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Journal of Applied Toxicology : JAT Apr 2023In this review, we summarized the current literature on the impact of phenothiazine derivatives on autophagy in vitro. Phenothiazines are antipsychotic drugs used in the... (Review)
Review
In this review, we summarized the current literature on the impact of phenothiazine derivatives on autophagy in vitro. Phenothiazines are antipsychotic drugs used in the treatment of schizophrenia, which is related to altered neurotransmission and dysregulation of neuronal autophagy. Thus, phenothiazine derivatives can impact autophagy. We identified 35 papers, where the use of the phenothiazines in the in vitro autophagy assays on normal and cancer cell lines, Caenorhabditis elegans, and zebrafish were discussed. Chlorpromazine, fluphenazine, mepazine, methotrimeprazine, perphenazine, prochlorperazine, promethazine, thioridazine, trifluoperazine, and novel derivatives can modulate autophagy. Stimulation of autophagy by phenothiazines may be either mammalian target of rapamycin (mTOR)-dependent or mTOR-independent. The final effect depends on the used concentration as well as the cell line. A further investigation of the mechanisms of autophagy regulation by phenothiazine derivatives is required to understand the biological actions and to increase the therapeutic potential of this class of drugs.
Topics: Animals; Antipsychotic Agents; Zebrafish; Promazine; Phenothiazines; Chlorpromazine; Mammals
PubMed: 36165981
DOI: 10.1002/jat.4397 -
Oncology Letters Jun 2022Glioblastoma multiforme is the most frequent type of malignant brain tumor, and is one of the most lethal and untreatable human tumors with a very poor survival rate....
Perphenazine and prochlorperazine decrease glioblastoma U-87 MG cell migration and invasion: Analysis of the ABCB1 and ABCG2 transporters, E-cadherin, α-tubulin and integrins (α3, α5, and β1) levels.
Glioblastoma multiforme is the most frequent type of malignant brain tumor, and is one of the most lethal and untreatable human tumors with a very poor survival rate. Therefore, novel and effective strategies of treatment are required. Integrins play a crucial role in the regulation of cellular adhesion and invasion. Integrins and α-tubulin are very important in cell migration, whereas E-cadherin plays a main role in tumor metastasis. Notably, drugs serve a crucial role in glioblastoma treatment; however, they have to penetrate the blood-brain barrier (BBB) to be effective. ABC transporters, including ATP binding cassette subfamily B member 1 (ABCB1) and ATP binding cassette subfamily G member 2 (ABCG2), are localized in the brain endothelial capillaries of the BBB, have a crucial role in the development of multidrug resistance and are modulated by phenothiazine derivatives. The impact of perphenazine and prochlorperazine on the motility of human Uppsala 87 malignant glioma (U87-MG) cells was evaluated using a wound-healing assay, cellular migration and invasion were assessed by Transwell assay, and the protein expression levels of ABCB1, ABCG2, E-cadherin, α-tubulin and integrins were determined by western blotting. The present study explored the effects of perphenazine and prochlorperazine on the levels of ABCB1, ABCG2, E-cadherin, α-tubulin and integrins (α3, α5, and β1), as well as on the migratory and invasive ability of U87-MG cells. The results suggested that perphenazine and prochlorperazine may modulate the expression levels of multidrug resistance proteins (they decreased ABCB1 and increased ABCG2 expression), E-cadherin, α-tubulin and integrins, and could impair the migration and invasion of U-87 MG cells. In conclusion, the decrease in migratory and invasive ability following treatment with phenothiazine derivatives due to the increase in ABCG2 and E-cadherin expression, and decrease in α-tubulin and integrins expression, may suggest that research on perphenazine and prochlorperazine in the treatment of glioblastoma is worth continuing.
PubMed: 35527777
DOI: 10.3892/ol.2022.13302 -
Current Neuropharmacology 2023Since the early clinical efficacy of antipsychotics has not yet been well perceived, this study sought to decide whether the efficacy of antipsychotics at week 2 can... (Randomized Controlled Trial)
Randomized Controlled Trial Clinical Trial
BACKGROUND
Since the early clinical efficacy of antipsychotics has not yet been well perceived, this study sought to decide whether the efficacy of antipsychotics at week 2 can predict subsequent responses at week 6 and identify how such predictive capacities vary among different antipsychotics and psychotic symptoms.
METHODS
A total of 3010 patients with schizophrenia enrolled in a randomized controlled trial (RCT) and received a 6-week treatment with one antipsychotic drug randomly chosen from five atypical antipsychotics (risperidone 2-6 mg/d, olanzapine 5-20 mg/d, quetiapine 400-750 mg/d, aripiprazole 10-30 mg/d, and ziprasidone 80-160 mg/d) and two typical antipsychotics (perphenazine 20-60 mg/d and haloperidol 6-20 mg/d). Early efficacy was defined as the reduction rate using the Positive and Negative Syndrome Scale (PANSS) total score at week 2. With cut-offs at 50% reduction, logistic regression, receiver operating characteristic (ROC) and random forests were adopted.
RESULTS
The reduction rate of PANSS total score and improvement of psychotic symptoms at week 2 enabled subsequent responses to 7 antipsychotics to be predicted, in which improvements in delusions, lack of judgment and insight, unusual thought content, and suspiciousness/ persecution were endowed with the greatest weight.
CONCLUSION
It is robust enough to clinically predict treatment responses to antipsychotics at week 6 using the reduction rate of PANSS total score and symptom relief at week 2. Psychiatric clinicians had better determine whether to switch the treatment plan by the first 2 weeks.
Topics: Humans; Antipsychotic Agents; Benzodiazepines; Schizophrenia; Aripiprazole; Olanzapine; Risperidone; Quetiapine Fumarate; Haloperidol; Treatment Outcome
PubMed: 36411567
DOI: 10.2174/1570159X21666221118164612 -
Acta Poloniae Pharmaceutica Jul 2016Fluphenazine and perphenazine as a phenothiazine-class antipsychotic drugs are widely used to treat psychoses and schizophrenia, however their use is associated with...
Fluphenazine and perphenazine as a phenothiazine-class antipsychotic drugs are widely used to treat psychoses and schizophrenia, however their use is associated with significant side effects such as extrapyramidal symptoms as well as ocular and skin disorders. The aim of this study was to examine the effect of fluphenazine and perphenazine on cell viability, melanogenesis and antioxidant defense system in normal human melanocytes. It has been shown that both phenothiazines induce concentration-dependent loss in cell viability. The value of EC₅₀. was calculated to be 1.24 and 2.76 μM for fluphenazine and perphenazine, respectively. Fluphenazine in concentration of 1.0 μM and perphenazine in concentrations of 1.0 and 3.0 μM inhibied melanogenesis and decreased microphthalmia-associated transcription factor content. To study the effect of both analyzed drugs on antioxidant defense system in melanocytes, the level of hydrogen peroxide and the activities of antioxidant enzymes: superoxide dismutase, catalase and glutathione peroxidase were determined. Fluphenazine and perphenazine in higher analyzed concentrations caused depletion of melanocytes antioxidant status, what indicated the induction of oxidative stress. The observed changes in melanization process and antioxidant defense system in pigmented cells exposed to fluphenazine and perphenazine in vibo suggest a significant role of melanin and melanocytes in the mechanisms of undesirable side effects of these drugs in vivo, especially directed to pigmented tissues. Moreover, the presented differences in modulation of biochemical processes in melanocytes may be an explanation for various toxic activity of the analyzed phenothiazine derivatives in vivo.
Topics: Catalase; Cells, Cultured; Fluphenazine; Humans; Melanins; Melanocytes; Oxidative Stress; Perphenazine; Superoxide Dismutase
PubMed: 29648716
DOI: No ID Found -
Frontiers in Psychiatry 2023Our objective was to conduct a systematic review and meta-analysis of adverse effects on sleep in patients with schizophrenia receiving antipsychotic treatment.
INTRODUCTION
Our objective was to conduct a systematic review and meta-analysis of adverse effects on sleep in patients with schizophrenia receiving antipsychotic treatment.
METHODS
A systematic search was performed in PubMed, Cochrane Central, Embase, Toxline, Ebsco, Virtual Health Library, Web of Science, SpringerLink, and in Database of abstracts of Reviews of Effects of Randomized Clinical Trials to identify eligible studies published from January 1990 to October 2021. The methodological quality of the studies was evaluated using the CONSORT list, and the Cochrane bias tool. Network meta-analysis was performed using the Bayesian random-effects model, with multivariate meta-regression to assess the association of interest.
RESULTS
87 randomized clinical trials were identified that met the inclusion criteria, and 70 articles were included in the network meta-analysis. Regarding the methodological quality of the studies, 47 had a low or moderate bias risk. The most common adverse effects on sleep reported in the studies were insomnia, somnolence, and sedation. The results of the network meta-analysis showed that ziprasidone was associated with an increased risk of insomnia (OR, 1.56; 95% credible interval CrI, 1.18-2.06). Several of the included antipsychotics were associated with a significantly increased risk of somnolence; haloperidol (OR, 1.90; 95% CrI, 1.12-3.22), lurasidone (OR, 2.25; 95% CrI, 1.28-3.97) and ziprasidone (OR, 1.79; 95% CrI, 1.06-3.02) had the narrowest confidence intervals. In addition, perphenazine (OR, 5.33; 95% CrI, 1.92-14.83), haloperidol (OR, 2.61; 95% CrI, 1.14-5.99), and risperidone (OR, 2.41; 95% CrI, 1.21-4.80) were associated with an increased risk of sedation compared with placebo, and other antipsychotics did not differ. According to the SUCRAs for insomnia, chlorpromazine was ranked as the lowest risk of insomnia (57%), followed by clozapine (20%), while flupentixol (26 %) and perospirone (22.5%) were associated with a lower risk of somnolence. On the other hand, amisulpride (89.9%) was the safest option to reduce the risk of sedation.
DISCUSSION
Insomnia, sedation, and somnolence were the most frequent adverse effects on sleep among the different antipsychotics administered. The evidence shows that chlorpromazine, clozapine, flupentixol, perospirone, and amisulpride had favorable safety profiles. In contrast, ziprasidone, perphenazine, haloperidol, and risperidone were the least safe for sleep.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42017078052, identifier: PROSPERO 2017 CRD42017078052.
PubMed: 37441144
DOI: 10.3389/fpsyt.2023.1189768 -
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 -
Journal of Clinical PsychopharmacologyDrug-associated liver injury is one of the most common causes for acute liver failure and market withdrawal of approved drugs. In addition, the potential for...
BACKGROUND
Drug-associated liver injury is one of the most common causes for acute liver failure and market withdrawal of approved drugs. In addition, the potential for hepatotoxicity related to specific substances has to be considered in psychopharmacotherapy. However, systematic evaluations of hepatotoxicity related to antipsychotics are limited.
METHODS
We conducted an exploratory case/non-case study and evaluated pharmacovigilance data from VigiBase related to 30 antipsychotics marketed in the European Union. Reporting odds ratios were calculated for antipsychotics associated with the Standardized Medical Dictionary of Regulatory Activities queries "Drug-related hepatic disorders-comprehensive search" (DRHD-CS) and "Drug-related hepatic disorders-severe events only" (DRHD-SEO).
RESULTS
We found several signals for drug-associated liver injury including signals for severe events: 17 of 30 antipsychotics were associated with DRHD-CS and 10 of 30 antipsychotics with DRHD-SEO. Amisulpride, fluphenazine, levomepromazine, loxapine, olanzapine, perazine, perphenazine, pipamperone, sulpiride, and thioridazine were associated with both, DRHD-CS and DRHD-SEO. No association with fatal outcomes was detected.
CONCLUSIONS
Several common antipsychotics are associated with hepatotoxicity, partly also with severe hepatotoxicity. Our data do not allow to account for patient-related risk factors for drug-associated liver injury. This should be addressed in further studies.
Topics: Amisulpride; Antipsychotic Agents; Chemical and Drug Induced Liver Injury; Humans; Pharmacovigilance
PubMed: 35730552
DOI: 10.1097/JCP.0000000000001576 -
British Journal of Clinical Pharmacology May 2021To investigate the impact of cytochrome P450 2D6 (CYP2D6) on dose-adjusted serum concentrations of flupentixol, haloperidol, perphenazine and zuclopenthixol in a...
AIMS
To investigate the impact of cytochrome P450 2D6 (CYP2D6) on dose-adjusted serum concentrations of flupentixol, haloperidol, perphenazine and zuclopenthixol in a therapeutic drug monitoring (TDM) cohort of psychiatric patients. We also studied the functional impact of CYP2D6*41 on dose-adjusted serum concentrations in the perphenazine-treated patients.
METHODS
Serum concentrations of flupentixol, haloperidol, perphenazine and zuclopenthixol from CYP-genotyped patients were extracted retrospectively from a routine TDM database in the period March 2005 to May 2019. Samples were divided into three CYP2D6 phenotype subgroups according to genotype; normal metabolizers (NMs), intermediate metabolizers (IMs) and poor metabolizers (PMs). The effect of CYP2D6 phenotype on dose-adjusted serum concentrations of the four antipsychotics was evaluated by multivariable mixed model analyses.
RESULTS
Mean dose-adjusted serum concentrations of perphenazine (564 samples) were 3.9-fold and 1.6-fold higher in CYP2D6 PMs and IMs, respectively, compared with NMs (P < .001 and P < .01). For zuclopenthixol (658 samples), mean dose-adjusted serum concentrations were about 1.5-fold and 1.3-fold higher in CYP2D6 PMs and IMs, respectively, compared with NMs (P < .01 and P < .001). CYP2D6 was of minor or no importance to haloperidol (320 samples) and flupentixol (115 samples). In our data material, the genotype CYP2D6 *1/*41 appears to have a similar impact on dose-adjusted serum concentrations of perphenazine as *1/null (null = variant allele encoding no enzyme function).
CONCLUSIONS
This study shows that CYP2D6 is important for the metabolism of perphenazine and zuclopenthixol, but not for haloperidol and flupentixol. The CYP2D6*41 allele appears to have a reduced function close to nonfunctional variant alleles.
Topics: Clopenthixol; Cytochrome P-450 CYP2D6; Flupenthixol; Genotype; Haloperidol; Humans; Perphenazine; Retrospective Studies
PubMed: 33118660
DOI: 10.1111/bcp.14626 -
Toxicology Letters Aug 2022Antipsychotic drugs represent a class of lysosomotropic drugs widely used in clinical practice. However, the hepatotoxicity of these drugs has been reported in recent...
Antipsychotic drugs represent a class of lysosomotropic drugs widely used in clinical practice. However, the hepatotoxicity of these drugs has been reported in recent years. Therefore, understanding the changes in cellular homeostasis mediated by these drugs is of great significance for revealing the true mechanisms underlying hepatotoxicity. Perphenazine is a classical antipsychotic drug that can reportedly induce extrapyramidal and sympatholytic side effects. The present research focuses on the toxicity effect of perphenazine on normal human hepatocytes. To assess the hepatotoxicity of continuous administration of perphenazine and investigate potential mechanisms related to apoptosis, human normal L02 hepatocytes were exposed to 10-40 μM perphenazine in vitro. The results showed that perphenazine inhibited cell viability in a concentration and time-dependent manner. Furthermore, 30 μM perphenazine induced intense lysosome vacuolation, impaired lysosomal membrane, and induced lysosomal membrane permeabilization (LMP), ultimately triggering lysosomal cell death in L02 cells. Knockdown cathepsin D(CTSD) also ameliorated perphenazine-induced liver injury via the inhibition of LMP. In vivo, ICR mice received intragastric administration of 10-180 mg/kg B.W. perphenazine every other day for 21 days. 180 mg/kg perphenazine significantly increased histological injury and aminotransferases compared with control. Taken together, our findings suggest that perphenazine can trigger hepatotoxicity through lysosome disruption both in vitro and in vivo.
Topics: Animals; Apoptosis; Chemical and Drug Induced Liver Injury; Humans; Lysosomes; Mice; Mice, Inbred ICR; Perphenazine
PubMed: 35914675
DOI: 10.1016/j.toxlet.2022.07.814 -
Central Nervous System Agents in... 2017Piroxicam has been reported to be convertible to Central Nervous System (CNS) acting agents. It has serious depressant effects at high doses. (Review)
Review
BACKGROUND
Piroxicam has been reported to be convertible to Central Nervous System (CNS) acting agents. It has serious depressant effects at high doses.
OBJECTIVE
In view of this, structures of piroxicam metabolites were assessed for possible conversion to CNS depressants.
METHODS
Literature search was carried out with intent to identifying piroxicam metabolites and the possibility of converting them to CNS acting depressants.
RESULTS
Piroxicam is convertible to hydroxymethylated metabolite which may be converted to barbiturates such as thiopentone and thiamylal. Whereas cyclodehydrated metabolite may be converted to acetylcyclodehydrated compound that may be in turn converted to acetylacetone and cyclohexamide. However, carboxybenzothiazine metabolite may be converted to carboxamide compound, benzolactone which is convertible to phenazone. Carboxybenzothiazine is also convertible to 2-aminopyridine mepyramine and triplenamine. Conversion of carboxybenzothiazine to gamma aminobutyric acid and phenothiazines such as chlorpromazine, thioridazine, fluphenazine and perphenazine is highly possible.
CONCLUSION
Structurally, barbituric compounds, carboxamide, cyclodehydrated, benzothiazine and carboxybenzothiazine metabolites may act via dopamine and adrenergic receptors causing depression of CNS activities. Piroxicam metabolites may also act via histamine, melatonin and potassium channel receptors causing CNS depression.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Central Nervous System Depressants; Depression; Humans; Piroxicam
PubMed: 27834137
DOI: 10.2174/1871524917666161111093759