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[PMID]:29184992
[Au] Autor:Le T; Zhang Z; Wu J; Shi H; Cao X
[Ad] Endereço:College of Life Science, Chongqing Normal University, Chongqing, 401331, China. hnxylt@163.com.
[Ti] Título:A fluorescent immunochromatographic strip test using a quantum dot-antibody probe for rapid and quantitative detection of 1-aminohydantoin in edible animal tissues.
[So] Source:Anal Bioanal Chem;410(2):565-572, 2018 Jan.
[Is] ISSN:1618-2650
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:A rapid, simple, and sensitive fluorescent immunochromatographic strip test (ICST) based on quantum dots (QDs) has been developed to detect 1-aminohydantoin (AHD), a major metabolite of nitrofurantoin in animal tissues. To achieve this, QD-labeled antibody conjugates, which consist of CdSe/ZnS QDs and monoclonal antibodies, were prepared by an activated ester method. Under optimal conditions, with the nitrophenyl derivative of AHD as the target, the ICST had a linear range from 0.1 to 100 ng/mL, with a correlation coefficient of 0.9656 and a 50% inhibitory concentration of 4.51 ng/mL. The limit of detection was 0.14 ng/g, which was below the minimum required performance limit of 1 µg/kg for AHD established by the European Commission. The recoveries for AHD ranged from 81.5% to 108.2%, with coefficients of variation below 13%, based on intraday and interday analysis. Furthermore, for AHD in real samples, the ICST showed high reliability and high correlation with liquid chromatography-tandem mass spectrometry (correlation coefficient of 0.9916). To the best of our knowledge, this is the first report of a novel and sensitive method based on a fluorescent ICST to detect AHD below the minimum required performance limit. The ICST demonstrated high reliability, and could be ideally suited for rapid, simple, and on-site screening of AHD contamination in animal tissues. Graphical abstract A rapid, simple, and sensitive fluorescent immunochromatographic strip test that is based on quantum dots was developed to detect 1-aminohydantoin (AHD), a major metabolite of nitrofurantoin in animal tissues. 2-NBA 2-nitrobenzaldehyde, NP nitrophenyl.
[Mh] Termos MeSH primário: Anticorpos Imobilizados/química
Análise de Alimentos/métodos
Contaminação de Alimentos/análise
Hidantoínas/análise
Imunocromatografia/instrumentação
Pontos Quânticos/química
Fitas Reagentes/análise
[Mh] Termos MeSH secundário: Animais
Anticorpos Monoclonais/química
Desenho de Equipamento
Peixes
Fluorescência
Imunocromatografia/métodos
Limite de Detecção
Reprodutibilidade dos Testes
[Pt] Tipo de publicação:EVALUATION STUDIES; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (1-aminohydantoin); 0 (Antibodies, Immobilized); 0 (Antibodies, Monoclonal); 0 (Hydantoins); 0 (Reagent Strips)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171130
[St] Status:MEDLINE
[do] DOI:10.1007/s00216-017-0756-1


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[PMID]:28845978
[Au] Autor:Alenko A; Fleming AM; Burrows CJ
[Ad] Endereço:Department of Chemistry, University of Utah , 315 South 1400 East, Salt Lake City, Utah 84112-0850, United States.
[Ti] Título:Reverse Transcription Past Products of Guanine Oxidation in RNA Leads to Insertion of A and C opposite 8-Oxo-7,8-dihydroguanine and A and G opposite 5-Guanidinohydantoin and Spiroiminodihydantoin Diastereomers.
[So] Source:Biochemistry;56(38):5053-5064, 2017 Sep 26.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Reactive oxygen species, both endogenous and exogenous, can damage nucleobases of RNA and DNA. Among the nucleobases, guanine has the lowest redox potential, making it a major target of oxidation. Although RNA is more prone to oxidation than DNA is, oxidation of guanine in RNA has been studied to a significantly lesser extent. One of the reasons for this is that many tools that were previously developed to study oxidation of DNA cannot be used on RNA. In the study presented here, the lack of a method for seeking sites of modification in RNA where oxidation occurs is addressed. For this purpose, reverse transcription of RNA containing major products of guanine oxidation was used. Extension of a DNA primer annealed to an RNA template containing 8-oxo-7,8-dihydroguanine (OG), 5-guanidinohydantoin (Gh), or the R and S diastereomers of spiroiminodihydantoin (Sp) was studied under standing start conditions. SuperScript III reverse transcriptase is capable of bypassing these lesions in RNA inserting predominantly A opposite OG, predominantly G opposite Gh, and almost an equal mixture of A and G opposite the Sp diastereomers. These data should allow RNA sequencing of guanine oxidation products by following characteristic mutation signatures formed by the reverse transcriptase during primer elongation past G oxidation sites in the template RNA strand.
[Mh] Termos MeSH primário: Guanidinas/química
Guanina/análogos & derivados
Guanosina/análogos & derivados
Hidantoínas/química
RNA/química
Transcrição Reversa
Compostos de Espiro/química
[Mh] Termos MeSH secundário: Adenina/química
Guanina/química
Guanosina/química
Guanosina/genética
Cinética
Oxirredução
DNA Polimerase Dirigida por RNA/química
DNA Polimerase Dirigida por RNA/metabolismo
Estereoisomerismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Guanidines); 0 (Hydantoins); 0 (Spiro Compounds); 0 (guanidinohydantoin); 0 (spiroiminodihydantoin); 12133JR80S (Guanosine); 5614-64-2 (8-hydroxyguanine); 5Z93L87A1R (Guanine); 63231-63-0 (RNA); EC 2.7.7.49 (RNA-Directed DNA Polymerase); JAC85A2161 (Adenine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170829
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00730


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[PMID]:28711352
[Au] Autor:Tong L; Kim SH; Chen L; Kosinski A; Shankar BB; Girijavallabhan V; Yang DY; Yu W; Zhou G; Shih NY; Chen S; Hu M; Lundell D; Niu X; Umland S; Kozlowski JA
[Ad] Endereço:Department of Medicinal Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: ling.tong@merck.com.
[Ti] Título:Development of a prodrug of hydantoin based TACE inhibitor.
[So] Source:Bioorg Med Chem Lett;27(16):3704-3708, 2017 08 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors led to fused bi-heteroaryl hydantoin series that demonstrate sub-nanomolar potency (Ki) as well as excellent activity in human whole blood (hWBA). However, lead compound 2 posed some formulation challenges which prevented it for further development. A prodrug approach was investigated to address this issue. The pivalate prodrug 3 can be formulated as stable neutral form and demonstrated improved DMPK properties when compared with parent compound.
[Mh] Termos MeSH primário: Proteína ADAM17/antagonistas & inibidores
Hidantoínas/química
Hidantoínas/síntese química
Hidantoínas/farmacologia
Ácidos Pentanoicos/química
Pró-Fármacos/síntese química
Pró-Fármacos/farmacologia
[Mh] Termos MeSH secundário: Proteína ADAM17/metabolismo
Administração Oral
Animais
Área Sob a Curva
Cães
Ativação Enzimática/efeitos dos fármacos
Meia-Vida
Haplorrinos
Seres Humanos
Hidantoínas/administração & dosagem
Hidantoínas/farmacocinética
Ácidos Pentanoicos/administração & dosagem
Ácidos Pentanoicos/farmacocinética
Pró-Fármacos/administração & dosagem
Pró-Fármacos/farmacocinética
Curva ROC
Ratos
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hydantoins); 0 (Pentanoic Acids); 0 (Prodrugs); 813RE8BX41 (pivalic acid); EC 3.4.24.86 (ADAM17 Protein)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170717
[St] Status:MEDLINE


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[PMID]:28613895
[Au] Autor:Durham TB; Marimuthu J; Toth JL; Liu C; Adams L; Mudra DR; Swearingen C; Lin C; Chambers MG; Thirunavukkarasu K; Wiley MR
[Ad] Endereço:Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
[Ti] Título:A Highly Selective Hydantoin Inhibitor of Aggrecanase-1 and Aggrecanase-2 with a Low Projected Human Dose.
[So] Source:J Med Chem;60(13):5933-5939, 2017 Jul 13.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Aggrecanase-1 and -2 (ADAMTS-4 and ADAMTS-5) are zinc metalloproteases involved in the degradation of aggrecan in cartilage. Inhibitors could provide a means of altering the progression of osteoarthritis. We report the identification of 7 which had good oral pharmacokinetics in rats and showed efficacy in a rat chemical model of osteoarthritis. The projected human dose required to achieve sustained plasma levels ≥10 times the hADAMTS-5 IC is 5 mg q.d.
[Mh] Termos MeSH primário: Proteína ADAMTS4/antagonistas & inibidores
Proteína ADAMTS5/antagonistas & inibidores
Inibidores Enzimáticos/química
Inibidores Enzimáticos/uso terapêutico
Hidantoínas/química
Hidantoínas/uso terapêutico
Osteoartrite/tratamento farmacológico
[Mh] Termos MeSH secundário: Proteína ADAMTS4/metabolismo
Proteína ADAMTS5/metabolismo
Agrecanas/metabolismo
Animais
Inibidores Enzimáticos/sangue
Inibidores Enzimáticos/farmacologia
Seres Humanos
Hidantoínas/sangue
Hidantoínas/farmacologia
Masculino
Simulação de Acoplamento Molecular
Osteoartrite/enzimologia
Osteoartrite/metabolismo
Ratos
Ratos Endogâmicos Lew
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aggrecans); 0 (Enzyme Inhibitors); 0 (Hydantoins); EC 3.4.24.- (ADAMTS5 Protein); EC 3.4.24.82 (ADAMTS4 Protein)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170801
[Lr] Data última revisão:
170801
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170615
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00650


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[PMID]:28558971
[Au] Autor:Tong L; Kim SH; Rosner K; Yu W; Shankar BB; Chen L; Li D; Dai C; Girijavallabhan V; Popovici-Muller J; Yang L; Zhou G; Kosinski A; Siddiqui MA; Shih NY; Guo Z; Orth P; Chen S; Lundell D; Niu X; Umland S; Kozlowski JA
[Ad] Endereço:Department of Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: ling.tong@merck.com.
[Ti] Título:Fused bi-heteroaryl substituted hydantoin compounds as TACE inhibitors.
[So] Source:Bioorg Med Chem Lett;27(14):3037-3042, 2017 07 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:We have identified a series of hydantoin-derived TNF-a converting enzyme (TACE) inhibitors containing a pendant fused bi-heteroaryl group, which demonstrate sub-nanomolar potency (Ki), excellent activity in human whole blood assay, and improved DMPK profiles over prior series.
[Mh] Termos MeSH primário: Proteína ADAM17/antagonistas & inibidores
Hidantoínas/química
Inibidores de Proteases/química
[Mh] Termos MeSH secundário: Proteína ADAM17/metabolismo
Animais
Área Sob a Curva
Cães
Ativação Enzimática/efeitos dos fármacos
Meia-Vida
Haplorrinos
Seres Humanos
Hidantoínas/síntese química
Hidantoínas/farmacologia
Inibidores de Proteases/síntese química
Inibidores de Proteases/farmacologia
Curva ROC
Ratos
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hydantoins); 0 (Protease Inhibitors); EC 3.4.24.86 (ADAM17 Protein); EC 3.4.24.86 (ADAM17 protein, human)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171124
[Lr] Data última revisão:
171124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170601
[St] Status:MEDLINE


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[PMID]:28544596
[Au] Autor:Ouhaddi Y; Nebbaki SS; Habouri L; Afif H; Lussier B; Kapoor M; Narumiya S; Pelletier JP; Martel-Pelletier J; Benderdour M; Fahmi H
[Ad] Endereço:University of Montreal Hospital Research Center and University of Montreal, Montreal, Quebec, Canada.
[Ti] Título:Exacerbation of Aging-Associated and Instability-Induced Murine Osteoarthritis With Deletion of D Prostanoid Receptor 1, a Prostaglandin D Receptor.
[So] Source:Arthritis Rheumatol;69(9):1784-1795, 2017 Sep.
[Is] ISSN:2326-5205
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: D prostanoid receptor 1 (DP1), a receptor for prostaglandin D , plays important roles in inflammation and cartilage metabolism. However, its role in the pathogenesis of osteoarthritis (OA) remains unknown. This study was undertaken to explore the roles of DP1 in the development of OA in murine models and to evaluate the efficacy of a DP1 selective agonist in the treatment of OA. METHODS: The development of aging-associated OA and destabilization of the medial meniscus (DMM)-induced OA was compared between DP1-deficient (DP1 ) and wild-type (WT) mice. The progression of OA was assessed by histology, immunohistochemistry, and micro-computed tomography. Cartilage explants from DP1 and WT mice were treated with interleukin-1α (IL-1α) ex vivo, to evaluate proteoglycan degradation. The effect of intraperitoneal administration of the DP1 selective agonist BW245C on OA progression was evaluated in WT mice. RESULTS: Compared to WT mice, DP1 mice had exacerbated cartilage degradation in both models of OA, and this was associated with increased expression of matrix metalloproteinase 13 and ADAMTS-5. In addition, DP1 mice demonstrated enhanced subchondral bone changes. Cartilage explants from DP1 mice showed enhanced proteoglycan degradation following treatment with IL-1α. Intraperitoneal injection of BW245C attenuated the severity of DMM-induced cartilage degradation and bony changes in WT mice. CONCLUSION: These findings indicate a critical role for DP1 signaling in OA pathogenesis. Modulation of the functions of DP1 may constitute a potential therapeutic target for the development of novel OA treatments.
[Mh] Termos MeSH primário: Artrite Experimental/genética
Artrite Experimental/patologia
Osteoartrite do Joelho/genética
Osteoartrite do Joelho/patologia
Receptores de Prostaglandina/deficiência
[Mh] Termos MeSH secundário: Proteína ADAMTS5/metabolismo
Animais
Cartilagem/efeitos dos fármacos
Cartilagem/patologia
Progressão da Doença
Hidantoínas/farmacologia
Interleucina-1alfa/farmacologia
Metaloproteinase 13 da Matriz/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Proteoglicanas/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hydantoins); 0 (Interleukin-1alpha); 0 (Proteoglycans); 0 (Receptors, Prostaglandin); 0 (prostanoid D receptor 1, mouse); 75693-75-3 (BW 245C); EC 3.4.24.- (ADAMTS5 Protein); EC 3.4.24.- (Matrix Metalloproteinase 13); EC 3.4.24.- (Mmp13 protein, mouse)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170921
[Lr] Data última revisão:
170921
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170526
[St] Status:MEDLINE
[do] DOI:10.1002/art.40160


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[PMID]:28514164
[Au] Autor:Kolbanovskiy M; Chowdhury MA; Nadkarni A; Broyde S; Geacintov NE; Scicchitano DA; Shafirovich V
[Ad] Endereço:Department of Chemistry, New York University , 100 Washington Square East, New York, New York 10003-5180, United States.
[Ti] Título:The Nonbulky DNA Lesions Spiroiminodihydantoin and 5-Guanidinohydantoin Significantly Block Human RNA Polymerase II Elongation in Vitro.
[So] Source:Biochemistry;56(24):3008-3018, 2017 Jun 20.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The most common, oxidatively generated lesion in cellular DNA is 8-oxo-7,8-dihydroguanine, which can be oxidized further to yield highly mutagenic spiroiminodihydantoin (Sp) and 5-guanidinohydantoin (Gh) in DNA. In human cell-free extracts, both lesions can be excised by base excision repair and global genomic nucleotide excision repair. However, it is not known if these lesions can be removed by transcription-coupled DNA repair (TCR), a pathway that clears lesions from DNA that impede RNA synthesis. To determine if Sp or Gh impedes transcription, which could make each a viable substrate for TCR, either an Sp or a Gh lesion was positioned on the transcribed strand of DNA under the control of a promoter that supports transcription by human RNA polymerase II. These constructs were incubated in HeLa nuclear extracts that contained active RNA polymerase II, and the resulting transcripts were resolved by denaturing polyacrylamide gel electrophoresis. The structurally rigid Sp strongly blocks transcription elongation, permitting 1.6 ± 0.5% nominal lesion bypass. In contrast, the conformationally flexible Gh poses less of a block to human RNAPII, allowing 9 ± 2% bypass. Furthermore, fractional lesion bypass for Sp and Gh is minimally affected by glycosylase activity found in the HeLa nuclear extract. These data specifically suggest that both Sp and Gh may well be susceptible to TCR because each poses a significant block to human RNA polymerase II progression. A more general principle is also proposed: Conformational flexibility may be an important structural feature of DNA lesions that enhances their transcriptional bypass.
[Mh] Termos MeSH primário: Guanidinas/farmacologia
Guanosina/análogos & derivados
Hidantoínas/farmacologia
RNA Polimerase II/antagonistas & inibidores
Compostos de Espiro/farmacologia
Elongação da Transcrição Genética/efeitos dos fármacos
[Mh] Termos MeSH secundário: Dano ao DNA
Reparo do DNA
Guanidinas/síntese química
Guanidinas/química
Guanosina/síntese química
Guanosina/química
Guanosina/farmacologia
Células HeLa
Seres Humanos
Hidantoínas/síntese química
Hidantoínas/química
Conformação Molecular
RNA Polimerase II/genética
RNA Polimerase II/metabolismo
Compostos de Espiro/síntese química
Compostos de Espiro/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Guanidines); 0 (Hydantoins); 0 (Spiro Compounds); 0 (guanidinohydantoin); 0 (spiroiminodihydantoin); 12133JR80S (Guanosine); EC 2.7.7.- (RNA Polymerase II)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170518
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00295


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[PMID]:28267474
[Au] Autor:Robinson VM; Bharucha DB; Mahaffey KW; Dorian P; Kowey PR; SHIELD-2 Investigators
[Ad] Endereço:Lankenau Medical Center and Lankenau Institute for Medical Research, Wynnewood, PA.
[Ti] Título:Results of a curtailed randomized controlled trial, evaluating the efficacy and safety of azimilide in patients with implantable cardioverter-defibrillators: The SHIELD-2 trial.
[So] Source:Am Heart J;185:43-51, 2017 Mar.
[Is] ISSN:1097-6744
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Frequent hospital attendances in patients with implantable cardioverter-defibrillators (ICDs) result in significant morbidity and health care costs. Current drugs to reduce ICD shocks and hospital visits have limited efficacy and considerable toxicity. We evaluated the efficacy and safety of azimilide, a novel oral class III antiarrhythmic, for use in ICD patients. METHODS: A total of 240 patients were enrolled in a prospective, randomized, double-blind, placebo-controlled trial to evaluate the effect of oral azimilide 75 mg daily in ICD patients with previously documented ventricular tachycardia or ventricular fibrillation, and a left ventricular ejection fraction ≤40%. The primary outcome metric was the adjudicated time-to-first unplanned cardiovascular (CV) hospitalization, or CV emergency department (ED) visit, or CV death. The trial was prematurely discontinued due to withdrawal of study sponsorship. RESULTS: Azimilide demonstrated numerical but statistically nonsignificant reductions in the primary composite outcome (odds ratio [OR] 0.79, 95% CI 0.44-1.44), unplanned CV hospitalizations (OR 0.75, 95% CI 0.41-1.38), ED visits (OR 0.68, 95% CI 0.35-1.31), and all-cause shocks (OR 0.58, 95% CI 0.32-1.05). The incidence of adverse events was lower in the azimilide group. Neutropenia was not observed (absolute neutrophil count <1000 µ/L), and there was one possible torsade de pointes case that led to a successful ICD discharge. CONCLUSION: The SHIELD-2 trial was statistically underpowered due to early trial termination and did not meet its primary objective. Despite this limitation, azimilide showed promise as a safe and effective drug in reducing all-cause shocks, unplanned hospitalizations, and ED visits in ICD patients.
[Mh] Termos MeSH primário: Antiarrítmicos/uso terapêutico
Morte Súbita Cardíaca/prevenção & controle
Desfibriladores Implantáveis
Insuficiência Cardíaca/terapia
Hidantoínas/uso terapêutico
Piperazinas/uso terapêutico
Taquicardia Ventricular/terapia
Fibrilação Ventricular/terapia
[Mh] Termos MeSH secundário: Idoso
Doenças Cardiovasculares/mortalidade
Morte Súbita Cardíaca/etiologia
Método Duplo-Cego
Término Precoce de Ensaios Clínicos
Cardioversão Elétrica
Serviço Hospitalar de Emergência/utilização
Feminino
Insuficiência Cardíaca/complicações
Insuficiência Cardíaca/fisiopatologia
Hospitalização/estatística & dados numéricos
Seres Humanos
Masculino
Meia-Idade
Razão de Chances
Modelos de Riscos Proporcionais
Volume Sistólico
Taquicardia Ventricular/etiologia
Fibrilação Ventricular/etiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Anti-Arrhythmia Agents); 0 (Hydantoins); 0 (Piperazines); 74QU6P2934 (azimilide)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170531
[Lr] Data última revisão:
170531
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170308
[St] Status:MEDLINE


  9 / 2360 MEDLINE  
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[PMID]:28242439
[Au] Autor:Boddum K; Hougaard C; Xiao-Ying Lin J; von Schoubye NL; Jensen HS; Grunnet M; Jespersen T
[Ad] Endereço:Cardiac Physiology Laboratory, University of Copenhagen, Faculty of Health Sciences, Department of Biomedical Sciences, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark. Electronic address: kimboddum@sund.ku.dk.
[Ti] Título:K 3.1/K 3.2 channel positive modulators enable faster activating kinetics and increase firing frequency in fast-spiking GABAergic interneurons.
[So] Source:Neuropharmacology;118:102-112, 2017 May 15.
[Is] ISSN:1873-7064
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Due to their fast kinetic properties, K 3.1 voltage gated potassium channels are important in setting and controlling firing frequency in neurons and pivotal in generating high frequency firing of interneurons. Pharmacological activation of K 3.1 channels may possess therapeutic potential for treatment of epilepsy, hearing disorders, schizophrenia and cognitive impairments. Here we thoroughly investigate the selectivity and positive modulation of the two small molecules, EX15 and RE01, on K 3 channels. Selectivity studies, conducted in Xenopus laevis oocytes confirmed a positive modulatory effect of the two compounds on K 3.1 and to a minor extent on K 3.2 channels. RE01 had no effect on the K 3.3 and K 3.4 channels, whereas EX15 had an inhibitory impact on the K 3.4 mediated current. Voltage-clamp experiments in monoclonal hK 3.1b/HEK293 cells (34 °C) revealed that the two compounds indeed induced larger currents and faster activation kinetics. They also decrease the speed of deactivation and shifted the voltage dependence of activation, to a more negative activation threshold. Application of action potential clamping and repetitive stimulation protocols of hK 3.1b expressing HEK293 cells revealed that EX15 and RE01 significantly increased peak amplitude, half width and decay time of K 3.1 mediated currents, even during high-frequency action potential clamping (250 Hz). In rat hippocampal slices, EX15 and RE01 increased neuronal excitability in fast-spiking interneurons in dentate gyrus. Action potential frequency was prominently increased at minor depolarizing steps, whereas more marginal effects of EX15 and RE01 were observed after stronger depolarizations. In conclusion, our results suggest that EX15 and RE01 positive modulation of K 3.1 and K 3.2 currents facilitate increased firing frequency in fast-spiking GABAergic interneurons.
[Mh] Termos MeSH primário: Potenciais de Ação/fisiologia
Fenômenos Biofísicos/fisiologia
Neurônios GABAérgicos/fisiologia
Hidantoínas/farmacologia
Piridinas/farmacologia
Canais de Potássio Shaw/metabolismo
[Mh] Termos MeSH secundário: 2-Amino-5-fosfonovalerato/farmacologia
Potenciais de Ação/efeitos dos fármacos
Animais
Fenômenos Biofísicos/efeitos dos fármacos
Encéfalo/citologia
Antagonistas de Aminoácidos Excitatórios/farmacologia
Antagonistas GABAérgicos/farmacologia
Neurônios GABAérgicos/efeitos dos fármacos
Células HEK293
Seres Humanos
Cinética
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Oócitos
Piridazinas/farmacologia
Quinoxalinas/farmacologia
Ratos
Ratos Sprague-Dawley
Proteínas Repressoras/farmacologia
Proteínas de Saccharomyces cerevisiae/farmacologia
Canais de Potássio Shaw/genética
Xenopus laevis
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (EX15 hydantoin compound); 0 (Excitatory Amino Acid Antagonists); 0 (GABA Antagonists); 0 (Hydantoins); 0 (Pyridazines); 0 (Pyridines); 0 (Quinoxalines); 0 (ROX1 protein, S cerevisiae); 0 (Repressor Proteins); 0 (Saccharomyces cerevisiae Proteins); 0 (Shaw Potassium Channels); 62T278S1MX (FG 9041); 76726-92-6 (2-Amino-5-phosphonovalerate); 99460MG420 (gabazine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170301
[St] Status:MEDLINE


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[PMID]:28150586
[Au] Autor:Zivanovic MN; Kosaric JV; Smit B; Seklic DS; Pavlovic RZ; Markovic SD
[Ad] Endereço:Department of Biology and Ecology, Faculty of Science, University of Kragujevac, Radoja Domanovica 12, 34000 Kragujevac, Serbia. zivanovicm@kg.ac.rs.
[Ti] Título:Novel seleno-hydantoin palladium(II) complex - antimigratory, cytotoxic and prooxidative potential on human colon HCT-116 and breast MDA-MB-231 cancer cells.
[So] Source:Gen Physiol Biophys;36(2):187-196, 2017 Apr.
[Is] ISSN:0231-5882
[Cp] País de publicação:Slovakia
[La] Idioma:eng
[Ab] Resumo:Selenium and palladium containing compounds separately exert multifunctional effects on cells. While selenium containing compounds usually exert antioxidative properties, palladium(II) containing compounds are cytotoxic and prooxidative. Here we investigated biological effects of bicyclic seleno-hydantoin cis-7a-ethyl-5-methyl-5-phenylselanylmethyl-tetrahydro-pyrrolo[1,2-c]imidazole-1,3-dione (Hid-Se), and its palladium(II) complex, trans-bis-(cis-7a-ethyl-5-methyl-5-phenylselanylmethyl-tetrahydro-pyrrolo[1,2-c]imidazole-1,3-dionato) palladium(II) chloride ((Hid-Se)2Pd) on human colon HCT-116 and breast MDA-MB-231 cancer cell lines. Hid-Se and (Hid-Se)2Pd showed prooxidative and cytotoxic character. In all performed experiments (Hid-Se)2Pd proved to be more active, i.e. this substance exerted greater prooxidative effect, cytotoxicity and influence on cell migration potential. Even though Hid-Se and (Hid-Se)2Pd enhanced migration of HCT-116 cells, very important feature of these substances is the strong antimigratory potential on metastatic MDA-MB-231 cells.
[Mh] Termos MeSH primário: Movimento Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Neoplasias Experimentais/tratamento farmacológico
Neoplasias Experimentais/fisiopatologia
Paládio/administração & dosagem
Selênio/administração & dosagem
[Mh] Termos MeSH secundário: Antineoplásicos/administração & dosagem
Relação Dose-Resposta a Droga
Composição de Medicamentos/métodos
Células HCT116
Seres Humanos
Hidantoínas/química
Neoplasias Experimentais/patologia
Oxidantes/administração & dosagem
Paládio/química
Espécies Reativas de Oxigênio/metabolismo
Selênio/química
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Hydantoins); 0 (Oxidants); 0 (Reactive Oxygen Species); 5TWQ1V240M (Palladium); H6241UJ22B (Selenium)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170619
[Lr] Data última revisão:
170619
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170203
[St] Status:MEDLINE
[do] DOI:10.4149/gpb_2016036



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