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[PMID]:29339255
[Au] Autor:Sun G; Wang J; Guo X; Lei M; Zhang Y; Wang X; Shen X; Hu L
[Ad] Endereço:Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Stake Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 2100
[Ti] Título:Design, synthesis and biological evaluation of LX2343 derivatives as neuroprotective agents for the treatment of Alzheimer's disease.
[So] Source:Eur J Med Chem;145:622-633, 2018 Feb 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A series of LX2343 derivatives were designed, synthesized and evaluated as neuroprotective agents for Alzheimer's disease (AD) in vitro. Most of the compounds displayed potent neuroprotective activities. Especially for compound A6, exhibited a remarkable EC value of 0.22 µM. Further investigation demonstrated that compound A6 can significantly reduce Aß production and increase Aß clearance, and alleviate Tau hyperphosphorylation. Most importantly, compound A6 could ameliorate learning and memory impairments in APP/PS1 transgenic mice. The present study evidently showed that compound A6 is a potent neuroprotective agent and might serve as a promising lead candidate for the treatment of Alzheimer's disease.
[Mh] Termos MeSH primário: Acetamidas/farmacologia
Doença de Alzheimer/tratamento farmacológico
Desenho de Drogas
Fármacos Neuroprotetores/farmacologia
Sulfonamidas/farmacologia
[Mh] Termos MeSH secundário: Acetamidas/síntese química
Acetamidas/química
Peptídeos beta-Amiloides/antagonistas & inibidores
Peptídeos beta-Amiloides/metabolismo
Animais
Relação Dose-Resposta a Droga
Células HEK293
Seres Humanos
Aprendizagem em Labirinto/efeitos dos fármacos
Transtornos da Memória/tratamento farmacológico
Camundongos
Camundongos Transgênicos
Estrutura Molecular
Fármacos Neuroprotetores/síntese química
Fármacos Neuroprotetores/química
Relação Estrutura-Atividade
Sulfonamidas/síntese química
Sulfonamidas/química
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetamides); 0 (Amyloid beta-Peptides); 0 (LX2343); 0 (Neuroprotective Agents); 0 (Sulfonamides)
[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:180118
[St] Status:MEDLINE


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[PMID]:29183075
[Au] Autor:Van Wagoner RM; Eichner A; Bhasin S; Deuster PA; Eichner D
[Ad] Endereço:Sports Medicine Research and Testing Laboratory, Salt Lake City, Utah.
[Ti] Título:Chemical Composition and Labeling of Substances Marketed as Selective Androgen Receptor Modulators and Sold via the Internet.
[So] Source:JAMA;318(20):2004-2010, 2017 11 28.
[Is] ISSN:1538-3598
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Importance: Recent reports have described the increasing use of nonsteroidal selective androgen receptor modulators, which have not been approved by the US Food and Drug Administration (FDA), to enhance appearance and performance. The composition and purity of such products is not known. Objective: To determine the chemical identity and the amounts of ingredients in dietary supplements and products marketed and sold through the internet as selective androgen receptor modulators and compare the analyzed contents with product labels. Design and Setting: Web-based searches were performed from February 18, 2016, to March 25, 2016, using the Google search engine on the Chrome and Internet Explorer web browsers to identify suppliers selling selective androgen receptor modulators. The products were purchased and the identities of the compounds and their amounts were determined from April to August 2016 using chain-of-custody and World Anti-Doping Association-approved analytical procedures. Analytical findings were compared against the label information. Exposures: Products marketed and sold as selective androgen receptor modulators. Main Outcomes and Measures: Chemical identities and the amount of ingredients in each product marketed and sold as selective androgen receptor modulators. Results: Among 44 products marketed and sold as selective androgen receptor modulators, only 23 (52%) contained 1 or more selective androgen receptor modulators (Ostarine, LGD-4033, or Andarine). An additional 17 products (39%) contained another unapproved drug, including the growth hormone secretagogue ibutamoren, the peroxisome proliferator-activated receptor-δ agonist GW501516, and the Rev-ErbA agonist SR9009. Of the 44 tested products, no active compound was detected in 4 (9%) and substances not listed on the label were contained in 11 (25%). In only 18 of the 44 products (41%), the amount of active compound in the product matched that listed on the label. The amount of the compounds listed on the label differed substantially from that found by analysis in 26 of 44 products (59%). Conclusions and Relevance: In this limited investigation involving chemical analyses of 44 products marketed as selective androgen receptor modulators and sold via the internet, most products contained unapproved drugs and substances. Only 52% contained selective androgen receptor modulators and many were inaccurately labeled.
[Mh] Termos MeSH primário: Anabolizantes/química
Comércio
Rotulagem de Medicamentos
Internet
Substâncias para Melhoria do Desempenho/química
Receptores Androgênicos
[Mh] Termos MeSH secundário: Acetamidas/análise
Aminofenóis/análise
Anilidas/análise
Aprovação de Drogas
Tráfico de Drogas
Nitrilos/análise
Pirrolidinas/análise
Estados Unidos
United States Food and Drug Administration
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (4-(2-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile); 0 (Acetamides); 0 (Aminophenols); 0 (Anabolic Agents); 0 (Anilides); 0 (Nitriles); 0 (Performance-Enhancing Substances); 0 (Pyrrolidines); 0 (Receptors, Androgen); 7UT2HAH49H (andarine); O3571H3R8N (ostarine)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180228
[Lr] Data última revisão:
180228
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171129
[St] Status:MEDLINE
[do] DOI:10.1001/jama.2017.17069


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[PMID]:28456772
[Au] Autor:Sano T; Utsumi D; Amagase K; Matsumoto K; Tominaga M; Higuchi K; Takeuchi T; Kato S
[Ad] Endereço:Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Yamashina, Kyoto, Japan. beatatsuo0507@gmail.com.
[Ti] Título:Lafutidine, a histamine H2 receptor antagonist with mucosal protective properties, attenuates 5-fluorouracil-induced intestinal mucositis in mice through activation of extrinsic primary afferent neurons.
[So] Source:J Physiol Pharmacol;68(1):79-90, 2017 Feb.
[Is] ISSN:1899-1505
[Cp] País de publicação:Poland
[La] Idioma:eng
[Ab] Resumo:Intestinal mucositis accompanied by severe diarrhea is one of the most common side effects during cancer chemotherapy. Lafutidine, a histamine H2 receptor antagonist with mucosal protective properties via sensory afferent neurons, is used for the treatment of upper gastrointestinal diseases. The present study investigated the effects of lafutidine on 5-fluorouracil (5-FU)-induced intestinal mucositis induced in mice. Male C57BL/6 wild-type (WT), sensory deafferented mice, and transient receptor potential vanilloid subfamily 1 knockout (TRPV1KO) mice were used. Animals were administered 5-FU once daily, while lafutidine and famotidine were administered twice daily for 6 days. Repeated administration of 5-FU caused severe intestinal mucositis, characterized by shortening of villi and destruction of crypts and was accompanied by diarrhea and body weight loss. Daily administration of lafutidine reduced the severity of intestinal mucositis, diarrhea and body weight loss in a dose-dependent manner, while famotidine had no effect on intestinal mucositis. The preventive effects of lafutidine were completely abolished in sensory deafferented and TRPV1-KO mice. Lafutidine significantly suppressed 5-FU-increased MPO activity and inflammatory cytokine expression on day 6, but not apoptosis induction in intestinal crypts on day 1. Lafutidine induced Alcian Blue and PAS-positive mucus production in the small intestine. These findings suggest that lafutidine attenuates 5-FU-induced intestinal mucositis, most likely by increasing mucus production via activation of sensory afferent neurons. Furthermore, intact TRPV1 signaling is essential for the activation of sensory afferent neurons induced by lafutidine. Therefore, lafutidine is more useful than other common antacids for the treatment of intestinal mucositis during cancer chemotherapy.
[Mh] Termos MeSH primário: Acetamidas/uso terapêutico
Diarreia/tratamento farmacológico
Antagonistas dos Receptores Histamínicos H2/uso terapêutico
Mucosite/tratamento farmacológico
Piperidinas/uso terapêutico
Piridinas/uso terapêutico
[Mh] Termos MeSH secundário: Acetamidas/farmacologia
Animais
Antimetabólitos Antineoplásicos
Diarreia/metabolismo
Diarreia/patologia
Famotidina/uso terapêutico
Fluoruracila
Antagonistas dos Receptores Histamínicos H2/farmacologia
Interleucina-1beta/genética
Intestinos/efeitos dos fármacos
Intestinos/metabolismo
Intestinos/patologia
Masculino
Camundongos Endogâmicos C57BL
Camundongos Knockout
Mucosite/induzido quimicamente
Mucosite/patologia
Peroxidase/metabolismo
Piperidinas/farmacologia
Piridinas/farmacologia
RNA Mensageiro/metabolismo
Fator de Necrose Tumoral alfa/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetamides); 0 (Antimetabolites, Antineoplastic); 0 (Histamine H2 Antagonists); 0 (IL1B protein, mouse); 0 (Interleukin-1beta); 0 (Piperidines); 0 (Pyridines); 0 (RNA, Messenger); 0 (Tumor Necrosis Factor-alpha); 49S4O7ADLC (lafutidine); 5QZO15J2Z8 (Famotidine); EC 1.11.1.7 (Peroxidase); U3P01618RT (Fluorouracil)
[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:170501
[St] Status:MEDLINE


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[PMID]:27776567
[Au] Autor:Roopan S; Larsen ER
[Ad] Endereço:1Psychiatric Department Kolding-Vejle,Region of Southern Denmark,Denmark.
[Ti] Título:Use of antidepressants in patients with depression and comorbid diabetes mellitus: a systematic review.
[So] Source:Acta Neuropsychiatr;29(3):127-139, 2017 Jun.
[Is] ISSN:1601-5215
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Depression may be difficult to treat and with comorbid diabetes mellitus (DM) it is an even bigger challenge. This article aims to evaluate antidepressants most suitable for patients with depression and comorbid DM. Design and methods Initially we searched for randomised, controlled double-blind trials of treatment with antidepressants in depressed with DM but there were only a few studies and many of them were small trials. Thus, we decided to include studies that were not only randomised-controlled trials. In total, we ended up with 18 articles for our purposes. RESULTS: The combination of depression and DM may be harmful as depression has a strong impact on psychosocial and medical outcomes in patients with DM. Almost all of the trials in this review showed a reduction in depressive symptoms after treatment with an antidepressant in the acute as well as during maintenance phase. It showed that depression improvement had a favourable effect on glycaemic control that was weight independent. Some studies included only subjects with minor depression or with suboptimal-controlled diabetes making it difficult to show an effect. CONCLUSION: From these data, we will recommend choosing an selective serotonin reuptake inhibitor (SSRI) if possible to treat a depression among patients with diabetes. If treatment with a tricyclic antidepressant is needed, closer glycaemic monitoring is recommended. Bear in mind that there is a possible risk of hypoglycemia when using SSRIs. Agomelatine and bupropion have shown promising results, but need to be investigated in more trials.
[Mh] Termos MeSH primário: Antidepressivos/uso terapêutico
Comorbidade
Depressão/tratamento farmacológico
Diabetes Mellitus/psicologia
[Mh] Termos MeSH secundário: Acetamidas/efeitos adversos
Acetamidas/uso terapêutico
Adulto
Idoso
Antidepressivos/efeitos adversos
Antidepressivos de Segunda Geração/administração & dosagem
Antidepressivos de Segunda Geração/uso terapêutico
Antidepressivos Tricíclicos/efeitos adversos
Antidepressivos Tricíclicos/uso terapêutico
Bupropiona/efeitos adversos
Bupropiona/uso terapêutico
Depressão/complicações
Diabetes Mellitus/tratamento farmacológico
Método Duplo-Cego
Feminino
Seres Humanos
Hiperglicemia/induzido quimicamente
Hiperglicemia/complicações
Hipnóticos e Sedativos/efeitos adversos
Hipnóticos e Sedativos/uso terapêutico
Hipoglicemia/induzido quimicamente
Hipoglicemia/complicações
Masculino
Meia-Idade
Ensaios Clínicos Controlados Aleatórios como Assunto
Inibidores da Captação de Serotonina/efeitos adversos
Inibidores da Captação de Serotonina/uso terapêutico
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Acetamides); 0 (Antidepressive Agents); 0 (Antidepressive Agents, Second-Generation); 0 (Antidepressive Agents, Tricyclic); 0 (Hypnotics and Sedatives); 0 (Serotonin Uptake Inhibitors); 01ZG3TPX31 (Bupropion); 138112-76-2 (S 20098)
[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:161026
[St] Status:MEDLINE
[do] DOI:10.1017/neu.2016.54


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[PMID]:28460320
[Au] Autor:Redecker J; Wittstock M; Rösche J
[Ad] Endereço:Department of Neurology, University of Rostock, Germany.
[Ti] Título:The efficacy of different kinds of intravenously applied antiepileptic drugs in the treatment of status epilepticus. How can it be determined?
[So] Source:Epilepsy Behav;71(Pt A):35-38, 2017 Jun.
[Is] ISSN:1525-5069
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We explored the influence of four different efficacy criteria on the results of observational studies concerning the treatment of status epilepticus (SE) and its subtypes. We compared and contrasted the results of four different efficacy criteria for the effectiveness of phenytoin, valproate, levetiracetam, and lacosamide. Criterion 1=the last antiepileptic drug (AED) administered before SE termination. Criterion 2=the last drug introduced into the antiepileptic therapy within 72h before the cessation of SE and without changes in dosage or number of the co-medication. Criterion 3=the last drug introduced into the antiepileptic therapy or increased in dose within 24h before termination of the SE without changes in the co-medication. Criterion 4=the last drug introduced into the antiepileptic therapy within 72h before the cessation of SE even allowing changes in the co-medication. We used two-tailed χ -tests with the Yates adjustment for small samples to evaluate statistical differences between efficacy rates of different AEDs in the entire group and in subgroups of SE according to the second level of subdivisions in axis 1 and according to axis 2 of the new ILAE classification. A total of 145 treatment episodes in 124 patients (47 male, 77 female) were evaluated. There were 23 significant differences in efficacy according to the different criteria. Only criteria 1 and 3 led to significant results in our analysis. When incorporating theoretical considerations and the results of this study, criterion 3 seems to be the most appropriate measure for the evaluation of efficacy of an AED in the treatment of SE, because it seems to be more reasonable than criterion 1.
[Mh] Termos MeSH primário: Anticonvulsivantes/administração & dosagem
Estado Epiléptico/diagnóstico
Estado Epiléptico/tratamento farmacológico
[Mh] Termos MeSH secundário: Acetamidas/administração & dosagem
Administração Intravenosa
Adulto
Idoso
Idoso de 80 Anos ou mais
Feminino
Comportamentos Relacionados com a Saúde
Seres Humanos
Masculino
Meia-Idade
Fenitoína/administração & dosagem
Piracetam/administração & dosagem
Piracetam/análogos & derivados
Estudos Retrospectivos
Resultado do Tratamento
Ácido Valproico/administração & dosagem
[Pt] Tipo de publicação:JOURNAL ARTICLE; OBSERVATIONAL STUDY
[Nm] Nome de substância:
0 (Acetamides); 0 (Anticonvulsants); 230447L0GL (etiracetam); 563KS2PQY5 (lacosamide); 614OI1Z5WI (Valproic Acid); 6158TKW0C5 (Phenytoin); ZH516LNZ10 (Piracetam)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180206
[Lr] Data última revisão:
180206
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE


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[PMID]:29186951
[Au] Autor:Vismeh R; Haddad D; Moore J; Nielson C; Bals B; Campbell T; Julian A; Teymouri F; Jones AD; Bringi V
[Ad] Endereço:Michigan Biotechnology Institute , Lansing, Michigan 48910, United States.
[Ti] Título:Exposure Assessment of Acetamide in Milk, Beef, and Coffee Using Xanthydrol Derivatization and Gas Chromatography/Mass Spectrometry.
[So] Source:J Agric Food Chem;66(1):298-305, 2018 Jan 10.
[Is] ISSN:1520-5118
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Acetamide has been classified as a possible human carcinogen, but uncertainties exist about its levels in foods. This report presents evidence that thermal decomposition of N-acetylated sugars and amino acids in heated gas chromatograph injectors contributes to artifactual acetamide in milk and beef. An alternative gas chromatography/mass spectrometry protocol based on derivatization of acetamide with 9-xanthydrol was optimized and shown to be free of artifactual acetamide formation. The protocol was validated using a surrogate analyte approach based on d -acetamide and applied to analyze 23 pasteurized whole milk, 44 raw sirloin beef, and raw milk samples from 14 different cows, and yielded levels about 10-fold lower than those obtained by direct injection without derivatization. The xanthydrol derivatization procedure detected acetamide in every food sample tested at 390 ± 60 ppb in milk, 400 ± 80 ppb in beef, and 39 000 ± 9000 ppb in roasted coffee beans.
[Mh] Termos MeSH primário: Acetamidas/análise
Café/química
Contaminação de Alimentos/análise
Cromatografia Gasosa-Espectrometria de Massas/métodos
Carne/análise
Leite/química
[Mh] Termos MeSH secundário: Animais
Bovinos
Xantenos/química
[Pt] Tipo de publicação:EVALUATION STUDIES; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetamides); 0 (Coffee); 0 (Xanthenes); 7131M69IKF (xanthydrol); 8XOE1JSO29 (acetamide)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180205
[Lr] Data última revisão:
180205
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171201
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jafc.7b02229


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[PMID]:29193819
[Au] Autor:Denton CP; Hachulla É; Riemekasten G; Schwarting A; Frenoux JM; Frey A; Le Brun FO; Herrick AL; Raynaud Study Investigators
[Ad] Endereço:Royal Free Hospital, London, UK.
[Ti] Título:Efficacy and Safety of Selexipag in Adults With Raynaud's Phenomenon Secondary to Systemic Sclerosis: A Randomized, Placebo-Controlled, Phase II Study.
[So] Source:Arthritis Rheumatol;69(12):2370-2379, 2017 12.
[Is] ISSN:2326-5205
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: To determine the effect of selexipag, an oral, selective IP prostacyclin receptor agonist, on the frequency of attacks of Raynaud's phenomenon (RP) in patients with systemic sclerosis (SSc). METHODS: Patients with SSc-related RP were randomized 1:1 to placebo (n = 38) or selexipag (n = 36) in individualized doses (maximum of 1,600 µg twice daily) during a 3-week titration period. The primary end point was the weekly average number of RP attacks during the study maintenance period, analyzed using a Bayesian approach with a negative binomial model adjusted for baseline number of RP attacks. Other outcome measures included Raynaud's Condition Score (RCS), RP attack duration, and treatment-emergent adverse events (AEs). RESULTS: Baseline characteristics were comparable between treatment groups. For 83.3% of patients, the individualized maintenance dosage of selexipag was ≤800 µg twice daily. No significant difference was observed between placebo and selexipag in weekly average number of electronic diary (eDiary)-recorded RP attacks during the maintenance period (14.2 attacks during the maintenance period and 21.5 attacks during the baseline week in the placebo group [n = 32] versus 18.0 attacks during the maintenance period and 22.4 attacks during the baseline week in the selexipag group [n = 27]; adjusted mean treatment difference of 3.4 in favor of placebo). No significant treatment effect was observed on RCS or RP attack duration. In the double-blind period, 86.8% of placebo-treated patients and 100% of selexipag-treated patients reported ≥1 AE; 55.3% and 91.7%, respectively, reported ≥1 prostacyclin-associated AE. CONCLUSION: Treatment with selexipag did not reduce the number of RP attacks compared with placebo. The safety profile of selexipag was similar to that previously reported. This study provides important information about the feasibility of eDiary reporting of RP attacks in clinical trials.
[Mh] Termos MeSH primário: Acetamidas/administração & dosagem
Anti-Hipertensivos/administração & dosagem
Pirazinas/administração & dosagem
Doença de Raynaud/tratamento farmacológico
Escleroderma Sistêmico/complicações
[Mh] Termos MeSH secundário: Adulto
Teorema de Bayes
Método Duplo-Cego
Feminino
Seres Humanos
Masculino
Meia-Idade
Doença de Raynaud/etiologia
Índice de Gravidade de Doença
Resultado do Tratamento
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Acetamides); 0 (Antihypertensive Agents); 0 (Pyrazines); 5EXC0E384L (selexipag)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180119
[Lr] Data última revisão:
180119
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171202
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1002/art.40242


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[PMID]:29176325
[Au] Autor:Dibué-Adjei M; Kamp MA; Alpdogan S; Tevoufouet EE; Neiss WF; Hescheler J; Schneider T
[Ad] Endereço:Institute for Neurophysiology, Cologne, Germany.
[Ti] Título:Cav2.3 (R-Type) Calcium Channels are Critical for Mediating Anticonvulsive and Neuroprotective Properties of Lamotrigine In Vivo.
[So] Source:Cell Physiol Biochem;44(3):935-947, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: Lamotrigine (LTG) is a popular modern antiepileptic drug (AED), however, its mechanism of action has yet to be fully understood, as it is known to modulate many members of several ion channel families. In heterologous systems, LTG inhibits Cav2.3 (R-type) calcium currents, which contribute to kainic-acid- (KA) induced epilepsy in vivo. To gain insight into the role of R-type currents in LTG drug action in vivo, we compared the effects of LTG to topiramate and lacosamide in Cav2.3-deficient mice and controls on KA-induced seizures. METHODS: Behavioral seizure rating and quantitative electrocorticography were performed after injection of 20 mg/kg [and 30 mg/kg] KA. One hour before KA injection, mice were pretreated with either 30 mg/kg LTG, 50 mg/kg topiramate (TPM) or 30 mg/kg lacosamide (LSM). RESULTS: Ablation of Cav2.3 reduced total seizure scores by 28.6% (p=0.0012) and pretreatment with LTG reduced seizure activity of control mice by 23.2% (p=0.02). In Cav2.3-deficient mice LTG pretreatment increased seizure activity by 22.1% (p=0.018) and increased the percentage of degenerated CA1 pyramidal neurons (p=0.02). All three tested AEDs reduced seizure activity in control mice, however only the non-calcium channel modulating AED, LSM had an anticonvulsive effect in Cav2.3-deficient mice. Furthermore LTG altered electrocorticographic parameters differently in the two genotypes, decreasing relative power of ictal spikes in control mice compared to Cav2.3-defcient mice. CONCLUSION: These findings give first in vivo evidence for an essential role for Cav2.3 in LTG pharmacology and shed light on a paradoxical effect of LTG in their absence. Furthermore, LTG appears to promote ictal activity in Cav2.3-deficient mice resulting in increased neurotoxicity in the CA1 region. This paradoxical mechanism, possibly reflecting rebound hyperexcitation of pyramidal CA1 neurons after increased inhibition, may be key in understanding LTG-induced seizure aggravation, observed in clinical practice.
[Mh] Termos MeSH primário: Anticonvulsivantes/farmacologia
Comportamento Animal/efeitos dos fármacos
Canais de Cálcio Tipo R/genética
Epilepsia/patologia
Fármacos Neuroprotetores/farmacologia
Triazinas/farmacologia
[Mh] Termos MeSH secundário: Acetamidas/farmacologia
Acetamidas/uso terapêutico
Animais
Anticonvulsivantes/uso terapêutico
Canais de Cálcio Tipo R/deficiência
Eletrocorticografia
Epilepsia/induzido quimicamente
Epilepsia/prevenção & controle
Frutose/análogos & derivados
Frutose/farmacologia
Frutose/uso terapêutico
Genótipo
Imuno-Histoquímica
Ácido Caínico/toxicidade
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Fármacos Neuroprotetores/uso terapêutico
Células Piramidais/efeitos dos fármacos
Células Piramidais/patologia
Triazinas/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetamides); 0 (Anticonvulsants); 0 (Calcium Channels, R-Type); 0 (Neuroprotective Agents); 0 (Triazines); 0H73WJJ391 (topiramate); 30237-26-4 (Fructose); 563KS2PQY5 (lacosamide); SIV03811UC (Kainic Acid); U3H27498KS (lamotrigine)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180118
[Lr] Data última revisão:
180118
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1159/000485361


  9 / 9864 MEDLINE  
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[PMID]:28745530
[Au] Autor:Fatouh AM; Elshafeey AH; Abdelbary A
[Ad] Endereço:a Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy , Cairo University , Cairo , Egypt.
[Ti] Título:Agomelatine-based in situ gels for brain targeting via the nasal route: statistical optimization, in vitro, and in vivo evaluation.
[So] Source:Drug Deliv;24(1):1077-1085, 2017 Nov.
[Is] ISSN:1521-0464
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Agomelatine (AGM) is an antidepressant drug with a low absolute bioavailability due to the hepatic first pass metabolism. AGM-loaded solid lipid nanoparticles were formulated in the form of an in situ gel to prolong the intranasal retention time and subsequently to increase the absorbed amount of AGM. The optimized in situ gel formula had a sol-gel transition temperature of 31 °C ± 1.40, mucociliary transport time of 27 min ±1.41%, released after 1 and 8 h of 46.3% ± 0.85 and 70.90% ± 1.48. The pharmacokinetic study of the optimized in situ gel revealed a significant increase in the peak plasma concentration, area under plasma concentration versus time curve and absolute bioavailability compared to that of the oral suspension of Valdoxan® with the values of 247 ± 64.40 ng/mL, 6677.41 ± 1996 ng.min/mL, and 37.89%, respectively. It also gave drug targeting efficiency index of 141.42 which revealed more successful brain targeting by the intranasal route compared to the intravenous route and it had direct transport percent index of 29.29 which indicated a significant contribution of the direct nose to brain pathway in the brain drug delivery.
[Mh] Termos MeSH primário: Acetamidas/farmacologia
[Mh] Termos MeSH secundário: Administração Intranasal
Encéfalo
Géis
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetamides); 0 (Gels); 138112-76-2 (S 20098)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171214
[Lr] Data última revisão:
171214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170727
[St] Status:MEDLINE
[do] DOI:10.1080/10717544.2017.1357148


  10 / 9864 MEDLINE  
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[PMID]:29053775
[Au] Autor:Datta G; Colasanti A; Rabiner EA; Gunn RN; Malik O; Ciccarelli O; Nicholas R; Van Vlierberghe E; Van Hecke W; Searle G; Santos-Ribeiro A; Matthews PM
[Ad] Endereço:Division of Brain Sciences, Imperial College London, UK.
[Ti] Título:Neuroinflammation and its relationship to changes in brain volume and white matter lesions in multiple sclerosis.
[So] Source:Brain;140(11):2927-2938, 2017 Nov 01.
[Is] ISSN:1460-2156
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Brain magnetic resonance imaging is an important tool in the diagnosis and monitoring of multiple sclerosis patients. However, magnetic resonance imaging alone provides limited information for predicting an individual patient's disability progression. In part, this is because magnetic resonance imaging lacks sensitivity and specificity for detecting chronic diffuse and multi-focal inflammation mediated by activated microglia/macrophages. The aim of this study was to test for an association between 18 kDa translocator protein brain positron emission tomography signal, which arises largely from microglial activation, and measures of subsequent disease progression in multiple sclerosis patients. Twenty-one patients with multiple sclerosis (seven with secondary progressive disease and 14 with a relapsing remitting disease course) underwent T1- and T2-weighted and magnetization transfer magnetic resonance imaging at baseline and after 1 year. Positron emission tomography scanning with the translocator protein radioligand 11C-PBR28 was performed at baseline. Brain tissue and lesion volumes were segmented from the T1- and T2-weighted magnetic resonance imaging and relative 11C-PBR28 uptake in the normal-appearing white matter was estimated as a distribution volume ratio with respect to a caudate pseudo-reference region. Normal-appearing white matter distribution volume ratio at baseline was correlated with enlarging T2-hyperintense lesion volumes over the subsequent year (ρ = 0.59, P = 0.01). A post hoc analysis showed that this association reflected behaviour in the subgroup of relapsing remitting patients (ρ = 0.74, P = 0.008). By contrast, in the subgroup of secondary progressive patients, microglial activation at baseline was correlated with later progression of brain atrophy (ρ = 0.86, P = 0.04). A regression model including the baseline normal-appearing white matter distribution volume ratio, T2 lesion volume and normal-appearing white matter magnetization transfer ratio for all of the patients combined explained over 90% of the variance in enlarging lesion volume over the subsequent 1 year. Glial activation in white matter assessed by translocator protein PET significantly improves predictions of white matter lesion enlargement in relapsing remitting patients and is associated with greater brain atrophy in secondary progressive disease over a period of short term follow-up.
[Mh] Termos MeSH primário: Encéfalo/diagnóstico por imagem
Inflamação/diagnóstico por imagem
Esclerose Múltipla Crônica Progressiva/diagnóstico por imagem
Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem
Substância Branca/diagnóstico por imagem
[Mh] Termos MeSH secundário: Acetamidas
Adulto
Atrofia
Encéfalo/patologia
Radioisótopos de Carbono
Feminino
Seres Humanos
Processamento de Imagem Assistida por Computador
Imagem por Ressonância Magnética
Masculino
Microglia
Meia-Idade
Tamanho do Órgão
Tomografia por Emissão de Pósitrons
Piridinas
Receptores de GABA
Substância Branca/patologia
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetamides); 0 (Carbon Radioisotopes); 0 (N-(2-methoxybenzyl)-N-(4-phenoxypyridin-3-yl)acetamide); 0 (Pyridines); 0 (Receptors, GABA); 0 (TSPO protein, human)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171021
[St] Status:MEDLINE
[do] DOI:10.1093/brain/awx228



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