Pharmacological treatments for psychotic depression: a systematic review and network meta-analysis.

BACKGROUND: There are no recommendations based on the efficacy of specific drugs for the treatment of psychotic depression. To address this evidence gap, we did a network meta-analysis to assess and compare the efficacy and safety of pharmacological treatments for psychotic depression. METHODS: In this systematic review and network meta-analysis, we searched ClinicalTrials.gov, CENTRAL, Embase, PsycINFO, PubMed, Scopus, and Web of Science from inception to Nov 23, 2023 for randomised controlled trials published in any language that assessed pharmacological treatments for individuals of any age with a diagnosis of a major depressive episode with psychotic features, in the context of major depressive disorder or bipolar disorder in any setting. We excluded continuation or maintenance trials. We screened the study titles and abstracts identified, and we extracted data from relevant studies after full-text review. If full data were not available, we requested data from study authors twice. We analysed treatments for individual drugs (or drug combinations) and by grouping them on the basis of mechanisms of action. The primary outcomes were response rate (ie, the proportion of participants who responded to treatment) and acceptability (ie, the proportion who discontinued treatment for any reason). We calculated risk ratios and did separate frequentist network meta-analyses by using random-effects models. The risk of bias of individual studies was assessed with the Cochrane risk-of-bias tool and the confidence in the evidence with the Confidence-In-Network-Meta-Analysis (CINeMA). This study was registered with PROSPERO, CRD42023392926. FINDINGS: Of 6313 reports identified, 16 randomised controlled trials were included in the systematic review, and 14 were included in the network meta-analyses. The 16 trials included 1161 people with psychotic depression (mean age 50·5 years [SD 11·4]). 516 (44·4%) participants were female and 422 (36·3%) were male; sex data were not available for the other 223 (19·2%). 489 (42·1%) participants were White, 47 (4·0%) were African American, and 12 (1·0%) were Asian; race or ethnicity data were not available for the other 613 (52·8%). Only the combination of fluoxetine plus olanzapine was associated with a higher proportion of participants with a treatment response compared with placebo (risk ratio 1·91 [95% CI 1·27-2·85]), with no differences in terms of safety outcomes compared with placebo. When treatments were grouped by mechanism of action, the combination of a selective serotonin reuptake inhibitor with a second-generation antipsychotic was associated with a higher proportion of treatment responses than was placebo (1·89 [1·17-3·04]), with no differences in terms of safety outcomes. In head-to-head comparisons of active treatments, a significantly higher proportion of participants had a response to amitriptyline plus perphenazine (3·61 [1·23-10·56]) and amoxapine (3·14 [1·01-9·80]) than to perphenazine, and to fluoxetine plus olanzapine compared with olanzapine alone (1·60 [1·09-2·34]). Venlafaxine, venlafaxine plus quetiapine (2·25 [1·09-4·63]), and imipramine (1·95 [1·01-3·79]) were also associated with a higher proportion of treatment responses overall. In head-to-head comparisons grouped by mechanism of action, antipsychotic plus antidepressant combinations consistently outperformed monotherapies from either drug class in terms of the proportion of participants with treatment responses. Heterogeneity was low. No high-risk instances were identified in the bias assessment for our primary outcomes. INTERPRETATION: According to the available evidence, the combination of a selective serotonin reuptake inhibitor and a second-generation antipsychotic-and particularly of fluoxetine and olanzapine-could be the optimal treatment choice for psychotic depression. These findings should be taken into account in the development of clinical practice guidelines. However, these conclusions should be interpreted cautiously in view of the low number of included studies and the limitations of these studies. FUNDING: None.

The Role of Total White Blood Cell Count in Antipsychotic Treatment for Patients with Schizophrenia.

BACKGROUND: Total white blood cell count (TWBCc), an index of chronic and low-grade inflammation, is associated with clinical symptoms and metabolic alterations in patients with schizophrenia. The effect of antipsychotics on TWBCc, predictive values of TWBCc for drug response, and role of metabolic alterations require further study. METHODS: Patients with schizophrenia were randomized to monotherapy with risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, perphenazine or haloperidol in a 6-week pharmacological trial. We repeatedly measured clinical symptoms, TWBCc, and metabolic measures (body mass index, blood pressure, waist circumference, fasting blood lipids and glucose). We used mixed-effect linear regression models to test whether TWBCc can predict drug response. Mediation analysis to investigate metabolic alteration effects on drug response. RESULTS: At baseline, TWBCc was higher among patients previously medicated. After treatment with risperidone, olanzapine, quetiapine, perphenazine, and haloperidol, TWBCc decreased significantly (p < 0.05). Lower baseline TWBCc predicted greater reductions in Positive and Negative Syndrome Scale (PANSS) total and negative scores over time (p < 0.05). We found significant mediation of TWBCc for effects of waist circumference, fasting low-density lipoprotein cholesterol, and glucose on reductions in PANSS total scores and PANSS negative subscale scores (p < 0.05). CONCLUSION: TWBCc is affected by certain antipsychotics among patients with schizophrenia, with decreases observed following short-term, but increases following long-term treatment. TWBCc is predictive of drug response, with lower TWBCc predicting better responses to antipsychotics. It also mediates the effects of certain metabolic measures on improvement of negative symptoms. This indicates that the metabolic state may affect clinical manifestations through inflammation.

Bile Is a Selective Elevator for Mucosal Mechanics and Transport.

Mucus mechanically protects the intestinal epithelium and impacts the absorption of drugs, with a largely unknown role for bile. We explored the impacts of bile on mucosal biomechanics and drug transport within mucus. Bile diffused with square-root-of-time kinetics and interplayed with mucus, leading to transient stiffening captured in Brillouin images and a concentration-dependent change from subdiffusive to Brownian-like diffusion kinetics within the mucus demonstrated by differential dynamic microscopy. Bile-interacting drugs, Fluphenazine and Perphenazine, diffused faster through mucus in the presence of bile, while Metoprolol, a drug with no bile interaction, displayed consistent diffusion. Our findings were corroborated by rat studies, where co-dosing of a bile acid sequestrant substantially reduced the bioavailability of Perphenazine but not Metoprolol. We clustered over 50 drugs based on their interactions with bile and mucin. Drugs that interacted with bile also interacted with mucin but not vice versa. This study detailed the dynamics of mucus biomechanics under bile exposure and linked the ability of a drug to interact with bile to its abbility to interact with mucus.

Perphenazine-Macrocycle Conjugates Rapidly Sequester the Aß42 Monomer and Prevent Formation of Toxic Oligomers and Amyloid.

Alzheimer's disease is imposing a growing social and economic burden worldwide, and effective therapies are urgently required. One possible approach to modulation of the disease outcome is to use small molecules to limit the conversion of monomeric amyloid (Aß42) to cytotoxic amyloid oligomers and fibrils. We have synthesized modulators of amyloid assembly that are unlike others studied to date: these compounds act primarily by sequestering the Aß42 monomer. We provide kinetic and nuclear magnetic resonance data showing that these perphenazine conjugates divert the Aß42 monomer into amorphous aggregates that are not cytotoxic. Rapid monomer sequestration by the compounds reduces fibril assembly, even in the presence of pre-formed fibrillar seeds. The compounds are therefore also able to disrupt monomer-dependent secondary nucleation, the autocatalytic process that generates the majority of toxic oligomers. The inhibitors have a modular design that is easily varied, aiding future exploration and use of these tools to probe the impact of distinct Aß42 species populated during amyloid assembly.

A ratiometric electrochemical sensor based on Cu-coordinated molecularly imprinted polymer and porous carbon supported Ag nanoparticles for highly sensitive and selective detection of perphenazine.

In this work, a ratiometric electrochemical sensor was developed for the detection of perphenazine (PPZ). The sensor was constructed by electrodepositing Cu-coordinated molecularly imprinted polymer (Cu-MIP) on Ag nanoparticles (NPs) modified flexible porous carbon cloth. The Cu-MIP showed highly electrochemical response because of the enhanced adsorptive ability and electronic properties of Cu2+ chelation; Ag NPs could provide a stable and effective reference signal for ratiometric quantification. Thus the resulted sensor not only displayed high selectivity and sensitivity, but also exhibited satisfactory reproducibility and anti-interference ability. Under the optimum conditions, the quantitative detection of PPZ was performed with differential pulse voltammetry. It was found that the peak current ratio of PPZ and Ag NP was linear to the concentration of PPZ in the range of 1-700 nmol L-1 (R2 = 0.9968), and the limit of detection was 0.43 nmol L-1 (S/N = 3). The practicability of the sensor was examined by determining human serum and pharmaceutical samples, and satisfactory results and recoveries (ranging from 92.46% to 104.90%) were achieved.

Bile and excipient interactions directing drug pharmacokinetics in rats.

Bile solubilization plays a major role in the absorption of poorly water-soluble drugs. Excipients used in oral drug formulations impact bile-colloidal properties and their molecular interactions. Polymer-induced changes of bile colloids, e.g., by Eudragit E, reduced the flux of the bile interacting drug Perphenazine whereas bile non-interacting Metoprolol was not impacted. This study corroborates these in vitro findings in rats. Eudragit E significantly reduced systemic availability of Perphenazine but not Metoprolol compared to the oral administrations without polymer. This study confirms the necessity to carefully select polymers for bile interacting drugs whereas non-bile interacting drugs are more robust in terms of excipient choice for formulation. The perspective of bile interaction may introduce interesting biopharmaceutical leverage for better performing oral formulations of tomorrow.

Simultaneous spectrophotometric determination of fluphenazine HCl and nortriptyline HCl in presence of their potential impurities perphenazine and dibenzosuberone in bulk and pharmaceutical formulation.

Fluphenazine HCl (FLU) is an anxiolytic, while Nortriptyline HCl (NOR) is an anti-depressant. They are co-formulated together to treat depression and schizophrenia. Perphenazine (PER) and dibenzosuberone (DBZ) are the pharmacopeial impurities of FLU and NOR, respectively. Four spectrophotometric and multivariate chemometric methods were developed to determine the two drugs together or in presence of their two impurities in their bulk and pharmaceutical formulation. Method (A) is the triple divisor-ratio derivative (TDR) method, where the zero order spectrum of each component was divided by a mixture of the other 3 components, then the peak amplitudes of the first derivative spectra of FLU, NOR and DBZ were measured at 265, 245.4 and 283.2 nm, respectively. Method (B) is the double divisor-ratio difference-dual wavelength (DD-RD-DW) method, in which each component spectrum mixture was divided by a binary mixture of 2 of the interfering components. In the resulting ratio spectra, the amplitude difference is calculated between 2 wavelengths at which the third interfering component has zero difference. Methods (C and D) are the principle component analysis (PCA) and partial least squares (PLS) models. Methods (A and B) failed to quantify PER (FLU impurity), while (C and D) succeeded to quantify all components. The four methods have been applied for the prediction of the FLU and NOR in their pharmaceutical formulation with good accuracy and precision. The proposed methods have been validated according to the ICH guidelines and the results were within the acceptable limits.

Association of Maternal Antipsychotic Prescription During Pregnancy With Standardized Test Scores of Schoolchildren in Denmark.

Importance: An increasing number of individuals fill antipsychotic prescriptions during pregnancy, and concerns have been raised about prenatal antipsychotic exposure on neurodevelopmental outcomes. Objective: To examine whether maternal prescription fill for antipsychotics during pregnancy was associated with performance in standardized tests among schoolchildren. Design, Setting, and Participants: This register-based cohort study included 667 517 children born in Denmark from January 1, 1997, to December 31, 2009, and who were attending public primary and lower secondary school. All children had completed at least 1 language (Danish) or mathematics test as part of the Danish National School Test Program between 2010 and 2018. Data were analyzed from November 1, 2021, to March 31, 2022. Exposures: Antipsychotic prescriptions filled by pregnant individuals were obtained from the Danish National Prescription Register. Main Outcomes and Measures: Differences in standardized test scores (range, 1-100; higher scores indicate better test results) in language and mathematics between children of mothers with and without antipsychotic prescription fills during pregnancy were estimated using linear regression models. Seven sensitivity analyses, including a sibling-controlled analysis, were performed. Results: Of the 667 517 children included (51.2% males), 1442 (0.2%) children were born to mothers filling an antipsychotic prescription during pregnancy. The mean (SD) age of children at the time of testing spanned from 8.9 (0.4) years in grade 2 to 14.9 (0.4) years in grade 8. Maternal prescription fill for antipsychotics was not associated with performance in language (crude mean test score: 50.0 [95% CI, 49.1-50.9] for the exposed children vs 55.4 [95% CI, 55.4-55.5] for the unexposed children; adjusted difference, 0.5 [95% CI, -0.8 to 1.7]) or in mathematics (crude mean test score: 48.1 [95% CI, 47.0-49.3] for the exposed children vs 56.1 [95% CI, 56.1-56.2] for the unexposed children; adjusted difference, 0.4 [95% CI, -1.0 to 1.8]). There was no evidence that results were modified by the timing of filling prescriptions, classes (first-generation and second-generation) of antipsychotics, or the most commonly prescribed antipsychotic monotherapies, including chlorprotixene, flupentixol, olanzapine, zuclopenthixol, quetiapine, perphenazine, and methotrimeprazine. The results remained robust across sensitivity analyses, including sibling-controlled analyses, negative control exposures analyses, and probabilistic bias analyses. Conclusions and Relevance: In this register-based cohort study, maternal prescription fill for antipsychotics during pregnancy did not appear to be associated with standardized test scores in the offspring. The findings provide further reassuring data on offspring neurodevelopmental outcomes associated with antipsychotic treatment during pregnancy.

Lysosomal membrane permeabilization mediated apoptosis involve in perphenazine-induced hepatotoxicity in vitro and in vivo.

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.

Optimal Doses of Specific Antipsychotics for Relapse Prevention in a Nationwide Cohort of Patients with Schizophrenia.

BACKGROUND AND HYPOTHESIS: Optimal doses of most antipsychotics in the maintenance treatment of schizophrenia are unknown. We aimed to study the risk of severe relapse indicated by rehospitalization for different dose categories of 15 most frequently used antipsychotics in monotherapy in Finland. STUDY METHODS: We studied the risk of rehospitalization (Adjusted Hazard Ratio, aHR) associated with six antipsychotic monotherapy dose categories (as time-varying dose, measured in defined daily dose, DDDs/day) in a nationwide cohort of persons diagnosed with schizophrenia (n = 61 889), using within-individual analyses to eliminate selection bias. STUDY RESULTS: Among the 15 most widely used antipsychotics, 13 had a U- or J-shaped dose-response curve, showing the lowest risks of relapse for doses of 0.6-<1.1 DDDs/day vs nonuse of antipsychotics. The exceptions were oral perphenazine (aHR = 0.72, 95% CI = 0.68-0.76, <0.6 DDDs/day), and olanzapine-long-acting injectable (LAI), which had the lowest aHR of any antipsychotic (aHR = 0.17, 95% CI = 0.11-0.25, 1.4-<1.6 DDDs/day). Certain risperidone and perphenazine doses <0.9 DDD/day were associated with 21%-45% lower risk of rehospitalization (P < .001) than the standard dose of 0.9-1.1 DDD/day (ie, 5 mg for risperidone and 30 mg for perphenazine). CONCLUSIONS: For most antipsychotics, the risk of severe relapse was the lowest during use of standard dose. Our results suggest that olanzapine LAI is highly effective in dose ranges >0.9 DDD/day, and especially at 1.4-<1.6 DDDs/day (405 mg/4 weeks) associated with substantially lower risk of rehospitalization than any dose of any other antipsychotic. The current WHO standard dose definitions appear to be clearly too high for perphenazine and somewhat too high for risperidone.

Development of Perphenazine-Loaded Solid Lipid Nanoparticles: Statistical Optimization and Cytotoxicity Studies.

OBJECTIVE: Perphenazine (PPZ), as a typical antipsychotic medical substance, has the same effectiveness compared to atypical antipsychotic medications for the treatment of schizophrenia. Despite the lipophilic essence, PPZ encounters limited bioavailability caused by the first-pass metabolism following oral administration. In the present study, PPZ-containing solid lipid nanoparticles (PPZ-SLNs) were prepared and optimized based on different factors, including lipid and surfactant amount, to develop appropriate and safe novel oral dosage forms of PPZ. METHODS: The solvent emulsification-evaporation method was utilized to form SLNs by using soybean lecithin, glycerol monostearate (GMS), and Tween 80. Statistical optimization was done by the Box-Behnken design method to achieve formulation with optimized particle size, entrapment efficiency, and zeta potential. Also, transmission electron microscopy, in vitro release behavior, differential scanning calorimetry (DSC), and powder X-ray diffractometry (P-XRD) studies and cytotoxicity studies were assessed. RESULTS: Optimization exhibited the significant effect of various excipients on SLN characteristics. Our finding indicated that the mean particle size, zeta potential, and entrapment efficiency of optimized PPZ-SLN were, respectively, 104 ± 3.92 nm, -28 ± 2.28 mV, and 83% ± 1.29. Drug release of PPZ-SLN was observed to be greater than 90% for 48 h that emphasized a sustained-release pattern. The DSC and P-XRD studies revealed the amorphous state of PPZ-SLN. FTIR spectra showed no incompatibility between the drug and the lipid. Performing cytotoxicity studies indicated no significant cytotoxicity on HT-29 cell culture. CONCLUSION: Our study suggests that PPZ-SLNs can make a promising vehicle for a suitable therapy of schizophrenia for the oral drug delivery system.

Effect of Selected Anionic and Cationic Drugs Affecting the Central Nervous System on Electrical Properties of Phosphatidylcholine Liposomes: Experiment and Theory.

Interactions between phospholipid membranes and selected drugs affecting the central nervous system (CNS) were investigated. Small, unilamellar liposomes were used as biomimetic cell membrane models. Microelectrophoretic experiments on two-component liposomes were performed using the electrophoretic light scattering technique (ELS). The effect of both positively (perphenazine, PF) and negatively (barbituric acid, BA) charged drugs on zwitterionic L-α-phosphatidylcholine (PC) membranes were analyzed. Experimental membrane surface charge density (δ) data were determined as a function of pH. Quantitative descriptions of the adsorption equilibria formed due to the binding of solution ions to analyzed two-component membranes are presented. Binding constants of the solution ions with perphenazine and barbituric acid-modified membranes were determined. The results of our research show that both charged drugs change surface charge density values of phosphatidylcholine membranes. It can be concluded that perphenazine and barbituric acid are located near the membrane surface, interacting electrostatically with phosphatidylcholine polar heads.

Preparation, characterization, and in vivo evaluation of perphenazine-loaded nanostructured lipid carriers for oral bioavailability improvement.

OBJECTIVE: The main scope of the present investigation was to improve the bioavailability of perphenazine (PPZ) by incorporating it into the nanostructured lipid carriers (NLCs). SIGNIFICANCE: As a result of lipophilic nature and poor aqueous solubility, as well as extensive hepatic metabolism, PPZ has low systemic bioavailability via the oral route. NLCs have shown potentials to surmount the oral delivery drawbacks of poorly water-soluble drugs. METHODS: The PPZ-NLCs were prepared by the emulsification-solvent evaporation method and subjected for particle size, zeta potential, and entrapment efficiency (EE) analysis. The optimized NLCs were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and powder X-ray diffractometry (PXRD). Besides, in vitro release behavior, storage stability, and pharmacokinetic studies followed by a single-dose oral administration in rats were performed. RESULTS: Optimized PPZ-NLCs showed a particle size of less than 180 nm with appropriate EE of more than 95%. Microscopic images captured with SEM and TEM exhibited that NLCs were approximately spherical in shape. DSC and PXRD analysis confirmed reduced crystallinity of PPZ after incorporation in NLCs. FTIR spectra demonstrated no chemical interactions between PPZ and NLC components. In vitro release studies confirmed the extended-release properties of NLC formulations. PPZ-NLCs exhibited good stability at 4 °C within three months. The oral bioavailability of NLC-6 and NLC-12 was enhanced about 3.12- and 2.49-fold, respectively, compared to the plain drug suspension. CONCLUSION: NLC can be designated as an effective nanocarrier for oral delivery of PPZ.

A Transcriptome-Based Drug Discovery Paradigm for Neurodevelopmental Disorders.

Advances in genetic discoveries have created substantial opportunities for precision medicine in neurodevelopmental disorders. Many of the genes implicated in these diseases encode proteins that regulate gene expression, such as chromatin-associated proteins, transcription factors, and RNA-binding proteins. The identification of targeted therapeutics for individuals carrying mutations in these genes remains a challenge, as the encoded proteins can theoretically regulate thousands of downstream targets in a considerable number of cell types. Here, we propose the application of a drug discovery approach originally developed for cancer called "transcriptome reversal" for these neurodevelopmental disorders. This approach attempts to identify compounds that reverse gene-expression signatures associated with disease states. ANN NEUROL 2021;89:199-211.

Pharmacokinetics and brain distribution studies of perphenazine-loaded solid lipid nanoparticles.

BACKGROUND: Perphenazine (PPZ) is a typical antipsychotic that is mainly administrated for the treatment of schizophrenia. Due to its highly lipophilic nature and extensive hepatic first-pass metabolism, its oral bioavailability is low (40%). OBJECTIVE: The novel nanocarriers like solid lipid nanoparticles (SLN) have been reported to be highly effective for improving the therapeutic effect of drugs. Therefore the main scope of the present investigation was the evaluation of in vivo characteristics of PPZ-SLN in terms of pharmacokinetic parameters and brain distribution. METHODS: The PPZ-SLN was prepared by the solvent-emulsification and evaporation method. The storage stability of PPZ-SLN and empty SLN powders was studied for 3 months. In vivo pharmacokinetic studies and brain distribution evaluations were performed following a single oral dose administration of PPZ and PPZ-SLN suspensions on male Wistar rats. An HPLC method was established and validated for the quantitative determination of PPZ in plasma and brain samples. RESULTS: The storage stability studies revealed the good storage stability of the both PPZ-SLN and empty SLN at 4 °C. Compared to PPZ suspension, the relative bioavailability and the brain distribution of PPZ-SLN were increased up to 2-fold and 16-fold, respectively. Mean residence time (MRT) and half-life (t1/2) of PPZ-SLN were significantly (p value < 0.01) increased in both plasma and brain homogenate compared to PPZ suspension. CONCLUSION: The significant improvement in the pharmacokinetic properties of PPZ following one oral dose indicates that SLN is a promising drug delivery system for PPZ and shows a high potential for successful brain delivery of this antipsychotic.

Impact of CYP2D6 on serum concentrations of flupentixol, haloperidol, perphenazine and zuclopenthixol.

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.

In vitro anticancer activity of fluphenazine, perphenazine and prochlorperazine. A review.

Drug repositioning is an approach that could accelerate the clinical use of compounds in different diseases. The goal is to take advantage of the fact that approved drugs have been tested on humans and detailed information is available on their pharmacology, toxicity and formulation. It can significantly reduce the costs and time needed to implement necessary therapies on the market. In recent years, phenothiazines are being tested for cancer, viral, bacterial, fungal and other diseases. Most research focuses on chlorpromazine as a model drug in this class, but other drugs such as fluphenazine, perphenazine and prochlorperazine have been proven to inhibit the viability of different cancer cell lines. In this study, we performed an extensive literature search to find and summarize all papers on the chosen phenothiazines and their potential in treating different types of cancerin vitro for further animal/clinical trials. Fluphenazine, perphenazine and prochlorperazine possess anticancer activity towards different types of human cancer. The antitumor activity is mainly mediated by an effect of the drugs on the cell cycle, proliferation or apoptosis. Possible molecular targets of phenothiazine derivatives are the drug's efflux pumps (ABCB1 and P-glycoprotein) and two parallel pathways (AKT and Wnt) regulated by the D2 receptor antagonists. The drugs have the potential to reduce the viability of human cancer cell lines, fragment the DNA, stimulate apoptosis, inhibit cell migration and invasiveness as well as impair the production of reactive oxygen species. In addition, due to the sedative and antiemetic properties antipsychotics can be used as an adjuvant for the treatment of chemotherapy side effects.

Structure-function relationship of Gossypium hirsutum NAC transcription factor, GhNAC4 with regard to ABA and abiotic stress responses.

Our previous study demonstrated that the expression of GhNAC4, a NAC transcription factor from cotton, was induced by abiotic stresses and abscisic acid (ABA). In the present study, we investigated the molecular mechanisms underlying ABA and stress response of GhNAC4. Overexpression of GhNAC4 in transgenic tobacco conferred tolerance to salinity and drought treatments with associated enhanced expression of several stress-responsive marker genes. GhNAC4 is a protein that is translocated to the nucleus where it exhibits transcriptional activation property and also forms homo-dimers. In this study, we also investigated the domains essential for the biochemical functions of GhNAC4. We developed transgenic tobacco plants overexpressing the GhNAC4 NAC-domain and the transcriptional regulatory (TR) domain separately. NAC-domain transgenics showed hypersensitivity to exogenous ABA while TR-domain transgenics exhibited reduced sensitivity. Abiotic stress assays indicated that transgenic plants expressing both the domains separately were more tolerant than wild type plants with the NAC-domain transgenics showing increased tolerance as compared to TR-domain transgenics. Expression analysis revealed that various stress-responsive genes were upregulated in both NAC-domain and TR-domain transgenics under salinity and drought treatments. These results suggest that the stress tolerance ability of GhNAC4 is associated with both the component domains while the ABA responsiveness is largely associated with N-terminal NAC-domain.