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Pesquisa : B01.050.050.199.520.760.275 [Categoria DeCS]
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  1 / 190 MEDLINE  
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[PMID]:28280248
[Au] Autor:Moore JJ; Ravassard PM; Ho D; Acharya L; Kees AL; Vuong C; Mehta MR
[Ad] Endereço:W. M. Keck Center for Neurophysics, Integrative Center for Learning and Memory, and Brain Research Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. jason.moore@ucla.edu mayankmehta@ucla.edu.
[Ti] Título:Dynamics of cortical dendritic membrane potential and spikes in freely behaving rats.
[So] Source:Science;355(6331), 2017 Mar 24.
[Is] ISSN:1095-9203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Neural activity in vivo is primarily measured using extracellular somatic spikes, which provide limited information about neural computation. Hence, it is necessary to record from neuronal dendrites, which can generate dendritic action potentials (DAPs) in vitro, which can profoundly influence neural computation and plasticity. We measured neocortical sub- and suprathreshold dendritic membrane potential (DMP) from putative distal-most dendrites using tetrodes in freely behaving rats over multiple days with a high degree of stability and submillisecond temporal resolution. DAP firing rates were several-fold larger than somatic rates. DAP rates were also modulated by subthreshold DMP fluctuations, which were far larger than DAP amplitude, indicating hybrid, analog-digital coding in the dendrites. Parietal DAP and DMP exhibited egocentric spatial maps comparable to pyramidal neurons. These results have important implications for neural coding and plasticity.
[Mh] Termos MeSH primário: Córtex Cerebral/fisiologia
Dendritos/fisiologia
Potenciais da Membrana
[Mh] Termos MeSH secundário: Potenciais de Ação
Animais
Comportamento Animal/fisiologia
Córtex Cerebral/citologia
Eletrodos Implantados
Masculino
Neuroglia/fisiologia
Células Piramidais/fisiologia
Ratos
Ratos Endogâmicos LEC
Sono/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171103
[Lr] Data última revisão:
171103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170311
[St] Status:MEDLINE


  2 / 190 MEDLINE  
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[PMID]:28152139
[Au] Autor:Shu DY; Wojciechowski MC; Lovicu FJ
[Ad] Endereço:Discipline of Anatomy and Histology, Bosch Institute, University of Sydney, New South Wales, Australia 2Save Sight Institute, University of Sydney, New South Wales, Australia.
[Ti] Título:Bone Morphogenetic Protein-7 Suppresses TGFß2-Induced Epithelial-Mesenchymal Transition in the Lens: Implications for Cataract Prevention.
[So] Source:Invest Ophthalmol Vis Sci;58(2):781-796, 2017 Feb 01.
[Is] ISSN:1552-5783
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose: Epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs) is a key pathologic mechanism underlying cataract. Two members of the transforming growth factor-ß (TGFß) superfamily, TGFß and bone morphogenetic protein-7 (BMP-7) have functionally distinct roles in EMT. While TGFß is a potent inducer of EMT, BMP-7 counteracts the fibrogenic activity of TGFß. We examine the modulating effect of BMP-7 on TGFß-induced EMT in LECs. Methods: Rat lens epithelial explants were treated exogenously with TGFß2 alone or in combination with BMP-7 for up to 5 days. Expression levels of E-cadherin, ß-catenin, α-smooth muscle actin (α-SMA), and phosphorylated downstream Smads were determined using immunofluorescence and Western blotting. Reverse transcriptase quantitative PCR (RT-qPCR) was used to study gene expression levels of EMT markers and downstream BMP target genes, including the Inhibitors of differentiation (Id). Results: Transforming growth factor-ß2 induced LECs to transdifferentiate into myofibroblastic cells. Addition of BMP-7 suppressed TGFß2-induced α-SMA protein levels and mesenchymal gene expression, with retention of E-cadherin and ß-catenin expression to the cell membrane. Addition of BMP-7 prevented lens capsular wrinkling and cellular loss associated with TGFß2-induced EMT over the 5-day treatment period. The inhibitory effect of BMP-7 was accompanied by an early induction of pSmad1/5 and suppression of TGFß2-induced pSmad2/3. Treatment with TGFß2 alone suppressed gene expression of Id2/3 and addition of BMP-7 restored Id2/3 expression. Conclusions: Exogenous administration of BMP-7 abrogated TGFß2-induced EMT in rat lens epithelial explants. Understanding the complex interplay between the TGFß- and BMP-7-associated Smad signaling pathways and their downstream target genes holds therapeutic promise in cataract prevention.
[Mh] Termos MeSH primário: Proteína Morfogenética Óssea 7/farmacologia
Transição Epitelial-Mesenquimal/efeitos dos fármacos
Cristalino/efeitos dos fármacos
Fator de Crescimento Transformador beta2/farmacologia
[Mh] Termos MeSH secundário: Actinas/metabolismo
Animais
Proteína Morfogenética Óssea 7/fisiologia
Caderinas/metabolismo
Catarata/metabolismo
Diferenciação Celular/efeitos dos fármacos
Membrana Celular/metabolismo
Células Epiteliais/efeitos dos fármacos
Células Epiteliais/metabolismo
Cristalino/fisiologia
Células Mesenquimais Estromais/metabolismo
Modelos Animais
Ratos
Ratos Endogâmicos LEC
Ratos Wistar
Proteínas Smad/metabolismo
Fator de Crescimento Transformador beta2/antagonistas & inibidores
beta Catenina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ACTA2 protein, human); 0 (Actins); 0 (BMP7 protein, human); 0 (Bone Morphogenetic Protein 7); 0 (Cadherins); 0 (Smad Proteins); 0 (Transforming Growth Factor beta2); 0 (beta Catenin)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170621
[Lr] Data última revisão:
170621
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170203
[St] Status:MEDLINE
[do] DOI:10.1167/iovs.16-20611


  3 / 190 MEDLINE  
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[PMID]:27846607
[Au] Autor:Ishiyama S; Brecht M
[Ad] Endereço:Bernstein Center for Computational Neuroscience Berlin, Institut für Biologie, Humboldt-Universität zu Berlin, 10115 Berlin, Germany.
[Ti] Título:Neural correlates of ticklishness in the rat somatosensory cortex.
[So] Source:Science;354(6313):757-760, 2016 11 11.
[Is] ISSN:1095-9203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Rats emit ultrasonic vocalizations in response to tickling by humans. Tickling is rewarding through dopaminergic mechanisms, but the function and neural correlates of ticklishness are unknown. We confirmed that tickling of rats evoked vocalizations, approach, and unsolicited jumps (Freudensprünge). Recordings in the trunk region of the rat somatosensory cortex showed intense tickling-evoked activity in most neurons, whereas a minority of cells were suppressed by tickling. Tickling responses predicted nontactile neural responses to play behaviors, which suggests a neuronal link between tickling and play. Anxiogenic conditions suppressed tickling-evoked vocalizations and trunk cortex activity. Deep-layer trunk cortex neurons discharged during vocalizations, and deep-layer microstimulation evoked vocalizations. Our findings provide evidence for deep-layer trunk cortex activity as a neural correlate of ticklishness.
[Mh] Termos MeSH primário: Neurônios Dopaminérgicos/fisiologia
Córtex Somatossensorial/fisiologia
Tato/fisiologia
Vocalização Animal
[Mh] Termos MeSH secundário: Animais
Masculino
Ratos
Ratos Endogâmicos LEC
Recompensa
Ultrassom
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170626
[Lr] Data última revisão:
170626
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161116
[St] Status:MEDLINE


  4 / 190 MEDLINE  
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[PMID]:27013730
[Au] Autor:Grosmark AD; Buzsáki G
[Ad] Endereço:Department of Neuroscience, Columbia University Medical Center, New York, NY 10019, USA. The Neuroscience Institute, School of Medicine, New York University, New York, NY 10016, USA.
[Ti] Título:Diversity in neural firing dynamics supports both rigid and learned hippocampal sequences.
[So] Source:Science;351(6280):1440-3, 2016 Mar 25.
[Is] ISSN:1095-9203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cell assembly sequences during learning are "replayed" during hippocampal ripples and contribute to the consolidation of episodic memories. However, neuronal sequences may also reflect preexisting dynamics. We report that sequences of place-cell firing in a novel environment are formed from a combination of the contributions of a rigid, predominantly fast-firing subset of pyramidal neurons with low spatial specificity and limited change across sleep-experience-sleep and a slow-firing plastic subset. Slow-firing cells, rather than fast-firing cells, gained high place specificity during exploration, elevated their association with ripples, and showed increased bursting and temporal coactivation during postexperience sleep. Thus, slow- and fast-firing neurons, although forming a continuous distribution, have different coding and plastic properties.
[Mh] Termos MeSH primário: Hipocampo/fisiopatologia
Aprendizagem/fisiologia
Células Piramidais/fisiologia
[Mh] Termos MeSH secundário: Potenciais de Ação
Animais
Hipocampo/citologia
Masculino
Aprendizagem em Labirinto
Plasticidade Neuronal
Ratos
Ratos Endogâmicos LEC
Sono/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Mês de entrada:1604
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160326
[St] Status:MEDLINE
[do] DOI:10.1126/science.aad1935


  5 / 190 MEDLINE  
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[PMID]:26722001
[Au] Autor:Ferenczi EA; Zalocusky KA; Liston C; Grosenick L; Warden MR; Amatya D; Katovich K; Mehta H; Patenaude B; Ramakrishnan C; Kalanithi P; Etkin A; Knutson B; Glover GH; Deisseroth K
[Ad] Endereço:Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
[Ti] Título:Prefrontal cortical regulation of brainwide circuit dynamics and reward-related behavior.
[So] Source:Science;351(6268):aac9698, 2016 Jan 01.
[Is] ISSN:1095-9203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Motivation for reward drives adaptive behaviors, whereas impairment of reward perception and experience (anhedonia) can contribute to psychiatric diseases, including depression and schizophrenia. We sought to test the hypothesis that the medial prefrontal cortex (mPFC) controls interactions among specific subcortical regions that govern hedonic responses. By using optogenetic functional magnetic resonance imaging to locally manipulate but globally visualize neural activity in rats, we found that dopamine neuron stimulation drives striatal activity, whereas locally increased mPFC excitability reduces this striatal response and inhibits the behavioral drive for dopaminergic stimulation. This chronic mPFC overactivity also stably suppresses natural reward-motivated behaviors and induces specific new brainwide functional interactions, which predict the degree of anhedonia in individuals. These findings describe a mechanism by which mPFC modulates expression of reward-seeking behavior, by regulating the dynamical interactions between specific distant subcortical regions.
[Mh] Termos MeSH primário: Anedonia/fisiologia
Corpo Estriado/fisiologia
Neurônios Dopaminérgicos/fisiologia
Motivação
Córtex Pré-Frontal/fisiologia
Recompensa
[Mh] Termos MeSH secundário: Animais
Mapeamento Encefálico
Corpo Estriado/citologia
Corpo Estriado/efeitos dos fármacos
Transtorno Depressivo/fisiopatologia
Dopamina/farmacologia
Neurônios Dopaminérgicos/efeitos dos fármacos
Feminino
Imagem por Ressonância Magnética
Masculino
Mesencéfalo/citologia
Mesencéfalo/efeitos dos fármacos
Mesencéfalo/fisiologia
Rede Nervosa/fisiologia
Oxigênio/sangue
Córtex Pré-Frontal/citologia
Córtex Pré-Frontal/efeitos dos fármacos
Ratos
Ratos Endogâmicos LEC
Ratos Sprague-Dawley
Esquizofrenia/fisiopatologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
S88TT14065 (Oxygen); VTD58H1Z2X (Dopamine)
[Em] Mês de entrada:1601
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160102
[St] Status:MEDLINE
[do] DOI:10.1126/science.aac9698


  6 / 190 MEDLINE  
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[PMID]:26160946
[Au] Autor:Pfeiffer BE; Foster DJ
[Ad] Endereço:Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
[Ti] Título:PLACE CELLS. Autoassociative dynamics in the generation of sequences of hippocampal place cells.
[So] Source:Science;349(6244):180-3, 2015 Jul 10.
[Is] ISSN:1095-9203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Neuronal circuits produce self-sustaining sequences of activity patterns, but the precise mechanisms remain unknown. Here we provide evidence for autoassociative dynamics in sequence generation. During sharp-wave ripple (SWR) events, hippocampal neurons express sequenced reactivations, which we show are composed of discrete attractors. Each attractor corresponds to a single location, the representation of which sharpens over the course of several milliseconds, as the reactivation focuses at that location. Subsequently, the reactivation transitions rapidly to a spatially discontiguous location. This alternation between sharpening and transition occurs repeatedly within individual SWRs and is locked to the slow-gamma (25 to 50 hertz) rhythm. These findings support theoretical notions of neural network function and reveal a fundamental discretization in the retrieval of memory in the hippocampus, together with a function for gamma oscillations in the control of attractor dynamics.
[Mh] Termos MeSH primário: Hipocampo/citologia
Hipocampo/fisiologia
Rememoração Mental/fisiologia
Neurônios/fisiologia
[Mh] Termos MeSH secundário: Animais
Ritmo Gama
Masculino
Vias Neurais
Ratos
Ratos Endogâmicos LEC
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Em] Mês de entrada:1507
[Cu] Atualização por classe:150710
[Lr] Data última revisão:
150710
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150711
[St] Status:MEDLINE
[do] DOI:10.1126/science.aaa9633


  7 / 190 MEDLINE  
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[PMID]:25931556
[Au] Autor:Ciocchi S; Passecker J; Malagon-Vina H; Mikus N; Klausberger T
[Ad] Endereço:Center for Brain Research, Department for Cognitive Neurobiology, Medical University Vienna, Spitalgasse 4, 1090 Vienna, Austria. stephane.ciocchi@meduniwien.ac.at thomas.klausberger@meduniwien.ac.at.
[Ti] Título:Brain computation. Selective information routing by ventral hippocampal CA1 projection neurons.
[So] Source:Science;348(6234):560-3, 2015 May 01.
[Is] ISSN:1095-9203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The hippocampus computes diverse information involving spatial memory, anxiety, or reward and directly projects to several brain areas. Are different computations transmitted to all downstream targets uniformly, or does the hippocampus selectively route information according to content and target region? By recording from ventral hippocampal CA1 neurons in rats during different behavioral tasks and determining axonal projections with optogenetics, we observed subsets of neurons changing firing at places of elevated anxiety or changing activity during goal approach. Anxiety-related firing was selectively increased in neurons projecting to the prefrontal cortex. Goal-directed firing was most prominent in neurons targeting the nucleus accumbens; and triple-projecting neurons, targeting the prefrontal cortex, amygdala, and nucleus accumbens, were most active during tasks and sharp wave/ripples. Thus, hippocampal neurons route distinct behavior-contingent information selectively to different target areas.
[Mh] Termos MeSH primário: Região CA1 Hipocampal/fisiologia
Processos Mentais/fisiologia
Aprendizagem Espacial
[Mh] Termos MeSH secundário: Animais
Ansiedade/fisiopatologia
Comunicação Celular
Masculino
Neurônios/fisiologia
Núcleo Accumbens/fisiologia
Optogenética
Córtex Pré-Frontal/fisiologia
Ratos
Ratos Endogâmicos LEC
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Mês de entrada:1505
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150502
[St] Status:MEDLINE
[do] DOI:10.1126/science.aaa3245


  8 / 190 MEDLINE  
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[PMID]:25700518
[Au] Autor:Winter SS; Clark BJ; Taube JS
[Ad] Endereço:Department of Psychological and Brain Sciences, Center for Cognitive Neuroscience, Dartmouth College, Hanover, NH 03755, USA.
[Ti] Título:Spatial navigation. Disruption of the head direction cell network impairs the parahippocampal grid cell signal.
[So] Source:Science;347(6224):870-874, 2015 Feb 20.
[Is] ISSN:1095-9203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Navigation depends on multiple neural systems that encode the moment-to-moment changes in an animal's direction and location in space. These include head direction (HD) cells representing the orientation of the head and grid cells that fire at multiple locations, forming a repeating hexagonal grid pattern. Computational models hypothesize that generation of the grid cell signal relies upon HD information that ascends to the hippocampal network via the anterior thalamic nuclei (ATN). We inactivated or lesioned the ATN and subsequently recorded single units in the entorhinal cortex and parasubiculum. ATN manipulation significantly disrupted grid and HD cell characteristics while sparing theta rhythmicity in these regions. These results indicate that the HD signal via the ATN is necessary for the generation and function of grid cell activity.
[Mh] Termos MeSH primário: Núcleos Anteriores do Tálamo/fisiologia
Córtex Entorrinal/fisiologia
Rede Nervosa/fisiologia
Neurônios/fisiologia
Orientação/fisiologia
Navegação Espacial/fisiologia
[Mh] Termos MeSH secundário: Animais
Núcleos Anteriores do Tálamo/efeitos dos fármacos
Córtex Entorrinal/citologia
Feminino
Cabeça
Hipocampo/citologia
Hipocampo/fisiologia
Lidocaína/farmacologia
Rede Nervosa/citologia
Rede Nervosa/efeitos dos fármacos
Ratos
Ratos Endogâmicos LEC
Transdução de Sinais
Ritmo Teta
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
98PI200987 (Lidocaine)
[Em] Mês de entrada:1503
[Cu] Atualização por classe:170718
[Lr] Data última revisão:
170718
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150221
[St] Status:MEDLINE
[do] DOI:10.1126/science.1259591


  9 / 190 MEDLINE  
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[PMID]:25385101
[Au] Autor:Schlosser MJ; Hosako H; Radovsky A; Butt MT; Draganov D; Vija J; Oleson F
[Ad] Endereço:MSR Pharma Services, Lincolnshire, Illinois, USA.
[Ti] Título:Lack of neuropathological changes in rats administered tedizolid phosphate for nine months.
[So] Source:Antimicrob Agents Chemother;59(1):475-81, 2015 Jan.
[Is] ISSN:1098-6596
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Tedizolid, a novel oxazolidinone antibacterial, was administered to Long Evans rats by oral gavage once daily for up to 9 months at doses near the maximum tolerated dose (MTD) to evaluate for potential neurotoxicity. Mean plasma exposures of tedizolid at the low-, medium-, and high-dose levels (7.5, 15, and 30 mg/kg of body weight/day for males; 2.5, 5, and 10 mg/kg/day for females) were similar between males and females and were 1.8-, 3.9-, and 8.0-fold greater than exposures in patients at the therapeutic dose (200 mg once daily). Evaluated endpoints included survival, clinical observations, body weight, and food consumption. At 1, 3, 6, and 9 months, ophthalmic examinations, functional observational batteries, and locomotor activity measures were conducted, brain weights/sizes were recorded, and perfusion-fixed tissues were collected from 12 rats/sex/group/time point. A detailed morphological assessment was conducted on brain, eyes, optic nerve/tract, spinal cord, peripheral nerves (includes sciatic, sural, tibial, peroneal, trigeminal), and skeletal muscle. At the end of 9 months, less body weight gain was seen in high-dose males (-6.7%) and females (-5.8%) compared with that seen in controls. There were no tedizolid-related adverse neurobehavioral effects or tedizolid-related histopathologic changes in the central/peripheral nervous systems, including the optic nerve. Results of this study indicate that tedizolid was not neurotoxic when administered long term to pigmented rats at doses near the MTD, which were up to 8-fold higher than the human therapeutic exposure.
[Mh] Termos MeSH primário: Antibacterianos/efeitos adversos
Linezolida/efeitos adversos
Síndromes Neurotóxicas/mortalidade
Organofosfatos/efeitos adversos
Oxazóis/efeitos adversos
[Mh] Termos MeSH secundário: Animais
Antibacterianos/administração & dosagem
Antibacterianos/farmacologia
Feminino
Linezolida/administração & dosagem
Linezolida/farmacologia
Masculino
Organofosfatos/administração & dosagem
Organofosfatos/farmacologia
Oxazóis/administração & dosagem
Oxazóis/farmacologia
Ratos
Ratos Endogâmicos LEC
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Organophosphates); 0 (Oxazoles); ISQ9I6J12J (Linezolid); O7DRJ6R4DW (torezolid phosphate)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141112
[St] Status:MEDLINE
[do] DOI:10.1128/AAC.03950-14


  10 / 190 MEDLINE  
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[PMID]:25331703
[Au] Autor:Flanagan S; McKee EE; Das D; Tulkens PM; Hosako H; Fiedler-Kelly J; Passarell J; Radovsky A; Prokocimer P
[Ad] Endereço:Cubist Pharmaceuticals, San Diego, California, USA shawn.flanagan@cubist.com.
[Ti] Título:Nonclinical and pharmacokinetic assessments to evaluate the potential of tedizolid and linezolid to affect mitochondrial function.
[So] Source:Antimicrob Agents Chemother;59(1):178-85, 2015 Jan.
[Is] ISSN:1098-6596
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Prolonged treatment with the oxazolidinone linezolid is associated with myelosuppression, lactic acidosis, and neuropathies, toxicities likely caused by impairment of mitochondrial protein synthesis (MPS). To evaluate the potential of the novel oxazolidinone tedizolid to cause similar side effects, nonclinical and pharmacokinetic assessments were conducted. In isolated rat heart mitochondria, tedizolid inhibited MPS more potently than did linezolid (average [± standard error of the mean] 50% inhibitory concentration [IC50] for MPS of 0.31 ± 0.02 µM versus 6.4 ± 1.2 µM). However, a rigorous 9-month rat study comparing placebo and high-dose tedizolid (resulting in steady-state area under the plasma concentration-time curve values about 8-fold greater than those with the standard therapeutic dose in humans) showed no evidence of neuropathy. Additional studies explored why prolonged, high-dose tedizolid did not cause these mitochondriopathic side effects despite potent MPS inhibition by tedizolid. Murine macrophage (J774) cell fractionation studies found no evidence of a stable association of tedizolid with eukaryotic mitochondria. Monte Carlo simulations based on population pharmacokinetic models showed that over the course of a dosing interval using standard therapeutic doses, free plasma concentrations fell below the respective MPS IC50 in 84% of tedizolid-treated patients (for a median duration of 7.94 h) and 38% of linezolid-treated patients (for a median duration of 0 h). Therapeutic doses of tedizolid, but not linezolid, may therefore allow for mitochondrial recovery during antibacterial therapy. The overall results suggest that tedizolid has less potential to cause myelosuppression and neuropathy than that of linezolid during prolonged treatment courses. This, however, remains a hypothesis that must be confirmed in clinical studies.
[Mh] Termos MeSH primário: Antibacterianos/farmacocinética
Linezolida/farmacocinética
Mitocôndrias/efeitos dos fármacos
Oxazolidinonas/farmacocinética
Tetrazóis/farmacocinética
[Mh] Termos MeSH secundário: Animais
Antibacterianos/efeitos adversos
Antibacterianos/farmacologia
Avaliação Pré-Clínica de Medicamentos/métodos
Feminino
Seres Humanos
Técnicas In Vitro
Linezolida/efeitos adversos
Linezolida/farmacologia
Masculino
Camundongos
Mitocôndrias/metabolismo
Proteínas Mitocondriais/biossíntese
Método de Monte Carlo
Síndromes Neurotóxicas/etiologia
Oxazolidinonas/efeitos adversos
Oxazolidinonas/farmacologia
Ratos Endogâmicos LEC
Tetrazóis/efeitos adversos
Tetrazóis/farmacologia
Testes de Toxicidade Crônica/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Mitochondrial Proteins); 0 (Oxazolidinones); 0 (Tetrazoles); 97HLQ82NGL (torezolid); ISQ9I6J12J (Linezolid)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141022
[St] Status:MEDLINE
[do] DOI:10.1128/AAC.03684-14



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