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The Cochrane Database of Systematic... Nov 2017Oral zuclopenthixol dihydrochloride (Clopixol) is an anti-psychotic treatment for people with psychotic symptoms, especially those with schizophrenia. It is associated... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Oral zuclopenthixol dihydrochloride (Clopixol) is an anti-psychotic treatment for people with psychotic symptoms, especially those with schizophrenia. It is associated with neuroleptic malignant syndrome, a prolongation of the QTc interval, extra-pyramidal reactions, venous thromboembolism and may modify insulin and glucose responses.
OBJECTIVES
To determine the effects of zuclopenthixol dihydrochloride for treatment of schizophrenia.
SEARCH METHODS
We searched the Cochrane Schizophrenia Group's Trials Register (latest search 09 June 2015). There were no language, date, document type, or publication status limitations for inclusion of records in the register.
SELECTION CRITERIA
All randomised controlled trials (RCTs) focusing on zuclopenthixol dihydrochloride for schizophrenia. We included trials meeting our inclusion criteria and reporting useable data.
DATA COLLECTION AND ANALYSIS
We extracted data independently. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. For continuous data, we estimated the mean difference (MD) between groups and its 95% CI. We employed a random-effect model for analyses. We assessed risk of bias for included studies and created 'Summary of findings' tables using GRADE.
MAIN RESULTS
We included 20 trials, randomising 1850 participants. Data were reported for 12 comparisons, predominantly for the short term (up to 12 weeks) and inpatient populations. Overall risk of bias for included studies was low to unclear.Data were unavailable for many of our pre-stated outcomes of interest. No data were available, across all comparisons, for death, duration of stay in hospital and general functioning.Zuclopenthixol dihydrochloride versus: 1. placeboMovement disorders (EPSEs) were similar between groups (1 RCT, n = 28, RR 6.07 95% CI 0.86 to 43.04 very low-quality evidence). There was no clear difference in numbers leaving the study early (2 RCTs, n = 100, RR 0.29, 95% CI 0.01 to 6.60, very low-quality evidence). 2. chlorpromazineNo clear differences were found for the outcomes of global state (average CGI-SI endpoint score) (1 RCT, n = 60, MD 0.00, 95% CI -0.49 to 0.49) or movement disorders (EPSEs) (3 RCTs, n = 199, RR 0.94, 95% CI 0.61 to 1.45), both very low-quality evidence. More people left the study early for any reason from the zuclopenthixol group (6 RCTs, n = 766, RR 0.54, 95% CI 0.36 to 0.81, low-quality evidence). 3. chlorprothixeneThere was no clear difference in numbers leaving the study early for any reason (1 RCT, n = 20, RR 1.00, 95% CI 0.34 to 2.93, very low-quality evidence). 4. clozapineNo useable data were presented. 5. haloperidolNo clear differences between treatment groups were found for the outcomes global state score (average CGI endpoint score) (1 RCT, n = 49, MD 0.13, 95% CI -0.30 to 0.55) or leaving the study early (2 RCTs, n = 141, RR 0.99, 95% CI 0.72 to 1.35), both very low-quality evidence. 6. perphenazineThose receiving zuclopenthixol were more likely to require medication in the short term for EPSEs than perphenazine (1 RCT, n = 50, RR 1.90, 95% CI 1.12 to 3.22, very low-quality evidence). Similar numbers left the study early (2 RCTs, n = 104, RR 0.63, 95% CI 0.27 to 1.47, very low-quality evidence). 7. risperidoneThose receiving zuclopenthixol were more likely to require medications for EPSEs than risperidone (1 RCT, n = 98,RR 1.92, 95% CI 1.12 to 3.28, very low quality evidence). There was no clear difference in numbers leaving the study early ( 3 RCTs, n = 154, RR 1.30, 95% CI 0.84 to 2.02) or in mental state (average PANSS total endpoint score) (1 RCT, n = 25, MD -3.20, 95% CI -7.71 to 1.31), both very low-quality evidence). 8. sulpirideNo clear differences were found for global state (average CGI endpoint score) ( 1 RCT, n = 61, RR 1.18, 95% CI 0.49 to 2.85, very low-quality evidence), requiring hypnotics/sedatives (1 RCT, n = 61, RR 0.60, 95% CI 0.27 to 1.32, very low-quality evidence) or leaving the study early (1 RCT, n = 61, RR 2.07 95% CI 0.97 to 4.40, very low-quality evidence). 9. thiothixeneNo clear differences were found for the outcomes of 'global state (average CGI endpoint score) (1 RCT, n = 20, RR 0.50, 95% CI 0.17 to 1.46) or leaving the study early (1 RCT, n = 20, RR 0.57, 95% CI 0.24 to 1.35), both very low-quality evidence). 10. trifluoperazineNo useable data were presented. 11. zuclopenthixol depotThere was no clear difference in numbers leaving the study early (1 RCT, n = 46, RR 1.95, 95% CI 0.36 to 10.58, very low-quality evidence). 12. Zuclopenthixol dihydrochloride (cis z isomer) versus zuclopenthixol (cis z/trans e isomer)There were no clear differences in reported side-effects ( 1 RCT, n = 57, RR 1.34, 95% CI 0.82 to 2.18, very low-quality evidence) and in numbers leaving the study early (4 RCTs, n = 140, RR 2.15, 95% CI 0.49 to 9.41, very low-quality evidence).
AUTHORS' CONCLUSIONS
Zuclopenthixol dihydrochloride appears to cause more EPSEs than clozapine, risperidone or perphenazine, but there was no difference in EPSEs when compared to placebo or chlorpromazine. Similar numbers required hypnotics/sedatives when zuclopenthixol dihydrochloride was compared to sulpiride, and similar numbers of reported side-effects were found when its isomers were compared. The other comparisons did not report adverse-effect data.Reported data indicate zuclopenthixol dihydrochloride demonstrates no difference in mental or global states compared to placebo, chlorpromazine, chlorprothixene, clozapine, haloperidol, perphenazine, sulpiride, thiothixene, trifluoperazine, depot and isomers. Zuclopenthixol dihydrochloride, when compared with risperidone, is favoured when assessed using the PANSS in the short term, but not in the medium term.The data extracted from the included studies are mostly equivocal, and very low to low quality, making it difficult to draw firm conclusions. Prescribing practice is unlikely to change based on this meta-analysis. Recommending any particular course of action about side-effect medication other than monitoring, using rating scales and clinical assessment, and prescriptions on a case-by-case basis, is also not possible.There is a need for further studies covering this topic with more antipsychotic comparisons for currently relevant outcomes.
Topics: Antipsychotic Agents; Clopenthixol; Humans; Movement Disorders; Randomized Controlled Trials as Topic; Schizophrenia
PubMed: 29144549
DOI: 10.1002/14651858.CD005474.pub2 -
European Journal of Pharmacology Nov 2020In 2020 the whole world focused on antivirus drugs towards SARS-CoV-2. Most of the researchers focused on drugs used in other viral infections or malaria. We have not... (Review)
Review
In 2020 the whole world focused on antivirus drugs towards SARS-CoV-2. Most of the researchers focused on drugs used in other viral infections or malaria. We have not seen such mobilization towards one topic in this century. The whole situation makes clear that progress needs to be made in antiviral drug development. The first step to do it is to characterize the potential antiviral activity of new or already existed drugs on the market. Phenothiazines are antipsychotic agents used previously as antiseptics, anthelminthics, and antimalarials. Up to date, they are tested for a number of other disorders including the broad spectrum of viruses. The goal of this paper was to summarize the current literature on activity toward RNA-viruses of such drugs like chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine. We identified 49 papers, where the use of the phenothiazines for 23 viruses from different families were tested. Chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine possess anti-viral activity towards different types of viruses. These drugs inhibit clathrin-dependent endocytosis, cell-cell fusion, infection, replication of the virus, decrease viral invasion as well as suppress entry into the host cells. Additionally, since the drugs display activity at nontoxic concentrations they have therapeutic potential for some viruses, still, further research on animal and human subjects are needed in this field to verify cell base research.
Topics: Animals; Antipsychotic Agents; Antiviral Agents; Betacoronavirus; COVID-19; Chlorpromazine; Coronavirus Infections; Fluphenazine; Humans; Pandemics; Perphenazine; Phenothiazines; Pneumonia, Viral; Prochlorperazine; RNA Viruses; SARS-CoV-2; Thioridazine; COVID-19 Drug Treatment
PubMed: 32949606
DOI: 10.1016/j.ejphar.2020.173553 -
British Journal of Clinical Pharmacology May 2021To investigate the impact of cytochrome P450 2D6 (CYP2D6) on dose-adjusted serum concentrations of flupentixol, haloperidol, perphenazine and zuclopenthixol in a...
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.
Topics: Clopenthixol; Cytochrome P-450 CYP2D6; Flupenthixol; Genotype; Haloperidol; Humans; Perphenazine; Retrospective Studies
PubMed: 33118660
DOI: 10.1111/bcp.14626 -
Developmental Medicine and Child... Dec 2017To evaluate the actual evidence of efficacy of oral pharmacological treatments in the management of dyskinetic cerebral palsy (CP). (Review)
Review
AIM
To evaluate the actual evidence of efficacy of oral pharmacological treatments in the management of dyskinetic cerebral palsy (CP).
METHOD
A systematic review was performed according to the American Academy for Cerebral Palsy and Developmental Medicine (AACPDM) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology. Articles were searched for in PubMed/MEDLINE, Scopus, Web of Science, Cochrane Library, Database of Reviews of Effectiveness, OTSeeker, Physiotherapy Evidence Database, REHABDATA, and ClinicalTrials.gov.
RESULTS
Sixteen articles met the eligibility criteria. Eight studies on trihexyphenidyl and two on levodopa showed contradictory results. Low efficacy was reported for diazepam, dantrolene sodium, perphenazine, and etybenzatropine. Tetrabenazine, gabapentin and levetiracetam should be studied in more detail. The updated available evidence does not support any therapeutic algorithm for the management of dyskinetic CP.
INTERPRETATION
This lack of evidence is partially owing to the inconsistency of classifications of patients and of outcome measures used in the reviewed studies. Further randomized, double-blind, placebo-controlled pharmacological trials, optimized for different age groups, based on valid, reliable, and disease-specific rating scales are strongly needed. Outcome measures should be selected within the framework of the International Classification of Functioning, Disability and Health.
WHAT THIS PAPER ADDS
Evidence to prove (or disprove) the efficacy of oral drugs in dyskinetic cerebral palsy is low. The most investigated drugs, trihexyphenidyl and levodopa, show contradictory results. Tetrabenazine, levetiracetam, and gabapentin efficacy should be studied in more detail. Lack of evidence is partially due to the inconsistency of classifications and outcome measures used. Outcome measures should be selected within the framework of the International Classification of Functioning, Disability and Health in next clinical trials.
Topics: Anticonvulsants; Cerebral Palsy; Dyskinesias; Humans; Neurotransmitter Agents; Outcome Assessment, Health Care
PubMed: 28872668
DOI: 10.1111/dmcn.13532 -
The Cochrane Database of Systematic... Oct 2014Antipsychotic drugs are the core treatment for schizophrenia. Treatment guidelines state that there is no difference in efficacy between the various first-generation... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Antipsychotic drugs are the core treatment for schizophrenia. Treatment guidelines state that there is no difference in efficacy between the various first-generation antipsychotics, however, low-potency first-generation antipsychotic drugs are sometimes perceived as less efficacious than high-potency first-generation compounds by clinicians, and they also seem to differ in their side effects.
OBJECTIVES
To review the effects of high-potency, first-generation perphenazine compared with low-potency, first-generation antipsychotic drugs for people with schizophrenia.
SEARCH METHODS
We searched the Cochrane Schizophrenia Group Trials Register (October 2010).
SELECTION CRITERIA
We included all randomised controlled trials (RCTs) comparing perphenazine with first-generation, low-potency antipsychotic drugs for people with schizophrenia or schizophrenia-like psychoses.
DATA COLLECTION AND ANALYSIS
We extracted data independently. For dichotomous data we calculated risk ratios (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis and using a random-effects model.
MAIN RESULTS
The review currently includes four relevant randomised trials with 365 participants. The size of the included studies was between 42 and 158 participants with a study length between one and four months. Overall, the methods of sequence generation and allocation concealment were poorly reported. Most studies were rated as low risk of bias in terms of blinding. Overall, attrition bias in the studies was high.The effects of perphenazine and low-potency antipsychotic drugs seemed to be similar in terms of the primary outcome - response to treatment (perphenazine 58%, low-potency antipsychotics 59%, 2 RCTs, n = 138, RR 0.97 CI 0.74 to 1.26 - moderate quality of evidence). There was also no clear evidence of a difference in acceptability of treatment with the number of participants leaving the studies early due to any reason, however results were imprecise (perphenazine 30%, low-potency antipsychotics 28%, 3 RCTs, n = 323, RR 0.78 CI 0.35 to 1.76, very low quality of evidence).There were low numbers of studies available for the outcomes experiencing at least one adverse effect (perphenazine 33%, low-potency antipsychotics 47%, 2 RCTs, n = 165, RR 0.83 CI 0.36 to 1.95, low quality evidence) and experiencing at least one movement disorder (perphenazine 22%, low-potency first-generation antipsychotics 0%, 1 RCT, n = 69, RR 15.62 CI 0.94 to 260.49, low quality evidence), and the confidence intervals for the estimated effects did not exclude important differences. Akathisia was more frequent in the perphenazine group (perphenazine 25%, low-potency antipsychotics 22%, 2 RCTs, n = 227, RR 9.45 CI 1.69 to 52.88), whereas severe toxicity was less so (perphenazine 42%, low-potency antipsychotics 69%, 1 RCT, n = 96, RR 0.61 CI 0.41 to 0.89).There were three deaths in the low-potency group by four months but the difference between groups was not significant (perphenazine 0%, low-potency antipsychotics 2%, 1 RCT, n = 96, RR 0.14 CI 0.01 to 2.69, moderate quality evidence). No data were available for our prespecified outcomes of interest sedation or quality of life. Data were not available for other outcomes such as relapse, service use, costs and satisfaction with care.The event rates reported quote simple aggregates and are not based on the RRs.
AUTHORS' CONCLUSIONS
The results do not show a superiority in efficacy of high-potency perphenazine compared with low-potency first-generation antipsychotics. There is some evidence that perphenazine is more likely to cause akathisia and less likely to cause severe toxicity, but most adverse effect results were equivocal. The number of studies as well as the quality of studies is low, with quality of evidence for the main outcomes ranging from moderate to very low, so more randomised evidence would be needed for conclusions to be made.
Topics: Adult; Antipsychotic Agents; Humans; Perphenazine; Randomized Controlled Trials as Topic; Schizophrenia
PubMed: 25290157
DOI: 10.1002/14651858.CD009369.pub2 -
Texas Heart Institute Journal 2003A 66-year-old woman presented with new-onset complete left bundle branch block and congestive heart failure. She had had chronic paranoid schizophrenia for 35 years and...
A 66-year-old woman presented with new-onset complete left bundle branch block and congestive heart failure. She had had chronic paranoid schizophrenia for 35 years and had been taking medications to control her psychiatric disorder for the past 10 years. A 2-dimensional echocardiogram performed at the onset of congestive heart failure showed dilated cardiomyopathy with global impairment of left ventricular function (ejection fraction <0.25). Despite withdrawal of the medications most likely responsible for the heart problems (perphenazine, 2 mg; and amitriptyline, 25 mg), the patient died of refractory congestive heart failure 2 years later. Histologic examination at autopsy showed evidence of persistent toxic myocarditis with fibrosis of the heart and persistent chronic hepatitis. These autopsy findings were considered to be drug related.
Topics: Adrenergic Uptake Inhibitors; Aged; Amitriptyline; Antipsychotic Agents; Female; Heart Failure; Humans; Myocarditis; Perphenazine; Schizophrenia, Paranoid
PubMed: 12638679
DOI: No ID Found -
Frontiers in Oncology 2015Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase that is required for normal cell growth and development. PP2A is a potent tumor suppressor, which is... (Review)
Review
Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase that is required for normal cell growth and development. PP2A is a potent tumor suppressor, which is inactivated in cancer cells as a result of genetic deletions and mutations. In myeloid leukemias, genes encoding PP2A subunits are generally intact. Instead, PP2A is functionally inhibited by post-translational modifications of its catalytic C subunit, and interactions with negative regulators by its regulatory B and scaffold A subunits. Here, we review the molecular mechanisms of genetic and functional inactivation of PP2A in human cancers, with a particular focus on human acute myeloid leukemias (AML). By analyzing expression of genes encoding PP2A subunits using transcriptome sequencing, we find that PP2A dysregulation in AML is characterized by silencing and overexpression of distinct A scaffold and B regulatory subunits, respectively. We review the mechanisms of functional PP2A activation by drugs such as fingolimod, forskolin, OP449, and perphenazine. This analysis yields two non-mutually exclusive mechanisms for therapeutic PP2A re-activation: (i) allosteric activation of the phosphatase activity, and (ii) stabilization of active holo-enzyme assembly and displacement of negative regulatory factors from A and B subunits. Future studies should allow the development of specific and potent pharmacologic activators of PP2A, and definition of susceptible disease subsets based on specific mechanisms of PP2A dysregulation.
PubMed: 25699237
DOI: 10.3389/fonc.2015.00016 -
The Cochrane Database of Systematic... Oct 2004Acute psychotic illnesses, especially when associated with agitated or violent behaviour, require urgent pharmacological tranquillisation or sedation. Clotiapine, a... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Acute psychotic illnesses, especially when associated with agitated or violent behaviour, require urgent pharmacological tranquillisation or sedation. Clotiapine, a dibenzothiazepine neuroleptic, is being used for this purpose in several countries.
OBJECTIVES
To estimate the effects of clotiapine when compared to other 'standard' or 'non-standard' treatments for acute psychotic illnesses in controlling disturbed behaviour and reducing psychotic symptoms.
SEARCH STRATEGY
We updated previous searches by searching the Cochrane Schizophrenia Group Register (April 2004)
SELECTION CRITERIA
The review included randomised clinical trials comparing clotiapine with any other treatment for people with acute psychotic illnesses.
DATA COLLECTION AND ANALYSIS
Relevant studies were selected for inclusion, their quality was assessed and data extracted. Data were excluded where more than 50% of participants in any group were lost to follow up. For binary outcomes we calculated a standard estimation of the risk ratio (RR) and its 95% confidence interval (CI). For continuous outcomes, endpoint data were preferred to change data. Non-skewed data from valid scales were summated using a weighted mean difference (WMD).
MAIN RESULTS
We identified five relevant trials. None compared clotiapine with placebo, but control drugs were either antipsychotics (chlorpromazine, perphenazine, trifluoperazine and zuclopenthixol acetate) or benzodiazepines (lorazepam). Versus the antipsychotics, the results for 'no important global improvement' did not suggest clotiapine to be superior, or inferior, to chlorpromazine, perphenazine, or trifluoperazine (n = 83, 3 RCTs, RR 0.82 CI 0.22 to 3.05, I-squared 58%). Use of clotiapine when compared with chlorpromazine did change the proportion of people ready for hospital discharge by the end of the study (n = 49, 1 RCT, RR 1.04 95%CI 0.96 to 2.12). Overall, attrition rates were low. No significant difference was found for those allocated to clotiapine compared with people randomised to other antipsychotics (n = 121, RR 2.26 95%CI 0.40 to 13). Weak data suggests that clotiapine may result in less need for antiparkinsonian treatment compared with zuclopenthixol acetate (n = 38, RR 0.43 95%CI 0.02 to 0.98). Compared with lorazepam, clotiapine, when used to control aggressive/violent outbursts for people already treated with haloperidol, did not significantly improve mental state (WMD -3.36 95%CI -8.09 to 1.37). We could not pool much data due to skew or inadequate presentation of results. Economic outcomes and satisfaction with care were not addressed.
REVIEWERS' CONCLUSIONS
We found no evidence to support the use of clotiapine in preference to other 'standard' or 'non-standard' treatments for management of people with acute psychotic illness. All trials in this review have important methodological problems. We do not wish to discourage clinicians from using clotiapine in the psychiatric emergency, but well-designed, conducted and reported trials are needed to properly determine the efficacy of this drug.
Topics: Acute Disease; Antipsychotic Agents; Dibenzothiazepines; Humans; Psychotic Disorders; Randomized Controlled Trials as Topic
PubMed: 15495032
DOI: 10.1002/14651858.CD002304.pub2 -
Canadian Medical Association Journal May 1972
Topics: Adolescent; Amitriptyline; Chlorprothixene; Diazepam; Female; Haloperidol; Humans; Lactation Disorders; Perphenazine; Pregnancy; Thioridazine; Tranquilizing Agents; Trifluoperazine
PubMed: 5064121
DOI: No ID Found -
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