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The Medical Letter on Drugs and... Aug 2023
Topics: Humans; Anxiety Disorders
PubMed: 37516898
DOI: 10.58347/tml.2023.1682a -
The Medical Letter on Drugs and... Dec 2023
Topics: Humans; Antidepressive Agents; Selective Serotonin Reuptake Inhibitors
PubMed: 38133585
DOI: 10.58347/tml.2023.1691a -
ACS Chemical Neuroscience Dec 2023The discovery of monoamine oxidase inhibitors (MAOIs) in the 1950s marked a significant breakthrough in medicine, creating a powerful new category of drug: the... (Review)
Review
The discovery of monoamine oxidase inhibitors (MAOIs) in the 1950s marked a significant breakthrough in medicine, creating a powerful new category of drug: the antidepressant. In the years and decades that followed, MAOIs have been used in the treatment of several pathologies including Parkinson's disease, Alzheimer's disease, and various cancers and as anti-inflammatory agents. Despite once enjoying widespread use, MAOIs have dwindled in popularity due to side effects, food-drug interactions, and the introduction of other antidepressant drug classes such as tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). The recently published prescriber's guide for the use of MAOIs in treating depression has kindled a resurgence of their use in the clinical space. It is therefore timely to review key aspects of the four "classic" MAOIs: high-dose selegiline, isocarboxazid, phenelzine, and tranylcypromine. This review discusses their chemical synthesis, metabolism, pharmacology, adverse effects, and the history and importance of these drugs within the broader field of chemical neuroscience.
Topics: Tranylcypromine; Phenelzine; Isocarboxazid; Selegiline; Antidepressive Agents; Monoamine Oxidase Inhibitors
PubMed: 37966854
DOI: 10.1021/acschemneuro.3c00591 -
BMC Pharmacology & Toxicology Dec 2023The main purpose was to evaluate the efficacy and tolerability of different medications used to treat bulimia nervosa (BN). (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The main purpose was to evaluate the efficacy and tolerability of different medications used to treat bulimia nervosa (BN).
METHODS
Randomized controlled trials (RCTs) were identified from published sources through searches in PubMed, Cochrane Library, Web of Science, and Embase from inception to November 2022. Primary outcomes were changes in the frequency of binge eating episodes and vomiting episodes from baseline to endpoint. Secondary outcomes were differences in the improvement of scores in depressive symptoms, tolerability (dropout due to adverse events) and weight change.
RESULTS
The literature search ultimately included 11 drugs, 33 studies and 6 types of drugs, 8 trials with TCAs (imipramine, desipramine), 14 with SSRIs (fluoxetine, citalopram and fluvoxamine), 6 with MAOIs (phenelzine, moclobemide and brofaromine), 3 with antiepileptic drugs (topiramate), 1 with mood stabilizers (lithium), and 1 with amphetamine-type appetite suppressant (fenfluramine). The reduction in binge eating episodes was more likely due to these drugs than the placebo, and the SMD was -0.4 (95% CI -0.61 ~ -0.19); the changes in the frequency of vomiting episodes (SMD = -0.16, 95% CI -0.3 ~ -0.03); weight (WMD = -3.05, 95% CI -5.97 ~ -0.13); and depressive symptoms (SMD = -0.32, 95% CI -0.51 ~ -0.13). However, no significant difference was found in dropout due to adverse events (RR = 1.66, 95% CI 1.14 ~ 2.41).
CONCLUSIONS
This meta-analysis indicates that most pharmacotherapies decreased the frequency of binge-eating and vomiting episodes, body weight, and depressive symptoms in BN patients, but the efficacy was not significant. In each drug the efficacy is different, treating different aspects, different symptoms to improve the clinical performance of bulimia nervosa.
Topics: Humans; Bulimia Nervosa; Bulimia; Fluoxetine; Selective Serotonin Reuptake Inhibitors; Vomiting
PubMed: 38042827
DOI: 10.1186/s40360-023-00713-7 -
Reviews in Medical Virology Sep 2023Monoamine oxidase (MAO) is a membrane-bound mitochondrial enzyme that maintains the steady state of neurotransmitters and other biogenic amines in biological systems... (Review)
Review
Monoamine oxidase (MAO) is a membrane-bound mitochondrial enzyme that maintains the steady state of neurotransmitters and other biogenic amines in biological systems through catalytic oxidation and deamination. MAO dysfunction is closely related to human neurological and psychiatric diseases and cancers. However, little is known about the relationship between MAO and viral infections in humans. This review summarises current research on how viral infections participate in the occurrence and development of human diseases through MAO. The viruses discussed in this review include hepatitis C virus, dengue virus, severe acute respiratory syndrome coronavirus 2, human immunodeficiency virus, Japanese encephalitis virus, Epstein-Barr virus, and human papillomavirus. This review also describes the effects of MAO inhibitors such as phenelzine, clorgyline, selegiline, M-30, and isatin on viral infectious diseases. This information will not only help us to better understand the role of MAO in the pathogenesis of viruses but will also provide new insights into the treatment and diagnosis of these viral diseases.
Topics: Humans; Monoamine Oxidase; Epstein-Barr Virus Infections; COVID-19; Herpesvirus 4, Human; Monoamine Oxidase Inhibitors
PubMed: 37294534
DOI: 10.1002/rmv.2465 -
Drug and Chemical Toxicology Jan 2024Acetaminophen (APAP) overdosing is the most common cause of drug-induced liver failure. Despite extensive study, N-acetylcysteine is currently the only antidote utilized...
Acetaminophen (APAP) overdosing is the most common cause of drug-induced liver failure. Despite extensive study, N-acetylcysteine is currently the only antidote utilized for treatment. The purpose of this study was to evaluate the effect and mechanisms of phenelzine, an FDA-approved antidepressant, on APAP-induced toxicity in HepG2 cells. The human liver hepatocellular cell line HepG2 was used to investigate APAP-induced cytotoxicity. The protective effects of phenelzine were determined by examining the cell viability, combination index calculation, Caspase 3/7 activation, Cytochrome c release, HO levels, NO levels, GSH activity, PERK protein levels, and pathway enrichment analysis. Elevated HO production and decreased glutathione (GSH) levels were indicators of APAP-induced oxidative stress. The combination index of 2.04 indicated that phenelzine had an antagonistic effect on APAP-induced toxicity. When compared to APAP alone, phenelzine treatment considerably reduced caspase 3/7 activation, cytochrome c release, and HO generation. However, phenelzine had minimal effect on NO and GSH levels and did not alleviate ER stress. Pathway enrichment analysis revealed a potential connection between APAP toxicity and phenelzine metabolism. These findings suggested that phenelzine's protective effect against APAP-induced cytotoxicity could be attributed to the drug's capacity to reduce APAP-mediated apoptotic signaling.
Topics: Humans; Acetaminophen; Hep G2 Cells; Phenelzine; Caspase 3; Cytochromes c; Hydrogen Peroxide; Liver; Oxidative Stress; Apoptosis; Chemical and Drug Induced Liver Injury; Glutathione
PubMed: 37246945
DOI: 10.1080/01480545.2023.2217696 -
European Journal of Clinical... Feb 2024Serotonin syndrome is a rare and potentially fatal adverse drug reaction caused by serotonergic drugs and is due to an increase in serotonin concentration or activation...
BACKGROUND
Serotonin syndrome is a rare and potentially fatal adverse drug reaction caused by serotonergic drugs and is due to an increase in serotonin concentration or activation of the 5-HT receptor in the central nervous system. We analysed adverse events in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) data set to investigate the main drug classes related to reports of serotonin syndrome and the reporting risk in relation to age and sex.
METHODS
We analysed data from the FAERS database to evaluate the main drug classes related to reports of the serotonin syndrome, and the reporting risk in relation to age and sex.
RESULTS
We found 8,997 cases of serotonin syndrome; selective serotonin reuptake inhibitors (SSRIs) was the class of drugs with most reports, followed by opioids and other antidepressants. The highest Reporting Odds Ratios (ROR) for drug classes was for monoamine oxidase (MAO) inhibitors (45.99, 95% confidence interval (CI): 41.21-51.33) and SSRIs (32.66, 95% CI: 31.33-34.04), while the ten active substances with the highest ROR were moclobemide, isocarboxazid, oxitriptane, tranylcypromine, melitracen, phenelzine, linezolid, amoxapine, reboxetine and tryptophan; with values of ROR ranging from 44.19 (95% CI: 25.38-76.94) of tryptophan to 388.36 (95% CI: 314.58-479.46) of moclobemide. The ROR for the most commonly involved drugs was higher in the group of older adults (65 > years old), and higher in males.
CONCLUSION
Prescribers need to be vigilant about drugs that can raise serotonin concentration or influence serotonergic neurotransmission, also when using drugs with less well-known risk for serotonin syndrome, like linezolid and triptans.
Topics: Male; Humans; Aged; United States; Serotonin Syndrome; Serotonin; Selective Serotonin Reuptake Inhibitors; Pharmaceutical Preparations; Pharmacovigilance; Moclobemide; Linezolid; Tryptophan; Monoamine Oxidase Inhibitors; Adverse Drug Reaction Reporting Systems; United States Food and Drug Administration
PubMed: 38032391
DOI: 10.1007/s00228-023-03596-z -
Molecules (Basel, Switzerland) Jan 2024Lysine-specific demethylase 1 (LSD1/KDM1A) has emerged as a promising therapeutic target for treating various cancers (such as breast cancer, liver cancer, etc.) and... (Review)
Review
Lysine-specific demethylase 1 (LSD1/KDM1A) has emerged as a promising therapeutic target for treating various cancers (such as breast cancer, liver cancer, etc.) and other diseases (blood diseases, cardiovascular diseases, etc.), owing to its observed overexpression, thereby presenting significant opportunities in drug development. Since its discovery in 2004, extensive research has been conducted on LSD1 inhibitors, with notable contributions from computational approaches. This review systematically summarizes LSD1 inhibitors investigated through computer-aided drug design (CADD) technologies since 2010, showcasing a diverse range of chemical scaffolds, including phenelzine derivatives, tranylcypromine (abbreviated as TCP or 2-PCPA) derivatives, nitrogen-containing heterocyclic (pyridine, pyrimidine, azole, thieno[3,2-b]pyrrole, indole, quinoline and benzoxazole) derivatives, natural products (including sanguinarine, phenolic compounds and resveratrol derivatives, flavonoids and other natural products) and others (including thiourea compounds, Fenoldopam and Raloxifene, (4-cyanophenyl)glycine derivatives, propargylamine and benzohydrazide derivatives and inhibitors discovered through AI techniques). Computational techniques, such as virtual screening, molecular docking and 3D-QSAR models, have played a pivotal role in elucidating the interactions between these inhibitors and LSD1. Moreover, the integration of cutting-edge technologies such as artificial intelligence holds promise in facilitating the discovery of novel LSD1 inhibitors. The comprehensive insights presented in this review aim to provide valuable information for advancing further research on LSD1 inhibitors.
Topics: Enzyme Inhibitors; Lysine; Molecular Docking Simulation; Artificial Intelligence; Drug Design; Histone Demethylases; Biological Products; Structure-Activity Relationship
PubMed: 38276629
DOI: 10.3390/molecules29020550 -
Bioorganic & Medicinal Chemistry Sep 2023Monoamine oxidases (MAOA/MAOB) are enzymes known for their role in neurotransmitter regulation in the central nervous system (CNS). Irreversible and non-selective MAO...
Monoamine oxidases (MAOA/MAOB) are enzymes known for their role in neurotransmitter regulation in the central nervous system (CNS). Irreversible and non-selective MAO inhibitors (MAOi's) were the first class of antidepressants, thus subsequent work on drugs such as the selective MAOA inhibitor clorgyline has focussed on selectivity and increased CNS penetration. MAOA is highly expressed in high grade and metastatic prostate cancer with a proposed effect on prostate cancer growth, recurrence, and drug resistance. A Phase II Clinical Trial has demonstrated the therapeutic effects of the irreversible nonselective MAOi phenelzine for prostate cancer. However, neurologic adverse effects led to early withdrawal in 25% of the enrolled patient-population. In this work, we revised the clorgyline scaffold with the goal of decreasing CNS penetration to minimize CNS-related side effects while retaining or enhancing MAOA inhibition potency and selectivity. Using the known co-crystal structure of clorgyline bound with FAD co-factor in the hMAOA active site as a reference, we designed and synthesized a series of compounds predicted to have lower CNS penetration (logBB). All synthesized derivatives displayed favorable drug-like characteristics such as predicted Caco-2 permeability and human oral absorption, and exhibited highly selective hMAOA binding interactions. Introduction of an HBD group (NH or OH) at position 5 of the phenyl ring clorgyline resulted in 3x more potent hMAOA inhibition with equivalent or better hMAOB selectivity, and similar prostate cancer cell cytotoxicity. In contrast, introduction of larger substituents at this position or at the terminal amine significantly reduced the hMAOA inhibition potency, attributed in part to a steric clash within the binding pocket of the MAOA active site. Replacement of the N-methyl group by a more polar, but larger 2-hydroxyethyl group did not enhance potency. However, introduction of a polar 2-hydroxy in the propyl chain retained the highly selective MAOA inhibition and cancer cell cytotoxicity of clorgyline while reducing its CNS score from 2 to 0. We believe that these results identify a new class of peripherally directed MAOIs that may allow safer therapeutic targeting of MAOA for a variety of anti-cancer and anti-inflammatory indications.
Topics: Humans; Male; Antidepressive Agents; Brain; Caco-2 Cells; Clorgyline; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Prostatic Neoplasms
PubMed: 37544256
DOI: 10.1016/j.bmc.2023.117425