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Drug Development and Industrial Pharmacy Jan 2021Perphenazine (PPZ) is a typical antipsychotic that is mainly administrated for the treatment of schizophrenia. Due to its highly lipophilic nature and extensive hepatic...
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 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. 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 (t) of PPZ-SLN were significantly ( 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.
Topics: Animals; Biological Availability; Brain; Drug Carriers; Lipids; Male; Nanoparticles; Perphenazine; Rats; Rats, Wistar
PubMed: 33307865
DOI: 10.1080/03639045.2020.1862172 -
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 -
Spectrochimica Acta. Part A, Molecular... Dec 2022Fluphenazine HCl (FLU) is an anxiolytic, while Nortriptyline HCl (NOR) is an anti-depressant. They are co-formulated together to treat depression and schizophrenia....
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.
Topics: Dibenzocycloheptenes; Drug Compounding; Fluphenazine; Nortriptyline; Perphenazine; Spectrophotometry
PubMed: 35933777
DOI: 10.1016/j.saa.2022.121695 -
Psychological Medicine Mar 2021Individuals diagnosed with psychiatric disorders who are prescribed antipsychotics have lower rates of violence and crime but the differential effects of specific...
BACKGROUND
Individuals diagnosed with psychiatric disorders who are prescribed antipsychotics have lower rates of violence and crime but the differential effects of specific antipsychotics are not known. We investigated associations between 10 specific antipsychotic medications and subsequent risks for a range of criminal outcomes.
METHODS
We identified 74 925 individuals who were ever prescribed antipsychotics between 2006 and 2013 using nationwide Swedish registries. We tested for five specific first-generation antipsychotics (levomepromazine, perphenazine, haloperidol, flupentixol, and zuclopenthixol) and five second-generation antipsychotics (clozapine, olanzapine, quetiapine, risperidone, and aripiprazole). The outcomes included violent, drug-related, and any criminal arrests and convictions. We conducted within-individual analyses using fixed-effects Poisson regression models that compared rates of outcomes between periods when each individual was either on or off medication to account for time-stable unmeasured confounders. All models were adjusted for age and concurrent mood stabilizer medications.
RESULTS
The relative risks of all crime outcomes were substantially reduced [range of adjusted rate ratios (aRRs): 0.50-0.67] during periods when the patients were prescribed antipsychotics v. periods when they were not. We found that clozapine (aRRs: 0.28-0.44), olanzapine (aRRs: 0.46-0.72), and risperidone (aRRs: 0.53-0.64) were associated with lower arrest and conviction risks than other antipsychotics, including quetiapine (aRRs: 0.68-0.84) and haloperidol (aRRs: 0.67-0.77). Long-acting injectables as a combined medication class were associated with lower risks of the outcomes but only risperidone was associated with lower risks of all six outcomes (aRRs: 0.33-0.69).
CONCLUSIONS
There is heterogeneity in the associations between specific antipsychotics and subsequent arrests and convictions for any drug-related and violent crimes.
PubMed: 33691828
DOI: 10.1017/S0033291721000556 -
Journal of AOAC International Apr 2022Anesthetics and sedatives are frequently used to prevent abrasions caused by stress and to facilitate fish management. However, drug residues may persist and cause...
BACKGROUND
Anesthetics and sedatives are frequently used to prevent abrasions caused by stress and to facilitate fish management. However, drug residues may persist and cause changes in fish conditions and induce side effects. In addition, drugs that are not permitted for use in edible fish are sometimes potentially used in fish. The drugs can also be found in wastewater and are likely to be detected in fish.
OBJECTIVE
The purpose of this study was to establish a quantitative analytical method for 10 anesthetic and sedative (azaperone, chlorpromazine, diazepam, estazolam, haloperidol, nitrazepam, nordiazepam, oxazepam, perphenazine, and temazepam) residues in fish sold in Korean markets.
METHOD
Shrimp, flounder, and eel samples were selected as matrices. Acetonitrile (ACN) containing 0.1% formic acid was selected as an extraction solvent for shrimp and 100% ACN for flounder and eel. The QuEChERS method with C18 and primary secondary amine (PSA) was used as the extraction procedure, and the analysis was performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS).
RESULTS
Limit of quantitation, recovery, accuracy, and precision were validated, and satisfactory results were obtained for the drugs. All results applied to the real samples were negative.
CONCLUSIONS
An optimal validation method was studied. Since the results for all samples were negative, it is considered that additional studies are needed by increasing the number of drugs.
HIGHLIGHTS
The most effective QuEChERS pretreatment method and conditions of LC-MS/MS for the analysis of anesthetics and sedatives in fish were established.
Topics: Anesthetics; Animals; Chromatography, Liquid; Drug Residues; Fishes; Hypnotics and Sedatives; Limit of Detection; Tandem Mass Spectrometry
PubMed: 34894253
DOI: 10.1093/jaoacint/qsab155 -
Bioorganic & Medicinal Chemistry Letters Jul 2020Endometrial cancer (EC) is one of the most common and fatal gynecological cancers worldwide, but there is no effective treatment for the EC patients of progesterone...
Endometrial cancer (EC) is one of the most common and fatal gynecological cancers worldwide, but there is no effective treatment for the EC patients of progesterone resistance. Repurposing of existing drugs is a good strategy to discover new candidate drugs. In this text, perphenazine (PPZ), approved for psychosis therapy, was identified as a potential agent for the treatment of both progesterone sensitive and resistant endometrial cancer for the first time. Specifically, perphenazine exhibited good cell proliferation inhibition in Ishikawa (ISK) and KLE cell lines according to the CCK-8 assay and colony formation assay. It also reduced the cell migration of ISK and KLE cell lines in the light of the transwell migration assay. Annexin-V/PI double staining assay suggested that perphenazine could effectively induce ISK and KLE cell apoptosis. Moreover, results of western blot assay indicated perphenazine obviously inhibited the phosphorylation of Akt. Delightedly, PPZ also could significantly attenuate xenograft tumor growth at both 3 mg/kg and 15 mg/kg in mice without influencing the body weights.
Topics: Antineoplastic Agents; Antipsychotic Agents; Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Dose-Response Relationship, Drug; Drug Repositioning; Drug Screening Assays, Antitumor; Endometrial Neoplasms; Female; Humans; Molecular Structure; Perphenazine; Structure-Activity Relationship
PubMed: 32527541
DOI: 10.1016/j.bmcl.2020.127239 -
Environmental Pollution (Barking, Essex... Mar 2023Despite increasing reports of pharmaceuticals in surface waters, aquatic hazard information remains limited for many contaminants, particularly for sublethal, chronic... (Review)
Review
Despite increasing reports of pharmaceuticals in surface waters, aquatic hazard information remains limited for many contaminants, particularly for sublethal, chronic responses plausibly linked to molecular initiation events that are largely conserved across vertebrates. Here, we critically examined available refereed information on the occurrence of 67 antipsychotics in wastewater effluent and surface waters. Because the majority of sewage remains untreated around the world, we also examined occurrence in sewage influents. When sufficient information was available, we developed probabilistic environmental exposure distributions (EEDs) for each compound in each matrix by geographic region. We then performed probabilistic environmental hazard assessments (PEHAs) using therapeutic hazard values (THVs) of each compound, due to limited sublethal aquatic toxicology information for this class of pharmaceuticals. From these PEHAs, we determined predicted exceedances of the respective THVs for each chemical among matrices and regions, noting that THV values of antipsychotic contaminants are typically lower than other classes of human pharmaceuticals. Diverse exceedances were observed, and these aquatic hazards varied by compound, matrix and geographic region. In wastewater effluent discharges and surface waters, sulpiride was the most detected antipsychotic; however, percent exceedances of the THV were minimal (0.6%) for this medication. In contrast, we observed elevated aquatic hazards for chlorpromazine (30.5%), aripiprazole (37.5%), and perphenazine (68.7%) in effluent discharges, and for chlorprothixene (35.4%) and flupentixol (98.8%) in surface waters. Elevated aquatic hazards for relatively understudied antipsychotics were identified, which highlight important data gaps for future environmental chemistry and toxicology research.
Topics: Animals; Humans; Sewage; Antipsychotic Agents; Wastewater; Environmental Exposure; Pharmaceutical Preparations; Water Pollutants, Chemical; Environmental Monitoring
PubMed: 36646406
DOI: 10.1016/j.envpol.2023.121042 -
Neuroscience and Biobehavioral Reviews Jul 2021Cognitive deficits are a core aspect of psychotic disorders; however, it is not clear to which extent different pharmacological treatments could distinctly impact these... (Review)
Review
Cognitive deficits are a core aspect of psychotic disorders; however, it is not clear to which extent different pharmacological treatments could distinctly impact these outcomes. Hence, we conducted a systematic review and ten network meta-analyses of randomized controlled trials to compare the effect of antipsychotics on cognitive performance of individuals with psychotic disorders. Fifty-four trials were included in the analyses, enrolling 5866 patients. Compared to other antipsychotics, amisulpride performed better on verbal learning; quetiapine on composite score, attention and verbal learning; lurasidone on composite score; olanzapine on composite score and most cognitive domains; perphenazine on composite score, executive function, working memory, and verbal learning; risperidone on executive function and verbal learning; sertindole on processing speed; and ziprasidone on composite score, working memory, and verbal learning. Oppositely, haloperidol performed poorer on all cognitive domains, occupying the last positions in all rankings; and clozapine performed poorer on composite score, executive function, verbal learning, and visuoconstruction. We hope that these results should be taken into account when assessing and treating individuals with psychosis.
Topics: Antipsychotic Agents; Benzodiazepines; Cognition; Humans; Network Meta-Analysis; Psychotic Disorders; Randomized Controlled Trials as Topic; Schizophrenia
PubMed: 33812977
DOI: 10.1016/j.neubiorev.2021.03.028 -
The Role of Total White Blood Cell Count in Antipsychotic Treatment for Patients with Schizophrenia.Current Neuropharmacology 2024Total white blood cell count (TWBCc), an index of chronic and low-grade inflammation, is associated with clinical symptoms and metabolic alterations in patients with... (Randomized Controlled Trial)
Randomized Controlled Trial Clinical Trial
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 ( < 0.05). Lower baseline TWBCc predicted greater reductions in Positive and Negative Syndrome Scale (PANSS) total and negative scores over time ( < 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 ( < 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.
Topics: Humans; Antipsychotic Agents; Schizophrenia; Olanzapine; Risperidone; Quetiapine Fumarate; Haloperidol; Perphenazine; Benzodiazepines; Glucose; Inflammation
PubMed: 36600620
DOI: 10.2174/1570159X21666230104090046 -
Molecular Pharmaceutics Dec 2023Mucus 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...
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.
Topics: Rats; Animals; Bile; Elevators and Escalators; Perphenazine; Mucus; Mucins
PubMed: 37906224
DOI: 10.1021/acs.molpharmaceut.3c00550