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Registro de Ensaios Clínicos
Registro de Ensaios Clínicos
Registro de Ensaios Clínicos
Registro de Ensaios Clínicos
Registro de Ensaios Clínicos
Registro de Ensaios Clínicos
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[PMID]:29318278
[Au] Autor:Atri A; Frölich L; Ballard C; Tariot PN; Molinuevo JL; Boneva N; Windfeld K; Raket LL; Cummings JL
[Ad] Endereço:Ray Dolby Brain Health Center, California Pacific Medical Center, San Francisco.
[Ti] Título:Effect of Idalopirdine as Adjunct to Cholinesterase Inhibitors on Change in Cognition in Patients With Alzheimer Disease: Three Randomized Clinical Trials.
[So] Source:JAMA;319(2):130-142, 2018 01 09.
[Is] ISSN:1538-3598
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Importance: New therapeutic approaches for Alzheimer disease (AD) are needed. Objective: To assess whether idalopirdine, a selective 5-hydroxytryptamine-6 receptor antagonist, is effective for symptomatic treatment of mild to moderate AD. Design, Setting, and Participants: Three randomized clinical trials that included 2525 patients aged 50 years or older with mild to moderate AD (study 1: n = 933 patients at 119 sites; study 2: n = 858 at 158 sites; and study 3: n = 734 at 126 sites). The 24-week studies were conducted from October 2013 to January 2017; final follow-up on January 12, 2017. Interventions: Idalopirdine (10, 30, or 60 mg/d) or placebo added to cholinesterase inhibitor treatment (donepezil in studies 1 and 2; donepezil, rivastigmine, or galantamine in study 3). Main Outcomes and Measures: Primary end point in all 3 studies: change in cognition total score (range, 0-70; a lower score indicates less impairment) from baseline to 24 weeks measured by the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog); key secondary end points: Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Scale and 23-item Activities of Daily Living Inventory scores. Dose group efficacy required a significant benefit over placebo for the primary end point and 1 or more key secondary end points. Safety data and adverse event profiles were recorded. Results: Among 2525 patients randomized in the 3 trials (mean age, 74 years; mean baseline ADAS-Cog total score, 26; between 62% and 65% of participants were women), 2254 (89%) completed the studies. In study 1, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.37 for the 60-mg dose of idalopirdine group, 0.61 for the 30-mg dose group, and 0.41 for the placebo group (adjusted mean difference vs placebo, 0.05 [95% CI, -0.88 to 0.98] for the 60-mg dose group and 0.33 [95% CI, -0.59 to 1.26] for the 30-mg dose group). In study 2, the mean change in ADAS-Cog total score between baseline and 24 weeks was 1.01 for the 30-mg dose of idalopirdine group, 0.53 for the 10-mg dose group, and 0.56 for the placebo group (adjusted mean difference vs placebo, 0.63 [95% CI, -0.38 to 1.65] for the 30-mg dose group; given the gated testing strategy and the null findings at the 30-mg dose, statistical comparison of the 10-mg dose was not performed). In study 3, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.38 for the 60-mg dose of idalopirdine group and 0.82 for the placebo group (adjusted mean difference vs placebo, -0.55 [95% CI, -1.45 to 0.36]). Treatment-emergent adverse events occurred in between 55.4% and 69.7% of participants in the idalopirdine groups vs between 56.7% and 61.4% of participants in the placebo groups. Conclusions and Relevance: In patients with mild to moderate AD, the use of idalopirdine compared with placebo did not improve cognition over 24 weeks of treatment. These findings do not support the use of idalopirdine for the treatment of AD. Trial Registration: clinicaltrials.gov Identifiers: NCT01955161, NCT02006641, and NCT02006654.
[Mh] Termos MeSH primário: Doença de Alzheimer/tratamento farmacológico
Benzilaminas/uso terapêutico
Inibidores da Colinesterase/uso terapêutico
Indóis/uso terapêutico
Antagonistas da Serotonina/uso terapêutico
[Mh] Termos MeSH secundário: Acidentes por Quedas
Idoso
Idoso de 80 Anos ou mais
Doença de Alzheimer/psicologia
Benzilaminas/administração & dosagem
Benzilaminas/efeitos adversos
Inibidores da Colinesterase/efeitos adversos
Cognição/efeitos dos fármacos
Relação Dose-Resposta a Droga
Método Duplo-Cego
Quimioterapia Combinada
Feminino
Galantamina/uso terapêutico
Seres Humanos
Indanos/uso terapêutico
Indóis/administração & dosagem
Indóis/efeitos adversos
Masculino
Meia-Idade
Piperidinas/uso terapêutico
Rivastigmina/uso terapêutico
Antagonistas da Serotonina/administração & dosagem
Antagonistas da Serotonina/efeitos adversos
Falha de Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 ((2-(6-fluoro-1H-indol-3-yl)-ethyl)-(3-(2,2,3,3-tetrafluoropropoxy)benzyl)amine); 0 (Benzylamines); 0 (Cholinesterase Inhibitors); 0 (Indans); 0 (Indoles); 0 (Piperidines); 0 (Serotonin Antagonists); 0D3Q044KCA (Galantamine); 8SSC91326P (donepezil); PKI06M3IW0 (Rivastigmine)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180311
[Lr] Data última revisão:
180311
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180111
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1001/jama.2017.20373


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[PMID]:29467153
[Au] Autor:Le Couteur DG; Bateman B; Brayne C
[Ad] Endereço:Centre for Education and Research on Ageing, Concord Hospital and University of Sydney, Sydney, Australia.
[Ti] Título:Idalopirdine: another disappointment for people with dementia.
[So] Source:BMJ;360:k753, 2018 02 21.
[Is] ISSN:1756-1833
[Cp] País de publicação:England
[La] Idioma:eng
[Mh] Termos MeSH primário: Benzilaminas/uso terapêutico
Demência/tratamento farmacológico
Indóis/uso terapêutico
Antagonistas da Serotonina/uso terapêutico
[Mh] Termos MeSH secundário: Ensaios Clínicos como Assunto
Seres Humanos
Falha de Tratamento
[Pt] Tipo de publicação:EDITORIAL
[Nm] Nome de substância:
0 ((2-(6-fluoro-1H-indol-3-yl)-ethyl)-(3-(2,2,3,3-tetrafluoropropoxy)benzyl)amine); 0 (Benzylamines); 0 (Indoles); 0 (Serotonin Antagonists)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180223
[St] Status:MEDLINE
[do] DOI:10.1136/bmj.k753


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[PMID]:29335437
[Au] Autor:Zhang S; Zhang M; Jing Y; Yin X; Ma P; Zhang Z; Wang X; Di W; Zhuang G
[Ad] Endereço:State Key Laboratory of Oncogenes and Related Genes, Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
[Ti] Título:Deubiquitinase USP13 dictates MCL1 stability and sensitivity to BH3 mimetic inhibitors.
[So] Source:Nat Commun;9(1):215, 2018 01 15.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:MCL1 is a pivot member of the anti-apoptotic BCL-2 family proteins. While a distinctive feature of MCL1 resides in its efficient ubiquitination and destruction, the deubiquitinase USP9X has been implicated in the preservation of MCL1 expression by removing the polyubiquitin chains. Here we perform an unbiased siRNA screen and identify that the second deubiquitinase, USP13, regulates MCL1 stability in lung and ovarian cancer cells. Mechanistically, USP13 interacts with and stabilizes MCL1 via deubiquitination. As a result, USP13 depletion using CRISPR/Cas9 nuclease system inhibits tumor growth in xenografted nude mice. We further report that genetic or pharmacological inhibition of USP13 considerably reduces MCL1 protein abundance and significantly increases tumor cell sensitivity to BH3 mimetic inhibitors targeting BCL-2 and BCL-XL. Collectively, we nominate USP13 as a novel deubiquitinase which regulates MCL1 turnover in diverse solid tumors and propose that USP13 may be a potential therapeutic target for the treatment of various malignancies.
[Mh] Termos MeSH primário: Endopeptidases/metabolismo
Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo
Neoplasias/metabolismo
Ensaios Antitumorais Modelo de Xenoenxerto
[Mh] Termos MeSH secundário: Compostos de Anilina/farmacologia
Animais
Benzilaminas/farmacologia
Sistemas CRISPR-Cas
Linhagem Celular Tumoral
Endopeptidases/genética
Células HEK293
Seres Humanos
Camundongos Endogâmicos BALB C
Camundongos Nus
Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores
Proteína de Sequência 1 de Leucemia de Células Mieloides/genética
Neoplasias/tratamento farmacológico
Neoplasias/genética
Ligação Proteica
Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores
Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
Quinazolinas/farmacologia
Interferência de RNA
Sulfonamidas/farmacologia
Ubiquitinação/efeitos dos fármacos
Proteína bcl-X/antagonistas & inibidores
Proteína bcl-X/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Aniline Compounds); 0 (Benzylamines); 0 (MCL1 protein, human); 0 (Myeloid Cell Leukemia Sequence 1 Protein); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (Quinazolines); 0 (Sulfonamides); 0 (bcl-X Protein); 0 (spautin-1); EC 3.4.- (Endopeptidases); EC 3.4.- (USP13 protein, human); XKJ5VVK2WD (navitoclax)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180117
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02693-9


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[PMID]:27779493
[Au] Autor:Sales AJ; Hiroaki-Sato VA; Joca SR
[Ad] Endereço:aDepartment of Pharmacology, School of Medicine of Ribeirão Preto bDepartment of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto cCenter for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
[Ti] Título:Participation of hippocampal nitric oxide synthase and soluble guanylate cyclase in the modulation of behavioral responses elicited by the rat forced swimming test.
[So] Source:Behav Pharmacol;28(1):19-29, 2017 02.
[Is] ISSN:1473-5849
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Systemic or hippocampal administration of nitric oxide (NO) synthase inhibitors induces antidepressant-like effects in animals, implicating increased hippocampal levels of NO in the neurobiology of depression. However, the role played by different NO synthase in this process has not been clearly defined. As stress is able to induce neuroinflammatory mechanisms and trigger the expression of inducible nitric oxide synthase (iNOS) in the brain, as well as upregulate neuronal nitric oxide synthase (nNOS) activity, the aim of the present study was to investigate the possible differential contribution of hippocampal iNOS and nNOS in the modulation of the consequences of stress elicited by the forced swimming test. Male Wistar rats received intrahippocampal injections, immediately after the pretest or 1 h before the forced swimming test, of selective inhibitors of nNOS (N-propyl-L-arginine), iNOS (1400W), or sGC (ODQ), the main pharmacological target for NO. Stress exposure increased nNOS and phospho-nNOS levels at all time points, whereas iNOS expression was increased only 24 h after the pretest. All drugs induced an antidepressant-like effect. However, whereas the nNOS inhibitor was equally effective when injected at different times, the iNOS inhibitor was more effective 24 h after the pretest. These results suggest that hippocampal nNOS and iNOS contribute to increase in NO levels in response to stress, although with a differential time course after stress exposure.
[Mh] Termos MeSH primário: Óxido Nítrico Sintase Tipo II/metabolismo
Óxido Nítrico Sintase Tipo I/metabolismo
Guanilil Ciclase Solúvel/metabolismo
Estresse Psicológico/metabolismo
[Mh] Termos MeSH secundário: Amidinas/farmacologia
Animais
Arginina/análogos & derivados
Arginina/farmacologia
Benzilaminas/farmacologia
Modelos Animais de Doenças
Hipocampo/metabolismo
Masculino
Óxido Nítrico/metabolismo
Oxidiazóis/farmacologia
Ratos
Ratos Wistar
Natação
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (1H-(1,2,4)oxadiazolo(4,3-a)-quiloxalin-1-one); 0 (Amidines); 0 (Benzylamines); 0 (N(omega)-propylarginine); 0 (N-(3-(aminomethyl)benzyl)acetamidine); 0 (Oxadiazoles); 31C4KY9ESH (Nitric Oxide); 94ZLA3W45F (Arginine); EC 1.14.13.39 (Nitric Oxide Synthase Type I); EC 1.14.13.39 (Nitric Oxide Synthase Type II); EC 4.6.1.2 (Soluble Guanylyl Cyclase)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180228
[Lr] Data última revisão:
180228
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE
[do] DOI:10.1097/FBP.0000000000000263


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[PMID]:29217195
[Au] Autor:Bo T; Yamamori T; Suzuki M; Sakai Y; Yamamoto K; Inanami O
[Ad] Endereço:Laboratory of Radiation Biology, Department of Applied Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
[Ti] Título:Calmodulin-dependent protein kinase II (CaMKII) mediates radiation-induced mitochondrial fission by regulating the phosphorylation of dynamin-related protein 1 (Drp1) at serine 616.
[So] Source:Biochem Biophys Res Commun;495(2):1601-1607, 2018 01 08.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mitochondrial dynamics are suggested to be indispensable for the maintenance of cellular quality and function in response to various stresses. While ionizing radiation (IR) stimulates mitochondrial fission, which is mediated by the mitochondrial fission protein, dynamin-related protein 1 (Drp1), it remains unclear how IR promotes Drp1 activation and subsequent mitochondrial fission. Therefore, we conducted this study to investigate these concerns. First, we found that X-irradiation triggered Drp1 phosphorylation at serine 616 (S616) but not at serine 637 (S637). Reconstitution analysis revealed that introduction of wild-type (WT) Drp1 recovered radiation-induced mitochondrial fission, which was absent in Drp1-deficient cells. Compared with cells transfected with WT or S637A Drp1, the change in mitochondrial shape following irradiation was mitigated in S616A Drp1-transfected cells. Furthermore, inhibition of CaMKII significantly suppressed Drp1 S616 phosphorylation and mitochondrial fission induced by IR. These results suggest that Drp1 phosphorylation at S616, but not at S637, is prerequisite for radiation-induced mitochondrial fission and that CaMKII regulates Drp1 phosphorylation at S616 following irradiation.
[Mh] Termos MeSH primário: Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo
Dinaminas/metabolismo
Dinâmica Mitocondrial/fisiologia
Dinâmica Mitocondrial/efeitos da radiação
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Benzilaminas/farmacologia
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores
Células Cultivadas
Dinaminas/química
Dinaminas/genética
Camundongos
Mitocôndrias/metabolismo
Mitocôndrias/efeitos da radiação
Dinâmica Mitocondrial/efeitos dos fármacos
Mutagênese Sítio-Dirigida
Fosforilação/efeitos dos fármacos
Fosforilação/efeitos da radiação
Inibidores de Proteínas Quinases/farmacologia
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Serina/química
Sulfonamidas/farmacologia
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Benzylamines); 0 (KN 92); 0 (Protein Kinase Inhibitors); 0 (Recombinant Proteins); 0 (Sulfonamides); 139298-40-1 (KN 93); 452VLY9402 (Serine); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2); EC 3.6.5.5 (Dnm1l protein, mouse); EC 3.6.5.5 (Dynamins)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171209
[St] Status:MEDLINE


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[PMID]:29261743
[Au] Autor:Bharani KL; Derex R; Granholm AC; Ledreux A
[Ad] Endereço:Department of Neurosciences, Medical University of South Carolina, BSB, Charleston, SC, United States of America.
[Ti] Título:A noradrenergic lesion aggravates the effects of systemic inflammation on the hippocampus of aged rats.
[So] Source:PLoS One;12(12):e0189821, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Neuroinflammation is potentiated by early degeneration of the locus coeruleus noradrenergic pathway (LC-NE) commonly seen in aging-related neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. In animal models, lipopolysaccharide (LPS) induces strong peripheral immune responses that can cause cognitive changes secondary to neuroinflammation. The influence of the peripheral immune response on cognition might be exacerbated by LC-NE degeneration, but this has not been well characterized previously. In this study, we investigated how systemic inflammation affects neuroinflammation and cognition in aged rats that have had either normal or damaged LC-NE transmitter systems. Rats were first exposed to the selective noradrenergic (NE) neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) to induce degeneration of central NE pathways. Two weeks later, the rats received a low dose of LPS. This resulted in 3 treatment groups (Control, LPS-, and DSP4+LPS-treated rats) studied at 4 hours (short-term subgroup) and 7 days (long-term subgroup) following the LPS injection. DSP4+LPS-treated rats exhibited increased serum levels of several pro-inflammatory cytokines, increased astroglial and microglial activation in the hippocampus, and poorer performance in the novel object recognition task (NORT) compared to controls and LPS-treated rats. Additionally, serum and brain tissue levels of brain-derived neurotrophic factor (BDNF) were modulated over time in the DSP4+LPS group compared to the other two groups. Specifically, DSP4+LPS-treated rats in the short-term subgroup had lower hippocampal BDNF levels (~25%) than controls and LPS-treated rats, which negatively correlated with hippocampal astrogliosis and positively correlated with hippocampal IL-1ß levels. Serum and hippocampal BDNF levels in the DSP4+LPS-treated rats in the long-term subgroup returned to levels similar to the control group. These results show that systemic inflammation in LC-NE-lesioned aged rats promotes an exacerbated systemic and central inflammatory response compared to LC-NE-intact rats and alters BDNF levels, indicating the important role of this neurotransmitter system in response to neuroinflammation.
[Mh] Termos MeSH primário: Envelhecimento/patologia
Hipocampo/patologia
Inflamação/patologia
Norepinefrina/metabolismo
[Mh] Termos MeSH secundário: Análise de Variância
Animais
Astrócitos/patologia
Benzilaminas
Fator Neurotrófico Derivado do Encéfalo/sangue
Fator Neurotrófico Derivado do Encéfalo/metabolismo
Proteínas de Ligação ao Cálcio/metabolismo
Quimiocinas/sangue
Discriminação (Psicologia)
Imunofluorescência
Proteína Glial Fibrilar Ácida/metabolismo
Hipocampo/fisiopatologia
Inflamação/sangue
Interleucina-1beta/metabolismo
Lipopolissacarídeos
Locomoção
Masculino
Proteínas dos Microfilamentos/metabolismo
Microglia/patologia
Degeneração Neural/patologia
Ratos Endogâmicos F344
Análise e Desempenho de Tarefas
Tirosina 3-Mono-Oxigenase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aif1 protein, rat); 0 (Benzylamines); 0 (Brain-Derived Neurotrophic Factor); 0 (Calcium-Binding Proteins); 0 (Chemokines); 0 (Glial Fibrillary Acidic Protein); 0 (Interleukin-1beta); 0 (Lipopolysaccharides); 0 (Microfilament Proteins); EC 1.14.16.2 (Tyrosine 3-Monooxygenase); PQ1P7JP5C1 (DSP 4); X4W3ENH1CV (Norepinephrine)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180108
[Lr] Data última revisão:
180108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171221
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0189821


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[PMID]:29072707
[Au] Autor:Britton J; Jamison TF
[Ad] Endereço:Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
[Ti] Título:The assembly and use of continuous flow systems for chemical synthesis.
[So] Source:Nat Protoc;12(11):2423-2446, 2017 Nov.
[Is] ISSN:1750-2799
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The adoption of and opportunities in continuous flow synthesis ('flow chemistry') have increased significantly over the past several years. Continuous flow systems provide improved reaction safety and accelerated reaction kinetics, and have synthesised several active pharmaceutical ingredients in automated reconfigurable systems. Although continuous flow platforms are commercially available, systems constructed 'in-lab' provide researchers with a flexible, versatile, and cost-effective alternative. Herein, we describe the assembly and use of a modular continuous flow apparatus from readily available and affordable parts in as little as 30 min. Once assembled, the synthesis of a sulfonamide by reacting 4-chlorobenzenesulfonyl chloride with dibenzylamine in a single reactor coil with an in-line quench is presented. This example reaction offers the opportunity to learn several important skills including reactor construction, charging of a back-pressure regulator, assembly of stainless-steel syringes, assembly of a continuous flow system with multiple junctions, and yield determination. From our extensive experience of single-step and multistep continuous flow synthesis, we also describe solutions to commonly encountered technical problems such as precipitation of solids ('clogging') and reactor failure. Following this protocol, a nonspecialist can assemble a continuous flow system from reactor coils, syringes, pumps, in-line liquid-liquid separators, drying columns, back-pressure regulators, static mixers, and packed-bed reactors.
[Mh] Termos MeSH primário: Técnicas de Química Sintética/instrumentação
Reologia/instrumentação
Sulfonamidas/síntese química
[Mh] Termos MeSH secundário: Benzilaminas/química
Técnicas de Química Sintética/métodos
Clorobenzenos/química
Cinética
Reologia/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzylamines); 0 (Chlorobenzenes); 0 (Sulfonamides); 3G0YFX01C6 (dibenzylamine)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171102
[Lr] Data última revisão:
171102
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171027
[St] Status:MEDLINE
[do] DOI:10.1038/nprot.2017.102


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[PMID]:28984761
[Au] Autor:Gao JH; Chu XC; Wang LL; Ning B; Zhao CX
[Ad] Endereço:Department of Joint Surgery, People's Hospital of Dongying, Dongying P.R. China.
[Ti] Título:Effects of different anticoagulant drugs on the prevention of complications in patients after arthroplasty: A network meta-analysis.
[So] Source:Medicine (Baltimore);96(40):e8059, 2017 Oct.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: After arthroplasty treatment, some complications commonly occur, such as early revision, infection/dislocation, and venous thromboembolism (VTE). This study aims to use a network meta-analysis to compare effects of 9 anticoagulant drugs (edoxaban, dabigatan, apixaban, rivaroxaban, warfarin, heparin, bemiparin, ximelagatran, and enoxaparin) in preventing postoperative complications in arthroplasty patients. METHODS: After retrieving PubMed, Embase, and Cochrane Library database from the inception to November 2016, randomized controlled trials were enrolled. The integration of direct and indirect evidences was performed to calculate odd ratios and the surface under the cumulative ranking curves. Nineteen eligible randomized controlled trials were included. RESULTS: The network meta-analysis results showed that compared with warfarin, edoxaban, apixaban, and rivaroxaban had a lower incidence rate in asymptomatic deep venous thrombosis, which indicated that edoxaban, apixaban, and rivaroxaban had better effects on prevention. Similarly, in comparison to enoxaparin, edoxaban and rivaroxaban had better effect; rivaroxaban was better than ximelagatran in preventive effects. Compared with apixaban, edoxaban, dabigatan, rivaroxaban, and enoxaparin had a higher incidence rate in clinically relevant non-major bleeding, which showed that preventive effects were relatively poor. In addition, the results of the surface under the cumulative ranking curves showed that rivaroxaban and bemiparin worked best on symptomatic deep venous thrombosis and pulmonary embolism. In terms of bleeding, apixaban and warfarin had better preventive effects. CONCLUSION: Our findings suggested that rivaroxaban may work better in terms of symptomatic deep venous thrombosis and pulmonary embolism, whereas apixaban had better preventive effects in bleeding.
[Mh] Termos MeSH primário: Anticoagulantes/uso terapêutico
Artroplastia/efeitos adversos
Complicações Pós-Operatórias/prevenção & controle
Embolia Pulmonar/prevenção & controle
Tromboembolia Venosa/prevenção & controle
[Mh] Termos MeSH secundário: Azetidinas/uso terapêutico
Benzilaminas/uso terapêutico
Dabigatrana/uso terapêutico
Enoxaparina/uso terapêutico
Heparina/uso terapêutico
Heparina de Baixo Peso Molecular/uso terapêutico
Seres Humanos
Metanálise em Rede
Complicações Pós-Operatórias/etiologia
Embolia Pulmonar/etiologia
Pirazóis/uso terapêutico
Piridinas/uso terapêutico
Piridonas/uso terapêutico
Rivaroxabana/uso terapêutico
Tiazóis/uso terapêutico
Resultado do Tratamento
Tromboembolia Venosa/etiologia
Varfarina/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS
[Nm] Nome de substância:
0 (Anticoagulants); 0 (Azetidines); 0 (Benzylamines); 0 (Enoxaparin); 0 (Heparin, Low-Molecular-Weight); 0 (Pyrazoles); 0 (Pyridines); 0 (Pyridones); 0 (Thiazoles); 3Z9Y7UWC1J (apixaban); 49HFB70472 (ximelagatran); 5Q7ZVV76EI (Warfarin); 9005-49-6 (Heparin); 9NDF7JZ4M3 (Rivaroxaban); I0VM4M70GC (Dabigatran); NDU3J18APO (edoxaban); PUE0TO3XDR (bemiparin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171007
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000008059


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[PMID]:28934241
[Au] Autor:Lundgren H; Martinsson K; Cederbrant K; Jirholt J; Mucs D; Madeyski-Bengtson K; Havarinasab S; Hultman P
[Ad] Endereço:Division of Molecular and Immunological Pathology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Östergötland County Council, Linköping, Sweden.
[Ti] Título:HLA-DR7 and HLA-DQ2: Transgenic mouse strains tested as a model system for ximelagatran hepatotoxicity.
[So] Source:PLoS One;12(9):e0184744, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The oral thrombin inhibitor ximelagatran was withdrawn in the late clinical trial phase because it adversely affected the liver. In approximately 8% of treated patients, drug-induced liver injury (DILI) was expressed as transient alanine transaminase (ALT) elevations. No evidence of DILI had been revealed in the pre-clinical in vivo studies. A whole genome scan study performed on the clinical study material identified a strong genetic association between the major histocompatibility complex alleles for human leucocyte antigens (HLA) (HLA-DR7 and HLA-DQ2) and elevated ALT levels in treated patients. An immune-mediated pathogenesis was suggested. Here, we evaluated whether HLA transgenic mice models could be used to investigate whether the expression of relevant HLA molecules was enough to reproduce the DILI effects in humans. In silico modelling performed in this study revealed association of both ximelagatran (pro-drug) and melagatran (active drug) to the antigen-presenting groove of the homology modelled HLA-DR7 molecule suggesting "altered repertoire" as a key initiating event driving development of DILI in humans. Transgenic mouse strains (tgms) expressing HLA of serotype HLA-DR7 (HLA-DRB1*0701, -DRA*0102), and HLA-DQ2 (HLA-DQB1*0202,-DQA1*0201) were created. These two lines were crossed with a human (h)CD4 transgenic line, generating the two tgms DR7xhCD4 and DQ2xhCD4. To investigate whether the DILI effects observed in humans could be reproduced in tgms, the mice were treated for 28 days with ximelagatran. Results revealed no signs of DILI when biomarkers for liver toxicity were measured and histopathology was evaluated. In the ximelagatran case, presence of relevant HLA-expression in a pre-clinical model did not fulfil the prerequisite for reproducing DILI observed in patients. Nonetheless, for the first time an HLA-transgenic mouse model has been investigated for use in HLA-associated DILI induced by a low molecular weight compound. This study shows that mimicking of genetic susceptibility, expressed as DILI-associated HLA-types in mice, is not sufficient for reproducing the complex pathogenesis leading to DILI in man.
[Mh] Termos MeSH primário: Azetidinas/toxicidade
Benzilaminas/toxicidade
Doença Hepática Induzida por Substâncias e Drogas
Modelos Animais de Doenças
Antígenos HLA-DQ
Antígeno HLA-DR7
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Doença Hepática Induzida por Substâncias e Drogas/imunologia
Feminino
Antígenos HLA-DQ/genética
Antígenos HLA-DQ/metabolismo
Antígeno HLA-DR7/genética
Antígeno HLA-DR7/metabolismo
Seres Humanos
Linfócitos/metabolismo
Masculino
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Simulação de Acoplamento Molecular
Fenótipo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Azetidines); 0 (Benzylamines); 0 (HLA-DQ Antigens); 0 (HLA-DQ2 antigen); 0 (HLA-DR7 Antigen); 49HFB70472 (ximelagatran)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170922
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184744


  10 / 3449 MEDLINE  
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[PMID]:28926619
[Au] Autor:Herold M; Breuer J; Hucke S; Knolle P; Schwab N; Wiendl H; Klotz L
[Ad] Endereço:Department of Neurology, University of Muenster, Albert-Schweitzer-Campus 1, Muenster, Germany.
[Ti] Título:Liver X receptor activation promotes differentiation of regulatory T cells.
[So] Source:PLoS One;12(9):e0184985, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The nuclear receptor Liver X Receptor (LXR) is a ligand-activated transcription factor that has been implicated in control of chronic inflammation by downregulating pro-inflammatory T cell responses. An impaired function of regulatory T cells, a subset of CD4+ T cells with a crucial role in maintaining lymphocytes homeostasis and immune regulation, is frequently observed in chronic inflammatory diseases. We observed that pharmacological activation of LXR in T cells not only resulted in a thorough suppression of Th1 and Th17 polarization in vitro, but also significantly induced regulatory T cells (Treg) cell differentiation in a receptor-specific fashion. In line with this, systemic LXR activation by oral treatment of mice with the LXR agonist GW3965 induced gut-associated regulatory T cells in vivo. Importantly, such LXR-activated Tregs had a higher suppressive capacity in functional in vitro coculture assays with effector T cells. Our data thus point towards a dual role of LXR-mediated control of inflammation by suppression of pro-inflammatory T cells and reciprocal induction of regulatory T cells.
[Mh] Termos MeSH primário: Receptores X do Fígado/metabolismo
Linfócitos T Reguladores/metabolismo
[Mh] Termos MeSH secundário: Administração Oral
Animais
Benzoatos/farmacologia
Benzilaminas/farmacologia
Linfócitos T CD4-Positivos/citologia
Linfócitos T CD4-Positivos/metabolismo
Diferenciação Celular/efeitos dos fármacos
Técnicas de Cocultura
Citocinas/análise
Ensaio de Imunoadsorção Enzimática
Intestinos/imunologia
Intestinos/metabolismo
Receptores X do Fígado/agonistas
Receptores X do Fígado/genética
Linfonodos/efeitos dos fármacos
Linfonodos/imunologia
Camundongos
Camundongos Knockout
Linfócitos T Reguladores/citologia
Linfócitos T Reguladores/efeitos dos fármacos
Células Th1/citologia
Células Th1/efeitos dos fármacos
Células Th1/imunologia
Células Th17/citologia
Células Th17/efeitos dos fármacos
Células Th17/imunologia
Fator de Crescimento Transformador beta/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzoates); 0 (Benzylamines); 0 (Cytokines); 0 (GW 3965); 0 (Liver X Receptors); 0 (Transforming Growth Factor beta)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171020
[Lr] Data última revisão:
171020
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170920
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184985



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