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ACS Pharmacology & Translational Science Dec 2021Lysine-specific demethylase 1 (LSD1 or KDM1A) is a chromatin modifying enzyme playing a key role in the cell cycle and cell differentiation and proliferation through the...
Lysine-specific demethylase 1 (LSD1 or KDM1A) is a chromatin modifying enzyme playing a key role in the cell cycle and cell differentiation and proliferation through the demethylation of histones and nonhistone substrates. In addition to its enzymatic activity, LSD1 plays a fundamental scaffolding role as part of transcription silencing complexes such as rest co-repressor (CoREST) and nucleosome remodeling and deacetylase (NuRD). A host of classical amine oxidase inhibitors such as tranylcypromine, pargyline, and phenelzine together with LSD1 tool compounds such as SP-2509 and GSK-LSD1 have been extensively utilized in LSD1 mechanistic cancer studies. Additionally, several optimized new chemical entities have reached clinical trials in oncology such as ORY-1001 (iadademstat), GSK2879552, SP-2577 (seclidemstat), IMG-7289 (bomedemstat), INCB059872, and CC-90011 (pulrodemstat). Despite this, no single study exists that characterizes them all under the same experimental conditions, preventing a clear interpretation of published results. Herein, we characterize the whole LSD1 small molecule compound class as inhibitors of LSD1 catalytic activity, disruptors of SNAIL/GFI1 (SNAG)-scaffolding protein-protein interactions, inducers of cell differentiation, and potential anticancer treatments for hematological and solid tumors to yield an updated, unified perspective of this field. Our results highlight significant differences in potency and selectivity among the clinical compounds with iadademstat being the most potent and reveal that most of the tool compounds have very low activity and selectivity, suggesting some conclusions derived from their use should be taken with caution.
PubMed: 34927013
DOI: 10.1021/acsptsci.1c00223 -
The Mental Health Clinician Nov 2021Transcranial magnetic stimulation (TMS) is a noninvasive procedure used in the treatment of depression. We observed TMS-associated mania with psychotic symptoms in a...
Transcranial magnetic stimulation (TMS) is a noninvasive procedure used in the treatment of depression. We observed TMS-associated mania with psychotic symptoms in a 55-year-old male diagnosed with MDD and generalized anxiety disorder without history of psychosis or mania. Owing to poor pharmacotherapeutic response and worsening symptomatology, TMS was introduced while continuing phenelzine; this was initially successful in demonstrating positive effects on mood. However, the patient began to develop symptoms consistent with mania with psychosis and was hospitalized. Both TMS and phenelzine were discontinued, leading to significant improvement of the symptoms of mania and psychosis. Phenelzine was later reintroduced for maintenance treatment of depression and anxiety, with no recurrence of mania or psychosis. This case report implicates TMS as a possible cause of mania and psychosis symptoms.
PubMed: 34824963
DOI: 10.9740/mhc.2021.11.373 -
Journal of Neural Transmission (Vienna,... Nov 2021The classic monoamine oxidase inhibitors (MAOIs) tranylcypromine (TCP) and phenelzine (PLZ) are powerful antidepressants that come with an equally powerful stigma, and...
The classic monoamine oxidase inhibitors (MAOIs) tranylcypromine (TCP) and phenelzine (PLZ) are powerful antidepressants that come with an equally powerful stigma, and are thus rarely prescribed-despite their well-established effectiveness. Some of these preconceptions appear to stem from unclarity, as the etiology of a rare but important side effect, 'spontaneous hypertension' (SH)-a significant increase in blood pressure absent dietary tyramine ingestion-remains improperly elucidated. This paper aims at uprooting some of the stigma surrounding MAOIs by advancing the trace amine (TA) theory as the causative underpinning of SH. This theory posits that SH results from the considerable influx of TAs observed following TCP- or PLZ-administration. TAs are known, albeit at greatly supraphysiological levels, to raise blood pressure on account of their propensity to exert potent indirect sympathomimetic effects; additionally, some research posits that TAs may induce vasoconstrictive effects partly or wholly separate therefrom, which would then constitute a second hypertensive mechanism. TAs are endogenous to the human body in low quantities. Both TCP and PLZ cause marked elevations of 2-phenylethylamine (PEA), meta- and para-tyramine (m-/p-TYR), octopamine (OA), and tryptamine (TRYP), following both acute and (sub)chronic administration. This paper holds that TYR plays a pivotal role in causing SH, due to its strong pressor effect. Cautious treatment of SH is advised, given its typically self-limiting nature. The risk of hypotensive overshoots must be taken into account. For severe cases, this paper urges reconsideration, following suitable confirmation trials, of antipsychotics (notably risperidone) as these agents may reduce striatal p-TYR levels.
Topics: Antidepressive Agents; Humans; Hypertension; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Tranylcypromine; Tyramine
PubMed: 34373944
DOI: 10.1007/s00702-021-02399-9 -
Journal of Clinical PsychopharmacologyDespite the availability of a range of efficacious evidence-based treatments for obsessive-compulsive disorder (OCD), not all patients experience sufficient benefit or...
PURPOSE/BACKGROUND
Despite the availability of a range of efficacious evidence-based treatments for obsessive-compulsive disorder (OCD), not all patients experience sufficient benefit or are able to tolerate them in practice. Monoamine oxidase inhibitors (MAOIs) show efficacy in the treatment of depression and certain anxiety disorders (such as social anxiety disorder).
METHODS/PROCEDURES
We survey the evidence base from case reports, and clinical trials, regarding use of MAOIs in OCD. We then present new data from a case series collected in routine clinical practice in a specialist clinical service.
FINDINGS/RESULTS
In 9 treatment-resistant patients whose OCD had not improved with at least 2 standard treatment trials, 3 had marked clinical improvement (>35% improvement on YBOCS) on phenelzine, 3 had some improvement (15-34.9%), and 3 showed minimal or no improvement (<15%). In the 3 patients who experienced minimal/no improvement, 2 had discontinued early because of lack of tolerability, and the other patient discontinued after 4 weeks because of perceived lack of symptom benefit.
IMPLICATIONS/CONCLUSIONS
We suggest that (1) MAOIs in treatment-resistant OCD require appropriate research scrutiny in large-scale randomized controlled trials; and (2) MAOIs merit consideration as a treatment option in individual cases of OCD, particularly in specialist settings where first-line interventions have proven inadequate to manage severe symptoms.
Topics: Adult; Behavioral Symptoms; Clinical Trials as Topic; Drug Resistance; Female; Humans; Male; Monoamine Oxidase Inhibitors; Obsessive-Compulsive Disorder; Phenelzine; Risk Assessment; Treatment Outcome
PubMed: 34108430
DOI: 10.1097/JCP.0000000000001418 -
Neuroscience Bulletin Aug 2021Traumatic brain injury (TBI)-induced coagulopathy has increasingly been recognized as a significant risk factor for poor outcomes, but the pathogenesis remains poorly...
Traumatic brain injury (TBI)-induced coagulopathy has increasingly been recognized as a significant risk factor for poor outcomes, but the pathogenesis remains poorly understood. In this study, we aimed to investigate the causal role of acrolein, a typical lipid peroxidation product, in TBI-induced coagulopathy, and further explore the underlying molecular mechanisms. We found that the level of plasma acrolein in TBI patients suffering from coagulopathy was higher than that in those without coagulopathy. Using a controlled cortical impact mouse model, we demonstrated that the acrolein scavenger phenelzine prevented TBI-induced coagulopathy and recombinant ADAMTS-13 prevented acrolein-induced coagulopathy by cleaving von Willebrand factor (VWF). Our results showed that acrolein may contribute to an early hypercoagulable state after TBI by regulating VWF secretion. mRNA sequencing (mRNA-seq) and transcriptome analysis indicated that acrolein over-activated autophagy, and subsequent experiments revealed that acrolein activated autophagy partly by regulating the Akt/mTOR pathway. In addition, we demonstrated that acrolein was produced in the perilesional cortex, affected endothelial cell integrity, and disrupted the blood-brain barrier. In conclusion, in this study we uncovered a novel pro-coagulant effect of acrolein that may contribute to TBI-induced coagulopathy and vascular leakage, providing an alternative therapeutic target.
Topics: Acrolein; Animals; Autophagy; Blood Coagulation Disorders; Brain Injuries, Traumatic; Humans; Mice; von Willebrand Factor
PubMed: 33939120
DOI: 10.1007/s12264-021-00681-0 -
Pathogens (Basel, Switzerland) Apr 2021Non-typhoidal ingeniously scavenges energy for growth from tyramine (TYR) and d-glucuronic acid (DGA), both of which occur in the host as the metabolic byproducts of...
Non-typhoidal ingeniously scavenges energy for growth from tyramine (TYR) and d-glucuronic acid (DGA), both of which occur in the host as the metabolic byproducts of the gut microbial metabolism. A critical first step in energy scavenging from TYR and DGA in involves TYR-oxidation via TYR-oxidoreductase and production of free-DGA via β-glucuronidase (GUS)-mediated hydrolysis of d-glucuronides (conjugated form of DGA), respectively. Here, we report that utilizes TYR and DGA as sole sources of energy in a serotype-independent manner. Using colorimetric and radiometric approaches, we report that genes , , and encode TYR-oxidoreductases. Some serotypes produce GUS, thus can also scavenge energy from d-glucuronides. We repurposed phenelzine (monoaminoxidase-inhibitor) and amoxapine (GUS-inhibitor) to inhibit the TYR-oxidoreductases and GUS encoded by , respectively. We show that phenelzine significantly inhibits the growth of by inhibiting TYR-oxidoreductases SEN2971, SEN3065, and SEN2426. Similarly, amoxapine significantly inhibits the growth of by inhibiting GUS-mediated hydrolysis of d-glucuronides. Because TYR and DGA serve as potential energy sources for growth in vivo, the data and the novel approaches used here provides a better understanding of the role of TYR and DGA in pathogenesis and nutritional virulence.
PubMed: 33924374
DOI: 10.3390/pathogens10040469 -
Cellular and Molecular Neurobiology Jan 2022Phenelzine (PLZ) is a monoamine oxidase (MAO)-inhibiting antidepressant with anxiolytic properties. This multifaceted drug has a number of pharmacological and... (Review)
Review
Phenelzine (PLZ) is a monoamine oxidase (MAO)-inhibiting antidepressant with anxiolytic properties. This multifaceted drug has a number of pharmacological and neurochemical effects in addition to inhibition of MAO, and findings on these effects have contributed to a body of evidence indicating that PLZ also has neuroprotective/neurorescue properties. These attributes are reviewed in this paper and include catabolism to the active metabolite β-phenylethylidenehydrazine (PEH) and effects of PLZ and PEH on the GABA-glutamate balance in brain, sequestration of reactive aldehydes, and inhibition of primary amine oxidase. Also discussed are the encouraging findings of the effects of PLZ in animal models of stroke, spinal cord injury, traumatic brain injury, and multiple sclerosis, as well other actions such as reduction of nitrative stress, reduction of the effects of a toxin on dopaminergic neurons, potential anticonvulsant actions, and effects on brain-derived neurotrophic factor, neural cell adhesion molecules, an anti-apoptotic factor, and brain levels of ornithine and N-acetylamino acids.
Topics: Animals; Antidepressive Agents; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neuroprotective Agents; Phenelzine; Rats; Rats, Sprague-Dawley
PubMed: 33839994
DOI: 10.1007/s10571-021-01078-3 -
Frontiers in Genetics 2021Variability in the enzymatic activity of -acetyltransferase 2 (NAT2) is an important contributor to interindividual differences in drug responses. However, there is...
Variability in the enzymatic activity of -acetyltransferase 2 (NAT2) is an important contributor to interindividual differences in drug responses. However, there is little information on functional differences in -acetylation activities according to NAT2 phenotypes, i.e., rapid, intermediate, slow, and ultra-slow acetylators, between different substrate drugs. Here, we estimated genotypes in 990 Japanese individuals and compared the frequencies of different genotypes with those of different populations. We then calculated kinetic parameters of four NAT2 alleles (NAT24, 5, 6, and 7) for -acetylation of aminoglutethimide, diaminodiphenyl sulfone, hydralazine, isoniazid, phenelzine, procaineamide, sulfamethazine (SMZ), and sulfapyrizine. NAT25, 6, and 7 exhibited significantly reduced -acetylation activities with lower Vmax and CLint values of all drugs when compared with NAT24. Hierarchical clustering analysis revealed that 10 genotypes were categorized into three or four clusters. According to the results of metabolic experiments using SMZ as a substrate, the frequencies of ultra-slow acetylators were calculated to be 29.05-54.27% in Europeans, Africans, and South East Asians, whereas Japanese and East Asian populations showed lower frequencies (4.75 and 11.11%, respectively). Our findings will be helpful for prediction of responses to drugs primarily metabolized by NAT2.
PubMed: 33815485
DOI: 10.3389/fgene.2021.652704 -
Clinical Pharmacology : Advances and... 2021[This retracts the article DOI: 10.2147/CPAA.S67271.].
[This retracts the article DOI: 10.2147/CPAA.S67271.].
PubMed: 33688272
DOI: 10.2147/CPAA.S308255 -
The Medical Letter on Drugs and... Jan 2021
Review
Topics: Antiparkinson Agents; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Clinical Trials as Topic; Humans; Oxadiazoles; Parkinson Disease
PubMed: 33646998
DOI: No ID Found