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[PMID]:29352477
[Au] Autor:Bergman H; Bhoopathi PS; Soares-Weiser K
[Ad] Endereço:Cochrane Response, Cochrane, St Albans House, 57-59 Haymarket, London, UK, SW1Y 4QX.
[Ti] Título:Benzodiazepines for antipsychotic-induced tardive dyskinesia.
[So] Source:Cochrane Database Syst Rev;1:CD000205, 2018 01 20.
[Is] ISSN:1469-493X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Tardive dyskinesia (TD) is a disfiguring movement disorder, often of the orofacial region, frequently caused by using antipsychotic drugs. A wide range of strategies have been used to help manage TD, and for those who are unable to have their antipsychotic medication stopped or substantially changed, the benzodiazepine group of drugs have been suggested as a useful adjunctive treatment. However, benzodiazepines are very addictive. OBJECTIVES: To determine the effects of benzodiazepines for antipsychotic-induced tardive dyskinesia in people with schizophrenia, schizoaffective disorder, or other chronic mental illnesses. SEARCH METHODS: On 17 July 2015 and 26 April 2017, we searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (including trial registers), inspected references of all identified studies for further trials and contacted authors of each included trial for additional information. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) focusing on people with schizophrenia (or other chronic mental illnesses) and antipsychotic-induced TD that compared benzodiazepines with placebo, no intervention, or any other intervention for the treatment of TD. DATA COLLECTION AND ANALYSIS: We independently extracted data from the included studies and ensured that they were reliably selected, and quality assessed. For homogenous dichotomous data, we calculated random effects, risk ratio (RR), and 95% confidence intervals (CI). We synthesised continuous data from valid scales using mean differences (MD). For continuous outcomes, we preferred endpoint data to change data. We assumed that people who left early had no improvement. MAIN RESULTS: The review now includes four trials (total 75 people, one additional trial since 2006, 21 people) randomising inpatients and outpatients in China and the USA. Risk of bias was mostly unclear as reporting was poor. We are uncertain about all the effects as all evidence was graded at very low quality. We found no significant difference between benzodiazepines and placebo for the outcome of 'no clinically important improvement in TD' (2 RCTs, 32 people, RR 1.12, 95% CI 0.60 to 2.09, very low quality evidence). Significantly fewer participants allocated to clonazepam compared with phenobarbital (as active placebo) experienced no clinically important improvement (RR 0.44, 95% CI 0.20 to 0.96, 1 RCT, 21 people, very low quality evidence). For the outcome 'deterioration of TD symptoms,' we found no clear difference between benzodiazepines and placebo (2 RCTs, 30 people, RR 1.48, 95% CI 0.22 to 9.82, very low quality evidence). All 10 participants allocated to benzodiazepines experienced any adverse event compared with 7/11 allocated to phenobarbital (RR 1.53, 95% CI 0.97 to 2.41, 1 RCT, 21 people, very low quality evidence). There was no clear difference in the incidence of participants leaving the study early for benzodiazepines compared with placebo (3 RCTs, 56 people, RR 2.73, 95% CI 0.15 to 48.04, very low quality evidence) or compared with phenobarbital (as active placebo) (no events, 1 RCT, 21 people, very low quality evidence). No trials reported on social confidence, social inclusion, social networks, or personalised quality of life, which are outcomes designated important by patients. No trials comparing benzodiazepines with placebo or treatment as usual reported on adverse effects. AUTHORS' CONCLUSIONS: There is only evidence of very low quality from a few small and poorly reported trials on the effect of benzodiazepines as an adjunctive treatment for antipsychotic-induced TD. These inconclusive results mean routine clinical use is not indicated and these treatments remain experimental. New and better trials are indicated in this under-researched area; however, as benzodiazepines are addictive, we feel that other techniques or medications should be adequately evaluated before benzodiazepines are chosen.
[Mh] Termos MeSH primário: Ansiolíticos/uso terapêutico
Benzodiazepinas/uso terapêutico
Discinesia Induzida por Medicamentos/tratamento farmacológico
Moduladores GABAérgicos/uso terapêutico
[Mh] Termos MeSH secundário: Antipsicóticos/efeitos adversos
Clonazepam/uso terapêutico
Discinesia Induzida por Medicamentos/etiologia
Seres Humanos
Fenobarbital/uso terapêutico
Ensaios Clínicos Controlados Aleatórios como Assunto
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Anti-Anxiety Agents); 0 (Antipsychotic Agents); 0 (GABA Modulators); 12794-10-4 (Benzodiazepines); 5PE9FDE8GB (Clonazepam); YQE403BP4D (Phenobarbital)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180121
[St] Status:MEDLINE
[do] DOI:10.1002/14651858.CD000205.pub3


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[PMID]:28452409
[Au] Autor:Grunebaum MF; Ellis SP; Keilp JG; Moitra VK; Cooper TB; Marver JE; Burke AK; Milak MS; Sublette ME; Oquendo MA; Mann JJ
[Ad] Endereço:Molecular Imaging and Neuropathology Division, Department of Psychiatry, Columbia University Medical Center (CUMC) and New York State Psychiatric Institute, New York, NY, USA.
[Ti] Título:Ketamine versus midazolam in bipolar depression with suicidal thoughts: A pilot midazolam-controlled randomized clinical trial.
[So] Source:Bipolar Disord;19(3):176-183, 2017 May.
[Is] ISSN:1399-5618
[Cp] País de publicação:Denmark
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES: To evaluate feasibility and effects of a sub-anesthetic infusion dose of ketamine versus midazolam on suicidal ideation in bipolar depression. Neurocognitive, blood and saliva biomarkers were explored. METHODS: Sixteen participants with bipolar depression and a Scale for Suicidal Ideation (SSI) score of ≥4 were randomized to ketamine (0.5 mg/kg) or midazolam (0.02 mg/kg). Current pharmacotherapy was maintained excluding benzodiazepines within 24 hours. The primary clinical outcome was SSI score on day 1 post-infusion. RESULTS: Results supported feasibility. Mean reduction of SSI after ketamine infusion was almost 6 points greater than after midazolam, although this was not statistically significant (estimate=5.84, SE=3.01, t=1.94, P=.074, 95% confidence interval ([CI)]=-0.65 to 12.31). The number needed to treat for response (SSI <4 and at least 50% below baseline) was 2.2, and for remission (SSI=0) was 3.2. The strongest neurocognitive correlation was between memory improvement on the Selective Reminding Test (SRT) and reduction in SSI score on day 1 after ketamine (ρ=-.89, P=.007). Pre- to post-infusion decrease in serum brain derived neurotrophic factor (BDNF) correlated with reduction in SSI from baseline to day 1 after ketamine (n=5, ρ=0.90, P=.037) but not midazolam (P=.087). CONCLUSIONS: The study demonstrated feasibility. Suicidal thoughts were lower after ketamine than after midazolam at a trend level of significance, likely due to the small pilot sample. Memory improvement and BDNF are promising biomarkers. Replication is needed in an adequately powered full-scale trial.
[Mh] Termos MeSH primário: Transtorno Bipolar
Ketamina
Memória/efeitos dos fármacos
Midazolam
Ideação Suicida
[Mh] Termos MeSH secundário: Adulto
Anestésicos Dissociativos/administração & dosagem
Anestésicos Dissociativos/efeitos adversos
Biomarcadores/análise
Transtorno Bipolar/diagnóstico
Transtorno Bipolar/tratamento farmacológico
Transtorno Bipolar/psicologia
Fator Neurotrófico Derivado do Encéfalo/análise
Relação Dose-Resposta a Droga
Método Duplo-Cego
Monitoramento de Medicamentos/métodos
Feminino
Moduladores GABAérgicos/administração & dosagem
Moduladores GABAérgicos/efeitos adversos
Seres Humanos
Ketamina/administração & dosagem
Ketamina/efeitos adversos
Masculino
Midazolam/administração & dosagem
Midazolam/efeitos adversos
Meia-Idade
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Anesthetics, Dissociative); 0 (Biomarkers); 0 (Brain-Derived Neurotrophic Factor); 0 (GABA Modulators); 0 (brain-derived neurotrophic factor, human); 690G0D6V8H (Ketamine); R60L0SM5BC (Midazolam)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1111/bdi.12487


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[PMID]:28796283
[Au] Autor:Goh ET; Andersen ML; Morgan MY; Gluud LL
[Ad] Endereço:UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, Rowland Hill Street, Hampstead, London, UK, NW3 2PF.
[Ti] Título:Flumazenil versus placebo or no intervention for people with cirrhosis and hepatic encephalopathy.
[So] Source:Cochrane Database Syst Rev;8:CD002798, 2017 08 10.
[Is] ISSN:1469-493X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Hepatic encephalopathy is a common complication of cirrhosis which results in poor brain functioning. The spectrum of changes associated with hepatic encephalopathy ranges from the clinically 'indiscernible' or minimal hepatic encephalopathy to the clinically 'obvious' or overt hepatic encephalopathy. Flumazenil is a synthetic benzodiazepine antagonist with high affinity for the central benzodiazepine recognition site. Flumazenil may benefit people with hepatic encephalopathy through an indirect negative allosteric modulatory effect on gamma-aminobutyric acid receptor function. The previous version of this review, which included 13 randomised clinical trials, found no effect of flumazenil on all-cause mortality, based on an analysis of 10 randomised clinical trials, but found a beneficial effect on hepatic encephalopathy, based on an analysis of eight randomised clinical trials. OBJECTIVES: To evaluate the beneficial and harmful effects of flumazenil versus placebo or no intervention for people with cirrhosis and hepatic encephalopathy. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, and LILACS; meeting and conference proceedings; and bibliographies in May 2017. SELECTION CRITERIA: We included randomised clinical trials regardless of publication status, blinding, or language in the analyses of benefits and harms, and observational studies in the assessment of harms. DATA COLLECTION AND ANALYSIS: Two review authors extracted data independently. We undertook meta-analyses and presented results using risk ratios (RR) with 95% confidence intervals (CI) and I values as a marker of heterogeneity. We assessed bias control using the Cochrane Hepato-Biliary Group domains; determined the quality of the evidence using GRADE; evaluated the risk of small-study effects in regression analyses; and conducted trial sequential, subgroup, and sensitivity analyses. MAIN RESULTS: We identified 14 eligible randomised clinical trials with 867 participants, the majority of whom had an acute episode of overt hepatic encephalopathy. In addition, we identified one ongoing randomised clinical trial. We were unable to gather outcome data from two randomised clinical trials with 25 participants. Thus, our analyses include 842 participants from 12 randomised clinical trials comparing flumazenil versus placebo. We classified one randomised clinical trial at low risk of bias in the overall assessment and the remaining randomised clinical trials at high risk of bias. The duration of follow-up ranged from a few minutes to two weeks, but it was less than one day in the majority of the trials.In total, 32/433 (7.4%) participants allocated to flumazenil versus 38/409 (9.3%) participants allocated to placebo died (RR 0.75, 95% CI 0.48 to 1.16; 11 randomised clinical trials; low quality evidence). The Trial Sequential Analysis and the one randomised clinical trial assessed as low risk of bias (RR 0.76, 95% CI 0.37 to 1.53) found no beneficial or harmful effects of flumazenil on all-cause mortality. The methods used to evaluate hepatic encephalopathy included several different clinical scales, electrophysiological variables, and psychometric tests. Flumazenil was associated with a beneficial effect on hepatic encephalopathy when including all randomised clinical trials (RR 0.75, 95% CI 0.71 to 0.80; 824 participants; nine randomised clinical trials; low quality evidence), or just the trial at low risk of bias (RR 0.78, 95% CI 0.72 to 0.84; 527 participants). The Trial Sequential Analysis supported a beneficial effect of flumazenil on hepatic encephalopathy. The randomised clinical trials included little information about causes of death and little information on non-fatal serious adverse events. AUTHORS' CONCLUSIONS: We found low quality evidence suggesting a short-term beneficial effect of flumazenil on hepatic encephalopathy in people with cirrhosis, but no evidence of an effect on all-cause mortality. Additional evidence from large, high quality randomised clinical trials is needed to evaluate the potential benefits and harms of flumazenil in people with cirrhosis and hepatic encephalopathy.
[Mh] Termos MeSH primário: Flumazenil/uso terapêutico
Moduladores GABAérgicos/uso terapêutico
Encefalopatia Hepática/tratamento farmacológico
Cirrose Hepática/complicações
[Mh] Termos MeSH secundário: Causas de Morte
Flumazenil/efeitos adversos
Moduladores GABAérgicos/efeitos adversos
Encefalopatia Hepática/etiologia
Encefalopatia Hepática/mortalidade
Seres Humanos
Cirrose Hepática/mortalidade
Placebos/uso terapêutico
Ensaios Clínicos Controlados Aleatórios como Assunto
Conduta Expectante
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (GABA Modulators); 0 (Placebos); 40P7XK9392 (Flumazenil)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170920
[Lr] Data última revisão:
170920
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170811
[St] Status:MEDLINE
[do] DOI:10.1002/14651858.CD002798.pub4


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[PMID]:28733205
[Au] Autor:Garlet QI; Pires LDC; Milanesi LH; Marafiga JR; Baldisserotto B; Mello CF; Heinzmann BM
[Ad] Endereço:Post-Graduation Program in Pharmacology, Federal University of Santa Maria, Santa Maria, RS, Brazil.
[Ti] Título:(+)-Dehydrofukinone modulates membrane potential and delays seizure onset by GABAa receptor-mediated mechanism in mice.
[So] Source:Toxicol Appl Pharmacol;332:52-63, 2017 Oct 01.
[Is] ISSN:1096-0333
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:(+)-Dehydrofukinone (DHF), isolated from Nectandra grandiflora (Lauraceae) essential oil, induces sedation and anesthesia by modulation of GABAa receptors. However, no study has addressed whether DHF modulates other cellular events involved in the control of cellular excitability, such as seizure behavior. Therefore, the aim of the present study was to investigate the effect of DHF on cellular excitability and seizure behavior in mice. For this purpose, we used isolated nerve terminals (synaptosomes) to examine the effect of DHF on the plasma membrane potential, the involvement of GABAa receptors and the downstream activation of Ca mobilization. Finally, we performed an in vivo assay in order to verify whether DHF could impact on seizures induced by pentylenetetrazole (PTZ) in mice. The results showed that DHF induced a GABA-dependent sustained hyperpolarization, sensitive to flumazenil and absent in low-[Cl ] medium. Additionally, (1-100µM) DHF decreased KCl-evoked calcium mobilization over time in a concentration-dependent manner and this effect was prevented by flumazenil. DHF increased the latency to myoclonic jerks (10mg/kg), delayed the onset of generalized tonic-clonic seizures (10, 30 and 100mg/kg), and these effects were also blocked by the pretreatment with flumazenil. Our data indicate that DHF has anticonvulsant properties and the molecular target underlying this effect is likely to be the facilitation of GABAergic neuronal inhibition. The present study highlights the therapeutic potential of the natural compound DHF as a suppressor of neuronal excitability.
[Mh] Termos MeSH primário: Moduladores GABAérgicos/farmacologia
Potenciais da Membrana/efeitos dos fármacos
Receptores de GABA-A/metabolismo
Convulsões/tratamento farmacológico
Sesquiterpenos/farmacologia
[Mh] Termos MeSH secundário: Animais
Anticonvulsivantes/farmacologia
Feminino
Flumazenil/farmacologia
Camundongos
Pentilenotetrazol
Convulsões/induzido quimicamente
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anticonvulsants); 0 (GABA Modulators); 0 (Receptors, GABA-A); 0 (Sesquiterpenes); 0 (dehydrofukinone); 40P7XK9392 (Flumazenil); WM5Z385K7T (Pentylenetetrazole)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170723
[St] Status:MEDLINE


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[PMID]:28428226
[Au] Autor:Nik AM; Pressly B; Singh V; Antrobus S; Hulsizer S; Rogawski MA; Wulff H; Pessah IN
[Ad] Endereço:Department of Molecular Biosciences, School of Veterinary Medicine (A.M.N., S.A., S.H., I.N.P.), and Department of Pharmacology (B.P., V.S., M.A.R., H.W.), School of Medicine, University of California Davis, Davis, California; Department of Neurology, School of Medicine, University of California Dav
[Ti] Título:Rapid Throughput Analysis of GABA Receptor Subtype Modulators and Blockers Using DiSBAC (3) Membrane Potential Red Dye.
[So] Source:Mol Pharmacol;92(1):88-99, 2017 Jul.
[Is] ISSN:1521-0111
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Fluorometric imaging plate reader membrane potential dye (FMP-Red-Dye) is a proprietary tool for basic discovery and high-throughput drug screening for G-protein-coupled receptors and ion channels. We optimized and validated this potentiometric probe to assay functional modulators of heterologous expressed GABA receptor (GABA R) isoforms (synaptic 1 3 2, extrasynaptic 4 3 , and 3 homopentomers). High-resolution mass spectrometry identified FMP-Red-Dye as 5,5'-(1-propen-1-yl-3-ylidene)bis[1,3-dimethyl-2-thio-barbituric acid]. GABA R-expressing cells equilibrated with FMP-Red-Dye exhibited depolarized equilibrium membrane potentials compared with GABA R-null cells. The channel blockers picrotoxin, fipronil, and tetramethylenedisulfotetramine, and the competitive antagonist bicuculline reduced fluorescence near the levels in GABA R-null cells indicating that FMR-Red-Dye, a barbiturate derivative, activates GABA R-mediated outward Cl current in the absence of GABA. GABA caused concentration-dependent increases in fluorescence with rank order of potencies among GABA R isoforms consistent with results from voltage-clamp experiments (EC values for 4 3 , 1 3 2, and homopentamers were 6 ± 1, 40 ± 11, and >18 mM, respectively), whereas GABA R-null cells were unresponsive. Neuroactive steroids (NAS) increased fluorescence of GABA R expressing cells in the absence of GABA and demonstrated positive allosteric modulation in the presence of GABA, whereas benzodiazepines only exhibited positive allosteric modulator (PAM) activity. Of 20 NAS tested, allopregnanolone, (3 ,5 ,20E)-3-hydroxy-13,24-cyclo-18-norcholan-20-ene-21-carbonitrile, eltanolone, 5 -pregnan-3 ,21-diol-20-one, and ganaxolone showed the highest potency. The FMP-Red-Dye-based assay described here provides a sensitive and quantitative method of assessing the activity of GABA R agonists, antagonists, and PAMs on diverse GABA R isoforms. The assay has a wide range of applications, including screening for antiseizure agents and identifying channel blockers of interest to insecticide discovery or biosecurity.
[Mh] Termos MeSH primário: Corantes Fluorescentes/metabolismo
Antagonistas GABAérgicos/metabolismo
Moduladores GABAérgicos/metabolismo
Potenciais da Membrana/fisiologia
Subunidades Proteicas/metabolismo
Receptores de GABA-A/metabolismo
[Mh] Termos MeSH secundário: Animais
Relação Dose-Resposta a Droga
Corantes Fluorescentes/farmacologia
Antagonistas GABAérgicos/farmacologia
Moduladores GABAérgicos/farmacologia
Células HEK293
Seres Humanos
Potenciais da Membrana/efeitos dos fármacos
Camundongos
Subunidades Proteicas/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fluorescent Dyes); 0 (GABA Antagonists); 0 (GABA Modulators); 0 (Protein Subunits); 0 (Receptors, GABA-A)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171123
[Lr] Data última revisão:
171123
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170422
[St] Status:MEDLINE
[do] DOI:10.1124/mol.117.108563


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[PMID]:28411234
[Au] Autor:Koenig MK; Hodgeman R; Riviello JJ; Chung W; Bain J; Chiriboga CA; Ichikawa K; Osaka H; Tsuji M; Gibson KM; Bonnen PE; Pearl PL
[Ad] Endereço:From Child and Adolescent Neurology (M.K.K.), University of Texas Medical School, Houston; Neurology (R.H., P.L.P.), Boston Children's Hospital, Harvard Medical School, MA; Child Neurology (J.J.R., W.C., J.B., C.A.C.), Columbia University School of Medicine, New York, NY; Neurology (K.I., M.T.), Kan
[Ti] Título:Phenotype of GABA-transaminase deficiency.
[So] Source:Neurology;88(20):1919-1924, 2017 May 16.
[Is] ISSN:1526-632X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: We report a case series of 10 patients with γ-aminobutyric acid (GABA)-transaminase deficiency including a novel therapeutic trial and an expanded phenotype. METHODS: Case ascertainment, literature review, comprehensive evaluations, and long-term treatment with flumazenil. RESULTS: All patients presented with neonatal or early infantile-onset encephalopathy; other features were hypotonia, hypersomnolence, epilepsy, choreoathetosis, and accelerated linear growth. EEGs showed burst-suppression, modified hypsarrhythmia, multifocal spikes, and generalized spike-wave. Five of the 10 patients are currently alive with age at last follow-up between 18 months and 9.5 years. Treatment with continuous flumazenil was implemented in 2 patients. One patient, with a milder phenotype, began treatment at age 21 months and has continued for 20 months with improved alertness and less excessive adventitious movements. The second patient had a more severe phenotype and was 7 years of age at initiation of flumazenil, which was not continued. CONCLUSIONS: GABA-transaminase deficiency presents with neonatal or infantile-onset encephalopathy including hypersomnolence and choreoathetosis. A widened phenotypic spectrum is reported as opposed to lethality by 2 years of age. The GABA-A benzodiazepine receptor antagonist flumazenil may represent a therapeutic strategy.
[Mh] Termos MeSH primário: 4-Aminobutirato Transaminase/deficiência
Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico
Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia
[Mh] Termos MeSH secundário: Erros Inatos do Metabolismo dos Aminoácidos/tratamento farmacológico
Erros Inatos do Metabolismo dos Aminoácidos/mortalidade
Encéfalo/diagnóstico por imagem
Encéfalo/fisiopatologia
Criança
Pré-Escolar
Diagnóstico Diferencial
Feminino
Flumazenil/uso terapêutico
Seguimentos
Moduladores GABAérgicos/uso terapêutico
Seres Humanos
Lactente
Masculino
Fenótipo
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (GABA Modulators); 40P7XK9392 (Flumazenil); EC 2.6.1.19 (4-Aminobutyrate Transaminase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170606
[Lr] Data última revisão:
170606
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170416
[St] Status:MEDLINE
[do] DOI:10.1212/WNL.0000000000003936


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[PMID]:28242100
[Au] Autor:Sacre L; Ali SM; Villa A; Jouffroy R; Raphalen JH; Garnier R; Baud FJ
[Ad] Endereço:UMR 8257 cognitive action group, Paris Descartes university, 45, rue des Saints-Pères, 75270 Paris cedex 06, France; Paris poison control centre, hôpital Fernand-Widal, 200, rue du Faubourg-Saint-Denis, 75010 Paris, France. Electronic address: lynnsacre@hotmail.com.
[Ti] Título:Toxicodynetics in nordiazepam and oxazepam overdoses.
[So] Source:Ann Pharm Fr;75(3):163-171, 2017 May.
[Is] ISSN:0003-4509
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES: Toxicodynetics aims at defining the time-course of major clinical events in drug overdose. We report the toxicodynetics in mono-intoxications with oxazepam and nordiazepam. METHODS: Cases of oxazepam or nordiazepam overdoses collected at the Paris poison control centre from 1999 to 2014 on the basis of self-report. A particular attention was paid to eliminate the concomitant alcohol or psychotropic co-ingestions. The toxicodynetic parameters were assessed as previously described. Results are expressed using 10-90 percentiles. In adults, the dose was normalized (TI, toxic Index) by dividing the supposed ingested dose by the maximal recommended dose. RESULTS: Two hundred and fifty-one and 74 cases of oxazepam and nordiazepam poisonings were included, respectively. The Emax for oxazepam and nordiazepam were sleepiness or obtundation in 106 and 36 cases, respectively. Coma was used to qualify only one oxazepam overdose. The median delay in onset of the Emax was 1.5h (0.33-15) in nordiazepam and 4h (0.5-15) in oxazepam overdose. In both overdoses, the onset of Emax occurred on an "on-off" mode. In adults, the greatest TIs in nordiazepam and oxazepam overdoses were 45 and 26.7, respectively. The TI in the oxazepam-induced coma was 26.7, the largest dose. CONCLUSION: Data collected in PCC allow determining a number of toxicodynetic parameters. Toxicodynetics showed that nordiazepam is not a cause of coma even in large overdose while oxazepam causes coma only at a very high dose. Deep coma in nordiazepam overdose whatever the dose and deep coma in overdose with oxazepam involving TI less than 20 result from unrecognized drug-drug interaction.
[Mh] Termos MeSH primário: Overdose de Drogas/metabolismo
Moduladores GABAérgicos/efeitos adversos
Moduladores GABAérgicos/farmacocinética
Nordazepam/efeitos adversos
Nordazepam/farmacocinética
Oxazepam/efeitos adversos
Oxazepam/farmacocinética
Toxicocinética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Envelhecimento/metabolismo
Depressores do Sistema Nervoso Central/efeitos adversos
Criança
Pré-Escolar
Etanol/efeitos adversos
Feminino
Seres Humanos
Masculino
Meia-Idade
Estudos Retrospectivos
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; OBSERVATIONAL STUDY
[Nm] Nome de substância:
0 (Central Nervous System Depressants); 0 (GABA Modulators); 3K9958V90M (Ethanol); 67220MCM01 (Nordazepam); 6GOW6DWN2A (Oxazepam)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170814
[Lr] Data última revisão:
170814
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170301
[St] Status:MEDLINE


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[PMID]:28111292
[Au] Autor:Álvaro-Bartolomé M; Salort G; García-Sevilla JA
[Ad] Endereço:Laboratory of Neuropharmacology, IUNICS-IdISPa, University of the Balearic Islands (UIB), Palma de Mallorca, Spain; Redes Temáticas de Investigación Cooperativa en Salud-Red de Trastornos Adictivos (RETICS-RTA), ISCIII, Madrid, Spain.
[Ti] Título:Disruption of brain MEK-ERK sequential phosphorylation and activation during midazolam-induced hypnosis in mice: Roles of GABA receptor, MEK1 inactivation, and phosphatase MKP-3.
[So] Source:Prog Neuropsychopharmacol Biol Psychiatry;75:84-93, 2017 Apr 03.
[Is] ISSN:1878-4216
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Midazolam is a positive allosteric modulator at GABA receptor that induces a short hypnosis and neuroplasticity, in which the sequential phosphorylation of MEK1/2 and ERK1/2 was shown to play a role. This study investigated the parallel activation of p-MEK and p-ERK and regulatory mechanisms induced by midazolam through the stimulation of GABA receptors in the mouse brain. During the time course of midazolam (60mg/kg)-induced sleep in mice (lasting for about 2h) p-Ser217/221 MEK1/2 was increased (+146% to +258%) whereas, unexpectedly, p-Tyr204/Thr202 ERK1/2 was found decreased (-16% to -38%), revealing uncoupling of MEK to ERK signals in various brain regions. Midazolam-induced p-MEK1/2 upregulation was prevented by pretreatment (30min) with flumazenil (10mg/kg), indicating the involvement of GABA receptors. Also unexpectedly, midazolam-induced p-ERK1/2 downregulation was not prevented by flumazenil (10 or 30mg/kg). Notably, during midazolam-induced sleep the content of inactivated p-Thr286 MEK1, which can dampen ERK1/2 activation, was increased (+33% to +149%) through a mechanism sensitive to flumazenil (10mg/kg). Midazolam also increased MKP-3 (+13% to +73%) content and this upregulation was prevented by flumazenil (10mg/kg); an effect suggesting ERK inactivation because MKP-3 is the phosphatase selective for ERK1/2 dephosphorylation. The results indicate that during midazolam-induced sleep in mice there is an uncoupling of p-MEK (increased) to p-ERK (decreased) signals. p-ERK1/2 downregulation (not involving GABA receptors) is the result of increased inactivated MEK1 and phosphatase MKP-3 (both effects involving GABA receptors). These findings are relevant for the neurobiology and clinical use of benzodiazepines.
[Mh] Termos MeSH primário: Encéfalo/efeitos dos fármacos
Fosfatase 6 de Especificidade Dupla/metabolismo
Moduladores GABAérgicos/toxicidade
Midazolam/toxicidade
Proteína Quinase 1 Ativada por Mitógeno/metabolismo
Transdução de Sinais/efeitos dos fármacos
Sono/efeitos dos fármacos
[Mh] Termos MeSH secundário: Análise de Variância
Animais
Encéfalo/enzimologia
Encéfalo/ultraestrutura
Relação Dose-Resposta a Droga
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Flumazenil/farmacologia
Masculino
Camundongos
Fosforilação/efeitos dos fármacos
Frações Subcelulares/efeitos dos fármacos
Frações Subcelulares/metabolismo
Fatores de Tempo
Regulação para Cima/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (GABA Modulators); 40P7XK9392 (Flumazenil); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1); EC 3.1.3.48 (Dual Specificity Phosphatase 6); R60L0SM5BC (Midazolam)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170124
[St] Status:MEDLINE


  9 / 2705 MEDLINE  
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[PMID]:28109985
[Au] Autor:Althaus AL; McCarren HS; Alqazzaz A; Jackson C; McDonough JH; Smith CD; Hoffman E; Hammond RS; Robichaud AJ; Doherty JJ
[Ad] Endereço:Drug Discovery, Sage Therapeutics, Inc., Cambridge, MA, USA. Electronic address: alison.althaus@sagerx.com.
[Ti] Título:The synthetic neuroactive steroid SGE-516 reduces status epilepticus and neuronal cell death in a rat model of soman intoxication.
[So] Source:Epilepsy Behav;68:22-30, 2017 Mar.
[Is] ISSN:1525-5069
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Organophosphorus nerve agents (OPNAs) are irreversible inhibitors of acetylcholinesterase that pose a serious threat to public health because of their use as chemical weapons. Exposure to high doses of OPNAs can dramatically potentiate cholinergic synaptic activity and cause status epilepticus (SE). Current standard of care for OPNA exposure involves treatment with cholinergic antagonists, oxime cholinesterase reactivators, and benzodiazepines. However, data from pre-clinical models suggest that OPNA-induced SE rapidly becomes refractory to benzodiazepines. Neuroactive steroids (NAS), such as allopregnanolone, retain anticonvulsant activity in rodent models of benzodiazepine-resistant SE, perhaps because they modulate a broader variety of GABA receptor subtypes. SGE-516 is a novel, next generation NAS and a potent and selective GABA receptor positive allosteric modulator (PAM). The present study first established that SGE-516 reduced electrographic seizures in the rat lithium-pilocarpine model of pharmacoresistant SE. Then the anticonvulsant activity of SGE-516 was investigated in the soman-intoxication model of OPNA-induced SE. SGE-516 (5.6, 7.5, and 10mg/kg, IP) significantly reduced electrographic seizure activity compared to control when administered 20min after SE onset. When 10mg/kg SGE-516 was administered 40min after SE onset, seizure activity was still significantly reduced compared to control. In addition, all cohorts of rats treated with SGE-516 exhibited significantly reduced neuronal cell death as measured by FluoroJade B immunohistochemistry. These data suggest synthetic NASs that positively modulate both synaptic and extrasynaptic GABA receptors may be candidates for further study in the treatment of OPNA-induced SE.
[Mh] Termos MeSH primário: Anticonvulsivantes/farmacologia
Morte Celular/efeitos dos fármacos
Moduladores GABAérgicos/farmacologia
Neurônios/efeitos dos fármacos
Neurotransmissores/farmacologia
Convulsões/tratamento farmacológico
Soman
Estado Epiléptico/tratamento farmacológico
[Mh] Termos MeSH secundário: Animais
Anticonvulsivantes/uso terapêutico
Convulsivantes
Moduladores GABAérgicos/uso terapêutico
Masculino
Neurotransmissores/uso terapêutico
Pilocarpina
Ratos
Ratos Sprague-Dawley
Convulsões/induzido quimicamente
Estado Epiléptico/induzido quimicamente
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anticonvulsants); 0 (Convulsants); 0 (GABA Modulators); 0 (Neurotransmitter Agents); 01MI4Q9DI3 (Pilocarpine); 96-64-0 (Soman)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170809
[Lr] Data última revisão:
170809
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170123
[St] Status:MEDLINE


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[PMID]:28099183
[Au] Autor:Sahraian A; Jahromi LR; Ghanizadeh A; Mowla A
[Ad] Endereço:From the *Substance Abuse Research Center, and †Research Center for Psychiatry and Behavioral Sciences, Department of Psychiatry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
[Ti] Título:Memantine as an Adjuvant Treatment for Obsessive Compulsive Symptoms in Manic Phase of Bipolar Disorder: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.
[So] Source:J Clin Psychopharmacol;37(2):246-249, 2017 Apr.
[Is] ISSN:1533-712X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:PURPOSE/BACKGROUND: The aim of this study is to examine the effects of memantine as an adjuvant treatment for obsessive compulsive (OC) symptoms in patients with bipolar disorder (BD) type I, manic phase. METHODS/PROCEDURES: In this 16-week double-blind placebo-controlled randomized clinical trial, 58 patients in the manic phase of BD who had OC symptoms were randomly allocated to receive memantine or placebo plus their routine medications (lithium + olanzapine + clonazepam). The Yale Brown Obsessive Compulsive Behavior Scale was used to assess the outcomes. Adverse effects were also recorded. FINDINGS/RESULTS: Thirty-eight patients (19 in the memantine group and 19 in the placebo group) completed the trial. Throughout the trial, the mean score decreased from 20.26 ± 5.91 to 9.73 ± 5.44 in the memantine group (P < 0.000) and from 22.89 ± 5.70 to 16.63 ± 4.00 in the placebo group (P < 0.000). At the end of the study, 15 (78.94%) patients in the memantine group and 7 (36.84%) patients in the placebo group demonstrated more than 34% decline in the Yale Brown Obsessive Compulsive Behavior Scale score (P < 0.01). No serious adverse effects were reported. IMPLICATIONS/CONCLUSIONS: Our double-blind controlled clinical trial showed that memantine is an effective adjuvant agent for reducing OC symptoms in patients with BD. However, it needs to be noted that our study is preliminary, and larger double-blind controlled studies are needed to confirm the results.
[Mh] Termos MeSH primário: Antimaníacos/farmacologia
Antipsicóticos/farmacologia
Transtorno Bipolar/tratamento farmacológico
Antagonistas de Aminoácidos Excitatórios/farmacologia
Moduladores GABAérgicos/farmacologia
Memantina/farmacologia
Transtorno Obsessivo-Compulsivo/tratamento farmacológico
Avaliação de Resultados (Cuidados de Saúde)
[Mh] Termos MeSH secundário: Adjuvantes Farmacêuticos
Adulto
Antimaníacos/administração & dosagem
Antipsicóticos/administração & dosagem
Benzodiazepinas/administração & dosagem
Benzodiazepinas/farmacologia
Transtorno Bipolar/complicações
Clonazepam/administração & dosagem
Clonazepam/farmacologia
Método Duplo-Cego
Quimioterapia Combinada
Antagonistas de Aminoácidos Excitatórios/administração & dosagem
Feminino
Moduladores GABAérgicos/administração & dosagem
Seres Humanos
Compostos de Lítio/administração & dosagem
Compostos de Lítio/farmacologia
Masculino
Memantina/administração & dosagem
Meia-Idade
Transtorno Obsessivo-Compulsivo/etiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Adjuvants, Pharmaceutic); 0 (Antimanic Agents); 0 (Antipsychotic Agents); 0 (Excitatory Amino Acid Antagonists); 0 (GABA Modulators); 0 (Lithium Compounds); 12794-10-4 (Benzodiazepines); 5PE9FDE8GB (Clonazepam); N7U69T4SZR (olanzapine); W8O17SJF3T (Memantine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170626
[Lr] Data última revisão:
170626
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170119
[St] Status:MEDLINE
[do] DOI:10.1097/JCP.0000000000000651



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