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Australian Journal of General Practice Dec 2019Evidence exists for the use of palliative sedation for people approaching the last days of life with refractory and intolerable symptoms. It is a third-line intervention... (Review)
Review
BACKGROUND
Evidence exists for the use of palliative sedation for people approaching the last days of life with refractory and intolerable symptoms. It is a third-line intervention that deliberately lowers the conscious state to relieve intolerable and refractory symptoms. This level of intervention is not routinely used in primary care, and there is a lack of guidelines for palliative sedation in this context.
OBJECTIVE
This article provides some key information about palliative sedation and global issues faced by all individuals involved. A tertiary centre case study is used to illustrate the key points. Given this form of therapy may be required for palliative patients in the community, another aim of this article is to provide an overview for primary care practitioners to raise their awareness of such therapy and the issues related to it.
DISCUSSION
While palliative sedation has been regarded as 'controversial' in early palliative care literature, there has been an increased effort to formulate standardised guidelines to define and ethically justify this procedure.
Topics: Aged; Analgesics; Conscious Sedation; Dehydration; Dyspnea; Humans; Hydromorphone; Hypnotics and Sedatives; Male; Methotrimeprazine; Midazolam; Multiple Myeloma; Multiple Organ Failure; Pain; Palliative Care; Phenobarbital; Propofol; Psychomotor Agitation; Sepsis; Terminal Care
PubMed: 31774984
DOI: 10.31128/AJGP-05-19-4938 -
EMBO Molecular Medicine Jan 2024Japanese encephalitis virus (JEV) pathogenesis is driven by a combination of neuronal death and neuroinflammation. We tested 42 FDA-approved drugs that were shown to...
Japanese encephalitis virus (JEV) pathogenesis is driven by a combination of neuronal death and neuroinflammation. We tested 42 FDA-approved drugs that were shown to induce autophagy for antiviral effects. Four drugs were tested in the JE mouse model based on in vitro protective effects on neuronal cell death, inhibition of viral replication, and anti-inflammatory effects. The antipsychotic phenothiazines Methotrimeprazine (MTP) & Trifluoperazine showed a significant survival benefit with reduced virus titers in the brain, prevention of BBB breach, and inhibition of neuroinflammation. Both drugs were potent mTOR-independent autophagy flux inducers. MTP inhibited SERCA channel functioning, and induced an adaptive ER stress response in diverse cell types. Pharmacological rescue of ER stress blocked autophagy and antiviral effect. MTP did not alter translation of viral RNA, but exerted autophagy-dependent antiviral effect by inhibiting JEV replication complexes. Drug-induced autophagy resulted in reduced NLRP3 protein levels, and attenuation of inflammatory cytokine/chemokine release from infected microglial cells. Our study suggests that MTP exerts a combined antiviral and anti-inflammatory effect in JEV infection, and has therapeutic potential for JE treatment.
Topics: Animals; Mice; Encephalitis Virus, Japanese; Methotrimeprazine; Neuroinflammatory Diseases; Encephalitis, Japanese; Antiviral Agents; Autophagy; Anti-Inflammatory Agents
PubMed: 38177535
DOI: 10.1038/s44321-023-00014-w -
BMJ Open Sep 2019Methotrimeprazine is commonly used for the management of nausea but never tested formally against other drugs used in this setting. The aim was to demonstrate superior... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
Methotrimeprazine is commonly used for the management of nausea but never tested formally against other drugs used in this setting. The aim was to demonstrate superior antiemetic efficacy.
DESIGN
Double-blind, randomised, controlled trial of methotrimeprazine versus haloperidol.
SETTING
11 palliative care sites in Australia.
PARTICIPANTS
Participants were >18 years, had cancer, an average nausea score of ≥3/10 and able to tolerate oral medications. Ineligible patients had acute nausea related to treatment, nausea for which a specific antiemetic was indicated, were about to undergo a procedure or had received either of the study drugs or a change in glucocorticoid dose within the previous 48 hours.
INTERVENTIONS
Based on previous studies, haloperidol was used as the control. Participants were randomised to encapsulated methotrimeprazine 6·25 mg or haloperidol 1·5 mg one time or two times per day and assessed every 24 hours for 72 hours.
MAIN OUTCOME MEASURES
A ≥two-point reduction in nausea score at 72 hours from baseline. Secondary outcome measures were as follows: complete response at 72 hours (end nausea score less than 3), response at 24 and 48 hours, vomiting episodes, use of rescue antiemetics, harms and global impression of change.
RESULTS
Response to treatment at 72 hours was 75% (44/59) in the haloperidol (H) arm and 63% (36/57) in the methotrimeprazine (M) arm with no difference between groups (intention-to-treat analysis). Complete response rates were 56% (H) and 51% (M). In the analysis, there was no difference in response rates: (85% (44/52) (H) and 74% (36/49) (M). Complete response rates were 64% (H) and 59% (M). Toxicity worse than baseline was minimal with a trend towards greater sedation in the methotrimeprazine arm.
CONCLUSION
This study did not demonstrate any difference in response rate between methotrimeprazine and haloperidol in the control of nausea.
TRIAL REGISTRATION NUMBER
ACTRN 12615000177550.
Topics: Antiemetics; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Monitoring; Drug Therapy, Combination; Female; Glucocorticoids; Haloperidol; Humans; Male; Methotrimeprazine; Middle Aged; Nausea; Neoplasms; Palliative Care; Treatment Outcome
PubMed: 31515428
DOI: 10.1136/bmjopen-2019-029942 -
Frontiers in Pharmacology 2020Drug repurposing is a rapid approach to identify therapeutics for the treatment of emerging infectious diseases such as COVID-19. To address the urgent need for...
Drug repurposing is a rapid approach to identify therapeutics for the treatment of emerging infectious diseases such as COVID-19. To address the urgent need for treatment options, we carried out a quantitative high-throughput screen using a SARS-CoV-2 cytopathic assay with a compound collection of 8,810 approved and investigational drugs, mechanism-based bioactive compounds, and natural products. Three hundred and nineteen compounds with anti-SARS-CoV-2 activities were identified and confirmed, including 91 approved drugs and 49 investigational drugs. The anti-SARS-CoV-2 activities of 230 of these confirmed compounds, of which 38 are approved drugs, have not been previously reported. Chlorprothixene, methotrimeprazine, and piperacetazine were the three most potent FDA-approved drugs with anti-SARS-CoV-2 activities. These three compounds have not been previously reported to have anti-SARS-CoV-2 activities, although their antiviral activities against SARS-CoV and Ebola virus have been reported. These results demonstrate that this comprehensive data set is a useful resource for drug repurposing efforts, including design of new drug combinations for clinical trials for SARS-CoV-2.
PubMed: 33708112
DOI: 10.3389/fphar.2020.592737 -
BioRxiv : the Preprint Server For... Aug 2020Drug repurposing is a rapid approach to identifying therapeutics for the treatment of emerging infectious diseases such as COVID-19. To address the urgent need for...
Drug repurposing is a rapid approach to identifying therapeutics for the treatment of emerging infectious diseases such as COVID-19. To address the urgent need for treatment options, we carried out a quantitative high-throughput screen using a SARS-CoV-2 cytopathic assay with a compound collection of 8,810 approved and investigational drugs, mechanism-based bioactive compounds, and natural products. Three hundred and nineteen compounds with anti-SARS-CoV-2 activities were identified and confirmed, including 91 approved drug and 49 investigational drugs. Among these confirmed compounds, the anti-SARS-CoV-2 activities of 230 compounds, including 38 approved drugs, have not been previously reported. Chlorprothixene, methotrimeprazine, and piperacetazine were the three most potent FDA approved drugs with anti-SARS-CoV-2 activities. These three compounds have not been previously reported to have anti-SARS-CoV-2 activities, although their antiviral activities against SARS-CoV and Ebola virus have been reported. These results demonstrate that this comprehensive data set of drug repurposing screen for SARS-CoV-2 is useful for drug repurposing efforts including design of new drug combinations for clinical trials.
PubMed: 32839771
DOI: 10.1101/2020.08.18.255877 -
Molecules (Basel, Switzerland) Feb 2023Antipsychotics have narrow therapeutic windows, and their monitoring in biological fluids is therefore important; consequently, stability in those fluids must be...
Antipsychotics have narrow therapeutic windows, and their monitoring in biological fluids is therefore important; consequently, stability in those fluids must be investigated during method development and validation. This work evaluates the stability of chlorpromazine, levomepromazine, cyamemazine, clozapine, haloperidol, and quetiapine in oral fluid (OF) samples, using the dried saliva spots (DSS) sampling approach and gas chromatography coupled to tandem mass spectrometry. Since many parameters can influence the stability of the target analytes, design of experiments was adopted to check the crucial factors that affect that stability in a multivariate fashion. The studied parameters were the presence of preservatives at different concentrations, temperature, light, and time. It was possible to observe that antipsychotic stability improved when OF samples in DSS were stored at 4 °C, with a low ascorbic acid concentration, and in the absence of light. With these conditions, chlorpromazine and quetiapine were stable for 14 days, clozapine and haloperidol were stable for 28 days, levomepromazine remained stable for 44 days, and cyamemazine was stable for the entire monitored period (146 days). This is the first study that evaluates the stability of these antipsychotics in OF samples after application to DSS cards.
Topics: Antipsychotic Agents; Clozapine; Quetiapine Fumarate; Haloperidol; Chlorpromazine; Methotrimeprazine; Gas Chromatography-Mass Spectrometry
PubMed: 36903275
DOI: 10.3390/molecules28052030 -
JAMA Internal Medicine Oct 2022An increasing number of individuals fill antipsychotic prescriptions during pregnancy, and concerns have been raised about prenatal antipsychotic exposure on...
IMPORTANCE
An increasing number of individuals fill antipsychotic prescriptions during pregnancy, and concerns have been raised about prenatal antipsychotic exposure on neurodevelopmental outcomes.
OBJECTIVE
To examine whether maternal prescription fill for antipsychotics during pregnancy was associated with performance in standardized tests among schoolchildren.
DESIGN, SETTING, AND PARTICIPANTS
This register-based cohort study included 667 517 children born in Denmark from January 1, 1997, to December 31, 2009, and who were attending public primary and lower secondary school. All children had completed at least 1 language (Danish) or mathematics test as part of the Danish National School Test Program between 2010 and 2018. Data were analyzed from November 1, 2021, to March 31, 2022.
EXPOSURES
Antipsychotic prescriptions filled by pregnant individuals were obtained from the Danish National Prescription Register.
MAIN OUTCOMES AND MEASURES
Differences in standardized test scores (range, 1-100; higher scores indicate better test results) in language and mathematics between children of mothers with and without antipsychotic prescription fills during pregnancy were estimated using linear regression models. Seven sensitivity analyses, including a sibling-controlled analysis, were performed.
RESULTS
Of the 667 517 children included (51.2% males), 1442 (0.2%) children were born to mothers filling an antipsychotic prescription during pregnancy. The mean (SD) age of children at the time of testing spanned from 8.9 (0.4) years in grade 2 to 14.9 (0.4) years in grade 8. Maternal prescription fill for antipsychotics was not associated with performance in language (crude mean test score: 50.0 [95% CI, 49.1-50.9] for the exposed children vs 55.4 [95% CI, 55.4-55.5] for the unexposed children; adjusted difference, 0.5 [95% CI, -0.8 to 1.7]) or in mathematics (crude mean test score: 48.1 [95% CI, 47.0-49.3] for the exposed children vs 56.1 [95% CI, 56.1-56.2] for the unexposed children; adjusted difference, 0.4 [95% CI, -1.0 to 1.8]). There was no evidence that results were modified by the timing of filling prescriptions, classes (first-generation and second-generation) of antipsychotics, or the most commonly prescribed antipsychotic monotherapies, including chlorprotixene, flupentixol, olanzapine, zuclopenthixol, quetiapine, perphenazine, and methotrimeprazine. The results remained robust across sensitivity analyses, including sibling-controlled analyses, negative control exposures analyses, and probabilistic bias analyses.
CONCLUSIONS AND RELEVANCE
In this register-based cohort study, maternal prescription fill for antipsychotics during pregnancy did not appear to be associated with standardized test scores in the offspring. The findings provide further reassuring data on offspring neurodevelopmental outcomes associated with antipsychotic treatment during pregnancy.
Topics: Antipsychotic Agents; Child; Clopenthixol; Cohort Studies; Denmark; Female; Flupenthixol; Humans; Male; Methotrimeprazine; Olanzapine; Perphenazine; Pregnancy; Prescriptions; Quetiapine Fumarate
PubMed: 35969410
DOI: 10.1001/jamainternmed.2022.3388 -
European Journal of Hospital Pharmacy :... Mar 2023Patients in the acute phase of agitation can require the administration of multiple drugs by intramuscular injection in order to temporarily stabilise their condition....
BACKGROUND
Patients in the acute phase of agitation can require the administration of multiple drugs by intramuscular injection in order to temporarily stabilise their condition. Administration of multiple psychotropic medications in a single syringe can be beneficial to both the patient and healthcare professionals. However, there are very little data in the literature regarding psychotropic drug compatibility in syringes for acute agitation.
OBJECTIVE
The aim of this study was to assess the visual compatibility of various combinations of 12 intramuscular psychotropic medications in syringes, and to validate compatibility with the use of a particle counter. The medications evaluated were benztropine mesylate, diazepam, dimenhydrinate, diphenhydramine hydrochloride, haloperidol lactate, hydroxyzine, lorazepam, loxapine, methotrimeprazine, midazolam, olanzapine and zuclopenthixol acetate.
METHODS
Compounded solutions of medication combinations underwent visual inspection initially and after 0.25, 0.5, 1, 2 and 4 hours using a white background and a black background. In order to validate the compatibility results, the presence of particulate matter was determined by light obscuration.
RESULTS
This study identified 35 combinations that were visually compatible and 35 that were visually incompatible. We chose eight highly clinically relevant combinations to test using the requirements of the United States Pharmacopoeia (USP) chapter 788 (Particulate Matter in Injections). Of those eight, six were physically compatible, including the triple combinations of lorazepam and haloperidol with either benztropine or diphenhydramine.
CONCLUSION
These physical compatibility results will give healthcare professionals an idea of the possible compatible combinations of psychotropic drugs in syringes, and thus complete some of the missing data in the literature.
Topics: Humans; Haloperidol; Lorazepam; Syringes; Psychotropic Drugs; Diphenhydramine
PubMed: 36002244
DOI: 10.1136/ejhpharm-2022-003378 -
Levomepromazine and clozapine induce the main human cytochrome P450 drug metabolizing enzyme CYP3A4.Pharmacological Reports : PR Feb 2021Cytochrome P450 (CYP) enzymes are involved in the metabolism of many important endogenous substrates (steroids, melatonin), drugs and toxic xenobiotics. Their induction...
BACKGROUND
Cytochrome P450 (CYP) enzymes are involved in the metabolism of many important endogenous substrates (steroids, melatonin), drugs and toxic xenobiotics. Their induction accelerates drug metabolism and elimination. The present study aimed at examining the inducing abilities of two antipsychotic drugs levomepromazine and clozapine for the main CYPs.
METHODS
The experiments were performed using cryopreserved human hepatocytes. The hepatotoxicity of levomepromazine and clozapine was assessed after exposure to the neuroleptics (LDH test). CYP activities were measured in the incubation medium using the CYP-specific reactions: caffeine 3-N-demethylation (CYP1A1/2), diclofenac 4'-hydroxylation (CYP2C9), perazine N-demethylation (CYP2C19) and testosterone 6β-hydroxylation (CYP3A4). In parallel, CYP mRNA levels were measured in neuroleptic-treated hepatocytes.
RESULTS
The results indicate that levomepromazine and clozapine induce the expression of main CYP enzyme CYP3A4 in human hepatocytes. Levomepromazine and clozapine at concentrations of 2.5 and 10 µM, respectively, caused a significant increase in the mRNA level and activity of CYP3A4. Both neuroleptics did not produce any changes in CYP1A1/2, CYP2C9 and CYP2C19.
CONCLUSION
Levomepromazine and clozapine induce CYP3A4 in human hepatocytes in vitro. Further in vivo studies are advisable to confirm the CYP3A4 induction by levomepromazine and clozapine in the liver, and to assess the effect of these drugs on their own metabolism and on the biotransformation of other co-administered drugs which are the CYP3A4 substrates.
Topics: Antipsychotic Agents; Cells, Cultured; Clozapine; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Enzyme Induction; Hepatocytes; Humans; Liver; Methotrimeprazine; RNA, Messenger
PubMed: 32888176
DOI: 10.1007/s43440-020-00157-4 -
Neuropsychopharmacology Reports Mar 2024Constipation is a common adverse effect of antipsychotics, but little investigation has been conducted. We aimed to address the factors associated with the initiation of...
BACKGROUND
Constipation is a common adverse effect of antipsychotics, but little investigation has been conducted. We aimed to address the factors associated with the initiation of laxative use in the same patients with schizophrenia over a 20-year period.
METHODS
We enrolled patients with schizophrenia attending each hospital (n = 14) from April 1, 2021, and retrospectively examined all prescriptions as of April 1, 2016, 2011, 2006, and 2001, every 5 years starting in 2021, for this population. 716 participants with complete data were included in the analysis. The Cochran Q test followed by Bonferroni correction and the Cochran-Armitage trend test were used to determine the differences and trends of the frequency of each laxative. Multivariate logistic regression analysis was performed to assess the factors on the initiation of laxative use over a 20-year period.
RESULTS
Of the patients, 25.1% were treated with laxatives in 2001, and 34.1% were treated in 2021. The numbers of patients treated with any laxatives significantly differed over the 20-year period, with a significant increasing trend. In all laxatives, the numbers of patients treated with magnesium oxide, lubiprostone and elobixibat differed with a significant increasing trend. Female sex, age, the total DZP equivalent dose, and the doses of levomepromazine maleate, olanzapine, quetiapine, zotepine, lithium, and carbamazepine in 2021 were significant factors associated with the initiation of laxative use over the 20-year period.
CONCLUSIONS
Careful monitoring is needed for patients treated with levomepromazine maleate, olanzapine, quetiapine and zotepine. Optimizing prescriptions according to treatment guidelines could reduce antipsychotic-induced constipation.
Topics: Humans; Female; Laxatives; Schizophrenia; Olanzapine; Retrospective Studies; Quetiapine Fumarate; Antipsychotic Agents; Constipation; Dibenzothiepins; Methotrimeprazine
PubMed: 37698084
DOI: 10.1002/npr2.12378