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1.
J Pharmacol Sci ; 140(2): 197-200, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31178327

RESUMO

Antipsychotics are often the first-line treatment for behavioral and psychological symptoms of dementia. However, the potential anticholinergic effects of antipsychotics could counteract the therapeutic effects of cholinesterase inhibitors used to treat dementia. We investigated the inhibitory effects of 26 antipsychotics on [N-Methyl-3H]scopolamine specific binding in mouse cerebral cortex. At 10-5 M, chlorpromazine, levomepromazine, prochlorperazine, timiperone, zotepine, pimozide, blonanserin, olanzapine, quetiapine, and clozapine inhibited [N-Methyl-3H]scopolamine binding by > 45%. Furthermore, the pKi values of chlorpromazine, levomepromazine, zotepine, olanzapine, and clozapine overlapped with their clinically achievable blood concentrations. Therefore, the anticholinergic properties of these antipsychotics could attenuate the effects of cholinesterase inhibitors.


Assuntos
Antipsicóticos/metabolismo , Antipsicóticos/farmacologia , Córtex Cerebral/metabolismo , Antagonistas Colinérgicos/metabolismo , Inibidores da Colinesterase/metabolismo , Receptores Muscarínicos/metabolismo , Escopolamina/metabolismo , Animais , Clorpromazina/farmacologia , Depressão Química , Interações Medicamentosas , Masculino , Metotrimeprazina/farmacologia , Camundongos Endogâmicos , Proclorperazina/farmacologia , Ligação Proteica
2.
Palliat Med ; 33(1): 109-113, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30404581

RESUMO

BACKGROUND:: This case report describes a patient with known idiopathic Parkinson's disease, being managed with transdermal rotigotine, whose refractory nausea and vomiting was successfully controlled with subcutaneous levomepromazine. No drug-induced extrapyramidal side effects emerged. CASE PRESENTATION:: A patient was found to have a locally advanced serous carcinoma, causing secondary bowel obstruction. Furthermore, due to compromised oral access, the patient's oral antiparkinsonian medications for motor control were converted to transdermal rotigotine. Unfortunately, the patient's nausea and vomiting was refractory to a number of recommended antiemetic options. CASE MANAGEMENT:: Low dose levomepromazine was administered on a, 'when required' basis, via subcutaneous injection. CASE OUTCOME:: After the first dose of levomepromazine, the patient's nausea and vomiting completely subsided and no extrapyramidal side effects were observed. This was confirmed by daily assessments, revealing no worsening of the motor symptoms associated with idiopathic Parkinson's disease. CONCLUSIONS:: The pharmacology of rotigotine and levomepromazine appear complementary and may allow for the simultaneous use of both drugs, with favourable outcomes. This case report highlights that rotigotine may afford protection against antipsychotic induced extrapyramidal side effects, while preserving antiemetic effects. Such combinations may have a role in the end-of-life management of idiopathic Parkinson's disease.


Assuntos
Antipsicóticos/uso terapêutico , Metotrimeprazina/uso terapêutico , Náusea/tratamento farmacológico , Náusea/etiologia , Doença de Parkinson/complicações , Tetra-Hidronaftalenos/uso terapêutico , Tiofenos/uso terapêutico , Vômito/tratamento farmacológico , Vômito/etiologia , Administração Cutânea , Idoso , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/uso terapêutico , Antipsicóticos/administração & dosagem , Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/uso terapêutico , Feminino , Humanos , Metotrimeprazina/administração & dosagem , Tetra-Hidronaftalenos/administração & dosagem , Tiofenos/administração & dosagem , Adesivo Transdérmico , Resultado do Tratamento
3.
Early Interv Psychiatry ; 13(3): 589-597, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-29498481

RESUMO

AIM: Early clinical response predicts symptomatic remission and recovery in the maintenance treatment phase of first-episode schizophrenia (FES). However, little is known about predictors of symptomatic remission during acute treatment of severely ill patients with FES. Here, we conducted a secondary analysis of our retrospective observational study, which examined response, remission and treatment-resistance rates in seriously ill patients with FES spectrum disorders involuntarily hospitalized and treated with algorithm-based pharmacotherapy. METHODS: We performed a retrospective chart review of 131 involuntarily admitted patients with schizophrenia or schizoaffective disorder. Our algorithm aimed to delay olanzapine treatment, standardize medications and suggest initiation of clozapine after failure of third-line antipsychotic treatment. The duration of each adequate antipsychotic treatment at an optimal dosage was 4 weeks or more. Remission was defined using the symptom-severity component of consensus remission criteria. A logistic regression model was applied to identify significant predictors of remission at discharge. RESULTS: Overall, 74 patients (56%) were in remission at discharge. Non-remitters were hampered from becoming remitters mainly by the presence of negative symptoms. There were no differences in first-line antipsychotics, dosage of antipsychotics at time of response and adherence rates to algorithm-based pharmacotherapy between remitters and non-remitters. Shorter duration of untreated psychosis, favourable early response and less negative symptoms at baseline were identified as independent predictors of remission at discharge. CONCLUSIONS: The importance of early intervention and specific and adequate treatments of negative symptoms is highlighted.


Assuntos
Algoritmos , Antipsicóticos/uso terapêutico , Internação Compulsória de Doente Mental , Transtornos Psicóticos/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Psicologia do Esquizofrênico , Administração Oral , Adulto , Antipsicóticos/efeitos adversos , Clozapina/efeitos adversos , Clozapina/uso terapêutico , Quimioterapia Combinada , Feminino , Haloperidol/efeitos adversos , Haloperidol/uso terapêutico , Humanos , Injeções Intramusculares , Masculino , Metotrimeprazina/efeitos adversos , Metotrimeprazina/uso terapêutico , Olanzapina/efeitos adversos , Olanzapina/uso terapêutico , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/psicologia , Fumarato de Quetiapina/efeitos adversos , Fumarato de Quetiapina/uso terapêutico , Estudos Retrospectivos , Risperidona/efeitos adversos , Risperidona/uso terapêutico , Esquizofrenia/diagnóstico , Falha de Tratamento , Resultado do Tratamento
4.
J Pharm Biomed Anal ; 158: 294-299, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-29906685

RESUMO

A high-performance liquid chromatography method for the determination of dextromepromazine, levomepromazine sulfoxide and 2-methoxyphenothiazine in levomepromazine samples was developed. The separation of the analytes was achieved within 10 min on a stationary phase containing cellulose tris(4-methylbenzoate) as chiral selector. The mobile phase consisted of 0.1% diethylamine in methanol with a flow rate of 1.0 mL/min. The method was validated according to the International Council for Harmonization guideline Q2(R1). The detection limits based on a signal-to-noise ratio of 3 were in the range of 0.002 to 0.005 µg/mL. The method proved to be precise and accurate in the concentration range of 0.025-1.0 % for levomepromazine sulfoxide and 2-methoxyphenothiazine and 0.025% to 3.0% for dextromepromazine relative to a concentration of 0.1 mg/mL of levomepromazine, with the exception of levomepromazine sulfoxide at the 0.1% level. The method was subsequently applied to the analysis of finished pharmaceutical products as well as of reference substances of the European Pharmacopoeia.


Assuntos
Fracionamento Químico/métodos , Antagonistas de Dopamina/análise , Metotrimeprazina/análise , Benzoatos/química , Celulose/análogos & derivados , Celulose/química , Fracionamento Químico/instrumentação , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Antagonistas de Dopamina/química , Limite de Detecção , Metotrimeprazina/química , Padrões de Referência , Estereoisomerismo
5.
Palliat Med ; 32(7): 1189-1197, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29557260

RESUMO

BACKGROUND: Sedatives are frequently used towards the end of life. However, there is scarce information when their use is labelled as 'palliative sedation'. AIM: To assess the use and labelling of 'continuous administration of sedatives within the last 7 days of life', based on objective operational criteria, on a palliative care unit. DESIGN: Retrospective cohort study, using medical records. Explorative statistical analysis (SPSS 23). SETTING/PARTICIPANTS: Patients who died on a palliative care unit from August 2014 to July 2015. Sedatives recorded were benzodiazepines, levomepromazine, haloperidol ⩾5 mg/day and propofol. RESULTS: Of the 192 patients, 149 (78%) patients received continuous sedatives within the last week of life. The prevalence of delirium/agitation was significantly higher in patients with continuous sedatives compared to those without continuous sedatives at admission to the unit (35% vs 16%, p = 0.02) and on the day before death (58% vs 40%, p = 0.04). The term '(palliative) sedation' was used in the records for 22 of 149 (15%) patients with continuous sedatives. These patients had significantly higher total daily midazolam doses 2 days before death (median (range), 15.0 (6.0-185.0) mg vs 11.5 (1.0-70.0) mg, p = 0.04) and on the day of death (median (range), 19.5 (7.5-240.0) mg vs 12.5 (2.0-65.0) mg, p = 0.01). The dose range was large in both groups. CONCLUSION: The prevalence of delirium/agitation was associated with the administration of continuous sedatives. There was no consistent pattern regarding labelling the use of continuous sedatives as '(palliative) sedation'. Multicentre mixed-methods research is needed for a better characterization of sedation practices in palliative care.


Assuntos
Antipsicóticos/uso terapêutico , Benzodiazepinas/uso terapêutico , Sedação Consciente/métodos , Delírio/tratamento farmacológico , Haloperidol/uso terapêutico , Hipnóticos e Sedativos/uso terapêutico , Metotrimeprazina/uso terapêutico , Cuidados Paliativos/métodos , Agitação Psicomotora/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Delírio/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Agitação Psicomotora/epidemiologia , Estudos Retrospectivos , Assistência Terminal/métodos , Adulto Jovem
6.
J Pharm Biomed Anal ; 146: 402-409, 2017 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-28926734

RESUMO

Using a quality by design approach, a capillary electrophoresis method for the simultaneous determination of dextromepromazine and the oxidation product levomepromazine sulfoxide in levomepromazine was developed. The analytical target profile was defined that the method should be able to quantify 0.1% of both impurities with a precision of ≤10%. Hydroxypropyl-γ-cyclodextrin was used as chiral selector. The critical process parameters cyclodextrin concentration, buffer pH and concentration as well as temperature and applied voltage were studied using a fractional factorial resolution V+ design for defining the knowledge space. A central composite face centered design was used as response surface methodology for deriving the design space by Monte Carlo simulations. The selected working point was a 100mM citric acid buffer, pH 2.85, containing 3.6mg/mL hydroxypropyl-γ-cyclodextrin, a temperature of 15°C and a voltage of 25kV. Robustness was estimated using a Plackett-Burman design. The method was subsequently validated in the relative concentration range of 0.1%-1.0% of the impurities for a solution containing 0.25mg/mL levomepromazine. The method was applied to the determination of the purity of the reference substance of the European Pharmacopoeia and of the drug in a commercial injection solution.


Assuntos
Metotrimeprazina/análogos & derivados , Metotrimeprazina/química , Sulfóxidos/química , Bioensaio/métodos , Cromatografia Capilar Eletrocinética Micelar/métodos , Contaminação de Medicamentos , Concentração de Íons de Hidrogênio , Método de Monte Carlo , Reprodutibilidade dos Testes , gama-Ciclodextrinas/química
7.
Vertex ; 28(136): 411-415, 2017 Nov.
Artigo em Espanhol | MEDLINE | ID: mdl-29522601

RESUMO

INTRODUCTION: Sedation of patients in pediatric ICU extubated and in weaning of mechanic ventilation is diffcult under regular sedation, because of the tolerance and/or abstinence generated by its sustained use. The objective of this study is to describe the use of Levomepromazine as sedative coadjuvant in these patients. POPULATION AND METHODS: Observational and longitudinal study in intensive care from Juan P. Garrahan Pediatric Hospital. Patients older than 2 years were included, extubated and in weaning of mechanic ventilation with requirements of additional sedation. The level of basal sedation and post-intervention (levomepromazine 0.5 mg/kg every 8 hours) were evaluated with Ramsay and Khalil scales. Doses of regular sedatives were compared before and after the indication. It was considered positive an increase of 1 in the scales, or a decrease of 20% in the regular sedatives doses. RESULTS: 36 patients, medium age of 8,5 years, average doses of levomepromazine 0.38 mg/kg. 97% showed positive result. The regular sedative doses were reduced more than 20% after the intervention. No adverse effects or deceased were registered.


Assuntos
Hipnóticos e Sedativos/uso terapêutico , Metotrimeprazina/uso terapêutico , Adolescente , Criança , Pré-Escolar , Quimioterapia Combinada , Humanos , Unidades de Terapia Intensiva Pediátrica
9.
J Mol Model ; 22(10): 237, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27624166

RESUMO

Levomepromazine, an "older" typical neuroleptic, is widely applied in psychiatry for the treatment of schizophrenia. The biotransformation of Levomepromazine remains elusive up to now, but found to result in the formation of different derivatives that may contribute to the therapeutic and/or side-effects of the parent drug. The present work aims to resolve the metabolic details of Levomepromazine catalyzed by cytochrome P450, an important heme-containing enzyme superfamily, based on DFT calculation. Two main metabolic pathways have been addressed, S-oxidation and N-demethylation. The mechanistic conclusions have revealed a stepwise transfer of two electrons mechanism in S-oxidation reaction. N-demethylation is a two-step reaction, including the rate-determining N-methyl hydroxylation which proceeds via the single electron transfer (SET) mechanism and the subsequent C-N bond fission through a water-assisted enzymatic proton-transfer process. N-demethylation is more feasible than S-oxidation due to its lower activation energy and N-desmethyllevomepromazine therefore is the most plausible metabolite of Levomepromazine. Each metabolic pathway proceeds in a spin-selective manner (SSM) mechanism, predominately via the LS state of Cpd I. Our observations are in good accordance with the experimental results, which can provide some general implications for the metabolic mechanism of Levomepromazine-like drugs. Graphical abstract The metabolic mechanisms of levmepromazine by cytochrome P450.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Metotrimeprazina/metabolismo , Catálise , Elétrons , Humanos , Hidroxilação , Redes e Vias Metabólicas/fisiologia , Metotrimeprazina/análogos & derivados , Oxirredução , Prótons
11.
Cochrane Database Syst Rev ; (11): CD009420, 2015 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-26524693

RESUMO

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.


Assuntos
Antieméticos/uso terapêutico , Metotrimeprazina/uso terapêutico , Náusea/tratamento farmacológico , Cuidados Paliativos , Vômito/tratamento farmacológico , Adulto , Antieméticos/efeitos adversos , Feminino , Humanos , Metotrimeprazina/efeitos adversos , Gravidez
12.
Pharmacol Rep ; 67(6): 1178-82, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26481538

RESUMO

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 6ß-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.


Assuntos
Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Metotrimeprazina/farmacologia , Antipsicóticos/farmacologia , Relação Dose-Resposta a Droga , Humanos , Técnicas In Vitro , Isoenzimas/antagonistas & inibidores , Cinética , Fígado/enzimologia
13.
Forensic Sci Int ; 249: 165-72, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25700112

RESUMO

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.


Assuntos
Antipsicóticos/análise , Fixadores , Formaldeído , Rim/química , Fígado/química , Entorpecentes/análise , Preservação de Órgãos/métodos , Adulto , Bromazepam/análise , Clorpromazina/análise , Ciclopropanos/análise , Estabilidade de Medicamentos , Toxicologia Forense , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Masculino , Metanfetamina/análise , Metotrimeprazina/análise , Milnaciprano , N-Metil-3,4-Metilenodioxianfetamina/análise , Prometazina/análise , Fatores de Tempo
15.
Palliat Support Care ; 13(3): 619-24, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24762539

RESUMO

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.


Assuntos
Sedação Consciente/normas , Serviços de Assistência Domiciliar , Neoplasias/terapia , Cuidados Paliativos/métodos , Sedação Consciente/métodos , Estudos Transversais , Feminino , Humanos , Masculino , Metotrimeprazina/uso terapêutico , Midazolam/uso terapêutico , Neoplasias/complicações , Estudos Retrospectivos
16.
Pharmacol Rep ; 66(6): 1122-6, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25443744

RESUMO

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.


Assuntos
Amitriptilina/farmacologia , Carbamazepina/farmacologia , Metotrimeprazina/farmacocinética , Microssomos Hepáticos/metabolismo , Amitriptilina/administração & dosagem , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/farmacologia , Antidepressivos Tricíclicos/administração & dosagem , Antidepressivos Tricíclicos/farmacologia , Antipsicóticos/administração & dosagem , Antipsicóticos/farmacocinética , Carbamazepina/administração & dosagem , Relação Dose-Resposta a Droga , Interações Medicamentosas , Humanos , Técnicas In Vitro , Metotrimeprazina/administração & dosagem
17.
Pharmacology ; 94(5-6): 207-13, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25402013

RESUMO

BACKGROUND: Morphine is co-administered with adjuvant drugs to treat pain, nausea, vomiting, dyspnoea and delirium in cancer patients. AIM OF THE STUDY: To investigate analgesic effects of morphine when co-administered with adjuvant drugs. MATERIAL AND METHODS: Two-month-old male Wistar rats received single morphine doses alone (0.45 and 0.9 mg/kg) or with midazolam (0.3 mg/kg), haloperidol (0.15 and 0.45 mg/kg), levomepromazine (0.35 mg/kg), metoclopramide (1.0 mg/kg), and hyoscine butylbromide (1.7 mg/kg) as single subcutaneous injections. Analgesia was measured by the tail-flick test after 15, 30, 45, 60, and 90 min of drug administration. In the case of significant analgesia enhancement, analgesic and sedative effects were explored in 3-, 5-, 6-, 8-, and 11-month-old rats. RESULTS: Significant morphine (0.9 mg/kg) analgesia enhancement was observed 60 min after haloperidol (0.15 and 0.45 mg/kg) and hyoscine butylbromide co-administration. The addition of haloperidol to morphine significantly increased analgesia in 6-, 8- and 11-month-old rats while in the case of hyoscine butylbromide co-administration this effect was observed only in 11-month-old rats. CONCLUSIONS: Haloperidol and hyoscine butylbromide enhanced morphine analgesia. Future studies may explore the repeated administration of these drug combinations in rats and humans.


Assuntos
Adjuvantes Farmacêuticos/uso terapêutico , Analgésicos Opioides/uso terapêutico , Morfina/uso terapêutico , Dor/tratamento farmacológico , Animais , Brometo de Butilescopolamônio/uso terapêutico , Interações Medicamentosas , Quimioterapia Combinada , Haloperidol/uso terapêutico , Masculino , Metotrimeprazina/uso terapêutico , Metoclopramida/uso terapêutico , Midazolam/uso terapêutico , Ratos Wistar
18.
Nat Chem Biol ; 10(8): 677-85, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24974230

RESUMO

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.


Assuntos
Esclerose Amiotrófica Lateral/metabolismo , Autofagia , Proteínas de Ligação a DNA/metabolismo , Neurônios/metabolismo , Sequência de Aminoácidos , Esclerose Amiotrófica Lateral/patologia , Animais , Astrócitos/metabolismo , Autofagia/efeitos dos fármacos , Sobrevivência Celular , Células Cultivadas , Proteínas de Ligação a DNA/genética , Flufenazina/farmacologia , Meia-Vida , Humanos , Células-Tronco Pluripotentes Induzidas/fisiologia , Metotrimeprazina/farmacologia , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Dados de Sequência Molecular , Mutação , Ratos , Reprodutibilidade dos Testes , Análise de Célula Única/métodos , Bibliotecas de Moléculas Pequenas/farmacologia , Células-Tronco/metabolismo
19.
Biochem Pharmacol ; 90(2): 188-95, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24841887

RESUMO

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.


Assuntos
Antipsicóticos/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Isoenzimas/metabolismo , Fígado/enzimologia , Metotrimeprazina/metabolismo , Microssomos Hepáticos/enzimologia , Biocatálise , Humanos , Inativação Metabólica , Cinética , Fígado/efeitos dos fármacos , Microssomos Hepáticos/efeitos dos fármacos , Especificidade por Substrato
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