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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 -
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 -
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 -
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 -
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 -
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 -
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 -
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