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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 -
British Journal of Clinical Pharmacology Dec 2000To identify the human cytochrome P450 (CYP) isoforms mediating the N-dealkylation of the antipsychotic drug perphenazine in vitro and estimate the relative contributions...
AIMS
To identify the human cytochrome P450 (CYP) isoforms mediating the N-dealkylation of the antipsychotic drug perphenazine in vitro and estimate the relative contributions of the CYP isoforms involved.
METHODS
cDNA-expressed CYP isoforms were used to identify the isoforms that are able to mediate the N-dealkylation of perphenazine, which is considered a major metabolic pathway for the drug. Using human liver microsomal preparations (HLM), inhibition studies were carried out to establish the relative contributions of the CYP isoforms involved in the N-dealkylation reaction.
RESULTS
CYP isoforms 1A2, 3A4, 2C8, 2C9, 2C18, 2C19 and 2D6 were able to mediate the N-dealkylation of perphenazine. Reaction velocities and their relative abundance in HLM suggested that CYP1A2, 3A4, 2C19 and 2D6 were the most important contributors to N-dealkylation. Apparent Km values of CYP1A2 and CYP2D6 were in the range 1-2 microM, and Km values of CYP2C19 and CYP3A4 were 14 microM and 7.9 microM, respectively. Ketoconazole inhibition of N-dealkylation mediated by a mixed HLM indicated that CYP3A4 accounted for about 40% of perphenazine N-dealkylation at therapeutically relevant concentrations. The contribution of the CYP isoforms 1A2, 2C19 and 2D6 amounted to 20-25% each as measured by the percentage inhibition obtained by addition of furafylline, fluvoxamine or quinidine, respectively. HLM-mediated N-dealkylation of perphenazine accounted for 57% of the total amount of substrate consumed during incubation.
CONCLUSIONS
The present in vitro study suggests that CYP isoforms 1A2, 3A4, 2C19 and 2CD6 are primarily involved in the N-dealkylation of perphenazine. The relatively modest role of CYP2D6 is at variance with in vivo studies, which indicate a greater contribution of this isoform. Alternative metabolic pathways, corresponding to 43% of the HLM-mediated metabolism of the drug, may depend more strongly on CYP2D6.
Topics: Alkylation; Antipsychotic Agents; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Enzyme Inhibitors; Humans; In Vitro Techniques; Isoenzymes; Microsomes, Liver; Perphenazine; Recombinant Proteins; Substrate Specificity
PubMed: 11136295
DOI: 10.1046/j.1365-2125.2000.00298.x -
Journal of Clinical and Diagnostic... Jun 2016Parkinsonism is a neurodegenerative disease that is defined by certain symptoms such as muscle rigidity, impaired movement, catatonia, tremor and disorientation of body.
INTRODUCTION
Parkinsonism is a neurodegenerative disease that is defined by certain symptoms such as muscle rigidity, impaired movement, catatonia, tremor and disorientation of body.
AIM
The aim was to investigate the effect of red lentil extract on perphenazine-induced Catatonia in model of rat.
MATERIALS AND METHODS
This experimental study was done on 48 male albino rats (weight 180-200g) of the Sprague-Dawley strain. Animals were randomly divided into six groups and were pre-treated with a single dose of red lentil extract (200, 400, 800 and 1000 mg/kg), most effective dose of bromocriptine (30mg/kg) and normal saline (5ml/kg) via intraperitoneal (IP) route. perphenazine (5 mg/kg) was after 30 minutes, administered (IP) to induce catatonia. The scoring method of Morpurgo was used to determine the muscular rigidity of animals.
RESULTS
The results showed that the 200mg/kg red lentil extract treated group had no significant reduction in catatonic responses after perphenazine administration in comparison with control group while the groups that received 800 and 1000mg/kg of red lentil extract showed significant difference (p<0.05) at all the time points.
CONCLUSION
The results revealed that hydroalcoholic extract of red lentil has protective effect on Catatonia induced by perphenazine in rats. So this extract may be probably beneficial for catatonia in Parkinsonism.
PubMed: 27504309
DOI: 10.7860/JCDR/2016/17813.7977 -
Pharmaceutics Feb 2023Therapeutic drug monitoring is a tool for optimising the pharmacological treatment of diseases where the therapeutic effect is difficult to measure or monitor....
Therapeutic drug monitoring is a tool for optimising the pharmacological treatment of diseases where the therapeutic effect is difficult to measure or monitor. Therapeutic reference ranges and dose-effect relation are the main requirements for this drug titration tool. Defining and updating therapeutic reference ranges are difficult, and there is no standardised method for the calculation and clinical qualification of these. The study presents a basic model for validating and selecting routine laboratory data. The programmed algorithm was applied on data sets of antidepressants and antipsychotics from three public hospitals in Denmark. Therapeutic analytical ranges were compared with the published therapeutic reference ranges by the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) and in additional literature. For most of the drugs, the calculated therapeutic analytical ranges showed good concordance between the laboratories and to published therapeutic reference ranges. The exceptions were flupentixol, haloperidol, paroxetine, perphenazine, and venlafaxine + o-desmethyl-venlafaxine (total plasma concentration), where the range was considerably higher for the laboratory data, while the calculated range of desipramine, sertraline, ziprasidone, and zuclopenthixol was considerably lower. In most cases, we identified additional literature supporting our data, highlighting the need of a critical re-examination of current therapeutic reference ranges in Denmark. An automated approach can aid in the evaluation of current and future therapeutic reference ranges by providing additional information based on big data from multiple laboratories.
PubMed: 36839995
DOI: 10.3390/pharmaceutics15020673 -
British Journal of Clinical Pharmacology Jan 19791. A gas chromatographic method was applied to study plasma levels of perphenazine (PPZ) and its major metabolites in man before and during simultaneous antiparkinson... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
1. A gas chromatographic method was applied to study plasma levels of perphenazine (PPZ) and its major metabolites in man before and during simultaneous antiparkinson treatment. Twenty-six psychotic patients received various forms of PPZ administration as well as antiparkinson drugs. 2. Biperidine (5 mg) was administered intravenously to each of five patients, who 5 days earlier had had a single dose of PPZ-enanthate i.m. No significant alterations in plasma concentrations of PPZ were observed. 3. In fourteen patients receiving oral PPZ treatment the plasma levels of PPZ and its metabolites did not deviate significantly from controls after addition of biperidine or orphenadine given for 3 weeks in fixed oral doses. 4. The ratio between PPZ plasma concentration measured 4 and 7 h after the morning dose was not affected by concomitant antiparkinson therapy. 5. It is concluded that no clinically relevant pharmacokinetic interaction takes place between PPZ and two generally used antiparkinson drugs during steady-state conditions in psychotic patients.
Topics: Administration, Oral; Adult; Biperiden; Drug Interactions; Female; Humans; Infusions, Parenteral; Male; Middle Aged; Orphenadrine; Parasympatholytics; Perphenazine
PubMed: 760745
DOI: 10.1111/j.1365-2125.1979.tb00900.x -
BJPsych Open Oct 2020Understanding the patterns of treatment response is critical for the treatment of patients with schizophrenia; one way to achieve this is through using a longitudinal...
BACKGROUND
Understanding the patterns of treatment response is critical for the treatment of patients with schizophrenia; one way to achieve this is through using a longitudinal dynamic process study design.
AIMS
This study aims to explore the response trajectory of antipsychotics and compare the treatment responses of seven different antipsychotics over 6 weeks in patients with schizoprenia (trial registration: Chinese Clinical Trials Registry Identifier: ChiCTR-TRC-10000934).
METHOD
Data were collected from a multicentre, randomised open-label clinical trial. Patients were evaluated with the Positive and Negative Syndrome Scale (PANSS) at baseline and follow-up at weeks 2, 4 and 6. Trajectory groups were classified by the method of k-means cluster modelling for longitudinal data. Trajectory analyses were also employed for the seven antipsychotic groups.
RESULTS
The early treatment response trajectories were classified into a high-trajectory group of better responders and a low-trajectory group of worse responders. The results of trajectory analysis showed differences compared with the classification method characterised by a 50% reduction in PANSS scores at week 6. A total of 349 patients were inconsistently grouped by the two methods, with a significant difference in the composition ratio of treatment response groups using these two methods (χ2 = 43.37, P < 0.001). There was no differential contribution of high- and low trajectories to different drugs (χ2 = 12.52, P = 0.051); olanzapine and risperidone, which had a larger proportion in the >50% reduction at week 6, performed better than aripiprazole, quetiapine, ziprasidone and perphenazine.
CONCLUSIONS
The trajectory analysis of treatment response to schizophrenia revealed two distinct trajectories. Comparing the treatment responses to different antipsychotics through longitudinal analysis may offer a new perspective for evaluating antipsychotics.
PubMed: 33090091
DOI: 10.1192/bjo.2020.105 -
Schizophrenia Bulletin Jan 2022People with schizophrenia/schizoaffective disorder (schizophrenia) die early, largely due to cardiovascular-related mortality. Antipsychotics are associated with lower...
Antipsychotics Use Is Associated With Greater Adherence to Cardiometabolic Medications in Patients With Schizophrenia: Results From a Nationwide, Within-subject Design Study.
BACKGROUND
People with schizophrenia/schizoaffective disorder (schizophrenia) die early, largely due to cardiovascular-related mortality. Antipsychotics are associated with lower mortality. We aimed to explore whether antipsychotic use can reduce discontinuation of medications for cardiovascular risk factors and diseases ("cardiometacolic drugs"), using a within-study design controlling for subject-related factors.
METHODS
Persons diagnosed with schizophrenia between 1972 and 2014, aged <65 years at cohort entry were identified in Finnish national databases. Four subcohorts were formed based on cardiometabolic drug use during the follow-up period, 1996-2017, namely statin (n = 14,047), antidiabetic (n = 13,070), antihypertensive (n = 17,227), and beta-blocker (n = 21,464) users. To control for subject-related factors, including likelihood of adherence as a trait characteristic, we conducted a within-subject study comparing the risk of discontinuation of each cardiometabolic drug during periods on vs off antipsychotics within each subject. We also accounted for number of psychiatric and nonpsychiatric visits in sensitivity analyses.
RESULTS
In 52,607 subjects with schizophrenia, any antipsychotic use vs nonuse was associated with decreased discontinuation risk of antidiabetics (adjusted hazard ratio [aHR] = 0.56, 95% confidence interval [CI] = 0.47-0.66), statins (aHR = 0.61, 95%CI = 0.53-0.70), antihypertensives (aHR = 0.63, 95%CI = 0.56-0.71), and beta-blockers (aHR = 0.79, 95%CI = 0.73-0.87). Antipsychotics ranking best for discontinuation of all cardiometabolic drug categories were clozapine (aHR range = 0.34-0.55), followed by olanzapine (aHR = 0.43-0.71). For statins, aHRs ranged from aHR = 0.30 (95%CI = 0.09-0.98) (flupentixol-long-acting injectable (LAI) to aHR = 0.71 (95%CI = 0.52-0.97) (risperidone-LAI), for anti-diabetic medications from aHR = 0.37 (95%CI = 0.28-0.50) (clozapine) to aHR = 0.70 (95%CI = 0.53-0.92) (quetiapine), for antihypertensives from aHR = 0.14 (95%CI = 0.04-0.46) (paliperidone-LAI) to aHR = 0.69 (95%CI = 0.54-0.88) (perphenazine), for beta-blockers from aHR = 0.55 (95%CI = 0.48-0.63) (clozapine) to aHR = 0.76 (95%CI = 0.59-0.99) (perphenazine-LAI). The decreased risk of discontinuation associated with antipsychotic use somewhat varied between age strata. Sensitivity analyses confirmed main findings.
DISCUSSION
In this national database within-subject design study, current antipsychotic use was associated with substantially decreased risk of discontinuation of statins, anti-diabetics, antihypertensives, and beta-blockers, which might explain reduced cardiovascular mortality observed with antipsychotics in people with schizophrenia.
Topics: Adrenergic beta-Antagonists; Adult; Antihypertensive Agents; Antipsychotic Agents; Cardiovascular Diseases; Comorbidity; Female; Finland; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Male; Medication Adherence; Metabolic Diseases; Middle Aged; Schizophrenia
PubMed: 34286338
DOI: 10.1093/schbul/sbab087 -
Immunity, Inflammation and Disease May 2024Esophageal cancer (ESCA) is a highly invasive malignant tumor with poor prognosis. This study aimed to discover a generalized and high-sensitivity immune prognostic...
BACKGROUND
Esophageal cancer (ESCA) is a highly invasive malignant tumor with poor prognosis. This study aimed to discover a generalized and high-sensitivity immune prognostic signature that could stratify ESCA patients and predict their overall survival, and to discover potential therapeutic drugs by the connectivity map.
METHODS
The key gene modules significantly related to clinical traits (survival time and state) of ESCA patients were selected by weighted gene coexpression network analysis (WCGNA), then the univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analyses were used to construct a 15-immune-related gene prognostic signature.
RESULTS
The immune-related risk model was related to clinical and pathologic factors and remained an effective independent prognostic factor. Enrichment analyses revealed that the differentially expressed genes (DEGs) of the high- and low-risk groups were associated with tumor cell proliferation and immune mechanisms. Based on the gathered data, a small molecule drug named perphenazine (PPZ) was elected. The pharmacological analysis indicates that PPZ could help in adjuvant therapy of ESCA through regulation of metabolic process and cellular proliferation, enhancement of immunologic functions, and inhibition of inflammatory reactions. Furthermore, molecular docking was performed to explore and verify the PPZ-core target interactions.
CONCLUSION
We succeed in structuring the immune-related prognostic model, which could be used to distinguish and predict patients' survival outcome, and screening a small molecule drug named PPZ. Prospective studies also are needed to further validate its analytical accuracy for estimating prognoses and confirm the potential use of PPZ for treating ESCA.
Topics: Esophageal Neoplasms; Humans; Network Pharmacology; Prognosis; Computational Biology; Gene Regulatory Networks; Gene Expression Regulation, Neoplastic; Gene Expression Profiling; Biomarkers, Tumor; Molecular Docking Simulation; Antineoplastic Agents; Male; Female
PubMed: 38804848
DOI: 10.1002/iid3.1266 -
European Journal of Anaesthesiology Apr 2014Perphenazine is a treatment option in postoperative nausea and vomiting (PONV) prophylaxis. Chronic administration and high dose are known to cause extrapyramidal system...
BACKGROUND
Perphenazine is a treatment option in postoperative nausea and vomiting (PONV) prophylaxis. Chronic administration and high dose are known to cause extrapyramidal system (EPS) dysfunction at a frequency of 8%, but the incidence of acute EPS after a single 4 or 8 mg dose is unknown.
OBJECTIVE
A retrospective analysis of patient medication billing data and departmental quality records was performed (January 2001 to 10 July 2012) to identify patients who experienced EPS dysfunction after oral perphenazine.
DESIGN
A retrospective analysis.
SETTING
Surgical outpatients presenting to any one of 10 hospitals in the area of Pittsburgh, Pennsylvania, USA.
PATIENTS
Overall, 45 766 patients received 4 or 8 mg of perphenazine before same-day surgery.
MAIN OUTCOME MEASURES
EPS dysfunction was defined as acute dystonia, akathisia or pseudoparkinsonism. Records were reviewed to determine the likely number of reactions to perphenazine, the nature of these reactions and impact on patient care.
RESULTS
There were four 'likely' cases of EPS dysfunction, and two 'possible' cases. Five reported events were consistent with akathisia, with the sixth being a dystonic reaction. All six patients had resolution of symptoms, with five receiving intravenous diphenhydramine for treatment. The incidence of EPS dysfunction was 1.3 events per 10 000 patients (95% confidence interval (CI) 0.4 to 3.0, based on six events). All patients who experienced reactions pre-operatively were able to proceed to surgery without complications or delay. One patient required unplanned admission and 3-h observation owing to sedation from diphenhydramine. The incidence of EPS dysfunction after oral perphenazine is low. Reactions that did occur were mild and easily treated.
CONCLUSION
Given the infrequent side effects, this single, low dose of perphenazine should be encouraged as a low-risk adjunct to any multimodal PONV prophylaxis regimen, based on the selection criteria described.
Topics: Administration, Oral; Adolescent; Adult; Ambulatory Surgical Procedures; Basal Ganglia Diseases; Dopamine Antagonists; Dose-Response Relationship, Drug; Humans; Incidence; Male; Middle Aged; Perphenazine; Postoperative Nausea and Vomiting; Retrospective Studies; Young Adult
PubMed: 24503705
DOI: 10.1097/EJA.0000000000000048 -
Free Radical Biology & Medicine Aug 2016Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by progressive loss of motor neurons, gliosis, neuroinflammation and...
Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by progressive loss of motor neurons, gliosis, neuroinflammation and oxidative stress. The aim of this study was to evaluate the involvement of NADPH oxidases (NOX) in the oxidative damage and progression of ALS neuropathology. We examined the pattern of NOX expression in spinal cords of patients and mouse models of ALS and analyzed the impact of genetic deletion of the NOX1 and 2 isoforms as well as pharmacological NOX inhibition in the SOD1(G93A) ALS mouse model. A substantial (10-60 times) increase of NOX2 expression was detected in three etiologically different ALS mouse models while up-regulation of some other NOX isoforms was model-specific. In human spinal cord samples, high NOX2 expression was detected in microglia. In contrast to previous publications, survival of SOD1(G93A) mice was not modified upon breeding with constitutive NOX1 and NOX2 deficient mice. As genetic deficiency of a single NOX isoform is not necessarily predictive of a pharmacological intervention, we treated SOD1(G93A) mice with broad-spectrum NOX inhibitors perphenazine and thioridazine. Both compounds reached in vivo CNS concentrations compatible with NOX inhibition and thioridazine significantly decreased superoxide levels in the spinal cord of SOD1(G93A) mice in vivo. Yet, neither perphenazine nor thioridazine prolonged survival. Thioridazine, but not perphenazine, dampened the increase of microglia markers in SOD1(G93A) mice. Thioridazine induced an immediate and temporary enhancement of motor performance (rotarod) but its precise mode of action needs further investigation. Additional studies using specific NOX inhibitors will provide further evidence on the relevance of NOX as drug targets for ALS and other neurodegenerative disorders.
Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Animals; Disease Models, Animal; Female; Gene Expression Regulation; Humans; Male; Mice; Middle Aged; Motor Neurons; NADPH Oxidase 1; NADPH Oxidase 2; Perphenazine; Spinal Cord; Superoxide Dismutase-1; Thioridazine
PubMed: 27212019
DOI: 10.1016/j.freeradbiomed.2016.05.016