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1.
Pharm Res ; 36(12): 171, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31654287

RESUMO

PURPOSE: Physiologically-based pharmacokinetic (PBPK) modeling offers a unique modality to predict age-specific pharmacokinetics. The objective of this study was to assess the ability of PBPK model to predict plasma exposure of oxycodone, a widely used opioid for pain management, in adults and children. METHODS: A full PBPK model of oxycodone following intravenous and oral administration was developed using a 'bottom-up' and 'top-down' combined strategy. The model was then extrapolated to pediatrics through a reasonable scaling method. The adult and pediatric model was evaluated using data from 17 clinical PK studies by testing predicted/observed goodness of fit. The mean fold error for PK parameters was calculated. Finally, we used the validated PBPK model to visualize adult-children dose conversion for oxycodone. RESULTS: The developed PBPK model successfully predicted the oxycodone disposition in adults, wherein the predicted versus observed AUC, Cmax, and tmax were within 0.90 to 1.20-fold difference. After scaling anatomy/physiology, protein binding, and clearance, the model showed satisfactory prediction performance for pediatric populations as predicted AUC were within the 1.50-fold range of the observed values. According to the application of PBPK model, we found that different intravenous doses should be given in children of different ages compared to a standard 0.1 mg/kg in adults, while a progressive increasing dose with age growth following oral administration is recommended for children. CONCLUSIONS: The current example provides the opportunity for using the PBPK model to guide dose adjustment of oxycodone in the design of future pediatric clinical studies.


Assuntos
Analgésicos Opioides/farmacocinética , Oxicodona/farmacocinética , Administração Intravenosa , Administração Oral , Adolescente , Adulto , Analgésicos Opioides/administração & dosagem , Criança , Pré-Escolar , Simulação por Computador , Relação Dose-Resposta a Droga , Humanos , Lactente , Recém-Nascido , Taxa de Depuração Metabólica , Modelos Biológicos , Oxicodona/administração & dosagem , Pediatria
2.
MBio ; 10(5)2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481383

RESUMO

Eukaryotic cells share a basic scheme of internal organization featuring membrane-based organelles. The use of fluorescent proteins (FPs) greatly facilitated live-cell imaging of organelle dynamics and protein trafficking. One major limitation of this approach is that the fusion of an FP to a target protein can and often does compromise the function of the target protein and alter its subcellular localization. The optimization process to obtain a desirable fusion construct can be time-consuming or even unsuccessful. In this work, we set out to provide a validated set of FP-based markers for major organelles in the budding yeast (Saccharomyces cerevisiae). Out of over 160 plasmids constructed, we present a final set of 42 plasmids, the recommendations for which are backed up by meticulous evaluations. The tool set includes three colors (green, red, and blue) and covers the endoplasmic reticulum (ER), nucleus, Golgi apparatus, endosomes, vacuoles, mitochondria, peroxisomes, and lipid droplets. The fidelity of the markers was established by systematic cross-comparison and quantification. Functional assays were performed to examine the impact of marker expression on the secretory pathway, endocytic pathway, and metabolic activities of mitochondria and peroxisomes. Concomitantly, our work constitutes a reassessment of organelle identities in this model organism. Our data support the recognition that "late Golgi" and "early endosomes," two seemingly distinct terms, denote the same compartment in yeast. Conversely, all other organelles can be visually separated from each other at the resolution of conventional light microscopy, and quantification results justify their classification as distinct entities.IMPORTANCE Cells contain elaborate internal structures. For eukaryotic cells, like those in our bodies, the internal space is compartmentalized into membrane-bound organelles, each tasked with specialized functions. Oftentimes, one needs to visualize organelles to understand a complex cellular process. Here, we provide a validated set of fluorescent protein-based markers for major organelles in budding yeast. Yeast is a commonly used model when investigating basic mechanisms shared among eukaryotes. Fluorescent proteins are produced by cells themselves, avoiding the need for expensive chemical dyes. Through extensive cross-comparison, we make sure that each of our markers labels and only labels the intended organelle. We also carefully examined if the presence of our markers has any negative impact on the functionality of the cells and found none. Our work also helps answer a related question: are the structures we see really what we think they are?

3.
Opt Express ; 24(20): 22606-22615, 2016 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-27828331

RESUMO

Functional integration is crucial and has become a research interest in recent years; however, available efforts suffer from low efficiency and narrow operating bandwidth. Here, we propose a novel strategy to design bifunctional meta-surface with high efficiency and largely enhanced bandwidth in reflection geometry. For demonstration, we designed and fabricated a bifunctional meta-surface which enables both focusing and anomalous reflection under different polarizations. The working bandwidth is significantly extended by using the dual-resonant three-turn meander-line resonator (TMLR) element which provides an almost consistent phase response within a large frequency interval. For potential applications, we engineered a bifunctional antenna by launching the designed meta-surface with proper feed sources. Numerical and experimental results coincide well, indicating bifunctionalities of high gain pencil-beam radiation (reflectarray) and beam steering radiation with comparable performances. Our results can stimulate the realizations of high-performance meta-surfaces and antenna systems.

4.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 38(5): 885-8, 2007 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-17953385

RESUMO

OBJECTIVE: To prepare a peroral thymopentin-loaded N-trimethyl chitosan chloride-nanoparticle (Tp5-TMC-NP) ,and observe the pharmacodynamic action when the Tp5-TMC-NP is taken by way of the mouth. METHODS: N-trimethyl chitosan chloride was first synthesized, and then Tp5-TMC-NP was prepared with the formulation technology optimized by the Central Composite Design. The influence of Tp5-TMC-NP on the ratio of CD4+/CD8+ of T-lymphocytes were determined by flow cytometer. RESULTS: The regular global Tp5-TMC-NP prepared with the optimized formulation craft had the mean diameter of 110.6 nm and got the entrapment efficiency of 78.8%. The ratio of lymphocyte CD4+/CD8+ of Wistar rat administered with Tp5-TMC-NP perfusing stomach had 2.59 times higher than that with Tp5. CONCLUSION: Taken orally the Tp5-TMC-NP has much higher efficiency than Tp5.


Assuntos
Quitosana/administração & dosagem , Portadores de Fármacos/administração & dosagem , Nanopartículas/administração & dosagem , Timopentina/administração & dosagem , Administração Oral , Animais , Relação CD4-CD8 , Ratos , Ratos Wistar , Timopentina/farmacocinética
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