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European Journal of Pharmacology Nov 2020In 2020 the whole world focused on antivirus drugs towards SARS-CoV-2. Most of the researchers focused on drugs used in other viral infections or malaria. We have not... (Review)
Review
In 2020 the whole world focused on antivirus drugs towards SARS-CoV-2. Most of the researchers focused on drugs used in other viral infections or malaria. We have not seen such mobilization towards one topic in this century. The whole situation makes clear that progress needs to be made in antiviral drug development. The first step to do it is to characterize the potential antiviral activity of new or already existed drugs on the market. Phenothiazines are antipsychotic agents used previously as antiseptics, anthelminthics, and antimalarials. Up to date, they are tested for a number of other disorders including the broad spectrum of viruses. The goal of this paper was to summarize the current literature on activity toward RNA-viruses of such drugs like chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine. We identified 49 papers, where the use of the phenothiazines for 23 viruses from different families were tested. Chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine possess anti-viral activity towards different types of viruses. These drugs inhibit clathrin-dependent endocytosis, cell-cell fusion, infection, replication of the virus, decrease viral invasion as well as suppress entry into the host cells. Additionally, since the drugs display activity at nontoxic concentrations they have therapeutic potential for some viruses, still, further research on animal and human subjects are needed in this field to verify cell base research.
Topics: Animals; Antipsychotic Agents; Antiviral Agents; Betacoronavirus; COVID-19; Chlorpromazine; Coronavirus Infections; Fluphenazine; Humans; Pandemics; Perphenazine; Phenothiazines; Pneumonia, Viral; Prochlorperazine; RNA Viruses; SARS-CoV-2; Thioridazine; COVID-19 Drug Treatment
PubMed: 32949606
DOI: 10.1016/j.ejphar.2020.173553 -
International Journal of Molecular... May 2020Developing dermatitis therapeutics has been faced with challenges including adverse effects of topical steroid and high cost of new developing drugs. Here, we found the...
Developing dermatitis therapeutics has been faced with challenges including adverse effects of topical steroid and high cost of new developing drugs. Here, we found the expression levels of dopamine receptor D2 is higher in skin biopsies of dermatitis patients and an oxazolone-induced animal model of dermatitis. We used perphenazine, an FDA-approved dopamine receptor antagonist to determine the therapeutic effect. Two different animal models including 12-o-tetradecanoylphorbol-13-acetate (TPA) and oxazolone (OXA)-induced dermatitis were employed. TPA and OXA-mediated ear swelling was attenuated by perphenazine. Moreover, perphenazine inhibited infiltrated mast cells into lesion area. We found levels of serum IgE, histamine and cytokines are decreased in mice cotreated with perphenazine and OXA compared to OXA-treated mice. Overall, this is a first study showing that the FDA-approved, anti-psychotic drug, perphenazine, alleviates animal models of dermatitis.
Topics: Animals; Cytokines; Dermatitis, Allergic Contact; Dopamine Antagonists; Immunoglobulin G; Mast Cells; Mice; Mice, Inbred C57BL; NIH 3T3 Cells; Oxazolone; Perphenazine; Tetradecanoylphorbol Acetate; Th2 Cells
PubMed: 32375285
DOI: 10.3390/ijms21093241 -
Cell Apr 2020Protein phosphatase 2A (PP2A) enzymes can suppress tumors, but they are often inactivated in human cancers overexpressing inhibitory proteins. Here, we identify a class...
Protein phosphatase 2A (PP2A) enzymes can suppress tumors, but they are often inactivated in human cancers overexpressing inhibitory proteins. Here, we identify a class of small-molecule iHAPs (improved heterocyclic activators of PP2A) that kill leukemia cells by allosterically assembling a specific heterotrimeric PP2A holoenzyme consisting of PPP2R1A (scaffold), PPP2R5E (B56ε, regulatory), and PPP2CA (catalytic) subunits. One compound, iHAP1, activates this complex but does not inhibit dopamine receptor D2, a mediator of neurologic toxicity induced by perphenazine and related neuroleptics. The PP2A complex activated by iHAP1 dephosphorylates the MYBL2 transcription factor on Ser241, causing irreversible arrest of leukemia and other cancer cells in prometaphase. In contrast, SMAPs, a separate class of compounds, activate PP2A holoenzymes containing a different regulatory subunit, do not dephosphorylate MYBL2, and arrest tumor cells in G1 phase. Our findings demonstrate that small molecules can serve as allosteric switches to activate distinct PP2A complexes with unique substrates.
Topics: Apoptosis; Cell Cycle Proteins; Cell Line, Tumor; Enzyme Activators; G1 Phase; Humans; Multiprotein Complexes; Phenothiazines; Phosphorylation; Protein Phosphatase 2; Protein Subunits; Trans-Activators; Transcription Factors
PubMed: 32315619
DOI: 10.1016/j.cell.2020.03.051 -
Psychotherapy and Psychosomatics 2020Studies on psychotropic medications decrease, discontinuation, or switch have uncovered withdrawal syndromes. The present overview aimed at analyzing the literature to... (Review)
Review
Studies on psychotropic medications decrease, discontinuation, or switch have uncovered withdrawal syndromes. The present overview aimed at analyzing the literature to illustrate withdrawal after decrease, discontinuation, or switch of psychotropic medications based on the drug class (i.e., benzodiazepines, nonbenzodiazepine benzodiazepine receptor agonists, antidepressants, ketamine, antipsychotics, lithium, mood stabilizers) according to the diagnostic criteria of Chouinard and Chouinard [Psychother Psychosom. 2015;84(2):63-71], which encompass new withdrawal symptoms, rebound symptoms, and persistent post-withdrawal disorders. All these drugs may induce withdrawal syndromes and rebound upon discontinuation, even with slow tapering. However, only selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors, and antipsychotics were consistently also associated with persistent post-withdrawal disorders and potential high severity of symptoms, including alterations of clinical course, whereas the distress associated with benzodiazepines discontinuation appears to be short-lived. As a result, the common belief that benzodiazepines should be substituted by medications that cause less dependence such as antidepressants and antipsychotics runs counter the available literature. Ketamine, and probably its derivatives, may be classified as at high risk for dependence and addiction. Because of the lag phase that has taken place between the introduction of a drug into the market and the description of withdrawal symptoms, caution is needed with the use of newer antidepressants and antipsychotics. Within medication classes, alprazolam, lorazepam, triazolam, paroxetine, venlafaxine, fluphenazine, perphenazine, clozapine, and quetiapine are more likely to induce withdrawal. The likelihood of withdrawal manifestations that may be severe and persistent should thus be taken into account in clinical practice and also in children and adolescents.
Topics: Humans; Mental Disorders; Psychotropic Drugs; Randomized Controlled Trials as Topic; Substance Withdrawal Syndrome
PubMed: 32259826
DOI: 10.1159/000506868 -
Translational Psychiatry Mar 2020Genome-wide association study (GWAS) has determined the metabotropic glutamate receptor 7 (GRM7) gene as potential locus for schizophrenia risk variants; However, the...
Genome-wide association study (GWAS) has determined the metabotropic glutamate receptor 7 (GRM7) gene as potential locus for schizophrenia risk variants; However, the relationship between the GRM7 variants and the risk of schizophrenia is still uncertain, and there are significant individual variations in response to the antipsychotic drugs. In order to identify susceptible gene and drug-response-related markers, 2413 subjects in our research were chosen for determining drug-response-related markers in schizophrenia. The rs1516569 variant (OR = 0.95, P < 3.47 × 10) was a significant risk factor, and a single-nucleotide polymorphism of GRM7 gene- rs9883258 (OR = 0.84, P = 2.18 × 10) has been determined as potential biomarkers for therapeutic responses of seven commonly used antipsychotic drugs (aripiprazole, haloperidol, olanzapine, perphenazine, quetiapine, risperidone and ziprasidone) in Chinese Han population; Significant associations with treatment response for several single-nucleotide polymorphisms in every antipsychotic drugs, such as rs779746 (OR = 1.39, P = 0.03), rs480409 (OR = 0.73, P = 0.04), rs78137319 (OR = 3.09, P = 0.04), rs1154370 (OR = 1.51, P = 0.006) have been identified in our study. Hence our research elucidates that GRM7 variants play the critical role of predicting the risk of schizophrenia and antipsychotic effect of seven common drugs.
Topics: Antipsychotic Agents; Benzodiazepines; Genome-Wide Association Study; Humans; Quetiapine Fumarate; Receptors, Metabotropic Glutamate; Risk Factors; Risperidone; Schizophrenia
PubMed: 32127521
DOI: 10.1038/s41398-020-0763-4 -
World Psychiatry : Official Journal of... Feb 2020Antipsychotics are used for many psychiatric conditions in youth. Although developmentally inappropriate weight gain and metabolic abnormalities, which are risk factors...
Metformin add-on vs. antipsychotic switch vs. continued antipsychotic treatment plus healthy lifestyle education in overweight or obese youth with severe mental illness: results from the IMPACT trial.
Antipsychotics are used for many psychiatric conditions in youth. Although developmentally inappropriate weight gain and metabolic abnormalities, which are risk factors for premature cardiovascular mortality, are especially frequent in youth, optimal strategies to reduce pediatric antipsychotic-induced overweight/obesity are unclear. The Improving Metabolic Parameters in Antipsychotic Child Treatment (IMPACT) was a randomized, parallel group, 24-week clinical trial which enrolled overweight/obese, psychiatrically stable youth, aged 8-19 years, with a DSM-IV diagnosis of severe mental illness (schizophrenia spectrum disorder, bipolar spectrum disorder or psychotic depression), at four US universities. All of them had developed substantial weight gain following treatment with a second-generation antipsychotic. The centralized, computer-based randomization system assigned participants to unmasked treatment groups: metformin (MET); antipsychotic switch (aripiprazole or, if already exposed to that drug, perphenazine or molindone; SWITCH); or continued baseline antipsychotic (CONTROL). All participants received healthy lifestyle education. The primary outcome was body mass index (BMI) z-score change from baseline, analyzed using estimated least squares means. Altogether, 127 participants were randomized: 49 to MET, 31 to SWITCH, and 47 to CONTROL. BMI z-score decreased significantly with MET (week 24: -0.09±0.03, p=0.002) and SWITCH (week 24: -0.11±0.04, p=0.003), while it increased non-significantly with CONTROL (week 24: +0.04±0.03). On 3-way comparison, BMI z-score changes differed significantly (p=0.001). MET and SWITCH were each superior to CONTROL (p=0.002), with effect sizes of 0.68 and 0.81 respectively, while MET and SWITCH did not differ. More gastrointestinal problems occurred in MET than in SWITCH or CONTROL. The data safety monitoring board closed the perphenazine-SWITCH arm because 35.2% of subjects discontinued treatment due to psychiatric worsening. These data suggest that pediatric antipsychotic-related overweight/obesity can be reduced by adding metformin or switching to a lower risk antipsychotic. Healthy lifestyle education is not sufficient to prevent ongoing BMI z-score increase.
PubMed: 31922663
DOI: 10.1002/wps.20714 -
Bioorganic & Medicinal Chemistry Letters Sep 2019Inspired by the cytotoxicity of perphenazine toward cancer cells and its ability to activate the serine/threonine protein phosphatase 2A (PP2A), we prepared series of...
Inspired by the cytotoxicity of perphenazine toward cancer cells and its ability to activate the serine/threonine protein phosphatase 2A (PP2A), we prepared series of ether-carbon linked analogs of a constrained synthetic sphingolipid analog 3, known for its cytotoxicity, nutrient transporter down-regulation and vacuolation properties, incorporating the tricyclic neuroleptics phenoxazine and phenothiazine to represent hybrid structures with possible synergistic cytotoxic activity. While the original activity of the lead compound 3 was diminished by fusion with the phenoxazine or phenothiazine tethered moieties, the corresponding 3-pyridyltetryl ether analog 10 showed cytotoxicity and nutrient transporter down-regulation similar to the lead compound 3, although it separated these PP2A-dependent phenotypes from that of vacuolation.
Topics: Animals; Antineoplastic Agents; Cell Line; Cell Survival; Dose-Response Relationship, Drug; Drug Design; Enzyme Inhibitors; Mice; Molecular Structure; Oxazines; Phenothiazines; Protein Phosphatase 2; Sphingolipids; Structure-Activity Relationship
PubMed: 31383588
DOI: 10.1016/j.bmcl.2019.07.023 -
Schizophrenia Research Sep 2019
Randomized Controlled Trial
Topics: Adult; Antipsychotic Agents; Deprescriptions; Female; Humans; Kaplan-Meier Estimate; Male; Medication Adherence; Mental Status and Dementia Tests; Olanzapine; Perphenazine; Proportional Hazards Models; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome
PubMed: 31378553
DOI: 10.1016/j.schres.2019.07.033 -
The Mental Health Clinician Jul 2019In addition to clozapine, there is a growing body of evidence that supports therapeutic drug monitoring (TDM) for additional antipsychotics commonly used in the United...
INTRODUCTION
In addition to clozapine, there is a growing body of evidence that supports therapeutic drug monitoring (TDM) for additional antipsychotics commonly used in the United States.
METHODS
The Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) published TDM guidelines for several psychiatric medications. Sources were identified that the authors used to establish therapeutic reference ranges for haloperidol, fluphenazine, perphenazine, and olanzapine-4 antipsychotics commonly used in the United States with a "strong recommendation" for TDM. The sources were then reviewed for content and appropriateness for utilization in establishing the reference ranges.
RESULTS
Olanzapine had 15 citations, haloperidol had 9, perphenazine had 4, and fluphenazine had 2. The studies' methods were reviewed along with the proposed therapeutic reference ranges.
DISCUSSION
Several limitations of the guidelines were identified. Reference ranges were suggested based on studies of patients with various diagnoses; some patients had an acute exacerbation, and others were in a maintenance phase. An additional publication was identified that reviewed similar (and additional) TDM studies; those conclusions were in slight contrast with those of the AGNP guidelines. In the future, guidance should be given to those looking to conduct TDM studies to standardize methods and make meta-analysis of this data more feasible.
PubMed: 31293849
DOI: 10.9740/mhc.2019.07.287