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1.
Molecules ; 24(18)2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31505754

RESUMO

Novel derivatives of some non steroidal anti-inflammatory drugs, as well as of the antioxidants α-lipoic acid, trolox and (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid with lorazepam were synthesised by a straightforward method at satisfactory to high yields (40%-93%). All the tested derivatives strongly decreased lipidemic indices in rat plasma after Triton induced hyperlipidaemia. They also reduced acute inflammation and a number of them demonstrated lipoxygenase inhibitory activity. Those compounds acquiring antioxidant moiety were inhibitors of lipid peroxidation and radical scavengers. Therefore, the synthesised compounds may add to the current knowledge about multifunctional agents acting against various disorders implicating inflammation, dyslipidaemia and oxidative stress.


Assuntos
Hiperlipidemias/tratamento farmacológico , Inflamação/tratamento farmacológico , Lorazepam/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Acrilatos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Carragenina/química , Carragenina/farmacologia , Cromanos/química , Cromanos/farmacologia , Humanos , Hiperlipidemias/patologia , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Inibidores de Lipoxigenase/farmacologia , Lorazepam/análogos & derivados , Ratos , Ácido Tióctico/análogos & derivados , Ácido Tióctico/farmacologia
2.
Forensic Sci Int ; 303: 109959, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31546164

RESUMO

The organ distribution of 3-fluorophenmetrazine (3-FPM), pyrazolam, diclazepam as well as its main metabolites delorazepam, lormetazepam and lorazepam, was investigated. A solid phase extraction (SPE) and a QuEChERS (acronym for quick, easy, cheap, effective, rugged and safe) - approach were used for the extraction of the analytes from human tissues, body fluids and stomach contents. The detection was performed on a liquid chromatography-tandem mass spectrometry system (LCMS/MS). The analytes of interest were detected in all body fluids and tissues. Results showed femoral blood concentrations of 10 µg/L for 3-FPM, 28 µg/L for pyrazolam, 1 µg/L for diclazepam, 100 µg/L for delorazepam, 6 µg/L for lormetazepam, and 22 µg/L for lorazepam. Tissues (muscle, kidney and liver) and bile exhibited higher concentrations of the mentioned analytes than in blood. Additional positive findings in femoral blood were for 2-fluoroamphetamine (2-FA, approx. 89 µg/L), 2-flourometamphetamine (2-FMA, hint), methiopropamine (approx. 2.2 µg/L), amphetamine (approx. 21 µg/L) and caffeine (positive). Delorazepam showed the highest ratio of heart (C) and femoral blood (P) concentration (C/P ratio = 2.5), supported by the concentrations detected in psoas muscle (430 µg/kg) and stomach content (approx. 210 µg/L, absolute 84 µg). The C/P ratio indicates that delorazepam displays susceptibility for post-mortem redistribution (PMR), supported by the findings in muscle tissue. 3-FPM, pyrazolam, diclazepam, lorazepam and lormetazepam did apparently not exhibit any PMR. The cause of death, in conjunction with autopsy findings was concluded as a positional asphyxia promoted by poly-drug intoxication by arising from designer benzodiazepines and the presence of synthetic stimulants.


Assuntos
Benzodiazepinas/farmacocinética , Drogas Desenhadas/farmacocinética , Diazepam/análogos & derivados , Fenmetrazina/análogos & derivados , Mudanças Depois da Morte , Adulto , Benzodiazepinas/análise , Bile/química , Líquidos Corporais/química , Química Encefálica , Drogas Desenhadas/análise , Diazepam/análise , Diazepam/farmacocinética , Toxicologia Forense , Conteúdo Gastrointestinal/química , Humanos , Rim/química , Fígado/química , Lorazepam/análogos & derivados , Lorazepam/análise , Lorazepam/farmacocinética , Pulmão/química , Masculino , Nordazepam/análogos & derivados , Nordazepam/análise , Nordazepam/farmacocinética , Líquido Pericárdico/química , Fenmetrazina/análise , Fenmetrazina/farmacocinética , Músculos Psoas/química , Espectrometria de Massas em Tandem
6.
Int J Legal Med ; 131(4): 979-988, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28160051

RESUMO

Designer benzodiazepines (DBZDs) have become of particular importance in the past few years. The metabolite monitoring of DBZD in biological fluids could be of great interest in clinical and forensic toxicology. However, DBZD metabolites are not known or not commercially available. The identification of some DBZD metabolites has been mostly explored by self-administration studies or by in vitro studies followed by high-resolution mass spectrometry. The question arose whether a unit resolution instrument could be efficient enough to allow the identification of DBZD metabolites. In this study, we used an in vitro experiment where eight DBZDs (diclazepam, flubromazepam, etizolam, deschloroetizolam, flubromazolam, nifoxipam, meclonazepam and clonazolam) were incubated with human liver microsomes (HLMs) and metabolite identification was carried out by using a UHPLC coupled to a QTRAP triple quadrupole linear iontrap tandem mass spectrometer system. Post-mortem samples obtained from a real poisoning case, involving deschloroetizolam and diclazepam, were also analysed and discussed. Our study using HLM allowed the identification of 26 metabolites of the 8 DBZDs. These were denitro-, mono- or di-hydroxylated and desmethyl metabolites. In the forensic case, diclazepam was not detected whereas its metabolites (lormetazepam and lorazepam) were present at high concentrations in urine. We also identified hydroxy-deschloroetizolam in urine, while the parent compound was not detected in this matrix. This supports the approach that LC coupled to a simple QTRAP could be used by laboratories to identify other not-known/not-commercialized new psychoactive substance (NPS) metabolites.


Assuntos
Benzodiazepinas/química , Drogas Desenhadas/química , Microssomos Hepáticos/química , Adulto , Benzodiazepinas/análise , Cromatografia Líquida , Drogas Desenhadas/análise , Humanos , Lorazepam/análogos & derivados , Lorazepam/urina , Masculino , Oxazepam/urina , Transtornos Relacionados ao Uso de Substâncias/urina , Espectrometria de Massas em Tandem
7.
Compr Psychiatry ; 69: 211-5, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27423363

RESUMO

OBJECTIVE: The use of benzodiazepines (BDZs) represents a critical issue since a long-term treatment may lead to dependence. This study aimed at evaluating socio-demographic and clinical characteristics of BZD long-term users who followed a detoxification program at a tertiary care center. METHOD: Two hundred-five inpatients were evaluated. Socio-demographic (e.g., gender, age, education) and clinical information (e.g., BZD used, dose, reason of prescription) was collected. BZDs dose was standardized as diazepam dose equivalents and was compared via the Defined Daily Dose (DDD). Chi-square, Fisher test, ANOVA and Bonferroni analyses were performed. RESULTS: Females were more frequently BDZ long-term users than males. Hypnotic BZDs were frequently prescribed for problems different from sleep disturbances. Lorazepam, alprazolam, and lormetazepam were the most prescribed drugs. Lorazepam was more frequently used by males, consumed for a long period, in pills, and prescribed for anxiety. Lormetazepam was more frequently consumed by females with a high school education, having a psychiatric disorder, taken in drops and prescribed for insomnia. Lormetazepam had the highest DDD. CONCLUSION: A specific profile of BZD long-term user seems to exist and presents different socio-demographic and clinical characteristics according to the benzodiazepine taken into account.


Assuntos
Benzodiazepinas/efeitos adversos , Benzodiazepinas/uso terapêutico , Assistência de Longa Duração , Transtornos Relacionados ao Uso de Substâncias/psicologia , Transtornos Relacionados ao Uso de Substâncias/reabilitação , Adulto , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/psicologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Lorazepam/análogos & derivados , Lorazepam/uso terapêutico , Masculino , Pessoa de Meia-Idade , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Distúrbios do Início e da Manutenção do Sono/psicologia , Transtornos Relacionados ao Uso de Substâncias/diagnóstico , Centros de Atenção Terciária
8.
Anal Chim Acta ; 878: 78-86, 2015 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-26002328

RESUMO

The recent technological advancements of liquid chromatography-tandem mass spectrometry allow the simultaneous determination of tens, or even hundreds, of target analytes. In such cases, the traditional approach to quantitative method validation presents three major drawbacks: (i) it is extremely laborious, repetitive and rigid; (ii) it does not allow to introduce new target analytes without starting the validation from its very beginning and (iii) it is performed on spiked blank matrices, whose very nature is significantly modified by the addition of a large number of spiking substances, especially at high concentration. In the present study, several predictive chemometric models were developed from closed sets of analytes in order to estimate validation parameters on molecules of the same class, but not included in the original training set. Retention time, matrix effect, recovery, detection and quantification limits were predicted with partial least squares regression method. In particular, iterative stepwise elimination, iterative predictors weighting and genetic algorithms approaches were utilized and compared to achieve effective variables selection. These procedures were applied to data reported in our previously validated ultra-high performance liquid chromatography-tandem mass spectrometry multi-residue method for the determination of pharmaceutical and illicit drugs in oral fluid samples in accordance with national and international guidelines. Then, the partial least squares model was successfully tested on naloxone and lormetazepam, in order to introduce these new compounds in the oral fluid validated method, which adopts reverse-phase chromatography. Retention time, matrix effect, recovery, limit of detection and limit of quantification parameters for naloxone and lormetazepam were predicted by the model and then positively compared with their corresponding experimental values. The whole study represents a proof-of-concept of chemometrics potential to reduce the routine workload during multi-residue methods validation and suggests a rational alternative to ever-expanding procedures progressively drifting apart from real sample analysis.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas em Tandem/métodos , Humanos , Hipnóticos e Sedativos/análise , Análise dos Mínimos Quadrados , Limite de Detecção , Lorazepam/análogos & derivados , Lorazepam/análise , Naloxona/análise , Antagonistas de Entorpecentes/análise , Estudos de Validação como Assunto
10.
J Anal Toxicol ; 38(3): 171-6, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24488113

RESUMO

This study examined the potential of abalone ß-glucuronidase as a viable and cost effective alternative to current hydrolysis procedures using acid, Helix pomatia ß-glucuronidase and Escherichia coli ß-glucuronidase. Abalone ß-glucuronidase successfully hydrolyzed oxazepam-glucuronide and lorazepam-glucuronide within 5% of the spiked control concentration. Benzodiazepines present in authentic urine specimens were within 20% of the concentrations obtained with the current hydrolysis procedure using H. pomatia ß-glucuronidase. JWH 018 N-(5-hydroxypentyl) ß-d-glucuronide was hydrolyzed within 10% of the control concentration. Authentic urine specimens showed improved glucuronide cleavage using abalone ß-glucuronidase with up to an 85% increase of drug concentration, compared with the results obtained using E. coli ß-glucuronidase. The JWH 018 and JWH 073 carboxylic acid metabolites also showed increased drug concentrations of up to 24%. Abalone ß-glucuronidase was able to completely hydrolyze a morphine-3-glucuronide control, but only 82% of total morphine was hydrolyzed in authentic urine specimens compared with acid hydrolysis results. Hydrolysis of codeine and hydromorphone varied between specimens, suggesting that abalone ß-glucuronidase may not be as efficient in hydrolyzing the glucuronide linkages in opioid compounds compared with acid hydrolysis. Abalone ß-glucuronidase demonstrates effectiveness as a low cost option for enzyme hydrolysis of benzodiazepines and synthetic cannabinoids.


Assuntos
Gastrópodes/enzimologia , Glucuronidase/metabolismo , Urinálise/métodos , Analgésicos Opioides/urina , Animais , Benzodiazepinas/urina , Canabinoides/urina , Codeína/metabolismo , Análise Custo-Benefício , Escherichia coli/enzimologia , Hidrólise , Lorazepam/análogos & derivados , Lorazepam/metabolismo , Derivados da Morfina/metabolismo , Oxazepam/análogos & derivados , Oxazepam/metabolismo , Manejo de Espécimes
11.
Rev Esp Salud Publica ; 87(3): 247-55, 2013.
Artigo em Espanhol | MEDLINE | ID: mdl-23892676

RESUMO

BACKGROUND: For years, anxiolytics and hypnotics have been one of the most prescribed drug classes in most developed countries. The main aim of this study is to explore the pattern of use of anxiolytic and hypnotic drugs during the period 2000-2011, comparing their growth with that of five european countries. METHOD: We performed an ecological and descriptive study of anxiolytics and hypnotics consumption in Spain. Consumption data were obtained from the databases of medications dispensed in community pharmacies and charged through official prescriptions to the totality of the Spanish National Health System. Annual and total-period consumptions were expressed in defined daily doses (DDD) per 1000 inhabitants per day (DDD/1000 person/day) by each treatment subgroup, active substance and attending the plasma half-life of the medication. Approximate comparisons were also made with some European countries. RESULTS: The use of anxiolytics and hypnotics drugs was 56.7 DDD/1000 person/day in 2000 and 82.9 DDD/1000 person/day in 2011 (a +46.1% increase across the period). Lorazepam and alprazolam were the most used anxiolytics (20.5 and 15.6 DDD/1000 person/day in 2011, respectively), whereas lormetazepam was among the hypnotics (18.3 DDD/1000 person/day in 2011). In relative terms, hypnotics´ lormetazepam and zolpidem increased their use by 103.3% and 85.1%, respectively; while anxiolytics´ lorazepam and hydroxyzine increased 75.1% and 72.8%, respectively. In Spain (period 2003-2010), the total increase in the consumption of anxiolytics and hypnotics was +34.3%, with 24.0% for Portugal, 4.0% for Italy, but a reduction of -6.1% for France. CONCLUSIONS: A considerable increase in anxiolytics and hypnotics´ consumption has occurred in Spain during the last decade, being the growth higher than that reported in other European countries.


Assuntos
Ansiolíticos/uso terapêutico , Hipnóticos e Sedativos/uso terapêutico , Alprazolam/uso terapêutico , Bases de Dados Factuais , Prescrições de Medicamentos/estatística & dados numéricos , Europa (Continente) , Humanos , Hidroxizina/uso terapêutico , Lorazepam/análogos & derivados , Lorazepam/uso terapêutico , Piridinas/uso terapêutico , Espanha , Zolpidem
13.
Traffic Inj Prev ; 13(3): 286-92, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22607251

RESUMO

OBJECTIVES: It is generally assumed that there are minimal gender differences in the safety and efficacy of central nervous system drugs, as is evidenced by men and women receiving the same drug dosage. There is, however, evidence that drugs may have a differential effect on performance in men and women, given reported differences in pharmacokinetics as well as the presence or absence and severity of adverse effects. It is especially important to verify whether gender differences in performance exist in case of activities that have potentially dangerous outcomes such as driving a car. This review summarizes the current scientific evidence on gender differences in driving performance after treatment with hypnotic drugs. METHODS: A literature search was conducted to obtain all studies that conducted on-road driving tests to examine the effects hypnotic drugs on driving. Cross-references were checked and technical reports and raw data were obtained, if possible. RESULTS: Fourteen studies were evaluated. Many studies did not allow analyses of gender effects because only women were included. Others did not report data on gender analyses. Technical reports and additional data analyses revealed significant gender differences in driving performance the morning following bedtime administration of flurazepam (30 mg) and after middle-of-the-night administration of zolpidem (10 mg). No significant gender differences were found for ramelteon (8 mg), lormetazepam (1 and 2 mg), zaleplon (10 and 20 mg), and zopiclone (7.5 mg). CONCLUSIONS: Although the available data are limited, the results show that significant gender differences have been found for some drugs but not others. Therefore, in the future more research is needed to reveal potential gender differences and to determine what mediates them.


Assuntos
Condução de Veículo/psicologia , Hipnóticos e Sedativos/farmacologia , Desempenho Psicomotor/efeitos dos fármacos , Fatores Sexuais , Acetamidas/administração & dosagem , Acetamidas/farmacologia , Compostos Azabicíclicos/administração & dosagem , Compostos Azabicíclicos/farmacologia , Planejamento Ambiental/estatística & dados numéricos , Feminino , Flurazepam/administração & dosagem , Flurazepam/farmacologia , Humanos , Hipnóticos e Sedativos/administração & dosagem , Indenos/administração & dosagem , Indenos/farmacologia , Lorazepam/administração & dosagem , Lorazepam/análogos & derivados , Lorazepam/farmacologia , Masculino , Piperazinas/administração & dosagem , Piperazinas/farmacologia , Piridinas/administração & dosagem , Piridinas/farmacologia , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Transtornos do Sono-Vigília/tratamento farmacológico , Zolpidem
14.
Sleep Med ; 13(5): 463-8, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22342027

RESUMO

OBJECTIVE: This study was conducted to evaluate the effectiveness of a cognitive behavioral self-help program (SHP) in combination with pharmacotherapy in patients with primary insomnia in general practice. PARTICIPANTS: Patients were recruited from 31 general practitioners (GPs) in the Hamburg area, who were randomly assigned to the two different study conditions. Eighty patients completed the study. They had suffered from insomnia for several years and showed a high impairment according to the Pittsburgh Sleep Quality Index. INTERVENTION: According to assignment of their GP the patients either received a progressively reduced 4-week pharmacotherapy or a combination of pharmacotherapy and a SHP consisting of six chapters on progressive muscle relaxation, cognitive relaxation, modified stimulus control, thought stopping, and cognitive restructuring. MEASURES AND RESULTS: After study enrollment patients had short weekly consultations with their GPs during treatment to receive sleep medication and questionnaires. They completed questionnaires measuring general sleep quality and sleep-disruptive beliefs and also sleep diaries before treatment, during treatment, immediately following treatment, and at a 6-week and 6-month follow-up time point. For collection of changes in mood the Beck Depression Inventory was used. The whole sample showed reductions of sleep onset latency and time awake after sleep onset. Total sleep time increased and mood improved. Patients additionally working with the SHP showed significantly more improvements in sleep quality and negative sleep-related cognitions like ruminating and focusing on sleep. Treatment effects were significant at the end of therapy and remained stable at the six-week and six-month follow-up. CONCLUSION: This study supports the use of a cognitive-behavioral SHP on primary insomnia in the setting of a general practice and should be investigated in more detail. Also, regular appointments and the utilization of sleep logs seem to have a positive influence on sleep disorders.


Assuntos
Terapia Cognitivo-Comportamental/métodos , Distúrbios do Início e da Manutenção do Sono/terapia , Terapia Combinada , Feminino , Medicina Geral/métodos , Humanos , Hipnóticos e Sedativos/uso terapêutico , Lorazepam/análogos & derivados , Lorazepam/uso terapêutico , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Resultado do Tratamento
15.
Eur J Ophthalmol ; 19(6): 1065-8, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19882565

RESUMO

PURPOSE: To report the first case of amblyopia due to a conversion disorder in a child. METHODS: A 9-year-old girl without allergies or family or personal antecedents of interest presented to our clinic. She manifested a progressive visual loss after an episode of lumbar pain. This progressive loss led the patient in a 6-month period to legal bilateral blindness: visual acuity inferior to 2/20 in both eyes and severe constriction of both visual fields. RESULTS: Several pathologic processes were discarded by means of multiple explorations and a general multidisciplinary analysis: physical pathology, simulating patient, schizophrenia, and the Briquet syndrome. Finally, she was diagnosed with a conversion somatoform disorder leading to a bilateral blindness. For 6 months, the patient was successfully treated with psychotherapy and a pharmacologic protocol. Total recovery was achieved with final visual acuity of 20/20 in both eyes and normal visual fields. CONCLUSION: Conversion disorders should be considered as an additional etiology of visual loss in children. In these cases, the analysis and multidisciplinary treatment is crucial for a successful outcome.


Assuntos
Ambliopia/etiologia , Cegueira/etiologia , Transtorno Conversivo/complicações , Ambliopia/fisiopatologia , Cegueira/fisiopatologia , Criança , Transtorno Conversivo/diagnóstico , Transtorno Conversivo/tratamento farmacológico , Quimioterapia Combinada , Feminino , Fluoxetina/uso terapêutico , Humanos , Hipnóticos e Sedativos/uso terapêutico , Lorazepam/análogos & derivados , Lorazepam/uso terapêutico , Inibidores de Captação de Serotonina/uso terapêutico , Acuidade Visual/fisiologia
16.
J Sep Sci ; 32(13): 2266-72, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19569106

RESUMO

The use of fingerprints as an alternative biological matrix to test for the presence of drugs and/or their metabolites is a novel area of research in analytical toxicology. This investigation describes quantitative analysis for the benzodiazepine lorazepam and its 3-O-glucuronide conjugate in fingerprints following the oral administration of a single 2 mg dose of lorazepam to five volunteers. Creatinine was also measured to investigate whether the amount of drug relative to that of creatinine would help to account for the variable amount of secretory material deposited. Fingerprints were deposited on glass cover slips and extracted by dissolving them in a solution of dichloromethane/methanol, containing tetradeuterated lorazepam as an internal standard. The samples were evaporated, reconstituted with mobile phase and analysed by LC-MS/MS. Chromatography was achieved using an RP (C18) column for the analysis of lorazapem and its glucuronide, and a hydrophilic interaction column (HILIC) for the analysis of creatinine. Lorazepam and its glucuronide were only detected where ten prints had been combined, up to 12 h following drug administration. In every case, the amount of lorazepam glucuronide exceeded that of lorazepam, the peak amounts being 210 and 11 pg, respectively. Adjusting for creatinine smoothed the elimination profile. To our knowledge, this represents the first time a drug glucuronide has been detected in deposited fingerprints.


Assuntos
Ansiolíticos/química , Cromatografia Líquida/métodos , Dermatoglifia , Lorazepam/análogos & derivados , Lorazepam/química , Pele/metabolismo , Espectrometria de Massas em Tandem/métodos , Adulto , Cromatografia Líquida/instrumentação , Creatinina/análise , Feminino , Humanos , Lorazepam/administração & dosagem , Lorazepam/análise , Lorazepam/metabolismo , Masculino , Estrutura Molecular , Espectrometria de Massas em Tandem/instrumentação , Adulto Jovem
18.
J Pharmacol Sci ; 107(3): 349-54, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18603828

RESUMO

Anxiolytic-like effects of some short-acting benzodiazepine hypnotics were examined with experimental paradigms of anxiety using an elevated plus-maze in male ICR mice. Diazepam was used as a positive control. The drug at a dose of 1 mg/kg significantly increased the percentage of time spent in the open arms and percentage of the number of open arm entries in the elevated plus-maze. Triazolam, brotizolam, rilmazafone, and lormetazepam also showed an anxiolytic-like effect as indicated by the significant increase in the percentage of time spent in the open arms and percentage of the number of open arm entries. Effects of short-acting benzodiazepine hypnotics used in the study were more potent than those of diazepam. In addition, the doses affecting the elevated plus-maze by benzodiazepine hypnotics were much smaller than those that showed muscle-relaxant activity measured by the rotarod test, indicating that anxiolytic-like effects of benzodiazepine hypnotics had high specificity and selectivity.


Assuntos
Ansiolíticos/farmacologia , Hipnóticos e Sedativos/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Animais , Ansiolíticos/uso terapêutico , Ansiedade/prevenção & controle , Azepinas/farmacologia , Benzodiazepinas/farmacologia , Diazepam/farmacologia , Hipnóticos e Sedativos/uso terapêutico , Lorazepam/análogos & derivados , Lorazepam/farmacologia , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Triazolam/farmacologia
19.
J Anal Toxicol ; 31(4): 224-6, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17555647

RESUMO

Lormetazepam (Loramet is a benzodiazepine mainly used as an hypnotic to treat insomnia. Lorazepam (Temesta) is used as an anxiolytic, tranquilizer, sedative, and anticonvulsant, and it is the major metabolite of lormetazepam. In this study, we designed a method to simultaneously detect and quantify these substances in human breast milk. Solid-phase extraction of 2 mL of milk was followed by derivatization with a trimethylsilyl reagent. Separation and detection was performed using gas chromatography coupled to mass spectrometry in the negative chemical ionization mode. Calibration curves were linear in the ranges of 10-200 and 1-20 ng/mL for lorazepam and lormetazepam, respectively. Limits of detection were estimated at 0.016 ng/mL for lormetazepam and 0.100 ng/mL for lorazepam. Our method was applied to real case samples from a woman receiving both benzodiazepines. Lorazepam concentrations varied from 55.3 to 123.1 ng/mL, and lormetazepam concentrations varied from 1.7 to 7.3 ng/mL.


Assuntos
Cromatografia Gasosa-Espectrometria de Massas , Hipnóticos e Sedativos/análise , Lorazepam/análogos & derivados , Lorazepam/análise , Leite Humano/química , Adulto , Feminino , Humanos , Reprodutibilidade dos Testes
20.
Clin Drug Investig ; 27(5): 325-32, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17451280

RESUMO

BACKGROUND AND OBJECTIVE: Sleep architecture changes with age, both in terms of efficiency and total duration of sleep. Hypnotic benzodiazepines promote rapid onset of sleep, uninterrupted sleep and longer duration of sleep in the absence of carryover sedation the following morning; therefore, these may be appropriate for use in older patients. This study was performed to evaluate the efficacy and safety of lormetazepam in elderly patients with primary insomnia when used in association with sleep hygiene training (SHT). The impact of restored sleep on daily sleepiness was also investigated. PATIENTS AND METHODS: In this open-label study, 30 elderly outpatients with insomnia were randomised to receive 2 weeks of treatment with lormetazepam 0.5mg + SHT or SHT alone, followed by a 1-week observation period. Details on sleep latency, number of awakenings and freshness on awakening were recorded by patients in a daily sleep diary. The Epworth Sleepiness Scale (ESS) and Stanford Sleepiness Scale (SSS) were used to measure daily sleepiness. RESULTS: Addition of lormetazepam to SHT improved all sleep parameters measured compared with SHT alone. Mean duration of sleep improved significantly from baseline (mean rank=1.00) in the lormetazepam + SHT group after 2 weeks of treatment (mean rank 2.87; Friedmann test=27.448; p<0.001), but declined significantly in the group receiving SHT alone (from mean rank 2.33 to 1.57; Friedmann test=6.465; p<0.05). Mean duration of sleep increased by approximately 150 minutes each night in the lormetazepam + SHT group but decreased by more than 30 minutes in the SHT-only group. Improvement in sleep quality from baseline was statistically significant only in the lormetazepam + SHT group: for both deepness of sleep and the perception of awakening refreshed, mean scores increased from approximately 3 at baseline to approximately 8 (on a scale of 1-10) after 2 weeks in this group. Sleep latency also decreased significantly in the lormetazepam + SHT group: after 2 weeks, on average patients were awakening less than once per night. SSS and ESS scores also improved significantly in the lormetazepam + SHT group; in contrast, in the SHT-only group, the mean ESS score worsened significantly from baseline and the mean SSS score remained relatively constant. No rebound insomnia was reported during follow-up in patients in the lormetazepam group. Vital signs did not change from baseline and no adverse events were reported for either group. CONCLUSION: Management of insomnia in the elderly appears to have a better outcome when pharmacotherapy is combined with SHT rather than SHT alone. The earlier improvement in sleep quality with lormetazepam when used in combination with a sleep training programme may help to maintain adherence to treatment.


Assuntos
Hipnóticos e Sedativos/uso terapêutico , Lorazepam/análogos & derivados , Distúrbios do Início e da Manutenção do Sono/terapia , Idoso , Terapia Combinada , Feminino , Humanos , Lorazepam/uso terapêutico , Masculino , Sono
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