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ACS Chemical Neuroscience Jan 2023Alzheimer's disease is imposing a growing social and economic burden worldwide, and effective therapies are urgently required. One possible approach to modulation of the...
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 (Aβ42) 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 Aβ42 monomer. We provide kinetic and nuclear magnetic resonance data showing that these perphenazine conjugates divert the Aβ42 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 Aβ42 species populated during amyloid assembly.
Topics: Humans; Perphenazine; Amyloid beta-Peptides; Amyloid; Alzheimer Disease; Amyloidogenic Proteins; Peptide Fragments
PubMed: 36542544
DOI: 10.1021/acschemneuro.2c00498 -
Die Pharmazie Jan 2018Phenothiazine derivatives possess biological properties very useful for cancer therapy, such as antiemetic and sedative activity as well as good blood-brain barrier...
Phenothiazine derivatives possess biological properties very useful for cancer therapy, such as antiemetic and sedative activity as well as good blood-brain barrier permeability. Our goal was to determine if perphenazine and prochlorperazine are possessing cytotoxic activity towards U87-MG cells. It has been shown that the analyzed drugs induce concentration-dependent loss in cell viability, what correlates with their chemical structure. The calculated EC50 values for perphenazine (0.98 μM) and prochlorperazine (0.97 μM) are related to their toxic concentrations in human plasma. The obtained results suggest that perphenazine and prochlorperazine may have a potential for the development of new and effective anticancer therapies.
Topics: Antineoplastic Agents; Antipsychotic Agents; Brain Neoplasms; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Glioblastoma; Humans; Perphenazine; Prochlorperazine
PubMed: 29441946
DOI: 10.1691/ph.2018.7806 -
Biomedicine & Pharmacotherapy =... Jul 2018Today, the role of oxidative stress in development of schizophrenia has gained attention. Also, some atypical antipsychotic agents showed antioxidant properties.... (Observational Study)
Observational Study
BACKGROUND AND OBJECTIVE
Today, the role of oxidative stress in development of schizophrenia has gained attention. Also, some atypical antipsychotic agents showed antioxidant properties. Therefore, in this study, we evaluated the level of oxidative stress parameters between patients treated with perphenazine, clozapine and risperidone and their relationship with schizophrenia symptoms' severity.
MATERIALS AND METHODS
This was a descriptive study on 100 patients with chronic schizophrenia. Patient selection was done based on the DSM-IV-TR criteria for at least 3 months regular use of clozapine or risperidone or perphenazine and a minimum period of 2 years of schizophrenia. Ten ml of patient's blood samples were used to assess serum levels of glutathione (GSH), protein carbonyl, lipid peroxidation (LPO), superoxide dismutase (SOD) and Ferric Reducing Ability of Plasma (FRAP). Also, the severity of symptoms was assessed with the positive and negative syndrome scale (PANSS scale). P-values of less than 0.05 were considered significant.
RESULTS
The results showed a significant difference between clozapine and risperidone with perphenazine in all subscales of PANSS. Also, there was a positive correlation between MDA and PANSS all subscales in risperidone and perphenazine groups and a negative correlation between MDA and PANSS in all subscales in the clozapine group. Serum level of GSH and negative symptoms in patients receiving clozapine showed a negative correlation. The results also represented that clozapine significantly increased SOD levels in comparison to perphenazine and risperidone and reduced LPO in comparison to perphenazine and risperidone, While the protein carbonyl level did not show a significant difference between three groups (p-value = 0.8).
CONCLUSION
This study showed that clozapine, as an atypical antipsychotic agent, has significant antioxidant effects compared to risperidone and perphenazine. Especially, it increased SOD and GSH levels and reduced LPO in patients with schizophrenia. Therefore, clozapine's antioxidant effect may be contributive to improving negative symptoms of schizophrenic patients.
Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Biomarkers; Clozapine; Humans; Middle Aged; Oxidative Stress; Perphenazine; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Young Adult
PubMed: 29710513
DOI: 10.1016/j.biopha.2018.04.109 -
Schizophrenia Bulletin Jun 2022Optimal doses of most antipsychotics in the maintenance treatment of schizophrenia are unknown. We aimed to study the risk of severe relapse indicated by...
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.
Topics: Antipsychotic Agents; Delayed-Action Preparations; Humans; Olanzapine; Perphenazine; Recurrence; Risperidone; Schizophrenia; Secondary Prevention
PubMed: 35524479
DOI: 10.1093/schbul/sbac039 -
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 -
Health Psychology Research 2022Phenothiazines, a diverse class of drugs, can be used to treat multiple mental health and physical conditions. Phenothiazines have been used for decades to treat mental...
Phenothiazines, a diverse class of drugs, can be used to treat multiple mental health and physical conditions. Phenothiazines have been used for decades to treat mental illnesses, including schizophrenia, mania in bipolar disorder, and psychosis. Additionally, these drugs offer relief for physical illnesses, including migraines, hiccups, nausea, and vomiting in both adults and children. Further research is needed to prove the efficacy of phenothiazines in treating physical symptoms. Phenothiazines are dopaminergic antagonists that inhibit D2 receptors with varying potency. High potency phenothiazines such as perphenazine are used to treat various psychiatric conditions such as the positive symptoms of schizophrenia, the symptoms of psychosis, and mania that can occur with bipolar disorder. Low/mid potency phenothiazines such as chlorpromazine antipsychotic drugs that have been used to treat schizophrenia and schizophrenia-like disorders since the 1950s and are utilized in numerous disease states. The present investigation aims to elucidate the effects of phenothiazines in clinical practice.
PubMed: 36425230
DOI: 10.52965/001c.38930 -
The Annals of Pharmacotherapy Oct 2020Osteoporosis, which is a major public health concern, has been known to reduce health-related quality of life. Some studies have suggested that antipsychotics could...
BACKGROUND
Osteoporosis, which is a major public health concern, has been known to reduce health-related quality of life. Some studies have suggested that antipsychotics could perhaps cause osteoporosis by increasing serum prolactin levels. However, the association between antipsychotics and the risk for developing osteoporosis has been controversial.
OBJECTIVE
The present study aimed to assess the association between antipsychotic use and onset of osteoporosis in real-world settings.
METHODS
A multimethod data-mining approach using different algorithms and databases was used. First, disproportionality analysis was conducted using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database (2004-2017) with reporting odds ratio (ROR) and information component (IC) being used to indicate a signal. Furthermore, a sequence symmetry analysis using data from a large Japanese administrative claims database (2005-2017; JMDC Inc, Japan) was conducted. Short-term intervals (ie, 12, 24, and 36 months) were set to investigate the association between antipsychotic use and onset of osteoporosis using the adjusted sequence ratio (SR) to indicate a signal.
RESULTS
No potential association between osteoporosis and all antipsychotics was observed in the FAERS database, except for perphenazine, which exhibited significant signals using both ROR and IC. Moreover, no potential association between osteoporosis and antipsychotics was observed in the JMDC claims database, except for sulpiride and aripiprazole. None of the antipsychotics indicated significant signals using all analyzed items (ROR, IC, and adjusted SR).
CONCLUSION AND RELEVANCE
Real-world data show no association between antipsychotic use and the onset of osteoporosis. Further pharmacoepidemiological studies are needed for causality assessment.
Topics: Adverse Drug Reaction Reporting Systems; Algorithms; Antipsychotic Agents; Data Mining; Databases, Factual; Humans; Odds Ratio; Osteoporosis; Pharmacovigilance; Prolactin; United States; United States Food and Drug Administration
PubMed: 32186394
DOI: 10.1177/1060028020913974 -
Frontiers in Psychiatry 2022Antipsychotics contribute to the development of type 2 diabetes mellitus (T2DM) in individuals with schizophrenia. However, the extent of the relationship between...
BACKGROUND
Antipsychotics contribute to the development of type 2 diabetes mellitus (T2DM) in individuals with schizophrenia. However, the extent of the relationship between antipsychotic use and T2DM varies in different settings, and the magnitude of the drug-specific effects fluctuates widely. This study aimed to explore the association of T2DM with antipsychotic use among enrollees with schizophrenia in China's National Basic Public Health Service Program (NBPHSP) and the drug-specific relationship with T2DM among patients receiving antipsychotic monotherapy.
METHODS
We recruited diabetes-free patients with schizophrenia who were enrolled in the NBPHSP of Hunan Province from October 2009 to December 2018. The participants were classified into the following three groups: regular antipsychotic use, intermittent antipsychotic use, and antipsychotic-free groups. The patients were followed up until they received a T2DM diagnosis or until April 2019. Cox regression models were constructed to calculate the overall and drug-specific hazard ratios (HRs) to determine the antipsychotic-T2DM relationship. Interactive and subgroup analyses were performed to assess the heterogeneity of the effects across subgroups.
RESULTS
A total of 122,064 NBPHSP enrollees with schizophrenia were followed up for 1,507,829 cumulative person-years, and 2,313 (1.89%) patients developed T2DM. Patients who regularly and intermittently used antipsychotics had 117% (HR: 2.17, 95% CI: 1.83-2.57) and 53% (HR: 1.53, 95% CI: 1.23-1.90) higher risks of developing T2DM than antipsychotic-free patients, respectively. Regarding monotherapy, the T2DM risk increased by 66, 80, 62, and 64% after the regular use of clozapine, risperidone, chlorpromazine, and perphenazine, respectively. In addition, the antipsychotic-related risk of T2DM decreased as the patient's baseline body mass index, and baseline fasting plasma glucose level, as well as the dietary proportion of animal products, increased.
CONCLUSION
Antipsychotics, especially clozapine, risperidone, chlorpromazine, and perphenazine, increased the T2DM risk among NBPHSP enrollees with schizophrenia. Mental health officers should accurately identify enrollees at a high risk of T2DM and take appropriate preventive measures to reduce the incidence of T2DM among patients with schizophrenia.
PubMed: 35280179
DOI: 10.3389/fpsyt.2022.754775 -
BioMed Research International 2021Perphenazine (PPZ), as a typical antipsychotic medical substance, has the same effectiveness compared to atypical antipsychotic medications for the treatment of...
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, 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.
Topics: Calorimetry, Differential Scanning; Cell Death; Cell Survival; Drug Liberation; HT29 Cells; Humans; Lipids; Models, Biological; Nanoparticles; Particle Size; Perphenazine; Reproducibility of Results; Spectroscopy, Fourier Transform Infrared; Static Electricity; Statistics as Topic; X-Ray Diffraction
PubMed: 33997026
DOI: 10.1155/2021/6619195 -
Clinical Pharmacology and Therapeutics Mar 2018Although pregnancy is known to cause changes in drug pharmacokinetics, little is known about its impact on serum levels of antipsychotics. In this study we...
Although pregnancy is known to cause changes in drug pharmacokinetics, little is known about its impact on serum levels of antipsychotics. In this study we retrospectively assessed 201 routine serum antipsychotic therapeutic drug monitoring concentration measurements obtained from a total of 110 pregnancies in 103 women, and 512 measurements from the same women before and after pregnancy. Serum concentrations in the third trimester were significantly lower than baseline for quetiapine (-76%; confidence interval (CI), -83%, -66%; P < 0.001) and aripiprazole (-52%; CI, -62%, -39%; P < 0.001), but not for olanzapine (-9%; CI, -28%, +14%; P = 0.40). For the remaining antipsychotics (perphenazine, haloperidol, ziprasidone, risperidone, and clozapine), our dataset was limited, but it indicates that concentrations may decline at least for perphenazine and possibly also for haloperidol. Even though the clinical consequence of the serum concentrations decline remains to be elucidated, our results warrant close clinical monitoring throughout pregnancy, preferentially supported by therapeutic drug monitoring.
Topics: Adult; Antipsychotic Agents; Drug Administration Schedule; Drug Monitoring; Female; Humans; Norway; Pregnancy; Pregnancy Trimester, Third; Registries; Retrospective Studies; Young Adult
PubMed: 28643331
DOI: 10.1002/cpt.770