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  1 / 6415 MEDLINE  
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[PMID]:29277915
[Au] Autor:Zhang X; Ping HY; Li JH; Duan SX; Jiang XW
[Ad] Endereço:Department of Pediatric Surgery, The Affiliated Maternal and Child Health Hospital of Shenzhen University Medical College, Shenzhen, China.
[Ti] Título:Diethylstilbestrol regulates mouse gubernaculum testis cell proliferation via PLC-Ca -CREB pathway.
[So] Source:Cell Biochem Funct;36(1):13-17, 2018 Jan.
[Is] ISSN:1099-0844
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Recent evidence suggested a positive correlation between environmental estrogens (EEs) and high incidence of abnormalities in male urogenital system, but the mechanism remains unclear. Diethylstilbestrol (DES) is a nonsteroidal synthetic estrogen that disrupts the morphology and proliferation of gubernaculum testis cells, but the underlying mechanism is unclear. In this study, mouse gubernaculum testis cells were pretreated with phospholipase C (PLC) inhibitor U-73122 and then treated with DES. The results demonstrated that U-73122 impaired DES-evoked intracellular Ca2+ mobilization in gubernaculum testis cells and inhibited DES-induced proliferation of gubernaculum testis cells. Mechanistically, we found that U-73122 inhibited DES-induced activation of cAMP-response element binding protein (CREB) in gubernaculum testis cells. In conclusion, these data suggest that the effects of DES on mouse gubernaculum testis cells are mediated by PLC-Ca -CREB pathway. SIGNIFICANCE OF THE STUDY: Environmental estrogens remain a serious threat to male reproductive health, and it is important to understand the mechanism by which EEs affect the male productive system. Here we explore potential mechanisms how the proliferation and contractility of gubernaculum testis cells are regulated by diethylstilbestrol. Our findings provide the first evidence that PLC-Ca -CREB signalling pathway mediates the nongenomic effects of diethylstilbestrol on gubernaculum testis cells. These findings provide new insight into the role of diethylstilbestrol in the aetiology of male reproductive dysfunction and will help develop better approaches for the prevention and therapy of male reproductive malformation.
[Mh] Termos MeSH primário: Cálcio/metabolismo
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo
Dietilestilbestrol/farmacologia
Gubernáculo/efeitos dos fármacos
Testículo/efeitos dos fármacos
Fosfolipases Tipo C/metabolismo
[Mh] Termos MeSH secundário: Animais
Proliferação Celular/efeitos dos fármacos
Células Cultivadas
Estrenos/farmacologia
Gubernáculo/citologia
Gubernáculo/metabolismo
Masculino
Camundongos
Pirrolidinonas/farmacologia
Testículo/citologia
Testículo/metabolismo
Fosfolipases Tipo C/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cyclic AMP Response Element-Binding Protein); 0 (Estrenes); 0 (Pyrrolidinones); 112648-68-7 (1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione); 731DCA35BT (Diethylstilbestrol); EC 3.1.4.- (Type C Phospholipases); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171227
[St] Status:MEDLINE
[do] DOI:10.1002/cbf.3312


  2 / 6415 MEDLINE  
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[PMID]:28459440
[Au] Autor:Lauinger L; Li J; Shostak A; Cemel IA; Ha N; Zhang Y; Merkl PE; Obermeyer S; Stankovic-Valentin N; Schafmeier T; Wever WJ; Bowers AA; Carter KP; Palmer AE; Tschochner H; Melchior F; Deshaies RJ; Brunner M; Diernfellner A
[Ad] Endereço:Heidelberg University Biochemistry Center, Heidelberg, Germany.
[Ti] Título:Thiolutin is a zinc chelator that inhibits the Rpn11 and other JAMM metalloproteases.
[So] Source:Nat Chem Biol;13(7):709-714, 2017 Jul.
[Is] ISSN:1552-4469
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Thiolutin is a disulfide-containing antibiotic and anti-angiogenic compound produced by Streptomyces. Its biological targets are not known. We show that reduced thiolutin is a zinc chelator that inhibits the JAB1/MPN/Mov34 (JAMM) domain-containing metalloprotease Rpn11, a deubiquitinating enzyme of the 19S proteasome. Thiolutin also inhibits the JAMM metalloproteases Csn5, the deneddylase of the COP9 signalosome; AMSH, which regulates ubiquitin-dependent sorting of cell-surface receptors; and BRCC36, a K63-specific deubiquitinase of the BRCC36-containing isopeptidase complex and the BRCA1-BRCA2-containing complex. We provide evidence that other dithiolopyrrolones also function as inhibitors of JAMM metalloproteases.
[Mh] Termos MeSH primário: Quelantes/farmacologia
Inibidores Enzimáticos/farmacologia
Metaloproteases/antagonistas & inibidores
Transativadores/antagonistas & inibidores
Zinco/química
[Mh] Termos MeSH secundário: Quelantes/química
Relação Dose-Resposta a Droga
Inibidores Enzimáticos/química
Células HeLa
Seres Humanos
Metaloproteases/metabolismo
Complexo de Endopeptidases do Proteassoma/metabolismo
Pirrolidinonas/química
Pirrolidinonas/metabolismo
Pirrolidinonas/farmacologia
Relação Estrutura-Atividade
Transativadores/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chelating Agents); 0 (Enzyme Inhibitors); 0 (PSMD14 protein, human); 0 (Pyrrolidinones); 0 (Trans-Activators); 02C005Q20B (acetopyrrothine); EC 3.4.- (Metalloproteases); EC 3.4.25.1 (Proteasome Endopeptidase Complex); J41CSQ7QDS (Zinc)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180202
[Lr] Data última revisão:
180202
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE
[do] DOI:10.1038/nchembio.2370


  3 / 6415 MEDLINE  
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[PMID]:29216591
[Au] Autor:Sun Y; Jensen H; Petersen NJ; Larsen SW; Østergaard J
[Ad] Endereço:Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen, Denmark. Electronic address: yu.sun@sund.ku.dk.
[Ti] Título:Concomitant monitoring of implant formation and drug release of in situ forming poly (lactide-co-glycolide acid) implants in a hydrogel matrix mimicking the subcutis using UV-vis imaging.
[So] Source:J Pharm Biomed Anal;150:95-106, 2018 Feb 20.
[Is] ISSN:1873-264X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:For poly (lactide-co-glycolide acid) (PLGA)-based in situ forming implants, the rate of implant formation plays an important role in determining the overall drug release kinetics. Currently, in vitro techniques capable of characterizing the processes of drug release and implant formation at the same time are not available. A hydrogel-based in vitro experimental setup was recently developed requiring only microliter of formulation and forming a closed system potentially suitable for interfacing with various spectroscopic techniques. The aim of the present proof-of-concept study was to investigate the feasibility of concomitant UV imaging, Vis imaging and light microscopy for detailed characterization of the behavior of in situ forming PLGA implants in the hydrogel matrix mimicking the subcutis. The model compounds, piroxicam and α-lactalbumin were added to PLGA-1-methyl-2-pyrrolidinone and PLGA-triacetin solutions. Upon bringing the PLGA-solvent-compound pre-formulation in contact with the hydrogel, Vis imaging and light microscopy were applied to visualize the depot formation and UV imaging was used to quantify drug transport in the hydrogel. As compared to piroxicam, the α-lactalbumin invoked an acceleration of phase separation and an increase of implant size. α-Lactalbumin was released faster from the PLGA-1-methyl-2-pyrrolidinone system than the PLGA-triacetin system opposite to the piroxicam release pattern. A linear relationship between the rate of implant formation and initial compound release within the first 4h was established for the PLGA-NMP systems. This implies that phase separation may be one of the controlling factors in drug release. The rate of implant formation may be an important parameter for predicting and tailoring drug release. The approach combining UV imaging, Vis imaging and light microscopy may facilitate understanding of release processes and holds potential for becoming a useful tool in formulation development of in situ forming implants.
[Mh] Termos MeSH primário: Sistemas de Liberação de Medicamentos
Lactalbumina/administração & dosagem
Ácido Láctico/química
Piroxicam/administração & dosagem
Ácido Poliglicólico/química
[Mh] Termos MeSH secundário: Química Farmacêutica/métodos
Portadores de Fármacos/química
Implantes de Medicamento
Liberação Controlada de Fármacos
Hidrogéis
Pirrolidinonas/química
Espectrofotometria Ultravioleta/métodos
Análise Espectral/métodos
Tela Subcutânea/metabolismo
Triacetina/química
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Drug Carriers); 0 (Drug Implants); 0 (Hydrogels); 0 (Pyrrolidinones); 0 (polylactic acid-polyglycolic acid copolymer); 13T4O6VMAM (Piroxicam); 26009-03-0 (Polyglycolic Acid); 33X04XA5AT (Lactic Acid); 9013-90-5 (Lactalbumin); JR9CE63FPM (N-methylpyrrolidone); XHX3C3X673 (Triacetin)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180130
[Lr] Data última revisão:
180130
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171208
[St] Status:MEDLINE


  4 / 6415 MEDLINE  
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[PMID]:29216311
[Au] Autor:Morimoto M; Amano Y; Oka M; Harada A; Fujita H; Hikichi Y; Tozawa R; Yamaoka M; Hara T
[Ad] Endereço:Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
[Ti] Título:Amelioration of sexual behavior and motor activity deficits in a castrated rodent model with a selective androgen receptor modulator SARM-2f.
[So] Source:PLoS One;12(12):e0189480, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Sarcopenia and cachexia present characteristic features of a decrease in skeletal muscle mass and strength, anorexia, and lack of motivation. Treatments for these diseases have not yet been established, although selective androgen receptor modulators (SARMs) are considered as therapeutic targets. We previously reported that a novel SARM compound, SARM-2f, exhibits anabolic effect on muscles, with less stimulatory effect on prostate weight compared with testosterone, in rat Hershberger assays and cancer cachexia models. In this study, we studied the mechanism of action for SARM-2f selectivity and also assessed whether the muscle increase by this compound might lead to improvement of muscle function and physical activity. First, we examined the tissue distribution of SARM-2f. Tissue concentration was 1.2-, 1.6-, and 1.9-fold as high as the plasma concentration in the levator ani muscle, brain, and prostate, respectively. This result showed that the tissue-selective pharmacological effect did not depend on SARM-2f concentration in the tissues. The ability of SARM-2f to influence androgen receptor (AR)-mediated transcriptional activation was examined by reporter assays using human normal prostate epithelial cells (PrEC) and skeletal muscle cells (SKMC). SARM-2f exerted higher activity against AR in SKMC than in PrEC. Mammalian two hybrid assays showed different co-factor recruitment patterns between SARM-2f and dihydrotestosterone. Next, we studied the effect of SARM-2f on motivation and physical functions such as sexual behavior and motor activities in castrated rat or mouse models. SARM-2f restored the sexual behavior that was lost by castration in male rats. SARM-2f also increased voluntary running distance and locomotor activities. These results suggest that tissue-specific AR regulation by SARM-2f, but not tissue distribution, might account for its tissue specific androgenic effect, and that the muscle mass increase by SARM-2f leads to improvement of physical function. Together, these findings suggest that SARM-2f might represent an effective treatment for sarcopenia and cachexia.
[Mh] Termos MeSH primário: Atividade Motora
Orquiectomia
Pirrolidinonas/farmacologia
Receptores Androgênicos/efeitos dos fármacos
Comportamento Sexual Animal
[Mh] Termos MeSH secundário: Animais
Feminino
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Pirrolidinonas/farmacocinética
Ratos
Ratos Sprague-Dawley
Receptores Androgênicos/fisiologia
Distribuição Tecidual
Transcrição Genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (4-(2-ethyl-3-hydroxy-5-oxopyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile); 0 (Pyrrolidinones); 0 (Receptors, Androgen)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180122
[Lr] Data última revisão:
180122
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171208
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0189480


  5 / 6415 MEDLINE  
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[PMID]:28462836
[Au] Autor:Muralidharan VP; Alagumuthu M; Iyer SK
[Ad] Endereço:Department of Chemistry, School of Advanced Sciences, VIT University, Vellore 632014, India.
[Ti] Título:Iodine catalyzed three component synthesis of 1-((2-hydroxy naphthalen-1-yl)(phenyl)(methyl))pyrrolidin-2-one derivatives: Rationale as potent PI3K inhibitors and anticancer agents.
[So] Source:Bioorg Med Chem Lett;27(11):2510-2514, 2017 06 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A series of 1-((2-hydroxynaphthalen-1-yl)(phenyl)(methyl))pyrrolidin-2-one derivatives by an efficient iodine catalyzed domino reaction involving various aromatic aldehydes, 2-pyrrolidinone and ß-naphthol was achieved and the structures were elucidated by FTIR H NMR, C NMR, and HRMS. Subsequently they were evaluated for cytotoxicity against breast cancer (MCF-7), colon cancer (HCT116) cell lines. In the cytotoxicity, the relative inhibition activity was remarkably found to be high in MCF-7 cell lines as 79% (4c), 83% (4f) and the IC values were 1.03µM (4c), 0.98µM (4f). Compounds 4a, 4e, 4k-m, and 4q were found to be inactive and rest showed a moderate activity. In order to get more insight into the binding mode and inhibitor binding affinity, compounds (4a-q) were docked into the active site phosphoinositide 3-kinase (PI3K) (PDB ID: 4JPS) which is a crucial regulator of apoptosis or programmed cell death. Results suggested that the hydrophobic interactions in the binding pockets of PI3K exploited affinity of the most favourable binding ligands (4c and 4f: inhibitory constant (ki)=66.22nM and 107.39nM). The SAR studies demonstrated that the most potent compounds are 4c and 4f and can be developed into precise PI3K inhibitors with the capability to treat various cancers.
[Mh] Termos MeSH primário: Antineoplásicos/síntese química
Iodo/química
Fosfatidilinositol 3-Quinases/antagonistas & inibidores
Pirrolidinonas/química
[Mh] Termos MeSH secundário: Antineoplásicos/química
Antineoplásicos/toxicidade
Apoptose/efeitos dos fármacos
Sítios de Ligação
Catálise
Desenho de Drogas
Células HCT116
Seres Humanos
Células MCF-7
Simulação de Acoplamento Molecular
Fosfatidilinositol 3-Quinases/metabolismo
Pirrolidinonas/síntese química
Pirrolidinonas/toxicidade
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Pyrrolidinones); 9679TC07X4 (Iodine); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); KKL5D39EOL (2-pyrrolidone)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171124
[Lr] Data última revisão:
171124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE


  6 / 6415 MEDLINE  
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[PMID]:28850675
[Au] Autor:Niespodziany I; Rigo JM; Moonen G; Matagne A; Klitgaard H; Wolff C
[Ad] Endereço:UCB Pharma, Braine-l'Alleud, Belgium.
[Ti] Título:Brivaracetam does not modulate ionotropic channels activated by glutamate, γ-aminobutyric acid, and glycine in hippocampal neurons.
[So] Source:Epilepsia;58(11):e157-e161, 2017 Nov.
[Is] ISSN:1528-1167
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Brivaracetam (BRV) is a selective, high-affinity ligand for synaptic vesicle protein 2A (SV2A), recently approved as adjunctive treatment for drug-refractory partial-onset seizures in adults. BRV binds SV2A with higher affinity than levetiracetam (LEV), and was shown to have a differential interaction with SV2A. Because LEV was reported to interact with multiple excitatory and inhibitory ligand-gated ion channels and that may impact its pharmacological profile, we were interested in determining whether BRV directly modulates inhibitory and excitatory ionotropic receptors in central neurons. Voltage-clamp experiments were performed in primary cultures of mouse hippocampal neurons. At a supratherapeutic concentration of 100 µm, BRV was devoid of any direct effect on currents gated by γ-aminobutyric acidergic type A, glycine, kainate, N-methyl-d-aspartate, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid. Similarly to LEV, BRV reveals a potent ability to oppose the action of negative modulators on the inhibitory receptors. In conclusion, these results show that BRV contrasts with LEV by not displaying any direct action on inhibitory or excitatory postsynaptic ligand-gated receptors at therapeutic concentrations and thereby support BRV's role as a selective SV2A ligand. These findings add further evidence to the validity of SV2A as a relevant antiepileptic drug target and emphasize the potential for exploring further presynaptic mechanisms as a novel approach to antiepileptic drug discovery.
[Mh] Termos MeSH primário: Ácido Glutâmico/farmacologia
Glicina/farmacologia
Hipocampo/fisiologia
Glicoproteínas de Membrana/fisiologia
Proteínas do Tecido Nervoso/fisiologia
Pirrolidinonas/farmacologia
Ácido gama-Aminobutírico/farmacologia
[Mh] Termos MeSH secundário: Animais
Anticonvulsivantes/farmacologia
Células Cultivadas
Relação Dose-Resposta a Droga
Hipocampo/efeitos dos fármacos
Glicoproteínas de Membrana/agonistas
Camundongos
Proteínas do Tecido Nervoso/agonistas
Neurônios/efeitos dos fármacos
Neurônios/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anticonvulsants); 0 (Membrane Glycoproteins); 0 (Nerve Tissue Proteins); 0 (Pyrrolidinones); 0 (Sv2a protein, mouse); 3KX376GY7L (Glutamic Acid); 56-12-2 (gamma-Aminobutyric Acid); TE7660XO1C (Glycine); U863JGG2IA (brivaracetam)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170830
[St] Status:MEDLINE
[do] DOI:10.1111/epi.13890


  7 / 6415 MEDLINE  
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[PMID]:28829199
[Au] Autor:Russo E; Citraro R; Mula M
[Ad] Endereço:a Science of Health Department, School of Medicine and Surgery , University of Catanzaro , Catanzaro , Italy.
[Ti] Título:The preclinical discovery and development of brivaracetam for the treatment of focal epilepsy.
[So] Source:Expert Opin Drug Discov;12(11):1169-1178, 2017 Nov.
[Is] ISSN:1746-045X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Brivaracetam (BRV) is a new AED currently licensed for the adjunctive treatment of adult patients with focal epilepsies. It is a ligand of the ubiquitous synaptic vesicle glycoprotein 2A (SV2A). Areas covered: This paper covers the preclinical and subsequent clinical development of BRV focusing on the discovery of the SV2A protein as the main target for levetiracetam (LEV) and the main similarities and differences between LEV and BRV in terms of pharmacodynamic and pharmacokinetic properties. Phase II and Phase III studies are also presented and data from post-marketing phase IV studies are discussed. Expert opinion: The preclinical development of BRV is quite unique and has raised several doubts on current methodologies adopted for AED development, reinforcing the need for new approaches. The preclinical and clinical profile suggest that BRV is potentially an ideal compound in the emergency setting given the rapid onset of action associated with being water soluble and, therefore, available in intravenous formulation. In addition, data from Phase III studies have already suggested that BRV may be effective not only in focal epilepsies but also in generalised syndromes. Further data from special populations such as children and women of child bearing age are urgently needed.
[Mh] Termos MeSH primário: Anticonvulsivantes/uso terapêutico
Epilepsias Parciais/tratamento farmacológico
Pirrolidinonas/uso terapêutico
[Mh] Termos MeSH secundário: Adulto
Animais
Anticonvulsivantes/farmacocinética
Anticonvulsivantes/farmacologia
Descoberta de Drogas/métodos
Epilepsias Parciais/fisiopatologia
Seres Humanos
Ligantes
Glicoproteínas de Membrana/metabolismo
Proteínas do Tecido Nervoso/metabolismo
Piracetam/análogos & derivados
Piracetam/farmacocinética
Piracetam/farmacologia
Piracetam/uso terapêutico
Pirrolidinonas/farmacocinética
Pirrolidinonas/farmacologia
Solubilidade
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Anticonvulsants); 0 (Ligands); 0 (Membrane Glycoproteins); 0 (Nerve Tissue Proteins); 0 (Pyrrolidinones); 148845-93-6 (SV2A protein, human); 230447L0GL (etiracetam); U863JGG2IA (brivaracetam); ZH516LNZ10 (Piracetam)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171023
[Lr] Data última revisão:
171023
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170823
[St] Status:MEDLINE
[do] DOI:10.1080/17460441.2017.1366985


  8 / 6415 MEDLINE  
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[PMID]:28662341
[Au] Autor:Pant S; Patel M; Kurkjian C; Hemphill B; Flores M; Thompson D; Bendell J
[Ad] Endereço:a Stephenson Cancer Center/Sarah Cannon Research Institute , Oklahoma City , Oklahoma , USA.
[Ti] Título:A Phase II Study of the c-Met Inhibitor Tivantinib in Combination with FOLFOX for the Treatment of Patients with Previously Untreated Metastatic Adenocarcinoma of the Distal Esophagus, Gastroesophageal Junction, or Stomach.
[So] Source:Cancer Invest;35(7):463-472, 2017 Aug 09.
[Is] ISSN:1532-4192
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: This phase I/II study was designed to determine the maximum tolerated dose of tivantinib in combination with standard dose FOLFOX for the treatment of patients with advanced solid tumors and to evaluate the safety and efficacy of this combination for patients with previously untreated metastatic adenocarcinoma of the distal esophagus, gastroesophageal (GE) junction, or stomach. METHODS: Patients with advanced solid tumors for which FOLFOX would be appropriate chemotherapy received escalating doses of tivantinib BID (days 1-14) in a standard 3 + 3 design in phase I. In phase II, patients with advanced GE cancer received standard FOLFOX day 1 and tivantinib (360 mg PO BID) days 1-14 of each 2-week cycle. Restaging occurred every four cycles. The primary phase II endpoint was response rate (RR). RESULTS: Forty-nine patients were enrolled (15 on phase I and 34 on phase II). The expansion dose was established as tivantinib 360 mg BID in combination with FOLFOX. Thirty-two phase II patients were treated for a median of eight cycles (range, 1-38), with an overall RR of 38%. Treatment-related toxicities included neutropenia, fatigue, diarrhea, nausea, and peripheral neuropathy. Median progression-free survival (PFS) was 6.1 hmonths with a median time to progression of 7.0 months. Median overall survival was 9.6 months. Two patients remain on study at the time of this analysis. CONCLUSIONS: The combination treatment of tivantinib plus FOLFOX in patients with advanced GE cancer showed a response and PFS in the range of historical controls for first-line FOLFOX therapy. However, two patients had extended time on study treatment (36 and 45 cycles) at the time of data cutoff.
[Mh] Termos MeSH primário: Adenocarcinoma/tratamento farmacológico
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
Neoplasias Esofágicas/tratamento farmacológico
Junção Esofagogástrica/efeitos dos fármacos
Inibidores de Proteínas Quinases/administração & dosagem
Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores
Pirrolidinonas/administração & dosagem
Quinolinas/administração & dosagem
Neoplasias Gástricas/tratamento farmacológico
[Mh] Termos MeSH secundário: Adenocarcinoma/enzimologia
Adenocarcinoma/secundário
Adulto
Idoso
Idoso de 80 Anos ou mais
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
Intervalo Livre de Doença
Relação Dose-Resposta a Droga
Esquema de Medicação
Neoplasias Esofágicas/enzimologia
Neoplasias Esofágicas/patologia
Junção Esofagogástrica/enzimologia
Junção Esofagogástrica/patologia
Feminino
Fluoruracila/administração & dosagem
Fluoruracila/efeitos adversos
Seres Humanos
Estimativa de Kaplan-Meier
Leucovorina/administração & dosagem
Leucovorina/efeitos adversos
Masculino
Dose Máxima Tolerável
Meia-Idade
Compostos Organoplatínicos/administração & dosagem
Compostos Organoplatínicos/efeitos adversos
Inibidores de Proteínas Quinases/efeitos adversos
Proteínas Proto-Oncogênicas c-met/metabolismo
Pirrolidinonas/efeitos adversos
Quinolinas/efeitos adversos
Transdução de Sinais/efeitos dos fármacos
Neoplasias Gástricas/enzimologia
Neoplasias Gástricas/patologia
Fatores de Tempo
Resultado do Tratamento
Estados Unidos
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE; MULTICENTER STUDY
[Nm] Nome de substância:
0 (ARQ 197); 0 (Organoplatinum Compounds); 0 (Protein Kinase Inhibitors); 0 (Pyrrolidinones); 0 (Quinolines); EC 2.7.10.1 (MET protein, human); EC 2.7.10.1 (Proto-Oncogene Proteins c-met); Q573I9DVLP (Leucovorin); U3P01618RT (Fluorouracil)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170630
[St] Status:MEDLINE
[do] DOI:10.1080/07357907.2017.1337782


  9 / 6415 MEDLINE  
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[PMID]:28644035
[Au] Autor:Tercel M; Lee HH; Mehta SY; Youte Tendoung JJ; Bai SY; Liyanage HDS; Pruijn FB
[Ad] Endereço:Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland , Private Bag 92019, Auckland 1142, New Zealand.
[Ti] Título:Influence of a Basic Side Chain on the Properties of Hypoxia-Selective Nitro Analogues of the Duocarmycins: Demonstration of Substantial Anticancer Activity in Combination with Irradiation or Chemotherapy.
[So] Source:J Med Chem;60(13):5834-5856, 2017 Jul 13.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A new series of nitro analogues of the duocarmycins was prepared and evaluated for hypoxia-selective anticancer activity. The compounds incorporate 13 different amine-containing side chains designed to bind in the minor groove of DNA while spanning a wide range of base strength from pK 9.64 to 5.24. The most favorable in vitro properties were associated with strongly basic side chains, but the greatest in vivo antitumor activity was found for compounds containing a weakly basic morpholine. This applies to single-agent activity and for activity in combination with irradiation or chemotherapy (gemcitabine or docetaxel). In combination with a single dose of γ irradiation 50 at 42 µmol/kg eliminated detectable clonogens in some SiHa cervical carcinoma xenografts, and in combination with gemcitabine using a well-tolerated multidose schedule, the same compound caused regression of all treated A2780 ovarian tumor xenografts. In the latter experiment, three of seven animals receiving the combination treatment were completely tumor free at day 100.
[Mh] Termos MeSH primário: Antineoplásicos/química
Antineoplásicos/uso terapêutico
Indóis/química
Indóis/uso terapêutico
Neoplasias Ovarianas/tratamento farmacológico
Ovário/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/farmacologia
Hipóxia Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Terapia Combinada
Ensaios de Seleção de Medicamentos Antitumorais
Feminino
Seres Humanos
Indóis/farmacologia
Camundongos
Camundongos Nus
Nitrocompostos/química
Nitrocompostos/farmacologia
Nitrocompostos/uso terapêutico
Neoplasias Ovarianas/patologia
Neoplasias Ovarianas/radioterapia
Ovário/patologia
Ovário/efeitos da radiação
Pirrolidinonas/química
Pirrolidinonas/farmacologia
Pirrolidinonas/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Indoles); 0 (Nitro Compounds); 0 (Pyrrolidinones); PJV9990868 (duocarmycin A)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170624
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00563


  10 / 6415 MEDLINE  
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[PMID]:28642233
[Au] Autor:Borroni E; Bohrmann B; Grueninger F; Prinssen E; Nave S; Loetscher H; Chinta SJ; Rajagopalan S; Rane A; Siddiqui A; Ellenbroek B; Messer J; Pähler A; Andersen JK; Wyler R; Cesura AM
[Ad] Endereço:Roche Innovation Center Basel, Pharma Research and Early Development, F. Hoffmann-La Roche Ltd., Basel, Switzerland (E.B., B.B., F.G., E.P., S.N., H.L., J.M., A.P., and R.W.); Buck Institute for Research on Aging, Novato, California (S.C., S.R., A.R., A.S., and J.A.); and Evotec International GmbH,
[Ti] Título:Sembragiline: A Novel, Selective Monoamine Oxidase Type B Inhibitor for the Treatment of Alzheimer's Disease.
[So] Source:J Pharmacol Exp Ther;362(3):413-423, 2017 Sep.
[Is] ISSN:1521-0103
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Monoamine oxidase B (MAO-B) has been implicated in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. Increased MAO-B expression in astroglia has been observed adjacent to amyloid plaques in AD patient brains. This phenomenon is hypothesized to lead to increased production of hydrogen peroxide and reactive oxygen species (ROS), thereby contributing to AD pathology. Therefore, reduction of ROS-induced oxidative stress via inhibition of MAO-B activity may delay the progression of the disease. In the present study we report the pharmacological properties of sembragiline, a novel selective MAO-B inhibitor specifically developed for the treatment of AD, and on its effect on ROS-mediated neuronal injury and astrogliosis in MAO-B transgenic animals. Sembragiline showed potent and long-lasting MAO-B-selective inhibition and did not inhibit MAO-A at doses where full inhibition of MAO-B was observed. Such selectivity should translate into a favorable clinical safety profile. Indeed, sembragiline neither induced the serotonin syndrome when administered together with the serotonin precursor l-5-hydroxytryptophan in combination with antidepressants such as fluoxetine, nor potentiated the pressor effect of tyramine. Additionally, in experiments using a transgenic animal model conditionally overexpressing MAO-B in astroglia, sembragiline protected against neuronal loss and reduced both ROS formation and reactive astrogliosis. Taken together, these findings warrant further investigation of the potential therapeutic benefit of MAO-B inhibitors in patients with AD and other neurologic disorders.
[Mh] Termos MeSH primário: Acetamidas/uso terapêutico
Doença de Alzheimer/tratamento farmacológico
Inibidores da Monoaminoxidase/uso terapêutico
Monoaminoxidase/efeitos dos fármacos
Pirrolidinonas/uso terapêutico
[Mh] Termos MeSH secundário: 5-Hidroxitriptofano/farmacologia
Acetamidas/farmacocinética
Animais
Astrócitos/efeitos dos fármacos
Astrócitos/metabolismo
Gliose/tratamento farmacológico
Gliose/patologia
Seres Humanos
Hipertensão/induzido quimicamente
Hipertensão/prevenção & controle
Masculino
Monoaminoxidase/genética
Monoaminoxidase/metabolismo
Inibidores da Monoaminoxidase/farmacocinética
Atividade Motora/efeitos dos fármacos
Neurotransmissores/metabolismo
Pirrolidinonas/farmacocinética
Ratos
Ratos Transgênicos
Espécies Reativas de Oxigênio/metabolismo
Especificidade por Substrato
Distribuição Tecidual
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetamides); 0 (Monoamine Oxidase Inhibitors); 0 (Neurotransmitter Agents); 0 (Pyrrolidinones); 0 (Reactive Oxygen Species); 0 (sembragiline); C1LJO185Q9 (5-Hydroxytryptophan); EC 1.4.3.4 (Monoamine Oxidase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170814
[Lr] Data última revisão:
170814
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170624
[St] Status:MEDLINE
[do] DOI:10.1124/jpet.117.241653



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