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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 -
Neuropsychopharmacologia Hungarica : a... Sep 2012Main indication for antipsychotic medication is the treatment of schizophrenia and other psychotic disorders. Influential protocols in the treatment of schizophrenia... (Review)
Review
Main indication for antipsychotic medication is the treatment of schizophrenia and other psychotic disorders. Influential protocols in the treatment of schizophrenia recommend the use of antipsychotics in monotherapy. In case of therapy resistance, combination of antipsychotics is a feasible option. Applying antipsychotics in combination is common in clinical practice, although existing efficacy and safety data concerning antipsychotic combinations are scarce. Authors, after reviewing existing scientific data, make attempt to give recommendations for combined antipsychotic therapy in everyday clinical practice.
Topics: Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Haloperidol; Humans; Methotrimeprazine; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome
PubMed: 22987732
DOI: No ID Found -
Journal of Korean Medical Science Nov 2010Two schizophrenic patients who had been taking medication for a long period presented with visual disturbance of 6-month duration. Slit-lamp examination revealed fine,...
Two schizophrenic patients who had been taking medication for a long period presented with visual disturbance of 6-month duration. Slit-lamp examination revealed fine, discrete, and brownish deposits on the posterior cornea. In addition, bilateral star-shaped anterior subcapsular lens opacities, which were dense, dust-like granular deposits, were noted. Although we strongly suspected that the patient might have taken one of the drugs of the phenothiazine family, we were unable to obtain a history of medications other than haloperidol and risperidone, which were taken for 3 yr. We performed a drug profiling test using urine samples and detected methotrimeprazine. The patient underwent surgery for anterior subcapsular lens opacities. Visual acuity improved in both eyes, but the corneal deposits remained. We report an unusual case of methotrimeprazine-induced corneal deposits and cataract in a patient with psychosis, identified by using the urine drug profiling test.
Topics: Adult; Antipsychotic Agents; Cataract; Corneal Diseases; Female; Humans; Intellectual Disability; Male; Methotrimeprazine; Middle Aged; Schizophrenia; Visual Acuity
PubMed: 21060765
DOI: 10.3346/jkms.2010.25.11.1688 -
Canadian Medical Association Journal Apr 1983
Topics: Anxiety; Burns; Humans; Methotrimeprazine; Pain
PubMed: 6831331
DOI: No ID Found -
BMJ Supportive & Palliative Care Sep 2020Anticipatory prescribing (AP) of injectable medications in advance of clinical need is established practice in community end-of-life care. Changes to prescribing...
BACKGROUND
Anticipatory prescribing (AP) of injectable medications in advance of clinical need is established practice in community end-of-life care. Changes to prescribing guidelines and practice have been reported during the COVID-19 pandemic.
AIMS AND OBJECTIVES
To investigate UK and Ireland clinicians' experiences concerning changes in AP during the COVID-19 pandemic and their recommendations for change.
METHODS
Online survey of participants at previous AP national workshops, members of the Association for Palliative Medicine of Great Britain and Ireland and other professional organisations, with snowball sampling.
RESULTS
Two hundred and sixty-one replies were received between 9 and 19 April 2020 from clinicians in community, hospice and hospital settings across all areas of the UK and Ireland. Changes to AP local guidance and practice were reported: route of administration (47%), drugs prescribed (38%), total quantities prescribed (35%), doses and ranges (29%). Concerns over shortages of nurses and doctors to administer subcutaneous injections led 37% to consider drug administration by family or social caregivers, often by buccal, sublingual and transdermal routes. Clinical contact and patient assessment were more often remote via telephone or video (63%). Recommendations for regulatory changes to permit drug repurposing and easier community access were made.
CONCLUSIONS
The challenges of the COVID-19 pandemic for UK community palliative care has stimulated rapid innovation in AP. The extent to which these are implemented and their clinical efficacy need further examination.
Topics: Administration, Buccal; Administration, Sublingual; Analgesics, Non-Narcotic; Analgesics, Opioid; Betacoronavirus; COVID-19; Caregivers; Coronavirus Infections; Drug Administration Routes; Fentanyl; General Practitioners; Hospice Care; Hospices; Humans; Hypnotics and Sedatives; Ireland; Lorazepam; Methotrimeprazine; Muscarinic Antagonists; Nurse Specialists; Palliative Care; Palliative Medicine; Pandemics; Physicians; Pneumonia, Viral; Practice Guidelines as Topic; Practice Patterns, Physicians'; SARS-CoV-2; Surveys and Questionnaires; Telemedicine; Terminal Care; Transdermal Patch; United Kingdom
PubMed: 32546559
DOI: 10.1136/bmjspcare-2020-002394 -
Journal of Pediatric Intensive Care Jun 2014Sedation and analgesia using opioids and benzodiazepines is frequently required in critically ill children to minimize pain and anxiety. In some patients, difficult...
Sedation and analgesia using opioids and benzodiazepines is frequently required in critically ill children to minimize pain and anxiety. In some patients, difficult sedation occurs when tolerance or unacceptable side effects limit the efficacy of conventional analgo-sedative treatment. We describe seven patients (age range 1 to 17 yr) where difficult sedation was successfully managed with enteral levomepromazine (LMZ). LMZ is a neuroleptic antipsychotic agent that exhibits potent analgo-sedative properties without respiratory depression, through non-opioid and non-benzodiazepine pathways. We describe its use in our pediatric intensive care unit to control agitation in patients with known behavioral disorders who frequently pose a significant sedation challenge. We also illustrate its successful use in cases of withdrawal syndrome and delirium, and discuss the association of fever and its distinction from neuroleptic malignant syndrome in two patients. LMZ should be considered as a useful sedative in critically ill children where difficult sedation occurs and conventional agents are exhausted.
PubMed: 31214452
DOI: 10.3233/PIC-14089 -
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 -
Acta Cirurgica Brasileira 2005This study aimed at quantifies the pain in dogs under dissociative anesthesia, across thermal and pressoric stimulus and quantify the reasonable period between two...
[The algimetry evaluation by thermic and pressoric nociceptive stimulus in dogs pre treated with methotrimeprazine, midazolam and ketamine with or without butorphanol or buprenorphine].
PURPOSE
This study aimed at quantifies the pain in dogs under dissociative anesthesia, across thermal and pressoric stimulus and quantify the reasonable period between two different opioids analgesics.
METHODS
In this study, 30 dogs were used and, divided into three groups of 10 animals each, in which the animals of GI received methotrimeprazine and midazolam put on the same syringe with ketamine. The animals of GII received the same treatment of GI but associated with butorphanol and finally the animals of GIII received the same treatment of GI but associated with buprenorphine. The routine parametric evaluations has been proceeded, although using the thermo algimetry measured in degrees C with the average of 52 degrees C and the pressoric algimetry in Kg.
RESULTS
In the thermo algimetry, there has been significant difference in GI at the moments M0, M1, M4 and M5; in GII it was found at M0, M1, M5 and M6 and in GIII it was observed the significant at M0 and M1. It has also been shown in pressoric algimetry significant difference in GI at the moments M0, M2 and M3. Among GII it has observed significant difference at all moments and it has found at M0, M9 in GIII. Thus, it has observed significant differences between all groups; for such the M2 of GII smaller than the others; and M4, M5 of GIII bigger than GI and GII. In the assessment of all periods it was observed significant latent period bigger in GI, however, with reasonable period and short recovery in GII and GIII. In the order hand, the postural tonus recovery it was longer in GIII, followed by GII and finally GI.
CONCLUSION
The used method for the measurement of algic stimulus was efficient, noticing a reasonable analgesic period of 3 hours for butorphanol and 6 hours for buprenorphine.
Topics: Analgesics; Animals; Buprenorphine; Butorphanol; Dogs; Drug Therapy, Combination; Female; Ketamine; Male; Methotrimeprazine; Midazolam; Pain Measurement; Pressure; Temperature
PubMed: 15810464
DOI: 10.1590/s0102-86502005000100007 -
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