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1.
Eur J Pediatr ; 179(2): 177-189, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31858254

RESUMO

The aim of the present study was to perform a critical reflection about intervention options for bruxism reduction in children and adolescents. Search was conducted based on the PICO-structured question: "What are the intervention options to reduce bruxism in children/adolescents?". No language, year, or study design restrictions were imposed. Studies reporting interventions to reduce bruxism in children (< 10) and adolescents (10 to 19 years old) were included. Reviews and letters to editors were not included. From 2723 records, 17 papers were included. Included studies were primarily randomized clinical trials performed in Brazil (35.3%) and using different criteria for the diagnosis of bruxism. Reduction in self-reported bruxism and headaches associated with bruxism were observed in studies that used medications (hydroxyzine/trazodone/flurazepam), occlusal splints, orthodontic interventions, and psychological and physical therapy interventions. Reduction in Rhythmic Masticatory Muscle Activity was observed with the use of the occlusal splint and in orthodontic interventions. Alternative treatments (medicinal extracts such as Melissa officinalis-L) have shown inconclusive results.Conclusions: Several intervention options are available to inhibit or reduce bruxism activity. The respective indication, contraindications, and side effects of each treatment option must be assessed individually and carefully, taking into account that bruxism is not considered a disorder in otherwise healthy individuals.What is known• Biological and psychological factors have been strongly correlated to the development of bruxism• Bruxism prevalence ranging from 6 to 50% in childrenWhat is new• Reduction in self-reported bruxism and headaches associated with bruxism were observed in studies that used medication (Hydroxyzine/ Trazodone/ Flurazepam), occlusal splints, orthodontic interventions, psychological, and physical therapy interventions• A reduction in Rhythmic Masticatory Muscle Activity was observed with the use of the occlusal splint and orthodontic interventions. Alternative treatments (medicinal extracts such as Melissa officinalis L) show inconclusive results in respect of the reduction in bruxism.


Assuntos
Flurazepam/uso terapêutico , Placas Oclusais/estatística & dados numéricos , Satisfação do Paciente/estatística & dados numéricos , Bruxismo do Sono/epidemiologia , Bruxismo do Sono/terapia , Trazodona/uso terapêutico , Adolescente , Fatores Etários , Criança , Feminino , Humanos , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Bruxismo do Sono/diagnóstico , Resultado do Tratamento , Estados Unidos
2.
Drug Test Anal ; 11(3): 541-549, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30578721

RESUMO

The number of newly appearing benzodiazepine derivatives on the new psychoactive substances (NPS) drug market has increased over the last couple of years totaling 23 'designer benzodiazepines' monitored at the end of 2017 by the European Monitoring Centre for Drugs and Drug Addiction. In the present study, three benzodiazepines [flunitrazolam, norflurazepam, and 4'-chlorodiazepam (Ro5-4864)] offered as 'research chemicals' on the Internet were characterized and their main in vitro phase I metabolites tentatively identified after incubation with pooled human liver microsomes. For all compounds, the structural formula declared by the vendor was confirmed by gas chromatography-mass spectrometry (GC-MS), liquid chromatography-tandem mass spectrometry (LC MS/MS), liquid chromatography-quadrupole time of flight-mass spectrometry (LC-QTOF-MS) analysis and nuclear magnetic resonance (NMR) spectroscopy. The metabolic steps of flunitrazolam were monohydroxylation, dihydroxylation, and reduction of the nitro function. The detected in vitro phase I metabolites of norflurazepam were hydroxynorflurazepam and dihydroxynorflurazepam. 4'-Chlorodiazepam biotransformation consisted of N-dealkylation and hydroxylation. It has to be noted that 4'-chlorodiazepam and its metabolites show almost identical LC-MS/MS fragmentation patterns to diclazepam and its metabolites (delorazepam, lormetazepam, and lorazepam), making a sufficient chromatographic separation inevitable. Sale of norflurazepam, the metabolite of the prescribed benzodiazepines flurazepam and fludiazepam, presents the risk of incorrect interpretation of analytical findings.


Assuntos
Benzodiazepinas/metabolismo , Benzodiazepinonas/metabolismo , Drogas Desenhadas/metabolismo , Flurazepam/análogos & derivados , Desentoxicação Metabólica Fase I , Microssomos Hepáticos/metabolismo , Biotransformação , Cromatografia Líquida , Flurazepam/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Técnicas In Vitro , Detecção do Abuso de Substâncias/métodos , Espectrometria de Massas em Tandem
3.
Eur J Pharmacol ; 784: 81-9, 2016 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-27179992

RESUMO

The fastest inhibitory mechanism in the CNS is mediated by ionotropic GABAA receptors and it is known that subunit composition critically determines their properties. While a typical GABAA receptor consists of two α, two ß and one γ/δ subunit, there are some exceptions, e.g. αß receptors. Functional α1γ2 GABAA receptors can be expressed in recombinant model (Verdoorn et al., 1990) and although their role remains unknown, it seems appealing to extend their characterization to further explore the structure-function relationship of GABAA receptors. Intriguingly, this receptor is lacking canonical GABA binding sites but it can be activated by GABA and dose-response relationships for α1ß2γ2L and α1γ2L receptors overlap. Deactivation kinetics was similar for both receptors but the percentage of the fast component was smaller in the case of α1γ2L receptors and, consequently, the mean deactivation time constant was slower. The rate and extent of macroscopic desensitization were smaller in the case of α1γ2L receptors but they showed slower recovery. Both receptor types had a similar proton sensitivity showing only subtle but significant differences in pH effects on deactivation. Flurazepam exerted a similar effect on both receptors but the rapid deactivation components were differently affected and an opposite effect was observed on desensitization extent. Rebound currents evoked by pentobarbital were undistinguishable for both receptor types. Taking altogether, although some significant differences were found, α1ß2γ2L and α1γ2L receptors showed unforeseen similarity. We propose that functioning of GABAA receptors might rely on subunit-subunit cooperative interactions to a larger extent than believed so far.


Assuntos
Subunidades Proteicas/metabolismo , Receptores de GABA-A/química , Receptores de GABA-A/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Flurazepam/farmacologia , Células HEK293 , Humanos , Cinética , Ligação Proteica , Ácido gama-Aminobutírico/farmacologia
4.
Forensic Sci Int ; 257: 84-92, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26282513

RESUMO

Benzodiazepines and zolpidem are generally prescribed as sedative, hypnotics, anxiolytics or anticonvulsants. These drugs, however, are frequently misused in drug-facilitated crime. Therefore, a rapid and simple liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed for identification and quantification of benzodiazepines, zolpidem and their metabolites in urine using deuterium labeled internal standards (IS). Urine samples (120 µL) mixed with 80 µL of the IS solution were centrifuged. An aliquot (5 µL) of the sample solution was directly injected into the LC-MS/MS system for analysis. The mobile phases consisted of water and acetonitrile containing 2mM ammonium trifluoroacetate and 0.2% acetic acid. The analytical column was a Zorbax SB-C18 (100 mm × 2.1 mm i.d., 3.5 µm, Agilent). The separation and detection of 18 analytes were achieved within 10 min. Calibration curves were linear over the concentration ranges of 0.5-20 ng/mL (zolpidem), 1.0-40 ng/mL (flurazepam and temazepam), 2.5-100 ng/mL (7-aminoclonazepam, 1-hydroxymidazolam, midazolam, flunitrazepam and alprazolam), 5.0-200 ng/mL (zolpidem phenyl-4-carboxylic acid, α-hydroxyalprazolam, oxazepam, nordiazepam, triazolam, diazepam and α-hydroxytriazolam), 10-400 ng/mL (lorazepam and desalkylflurazepam) and 10-100 ng/mL (N-desmethylflunitrazepam) with the coefficients of determination (r(2)) above 0.9971. The dilution integrity of the analytes was examined for supplementation of short linear range. Dilution precision and accuracy were tested using two, four and ten-folds dilutions and they ranged from 3.7 to 14.4% and -12.8 to 12.5%, respectively. The process efficiency for this method was 63.0-104.6%. Intra- and inter-day precisions were less than 11.8% and 9.1%, while intra- and inter-day accuracies were less than -10.0 to 8.2%, respectively. The lower limits of quantification were lower than 10 ng/mL for each analyte. The applicability of the developed method was successfully verified with human urine samples from drug users (n=21). Direct urine sample injection and optimized mobile phases were introduced for simple sample preparation and high-sensitivity with the desired separation.


Assuntos
Benzodiazepinas/urina , Cromatografia Líquida/métodos , Hipnóticos e Sedativos/urina , Piridinas/urina , Espectrometria de Massas em Tandem/métodos , Alprazolam/análogos & derivados , Alprazolam/urina , Flurazepam/análogos & derivados , Flurazepam/urina , Toxicologia Forense/métodos , Humanos , Limite de Detecção , Triazolam/análogos & derivados , Triazolam/urina , Zolpidem
5.
Neuropharmacology ; 95: 309-20, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25839897

RESUMO

Gene expression studies identified the interleukin-1 receptor type I (IL-1R1) as part of a pathway associated with a genetic predisposition to high alcohol consumption, and lack of the endogenous IL-1 receptor antagonist (IL-1ra) strongly reduced ethanol intake in mice. Here, we compared ethanol-mediated behaviors in mice lacking Il1rn or Il1r1. Deletion of Il1rn (the gene encoding IL-1ra) increases sensitivity to the sedative/hypnotic effects of ethanol and flurazepam and reduces severity of acute ethanol withdrawal. Conversely, deletion of Il1r1 (the gene encoding the IL-1 receptor type I, IL-1R1) reduces sensitivity to the sedative effects of ethanol and flurazepam and increases the severity of acute ethanol withdrawal. The sedative effects of ketamine and pentobarbital were not altered in the knockout (KO) strains. Ethanol intake and preference were not changed in mice lacking Il1r1 in three different tests of ethanol consumption. Recovery from ethanol-induced motor incoordination was only altered in female mice lacking Il1r1. Mice lacking Il1rn (but not Il1r1) showed increased ethanol clearance and decreased ethanol-induced conditioned taste aversion. The increased ethanol- and flurazepam-induced sedation in Il1rn KO mice was decreased by administration of IL-1ra (Kineret), and pre-treatment with Kineret also restored the severity of acute ethanol withdrawal. Ethanol-induced sedation and withdrawal severity were changed in opposite directions in the null mutants, indicating that these responses are likely regulated by IL-1R1 signaling, whereas ethanol intake and preference do not appear to be solely regulated by this pathway.


Assuntos
Comportamento Animal/efeitos dos fármacos , Benzodiazepinas/farmacologia , Etanol/farmacologia , Hipnóticos e Sedativos/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Receptores Tipo I de Interleucina-1/metabolismo , Consumo de Bebidas Alcoólicas/metabolismo , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Comportamento Animal/fisiologia , Feminino , Flurazepam/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Ketamina/farmacologia , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Pentobarbital/farmacologia , Receptores Tipo I de Interleucina-1/genética , Índice de Gravidade de Doença , Síndrome de Abstinência a Substâncias/metabolismo , Percepção Gustatória/efeitos dos fármacos , Percepção Gustatória/fisiologia
6.
J Neurosci ; 34(31): 10219-33, 2014 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-25080584

RESUMO

Rapid activation of postsynaptic GABAA receptors (GABAARs) is crucial in many neuronal functions, including the synchronization of neuronal ensembles and controlling the precise timing of action potentials. Although the γ2 subunit is believed to be essential for the postsynaptic clustering of GABAARs, synaptic currents have been detected in neurons obtained from γ2(-/-) mice. To determine the role of the γ2 subunit in synaptic GABAAR enrichment, we performed a spatially and temporally controlled γ2 subunit deletion by injecting Cre-expressing viral vectors into the neocortex of GABAARγ2(77I)lox mice. Whole-cell recordings revealed the presence of miniature IPSCs in Cre(+) layer 2/3 pyramidal cells (PCs) with unchanged amplitudes and rise times, but significantly prolonged decays. Such slowly decaying currents could be evoked in PCs by action potentials in presynaptic fast-spiking interneurons. Freeze-fracture replica immunogold labeling revealed the presence of the α1 and ß3 subunits in perisomatic synapses of cells that lack the γ2 subunit. Miniature IPSCs in Cre(+) PCs were insensitive to low concentrations of flurazepam, providing a pharmacological confirmation of the lack of the γ2 subunit. Receptors assembled from only αß subunits were unlikely because Zn(2+) did not block the synaptic currents. Pharmacological experiments indicated that the αßγ3 receptor, rather than the αßδ, αßε, or αßγ1 receptors, was responsible for the slowly decaying IPSCs. Our data demonstrate the presence of IPSCs and the synaptic enrichment of the α1 and ß3 subunits and suggest that the γ3 subunit is the most likely candidate for clustering GABAARs at synapses in the absence of the γ2 subunit.


Assuntos
Neurônios/fisiologia , Receptores de GABA-A/deficiência , Sinapses/fisiologia , Animais , Ansiolíticos/farmacologia , Carbolinas/farmacologia , Convulsivantes/farmacologia , Desoxicorticosterona/análogos & derivados , Desoxicorticosterona/farmacologia , Estimulação Elétrica , Feminino , Flurazepam/farmacologia , GABAérgicos/farmacologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Técnicas In Vitro , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Lisina/análogos & derivados , Lisina/metabolismo , Masculino , Potenciais da Membrana/fisiologia , Camundongos , Camundongos Transgênicos , Neocórtex/citologia , Neurônios/ultraestrutura , Receptores de GABA-A/genética , Sinapses/ultraestrutura
7.
Forensic Sci Int ; 241: e5-12, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24856286

RESUMO

Quazepam (QZP), which is a long-acting benzodiazepine-type hypnotic, and its 4 metabolites, 2-oxoquazepam, N-desalkyl-2-oxoquazepam (DOQ), 3-hydroxy-2-oxoquazepam (HOQ), and 3-hydroxy-N-desalkyl-2-oxoquazepam, in human blood, urine, and bile were quantitatively analyzed by liquid chromatography-tandem mass spectrometry. The analytes were extracted from blood by protein precipitation followed by solid phase extraction, and from urine and bile by liquid-liquid extraction and cleanup using a PSA solid phase extraction cartridge. This method was applied to a medico-legal autopsy case, in which the deceased had been prescribed QZP approximately 3 weeks before his death. In blood, the concentrations of free DOQ (160±7 ng/mL for heart blood and 181±12 ng/mL for femoral blood) were the highest of all the analytes and in agreement with the concentration at a steady state. This indicates that the deceased consecutively received QZP for at least several days until the concentrations reached approximately the same level as that in the steady state. An extremely high concentration of total HOQ (the sum of conjugated and free HOQ) in bile was also found (56,200±1900 ng/mL). This accumulation of HOQ in bile is probably due to enterohepatic circulation. This study demonstrates that the combination of the concentrations of QZP and its metabolites in biological matrices can provide more information about the amount and frequency of QZP administration.


Assuntos
Benzodiazepinas/análise , Hipnóticos e Sedativos/análise , Benzodiazepinas/farmacocinética , Benzodiazepinonas/análise , Bile/química , Cromatografia Líquida , Flurazepam/análogos & derivados , Flurazepam/análise , Toxicologia Forense , Humanos , Hipnóticos e Sedativos/farmacocinética , Masculino , Pessoa de Meia-Idade , Estrutura Molecular , Espectrometria de Massas em Tandem
8.
J Mol Model ; 19(12): 5489-500, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24241181

RESUMO

Gamma-aminobutyric type A receptor (GABAAR) is a member of the Cys-loop family of pentameric ligand gated ion channels (pLGICs). It has been identified as a key target for many clinical drugs. In the present study, we construct the structure of human 2α12ß2γ2 GABA(A)R using a homology modeling method. The structures of ten benzodiazepine type drugs and two non-benzodiazepine type drugs were then docked into the potential benzodiazepine binding site on the GABA(A)R. By analyzing the docking results, the critical residues His102 (α1), Phe77 (γ2) and Phe100 (α1) were identified in the binding site. To gain insight into the binding affinity, molecular dynamics (MD) simulations were performed for all the receptor-ligand complexes. We also examined single mutant GABA(A)R (His102A) in complexes with the three drugs (flurazepam, eszopiclone and zolpidem) to elucidate receptor-ligand interactions. For each receptor-ligand complex (with flurazepam, eszopiclone and zolpidem), we calculated the average distance between the C(α) of the mutant residue His102A (α1) to the center of mass of the ligands. The results reveal that the distance between the C(α) of the mutant residue His102A (α1) to the center of flurazepam is larger than that between His102 (α1) to flurazepam in the WT type complex. Molecular mechanic-generalized Born surface area (MM-GBSA)-based binding free energy calculations were performed. The binding free energy was decomposed into ligand-residue pairs to create a ligand-residue interaction spectrum. The predicted binding free energies correlated well (R(2) = 0.87) with the experimental binding free energies. Overall, the major interaction comes from a few groups around His102 (α1), Phe77 (γ2) and Phe100 (α1). These groups of interaction consist of at least of 12 residues in total with a binding energy of more than 1 kcal mol(-1). The simulation study disclosed herein provides a meaningful insight into GABA(A)R-ligand interactions and helps to arrive at a binding mode hypothesis with implications for drug design.


Assuntos
Simulação de Acoplamento Molecular , Ligação Proteica , Receptores de GABA-A/química , Sequência de Aminoácidos , Compostos Azabicíclicos/química , Sítios de Ligação , Zopiclona , Flurazepam/química , Humanos , Ligantes , Modelos Moleculares , Piperazinas/química , Piridinas/química , Receptores de GABA-A/metabolismo , Zolpidem
9.
Artigo em Inglês | MEDLINE | ID: mdl-23841956

RESUMO

Folie à deux is a relatively rare mental disorder first described in France in 1877 by Lasègue and Falret. However, folie à deux is still a matter of study and debate today as it remains a challenge for psychiatrists. The aim of our work is to report a clinical case of folie à deux, subtype A of Gralnick, between an inducer daughter and an induced mother who lived quite socially isolated and had a strong and close relationship. In the clinical case presented, folie à deux was easily diagnosed but its treatment proved to be a higher challenge. The main diagnosis of the inducer patient was also quite interesting. Many years after it was first described, folie à deux is still an interesting and challenging disorder to psychiatrists, especially concerning its pathophysiology and treatment.


Assuntos
Transtorno Paranoide Compartilhado/diagnóstico , Transtorno Paranoide Compartilhado/tratamento farmacológico , Adulto , Antipsicóticos/uso terapêutico , Diagnóstico Diferencial , Feminino , Flurazepam/uso terapêutico , Humanos , Pessoa de Meia-Idade , Relações Mãe-Filho , Cooperação do Paciente , Piperazinas/uso terapêutico , Transtorno Paranoide Compartilhado/psicologia , Isolamento Social/psicologia , Tiazóis/uso terapêutico , Recusa do Paciente ao Tratamento
11.
Psychopharmacology (Berl) ; 229(4): 571-8, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23624775

RESUMO

RATIONALE: Sesamol, a natural compound with anti-inflammatory, antioxidant and neuroprotective properties, has shown promising antidepressant-like effects. However, its molecular target(s) have not been well defined, which merits further investigation. OBJECTIVES: Based on the interaction between the neurotrophin and endocannabinoid (eCB) systems and their contribution to emotional reactivity and antidepressant action, we aimed to investigate the involvement of nerve growth factor (NGF) and eCB signalling in the mechanism of action of sesamol. METHODS: Following acute and 4-week intraperitoneal (i.p.) administration of sesamol (40, 80 and 100 mg/kg), the classical antidepressant amitriptyline (2.5, 5 and 10 mg/kg) or the benzodiazepine flurazepam (5, 10 and 20 mg/kg), brain regional levels of NGF and eCB contents were quantified in rats by Bio-Rad protein assay and isotope-dilution liquid chromatography/mass spectrometry, respectively. In the case of any significant change, the cannabinoid CB1 and CB2 receptor antagonists (AM251 and SR144528) were administered i.p. 30 min prior to the injection of sesamol, amitriptyline or flurazepam. RESULTS: Following the chronic treatment, sesamol, similar to amitriptyline, resulted in the sustained elevation of NGF and eCB contents in dose-dependent and brain region-specific fashion. Neither acute nor chronic treatment with flurazepam altered brain NGF or eCB contents. Pretreatment with 3 mg/kg AM251, but not SR144528, prevented the elevation of NGF protein levels. AM251 exerted no effect by itself. CONCLUSIONS: Sesamol, similar to amitriptyline, is able to affect brain NGF and eCB signalling under the regulatory drive of the CB1 receptors.


Assuntos
Benzodioxóis/farmacologia , Endocanabinoides/metabolismo , Fator de Crescimento Neural/metabolismo , Fenóis/farmacologia , Receptor CB1 de Canabinoide/metabolismo , Amitriptilina/administração & dosagem , Amitriptilina/farmacologia , Animais , Antidepressivos Tricíclicos/administração & dosagem , Antidepressivos Tricíclicos/farmacologia , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Benzodioxóis/administração & dosagem , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Canfanos/farmacologia , Relação Dose-Resposta a Droga , Flurazepam/administração & dosagem , Flurazepam/farmacologia , Injeções Intraperitoneais , Masculino , Terapia de Alvo Molecular , Fenóis/administração & dosagem , Piperidinas/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Wistar , Receptor CB2 de Canabinoide/metabolismo , Transdução de Sinais/efeitos dos fármacos
12.
Neural Plast ; 2012: 405926, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22830051

RESUMO

Cessation of one-week oral administration of the benzodiazepine flurazepam (FZP) to rats results in withdrawal anxiety after 1 day of withdrawal. FZP withdrawal is correlated with synaptic incorporation of homomeric GluA1-containing α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) in the proximal stratum radiatum of CA1 neurons. After 2 days of withdrawal, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) phosphorylates GluA1 subunits at Ser(831), increasing channel conductance. Secondary to AMPAR potentiation, GluN2B-containing N-methyl-D-aspartate receptors (NMDARs), known binding partners of CaMKII, are selectively removed from the postsynaptic density (PSD). While activation of synaptic CaMKII is known to involve translocation to the PSD, CaMKII bound to NMDARs may be removed from the PSD. To distinguish these possibilities, the current studies used postembedding immunogold electron microscopy to investigate alterations in CaMKII signaling at CA1 stratum radiatum synapses after 2 days of FZP withdrawal. These studies revealed decreased total, but not autophosphorylated (Thr(286)) CaMKIIα expression in CA1 PSDs. The removal of CaMKII-GluN2B complexes from the PSD during drug withdrawal may serve as a homeostatic mechanism to limit AMPAR-mediated CA1 neuron hyperexcitability and benzodiazepine withdrawal anxiety.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/fisiologia , Flurazepam/efeitos adversos , Glutamatos/fisiologia , Hipocampo/fisiologia , Hipnóticos e Sedativos/efeitos adversos , Transdução de Sinais/fisiologia , Síndrome de Abstinência a Substâncias/fisiopatologia , Sinapses/fisiologia , Animais , Região CA1 Hipocampal/fisiologia , Espinhas Dendríticas/fisiologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Homeostase/fisiologia , Imuno-Histoquímica , Masculino , Microscopia Eletrônica , Fosforilação , Terminações Pré-Sinápticas/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/fisiologia , Treonina/metabolismo , Inclusão do Tecido
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.
Int Psychogeriatr ; 24(4): 577-86, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22059800

RESUMO

BACKGROUND: The use of benzodiazepines is associated with increased risk of fall-related injuries in the elderly. However, it is unclear if the risks vary across the products and how they depend on the pattern of use and dosage. Specifically, the possibility of cumulative effects of past benzodiazepine use has not been thoroughly investigated. METHODS: We used the administrative database for a cohort of 23,765 new users of benzodiazepines, aged 65 years and older, in Quebec, Canada, between 1990 and 1994. The associations between the use of seven benzodiazepines and the risk of fall-related injuries were assessed using several statistical models, including a novel weighted cumulative exposure model. That model assigns to each dose taken in the past a weight that represents the importance of that dose in explaining the current risk of fall. RESULTS: For flurazepam, the best-fitting model indicated a cumulative effect of doses taken in the last two weeks. Uninterrupted use of flurazepam in the past months was associated with a highly significant increase in the risk of fall-related injuries (HR = 2.83, 95% CI: 1.45-4.34). The cumulative effect of a 30-day exposure to alprazolam was 1.27 (1.13-1.42). For temazepam, the results suggested a potential withdrawal effect. CONCLUSIONS: Mechanisms affecting the risk of falls differ across benzodiazepines, and may include cumulative effects of use in the previous few weeks. Thus, benzodiazepine-specific analyses that account for individual patterns of use should be preferred over simpler analyses that group different benzodiazepines together and limit exposure to current use or current dose.


Assuntos
Acidentes por Quedas/estatística & dados numéricos , Benzodiazepinas/efeitos adversos , Idoso , Alprazolam/efeitos adversos , Bromazepam/efeitos adversos , Clordiazepóxido/efeitos adversos , Clonazepam/efeitos adversos , Feminino , Flurazepam/efeitos adversos , Humanos , Lorazepam/efeitos adversos , Masculino , Modelos de Riscos Proporcionais , Fatores de Risco , Temazepam/efeitos adversos
15.
Stat Med ; 31(11-12): 1014-30, 2012 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-22095719

RESUMO

Pharmacoepidemiology investigates associations between time-varying medication use/dose and risk of adverse events. Applied research typically relies on a priori chosen simple conventional models, such as current dose or any use in the past 3 months. However, different models imply different risk predictions, and only one model can be etiologically correct in any specific applications. We first formally defined several candidate models mapping the time vector of past drug doses (X (t), t = 1, … ,u) into the value of a time-varying exposure metric M(u) at current time u. In addition to conventional one-parameter models, we considered two-parameter models accounting for recent dose increase or withdrawal and a flexible spline-based weighted cumulative exposure (WCE) model that defines M(u) as the weighted sum of past doses. In simulations, we generated event times assuming one of the models was correct and then analyzed the data with all candidate models. We demonstrated that the minimum AIC criterion is able to identify the correct model as the best-fitting model or one of the equivalent (within 4 AIC points of the minimum) models in a vast majority of simulated samples, especially with 500 or more events. We also showed how relying on an incorrect a priori chosen model may largely reduce the power to test for an association. Finally, we demonstrated how the flexible WCE estimates may help with model diagnostics even if the correct model is not WCE. We illustrated the practical advantages of AIC-based a posteriori model selection and WCE modeling in a real-life pharmacoepidemiology example.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Modelos Estatísticos , Farmacoepidemiologia/estatística & dados numéricos , Acidentes por Quedas/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Ansiolíticos/efeitos adversos , Simulação por Computador/estatística & dados numéricos , Flurazepam/efeitos adversos , Humanos
16.
Br J Pharmacol ; 162(3): 673-87, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20942818

RESUMO

BACKGROUND AND SIGNIFICANCE: Although the functional effects of benzodiazepines (BZDs) on GABA(A) receptors have been well characterized, the structural mechanism by which these modulators alter activation of the receptor by GABA is still undefined. EXPERIMENTAL APPROACH: We used disulphide trapping between engineered cysteines to probe BZD-induced conformational changes within the γ2 subunit and at the α1/γ2 coupling interface (Loops 2, 7 and 9) of α1ß2γ2 GABA(A) receptors. KEY RESULTS: Crosslinking γ2 Loop 9 to γ2ß-strand 9 (via γ2 S195C/F203C and γ2 S187C/L206C) significantly decreased maximum potentiation by flurazepam, suggesting that modulation of GABA-induced current (I(GABA)) by flurazepam involves movements of γ2 Loop 9 relative to γ2ß-strand 9. In contrast, tethering γ2ß-strand 9 to the γ2 pre-M1 region (via γ2S202C/S230C) significantly enhanced potentiation by both flurazepam and zolpidem, indicating γ2S202C/S230C trapped the receptor in a more favourable conformation for positive modulation by BZDs. Intersubunit disulphide bonds formed at the α/γ coupling interface between α1 Loop 2 and γ2Loop 9 (α1D56C/γ2L198C) prevented flurazepam and zolpidem from efficiently modulating I(GABA) . Disulphide trapping α1 Loop 2 (α1D56C) to γ2ß-strand 1 (γ2P64C) decreased maximal I(GABA) as well as flurazepam potentiation. None of the disulphide bonds affected the ability of the negative modulator, 3-carbomethoxy-4-ethyl-6,7-dimethoxy-ß-carboline (DMCM), to inhibit I(GABA) . CONCLUSIONS AND IMPLICATIONS: Positive modulation of GABA(A) receptors by BZDs requires reorganization of the loops in the α1/γ2 coupling interface. BZD-induced movements at the α/γ coupling interface likely synergize with rearrangements induced by GABA binding at the ß/α subunit interfaces to enhance channel activation by GABA.


Assuntos
Benzodiazepinas/farmacologia , Carbolinas/farmacologia , Flurazepam/farmacologia , Receptores de GABA-A/metabolismo , Ácido gama-Aminobutírico/farmacologia , Animais , Benzodiazepinas/metabolismo , Carbolinas/metabolismo , Dissulfetos/metabolismo , Ditiotreitol/metabolismo , Relação Dose-Resposta a Droga , Flurazepam/metabolismo , Peróxido de Hidrogênio/metabolismo , Mutagênese Sítio-Dirigida , Oócitos , Técnicas de Patch-Clamp , Xenopus laevis , Ácido gama-Aminobutírico/metabolismo
17.
Neurosci Lett ; 488(1): 31-5, 2011 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-21056629

RESUMO

Knock-in mice were constructed with mutations in the α1 (H(270), A(277)) and α2 (H(270), A(277)) subunits of the GABAA receptor, which resulted in receptors that lacked modulation by ethanol but retained normal responses to GABA in vitro. A key question is whether these mutant receptors also function normally in vivo. Perturbation of brain function was evaluated by gene expression profiling in the cerebral cortex and by behavioral pharmacology experiments with GABAergic drugs. Analysis of individual transcripts found only six transcripts that were changed in α1 knock-in mice and three in the α2 mutants (p<0.05, corrected for multiple comparisons). Two transcripts that are sensitive to neuronal activity, Arc and Fos, increased about 250% in the α2 mutants, and about 50% in the α1 mutants. Behavioral effects (loss of righting reflex, rotarod) of flurazepam and pentobarbital were not different between α2 mutants and wild-type, but they were enhanced for α1 knock-in mice. These results indicate that introduction of these mutations in the α2 subunit of the GABAA receptor does not produce marked perturbation of brain function, as measured by gene expression and GABAergic behavioral responses, but the same mutations in the α1 subunit produce more pronounced changes, especially in GABAergic function.


Assuntos
Comportamento Animal/fisiologia , Regulação da Expressão Gênica/genética , Mutação/genética , Receptores de GABA-A , Animais , Comportamento Animal/efeitos dos fármacos , Proteínas do Citoesqueleto/metabolismo , Flurazepam/farmacologia , Flurazepam/uso terapêutico , Moduladores GABAérgicos/farmacologia , Moduladores GABAérgicos/uso terapêutico , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Transtornos dos Movimentos/tratamento farmacológico , Transtornos dos Movimentos/genética , Proteínas do Tecido Nervoso/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Pentobarbital/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo
18.
Neuropsychopharmacology ; 35(9): 1897-909, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20445501

RESUMO

Benzodiazepine withdrawal anxiety is associated with potentiation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor (AMPAR) currents in hippocampal CA1 pyramidal neurons attributable to increased synaptic incorporation of GluA1-containing AMPARs. The contribution of calcium/calmodulin-dependent protein kinase II (CaMKII) to enhanced glutamatergic synaptic strength during withdrawal from 1-week oral flurazepam (FZP) administration was further examined in hippocampal slices. As earlier reported, AMPAR-mediated miniature excitatory postsynaptic current (mEPSC) amplitude increased in CA1 neurons from 1- and 2-day FZP-withdrawn rats, along with increased single-channel conductance in neurons from 2-day rats, estimated by non-stationary noise analysis. Input-output curve slope was increased without a change in paired-pulse facilitation, suggesting increased AMPAR postsynaptic efficacy rather than altered glutamate release. The increased mEPSC amplitude and AMPAR conductance were related to CaMKII activity, as intracellular inclusion of CaMKIINtide or autocamtide-2-related inhibitory peptide, but not scrambled peptide, prevented both AMPAR amplitude and conductance changes. mEPSC inhibition by 1-naphthyl acetyl spermine and the negative shift in rectification index at both withdrawal time points were consistent with functional incorporation of GluA2-lacking AMPARs. GluA1 but not GluA2 or GluA3 levels were increased in immunoblots of postsynaptic density (PSD)-enriched subcellular fractions of CA1 minislices from 1-day FZP-withdrawn rats, when mEPSC amplitude, but not conductance, was increased. Both GluA1 expression levels and CaMKII alpha-mediated GluA1 Ser(831) phosphorylation were increased in PSD-subfractions from 2-day FZP-withdrawn rats. As phospho-Thr(286)CaMKII alpha was unchanged, CaMKII alpha may be activated through an alternative signaling pathway. Synaptic insertion and subsequent CaMKII alpha-mediated Ser(831) phosphorylation of GluA1 homomers contribute to benzodiazepine withdrawal-induced AMPAR potentiation and may represent an important hippocampal pathway mediating both drug-induced and activity-dependent plasticity.


Assuntos
Benzodiazepinas/administração & dosagem , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Ácido Glutâmico/metabolismo , Hipocampo , Plasticidade Neuronal/efeitos dos fármacos , Células Piramidais/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Fenômenos Biofísicos/efeitos dos fármacos , Biofísica , Modelos Animais de Doenças , Interações Medicamentosas , Estimulação Elétrica , Inibidores Enzimáticos/farmacologia , Fármacos Atuantes sobre Aminoácidos Excitatórios/farmacologia , Flurazepam/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Hipnóticos e Sedativos/farmacologia , Técnicas In Vitro , Masculino , Técnicas de Patch-Clamp , Células Piramidais/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de Glutamato/metabolismo , Frações Subcelulares/efeitos dos fármacos , Frações Subcelulares/metabolismo , Síndrome de Abstinência a Substâncias/patologia , Síndrome de Abstinência a Substâncias/fisiopatologia , Fatores de Tempo
19.
Zhongguo Dang Dai Er Ke Za Zhi ; 12(1): 56-61, 2010 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-20113637

RESUMO

OBJECTIVE: Benzodiazepines (BDZ) have many effects on various kinds of epilepsies, but long-term treatment with BDZ often leads to drug tolerance. This study aimed to seek drugs which can reverse the tolerance of flurazepam (FZP), and to explore the role of neuropeptide Y (NPY) in the reversal effect. METHODS: A rat model of anticonvulsant tolerance to FZP was prepared. The rats with FZP tolerance were randomly assigned to seven groups: FZP-tolerance, and nifedipine, levetiracetam, topiramate, flumazenil, L-NAME and pyridoxamine treatment groups. The tolerance to FZP was evaluated through pentylenetetrazol (PTZ) infusion into a tail vein. The latency to onset of clonic seizure and the PTZ threshold were recorded. The mRNA of NPY receptor Y2 in the hippocampus was determined by RT-PCR, and the distribution of NPY in the hippocampus was examined by immunohistochemistry. RESULTS: In comparison with the blank control group, the average latency to the onset of clonic seizure was shortened, the average PTZ threshold decreased and the expression of NYT and NPY receptor Y2 mRNA decreased significantly in the FZP-tolerance group (p<0.01). In comparison with the FZP-tolerance group, the average latency to onset of clonic seizure was prolonged by 2 times and the average PTZ threshold doubled in the topiramate treatment group. The average latency to onset of clonic seizure was prolonged by 1 time and the average PTZ threshold increased 1 time in the nifedipine, the levetiracetam and the flumazenil treatment groups. The mRNA expression of NPY receptor Y2 increased by 1 or 2 times in the flumazenil, the nifedipine and the topiramate treatment groups when compared with the FZP-tolerance group. CONCLUSIONS: Nifedipine, levetiracetam, topiramate and flumazenil can reverse the anticonvulsant tolerance to flurazepam. NPY may play a role in mediating the reversal effect.


Assuntos
Anticonvulsivantes/farmacologia , Flurazepam/farmacologia , Animais , Tolerância a Medicamentos , Hipocampo/química , Hipocampo/efeitos dos fármacos , Masculino , Neuropeptídeo Y/análise , Neuropeptídeo Y/fisiologia , Pentilenotetrazol , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Tempo de Reação , Receptores de Neuropeptídeo Y/genética , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico
20.
Int J Geriatr Psychiatry ; 25(12): 1259-65, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20054834

RESUMO

OBJECTIVE: Benzodiazepines (BZDs) have been reported to cause negative impacts on body stability and cognitive functions, which in turn could result in lethal incidents, including falls, especially in the elderly. This fact notwithstanding, no systematic trial has evaluated the feasibility and benefits of discontinuing BZD-derivative hypnotics in this population, which was addressed in this study. METHODS: In this 8-week open-label study, subjects aged ≥ 60 living in a nursing home who received BZD as a hypnotic were recruited. The BZD dose was tapered off over 3 weeks. The following assessments were performed 12 h post-dose at baseline and at endpoint: the Clinical Stabilometric Platform (CSP), the Critical Flicker Fusion Test (CFF), the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and the Leeds Sleep Evaluation Questionnaire (LSEQ). RESULTS: Thirty subjects were enrolled (mean ± SD age = 79.1 ± 8.9 years, mean ± SD flurazepam equivalent BZD dose = 19.5 ± 10.9 mg/day). Psychiatric diagnoses (DSM-IV) of subjects were as follows: schizophrenia (n = 12), primary insomnia (n = 9), dementia (n = 7), and bipolar disorder (n = 2). In 26 completers, significant changes were found in a total length and a range of trunk motion with eyes closed. Significant improvements were also observed in the CFF and RBANS immediate memory, language, and attention index scores. Subjective worsening in sleep was not reported in those completers, assessed with the LSEQ. CONCLUSIONS: Our results suggest that discontinuation of BZD hypnotics is feasible in a majority of elderly persons and leads to an improvement in the stability of body and a recovery in cognitive functions during the daytime.


Assuntos
Cognição/efeitos dos fármacos , Flurazepam/uso terapêutico , Hipnóticos e Sedativos/uso terapêutico , Equilíbrio Postural/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Feminino , Fusão Flicker/efeitos dos fármacos , Avaliação Geriátrica , Humanos , Masculino , Testes Neuropsicológicos , Sono/efeitos dos fármacos , Inquéritos e Questionários
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