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Heliyon Nov 2023Adverse events (AEs) of antipsychotic drugs include neuroleptic malignant syndrome (NMS), which presents complex clinical symptoms, resulting in a fatal outcome. In this...
Adverse events (AEs) of antipsychotic drugs include neuroleptic malignant syndrome (NMS), which presents complex clinical symptoms, resulting in a fatal outcome. In this study, the association between antipsychotic drugs and NMS was comprehensively evaluated by cluster and association analyses using the Japanese Adverse Drug Event Report (JADER) database. The analyses were performed using 20 typical antipsychotics (TAPs) alongside 9 atypical antipsychotics (AAPs). The Standardised MedDRA Queries (SMQ) database was used to analyze NMS (SMQ code: 20000044). Reporting odds ratios (RORs) were used for AE signal detection. The relationship between antipsychotic drugs and AEs for NMS was investigated by performing hierarchical cluster analysis using Ward's method. Between April 2004 and September 2021, the total number of JADER reports was 705,294. RORs (95 % confidence interval) of NMS for haloperidol, chlorpromazine, risperidone, and aripiprazole were 12.1 (11.1-13.3), 6.3 (5.7-7.0), 6.2 (5.8-6.6), and 4.7 (4.4-5.1), respectively. Three clusters were formed, with characteristics as follows: Cluster 1 consisted of only TAPs, such as bromperidol and fluphenazine, whilst having a high reporting rate of hypotension, tachycardia, dyskinesia, and dystonia. Cluster 2 consisted of all AAPs alongside several TAPs, such as haloperidol and chlorpromazine, with higher reporting rates of disturbance of consciousness, extrapyramidal disorders (excluding dyskinesia and dystonia), and serotonin syndrome. Cluster 3 consisted of only perphenazine, whilst having a higher reporting rate of coma, leukocytosis, and Parkinsonism. The results of this study may therefore aid in the management of NMS using antipsychotic drugs.
PubMed: 38034668
DOI: 10.1016/j.heliyon.2023.e21891 -
The Mental Health Clinician Sep 2017Providing clinicians with an easy to grasp and understandable representation of pharmacology is important to allow optimal clinical decisions to be made. Two of the most...
INTRODUCTION
Providing clinicians with an easy to grasp and understandable representation of pharmacology is important to allow optimal clinical decisions to be made. Two of the most clinically relevant dimensions are receptor binding affinity and functional activity. The binding affinity for an agonist is described by the dissociation constant ( ), and an antagonist by the inhibition constant ( ). Functionally, medications can act as superagonists, agonists, partial agonists, antagonists, partial inverse agonists, or inverse agonists at several receptor sites, transporters, or ion channels. Comprehending the differences between agents is complicated by the number and types of binding sites.
METHODS
Binding and functional data are obtained from primary literature, product labels, human cloned receptor binding, and other sources. Binding affinities are converted into ratios relative to the putative primary receptor for that category of agent. Antipsychotic binding is referenced to dopamine type 2 long (D2L) receptor binding. Binding affinity ratios (BARs) generate a 6-spoked diagram, with D2L as the hub. The most avidly bound sites are the spokes, and the disk diameter represents the BAR. Where functional data are available, they are shown as a pie chart shading the binding site's disk.
RESULTS
Binding and function diagrams are shown for the antipsychotics where binding data are available and are compared to previous methods of pharmacologic comparisons of antipsychotics.
DISCUSSION
Use of graphic models of psychotropic pharmacology improves clinician comprehension and may serve as an aid to improve rational therapeutics and patient outcomes.
PubMed: 29955524
DOI: 10.9740/mhc.2017.09.201 -
The Cochrane Database of Systematic... Jan 2018Up to 75% of people with serious mental illness (SMI) such as schizophrenia and bipolar disorder have co-occurring substance use disorders (dual diagnosis). Dual... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Up to 75% of people with serious mental illness (SMI) such as schizophrenia and bipolar disorder have co-occurring substance use disorders (dual diagnosis). Dual diagnosis can have an adverse effect on treatment and prognosis of SMI.
OBJECTIVES
To evaluate the effects of risperidone compared to treatment with other antipsychotics (first-generation and other second-generation antipsychotics) used in people with serious mental illness and co-occurring substance misuse.
SEARCH METHODS
On 6 January 2016 and 9 October 2017, we searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (including trial registers).
SELECTION CRITERIA
We selected randomised trials of risperidone versus any other antipsychotic in people with SMI and substance abuse (dual diagnosis). We included trials meeting our inclusion criteria and reporting useable data. We excluded trials that either did not meet our inclusion criteria or met our inclusion criteria but did not report any useable data.
DATA COLLECTION AND ANALYSIS
We independently inspected citations and selected studies. For included studies, we independently extracted data and appraised study quality. For binary outcomes we calculated the risk ratios (RRs) and their 95% confidence intervals. For continuous outcomes we calculated the mean differences (MDs) and their 95% confidence intervals. We pooled data using random-effects meta-analyses and assessed the quality of evidence, creating a 'Summary of findings' table using the GRADE approach.
MAIN RESULTS
We identified eight randomised trials containing a total of 1073 participants with SMI and co-occurring substance misuse. Seven of these contributed useable data to the review. There was heterogeneity in trial design and measurement. Risperidone was compared to clozapine, olanzapine, perphenazine, quetiapine and ziprasidone. Few trials compared risperidone with first-generation agents. Few trials examined participants with a dual diagnosis from the outset and most trials only contained separate analyses of subgroups with a dual diagnosis or were secondary data analyses of subgroups of people with a dual diagnosis from existing larger trials.For risperidone versus clozapine we found no clear differences between these two antipsychotics in the reduction of positive psychotic symptoms (1 randomised controlled trial (RCT), n = 36, mean difference (MD) 0.90, 95% CI -2.21 to 4.01, very low quality evidence), or reduction in cannabis use (1 RCT, n = 14, risk ratio (RR) 1.00, 95% CI 0.30 to 3.35, very low quality evidence), improvement in subjective well-being (1 RCT, n = 36, MD -6.00, 95% CI -14.82 to 2.82, very low quality evidence), numbers discontinuing medication (1 RCT, n = 36, RR 4.05, 95% CI 0.21 to 78.76, very low quality evidence), extrapyramidal side-effects (2 RCTs, n = 50, RR 2.71, 95% CI 0.30 to 24.08; I² = 0%, very low quality evidence), or leaving the study early (2 RCTs, n = 45, RR 0.49, 95% CI 0.10 to 2.51; I² = 34%, very low quality evidence). Clozapine was associated with lower levels of craving for cannabis (1 RCT, n = 28, MD 7.00, 95% CI 2.37 to 11.63, very low quality evidence).For risperidone versus olanzapine we found no clear differences in the reduction of positive psychotic symptoms (1 RCT, n = 37, MD -1.50, 95% CI -3.82 to 0.82, very low quality evidence), reduction in cannabis use (1 RCT, n = 41, MD 0.40, 95% CI -4.72 to 5.52, very low quality evidence), craving for cannabis (1 RCT, n = 41, MD 5.00, 95% CI -4.86 to 14.86, very low quality evidence), parkinsonism (1 RCT, n = 16, MD -0.08, 95% CI -1.21 to 1.05, very low quality evidence), or leaving the study early (2 RCT, n = 77, RR 0.68, 95% CI 0.34 to 1.35; I² = 0%, very low quality evidence).For risperidone versus perphenazine, we found no clear differences in the number of participants leaving the study early (1 RCT, n = 281, RR 1.05, 95% CI 0.92 to 1.20, low-quality evidence).For risperidone versus quetiapine, we found no clear differences in the number of participants leaving the study early (1 RCT, n = 294, RR 0.96, 95% CI 0.86 to 1.07, low-quality evidence).For risperidone versus ziprasidone, we found no clear differences in the number of participants leaving the study early (1 RCT, n = 240, RR 0.96, 95% CI 0.85 to 1.10, low-quality evidence).For many comparisons, important outcomes were missing; and no data were reported in any study for metabolic disturbances, global impression of illness severity, quality of life or mortality.
AUTHORS' CONCLUSIONS
There is not sufficient good-quality evidence available to determine the effects of risperidone compared with other antipsychotics in people with a dual diagnosis. Few trials compared risperidone with first-generation agents, leading to limited applicability to settings where access to second-generation agents is limited, such as in low- and middle-income countries. Moreover, heterogeneity in trial design and measurement of outcomes precluded the use of many trials in our analyses. Future trials in this area need to be sufficiently powered but also need to conform to consistent methods in study population selection, use of measurement scales, definition of outcomes, and measures to counter risk of bias. Investigators should adhere to CONSORT guidelines in the reporting of results.
Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Diagnosis, Dual (Psychiatry); Humans; Mental Disorders; Olanzapine; Patient Dropouts; Perphenazine; Piperazines; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Substance-Related Disorders; Thiazoles
PubMed: 29355909
DOI: 10.1002/14651858.CD011057.pub2 -
Annals of Neurology Feb 2021Advances in genetic discoveries have created substantial opportunities for precision medicine in neurodevelopmental disorders. Many of the genes implicated in these...
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.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticonvulsants; Antidepressive Agents; Antipsychotic Agents; Carbamazepine; Computer Simulation; Drug Discovery; Epirizole; Gene Expression Profiling; Gene Expression Regulation; Humans; Induced Pluripotent Stem Cells; MCF-7 Cells; Mice; Naloxone; Narcotic Antagonists; Neural Stem Cells; Neurodevelopmental Disorders; Neurons; PC-3 Cells; Perphenazine; Primary Cell Culture; RNA-Seq; Risperidone; Single-Cell Analysis; Transcriptome; Trazodone; Trimipramine
PubMed: 33159466
DOI: 10.1002/ana.25950 -
The Journal of Toxicological Sciences May 1992The effects of acute administration of chlorpromazine (CPZ) and perphenazine (PPZ) on hepatic microsomal phospholipids (PLs) and enzyme activities in the male rat were... (Comparative Study)
Comparative Study
The effects of acute administration of chlorpromazine (CPZ) and perphenazine (PPZ) on hepatic microsomal phospholipids (PLs) and enzyme activities in the male rat were examined in order to elucidate the relationship between individual PLs and drug-metabolizing activity. Cytochrome P-450 and aniline (AN) hydroxylation activity were initially decreased in CPZ-treated rats, but cytochrome P-450 subsequently recovered to a level not significantly different from the control and AN hydroxylation was markedly increased, while in PPZ-treated rats, they remained depressed. CPZ increased the activities of glycerophosphate acyltransferase (GPA) and choline phosphotransferase (CPT), while PPZ increased the activities of phosphatidate cytidylyltransferase (PCT), phosphatidate phosphohydrolase (PPH) and CPT. Concurrently, CPZ raised microsomal phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine-inositol (PSI) and sphingomyelin (SM), while PPZ increased PC and PE, but did not affect the levels of PSI and SM. Acyl components of phospholipids were also modified. CPZ significantly decreased the ratio of saturated to unsaturated fatty acids, particularly in the PC and PE fractions, while the effect of PPZ was only slight. The results imply that an increase of AN hydroxylation activity may involve the incorporation of unsaturated fatty acids into enzyme-associated PC and PE.
Topics: Aniline Hydroxylase; Animals; Chlorpromazine; Cytochrome P-450 Enzyme System; Diacylglycerol Cholinephosphotransferase; Fatty Acids; Glycerol-3-Phosphate O-Acyltransferase; Male; Microsomes, Liver; Nucleotidyltransferases; Perphenazine; Phosphatidate Phosphatase; Phospholipids; Rats; Rats, Inbred Strains
PubMed: 1324328
DOI: 10.2131/jts.17.69 -
Journal of Pharmacy & Pharmaceutical... Aug 2005The present study evaluates some azetidin-2-ones derivatives for their central nervous system (CNS) modulating activities. The compounds were chosen from a series (5a-o)... (Comparative Study)
Comparative Study
PURPOSE
The present study evaluates some azetidin-2-ones derivatives for their central nervous system (CNS) modulating activities. The compounds were chosen from a series (5a-o) which were previously synthesized and evaluated for hypolipidemic and antihyperglycemic activity based on the predictions made by the computer software "Prediction of Activity Spectra for Substances (PASS)".
MATERIAL AND METHODS
The test compounds were predicted to have a variety of biological activities but those with the best potential for CNS modulating activity were selected for evaluation of a particular CNS activity as 5a for anti-anxiety, 5b, 5n and 5j for nootropic activity and compound 5c anti-catatonic and anti-dyskinetic activities. Test compound 5a was evaluated for anti-anxiety activity in mirrored chamber model and for pentobarbitone induced sleep potentiation in mice. Test compounds 5b, 5n and 5j were evaluated for nootropic activity in mice by examining the effect on transfer latency on elevated plus maze (EPM) in mice and compound 5c was tested for anti-catatonic activity in perphenazine-induced catatonia and anti-dyskinetic effects in reserpine induced orofacial dyskinesia in rats, respectively.
RESULTS AND DISCUSSION
The test compound 5a showed significant anxiolytic activity in the mirror chamber paradigm and showed potentiation of the pentobarbitone-induced hypnosis, which was comparable to diazepam. The nootropic activity of compounds 5b, 5n and 5j were found to be significant in elevated and maze test. The test compound 5c significantly prevented the perphenazine-induced catalepsy in a dose dependent manner. Potentiation of anti-catatonic effect of sub-effective dose of L-dopa and reversal of sulpiride-induced catalepsy was also observed by compound 5c. It indicated that the test compound might be showing anticatatonic effect by dopaminergic stimulation probably through D2 dopaminergic receptors. Compound 5c significantly reduced the vacuous chewing movements, tongue protrusions and jaw tremors induced by reserpine. It further supports the dopaminergic agonism by the test compound as reserpine induces oral dyskinetic features by depleting catecholamine (dopamine and nor- epinephrine).
CONCLUSION
It was concluded that azetidinones possess considerable CNS activities and can be further explored to find additional CNS active compounds.
Topics: Animals; Anxiety; Azetidines; Central Nervous System Agents; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Maze Learning; Mice; Predictive Value of Tests; Rats; Rats, Wistar; Sleep
PubMed: 16124929
DOI: No ID Found -
British Journal of Cancer Aug 2017Demand for cholesterol is high in certain cancers making them potentially sensitive to therapeutic strategies targeting cellular cholesterol homoeostasis. A potential...
BACKGROUND
Demand for cholesterol is high in certain cancers making them potentially sensitive to therapeutic strategies targeting cellular cholesterol homoeostasis. A potential approach involves disruption of intracellular cholesterol transport, which occurs in Niemann-Pick disease as a result of acid sphingomyelinase (ASM) deficiency. Hence, a class of lysosomotropic compounds that were identified as functional ASM inhibitors (FIASMAs) might exhibit chemotherapeutic activity by disrupting cancer cell cholesterol homoeostasis.
METHODS
Here, the chemotherapeutic utility of ASM inhibition was investigated. The effect of FIASMAs on intracellular cholesterol levels, cholesterol homoeostasis, cellular endocytosis and signalling cascades were investigated. The in vivo efficacy of ASM inhibition was demonstrated using melanoma xenografts and a nanoparticle formulation was developed to overcome dose-limiting CNS-associated side effects of certain FIASMAs.
RESULTS
Functional ASM inhibitors inhibited intracellular cholesterol transport leading to disruption of autophagic flux, cellular endocytosis and receptor tyrosine kinase signalling. Consequently, major oncogenic signalling cascades on which cancer cells were reliant for survival were inhibited. Two tested ASM inhibitors, perphenazine and fluphenazine that are also clinically used as antipsychotics, were effective in inhibiting xenografted tumour growth. Nanoliposomal encapsulation of the perphenazine enhanced its chemotherapeutic efficacy while decreasing CNS-associated side effects.
CONCLUSIONS
This study suggests that disruption of intracellular cholesterol transport by targeting ASM could be utilised as a potential chemotherapeutic approach for treating cancer.
Topics: Administration, Intravenous; Administration, Oral; Animals; Antidepressive Agents, Tricyclic; Antipsychotic Agents; Autophagy; Biological Transport; Cell Survival; Cholesterol; Desipramine; Endocytosis; Endosomes; Female; Flupenthixol; Fluphenazine; Gene Expression Regulation; Gene Knockdown Techniques; HCT116 Cells; Homeostasis; Humans; Inhibitory Concentration 50; Liposomes; Lysosomes; MCF-7 Cells; Melanoma; Mice; Nortriptyline; Perphenazine; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; STAT3 Transcription Factor; Signal Transduction; Sphingomyelin Phosphodiesterase; bcl-2-Associated X Protein
PubMed: 28697173
DOI: 10.1038/bjc.2017.200 -
Schizophrenia Bulletin Oct 2018Very little is known about the comparative long-term effectiveness of novel antipsychotics in relapse prevention, especially in first-episode schizophrenia. Nationwide... (Comparative Study)
Comparative Study
Very little is known about the comparative long-term effectiveness of novel antipsychotics in relapse prevention, especially in first-episode schizophrenia. Nationwide data from Finnish health care registers were gathered prospectively for all persons with periods of inpatient care due to schizophrenia in Finland during 1972-2014. Altogether 62250 persons were included in the prevalent cohort, and 8719 in the incident (first-episode schizophrenia) cohort. The follow-up for antipsychotic use started at 1996 for the prevalent cohort, and at the first discharge from inpatient care for the incident cases. Within-individual Cox regression models for risk of psychiatric and all-cause hospitalization were constructed to compare risk during antipsychotic use and no use using individual as his/her own control to eliminate selection bias. With follow-up time up to 20 years (median = 14.1, interquartile range = 6.9-20.0), 59% of the prevalent cohort were readmitted to psychiatric inpatient care. Olanzapine long-acting injection (LAI; adjusted hazard ratio = 0.46, 95% confidence interval = 0.36-0.61), clozapine (0.51, 0.49-0.53), and paliperidone LAI (0.51, 0.40-0.66) were associated with the lowest risk of psychiatric rehospitalization in the prevalent cohort. Among first-episode patients, the lowest risks were observed for flupentixol LAI (0.24, 0.12-0.49), olanzapine LAI (0.26, 0.16-0.44), and perphenazine LAI (0.39, 0.31-0.50). Clozapine and LAIs were associated with the lowest risk of all-cause hospitalization in both cohorts. Clozapine and LAIs are the most effective treatments in preventing psychiatric and all-cause hospitalization among chronic and first-episode patients with schizophrenia.
Topics: Adult; Aged; Antipsychotic Agents; Clozapine; Female; Finland; Flupenthixol; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Olanzapine; Paliperidone Palmitate; Patient Readmission; Perphenazine; Prevalence; Schizophrenia; Secondary Prevention; Young Adult
PubMed: 29272458
DOI: 10.1093/schbul/sbx176 -
British Medical Journal Apr 1967
Topics: Adult; Female; Fluphenazine; Humans; Male; Movement Disorders; Perphenazine; Pregnancy; Trifluoperazine
PubMed: 6021008
DOI: 10.1136/bmj.2.5543.55-a -
The Cornell Veterinarian Jul 1963
Topics: Animals; Cattle; Cattle Diseases; Perphenazine; Streptomycin; Tetanus; Tetanus Toxoid
PubMed: 14043822
DOI: No ID Found