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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 -
The Cochrane Database of Systematic... Oct 2010Levomepromazine is an 'older' typical antipsychotic medication licensed for use in schizophrenia but sparingly prescribed in the United Kingdom. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Levomepromazine is an 'older' typical antipsychotic medication licensed for use in schizophrenia but sparingly prescribed in the United Kingdom.
OBJECTIVES
To determine the clinical effects and safety of levomepromazine compared with placebo or antipsychotic medications for schizophrenia and schizophreniform psychoses.
SEARCH STRATEGY
We searched the Cochrane Schizophrenia Group's Register (December 2008) which is based on regular searches of, amongst others, BIOSIS, CENTRAL CINAHL, EMBASE, MEDLINE and PsycINFO. References of all identified studies were inspected for further trials. We also contacted relevant pharmaceutical companies for additional information.
SELECTION CRITERIA
All randomised trials comparing levomepromazine with placebo or other antipsychotics for schizophrenia and schizophreniform psychoses were included.
DATA COLLECTION AND ANALYSIS
Data were extracted independently. For dichotomous outcomes, we calculated relative risk (RR) (random-effects model), 95% confidence intervals (CI) and, where appropriate, number needed to treat (NNT) was calculated. We avoided the use of number needed to harm (NNH), as an alternative we used number needed to treat for an additional beneficial outcome (NNTB) and number needed to treat for an additional harmful outcome (NNTH) to indicate the direction of effect. For continuous outcomes, we calculated weighted mean differences (WMD).
MAIN RESULTS
The review currently includes 4 RCTs with 192 participants. For our primary outcome of leaving the study early, levomepromazine was not significantly different compared with other antipsychotics. The levomepromazine arm was significantly better on CGI severity compared with chlorpromazine (n=38, 1 RCT, WMD -0.80 CI -1.51 to -0.09). Risperidone was better for CGI endpoint scores (n=42, 1 RCT, RR 2.33 CI 1.11 to 4.89, NNT 3 CI 2 to 10) compared with levomepromazine. Recipients given levomepromazine had a better BPRS endpoint score (n=38, 1 RCT, WMD -9.00, CI -17.46 to -0.54) and PANSS total score (n=38, 1 RCT, WMD -15.90, CI -30.30 to -1.50) than chlorpromazine. Risperidone recipients noticed a significant difference for the outcome 'at least 20% reduction' on BPRS endpoint score (n=42, 1 RCT, RR 3.33 CI 1.07 to 10.42, NNT 3 CI 2 to 14) compared with levomepromazine. Levomepromazine caused less tremor (n=41, 1 RCT RR 0.12 CI 0.02 to 0.87 NNTB 3 CI 2 to 8), less antiparkinsonian medication administration (n=79, 2 RCTs, RR 0.39 CI 0.17 to 0.90, NNTB 5, CI 2 to 21) compared with haloperidol. Levomepromazine caused less akathisia compared with chlorpromazine, but more hypotension compared with risperidone (n=42, 1 RCT, RR 2.50 CI 1.21 to 5.18, NNTH 3, CI 2 to 7). Dizziness was common with levomepromazine compared with other antipsychotic medications.
AUTHORS' CONCLUSIONS
Available data does not enable us to confidently comment on the effectiveness of levomepromazine for schizophrenia. Larger, more robust, studies comparing levomepromazine with other antipsychotics including clozapine are much needed.
Topics: Antipsychotic Agents; Chlorpromazine; Humans; Methotrimeprazine; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia
PubMed: 20927765
DOI: 10.1002/14651858.CD007779.pub2 -
Schizophrenia Bulletin Mar 2012
Meta-Analysis Review
Topics: Antipsychotic Agents; Humans; Methotrimeprazine; Psychotic Disorders; Schizophrenia
PubMed: 22114097
DOI: 10.1093/schbul/sbr174 -
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 -
Canadian Journal of Veterinary Research... Apr 2001The effects of atropine and methotrimeprazine on epinephrine-induced ventricular arrhythmias were evaluated in halothane-anesthetized dogs. Ten mixed-breed dogs were...
The effects of atropine and methotrimeprazine on epinephrine-induced ventricular arrhythmias were evaluated in halothane-anesthetized dogs. Ten mixed-breed dogs were assigned to 3 treatments (saline, atropine, and methotrimeprazine) in a randomized complete block design. Anesthesia was induced and maintained with halothane (1.5 minimum alveolar concentration) in oxygen. Controlled ventilation was used throughout to maintain eucapnia. Saline, atropine (0.05 mg/kg, i.v.) or methotrimeprazine (0.5 mg/kg, i.v.) were administered and, 5 minutes later the arrhythmogenic dose of epinephrine (ADE) was measured by i.v. infusion of progressively increasing infusion rates of epinephrine, until the ventricular arrhythmia criterion was met (at least 4 ectopic ventricular contractions (EVCs) during a 15-second period). Data were analyzed using a student's t-test for ADE values and multivariate profile analysis for heart rate (HR), arterial blood pressure (ABP), and rate pressure product (RPP). The ADE increased in atropine- and methotrimeprazine-treated groups, whereas 1 and 4 animals from these groups did not develop any ventricular arrhythmia, respectively. Epinephrine induced multiform premature ventricular contractions (PVCs) in the atropine group, whereas ventricular escape beats were observed in the control and methotrimeprazine groups. Heart rate and RPP decreased, and ABP increased at the time of ADE observation in the control group. Epinephrine infusion in the atropine group caused marked increases in HR, ABP, and RPP, which were associated with pulsus alternans in 2 animals. It was concluded that 1) the presence of cholinergic blockade influences the type of ventricular arrhythmia induced by epinephrine; 2) increased ADE values recorded following atropine administration must be cautiously interpreted, since in this situation the PVCs were associated with signs of increased myocardial work and ventricular failure; and 3) the use of a broader arrhythmia criterion (EVCs instead of PVCs) may not allow a direct comparison between ADE values, since it includes ventricular arrhythmias mediated by different mechanisms.
Topics: Analgesics, Non-Narcotic; Anesthetics, Inhalation; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atropine; Blood Pressure; Dog Diseases; Dogs; Electrocardiography; Epinephrine; Female; Halothane; Heart Rate; Infusions, Parenteral; Male; Methotrimeprazine; Random Allocation
PubMed: 11346256
DOI: No ID Found -
The Cochrane Database of Systematic... Nov 2015This is an updated version of the original Cochrane Review published in Issue 4, 2013, on Levomepromazine for nausea and vomiting in palliative care.Nausea and vomiting... (Review)
Review
BACKGROUND
This is an updated version of the original Cochrane Review published in Issue 4, 2013, on Levomepromazine for nausea and vomiting in palliative care.Nausea and vomiting are common, distressing symptoms for patients receiving palliative care. There are several drugs which can be used to treat these symptoms, known as antiemetics. Levomepromazine is an antipsychotic drug is commonly used as an antiemetic to alleviate nausea and vomiting in palliative care settings.
OBJECTIVES
To evaluate the efficacy of, and adverse events associated with, levomepromazine for the treatment of nausea and vomiting in palliative care patients.
SEARCH METHODS
For this update we searched electronic databases, including those of Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE, up to February 2015. We searched clinical trial registers on 7 October 2015 for ongoing trials.
SELECTION CRITERIA
Randomised controlled trials of levomepromazine for the treatment of nausea or vomiting, or both, in adults receiving palliative care. We excluded studies in which symptoms were thought to be due to pregnancy or surgery.
DATA COLLECTION AND ANALYSIS
We assessed the potential relevance of studies based on titles and abstracts. We obtained copies of any study reports that appeared to meet the inclusion criteria for further assessment. At least two review authors read each paper to determine suitability for inclusion and discussed discrepancies in order to achieve a consensus.
MAIN RESULTS
In the original review, we identified 421 abstracts using the search strategy. We considered eight studies for inclusion but ultimately excluded them all from the review. We updated the search in February 2015 and identified 35 abstracts, but again none met the inclusion criteria. We identified two trials from clinical trial registers, one of which is ongoing and one of which was closed due to poor recruitment.
AUTHORS' CONCLUSIONS
As in the initial review, we identified no published randomised controlled trials examining the use of levomepromazine for the management of nausea and vomiting in adults receiving palliative care, and our conclusion (that further studies of levomepromazine and other antiemetic agents are needed to provide better evidence for their use in this setting) remains unchanged. We did, however, identify one ongoing study that we hope will contribute to the evidence base for this intervention in future updates of this review.
Topics: Adult; Antiemetics; Female; Humans; Methotrimeprazine; Nausea; Palliative Care; Pregnancy; Vomiting
PubMed: 26524693
DOI: 10.1002/14651858.CD009420.pub3 -
Acta Cirurgica Brasileira 2006To evaluate the parameters of dogs anesthetized by different dissociative drugs protocols through continuous intravenous infusion.
PURPOSE
To evaluate the parameters of dogs anesthetized by different dissociative drugs protocols through continuous intravenous infusion.
METHODS
Thirty healthy dogs of both sexes were assigned randomly to three groups (G1, G2, and G3). G1 was administered with methotrimeprazine as a pre-anesthetic medication, intravenously midazolam-ketamine as bolus for induction and midazolam-ketamine by continuous intravenous infusion for a 60 minute-period of maintenance. G2: the same as for G1. plus an increase in the midazolam dose during maintenance. G3: the same treatment as for G2, plus the addition of xylazine during maintenance. Immediately after induction the anesthetic maintenance started, and measures were taken 15 minutes after pre-medication, at 10 minutes intervals, during maintenance (M0 to M7).
RESULTS
Bradycardia, atrioventricular blockage, bradypnea and hypoxemia were shown in G3. G1 and G2 showed a slight hypotension only.
CONCLUSION
There were some advantages by using the continuous intravenous via: no parameters oscillation and reduction in the anesthetic recovery period. The increase in midazolam dose brought about little parametric variations which were greater when xylazine was used, with a consequent hypoxemia, bradyarrhytmia, and decrease in respiratory frequency and minute volume.
Topics: Anesthesia Recovery Period; Anesthesia, Intravenous; Anesthetics, Combined; Anesthetics, Intravenous; Animals; Blood Pressure; Body Temperature; Dogs; Female; Heart Rate; Ketamine; Male; Methotrimeprazine; Midazolam; Preanesthetic Medication; Random Allocation; Time Factors; Xylazine
PubMed: 16981033
DOI: No ID Found -
Journal of Pain and Symptom Management Jun 2009
Topics: Aged; Analgesics, Non-Narcotic; Antipsychotic Agents; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Lupus Erythematosus, Systemic; Methotrimeprazine; Palliative Care
PubMed: 19500717
DOI: 10.1016/j.jpainsymman.2008.12.001 -
British Journal of Anaesthesia May 1983Interactions between morphine and methotrimeprazine have been studied in mice and man with respect to analgesia or antinociceptive activity, respiratory effects and... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Interactions between morphine and methotrimeprazine have been studied in mice and man with respect to analgesia or antinociceptive activity, respiratory effects and sedation. The volunteer study was a double-blind cross-over trial with 10 volunteers. In mice, methotrimeprazine only possessed antinociceptive activity in doses which caused marked sedation. However, small non-sedative doses of methotrimeprazine potentiated the analgesic action of morphine. The volunteer study did not confirm this finding in man. Methotrimeprazine 7.5 mg i.m. caused significant sedation, but did not alter the effects of morphine 5 mg on pain threshold or ventilatory response to carbon dioxide.
Topics: Adult; Analgesia; Animals; Drug Synergism; Female; Humans; Hypnotics and Sedatives; Male; Methotrimeprazine; Mice; Morphine; Motor Activity; Pain; Reaction Time; Respiration; Sensory Thresholds
PubMed: 6849726
DOI: 10.1093/bja/55.5.437