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Molecules (Basel, Switzerland) Oct 2019Drug-drug interactions (DDIs) severity assessment is a crucial problem because polypharmacy is increasingly common in modern medical practice. Many DDIs are caused by...
Drug-drug interactions (DDIs) severity assessment is a crucial problem because polypharmacy is increasingly common in modern medical practice. Many DDIs are caused by alterations of the plasma concentrations of one drug due to another drug inhibiting and/or inducing the metabolism or transporter-mediated disposition of the victim drug. Accurate assessment of clinically relevant DDIs for novel drug candidates represents one of the significant tasks of contemporary drug research and development and is important for practicing physicians. This work is a development of our previous investigations and aimed to create a model for the severity of DDIs prediction. PASS program and PoSMNA descriptors were implemented for prediction of all five classes of DDIs severity according to OpeRational ClassificAtion (ORCA) system: contraindicated (class 1), provisionally contraindicated (class 2), conditional (class 3), minimal risk (class 4), no interaction (class 5). Prediction can be carried out both for known drugs and for new, not yet synthesized substances using only their structural formulas. Created model provides an assessment of DDIs severity by prediction of different ORCA classes from the first most dangerous class to the fifth class when DDIs do not take place in the human organism. The average accuracy of DDIs class prediction is about 0.75.
Topics: Drug Interactions; Enzyme Activation; Enzyme Inhibitors; Phenelzine; Tranylcypromine
PubMed: 31683720
DOI: 10.3390/molecules24213955 -
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 -
Nature Communications Jan 2018Here we report corin, a synthetic hybrid agent derived from the class I HDAC inhibitor (entinostat) and an LSD1 inhibitor (tranylcypromine analog). Enzymologic analysis...
Here we report corin, a synthetic hybrid agent derived from the class I HDAC inhibitor (entinostat) and an LSD1 inhibitor (tranylcypromine analog). Enzymologic analysis reveals that corin potently targets the CoREST complex and shows more sustained inhibition of CoREST complex HDAC activity compared with entinostat. Cell-based experiments demonstrate that corin exhibits a superior anti-proliferative profile against several melanoma lines and cutaneous squamous cell carcinoma lines compared to its parent monofunctional inhibitors but is less toxic to melanocytes and keratinocytes. CoREST knockdown, gene expression, and ChIP studies suggest that corin's favorable pharmacologic effects may rely on an intact CoREST complex. Corin was also effective in slowing tumor growth in a melanoma mouse xenograft model. These studies highlight the promise of a new class of two-pronged hybrid agents that may show preferential targeting of particular epigenetic regulatory complexes and offer unique therapeutic opportunities.
Topics: Aged; Animals; Antineoplastic Agents; Benzamides; Cell Line, Tumor; Cell Proliferation; Co-Repressor Proteins; Drug Design; Drug Screening Assays, Antitumor; Female; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Male; Melanoma; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Nerve Tissue Proteins; Oligonucleotide Array Sequence Analysis; Pyridines; Repressor Proteins; Skin Neoplasms; Tranylcypromine; Xenograft Model Antitumor Assays
PubMed: 29302039
DOI: 10.1038/s41467-017-02242-4 -
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 -
Frontiers in Neuroscience 2020Besides several endogenous elements, exogenous factors, including exposure to pesticides, have been recognized as putative factors contributing to the onset and...
Besides several endogenous elements, exogenous factors, including exposure to pesticides, have been recognized as putative factors contributing to the onset and development of neurodegenerative diseases, including Parkinson's disease (PD). Considering the availability, success rate, and limitations associated with the current arsenals to fight PD, there is an unmet need for novel therapeutic interventions. Therefore, based on the previously reported beneficial functions of the L1 cell adhesion molecule, we hypothesized that L1 mimetic compounds may serve to neutralize neurotoxicity triggered by the pesticide paraquat (PQ). In this study, we attempt to use PQ for inducing PD-like pathology and the L1 mimetic compounds phenelzine sulfate (PS) and tacrine (TC) as potential candidates for the amelioration of PD symptoms using zebrafish as a model system. Administration of PQ together with the L1 mimetic compounds PS or TC (250 nM) improved survival of zebrafish larvae, protected them from locomotor deficits, and increased their sensorimotor reflexes. Moreover, application of PQ together with PS (500 nM) or TC (1000 nM) in adult zebrafish counteracted PQ-induced toxicity, maintaining normal locomotor functions and spatial memory in an open field and T-maze task, respectively. Both L1 mimetic compounds prevented reduction in tyrosine hydroxylase and dopamine levels, reduced reactive oxygen species (ROS) generation, protected against impairment of mitochondrial viability, improved the antioxidant enzyme system, and prevented a decrease in ATP levels. Altogether, our findings highlight the beneficial functions of the agonistic L1 mimetics PS and TC by improving several vital cell functions against PQ-triggered neurotoxicity.
PubMed: 32547358
DOI: 10.3389/fnins.2020.00458 -
Experimental and Therapeutic Medicine Sep 2018Lipid peroxidation is associated with several metabolic diseases. Lipid peroxidation causes cellular damage through reactive aldehyde species such as 4-hydroxyonenal...
Lipid peroxidation is associated with several metabolic diseases. Lipid peroxidation causes cellular damage through reactive aldehyde species such as 4-hydroxyonenal (4-HNE). The exact mechanism(s) by which 4-HNE causes damage in the intravascular compartment is not yet exactly understood. Using an system, the damage induced by 4-HNE on the blood was investigated by measuring protein carbonyl groups and thiobarbituric acid reactive substances (TBARS) following 4-HNE treatment. The findings demonstrated that treatment with 4-HNE increased the carbonylation of protein and the formation of TBARS in the blood plasma. It was also tested whether phenelzine, a scavenger of aldehyde species, or U-83836E, a scavenger of lipid peroxy radicals, attenuated the damage caused by 4-HNE. It was demonstrated that phenelzine or U-83836E both mitigated the effects of 4-HNE on the proteins and the lipids of the blood plasma. The findings of the current study suggest that phenelzine, U-83836E or functionally similar therapeutics may prevent or treat diseases that involve an increased production of 4-HNE in the intravascular compartment.
PubMed: 30186450
DOI: 10.3892/etm.2018.6419 -
Neuroscience Jul 2018The putative strong anti-nociceptive properties of the antidepressant phenelzine (PLZ) have not been widely explored as a treatment for pain. Antinociceptive effects of...
The putative strong anti-nociceptive properties of the antidepressant phenelzine (PLZ) have not been widely explored as a treatment for pain. Antinociceptive effects of PLZ were identified in the formalin model of tonic pain (Mifflin et al., 2016) and in allodynia associated with experimental autoimmune encephalomyelitis, (EAE) a mouse model of multiple sclerosis (Potter et al., 2016). Here, we further clarify the specific types of stimuli and contexts in which PLZ modulates nociceptive sensitivity. Our findings indicate that PLZ selectively inhibits ongoing inflammatory pain while sparing transient reflexive and acute nociception. We also investigated the cellular mechanisms of action of PLZ in the dorsal horn, and as expected of a monoamine-oxidase inhibitor, PLZ increased serotonin (5HT) immunoreactivity. We next used two approaches to test the hypothesis that PLZ inhibits the activation of spinal nociresponsive neurons. First, we evaluated the formalin-evoked protein expression of the immediate early gene, c-fos. PLZ reduced Fos expression in the superficial dorsal horn. Second, we evaluated the effects of PLZ on intracellular calcium responses to superfusion of glutamate (0.3-1.0 mM) in an ex vivo lumbar spinal cord slice preparation. Superfusion with PLZ (100-300 μM) reduced 1 mM glutamate-evoked calcium responses. This was blocked by pretreatment with the 5HT1A-receptor antagonist WAY-100,635, but not the alpha-2 adrenergic antagonist idazoxan. We conclude that PLZ exerts antinociceptive effects through a 5-HT/5HT1AR-dependent inhibition of neuronal responses within nociceptive circuits of the dorsal horn.
Topics: Animals; Antidepressive Agents; Female; Hyperalgesia; Mice; Mice, Inbred C57BL; Neurons; Pain; Phenelzine; Receptors, Serotonin, 5-HT1; Serotonin; Spinal Cord Dorsal Horn
PubMed: 29752984
DOI: 10.1016/j.neuroscience.2018.04.047 -
Journal of Neurochemistry Oct 2017Brain-derived neurotrophic factor (BDNF) promotes maturation of cholinergic neurons. However, how activity-dependent BDNF expression affects specific cholinergic gene...
Brain-derived neurotrophic factor (BDNF) promotes maturation of cholinergic neurons. However, how activity-dependent BDNF expression affects specific cholinergic gene expression remains unclear. This study addressed this question by determining mRNA levels of 22 acetylcholine receptor subunits, the choline transporter (CHT), and the choline acetyltransferase (ChAT) in mice deficient in activity-dependent BDNF via promoter IV (KIV) and control wild-type mice. Quantitative RT-PCR revealed significant reductions in nicotinic acetylcholine receptor alpha 5 (CHRNA5) in the frontal cortex and hippocampus and M5 muscarinic acetylcholine receptor (CHRM5) in the hippocampus, but significant increases in M2 muscarinic acetylcholine receptor (CHRM2) in the frontal cortex of KIV mice compared to wild-type mice. Three-week treatments with fluoxetine, phenelzine, duloxetine, imipramine, or an enriched environment treatment (EET) did not affect the altered expression of these genes except that EET increased CHRNA5 levels only in KIV frontal cortex. EET also increased levels of CHRNA7, CHT, and ChAT, again only in the KIV frontal cortex. The imipramine treatment was most prominent among the four antidepressants; it up-regulated hippocampal CHRM2 and frontal cortex CHRM5 in both genotypes, and frontal cortex CHRNA7 only in KIV mice. To the best of our knowledge, this is the first evidence that BDNF deficiency disturbs expression of CHRNA5, CHRM2, and CHRM5. Our results suggest that promoter IV-BDNF deficiency - which occurs under chronic stress - causes cholinergic dysfunctions via these receptors. EET is effective on CHRNA5, while its compensatory induction of other cholinergic genes or drugs targeting CHRNA5, CHRM2, and CHRM5 may become an alternative strategy to reverse these BDNF-linked cholinergic dysfunctions.
Topics: Animals; Antidepressive Agents; Brain-Derived Neurotrophic Factor; Environment; Female; Frontal Lobe; Gene Expression; Hippocampus; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Promoter Regions, Genetic; Receptor, Muscarinic M2; Receptor, Muscarinic M5; Receptors, Nicotinic
PubMed: 28722769
DOI: 10.1111/jnc.14129 -
Pharmaceuticals (Basel, Switzerland) Mar 2020Treatment with several antipsychotic drugs exhibits a tendency to induce weight gain and diabetic complications. The proposed mechanisms by which the atypical...
Opipramol Inhibits Lipolysis in Human Adipocytes without Altering Glucose Uptake and Differently from Antipsychotic and Antidepressant Drugs with Adverse Effects on Body Weight Control.
Treatment with several antipsychotic drugs exhibits a tendency to induce weight gain and diabetic complications. The proposed mechanisms by which the atypical antipsychotic drug olanzapine increases body weight include central dysregulations leading to hyperphagia and direct peripheral impairment of fat cell lipolysis. Several investigations have reproduced in vitro direct actions of antipsychotics on rodent adipocytes, cultured preadipocytes, or human adipose tissue-derived stem cells. However, to our knowledge, no such direct action has been described in human mature adipocytes. The aim of the present study was to compare in human adipocytes the putative direct alterations of lipolysis by antipsychotics (haloperidol, olanzapine, ziprazidone, risperidone), antidepressants (pargyline, phenelzine), or anxiolytics (opipramol). Lipolytic responses to the tested drugs, and to recognized lipolytic (e.g., isoprenaline) or antilipolytic agents (e.g., insulin) were determined, together with glucose transport and amine oxidase activities in abdominal subcutaneous adipocytes from individuals undergoing plastic surgery. None of the tested drugs were lipolytic. Surprisingly, only opipramol exhibited substantial antilipolytic properties in the micromolar to millimolar range. An opipramol antilipolytic effect was evident against isoprenaline-, forskolin-, or atrial natriuretic peptide-stimulated lipolysis. Opipramol did not impair insulin activation of glucose transport but inhibited monoamine oxidase (MAO) activity to the same extent as antidepressants recognized as MAO inhibitors (pargyline, harmine, or phenelzine), whereas antipsychotics were inefficient. Considering its unique properties, opipramol, which is not associated with weight gain in treated patients, is a good candidate for drug repurposing because it limits exaggerated lipolysis, prevents hydrogen peroxide release by amine oxidases in adipocytes, and is thereby of potential use to limit lipotoxicity and oxidative stress, two deleterious complications of diabetes and obesity.
PubMed: 32151075
DOI: 10.3390/ph13030041 -
The Primary Care Companion For CNS... Dec 2016
Topics: Brain; Cerebrovascular Disorders; Diagnosis, Differential; Female; Humans; Middle Aged; Monoamine Oxidase Inhibitors; Phenelzine; Tranylcypromine
PubMed: 27922229
DOI: 10.4088/PCC.16l01945