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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]:29268129
[Au] Autor:Cen J; Guo H; Hong C; Lv J; Yang Y; Wang T; Fang D; Luo W; Wang C
[Ad] Endereço:Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, China.
[Ti] Título:Development of tacrine-bifendate conjugates with improved cholinesterase inhibitory and pro-cognitive efficacy and reduced hepatotoxicity.
[So] Source:Eur J Med Chem;144:128-136, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A novel series of tacrine-bifendate (THA-DDB) conjugates (7a-e) were synthesized and evaluated as potential anti-Alzheimer's agents. These compounds showed potent cholinesterase and self-induced ß-amyloid (Aß) aggregation inhibitory activities. A Lineweaver-Burk plot and molecular modeling study showed that these compounds can target both catalytic active site (CAS) and peripheral anionic site (PAS) of acetylcholinesterase (AChE). The cytotoxicity of the conjugate 7d against PC12 and HepG2 cells and hepatotoxicity against human hepatocyte cell line (HL-7702) were found to be considerably less compared to THA. Moreover, treatment with 7d did not exhibit significant hepatotoxicity in mice. Finally, in vivo studies confirmed that 7d significantly ameliorates the cognitive performances of scopolamine-treated ICR mice. Therefore, 7d has high potential for the treatment of Alzheimer's disease and warrants further investigation.
[Mh] Termos MeSH primário: Compostos de Bifenilo/química
Compostos de Bifenilo/farmacologia
Inibidores da Colinesterase/química
Inibidores da Colinesterase/farmacologia
Cognição/efeitos dos fármacos
Tacrina/análogos & derivados
Tacrina/farmacologia
[Mh] Termos MeSH secundário: Acetilcolinesterase/metabolismo
Doença de Alzheimer/tratamento farmacológico
Doença de Alzheimer/patologia
Animais
Compostos de Bifenilo/toxicidade
Linhagem Celular
Doença Hepática Induzida por Substâncias e Drogas/etiologia
Doença Hepática Induzida por Substâncias e Drogas/patologia
Inibidores da Colinesterase/toxicidade
Colinesterases/metabolismo
Desenho de Drogas
Células Hep G2
Seres Humanos
Fígado/efeitos dos fármacos
Fígado/patologia
Masculino
Camundongos Endogâmicos ICR
Células PC12
Ratos
Tacrina/toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biphenyl Compounds); 0 (Cholinesterase Inhibitors); 0G32E321W1 (bifendate); 4VX7YNB537 (Tacrine); EC 3.1.1.7 (Acetylcholinesterase); EC 3.1.1.8 (Cholinesterases)
[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:171222
[St] Status:MEDLINE


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[PMID]:28741230
[Au] Autor:Velayudhan L; Ffytche D; Ballard C; Aarsland D
[Ad] Endereço:Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and Neurosciences, Kings College London, Box PO 70, De Crespigny Park, London, SE5 8AF, UK.
[Ti] Título:New Therapeutic Strategies for Lewy Body Dementias.
[So] Source:Curr Neurol Neurosci Rep;17(9):68, 2017 Sep.
[Is] ISSN:1534-6293
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:This article reviews current treatment strategies and recent advances for the Lewy body dementias (LBDs). Current available symptom treatment strategies are based on monoaminergic, cholinergic and glutaminergic neurotransmitter systems. Relatively robust evidence exists for cholinesterase inhibitors for cognitive impairment in LBD and in Parkinson's disease for antidepressants, clozapine and recently pimavanserin for psychosis. interpidine (RVT 101) and nelotanserin are currently under investigation. Non-pharmacological interventions, such as cognitive stimulation, physical exercises and neuromodulation strategies, may be useful in Parkinson's disease but have not yet been tested in dementias. Disease-modifying approaches are aimed at preventing, slowing or ameliorating the production, aggregation and deposition of pathological proteins, including immunotherapy targeting α-synuclein and an ongoing trial using ambroxol which increases glucocerebrosidase activity to lower the levels of the protein alpha-synuclein. Other disease-modifying clinical trials are using agents to augment insulin signalling, stem cell therapy, reducing amyloid pathology and gene therapy.
[Mh] Termos MeSH primário: Gerenciamento Clínico
Doença por Corpos de Lewy/diagnóstico
Doença por Corpos de Lewy/terapia
[Mh] Termos MeSH secundário: Inibidores da Colinesterase/uso terapêutico
Terapia Genética/tendências
Seres Humanos
Doença por Corpos de Lewy/imunologia
Doença de Parkinson/diagnóstico
Doença de Parkinson/imunologia
Doença de Parkinson/terapia
Piperidinas/uso terapêutico
Transplante de Células-Tronco/tendências
Ureia/análogos & derivados
Ureia/uso terapêutico
alfa-Sinucleína/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Cholinesterase Inhibitors); 0 (Piperidines); 0 (alpha-Synuclein); 8W8T17847W (Urea); JZ963P0DIK (pimavanserin)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE
[do] DOI:10.1007/s11910-017-0778-2


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[PMID]:28452906
[Au] Autor:Hsu CW; Lee Y; Lee CY; Lin PY
[Ad] Endereço:Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
[Ti] Título:Reversible Pisa Syndrome Induced by Rivastigmine in a Patient With Early-Onset Alzheimer Disease.
[So] Source:Clin Neuropharmacol;40(3):147-148, 2017 May/Jun.
[Is] ISSN:1537-162X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pisa syndrome (PS) is a state of dystonic muscle contraction with a marked truncal deviation to one side. It is an uncommon adverse effect of antipsychotic drugs, but is rarely reported in patients receiving acetylcholinesterase inhibitors, especially rivastigmine. We present a 57-year-old female patient with Alzheimer disease who began to develop symptoms of dementia at the age of 51 years. She was observed to have symptoms of PS after continuous use of rivastigmine (9 mg/d) for nearly 2 years. The PS symptoms improved after the dose of rivastigmine was reduced but recurred when the dose was added back to 9 mg/d. Finally, after we decreased the dose to 4.5 mg/d, her PS symptoms were remitted. This report reminds us that clinicians need to be cautious about the risk of PS when prescribing rivastigmine in a patient with early-onset Alzheimer disease.
[Mh] Termos MeSH primário: Doença de Alzheimer/tratamento farmacológico
Inibidores da Colinesterase/efeitos adversos
Fármacos Neuroprotetores/efeitos adversos
Síndromes Neurotóxicas/terapia
Rivastigmina/efeitos adversos
[Mh] Termos MeSH secundário: Inibidores da Colinesterase/administração & dosagem
Inibidores da Colinesterase/uso terapêutico
Relação Dose-Resposta a Droga
Monitoramento de Medicamentos
Distúrbios Distônicos/etiologia
Distúrbios Distônicos/prevenção & controle
Feminino
Seres Humanos
Meia-Idade
Neuroimagem
Fármacos Neuroprotetores/administração & dosagem
Fármacos Neuroprotetores/uso terapêutico
Síndromes Neurotóxicas/diagnóstico por imagem
Síndromes Neurotóxicas/fisiopatologia
Rivastigmina/administração & dosagem
Rivastigmina/uso terapêutico
Resultado do Tratamento
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cholinesterase Inhibitors); 0 (Neuroprotective Agents); PKI06M3IW0 (Rivastigmine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1097/WNF.0000000000000215


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[PMID]:29353726
[Au] Autor:Czarnecka K; Chufarova N; Halczuk K; Maciejewska K; Girek M; Skibinski R; Jonczyk J; Bajda M; Kabzinski J; Majsterek I; Szymanski P
[Ad] Endereço:Department of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Faculty of Pharmacy, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland. Electronic address: kamila.czarnecka@umed.lodz.pl.
[Ti] Título:Tetrahydroacridine derivatives with dichloronicotinic acid moiety as attractive, multipotent agents for Alzheimer's disease treatment.
[So] Source:Eur J Med Chem;145:760-769, 2018 Feb 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A novel series of 9-amino-1,2,3,4-tetrahydroacridine and 5,6-dichloronicotinic acid moiety were conjugated with different linkers. Afterwards new derivatives were evaluated as potential multifunctional acetylcholinesterase inhibitors (AChEIs), anti-Alzheimer's disease (AD) drug candidates. All the compounds were synthesized and tested for capacity for the inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. Specifically, the most promising derivative 3b (IC = 1.02 nM) had higher inhibitory potency compared to the reference drug, tacrine. Consequently, kinetic studies of 3b compound showed a mixed-type inhibition of both AChE and BuChE. Afterwards the best potent AChE inhibitor has been examined on amyloid ß (Aß) self-induced aggregation. Furthermore, 3b compound was tested in various concentrations and had moderate activity against Aß aggregation. Inhibition of Aß aggregation was 46.63% and 19.41% at 50 µM and 5  µM concentrations, respectively. Moreover, no cytotoxicity was observed for the mentioned concentrations. Therefore, 3b compound is a promising multipotent agent for the treatment of AD.
[Mh] Termos MeSH primário: Acetilcolinesterase/metabolismo
Acridinas/farmacologia
Doença de Alzheimer/tratamento farmacológico
Butirilcolinesterase/metabolismo
Inibidores da Colinesterase/farmacologia
Ácidos Nicotínicos/farmacologia
[Mh] Termos MeSH secundário: Acridinas/química
Doença de Alzheimer/metabolismo
Peptídeos beta-Amiloides/antagonistas & inibidores
Peptídeos beta-Amiloides/metabolismo
Animais
Inibidores da Colinesterase/síntese química
Inibidores da Colinesterase/química
Relação Dose-Resposta a Droga
Electrophorus
Cavalos
Seres Humanos
Modelos Moleculares
Estrutura Molecular
Ácidos Nicotínicos/química
Relação Estrutura-Atividade
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (5,6-dichloronicotinic acid); 0 (Acridines); 0 (Amyloid beta-Peptides); 0 (Cholinesterase Inhibitors); 0 (Nicotinic Acids); EC 3.1.1.7 (Acetylcholinesterase); EC 3.1.1.8 (Butyrylcholinesterase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180123
[St] Status:MEDLINE


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[PMID]:29335209
[Au] Autor:Chierrito TPC; Pedersoli-Mantoani S; Roca C; Sebastian-Pérez V; Martínez-Gonzalez L; Pérez DI; Perez C; Canales A; Cañada FJ; Campillo NE; Carvalho I; Martinez A
[Ad] Endereço:Centro de Investigaciones Biologicas (CIB-CSIC), Ramiro de Maetzu 9, Madrid, Spain; School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Avenida do Café, s/ n, 14040-903, Ribeirão Preto, SP, Brazil.
[Ti] Título:Chameleon-like behavior of indolylpiperidines in complex with cholinesterases targets: Potent butyrylcholinesterase inhibitors.
[So] Source:Eur J Med Chem;145:431-444, 2018 Feb 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Alzheimer's disease (AD) is the most common form of dementia worldwide with an increasing prevalence for the next years. The multifactorial nature of AD precludes the design of new drugs directed to a single target being probably one of the reasons for recent failures. Therefore, dual binding site acetylcholinesterase (AChE) inhibitors have been revealed as cognitive enhancers and ß-amyloid modulators offering an alternative in AD therapy field. Based on the dual ligands NP61 and donepezil, the present study reports the synthesis of a series of indolylpiperidines hybrids to optimize the NP61 structure preserving the indole nucleus, but replacing the tacrine moiety of NP61 by benzyl piperidine core found in donepezil. Surprisingly, this new family of indolylpiperidines derivatives showed very potent and selective hBuChE inhibition. Further studies of NMR and molecular dynamics have showed the capacity of these hybrid molecules to change their bioactive conformation depending on the binding site, being capable to inhibit with different shapes BuChE and residually AChE.
[Mh] Termos MeSH primário: Acetilcolinesterase/metabolismo
Butirilcolinesterase/metabolismo
Inibidores da Colinesterase/farmacologia
Indóis/farmacologia
Piperidinas/farmacologia
[Mh] Termos MeSH secundário: Inibidores da Colinesterase/síntese química
Inibidores da Colinesterase/química
Relação Dose-Resposta a Droga
Seres Humanos
Indóis/síntese química
Indóis/química
Estrutura Molecular
Piperidinas/síntese química
Piperidinas/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cholinesterase Inhibitors); 0 (Indoles); 0 (Indolylpiperidine); 0 (Piperidines); EC 3.1.1.7 (Acetylcholinesterase); EC 3.1.1.8 (Butyrylcholinesterase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180117
[St] Status:MEDLINE


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[PMID]:29324339
[Au] Autor:Azzouz R; Peauger L; Gembus V; Tîntas ML; Sopková-de Oliveira Santos J; Papamicaël C; Levacher V
[Ad] Endereço:VFP Therapies, 15 rue François Couperin, 76000 Rouen, France.
[Ti] Título:Novel donepezil-like N-benzylpyridinium salt derivatives as AChE inhibitors and their corresponding dihydropyridine "bio-oxidizable" prodrugs: Synthesis, biological evaluation and structure-activity relationship.
[So] Source:Eur J Med Chem;145:165-190, 2018 Feb 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:As an extension of our previous work on donepezil-based "bio-oxidizable" prodrug approach, two new classes of N-benzylpyridinium donepezil analogues in tetralone B2 and acetophenone B3 series and a new set of indanone derivatives B1 were investigated along with the corresponding dihydropyridine prodrugs A1-3. A total of fifty one N-benzylpyridinium quaternary donepezil analogues B1-3 and twenty two prodrugs A1-3 were synthesized and evaluated for their inhibitory activities against hAChE and eqBuChE. While most prodrugs A1-3 were demonstrated to be inactive against AChE (IC > 10 µM), a large number of the corresponding N-benzylpyridinium salt B1-3 exhibited appealing three-to-one-digit nanomolar hAChE inhibitory activities and even reaching subnanomolar activity (IC = 0.36 nM). In addition, in silico docking studies were conducted for several compounds to explain the more relevant in vitro results. Lastly, the influence of the two stereogenic centers in prodrugs A was also evaluated, highlighting not only marked differences in residual AChE inhibitory activity of the four separated isomers of prodrug 23h (IC ranging from 173 nM to 10 µM) but also significant variations of the oxidation rate between two separated diastereoisomers of prodrug 24a. This work provides useful information in the search of a preclinical candidate to conduct further development of this attractive "bio-oxidizable" prodrug strategy.
[Mh] Termos MeSH primário: Acetilcolinesterase/metabolismo
Inibidores da Colinesterase/farmacologia
Di-Hidropiridinas/farmacologia
Pró-Fármacos/farmacologia
Compostos de Piridínio/farmacologia
[Mh] Termos MeSH secundário: Animais
Butirilcolinesterase/metabolismo
Inibidores da Colinesterase/síntese química
Inibidores da Colinesterase/química
Di-Hidropiridinas/química
Relação Dose-Resposta a Droga
Electrophorus
Cavalos
Simulação de Acoplamento Molecular
Estrutura Molecular
Pró-Fármacos/síntese química
Pró-Fármacos/química
Compostos de Piridínio/síntese química
Compostos de Piridínio/química
Sais/síntese química
Sais/química
Sais/farmacologia
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cholinesterase Inhibitors); 0 (Dihydropyridines); 0 (Prodrugs); 0 (Pyridinium Compounds); 0 (Salts); 7M8K3P6I89 (1,4-dihydropyridine); EC 3.1.1.7 (Acetylcholinesterase); EC 3.1.1.8 (Butyrylcholinesterase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180112
[St] Status:MEDLINE


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[PMID]:29357379
[Au] Autor:Darwiche W; Gay-Quéheillard J; Delanaud S; El Khayat El Sabbouri H; Khachfe H; Joumaa W; Bach V; Ramadan W
[Ad] Endereço:PériTox, Périnatalité & Risques Toxiques, UMR-I 01 INERIS, Amiens, France.
[Ti] Título:Impact of chronic exposure to the pesticide chlorpyrifos on respiratory parameters and sleep apnea in juvenile and adult rats.
[So] Source:PLoS One;13(1):e0191237, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The widely used organophosphorus pesticide chlorpyrifos (CPF) is often detected in food. CPF inhibits acetylcholinesterase and can modify muscle contractility and respiratory patterns. We studied the effects of chronic exposure to CPF on respiratory parameters and diaphragm contractility in 21- and 60-days old rats. Pregnant rats were exposed to oral CPF (1 or 5 mg/ kg /day: CPF-1 or CPF-5 groups vs vehicle: controls) from gestation onset up to weaning of the pups that were individually gavaged (CPF or vehicle) thereafter. Two developmental time points were studied: weaning (day 21) and adulthood (day 60). Whole-body plethysmography was used to score breathing patterns and apnea index during sleep. Then, diaphragm strips were dissected for the assessment of contractility and acetylcholinesterase activity. Results showed that the sleep apnea index was higher in CPF-exposed rats than in controls. In adult rats, the expiratory time and tidal volume were higher in CPF-exposed animals than in controls. At both ages, the diaphragm's amplitude of contraction and fatigability index were higher in the CPF-5 group, due to lower acetylcholinesterase activity. We conclude that chronic exposure to CPF is associated with higher sleep apnea index and diaphragm contractility, and modifies respiratory patterns in sleeping juvenile and adult rats.
[Mh] Termos MeSH primário: Clorpirifos/toxicidade
Praguicidas/toxicidade
Respiração/efeitos dos fármacos
Síndromes da Apneia do Sono/induzido quimicamente
[Mh] Termos MeSH secundário: Acetilcolinesterase/metabolismo
Animais
Clorpirifos/administração & dosagem
Inibidores da Colinesterase/administração & dosagem
Inibidores da Colinesterase/toxicidade
Diafragma/efeitos dos fármacos
Diafragma/fisiopatologia
Feminino
Masculino
Contração Muscular/efeitos dos fármacos
Pletismografia Total
Gravidez
Efeitos Tardios da Exposição Pré-Natal/fisiopatologia
Ratos
Síndromes da Apneia do Sono/fisiopatologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cholinesterase Inhibitors); 0 (Pesticides); EC 3.1.1.7 (Acetylcholinesterase); JCS58I644W (Chlorpyrifos)
[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:180123
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191237


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[PMID]:29447012
[Au] Autor:Gao X; Tang J; Liu H; Liu L; Kang L; Chen W
[Ad] Endereço:a Key Laboratory Breeding Base of Hu'nan Oriented Fundamental and Applied Research of Innovative Pharmaceutics, College of Pharmacy , Changsha Medical University , Changsha , China.
[Ti] Título:Structure-activity relationship investigation of tertiary amine derivatives of cinnamic acid as acetylcholinesterase and butyrylcholinesterase inhibitors: compared with that of phenylpropionic acid, sorbic acid and hexanoic acid.
[So] Source:J Enzyme Inhib Med Chem;33(1):519-524, 2018 Dec.
[Is] ISSN:1475-6374
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:In the present investigation, 48 new tertiary amine derivatives of cinnamic acid, phenylpropionic acid, sorbic acid and hexanoic acid (4d-6g, 10d-12g, 16d-18g and 22d-24g) were designed, synthesized and evaluated for the effect on AChE and BChE in vitro. The results revealed that the alteration of aminoalkyl types and substituted positions markedly influences the effects in inhibiting AChE. Almost of all cinnamic acid derivatives had the most potent inhibitory activity than that of other acid derivatives with the same aminoalkyl side chain. Unsaturated bond and benzene ring in cinnamic acid scaffold seems important for the inhibitory activity against AChE. Among them, compound 6g revealed the most potent AChE inhibitory activity (IC value: 3.64 µmol/L) and highest selectivity over BChE (ratio: 28.6). Enzyme kinetic study showed that it present a mixed-type inhibition against AChE. The molecular docking study suggested that it can bind with the catalytic site and peripheral site of AChE.
[Mh] Termos MeSH primário: Aminas/farmacologia
Caproatos/farmacologia
Inibidores da Colinesterase/farmacologia
Cinamatos/farmacologia
Fenilpropionatos/farmacologia
Ácido Sórbico/farmacologia
[Mh] Termos MeSH secundário: Acetilcolinesterase/metabolismo
Aminas/síntese química
Aminas/química
Animais
Butirilcolinesterase/metabolismo
Caproatos/química
Inibidores da Colinesterase/síntese química
Inibidores da Colinesterase/química
Cinamatos/química
Relação Dose-Resposta a Droga
Simulação de Acoplamento Molecular
Estrutura Molecular
Fenilpropionatos/química
Ratos
Ratos Sprague-Dawley
Ácido Sórbico/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amines); 0 (Caproates); 0 (Cholinesterase Inhibitors); 0 (Cinnamates); 0 (Phenylpropionates); 1F8SN134MX (hexanoic acid); 5Q445IN5CU (3-phenylpropionic acid); EC 3.1.1.7 (Acetylcholinesterase); EC 3.1.1.8 (Butyrylcholinesterase); U14A832J8D (cinnamic acid); X045WJ989B (Sorbic Acid)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180219
[Lr] Data última revisão:
180219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180216
[St] Status:MEDLINE
[do] DOI:10.1080/14756366.2018.1436053


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[PMID]:29295712
[Au] Autor:Ovais M; Ayaz M; Khalil AT; Shah SA; Jan MS; Raza A; Shahid M; Shinwari ZK
[Ad] Endereço:Department of Biotechnology, Quaid-i-Azam University, Islamabad, 44000, Pakistan.
[Ti] Título:HPLC-DAD finger printing, antioxidant, cholinesterase, and α-glucosidase inhibitory potentials of a novel plant Olax nana.
[So] Source:BMC Complement Altern Med;18(1):1, 2018 Jan 03.
[Is] ISSN:1472-6882
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The medicinal importance of a novel plant Olax nana Wall. ex Benth. (family: Olacaceae) was revealed for the first time via HPLC-DAD finger printing, qualitative phytochemical analysis, antioxidant, cholinesterase, and α-glucosidase inhibitory assays. METHODS: The crude methanolic extract of O. nana (ON-Cr) was subjected to qualitative phytochemical analysis and HPLC-DAD finger printing. The antioxidant potential of ON-Cr was assessed via 1,1-diphenyl,2-picrylhydrazyl (DPPH), 2,2-azinobis[3-ethylbenzthiazoline]-6-sulfonic acid (ABTS) and hydrogen peroxide (H O ) free radical scavenging assays. Furthermore, acetylcholinesterase (AChE) & butyrylcholinesterase (BChE) inhibitory activities were performed using Ellman's assay, while α- glucosidase inhibitory assay was carried out using a standard protocol. RESULTS: The qualitative phytochemical analysis of ON-Cr revealed the presence of secondary metabolites like alkaloids, flavonoids, tannins, sterols, saponins and terpenoids. The HPLC-DAD finger printing revealed the presence of 40 potential compounds in ON-Cr. Considerable anti-radical activities was revealed by ON-Cr in the DPPH, ABTS and H O free radical scavenging assays with IC values of 71.46, 72.55 and 92.33 µg/mL, respectively. Furthermore, ON-Cr showed potent AChE and BChE inhibitory potentials as indicated by their IC values of 33.2 and 55.36 µg/mL, respectively. In the α-glucosidase inhibition assay, ON-Cr exhibited moderate inhibitory propensity with an IC value of 639.89 µg/mL. CONCLUSIONS: This study investigated Olax nana for the first time for detailed qualitative phytochemical tests, HPLC-DAD finger printing analysis, antioxidant, anticholinesterase and α-glucosidase inhibition assays. The antioxidant and cholinesterase inhibitory results were considerable and can provide scientific basis for further studies on the neuroprotective and anti-Alzheimer's potentials of this plant. ON-Cr may further be subjected to fractionation and polarity guided fractionation to narrow down the search for isolation of bioactive compounds.
[Mh] Termos MeSH primário: Antioxidantes/análise
Inibidores da Colinesterase/análise
Cromatografia Líquida de Alta Pressão/métodos
Inibidores de Glicosídeo Hidrolases/análise
Olacaceae/química
Extratos Vegetais/análise
[Mh] Termos MeSH secundário: Antioxidantes/química
Antioxidantes/metabolismo
Benzotiazóis/análise
Benzotiazóis/metabolismo
Compostos de Bifenilo/análise
Compostos de Bifenilo/metabolismo
Inibidores da Colinesterase/química
Inibidores da Colinesterase/metabolismo
Inibidores de Glicosídeo Hidrolases/química
Inibidores de Glicosídeo Hidrolases/metabolismo
Peróxido de Hidrogênio/análise
Peróxido de Hidrogênio/metabolismo
Picratos/análise
Picratos/metabolismo
Extratos Vegetais/química
Extratos Vegetais/metabolismo
Ácidos Sulfônicos/análise
Ácidos Sulfônicos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antioxidants); 0 (Benzothiazoles); 0 (Biphenyl Compounds); 0 (Cholinesterase Inhibitors); 0 (Glycoside Hydrolase Inhibitors); 0 (Picrates); 0 (Plant Extracts); 0 (Sulfonic Acids); 28752-68-3 (2,2'-azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid); BBX060AN9V (Hydrogen Peroxide); DFD3H4VGDH (1,1-diphenyl-2-picrylhydrazyl)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180216
[Lr] Data última revisão:
180216
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180104
[St] Status:MEDLINE
[do] DOI:10.1186/s12906-017-2057-9



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