatening, and the risk for dietary and drug interactions. For these reasons, MAOIs are not recommended to be prescribed along with other antidepressants or certain prescription or nonprescription drugs. Pharmacologic options are limited for individuals with TRD, however, and there is a paucity of data on the efficacy of MAOIs in combination with other antidepressants for the management of TRD. We performed a search of the PubMed database (inception through January 25, 2015) to identify cases that illustrate the potential utility, as well as risks, of combination treatment with MAOIs and other antidepressants for the management of TRD; 18 articles met the criteria for our search. In addition, we performed a retrospective case series by reviewing the medical records of 29 adults treated for depression with an MAOI plus another psychotropic agent (an antidepressant or stimulant medication) between 2003 and 2012 at a large Midwestern teaching hospital. We compared the findings of the published experience with our local experience to allow for more informed decisions regarding pharmacotherapy in patients with TRD. We separated the local experience into two groups: 15 cases with the selective MAO type B inhibitor selegiline combined with medications presumed to increase the risk of serotonin syndrome and 14 cases with nonselective MAOIs (phenelzine and tranylcypromine) combined with other contraindicated medications. Although risks of combination treatment certainly exist with selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, or clomipramine, the current literature supports cautious use of combining MAOIs with other antidepressants in patients with TRD who have failed multiple treatment modalities. In addition, the data from the 29 patients receiving combination therapy with an MAOI and another antidepressant or stimulant medication revealed that 21% improved significantly, with no complications. This case series and literature review suggest that when used under close supervision and under the care of an experienced clinician in psychiatry, combination therapy may be a consideration for the management of TRD in patients not responding to monotherapy or other combinations of antidepressants.
Topics: Antidepressive Agents; Central Nervous System Stimulants; Contraindications; Depression; Depressive Disorder, Major; Drug Interactions; Drug Therapy, Combination; Humans; Monoamine Oxidase Inhibitors; Treatment Failure
PubMed: 25884531
DOI: 10.1002/phar.1576 -
Case Reports in Medicine 2015A 27-year-old Caucasian female with a history of depression was admitted to our local hospital with vague events that occurred a day before. This included an episode of...
A 27-year-old Caucasian female with a history of depression was admitted to our local hospital with vague events that occurred a day before. This included an episode of dysarthria, and unsteadiness, followed by feeling generally unwell. Two weeks prior to presentation she was commenced on phenelzine. During clinical assessment she suddenly deteriorated with a dramatic fall in her conscious level. Moreover, she became hyperthermic, tachycardic, and diaphoretic, and developed increased tone in all muscles and ocular clonus. Rectal diazepam was administered but failed to control the symptoms. Consequently, she was transferred to the intensive care unit for intubation and muscle relaxants were commenced. She responded well and recovered next day without complications. Her symptoms and signs were consistent with the serotonin syndrome with phenelzine being the likely cause. To the best of our knowledge, this is the first reported case to associate the condition with phenelzine alone at therapeutic dose.
PubMed: 25861278
DOI: 10.1155/2015/931963 -
Tijdschrift Voor Psychiatrie 2014Irreversible monoamine oxidase inhibitors (imaoi) are rarely used in Flanders. Such an anti-imaoi policy is not in keeping with the role that imaoi now play in the... (Review)
Review
BACKGROUND
Irreversible monoamine oxidase inhibitors (imaoi) are rarely used in Flanders. Such an anti-imaoi policy is not in keeping with the role that imaoi now play in the general guidelines for the treatment of depressive disorders.
AIM
To provide an overview of the history and the current use of imaoi in Flanders.
METHOD
We searched the literature and the literature used in the psychiatric courses taught at Ghent University and the Catholic University of Leuven and we consulted the Acta (Neurologica et) Psychiatrica Belgica. The information we collected was supplemented by personal communications from experts and by data about the period of commercialisation, the pharmaceutical companies producing imaoi and the use of imaoi.
RESULTS
imaoi were introduced rapidly onto the Flemish market but their popularity was short-lived. University courses did not give much attention to imaoi and the attitude to these inhibitors was negative. At the moment, phenelzine is the only imaoi available on the Flemish market and is only rarely prescribed.
CONCLUSION
Following the international trend, imaoi in Flanders initially enjoyed a short period of popularity. However, the limited use of phenelzine at present is not in line with the current guidelines for the treatment of depressive disorders. Practitioners and health professionals need to be better informed. Better education and wider use of imaoi in Flanders are recommended.
Topics: Antidepressive Agents; Belgium; Depression; Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Practice Patterns, Physicians'
PubMed: 25327346
DOI: No ID Found -
Clinical Pharmacology : Advances and... 2014The subject of this literature review is the alleged relationship between L-tyrosine, phenelzine, and hypertensive crisis. Phenelzine (Nardil(®)) prescribing... (Review)
Review
The subject of this literature review is the alleged relationship between L-tyrosine, phenelzine, and hypertensive crisis. Phenelzine (Nardil(®)) prescribing information notes: "The potentiation of sympathomimetic substances and related compounds by MAO inhibitors may result in hypertensive crises (see WARNINGS). Therefore, patients being treated with NARDIL should not take […] L-tyrosine […]". Interest in the scientific foundation of this claim was generated during routine patient care. A comprehensive literature search of Google Scholar and PubMed revealed no reported cases of hypertensive crisis associated with concomitant administration of L-tyrosine and phenelzine. Review of current US Food and Drug Administration nutritional guidelines relating to ongoing phenelzine studies reveals no mention and requires no consideration of L-tyrosine ingestion in combination with phenelzine. This paper is intended to provide an objective review of the science to then allow the reader to formulate the final opinion.
PubMed: 25092999
DOI: 10.2147/CPAA.S67271 -
ACS Chemical Biology Jun 2014Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme that oxidatively cleaves methyl groups from monomethyl and dimethyl Lys4 of histone H3 (H3K4Me1, H3K4Me2)...
Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme that oxidatively cleaves methyl groups from monomethyl and dimethyl Lys4 of histone H3 (H3K4Me1, H3K4Me2) and can contribute to gene silencing. This study describes the design and synthesis of analogues of a monoamine oxidase antidepressant, phenelzine, and their LSD1 inhibitory properties. A novel phenelzine analogue (bizine) containing a phenyl-butyrylamide appendage was shown to be a potent LSD1 inhibitor in vitro and was selective versus monoamine oxidases A/B and the LSD1 homologue, LSD2. Bizine was found to be effective at modulating bulk histone methylation in cancer cells, and ChIP-seq experiments revealed a statistically significant overlap in the H3K4 methylation pattern of genes affected by bizine and those altered in LSD1-/- cells. Treatment of two cancer cell lines, LNCaP and H460, with bizine conferred a reduction in proliferation rate, and bizine showed additive to synergistic effects on cell growth when used in combination with two out of five HDAC inhibitors tested. Moreover, neurons exposed to oxidative stress were protected by the presence of bizine, suggesting potential applications in neurodegenerative disease.
Topics: Animals; Blotting, Western; Cell Survival; Cells, Cultured; DNA Methylation; Embryo, Mammalian; Enzyme Inhibitors; Fetus; Histone Demethylases; Histones; Humans; Monoamine Oxidase; Neurons; Phenelzine; Rats; Rats, Sprague-Dawley
PubMed: 24707965
DOI: 10.1021/cb500018s