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Journal of Pain and Symptom Management May 2024Antipsychotics are often used in managing symptoms of terminal delirium, but evidence is limited. (Observational Study)
Observational Study
CONTEXT
Antipsychotics are often used in managing symptoms of terminal delirium, but evidence is limited.
OBJECTIVES
To explore the comparative effectiveness of haloperidol with as-needed benzodiazepines (HPD) vs. chlorpromazine (CPZ) vs. levomepromazine (LPZ) for agitated delirium in the last days.
METHODS
A prospective observational study was conducted in two palliative care units in Japan. Adult cancer patients who developed agitated delirium with a modified Richmond Agitation-Sedation Scale (RASS-PAL) of one or more were included; palliative care specialist physicians determined that the etiology was irreversible; and estimated survival was 3 weeks or less. Patients treated with HPD, CPZ, or LPZ were analyzed. We measured RASS, NuDESC, Agitation Distress Scale (ADS), and Communication Capacity Scale (CCS) on Days 1 and 3.
RESULTS
A total of 277 patients were enrolled, and 214 were analyzed (112 in HPD, 50 in CPZ, and 52 in LPZ). In all groups, the mean RASS-PAL score significantly decreased on Day 3 (1.37 to -1.01, 1.87 to -1.04, 1.79 to -0.62, respectively; P < 0.001); the NuDESC and ADS scores also significantly decreased. The percentages of patients with moderate to severe agitation and those with full communication capacity on Day 3 were not significantly different. The treatments were well-tolerated. While one-fourth of HPD group changed antipsychotics, 88% or more of CPZ and LPZ groups continued the initial antipsychotics.
CONCLUSION
Haloperidol with as-needed benzodiazepine, chlorpromazine, or levomepromazine may be effective and safe for terminal agitation. Chlorpromazine and levomepromazine may have an advantage of no need to change medications.
Topics: Adult; Humans; Haloperidol; Methotrimeprazine; Chlorpromazine; Antipsychotic Agents; Benzodiazepines; Terminal Care; Delirium
PubMed: 38355071
DOI: 10.1016/j.jpainsymman.2024.02.008 -
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 -
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 -
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 -
Neurotoxicity Research Dec 2022Glioblastoma multiforme is the most common malignant primary brain tumor in adults. Despite new treatments developed including immunomodulation using vaccines and cell...
Glioblastoma multiforme is the most common malignant primary brain tumor in adults. Despite new treatments developed including immunomodulation using vaccines and cell therapies, mortality remains high due to the resistance mechanisms presented by these tumor cells and the function of the blood-brain barrier that prevents the entry of most drugs. In this context of searching for new glioblastoma therapies, the study of the existing drugs to treat neurological disorder is gaining great relevance. The aim of this study was to determine, through a preliminary in vitro study on human glioblastoma (A172, LN229), anaplastic glioma (SF268) and neuroblastoma (SK-N-SH) cell lines, the possible antitumor activity of the active principles of several drugs (levomepromazine, haloperidol, lacosamide, valproic acid, levetiracetam, glatiramer acetate, fingolimod, biperiden and dextromethorphan) with the ability to cross the blood-brain barrier and that are commonly used in neurological disorders. Results showed that levetiracetam, valproic acid, and haloperidol were able to induce a relevant synergistic antitumor effect when associated with the chemotherapy currently used in clinic (temozolomide). Regarding the mechanism of action, haloperidol, valproic acid and levomepromazine caused cell death by apoptosis, while biperiden and dextromethorphan induced autophagy. Fingolimod appeared to have anoikis-related cell death. Thus, the assayed drugs which are able to cross the blood-brain barrier could represent a possibility to improve the treatment of neural tumors, though future in vivo studies and clinical trials will be necessary to validate it.
Topics: Adult; Humans; Glioblastoma; Valproic Acid; Levetiracetam; Methotrimeprazine; Haloperidol; Biperiden; Dextromethorphan; Fingolimod Hydrochloride; Brain Neoplasms; Cell Line, Tumor; Apoptosis
PubMed: 36447028
DOI: 10.1007/s12640-022-00606-3 -
Journal of Applied Toxicology : JAT Apr 2023In this review, we summarized the current literature on the impact of phenothiazine derivatives on autophagy in vitro. Phenothiazines are antipsychotic drugs used in the... (Review)
Review
In this review, we summarized the current literature on the impact of phenothiazine derivatives on autophagy in vitro. Phenothiazines are antipsychotic drugs used in the treatment of schizophrenia, which is related to altered neurotransmission and dysregulation of neuronal autophagy. Thus, phenothiazine derivatives can impact autophagy. We identified 35 papers, where the use of the phenothiazines in the in vitro autophagy assays on normal and cancer cell lines, Caenorhabditis elegans, and zebrafish were discussed. Chlorpromazine, fluphenazine, mepazine, methotrimeprazine, perphenazine, prochlorperazine, promethazine, thioridazine, trifluoperazine, and novel derivatives can modulate autophagy. Stimulation of autophagy by phenothiazines may be either mammalian target of rapamycin (mTOR)-dependent or mTOR-independent. The final effect depends on the used concentration as well as the cell line. A further investigation of the mechanisms of autophagy regulation by phenothiazine derivatives is required to understand the biological actions and to increase the therapeutic potential of this class of drugs.
Topics: Animals; Antipsychotic Agents; Zebrafish; Promazine; Phenothiazines; Chlorpromazine; Mammals
PubMed: 36165981
DOI: 10.1002/jat.4397 -
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 -
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 -
Psychiatria Danubina 2022To assess potential benefits of quetiapine for persistent sleep disturbances in patients with posttraumatic stress disorder (PTSD) on stable combined SSRI and...
Quetiapine Add-On Therapy May Improve Persistent Sleep Disturbances in Patients with PTSD on Stabile Combined SSRI and Benzodiazepine Combination: A One-Group Pretest-Posttest Study.
BACKGROUND
To assess potential benefits of quetiapine for persistent sleep disturbances in patients with posttraumatic stress disorder (PTSD) on stable combined SSRI and benzodiazepine therapy, who previously failed to respond to various benzodiazepine and non-benzodiazepine hypnotic adjuvant treatment as well as to first-generation antipsychotic add-on treatment.
SUBJECTS AND METHODS
Fifty-two male PTSD outpatients on stable combination treatment with SSRI and benzodiazepines, with persistent sleep disturbances not responding to prescription of zolpidem, flurazepam, nitrazepam, promazine, and levopromazine, were assessed for sleep disturbances improvements after prescription of quetiapine in the evening. Each patient met both ICD-10 and DSM-IV criteria for PTSD. Psychiatric comorbidity and premorbidity were excluded using the Mini-International Neuropsychiatric Interview (MINI). Improvement on the CAPS recurrent distressing dream item, reduction in the amount of time needed to fall asleep, prolongation of sleep duration, and reduction in average number of arousals per night in the last 7 days before the assessment period were used as efficacy measures.
RESULTS
All sleep-related parameters improved significantly at the end of a five-week follow-up: sleep duration increased by one hour (p<0.001), sleep latency decreased by 52.5 minutes (p<0.001), median number of arousals per night decreased from two to one (p<0.001), CAPS recurrent distressing dream item median decreased from five to four (p<0.001), and the number of patients dissatisfied with their sleep quality and quantity decreased from 45 to two (p<0.001).
CONCLUSION
Quetiapine prescribed in the evening may be successful therapy for persistent sleep disturbances in patients with PTSD and generally good response to an SSRI and benzodiazepine combination, who previously failed to respond to some of the usual hypnotic medication or addition of first-generation antipsychotics: zolpidem, flurazepam, nitrazepam, promazine, and levopromazine.
Topics: Antipsychotic Agents; Benzodiazepines; Flurazepam; Humans; Hypnotics and Sedatives; Male; Methotrimeprazine; Nitrazepam; Promazine; Quetiapine Fumarate; Sleep; Sleep Wake Disorders; Stress Disorders, Post-Traumatic; Zolpidem
PubMed: 35772134
DOI: 10.24869/psyd.2022.245 -
Supportive Care in Cancer : Official... Dec 2021Nausea and vomiting are a common clinical symptom in the advanced cancer patient. Pharmacologic management is important. Evidence for drug choices and guidelines are...
BACKGROUND
Nausea and vomiting are a common clinical symptom in the advanced cancer patient. Pharmacologic management is important. Evidence for drug choices and guidelines are needed to help clinicians manage nausea and vomiting in this population METHODS: Evidence from a systematic review published in 2010, initial MASCC guidelines developed from a systematic review of literature to 2015, and a new systematic review of randomized trials published between 2015 and February 2, 2021, was combined to establish a new guideline.
RESULTS
A search of the literature between 2015 and February 2, 2021, revealed 257 abstracts of which there was one systematic review and 4 randomized trials which were used to modify the guideline. The new guideline is as follows: First Line: Metoclopramide (II) multiple small RCTs including a placebo-controlled trial, haloperidol (II) multiple non-placebo-controlled RCTs, high consensus. Second line: Methotrimeprazine (II) 1 well-powered non-placebo-controlled RCT, olanzapine (II) 1 placebo-controlled pilot RCT, high consensus. Third line: Tropisetron (II) large unblinded lower quality non-placebo-controlled RCT, levosulpiride (II) 1 blinded non-placebo-controlled pilot RCT, high consensus.
DISCUSSION
Haloperidol, metoclopramide, methotrimeprazine, olanzapine tropisetron, and levosulpiride have been antiemetics used in randomized trials with antiemetic activity demonstrated. There are only three placebo-controlled randomized trials we could find in our literature review. Placebo responses varied significantly between two randomized trials. More randomized placebo-controlled trials with either metoclopramide or haloperidol rescue are needed to clarify antiemetic choices in advanced cancer.
CONCLUSION
First-line antiemetics for nausea and vomiting in advanced cancer are metoclopramide and haloperidol, and second-line medications are methotrimeprazine and olanzapine.
Topics: Antiemetics; Humans; Metoclopramide; Nausea; Neoplasms; Vomiting
PubMed: 34398289
DOI: 10.1007/s00520-021-06437-w