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European Neuropsychopharmacology : the... Oct 2016
Topics: Administration, Rectal; Antipsychotic Agents; Clopenthixol; Clozapine; Constipation; Drug Administration Schedule; Drug Monitoring; Drug Therapy, Combination; Humans; Intensive Care Units; Laxatives; Methotrimeprazine; Plant Gums; Polyethylene Glycols; Severity of Illness Index; Sterculia; Surface-Active Agents
PubMed: 27546374
DOI: 10.1016/j.euroneuro.2016.08.004 -
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 -
The Cochrane Database of Systematic... Nov 2015Nausea and vomiting are common symptoms in patients with terminal, incurable illnesses. Both nausea and vomiting can be distressing. Haloperidol is commonly prescribed... (Review)
Review
BACKGROUND
Nausea and vomiting are common symptoms in patients with terminal, incurable illnesses. Both nausea and vomiting can be distressing. Haloperidol is commonly prescribed to relieve these symptoms. This is an updated version of the original Cochrane review published in Issue 2, 2009, of Haloperidol for the treatment of nausea and vomiting in palliative care patients.
OBJECTIVES
To evaluate the efficacy and adverse events associated with the use of haloperidol for the treatment of nausea and vomiting in palliative care patients.
SEARCH METHODS
For this updated review, we performed updated searches of CENTRAL, EMBASE and MEDLINE in November 2013 and in November 2014. We searched controlled trials registers in March 2015 to identify any ongoing or unpublished trials. We imposed no language restrictions. For the original review, we performed database searching in August 2007, including CENTRAL, MEDLINE, EMBASE, CINAHL and AMED, using relevant search terms and synonyms. Handsearching complemented the electronic searches (using reference lists of included studies, relevant chapters and review articles) for the original review.
SELECTION CRITERIA
We considered randomised controlled trials (RCTs) of haloperidol for the treatment of nausea or vomiting, or both, in any setting, for inclusion. The studies had to be conducted with adults receiving palliative care or suffering from an incurable progressive medical condition. We excluded studies where nausea or vomiting, or both, were thought to be secondary to pregnancy or surgery.
DATA COLLECTION AND ANALYSIS
We imported records from each of the electronic databases into a bibliographic package and merged them into a core database where we inspected titles, keywords and abstracts for relevance. If it was not possible to accept or reject an abstract with certainty, we obtained the full text of the article for further evaluation. The two review authors independently assessed studies in accordance with the inclusion criteria. There were no differences in opinion between the authors with regard to the assessment of studies.
MAIN RESULTS
We considered 27 studies from the 2007 search. In this update we considered a further 38 studies from the 2013 search, and two in the 2014 search. We identified one RCT of moderate quality with low risk of bias overall which met the inclusion criteria for this update, comparing ABH (Ativan®, Benadryl®, Haldol®) gel, applied to the wrist, with placebo for the relief of nausea in 22 participants. ABH gel includes haloperidol as well as diphenhydramine and lorazepam. The gel was not significantly better than placebo in this small study; however haloperidol is reported not to be absorbed significantly when applied topically, therefore the trial does not address the issue of whether haloperidol is effective or well-tolerated when administered by other routes (e.g. by mouth, subcutaneously or intravenously). We identified one ongoing trial of haloperidol for the management of nausea and vomiting in patients with cancer, with initial results published in a conference abstract suggesting that haloperidol is effective for 65% of patients. The trial had not been fully published at the time of our review. A further trial has opened, comparing oral haloperidol with oral methotrimeprazine (levomepromazine) for patients with cancer and nausea unrelated to their treatment, which we aim to include in the next review update.
AUTHORS' CONCLUSIONS
Since the last version of this review, we found one new study for inclusion but the conclusion remains unchanged. There is incomplete evidence from published RCTs to determine the effectiveness of haloperidol for nausea and vomiting in palliative care. Other than the trial of ABH gel vs placebo, we did not identify any fully published RCTs exploring the effectiveness of haloperidol for nausea and vomiting in palliative care patients for this update, but two trials are underway.
Topics: Antiemetics; Diphenhydramine; Gels; Haloperidol; Humans; Lorazepam; Nausea; Palliative Care; Randomized Controlled Trials as Topic; Vomiting
PubMed: 26524474
DOI: 10.1002/14651858.CD006271.pub3 -
Pharmacological Reports : PR Dec 2015Inhibition of cytochrome P450 (CYP) isoenzymes is the most common cause of harmful drug-drug interactions. The present study was aimed at examining the inhibitory effect...
BACKGROUND
Inhibition of cytochrome P450 (CYP) isoenzymes is the most common cause of harmful drug-drug interactions. The present study was aimed at examining the inhibitory effect of the phenothiazine neuroleptic levomepromazine on main CYP isoenzymes in human liver.
METHODS
The experiment was performed in vitro using the human cDNA-expressed CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 (Supersomes). CYP isoenzyme activities were determined using the CYP-specific reactions: caffeine 3-N-demethylation (CYP1A2), diclofenac 4'-hydroxylation (CYP2C9), perazine N-demethylation (CYP2C19), bufuralol 1'-hydroxylation (CYP2D6) and testosterone 6β-hydroxylation (CYP3A4). The rates of the CYP-specific reactions were assessed in the absence and presence of levomepromazine (1-50 μM). The concentrations of CYP-specific substrates and their metabolites formed by CYP isoenzymes were measured by HPLC with UV or fluorimetric detection.
RESULTS
Levomepromazine potently inhibited CYP2D6 (K(i) = 6 μM) in a competitive manner. Moreover, the neuroleptic moderately diminished the activity of CYP1A2 (K(i) = 47 μM) and CYP3A4 (K(i) = 34 μM) via a mixed mechanism. On the other hand, levomepromazine did not affect the activities of CYP2C9 and CYP2C19.
CONCLUSION
The inhibition of CYP1A2, CYP2D6 and CYP3A4 by levomepromazine, demonstrated in vitro in the present study, should also be observed in vivo (especially the CYP2D6 inhibition by levomepromazine), since the calculated K(i) values are below or close to the presumed concentration range for levomepromazine in the liver in vivo. Therefore pharmacokinetic interactions involving levomepromazine and CYP2D6, CYP1A2 or CYP3A4 substrates are likely to occur in patients during co-administration of the above-mentioned substrates/drugs.
Topics: Antipsychotic Agents; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Humans; In Vitro Techniques; Isoenzymes; Kinetics; Liver; Methotrimeprazine
PubMed: 26481538
DOI: 10.1016/j.pharep.2015.04.005 -
Actas Dermo-sifiliograficas 2015
Topics: Brain Injuries, Traumatic; Cheilitis; Chlorpromazine; Dermatitis, Photoallergic; Dopamine Antagonists; Drug Substitution; Eyelid Diseases; Female; Hand Dermatoses; Humans; Irritable Bowel Syndrome; Methotrimeprazine; Middle Aged; Patch Tests
PubMed: 25704376
DOI: 10.1016/j.ad.2014.12.006 -
Forensic Science International Apr 2015Forensic toxicological drug analyses of human specimens are usually performed immediately after autopsy or on frozen preserved tissues. Occasionally, cases require...
Forensic toxicological drug analyses of human specimens are usually performed immediately after autopsy or on frozen preserved tissues. Occasionally, cases require analysis of drugs from tissues fixed in formalin solution. To improve the estimation of the level of drug in tissues following formalin fixation, we studied drug concentrations in human tissues, liver and kidney, that were collected from a drug-positive autopsy case. Parts of tissues were preserved in formalin solution for 1, 3, 6 and 13 months. Tissues obtained before and after preservation, along with tissue-exposed fixatives, were assayed using gas chromatography-mass spectrometry; all of the samples were assayed for the presence of drugs and changes in the drug concentrations both before and after preservation in formalin. Concentrations of assayed drugs decreased upon fixation in formalin; levels of these drugs did not necessarily show further decreases during subsequent storage in fixative, up to 13 months. Distinct trends in drug levels were found in liver and kidney. In liver, the levels of chlorpromazine, levomepromazine, and promethazine decreased to 23-39% at 1 month after preservation; all 3 of these drugs were detected at all tested time points of preservation. Bromazepam was not detected at 13 months after preservation. Milnacipran was the most unstable after preservation in formalin solution among all of the assayed drugs. In kidney, all assayed drugs exhibited reduced stability during preservation compared to levels in liver. Methamphetamine and methylenedioxymethamphetamine were not detected in any time points of tissues. The proportions of the drugs that remained within the tissues differed between liver and kidney. Also, S-oxide compounds of chlorpromazine and levomepromazine, which were not observed before preservation, were detected in fixed liver tissues and their fixatives at 3, 6 and 13 months of preservation. These results suggest that analyses in formalin-fixed tissues need to include analysis of various organ-tissues and their fixatives at multiple time points for the duration of preservation. These analyses should include detection of chemical degradation/denaturation products, such as S-oxides of chlorpromazine and levomepromazine.
Topics: Adult; Antipsychotic Agents; Bromazepam; Chlorpromazine; Cyclopropanes; Drug Stability; Fixatives; Forensic Toxicology; Formaldehyde; Gas Chromatography-Mass Spectrometry; Humans; Kidney; Liver; Male; Methamphetamine; Methotrimeprazine; Milnacipran; N-Methyl-3,4-methylenedioxyamphetamine; Narcotics; Organ Preservation; Promethazine; Time Factors
PubMed: 25700112
DOI: 10.1016/j.forsciint.2015.01.028 -
Pharmacological Reports : PR Dec 2014Joint administration of phenothiazine neuroleptics and an antidepressant or carbamazepine is applied in the therapy of many complex psychiatric disorders. The aim of the...
BACKGROUND
Joint administration of phenothiazine neuroleptics and an antidepressant or carbamazepine is applied in the therapy of many complex psychiatric disorders. The aim of the present study was to investigate possible effects of the tricyclic antidepressant drug amitriptyline and the anticonvulsant drug carbamazepine on the metabolism of the aliphatic-type phenothiazine neuroleptic levomepromazine in human liver.
METHODS
The experiment was performed in vitro using human liver microsomes. The rates of levomepromazine 5-sulfoxidation and N-demethylation (levomepromazine concentrations: 5, 10, 25 and 50μM) were assessed in the absence and presence of amitriptyline or carbamazepine added in vitro (drug concentrations: 1, 2.5, 5, 10, 25μM).
RESULTS
A kinetic analysis of levomepromazine metabolism carried out in the absence or presence of carbamazepine showed that the anticonvulsant drug potently inhibited levomepromazine 5-sulfoxidation (Ki=7.6μM, non-competitive inhibition), and moderately decreased the rate of levomepromazine N-demethylation (Ki=15.4μM, mixed inhibition) at therapeutic drug concentrations. On the other hand, amitriptyline weakly diminished the rate of levomepromazine 5-sulfoxidation (Ki=63μM, mixed inhibition) and N-demethylation (Ki=47.7μM, mixed inhibition).
CONCLUSION
Regarding the central and peripheral effects of levomepromazine and some of its metabolites, the observed metabolic interaction between this neuroleptic and carbamazepine may be of pharmacological and clinical importance.
Topics: Amitriptyline; Anticonvulsants; Antidepressive Agents, Tricyclic; Antipsychotic Agents; Carbamazepine; Dose-Response Relationship, Drug; Drug Interactions; Humans; In Vitro Techniques; Methotrimeprazine; Microsomes, Liver
PubMed: 25443744
DOI: 10.1016/j.pharep.2014.07.012 -
Nature Chemical Biology Aug 2014Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have distinct clinical features but a common pathology--cytoplasmic inclusions rich in transactive...
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have distinct clinical features but a common pathology--cytoplasmic inclusions rich in transactive response element DNA-binding protein of 43 kDa (TDP43). Rare TDP43 mutations cause ALS or FTD, but abnormal TDP43 levels and localization may cause disease even if TDP43 lacks a mutation. Here we show that individual neurons vary in their ability to clear TDP43 and are exquisitely sensitive to TDP43 levels. To measure TDP43 clearance, we developed and validated a single-cell optical method that overcomes the confounding effects of aggregation and toxicity and discovered that pathogenic mutations shorten TDP43 half-life. New compounds that stimulate autophagy improved TDP43 clearance and localization and enhanced survival in primary murine neurons and in human stem cell-derived neurons and astrocytes harboring mutant TDP43. These findings indicate that the levels and localization of TDP43 critically determine neurotoxicity and show that autophagy induction mitigates neurodegeneration by acting directly on TDP43 clearance.
Topics: Amino Acid Sequence; Amyotrophic Lateral Sclerosis; Animals; Astrocytes; Autophagy; Cell Survival; Cells, Cultured; DNA-Binding Proteins; Fluphenazine; Half-Life; Humans; Induced Pluripotent Stem Cells; Methotrimeprazine; Mice; Microtubule-Associated Proteins; Molecular Sequence Data; Mutation; Neurons; Rats; Reproducibility of Results; Single-Cell Analysis; Small Molecule Libraries; Stem Cells
PubMed: 24974230
DOI: 10.1038/nchembio.1563 -
Biochemical Pharmacology Jul 2014The aim of the present study was to identify cytochrome P450 isoenzymes (CYPs) involved in the 5-sulfoxidation and N-demethylation of the aliphatic-type phenothiazine...
The aim of the present study was to identify cytochrome P450 isoenzymes (CYPs) involved in the 5-sulfoxidation and N-demethylation of the aliphatic-type phenothiazine neuroleptic levomepromazine in human liver. Experiments were performed in vitro using cDNA-expressed human CYP isoforms (Supersomes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4), liver microsomes from different donors and CYP-selective inhibitors. The obtained results indicate that CYP3A4 is the main isoform responsible for levomepromazine 5-sulfoxidation (72%) and N-demethylation (78%) at a therapeutic concentration of the drug (10μM). CYP1A2 contributes to a lesser degree to levomepromazine 5-sulfoxidation (20%). The role of CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1 in catalyzing the above-mentioned reactions is negligible (0.1-8%). Moreover, at a higher, toxicological concentration of the neuroleptic (100μM), the relative contribution of CYP1A2 to levomepromazine metabolism visibly increases (from 20% to 28% for 5-sufoxidation, and from 8% to 32% for N-demethylation), while the role of CYP3A4 significantly decreases (from 72% to 59% for 5-sulfoxidation, and from 78% to 47% for N-demethylation). The obtained results indicate that the catalysis of levomepromazine 5-sulfoxidation and N-demethylation in humans shows a strict CYP3A4 preference, especially at a therapeutic drug concentration. Hence pharmacokinetic interactions involving levomepromazine and CYP3A4 substrates (e.g. tricyclic antidepressants, calcium channel antagonists, macrolide antibiotics, testosterone), inhibitors (e.g. ketoconazole, erythromycin, SSRIs) or inducers (e.g. rifampicin, carbamazepine) are likely to occur.
Topics: Antipsychotic Agents; Biocatalysis; Cytochrome P-450 Enzyme System; Humans; Inactivation, Metabolic; Isoenzymes; Kinetics; Liver; Methotrimeprazine; Microsomes, Liver; Substrate Specificity
PubMed: 24841887
DOI: 10.1016/j.bcp.2014.05.005 -
Palliative & Supportive Care Jun 2015Palliative sedation is a common treatment in palliative care. The home is a difficult environment for research, and there are few studies about sedation at home. Our aim...
OBJECTIVE
Palliative sedation is a common treatment in palliative care. The home is a difficult environment for research, and there are few studies about sedation at home. Our aim was to analyze this practice in a home setting.
METHOD
We conducted a retrospective cross-sectional descriptive study in a home cohort during 2011. The inclusion criteria were as follows: 18 years or older and enrolled in the Palliative Home Care Program (PHCP) with advanced cancer. The variables employed were: sex, age, primary tumor location, and place of death. We also registered indication, type, drug and dose, awareness of diagnosis and prognosis, consent, survival, presence or absence of rales, painful mouth, and ulcers in patients sedated at home. We also collected the opinions of family members and professionals about the suffering of sedated patients.
RESULTS
A total of 446 patients (56% at home) of the 617 admitted to the PHCP between January and December of 2011 passed away. The typical patient in our population was a 70-year-old man with a lung tumor. Some 35 (14%) home patients required sedation, compared to 93 (49%) at the hospital. The most frequent indication was delirium (70%), with midazolam the most common drug (mean dose, 40 mg). Survival was around three days. Rales were frequent (57%) as well as awareness of diagnosis and prognosis (77 and 71%, respectively). Perception of suffering after sedation was rare among relatives (17%) and professionals (8%). In most cases, the decision was made jointly by professionals and family members.
SIGNIFICANCE OF RESULTS
Our study confirmed the role of palliative sedation as an appropriate therapeutic tool in the home environment.
Topics: Conscious Sedation; Cross-Sectional Studies; Female; Home Care Services; Humans; Male; Methotrimeprazine; Midazolam; Neoplasms; Palliative Care; Retrospective Studies
PubMed: 24762539
DOI: 10.1017/S1478951514000200