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Sample records for auc

  1. The Open AUC Project.

    Science.gov (United States)

    Cölfen, Helmut; Laue, Thomas M; Wohlleben, Wendel; Schilling, Kristian; Karabudak, Engin; Langhorst, Bradley W; Brookes, Emre; Dubbs, Bruce; Zollars, Dan; Rocco, Mattia; Demeler, Borries

    2010-02-01

    Progress in analytical ultracentrifugation (AUC) has been hindered by obstructions to hardware innovation and by software incompatibility. In this paper, we announce and outline the Open AUC Project. The goals of the Open AUC Project are to stimulate AUC innovation by improving instrumentation, detectors, acquisition and analysis software, and collaborative tools. These improvements are needed for the next generation of AUC-based research. The Open AUC Project combines on-going work from several different groups. A new base instrument is described, one that is designed from the ground up to be an analytical ultracentrifuge. This machine offers an open architecture, hardware standards, and application programming interfaces for detector developers. All software will use the GNU Public License to assure that intellectual property is available in open source format. The Open AUC strategy facilitates collaborations, encourages sharing, and eliminates the chronic impediments that have plagued AUC innovation for the last 20 years. This ultracentrifuge will be equipped with multiple and interchangeable optical tracks so that state-of-the-art electronics and improved detectors will be available for a variety of optical systems. The instrument will be complemented by a new rotor, enhanced data acquisition and analysis software, as well as collaboration software. Described here are the instrument, the modular software components, and a standardized database that will encourage and ease integration of data analysis and interpretation software.

  2. Development of MWL-AUC / CCD-C-AUC / SLS-AUC detectors for the analytical ultracentrifuge

    OpenAIRE

    2009-01-01

    Analytical ultracentrifugation (AUC) has made an important contribution to polymer and particle characterization since its invention by Svedberg (Svedberg and Nichols 1923; Svedberg and Pederson 1940) in 1923. In 1926, Svedberg won the Nobel price for his scientific work on disperse systems including work with AUC. The first important discovery performed with AUC was to show the existence of macromolecules. Since that time AUC has become an important tool to study polymers in biophysics and b...

  3. AUK: a simple alternative to the AUC

    NARCIS (Netherlands)

    U. Kaymak (Uzay); A. Ben-David (Arie); R. Potharst (Rob)

    2010-01-01

    textabstractThe area under Receiver Operating Characteristic (ROC) curve, also known as the AUC-index, is commonly used for ranking the performance of data mining models. The AUC has many merits, such as objectivity and ease of interpretation. However, since it is class indifferent, its usefulness w

  4. Hydrodynamic Modeling and Its Application in AUC.

    Science.gov (United States)

    Rocco, Mattia; Byron, Olwyn

    2015-01-01

    The hydrodynamic parameters measured in an AUC experiment, s(20,w) and D(t)(20,w)(0), can be used to gain information on the solution structure of (bio)macromolecules and their assemblies. This entails comparing the measured parameters with those that can be computed from usually "dry" structures by "hydrodynamic modeling." In this chapter, we will first briefly put hydrodynamic modeling in perspective and present the basic physics behind it as implemented in the most commonly used methods. The important "hydration" issue is also touched upon, and the distinction between rigid bodies versus those for which flexibility must be considered in the modeling process is then made. The available hydrodynamic modeling/computation programs, HYDROPRO, BEST, SoMo, AtoB, and Zeno, the latter four all implemented within the US-SOMO suite, are described and their performance evaluated. Finally, some literature examples are presented to illustrate the potential applications of hydrodynamics in the expanding field of multiresolution modeling.

  5. Partial AUC maximization for essential gene prediction using genetic algorithms.

    Science.gov (United States)

    Hwang, Kyu-Baek; Ha, Beom-Yong; Ju, Sanghun; Kim, Sangsoo

    2013-01-01

    Identifying genes indispensable for an organism's life and their characteristics is one of the central questions in current biological research, and hence it would be helpful to develop computational approaches towards the prediction of essential genes. The performance of a predictor is usually measured by the area under the receiver operating characteristic curve (AUC). We propose a novel method by implementing genetic algorithms to maximize the partial AUC that is restricted to a specific interval of lower false positive rate (FPR), the region relevant to follow-up experimental validation. Our predictor uses various features based on sequence information, protein-protein interaction network topology, and gene expression profiles. A feature selection wrapper was developed to alleviate the over-fitting problem and to weigh each feature's relevance to prediction. We evaluated our method using the proteome of budding yeast. Our implementation of genetic algorithms maximizing the partial AUC below 0.05 or 0.10 of FPR outperformed other popular classification methods.

  6. Preparation and characterization of antibacterial Au/C core-shell composite

    Energy Technology Data Exchange (ETDEWEB)

    Gao Yanhong [Department of Chemistry and Institute of Nanochemistry, Jinan University, 601 Huangpudadaoxi Road, Guangzhou 510632, Guangdong (China); Centers for Disease Control and Prevention of Guangdong Province, Guangzhou 510300, Guangdong (China); Zhang Nianchun [Department of Chemistry and Institute of Nanochemistry, Jinan University, 601 Huangpudadaoxi Road, Guangzhou 510632, Guangdong (China); Zhong Yuwen [Centers for Disease Control and Prevention of Guangdong Province, Guangzhou 510300, Guangdong (China); Cai Huaihong [Department of Chemistry and Institute of Nanochemistry, Jinan University, 601 Huangpudadaoxi Road, Guangzhou 510632, Guangdong (China); Liu Yingliang, E-mail: tliuyl@jnu.edu.cn [Department of Chemistry and Institute of Nanochemistry, Jinan University, 601 Huangpudadaoxi Road, Guangzhou 510632, Guangdong (China)

    2010-09-01

    An environment-friendly oxidation-reduction method was used to prepare Au/C core-shell composite using carbon as core and gold as shell. The chemical structures and morphologies of Au/C core-shell composite and carbon sphere were characterized by X-ray diffraction, transmission electron microscope, energy dispersion X-ray spectrometry (EDS) and X-ray photoelectron spectroscopy (XPS). The antibacterial properties of the Au/C core-shell composite against Escherichia coli (E. coli), Staphylococcus aureus (S. aureus) and Candida albicans (C. albicans) were examined by the disk diffusion assay and minimal inhibition concentration (MIC) methods. In addition, antibacterial ability of Au/C core-shell composite was observed by atomic force microscope. Results demonstrated that gold homogeneously supported on the surface of carbon spheres without aggregation and showed efficient antibacterial abilities.

  7. Optimization of Cyclosporine Therapy with Predicted AUC in Renal Transplant Patients

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Background: Pre-dose concentration measurement is the most practical method to evaluate cyclosporine(CsA) therapy in renal transplant patients. But it gives no information about the total drug exposure,which relate to graft survival. A number of different new concepts of CsA monitoring,including approaches such as single,double,triple time-point and abbreviated area under curve(AUC) determinaiton,have been introduced. The full CsA AUC value is the most sensitive indicator of clinical outcome. However,its higher analytical costs and time-consuming sampling compromise the benefit of full AUC. Alternative method of predicted AUC by using 2 concentration-time points have been established and used for routine practice in our hospital. [Objectives] The purpose of this study is to determine more sensitive and more predictive markers for CsA dosage adjustment in renal transplant patients. [Methods] Total 44 patients completed the 12-hours CsA pharmacokinetic studies. They had stable renal function. None of them had history of gastrectomy,small bowel resection,cholecystectomy,cholestasis,or had use of medications that might cause an interaction with CsA before the study. Pharmacokinetic parameters were evaluated by use of noncompartmental methods. The correlation equations between drug concentration-time points and AUC were determined by simple and multiple linear regression models using one,two,or three concentration time points as independent variable. [Results] Most of Cmax achieved at about 1~2 hours after dosing,but some delayed absorption was observed at abour 3~5 hours after dosing. C0 and C1 are poorly correlated with AUC of CsA,two of three point have better correlation than single point. Depending on clinical outcomes,predicted AUC goes more reliable than single concentration-time point monitoring for consideration of total exposure amount of CsA. If Tmax of CsA concentration-time curve shifted(delayed) out of population range,the AUC prediction error will be

  8. Guidance to Achieve Accurate Aggregate Quantitation in Biopharmaceuticals by SV-AUC.

    Science.gov (United States)

    Arthur, Kelly K; Kendrick, Brent S; Gabrielson, John P

    2015-01-01

    The levels and types of aggregates present in protein biopharmaceuticals must be assessed during all stages of product development, manufacturing, and storage of the finished product. Routine monitoring of aggregate levels in biopharmaceuticals is typically achieved by size exclusion chromatography (SEC) due to its high precision, speed, robustness, and simplicity to operate. However, SEC is error prone and requires careful method development to ensure accuracy of reported aggregate levels. Sedimentation velocity analytical ultracentrifugation (SV-AUC) is an orthogonal technique that can be used to measure protein aggregation without many of the potential inaccuracies of SEC. In this chapter, we discuss applications of SV-AUC during biopharmaceutical development and how characteristics of the technique make it better suited for some applications than others. We then discuss the elements of a comprehensive analytical control strategy for SV-AUC. Successful implementation of these analytical control elements ensures that SV-AUC provides continued value over the long time frames necessary to bring biopharmaceuticals to market.

  9. An alternative approach to calculating Area-Under-the-Curve (AUC) in delay discounting research.

    Science.gov (United States)

    Borges, Allison M; Kuang, Jinyi; Milhorn, Hannah; Yi, Richard

    2016-09-01

    Applied to delay discounting data, Area-Under-the-Curve (AUC) provides an atheoretical index of the rate of delay discounting. The conventional method of calculating AUC, by summing the areas of the trapezoids formed by successive delay-indifference point pairings, does not account for the fact that most delay discounting tasks scale delay pseudoexponentially, that is, time intervals between delays typically get larger as delays get longer. This results in a disproportionate contribution of indifference points at long delays to the total AUC, with minimal contribution from indifference points at short delays. We propose two modifications that correct for this imbalance via a base-10 logarithmic transformation and an ordinal scaling transformation of delays. These newly proposed indices of discounting, AUClog d and AUCor d, address the limitation of AUC while preserving a primary strength (remaining atheoretical). Re-examination of previously published data provides empirical support for both AUClog d and AUCor d . Thus, we believe theoretical and empirical arguments favor these methods as the preferred atheoretical indices of delay discounting.

  10. [The Academy of Trauma Surgery (AUC). Service provider and management organization of the DGU].

    Science.gov (United States)

    Sturm, J A; Hoffmann, R

    2016-02-01

    At the beginning of this century the German Trauma Society (DGU) became extensively active with an initiative on quality promotion, development of quality assurance and transparency regarding treatment of the severely injured. A white book on "Medical care of the severely injured" was published, focusing on the requirements on structural quality and especially procedural quality. The impact of the white book was immense and a trauma network with approved trauma centers, structured and graded for their individual trauma care performance, was developed. In order to monitor and document the required quality of care, a registry was needed. Furthermore, for cooperation within the trauma networks innovative methods for digital transfer of radiological images and patient documents became necessary. Finally, the auditing criteria for trauma centers had and still have to be completed with advanced medical education and training programs. In order to realize the implementation of such a broad spectrum of economically relevant and increasingly complex activities the Academy of Trauma Surgery (AUC) was established as a subsidiary of the DGU in 2004. The AUC currently has four divisions: 1) networks and health care structures, 2) registries and research management, 3) telemedicine, 4) medical education and training, all of which serve the goal of the initiative. The AUC is a full service provider and management organization in compliance with the statutes of the DGU. According to these statutes the business operations of the AUC also cover projects for numerous groups of patients, projects for the joint society the German Society for Orthopedics and Trauma (DGOU) as well as other medical institutions. This article describes the success stories of the trauma network (TraumaNetzwerk DGU®), the TraumaRegister DGU®, the telecooperation platform TKmed®, the new and fast-growing orthogeriatric center initiative (AltersTraumaZentrum DGU®) and the division of medical education and

  11. Survival associated pathway identification with group Lp penalized global AUC maximization

    Directory of Open Access Journals (Sweden)

    Liu Zhenqiu

    2010-08-01

    Full Text Available Abstract It has been demonstrated that genes in a cell do not act independently. They interact with one another to complete certain biological processes or to implement certain molecular functions. How to incorporate biological pathways or functional groups into the model and identify survival associated gene pathways is still a challenging problem. In this paper, we propose a novel iterative gradient based method for survival analysis with group Lp penalized global AUC summary maximization. Unlike LASSO, Lp (p 1. We first extend Lp for individual gene identification to group Lp penalty for pathway selection, and then develop a novel iterative gradient algorithm for penalized global AUC summary maximization (IGGAUCS. This method incorporates the genetic pathways into global AUC summary maximization and identifies survival associated pathways instead of individual genes. The tuning parameters are determined using 10-fold cross validation with training data only. The prediction performance is evaluated using test data. We apply the proposed method to survival outcome analysis with gene expression profile and identify multiple pathways simultaneously. Experimental results with simulation and gene expression data demonstrate that the proposed procedures can be used for identifying important biological pathways that are related to survival phenotype and for building a parsimonious model for predicting the survival times.

  12. Thermal Analysis of the Decomposition of Ammonium Uranyl Carbonate (AUC) in Different Atmospheres

    DEFF Research Database (Denmark)

    Hälldahl, L.; Sørensen, Ole Toft

    1979-01-01

    The intermediate products formed during thermal decomposition of ammonium uranyl carbonate (AUC) in different atmospheres, (air, helium and hydrogen) have been determined by thermal analysis, (TG, and DTA) and X-ray analysis. The endproducts observed are U3O8 and UO2 in air/He and hydrogen, respe......, respectively. The following intermediate products were observed in all atmospheres: http://www.sciencedirect.com.globalproxy.cvt.dk/cache/MiamiImageURL/B6THV-44K80TV-FB-1/0?wchp=dGLzVlz-zSkWW X-ray diffraction analysis showed that these phases were amorphous....

  13. Innovative preparation of Au/C by replication of gold-containing mesoporous silica catalysts

    KAUST Repository

    Kerdi, Fatmé

    2010-01-01

    A new strategy, based on the nanocasting concept, has been used to prepare gold nanoparticles (NPs) highly dispersed in meso-structured carbons. Gold is first introduced in various functionalized mesostructured silicas (MCM-48 and SBA-15) and particles are formed inside the porosity upon reduction of Au 3+ cations. Silica pores are then impregnated with a carbon precursor and the composite material is heated at 900°C under vacuum. Silica is then removed by acid leaching, leading to partially encapsulated gold particles in mesoporous carbon. Carbon prevents aggregation of gold particles at high temperature, both the mean size and distribution being similar to those observed in silica. However, while Au@SiO2 exhibit significant catalytic activity in the aerobic oxidation of trans-stilbene in the liquid phase, its Au@C mesostructured replica is quite inactive. © 2010 Elsevier B.V. All rights reserved.

  14. Effect of Truncating AUC at 12, 24 and 48 hr When Evaluating the Bioequivalence of Drugs with a Long Half-Life.

    Science.gov (United States)

    Moreno, Isabel; Ochoa, Dolores; Román, Manuel; Cabaleiro, Teresa; Abad-Santos, Francisco

    2016-01-01

    Bioequivalence studies of drugs with a long half-life require long periods of time for pharmacokinetic sampling. The latest update of the European guideline allows the area under the curve (AUC) truncated at 72 hr to be used as an alternative to AUC0-t as the primary parameter. The objective of this study was to evaluate the effect of truncating the AUC at 48, 24 and 12 hr on the acceptance of the bioequivalence criterion as compared with truncation at 72 hr in bioequivalence trials. The effect of truncated AUC on the within-individual coefficient of variation (CVw) and on the ratio of the formulations was also analysed. Twenty-eight drugs were selected from bioequivalence trials. Pharmacokinetic data were analysed using WinNonLin 2.0 based on the trapezoidal method. Analysis of variance (ANOVA) was performed to obtain the ratios and 90% confidence intervals for AUC at different time-points. The degree of agreement of AUC0-72 in relation to AUC0-48 and AUC0-24, according to the Landis and Koch classification, was 'almost perfect'. Statistically significant differences were observed when the CVw of AUC truncated at 72, 48 and 24 hr was compared with the CVw of AUC0-12. There were no statistically significant differences in the AUC ratio at any time-point. Compared to AUC0-72, Pearson's correlation coefficient for mean AUC, AUC ratio and AUC CVw was worse for AUC0-12 than AUC0-24 or AUC0-48. These preliminary results could suggest that AUC truncation at 24 or 48 hr is adequate to determine whether two formulations are bioequivalent.

  15. 求解AUC优化问题的对偶坐标下降方法%Dual Coordinate Descent Method for Solving AUC Optimization Problem

    Institute of Scientific and Technical Information of China (English)

    姜纪远; 陶卿; 高乾坤; 储德军

    2014-01-01

    AUC is widely used as a measure for the imbalanced classification problems. The AUC loss problem is a pairwise function between two instances from different classes, which is obviously different from that in standard binary classifications. How to improve its real convergence speed is an interesting problem. Recent study shows that the online method (OAM) using the reservoir sampling technique has better performance. However, there exist some shortcomings such as slow convergence rate and difficult parameter selection. This paper conducts a systematic investigation for solving AUC optimization problem by using the dual coordinate descent methods (AUC-DCD). It presents three kinds of algorithms: AUC-SDCD, AUC-SDCDperm and AUC-MSGD, where the first two algorithms depend on the size of training set while the last does not. Theoretical analysis shows that OAM is a special case of the AUC-DCD. Experimental results show that AUC-DCD is better than OAM on the AUC performance as well as the convergence rate. Therefore AUC-DCD is among the first optimization schemes suggested for efficiently solving AUC problems.%AUC被广泛作为衡量不平衡数据分类性能的评价标准.与二分类问题不同,AUC问题的损失函数由来自两个不同类别的样本对组成.如何提高其实际收敛速度,是一个值得研究的问题.目前的研究结果表明:使用reservoir sampling技术的在线方法(OAM)表现出很好的AUC性能,但OAM仍存在诸如收敛速度慢、参数选择复杂等缺点.针对 AUC 优化问题的对偶坐标下降(AUC-DCD)方法进行了系统的研究,给出3种算法,即 AUC-SDCD,AUC- SDCDperm和AUC-MSGD,其中,AUC-SDCD和AUC-SDCDperm与样本数目有关,AUC-MSGD与样本数目无关.理论分析指出,OAM是AUC-DCD的一种特殊情形.实验结果表明,AUC-DCD在AUC性能和收敛速度两方面均优于OAM.研究结果表明,AUC-DCD是求解AUC优化问题的首选方法.

  16. Validation of limited sampling models (LSM) for estimating AUC in therapeutic drug monitoring - is a separate validation group required?

    NARCIS (Netherlands)

    Proost, J. H.

    2007-01-01

    Objective: Limited sampling models (LSM) for estimating AUC in therapeutic drug monitoring are usually validated in a separate group of patients, according to published guidelines. The aim of this study is to evaluate the validation of LSM by comparing independent validation with cross-validation us

  17. First spectroscopic observation of gold(i) butadiynylide: Photodetachment velocity map imaging of the AuC4H anion

    Science.gov (United States)

    Visser, Bradley R.; Addicoat, Matthew A.; Gascooke, Jason R.; Lawrance, Warren D.; Metha, Gregory F.

    2016-07-01

    The velocity map imaging technique was used in the investigation of gold(i) butadiynylide, AuC4H-, with images recorded at two excitation wavelengths. The resultant photodetachment spectra show a well defined vibrational progression in the neutral with an energy spacing of 343 ± 3 cm-1. The adiabatic electron affinity was determined to be 1.775 ± 0.005 eV and assigned to the X1Σ+←X2Σ+ transition between the anionic and neutral ground states. Franck-Condon simulations performed on density functional theory optimized geometries assisted the assignment of linear geometries to the neutral and anion and the observed vibrational progression to that of the Au-C4H stretch.

  18. Synthesis of Au/C and Au/Pani for anode electrodes in glucose microfluidic fuel cell

    Energy Technology Data Exchange (ETDEWEB)

    Guerra-Balcazar, M.; Morales-Acosta, D.; Castaneda, F.; Arriaga, L.G. [Centro de Investigacion y Desarrollo Tecnologico en Electroquimica, 76703 Queretaro (Mexico); Ledesma-Garcia, J. [Division de Investigacion y Posgrado, Facultad de Ingenieria, Universidad Autonoma de Queretaro, 76010 Queretaro (Mexico)

    2010-06-15

    Gold nanoparticles have been prepared by two methods: chemical (ex-situ, Au/C) by two phase protocol, and electrochemical (in-situ, Au/Pani) by electroreduction of gold ions on a polyaniline film and compared as anode catalysts in a glucose microfluidic fuel cell. In this paper the structural characteristics and electrocatalytic properties were investigated by X-ray diffraction and electrochemical measurements. The catalytic behavior of both anodes was tested in a microfluidic fuel cell with a reference electrode incorporated, by means of linear sweep voltammetry (LSV), showing a cathodic shift in the glucose oxidation peak for Au/Pani. Results show a higher power density (0.5 mW cm{sup -} {sup 2}) for Au/C anode compared with an already reported value, where a glucose microfluidic fuel cell was used in similar conditions. (author)

  19. Nitrofurantoin safety and effectiveness in treating acute uncomplicated cystitis (AUC) in hospitalized adults with renal insufficiency: antibiotic stewardship implications.

    Science.gov (United States)

    Cunha, B A; Cunha, C B; Lam, B; Giuga, J; Chin, J; Zafonte, V F; Gerson, S

    2017-02-02

    Nitrofurantoin remains a key oral antibiotic stewardship program (ASP) option in the treatment of acute uncomplicated cystitis (AUC) due to multi-drug resistant (MDR) Gram negative bacilli (GNB). However, there have been concerns regarding decreased nitrofurantoin efficacy with renal insufficiency. In our experience over the past three decades, nitrofurantoin has been safe and effective in treating AUC in hospitalized adults with renal insufficiency. Accordingly, we retrospectively reviewed our recent experience treating AUC in hospitalized adults with decreased renal function (CrCl urinary tract infections. Urinary isolated susceptibility testing was done by micro broth dilution (MBD). Treatment duration was 5-7 days. Cure was defined as eradication of the uropathogen and failure was defined as minimal/no decrease in urine colony counts. Of 26 evaluable patients with renal insufficiency (CrCl < 60 ml/min), nitrofurantoin eradicated the uropathogen in 18/26 (69%) of patients, and failed in 8/26 (31%). Of the eight failures, five were due to intrinsically resistant uropathogens, e.g., Proteus sp., and one failure was related to an alkaline urine. Of the treatment failures, only two were due to renal insufficiency, i.e., CrCl < 30 ml/min. Since there are few oral antibiotics available to treat AUC due to MDR GNB uropathogens, these results have important ASP implications. Currently, nitfurantoin is not recommended if CrCl < 60 ml/min. In our experience, used appropriately against susceptible uropathogens, nitrofurantoin was highly effective in nearly all patients with CrCl = 30-60 ml/min., and only failed in two patients due to renal insufficiency (CrCl < 30 ml/ml).

  20. How to interpret a small increase in AUC with an additional risk prediction marker: decision analysis comes through.

    Science.gov (United States)

    Baker, Stuart G; Schuit, Ewoud; Steyerberg, Ewout W; Pencina, Michael J; Vickers, Andrew; Vickers, Andew; Moons, Karel G M; Mol, Ben W J; Lindeman, Karen S

    2014-09-28

    An important question in the evaluation of an additional risk prediction marker is how to interpret a small increase in the area under the receiver operating characteristic curve (AUC). Many researchers believe that a change in AUC is a poor metric because it increases only slightly with the addition of a marker with a large odds ratio. Because it is not possible on purely statistical grounds to choose between the odds ratio and AUC, we invoke decision analysis, which incorporates costs and benefits. For example, a timely estimate of the risk of later non-elective operative delivery can help a woman in labor decide if she wants an early elective cesarean section to avoid greater complications from possible later non-elective operative delivery. A basic risk prediction model for later non-elective operative delivery involves only antepartum markers. Because adding intrapartum markers to this risk prediction model increases AUC by 0.02, we questioned whether this small improvement is worthwhile. A key decision-analytic quantity is the risk threshold, here the risk of later non-elective operative delivery at which a patient would be indifferent between an early elective cesarean section and usual care. For a range of risk thresholds, we found that an increase in the net benefit of risk prediction requires collecting intrapartum marker data on 68 to 124 women for every correct prediction of later non-elective operative delivery. Because data collection is non-invasive, this test tradeoff of 68 to 124 is clinically acceptable, indicating the value of adding intrapartum markers to the risk prediction model.

  1. Au-C allotrope nano-composite films at extreme conditions generated by intense ultra-short laser

    Science.gov (United States)

    Khan, Saif A.; Saravanan, K.; Tayyab, M.; Bagchi, S.; Avasthi, D. K.

    2016-07-01

    Structural evolution of gold-carbon allotrope nano-composite films under relativistically intense, ultra-short laser pulse irradiation is studied in this work. Au-C nano-composite films, having 4 and 10 at.% of Au, were deposited by co-sputtering technique on silicon substrates. Au-C60 NC films with 2.5 at.% Au were deposited on 12 μm thick Al foil using co-evaporation technique. These samples were radiated with single pulse from 45 fs, 10 TW Ti:Sapphire Laser at RRCAT at an intensity of 3 × 1018 W cm-2. The morphological and compositional changes were investigated using scanning electron microscopy (SEM) and Rutherford back-scattering spectrometry (RBS) techniques. Laser pulse created three morphologically distinct zones around the point of impact on samples with silicon substrates. The gold content in 600 μm circular region around a point of impact is found to reduce by a factor of five. Annular rings of ∼70 nm in diameter were observed in case of Au-C NC film after irradiation. Laser pulse created a hole of about 400 μm in the sample with Al foil as substrate and wavy structures of 6 μm wavelength are found to be created around this hole. The study shows radial variation in nano-structure formation with varying local intensity of laser pulse.

  2. Reconstrucción de las redes sociales: el caso de las FARC, el ELN y las ACCU-AUC

    Directory of Open Access Journals (Sweden)

    Plata Caviedes, Juan Camilo

    2006-06-01

    Full Text Available It is explored a strategy to analyze the press releases made by the FARC, the ELN, and the ACCU-AUC. It is based on the minimal grammatical structure: Subject- Action - Object. Using this grammatical triplet, the network of connections are built up; and then, some of the Social Network Analysis tools are applied to it. Some mechanisms related with these structural properties are identified: a To define for each actor a distinctive set of relationships; b the part is different from the whole; c the emphasized topics do the work of putting near a set of nodes.

  3. Synthesis of gold nano-wire and nano-dumbbell shaped colloids and AuC60 nano-clusters

    Science.gov (United States)

    Landon, Preston B.; Jarvis, Brandon C.; Gilleland, Cody L.; Renfro, Tim; Gutierrez, Jose; Synowczynski, Jennifer; Hirsch, Samuel G.; Glosser, Robert

    2005-08-01

    A technique for the fabrication of colloidal gold nano-wire and nano-dumbbell shaped particles using carbon nanotubes and rod shaped viruses as templates is described. The gold (Au) encapsulation process was accomplished by the precipitation of gold chloride from aqueous solutions. When this process was conducted in the presence of hydroxylated C60, small pieces of phase-separated composites of AuC60 appeared to have formed. These nano-clusters may turn out to be large noble metal analogs of the alkali metal fullerides with the smallest geometrically possible Au aggregate consisting of 55 gold atoms. The existence of noble metal fullerene composites has been previously theorized. The alkali metal fullerides are examples of phase separated solids and have exhibited superconductivity with temperatures as high 33K. The mechanism required for the binding energy between C60 and gold has been observed to exist between C60 and many of the mirror metals (Al, Ag, Au, Cu, Ni). This binding energy is a charge transfer from the metal Fermi level into the C60 LUMO. If this bonding energy, is greater than the metals coagulation energy an Au/C60 size terminated mechanism during the formation of the gold aggregates by the adhesion of C60 to the surface is energetically favorable.

  4. Intranasal Pharmacokinetic Data for Triptans Such as Sumatriptan and Zolmitriptan Can Render Area Under the Curve (AUC) Predictions for the Oral Route: Strategy Development and Application

    DEFF Research Database (Denmark)

    Srinivas, Nuggehally R.; Syed, Muzeeb

    2016-01-01

    Limited pharmacokinetic sampling strategy may be useful for predicting the area under the curve (AUC) for triptans and may have clinical utility as a prospective tool for prediction. Using appropriate intranasal pharmacokinetic data, a Cmax vs. AUC relationship was established by linear regression......), mean negative error (MNE), root mean square error (RMSE), correlation coefficient (r), and the goodness of the AUC fold prediction were used to evaluate the two triptans. Also, data from the mean concentration profiles at time points of 1 hour (sumatriptan) and 3 hours (zolmitriptan) were used...

  5. Innovative Route to Prepare of Au/C Catalysts by Replication of Gold-containing Mesoporous Silicas

    Science.gov (United States)

    Kerdi, Fatmé; Caps, Valérie; Tuel, Alain

    Gold-catalyzed aerobic epoxidations in the liquid phase are generally performed in low-polarity solvents, in which conventional oxide-supported catalysts are poorly dispersed. To improve the wettability of the catalytic powder and, thus, the efficiency of the catalyst, gold nanoparticles (NPs) have been dispersed on meso-structured carbons. Gold is first introduced in functionalized mesostructured silica and particles are formed inside the porosity. Silica pores are then impregnated with a carbon precursor and the composite material is heated at 900 °C under vacuum or nitrogen. Silica is then removed by acid leaching, leading to partially encapsulated gold particles in mesoporous carbon. Carbon prevents aggregation of gold particles at high temperature, both the mean size and distribution being similar to those observed in silica. However, while Au@SiO2 exhibit significant catalytic activity in the aerobic oxidation of trans-stilbene in the liquid phase, its Au@C mesostructured replica is quite inactive.

  6. Innovative Route to Prepare of Au/C Catalysts by Replication of Gold-containing Mesoporous Silicas

    KAUST Repository

    Kerdi, Fatmé

    2011-12-23

    Gold-catalyzed aerobic epoxidations in the liquid phase are generally performed in low-polarity solvents, in which conventional oxide-supported catalysts are poorly dispersed. To improve the wettability of the catalytic powder and, thus, the efficiency of the catalyst, gold nanoparticles (NPs) have been dispersed on meso-structured carbons. Gold is first introduced in functionalized mesostructured silica and particles are formed inside the porosity. Silica pores are then impregnated with a carbon precursor and the composite material is heated at 900 °C under vacuum or nitrogen. Silica is then removed by acid leaching, leading to partially encapsulated gold particles in mesoporous carbon. Carbon prevents aggregation of gold particles at high temperature, both the mean size and distribution being similar to those observed in silica. However, while Au@SiO2 exhibit significant catalytic activity in the aerobic oxidation of trans-stilbene in the liquid phase, its Au@C mesostructured replica is quite inactive.

  7. Carbonated water (CW) process waste reuse for ammonium-uranyl-carbonate (AUC) production and its gains on the environmental, economic and social aspects

    Energy Technology Data Exchange (ETDEWEB)

    Carnaval, Joao Paulo R.; Santos, Rafael D. dos; Barbosa, Rodrigo A.; Lauer, Sergio, E-mail: joaocarnaval@inb.gov.br, E-mail: rafaelsantos@inb.gov.br, E-mail: rodrigobarbosa@inb.gov.br, E-mail: lauer@inb.gov.br [Industias Nucleares do Brasil S.A. (INB), Resende, RJ (Brazil)

    2013-07-01

    In the INB nuclear fuel cycle, the pellets production is based on UO{sub 2} powder made by AUC (Ammonium-Uranyl-Carbonate) route. AUC formation occurs by fluidising of UF{sub 6}, NH{sub 3} and CO{sub 2} in a vase containing usually pure water, and this exothermal reaction has AUC as direct product. The mass formed is filtered, washed with CW, washed again with methano solution, dried with air and conducted to the fluidized bed furnace, to be converted to UO{sub 2} powder. At this point, the dried AUC decompounds to UO{sub 3}, NH{sub 3} and C0{sub 2}, these 2 gases are absorbed at the gases washer, formin go the carbonated water (CW), whit is basically a (NH{sub 4}){sub 2}CO{sub 3} solution. The UO{sub 2+x} is reduced and stabilized to UO{sub 2} powder, which is conducted to pellets production. During the process, a considerable amount of this aqueous waste is generated and goes for effluent treatment. After that, the solution is sent for spray-dryer for power formation, and stock. This treatment demands equipment, energy and time, representing considerable costs of the company beyond the human risks involved on the drying step. The purpose of this work is to present a study of the carbonated water use as substitute of pure water in the AUC formation step. At this point, tests were made varying the CW loads for the AUC precipitation, and the control was made by the UO{sub 2} powder properties. The carbonated water used for AUC precipitation has been tested at several levels and the results has demonstrated full viability to become a definitive process step (INB, Resende site). It has been demonstrated the great resources economy caused by the waste reuse and the guarantee product quality. This represents such an environmental gain and also economic and social aspects got improved. (author)

  8. A perspective for biowaivers of human bioequivalence studies on the basis of the combination of the ratio of AUC to the dose and the biopharmaceutics classification system.

    Science.gov (United States)

    Sakuma, Shinji; Tachiki, Hidehisa; Uchiyama, Hitoshi; Fukui, Yasunobu; Takeuchi, Naohiro; Kumamoto, Kazuo; Satoh, Tomonori; Yamamoto, Yoshinobu; Ishii, Emi; Sakai, Yoshiyuki; Takeuchi, Susumu; Sugita, Masaru; Yamashita, Shinji

    2011-08-01

    The ratio of AUC to the dose (AUC/dose) was previously found as a parameter that predicts a risk of bioinequivalence of oral drug products. On the basis of the combination of this parameter and the biopharmaceutics classification system (BCS), a perspective for biowaivers of human bioequivalence studies is discussed. Databases of bioequivalence studies using immediate-release solid oral dosage forms were disclosed by 6 Japanese generic pharmaceutical companies, and the number of subjects required for demonstrating bioequivalence between generic and reference products was plotted as a function of AUC/dose for each BCS category. A small variation in the number of subjects was constantly observed in bioequivalence studies using dosage forms containing an identical BCS class 1 or class 3 drug, even though formulations of the generic product differ between companies. The variation was extremely enlarged when the drugs were substituted with BCS class 2 drugs. Rate-determining steps in oral absorption of highly water-soluble BCS class 1 and class 3 drugs are independent of formulations when there is no significant difference in the in vitro dissolution profiles between formulations. The small variation observed for both BCS categories indicates that the number of subjects converges into one value for each drug. Our analysis indicates the appropriateness of biowaiver of bioequivalence studies for immediate-release solid oral dosage forms containing not only BCS class 1 drugs but also class 3 drugs.

  9. Application of multi-SNP approaches Bayesian LASSO and AUC-RF to detect main effects of inflammatory-gene variants associated with bladder cancer risk.

    Directory of Open Access Journals (Sweden)

    Evangelina López de Maturana

    Full Text Available The relationship between inflammation and cancer is well established in several tumor types, including bladder cancer. We performed an association study between 886 inflammatory-gene variants and bladder cancer risk in 1,047 cases and 988 controls from the Spanish Bladder Cancer (SBC/EPICURO Study. A preliminary exploration with the widely used univariate logistic regression approach did not identify any significant SNP after correcting for multiple testing. We further applied two more comprehensive methods to capture the complexity of bladder cancer genetic susceptibility: Bayesian Threshold LASSO (BTL, a regularized regression method, and AUC-Random Forest, a machine-learning algorithm. Both approaches explore the joint effect of markers. BTL analysis identified a signature of 37 SNPs in 34 genes showing an association with bladder cancer. AUC-RF detected an optimal predictive subset of 56 SNPs. 13 SNPs were identified by both methods in the total population. Using resources from the Texas Bladder Cancer study we were able to replicate 30% of the SNPs assessed. The associations between inflammatory SNPs and bladder cancer were reexamined among non-smokers to eliminate the effect of tobacco, one of the strongest and most prevalent environmental risk factor for this tumor. A 9 SNP-signature was detected by BTL. Here we report, for the first time, a set of SNP in inflammatory genes jointly associated with bladder cancer risk. These results highlight the importance of the complex structure of genetic susceptibility associated with cancer risk.

  10. Dynamical coupling of PBPK/PD and AUC-based toxicity models for arsenic in tilapia Oreochromis mossambicus from blackfoot disease area in Taiwan

    Energy Technology Data Exchange (ETDEWEB)

    Liao, C.-M. [Ecotoxicological Modeling Center, Department of Bioenvironmental Systems Engineering, National Taiwan University, Taipei, Taiwan 10617 (China)]. E-mail: cmliao@ntu.edu.tw; Liang, H.-M. [Ecotoxicological Modeling Center, Department of Bioenvironmental Systems Engineering, National Taiwan University, Taipei, Taiwan 10617 (China); Chen, B.-C. [Department of Post-Modern Agriculture, Mingdao University, Changhua, Taiwan 52345 (China); Singh Sher [Center of Genomics Medicine, School of Medicine, National Taiwan University, Taipei, Taiwan 10617 (China); Tsai, J.-W. [Ecotoxicological Modeling Center, Department of Bioenvironmental Systems Engineering, National Taiwan University, Taipei, Taiwan 10617 (China); Chou, Y.-H. [Ecotoxicological Modeling Center, Department of Bioenvironmental Systems Engineering, National Taiwan University, Taipei, Taiwan 10617 (China); Lin, W.-T. [Environment Change Research Center, Academia Sinica, Nankang, Taipei, Taiwan 11517 (China)

    2005-05-01

    A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models were developed for arsenic (As) in tilapia Oreochromis mossambicus from blackfoot disease area in Taiwan. The PBPK/PD model structure consisted of muscle, gill, gut wall, alimentary canal, and liver, which were interconnected by blood circulation. We integrate the target organ concentrations and dynamic response describing uptake, metabolism, and disposition of As and the associated area-under-curve (AUC)-based toxicological dynamics following an acute exposure. The model validations were compared against the field observations from real tilapia farms and previously published uptake/depuration experimental data, indicating that predicted and measured As concentrations in major organs of tilapia were in good agreement. The model was utilized to reasonably simulate and construct a dose-dependent dynamic response between mortality effect and equilibrium target organ concentrations. Model simulations suggest that tilapia gills may serve as a surrogate sensitive biomarker of short-term exposure to As. This integrated As PBPK/PD/AUC model quantitatively estimates target organ concentration and dynamic response in tilapia and is a strong framework for future waterborne metal model development and for refining a biologically-based risk assessment for exposure of aquatic species to waterborne metals under a variety of scenarios. - Integrated toxicity models can identify dynamic responses of fish to arsenic.

  11. Preparation of Pt Au/C and Pt Au Bi/C electrocatalysts using electron beam irradiation for ethanol electro-oxidation in alkaline medium

    Energy Technology Data Exchange (ETDEWEB)

    Silva, Dionisio F.; Geraldes, Adriana N.; Cardoso, Elisangela S.Z.; Gomes, Thiago B.; Linardi, Marcelo; Oliveira Neto, Almir; Spinace, Estevam V., E-mail: dfsilva@ipen.b [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil)

    2011-07-01

    Pt Au/C (50:50) and PtAuBi/C electrocatalysts with Pt:Au:Bi atomic ratios of 50:40:10, 50:30:20 and 50:10:40 were prepared in water/2-propanol using electron beam irradiation. The materials were characterized by X-ray diffraction (XRD) and the electro-oxidation of ethanol was studied by chronoamperometry at room temperature. The X-ray diffraction measurements for all electrocatalysts prepared showed four peaks, which are associated with the planes of the face-centered cubic (fcc) structure characteristic of Pt and Pt alloys. For PtAuBi/C it was also observed the presence of a mixture of BiPt alloys and bismuth phases. The average crystallite sizes for Pt/C, PtAu/C, PtAuBi/C (50:40:10), PtAuBi/C (50:30:20) and PtAuBi/C (50:10:40) were in the range of 2.0 - 4.0 nm. The activity of the electrocatalysts for ethanol oxidation in alkaline medium showed that PtAuBi/C (50:40:10) had a higher performance for ethanol oxidation compared to others electrocatalysts prepared. (author)

  12. Biología reproductiva de Convolvulus chilensis (Convolvulaceae en una población de Aucó (centro-norte de Chile Reproductive biology of Convolvulus chilensis (Convolvulaceae in a population of Aucó (north-central Chile

    Directory of Open Access Journals (Sweden)

    Lorena H. Suárez

    2004-12-01

    Full Text Available Convolvulus chilensis es una hierba perenne, única representante endémica de la familia Convolvulaceae en Chile. Se estudió el sistema de reproducción, fenología, morfología y longevidad floral de C. chilensis en una población natural ubicada en la localidad de Aucó, dentro de la Reserva Nacional Las Chinchillas, IV Región, Chile. Se montó un experimento de polinización controlada considerando los tratamientos de polinización natural, polinización cruzada, autopolinización manual, autopolinización automática y apomixis, evaluándose su efecto sobre la formación de frutos y el número de semillas producidas por fruto. Adicionalmente, se compararon los siguientes atributos de la progenie según tipo de polinización (autopolinización o polinización cruzada: peso de semilla, germinación, altura y número de hojas de plántulas de ocho semanas en condiciones de invernadero. Se encontró que C. chilensis es una especie autocompatible, parcialmente autógama (capaz de autopolinizarse sin mediador y parcialmente apomíctica (capaz de producir semillas sin participación de gameto masculino. La longevidad floral fue estimada en 5,25 h. Durante este período, aproximadamente en 1,5 h hay disponibilidad de polen en los estambres. El período de floración se extiende por 22 semanas (agosto a enero. El tratamiento de apomixis presentó el menor porcentaje de formación de frutos y la menor cantidad de semillas por flor en comparación a los tratamientos de polinización natural, cruzada manual, autopolinización automática y autopolinización manual, los cuales no mostraron diferencias entre sí en ambos atributos. El tipo de polinización (autopolinización o polinización cruzada no afecta el desempeño de la progenie en los atributos de semilla y plántula evaluadosThe perennial herb Convolvulus chilensis is the only endemic species of the Convolvulaceae in Chile. The breeding system, phenology, morphology and floral longevity of C

  13. Limited sampling strategies for tacrolimus exposure (AUC0-24) prediction after Prograf(®) and Advagraf(®) administration in children and adolescents with liver or kidney transplants.

    Science.gov (United States)

    Almeida-Paulo, Gonzalo N; Lubomirov, Rubin; Alonso-Sanchez, Nazareth Laura; Espinosa-Román, Laura; Fernández Camblor, Carlota; Díaz, Carmen; Muñoz Bartola, Gema; Carcas-Sansuán, Antonio J

    2014-09-01

    To develop limited sampling strategies (LSSs) to predict total tacrolimus exposure (AUC0-24 ) after the administration of Advagraf(®) and Prograf(®) (Astellas Pharma S.A, Madrid, Spain) to pediatric patients with stable liver or kidney transplants. Forty-one pharmacokinetic profiles were obtained after Prograf(®) and Advagraf(®) administration. LSSs predicting AUC0-24 were developed by linear regression using three extraction time points. Selection of the most accurate LSS was made based on the r(2) , mean error, and mean absolute error. All selected LSSs had higher correlation with AUC0-24 than the correlation found between C0 and AUC0-24 . Best LSS for Prograf(®) in liver transplants was C0_1.5_4 (r(2)  = 0.939) and for kidney transplants C0_1_3 (r(2)  = 0.925). For Advagraf(®) , the best LSS in liver transplants was C0_1_2.5 (r(2)  = 0.938) and for kidney transplants was C0_0.5_4 (r(2)  = 0.931). Excluding transplant type variable, the best LSS for Prograf(®) is C0-1-3 (r(2)  = 0.920) and the best LSS for Advagraf(®) was C0_0.5_4 (r(2)  = 0.926). Considering transplant type irrespective of the formulation used, the best LSS for liver transplants was C0_2_3 (r(2)  = 0.913) and for kidney transplants was C0_0.5_4 (r(2)  = 0.898). Best LSS, considering all data together, was C0_1_4 (r(2)  = 0.898). We developed several LSSs to predict AUC0-24 for tacrolimus in children and adolescents with kidney or liver transplants after Prograf(®) and/or Advagraf(®) treatment.

  14. Análisis de las rupturas y continuidades estratégicas en sus ámbitos económico, social y político entre el bloque Élmer Cárdenas de las AUC (2002-2006) y la banda criminal los Urabeños (2006-2010) presentes en el Urabá chocoano

    OpenAIRE

    Ruiz González, Luis Enrique

    2012-01-01

    A partir de un análisis comparado, de orden cualitativo, se analiza la existencia de continuidades y rupturas estratégicas entre el Bloque Élmer Cárdenas de las AUC y los Urabeños, con el fin de caracterizar a ambos actores armados. La investigación expone similitudes relevantes entre ambos grupos armados a fin de dilucidar la naturaleza, aun discutida, de las llamadas bandas criminales y su relación con los predecesores bloques paramilitares, además de la incidencia en las actividades económ...

  15. UV-visible spectrophotometric simultaneous estimation of paracetamol and nabumetone by AUC method in combined tablet dosage form

    OpenAIRE

    Rote, Ambadas R.; Kumbhoje, Prasanna A.; Bhambar, Rajendra S.

    2012-01-01

    Introduction: The present study deals with development and validation of a simple, rapid, sensitive and economic area under curve method for simultaneous estimation of paracetamol and nabumetone in bulk and tablet dosage form. Materials and Method: Area under curve method includes determination of area of paracetamol and nabumetone at absorption maxima, which for paracetamol was 248.8 ± 10 nm and for nabumetone was 269.2 ± 10 nm. Beer's law was obeyed in the concentration range of 5–25 μg/mL ...

  16. Derecho interno, derechos humanos y desmovilización de las AUC en Colombia 2002-2007

    OpenAIRE

    Pineda Bermúdez, Judith Esther; Sosa Posada, Juan Esteban Sosa Posada

    2007-01-01

    En el presente trabajo se hace un análisis del Proceso de desmovilización de los Paramilitares en Colombia, y para tal efecto se realiza un breve estudio del Derecho Internacional Público y de los Derechos Humanos. Sobre la Ley de Justicia y Paz se realiza un análisis a partir de los conceptos de Derecho Internacional y Derecho Interno, lo cual nos permitió llegar a las conclusiones contenidas en este trabajo.

  17. Colombia’s Attempt at Peace: An Analysis of the Demobilization of the Auto-Defensas Unidas de Colombia (AUC)

    Science.gov (United States)

    2007-03-01

    Julio Cesar Turbay Ayala (1978-1982). Both attempted but failed to bring guerillas to the peace table. Their successor, Colombian President...FBI, seized a laptop computer belonging to former paramilitary commander, Rodrigo Toliver, alias Jorge 40.62 The computer’s files detailed the

  18. An element through the looking glass: Exploring the Au-C, Au-H and Au-O energy landscape

    OpenAIRE

    Rosca, Dragos-Adrian; Wright, Joseph; Bochmann, Manfred

    2015-01-01

    Gold, the archetypal “noble metal”, used to be considered of little interest in catalysis. It is now clear that this was a misconception, and a multitude of gold-catalysed transformations has been reported. However, one consequence of the long-held view of gold as inert metal is that its organometallic chemistry contains many “unknowns”, and catalytic cycles devised to explain gold's reactivity draw largely on analogies with other transition metals. How realistic are such mechanistic assumpti...

  19. Mesostructured Au/C materials obtained by replication of functionalized SBA-15 silica containing highly dispersed gold nanoparticles

    KAUST Repository

    Kerdi, Fatmé

    2011-04-01

    The preparation and characterization of highly dispersed gold nanoparticles in ordered mesoporous carbons CMK-3 are reported. These carbons were obtained using gold-containing functionalized SBA-15 silicas as hard templates. Two series of Au/SiO2 templates were prepared, depending on the nature of the functionalization molecule. While ammonium-functionalized silicas gave gold particles with a size determined by the pores of the silica support, the use of mercaptopropyltrimethoxysilane as grafting molecule afforded the possibility to control the particle size inside the mesopores. Both series gave highly ordered mesoporous carbons with gold particles incorporated in the carbon nanorods. However, the gold particle size in mesoporous carbons was the same for both series and apparently did not depend on the nature of the silica template. Both Au/SiO2 templates and their corresponding Au/CMK-3 materials have been characterized by X-ray diffraction, nitrogen adsorption/desorption, chemical analysis, solid-state nuclear magnetic resonance and transmission electron microscopy. They were also used as catalysts in the aerobic oxidation of cyclohexene and trans-stilbene in the liquid phase. © 2010 Elsevier Inc. All rights reserved.

  20. "Assessment of different bioequivalent metrics in Rifampin bioequivalence study "

    OpenAIRE

    "Rouini MR; Tajer Zadeh H; Valad Khani M "

    2002-01-01

    The use of secondary metrics has become special interest in bioequivalency studies. The applicability of partial area method, truncated AUC and Cmax/AUC has been argued by many authors. This study aims to evaluate the possible superiority of these metrics to primary metrics (i.e. AUCinf, Cmax and Tmax). The suitability of truncated AUC for assessment of absorption extent as well as Cmax/AUC and partial AUC for the evaluation of absorption rate in bioequivalency determination was investigated ...

  1. Quantification of the contribution of GLP-1 to mediating insulinotropic effects of DPP-4 inhibition with vildagliptin in healthy subjects and type 2-diabetic patients using exendin [9-39] as a GLP-1 receptor antagonist

    DEFF Research Database (Denmark)

    Nauck, Michael A; Kind, J; Köthe, Lars D;

    2016-01-01

    under the curve (AUCs) of integrated insulin secretion rates (total AUC(ISR)) and glucose (total AUC(glucose)) over 4 h after the meal. Vildagliptin treatment more than doubled responses of intact GLP-1 and glucose-dependent insulinotropic polypeptide and lowered glucose responses without changing AUC(ISR......)/AUC(glucose) in healthy subjects. Vildagliptin significantly increased this ratio by 10.5% in patients with type 2 diabetes, and exendin [9-39] reduced it (both P ISR)/AUC(glucose) ratio achieved with exendin [9-39] was significantly smaller after vildagliptin treatment than...

  2. Evaluation of Postprandial Glucose Excursion Using a Novel Minimally Invasive Glucose Area-Under-the-Curve Monitoring System

    Directory of Open Access Journals (Sweden)

    Sachi Kuranuki

    2013-01-01

    Full Text Available Objective: To develop a minimally invasive interstitial fluid extraction technology (MIET to monitor postprandial glucose area under the curve (AUC without blood sampling, we evaluated the accuracy of glucose AUC measured by MIET and compared with that by blood sampling after food intake. Methods: Interstitial fluid glucose AUC (IG-AUC following consumption of 6 different types of foods was measured by MIET. MIET consisted of stamping microneedle arrays, placing hydrogel patches on the areas, and calculating IG-AUC based on glucose levels in the hydrogels. Glycemic index (GI was determined using IG-AUC and reference AUC measured by blood sampling. Results: IG-AUC strongly correlated with reference AUC (R = 0.91, and GI determined using IG-AUC showed good correlation with that determined by reference AUC (R = 0.88. Conclusions: IG-AUC obtained by MIET can accurately predict the postprandial glucose excursion without blood sampling. In addition, feasibility of GI measurement by MIET was confirmed.

  3. HEAPA Filter Bank In-Place Leak Test for ACUs of Advanced Fuel Science Building in 2010

    Energy Technology Data Exchange (ETDEWEB)

    Ji, Chul Goo; Bae, Sang Oh [KAERI, Daejeon (Korea, Republic of)

    2010-12-15

    Air cleaning units installed in the Advanced Fuel Science Building were performed visual inspection, airflow capacity test, and HEAPA filter bank in-place leak test in accordance with ASME N-510-1989. All the above inspections was acceptable. Visual inspection was satisfied to AUC-556 and AUC-557. Airflow capacity was 96%(30,240 m{sup 3}/h) of design airflow capacity(31,500 m{sup 3}/h) for AUC-556 and was 97%(22,800 m{sup 3}/h) of design airflow capacity(22,800 m{sup 3}/h) for AUC-557, and was maintained within {+-}10% of the specified value. Penetration of HEAPA filter bank in-place leak test was 0.009% for AUC-556 and was 0.013% for AUC-557 and these values were maintained less than the acceptance criteria(0.05%)

  4. Successful weight loss maintenance includes long-term increased meal responses of GLP-1 and PYY3-36

    DEFF Research Database (Denmark)

    Iepsen, Eva W; Lundgren, Julie; Holst, Jens J

    2016-01-01

    -week very low-calorie diet (800kcal/day). After weight loss, participants entered a 52-week weight maintenance protocol. Plasma levels of GLP-1, PYY3-36, ghrelin, GIP and glucagon during a 600-kcal meal were measured before weight loss, after weight loss and after 1 year of weight maintenance. Area...... to postprandial secretion to a sustained weight loss. DESIGN: The study was designed as a longitudinal prospective intervention study with data obtained at baseline, after 8 weeks of weight loss and 1 year after weight loss. METHODS: Twenty healthy obese individuals obtained a 13% weight loss by adhering to an 8...... under the curve (AUC) was calculated as total AUC (tAUC) and incremental AUC (iAUC). RESULTS: Weight loss was successfully maintained for 52 weeks. iAUC for GLP-1 increased by 44% after weight loss (Pweight loss...

  5. "Assessment of different bioequivalent metrics in Rifampin bioequivalence study "

    Directory of Open Access Journals (Sweden)

    "Rouini MR

    2002-08-01

    Full Text Available The use of secondary metrics has become special interest in bioequivalency studies. The applicability of partial area method, truncated AUC and Cmax/AUC has been argued by many authors. This study aims to evaluate the possible superiority of these metrics to primary metrics (i.e. AUCinf, Cmax and Tmax. The suitability of truncated AUC for assessment of absorption extent as well as Cmax/AUC and partial AUC for the evaluation of absorption rate in bioequivalency determination was investigated following administration of same product as test and reference to 7 healthy volunteers. Among the pharmacokinetic parameters obtained, Cmax/AUCinf was a better indicator or absorption rate and the AUCinf was more sensitive than truncated AUC in evaluation of absorption extent.

  6. Pharmacokinetics and bioequivalence studies of galantamine hydrobromide dispersible tablet in healthy male Chinese volunteers.

    Science.gov (United States)

    Zhang, Li-jun; Fang, Xiao-ling; Li, Xue-ning; Wang, Qing-song; Han, Li-mei; Zhang, Zhi-wen; Sha, Xian-yi

    2007-03-01

    A randomized, two-way, crossover study was conducted in 18 healthy male Chinese volunteers to compare pharmacokinetics profiles of galantamine hydrobromide dispersible tablet with that of conventional tablet. A single oral dose of 10 mg galantamine was administrated to each volunteer. Plasma concentrations of galantamine were determined by a validated high-performance liquid chromatography (HPLC) method with fluorescence detection, which allowed 1 ng/mL to be assayed as the lowest quantifiable concentration. From plasma concentrations, AUC(0-->t) (the area under the plasma concentration-time curve from time 0 to the last sampling time, 32 hr), AUC(0-->infinity) (the area under the plasma concentration-time curve from time 0 to infinity), t((1/2)) (elimination of half-life of the terminal log linear phase), C(max) (maximum plasma drug concentration) and T(max) (time to reach C(max)) were evaluated through noncompartmental pharmacokinetic analysis. AUC(0-->t) and AUC(0-->infinity) were calculated by the linear-log trapezoidal rule method. C(max) and T(max) were obtained directly from the plasma concentration-time curve. Analysis of variance was carried out using logarithmically transformed AUC(0-->t), AUC(0-->infinity) and C(max). As far as AUC(0-->t), AUC(0-->infinity) and C(max) were concerned, there was no statistically significant difference between the test and reference formulations. Ninety percent confidence intervals (90% CI) for the ratio of AUC(0-->t), AUC(0-->infinity) and C(max) values for the test and reference formulations were 100.4-107.8%, 99.0-107.2% and 87.5-111.3%, respectively. As the 90% CIs of AUC(0-->t), AUC(0-->infinity) and C(max) were entirely within 80-125%, two formulations were considered bioequivalent.

  7. Proposal for defining the relevance of drug accumulation derived from single dose study data for modified release dosage forms.

    Science.gov (United States)

    Scheerans, Christian; Heinig, Roland; Mueck, Wolfgang

    2015-03-01

    Recently, the European Medicines Agency (EMA) published the new draft guideline on the pharmacokinetic and clinical evaluation of modified release (MR) formulations. The draft guideline contains the new requirement of performing multiple dose (MD) bioequivalence studies, in the case when the MR formulation is expected to show 'relevant' drug accumulation at steady state (SS). This new requirement reveals three fundamental issues, which are discussed in the current work: first, measurement for the extent of drug accumulation (MEDA) predicted from single dose (SD) study data; second, its relationship with the percentage residual area under the plasma concentration-time curve (AUC) outside the dosing interval (τ) after SD administration, %AUC(τ-∞)SD ; and third, the rationale for a threshold of %AUC(τ-∞)SD that predicts 'relevant' drug accumulation at SS. This work revealed that the accumulation ratio RA,AUC , derived from the ratio of the time-averaged plasma concentrations during τ at SS and after SD administration, respectively, is the 'preferred' MEDA for MR formulations. A causal relationship was derived between %AUC(τ-∞)SD and RA,AUC , which is valid for any drug (product) that shows (dose- and time-) linear pharmacokinetics regardless of the shape of the plasma concentration-time curve. Considering AUC thresholds from other guidelines together with the causal relationship between %AUC(τ-∞)SD and RA,AUC indicates that values of %AUC(τ-∞)SD ≤ 20%, resulting in RA,AUC ≤ 1.25, can be considered as leading to non-relevant drug accumulation. Hence, the authors suggest that 20% for %AUC(τ-∞)SD is a reasonable threshold and selection criterion between SD or MD study designs for bioequivalence studies of new MR formulations.

  8. Metabolomic Prediction of Pregnancy Viability in Superovulated Cattle Embryos and Recipients with Fourier Transform Infrared Spectroscopy

    Directory of Open Access Journals (Sweden)

    Marta Muñoz

    2014-01-01

    Full Text Available We analyzed embryo culture medium (CM and recipient blood plasma using Fourier transform infrared spectroscopy (FTIR metabolomics to identify spectral models predictive of pregnancy outcome. Embryos collected on Day 6 from superovulated cows in 2 countries were individually cultured in synthetic oviduct fluid medium with BSA for 24 h before embryo transfer. Spent CM, blank controls, and plasma samples (Day 0 and Day 7 were evaluated using FTIR. The spectra obtained were analyzed. The discrimination capability of the classifiers was assessed for accuracy, sensitivity (pregnancy, specificity (nonpregnancy, and area under the ROC curve (AUC. Endpoints considered were Day 60 pregnancy and birth. High AUC was obtained for Day 60 pregnancy in CM within individual laboratories (France AUC=0.751±0.039, Spain AUC=0.718±0.024, while cumulative data decreased the AUC (AUC=0.604 ± 0.029. Predictions for CM at birth were lower than Day 60 pregnancy. Predictions with plasma at birth improved cumulative over individual results (Day 0: France AUC=0.690±0.044; Spain AUC<0.55; cumulative AUC=0.747±0.032. Plasma generally predicted pregnancy and birth better than CM. These first results show that FTIR metabolomics could allow the identification of embryos and recipients with improved pregnancy viability, which may contribute to increasing the efficiency of selection schemes based on ET.

  9. Use of Contrast-Enhanced Ultrasound to Study Relationship between Serum Uric Acid and Renal Microvascular Perfusion in Diabetic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Ling Wang

    2015-01-01

    Full Text Available Purpose. To investigate the relationship between uric acid and renal microvascular perfusion in diabetic kidney disease (DKD using contrast-enhanced ultrasound (CEUS method. Materials and Methods. 79 DKD patients and 26 healthy volunteers were enrolled. Renal function and urine protein markers were tested. DKD patients were subdivided into two groups including a normal serum uric acid (SUA group and a high SUA group. Contrast-enhanced ultrasound (CEUS was performed, and low acoustic power contrast-specific imaging was used for quantitative analysis. Results. Normal controls (NCs had the highest levels of AUC, AUC1, and AUC2. Compared to the normal SUA DKD group, high SUA DKD patients had significantly higher IMAX, AUC, and AUC1 (P<0.05. DKD patients with low urinary uric acid (UUA excretion had significantly higher AUC2 compared to DKD patients with normal UUA (P<0.05. Conclusion. Hyperuricemia in DKD patients was associated with a renal ultrasound image suggestive of microvascular hyperperfusion. The CEUS parameter AUC1 holds promise as an indicator for renal microvascular hyperperfusion, while AUC2 might be a useful indicator of declining glomerular filtration rate in DKD patients with decreased excretion of uric acid.

  10. Bioequivalence Study of Tramadol + Paracetamol (37.5 + 325 mg In Healthy Human Volunteers in Fasting Condition

    Directory of Open Access Journals (Sweden)

    S. Dhanure

    2013-10-01

    Full Text Available The bioequivalence between test and reference Tramadol and Paracetamol (37.5 + 325 mg tablets was determined in 36 healthy subjects after a single dose in a randomized crossover study under fasting condition. Plasma concentrations were monitored over a period of 24 hour after the drug administration by validated LC/MS/MS analytical method. The pharmacokinetic parameters Cmax, AUC0-t, AUC0-∞, AUC0-t / AUC0-∞, Tmax, Kel and t½ were determined from plasma concentration time profile of both formulations and found to be acceptable. The calculated pharmacokinetic parameters were compared statistically to evaluate bioequivalence between the test and reference products. The analysis of variance did not show any significant difference between the two formulations and 90 % confidence intervals for the ratio of Cmax (92.29 -104.18 %, AUC0-t (99.52 - 104.11 % and AUC0-∞ (99.05 - 104.22 % for tramadol and Cmax (93.56 - 110.27 %, AUC0-t (96.37 - 102.70 % and AUC0-∞ (97.22-103.28 % for paracetamol test and reference products were within the 80 – 125 % interval, satisfying the bioequivalence criteria the US Food and Drug Administration Guidelines. These results indicate that the test and the reference products of Tramadol and Paracetamol are bioequivalent.

  11. Effect of Itraconazole and Rifampin on the Pharmacokinetics of Olaparib in Patients With Advanced Solid Tumors

    DEFF Research Database (Denmark)

    Dirix, Luc; Swaisland, Helen; Verheul, Henk M W;

    2016-01-01

    ; in Study 8, a separate group of patients received olaparib alone and co-administered with rifampin. No interaction between itraconazole and olaparib was concluded if two-sided 90% CIs for the treatment ratios of AUC and/or AUC0-t and Cmax fell within the bioequivalence range of 0.80-1.25. An interaction...

  12. An excellence initiative in liberal arts and science education: the case of Amsterdam University College

    NARCIS (Netherlands)

    Wende, van der Marijk; Wang, Q; Cheng, Y.

    2013-01-01

    Amsterdam University College (AUC) was established in 2009 as an excellence initiative jointly undertaken by the University of Amsterdam (UvA) and VU University Amsterdam (VU). AUC is a selective and residential honours college that offers an international liberal arts and sciences bachelor programm

  13. In Vitro Lipolysis Data Does Not Adequately Predict the In Vivo Performance of Lipid-Based Drug Delivery Systems Containing Fenofibrate

    DEFF Research Database (Denmark)

    Thomas, Nicky; Richter, Katharina; Pedersen, Thomas B

    2014-01-01

    time curves of all LbDDS were comparable, independent of the initial physical state of the drug. There was no correlation between the area under the solubilization-time curves (AUC in vitro ) of the intestinal step and the AUC in vivo . The study suggests careful interpretation of in vitro performance...... criteria and revision of LbDDS optimization towards increased solubilization....

  14. Impact of truncated area under the curve on failed bioequivalence studies: a computer simulation analysis.

    Science.gov (United States)

    Mahmood, Iftekhar

    2004-01-01

    The common measures used in a bioequivalence study are area under the curve (AUC) and the maximum plasma concentration. Estimation of AUC requires frequent blood samples. For long half-life drugs, sampling for long periods of time may become cumbersome. To resolve this issue some investigators have suggested the use of truncated AUC in bioequivalence studies for long half-life drugs. The suggested length of time for the truncated AUC is 72 hours. Many studies have been conducted to show that truncated AUC till 72 hours is a suitable approach. However, the suitability of truncated AUC for failed bioequivalence study has not been demonstrated. This report of simulated plasma concentration versus time data evaluates the suitability of truncated AUC for failed bioequivalence study of two hypothetical drugs. The results of the study indicate that the truncated approach for the estimation of the AUC for long half-life drugs in bioequivalence studies may be useful but it also increases the probability of accepting drugs as being bioequivalent when they are not.

  15. Inter- and Intra-individual Variability in the Pharmacokinetics of Agomelatine Tablets in Chinese Healthy Male Subjects.

    Science.gov (United States)

    Wang, X-l; Du, A-h; Zhang, D; Meng, L-j; Liu, M; Zhang, L-n; Zhao, H-n; Liu, H-c

    2015-10-01

    Agomelatine is an antidepressant with a unique action mechanism differing from conventional antidepressants. The high inter- and intra-individual variability of agomelatine was previously reported, but no exact data values about the inter- and intra-individual variability in AUC and Cmax were mentioned. The current study aimed to determine and evaluate the inter- and intra-individual variability in AUC and Cmax of agomelatine tablets in Chinese healthy male subjects, providing useful information for designing bioequivalence studies of agomelatine. Each of 12 Chinese healthy male subjects received a 25-mg agomelatine tablet on 2 separate periods, and plasma samples were collected up to 24 h after dose and analyzed for agomelatine. Inter- and intra-individual variability in the pharmacokinetic parameters (Cmax, AUC0-t and AUC0-∞) of agomelatine was assessed. High variations in the plasma concentrations of agomelatine could be observed at each sampling time between the different subjects and in one subject on different periods. The inter-individual CVs of Cmax, AUC0-t and AUC0-∞ were 102.20%, 131.74% and 130.59%, respectively. The intra-individual CVs of Cmax, AUC0-t and AUC0-∞ were 84.34%, 49.61% and 50.83%, respectively. The results showed high inter- and intra-individual variability in the pharmacokinetics of agomelatine in Chinese healthy male subjects, and the intra-individual variability at CV>80% should be considered in the design of bioequivalence studies.

  16. Population pharmacokinetics and limited sampling strategy for first-line tuberculosis drugs and moxifloxacin

    NARCIS (Netherlands)

    Magis-Escurra, C.; Later-Nijland, H. M. J.; Alffenaar, J. W. C.; Broeders, J.; Burger, D. M.; van Crevel, R.; Boeree, M. J.; Donders, A. R. T.; van Altena, R.; van der Werf, T. S.; Aarnoutse, R. E.

    2014-01-01

    Therapeutic drug monitoring (TDM) of tuberculosis (TB) drugs currently focuses on peak plasma concentrations, yet total exposure [area under the 24-h concentration-time curve (AUC(0-24))] is probably most relevant to the efficacy of these drugs. We therefore assessed population AUC(0-24) data for al

  17. Application of appropriate use criteria for percutaneous coronary intervention in Japan

    Science.gov (United States)

    Inohara, Taku; Kohsaka, Shun; Ueda, Ikuko; Yagi, Takashi; Numasawa, Yohei; Suzuki, Masahiro; Maekawa, Yuichiro; Fukuda, Keiichi

    2016-01-01

    The aim of this review was to summarize the concept of appropriate use criteria (AUC) regarding percutaneous coronary intervention (PCI) and document AUC use and impact on clinical practice in Japan, in comparison with its application in the United States. AUC were originally developed to subjectively evaluate the indications and performance of various diagnostic and therapeutic modalities, including revascularization techniques. Over the years, application of AUC has significantly impacted patient selection for PCI in the United States, particularly in non-acute settings. After the broad implementation of AUC in 2009, the rate of inappropriate PCI decreased by half by 2014. The effect was further accentuated by incorporation of financial incentives (e.g., restriction of reimbursement for inappropriate procedures). On the other hand, when the United States-derived AUC were applied to Japanese patients undergoing elective PCI from 2008 to 2013, about one-third were classified as inappropriate, largely due to the perception gap between American and Japanese experts. For example, PCI for low-risk non-left atrial ascending artery lesion was more likely to be classified as appropriate by Japanese standards, and anatomical imaging with coronary computed tomography angiography was used relatively frequently in Japan, but no scenario within the current AUC includes this modality. To extrapolate the current AUC to Japan or any other region outside of the United States, these local discrepancies must be taken into consideration, and scenarios should be revised to reflect contemporary practice. Understanding the concept of AUC as well as its perception gap between different counties will result in the broader implementation of AUC, and lead to the quality improvement of patients’ care in the field of coronary intervention. PMID:27621773

  18. Presentation of coefficient of variation for bioequivalence sample-size calculation
.

    Science.gov (United States)

    Lee, Yi Lin; Mak, Wen Yao; Looi, Irene; Wong, Jia Woei; Yuen, Kah Hay

    2017-03-03

    The current study aimed to further contribute information on intrasubject coefficient of variation (CV) from 43 bioequivalence studies conducted by our center. Consistent with Yuen et al. (2001), current work also attempted to evaluate the effect of different parameters (AUC0-t, AUC0-∞, and Cmax) used in the estimation of the study power. Furthermore, we have estimated the number of subjects required for each study by looking at the values of intrasubject CV of AUC0-∞ and have also taken into consideration the minimum sample-size requirement set by the US FDA. A total of 37 immediate-release and 6 extended-release formulations from 28 different active pharmaceutical ingredients (APIs) were evaluated. Out of the total number of studies conducted, 10 studies did not achieve satisfactory statistical power on two or more parameters; 4 studies consistently scored poorly across all three parameters. In general, intrasubject CV values calculated from Cmax were more variable compared to either AUC0-t and AUC0-∞. 20 out of 43 studies did not achieve more than 80% power when the value was calculated from Cmax value, compared to only 11 (AUC0-∞) and 8 (AUC0-t) studies. This finding is consistent with Steinijans et al. (1995) [2] and Yuen et al. (2001) [3]. In conclusion, the CV values obtained from AUC0-t and AUC0-∞ were similar, while those derived from Cmax were consistently more variable. Hence, CV derived from AUC instead of Cmax should be used in sample-size calculation to achieve a sufficient, yet practical, test power.
.

  19. Evaluation of fasting state-/oral glucose tolerance test-derived measures of insulin release for the detection of genetically impaired β-cell function.

    Directory of Open Access Journals (Sweden)

    Silke A Herzberg-Schäfer

    Full Text Available BACKGROUND: To date, fasting state- and different oral glucose tolerance test (OGTT-derived measures are used to estimate insulin release with reasonable effort in large human cohorts required, e.g., for genetic studies. Here, we evaluated twelve common (or recently introduced fasting state-/OGTT-derived indices for their suitability to detect genetically determined β-cell dysfunction. METHODOLOGY/PRINCIPAL FINDINGS: A cohort of 1364 White European individuals at increased risk for type 2 diabetes was characterized by OGTT with glucose, insulin, and C-peptide measurements and genotyped for single nucleotide polymorphisms (SNPs known to affect glucose- and incretin-stimulated insulin secretion. One fasting state- and eleven OGTT-derived indices were calculated and statistically evaluated. After adjustment for confounding variables, all tested SNPs were significantly associated with at least two insulin secretion measures (p≤0.05. The indices were ranked according to their associations' statistical power, and the ranks an index obtained for its associations with all the tested SNPs (or a subset were summed up resulting in a final ranking. This approach revealed area under the curve (AUC(Insulin(0-30/AUC(Glucose(0-30 as the best-ranked index to detect SNP-dependent differences in insulin release. Moreover, AUC(Insulin(0-30/AUC(Glucose(0-30, corrected insulin response (CIR, AUC(C-Peptide(0-30/AUC(Glucose(0-30, AUC(C-Peptide(0-120/AUC(Glucose(0-120, two different formulas for the incremental insulin response from 0-30 min, i.e., the insulinogenic indices (IGI(2 and IGI(1, and insulin 30 min were significantly higher-ranked than homeostasis model assessment of β-cell function (HOMA-B; p<0.05. AUC(C-Peptide(0-120/AUC(Glucose(0-120 was best-ranked for the detection of SNPs involved in incretin-stimulated insulin secretion. In all analyses, HOMA-β displayed the highest rank sums and, thus, scored last. CONCLUSIONS/SIGNIFICANCE: With AUC(Insulin(0

  20. Evaluation of a Bayesian Approach to Estimate Vancomycin Exposure in Obese Patients with Limited Pharmacokinetic Sampling: A Pilot Study.

    Science.gov (United States)

    Carreno, Joseph J; Lomaestro, Ben; Tietjan, John; Lodise, Thomas P

    2017-03-13

    This study evaluated the predictive performance of a Bayesian PK estimation method (ADAPT V) to estimate the 24-hour vancomycin area under the curve estimation (AUC) with limited PK sampling in adult obese patients receiving vancomycin for suspected or confirmed Gram-positive infections. This was an IRB-approved prospective evaluation of 12 patients. Patients had a median (95% CI) age of 61 years (39 - 71), creatinine clearance of 86 mL/min (75 - 120), and body mass index of 45 kg/m(2) (40 - 52). For each patient, five PK concentrations were measured and 4 different vancomycin population PK models were used as Bayesian priors to estimate the estimate vancomycin AUC (AUCFULL). Using each PK model as a prior, data-depleted PK subsets were used to estimate the 24-hour AUC (i.e. peak and trough data [AUCPT], midpoint and trough data [AUCMT], and trough only data [AUCT]). The 24-hour AUC derived from the full data set (AUCFULL) was compared to AUC derived from data depleted subsets (AUCPT, AUCMT, AUCT) for each model. For the 4 sets of analyses, AUCFULL estimates ranged from 437 to 489 mg-h/L. The AUCPT provided the best approximation of the AUCFULL; AUCMT and AUCT tended to overestimate AUCFULL Further prospective studies are needed to evaluate the impact of AUC monitoring in clinical practice but the findings from this study suggest the vancomycin AUC can be estimated good precision and accuracy with limited PK sampling using Bayesian PK estimation software.

  1. Disadvantages of using the area under the receiver operating characteristic curve to assess imaging tests: A discussion and proposal for an alternative approach

    Energy Technology Data Exchange (ETDEWEB)

    Halligan, Steve [University College London, Centre for Medical Imaging, University College Hospital, London (United Kingdom); Altman, Douglas G. [University of Oxford, Centre for Statistics in Medicine, Oxford (United Kingdom); Mallett, Susan [University of Oxford, Department of Primary Care Health Sciences, Oxford (United Kingdom)

    2015-04-01

    The objectives are to describe the disadvantages of the area under the receiver operating characteristic curve (ROC AUC) to measure diagnostic test performance and to propose an alternative based on net benefit. We use a narrative review supplemented by data from a study of computer-assisted detection for CT colonography. We identified problems with ROC AUC. Confidence scoring by readers was highly non-normal, and score distribution was bimodal. Consequently, ROC curves were highly extrapolated with AUC mostly dependent on areas without patient data. AUC depended on the method used for curve fitting. ROC AUC does not account for prevalence or different misclassification costs arising from false-negative and false-positive diagnoses. Change in ROC AUC has little direct clinical meaning for clinicians. An alternative analysis based on net benefit is proposed, based on the change in sensitivity and specificity at clinically relevant thresholds. Net benefit incorporates estimates of prevalence and misclassification costs, and it is clinically interpretable since it reflects changes in correct and incorrect diagnoses when a new diagnostic test is introduced. ROC AUC is most useful in the early stages of test assessment whereas methods based on net benefit are more useful to assess radiological tests where the clinical context is known. Net benefit is more useful for assessing clinical impact. (orig.)

  2. Effects of oral contraceptives on glucoregulatory responses to exercise.

    Science.gov (United States)

    Jankowski, Catherine M; Ben-Ezra, Vic; Gozansky, Wendolyn S; Scheaffer, Suzanne E

    2004-03-01

    Some of the effects of oral contraceptives (OCs) to alter glucoregulation may be ameliorated by exercise. To test this premise, the effects of acute aerobic exercise on postprandial glucose, insulin, and C-peptide responses (area under the curve [AUC]) were measured in 8 users of low-dose estrogen and progestin OCs (OC(+)) and 10 women not using OCs (OC(-)). They completed 2 randomly ordered intervention trials: (1) aerobic exercise on 3 consecutive days with a 2.5-hour, 75-g oral glucose tolerance test (OGTT) on day 4, and (2) no exercise for 3 days prior to the OGTT (control trial). The exercise was 50 minutes of treadmill walking at 70% (.-)VO(2max). The groups were similar in age (27 +/- 3 years), waist-to-hip ratio (0.74 +/- 0.01), and cardiorespiratory fitness (32.5 +/- 1.6 mL x kg body mass(-1) x min(-1)). Fasting plasma glucose, C-peptide, and insulin levels were similar (P >.05) between groups in the control trial. In both trials, glucose(AUC) was significantly greater (13%, P <.05) in OC(+). Exercise resulted in a significant (P <.05) decrease in fasting plasma glucose and insulin, insulin(AUC), glucose(AUC) x insulin(AUC), and C-peptide(AUC) in both groups, suggesting enhanced insulin action and/or reduced pancreatic insulin secretion. Hepatic insulin extraction ([C-peptide(AUC) - insulin(AUC)())]/C-peptide(AUC)) was increased following exercise only in OC(+). Thus, insulin action was enhanced in response to exercise in young sedentary women independent of OC use. The mechanisms for the acute exercise effect on insulin action may be different in OC users compared with normally menstruating women.

  3. Pharmacokinetics and bioavailability of single dose ibuprofen and pseudoephedrine alone or in combination: a randomized three-period, cross-over trial in healthy Indian volunteers

    Directory of Open Access Journals (Sweden)

    Prashant eKale

    2014-05-01

    Full Text Available Objective To compare the bioavailability of single dose ibuprofen 200 mg and pseudoephedrine hydrochloride 30 mg administered alone or in combination as an oral suspension. Methods This was a single-center, randomized, single-dose, open-label, 3-period, crossover study. After an overnight fast (≥10 hours, 18 healthy male subjects received either ibuprofen 200 mg (reference-A, pseudoephedrine 30 mg (reference-B or the combination (test-C as a suspension, on 3 separate visits, with blood sampling up to 36-hours post-dose. The primary pharmacokinetic parameters, maximum plasma concentration (Cmax and area under the plasma concentration–time curve (AUC from time zero to last measurable concentration (AUC0-t and extrapolated to infinity (AUC0- were compared by an analysis of variance using log-transformed data. Bioequivalence was concluded if the 90% confidence intervals (CIs of the adjusted geometric mean (gMean ratios for Cmax and AUC were within the predetermined range of 80%-125%, in accordance with regulatory requirements. Results For the test formulation, the ibuprofen gMean Cmax was 17.0 µg/mL (vs. 18.1 µg/mL for reference-A, AUC0-t was 57.1 (vs. 60.0 µg•h/mL and AUC0- was 59.9 µg•h/mL (vs. 63.1 µg•h/mL. The 90% CIs for the ratio (test/reference-A were 81.0-108.1% for Cmax, 91.5-98.4% for AUC0-t and 91.6-97.9% for AUC0-. For pseudoephedrine, the gMean Cmax for the test formulation was 97.2 ng/mL (vs. 98.5 ng/mL for reference-B, AUC0-t was 878.4 (vs. 842.8 ng•h/mL and AUC0- was 907.8 ng•h/mL (vs. 868.3 ng•h/mL. The 90% CIs for the ratio (test/reference-B were 92.4-106.9% for Cmax, 97.7-111.0% for AUC0-t and 97.9-111.3% for AUC0-. All treatments were well tolerated. Conclusion This oral suspension containing ibuprofen and pseudoephedrine combined in a new formulation met the regulatory criterion for bioequivalence compared with oral suspensions containing the individual components.

  4. Machine learning-based receiver operating characteristic (ROC) curves for crisp and fuzzy classification of DNA microarrays in cancer research.

    Science.gov (United States)

    Peterson, Leif E; Coleman, Matthew A

    2008-01-01

    Receiver operating characteristic (ROC) curves were generated to obtain classification area under the curve (AUC) as a function of feature standardization, fuzzification, and sample size from nine large sets of cancer-related DNA microarrays. Classifiers used included k nearest neighbor (kNN), näive Bayes classifier (NBC), linear discriminant analysis (LDA), quadratic discriminant analysis (QDA), learning vector quantization (LVQ1), logistic regression (LOG), polytomous logistic regression (PLOG), artificial neural networks (ANN), particle swarm optimization (PSO), constricted particle swarm optimization (CPSO), kernel regression (RBF), radial basis function networks (RBFN), gradient descent support vector machines (SVMGD), and least squares support vector machines (SVMLS). For each data set, AUC was determined for a number of combinations of sample size, total sum[-log(p)] of feature t-tests, with and without feature standardization and with (fuzzy) and without (crisp) fuzzification of features. Altogether, a total of 2,123,530 classification runs were made. At the greatest level of sample size, ANN resulted in a fitted AUC of 90%, while PSO resulted in the lowest fitted AUC of 72.1%. AUC values derived from 4NN were the most dependent on sample size, while PSO was the least. ANN depended the most on total statistical significance of features used based on sum[-log(p)], whereas PSO was the least dependent. Standardization of features increased AUC by 8.1% for PSO and -0.2% for QDA, while fuzzification increased AUC by 9.4% for PSO and reduced AUC by 3.8% for QDA. AUC determination in planned microarray experiments without standardization and fuzzification of features will benefit the most if CPSO is used for lower levels of feature significance (i.e., sum[-log(p)] ~ 50) and ANN is used for greater levels of significance (i.e., sum[-log(p)] ~ 500). When only standardization of features is performed, studies are likely to benefit most by using CPSO for low levels

  5. Bug bites and stings: When to see a dermatologist

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    Full Text Available ... AAD publications Make a difference Career planning Media Relations Toolkit AAD apps Academy meeting Chronic urticaria—for members Chronic urticaria—for public Dermatology World Dialogues in Dermatology JAAD Mohs AUC ...

  6. How to Stop Biting Your Nails

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    Full Text Available ... AAD publications Make a difference Career planning Media Relations Toolkit AAD apps Academy meeting Chronic urticaria—for members Chronic urticaria—for public Dermatology World Dialogues in Dermatology JAAD Mohs AUC ...

  7. Dandruff: How to Treat

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    Full Text Available ... AAD publications Make a difference Career planning Media Relations Toolkit AAD apps Academy meeting Chronic urticaria—for members Chronic urticaria—for public Dermatology World Dialogues in Dermatology JAAD Mohs AUC ...

  8. How to Stop Biting Your Nails

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    Full Text Available ... Contact us Support AAD Media AAD store Advertise Employment Website feedback AAD American Academy of Dermatology Excellence ... in Dermatology JAAD Mohs AUC MyDermPath+ Psoriasis Patient education resources Practice Management Center Coding and reimbursement Coding ...

  9. Dandruff: How to Treat

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    Full Text Available ... Contact us Support AAD Media AAD store Advertise Employment Website feedback AAD American Academy of Dermatology Excellence ... in Dermatology JAAD Mohs AUC MyDermPath+ Psoriasis Patient education resources Practice Management Center Coding and reimbursement Coding ...

  10. Bug bites and stings: When to see a dermatologist

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    Full Text Available ... Contact us Support AAD Media AAD store Advertise Employment Website feedback AAD American Academy of Dermatology Excellence ... in Dermatology JAAD Mohs AUC MyDermPath+ Psoriasis Patient education resources Practice Management Center Coding and reimbursement Coding ...

  11. Hidradenitis Suppurativa

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    ... for public Dermatology World Dialogues in Dermatology JAAD Mohs AUC MyDermPath+ Psoriasis Patient education resources Practice Management ... first FDA-approved treatment for HS The U.S. Food and Drug Administration (FDA) approved the first treatment ...

  12. Contact Dermatitis

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    ... for public Dermatology World Dialogues in Dermatology JAAD Mohs AUC MyDermPath+ Psoriasis Patient education resources Practice Management ... of contact with less irritating substances like: Water Foods Soap People often develop irritant contact dermatitis at ...

  13. How to Select Anti-Aging Skin Care Products

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    ... for public Dermatology World Dialogues in Dermatology JAAD Mohs AUC MyDermPath+ Psoriasis Patient education resources Practice Management ... clinical trials and received approval from the U.S. Food and Drug Administration (FDA). Select a product within ...

  14. How to Create an Anti-Aging Skin Care Plan

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    ... for public Dermatology World Dialogues in Dermatology JAAD Mohs AUC MyDermPath+ Psoriasis Patient education resources Practice Management ... lines and wrinkles, and leathery skin. Eat healthy foods: A healthy diet promotes healthy skin. Make sure ...

  15. Hives

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    ... for public Dermatology World Dialogues in Dermatology JAAD Mohs AUC MyDermPath+ Psoriasis Patient education resources Practice Management ... Things that commonly trigger an allergic reaction include: Foods: Fruits (especially citrus fruits), milk, eggs, peanuts, tree ...

  16. Is Sunscreen Safe?

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    ... for public Dermatology World Dialogues in Dermatology JAAD Mohs AUC MyDermPath+ Psoriasis Patient education resources Practice Management ... with some ingredients found in sunscreens? The U.S. Food and Drug Administration (FDA) regulates sunscreens. Before an ...

  17. Hair Loss (Alopecia)

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    ... for public Dermatology World Dialogues in Dermatology JAAD Mohs AUC MyDermPath+ Psoriasis Patient education resources Practice Management ... on the top of the scalp. The U.S. Food and Drug Administration (FDA) has approved minoxidil to ...

  18. Caring for Tattooed Skin

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    ... for public Dermatology World Dialogues in Dermatology JAAD Mohs AUC MyDermPath+ Psoriasis Patient education resources Practice Management ... removal kits are available online, but the U.S. Food and Drug Administration (FDA) warns that it does ...

  19. Types of Eczema (Dermatitis)

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    ... for public Dermatology World Dialogues in Dermatology JAAD Mohs AUC MyDermPath+ Psoriasis Patient education resources Practice Management ... may recommend a change to your diet. Eliminating foods that contain nickel or cobalt helps some people. ...

  20. Teaching Your Child Healthy Nail Care

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    ... for public Dermatology World Dialogues in Dermatology JAAD Mohs AUC MyDermPath+ Psoriasis Patient education resources Practice Management ... is especially hard on the nails. 5. Eat foods that contain plenty of protein and vitamin B7 ( ...

  1. Strategy for the Prediction of Steady-State Exposure of Digoxin to Determine Drug-Drug Interaction Potential of Digoxin With Other Drugs in Digitalization Therapy.

    Science.gov (United States)

    Srinivas, Nuggehally R

    2016-01-20

    Digoxin, a narrow therapeutic index drug, is widely used in congestive heart failure. However, the digitalization therapy involves dose titration and can exhibit drug-drug interaction. Ctrough versus area under the plasma concentration versus time curve in a dosing interval of 24 hours (AUC0-24h) and Cmax versus AUC0-24h for digoxin were established by linear regression. The predictions of digoxin AUC0-24h values were performed using published Ctrough or Cmax with appropriate regression lines. The fold difference, defined as the quotient of the observed/predicted AUC0-24h values, was evaluated. The mean square error and root mean square error, correlation coefficient (r), and goodness of the fold prediction were used to evaluate the models. Both Ctrough versus AUC0-24h (r = 0.9215) and Cmax versus AUC0-24h models for digoxin (r = 0.7781) showed strong correlations. Approximately 93.8% of the predicted digoxin AUC0-24h values were within 0.76-fold to 1.25-fold difference for Ctrough model. In sharp contrast, the Cmax model showed larger variability with only 51.6% of AUC0-24h predictions within 0.76-1.25-fold difference. The r value for observed versus predicted AUC0-24h for Ctrough (r = 0.9551; n = 177; P < 0.001) was superior to the Cmax (r = 0.6134; n = 275; P < 0.001) model. The mean square error and root mean square error (%) for the Ctrough model were 11.95% and 16.2% as compared to 67.17% and 42.3% obtained for the Cmax model. Simple linear regression models for Ctrough/Cmax versus AUC0-24h were derived for digoxin. On the basis of statistical evaluation, Ctrough was superior to Cmax model for the prediction of digoxin AUC0-24h and can be potentially used in a prospective setting for predicting drug-drug interaction or lack of it.

  2. Immunological and cardiometabolic risk factors in the prediction of type 2 diabetes and coronary events: MONICA/KORA Augsburg case-cohort study.

    Directory of Open Access Journals (Sweden)

    Christian Herder

    Full Text Available BACKGROUND: This study compares inflammation-related biomarkers with established cardiometabolic risk factors in the prediction of incident type 2 diabetes and incident coronary events in a prospective case-cohort study within the population-based MONICA/KORA Augsburg cohort. METHODS AND FINDINGS: Analyses for type 2 diabetes are based on 436 individuals with and 1410 individuals without incident diabetes. Analyses for coronary events are based on 314 individuals with and 1659 individuals without incident coronary events. Mean follow-up times were almost 11 years. Areas under the receiver-operating characteristic curve (AUC, changes in Akaike's information criterion (ΔAIC, integrated discrimination improvement (IDI and net reclassification index (NRI were calculated for different models. A basic model consisting of age, sex and survey predicted type 2 diabetes with an AUC of 0.690. Addition of 13 inflammation-related biomarkers (CRP, IL-6, IL-18, MIF, MCP-1/CCL2, IL-8/CXCL8, IP-10/CXCL10, adiponectin, leptin, RANTES/CCL5, TGF-β1, sE-selectin, sICAM-1; all measured in nonfasting serum increased the AUC to 0.801, whereas addition of cardiometabolic risk factors (BMI, systolic blood pressure, ratio total/HDL-cholesterol, smoking, alcohol, physical activity, parental diabetes increased the AUC to 0.803 (ΔAUC [95% CI] 0.111 [0.092-0.149] and 0.113 [0.093-0.149], respectively, compared to the basic model. The combination of all inflammation-related biomarkers and cardiometabolic risk factors yielded a further increase in AUC to 0.847 (ΔAUC [95% CI] 0.044 [0.028-0.066] compared to the cardiometabolic risk model. Corresponding AUCs for incident coronary events were 0.807, 0.825 (ΔAUC [95% CI] 0.018 [0.013-0.038] compared to the basic model, 0.845 (ΔAUC [95% CI] 0.038 [0.028-0.059] compared to the basic model and 0.851 (ΔAUC [95% CI] 0.006 [0.003-0.021] compared to the cardiometabolic risk model, respectively. CONCLUSIONS: Inclusion of multiple

  3. Association of Anthropometric Measurement Methods with Cardiovascular Disease Risk in Turkey

    Directory of Open Access Journals (Sweden)

    Kaan Sözmen

    2016-03-01

    Full Text Available Objective: The aim of this study is to compare the predic­tive power of anthropometric indices for risk of developing Coronary Heart Disease (CHD or CHD death. Methods: We used cross-sectional data from nationally representative Chronic Diseases and Risk Factors Sur­vey conducted by the Ministry of Health in 2011. Body mass index (BMI, waist circumference (WC, waist-to-hip ratio (WHR, waist to height ratio (WHtR, body adiposity index (BAI and A Body Shape Index (ABSI formed the anthropometric measures. For each participant risk of de­veloping CHD or dying from CVDs were calculated based on Framingham and SCORE risk equations. Predictive ability of anthropometric measurements was assessed by receiver operating characteristic (ROC curves. Results: Anthropometric measurements of central obe­sity recorded higher area under the ROC curve (AUC values than BMI in both men and women. While ABSI had the highest AUC values for Framingham 10-year pre­dicted risk (FRS for CHD death (AUC = 0.613, SCORE 10-year risk for CVD death (AUC = 0.633, in women AUC for ABSI was the highest for only SCORE risk threshold (AUC = 0.705. Among women, WHtR was found to be the best indicator for estimating CHD incidence (AUC = 0.706 and death from CVD (AUC = 0.696. Conclusion: Compared to traditional anthropometric measurements such as BMI, ABSI was a better indicator for given thresholds for estimating the risk of developing CHD and CVD death in men. Among women WHtR made better predictions for FRS thresholds, however, ABSI was better for predicting 10-year risk of CVD death calculated by SCORE risk equation.

  4. Comparative Bioavailability Study with Two Sodium Valproate Tablet Formulations in Healthy Subjects

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    Dhaneshwar Shep

    2011-04-01

    Full Text Available The aim was to assess the comparative bioavailability of two formulations (200 mg tablet of sodium valproate in healthy subjects. This open label randomized, two periods, two treatments, two sequence, 2-way crossover design study was conducted in 18 healthy Indian adult subjects. Subjects received sodium valproate 200 mg of either test or reference formulation with a washout period of 7 days. After study drug administration, serial blood samples were collected over a period of 60 hours. Plasma concentrations of Valproic acid were measured by pre-validated LC-MS-MS method. Pharmacokinetic (PK parameters Cmax, Tmax, t1/2, AUC0-t, AUC 0-∞, and kel were determined for the 2 sodium valproate formulations. Cmax, AUC0-t, and AUC0-∞ were used to test for bioequivalence after log-transformation of plasma data. The formulations were to be considered bioequivalent if the log-transformed ratios of Cmax, AUC0-t, and AUC0-∞ were within the predetermined bioequivalence range of 80% to 125%. A total of 18 healthy subjects were enrolled. No significant differences were found based on analysis of variance, with mean values and 90% confidence intervals of test/reference ratios for these parameters as follows: Cmax, 15.64 versus 15.20μg/ml (90.79 to 115.45; AUC0-t, 72.71 versus 66.95μg.h/ml (96.03 to 124.87; and AUC0-∞, 105.65 versus 98.11μg.h/ml (94.61 to 124.75. In these healthy Indian subjects, results from the PK analysis suggested that the test and reference formulations of sodium valproate 200 mg tablets were bioequivalent. Both the formulations were well tolerated.

  5. BIOEQUIVALENCE STUDY OF TWO ORAL FORMULATIONS OF METAMIZOLE 500 MG IN HEALTHY VOLUNTEERS

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    Dhaneshwar Shep *, Rakesh Ojha , Rajeshwari Rathod , Sweta Patel , Manish Nivsarkar , Sanjay Maroo and Harish Padh

    2012-06-01

    Full Text Available Background: Metamizole (Dipyrone is widely used and has effective analgesic, antipyretic, and antispasmodic properties. After oral or intravenous administration, dipyrone is rapidly hydrolyzed to the active moiety 4-methylaminoantipyrine. Aim: The aim of this study was to assess the bioequivalence of 2 oral formulations of Metamizole 500 mg. Methods: This double blind, randomized, single-dose, 2-period crossover study in healthy Indian adult volunteers was conducted at PERD Centre, Ahmedabad. Subjects received Metamizole 500 mg of either test or reference formulation with a washout period of 7 days. After study drug administration, serial blood samples were collected over a period of 24 hours. Plasma concentration of 4-methylaminoantipyrine was measured by pre-validated LC-MS method. Pharmacokinetic (PK parameters Cmax, Tmax, t1/2, AUC0-t, AUC0-∞, and kel, were determined for test and reference formulations. The formulations were to be considered bioequivalent if the log-transformed ratios of Cmax, AUC0-t, and AUC0-∞ were within the predetermined bioequivalence range of 80% to 125%. Results: A total of 14 subjects were enrolled. No significant differences were found based on analysis of variance, with mean values and 90% confidence intervals of test/reference ratios for these parameters as follows: Cmax, 18.24 versus 18.44 μg/mL (92.68 - 106.61; AUC0-t, 92.97 Versus 91.37 μg.hr/mL (89.49 - 113.09; and AUC0-∞, 96.64 Versus 94.65 μg.hr/mL (92.31 - 111.63. Conclusion: Since the 90% confidence intervals for Cmax, AUC0-t, and AUC0−∞ were within the interval of 80-125%, it was concluded that both formulations were bioequivalent, according to both the rate and extent of absorption.

  6. Is procalcitonin to C-reactive protein ratio useful for the detection of late onset neonatal sepsis?

    Science.gov (United States)

    Hahn, Won-Ho; Song, Joon-Hwan; Kim, Ho; Park, Suyeon

    2017-02-21

    Procalcitonin (PCT) has been reported as a sensitive marker for neonatal bacterial infections. Recently, small numbers of studies reported usefulness of PCT/C-reactive protein (CRP) ratio in detection of infectious conditions in adults. Thus, we conducted this study to evaluate PCT/CRP ratio in late onset neonatal sepsis. Serum PCT and CRP was measured in blood samples from 7-60 days after birth in 106 of neonates with late onset sepsis and 212 of controls who were matched with gestational age, postnatal age, birth weight and gender. Areas under ROC curve (AUC) were calculated and pairwise comparisons between ROC curves were performed. As a result, CRP (AUC 0.96) showed best performance in detection of sepsis from healthy controls compared with PCT (AUC 0.87) and PCT/CRP ratio (AUC 0.62); CRP > PCT > PCT/CRP ratio in pairwise comparison (Psepsis from healthy controls compared with PCT/CRP ratio (AUC 0.54); CRP = PCT > PCT/CRP ratio in pairwise comparison (Pdetection of blood culture proven sepsis from suspected sepsis, PCT (AUC 0.70) and PCT/CRP ratio (AUC 0.73) showed better performance compared with CRP (AUC 0.51); PCT = PCT/CRP ratio > CRP in pairwise comparison (Psepsis and healthy controls. However, PCT/CRP ratio seems to be helpful in distinguishing proven sepsis from suspected sepsis together with PCT. Further studies are warranted to elucidate the efficacy of PCT/CRP ratio with enrollment of enough numbers of infants.

  7. Bioequivalence of Alendronate and Vitamin D3 in a Combination Tablet Versus Corresponding-Dose Individual Tablets in Healthy Taiwanese Volunteers, Determined Using a Novel Plasma Alendronate Assay

    Directory of Open Access Journals (Sweden)

    D. Hamish Wright, PhD

    2015-12-01

    Conclusions: The combination tablet was considered bioequivalent to coadministration based on ALN AUC0–∞ and unadjusted vitamin D3 parameters. Slight differences for ALN AUC0–last and Cmax (upper 90% CIs outside the bounds were not considered clinically significant. The combination tablet was well tolerated. No serious adverse experiences were reported. © 2015. The Authors. Published by Elsevier Inc. All rights reserved.

  8. Randomized two-way cross-over bioequivalence study of two amoxicillin formulations and inter-ethnicity pharmacokinetic variation in healthy Malay volunteers.

    Science.gov (United States)

    Liew, Kai Bin; Loh, Gabriel Onn Kit; Tan, Yvonne Tze Fung; Peh, Kok Khiang

    2014-09-01

    The objectives of this study were to develop a new deproteinization method to extract amoxicillin from human plasma and evaluate the inter-ethnic variation of amoxicillin pharmacokinetics in healthy Malay volunteers. A single-dose, randomized, fasting, two-period, two-treatment, two-sequence crossover, open-label bioequivalence study was conducted in 18 healthy Malay adult male volunteers, with one week washout period. The drug concentration in the sample was analyzed using high-performance liquid chromatography (UV-vis HPLC). The mean (standard deviation) pharmacokinetic parameter results of Moxilen® were: peak concentration (Cmax ), 6.72 (1.56) µg/mL; area under the concentration-time graph (AUC0-8 ), 17.79 (4.29) µg/mL h; AUC0-∞ , 18.84 (4.62) µg/mL h. Those of YSP Amoxicillin® capsule were: Cmax , 6.69 (1.44) µg/mL; AUC0-8 , 18.69 (3.78) µg/mL h; AUC00-∞ , 19.95 (3.81) µg/mL h. The 90% confidence intervals for the logarithmic transformed Cmax , AUC0-8 and AUC0-∞ of Moxilen® vs YSP Amoxicillin® capsule was between 0.80 and 1.25. Both Cmax and AUC met the predetermined criteria for assuming bioequivalence. Both formulations were well tolerated. The results showed significant inter-ethnicity variation in pharmacokinetics of amoxicillin. The Cmax and AUC of amoxicillin in Malay population were slightly lower compared with other populations.

  9. Hierarchical and Multiscale Modeling for Elucidating the Androgren Receptor Signaling Pathway in Prostate Cancer

    Science.gov (United States)

    2009-10-01

    functional distances for lo- cal scales. This illustrates that diffusion at higher scales smooths or denoises the evaluation of functional distances...factor model with the satu- rated model (Lasso on the original features), SVD regression, and regression using the eigenvectors of the Laplacian...the other methods as measured by AUC. Method Sat SVD Lap MSF Avg AUC .886 .885 .914 .934 Std dev .028 .038 .037 .022 Table 1: Performance comparison

  10. ¿Tiene utilidad el tratamiento preoperatorio con ácido ursodeoxicólico en la reducción de las recidivas en la pancreatitis aguda biliar?

    Directory of Open Access Journals (Sweden)

    F. Borda

    Full Text Available En el presente trabajo se ha valorado la posible reducción de la tasa de recidivas en la pancreatitis aguda biliar mediante el tratamiento con ácido ursodeoxicólico (AUC entre el episodio de pancreatitis y el momento de la colecistectomía. Se estudiaron 72 primeros episodios consecutivos de pancreatitis aguda biliar, en pacientes no colecistectomizados, seguidos hasta la cirugía. Los casos se dividieron en grupo A (n = 30, tratados al alta con AUC 10 mg/kg/día, hasta la cirugía, y grupo B o control (n = 42. Se evaluaron las diferencias entre ambos grupos en cuanto a características del paciente, gravedad de la pancreatitis, características de la litiasis y demora hasta la cirugía. Analizamos las recidivas de la pancreatitis entre los grupos con y sin AUC. En el grupo con AUC comparamos la duración del tratamiento entre los pacientes con y sin recidiva de la pancreatitis. Los dos grupos no mostraron diferencias significativas en cuanto a ninguno de los parámetros estudiados. Registramos 7/30 (23,3% recidivas en el grupo AUC, frente a 9/42 (21,4% recidivas en el control (p = 0,85. Dentro del grupo AUC, la duración del tratamiento fue similar entre los casos que recidivaron: 4,9±4,5 meses y los no recidivados: 4,4±1,9 meses (p = 0,78. En nuestra experiencia, el empleo de AUC hasta el momento de la colecistectomía no reduce la incidencia de recidiva en los pacientes tras un primer episodio de pancreatitis aguda biliar. La duración del tratamiento con AUC tampoco parece relacionarse con la aparición o no de recidivas.

  11. Metabolomics provide new insights on lung cancer staging and discrimination from chronic obstructive pulmonary disease.

    Science.gov (United States)

    Deja, Stanislaw; Porebska, Irena; Kowal, Aneta; Zabek, Adam; Barg, Wojciech; Pawelczyk, Konrad; Stanimirova, Ivana; Daszykowski, Michal; Korzeniewska, Anna; Jankowska, Renata; Mlynarz, Piotr

    2014-11-01

    Chronic obstructive pulmonary disease (COPD) and lung cancer are widespread lung diseases. Cigarette smoking is a high risk factor for both the diseases. COPD may increase the risk of developing lung cancer. Thus, it is crucial to be able to distinguish between these two pathological states, especially considering the early stages of lung cancer. Novel diagnostic and monitoring tools are required to properly determine lung cancer progression because this information directly impacts the type of the treatment prescribed. In this study, serum samples collected from 22 COPD and 77 lung cancer (TNM stages I, II, III, and IV) patients were analyzed. Then, a collection of NMR metabolic fingerprints was modeled using discriminant orthogonal partial least squares regression (OPLS-DA) and further interpreted by univariate statistics. The constructed discriminant models helped to successfully distinguish between the metabolic fingerprints of COPD and lung cancer patients (AUC training=0.972, AUC test=0.993), COPD and early lung cancer patients (AUC training=1.000, AUC test=1.000), and COPD and advanced lung cancer patients (AUC training=0.983, AUC test=1.000). Decreased acetate, citrate, and methanol levels together with the increased N-acetylated glycoproteins, leucine, lysine, mannose, choline, and lipid (CH3-(CH2)n-) levels were observed in all lung cancer patients compared with the COPD group. The evaluation of lung cancer progression was also successful using OPLS-DA (AUC training=0.811, AUC test=0.904). Based on the results, the following metabolite biomarkers may prove useful in distinguishing lung cancer states: isoleucine, acetoacetate, and creatine as well as the two NMR signals of N-acetylated glycoproteins and glycerol.

  12. Transdermal fentanyl matrix patches Matrifen and Durogesic DTrans are bioequivalent

    DEFF Research Database (Denmark)

    Kress, Hans G; Boss, Hildegard; Delvin, Thomas

    2010-01-01

    least square means of the Test/Reference ratio (90% confidence intervals [CI]) were within the range of 80-125%, demonstrating bioequivalence of Matrifen and Durogesic DTrans: AUC(0-tlast) 92.5 (CI 88.7-96.4), AUC(0-inf) 91.7 (CI 88.0-95.7), and C(max) 98.3 (CI 92.9-104.1). After 72 h application...

  13. Comparative pharmacodynamics of posaconazole in neutropenic murine models of invasive pulmonary aspergillosis and mucormycosis.

    Science.gov (United States)

    Lewis, Russell E; Albert, Nathaniel D; Kontoyiannis, Dimitrios P

    2014-11-01

    We used two established neutropenic murine models of pulmonary aspergillosis and mucormycosis to explore the association between the posaconazole area under the concentration-time curve (AUC)-to-MIC ratio (AUC/MIC) and treatment outcome. Posaconazole serum pharmacokinetics were verified in infected mice to ensure that the studied doses reflected human exposures with the oral suspension, delayed-release tablet, and intravenous formulations of posaconazole. Sinopulmonary infections were then induced in groups of neutropenic mice with Aspergillus fumigatus strain 293 (posaconazole MIC, 0.5 mg/liter) or Rhizopus oryzae strain 969 (posaconazole MIC, 2 mg/liter) and treated with escalating daily dosages of oral posaconazole, which was designed to achieve AUCs ranging from 1.10 to 392 mg · h/liter. After 5 days of treatment, lung fungal burden was analyzed by quantitative real-time PCR. The relationships of the total drug AUC/MIC and the treatment response were similar in both models, with 90% effective concentrations (EC90s) corresponding to an AUC/MIC threshold of 76 (95% confidence interval [CI], 46 to 102) for strain 293 versus 87 (95% CI, 66 to 101) for strain 969. Using a provisional AUC/MIC target of >100, these exposures correlated with minimum serum posaconazole concentrations (Cmins) of 1.25 mg/liter for strain 293 and 4.0 mg/liter for strain 969. The addition of deferasirox, but not liposomal amphotericin or caspofungin, improved the activity of a suboptimal posaconazole regimen (AUC/MIC, 33) in animals with pulmonary mucormycosis. However, no combination was as effective as the high-dose posaconazole monotherapy regimen (AUC/MIC, 184). Our analysis suggests that posaconazole pharmacodynamics are similar for A. fumigatus and R. oryzae when indexed to pathogen MICs.

  14. Single dose bioequivalence study of two brands of olanzapine 10 mg tablets in Iranian healthy volunteers.

    Science.gov (United States)

    Zakeri-Milani, P; Islambulchilar, Z; Ghanbarzadeh, S; Valizadeh, H

    2013-07-01

    This single dose, randomized, open label, 2-period and crossover study in healthy Iranian adult volunteers was conducted to compare the bioavailability of 2 branded formulations of olanzapine 10 mg tablets. 24 volunteers received one tablet of each olanzapine 10 mg formulation. Drugs were administered after a 12 h overnight fast in each of 2 treatment days which separated by a 2-week washout period. Serial blood samples were collected over a period of 72 h. Plasma was analyzed using a validated high performance liquid chromatography method with ultraviolet detection in the range of 2-24 ng/mL with a lower limit of quantitation of 1.25 ng/mL. A non-compartmental method was employed to determine the pharmacokinetic properties (Cmax, Tmax, AUC0-t, AUC0-∞ and T1/2) to test to bioequivalence. Cmax, AUC0-t and AUC0-∞ were used to test the bioequivalence after log-transformation of plasma data. The mean (SD) Cmax, AUC0-t and AUC0-∞ for the test formulation were 15.82 (3.15) ng/mL, 447.19 (100.64) ng.h/L and 570.75 (130.55) ng.h/L respectively. Corresponding values for the test formulation were 15.72 (4.25) ng/mL, 440.37 (98.75) ng.h/mL and 558.66 (129.57) ng.h/mL. For test formulation vs. the reference formulation, the 90% CIs of the least squares mean test/reference ratios of Cmax, AUC0-t and AUC0-∞ were 97.6-110.0%, 96.4-109.4% and 97.3-109.2%. In these volunteers, based on the FDA regulatory definition, results from the pharmacokinetic analysis suggested that the test and reference formulations of olanzapine 10 mg tablets were bioequivalent.

  15. Effects of tylosin, tilmicosin and tulathromycin on inflammatory mediators in bronchoalveolar lavage fluid of lipopolysaccharide-induced lung injury.

    Science.gov (United States)

    Er, Ayse; Yazar, Enver

    2012-12-01

    The aim of this study was to determine the anti-inflammatory effects of macrolides through kinetic parameters in bronchoalveolar lavage fluid (BALF) of lipopolysaccharide-induced lung injury. Rats were divided into four groups: lipopolysaccharide (LPS), LPS + tylosin, LPS + tilmicosin and LPS + tulathromycin. BALF samples were collected at sampling times. TNF, IL-1β, IL-6, IL-10 and 13,14-dihydro-15-keto-prostaglandin F2α (PGM) and C-reactive protein (CRP) were analysed. Area under the curve (AUC) and maximum plasma concentration (Cmax) values of inflammatory mediators were determined by a pharmacokinetic computer programme. When inflammatory mediator concentrations were compared between the LPS group and other groups for each sampling time, the three macrolides had no pronounced depressor effect on cytokine levels, but they depressed PGM and CRP levels. In addition, tylosin and tilmicosin decreased the AUC0-24 level of TNF, while tilmicosin decreased the AUC0-24 level of IL-10. Tylosin and tulathromycin decreased the AUC0-24 of PGM, and all three macrolides decreased the AUC0-24 of CRP. Especially tylosin and tulathromycin may have more expressed anti-inflammatory effects than tilmicosin, via depressing the production of inflammatory mediators in the lung. The AUC may be used for determining the effects of drugs on inflammation. In this study, the antiinflammatory effects of these antibiotics were evaluated with kinetic parameters as a new and different approach.

  16. Average bioequivalence of single 500 mg doses of two oral formulations of levofloxacin: a randomized, open-label, two-period crossover study in healthy adult Brazilian volunteers

    Directory of Open Access Journals (Sweden)

    Eunice Kazue Kano

    2015-03-01

    Full Text Available Average bioequivalence of two 500 mg levofloxacin formulations available in Brazil, Tavanic(c (Sanofi-Aventis Farmacêutica Ltda, Brazil, reference product and Levaquin(c (Janssen-Cilag Farmacêutica Ltda, Brazil, test product was evaluated by means of a randomized, open-label, 2-way crossover study performed in 26 healthy Brazilian volunteers under fasting conditions. A single dose of 500 mg levofloxacin tablets was orally administered, and blood samples were collected over a period of 48 hours. Levofloxacin plasmatic concentrations were determined using a validated HPLC method. Pharmacokinetic parameters Cmax, Tmax, Kel, T1/2el, AUC0-t and AUC0-inf were calculated using noncompartmental analysis. Bioequivalence was determined by calculating 90% confidence intervals (90% CI for the ratio of Cmax, AUC0-t and AUC0-inf values for test and reference products, using logarithmic transformed data. Tolerability was assessed by monitoring vital signs and laboratory analysis results, by subject interviews and by spontaneous report of adverse events. 90% CIs for Cmax, AUC0-t and AUC0-inf were 92.1% - 108.2%, 90.7% - 98.0%, and 94.8% - 100.0%, respectively. Observed adverse events were nausea and headache. It was concluded that Tavanic(c and Levaquin(c are bioequivalent, since 90% CIs are within the 80% - 125% interval proposed by regulatory agencies.

  17. Two meals with different carbohydrate, fat and protein contents render equivalent postprandial plasma levels of calprotectin, cortisol, triglycerides and zonulin.

    Science.gov (United States)

    Ohlsson, Bodil; Darwiche, Gassan; Roth, Bodil; Höglund, Peter

    2016-11-01

    The aim was to compare postprandial plasma levels of calprotectin, cortisol, triglycerides and zonulin between a control breakfast and a moderately low-carbohydrate test breakfast, given randomly after 10-h fast. Blood samples were collected before and repeatedly after the meal. Plasma calprotectin, cortisol, triglycerides and zonulin were analyzed. The total area under the curve (tAUC) and change in AUC from baseline (dAUC) were calculated. Ratios between the test and control values were calculated to investigate equivalence. Healthy volunteers (8 men and 12 women; 46.0 ± 14.5 years) were included. tAUCs of cortisol and triglycerides did not differ between the breakfasts (p = 0.158 versus p = 0.579). Cortisol dAUCs were decreased and triglyceride dAUCs were increased after both breakfasts, with no differences between the breakfasts (p = 0.933 versus p = 0.277). Calprotectin and zonulin levels were unaffected. The meals were bioequivalent for cortisol, triglycerides and zonulin, but not for calprotectin.

  18. Comparative bioavailability of two tablet formulations of ranitidine hydrochloride in healthy volunteers.

    Science.gov (United States)

    Bawazir, S A; Gouda, M W; El-Sayed, Y M; Al-Khamis, K I; Al-Yamani, M J; Niazy, E M; Al-Rashood, K A

    1998-05-01

    This investigation was carried out to evaluate the bioavailability of a new tablet formulation of ranitidine HCl (300 mg), Ranid, relative to the reference product, Zantac, (300 mg) tablets. The bioavailability was carried out on 24 healthy male volunteers who received a single dose (300 mg) of the test (T) and the reference (R) products in the fasting state, in a randomized balanced 2-way crossover design. After dosing, serial blood samples were collected for a period of 16 hours. Plasma harvested from blood was analyzed for ranitidine by a sensitive and validated high-performance liquid chromatographic assay. The maximum plasma concentration (Cmax), area under the plasma concentration time curve up to the last measurable concentration (AUC0-t), and to infinity (AUC0-infinity) and the absorption rate (Cmax/AUC0-infinity) were analyzed statistically under the assumption of a multiplicative model. The time to maximum concentration (Tmax) was analyzed assuming an additive model. The parametric confidence intervals (90%) of the mean values of the pharmacokinetic characteristics (AUC0-t, AUC0-infinity), Cmax and Cmax/AUC0-infinity) for T/R ratio were in each case well within the bioequivalence acceptable range of 80-125%. The test formulation was found bioequivalent to the reference formulation by the Schuirmann's two one-sided t-tests and by Wilcoxon Mann Whitney two one-sided tests procedure. Therefore, the 2 formulations were considered to be bioequivalent.

  19. Big Data, Predictive Analytics, and Quality Improvement in Kidney Transplantation: A Proof of Concept.

    Science.gov (United States)

    Srinivas, T R; Taber, D J; Su, Z; Zhang, J; Mour, G; Northrup, D; Tripathi, A; Marsden, J E; Moran, W P; Mauldin, P D

    2017-03-01

    We sought proof of concept of a Big Data Solution incorporating longitudinal structured and unstructured patient-level data from electronic health records (EHR) to predict graft loss (GL) and mortality. For a quality improvement initiative, GL and mortality prediction models were constructed using baseline and follow-up data (0-90 days posttransplant; structured and unstructured for 1-year models; data up to 1 year for 3-year models) on adult solitary kidney transplant recipients transplanted during 2007-2015 as follows: Model 1: United Network for Organ Sharing (UNOS) data; Model 2: UNOS & Transplant Database (Tx Database) data; Model 3: UNOS, Tx Database & EHR comorbidity data; and Model 4: UNOS, Tx Database, EHR data, Posttransplant trajectory data, and unstructured data. A 10% 3-year GL rate was observed among 891 patients (2007-2015). Layering of data sources improved model performance; Model 1: area under the curve (AUC), 0.66; (95% confidence interval [CI]: 0.60, 0.72); Model 2: AUC, 0.68; (95% CI: 0.61-0.74); Model 3: AUC, 0.72; (95% CI: 0.66-077); Model 4: AUC, 0.84, (95 % CI: 0.79-0.89). One-year GL (AUC, 0.87; Model 4) and 3-year mortality (AUC, 0.84; Model 4) models performed similarly. A Big Data approach significantly adds efficacy to GL and mortality prediction models and is EHR deployable to optimize outcomes.

  20. Absolute bioavailability of evacetrapib in healthy subjects determined by simultaneous administration of oral evacetrapib and intravenous [(13) C8 ]-evacetrapib as a tracer.

    Science.gov (United States)

    Cannady, Ellen A; Aburub, Aktham; Ward, Chris; Hinds, Chris; Czeskis, Boris; Ruterbories, Kenneth; Suico, Jeffrey G; Royalty, Jane; Ortega, Demetrio; Pack, Brian W; Begum, Syeda L; Annes, William F; Lin, Qun; Small, David S

    2016-05-30

    This open-label, single-period study in healthy subjects estimated evacetrapib absolute bioavailability following simultaneous administration of a 130-mg evacetrapib oral dose and 4-h intravenous (IV) infusion of 175 µg [(13) C8 ]-evacetrapib as a tracer. Plasma samples collected through 168 h were analyzed for evacetrapib and [(13) C8 ]-evacetrapib using high-performance liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameter estimates following oral and IV doses, including area under the concentration-time curve (AUC) from zero to infinity (AUC[0-∞]) and to the last measureable concentration (AUC[0-tlast ]), were calculated. Bioavailability was calculated as the ratio of least-squares geometric mean of dose-normalized AUC (oral : IV) and corresponding 90% confidence interval (CI). Bioavailability of evacetrapib was 44.8% (90% CI: 42.2-47.6%) for AUC(0-∞) and 44.3% (90% CI: 41.8-46.9%) for AUC(0-tlast ). Evacetrapib was well tolerated with no reports of clinically significant safety assessment findings. This is among the first studies to estimate absolute bioavailability using simultaneous administration of an unlabeled oral dose with a (13) C-labeled IV microdose tracer at about 1/1000(th) the oral dose, with measurement in the pg/mL range. This approach is beneficial for poorly soluble drugs, does not require additional toxicology studies, does not change oral dose pharmacokinetics, and ultimately gives researchers another tool to evaluate absolute bioavailability.

  1. Fragments of Citrullinated and MMP-degraded Vimentin and MMP-degraded Type III Collagen Are Novel Serological Biomarkers to Differentiate Crohn's Disease from Ulcerative Colitis

    DEFF Research Database (Denmark)

    Mortensen, Joachim Høg; Godskesen, Line Elbjerg; Jensen, Michael Dam;

    2015-01-01

    BACKGROUND AND AIMS: A hallmark of inflammatory bowel disease [IBD] is chronic inflammation, which leads to excessive extracellular matrix [ECM] remodelling and release of specific protein fragments, called neoepitopes. We speculated that the biomarker profile panel for ulcerative colitis [UC......-degraded vimentin [VICM] were studied with a competitive ELISA assay system in a cohort including 164 subjects [CD n = 72, UC n = 60, and non-IBD controls n = 32] and a validation cohort of 61 subjects [CD n = 46, and UC n = 15]. Receiver operating characteristic curve analysis and logistic regression modelling....... Furthermore, the biomarkers C1M [AUC = 0.81], C3M [AUC = 0.83], VICM [AUC = 0.83], and P1NP [AUC = 0.77] were best to differentiate UC from non-IBD. The best combinations of biomarkers to differentiate CD from UC and UC from non-IBD were VICM, C3M, C4M [AUC = 0.90] and VICM, C3M [AUC = 0.98] respectively...

  2. Impact of area under the concentration-time curve to minimum inhibitory concentration ratio on vancomycin treatment outcomes in methicillin-resistant Staphylococcus aureus bacteraemia.

    Science.gov (United States)

    Song, Kyoung-Ho; Kim, Hong Bin; Kim, Hyung-sook; Lee, Myung Jin; Jung, Younghee; Kim, Gayeon; Hwang, Jeong-Hwan; Kim, Nak-Hyun; Kim, Moonsuk; Kim, Chung-Jong; Choe, Pyoeng Gyun; Chung, Jae-Yong; Park, Wan Beom; Kim, Eu Suk; Park, Kyoung Un; Kim, Nam Joong; Kim, Eui-Chong; Oh, Myoung-don

    2015-12-01

    There have been few clinical studies on the association between the vancomycin 24-h area under the concentration-time curve (AUC24) to minimum inhibitory concentration (MIC) ratio and vancomycin treatment outcomes in methicillin-resistant Staphylococcus aureus (MRSA) infections. To examine this association and to establish a suitable cut-off value for AUC24/MIC, a multicentre prospective observational study was conducted in patients with MRSA bacteraemia. Data were collected on all patients aged ≥18 years with MRSA bacteraemia treated with vancomycin for ≥72 h without dialysis. The MIC was determined by broth microdilution (BMD) and Etest. Treatment failure was defined as (i) 30-day mortality, (ii) persistent bacteraemia (≥7 days) and (iii) recurrence (≤30 days after completion of therapy). AUC24 was estimated by a Bayesian approach based on individual vancomycin concentrations. The AUC24/MIC cut-off value for differentiating treatment success and failure was calculated by Classification and Regression Tree (CART) analysis. In total, 117 patients were enrolled, among which vancomycin treatment failure occurred in 38 (32.5%). In univariate analysis, high vancomycin MIC and low trough levels were unrelated to treatment outcomes. In the CART analysis, low vancomycin AUC24/MIC [vancomycin treatment outcomes in MRSA bacteraemia, and seeking individualised AUC24/MIC ratios above target (>400) may improve treatment outcomes.

  3. Bayesian modeling and inference for diagnostic accuracy and probability of disease based on multiple diagnostic biomarkers with and without a perfect reference standard.

    Science.gov (United States)

    Jafarzadeh, S Reza; Johnson, Wesley O; Gardner, Ian A

    2016-03-15

    The area under the receiver operating characteristic (ROC) curve (AUC) is used as a performance metric for quantitative tests. Although multiple biomarkers may be available for diagnostic or screening purposes, diagnostic accuracy is often assessed individually rather than in combination. In this paper, we consider the interesting problem of combining multiple biomarkers for use in a single diagnostic criterion with the goal of improving the diagnostic accuracy above that of an individual biomarker. The diagnostic criterion created from multiple biomarkers is based on the predictive probability of disease, conditional on given multiple biomarker outcomes. If the computed predictive probability exceeds a specified cutoff, the corresponding subject is allocated as 'diseased'. This defines a standard diagnostic criterion that has its own ROC curve, namely, the combined ROC (cROC). The AUC metric for cROC, namely, the combined AUC (cAUC), is used to compare the predictive criterion based on multiple biomarkers to one based on fewer biomarkers. A multivariate random-effects model is proposed for modeling multiple normally distributed dependent scores. Bayesian methods for estimating ROC curves and corresponding (marginal) AUCs are developed when a perfect reference standard is not available. In addition, cAUCs are computed to compare the accuracy of different combinations of biomarkers for diagnosis. The methods are evaluated using simulations and are applied to data for Johne's disease (paratuberculosis) in cattle.

  4. Study on the relationship between pharmacokinetics and pharmacodynamics for statins in hyperlipidemia model in rats%他汀类药物在高脂血症大鼠体内的PK-PD关系研究

    Institute of Scientific and Technical Information of China (English)

    李静远; 蔡家利; 戴仁科; 谢水林; 邓继锋; 卢沛枫; 李认书; 孙鹤; 刘延淮

    2011-01-01

    AIM: To explore the relationship between exposure level (such as pharmacokinet-ics parameters) and pharmacodynamics for statins in hyperlipidemia model in rats. METHODS; The hyper- lipidemia rat model was established with the method of diet-induced, and the rats were given different does of statins to treat. The pharmacokinetics and pharmacodynamics parameters were determined, and the value of PK/PD were calculated, and their correlations were analyzed. RESULTS: TG-AUC showed a good linear relationship at the range of 0-10. 96 folds, Y=0. 01036X-7. 6445 (γ = 0. 9599), theintermediate data such as CHOL-AUC, LDL-C-AUC, HDL-C-AUC were on the low side, which resulted large deviation, so there was an extremely weak linear correlation in these groups. CONCLUSION: There was a good linear relationship between TG and AUC in the range of AUC (0 - 10.96 folds), it could be efficaciously used to predicted the pharmacodynamics upon the related datas for AUC.%目的:探讨他汀类药物在高脂血症大鼠体内暴露水平(药代动力学参数AUC)与药效之间的关系.方法:建立大鼠高脂血症模型,给予不同剂量的他汀类药物干预治疗,进行药代动力学和药效学测定,计算药代动力学/药效学(PK/PD)值,并进行相关分析.结果:TG-AUC在药代动力学(AUC)变化范围内(0~10.96倍)线性关系良好,Y=0.01036X-7.6445(γ=0.9599).胆固醇(CHOL)-AUC、低密度脂蛋白胆固醇(LDL-C)-AUC、高密度脂蛋白胆固醇(HDL-C)-AUC由于中间数据偏低,与预测样本数据偏差太大,线性关系不明显.结论:TG-AUC在药代动力学(AUC)变化范围内(0~10.96倍)线性关系良好,可以在知道药代动力学的相关数据基础上对药效进行预测.

  5. Bioequivalence studies of two different film-coated tablet formulations of valacyclovir of two different strengths in healthy volunteers.

    Science.gov (United States)

    Neves, Rita; Almeida, Susana; Filipe, Augusto; Spinola, Ana Cristina Franco; Abolfathi, Zohreh; Lévesque, Ann; Ortuño, Jordi; Torns, Alex

    2010-01-01

    These studies were conducted in order to assess the bioequivalence of two film-coated formulations containing 250 mg and 1000 mg of valacyclovir (INN: valaciclovir; CAS 124832-26-4), which is the L-valyl ester and a pro-drug of the antiviral drug acyclovir (INN: aciclovir). In the study with valacyclovir 250 mg, 36 healthy subjects were enrolled in a randomized, single-dose, open-label, 2-way crossover study, with a washout period of 10 days. In the study with valacyclovir 1000 mg, 46 healthy subjects were enrolled in a randomized, single-dose, open-label, 2-way crossover study, with a washout period of 7 days. Plasma samples were collected up to 36 h postdose for both studies. Valacyclovir levels were determined by liquid chromatography with tandem mass detection (ie, the LC/MS/MS method) (lower limit of quantification: 0.50 ng/ mL for valacyclovir and 9.93 ng/mL for acyclovir for the 250 mg study and 1.00 ng/mL for valacyclovir and 20.00 ng/ mL for acyclovir for the 1000 mg study). Pharmacokinetic parameters used for bioequivalence assessment were the area under the concentration-time curve from time zero to time of last non-zero concentration (AUC(0-t)) and from time zero to infinity (AUC(0-inf) and maximum observed concentration (C(max)). These parameters were determined from the valacyclovir concentration data using non-compartmental analysis. In the tained by analysis of variance (ANOVA) for valacyclovir were 107.54-124.26% for C(max), 95.45-103.46% for AUC(0-Inf) and 95.53-103.63% for AUC(0-t) whereas for acyclovir the 90% confidence intervals obtained were 103.19-117.02% for C(max), 99.61-106.92% for AUC(0-Inf) and 99.58-106.94% for AUC(0-t). In the study with valacyclovir 1000 mg formulations, the 90% confidence intervals obtained for valacyclovir were 93.20-107.35% for C(max), 90.87-96.27% for AUC(0-inf) and 90.87-96.27% for AUC(0-t) whereas for acyclovir the 90% CIs obtained were 95.98-104.94% for C(max), 97.13-103.94% for AUC(0-inf) and 97

  6. Pharmacokinetic/pharmacodynamic analysis of teicoplanin in patients with MRSA infections

    Directory of Open Access Journals (Sweden)

    Matsumoto K

    2016-03-01

    Full Text Available Kazuaki Matsumoto,1 Erika Watanabe,1 Naoko Kanazawa,1 Tomohide Fukamizu,1 Akari Shigemi,1 Yuta Yokoyama,1,2 Kazuro Ikawa,2 Norifumi Morikawa,2 Yasuo Takeda1 1Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, 2Department of Clinical Pharmacotherapy, Hiroshima University, Hiroshima, Japan Background: Teicoplanin is a glycopeptide antibiotic that has been used to treat serious, invasive infections caused by Gram-positive bacteria. The area under the drug concentration–time curve (AUC/minimum inhibitory concentration (MIC was identified as a pharmacokinetic–pharmacodynamic (PK–PD parameter of glycopeptide antibiotics that correlated with bacteriological responses and clinical outcomes. Although optimized dosing regimens based on PK–PD are needed, a PK–PD analysis of teicoplanin against methicillin-resistant Staphylococcus aureus (MRSA infections has not yet been performed. Thus, this study examined patients with MRSA infections, who were administered with teicoplanin in order to determine the target AUC/MIC ratio. Methods: This study retrospectively assessed data obtained as part of our routine therapeutic drug monitoring (TDM of teicoplanin therapy in 46 patients with MRSA infections at Kagoshima University Hospital. Serum concentrations of teicoplanin were determined using a fluorescence polarization immunoassay system and used for a Bayesian PK estimation to estimate AUC for 24 hours (AUC24. The MIC value for teicoplanin was determined using a standardized agar dilution method. The effects of teicoplanin were evaluated in terms of bacteriological responses by a quantitative assessment. Results: The estimated AUC24/MIC ratios with and without bacteriological responses were 926.6±425.2 µg·h/mL (n=34 and 642.2±193.9 µg·h/mL, respectively (n=12; P<0.05. On the basis of a logistic regression analysis, AUC24/MIC ratios of 500 µg·h/mL, 700 µg·h/mL, and

  7. Using Symptom and Interference Questionnaires to Identify Recovery Among Children With Anxiety Disorders.

    Science.gov (United States)

    Evans, Rachel; Thirlwall, Kerstin; Cooper, Peter; Creswell, Cathy

    2016-08-15

    Questionnaires are widely used in routine clinical practice to assess treatment outcomes for children with anxiety disorders. This study was conducted to determine whether 2 widely used child and parent report questionnaires of child anxiety symptoms and interference (Spence Child Anxiety Scale [SCAS-C/P] and Child Anxiety Impact Scale [CAIS-C/P]) accurately identify recovery from common child anxiety disorder diagnoses as measured by a 'gold-standard' diagnostic interview. Three hundred thirty-seven children (7-12 years, 51% female) and their parents completed the ADIS-IV-C/P diagnostic interview and questionnaire measures (SCAS-C/P and CAIS-C/P) before (Time 1) and after (Time 2) treatment or wait-list. Time 2 parent reported interference (CAIS-P) was found to be a good predictor of absence of any diagnoses (area under the curve [AUC] = .81). In terms of specific diagnoses, Time 2 SCAS-C/P separation anxiety subscale (SCAS-C/P-SA) identified recovery from separation anxiety disorder well (SCAS-C-SA, AUC = .80; SCAS-P-SA, AUC = .82) as did the CAIS-P (AUC = .79). The CAIS-P also successfully identified recovery from social phobia (AUC = .78) and generalized anxiety disorder (AUC = .76). These AUC values were supported by moderate to good sensitivity (.70-.78) and specificity (.70-.73) at the best identified cut-off scores. None of the measures successfully identified recovery from specific phobia. The results suggest that questionnaire measures, particularly the CAIS-P, can be used to identify whether children have recovered from common anxiety disorders, with the exception of specific phobias. Cut-off scores have been identified that can guide the use of routine outcome measures in clinical practice. (PsycINFO Database Record

  8. MR-sequences for prostate cancer diagnostics: validation based on the PI-RADS scoring system and targeted MR-guided in-bore biopsy

    Energy Technology Data Exchange (ETDEWEB)

    Schimmoeller, Lars; Quentin, Michael; Buchbender, Christian; Antoch, Gerald; Blondin, Dirk [University Dusseldorf, Medical Faculty, Department of Diagnostic and Interventional Radiology, Dusseldorf (Germany); Arsov, Christian; Hiester, Andreas; Rabenalt, Robert; Albers, Peter [University Dusseldorf, Medical Faculty, Department of Urology, Dusseldorf (Germany)

    2014-10-15

    This study evaluated the accuracy of MR sequences [T2-, diffusion-weighted, and dynamic contrast-enhanced (T2WI, DWI, and DCE) imaging] at 3T, based on the European Society of Urogenital Radiology (ESUR) scoring system [Prostate Imaging Reporting and Data System (PI-RADS)] using MR-guided in-bore prostate biopsies as reference standard. In 235 consecutive patients [aged 65.7 ± 7.9 years; median prostate-specific antigen (PSA) 8 ng/ml] with multiparametric prostate MRI (mp-MRI), 566 lesions were scored according to PI-RADS. Histology of all lesions was obtained by targeted MR-guided in-bore biopsy. In 200 lesions, biopsy revealed prostate cancer (PCa). The area under the curve (AUC) for cancer detection was 0.70 (T2WI), 0.80 (DWI), and 0.74 (DCE). A combination of T2WI + DWI, T2WI + DCE, and DWI + DCE achieved an AUC of 0.81, 0.78, and 0.79. A summed PI-RADS score of T2WI + DWI + DCE achieved an AUC of 0.81. For higher grade PCa (primary Gleason pattern ≥ 4), the AUC was 0.85 for T2WI + DWI, 0.84 for T2WI + DCE, 0.86 for DWI + DCE, and 0.87 for T2WI + DWI + DCE. The AUC for T2WI + DWI + DCE for transitional-zone PCa was 0.73, and for the peripheral zone 0.88. Regarding higher-grade PCa, AUC for transitional-zone PCa was 0.88, and for peripheral zone 0.96. The combination of T2WI + DWI + DCE achieved the highest test accuracy, especially in patients with higher-grade PCa. The use of ≤2 MR sequences led to lower AUC in higher-grade and peripheral-zone cancers. (orig.)

  9. Two-compartment model of radioimmunotherapy delivered through cerebrospinal fluid

    Energy Technology Data Exchange (ETDEWEB)

    He, Ping [Johns Hopkins University, Department of Biomedical Engineering, Baltimore, MD (United States); Kramer, Kim; Cheung, Nai-Kong V. [Memorial Sloan-Kettering Cancer Center, Department of Pediatrics, New York, NY (United States); Smith-Jones, Peter; Larson, Steven M. [Memorial Sloan-Kettering Cancer Center, Department of Radiology, New York, NY (United States); Zanzonico, Pat; Humm, John [Memorial Sloan-Kettering Cancer Center, Department of Medical Physics, New York, NY (United States)

    2011-02-15

    Radioimmunotherapy (RIT) using {sup 131}I-3F8 injected into cerebrospinal fluid (CSF) was a safe modality for the treatment of leptomeningeal metastases (JCO, 25:5465, 2007). A single-compartment pharmacokinetic model described previously (JNM 50:1324, 2009) showed good fitting to the CSF radioactivity data obtained from patients. We now describe a two-compartment model to account for the ventricular reservoir of {sup 131}I-3F8 and to identify limiting factors that may impact therapeutic ratio. Each parameter was examined for its effects on (1) the area under the radioactivity concentration curve of the bound antibody (AUC[C{sub IAR}]), (2) that of the unbound antibody AUC[C{sub IA}], and (3) their therapeutic ratio (AUC[C{sub IAR}]/AUC[C{sub IA}]). Data fitting showed that CSF kBq/ml data fitted well using the two-compartment model (R = 0.95 {+-} 0.03). Correlations were substantially better when compared to the one-compartment model (R = 0.92 {+-} 0.11 versus 0.77 {+-} 0.21, p = 0.005). In addition, we made the following new predictions: (1) Increasing immunoreactivity of {sup 131}I-3F8 from 10% to 90% increased both (AUC[C{sub IAR}]) and therapeutic ratio (AUC[C{sub IAR}]/AUC[C{sub IA}]) by 7.4 fold, (2) When extrapolated to the clinical setting, the model predicted that if {sup 131}I-3F8 could be split into 4 doses of 1.4 mg each and given at {>=}24 hours apart, an antibody affinity of K{sub D} of 4 x 10{sup -9} at 50% immunoreactivity were adequate in order to deliver {>=}100 Gy to tumor cells while keeping normal CSF exposure to <10 Gy. This model predicted that immunoreactivity, affinity and optimal scheduling of antibody injections were crucial in improving therapeutic index. (orig.)

  10. Disease Gene Prioritization Using Network and Feature

    Science.gov (United States)

    Agam, Gady; Balasubramanian, Sandhya; Xu, Jinbo; Gilliam, T. Conrad; Maltsev, Natalia; Börnigen, Daniela

    2015-01-01

    Abstract Identifying high-confidence candidate genes that are causative for disease phenotypes, from the large lists of variations produced by high-throughput genomics, can be both time-consuming and costly. The development of novel computational approaches, utilizing existing biological knowledge for the prioritization of such candidate genes, can improve the efficiency and accuracy of the biomedical data analysis. It can also reduce the cost of such studies by avoiding experimental validations of irrelevant candidates. In this study, we address this challenge by proposing a novel gene prioritization approach that ranks promising candidate genes that are likely to be involved in a disease or phenotype under study. This algorithm is based on the modified conditional random field (CRF) model that simultaneously makes use of both gene annotations and gene interactions, while preserving their original representation. We validated our approach on two independent disease benchmark studies by ranking candidate genes using network and feature information. Our results showed both high area under the curve (AUC) value (0.86), and more importantly high partial AUC (pAUC) value (0.1296), and revealed higher accuracy and precision at the top predictions as compared with other well-performed gene prioritization tools, such as Endeavour (AUC-0.82, pAUC-0.083) and PINTA (AUC-0.76, pAUC-0.066). We were able to detect more target genes (9/18/19/27) on top positions (1/5/10/20) compared to Endeavour (3/11/14/23) and PINTA (6/10/13/18). To demonstrate its usability, we applied our method to a case study for the prediction of molecular mechanisms contributing to intellectual disability and autism. Our approach was able to correctly recover genes related to both disorders and provide suggestions for possible additional candidates based on their rankings and functional annotations. PMID:25844670

  11. Pharmacokinetic evaluation of novel oral fluorouracil antitumor drug S-1 in Chinese cancer patients

    Institute of Scientific and Technical Information of China (English)

    Zhi-xiang ZHUANG; Hong ZHU; Ji WANG; Min-gao ZHU; Hui WANG; Wang-yang PU; Hua-hui BIAN

    2013-01-01

    Aim:S-1 is an oral anticancer fluoropyrimidine formulation consisting of tegafur,5-chloro-2,4-dihydroxypyridine and potassium oxonate.The aim of this study was to evaluate the pharmacokinetics and bioequivalence of a newly developed generic formulation of S-1 in Chinese cancer patients in comparison with the branded reference formulation of S-1.Methods:A single-dose,randomized-sequence,open-label,two-way self-crossover study was conducted in 30 Chinese cancer patients.The subjects alternatively received the two formulations (40 mg/m2,po) with a 7-d interval.Plasma concentrations of FT,CDHP,Oxo,and 5-Fu were determined using LC-MS/MS.Pharmacokinetic parameters,including C Tmax,t1/2,AUC0-t,and AUC0-∞ were determined using non-compartmental models with DAS2.0 software.Bioequivalence of the two formulations were to be evaluated according to 90% Cls for the log-transformed ratios of AUC and Cmax of S-1.Adverse events were evaluated through monitoring the symptom,physical and laboratory examinations,ECGs and subject interviews.Results:The mean values of Cmax,AUC0-t,and AUC0-∞ of FT,5-Fu,CDHP,and Oxo for the two formulations had no significant differences.The 90% Cls for natural log-transformed ratios of C AUC0-t,and AUC0-∞ were within the predetermined bioequivalence acceptance limits.A total of 11 mild adverse events,including fatigue,nausea and vomiting,anorexia,diarrhea and myelosuppression,were observed,and no serious and special adverse events were found.Conclusion:The newly developed generic formulation and reference formulation of S-1 have similar pharmacokinetics with one dose (40 mg/m2) in Chinese cancer patients.Both the formulations of S-1 are well tolerated.

  12. Evaluation of pharmacokinetic differences of acetaminophen in pseudo germ-free rats.

    Science.gov (United States)

    Lee, Soo Hyun; An, Ji Hye; Lee, Hwa Jeong; Jung, Byung Hwa

    2012-09-01

    To evaluate the metabolic interaction between host and gut microflora on drug metabolism, pseudo germ-free rats were prepared with an antibiotics cocktail to change their gut conditions. The usefulness of the pseudo germ-free model was evaluated for observing the DMPK of acetaminophen (APAP). Pseudo germ-free rats were prepared by orally administering antibiotic cocktails consisting of bacitracin, streptomycin and neomycin, and then APAP was orally administered to control and pseudo germ-free rats. The plasma concentration of APAP and its six metabolites were quantified using a validated LC-MS/MS method. A non-compartment model estimated the pharmacokinetic parameters of APAP and its metabolites, and the ratios of the area under curve (AUC; AUC(metabolite) /AUC(APAP) ) were also observed to evaluate the change of APAP metabolism. The AUCs of APAP and APAP-Glth (glutathione) were higher and the AUC(APAP-Sul) /AUC(APAP) (metabolic efficiency of sulfate conjugation) was lower in pseudo germ-free rats than those in the control rats. The decrease in metabolic efficiency of sulphate conjugation could result from the reduction of the sulphate supply, causing an increase of the AUC of APAP and APAP-Glth. The activities of gut microflora can affect the state of hepatic sulphate for drug conjugation, indirectly leading to characteristic APAP metabolism. These results indicate that gut microflora may play an important role in the pharmacokinetics and metabolism of APAP. Thus, the metabolic interaction between host and gut microflora should be considered upon drug administration and pseudo germ-free rats prepared in the present study can be competent for investigating the metabolic interaction between host and gut microflora on drug metabolism.

  13. New red blood cell and reticulocyte parameters and reference values for healthy individuals and in chronic kidney disease

    Directory of Open Access Journals (Sweden)

    Patrícia S. Scherer

    2015-04-01

    Full Text Available Introduction: The importance of local references values has been well described in the literature; this is because the characteristics of the population may influence the laboratory tests. Objective: To establish the reference range for traditional and extended red blood cell parameters and reticulocyte indices in order to investigate its application in patients with chronic kidney disease (CKD. Materials and methods: 249 blood donors (125 males and 124 females were selected to establish the reference values. The hemodialysis sample consisted of 62 patients with terminal CKD (48 male and 14 female. All analyzes were performed using the Sysmex XE-5000 automated hematology analyzer. Results: Differences between reference values was observed in relation to gender: red blood cells (RBC, hemoglobin (HGB, hematocrit (HCT, mean corpuscular hemoglobin concentration (MCHC, percentage of hyperchromic red blood cells (%HYPER, percentage of microcytosis (%MICRO, percentage of macrocytosis (%MACRO, absolute reticulocyte count (RET, reticulocyte hemoglobin content (RET-He, immature reticulocyte fraction (IFR, low fluorescence reticulocytes (LFR, medium fluorescence reticulocytes (MFR, and high fluorescence reticulocytes (HFR. Individuals with CKD presented RBC, HGB, HCT, MCHC, red cell distribution width expressed as coefficient of variation (RDW-CV, percentage of hypochromic red blood cells (%HYPO, percentage of reticulocytes (RET%, RET (female group, IFR, LFR, MFR, and HFR results compatible with the anemic state, which can be observed in 91.8% of patients. All studied parameters were in the area under the curve (AUC > 0.4. In male group, %HYPO (AUC: 0.806 and IFR (AUC: 0.762 presented higher AUC values, while female group presented %HYPO (AUC: 0.806, %HYPER (AUC: 0.815, and IFR (AUC: 0.660. Conclusion: The medical advancement, the development of new techniques and hematological parameters have revealed important information about functional integrity of

  14. Ability of Optic Nerve Head Examination, Heidelberg Retina Tomograph’s Moorfield’s Regression Analysis, and Glaucoma Probability Score

    Directory of Open Access Journals (Sweden)

    F. Saenz-Frances

    2015-01-01

    Full Text Available Purpose. To study whether a corneal thickness segmentation model, consisting in a central circular zone of 1 mm radius centered at the corneal apex (zone I and five concentric rings of 1 mm width (moving outwards: zones II to VI, could boost the diagnostic accuracy of Heidelberg Retina Tomograph’s (HRT’s MRA and GPS. Material and Methods. Cross-sectional study. 121 healthy volunteers and 125 patients with primary open-angle glaucoma. Six binary multivariate logistic regression models were constructed (MOD-A1, MOD-A2, MOD-B1, MOD-B2, MOD-C1, and MOD-C2. The dependent variable was the presence of glaucoma. In MOD-A1, the predictor was the result (presence of glaucoma of the analysis of the stereophotography of the optic nerve head (ONH. In MOD-B1 and MOD-C1, the predictor was the result of the MRA and GPS, respectively. In MOD-B2 and MOD-C2, the predictors were the same along with corneal variables: central, overall, and zones I to VI thicknesses. This scheme was reproduced for model MOD-A2 (stereophotography along with corneal variables. Models were compared using the area under the receiver operator characteristic curve (AUC. Results. MOD-A1-AUC: 0.771; MOD-A2-AUC: 0.88; MOD-B1-AUC: 0.736; MOD-B2-AUC: 0.845; MOD-C1-AUC: 0.712; MOD-C2-AUC: 0.838. Conclusion. Corneal thickness variables enhance ONH assessment and HRT’s MRA and GPS diagnostic capacity.

  15. Corneal Segmentation Analysis Increases Glaucoma Diagnostic Ability of Optic Nerve Head Examination, Heidelberg Retina Tomograph's Moorfield's Regression Analysis, and Glaucoma Probability Score.

    Science.gov (United States)

    Saenz-Frances, F; Jañez, L; Berrozpe-Villabona, C; Borrego-Sanz, L; Morales-Fernández, L; Acebal-Montero, A; Mendez-Hernandez, C D; Martinez-de-la-Casa, J M; Santos-Bueso, E; Garcia-Sanchez, J; Garcia-Feijoo, J

    2015-01-01

    Purpose. To study whether a corneal thickness segmentation model, consisting in a central circular zone of 1 mm radius centered at the corneal apex (zone I) and five concentric rings of 1 mm width (moving outwards: zones II to VI), could boost the diagnostic accuracy of Heidelberg Retina Tomograph's (HRT's) MRA and GPS. Material and Methods. Cross-sectional study. 121 healthy volunteers and 125 patients with primary open-angle glaucoma. Six binary multivariate logistic regression models were constructed (MOD-A1, MOD-A2, MOD-B1, MOD-B2, MOD-C1, and MOD-C2). The dependent variable was the presence of glaucoma. In MOD-A1, the predictor was the result (presence of glaucoma) of the analysis of the stereophotography of the optic nerve head (ONH). In MOD-B1 and MOD-C1, the predictor was the result of the MRA and GPS, respectively. In MOD-B2 and MOD-C2, the predictors were the same along with corneal variables: central, overall, and zones I to VI thicknesses. This scheme was reproduced for model MOD-A2 (stereophotography along with corneal variables). Models were compared using the area under the receiver operator characteristic curve (AUC). Results. MOD-A1-AUC: 0.771; MOD-A2-AUC: 0.88; MOD-B1-AUC: 0.736; MOD-B2-AUC: 0.845; MOD-C1-AUC: 0.712; MOD-C2-AUC: 0.838. Conclusion. Corneal thickness variables enhance ONH assessment and HRT's MRA and GPS diagnostic capacity.

  16. Sputum interleukin-6, tumor necrosis factor-α and Salivary cortisol as new biomarkers of depression in lung cancer patients.

    Science.gov (United States)

    Du, Yi-jie; Zhang, Hong-ying; Li, Bei; Wu, Xiao; Lv, Yu-bao; Jin, Hua-liang; Cao, Yu-xue; Sun, Jing; Luo, Qing-li; Gong, Wei-yi; Liu, Bao-jun; Wu, Jin-feng; Shi, Shen-xun; Dong, Jing-cheng

    2013-12-02

    Depression is common among lung cancer patients. Increasing evidence has suggested that hypothalamic-pituitary-adrenal (HPA) axis and pro-inflammatory cytokines may play a key role in the pathophysiology of depression as well as cancer. This pilot study investigated the efficacy of sputum interleukin (IL)-6, tumor necrosis factor (TNF)-α and salivary cortisol as new markers to support the diagnosis of depression in lung cancer patients. The diurnal rhythms of sputum IL-6, sputum TNF-α and salivary cortisol were measured in lung cancer patients with and without depression as well as depressed controls and healthy controls. The area under the diurnal variation curves (AUC) over the 24h time course and relative diurnal variation (VAR) were calculated. Receiver operating characteristic (ROC) analysis was performed. Patients with co-morbid depression and lung cancer showed highest level of sputum IL-6 AUC, sputum TNF-α AUC and lowest level of cortisol VAR (Pcortisol VAR demonstrated an optimal cutoff point at 77.8% (AUC=0.94; 95% CI, 0.85-0.98), which is associated with a sensitivity of 82.1% and a specificity of 96.0%. Sputum IL-6 AUC demonstrated a sensitivity of 74.4% and a specificity of 92.0% (AUC=0.81; 95% CI, 0.69-0.90). These findings suggested that higher 24h overall levels of sputum IL-6, TNF-α and flattened diurnal salivary cortisol slopes were associated with depression in lung cancer patients. Sputum IL-6 AUC and salivary cortisol VAR performed best as biomarkers in the diagnosis of depression in lung cancer patients.

  17. The predictive value of the ratio of neck circumference to thyromental distance in comparison with four predictive tests for difficult laryngoscopy in obstetric patients scheduled for caesarean delivery

    Directory of Open Access Journals (Sweden)

    Anahita Hirmanpour

    2014-01-01

    Full Text Available Background: Preoperative assessment of anatomical landmarks andclinical factors help detect potentially difficult laryngoscopies. The aim of the present study was to compare the ability to predict difficult visualization of the larynx from thefollowing preoperative airway predictive indices, in isolation and combination: Neck circumference to thyromental distance (NC/TMD, neck circumference (NC, modified Mallampatitest (MMT, the ratio of height to thyromental distance (RHTMD, and the upper-lip-bite test (ULBT. Materials and Methods: We collected data on657 consecutive patients scheduled for elective caesarean delivery under general anesthesia requiring endotracheal intubation and then evaluated all five factors before caesarean. An experienced anesthesiologist, not informed of the recorded preoperative airway evaluation, performed the laryngoscopy and grading (as per Cormack and Lehane′s classification. Sensitivity, specificity, and positive and negative predictive values for each airway predictor in isolation and in combination were determined. Results: Difficult laryngoscopy (Grade 3 or 4 occurred in 53 (8.06% patients. There were significant differences in thyromental distance (TMD, RHTMD, NC, and NC/TMD between difficult visualization of larynx and easy visualization of larynx patients (P < 0.05.The main end-point area under curve (AUC of the receiver-operating characteristic (ROC was lower for MMT (AUC = 0.497; 95% Confidence Interval = CI,0.045-0.536 and ULBT (AUC = 0.500, 95% CI, 0.461-0.539 compared to RHTMD, NC, TMD, and NC/TMD score ([AUC = 0.627, 95% CI, 0.589-0.664], [AUC = 0.691; 95% CI, 0.654-0.726], [AUC = 0.606; 95% CI, 0.567-0.643], [AUC = 0.689;95% CI, 0.625-0.724], respectively, and the differences of six ROC curves were statistically significant (P < 0.05. Conclusion: The NC/TM Discomparable with NC, RHTMD, and ULBT for the prediction of difficult laryngoscopy in caes are an delivery.

  18. Effect of intertrochanteric osteotomy on the proximal femur of rabbits: assessment with power Doppler sonography and scintigraphy

    Energy Technology Data Exchange (ETDEWEB)

    Doria, Andrea S. [University of Toronto (Canada). Hospital for Sick Children. Dept. of Diagnostic Imaging; Cunha, Fabiano G.; Modena; Marcelo; Godoy Junior, Rui de; Bolliger Neto, Raul; Guarniero, Roberto [Universidade de Sao Paulo (USP), SP (Brazil). Hospital das Clinicas. Dept. of Cirurgia Ortopedica]. E-mail: andrea.doria@sickkids.ca; Rodrigues, Consuelo Junqueira [Universidade de Sao Paulo (USP), SP (Brazil). Hospital das Clinicas. Dept. de Patologia; Garcez, Alexandre Teles; Melo, Ivani Bortoleti; Buchpiguel, Carlos; Molnar, Laszlo J. [Universidade de Sao Paulo (USP), SP (Brazil). Hospital das Clinicas. Dept. de Medicina Nuclear

    2007-07-01

    Objective: In bone injury, repair results in local increased vascularity and bone marrow remodeling. Characterizing the vascular and metabolic imaging patterns of the proximal femur following an intertrochanteric osteotomy may help clinicians decide proper management of the patient. Our objective was to measure Doppler sonography and scintigraphy interval changes in the proximal femur following intertrochanteric osteotomy and compare imaging and histomorphometric measurements in the late post-operative stage (6 weeks after surgery) in a rabbit model of bone injury. Materials and methods: Both hips of 12 adult rabbits were imaged with power Doppler sonography and scintigraphy prior to and after (7 days and 6 weeks) unilateral osteotomy. Accuracy of the imaging methods was evaluated using hip operative status and histomorphometric results (vascular fractional area and number of vessels per area unit) as reference standard measures. Results: A significant difference in the mean number of pixels was noted between operated and non-operated femura in late post-operative power Doppler examinations (P=0.049). Although without reaching statistical significance, the AUC of Doppler measurements (AUC=0.99) was numerically greater than the AUC of scintigraphy measurements (AUC=0.857{+-}0.099) (P=0.15) in differentiating proximal femura with regard to their fractional vascular areas in the late post-operative stage. In contrast, scintigraphy tended to perform better (AUC=0.984{+-}0.022) than Doppler ultrasound (AUC=0.746{+-}0.131) to demonstrate the vascularity intensity per area unit (P=0.07) in the late stage. Conclusion: Our results warrant further investigation to determine the value of different imaging modalities for assessment of pathologic changes following hip surgery. Power Doppler sonography demonstrated larger AUCs (representing higher accuracy) for the discrimination of vascular fractional areas and scintigraphy, for discrimination of the number of vessels per area

  19. NID2 and HOXA9 promoter hypermethylation as biomarkers for prevention and early detection in Oral Cavity Squamous Cell Carcinoma tissues and saliva

    Science.gov (United States)

    Guerrero-Preston, R; Soudry, E; Acero, J; Orera, M; Moreno-López, L; Macía-Colón, Germán; Jaffe, A; Berdasco, M; Ili-Gangas, C; Brebi-Mieville, P; Fu, Y; Engstrom, C; Irizarry, R; Esteller, M; Westra, W; Koch, W; Califano, J; Sidransky, D

    2011-01-01

    Differentially methylated oral squamous cell carcinoma (OSCC) biomarkers, identified in-vitro and validated in well-characterized surgical specimens, have shown poor clinical correlation in cohorts with different risk profiles. To overcome this lack of relevance we used the HumanMethylation27 BeadChip, publicly available methylation and expression array data, and Quantitative Methylation Specific PCR to uncover differential methylation in OSCC clinical samples with heterogeneous risk profiles. A two stage-design consisting of Discovery and Prevalence screens was used to identify differential promoter methylation and deregulated pathways in patients diagnosed with OSCC and head and neck squamous cell carcinoma. Promoter methylation of KIF1A (κ = 0.64), HOXA9 (κ = 0.60), NID2 (κ = 0.60), and EDNRB (κ = 0.60) had a moderate to substantial agreement with clinical diagnosis in the Discovery screen. HOXA9 had 68% sensitivity, 100% specificity and a 0.81 AUC. NID2 had 71% sensitivity, 100% specificity and a 0.79 AUC. In the Prevalence screen HOXA9 (κ = 0.82) and NID2 (κ = 0.80) had an almost perfect agreement with histologic diagnosis. HOXA9 had 85% sensitivity, 97% specificity and a 0.95 AUC. NID2 had 87% sensitivity, 95% specificity and a 0.91 AUC. A HOXA9 and NID2 gene panel had 94% sensitivity, 97% specificity and a 0.97 AUC. In saliva from OSCC cases and controls HOXA9 had 75% sensitivity, 53% specificity and a 0.75 AUC. NID2 had 87% sensitivity, 21% specificity and a 0.73 AUC. This Phase I Biomarker Development Trial identified a panel of differentially methylated genes in normal and OSCC clinical samples from patients with heterogeneous risk profiles. This panel may be useful for early detection and cancer prevention studies. PMID:21558411

  20. Pharmacokinetics and bioequivalence of ranitidine and bismuth derived from two compound preparations

    Institute of Scientific and Technical Information of China (English)

    Quan Zhou; Zou-Rong Ruan; Hong Yuan; Bo Jiang; Dong-Hang Xu

    2006-01-01

    AIM: To evaluate the bioequivalence of ranitidine and bismuth derived from two compound preparations.METHODS: The bioavailability was measured in 20healthy male Chinese volunteers following a single oral dose (equivalent to 200 mg of ranitidine and 220 mg of bismuth) of the test or reference products in the fasting state. Then blood samples were collected for 24 h.Plasma concentrations of ranitidine and bismuth were analyzed by high-performance liquid chromatography and inductively coupled plasma-mass spectrometry (ICPMS), respectively. The non-compartmental method was used for pharmacokinetic analysis. Log-transformed Cmax,AUC(0-t) and AUC(0-∞) were tested for bioequivalence using ANOVA and Schuirmann two-one sided t-test. Tmax was analyzed by Wilcoxon's test.RESULTS: Various pharmacokinetic parameters of ranitidine derived from the two compound preparations,including Cmax, AUC(0-t), AUC(0-∞), Tmax and T1/2, were nearly consistent with previous observations. These parameters derived from test and reference drug were as follows: Cmax(0.67 ± 0.21 vs 0.68 ± 0.22mg/L), AUC(0-t)(3.1 ± 0.6 vs 3.0 ± 0.7 mg/L per hour),AUC(0-∞)(3.3 ± 0.6 vs 3.2 ± 0.8 mg/L per hour),Tmax (2.3 ± 0.9 vs 2.1 ± 0.9 h) and T1/2 (2.8 ± 0.3 vs 3.1± 0.4 h). In addition, double-peak absorption profiles of ranitidine were found in some Chinese volunteers.For bismuth, those parameters derived from test and reference drug were as follows: Cmax (11.80 ± 7.36 vs 11.40 ± 6.55 μg/L),AUC(0-t) (46.65 ± 16.97 vs 47.03 ±21.49 μg/L per hour), Tmax (0.50 ± 0.20 vs 0.50 ± 0.20 h)and T1/2 (10.2 ± 2.3 vs 13.0 ± 6.9 h). Ninety percent of confidence intervals for the test/reference ratio of Cmax,AUC(0-t) and AUC(0-∞) derived from both ranitidine and bismuth were found within the bioequivalence acceptable range of 80%-125%. No significant difference was found in Tmax derived from both ranitidine and bismuth.CONCLUSION: The two compound preparations are bioequivalent and may be prescribed

  1. Selective CNS Uptake of the GCP-II Inhibitor 2-PMPA following Intranasal Administration.

    Directory of Open Access Journals (Sweden)

    Rana Rais

    Full Text Available Glutamate carboxypeptidase II (GCP-II is a brain metallopeptidase that hydrolyzes the abundant neuropeptide N-acetyl-aspartyl-glutamate (NAAG to NAA and glutamate. Small molecule GCP-II inhibitors increase brain NAAG, which activates mGluR3, decreases glutamate, and provide therapeutic utility in a variety of preclinical models of neurodegenerative diseases wherein excess glutamate is presumed pathogenic. Unfortunately no GCP-II inhibitor has advanced clinically, largely due to their highly polar nature resulting in insufficient oral bioavailability and limited brain penetration. Herein we report a non-invasive route for delivery of GCP-II inhibitors to the brain via intranasal (i.n. administration. Three structurally distinct classes of GCP-II inhibitors were evaluated including DCMC (urea-based, 2-MPPA (thiol-based and 2-PMPA (phosphonate-based. While all showed some brain penetration following i.n. administration, 2-PMPA exhibited the highest levels and was chosen for further evaluation. Compared to intraperitoneal (i.p. administration, equivalent doses of i.n. administered 2-PMPA resulted in similar plasma exposures (AUC0-t, i.n./AUC0-t, i.p. = 1.0 but dramatically enhanced brain exposures in the olfactory bulb (AUC0-t, i.n./AUC0-t, i.p. = 67, cortex (AUC0-t, i.n./AUC0-t, i.p. = 46 and cerebellum (AUC0-t, i.n./AUC0-t, i.p. = 6.3. Following i.n. administration, the brain tissue to plasma ratio based on AUC0-t in the olfactory bulb, cortex, and cerebellum were 1.49, 0.71 and 0.10, respectively, compared to an i.p. brain tissue to plasma ratio of less than 0.02 in all areas. Furthermore, i.n. administration of 2-PMPA resulted in complete inhibition of brain GCP-II enzymatic activity ex-vivo confirming target engagement. Lastly, because the rodent nasal system is not similar to humans, we evaluated i.n. 2-PMPA also in a non-human primate. We report that i.n. 2-PMPA provides selective brain delivery with micromolar concentrations. These studies

  2. Pharmacokinetics/Pharmacodynamics of Peptide Deformylase Inhibitor GSK1322322 against Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus in Rodent Models of Infection.

    Science.gov (United States)

    Hoover, Jennifer; Lewandowski, Thomas; Straub, Robert J; Novick, Steven J; DeMarsh, Peter; Aubart, Kelly; Rittenhouse, Stephen; Zalacain, Magdalena

    2015-10-19

    GSK1322322 is a novel inhibitor of peptide deformylase (PDF) with good in vitro activity against bacteria associated with community-acquired pneumonia and skin infections. We have characterized the in vivo pharmacodynamics (PD) of GSK1322322 in immunocompetent animal models of infection with Streptococcus pneumoniae and Haemophilus influenzae (mouse lung model) and with Staphylococcus aureus (rat abscess model) and determined the pharmacokinetic (PK)/PD index that best correlates with efficacy and its magnitude. Oral PK studies with both models showed slightly higher-than-dose-proportional exposure, with 3-fold increases in area under the concentration-time curve (AUC) with doubling doses. GSK1322322 exhibited dose-dependent in vivo efficacy against multiple isolates of S. pneumoniae, H. influenzae, and S. aureus. Dose fractionation studies with two S. pneumoniae and S. aureus isolates showed that therapeutic outcome correlated best with the free AUC/MIC (fAUC/MIC) index in S. pneumoniae (R(2), 0.83), whereas fAUC/MIC and free maximum drug concentration (fCmax)/MIC were the best efficacy predictors for S. aureus (R(2), 0.9 and 0.91, respectively). Median daily fAUC/MIC values required for stasis and for a 1-log10 reduction in bacterial burden were 8.1 and 14.4 for 11 S. pneumoniae isolates (R(2), 0.62) and 7.2 and 13.0 for five H. influenzae isolates (R(2), 0.93). The data showed that for eight S. aureus isolates, fAUC correlated better with efficacy than fAUC/MIC (R(2), 0.91 and 0.76, respectively), as efficacious AUCs were similar for all isolates, independent of their GSK1322322 MIC (range, 0.5 to 4 μg/ml). Median fAUCs of 2.1 and 6.3 μg · h/ml were associated with stasis and 1-log10 reductions, respectively, for S. aureus.

  3. Is saliva suitable as a biological fluid in relative bioavailability studies? Analysis of its performance in a 4 x 2 replicate crossover design.

    Science.gov (United States)

    Ruiz, M Esperanza; Fagiolino, Pietro; de Buschiazzo, Perla M; Volonté, M Guillermina

    2011-12-01

    The aim of the present study was to evaluate the suitability of saliva as a biological fluid in relative bioavailability (RBA) studies, with the focus on the statistical design and data variability. A randomized, open-label, four periods and two sequences (4 × 2) crossover RBA study in saliva of two phenytoin (PHT) 100 mg immediate-release capsules was performed. PHT is a narrow therapeutic index drug that has been widely used for epilepsy treatment for many years. Published information regarding its bioavailability is available, but plasma assessed. This study was designed and performed using saliva as the biological fluid and the simplest conditions that produce coherent results with previously published plasma studies. Pharmacokinetic parameters (C (max), T (max), AUC(0-t ), AUC(0-inf), C (max)/AUC(0-t ), K (e), and t (1/2)) for each volunteer at each period were calculated. Four different BE calculations were performed: individual bioequivalence, by the method of moments, and three average bioequivalence with data averaged over the two administrations and with data of periods 1-2 and 3-4. ANOVA calculation showed no significant subject-by-formulation interaction, period and sequence effects. The intra-subject variabilities were at least 20-fold lower than the inter-subject ones for C (max), AUC(0-t ) and AUC(0-inf). In all four BE calculations, the 90% CIs for the T/R ratios of studied pharmacokinetics parameters fell within the 80-125% range proposed by most regulatory agencies.

  4. Replicate study design in bioequivalency assessment, pros and cons: bioavailabilities of the antidiabetic drugs pioglitazone and glimepiride present in a fixed-dose combination formulation.

    Science.gov (United States)

    Karim, Aziz; Zhao, Zhen; Slater, Margaret; Bradford, Dawn; Schuster, Jennifer; Laurent, Aziz

    2007-07-01

    An open-label, randomized, 2-sequence, 4-period crossover (7-day washout period between treatment), replicate design study was conducted in 37 healthy subjects to assess intersubject and intrasubject variabilities in the peak (Cmax) and total (AUC) exposures to 2 oral antidiabetic drugs, pioglitazone and glimepiride, after single doses of 30 mg pioglitazone and 4 mg glimepiride, given under fasted state, as commercial tablets coadministered or as a single fixed-dose combination tablet. Variabilities for AUC(infinity) for coadministered and fixed-dose combination treatments were similar: 16% to 19% (intra) and 23% to 25% (inter) for pioglitazone and 18% to 19% (intra) and 29% to 30% for glimepiride (inter, excluding 1 poor metabolizer). Fixed-dose combination/coadministered least squares mean ratios of >or=0.86 and the 90% confidence intervals of these ratios for pioglitazone and glimepiride of between 0.80 and 1.25 for Cmax, AUC(lqc), and AUC(infinity) met the bioequivalency standards. Gender analysis showed that women showed mean of 16% and 30% higher exposure than men for glimepiride (excluding 1 poor metabolizer) and pioglitazone, respectively. There was considerable overlapping in the AUC(infinity) values, making gender-dependent dosing unnecessary. Patients taking pioglitazone and glimepiride as cotherapy may replace their medication with a single fixed-dose combination tablet containing these 2 oral antidiabetic drugs.

  5. A Suite of Tools for ROC Analysis of Spatial Models

    Directory of Open Access Journals (Sweden)

    Hermann Rodrigues

    2013-09-01

    Full Text Available The Receiver Operating Characteristic (ROC is widely used for assessing the performance of classification algorithms. In GIScience, ROC has been applied to assess models aimed at predicting events, such as land use/cover change (LUCC, species distribution and disease risk. However, GIS software packages offer few statistical tests and guidance tools for ROC analysis and interpretation. This paper presents a suite of GIS tools designed to facilitate ROC curve analysis for GIS users by applying proper statistical tests and analysis procedures. The tools are freely available as models and submodels of Dinamica EGO freeware. The tools give the ROC curve, the area under the curve (AUC, partial AUC, lower and upper AUCs, the confidence interval of AUC, the density of event in probability bins and tests to evaluate the difference between the AUCs of two models. We present first the procedures and statistical tests implemented in Dinamica EGO, then the application of the tools to assess LUCC and species distribution models. Finally, we interpret and discuss the ROC-related statistics resulting from various case studies.

  6. Comparison between the story recall test and the word-list learning test in Korean patients with mild cognitive impairment and early stage of Alzheimer's disease.

    Science.gov (United States)

    Baek, Min Jae; Kim, Hyun Jung; Kim, Sangyun

    2012-01-01

    Among verbal memory tests, two that are commonly used to measure the ability of verbal memory function in cognitive impairment are story recall tests and word-list learning tests. However, research is limited regarding which test might be more sensitive in discriminating between normal cognitive aging and patients with Alzheimer's disease (AD) in the Korean population. The purpose of the current study was to compare the word-list learning test (Seoul Verbal Learning Test; SVLT) and the story recall test (Korean Story Recall Test; KSRT) to determine which test is more sensitive in discriminating between individuals with normal cognitive aging and patients with mild cognitive impairment (MCI) and early stage of AD in Korea. A total of 53 healthy adults, 127 patients with MCI, and 72 patients with early stage of AD participated in this study. The receiver-operating characteristic (ROC) curve and area under the curve (AUC) were evaluated to compare these two tests. The results showed that the AUC of the SVLT was significantly larger than the AUC of the KSRT in all three groups (healthy adults vs. MCI and early stage of AD; healthy adults vs. MCI; healthy adults vs. early stage of AD). However, in comparison of patients with MCI and early stage of AD, the AUC of SVLT and the AUC of KSRT were not significant. The word-list learning test is a more useful tool for examining verbal memory function for older adults in Korea than the story recall test.

  7. Predictors of ertapenem therapeutic efficacy in the treatment of urinary tract infections (UTIs) in hospitalized adults: the importance of renal insufficiency and urinary pH.

    Science.gov (United States)

    Cunha, B A; Giuga, J; Gerson, S

    2016-04-01

    In hospitalized adults acute uncomplicated cystitis (AUC) and catheter associated bacteriuria (CAB) may be treated with oral antibiotics. With AUC or CAB due to extended spectrum ß-lactamase (ESBL) + Gram negative bacilli (GNB) physicians often use intravenous therapy, e.g., ertapenem. We reviewed our recent experience in hospitalized adults with AUC and CAB treated with ertapenem. Therapeutic efficacy of ertapenem was assessed by decreased pyuria/bacteriuria, and elimination of the uropathogen. The effectiveness of ertapenem in the presence of renal insufficiency (CrCl 3 days) in patients with decreased renal function and alkaline urinary pH. We reviewed 45 hospitalized adults with AUC or CAB to determine if renal insufficiency and or alkaline urinary pH affected ertapenem efficacy. In the 33 adult hospitalized patients with AUC and 12 with CAB, we found that ertapenem was consistently effective in eliminating the GNB bacteriuria. In hospitalized adults, the presence of renal insufficiency and acid urine, bacteriuria was eliminated in  3 days which has not been previously reported.

  8. Pharmacokinetic and Bioequivalence Studies of a Newly Developed Branded Generic of Candesartan Cilexetil Tablets in Healthy Volunteers.

    Science.gov (United States)

    Patel, Rajesh; Palmer, Jonathan L; Joshi, Shashidhar; Di Ció Gimena, Alejandro; Esquivel, Florencia

    2016-10-18

    Two bioavailability/bioequivalence studies were carried out to evaluate the pharmacokinetics of candesartan cilexetil 16-mg tablet formulations. A pilot study was used to optimize the formulation and manufacturing process prior to conducting the definitive study. The pilot study was a single-dose, randomized, 2-period crossover, and the definitive study was a single-dose, randomized, 3-period, 6-sequence crossover study in healthy adults. In the pilot study the test formulation was 24% and 18% greater for Cmax and AUC, respectively, compared with the innovator product. Following optimization two 16-mg candesartan cilexetil tablet formulations were taken forward into the second bioavailability study.  Eighteen healthy fasted adult subjects were dosed with either the test formulations or the innovator. The pharmacokinetic parameters Cmax , AUC0-t , and AUC0-∞ of candesartan were investigated together with safety and tolerability. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for candesartan, Cmax , AUC0-t , and AUC0-∞ were within the boundary of 0.8-1.25 for one of the test formulations (formulation 2). For test formulation 3 the 90%CI of GMR for Cmax was above (133%) the upper limit of 125% for bioequivalence. Test formulation 2 was found to be bioequivalent and met internationally acceptable regulatory requirements.

  9. How many studies are necessary to compare niche-based models for geographic distributions? Inductive reasoning may fail at the end.

    Science.gov (United States)

    Terribile, L C; Diniz-Filho, J A F; De Marco jr, P

    2010-05-01

    The use of ecological niche models (ENM) to generate potential geographic distributions of species has rapidly increased in ecology, conservation and evolutionary biology. Many methods are available and the most used are Maximum Entropy Method (MAXENT) and the Genetic Algorithm for Rule Set Production (GARP). Recent studies have shown that MAXENT perform better than GARP. Here we used the statistics methods of ROC - AUC (area under the Receiver Operating Characteristics curve) and bootstrap to evaluate the performance of GARP and MAXENT in generate potential distribution models for 39 species of New World coral snakes. We found that values of AUC for GARP ranged from 0.923 to 0.999, whereas those for MAXENT ranged from 0.877 to 0.999. On the whole, the differences in AUC were very small, but for 10 species GARP outperformed MAXENT. Means and standard deviations for 100 bootstrapped samples with sample sizes ranging from 3 to 30 species did not show any trends towards deviations from a zero difference in AUC values of GARP minus AUC values of MAXENT. Ours results suggest that further studies are still necessary to establish under which circumstances the statistical performance of the methods vary. However, it is also important to consider the possibility that this empirical inductive reasoning may fail in the end, because we almost certainly could not establish all potential scenarios generating variation in the relative performance of models.

  10. Pharmacokinetics and Comparative Bioavailability of Two Diltiazem Tablet Formulations in Healthy Volunteers

    Directory of Open Access Journals (Sweden)

    Simin Dadashzadeh

    2003-07-01

    Full Text Available The pharmacokinetic parameters and bioavailability of diltiazem following a single oral administration of a generic diltiazem 60 mg tablet (Sobhan Pharmaceuticals, Iran were compared to those of a reference product (Entrydil, Orion Pharmaceuticals, Finland. Twelve healthy male volunteers received a single oral dose of either formulation following overnight fasting in a double blind, randomized, crossover study. Blood samples were collected at selected times during 24 h and diltiazem plasma concentrations were determined with a sensitive HPLC method. Individual pharmacokinetic parameters, t1/2, t1/2(abs, K, Ka, Tmax, Cmax, Vd/F, Cl/F, AUC0-24 and AUC0-∞ were calculated. No significant differences were observed in pharmacokinetic parameters between two formulations. The 90% confidence intervals for the test/reference geometric mean ratios of Cmax, AUC0-24 AUC0-∞ and Cmax/AUC0-∞ were within the conventional bioequivalence range of 0.8 - 1.25. In-vitro parameters of mean dissolution time (MDT and time for 70 % dissolution (T70 were also determined. There was a significant difference between the MDT for two dosage forms (p<0.0001. It was concluded that despite of a higher dissolution rate, the test product of diltiazem is bioequivalent to the reference product with respect to the rate and extent of absorption.

  11. Development of a simple LC-MS/MS method for determination of rebamipide in human plasma and its application to a bioequivalence study.

    Science.gov (United States)

    Liu, Jian; Shen-Tu, Jianzhong; Wu, Lihua; Dou, Jing; Xu, Qiyang; Zhou, Huili; Wu, Guolan; Hu, Xingjiang

    2012-11-01

    The purpose of this study was to design a simple and rapid liquid chromatography-tandem mass spectrometric (LC-MS/MS) method for a rebamipide bioequivalence study in healthy Chinese male volunteers. In this method, sample pretreatment involved simple protein precipitation with venlafaxine as the internal standard. Analysis was achieved on a ZORBAX SB-C18 column with a concentration range of 6-1200 ng/mL. Rebamipide tablets from Yuanlijian (test, Hangzhou, China) and from Otsuka (reference, Hangzhou, China) were evaluated following a single 300 mg oral dose to 20 healthy volunteers. Bioequivalence was determined by calculating 90% confidence intervals (90% CI) for the ratio of Cmax, AUC(0-t) and AUC(0-infinity) values for the test and reference products, using logarithmic transformed data. The 90% confidence intervals for the ratio of Cmax (83.7-118.4%), AUC(0-t) (91.1-113.4%) and AUC(0-infinity) (90.6-113.2%) values for the test and reference products were within the interval (80.0-125.0% for AUC, and 70-143% for Cmax), proposed by State of Food and Drug Administration [SFDA, 2005. China]. It was concluded that the two rebamipide tablets were bioequivalent in their rate and extent of absorption and the method met the principle of quick and easy clinical analysis.

  12. Distribution of 2,4-dichlorophenoxyacetic acid (2,4-D) in maternal and fetal rabbits.

    Science.gov (United States)

    Sandberg, J A; Duhart, H M; Lipe, G; Binienda, Z; Slikker, W; Kim, C S

    1996-12-06

    The distribution of 2,4-dichlorophenoxyacetic acid (2,4-D) was examined in maternal and fetal rabbits. Pregnant New Zealand rabbits (28-30 d gestational age) were anesthetized with ketamine/xylazine and the femoral vein and artery were catheterized for compound administration and sampling. Dams received iv [14C]2,4-D (12.5 microCi/kg) with unlabeled sodium 2,4-D (1, 10, or 40 mg/kg) in saline. Blood and tissue were collected up to 2 h after dosing. Fetal to maternal plasma AUC ratios were 0.09, 0.07, and 0.16 after the 1, 10, or 40 mg/kg dose, respectively. Extraplasma AUCs were greatest in maternal kidney and uterus and lowest in maternal and fetal brain. A greater than fourfold elevation in fetal AUC was found when the dose was increased from 10 to 40 mg/kg, suggesting saturation of maternal plasma binding of 2,4-D. Although the in vitro fetal brain tissue to incubation media ratio was unity (1.03 +/- 0.1, mean +/- SD), fetal brain AUCs were 10% or less of the fetal plasma AUCs, indicating the brain barrier system to 2,4-D is functioning in the late-gestation fetal rabbit. However, its development may not be complete due to the higher brain tissue to plasma ratios in the fetus compared to the dam.

  13. Limited-sampling strategy models for estimating the pharmacokinetic parameters of 4-methylaminoantipyrine, an active metabolite of dipyrone

    Directory of Open Access Journals (Sweden)

    Suarez-Kurtz G.

    2001-01-01

    Full Text Available Bioanalytical data from a bioequivalence study were used to develop limited-sampling strategy (LSS models for estimating the area under the plasma concentration versus time curve (AUC and the peak plasma concentration (Cmax of 4-methylaminoantipyrine (MAA, an active metabolite of dipyrone. Twelve healthy adult male volunteers received single 600 mg oral doses of dipyrone in two formulations at a 7-day interval in a randomized, crossover protocol. Plasma concentrations of MAA (N = 336, measured by HPLC, were used to develop LSS models. Linear regression analysis and a "jack-knife" validation procedure revealed that the AUC0-¥ and the Cmax of MAA can be accurately predicted (R²>0.95, bias 0.85 of the AUC0-¥ or Cmax for the other formulation. LSS models based on three sampling points (1.5, 4 and 24 h, but using different coefficients for AUC0-¥ and Cmax, predicted the individual values of both parameters for the enrolled volunteers (R²>0.88, bias = -0.65 and -0.37%, precision = 4.3 and 7.4% as well as for plasma concentration data sets generated by simulation (R²>0.88, bias = -1.9 and 8.5%, precision = 5.2 and 8.7%. Bioequivalence assessment of the dipyrone formulations based on the 90% confidence interval of log-transformed AUC0-¥ and Cmax provided similar results when either the best-estimated or the LSS-derived metrics were used.

  14. How many studies are necessary to compare niche-based models for geographic distributions? Inductive reasoning may fail at the end

    Directory of Open Access Journals (Sweden)

    LC Terribile

    Full Text Available The use of ecological niche models (ENM to generate potential geographic distributions of species has rapidly increased in ecology, conservation and evolutionary biology. Many methods are available and the most used are Maximum Entropy Method (MAXENT and the Genetic Algorithm for Rule Set Production (GARP. Recent studies have shown that MAXENT perform better than GARP. Here we used the statistics methods of ROC - AUC (area under the Receiver Operating Characteristics curve and bootstrap to evaluate the performance of GARP and MAXENT in generate potential distribution models for 39 species of New World coral snakes. We found that values of AUC for GARP ranged from 0.923 to 0.999, whereas those for MAXENT ranged from 0.877 to 0.999. On the whole, the differences in AUC were very small, but for 10 species GARP outperformed MAXENT. Means and standard deviations for 100 bootstrapped samples with sample sizes ranging from 3 to 30 species did not show any trends towards deviations from a zero difference in AUC values of GARP minus AUC values of MAXENT. Ours results suggest that further studies are still necessary to establish under which circumstances the statistical performance of the methods vary. However, it is also important to consider the possibility that this empirical inductive reasoning may fail in the end, because we almost certainly could not establish all potential scenarios generating variation in the relative performance of models.

  15. Global and regional left ventricular strain indices in post-myocardial infarction patients with ventricular arrhythmias and moderately abnormal ejection fraction.

    Science.gov (United States)

    Nguyen, Bich Lien; Capotosto, Lidia; Persi, Alessandro; Placanica, Attilio; Rafique, Asim; Piccirillo, Gianfranco; Gaudio, Carlo; Gang, Eli S; Siegel, Robert J; Vitarelli, Antonio

    2015-02-01

    The aim of the study described here was to compare myocardial strains in ischemic heart patients with and without sustained ventricular tachycardia (VT) and moderately abnormal left ventricular ejection fraction (LVEF) to investigate which index could better predict VT on the basis of the analysis of global and regional left ventricular (LV) dysfunction. We studied 467 patients with previous myocardial infarction and LVEF >35%. Fifty-one patients had documented VT, and 416 patients presented with no VT. LV volumes and score index were obtained by 2-D echocardiography. Longitudinal, radial and circumferential strains were determined. Strains of the infarct, border and remote zones were also obtained. There were no differences in standard LV 2-D parameters between patients with and those without VT. Receiver operating characteristic values were -12.7% for global longitudinal strain (area under the curve [AUC] = 0.72), -4.8% for posterior-inferior wall circumferential strain (AUC = 0.80), 61 ms for LV mechanical dispersion (AUC = 0.84), -10.1% for longitudinal strain of the border zone (AUC = 0.86) and -9.2% for circumferential strain of the border zone (AUC = 0.89). In patients with previous myocardial infarction and moderately abnormal LVEF, peri-infarct circumferential strain was the strongest predictor of documented ventricular arrhythmias among all strain quantitative indices. Additionally, strain values from posterior-inferior wall infarctions had a higher association with arrhythmic events compared with global strain.

  16. Pharmacokinetic Comparison of Inhaled Fixed Combination vs. the Free Combination of Beclomethasone and Formoterol pMDIs in Asthmatic Children

    DEFF Research Database (Denmark)

    Chawes, Bl; Piccinno, A; Kreiner-Møller, Eskil;

    2012-01-01

    -way crossover single dose study. Blood was collected pre-dose up to 8h post-dose for pharmacokinetic evaluation (AUC(0-t) , AUC(0-∞) , AUC(0-0.5h) , C(max) , t(max) , t(1/2) ). Pharmacodynamics included heart rate, plasma potassium, urinary glucose and cortisol excretion. Peak expiratory flow...... and adverse events were monitored. RESULTS: 20 subjects were evaluable. The systemic exposure of B17MP and Formoterol administered as fixed combination did not exceed the free combination: B17MP AUC(0-t) (hours(2) pg/mL) ratio Test/Reference [90% CI], 0.81 [0.697-0.948] and Formoterol AUC(0-t) (hours(2) pg....../mL) ratio Test/Reference 0.97 [0.85-1.10]. All pharmacokinetic and pharmacodynamic endpoints showed non-superiority in favour of the Test drug. One adverse event (vertigo) occurred but was not considered treatment-related. CONCLUSION: BDP and Formoterol pharmacokinetic and pharmacodynamic effects are non...

  17. Using the Disease State Fingerprint Tool for Differential Diagnosis of Frontotemporal Dementia and Alzheimer's Disease

    Science.gov (United States)

    Muñoz-Ruiz, Miguel Ángel; Hall, Anette; Mattila, Jussi; Koikkalainen, Juha; Herukka, Sanna-Kaisa; Husso, Minna; Hänninen, Tuomo; Vanninen, Ritva; Liu, Yawu; Hallikainen, Merja; Lötjönen, Jyrki; Remes, Anne M.; Alafuzoff, Irina; Soininen, Hilkka; Hartikainen, Päivi

    2016-01-01

    Background Disease State Index (DSI) and its visualization, Disease State Fingerprint (DSF), form a computer-assisted clinical decision making tool that combines patient data and compares them with cases with known outcomes. Aims To investigate the ability of the DSI to diagnose frontotemporal dementia (FTD) and Alzheimer's disease (AD). Methods The study cohort consisted of 38 patients with FTD, 57 with AD and 22 controls. Autopsy verification of FTD with TDP-43 positive pathology was available for 14 and AD pathology for 12 cases. We utilized data from neuropsychological tests, volumetric magnetic resonance imaging, single-photon emission tomography, cerebrospinal fluid biomarkers and the APOE genotype. The DSI classification results were calculated with a combination of leave-one-out cross-validation and bootstrapping. A DSF visualization of a FTD patient is presented as an example. Results The DSI distinguishes controls from FTD (area under the receiver-operator curve, AUC = 0.99) and AD (AUC = 1.00) very well and achieves a good differential diagnosis between AD and FTD (AUC = 0.89). In subsamples of autopsy-confirmed cases (AUC = 0.97) and clinically diagnosed cases (AUC = 0.94), differential diagnosis of AD and FTD performs very well. Conclusions DSI is a promising computer-assisted biomarker approach for aiding in the diagnostic process of dementing diseases. Here, DSI separates controls from dementia and differentiates between AD and FTD. PMID:27703465

  18. Using the Disease State Fingerprint Tool for Differential Diagnosis of Frontotemporal Dementia and Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Miguel Ángel Muñoz-Ruiz

    2016-07-01

    Full Text Available Background: Disease State Index (DSI and its visualization, Disease State Fingerprint (DSF, form a computer-assisted clinical decision making tool that combines patient data and compares them with cases with known outcomes. Aims: To investigate the ability of the DSI to diagnose frontotemporal dementia (FTD and Alzheimer's disease (AD. Methods: The study cohort consisted of 38 patients with FTD, 57 with AD and 22 controls. Autopsy verification of FTD with TDP-43 positive pathology was available for 14 and AD pathology for 12 cases. We utilized data from neuropsychological tests, volumetric magnetic resonance imaging, single-photon emission tomography, cerebrospinal fluid biomarkers and the APOE genotype. The DSI classification results were calculated with a combination of leave-one-out cross-validation and bootstrapping. A DSF visualization of a FTD patient is presented as an example. Results: The DSI distinguishes controls from FTD (area under the receiver-operator curve, AUC = 0.99 and AD (AUC = 1.00 very well and achieves a good differential diagnosis between AD and FTD (AUC = 0.89. In subsamples of autopsy-confirmed cases (AUC = 0.97 and clinically diagnosed cases (AUC = 0.94, differential diagnosis of AD and FTD performs very well. Conclusions: DSI is a promising computer-assisted biomarker approach for aiding in the diagnostic process of dementing diseases. Here, DSI separates controls from dementia and differentiates between AD and FTD.

  19. Nuclear Magnetic Resonance Solution Structures of Lacticin Q and Aureocin A53 Reveal a Structural Motif Conserved among Leaderless Bacteriocins with Broad-Spectrum Activity.

    Science.gov (United States)

    Acedo, Jeella Z; van Belkum, Marco J; Lohans, Christopher T; Towle, Kaitlyn M; Miskolzie, Mark; Vederas, John C

    2016-02-02

    Lacticin Q (LnqQ) and aureocin A53 (AucA) are leaderless bacteriocins from Lactococcus lactis QU5 and Staphylococcus aureus A53, respectively. These bacteriocins are characterized by the absence of an N-terminal leader sequence and are active against a broad range of Gram-positive bacteria. LnqQ and AucA consist of 53 and 51 amino acids, respectively, and have 47% identical sequences. In this study, their three-dimensional structures were elucidated using solution nuclear magnetic resonance and were shown to consist of four α-helices that assume a very similar compact, globular overall fold (root-mean-square deviation of 1.7 Å) with a highly cationic surface and a hydrophobic core. The structures of LnqQ and AucA resemble the shorter two-component leaderless bacteriocins, enterocins 7A and 7B, despite having low levels of sequence identity. Homology modeling revealed that the observed structural motif may be shared among leaderless bacteriocins with broad-spectrum activity against Gram-positive organisms. The elucidated structures of LnqQ and AucA also exhibit some resemblance to circular bacteriocins. Despite their similar overall fold, inhibition studies showed that LnqQ and AucA have different antimicrobial potency against the Gram-positive strains tested, suggesting that sequence disparities play a crucial role in their mechanisms of action.

  20. Preliminary Study on Effects of Rolling Therapy on Muscular Tension of Gastrocnemius in Healthy Subjects%(扌衮)法对健康人腓肠肌肌张力影响的初步研究

    Institute of Scientific and Technical Information of China (English)

    程英武; 詹红生; 元唯安; 阴涛; 何天翔

    2007-01-01

    目的 观察(扌衮)法对健康人腓肠肌肌张力的影响.方法 选取30名健康志愿者,采用Myotonometer(R)测量右侧腓肠肌(扌衮)法干预前后肌弹性硬度变化,用压力-位移曲线线下面积(AUC)来描述肌肉弹性硬度和肌肉顺应性(弹性硬度的倒数)变化.以左侧腓肠肌作为空白对照.结果 手法干预前右侧腓肠肌静息状态AUC=18.94±2.4,干预后AUC=20.59±2.00(P<0.01);手法干预前右侧腓肠肌收缩时AUC=13.88±2.89,干预后AUC=14.55±3.69(P=0.06).结论 (扌衮)法可以显著降低健康人腓肠肌静息状态肌张力.

  1. Dose adjustment of carboplatin in patients on hemodialysis.

    Science.gov (United States)

    Guddati, Achuta K; Joy, Parijat S; Marak, Creticus P

    2014-03-01

    Carboplatin is one of the most prescribed cytotoxic drug, which is extensively used in the treatment regimens of several malignancies. The therapeutic efficiency of carboplatin has been found to correlate the area under curve (AUC). The Calvert formula has been extensively used to determine the dose of carboplatin for a fixed AUC and glomerular filtration rate (GFR). This formula has also been used in patients with end-stage renal disease on hemodialysis by assuming that the GFR is zero. This is applicable to patients who receive hemodialysis within 12-18 h after carboplatin infusion. After the first 24 h, a majority of the carboplatin is bound to proteins is not easily dialyzable and hence continues to remain in the blood stream despite repeated sessions of hemodialysis. We derive a correction factor to calculate the resultant AUC in such patients. The analysis done by using this correction factor shows that the AUC can increase by eightfold in patients who received the adjusted dose but whose hemodialysis was delayed beyond 24 h after infusion. The correction factor proposed here can also be used to calculate the dose adjustment required a priori in patients who may receive delayed hemodialysis. It is also useful to predict the AUC and estimate the resultant toxicity in such patients.

  2. Evaluation of Acid Tolerance of Drugs Using Rats and Dogs Controlled for Gastric Acid Secretion.

    Science.gov (United States)

    Kosugi, Yohei; Yamamoto, Syunsuke; Sano, Noriyasu; Furuta, Atsutoshi; Igari, Tomoko; Fujioka, Yasushi; Amano, Nobuyuki

    2015-09-01

    We attempted to establish animal models to evaluate the effects of drug degradation in the stomach on oral bioavailability. In addition, we assessed the utilization of animal studies in determining the need for enteric-coated formulations. In order to control the gastric pH in rats and dogs, appropriate dosing conditions were investigated using pentagastrin and rabeprazole, which stimulate and inhibit gastric acid secretion. Using animals controlled for gastric acid secretion, the area under curve (AUC) ratios (AUC with rabeprazole/AUC with pentagastrin) of all compounds unstable under acidic conditions were evaluated. The AUC ratios of omeprazole and erythromycin, which are administered orally to humans, as enteric-coated tablets, were greater than 1.9 in the rats and dogs controlled for gastric acid secretion. On the contrary, the AUC ratios of clarithromycin, azithromycin, and etoposide (commercially available as a standard immediate-release form) were less than 1.3 each. In conclusion, in vivo models using rats and dogs were optimized to evaluate the effects of gastric acid on the oral bioavailability of drugs, and demonstrated that in vivo models can lead to a better understanding of the oral bioavailability, with respect to the formulation development.

  3. Analytical Ultracentrifugation as a Tool to Study Nonspecific Protein–DNA Interactions

    Science.gov (United States)

    Yang, Teng-Chieh; Catalano, Carlos Enrique; Maluf, Nasib Karl

    2016-01-01

    Analytical ultracentrifugation (AUC) is a powerful tool that can provide thermodynamic information on associating systems. Here, we discuss how to use the two fundamental AUC applications, sedimentation velocity (SV), and sedimentation equilibrium (SE), to study nonspecific protein–nucleic acid interactions, with a special emphasis on how to analyze the experimental data to extract thermodynamic information. We discuss three specific applications of this approach: (i) determination of nonspecific binding stoichiometry of E. coli integration host factor protein to dsDNA, (ii) characterization of nonspecific binding properties of Adenoviral IVa2 protein to dsDNA using SE-AUC, and (iii) analysis of the competition between specific and nonspecific DNA-binding interactions observed for E. coli integration host factor protein assembly on dsDNA. These approaches provide powerful tools that allow thermodynamic interrogation and thus a mechanistic understanding of how proteins bind nucleic acids by both specific and nonspecific interactions. PMID:26412658

  4. Bioavailability of iron, zinc, folate, and vitamin C in the IRIS multi-micronutrient supplement: effect of combination with a milk-based cornstarch porridge.

    Science.gov (United States)

    Kamp, Fernanda; Jandel, Doris; Hoenicke, Imke; Pietrzk, Klaus; Gross, Rainer; Trugo, Nadia M; Donangelo, Carmen M

    2003-09-01

    The effect of combining a multi-micronutrient supplement with a milk-based cornstarch porridge on the bioavailability of iron, zinc, folate, and vitamin C was evaluated using the plasma curve response over time (8 hours) in healthy women. Three tests were carried out in a crossover design: S (multi-micronutrient supplement), MS (multi-micronutrient supplement plustest meal), and M (test meal). Relative bioavailability was determined as the percent ratio of the area under the curve (AUC) in MS corrected by M, and AUC in S. Compared to S, AUC in MS was smaller for iron (p porridge is small. Therefore, the tested meal is a suitable vehicle for the multi-micronutrient supplement.

  5. Diagnostic value of soluble CD163 serum levels in patients suspected of meningitis: comparison with CRP and procalcitonin

    DEFF Research Database (Denmark)

    Knudsen, Troels Bygum; Larsen, Klaus; Kristiansen, Thomas Birk;

    2007-01-01

    The aim of the study was to evaluate and compare the diagnostic value of sCD163 serum levels with CRP and PCT in meningitis and bacterial infection. An observational cohort study was conducted between February 2001 and February 2005. The study population comprised 55 patients suspected......-operating characteristic AUCs (areas under curves). Patients were classified by 2 sets of diagnostic criteria into: A) purulent meningitis, serous meningitis or non-meningitis, and B) systemic bacterial infection, local bacterial infection or non-bacterial disease. An elevated serum level of sCD163 was the most specific...... infection, the AUC of sCD163 (0.83) did not differ significantly from those of CRP or PCT. All markers had AUCs meningitis and other conditions. In conclusion, CRP and PCT had high diagnostic value and were superior as markers of bacterial infection compared to s...

  6. High-frequency Electrocardiogram Analysis in the Ability to Predict Reversible Perfusion Defects during Adenosine Myocardial Perfusion Imaging

    Science.gov (United States)

    Tragardh, Elin; Schlegel, Todd T.; Carlsson, Marcus; Pettersson, Jonas; Nilsson, Klas; Pahlm, Olle

    2007-01-01

    Background: A previous study has shown that analysis of high-frequency QRS components (HF-QRS) is highly sensitive and reasonably specific for detecting reversible perfusion defects on myocardial perfusion imaging (MPI) scans during adenosine. The purpose of the present study was to try to reproduce those findings. Methods: 12-lead high-resolution electrocardiogram recordings were obtained from 100 patients before (baseline) and during adenosine Tc-99m-tetrofosmin MPI tests. HF-QRS were analyzed regarding morphology and changes in root mean square (RMS) voltages from before the adenosine infusion to peak infusion. Results: The best area under the curve (AUC) was found in supine patients (AUC=0.736) in a combination of morphology and RMS changes. None of the measurements, however, were statistically better than tossing a coin (AUC=0.5). Conclusion: Analysis of HF-QRS was not significantly better than tossing a coin for determining reversible perfusion defects on MPI scans.

  7. Bioequivalence evaluation of epinephrine autoinjectors with attention to rapid delivery.

    Science.gov (United States)

    Sclar, David Alexander

    2013-01-01

    Timely and proper injection of epinephrine is critical to prevent serious consequences relating to anaphylaxis. In a recent bioavailability study comparing epinephrine delivery from the Auvi-Q™ and EpiPen(®) epinephrine autoinjectors, the Auvi-Q failed to meet the bioequivalence threshold when using partial area under the curve (AUC) analyses based on zero to Tmax recommended for highly variable drugs such as epinephrine. Peak plasma epinephrine concentrations for the EpiPen occurred 10 minutes (median Tmax) after dosing, while peak concentrations for the Auvi-Q occurred 20 minutes after dosing. Though bioequivalence may be concluded for Cmax, AUCinf, and AUC0-t, for fast-acting therapeutics used to treat life-threatening conditions, such as epinephrine, additional pharmacokinetic parameters such as AUC zero to Tmax may be important to evaluate when assessing bioequivalence.

  8. [Omeprazol and ezomeprazol pharmacokinetics, duration of antisecretory effect, and reasons for their probable changes in duodenal ulcer].

    Science.gov (United States)

    Serebrova, S Iu; Starodubtsev, A K; Pisarev, V V; Kondratenko, S N; Vasilenko, G F; Dobrovol'skiĭ, O V

    2009-01-01

    There were authentic distinctions between the groups of healthy volunteers and patients with a peptic ulcer disease in Cmax, Tmax, AUC(0-t), AUC(0-infinity), CIt, Vd of omeprazole and Cmax of esomeprazole (Nexium, AstraZeneca). When the pharmacokinetics of omeprazole and ezomeprazole were compared in both groups, there were authentic distinctions in Cmax, AU(0-t), AUC(0-infinity), CIt, T1/2. The patients who had taken omeprazole the time of hypoacide condition was much shorter than in other groups. Disintegration test modeling pHmax for pH oscillation with large amplitude, that is typical for ulcer disease, demonstrated a possibility of early partial release of omeprazole, its acid-depended degradation and reduction of its bioavailability.

  9. Heritability of metoprolol and torsemide pharmacokinetics

    DEFF Research Database (Denmark)

    Matthaei, Johannes; Brockmöller, Jürgen; Tzvetkov, Mladen;

    2015-01-01

    Genetic variation in the pharmacokinetics of metoprolol and torsemide due to polymorphisms in CYP2D6, CYP2C9 and OATP1B1 has been extensively studied. However, it is still unknown how much of variation in pharmacokinetics of these two clinically important drugs in total is due to genetic factors....... Metoprolol and torsemide were intravenously administered to 44 monozygotic and 14 dizygotic twin pairs. Metoprolol AUC varied 4.7-fold and torsemide AUC 3.5-fold. A very high fraction of AUC variations, 91% of metoprolol and 86% of torsemide, were found to be due to additive genetic effects. However, known...... of the heritable variability in the pharmacokinetics of metoprolol and torsemide remains to be elucidated. This article is protected by copyright. All rights reserved....

  10. Combining different views of mammographic texture resemblance (MTR) marker of breast cancer risk

    DEFF Research Database (Denmark)

    Sun, S.; Karemore, Gopal; Chernoff, Konstantin

    analysis (LDA, QDA) where respectively Fisher criterion and Likelihood ratio were used as combination scores. LDA and QDA parameters were obtained from the training set. Performance was evaluated by AUC statistics. Correlations were analyses as Pearson’s linear correlation coefficient. RESULTS...... No significant difference in age was found between cases and controls. The AUC values for RMLO, LMLO, RCC and LCC views are respectively 0.604, 0.579, 0.602 and 0.605. Combination of views yielded RMLO & LMLO: 0.600; RCC & LCC: 0.612; RMLO & RCC: 0.632; LMLO & LCC: 0.623. The correlation of scores from...... contralateral views was 0.72-0.75. Scatter plots are shown below. CONCLUSION The MTR AUCs are a little lower than earlier reported probably due to the smaller training set. MTR scores obtained from two contralateral views correlated well, but not as highly as previously reported on density (>0.85). We conclude...

  11. Differential islet and incretin hormone responses in morning versus afternoon after standardized meal in healthy men

    DEFF Research Database (Denmark)

    Lindgren, Ola; Mari, Andrea; Deacon, Carolyn F

    2009-01-01

    ) and total (t) glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) after meal ingestion and made an estimation of beta-cell function by model analysis of glucose and C-peptide. RESULTS: Peak glucose was lower in the morning than in the afternoon (6.1 +/- 0.2 vs. 7.4 +/- 0....../liter . min, P = 0.007) were all higher in the morning. AUC30(iGLP-1) (r = 0.68; P = 0.021) and AUC30(iGIP) (r = 0.78; P = 0.001) both correlated to AUC30(insulin). Model analysis of beta-cell function showed a higher first-hour potentiation factor in the morning (P = 0.009). This correlated negatively...... with the 60-min glucose level (r = -0.63; P cell function, and lower glucose after the morning...

  12. The combination of colesevelam with sitagliptin enhances glycemic control in diabetic ZDF rat model

    DEFF Research Database (Denmark)

    Shang, Quan; Liu, Matthew K; Saumoy, Monica;

    2012-01-01

    Bile acid sequestrants have been shown to reduce glucose levels in patients with type 2 diabetes. We previously reported that the bile acid sequestrant colesevelam HCl (Welchol) (COL) induced the release of glucagon-like peptide (GLP)-1 and improved glycemic control in insulin-resistant rats....... In the present study, we tested whether adding sitagliptin (Januvia) (SIT), which prolongs bioactive GLP-1 half life, to COL would further enhance glycemic control. Male Zucker diabetic fatty (ZDF) rats were assigned to four groups: diabetic model without treatment (the model), the model treated with 2% COL or 0.......4% (120 mg/day) SIT alone, or with the combination (COL+SIT). After 4 wk of treatment, the glucose area under the curve (AUC) was reduced more in the COL+SIT than the COL although both groups showed decreased glucose AUC with increased AUC of bioactive GLP-1 (GLP-1A) compared with the model group...

  13. Negligible effect of oral garlic oil on the oral absorption of pyridoxine in metadoxine in rats.

    Science.gov (United States)

    Lee, Dae Young; Kang, Hee Eun; Kim, Sang Geon; Lee, Myung Gull

    2010-07-01

    Metadoxine [an ion-pair between pyridoxine and pyrrolidone carboxylate (PCA)] plus garlic oil treatment synergistically reduces alcoholic steatosis compared to each agent alone. We evaluated the effect of garlic oil on the pharmacokinetics of pyridoxine. After the oral administration of metadoxine, the total area under the plasma concentration-time curve from time zero to time infinity (AUC) and the peak plasma concentration (C(max)) of pyridoxine were significantly greater (by 40.6%) and higher (by 63.9%), respectively, than after oral administration of pyridoxine plus PCA. Oral metadoxine plus garlic oil also gave larger AUC (31.8%) and higher C(max) (64.9%) than pyridoxine plus PCA. However, garlic oil did not change the AUC or C(max) of pyridoxine in metadoxine. Thus, garlic oil does not enhance the metadoxine activity by affecting the absorption of pyridoxine.

  14. A centrifugation-based physicochemical characterization method for the interaction between proteins and nanoparticles

    Science.gov (United States)

    Bekdemir, Ahmet; Stellacci, Francesco

    2016-10-01

    Nanomedicine requires in-depth knowledge of nanoparticle-protein interactions. These interactions are studied with methods limited to large or fluorescently labelled nanoparticles as they rely on scattering or fluorescence-correlation signals. Here, we have developed a method based on analytical ultracentrifugation (AUC) as an absorbance-based, label-free tool to determine dissociation constants (KD), stoichiometry (Nmax), and Hill coefficient (n), for the association of bovine serum albumin (BSA) with gold nanoparticles. Absorption at 520 nm in AUC renders the measurements insensitive to unbound and aggregated proteins. Measurements remain accurate and do not become more challenging for small (sub-10 nm) nanoparticles. In AUC, frictional ratio analysis allows for the qualitative assessment of the shape of the analyte. Data suggests that small-nanoparticles/protein complexes significantly deviate from a spherical shape even at maximum coverage. We believe that this method could become one of the established approaches for the characterization of the interaction of (small) nanoparticles with proteins.

  15. Power calculation for comparing diagnostic accuracies in a multi-reader, multi-test design.

    Science.gov (United States)

    Kim, Eunhee; Zhang, Zheng; Wang, Youdan; Zeng, Donglin

    2014-12-01

    Receiver operating characteristic (ROC) analysis is widely used to evaluate the performance of diagnostic tests with continuous or ordinal responses. A popular study design for assessing the accuracy of diagnostic tests involves multiple readers interpreting multiple diagnostic test results, called the multi-reader, multi-test design. Although several different approaches to analyzing data from this design exist, few methods have discussed the sample size and power issues. In this article, we develop a power formula to compare the correlated areas under the ROC curves (AUC) in a multi-reader, multi-test design. We present a nonparametric approach to estimate and compare the correlated AUCs by extending DeLong et al.'s (1988, Biometrics 44, 837-845) approach. A power formula is derived based on the asymptotic distribution of the nonparametric AUCs. Simulation studies are conducted to demonstrate the performance of the proposed power formula and an example is provided to illustrate the proposed procedure.

  16. Diagnostic Value of the Updated Diamond and Forrester Score to Predict Coronary Artery Disease in Patients with Acute-Onset Chest Pain

    DEFF Research Database (Denmark)

    Sørgaard, Mathias; Linde, Jesper James; Kofoed, Klaus Fuglsang;

    2016-01-01

    compared the diagnostic accuracy of PTP and stress testing assessed by the area under the receiver operating characteristic curve (AUC) to identify significant CAD, defined as at least 1 coronary artery branch with >70% diameter stenosis identified by CCTA. RESULTS: The diagnostic accuracy of PTP......OBJECTIVES: In the recently updated clinical guidelines from the European Society of Cardiology on the management of stable coronary artery disease (CAD), the updated Diamond Forrester score has been included as a pretest probability (PTP) score to select patients for further diagnostic testing. We...... was significantly higher than the stress test (AUC 0.80 vs. 0.69; p = 0.009), but the diagnostic accuracy of the combination of PTP and a stress test did not significantly increase when compared to PTP alone (AUC 0.86 vs. 0.80; p = 0.06). CONCLUSIONS: PTP using the updated Diamond and Forrester Score is a very...

  17. The effect of experimentally induced sleep disturbance on the pharmacokinetics of lorazepam in healthy volunteers.

    Science.gov (United States)

    Kotegawa, Tsutomu; Tsutsumi, Kimiko; Imai, Hiromitsu; Ohashi, Kyoichi; Nakano, Shigeyuki

    2014-06-01

    The aim of this study was to evaluate the effect of sleep disturbance on the pharmacokinetics, especially on the absorption, of lorazepam in humans. Eight healthy male volunteers received a single oral dose of lorazepam 1 mg before sleep on two occasions in a cross-over design. In either of the two doses, subjects were intermittently exposed to noise for 1.5 hours after oral lorazepam administration. Plasma lorazepam concentrations were measured by HPLC. The exposure to noise significantly prolonged tmax (control vs. noise: 2.0 vs. 3.0 hours) and significantly decreased AUC of lorazepam in the absorption phase. The reduction was 54% (95% CI, 15 - 75%) and 24% (3 - 40%) for AUC (0 - 1 hours) and AUC (0 - 3 hours), respectively. No significant changes were observed in other pharmacokinetic parameters. The results of this study suggest that the onset of drug action after oral lorazepam administration can be altered by sleep disturbance.

  18. Relationships among tonic and episodic aspects of motivation to eat, gut peptides, and weight before and after bariatric surgery

    DEFF Research Database (Denmark)

    Bryant, Eleanor J; King, Neil A; Falkén, Ylva

    2012-01-01

    )) participants immediately before and 3 days, 2 months, and 1 year after RYGB surgery. Subjective appetite and plasma levels of ghrelin, leptin, insulin, and glucagon-like peptide-1 (GLP-1) were measured for a 3-hour postprandial period. Eating behavior traits were also measured using the Three Factor Eating...... in subjective appetite ratings and alterations in appetite peptides favoring an anorectic response. Presurgery EE was significantly related to fasting and area under the curve (AUC) ghrelin; UE was associated with AUC desire to eat, and there was a significant association between fasting desire to eat...... and ghrelin (fasting and AUC). One year postsurgery, UE was positively related to fasting insulin, and CR was negatively associated with GLP-1. UE and subjective hunger were positively correlated, while the relationship between desire to eat and ghrelin remained. CONCLUSION: The relationships among subjective...

  19. Absence of food effect on the pharmacokinetics of telbivudine following oral administration in healthy subjects.

    Science.gov (United States)

    Zhou, Xiao-Jian; Lloyd, Deborah M; Chao, George C; Brown, Nathaniel A

    2006-03-01

    The influence of food on the pharmacokinetics of telbivudine, a candidate antiviral agent against hepatitis B virus (HBV), was investigated in healthy adult subjects following a 600-mg oral dose administered with and without a high-fat/high-calorie meal. Telbivudine was well tolerated under fasting and fed conditions. Oral absorption of telbivudine as measured by maximum plasma concentration (Cmax), time to reach Cmax (Tmax), and area under the plasma concentration-time curve (AUC(0-t) and AUC(0-infinity)) was not altered by food intake immediately before oral dosing. Values of Cmax, Tmax, and AUC were comparable when telbivudine was administered under fed and fasting conditions. Results from this study indicated that the absorption of telbivudine was not affected by a high-fat/high-calorie meal; telbivudine can therefore be administered orally with no regard to the timing of meals.

  20. Pharmacokinetic interaction between ϵ-acetamidocaproic acid (AACA) and cimetidine in indomethacin-induced acute gastric ulcer and control rats: inhibition of active renal secretion of AACA by cimetidine.

    Science.gov (United States)

    Choi, Y H; Lee, U; Suh, J H; Kim, Y G; Lee, M; Oh, E; Lee, M G

    2011-05-01

    After both the intravenous and oral administration of zinc acexamate [ZAC; ion-pairing between zinc and ϵ-acetamidocaproic acid (AACA)] and cimetidine together, the areas under the curve (AUCs) of AACA were significantly greater [by 28.2 and 98.9% after the intravenous and oral administration, respectively, for control rats and 13.5 and 16.9% for indomethacin-induced acute gastric ulcer (IAGU) rats, respectively] than those of ZAC alone due to the significantly slower renal clearance (CL(R)). The significantly greater AUCs of AACA after both the intravenous and oral administration of ZAC and cimetidine together in control and IAGU rats could have been due to the inhibition of active renal tubular secretion of AACA by cimetidine. After the intravenous and oral administration of both drugs together, the AUCs of cimetidine in control and IAGU rats were not different compared with those with cimetidine alone.

  1. Moxifloxacin pharmacokinetic profile and efficacy evaluation in empiric treatment of community-acquired pneumonia

    DEFF Research Database (Denmark)

    Öbrink-Hansen, Kristina; Hardlei, Tore Forsingdal; Brock, Birgitte

    2015-01-01

    for each patient were evaluated against epidemiological cutoff MIC values for Streptococcus pneumoniae, Haemophilus influenzae, and Legionella pneumophila. PK-PD targets adopted were a Cmax/MIC of ≥12.2 for all pathogens, an fAUC0-24/MIC of >34 for S. pneumoniae, and an fAUC0-24/MIC of >75 for H...... the pharmacokinetic (PK) profile of moxifloxacin at 400 mg/day in 18 patients treated empirically for community-acquired pneumonia. We developed a population pharmacokinetic model to assess the potential efficacy of moxifloxacin and to simulate the maximal MICs for which recommended pharmacokinetic....... influenzae and L. pneumophila. Individual predicted estimates for Cmax/MIC and fAUC0-24/MIC as well as simulated maximal MICs resulting in target attainment for oral and intravenous administration of the drug were suitable for S. pneumoniae and H. influenzae but not for L. pneumophila. These results indicate...

  2. Activated charcoal alone or after gastric lavage

    DEFF Research Database (Denmark)

    Christophersen, A B; Levin, D; Høgberg, Lotte Christine Groth

    2002-01-01

    interventions 1 h post ingestion, and to determine if activated charcoal was effective in reducing the systemic absorption of a drug, when administered 2 h post ingestion. METHODS: We performed a four-limbed randomized cross-over study in 12 volunteers, who 1 h after a standard meal ingested paracetamol 50 mg....... Serum paracetamol concentrations were determined by h.p.l.c. Percentage reductions in the area under the curve (AUC) were used to estimate the efficacy of each intervention (paired observations). RESULTS: There was a significant (Pparacetamol AUC with activated charcoal at 1 h...... the two interventions (95% confidence interval for the difference -3.8, 34.0). Furthermore, we found a significant (Pparacetamol AUC when activated charcoal was administered 2 h after tablet ingestion when compared with controls (median 22.7%, 95% confidence intervals 13...

  3. Patients with rheumatoid arthritis treated with methotrexate (MTX): concentrations of steady-state erythrocyte MTX correlate to plasma concentrations and clinical efficacy

    DEFF Research Database (Denmark)

    Hornung, N.; Ellingsen, T.; Attermann, J.;

    2008-01-01

    -six patients with RA were included in this open prospective study: 40 were included before initiation of MTX therapy. Laboratory analyses, intracellular MTX concentrations in erythrocytes (Ery-MTX), and clinical examinations including toxicity data were performed prospectively for 52 weeks. Plasma...... concentrations of MTX were measured and area under the plasma concentration versus time curve (AUC) was estimated along with other pharmacokinetic variables in a population based software model.RESULTS: Ery-MTX rose after initiation of therapy and reached a steady state after 6-8 weeks. The correlation between...... steady-state Ery-MTX and dose was poor (r(2) = 0.16), whereas steady-state Ery-MTX levels correlated strongly with the estimated AUC (r(2) = 0.51, log-transformed variables). Both steady-state Ery-MTX levels and estimated AUC were significantly higher in patients responding to MTX therapy than...

  4. Associations between HIV-RNA-based indicators and virological and clinical outcomes

    DEFF Research Database (Denmark)

    Laut, Kamilla G.; Shepherd, Leah C.; Pedersen, Court

    2016-01-01

    Objectives: To evaluate and compare the performance of six HIV-RNA-based quality of care indicators for predicting short-term and long-term outcomes. Design: Multinational cohort study. Methods: We included EuroSIDA patients on antiretroviral therapy (ART) with at least three viral load...... rate ratios for all outcomes tended to increase with increasing viraemia copy years, number of consecutive months with viral load ≥50 copies/ml, current viral load and with lower %FS, but the gradient of increased risk was weak across strata. None of the indicators reliably identified those at risk...... of long-term outcomes (AUC 0.54-0.58), but performed consistently better with short-term outcomes [triple class failure (AUC 0.67-0.76) and resistance (AUC 0.64-0.79)]. Goodness of fit varied with the outcome evaluated, but differences between indicators were small. Conclusion: Differences between quality...

  5. The diagnostic value of three sacroiliac joint pain provocation tests for sacroiliitis identified by magnetic resonance imaging

    DEFF Research Database (Denmark)

    Arnbak, Bodil Al-Mashhadi; Jurik, Anne Grethe; Jensen, Rikke Krüger

    2017-01-01

    OBJECTIVES: The aim of the current study was to investigate the diagnostic value of three sacroiliac (SI) joint pain provocation tests for sacroiliitis identified by magnetic resonance imaging (MRI) and stratified by gender. METHOD: Patients without clinical signs of nerve root compression were...... was 33 (range 18-40) years and 241 (53%) were women. The prevalence of SI joints with sacroiliitis was 5%. In the whole study group, only the thigh trust test was associated with sacroiliitis, the area under the receiver operating characteristic (ROC) curve (AUC) was 0.58 [95% confidence interval (CI) 0.......51-0.65], sensitivity 31% (95% CI 18-47), and specificity 85% (95% CI 82-87). In men, sacroiliitis was associated with all the SI joint tests assessed and multi-test regimens, with the greatest AUC found for at least one positive out of three tests [AUC 0.68 (95% CI 0.56-0.80), sensitivity 56% (95% CI 31...

  6. Bioequivalence of two lansoprazole delayed release capsules 30 mg in healthy male volunteers under fasting, fed and fasting-applesauce conditions: a partial replicate crossover study design to estimate the pharmacokinetics of highly variable drugs.

    Science.gov (United States)

    Thota, S; Khan, S M; Tippabhotla, S K; Battula, R; Gadiko, C; Vobalaboina, V

    2013-11-01

    An open-label, 2-treatment, 3-sequence, 3-period, single-dose, partial replicate crossover studies under fasting (n=48), fed (n=60) and fasting-applesauce (n=48) (sprinkled on one table spoonful of applesauce) modalities were conducted in healthy adult male volunteers to evaluate bioequivalence between 2 formulations of lansoprazole delayed release capsules 30 mg. In all the 3 studies, as per randomization, either test or reference formulations were administered in a crossover manner with a required washout period of at least 7 days. Blood samples were collected adequately (0-24 h) to determine lansoprazole plasma concentrations using a validated LC-MS/MS analytical method. To characterize the pharmacokinetic parameters (Cmax, AUC0-t, AUC0-∞, Tmax, Kel and T1/2) of lansoprazole, non-compartmental analysis and ANOVA was applied on ln-transformed values. The bioequivalence was tested based on within-subject variability of the reference formulation. In fasting and fed studies (within-subject variability>30%) bioequivalence was evaluated with scaled average bioequivalence, hence for the pharmacokinetic parameters Cmax, AUC0-t and AUC0-∞, the 95% upper confidence bound for (μT-μR)2-θσ2 WR was ≤0, and the point estimates (test-to-reference ratio) were within the regulatory acceptance limit 80.00-125.00%. In fasting-applesauce study (within-subject variability<30%) bioequivalence was evaluated with average bioequivalence, the 90% CI of ln-transformed data of Cmax, AUC0-t and AUC0-∞ were within the regulatory acceptance limit 80.00-125.00%. Based on these aforesaid statistical inferences, it was concluded that the test formulation is bioequivalent to reference formulation.

  7. Comparison of Glasgow-Blatchford score and full Rockall score systems to predict clinical outcomes in patients with upper gastrointestinal bleeding

    Directory of Open Access Journals (Sweden)

    Mokhtare M

    2016-10-01

    Full Text Available Marjan Mokhtare, Vida Bozorgi, Shahram Agah, Mehdi Nikkhah, Amirhossein Faghihi, Amirhossein Boghratian, Neda Shalbaf, Abbas Khanlari, Hamidreza Seifmanesh Colorectal Research Center, Rasoul Akram Hospital, Tehran, Iran Background: Various risk scoring systems have been recently developed to predict clinical outcomes in patients with upper gastrointestinal bleeding (UGIB. The two commonly used scoring systems include full Rockall score (RS and the Glasgow-Blatchford score (GBS. Bleeding scores were assessed in terms of prediction of clinical outcomes in patients with UGIB. Patients and methods: Two hundred patients (age >18 years with obvious symptoms of UGIB in the emergency department of Rasoul Akram Hospital were enrolled. Full RS and GBS were calculated. We followed the patients for records of rebleeding and 1-month mortality. A receiver operating characteristic curve by using areas under the curve (AUCs was used to statistically identify the best cutoff point. Results: Eighteen patients were excluded from the study due to failure to follow-up. Rebleeding and mortality rate were 9.34% (n=17 and 11.53% (n=21, respectively. Regarding 1-month mortality, full RS was better than GBS (AUC, 0.648 versus 0.582; P=0.021. GBS was more accurate in terms of detecting transfusion need (AUC, 0.757 versus 0.528; P=0.001, rebleeding rate (AUC, 0.722 versus 0.520; P=0.002, intensive care unit admission rate (AUC, 0.648 versus 0.582; P=0.021, and endoscopic intervention rate (AUC, 0.771 versus 0.650; P<0.001. Conclusion: We found the full RS system is better for 1-month mortality prediction while GBS system is better for prediction of other outcomes. Keywords: full Rockall score, Glasgow-Blatchford score, gastrointestinal bleeding, mortality, prognosis

  8. Multiparametric 3T MRI for the prediction of pathological downgrading after radical prostatectomy in patients with biopsy-proven Gleason score 3 + 4 prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Gondo, Tatsuo [Memorial Sloan-Kettering Cancer Center, Urology Service, Department of Surgery, New York, NY (United States); Tokyo Medical University, Department of Urology, Tokyo (Japan); Hricak, Hedvig; Sala, Evis; Vargas, Hebert Alberto [Memorial Sloan-Kettering Cancer Center, Department of Radiology, New York, NY (United States); Zheng, Junting; Moskowitz, Chaya S. [Memorial Sloan-Kettering Cancer Center, Department of Epidemiology and Biostatistics, New York, NY (United States); Bernstein, Melanie; Eastham, James A. [Memorial Sloan-Kettering Cancer Center, Urology Service, Department of Surgery, New York, NY (United States)

    2014-12-15

    The aim of this study was to assess the diagnostic performance of pre-treatment 3-Tesla (3T) multiparametric magnetic resonance imaging (mpMRI) for predicting Gleason score (GS) downgrading after radical prostatectomy (RP) in patients with GS 3 + 4 prostate cancer (PCa) on biopsy. We retrospectively reviewed 304 patients with biopsy-proven GS 3 + 4 PCa who underwent mpMRI before RP. On T2-weighted imaging and three mpMRI combinations (T2-weighted imaging + diffusion-weighted imaging [DWI], T2-weighted imaging + dynamic contrast-enhanced-MRI [DCE-MRI], and T2-weighted imaging + DWI + DCE-MRI), two radiologists (R1/R2) scored the presence of a dominant tumour using a 5-point Likert scale (1 = definitely absent to 5 = definitely present). Diagnostic performance in identifying downgrading was evaluated via areas under the curves (AUCs). Predictive accuracies of multivariate models were calculated. In predicting downgrading, T2-weighted imaging + DWI (AUC = 0.89/0.85 for R1/R2) performed significantly better than T2-weighted imaging alone (AUC = 0.72/0.73; p < 0.001/p = 0.02 for R1/R2), while T2-weighted imaging + DWI + DCE-MRI (AUC = 0.89/0.84 for R1/R2) performed no better than T2-weighted imaging + DWI (p = 0.48/p > 0.99 for R1/R2). On multivariate analysis, the clinical + mpMRI model incorporating T2-weighted imaging + DWI (AUC = 0.92/0.88 for R1/R2) predicted downgrading significantly better than the clinical model (AUC = 0.73; p < 0.001 for R1/R2). mpMRI improves the ability to identify a subgroup of patients with Gleason 3 + 4 PCa on biopsy who are candidates for active surveillance. DCE-MRI (compared to T2 + DWI) offered no additional benefit to the prediction of downgrading. (orig.)

  9. A simplified score to quantify comorbidity in COPD.

    Directory of Open Access Journals (Sweden)

    Nirupama Putcha

    Full Text Available Comorbidities are common in COPD, but quantifying their burden is difficult. Currently there is a COPD-specific comorbidity index to predict mortality and another to predict general quality of life. We sought to develop and validate a COPD-specific comorbidity score that reflects comorbidity burden on patient-centered outcomes.Using the COPDGene study (GOLD II-IV COPD, we developed comorbidity scores to describe patient-centered outcomes employing three techniques: 1 simple count, 2 weighted score, and 3 weighted score based upon statistical selection procedure. We tested associations, area under the Curve (AUC and calibration statistics to validate scores internally with outcomes of respiratory disease-specific quality of life (St. George's Respiratory Questionnaire, SGRQ, six minute walk distance (6MWD, modified Medical Research Council (mMRC dyspnea score and exacerbation risk, ultimately choosing one score for external validation in SPIROMICS.Associations between comorbidities and all outcomes were comparable across the three scores. All scores added predictive ability to models including age, gender, race, current smoking status, pack-years smoked and FEV1 (p<0.001 for all comparisons. Area under the curve (AUC was similar between all three scores across outcomes: SGRQ (range 0·7624-0·7676, MMRC (0·7590-0·7644, 6MWD (0·7531-0·7560 and exacerbation risk (0·6831-0·6919. Because of similar performance, the comorbidity count was used for external validation. In the SPIROMICS cohort, the comorbidity count performed well to predict SGRQ (AUC 0·7891, MMRC (AUC 0·7611, 6MWD (AUC 0·7086, and exacerbation risk (AUC 0·7341.Quantifying comorbidity provides a more thorough understanding of the risk for patient-centered outcomes in COPD. A comorbidity count performs well to quantify comorbidity in a diverse population with COPD.

  10. Genome-wide association study for biomarker identification of Rapamycin and Everolimus using a lymphoblastoid cell line system

    Directory of Open Access Journals (Sweden)

    Jing eJiang

    2013-08-01

    Full Text Available The mammalian target of rapamycin (mTOR inhibitors, a set of promising potential anti-cancer agents, has shown response variability among individuals. This study aimed to identify novel biomarkers and mechanisms that might influence the response to Rapamycin and Everolimus. Genome-wide association (GWA analyses involving single nucleotide polymorphisms (SNPs, mRNA and microRNAs microarray data were assessed for association with area under the cytotoxicity dose response curve (AUC of two mTOR inhibitors in 272 human lymphoblastoid cell lines (LCLs. Integrated analysis among SNPs, expression data, microRNA data and AUC values were also performed to help select candidate genes for further functional characterization. Functional validation of candidate genes using siRNA screening in multiple cell lines followed by MTS assays for the two mTOR inhibitors were performed. We found that 16 expression probe sets (genes that overlapped between the two drugs were associated with AUC values of two mTOR inhibitors. 127 and 100 SNPs had P<10-4, while 8 and 10 SNPs had P<10-5 with Rapamycin and Everolimus AUC, respectively. Functional studies indicated that 13 genes significantly altered cell sensitivity to either one or both drugs in at least one cell line. Additionally, one microRNA, miR-10a, was significantly associated with AUC values for both drugs and was shown to repress expression of genes that were associated with AUC and desensitize cells to both drugs. In summary, this study identified genes and a microRNA that might contribute to response to mTOR inhibitors.

  11. Actuarial Assessment of Sex Offender Recidivism Risk: A Validation of the German version of the Static-991

    Directory of Open Access Journals (Sweden)

    Martin Rettenberger

    2006-12-01

    Full Text Available The Static-99 and the RRASOR are actuarial risk assessment tools for evaluating the risk of sexual and violent recidivism in sexual offenders. The Static-99 was developed in 1999 by Karl R. Hanson (Canada and David Thornton (Great Britain and is in the mean time regularly used for risk assessment in North America and some countries in Europe. The RRASOR can be described as a predecessor of the Static-99 and was published by Hanson in 1997. At first we translated the revised version of the Static-99 (Harris, Phenix, Hanson & Thornton, 2003 and adapted the instrument and the manual to the forensic context in Germany and Austria (Rettenberger & Eher, 2006. In this retrospective study, interrater reliability and concurrent validity of the RRASOR and of the German adaption of the Static-99 is presented. Furthermore we evaluated the predictive accuracy of the Static-99 and the RRASOR and compared their results. The instruments were validated from file information of Austrian sexuel offenders, who were convicted between 1968 and 2002. Both the Static-99 and the RRASOR had good interrater reliability and concurrent validity. The Static-99 showed good predictive validity for general (r = .41, AUC = .74, sexual (r = .35, AUC = .74 and violent (r = .41, AUC = .76 recidivism, whereas the predictive accuracy of the RRASOR was moderate for general (r = .29, AUC = .66, sexual (r = .30, AUC = .68 and violent (r = .28, AUC = .67 recidivism. The Static-99 exhibited a higher accuracy for the prediction of sexual offender recidivism. Although further validation studies on German-speaking populations of sex offenders are necessary, these results support the utility of the German version of the revised version of the Static-99 in improving risk assessment of sexual offenders.

  12. Modelling the habitat suitability of cetaceans: Example of the sperm whale in the northwestern Mediterranean Sea

    Science.gov (United States)

    Praca, Emilie; Gannier, Alexandre; Das, Krishna; Laran, Sophie

    2009-04-01

    Cetaceans are mobile and spend long periods underwater. Because of this, modelling their habitat could be subject to a serious problem of false absence. Furthermore, extensive surveys at sea are time and money consuming, and presence-absence data are difficult to apply. This study compares the ability of two presence-absence and two presence-only habitat modelling methods and uses the example of the sperm whale ( Physeter macrocephalus) in the northwestern Mediterranean Sea. The data consist of summer visual and acoustical detections of sperm whales, compiled between 1998 and 2005. Habitat maps were computed using topographical and hydrological eco-geographical variables. Four methods were compared: principal component analysis (PCA), ecological niche factor analysis (ENFA), generalized linear model (GLM) and multivariate adaptive regression splines (MARS). The evaluation of the models was achieved by calculating the receiver operating characteristic (ROC) of the models and their respective area under the curve (AUC). Presence-absence methods (GLM, AUC=0.70, and MARS, AUC=0.79) presented better AUC than presence-only methods (PCA, AUC=0.58, and ENFA, AUC=0.66), but this difference was not statistically significant, except between the MARS and the PCA models. The four models showed an influence of both topographical and hydrological factors, but the resulting habitat suitability maps differed. The core habitat on the continental slope was well highlighted by the four models, while GLM and MARS maps also showed a suitable habitat in the offshore waters. Presence-absence methods are therefore recommended for modelling the habitat suitability of cetaceans, as they seem more accurate to highlight complex habitat. However, the use of presence-only techniques, in particular ENFA, could be very useful for a first model of the habitat range or when important surveys at sea are not possible.

  13. Drug brain distribution following intranasal administration of Huperzine A in situ gel in rats

    Institute of Scientific and Technical Information of China (English)

    Yan ZHAO; Peng YUE; Tao TAO; Qing-hua CHEN

    2007-01-01

    Aim: To determine the uptake extent of Huperzine A (Hup A) into the brain after intranasal administration of Hup A in situ gel to rats, and to compare the pharma-cokinetic parameters between intranasal administration and iv and po. Methods: Hup A was administered to male Sprague-Dawley rats via nasal, iv and oral routes at the dose of 166.7, 166.7, and 500μg/kg, respectively. Blood and brain tissue samples including the cerebrum, hippocampus, cerebellum and olfactory bulb were collected, and the concentrations of Hup A in the samples were assayed by HPLC. The area under the concentration-time curve (AUC,0→6h) and the ratio of the AUC,brain, to the AUC,plasma (drug targeting efficiency, DTE) were calculated toevaluate the brain targeting efficiency of the drug via 3 administration routes. Results: The AUC,0→6h of the drug in the cerebrum, hippocampus, cerebellum, left olfactory bulb and right olfactory bulb after intranasal administration of the Hup A in situ gel were 1.5, 1.3, 1.0, 1.2, and 1.0 times of those after iv administration of the injection, and 2.7, 2.2, 1.9, 3.1, and 2.6 times of those after administration of the oral formulation. The AUC,brain0→6h/AUC,plasma0→6h of Hup A in the cerebrum, hippocampus and left olfactory bulb following the intranasal administration dose were significantly higher (P0.05) than the iv dose. Conclusion: Intranasal delivery showed a viable, non-invasive strategy for delivering the drug into brain.

  14. Use of Sub-ensembles and Multi-template Observers to Evaluate Detection Task Performance for Data That are Not Multivariate Normal.

    Science.gov (United States)

    Li, Xin; Jha, Abhinav; Ghaly, Michael; Elshahaby, Fatma; Links, Jonathan; Frey, Eric

    2016-12-22

    The Hotelling Observer (HO) is widely used to evaluate image quality in medical imaging. However, applying it to data that are not multivariate-normally (MVN) distributed is not optimal. In this paper, we apply two multi-template linear observer strategies to handle such data. First, the entire data ensemble is divided into sub-ensembles that are exactly or approximately MVN and homoscedastic. Next, a different linear observer template is estimated for and applied to each sub-ensemble. The first multi-template strategy, adapted from previous work, applies the HO to each sub-ensemble, calculates the area under the receiver operating characteristics curve (AUC) for each sub-ensemble, and averages the AUCs from all the sub-ensembles. The second strategy applies the Linear Discriminant (LD) to estimate test statistics for each sub-ensemble and calculates a single global AUC using the pooled test statistics from all the sub-ensembles. We show that this second strategy produces the maximum AUC when only shifting of the HO test statistics is allowed. We compared these strategies to the use of a single HO template for the entire data ensemble by applying them to the non-MVN data obtained from reconstructed images of a realistic simulated population of myocardial perfusion SPECT studies with the goal of optimizing the reconstruction parameters. Of the strategies investigated, the multi-template LD strategy yielded the highest AUC for any given set of reconstruction parameters. The optimal reconstruction parameters obtained by the two multi-template strategies were comparable and produced higher AUCs for each sub-ensemble than the single-template HO strategy.

  15. Diagnostic Value of Serum Angiogenesis Markers in Ovarian Cancer Using Multiplex Immunoassay

    Directory of Open Access Journals (Sweden)

    Agnieszka Horala

    2017-01-01

    Full Text Available As cancer development involves pathological vessel formation, 16 angiogenesis markers were evaluated as potential ovarian cancer (OC biomarkers. Blood samples collected from 172 patients were divided based on histopathological result: OC (n = 38, borderline ovarian tumours (n = 6, non-malignant ovarian tumours (n = 62, healthy controls (n = 50 and 16 patients were excluded. Sixteen angiogenesis markers were measured using BioPlex Pro Human Cancer Biomarker Panel 1 immunoassay. Additionally, concentrations of cancer antigen 125 (CA125 and human epididymis protein 4 (HE4 were measured in patients with adnexal masses using electrochemiluminescence immunoassay. In the comparison between OC vs. non-OC, osteopontin achieved the highest area under the curve (AUC of 0.79 (sensitivity 69%, specificity 78%. Multimarker models based on four to six markers (basic fibroblast growth factor—FGF-basic, follistatin, hepatocyte growth factor—HGF, osteopontin, platelet-derived growth factor AB/BB—PDGF-AB/BB, leptin demonstrated higher discriminatory ability (AUC 0.80–0.81 than a single marker (AUC 0.79. When comparing OC with benign ovarian tumours, six markers had statistically different expression (osteopontin, leptin, follistatin, PDGF-AB/BB, HGF, FGF-basic. Osteopontin was the best single angiogenesis marker (AUC 0.825, sensitivity 72%, specificity 82%. A three-marker panel consisting of osteopontin, CA125 and HE4 better discriminated the groups (AUC 0.958 than HE4 or CA125 alone (AUC 0.941 and 0.932, respectively. Osteopontin should be further investigated as a potential biomarker in OC screening and differential diagnosis of ovarian tumours. Adding osteopontin to a panel of already used biomarkers (CA125 and HE4 significantly improves differential diagnosis between malignant and benign ovarian tumours.

  16. The impact of reliable prebolus T{sub 1} measurements or a fixed T{sub 1} value in the assessment of glioma patients with dynamic contrast enhancing MRI

    Energy Technology Data Exchange (ETDEWEB)

    Tietze, Anna [Aarhus University Hospital, Dept. of Neuroradiology, Aarhus (Denmark); Aarhus University, Center of Functionally Integrative Neuroscience, Aarhus (Denmark); Mouridsen, Kim; Mikkelsen, Irene Klaerke [Aarhus University, Center of Functionally Integrative Neuroscience, Aarhus (Denmark)

    2015-03-06

    Accurate quantification of hemodynamic parameters using dynamic contrast enhanced (DCE) MRI requires a measurement of tissue T{sub 1} prior to contrast injection (T{sub 1}). We evaluate (i) T{sub 1} estimation using the variable flip angle (VFA) and the saturation recovery (SR) techniques and (ii) investigate if accurate estimation of DCE parameters outperform a time-saving approach with a predefined T{sub 1} value when differentiating high- from low-grade gliomas. The accuracy and precision of T{sub 1} measurements, acquired by VFA and SR, were investigated by computer simulations and in glioma patients using an equivalence test (p > 0.05 showing significant difference). The permeability measure, K{sub trans}, cerebral blood flow (CBF), and - volume, V{sub p}, were calculated in 42 glioma patients, using fixed T{sub 1} of 1500 ms or an individual T{sub 1} measurement, using SR. The areas under the receiver operating characteristic curves (AUCs) were used as measures for accuracy to differentiate tumor grade. The T{sub 1} values obtained by VFA showed larger variation compared to those obtained using SR both in the digital phantom and the human data (p > 0.05). Although a fixed T{sub 1} introduced a bias into the DCE calculation, this had only minor impact on the accuracy differentiating high-grade from low-grade gliomas, (AUC{sub fix} = 0.906 and AUC{sub ind} = 0.884 for K{sub trans}; AUC{sub fix} = 0.863 and AUC{sub ind} = 0.856 for V{sub p;} p for AUC comparison > 0.05). T{sub 1} measurements by VFA were less precise, and the SR method is preferable, when accurate parameter estimation is required. Semiquantitative DCE values, based on predefined T{sub 1} values, were sufficient to perform tumor grading in our study. (orig.)

  17. Effect of blueberry juice on clearance of buspirone and flurbiprofen in human volunteers

    Science.gov (United States)

    Hanley, Michael J; Masse, Gina; Harmatz, Jerold S; Cancalon, Paul F; Dolnikowski, Gregory G; Court, Michael H; Greenblatt, David J

    2013-01-01

    Aim The present study evaluated the possibility of drug interactions involving blueberry juice (BBJ) and substrate drugs whose clearance is dependent on cytochromes P4503A (CYP3A) and P4502C9 (CYP2C9). Methods A 50:50 mixture of lowbush and highbush BBJ was evaluated in vitro as an inhibitor of CYP3A activity (hydroxylation of triazolam and dealkylation of buspirone) and of CYP2C9 activity (flurbiprofen hydroxylation) using human liver microsomes. In clinical studies, clearance of oral buspirone and oral flurbiprofen was studied in healthy volunteers with and without co-treatment with BBJ. Results BBJ inhibited CYP3A and CYP2C9 activity in vitro, with 50% inhibitory concentrations (IC50) of less than 2%, but without evidence of mechanism-based (irreversible) inhibition. Grapefruit juice (GFJ) also inhibited CYP3A activity, but inhibitory potency was increased by pre-incubation, consistent with mechanism-based inhibition. In clinical studies, GFJ significantly increased area under the plasma concentration−time curve (AUC) for the CYP3A substrate buspirone. The geometric mean ratio (GMR = AUC with GFJ divided by AUC with water) was 2.12. In contrast, the effect of BBJ (GMR = 1.39) was not significant. In the study of flurbiprofen (CYP2C9 substrate), the positive control inhibitor fluconazole significantly increased flurbiprofen AUC (GMR = 1.71), but BBJ had no significant effect (GMR = 1.03). Conclusion The increased buspirone AUC associated with BBJ is quantitatively small and could have occurred by chance. BBJ has no effect on flurbiprofen AUC. The studies provide no evidence for concern about clinically important pharmacokinetic drug interactions of BBJ with substrate drugs metabolized by CYP3A or CYP2C9. PMID:22943633

  18. Emtricitabine seminal plasma and blood plasma population pharmacokinetics in HIV-infected men in the EVARIST ANRS-EP 49 study.

    Science.gov (United States)

    Valade, Elodie; Tréluyer, Jean-Marc; Illamola, Silvia M; Bouazza, Naïm; Foissac, Frantz; De Sousa Mendes, Maïlys; Lui, Gabrielle; Chenevier-Gobeaux, Camille; Suzan-Monti, Marie; Rouzioux, Christine; Assoumou, Lambert; Viard, Jean-Paul; Hirt, Déborah; Urien, Saïk; Ghosn, Jade

    2015-11-01

    We aimed to describe blood plasma (BP) and seminal plasma (SP) pharmacokinetics of emtricitabine (FTC) in HIV-1-infected men, assess its penetration in the male genital tract, and evaluate its impact on seminal plasma HIV load (spVL) detection. Men from the EVARIST ANRS EP49 study receiving combined antiretroviral therapy with FTC and with suppressed BP viral load were included in the study. A total of 236 and 209 FTC BP and SP concentrations, respectively, were available. A population pharmacokinetic model was developed with Monolix 4.1.4. The impact of FTC seminal exposure on spVL detection was explored by receiver operating characteristic (ROC) curves and mixed-effects logistic regressions. FTC BP pharmacokinetics was described by a two-compartment model. The addition of an effect compartment with different input and output constants best described FTC SP pharmacokinetics. No covariates were found to explain the variability in SP. FTC exposures (area under the concentration-time curve from 0 to 24 h [AUC0-24]) were higher in SP than in BP (median AUC0-24, 38.04 and 12.95 mg · liter(-1) · h, respectively). The median (range) SP-to-BP AUC0-24 ratio was 2.91 (0.84 to 10.08). Less than 1% of FTC AUC0-24 ratios were lower than 1. The impact of FTC SP AUC0-24 or FTC SP-to-BP AUC0-24 ratio on spVL detection was not significant (P = 0.943 or 0.893, respectively). This is the first population model describing FTC pharmacokinetics simultaneously in both BP and SP. FTC distributes well in the male genital tract with higher FTC concentrations in SP than in BP. FTC seminal plasma exposures were considered efficient in the majority of men.

  19. Pulse pressure variation and prediction of fluid responsiveness in patients ventilated with low tidal volumes

    Directory of Open Access Journals (Sweden)

    Clarice Daniele Alves de Oliveira-Costa

    2012-07-01

    Full Text Available OBJECTIVE: To determine the utility of pulse pressure variation (ΔRESP PP in predicting fluid responsiveness in patients ventilated with low tidal volumes (V T and to investigate whether a lower ΔRESP PP cut-off value should be used when patients are ventilated with low tidal volumes. METHOD: This cross-sectional observational study included 37 critically ill patients with acute circulatory failure who required fluid challenge. The patients were sedated and mechanically ventilated with a V T of 6-7 ml/kg ideal body weight, which was monitored with a pulmonary artery catheter and an arterial line. The mechanical ventilation and hemodynamic parameters, including ΔRESP PP, were measured before and after fluid challenge with 1,000 ml crystalloids or 500 ml colloids. Fluid responsiveness was defined as an increase in the cardiac index of at least 15%. ClinicalTrial.gov: NCT01569308. RESULTS: A total of 17 patients were classified as responders. Analysis of the area under the ROC curve (AUC showed that the optimal cut-off point for ΔRESP PP to predict fluid responsiveness was 10% (AUC = 0.74. Adjustment of the ΔRESP PP to account for driving pressure did not improve the accuracy (AUC = 0.76. A ΔRESP PP>10% was a better predictor of fluid responsiveness than central venous pressure (AUC = 0.57 or pulmonary wedge pressure (AUC = 051. Of the 37 patients, 25 were in septic shock. The AUC for ΔRESP PP>10% to predict responsiveness in patients with septic shock was 0.484 (sensitivity, 78%; specificity, 93%. CONCLUSION: The parameter D RESP PP has limited value in predicting fluid responsiveness in patients who are ventilated with low tidal volumes, but a ΔRESP PP>10% is a significant improvement over static parameters. A ΔRESP PP > 10% may be particularly useful for identifying responders in patients with septic shock.

  20. A comparison of the ratio of patient′s height to thyromental distance with the modified Mallampati and the upper lip bite test in predicting difficult laryngoscopy

    Directory of Open Access Journals (Sweden)

    Mohammadreza Safavi

    2011-01-01

    Full Text Available Background: The aim of the present study was to compare the ability to predict difficult visualization of the larynx from the following preoperative airway predictive indices, in isolation and combination: modified Mallampati test (MMT, the ratio of height to thyromental distance (RHTMD and the Upper-Lip-Bite test (ULBT. Methods: We collected data on 603 consecutive patients scheduled for elective surgery under general anesthesia requiring endotracheal intubation and then evaluated all three factors before surgery. An experienced anesthesiologist, not informed of the recorded preoperative airway evaluation, performed the laryngoscopy and grading (as per Cormack and Lehane′s classification. Sensitivity, specificity, and positive and negative predictive value, Receiver operating characteristic (ROC Curve and the area under ROC curve (AUC for each airway predictor in isolation and in combination were determined. Results: Difficult laryngoscopy (Grade 3 or 4 occurred in 41 (6.8% patients. The main endpoint of the present study, the AUC of the ROC, was significantly lower for the MMT (AUC, 0.511; 95% CI, 0.470-0.552 than the ULBT (AUC, 0.709; 95% CI, 0.671-0.745, P=0.002 and the RHTMD score (AUC, 0.711; 95% CI, 0.673-0.747, P=0.001. There was no significant difference between the AUC of the ROC for the ULBT and the RHTMD score. By using discrimination analysis, the optimal cutoff point for the RHTMD for predicting difficult laryngoscopy was 21.06 (sensitivity, 75.6%; specificity, 58.5%. Conclusion: The RHTMD is comparable with ULBT for prediction of difficult laryngoscopy in general population.

  1. Bioequivalence studies for two different strengths of montelukast in healthy volunteers: 10 mg film-coated tablets and 5 mg chewable tablets.

    Science.gov (United States)

    Pedroso, P; Almeida, S; Filipe, A; Neves, R I; Boudreault, S; Jiménez, C

    2013-09-01

    In order to assess the bioequivalence of 2 different formulations of montelukast, a pivotal trial for the montelukast 10 mg film-coated tablets formulation and a pivotal trial for the montelukast 5 mg chewable tablets formulation were conducted.For the 10 mg study, 34 healthy subjects were enrolled in a single centre, randomised, single-dose, open-label, 2-way crossover study, with a minimum washout period of 7 days, while for the 5 mg study, 42 healthy subjects were included in another study with a similar design. For both studies, plasma samples were collected up to 24 h post-dosing and drug levels were determined by reverse liquid chromatography and detected by tandem mass spectrometry detection.Pharmacokinetic parameters used for bioequivalence assessment, area under the concentration-time curve from time zero to time of last non-zero concentration (AUC0-t) and from time zero to infinity (AUC0-inf) and maximum observed concentration (Cmax), were determined from the drug concentration data using non-compartmental analysis.In the 10 mg study, the 90% confidence intervals obtained by analysis of variance were 99.62-120.51% for Cmax, 102.25-117.37% for AUC0-t and 101.96-116.67% for AUC0-inf, which were within the predefined acceptable range of 80.00-125.00%.In the 5 mg study, the 90% confidence intervals were 91.14-98.46% for Cmax, 93.02-98.42% for AUC0-t and 93.09-98.63% for AUC0-inf, which were within the predefined acceptable range of 80.00-125.00%.Bioequivalence between formulations was concluded both in terms of rate and extent of absorption for both strengths.

  2. The diagnostic performance of an antibody enzyme-linked immunosorbent assay using serum and colostrum to determine the disease status of a Jersey dairy herd infected with Mycobacterium avium subspecies paratuberculosis.

    Science.gov (United States)

    Jenvey, Caitlin J; Reichel, Michael P; Cockcroft, Peter D

    2016-01-01

    Colostrum may have the ability to improve the diagnostic accuracy of some tests when compared to serum for important livestock diseases because of the high concentrations of immunoglobulins present within this sample type. The ELISA for Johne's disease is one such test, as it suffers from low sensitivity when testing serum samples collected during the subclinical stage of infection. Blood and colostrum samples were collected from 34 Jersey dairy cows and tested for antibodies against Mycobacterium avium subspecies paratuberculosis (MAP) by ELISA. Fecal samples were also collected and tested by a high-throughput Johne's polymerase chain reaction (HT-J PCR) assay and fecal culture (FC), with the latter being used as the reference test. A receiver operating characteristic (ROC) analysis was performed, and the area under the curve (AUC) was calculated. The HT-J PCR and FC results were also compared. Of the 34 cows in this study, 4 had FC results consistent with MAP infection. The HT-J PCR did not identify any FC-positive cows. Using a 1:20 dilution and sample-to-positive (S/P) ratio cutoff threshold of 0.15, the relative sensitivity values of both serum (AUC 0. 56) and colostrum (AUC 0.63) were 0%. With lower sample dilutions, the relative sensitivity values of serum were 0% (1:2, AUC 0.62; 1:5, AUC 0.55); however, the relative sensitivity value of colostrum was 75% (95% confidence interval [CI]: 19-99%) at a dilution of 1:5, S/P ratio cutoff threshold of 0.15, and AUC of 0.73 (95% CI: 0.55-0.87). The testing of colostrum samples for MAP-specific antibodies by ELISA may provide improved identification of animals in the early stages of infection with MAP when compared with serum samples.

  3. Pharmacokinetic Interactions Between Quinine and Lopinavir/Ritonavir in Healthy Thai Adults.

    Science.gov (United States)

    Rattanapunya, Siwalee; Cressey, Tim R; Rueangweerayut, Ronnatrai; Tawon, Yardpiroon; Kongjam, Panida; Na-Bangchang, Kesara

    2015-12-01

    This study aimed to investigate the pharmacokinetic interactions between quinine and lopinavir boosted with ritonavir (LPV/r) in healthy Thai adults (8 males and 12 females). Period 1 (day 1): subjects received a single oral dose of 600 mg quinine sulfate. Period 2: subjects received LPV/r (400/100 mg) twice daily. Period 3: subjects received a single quinine sulfate dose plus LPV/r twice a day. Intensive blood sampling was performed during each phase. Quinine AUC0-48h (area under the plasma concentration-time curve from time 0 to 48 hours), AUC0-∞ (area under the plasma concentration-time curve from time 0 to infinity), and Cmax (maximum concentration over the time-span specified), were 56%, 57%, and 47% lower, respectively, in the presence of LPV/r. 3-Hydroxyquinine AUC0-48h, AUC0-∞, and Cmax were significantly lower and the metabolite-to-parent ratio was significantly reduced. Lopinavir and ritonavir exposures were not significantly reduced with quinine coadministration, but Cmax of both drugs were significantly lower. The geometric mean ratio (GMR) and 90% CI of AUC0-48h, AUC0-∞, and Cmax for quinine, 3-hydroxyquinine, lopinavir, and ritonavir lay outside the bioequivalent range of 0.8-1.25. Drug treatments during all periods were generally well tolerated. The reduction in systemic exposure of quinine and 3-hydroxyquinine with concomitant LPV/r use raises concerns of suboptimal exposure. Studies in HIV/malaria coinfection patients are needed to determine the clinical impact to decide if any change to the quinine dose is warranted.

  4. Applying the J-optimal channelized quadratic observer to SPECT myocardial perfusion defect detection

    Science.gov (United States)

    Kupinski, Meredith K.; Clarkson, Eric; Ghaly, Michael; Frey, Eric C.

    2016-03-01

    To evaluate performance on a perfusion defect detection task from 540 image pairs of myocardial perfusion SPECT image data we apply the J-optimal channelized quadratic observer (J-CQO). We compare AUC values of the linear Hotelling observer and J-CQO when the defect location is fixed and when it occurs in one of two locations. As expected, when the location is fixed a single channels maximizes AUC; location variability requires multiple channels to maximize the AUC. The AUC is estimated from both the projection data and reconstructed images. J-CQO is quadratic since it uses the first- and second- order statistics of the image data from both classes. The linear data reduction by the channels is described by an L x M channel matrix and in prior work we introduced an iterative gradient-based method for calculating the channel matrix. The dimensionality reduction from M measurements to L channels yields better estimates of these sample statistics from smaller sample sizes, and since the channelized covariance matrix is L x L instead of M x M, the matrix inverse is easier to compute. The novelty of our approach is the use of Jeffrey's divergence (J) as the figure of merit (FOM) for optimizing the channel matrix. We previously showed that the J-optimal channels are also the optimum channels for the AUC and the Bhattacharyya distance when the channel outputs are Gaussian distributed with equal means. This work evaluates the use of J as a surrogate FOM (SFOM) for AUC when these statistical conditions are not satisfied.

  5. Intentions to perform non-pharmaceutical protective behaviors during influenza outbreaks in Sweden: a cross-sectional study following a mass vaccination campaign.

    Directory of Open Access Journals (Sweden)

    Toomas Timpka

    Full Text Available Failure to incorporate the beliefs and attitudes of the public into theoretical models of preparedness has been identified as a weakness in strategies to mitigate infectious disease outbreaks. We administered a cross-sectional telephone survey to a representative sample (n = 443 of the Swedish adult population to examine whether self-reported intentions to improve personal hygiene and increase social distancing during influenza outbreaks could be explained by trust in official information, self-reported health (SF-8, sociodemographic factors, and determinants postulated in protection motivation theory, namely threat appraisal and coping appraisal. The interviewees were asked to make their appraisals for two scenarios: a an influenza with low case fatality and mild lifestyle impact; b severe influenza with high case fatality and serious disturbances of societal functions. Every second respondent (50.0% reported high trust in official information about influenza. The proportion that reported intentions to take deliberate actions to improve personal hygiene during outbreaks ranged between 45-85%, while less than 25% said that they intended to increase social distancing. Multiple logistic regression models with coping appraisal as the explanatory factor most frequently contributing to the explanation of the variance in intentions showed strong discriminatory performance for staying home while not ill (mild outbreaks: Area under the curve [AUC] 0.85 (95% confidence interval 0.82;0.89, severe outbreaks AUC 0.82 (95% CI 0.77;0.85 and acceptable performance with regard to avoiding public transportation (AUC 0.78 (0.74;0.82, AUC 0.77 (0.72;0.82, using handwash products (AUC 0.70 (0.65;0.75, AUC 0.76 (0.71;0.80, and frequently washing hands (AUC 0.71 (0.66;0.76, AUC 0.75 (0.71;0.80. We conclude that coping appraisal was the explanatory factor most frequently included in statistical models explaining self-reported intentions to carry out non

  6. Bioavalaibility and pharmacokinetic comparison of two formulations of metformin 850 mg tablets in healthy Colombian volunteers

    Directory of Open Access Journals (Sweden)

    Gloria Holguín

    2011-03-01

    Full Text Available Purpose: The aim of this study was to compare the bioavailability of two formulations of metformin 850 mg tablets: Glucophage® from Merck Santè laboratories (reference product and Metformin from Winthrop Pharmaceuticals de Colombia SA (test product in healthy Colombian volunteers.Methods: A random, double blind, two-period, two-week wash out period, crossover study was performed in 24 healthy male and female volunteers for a single 850-mg dose of metformin tablets administrated with 240 ml of water after 12 hours of fasting. Once the drug was administrated, blood samples were collected before and within 24 hour, and plasma metformin concentration was determined by using a validated HPLC method. Pharmacokinetic parameters such as Cmax, AUC0-96h, AUC0-∞, and Tmax were determined. The formulations were considered bioequivalent if the logarithmic mean ratios of ln-transformed Cmax and AUC0-∞ values were within the equivalence range of 80%-125%.Results: ANOVA analysis of the ln-transformed Cmax and AUC0-∞ indicated that none of the effects examined (formulation, period, within and between-subjet variances and carry over was statistically significant. The mean (±SD of Cmax 1217.38 (± 251.72 ng/ml vs. 1305.25 (± 301.06 ng/ml, AUC0-96h 1363.49 (± 315.51 ng.h/ml vs. 1584.82 (± 368.75 ng.h/ml, AUC0-∞, 7155.75 (± 1440.74 ng.h/ml vs. 7777.08 (± 1896.49 ng.h/ml, and Tmax 2.57 (± 0.93 h vs. 2.22 (± 0.94 h were obtained with test and reference formulations, respectively. These pharmacokinetic parameters presented differences with the results from other published papers. The 90% confidence interval of the logarithmic ratio of AUC0-∞ and Cmax was within the range of 80-125%.Conclusions: In this study in healthy Colombian volunteers, a single 850-mg dose of metformin tablet test formulation met the criteria for bioequivalence to the reference formulation based on pharmacokinetic parameters AUC0-∞ and Cmax.

  7. Bioavalaibility and pharmacokinetic comparison of two formulations of metformin 850 mg tablets in healthy Colombian volunteers

    Directory of Open Access Journals (Sweden)

    Gloria Holguín

    2011-04-01

    Full Text Available urpose: The aim of this study was to compare the bioavailability of two formulations of metformin 850 mg tablets: Glucophage® from Merck Santè laboratories (reference product and Metformin from Winthrop Pharmaceuticals de Colombia SA (test product in healthy Colombian volunteers. Methods: A random, double blind, two-period, two-week wash out period, crossover study was performed in 24 healthy male and female volunteers for a single 850-mg dose of metformin tablets administrated with 240 ml of water after 12 hours of fasting. Once the drug was administrated, blood samples were collected before and within 24 hour, and plasma metformin concentration was determined by using a validated HPLC method. Pharmacokinetic parameters such as Cmax, AUC0-96h, AUC0-∞, and Tmax were determined. The formulations were considered bioequivalent if the logarithmic mean ratios of ln-transformed Cmax and AUC0-∞ values were within the equivalence range of 80%-125%. Results: ANOVA analysis of the ln-transformed Cmax and AUC0-∞ indicated that none of the effects examined (formulation, period, within and between-subjet variances and carry over was statistically significant. The mean (±SD of Cmax 1217.38 (± 251.72 ng/ml vs. 1305.25 (± 301.06 ng/ml, AUC0-96h 1363.49 (± 315.51 ng.h/ml vs. 1584.82 (± 368.75 ng.h/ml, AUC0-∞, 7155.75 (± 1440.74 ng.h/ml vs. 7777.08 (± 1896.49 ng.h/ml, and Tmax 2.57 (± 0.93 h vs. 2.22 (± 0.94 h were obtained with test and reference formulations, respectively. These pharmacokinetic parameters presented differences with the results from other published papers. The 90% confidence interval of the logarithmic ratio of AUC0-∞ and Cmax was within the range of 80-125%. Conclusions: In this study in healthy Colombian volunteers, a single 850-mg dose of metformin tablet test formulation met the criteria for bioequivalence to the reference formulation based on pharmacokinetic parameters AUC0-∞ and Cmax.

  8. The inflammatory marker suPAR after cardiac arrest

    DEFF Research Database (Denmark)

    Rundgren, Malin; Lyngbaek, Stig; Fisker, Helle;

    2015-01-01

    BACKGROUND: Soluble urokinase plasminogen activator receptor (suPAR) is released in response to inflammatory stimuli, and plasma levels are associated with long-term outcomes. The ischemia/reperfusion injury caused by cardiac arrest (CA) and resuscitation triggers an inflammatory response...... analysis shoved an AUC of 0.76 at 6 hours. In the subgroup of CA of cardiac cause, the AUC was 0.84. CONCLUSION: suPAR levels at 6 and 36 hours after CA were significantly higher in nonsurviving patients compared with survivors; however, the overlap in suPAR levels between the outcome groups...

  9. Prognostic factors for progression-free and overall survival in advanced biliary tract cancer

    DEFF Research Database (Denmark)

    Bridgewater, J; Lopes, A; Wasan, H

    2016-01-01

    BACKGROUND: Biliary tract cancer is an uncommon cancer with a poor outcome. We assembled data from the National Cancer Research Institute (UK) ABC-02 study and 10 international studies to determine prognostic outcome characteristics for patients with advanced disease. METHODS: Multivariable...... associated with PFS and OS. ROC analysis suggested the models generated from the ABC-02 study had a limited prognostic value [6-month PFS: area under the curve (AUC) 62% (95% CI 57-68); 1-year OS: AUC 64% (95% CI 58-69)]. CONCLUSION: These data propose a set of prognostic criteria for outcome in advanced...

  10. Pharmacokinetics of single oral dose trazodone: a randomized, two-period, cross-over trial in healthy, adult, human volunteers under fed condition

    Science.gov (United States)

    Kale, Prashant; Agrawal, Yadvendra K.

    2015-01-01

    Objective: To assess the bioequivalence of single dose trazodone hydrochloride USP 100 mg tablets administered as an oral dose under fed condition. Methods:This study was an open-label, balanced, randomized, two-sequence, two-treatment, two-period, single oral dose, crossover bioequivalence study in healthy, adult, human subjects under fed conditions. After an overnight fast of at least 10 h, the subjects were served a high fat and high calorie vegetarian breakfast, which they were required to consume within 30 min. A single oral dose (100 mg) of either the test or the reference product was administered to the subjects. The primary pharmacokinetic parameters, maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) from time zero to last measurable concentration (AUC0−t) and extrapolated to infinity (AUC0−∞) were compared by an analysis of variance using log-transformed data. Bioequivalence was concluded if the 90% confidence intervals (CIs) of the adjusted geometric mean (gMean) ratios for Cmax and AUC were within the predetermined range of 80–125%, in accordance with regulatory requirements. Results:For the test formulation, the trazodone gMean Cmax was 1480.9 ng/mL (vs. 1520.2 ng/mL for reference), AUC0−t was 18193.0 ng·h/mL (vs. 18209.8 ng·h/mL) and AUC0−∞ was 19346.3 ng·h/mL (vs. 19393.4 ng·h/mL). The 90% CIs for the ratio (test/reference) were 93.0–102.0% for Cmax, 96.7–103.2% for AUC0−t and 96.1–103.5% for AUC0−∞. There were no deaths or serious adverse events during the conduct of the study. Conclusion:Test product when compared with the Reference product meets the bioequivalence criteria with respect to the extent of absorption of trazodone under fed condition. PMID:26483693

  11. Pharmacokinetics of single oral dose trazodone : a randomized, two-period, cross-over trial in healthy, adult, human volunteers under fed condition

    Directory of Open Access Journals (Sweden)

    PRASHANT eKALE

    2015-10-01

    Full Text Available Objective To assess the bioequivalence of single dose trazodone hydrochloride USP 100 mg tablets administered as an oral dose under fed condition. Methods This study was an open-label, balanced, randomized, two-sequence, two-treatment, two-period, single oral dose, crossover bioequivalence study in healthy, adult, human subjects under fed conditions. After an overnight fast of at least 10 hours, the subjects were served a high fat and high calorie vegetarian breakfast, which they were required to consume within 30 minutes. A single oral dose (100 mg of either the test or the reference product was administered to the subjects. The primary pharmacokinetic parameters, maximum plasma concentration (Cmax and area under the plasma concentration–time curve (AUC from time zero to last measurable concentration (AUC0-t and extrapolated to infinity (AUC0- were compared by an analysis of variance using log-transformed data. Bioequivalence was concluded if the 90% confidence intervals (CIs of the adjusted geometric mean (gMean ratios for Cmax and AUC were within the predetermined range of 80%-125%, in accordance with regulatory requirements. Results For the test formulation, the trazodone gMean Cmax was 1480.9 ng/mL (vs. 1520.2 ng/mL for reference, AUC0-t was 18193.0 ng·h/mL (vs. 18209.8 ng·h/mL and AUC0- was 19346.3 ng·h/mL (vs. 19393.4 ng·h/mL. The 90% CIs for the ratio (test/reference were 93.0-102.0% for Cmax, 96.7-103.2% for AUC0-t and 96.1-103.5% for AUC0-. There were no deaths or serious adverse events during the conduct of the study. Conclusion Test product when compared with the Reference product meets the bioequivalence criteria with respect to the rate and extent of absorption of Trazodone under fed condition.

  12. PHARMACOKINETIC AND BIOEQUIVALENCE COMPARISON BETWEEN EXTENDED RELEASE CAPSULES OF VENLAFAXINE HYDROCHLORIDE 150MG: AN OPEN LABEL, BALANCED, RANDOMIZED-SEQUENCE, SINGLE-DOSE, TWO-PERIOD CROSSOVER STUDY IN HEALTHY INDIAN MALE VOLUNTEERS

    Directory of Open Access Journals (Sweden)

    I.Sarath chandiran

    2011-03-01

    Full Text Available This bioequivalence study was designed to determine the pharmacokinetic, bioavailability and bioequivalence of Venlafaxine HCl 150 mg Extended Release Capsules in comparison with Effexor®-XR 150mg Extended Release Capsules after single dose administration under fed conditions in 20 healthy adult male subjects. Therefore the design of an open label, balanced, randomized, two-sequence, single dose, two way crossover study with a washout period of at least 7 days was used.Each volunteer received a 150 mg capsule of the reference or test drug respectively. On the day of dosing, blood samples were collected before dosing and at various time points up to 72 hours after dosing. Analysis of venlafaxine and its metabolite O-Desmethylvenlafaxine concentrations was performed using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS method. The pharmacokinetic parameters including Cmax, AUC0-t, AUC0-inf, Tmax, t1/2 and Kel were analyzed using the non-compartmental model. Drug safety and tolerability were assessed.The pharmacokinetic parameters including Cmax, AUC0-t, AUC0-inf, Tmax, t1/2 and Kel were analyzed using the non-compartmental model. Drug safety and tolerability were assessed. The primary pharmacokinetic parameters (Cmax, AUC0-t and AUC0-inf 90%CI were within the 80 to 125% interval required for bioequivalence as stipulated in the current regulations of the USFDA acceptance criteria. The geometric mean ratios (Test/Reference between the two products of extended-release venlafaxine capsule under fed condition were 104.91% (92.86%-118.53% and 114.41% (103.43%-124.55% for Cmax ratios, 102.24% (95.95%-108.94% and 105.27% (96.76%-114.53% for AUC0-t ratios and 101.66% (95.73%-107.97% and 104.71% (96.13%-114.05% for AUC0-inf ratios of Venlafaxine and its metabolite O-Desmethylvenlafaxine (ODV respectively. 20 volunteers had completed both treatment periods. There was no significant difference of the Tmax parameter between the two

  13. Assessment of the accuracy of real-time continuous glucose monitoring system and its correlated factors

    Institute of Scientific and Technical Information of China (English)

    洛佩

    2014-01-01

    Objective To assess the factors that influence the accuracy of real-time continuous glucose monitoring system(RT-CGM).Methods A total of 79 diabetic patients wore RT-CGM for three days continuously while calibrating by interphalangeal glucose values 4-8 times a day.We counted matching rate of interphalangeal glucose values and RT-CGM probe value,and analyzed correlation of the matching rate with MAGE,SDBG,MBG,AUC10,AUC3.9,and NGE by Pearson correlation analysis and multiple linear

  14. Bioequivalence study of two losartan formulations administered orally in healthy male volunteers.

    Science.gov (United States)

    Bienert, Agnieszka; Brzezińiski, Rafał; Szałek, Edyta; Dubai, Vitali; Grześkowiak, Edmund; Dyderski, Stanisław; Drobnik, Leon; Wolc, Anna; Olejniczak-Rabinek, Magdalena

    2006-01-01

    The bioavailability of a new losartan preparation (2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol monopotassium salt, CAS 114798-26-4) was compared with the reference preparation of the drug in 24 healthy male volunteers, aged between 19 and 32. The open, randomized, single-blind two-sequence, two-period crossover study design was performed. Under fasting conditions, each subject received a single oral dose of 100 mg losartan as a test or reference formulation. The plasma concentrations of losartan and its active metabolite were analyzed by a rapid and sensitive HPLC method with UV detection. The pharmacokinetic parameters included AUC0-36h, AUC0-infinity, Cmax, t1/2, and Ke. Values of AUC0-infinity demonstrate nearly identical bioavailability of losartan from the examined formulations. The AUC0-infinity of losartan was 2019.92+/-1002.90 and 2028.58+/-837.45 ng x h/ml for the test and reference formulation, respectively. The AUC0-infinity of the metabolite was 10851.52+/-4438.66 and 11041.18 +/-5015.81 ng x h/ml for test and reference formulation, respectively. The maximum plasma concentration (Cmax) of losartan was 745.94+/-419.75 ng/ml for the test and 745.74+/-329.99 ng/ml for the reference product and the Cmax of the metabolite was 1805.77+/-765.39 and 1606.22 +/-977.22 ng/ml for the test and reference product, respectively. No statistical differences were observed for Cmax and the area under the plasma concentration-time curve for both losartan and its active metabolite. 90 % confidence limits calculated for Cmax and AUC from zero to infinity (AUC0-infinity) of losartan and its metabolite were included in the bioequivalence range (0.8-1.25 for AUC). This study shows that the test formulation is bioequivalent to the reference formulation for losartan and its main active metabolite.

  15. Bioavailability of IgG Administered by the Subcutaneous Route

    OpenAIRE

    Berger, Melvin; Jolles, Stephen; Orange, Jordan S.; Sleasman, John W

    2013-01-01

    Purpose US licensing studies of subcutaneous IgG (SCIG) calculate dose adjustments necessary to achieve area under the curve (AUC) of serum IgG vs. time on SCIG that is non-inferior to that on intravenous IgG (IVIG), within the FDA-set limit of ±20 %. The results are interpreted as showing that different SCIGs differ in bioavailability. We used three approaches to determine if the bioavailabilities were actually different. Methods Dose adjustments and AUCs from published licensing studies wer...

  16. In vivo doses of butadiene epoxides as estimated from in vitro enzyme kinetics by using cob(I)alamin and measured hemoglobin adducts: An inter-species extrapolation approach

    Energy Technology Data Exchange (ETDEWEB)

    Motwani, Hitesh V., E-mail: hitesh.motwani@mmk.su.se; Törnqvist, Margareta

    2014-12-15

    1,3-Butadiene (BD) is a rodent and human carcinogen. In the cancer tests, mice have been much more susceptible than rats with regard to BD-induced carcinogenicity. The species-differences are dependent on metabolic formation/disappearance of the genotoxic BD epoxy-metabolites that lead to variations in the respective in vivo doses, i.e. “area under the concentration-time curve” (AUC). Differences in AUC of the most gentoxic BD epoxy-metabolite, diepoxybutane (DEB), are considered important with regard to cancer susceptibility. The present work describes: the application of cob(I)alamin for accurate measurements of in vitro enzyme kinetic parameters associated with BD epoxy-metabolites in human, mouse and rat; the use of published data on hemoglobin (Hb) adduct levels of BD epoxides from BD exposure studies on the three species to calculate the corresponding AUCs in blood; and a parallelogram approach for extrapolation of AUC of DEB based on the in vitro metabolism studies and adduct data from in vivo measurements. The predicted value of AUC of DEB for humans from the parallelogram approach was 0.078 nM · h for 1 ppm · h of BD exposure compared to 0.023 nM · h/ppm · h as calculated from Hb adduct levels observed in occupational exposure. The corresponding values in nM · h/ppm · h were for mice 41 vs. 38 and for rats 1.26 vs. 1.37 from the parallelogram approach vs. experimental exposures, respectively, showing a good agreement. This quantitative inter-species extrapolation approach will be further explored for the clarification of metabolic rates/pharmacokinetics and the AUC of other genotoxic electrophilic compounds/metabolites, and has a potential to reduce and refine animal experiments. - Highlights: • In vitro metabolism to in vivo dose extrapolation of butadiene metabolites was proposed. • A parallelogram approach was introduced to estimate dose (AUC) in humans and rodents. • AUC of diepoxybutane predicted in humans was 0.078 nM h/ppm h

  17. Lung deposition of inhaled drugs increases with age

    DEFF Research Database (Denmark)

    Onhøj, J; Thorsson, L; Bisgaard, H

    2000-01-01

    versus time (AUC). Terminal half-life (T(1/2)) was evaluated. Dose to patient, AUC, and T(1/2) were similar in the three age groups (p > 0.35). Nebuchamber delivers the same dose of budesonide to young children and adults. Yet the plasma concentration of budesonide was similar in young children...... and adults. Therefore, lung dose is increased with age. This suggests that from a safety perspective, the prescribed dose of budesonide inhaled from a pMDI with Nebuchamber spacer need not be adjusted for age or use of facemask. Children and adults can use the same nominal dose of budesonide via Nebuchamber...

  18. Parameters of glucose metabolism and the aging brain

    DEFF Research Database (Denmark)

    Akintola, Abimbola A; van den Berg, Annette; Altmann-Schneider, Irmhild;

    2015-01-01

    Given the concurrent, escalating epidemic of diabetes mellitus and neurodegenerative diseases, two age-related disorders, we aimed to understand the relation between parameters of glucose metabolism and indices of pathology in the aging brain. From the Leiden Longevity Study, 132 participants (mean...... age 66 years) underwent a 2-h oral glucose tolerance test to assess glucose tolerance (fasted and area under the curve (AUC) glucose), insulin sensitivity (fasted and AUC insulin and homeostatic model assessment of insulin sensitivity (HOMA-IS)) and insulin secretion (insulinogenic index). 3-T brain...... different parameters of glucose metabolism (impairment of which is characteristic of diabetes mellitus) and brain aging....

  19. The effect of wound instillation of a novel purified capsaicin formulation on postherniotomy pain: A double-blind, randomized, placebo-controlled study

    DEFF Research Database (Denmark)

    Aasvang, Eske Kvanner; Hansen, J.B.; Malmstrom, J.;

    2008-01-01

    more often in the capsaicin-treated group. CONCLUSION: In the setting of a well-defined analgesic protocol standard, VAS AUC analysis and a mixed-effect analysis showed superior analgesia of capsaicin relative to placebo during the first 3-4 days after inguinal hernia repair Udgivelsesdato: 2008/7...... 4975) after open mesh groin hernia repair in 41 adult male patients. The primary end-point was average daily visual analog scale (VAS) pain scores during the first week after surgery assessed as area under the curve (AUC). Pain was recorded twice daily in a pain diary for 4 wk. Physical examination...

  20. Cyclosporine C2 levels have impact on incidence of rejection in de novo lung but not heart transplant recipients: the NOCTURNE study

    DEFF Research Database (Denmark)

    Iversen, Martin; Nilsson, Folke; Sipponen, Jorma

    2009-01-01

    BACKGROUND: Cyclosporine (CsA) absorption varies early after transplantation and can be accurately assessed by the area under the absorption curve (AUC). The 2-hour post-dose (C2) level of CsA in whole blood is reported to be a useful surrogate marker of CsA AUC in kidney and liver transplant...... monitoring, but should be further explored in thoracic organ recipients. METHODS: In a 12-month study we included de novo lung (n = 95) and heart (n = 96) recipients. All participants received cyclosporine (Sandimmun Neoral) monitored by C0 and blood was collected for analysis of C2 retrospectively...

  1. CT triage for lung malignancy

    DEFF Research Database (Denmark)

    Kusk, Martin Weber; Karstoft, Jens; Mussmann, Bo

    2015-01-01

    Background: Generation of multiplanar reformation (MPR) images has become automatic on most modern computed tomography (CT) scanners, potentially increasing the workload of the reporting radiologists. It is not always clear if this increases diagnostic performance in all clinical tasks. Purpose...... the performance of the four readers, using the area under the curve (AUC) as figure of merit. Results: No statistically significant difference of sensitivity and specificity was found for any of the readers when compared to the original reports. ROC analysis yielded AUCs in the range of 0.92–0.93 for all readers...

  2. Logistic回归和ROC曲线评价甲胎蛋白、癌胚抗原和糖链抗原19-9在肝癌诊断中的价值%The value of assessing AFP and CEA and CA19 -9 by using logistic regression and ROC curve in the diagnosis of liver cancer

    Institute of Scientific and Technical Information of China (English)

    戴大飞; 陈晓鹏

    2016-01-01

    目的 探讨应用Logistic回归和ROC曲线综合评价甲胎蛋白( AFP)、癌胚抗原( CEA)和糖链抗原19-9(CA19-9)在肝癌诊断中的价值. 方法 采用电化学发光原理测定AFP、CEA、CA19-9. 检测126例肝癌患者(肝癌组)、75例肝病患者(肝病组) ,通过ROC曲线分析AFP、CEA、CA19-9及三种肿瘤标志物联合检测的Logistic回归结果的ROC曲线值( AUC值). 结果 肝癌-肝良性疾病者中,除CEA外,其余2种肿瘤标志物均有显著性(P0.05). 在肝癌-肝良性疾病中,AUC( AFP) >AUC ( CA19-9)>AUC( CEA);三种肿瘤标志物联合检测的AUC值均高于三项肿瘤标志物单一检查的AUC.结论 联合检测血清AFP、CEA、CA19-9对肝癌具有较高的诊断价值,联合检测三种肿瘤标志物可提高肝癌的诊断率.%Objective To explore the value of assessing AFP and CEA and CA19 -9 by logistic regression and ROC curve in the diagnosis for liver cancer.Methods Serum AFP, CEA and CA19-9 ( using CLIA) levels were measured in 126 patients with liver cancer, 75 patients with benign liver disorders.The area under the ROC curves ( AUC ) of AFP, CEA and CA19 -9 from logistic regression results was compared.Results The serum concentrations of AFP and CA19 -9 in liver cancer patients were higher than those in patients with benign liver diseases (P0.05).In cancer-benign disorder group, the AUC of AFP was larger than the AUC of CA199.the AUC of CA19-9 was larger than the AUC of CEA.AUC value of AFP, CEA and CA19-9 combination detection was larger than AUC value of AFP, CEA and CA19-9 single detection.Conclusions The combination detection of serum AFP, CEA and CA19-9 have higher diagnostic value in liver cancer, also can improve the diagnosis rate of liver cancer.

  3. 不同糖代谢水平人群胰岛素分泌和胰岛素敏感性的分析%Differences in insulin sensitivity and insulin secretion in subjects with impaired glucose regulation

    Institute of Scientific and Technical Information of China (English)

    李国春; 巫开文; 袁辉; 周莉

    2013-01-01

    Objective To explore the defects in insulin secretion and insulin sensitivity contributing to the development and progression of type 2 diabetes mellitus(T2DM).Methods Plasma insulin and glucose were measured after oral glucose tolerance test (OGTT) to calculate the insulinognic index(IGI) , AUC ins12/0AUC glu120,HOMA-IR and Matsuda index in 267 subjects with normal glucose tolerance(NGT) ,prediabetes(preDM) ,and T2DM patients with disease duration 5 years.Results The mean IGI and AUC ins120/AUC glu120 levels were similar in NGT and preDM subjects(P>0.05) ,ins120/AUC glu120 levels was significantly decreased with the duration of diabetes, but with no difference of IGI.The mean Matsuda index decreased relative to the deteroration of glucose tolerance in NGT and preDM subjects(P=0.004) , however differences in the Matsuda index was not related to disease duration in T2DM(P>0.05).There was no significant difference in HOMA-IR to the impaired glucose regulation(P>0.05).Conclusion Defects in both insulin sensitivity and insulin secretion could contribute to T2DM,but decreased total insulin secretion might be more important in the progression of T2DM.The total insulin secretion might be play a even more important role in the progression of T2DM than early insulin secretion.%目的 研究胰岛素分泌和胰岛素敏感性在2型糖尿病(T2DM)发展和进程中的作用.方法 267例研究对象做口服葡萄糖耐量试验(OGTT),分别在0、30、60、90、120 min测葡萄糖和胰岛素水平,计算胰岛素分泌指数(IGI)、胰岛素抵抗指数(HOMA-IR)、120分钟胰岛素分泌(AUC ins120/AUC glu120)及Matsuda指数;依据OGTT结果及临床资料将研究对象分为糖耐量正常组(NGT),糖尿病前期组(preDM),糖尿病病程(DM)5年组,比较5组胰岛素分泌及胰岛素敏感性差异.结果 IGI和AUC ins120/AUC glu120在NGT、preDM组均无统计学差异(P>0.05);DM 5年组间 AUC ins120/AUC glu120显著降

  4. Dose-Dependent Change in Elimination Kinetics of Ethanol due to Shift of Dominant Metabolizing Enzyme from ADH 1 (Class I) to ADH 3 (Class III) in Mouse.

    Science.gov (United States)

    Haseba, Takeshi; Kameyama, Kouji; Mashimo, Keiko; Ohno, Youkichi

    2012-01-01

    ADH 1 and ADH 3 are major two ADH isozymes in the liver, which participate in systemic alcohol metabolism, mainly distributing in parenchymal and in sinusoidal endothelial cells of the liver, respectively. We investigated how these two ADHs contribute to the elimination kinetics of blood ethanol by administering ethanol to mice at various doses, and by measuring liver ADH activity and liver contents of both ADHs. The normalized AUC (AUC/dose) showed a concave increase with an increase in ethanol dose, inversely correlating with β. CL(T) (dose/AUC) linearly correlated with liver ADH activity and also with both the ADH-1 and -3 contents (mg/kg B.W.). When ADH-1 activity was calculated by multiplying ADH-1 content by its V(max⁡)/mg (4.0) and normalized by the ratio of liver ADH activity of each ethanol dose to that of the control, the theoretical ADH-1 activity decreased dose-dependently, correlating with β. On the other hand, the theoretical ADH-3 activity, which was calculated by subtracting ADH-1 activity from liver ADH activity and normalized, increased dose-dependently, correlating with the normalized AUC. These results suggested that the elimination kinetics of blood ethanol in mice was dose-dependently changed, accompanied by a shift of the dominant metabolizing enzyme from ADH 1 to ADH 3.

  5. Physiologically Based Pharmacokinetic Modeling Framework for Quantitative Prediction of an Herb–Drug Interaction

    Science.gov (United States)

    Brantley, S J; Gufford, B T; Dua, R; Fediuk, D J; Graf, T N; Scarlett, Y V; Frederick, K S; Fisher, M B; Oberlies, N H; Paine, M F

    2014-01-01

    Herb–drug interaction predictions remain challenging. Physiologically based pharmacokinetic (PBPK) modeling was used to improve prediction accuracy of potential herb–drug interactions using the semipurified milk thistle preparation, silibinin, as an exemplar herbal product. Interactions between silibinin constituents and the probe substrates warfarin (CYP2C9) and midazolam (CYP3A) were simulated. A low silibinin dose (160 mg/day × 14 days) was predicted to increase midazolam area under the curve (AUC) by 1%, which was corroborated with external data; a higher dose (1,650 mg/day × 7 days) was predicted to increase midazolam and (S)-warfarin AUC by 5% and 4%, respectively. A proof-of-concept clinical study confirmed minimal interaction between high-dose silibinin and both midazolam and (S)-warfarin (9 and 13% increase in AUC, respectively). Unexpectedly, (R)-warfarin AUC decreased (by 15%), but this is unlikely to be clinically important. Application of this PBPK modeling framework to other herb–drug interactions could facilitate development of guidelines for quantitative prediction of clinically relevant interactions. PMID:24670388

  6. Influence of food on the oral bioavailability of deramciclane from film-coated tablet in healthy male volunteers.

    Science.gov (United States)

    Drabant, Sándor; Nemes, Katalin Balogh; Horváth, Viola; Tolokán, Antal; Grézal, Gyula; Anttila, Markku; Gachályi, Béla; Kanerva, Harri; Al-Behaisi, Samar; Horvai, George; Klebovich, Imre

    2004-11-01

    The effect of a high-fat meal on the oral bioavailability of deramciclane 30 mg tablet was evaluated in 18 healthy male volunteers in a randomised, single dose, two-way crossover study. The drug was administered following an overnight fast or a standardised high-fat breakfast. The plasma concentrations of deramciclane and N-desmethylderamciclane were determined by using a validated HPLC-MS -MS/MS method. An effect of food on the bioavailability was indicated if the 90% confidence interval (CI) for the ratio of geometric means of fed and fasted treatments was not contained in the equivalence limit of 0.8-1.25 for AUC and C(max). The ratios of the mean C(max) and AUC(0-infinity) values of deramciclane were 1.24 (90% CI 1.12-1.38) and 1.31 (90% CI 1.21-1.41) in fed versus fasted subjects, which overlapped but exceeded the equivalence limit. In contrast to the parent compound, the 90% CI of the mean ratios for AUC(0-infinity) and C(max) of N-desmethylderamciclane were within the predefined range. The 24 and 31% increase in C(max) and AUC(0-infinity) of deramciclane, respectively, under fed condition is modest and probably has no clinical significance since it is relatively small compared to the inter-individual variability of these parameters.

  7. Development of an online, publicly accessible naive Bayesian decision support tool for mammographic mass lesions based on the American College of Radiology (ACR) BI-RADS lexicon

    Energy Technology Data Exchange (ETDEWEB)

    Benndorf, Matthias; Kotter, Elmar; Langer, Mathias [University Hospital Freiburg, Department of Radiology, Freiburg (Germany); Herda, Christoph [Kantonsspital Graubuenden, Chur (Switzerland); Wu, Yirong; Burnside, Elizabeth S. [University of Wisconsin-Madison School of Medicine and Public Health, Department of Radiology, Madison, WI (United States)

    2015-06-01

    To develop and validate a decision support tool for mammographic mass lesions based on a standardized descriptor terminology (BI-RADS lexicon) to reduce variability of practice. We used separate training data (1,276 lesions, 138 malignant) and validation data (1,177 lesions, 175 malignant). We created naive Bayes (NB) classifiers from the training data with tenfold cross-validation. Our ''inclusive model'' comprised BI-RADS categories, BI-RADS descriptors, and age as predictive variables; our ''descriptor model'' comprised BI-RADS descriptors and age. The resulting NB classifiers were applied to the validation data. We evaluated and compared classifier performance with ROC-analysis. In the training data, the inclusive model yields an AUC of 0.959; the descriptor model yields an AUC of 0.910 (P < 0.001). The inclusive model is superior to the clinical performance (BI-RADS categories alone, P < 0.001); the descriptor model performs similarly. When applied to the validation data, the inclusive model yields an AUC of 0.935; the descriptor model yields an AUC of 0.876 (P < 0.001). Again, the inclusive model is superior to the clinical performance (P < 0.001); the descriptor model performs similarly. We consider our classifier a step towards a more uniform interpretation of combinations of BI-RADS descriptors. We provide our classifier at www.ebm-radiology.com/nbmm/index.html. (orig.)

  8. Three-way, three-period, crossover bioequivalence study of single oral dose of three brands of 300 mg phenytoin sodium tablets marketed in India, on healthy Indian human volunteers

    Directory of Open Access Journals (Sweden)

    Maulik S Doshi

    2013-01-01

    Full Text Available Objective: To compare the bioavailability of two brands of phenytoin sodium tablets available in the Indian market using Eptoin TM as the reference. Materials and Methods: A randomized, assessor-blind, three-way crossover design study was carried out over a period of 6 months after approval from the Institutional Review Board (IRB. Twenty-two healthy male participants received a single oral 300 mg oral tablet of either of the formulations with a 2-week washout. Blood samples were collected predose and at regular intervals postdose. Plasma phenytoin levels were estimated by high-performance liquid chromatography. Calculation of C max , AUC 0-t , and AUC 0-∞ was done by the linear trapezoidal rule and 90-110% margin (90% confidence interval (CI was used to assess bioequivalence. Results: Twenty volunteers completed the study. It was seen that the log-transformed values of C max , AUC 0-t , and AUC 0-∞ of the test formulations were not within the specified limits. Conclusion: Bioinequivalence of available phenytoin brands indicates that switching brands could lead to variations in blood concentrations and thus impact safety and efficacy. If a brand switch is done for any reason, stringent drug-level monitoring is advised.

  9. Laborübungen zur Fabrik- und Materialflußsimulation im Lehrkomplex - Fabrikplanung/Materialflußgestaltung - (Grundkonzept)

    OpenAIRE

    Grundig, Claus-Gerold; Hartrampf, Dieter

    1995-01-01

    Aktuelle Entwicklungen in der Industriepraxis und der Wissenschaft machen deutlich, daß die Gestaltung und Steuerung effektiver Fabrik -und Materialflußprozesse den Einsatz moderner Analysemethoden sowohl im Planungs- als auch im Realisierungsstadium erforderlich macht. Die Anwendung der Simulationstechnik zur Analyse und zielgerichteten Synthese stochastischer, dynamischer und hochvernetzter Prozesse hat sich als ein elegantes Hilfsmittel allgemein durchgesetzt, eine steigende Tendenz auc...

  10. Paclitaxel and carboplatin concurrent with radiotherapy for primary cervical cancer

    NARCIS (Netherlands)

    De Vos, FYFL; Bos, AME; Gietema, JA; Pras, E; Van Der Zee, AGJ; De Vries, EGE; Willemse, PHB

    2004-01-01

    Background: Concurrent radiochemotherapy is currently considered the new standard treatment in locally advanced cervical cancer. Patients and Methods: Eight women with cervical cancer stage IB2-IVA were treated with standard radiation therapy in combination with standard carboplatin (AUC=2, once wee

  11. Femoral perfusion after pulsed electromagnetic field stimulation in a steroid-induced osteonecrosis model.

    Science.gov (United States)

    Ikegami, Akira; Ueshima, Keiichiro; Saito, Masazumi; Ikoma, Kazuya; Fujioka, Mikihiro; Hayashi, Shigeki; Ishida, Masashi; Fujiwara, Hiroyoshi; Mazda, Osam; Kubo, Toshikazu

    2015-07-01

    This study was designed to evaluate femoral perfusion after pulsed electromagnetic field (PEMF) stimulation in a steroid-induced osteonecrosis rabbit model by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Steroid-induced osteonecrosis was produced by single intramuscular injection of methylprednisolone in 15 rabbits. Eight rabbits underwent PEMF stimulation (PEMF group) and seven did not (control group). DCE-MRI was performed before PEMF stimulation, immediately before steroid administration, and 1, 5, 10, and 14 days after steroid administration. Regions of interest were set in the bilateral proximal femora. Enhancement ratio (ER), initial slope (IS), and area under the curve (AUC) were analyzed. ER, IS, and AUC in the control group significantly decreased after steroid administration compared with before administration (P<0.05). In PEMF group, IS significantly decreased; however, ER and AUC showed no significant differences after steroid administration compared with before. ER and IS in PEMF group were higher than in control group until 10th day, and AUC was higher until 5th day after steroid administration (P<0.05). PEMF stimulation restrains the decrease in blood flow after steroid administration.

  12. Regulation of diurnal variation of cholesterol 7alpha-hydroxylase (CYP7A1) activity in healthy subjects.

    Science.gov (United States)

    Kovár, J; Lenícek, M; Zimolová, M; Vítek, L; Jirsa, M; Pitha, J

    2010-01-01

    Cholesterol 7alpha-hydroxylase (CYP7A1), the key regulatory enzyme of bile acid synthesis, displays a pronounced diurnal variation. To better understand the regulation of CYP7A1 activity, three day-long examinations were carried out in 12 healthy men. The concentrations of 7alpha-hydroxycholest-4-en-3-one (C4), a surrogate marker of CYP7A1 activity, bile acids (BA), insulin, glucose, nonesterified fatty acids, triglycerides, and cholesterol were measured in serum in 90-min intervals from 7 AM till 10 PM. To lower and to increase BA concentration during the study, the subjects received cholestyramine and chenodeoxycholic acid (CDCA), respectively, in two examinations. No drug was used in the control examination. There was a pronounced diurnal variation of C4 concentration with a peak around 1 PM in most of the subjects. The area under the curve (AUC) of C4 concentration was five times higher and three times lower when subjects were treated with cholestyramine and CDCA, respectively. No relationship was found between AUC of C4 and AUC of BA concentration, but AUC of C4 correlated positively with that of insulin. Moreover, short-term treatment with cholestyramine resulted in about 10 % suppression of glycemia throughout the day. Our results suggest that insulin is involved in the regulation of diurnal variation of CYP7A1 activity in humans.

  13. The Pedagogy of Failure in the Global Market

    Science.gov (United States)

    Silk, Janet

    2011-01-01

    An American artist and art educator discusses her experience teaching at the American University in Cairo, Egypt (AUC). Students are confronted by local and international discourse about authenticity, integrity and influence. They express their frustration and anxiety about their chances for success in the global art market. The author questions…

  14. Using quantitative image analysis to classify axillary lymph nodes on breast MRI: A new application for the Z 0011 Era

    Energy Technology Data Exchange (ETDEWEB)

    Schacht, David V., E-mail: dschacht@radiology.bsd.uchicago.edu; Drukker, Karen, E-mail: kdrukker@uchicago.edu; Pak, Iris, E-mail: irisgpak@gmail.com; Abe, Hiroyuki, E-mail: habe@radiology.bsd.uchicago.edu; Giger, Maryellen L., E-mail: m-giger@uchicago.edu

    2015-03-15

    Highlights: •Quantitative image analysis showed promise in evaluating axillary lymph nodes. •13 of 28 features performed better than guessing at metastatic status. •When all features were used in together, a considerably higher AUC was obtained. -- Abstract: Purpose: To assess the performance of computer extracted feature analysis of dynamic contrast enhanced (DCE) magnetic resonance images (MRI) of axillary lymph nodes. To determine which quantitative features best predict nodal metastasis. Methods: This institutional board-approved HIPAA compliant study, in which informed patient consent was waived, collected enhanced T1 images of the axilla from patients with breast cancer. Lesion segmentation and feature analysis were performed on 192 nodes using a laboratory-developed quantitative image analysis (QIA) workstation. The importance of 28 features were assessed. Classification used the features as input to a neural net classifier in a leave-one-case-out cross-validation and evaluated with receiver operating characteristic (ROC) analysis. Results: The area under the ROC curve (AUC) values for features in the task of distinguishing between positive and negative nodes ranged from just over 0.50 to 0.70. Five features yielded AUCs greater than 0.65: two morphological and three textural features. In cross-validation, the neural net classifier obtained an AUC of 0.88 (SE 0.03) for the task of distinguishing between positive and negative nodes. Conclusion: QIA of DCE MRI demonstrated promising performance in discriminating between positive and negative axillary nodes.

  15. Effect of oral glucose administration on rebound growth hormone release in normal and obese women: the role of adiposity, insulin sensitivity and ghrelin.

    Directory of Open Access Journals (Sweden)

    Lara Pena-Bello

    Full Text Available Metabolic substrates and nutritional status play a major role in growth hormone (GH secretion. Uncovering the mechanisms involved in GH secretion following oral glucose (OG administration in normal and obese patients is a pending issue.The aim of this study was to investigate GH after OG in relation with adiposity, insulin secretion and action, and ghrelin secretion in obese and healthy women, to further elucidate the mechanism of GH secretion after OG and the altered GH secretion in obesity.We included 64 healthy and obese women. After an overnight fast, 75 g of OG were administered; GH, glucose, insulin and ghrelin were obtained during 300 minutes. Insulin secretion and action indices and the area under the curve (AUC were calculated for GH, glucose, insulin and ghrelin. Univariate and multivariate linear regression analyses were employed.The AUC of GH (μg/L•min was lower in obese (249.8±41.8 than in healthy women (490.4±74.6, P=0.001. The AUC of total ghrelin (pg/mL•min was lower in obese (240995.5±11094.2 than in healthy women (340797.5±37757.5, P=0.042. There were significant correlations between GH secretion and the different adiposity, insulin secretion and action, and ghrelin secretion indices. After multivariate analysis only ghrelin AUC remained a significant predictor for fasting and peak GH.

  16. Matrix formation in sustained release tablets: possible mechanism of dose dumping.

    Science.gov (United States)

    Krajacic, Aleksandra; Tucker, Ian G

    2003-01-30

    Conditions under which poly(ethyl acrylate, methyl methacrylate) 2:1 (poly(EA-MMA), Eudragit NE) forms a stable matrix were investigated in tablets with diclofenac sodium (DS) as an active substance. DS was granulated with the aqueous polymer dispersion. Granules and/or tablets were cured under various temperature and humidity conditions. A six position rotating disk (200 rpm) apparatus was used for the release studies conducted in 37 degrees C acid then phosphate buffer (0.4 M) pH 6.8 or buffer only as the dissolution media. Morphological characteristics of the tablet surface were observed under SEM. Changes in tablet structure upon curing were evaluated through changes in tablet mechanical characteristics. Modulus of rupture, Young's modulus, AUC, AUC(max), where AUC=AUC(max), were determined by the three-point bending test. Some poorly cured tablets dose-dumped when placed directly into buffer but not if first placed in acid and then buffer. A higher content of polymer in the matrix, led to formation of a stronger polymer network upon higher curing temperature and/or longer curing duration, whereas relative humidity had a minor effect.

  17. Validity of Outcome Prediction Scoring Systems in Korean Patients with Severe Adult Respiratory Distress Syndrome Receiving Extracorporeal Membrane Oxygenation Therapy.

    Science.gov (United States)

    Lee, Seunghyun; Yeo, Hye Ju; Yoon, Seong Hoon; Lee, Seung Eun; Cho, Woo Hyun; Jeon, Doo Soo; Kim, Yun Seong; Son, Bong Soo; Kim, Do Hyung

    2016-06-01

    Recently, several prognostic scoring systems for patients with severe acute respiratory distress syndrome (ARDS) requiring extracorporeal membrane oxygenation (ECMO) have been published. The aim of this study was to validate the established scoring systems for outcome prediction in Korean patients. We retrospectively reviewed the data of 50 patients on ECMO therapy in our center from 2012 to 2014. A calculation of outcome prediction scoring tools was performed and the comparison across various models was conducted. In our study, the overall hospital survival was 46% and successful weaning rate was 58%. The Predicting Death for Severe ARDS on V-V ECMO (PRESERVE) score showed good discrimination of mortality prediction for patients on ECMO with AUC of 0.80 (95% CI 0.66-0.90). The respiratory extracorporeal membrane oxygenation survival prediction (RESP) score and simplified acute physiology score (SAPS) II score also showed fair prediction ability with AUC of 0.79 (95% CI 0.65-0.89) and AUC of 0.78 (95% CI 0.64-0.88), respectively. However, the ECMOnet score failed to predict mortality with AUC of 0.51 (95% CI 0.37-0.66). When evaluating the predictive accuracy according to optimal cut-off point of each scoring system, RESP score had a best specificity of 91.3% and 66.7% of sensitivity, respectively. This study supports the clinical usefulness of the prognostic scoring tools for severe ARDS with ECMO therapy when applying to the Korean patients receiving ECMO.

  18. Association of neck circumference with general and abdominal obesity in children and adolescents: the weight disorders survey of the CASPIAN-IV study

    Science.gov (United States)

    Kelishadi, Roya; Djalalinia, Shirin; Motlagh, Mohammad Esmaiel; Rahimi, Ali; Bahreynian, Maryam; Arefirad, Tahereh; Ardalan, Gelayol; Safiri, Saeid; Hasani, Motahare; Asayesh, Hamid; Mansourian, Morteza; Qorbani, Mostafa

    2016-01-01

    Objectives This study aimed to evaluate the association of neck circumference (NC) with obesity to determine the sex-specific and age-specific optimal cut-off points of this measure in association with obesity in a national sample of the Iranian paediatric population. Methods This survey on weight disorders was conducted among a national sample of Iranian children and adolescents, aged 6–18 years. Using the area under the curve (AUC) of the receiver operator characteristic curves, we evaluated the association of NC with general and abdominal obesity. Results This national survey was conducted among 23 043 school students (50.8% boys) with a mean age (SD) of 12.55 (3.31) years. A significant association was documented between NC and other anthropometric measures in both sexes and in the whole population. In all age groups and genders, NC performed relatively well in classifying participants to overweight (AUC: 0.67 to 0.75, p<0.001), general obesity (AUC: 0.81 to 0.85, p<0.001) and abdominal obesity (AUC: 0.73 to 0.78, p<0.001). Conclusions NC can be considered as a simple time-saving clinical tool for obesity detection in large population-based studies in children and adolescents. It is significantly correlated with indices of adiposity and can reliably identify children with general and abdominal obesity in the Iranian paediatric population. PMID:27694487

  19. Reliability and validity of a continuous pain registration procedure

    NARCIS (Netherlands)

    van Wijk, A.J.; Lobbezoo, F.; Hoogstraten, J.

    2013-01-01

    Background Conventional pain rating scales [i.e. visual analogue scales (VAS) or numerical rating scales (NRS)] only provide a summary for different levels of pain felt, while the duration of these levels is not accounted for. If pain can be rated continuously, the area under the curve (AUC) of vary

  20. Comparing Postural Stability Entropy Analyses to Differentiate Fallers and Non-fallers.

    Science.gov (United States)

    Fino, Peter C; Mojdehi, Ahmad R; Adjerid, Khaled; Habibi, Mohammad; Lockhart, Thurmon E; Ross, Shane D

    2016-05-01

    The health and financial cost of falls has spurred research to differentiate the characteristics of fallers and non-fallers. Postural stability has received much of the attention with recent studies exploring various measures of entropy. This study compared the discriminatory ability of several entropy methods at differentiating two paradigms in the center-of-pressure of elderly individuals: (1) eyes open (EO) vs. eyes closed (EC) and (2) fallers (F) vs. non-fallers (NF). Methods were compared using the area under the curve (AUC) of the receiver-operating characteristic curves developed from logistic regression models. Overall, multiscale entropy (MSE) and composite multiscale entropy (CompMSE) performed the best with AUCs of 0.71 for EO/EC and 0.77 for F/NF. When methods were combined together to maximize the AUC, the entropy classifier had an AUC of for 0.91 the F/NF comparison. These results suggest researchers and clinicians attempting to create clinical tests to identify fallers should consider a combination of every entropy method when creating a classifying test. Additionally, MSE and CompMSE classifiers using polar coordinate data outperformed rectangular coordinate data, encouraging more research into the most appropriate time series for postural stability entropy analysis.

  1. IL-18 Serum Level in Adult Onset Still’s Disease: A Marker of Disease Activity

    Directory of Open Access Journals (Sweden)

    Serena Colafrancesco

    2012-01-01

    Conclusions. Higher levels of IL-18 are detected in active AODS patients and correlate with disease activity and inflammatory laboratory features. ROC-AUC analysis of the serum concentration of IL-18 suggests that it can be considered a diagnostic marker of AOSD. This paper supports the targeting of this cytokine as a possible therapeutic option in AOSD.

  2. The use of real-time optical feedback to improve outcomes

    Science.gov (United States)

    Magaña, Isidro B.; Adhikari, Pratik; Yendluri, Raghuvara B.; Goodrich, Glenn P.; Schwartz, Jon A.; O'Neal, D. P.

    2014-03-01

    More than a decade into the development of gold nanoparticles for cancer therapies, with multiple clinical trials underway, ongoing pre-clinical research continues towards better understanding in vivo interactions with the goal of treatment optimization through improved best practices. In an effort to collect information for healthcare providers, enabling informed decisions in a relevant time frame, instrumentation for real-time plasma concentration (multi-wavelength pulse photometry) and protocols for rapid elemental analysis (energy dispersive X-Ray fluorescence) of biopsied tumor tissue have been developed in a murine model. An initial analysis, designed to demonstrate the robust nature and utility of the techniques, revealed that area under the bioavailability curve (AUC) alone does not currently inform tumor accumulation with a high degree of accuracy (R2=0.32), This finding suggests that the control of additional experimental and physiological variables may yield more predictable tumor accumulation. Subject core temperature are blood pressure were monitored, but did not demonstrate clear trends. An effort to modulate AUC has produced an adjuvant therapy which is employed to enhance circulation parameters, including the AUC, of nanorods and gold nanoshells. Preliminary studies demonstrated a greater than 300% increase in average AUC through the use of a reticuloendothelial blockade agent versus control groups. Given a better understanding of the relative importance of the physiological factors which impact rates of tumor accumulation, a proposed set of experimental best practices is presented.

  3. Tibolone and its metabolites acutely relax rabbit coronary arteries in vitro

    DEFF Research Database (Denmark)

    Lund, Claus Otto; Nilas, Lisbeth; Pedersen, Susan Helene

    2004-01-01

    under curve (AUC). RESULTS: Tibolone and its metabolites induced a concentration-dependent vasodilatation comparable to that of 17 beta-estradiol with the rank of potency: 3 beta-OH-tibolone approximately = to tibolone>3 alpha-OH-tibolone>Delta 4-isomer (ANOVA). l-NAME partly inhibited the relaxation...

  4. In vivo antimicrobial activity of marbofloxacin against Pasteurella multocida in a tissue cage model in calves

    Directory of Open Access Journals (Sweden)

    Changfu eCao

    2015-07-01

    Full Text Available Marbofloxacin is a fluoroquinolone specially developed for use in veterinary medicine with broad-spectrum antibacterial activity. The objective of our study was to re-evaluate in vivo antimicrobial activity of marbofloxacin against Pasteurella multocida using subcutaneously implanted tissue cages in calves. Calves were infected by direct injection into tissue cages with Pasteurella multocida(type B, serotype 2, then intramuscularly received a range of marbofloxacin doses 24h after inoculation. The ratio of 24h area under the concentration-time curve divided by the minimum inhibitory concentration or the mutant prevention concentration (AUC24h/MIC or AUC24h/MPC was the pharmacokinetic-pharmacodynamic (PK/PD index that best described the effectiveness of marbofloxacin against Pasteurella multocida (R2=0.8514 by nonlinear regression analysis. Marbofloxacin exhibited a good antimicrobial activity in vivo. The levels of AUC24h/MIC and AUC24h/MPC that produced 50% (1.5log10CFU/mL reduction and 90% (3log10CFU/mL reduction of maximum response were 18.60h and 50.65h, 4.67h and 12.89h by using sigmoid Emax model WINNONLIN software, respectively. The in vivo PK/PD integrated methods by tissue cage model display the advantage of the evaluation of antimicrobial activity and the optimization of the dosage regimen for antibiotics in the presence of the host defenses, especially in target animal of veterinary interest.

  5. In vivo antimicrobial activity of marbofloxacin against Pasteurella multocida in a tissue cage model in calves.

    Science.gov (United States)

    Cao, Changfu; Qu, Ying; Sun, Meizhen; Qiu, Zhenzhen; Huang, Xianhui; Huai, Binbin; Lu, Yan; Zeng, Zhenling

    2015-01-01

    Marbofloxacin is a fluoroquinolone specially developed for use in veterinary medicine with broad-spectrum antibacterial activity. The objective of our study was to re-evaluate in vivo antimicrobial activity of marbofloxacin against Pasteurella multocida using subcutaneously implanted tissue cages in calves. Calves were infected by direct injection into tissue cages with P. multocida(type B, serotype 2), then intramuscularly received a range of marbofloxacin doses 24 h after inoculation. The ratio of 24 h area under the concentration-time curve divided by the minimum inhibitory concentration or the mutant prevention concentration (AUC24 h/MIC or AUC24 h/MPC) was the pharmacokinetic-pharmacodynamic (PK/PD) index that best described the effectiveness of marbofloxacin against P. multocida (R (2) = 0.8514) by non-linear regression analysis. Marbofloxacin exhibited a good antimicrobial activity in vivo. The levels of AUC24 h/MIC and AUC24 h/MPC that produced 50% (1.5log10 CFU/mL reduction) and 90% (3log10 CFU/mL reduction) of maximum response were 18.60 and 50.65 h, 4.67 and 12.89 h by using sigmoid Emax model WINNONLIN software, respectively. The in vivo PK/PD integrated methods by tissue cage model display the advantage of the evaluation of antimicrobial activity and the optimization of the dosage regimen for antibiotics in the presence of the host defenses, especially in target animal of veterinary interest.

  6. PLATELET INHIBITORY ACTIVITY AND PHARAMCOKINETCS OF PRASUGREL A NOVEL THIENOPYRIDINE P2Y12 INHIBITOR: A SINGLE DOSE CROSS OVER BIOEQUIVALENCE STUDY IN HEALTHY HUMAN VOLUNTEERS

    Directory of Open Access Journals (Sweden)

    Sahu Nimain Charan

    2013-08-01

    Full Text Available To compare the bioavailability and bioequivalence of two prasugrel formulations one as a test and the other was the standard. The study was performed according to a randomized, open label, balanced, two-treatment, two-period, two-sequence, single-dose, crossover under fasting period with minimum of seven days wash-out period and was evaluated in 20(+ 2 stand by subjects. To analyse pharmacokinetic properties, the blood samples were drawn taken up to 36 h after dosing. Plasma concentration of prasugrel was determined using liquid chromatography – tandem mass spectrometry method. Pharmacokinetic parameters tmax, Cmax, AUC0-t, AUC0-, t1/2 and λz (Kel were tested for bioequivalence after log-transformation of data and non-parametric evaluation was done for ratios of tmax. The point estimates and 90 % confidence intervals (CI for AUC0-t, AUC0-∞, and Cmax for active metabolite (R-138727 were 95.82-105.18, 96.00-104.69 and 90.80-103.20 respectively. These results indicated that the two formulations of Prasugrel were bioequivalent in case of active metabolite (R-138727, thus may be prescribed interchangeably.

  7. Simple and Robust Analysis of Cefuroxime in Human Plasma by LC-MS/MS: Application to a Bioequivalence Study.

    Science.gov (United States)

    Hu, Xingjiang; Huang, Mingzhu; Liu, Jian; Chen, Junchun; Shentu, Jianzhong

    2014-01-01

    A simple, robust LC-MS/MS assay for quantifying cefuroxime in human plasma was developed. Cefuroxime and tazobactam, as internal standard (IS), were extracted from human plasma by methanol to precipitate protein. Separation was achieved on a Zorbax SB-Aq (4.6 × 250 mm, 5  μ m) column under isocratic conditions. The calibration curve was linear in the concentration range of 0.0525-21.0  μ g/mL (r = 0.9998). The accuracy was higher than 90.92%, while the intra- and interday precision were less than 6.26%. The extraction procedure provides recovery ranged from 89.44% to 92.32%, for both analyte and IS. Finally, the method was successfully applied to a bioequivalence study of a single 500 mg dose of cefuroxime axetil in 22 healthy Chinese male subjects under fasting condition. Bioequivalence was determined by calculating 90% Cls for the ratios of C max, AUC0-t , and AUC0-∞ values for the test and reference products, using logarithmic transformed data. The 90% Cls for the ratios of C max (91.4%~104.2%), AUC0-t (97.4%~110.9%), and AUC0-∞ (97.6%~111.1%) values were within the predetermined range. It was concluded that the two formulations (test for capsule, reference for tablet) analyzed were bioequivalent in terms of rate and extent of absorption and the method met the principle of quick and easy clinical analysis.

  8. Piroxicam immediate release formulations: A fasting randomized open-label crossover bioequivalence study in healthy volunteers.

    Science.gov (United States)

    Helmy, Sally A; El-Bedaiwy, Heba M

    2014-11-01

    Piroxicam is a NSAID with analgesic and antipyretic properties, used for the treatment of rheumatoid diseases. The aim of this study was to evaluate the bioequivalence of two brands of piroxicam capsules (20 mg) in 24 Egyptian volunteers. The in vivo study was established according to a single-center, randomized, single-dose, laboratory-blinded, 2-period, 2-sequence, crossover study with a washout period of 3 weeks. Under fasting conditions, 24 healthy male volunteers were randomly selected to receive a single oral dose of one capsule (20 mg) of either test or reference product. Plasma samples were obtained over a 144-hour interval and analyzed for piroxicam by HPLC with UV detection. The pharmacokinetic parameters Cmax , tmax , AUC0-t , AUC0-∞ , Vd /F, Cl/F, and t1/2 were determined from plasma concentration-time profiles. The 90% confidence intervals for the ratio of log transformed values of Cmax , AUC0-t , and AUC0-∞ of the two treatments were within the acceptable range (0.8-1.25) for bioequivalence. From PK perspectives, the two piroxicam formulations were considered bioequivalent, based on the rate and extent of absorption. No adverse events occurred or were reported after a single 20-mg piroxicam and both formulations were well-tolerated.

  9. Effect of the Wetting Agent Sodium Lauryl Sulfate on the Pharmacokinetics of Alectinib: Results From a Bioequivalence Study in Healthy Subjects.

    Science.gov (United States)

    Morcos, Peter N; Parrott, Neil; Banken, Ludger; Timpe, Carsten; Lindenberg, Marc; Guerini, Elena; Dall, Georgina; Bogman, Katrijn; Sturm, Carolina; Zeaiter, Ali; Martin-Facklam, Meret; Phipps, Alex

    2016-08-22

    The anaplastic lymphoma kinase (ALK) inhibitor alectinib is an effective treatment for ALK-positive non-small-cell lung cancer. This bioequivalence study evaluated the in vivo performance of test 3 formulations with the reduced wetting agent sodium lauryl sulfate (SLS) content. This randomized, 4-period, 4-sequence, crossover study compared alectinib (600 mg) as 25%, 12.5%, and 3% SLS hard capsule formulations with the reference 50% SLS clinical formulation in healthy subjects under fasted conditions (n = 49), and following a high-fat meal (n = 48). Geometric mean ratios and 90% confidence intervals (CIs) for Cmax , AUC0-last , and AUC0-∞ of alectinib, its major active metabolite, M4, and alectinib plus M4 were determined for the test formulations versus the reference formulation. Bioequivalence was concluded if the 90%CIs were within the 80% to 125% boundaries. The 25% SLS formulation demonstrated bioequivalence to the reference 50% SLS formulation for Cmax , AUC0-last , and AUC0-∞ of alectinib, M4, and alectinib plus M4 under both fasted and fed conditions. Further reductions in SLS content (12.5% and 3% SLS) did not meet the bioequivalence criteria. Cross-group comparisons showed an approximately 3-fold positive food effect. Reducing SLS to 25% resulted in a formulation that is bioequivalent to the current 50% SLS formulation used in alectinib pivotal trials.

  10. Liberal Arts and Sciences Education for the 21st Century Knowledge Economy: A Case Study of Amsterdam University College, The Netherlands

    NARCIS (Netherlands)

    Klein Bog, Deirdre; Wende, van der Marijk; Jung, Insung; Nishimura, Mikiko; Sasao, Toshiaki

    2016-01-01

    This chapter describes how Amsterdam University College (AUC), a liberal arts and science honours college in The Netherlands, promotes internationalization and adopts a global approach in its curriculum and academic community. It shows how global learning outcomes and 21st century skills can be fost

  11. External Validation of Prediction Models for Pneumonia in Primary Care Patients with Lower Respiratory Tract Infection

    DEFF Research Database (Denmark)

    Schierenberg, Alwin; Minnaard, Margaretha C; Hopstaken, Rogier M

    2016-01-01

    , representing the performance of an individual model relative to the average dataset performance. Prediction models by van Vugt et al. and Heckerling et al. demonstrated the highest pooled AUC of 0.79 (95% CI 0.74-0.85) and 0.72 (0.68-0.76), respectively. Other models by Diehr et al., Singal et al., Melbye et...

  12. C2 (2-h) levels are not superior to trough levels as estimates of the area under the curve in tacrolimus-treated renal-transplant patients

    DEFF Research Database (Denmark)

    Jørgensen, Kaj; Povlsen, Johan; Madsen, Søren

    2002-01-01

    and AUC by Pearson's correlation coefficient, and pairs of correlation coefficients were compared by an asymptotic Wald-type test. RESULTS: AUC varied five-fold despite near-equal dosing. Pearson's correlation coefficient for trough level, 1, 2, 3, 4, and 6 h were 0.84, 0.60, 0.81, 0.95, 0.95, and 0.......94 on day 3 and 0.94, 0.69, 0.92, 0.96, 0.94, 0.92 on day 14. Three-, 4- and 6-h levels had significantly higher correlation coefficients compared to trough, 1- and 2-h levels. One-hour samples had significantly lower correlation coefficients compared to all other sampling times on day 14. The patient...... with the highest AUC developed nephrotoxicity despite trough levels in the desired range. CONCLUSIONS: Two-hour levels are not superior to trough levels in tacrolimus-treated renal transplant patients. Despite good correlation between trough level and AUC, some patients may still receive nephrotoxic doses despite...

  13. A review of pharmacokinetic drug-drug interactions with the anthelmintic medications albendazole and mebendazole.

    Science.gov (United States)

    Pawluk, Shane Ashley; Roels, Craig Allan; Wilby, Kyle John; Ensom, Mary H H

    2015-04-01

    Medications indicated for helminthes and other parasitic infections are frequently being used in mass populations in endemic areas. Currently, there is a lack of guidance for clinicians on how to appropriately manage drug interactions when faced with patients requiring short-term anthelmintic therapy with albendazole or mebendazole while concurrently taking other agents. The objective of this review was to systematically summarize and evaluate published literature on the pharmacokinetics of albendazole or mebendazole when taken with other interacting medications. A search of MEDLINE (1946 to October 2014), EMBASE (1974 to October 2014), International Pharmaceutical Abstracts (1970 to October 2014), Google, and Google Scholar was conducted for articles describing the pharmacokinetics of albendazole or mebendazole when given with other medications (and supplemented by a bibliographic review of all relevant articles). Altogether, 17 articles were included in the review. Studies reported data on pharmacokinetic parameters for albendazole or mebendazole when taken with cimetidine, dexamethasone, ritonavir, phenytoin, carbamazepine, phenobarbital, ivermectin, praziquantel, diethylcarbamazine, azithromycin, and levamisole. Cimetidine increased the elimination half-life of albendazole and maximum concentration (Cmax) of mebendazole; dexamethasone increased the area under the plasma concentration-time curve (AUC) of albendazole; levamisole decreased the Cmax of albendazole; anticonvulsants (phenytoin, phenobarbital, carbamazepine) decreased the AUC of albendazole; praziquantel increased the AUC of albendazole; and ritonavir decreased the AUC of both albendazole and mebendazole. No major interactions were found with ivermectin, azithromycin, or diethylcarbamazine. Future research is required to clarify the clinical relevance of the interactions observed.

  14. Treatment with liraglutide--a once-daily GLP-1 analog--does not reduce the bioavailability of ethinyl estradiol/levonorgestrel taken as an oral combination contraceptive drug.

    Science.gov (United States)

    Jacobsen, Lisbeth V; Vouis, Jan; Hindsberger, Charlotte; Zdravkovic, Milan

    2011-12-01

    Liraglutide is a once-daily human GLP-1 analog for treatment of type 2 diabetes. Like other GLP-1 analogs, liraglutide delays gastric emptying, which could potentially affect absorption of concomitantly administered oral drugs. This study investigated the effect of liraglutide on the pharmacokinetics of the components of an oral contraceptive (ethinyl estradiol/levonorgestrel). Postmeno-pausal healthy women (n = 21) were included. A single dose of this contraceptive was administered. Blood samples for ethinyl estradiol/levonorgestrel measurements were drawn until 74 hours post dosing of the contraceptive during liraglutide and placebo treatments. The 90% confidence interval (CI) of the ratio of the area under the curve (AUC) (1.06; 90% CI, 0.99-1.13) for ethinyl estradiol (during liraglutide and placebo) was within defined limits, demonstrating equivalence. The 90% CI for the ratio of AUC for levonorgestrel was not fully contained within the limits (1.18; 90% CI, 1.04-1.34) (levonorgestrel AUC was 18% greater with liraglutide vs placebo). However, equivalence was demonstrated for levonorgestrel AUC(0-t) (1.15; 90% CI, 1.06-1.24). Equivalence was not demonstrated for maximum concentration (C(max)); values for ethinyl estradiol and levonorgestrel C(max) were 12% and 13% lower with liraglutide versus placebo, respectively. Both reached C(max) ~1.5 hours later with liraglutide. No clinically relevant reduction in bioavailability of ethinyl estradiol/levonorgestrel occurred.

  15. Procalcitonin Improves the Glasgow Prognostic Score for Outcome Prediction in Emergency Patients with Cancer: A Cohort Study

    Directory of Open Access Journals (Sweden)

    Anna Christina Rast

    2015-01-01

    Full Text Available The Glasgow Prognostic Score (GPS is useful for predicting long-term mortality in cancer patients. Our aim was to validate the GPS in ED patients with different cancer-related urgency and investigate whether biomarkers would improve its accuracy. We followed consecutive medical patients presenting with a cancer-related medical urgency to a tertiary care hospital in Switzerland. Upon admission, we measured procalcitonin (PCT, white blood cell count, urea, 25-hydroxyvitamin D, corrected calcium, C-reactive protein, and albumin and calculated the GPS. Of 341 included patients (median age 68 years, 61% males, 81 (23.8% died within 30 days after admission. The GPS showed moderate prognostic accuracy (AUC 0.67 for mortality. Among the different biomarkers, PCT provided the highest prognostic accuracy (odds ratio 1.6 (95% confidence interval 1.3 to 1.9, P<0.001, AUC 0.69 and significantly improved the GPS to a combined AUC of 0.74 (P=0.007. Considering all investigated biomarkers, the AUC increased to 0.76 (P<0.001. The GPS performance was significantly improved by the addition of PCT and other biomarkers for risk stratification in ED cancer patients. The benefit of early risk stratification by the GPS in combination with biomarkers from different pathways should be investigated in further interventional trials.

  16. Absorption kinetics of two highly concentrated preparations of growth hormone: 12 IU/ml compared to 56 IU/ml

    DEFF Research Database (Denmark)

    Laursen, Torben; Susgaard, Søren; Jensen, Flemming Steen;

    1994-01-01

    in the interval 0.8-1.25, implying that the two preparations are bioequivalent. Neither AUC (P = 0.90), Cmax (p = 0.47) or Tmax (P = 0.86) for the two formulations of growth hormone were significantly different. Similar levels of serum IGF-I, IGFBP-3, insulin and blood glucose were obtained.(ABSTRACT TRUNCATED...

  17. Quercetin increases the bioavailability of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in rats

    NARCIS (Netherlands)

    Schutte, M.E.; Alink, G.M.; Freidig, A.P.; Spenkelink, A.; Vaessen, J.; Sandt, van de J.J.M.; Groten, J.P.; Rietjens, I.M.C.M.

    2008-01-01

    This study investigates whether the previous observation that quercetin increases the transport of PhIP through Caco-2 monolayers in vitro could be confirmed in an in vivo rat model. Co-administration of 1.45 micromol PhIP/kg bw and 30 micromol quercetin/kg bw significantly increased the blood AUC(0

  18. A Multilaboratory Comparison of Calibration Accuracy and the Performance of External References in Analytical Ultracentrifugation

    DEFF Research Database (Denmark)

    Zhao, Huaying; Ghirlando, Rodolfo; Alfonso, Carlos

    2015-01-01

    Analytical ultracentrifugation (AUC) is a first principles based method to determine absolute sedimentation coefficients and buoyant molar masses of macromolecules and their complexes, reporting on their size and shape in free solution. The purpose of this multi-laboratory study was to establish ...

  19. In vivo evaluation of lipid-based formulations for oral delivery of apomorphine and its diester prodrugs

    DEFF Research Database (Denmark)

    Borkar, Nrupa Nitin; Holm, René; Yang, Mingshi;

    2016-01-01

    in 1:3 and 4:1 ratio, respectively. Tmax of diesters was significantly increased (p≤0.05) compared to apomorphine in o/w emulsion, suggesting that esterification yielded prolonged drug absorption. Cmax, AUC and the relative bioavailability of apomorphine after DLA-SEDDS administration was higher (p≤0...

  20. Prognostic Aspects of DCE-MRI in Recurrent Rectal Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Gollub, M.J.; Gultekin, D.H.; Sohn, M. [Memorial Sloan-Kettering Cancer Center, Department of Radiology, New York, NY (United States); Cao, K. [Peking University Cancer Hospital and Institute, Department of Radiology, Beijing (China); Kuk, D.; Gonen, M. [Memorial Sloan-Kettering Cancer Center, Department of Epidemiology and Biostatistics, New York, NY (United States); Schwartz, L.H. [Columbia University Medical Center/New York Presbyterian Hospital, Department of Radiology, New York, NY (United States); Weiser, M.R.; Temple, L.K.; Nash, G.M.; Guillem, J.G.; Garcia-Aguilar, J.; Paty, P.B. [Memorial Sloan-Kettering Cancer Center, Department of Surgery, New York, NY (United States); Wang, M. [Fudan University Shanghai Cancer Center, Department of Colorectal Surgery, Shanghai (China); Goodman, K. [Memorial Sloan-Kettering Cancer Center, Department of Radiation Oncology, New York, NY (United States)

    2013-12-15

    To explore whether pre-reoperative dynamic contrast-enhanced (DCE)-MRI findings correlate with clinical outcome in patients who undergo surgical treatment for recurrent rectal carcinoma. A retrospective study of DCE-MRI in patients with recurrent rectal cancer was performed after obtaining an IRB waiver. We queried our PACS from 1998 to 2012 for examinations performed for recurrent disease. Two radiologists in consensus outlined tumour regions of interest on perfusion images. We explored the correlation between K{sup trans}, K{sub ep}, V{sub e}, AUC90 and AUC180 with time to re-recurrence of tumour, overall survival and resection margin status. Univariate Cox PH models were used for survival, while univariate logistic regression was used for margin status. Among 58 patients with pre-treatment DCE-MRI who underwent resection, 36 went directly to surgery and 18 had positive margins. K{sup trans} (0.55, P = 0.012) and K{sub ep} (0.93, P = 0.04) were inversely correlated with positive margins. No significant correlations were noted between K{sup trans}, K{sub ep}, V{sub e}, AUC90 and AUC180 and overall survival or time to re-recurrence of tumour. K{sup trans} and K{sub ep} were significantly associated with clear resection margins; however overall survival and time to re-recurrence were not predicted. Such information might be helpful for treatment individualisation and deserves further investigation. (orig.)

  1. CT colonography: effect of computer-aided detection of colonic polyps as a second and concurrent reader for general radiologists with moderate experience in CT colonography

    Energy Technology Data Exchange (ETDEWEB)

    Mang, Thomas; Ringel, Helmut; Weber, Michael [Medical University of Vienna, Department of Biomedical Imaging and Image-guided Therapy, Vienna (Austria); Bogoni, Luca; Anand, Vikram X.; Hermosillo, Gerardo; Raykar, Vikas; Salganicoff, Marcos; Wolf, Matthias [H IM SY US, Siemens Medical Solutions, Malvern, PA (United States); Chandra, Dass [Temple University, Philadelphia, PA (United States); Curtin, Andrew J. [Tristate Imaging Consultants, Abington, PA (United States); Lev-Toaff, Anna S. [University of Pennsylvania, Philadelphia, PA (United States); Noah, Ralph [Diagnostic Imaging Associates, Wilmington, DE (United States); Shaw, Robert [The Chester County Hospital, West Chester, PA (United States); Summerton, Susan [Albert Einstein Medical Center, Philadelphia, PA (United States); Tappouni, Rafel F.R. [Wake Forest University School of Medicine, Winston-Salem, NC (United States); Obuchowski, Nancy A. [Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio (United States)

    2014-07-15

    To assess the effectiveness of computer-aided detection (CAD) as a second reader or concurrent reader in helping radiologists who are moderately experienced in computed tomographic colonography (CTC) to detect colorectal polyps. Seventy CTC datasets (34 patients: 66 polyps ≥6 mm; 36 patients: no abnormalities) were retrospectively reviewed by seven radiologists with moderate CTC experience. After primary unassisted evaluation, a CAD second read and, after a time interval of ≥4 weeks, a CAD concurrent read were performed. Areas under the receiver operating characteristic (ROC) curve (AUC), along with per-segment, per-polyp and per-patient sensitivities, and also reading times, were calculated for each reader with and without CAD. Of seven readers, 86 % and 71 % achieved a higher accuracy (segment-level AUC) when using CAD as second and concurrent reader respectively. Average segment-level AUCs with second and concurrent CAD (0.853 and 0.864) were significantly greater (p < 0.0001) than average AUC in the unaided evaluation (0.781). Per-segment, per-polyp, and per-patient sensitivities for polyps ≥6 mm were significantly higher in both CAD reading paradigms compared with unaided evaluation. Second-read CAD reduced readers' average segment and patient specificity by 0.007 and 0.036 (p = 0.005 and 0.011), respectively. CAD significantly improves the sensitivities of radiologists moderately experienced in CTC for polyp detection, both as second reader and concurrent reader. (orig.)

  2. Continuous infusion of vancomycin : Effective, efficient and safe

    NARCIS (Netherlands)

    Van Maarseveen, E.; Touw, D.; Bouma, A.; Van Zanten, A.

    2011-01-01

    Aims: Vancomycin is an antibiotic which is used in (suspected or proven) bacteriaemia, peritonitis or osteomyelitis with grampositive micro-organisms. Currently in most Dutch hospitals vancomycin is administered as an intermittent infusion. As the killing of vancomycin is dependent of the AUC/MIC ra

  3. Looking forward in records of youth abused as children: risks for homicidal, violent, and delinquent offenses.

    Science.gov (United States)

    Hughes, John Russell; Zagar, Robert John; Busch, Kenneth G; Grove, William M; Arbit, Jack

    2009-02-01

    To study risks of abuse, violence, and homicide, 181 Abused Children (M age = 12.85 yr., SD = 2.74; 58 girls, 123 boys) were matched with 181 clinic-referred Controls. Data analysis was Shao's bootstrapped logistic regression with area under curve (AUC) and odds ratios (OR). Predictors of abused status were court contacts (OR = 2.04e+22) and poorer executive function (OR = .81; AUC = .99; 95% CI = .97-.99). Groups were tracked forward in records for 9 years (M = 8.78 yr., SD = 1.41). Looking forward, youth (M age = 21.63 yr., SD = 2.07) were classified into Abused Children Later Homicidal (5%, n = 10), Abused Children Later Violent (23%, n = 41), Abused Children Later Delinquent (28%, n = 50), Abused Children Later Nondelinquent (44%, n = 80), and Controls (n = 181). Data were analyzed with two more logistic regressions. Predictors of Abused Children Later Homicidal compared with Controls were number of court contacts (OR = 50,398.78) and poorer executive function (OR = 79.72; AUC = .91; 95% CI = .80-.95). The predictor of Abused Children Later Homicidal contrasted with Abused Children Later Nondelinquent was court contacts (OR = 2,077,089,352; AUC = .87; 95% CI = .65-.95). The common predictor for Abused Children and Abused Children Later Homicidal groups was court contacts.

  4. Effect of gastric emptying and entero-hepatic circulation on bioequivalence assessment of ranitidine.

    Science.gov (United States)

    Chrenova, J; Durisova, M; Mircioiu, C; Dedik, L

    2010-01-01

    The aim of study was to compare the bioavailability of ranitidine obtained from either Ranitidine (300 mg tablet; LPH® S.C. LaborMed Pharma S.A. Romania: the test formulation) and Zantac® (300 mg tablet; GlaxoSmithKline, Austria: the reference formulation). Twelve, Romanian, healthy volunteers were enrolled in the study. An open-label, two-period, crossover, randomized design was used. Plasma levels of ranitidine were determined using the validated, high-pressure liquid chromatography (HPLC) method. The physiologically motivated time-delayed model was used for the data evaluation and a paired Student's t-test and Schuirmann's two one-sided tests were carried out to compare parameters. Nonmodeling parameters (AUC(t), AUC, C(max), T(max)) were tested by the paired Student's t-test and the 90 confidence intervals of the geometric mean ratios were determined by Schuirmann's tests. Paired Student's t-test showed no significant differences between nonmodeling and modeling parameters. The results of the Schuirmann's tests however indicated significant statistical differences with reference to AUC(t), AUC, C(max), T(max) and other modeling parameters, especially MT(c) and τ(c). Schuirmann's tests revealed significant bioequivalence between ranitidine formulations using the modeling parameters MRT and n. The presented model can be useful as an additional tool to assess drug bioequivalence, by screening for disruptive parameters.

  5. The precision--recall curve overcame the optimism of the receiver operating characteristic curve in rare diseases

    DEFF Research Database (Denmark)

    Ozenne, Brice; Subtil, Fabien; Maucort-Boulch, Delphine

    2015-01-01

    OBJECTIVES: Compare the area under the receiver operating characteristic curve (AUC) vs. the area under the precision-recall curve (AUPRC) in summarizing the performance of a diagnostic biomarker according to the disease prevalence. STUDY DESIGN AND SETTING: A simulation study was performed...

  6. Faster Onset of Bronchodilation with Formoterol than with Salmeterol in Patients with Stable, Moderate-Severe Copd: Results of a Randomized, Double-Blind Clinical Study

    Directory of Open Access Journals (Sweden)

    John Kottakis

    2002-01-01

    Full Text Available OBJECTIVES: To compare the onset and magnitude of bronchodilation after dry powder inhalations of formoterol fumarate (Foradil Aerolizer versus salmeterol xinofoate (Serevent Diskus with respect to normalized (* forced expiratory volume in 1 s area under the curve 0 to 1 h after inhalation (FEV1 AUC*0-1 h.

  7. A patient-centered methodology that improves the accuracy of prognostic predictions in cancer.

    Directory of Open Access Journals (Sweden)

    Mohammed Kashani-Sabet

    Full Text Available Individualized approaches to prognosis are crucial to effective management of cancer patients. We developed a methodology to assign individualized 5-year disease-specific death probabilities to 1,222 patients with melanoma and to 1,225 patients with breast cancer. For each cancer, three risk subgroups were identified by stratifying patients according to initial stage, and prediction probabilities were generated based on the factors most closely related to 5-year disease-specific death. Separate subgroup probabilities were merged to form a single composite index, and its predictive efficacy was assessed by several measures, including the area (AUC under its receiver operating characteristic (ROC curve. The patient-centered methodology achieved an AUC of 0.867 in the prediction of 5-year disease-specific death, compared with 0.787 using the AJCC staging classification alone. When applied to breast cancer patients, it achieved an AUC of 0.907, compared with 0.802 using the AJCC staging classification alone. A prognostic algorithm produced from a randomly selected training subsample of 800 melanoma patients preserved 92.5% of its prognostic efficacy (as measured by AUC when the same algorithm was applied to a validation subsample containing the remaining patients. Finally, the tailored prognostic approach enhanced the identification of high-risk candidates for adjuvant therapy in melanoma. These results describe a novel patient-centered prognostic methodology with improved predictive efficacy when compared with AJCC stage alone in two distinct malignancies drawn from two separate populations.

  8. Molecular diagnosis of bacterial vaginosis: Does adjustment for total bacterial load or human cellular content improve diagnostic performance?

    Science.gov (United States)

    Plummer, E L; Garland, S M; Bradshaw, C S; Law, M G; Vodstrcil, L A; Hocking, J S; Fairley, C K; Tabrizi, S N

    2017-02-01

    We investigated the utility of quantitative PCR assays for diagnosis of bacterial vaginosis and found that while the best model utilized bacterial copy number adjusted for total bacterial load (sensitivity=98%, specificity=93%, AUC=0.95[95%CI=0.93,0.97]), adjusting for total bacterial or human cell load did not consistently increase the diagnostic performance of the assays.

  9. Associations between insulin action and integrity of brain microstructure differ with familial longevity and with age

    DEFF Research Database (Denmark)

    Akintola, Abimbola A; van den Berg, Annette; van Buchem, Mark A;

    2015-01-01

    [fasted glucose and glucose area-under-the-curve (AUC)], insulin resistance [fasted insulin, AUCinsulin, and homeostatic model assessment of insulin resistance (HOMA-IR)], and pancreatic Beta cell secretory capacity (insulinogenic index). 3 Tesla MRI and Magnetization Transfer (MT) imaging MT-ratio (MTR...

  10. Enhancing the Jamaica Defence Force Military Intelligence Unit’s Effectiveness to Conduct Counterdrug Missions

    Science.gov (United States)

    2006-06-16

    wing paramilitary groups, such as the AUC (Autodefensas Unidas de Colombia). Over recent years these groups have significantly improved the...online. Available from http:// europa . eu.int/scadplus. Internet. Accessed on 6 December 2005. 11Ann Rogers, “Confronting Cocaine Smuggling in the

  11. Role of leader peptide synthesis in tryptophanase operon expression in Escherichia coli K-12.

    OpenAIRE

    Stewart, V; Yanofsky, C

    1986-01-01

    We used site-directed mutagenesis to replace the Escherichia coli tryptophanase (tna) operon leader peptide start codon with AUC. This change greatly decreased the uninduced rate of tna operon expression, and it also lowered the response to inducer. We conclude that leader peptide synthesis plays an essential role in tna operon expression.

  12. Colombia: Issues for Congress

    Science.gov (United States)

    2007-11-09

    proyectos /justicia_y_paz.htm] on August 30, 2006; “Presidencia de la República de Colombia, “Listado de Privados de Libertad de las AUC Remitidos a...extradición: 8,” August 29, 2006, at [http://www.presidencia.gov.co/prensa_new/ proyectos /justicia_y_paz.htm

  13. Bilateral Image Subtraction and Multivariate Models for the Automated Triaging of Screening Mammograms

    Directory of Open Access Journals (Sweden)

    José Celaya-Padilla

    2015-01-01

    Full Text Available Mammography is the most common and effective breast cancer screening test. However, the rate of positive findings is very low, making the radiologic interpretation monotonous and biased toward errors. This work presents a computer-aided diagnosis (CADx method aimed to automatically triage mammogram sets. The method coregisters the left and right mammograms, extracts image features, and classifies the subjects into risk of having malignant calcifications (CS, malignant masses (MS, and healthy subject (HS. In this study, 449 subjects (197 CS, 207 MS, and 45 HS from a public database were used to train and evaluate the CADx. Percentile-rank (p-rank and z-normalizations were used. For the p-rank, the CS versus HS model achieved a cross-validation accuracy of 0.797 with an area under the receiver operating characteristic curve (AUC of 0.882; the MS versus HS model obtained an accuracy of 0.772 and an AUC of 0.842. For the z-normalization, the CS versus HS model achieved an accuracy of 0.825 with an AUC of 0.882 and the MS versus HS model obtained an accuracy of 0.698 and an AUC of 0.807. The proposed method has the potential to rank cases with high probability of malignant findings aiding in the prioritization of radiologists work list.

  14. Pharmacokinetics of intraarterial mitomycin C in hypoxic hepatic infusion with embolization in the treatment of liver metastases.

    Science.gov (United States)

    Cerretani, Daniela; Roviello, Franco; Pieraccini, Massimo; Civeli, Letizia; Correale, Pierpaolo; Francini, Guido; Marrelli, Daniele; De Manzoni, Giovanni; Pinto, Enrico; Giorgi, Giorgio

    2002-07-01

    1. The pharmacokinetics of mitomycin C (MMC) was evaluated during hypoxic hepatic infusion (HHMI) with arterial embolization for the treatment of unresectable liver metastases. 2. Ten patients with hepatic metastases from colorectal cancer were considered. Antiblastic infusion with MMC (20 mg/m2 at 30 ml/min) was initiated after 10 min of hepatic arterial occlusion. Peripheral venous blood samples were collected at different time intervals. MMC was assayed by high-pressure liquid chromatography (HPLC), and pharmacokinetic parameters were determined using an open, two-compartment model and linear kinetics. 3. Cmax of MMC during HHMI was 708 +/- 336.6 ng/ml, and tmax was 9.3 +/- 1.1 min. The plasma concentration-time curve showed a t1/2 alpha ranging from 1.5 to 9 min, followed by a t1/2 beta ranging from 31 to 93 min. The Cltot was 35.5 l/h/m2 with an area under the plasma concentration-time curve (AUC) ranging from 251 to 850 micrograms h/l. The same AUC parameter standardized for the amount of MMC was 15.5 mg-1. The HHMI model that we used revealed a significant increase in Cltot and a reduction in AUC when compared to the locoregional intraarterial and peripheral intravenous models (p < .001). 4. The reduction in AUC following HHMI explains the limited systemic toxicity in treated patients, with a greater total tumor exposure to the drug and improved drug activation.

  15. Fuzzy logic-based prognostic score for outcome prediction in esophageal cancer.

    Science.gov (United States)

    Wang, Chang-Yu; Lee, Tsair-Fwu; Fang, Chun-Hsiung; Chou, Jyh-Horng

    2012-11-01

    Given the poor prognosis of esophageal cancer and the invasiveness of combined modality treatment, improved prognostic scoring systems are needed. We developed a fuzzy logic-based system to improve the predictive performance of a risk score based on the serum concentrations of C-reactive protein (CRP) and albumin in a cohort of 271 patients with esophageal cancer before radiotherapy. Univariate and multivariate survival analyses were employed to validate the independent prognostic value of the fuzzy risk score. To further compare the predictive performance of the fuzzy risk score with other prognostic scoring systems, time-dependent receiver operating characteristic curve (ROC) analysis was used. Application of fuzzy logic to the serum values of CRP and albumin increased predictive performance for 1-year overall survival (AUC=0.773) compared with that of a single marker (AUC=0.743 and 0.700 for CRP and albumin, respectively), where the AUC denotes the area under curve. This fuzzy logic-based approach also performed consistently better than the Glasgow Prognostic Score (GPS) (AUC=0.745). Thus, application of fuzzy logic to the analysis of serum markers can more accurately predict the outcome for patients with esophageal cancer.

  16. Bioequivalence Studies of a Reformulated Dutasteride and Tamsulosin Hydrochloride Combination Capsule and a Commercially Available Formulation.

    Science.gov (United States)

    Kurczewski, Renee; Bowen, Chet; Collins, David; Zhu, John; Serbest, Gulyeter; Manyak, Michael

    2017-01-27

    A dutasteride 0.5 mg and tamsulosin hydrochloride 0.4 mg combination (DTC) capsule (Duodart(®) ) was reformulated to reduce the capsule size and enhance product stability. Bioequivalence of the reformulated DTC capsule with the commercial formulation was evaluated in 2 single-dose, open-label, randomized, 2-way crossover studies in healthy adult male volunteers. Subjects in a fasted or fed state received a single oral dose of either the reformulated DTC or the commercial formulation followed by a 28-day washout period between treatments. Blood samples were taken predose and up to 72 hours postdose for pharmacokinetic (PK) analysis of dutasteride and tamsulosin serum concentrations. From the serum concentration-vs-time data, a noncompartmental method was used to calculate the maximum observed serum concentration (Cmax ) and area under the serum concentration-time curve (AUC0-t ) for dutasteride and tamsulosin, and AUC0-∞ for tamsulosin. The 90% confidence intervals for the ratios of the Cmax and AUC0-t (for dutasteride and tamsulosin) and for AUC0-∞ (for tamsulosin) were all completely contained within the range of 80% to 125%; therefore, the reformulated DTC capsule is bioequivalent to the commercial formulation under both fed and fasted states.

  17. A preliminary model to avoid the overestimation of sample size in bioequivalence studies.

    Science.gov (United States)

    Ramírez, E; Abraira, V; Guerra, P; Borobia, A M; Duque, B; López, J L; Mosquera, B; Lubomirov, R; Carcas, A J; Frías, J

    2013-02-01

    Often the only available data in literature for sample size estimations in bioequivalence studies is intersubject variability, which tends to result in overestimation of sample size. In this paper, we proposed a preliminary model of intrasubject variability based on intersubject variability for Cmax and AUC data from randomized, crossovers, bioequivalence (BE) studies. From 93 Cmax and 121 AUC data from test-reference comparisons that fulfilled BE criteria, we calculated intersubject variability for the reference formulation and intrasubject variability from ANOVA. Lineal and exponential models (y=a(1-e-bx)) were fitted weighted by the inverse of the variance, to predict the intrasubject variability based on intersubject variability. To validate the model we calculated the coefficient of cross-validation of data from 30 new BE studies. The models fit very well (R2=0.997 and 0.990 for Cmax and AUC respectively) and the cross-validation correlation were 0.847 for Cmax and 0.572 for AUC. A preliminary model analyses allow us to estimate the intrasubject variability based on intersubject variability for sample size calculation purposes in BE studies. This approximation provides an opportunity for sample size reduction avoiding unnecessary exposure of healthy volunteers. Further modelling studies are desirable to confirm these results especially suggestions of the higher intersubject variability range.

  18. The Heathen Obama

    DEFF Research Database (Denmark)

    Christensen, Rune Reimer

    2008-01-01

    Om faren ved brugen af satire i fremstillinger af race i amerikansk kultur.  Forskningsbaseret bidrag til akademisk blog om amerikansk historie, kultur, og samfundsforhold. I samarbejde med bl.a. forskere fra KUA, RUC, AUC. Udgivelsesdato: 15.07...

  19. Computer-aided diagnosis in phase contrast imaging X-ray computed tomography for quantitative characterization of ex vivo human patellar cartilage.

    Science.gov (United States)

    Nagarajan, Mahesh B; Coan, Paola; Huber, Markus B; Diemoz, Paul C; Glaser, Christian; Wismuller, Axel

    2013-10-01

    Visualization of ex vivo human patellar cartilage matrix through the phase contrast imaging X-ray computed tomography (PCI-CT) has been previously demonstrated. Such studies revealed osteoarthritis-induced changes to chondrocyte organization in the radial zone. This study investigates the application of texture analysis to characterizing such chondrocyte patterns in the presence and absence of osteoarthritic damage. Texture features derived from Minkowski functionals (MF) and gray-level co-occurrence matrices (GLCM) were extracted from 842 regions of interest (ROI) annotated on PCI-CT images of ex vivo human patellar cartilage specimens. These texture features were subsequently used in a machine learning task with support vector regression to classify ROIs as healthy or osteoarthritic; classification performance was evaluated using the area under the receiver operating characteristic curve (AUC). The best classification performance was observed with the MF features perimeter (AUC: 0.94 ±0.08 ) and "Euler characteristic" (AUC: 0.94 ±0.07 ), and GLCM-derived feature "Correlation" (AUC: 0.93 ±0.07). These results suggest that such texture features can provide a detailed characterization of the chondrocyte organization in the cartilage matrix, enabling classification of cartilage as healthy or osteoarthritic with high accuracy.

  20. Systemic exposure to inhaled beclometasone/formoterol DPI is age and body size dependent

    DEFF Research Database (Denmark)

    Chawes, B L; Govoni, M; Kreiner-Møller, E;

    2014-01-01

    normalization for the BDP/formoterol dose in the three populations the AUC and peak concentration (C(max)) correlated inversely with age and body surface area of the patients (r ≤ -0.53; p ... inversely with age and body size suggesting that dry powder dosage regimens should be adjusted for age and body size to avoid high systemic drug levels in children....

  1. Meta-analysis of inter-patient pharmacokinetic variability of liposomal and non-liposomal anticancer agents

    Science.gov (United States)

    Schell, Ryan F.; Sidone, Brian J.; Caron, Whitney P.; Walsh, Mark D.; Zamboni, Beth A.; Ramanathan, Ramesh K.; Zamboni, William C.

    2013-01-01

    Purpose A meta-analysis was conducted to evaluate the inter-patient pharmacokinetic (PK) variability of liposomal and small molecule (SM) anticancer agents. Methods Inter-patient PK variability of 9 liposomal and SM formulations of the same drug were evaluated. PK variability was measured as coefficient of variance (CV%) of area under the plasma concentration versus time curve (AUC) and the fold-difference between AUCmax and AUCmin (AUC range). Results CV% of AUC and AUC ranges were 2.7-fold (P<0.001) and 16.7-fold (P=0.13) greater, respectively, for liposomal compared with SM drugs. There was an inverse linear relationship between the clearance (CL) of liposomal agents and PK variability with a lower CL associated with greater PK variability (R2 = 0.39). PK variability of liposomal agents was greater when evaluated from 0–336 h compared with 0–24 h. Conclusion PK variability of liposomes is significantly greater than SM. The factors associated with the PK variability of liposomal agents needs to be evaluated. PMID:23891988

  2. GIS-based groundwater spring potential assessment and mapping in the Birjand Township, southern Khorasan Province, Iran

    Science.gov (United States)

    Pourtaghi, Zohre Sadat; Pourghasemi, Hamid Reza

    2014-05-01

    Three statistical models—frequency ratio (FR), weights-of-evidence (WofE) and logistic regression (LR)—produced groundwater-spring potential maps for the Birjand Township, southern Khorasan Province, Iran. In total, 304 springs were identified in a field survey and mapped in a geographic information system (GIS), out of which 212 spring locations were randomly selected to be modeled and the remaining 92 were used for the model evaluation. The effective factors—slope angle, slope aspect, elevation, topographic wetness index (TWI), stream power index (SPI), slope length (LS), plan curvature, lithology, land use, and distance to river, road, fault—were derived from the spatial database. Using these effective factors, groundwater spring potential was calculated using the three models, and the results were plotted in ArcGIS. The receiver operating characteristic (ROC) curves were drawn for spring potential maps and the area under the curve (AUC) was computed. The final results indicated that the FR model (AUC = 79.38 %) performed better than the WofE (AUC = 75.69 %) and LR (AUC = 63.71 %) models. Sensitivity and factor analyses concluded that the bivariate statistical index model (i.e. FR) can be used as a simple tool in the assessment of groundwater spring potential when a sufficient number of data are obtained.

  3. Increased Systemic Exposure of Methotrexate by a Polyphenol-Rich Herb via Modulation on Efflux Transporters Multidrug Resistance-Associated Protein 2 and Breast Cancer Resistance Protein.

    Science.gov (United States)

    Yu, Chung-Ping; Hsieh, Yun-Chung; Shia, Chi-Sheng; Hsu, Pei-Wen; Chen, Jen-Yuan; Hou, Yu-Chi; Hsieh, Yo-Wen

    2016-01-01

    Scutellariae radix (SR, roots of Scutellaria baicalensis Georgi), a popular Chinese medicine, contains plenty of flavonoids such as baicalin, wogonoside, baicalein, and wogonin. Methotrexate (MTX), an important immunosuppressant with a narrow therapeutic index, is a substrate of multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP). This study investigated the effect of SR on MTX pharmacokinetics and the underlying mechanisms. Rats were orally administered MTX alone and with 1.0 or 2.0 g/kg of SR. The serum concentrations of MTX were determined by a fluorescence polarization immunoassay. Cell models were used to explore the involvement of MRP2 and BCRP in the interaction. The results showed that 1.0 g/kg of SR significantly increased Cmax, AUC(0-30), AUC(0-2880), and mean residence time (MRT) of MTX by 50%, 45%, 501%, and 347%, respectively, and 2.0 g/kg of SR significantly enhanced the AUC(0-2880) and MRT by 242% and 293%, respectively, but decreased AUC(0-30) by 41%. Cell line studies indicated that SR activated the BCRP-mediated efflux transport, whereas the serum metabolites of SR inhibited both the BCRP- and MRP2-mediated efflux transports. In conclusion, SR ingestion increased the systemic exposure and MRT of MTX via modulation on MRP2 and BCRP.

  4. Validation of Six Short and Ultra-short Screening Instruments for Depression for People Living with HIV in Ontario: Results from the Ontario HIV Treatment Network Cohort Study

    DEFF Research Database (Denmark)

    Choi, Stephanie KY; Boyle, Eleanor; Burchell, Ann;

    2015-01-01

    standard measured by Mini International Neuropsychiatric Interview (the “M.I.N.I.”). Results Overall, the three instruments identified depression with excellent accuracy and validity (area under the curve [AUC]>0.9) and good reliability (Kappa statistics: 0.71–0.79; Cronbach’s alpha: 0.87–0.93). We did...

  5. Comparing five different iterative reconstruction algorithms for computed tomography in an ROC study

    Energy Technology Data Exchange (ETDEWEB)

    Jensen, Kristin; Martinsen, Anne Catrine T. [Rikshospitalet, The Intervention Centre, Postboks 4950, Oslo (Norway); University of Oslo, lnstitute of Physics, Oslo (Norway); Tingberg, Anders [Lund University, Skaane University Hospital, Department of Medical Radiation Physics, Malmoe (Sweden); Aaloekken, Trond Mogens [Rikshospitalet, Department of Radiology and Nuclear Medicine, Postboks 4950, Oslo (Norway); Fosse, Erik [Rikshospitalet, The Intervention Centre, Postboks 4950, Oslo (Norway); University of Oslo, lnstitute of Clinical Medicine, Oslo (Norway)

    2014-12-15

    The purpose of this study was to evaluate lesion conspicuity achieved with five different iterative reconstruction techniques from four CT vendors at three different dose levels. Comparisons were made of iterative algorithm and filtered back projection (FBP) among and within systems. An anthropomorphic liver phantom was examined with four CT systems, each from a different vendor. CTDI{sub vol} levels of 5 mGy, 10 mGy and 15 mGy were chosen. Images were reconstructed with FBP and the iterative algorithm on the system. Images were interpreted independently by four observers, and the areas under the ROC curve (AUCs) were calculated. Noise and contrast-to-noise ratios (CNR) were measured. One iterative algorithm increased AUC (0.79, 0.95, and 0.97) compared to FBP (0.70, 0.86, and 0.93) at all dose levels (p < 0.001 and p = 0.047). Another algorithm increased AUC from 0.78 with FBP to 0.84 (p = 0.007) at 5 mGy. Differences at 10 and 15 mGy were not significant (p-values: 0.084-0.883). Three algorithms showed no difference in AUC compared to FBP (p-values: 0.008-1.000). All of the algorithms decreased noise (10-71 %) and improved CNR. Only two algorithms improved lesion detection, even though noise reduction was shown with all algorithms. (orig.)

  6. Optimizing Classification in Intelligence Processing

    Science.gov (United States)

    2010-12-01

    ACC Classification Accuracy AUC Area Under the ROC Curve CI Competitive Intelligence COMINT Communications Intelligence DoD Department of...indispensible tool to support a national leader’s decision making process, competitive intelligence (CI) has emerged in recent decades as an environment meant...effectiveness for the intelligence product in competitive intelligence environment: accuracy, objectivity, usability, relevance, readiness, and timeliness

  7. ε-Acetamidocaproic acid pharmacokinetics in rats with gastric ulcer or small bowel inflammation.

    Science.gov (United States)

    Lee, U; Choi, Y H; Kim, Y G; Lee, B K; Oh, E; Lee, M G

    2012-03-01

    The pharmacokinetics of ϵ-acetamidocaproic acid (AACA) were evaluated after the intravenous and oral administration of an antiulcer agent, zinc acexamate (ZAC) at a dose of 20 mg kg⁻¹ (ion pairing between zinc and AACA) in rats with indomethacin-induced acute gastric ulcer (IAGU) or indomethacin-induced small bowel inflammation (ISBI). In IAGU rats, the area under the curves (AUCs) of AACA were significantly smaller after both the intravenous (551 versus 1270 μg min ml⁻¹) and oral (397 versus 562 μg min ml⁻¹) administration of ZAC than controls, possible due to the significantly faster CL(R) of AACA. In ISBI rats, however, the AUCs of AACA were comparable with controls after both the intravenous and oral administration of ZAC. In IAGU rats, the significantly smaller AUCs of AACA were due to the significantly faster CL(R) (due to the decreased urinary pH by indomethacin treatment) than controls. AACA has a basic secondary amine group. On the other hand, the comparable AUCs of AACA in ISBI rats were due to the comparable CL(R)s between ISBI and control rats. AACA was excreted in the urine via active renal tubular secretion in all rats studied.

  8. Specific autoantibody profiles and disease subgroups correlate with circulating micro-RNA in systemic sclerosis

    DEFF Research Database (Denmark)

    Wuttge, D. M.; Carlsen, A. L.; Teku, G.;

    2015-01-01

    or more autoantibody groups, and five (miRNA-409, -184, -92a, -29a and -101) remained significant after correction for multiple comparisons. Multiple regression models accurately predicted ACA and anti-DNA topoisomerase I antibody positive patients (area under the curve (AUC) = 0.97 and 0.93, respectively...

  9. Insulin Resistance and Hypertension

    Institute of Scientific and Technical Information of China (English)

    张建华; 张春秀

    2002-01-01

    Summary: The insulin sensitivity in hypertensive patients with normal glucose tolerance (NGT),impaired glucose tolerance (IGT) and type 2 diabetes mellitus (DM) and the insulin resistance(IR) under the disorder of glucose metabolism and hypertension were studied. By glucose toler-ance test and insulin release test, insulin sensitivity index (ISI) and the ratio of area under glucosetolerance curve (AUCG) to area under insulin release curve (AUC1) were calculated and analyzed.The results showed that ISI was decreased to varying degrees in the patients with hypertension,the mildest in the group of NGT with hypertension, followed by the group of IGT without hyper-tension, the group of IGT with hypertension and DM (P=0). There was very significant differ-ence in the ratio of AUCG/AUC1 between the hypertensive patients with NGT and controls (P=0). It was concluded that a significant IR existed during the development of IGT both in hyperten-sion and nonhypertension. The increase of total insulin secretion (AUC1) was associated with non-hypertension simultaneously. IR of the hypertensive patients even existed in NGT and was wors-ened with the deterioration of glucose metabolism disorder, but the AUC1 in the HT groupchanged slightly. A relative deficiency of insulin secretion or dysfunction of β-cell of islet existed inIGT and DM of the hypertensive patients.

  10. From hybrid swarms to swarms of hybrids

    Science.gov (United States)

    Stohlgren, Thomas J.; Szalanski, Allen L; Gaskin, John F.; Young, Nicholas E.; West, Amanda; Jarnevich, Catherine S.; Tripodi, Amber

    2015-01-01

    Science has shown that the introgression or hybridization of modern humans (Homo sapiens) with Neanderthals up to 40,000 YBP may have led to the swarm of modern humans on earth. However, there is little doubt that modern trade and transportation in support of the humans has continued to introduce additional species, genotypes, and hybrids to every country on the globe. We assessed the utility of species distributions modeling of genotypes to assess the risk of current and future invaders. We evaluated 93 locations of the genus Tamarix for which genetic data were available. Maxent models of habitat suitability showed that the hybrid, T. ramosissima x T. chinensis, was slightly greater than the parent taxa (AUCs > 0.83). General linear models of Africanized honey bees, a hybrid cross of Tanzanian Apis mellifera scutellata and a variety of European honey bee including A. m. ligustica, showed that the Africanized bees (AUC = 0.81) may be displacing European honey bees (AUC > 0.76) over large areas of the southwestern U.S. More important, Maxent modeling of sub-populations (A1 and A26 mitotypes based on mDNA) could be accurately modeled (AUC > 0.9), and they responded differently to environmental drivers. This suggests that rapid evolutionary change may be underway in the Africanized bees, allowing the bees to spread into new areas and extending their total range. Protecting native species and ecosystems may benefit from risk maps of harmful invasive species, hybrids, and genotypes.

  11. Caffeine intake in pregnancy: Relationship between internal intake and effect on birth weight.

    Science.gov (United States)

    Partosch, F; Mielke, H; Stahlmann, R; Gundert-Remy, U

    2015-12-01

    We used a physiologically based kinetic model to simulate caffeine blood concentration-time profiles in non-pregnant and pregnant women. The model predicted concentration-time profile was in good accordance with experimental values. With 200 mg, the safe dose per occasion in non-pregnant women, AUC and peak concentration in pregnant women were nearly twice that of non-pregnant women. In order to derive a safe dose for the pregnant women we estimated the dose in the pregnant women model taken at once which would not exceed AUC and peak concentration in the non-pregnant women of 200 mg as single dose. The resulting dose is 100 mg caffeine per occasion which we recommend as safe. The caffeine dose of 200 mg per day is declared as safe for pregnant women with respect to the foetus by EFSA based on results on reduced birth weight in epidemiological studies. We modelled AUC and peak concentration for different caffeine doses to investigate the relationship between internal caffeine exposure and risk measures of reduced birth weight from epidemiological studies. The graphical analysis revealed that the reduction in birth weight was related to AUC and peak concentration up to a dose of 250 mg caffeine.

  12. Development and evaluation of a risk score for type 2 diabetes mellitus among middle-aged Chinese rural population based on the RuralDiab Study

    Science.gov (United States)

    Zhou, Hao; Li, Yuqian; Liu, Xiaotian; Xu, Fei; Li, Linlin; Yang, Kaili; Qian, Xinling; Liu, Ruihua; Bie, Ronghai; Wang, Chongjian

    2017-01-01

    The purpose of this study was to establish a simple and effective risk score for type 2 diabetes mellitus (T2DM) in middle-aged rural Chinese. Total of 5453 participants aged 30–59 years from the Rural Diabetes, Obesity and Lifestyle (RuralDiab) study were recruited for establishing the RuralDiab risk score by using logistic regression analysis. The RuralDiab risk score was validated in a prospective study from Henan Province of China, and compared with previous risk scores by using the receiver-operating characteristics cure. Ultimately, sex, age, family history of diabetes, physical activity, waist circumference, history of dyslipidemia, diastolic blood pressure, body mass index were included in the RuralDiab risk score (range from 0 to 36), and the optimal cutoff value was 17 with 67.9% sensitivity and 67.8% specificity. The area under the cures (AUC) of the RuralDiab risk score was 0.723(95%CI: 0.710–0.735) for T2DM in validation population, which was significant higher than the American Diabetes Association score (AUC: 0.636), the Inter99 score (AUC: 0.669), the Oman risk score (AUC: 0.675). The RuralDiab risk score was established and demonstrated an appropriate performance for predicting T2DM in middle-aged Chinese rural population. Further studies for validation should be implemented in different populations. PMID:28209984

  13. Comparison of Simple Versus Performance-Based Fall Prediction Models

    Directory of Open Access Journals (Sweden)

    Shekhar K. Gadkaree BS

    2015-05-01

    Full Text Available Objective: To compare the predictive ability of standard falls prediction models based on physical performance assessments with more parsimonious prediction models based on self-reported data. Design: We developed a series of fall prediction models progressing in complexity and compared area under the receiver operating characteristic curve (AUC across models. Setting: National Health and Aging Trends Study (NHATS, which surveyed a nationally representative sample of Medicare enrollees (age ≥65 at baseline (Round 1: 2011-2012 and 1-year follow-up (Round 2: 2012-2013. Participants: In all, 6,056 community-dwelling individuals participated in Rounds 1 and 2 of NHATS. Measurements: Primary outcomes were 1-year incidence of “any fall” and “recurrent falls.” Prediction models were compared and validated in development and validation sets, respectively. Results: A prediction model that included demographic information, self-reported problems with balance and coordination, and previous fall history was the most parsimonious model that optimized AUC for both any fall (AUC = 0.69, 95% confidence interval [CI] = [0.67, 0.71] and recurrent falls (AUC = 0.77, 95% CI = [0.74, 0.79] in the development set. Physical performance testing provided a marginal additional predictive value. Conclusion: A simple clinical prediction model that does not include physical performance testing could facilitate routine, widespread falls risk screening in the ambulatory care setting.

  14. Impact of Diabetes-Specific Nutritional Formulas versus Oatmeal on Postprandial Glucose, Insulin, GLP-1 and Postprandial Lipidemia

    Directory of Open Access Journals (Sweden)

    Adham Mottalib

    2016-07-01

    Full Text Available Diabetes-specific nutritional formulas (DSNFs are frequently used as part of medical nutrition therapy for patients with diabetes. This study aims to evaluate postprandial (PP effects of 2 DSNFs; Glucerna (GL and Ultra Glucose Control (UGC versus oatmeal (OM on glucose, insulin, glucagon-like peptide-1 (GLP-1, free fatty acids (FFA and triglycerides (TG. After an overnight fast, 22 overweight/obese patients with type 2 diabetes were given 200 kcal of each of the three meals on three separate days in random order. Blood samples were collected at baseline and at 30, 60, 90, 120, 180 and 240 min. Glucose area under the curve (AUC0–240 after GL and UGC was lower than OM (p < 0.001 for both. Insulin positive AUC0–120 after UGC was higher than after OM (p = 0.02. GLP-1 AUC0–120 and AUC0–240 after GL and UGC was higher than after OM (p < 0.001 for both. FFA and TG levels were not different between meals. Intake of DSNFs improves PP glucose for 4 h in comparison to oatmeal of similar caloric level. This is achieved by either direct stimulation of insulin secretion or indirectly by stimulating GLP-1 secretion. The difference between their effects is probably related to their unique blends of amino acids, carbohydrates and fat.

  15. Acoustic Response of Underwater Munitions near a Sediment Interface: Measurement Model Comparisons and Classification Schemes

    Science.gov (United States)

    2015-04-23

    random draws of 500 matrices that were cross-correlated with the seven most relevant matrices. Fifty test runs were performed so that AUC...is 40 m in length, where the APL-UW rail is 42 m long. When the area shaded in light tan contained targets, the source and receiving array were

  16. Outcome Prediction after Traumatic Brain Injury: Comparison of the Performance of Routinely Used Severity Scores and Multivariable Prognostic Models

    Science.gov (United States)

    Majdan, Marek; Brazinova, Alexandra; Rusnak, Martin; Leitgeb, Johannes

    2017-01-01

    Objectives: Prognosis of outcome after traumatic brain injury (TBI) is important in the assessment of quality of care and can help improve treatment and outcome. The aim of this study was to compare the prognostic value of relatively simple injury severity scores between each other and against a gold standard model – the IMPACT-extended (IMP-E) multivariable prognostic model. Materials and Methods: For this study, 866 patients with moderate/severe TBI from Austria were analyzed. The prognostic performances of the Glasgow coma scale (GCS), GCS motor (GCSM) score, abbreviated injury scale for the head region, Marshall computed tomographic (CT) classification, and Rotterdam CT score were compared side-by-side and against the IMP-E score. The area under the receiver operating characteristics curve (AUC) and Nagelkerke's R2 were used to assess the prognostic performance. Outcomes at the Intensive Care Unit, at hospital discharge, and at 6 months (mortality and unfavorable outcome) were used as end-points. Results: Comparing AUCs and R2s of the same model across four outcomes, only little variation was apparent. A similar pattern is observed when comparing the models between each other: Variation of AUCs 0.83 and R2 > 0.42 for all outcomes): AUCs were worse by 0.10–0.22 (P prognosis. However, it is confirmed that well-developed multivariable prognostic models outperform these scores significantly and should be used for prognosis in patients after TBI wherever possible.

  17. Dose-Dependent Change in Elimination Kinetics of Ethanol due to Shift of Dominant Metabolizing Enzyme from ADH 1 (Class I to ADH 3 (Class III in Mouse

    Directory of Open Access Journals (Sweden)

    Takeshi Haseba

    2012-01-01

    Full Text Available ADH 1 and ADH 3 are major two ADH isozymes in the liver, which participate in systemic alcohol metabolism, mainly distributing in parenchymal and in sinusoidal endothelial cells of the liver, respectively. We investigated how these two ADHs contribute to the elimination kinetics of blood ethanol by administering ethanol to mice at various doses, and by measuring liver ADH activity and liver contents of both ADHs. The normalized AUC (AUC/dose showed a concave increase with an increase in ethanol dose, inversely correlating with β. CLT (dose/AUC linearly correlated with liver ADH activity and also with both the ADH-1 and -3 contents (mg/kg B.W.. When ADH-1 activity was calculated by multiplying ADH-1 content by its Vmax⁡/mg (4.0 and normalized by the ratio of liver ADH activity of each ethanol dose to that of the control, the theoretical ADH-1 activity decreased dose-dependently, correlating with β. On the other hand, the theoretical ADH-3 activity, which was calculated by subtracting ADH-1 activity from liver ADH activity and normalized, increased dose-dependently, correlating with the normalized AUC. These results suggested that the elimination kinetics of blood ethanol in mice was dose-dependently changed, accompanied by a shift of the dominant metabolizing enzyme from ADH 1 to ADH 3.

  18. Therapeutic drug monitoring to individualize the dosing of pazopanib: a pharmacokinetic feasibility study

    NARCIS (Netherlands)

    Wit, D. de; Erp, N. van; Hartigh, J. den; Wolterbeek, R..; Hollander-van Deursen, M. den; Labots, M.; Guchelaar, H.J.; Verheul, H.M.; Gelderblom, H.

    2015-01-01

    BACKGROUND: Patients treated with the standard dose of pazopanib show a large interpatient variability in drug exposure defined as the area under the plasma concentration-time curve (AUC0-24h). The primary objective of this study was to evaluate the feasibility of pharmacokinetics (PK)-guided indivi

  19. Bioequivalence of two oral formulations of triflusal capsules in healthy volunteers.

    Science.gov (United States)

    Quetglas, Emilio García; Campanero, Miguel Angel; Sádaba, Belén; Escolar, Manuel; Azanza, Jose Ramón

    2008-01-01

    Triflusal (CAS 322-79-2) is an antiplatelet agent related to salicylates used in several European and Latin American countries in the treatment of cardiovascular diseases. The aim of this paper was to evaluate the bioequivalence of triflusal derived from two preparations using both parent drug and metabolite pharmacokinetic data. The bioavailabolity was measured in 24 healthy male Caucasian volunteers following a single oral dose (600 mg) of the test or reference products in the fasting state. Blood samples were collected for 120 h. Plasma concentrations of triflusal and its metabolite 3-hydroxy-4-trifluoromethylbenzoic acid (HTB) were analyzed by high-performance liquid chromatography with UV and fluorescence detection, respectively. The non-compartmental method was used for pharmacokinetic analysis. Log-transformed Cmax, AUC0-t and AUC0-infinity were tested for bioequivalence using ANOVA and Schuirmann's two-one sided t-test. Tmax was analyzed by nonparametric pharmacokinetic parameters of triflusal and HTB derived from the two formulations were nearly consistent with previous observations. Triflusal parameters derived from the test and reference drug were as follows: Cmax (16.85 +/- 11.41 vs 14.48 +/- 7.22 mg/l), AUC0-t (18.43 +/- 10.91 vs 16.22 +/- 7.58 mg/l per hour), Tmax (1 range 0.25-2h vs 0.875 range 0.25-1.5 h), and t(1/2) (0.49 +/- 00.27 vs 0.76 +/- 0.64). HTB parameters after test and reference formulation administration were as follows: Cmax (68.13 +/- 23.05 vs 65.51 +/- 19.44 mg/l), AUC0-t (2748.18 +/- 971.91 vs 2877.97 +/- 881.2 h x mg/l), AUC0-infinity (3350.15 +/- 1182.62 vs 3372.49 +/- 1110.35 h x mg/l), Tmax (2 range 1-10 h vs 2 range 0.75-12 h), and t(1/2) (42.19 +/- 7.82 vs 43.13 +/- 6.56 h). 90% of confidence intervals for the test/reference ratio of Cmax AUC0-t and AUC0-infinity derived from both triflusal and HTB were found within the range of 80%-125% acceptable for bioequivalence. No significant difference was found between the Tmax values

  20. Evaluation of the pharmacokinetic interaction between repeated doses of rifapentine or rifampin and a single dose of bedaquiline in healthy adult subjects.

    Science.gov (United States)

    Winter, Helen; Egizi, Erica; Murray, Stephen; Erondu, Ngozi; Ginsberg, Ann; Rouse, Doris J; Severynse-Stevens, Diana; Pauli, Elliott

    2015-02-01

    This study assessed the effects of rifapentine or rifampin on the pharmacokinetics of a single dose of bedaquiline and its M2 metabolite in healthy subjects using a two-period single-sequence design. In period 1, subjects received a single dose of bedaquiline (400 mg), followed by a 28-day washout. In period 2, subjects received either rifapentine (600 mg) or rifampin (600 mg) from day 20 to day 41, as well as a single bedaquiline dose (400 mg) on day 29. The pharmacokinetic profiles of bedaquiline and M2 were compared over 336 h after the administration of bedaquiline alone and in combination with steady-state rifapentine or rifampin. Coadministration of bedaquiline with rifapentine or rifampin resulted in lower bedaquiline exposures. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for the maximum observed concentration (Cmax), area under the concentration-time curve to the last available concentration time point (AUC0-t), and AUC extrapolated to infinity (AUC0-inf) of bedaquiline were 62.19% (53.37 to 72.47), 42.79% (37.77 to 48.49), and 44.52% (40.12 to 49.39), respectively, when coadministered with rifapentine. Similarly, the GMRs and 90% CIs for the Cmax, AUC0-t, and AUC0-inf of bedaquiline were 60.24% (51.96 to 69.84), 41.36% (37.70 to 45.36), and 47.32% (41.49 to 53.97), respectively, when coadministered with rifampin. The Cmax, AUC0-t, and AUC0-inf of M2 were also altered when bedaquiline was coadministered with rifapentine or rifampin. Single doses of bedaquiline, administered alone or with multiple doses of rifapentine or rifampin, were well tolerated, with no safety concerns related to coadministration. Daily administration of rifapentine to patients with tuberculosis presents the same drug interaction challenges as rifampin and other rifamycins. Strong inducers of the cytochrome P450 isoenzyme CYP3A4 should be avoided when considering the use of bedaquiline. (This study is registered at clinicaltrials.gov under identifier NCT02216331.).

  1. ACC/AATS/AHA/ASE/ASNC/SCAI/SCCT/STS 2016 Appropriate Use Criteria for Coronary Revascularization in Patients With Acute Coronary Syndromes : A Report of the American College of Cardiology Appropriate Use Criteria Task Force, American Association for Thoracic Surgery, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and the Society of Thoracic Surgeons.

    Science.gov (United States)

    Patel, Manesh R; Calhoon, John H; Dehmer, Gregory J; Grantham, James Aaron; Maddox, Thomas M; Maron, David J; Smith, Peter K

    2017-03-06

    The American College of Cardiology, Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons, and American Association for Thoracic Surgery, along with key specialty and subspecialty societies, have completed a 2-part revision of the appropriate use criteria (AUC) for coronary revascularization. In prior coronary revascularization AUC documents, indications for revascularization in acute coronary syndromes (ACS) and stable ischemic heart disease were combined into 1 document. To address the expanding clinical indications for coronary revascularization, and in an effort to align the subject matter with the most current American College of Cardiology/American Heart Association guidelines, the new AUC for coronary artery revascularization were separated into 2 documents addressing ACS and stable ischemic heart disease individually. This document presents the AUC for ACS. Clinical scenarios were developed to mimic patient presentations encountered in everyday practice and included information on symptom status, presence of clinical instability or ongoing ischemic symptoms, prior reperfusion therapy, risk level as assessed by noninvasive testing, fractional flow reserve testing, and coronary anatomy. This update provides a reassessment of clinical scenarios that the writing group felt to be affected by significant changes in the medical literature or gaps from prior criteria. The methodology used in this update is similar to the initial document but employs the recent modifications in the methods for developing AUC, most notably, alterations in the nomenclature for appropriate use categorization. A separate, independent rating panel scored the clinical scenarios on a scale of 1 to 9. Scores of 7 to 9 indicate that revascularization is considered appropriate for the clinical scenario presented. Scores of 1 to 3 indicate that revascularization is considered rarely appropriate for the clinical scenario, whereas scores in the mid-range (4 to 6

  2. Cellulose nanofibrils improve the properties of all-cellulose composites by the nano-reinforcement mechanism and nanofibril-induced crystallization

    Science.gov (United States)

    Yang, Quanling; Saito, Tsuguyuki; Berglund, Lars A.; Isogai, Akira

    2015-10-01

    All-cellulose nanocomposite films containing crystalline TEMPO-oxidized cellulose nanofibrils (TOCNs) of 0-1 wt% were fabricated by mixing aqueous TOCN dispersions with alkali/urea/cellulose (AUC) solutions at room temperature. The mixtures were cast on glass plates, soaked in an acid solution, and the regenerated gel-like films were washed with water and then dried. The TOCN did not form agglomerates in the composites, and had the structure of TOCN-COOH, forming hydrogen bonds with the hydroxyl groups of the regenerated cellulose molecules. X-ray diffraction analysis revealed that the matrix cellulose molecules increased the cellulose II crystal size upon incorporation of TOCN. As a result, the TOCN/AUC composite films had high Young's modulus, tensile strength, thermal stability and oxygen-barrier properties. The TOCN/AUC composite films are promising all-cellulose nanocomposites for versatile applications as new bio-based materials.All-cellulose nanocomposite films containing crystalline TEMPO-oxidized cellulose nanofibrils (TOCNs) of 0-1 wt% were fabricated by mixing aqueous TOCN dispersions with alkali/urea/cellulose (AUC) solutions at room temperature. The mixtures were cast on glass plates, soaked in an acid solution, and the regenerated gel-like films were washed with water and then dried. The TOCN did not form agglomerates in the composites, and had the structure of TOCN-COOH, forming hydrogen bonds with the hydroxyl groups of the regenerated cellulose molecules. X-ray diffraction analysis revealed that the matrix cellulose molecules increased the cellulose II crystal size upon incorporation of TOCN. As a result, the TOCN/AUC composite films had high Young's modulus, tensile strength, thermal stability and oxygen-barrier properties. The TOCN/AUC composite films are promising all-cellulose nanocomposites for versatile applications as new bio-based materials. Electronic supplementary information (ESI) available: Fig. S1-S3 show an AFM image of TOCN, SEM

  3. Development and optimization of SPECT gated blood pool cluster analysis for the prediction of CRT outcome

    Energy Technology Data Exchange (ETDEWEB)

    Lalonde, Michel, E-mail: mlalonde15@rogers.com; Wassenaar, Richard [Department of Physics, Carleton University, Ottawa, Ontario K1S 5B6 (Canada); Wells, R. Glenn; Birnie, David; Ruddy, Terrence D. [Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario K1Y 4W7 (Canada)

    2014-07-15

    Purpose: Phase analysis of single photon emission computed tomography (SPECT) radionuclide angiography (RNA) has been investigated for its potential to predict the outcome of cardiac resynchronization therapy (CRT). However, phase analysis may be limited in its potential at predicting CRT outcome as valuable information may be lost by assuming that time-activity curves (TAC) follow a simple sinusoidal shape. A new method, cluster analysis, is proposed which directly evaluates the TACs and may lead to a better understanding of dyssynchrony patterns and CRT outcome. Cluster analysis algorithms were developed and optimized to maximize their ability to predict CRT response. Methods: About 49 patients (N = 27 ischemic etiology) received a SPECT RNA scan as well as positron emission tomography (PET) perfusion and viability scans prior to undergoing CRT. A semiautomated algorithm sampled the left ventricle wall to produce 568 TACs from SPECT RNA data. The TACs were then subjected to two different cluster analysis techniques, K-means, and normal average, where several input metrics were also varied to determine the optimal settings for the prediction of CRT outcome. Each TAC was assigned to a cluster group based on the comparison criteria and global and segmental cluster size and scores were used as measures of dyssynchrony and used to predict response to CRT. A repeated random twofold cross-validation technique was used to train and validate the cluster algorithm. Receiver operating characteristic (ROC) analysis was used to calculate the area under the curve (AUC) and compare results to those obtained for SPECT RNA phase analysis and PET scar size analysis methods. Results: Using the normal average cluster analysis approach, the septal wall produced statistically significant results for predicting CRT results in the ischemic population (ROC AUC = 0.73;p < 0.05 vs. equal chance ROC AUC = 0.50) with an optimal operating point of 71% sensitivity and 60% specificity. Cluster

  4. Relative bioavailability of rifampicin in a three-drug fixed-dose combination formulation%三药固定剂量复方制剂的利福平相对生物利用度

    Institute of Scientific and Technical Information of China (English)

    R.C.Milán-Segovia; A.M.Domínguez-Ramírez; H.Jung-Cook; M.Maga(n)a-Aquino; M.C.Romero-Méndez; S.E.Medellíin-Garibay; M.Vigna-Pérez; S.Romano-Moreno; 金海霞

    2011-01-01

    背景:先前的一个利福平(RMP)监测性研究显示,结核病(TB)患者在使用常规的3药固定剂量复方制剂(3FDC)治疗时,RMP浓度很低.因此,我们对该制剂的生物利用度进行研究.目的:利用健康志愿者研究墨西哥卫生保健系统中常规使用的3FDC制剂相对于参比制剂的RMP相对生物利用度.设计:两周期、两序列的交叉研究.结果:受试制剂和参比制剂的药代动力学参数均值如下:达峰浓度(C_max)分别为3.13±2.01滩/而和9.95±2.66 μg/ml;对于血药浓度一时间曲线下面积(AUC),零到最后实测浓度的AUC(AUC_0-12h)分别为15.51±9.77 μg·h/ml和58.03±16.1 μg·h/ml,零到无限大时间的AUC(AUC_0-∞)分别为17.92±10.66 μg·h/ml和68.43±22.39 μg·h/ml.C_max的受试/参比均值比(90% CI)为25.36%(17.33~37.10);AUC0_12h为21.25%(14.61~30.89);AUC_0-∞为22.08% (15.44~31.56).这些结果不符合生物等效性标准.结论:受试制剂与参比制剂相比,显示吸收延迟和RMP生物利用度明显偏低.含RMP的常规制剂只有在其生物利用度评估后可确保与参比制剂互换,并确保在其使用过程中不出现RMP浓度明显偏低的危险时,才能应用.

  5. Pharmacokinetic profile of defibrotide in patients with renal impairment

    Science.gov (United States)

    Tocchetti, Paola; Tudone, Elena; Marier, Jean-Francois; Marbury, Thomas C; Zomorodi, Katie; Eller, Mark

    2016-01-01

    Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially life-threatening complication of hematopoietic stem cell transplant conditioning. Severe VOD/SOS, generally associated with multiorgan dysfunction (pulmonary or renal dysfunction), may be associated with >80% mortality. Defibrotide, recently approved in the US, has demonstrated efficacy treating hepatic VOD/SOS with multiorgan dysfunction. Because renal impairment is prevalent in patients with VOD/SOS, this Phase I, open-label, two-part study in adults examined the effects of hemodialysis and severe or end-stage renal disease (ESRD) on defibrotide pharmacokinetics (PK). Part 1 compared defibrotide PK during single 6.25 mg/kg doses infused with and without dialysis. Part 2 assessed defibrotide plasma PK after multiple 6.25 mg/kg doses in nondialysis-dependent subjects with severe/ESRD versus healthy matching subjects. Among six subjects enrolled in Part 1, percent ratios of least-squares mean and 90% confidence intervals (CIs) on dialysis and nondialysis days were 109.71 (CI: 97.23, 123.78) for maximum observed plasma concentration (Cmax); 108.39 (CI: 97.85, 120.07) for area under the concentration–time curve to the time of the last quantifiable plasma concentration (AUC0–t); and 109.98 (CI: 99.39, 121.70) for AUC extrapolated to infinity (AUC0–∞). These ranges were within 80%–125%, indicating no significant effect of dialysis on defibrotide exposure/clearance. In Part 2, defibrotide exposure parameters in six subjects with severe/ESRD after multiple doses (AUC0–t, 113 µg·h/mL; AUC over dosing interval, 113 µg·h/mL; Cmax, 53.8 µg/mL) were within 5%–8% of parameters after the first dose (AUC0–t, 117 µg·h/mL; AUC0–∞, 118 µg·h/mL; Cmax, 54.9 µg/mL), indicating no accumulation. Defibrotide peak and extent of exposures in those with severe/ESRD were ~35%–37% and 50%–60% higher, respectively, versus controls, following

  6. The advantages of combination therapy on hypertension: development of immediate release perindopril-indapamide tablet and assessment of bioequivalence studies.

    Science.gov (United States)

    Ölçer, A; Ölçer, M; İnce, I; Karasulu, E

    2016-03-01

    Hypertension has a major associated risk for organ damage and mortality, which is further heightened in patients with prior cardiovascular events, comorbid diabetes mellitus, microalbuminuria and renal impairment. Convers Plus tablet including perindopril erbumine (PE), which is an angiotensin converting enzyme (ACE) inhibitor, and indapamide, which is diuretic, was designed as a combined tablet to succes in the treatment of hypertension. Physico-pharmaceutical properties and characterization studies were evaluated in vitro conditions. Later on in vivo study was planned as a cross-designed, randomized, open-labeled, single-dose, single-center study via peroral route in 24 healthy male subjects. In this study, bioequivalence with primary pharmacokinetical target parameters reference (Bipreterax 4/1.25 mg Tablet-S.A.Servier Benelux N.V.) and test (Convers Plus 4/1.25 mg Tablet-ARGESAN Pharmaceutical Company) tablets have been found bioequivalent. The results of pharmacokinetic parameters for perindopril, perindoprilat and indapamide were found as Cmax = 23.179 µg/mL, tmax = 0.729 h, t1/2 = 1.429 h; AUC0-t = 26.998 µgs/mL, AUC0-inf = 27.117 µgs/mL; Cmax = 1.834 µg/mL, tmax = 8.792 h, t1/2 = 40.699 h; AUC0-t = 54.828 µgs/mL, AUC0-inf = 77.113 µgs/mL; Cmax = 18.994 µg/mL, tmax = 3.417 h, t1/2 = 16.626 h and AUC0-t = 385.829 µgs/mL, AUC0-inf = 410.728 µgs/mL respectively. In conclusion, physico-pharmaceutical properties and results of clinical trials show that Convers Plus tablets have been found as bioequivalent for perindopril, perindoprilat and indapamide in terms of AUC and Cmax, in 90% confidence limits.

  7. Bioequivalence between two commercial formulations of gliclazide in Colombia Bioequivalencia entre dos formulaciones comerciales de gliclazida en Colombia

    Directory of Open Access Journals (Sweden)

    Ignacio Rodríguez

    2001-01-01

    Full Text Available Two commercial formulations of Gliclazide 80 mg tablets were studied in order to evaluate both pharmaceutical and biological equivalence, Glidiab® Tecnoquímicas Laboratories and Diamicron® Euroetika-Elsevier Laboratories. After proving the pharmaceutical equivalence, a bioequivalence was tested in 14 healthy volunteers and the determination of gliclazide in plasma was carried out by high-performance liquid chromatography (HPLC. The evaluated pharmacokinetic parameters were: area under the curve (AUC from 0 to 60 hours, maximum concentration (Cmax and time to maximum concentration (Tmax. In statistical analysis the 90.0% confidence intervals for AUC, Cmax and Tmax, and acceptance range for bioequivalence of 80.0%-125.0% to AUC and Cmax and acceptance range of 80:0%-120.0% to Tmax, were applied. Both formulations presented inter and intra subject high variability and it was found that they are bioequivalent in relation to AUC but they are not bioequivalent in relation to Cmax and Tmax. Los formulaciones comerciales de Gliclazida de 80 mg – tabletas, los productos Glidiab® de Tecnoquímicas y Diamicron® de Euroetika-Elsevier, fueron sometidos a estudio para evaluar la equivalencia farmacéutica y la equivalencia biológica. Después de comprobar la equivalencia farmacéutica se llevó a cabo el estudio de la equivalencia biológica en 14 voluntarios sanos; la cuantificación de Gliclazida en plasma se realizó por la técnica de cromatografía líquida de alta resolución (HPLC. Los parámetros farmacocinéticos evaluados fueron: área bajo la curva (AUC de 0-60 horas, concentración máxima (Cmáx y el tiempo máximo (tmáx los cuales se analizaron estadísticamente con intervalos de confianza del 90.0% y un rango de aceptación para bioequivalencia del 80.0% al 125.0% para AUC y Cmáx y del 80.0% al 120.0% para el tmáx. Ambas formulaciones presentaron alta variabilidad inter e intrasujeto y se encontró que son bioequivalentes con

  8. Performance of Two Bioelectrical Impedance Analyses in the Diagnosis of Overweight and Obesity in Children and Adolescents: The FUPRECOL Study

    Science.gov (United States)

    Ramírez-Vélez, Robinson; Correa-Bautista, Jorge Enrique; Martínez-Torres, Javier; González-Ruíz, Katherine; González-Jiménez, Emilio; Schmidt-RioValle, Jacqueline; Garcia-Hermoso, Antonio

    2016-01-01

    This study aimed to determine thresholds for percentage of body fat (BF%) corresponding to the cut-off values for overweight/obesity as recommended by the International Obesity Task Force (IOTF), using two bioelectrical impedance analyzers (BIA), and described the likelihood of increased cardiometabolic risk in our cohort defined by the IOTF and BF% status. Participants included 1165 children and adolescents (54.9% girls) from Bogotá (Colombia). Body mass index (BMI) was calculated from height and weight. BF% of each youth was assessed first using the Tanita BC-418® followed by a Tanita BF-689®. The sensitivity and specificity of both devices and their ability to correctly classify children as overweight/obesity (≥2 standard deviation), as defined by IOTF, was investigated using receiver operating characteristic (ROC) by sex and age groups (9–11, 12–14, and 13–17 years old); Area under curve (AUC) values were also reported. For girls, the optimal BF% threshold for classifying into overweight/obesity was found to be between 25.2 and 28.5 (AUC = 0.91–0.97) and 23.9 to 26.6 (AUC = 0.90–0.99) for Tanita BC-418® and Tanita BF-689®, respectively. For boys, the optimal threshold was between 16.5 and 21.1 (AUC = 0.93–0.96) and 15.8 to 20.6 (AUC = 0.92–0.94) by Tanita BC-418® and Tanita BF-689®, respectively. All AUC values for ROC curves were statistically significant and there were no differences between AUC values measured by both BIA devices. The BF% values associated with the IOTF-recommended BMI cut-off for overweight/obesity may require age- and sex-specific threshold values in Colombian children and adolescents aged 9–17 years and could be used as a surrogate method to identify individuals at risk of excess adiposity. PMID:27782039

  9. Performance of Two Bioelectrical Impedance Analyses in the Diagnosis of Overweight and Obesity in Children and Adolescents: The FUPRECOL Study

    Directory of Open Access Journals (Sweden)

    Robinson Ramírez-Vélez

    2016-10-01

    Full Text Available This study aimed to determine thresholds for percentage of body fat (BF% corresponding to the cut-off values for overweight/obesity as recommended by the International Obesity Task Force (IOTF, using two bioelectrical impedance analyzers (BIA, and described the likelihood of increased cardiometabolic risk in our cohort defined by the IOTF and BF% status. Participants included 1165 children and adolescents (54.9% girls from Bogotá (Colombia. Body mass index (BMI was calculated from height and weight. BF% of each youth was assessed first using the Tanita BC-418® followed by a Tanita BF-689®. The sensitivity and specificity of both devices and their ability to correctly classify children as overweight/obesity (≥2 standard deviation, as defined by IOTF, was investigated using receiver operating characteristic (ROC by sex and age groups (9–11, 12–14, and 13–17 years old; Area under curve (AUC values were also reported. For girls, the optimal BF% threshold for classifying into overweight/obesity was found to be between 25.2 and 28.5 (AUC = 0.91–0.97 and 23.9 to 26.6 (AUC = 0.90–0.99 for Tanita BC-418® and Tanita BF-689®, respectively. For boys, the optimal threshold was between 16.5 and 21.1 (AUC = 0.93–0.96 and 15.8 to 20.6 (AUC = 0.92–0.94 by Tanita BC-418® and Tanita BF-689®, respectively. All AUC values for ROC curves were statistically significant and there were no differences between AUC values measured by both BIA devices. The BF% values associated with the IOTF-recommended BMI cut-off for overweight/obesity may require age- and sex-specific threshold values in Colombian children and adolescents aged 9–17 years and could be used as a surrogate method to identify individuals at risk of excess adiposity.

  10. Comparison of consumption behavior and appetite sensations among patients with type 2 diabetes mellitus after bariatric surgery

    Science.gov (United States)

    Yeh, Chun; Huang, Hsien-Hao; Chen, Shu-Chun; Chen, Tung-Fang

    2017-01-01

    Background The promising postsurgical weight loss and remission of type 2 diabetes (T2D) from bariatric surgery can be attributed to modified eating physiology after surgical procedures. We sought to investigate the changes in the parameters of consumption behaviors and appetite sensations induced by a mixed meal tolerance test, and to correlate these alterations with age, body mass index, C-peptide levels, and duration of T2D 1 year after bariatric surgery. Methods A total of 16 obese patients with T2D who underwent mini-gastric bypass (GB) and 16 patients who underwent sleeve gastrectomy (SG) were enrolled in this study and evaluated using a mixed meal tolerance test one year after surgery. A visual analogue scale was used for scoring appetite sensation at different time points. The area under the curve (AUC) and the incremental or decremental AUCAUC) were compared between the two groups. Results One year after surgery, a decreasing trend in the consumption time was observed in the GB group compared to the SG group, while the duration of T2D before surgery was negatively correlated with the post-operative consumed time in those after GB. Patients who underwent GB had significantly higher fasting scores for fullness and desire to eat, higher AUC0′–180′ of scores for desire to eat, as well as more effective post-meal suppression of hunger and desire to eat compared with those undergoing SG one year after surgery. Post-operative C-peptide levels were negatively correlated with ΔAUC0′–180′ for hunger and ΔAUC0′–180′ for desire to eat in the GB group, while negatively correlated with ΔAUC0′–180′ for fullness in the SG group. Discussion Patients with T2D after either GB or SG exhibit distinct nutrient-induced consumption behaviors and appetite sensations post-operatively, which may account for the differential effects on weight loss and glycemic control after different surgery. PMID:28344903

  11. Comparison of consumption behavior and appetite sensations among patients with type 2 diabetes mellitus after bariatric surgery

    Directory of Open Access Journals (Sweden)

    Chun Yeh

    2017-03-01

    Full Text Available Background The promising postsurgical weight loss and remission of type 2 diabetes (T2D from bariatric surgery can be attributed to modified eating physiology after surgical procedures. We sought to investigate the changes in the parameters of consumption behaviors and appetite sensations induced by a mixed meal tolerance test, and to correlate these alterations with age, body mass index, C-peptide levels, and duration of T2D 1 year after bariatric surgery. Methods A total of 16 obese patients with T2D who underwent mini-gastric bypass (GB and 16 patients who underwent sleeve gastrectomy (SG were enrolled in this study and evaluated using a mixed meal tolerance test one year after surgery. A visual analogue scale was used for scoring appetite sensation at different time points. The area under the curve (AUC and the incremental or decremental AUCAUC were compared between the two groups. Results One year after surgery, a decreasing trend in the consumption time was observed in the GB group compared to the SG group, while the duration of T2D before surgery was negatively correlated with the post-operative consumed time in those after GB. Patients who underwent GB had significantly higher fasting scores for fullness and desire to eat, higher AUC0′–180′ of scores for desire to eat, as well as more effective post-meal suppression of hunger and desire to eat compared with those undergoing SG one year after surgery. Post-operative C-peptide levels were negatively correlated with ΔAUC0′–180′ for hunger and ΔAUC0′–180′ for desire to eat in the GB group, while negatively correlated with ΔAUC0′–180′ for fullness in the SG group. Discussion Patients with T2D after either GB or SG exhibit distinct nutrient-induced consumption behaviors and appetite sensations post-operatively, which may account for the differential effects on weight loss and glycemic control after different surgery.

  12. P-gp/ABCB1 exerts differential impacts on brain and fetal exposure to norbuprenorphine.

    Science.gov (United States)

    Liao, Michael Z; Gao, Chunying; Shireman, Laura M; Phillips, Brian; Risler, Linda J; Neradugomma, Naveen K; Choudhari, Prachi; Prasad, Bhagwat; Shen, Danny D; Mao, Qingcheng

    2017-01-19

    Norbuprenorphine is the major active metabolite of buprenorphine which is commonly used to treat opiate addiction during pregnancy. Norbuprenorphine produces marked respiratory depression and was 10 times more potent than buprenorphine. Therefore, it is important to understand the mechanism that controls fetal exposure to norbuprenorphine, as exposure to this compound may pose a significant risk to the developing fetus. P-gp/ABCB1 and BCRP/ABCG2 are two major efflux transporters regulating tissue distribution of drugs. Previous studies have shown that norbuprenorphine, but not buprenorphine, is a P-gp substrate. In this study, we systematically examined and compared the roles of P-gp and BCRP in determining maternal brain and fetal distribution of norbuprenorphine using transporter knockout mouse models. We administered 1mg/kg norbuprenorphine by retro-orbital injection to pregnant FVB wild-type, Abcb1a(-/-)/1b(-/-), and Abcb1a(-/-)/1b(-/-)/Abcg2(-/-) mice on gestation day 15. The fetal AUC of norbuprenorphine was ∼64% of the maternal plasma AUC in wild-type mice, suggesting substantial fetal exposure to norbuprenorphine. The maternal plasma AUCs of norbuprenorphine in Abcb1a(-/-)/1b(-/-) and Abcb1a(-/-)/1b(-/-)/Abcg2(-/-) mice were ∼2 times greater than that in wild-type mice. Fetal AUCs in Abcb1a(-/-)/1b(-/-) and Abcb1a(-/-)/1b(-/-)/Abcg2(-/-) mice were also increased compared to wild-type mice; however, the fetal-to-maternal plasma AUC ratio remained relatively unchanged by the knockout of Abcb1a/1b or Abcb1a/1b/Abcg2. In contrast, the maternal brain-to-maternal plasma AUC ratio in Abcb1a(-/-)/1b(-/-) or Abcb1a(-/-)/1b(-/-)/Abcg2(-/-) mice was increased ∼30-fold compared to wild-type mice. Protein quantification by LC-MS/MS proteomics revealed significantly higher amounts of P-gp protein in the wild-type mice brain than that in the placenta. These results indicate that fetal exposure to norbuprenorphine is substantial and that P-gp has a minor impact on

  13. Use of microdosing and accelerator mass spectrometry to evaluate the pharmacokinetic linearity of a novel tricyclic GyrB/ParE inhibitor in rats.

    Science.gov (United States)

    Malfatti, Michael A; Lao, Victoria; Ramos, Courtney L; Ong, Voon S; Turteltaub, Kenneth W

    2014-11-01

    Determining the pharmacokinetics (PKs) of drug candidates is essential for understanding their biological fate. The ability to obtain human PK information early in the drug development process can help determine if future development is warranted. Microdosing was developed to assess human PKs, at ultra-low doses, early in the drug development process. Microdosing has also been used in animals to confirm PK linearity across subpharmacological and pharmacological dose ranges. The current study assessed the PKs of a novel antimicrobial preclinical drug candidate (GP-4) in rats as a step toward human microdosing studies. Dose proportionality was determined at 3 proposed therapeutic doses (3, 10, and 30 mg/kg of body weight), and PK linearity between a microdose and a pharmacological dose was assessed in Sprague-Dawley rats. Plasma PKs over the 3 pharmacological doses were proportional. Over the 10-fold dose range, the maximum concentration in plasma and area under the curve (AUC) increased 9.5- and 15.8-fold, respectively. PKs from rats dosed with a (14)C-labeled microdose versus a (14)C-labeled pharmacological dose displayed dose linearity. In the animals receiving a microdose and the therapeutically dosed animals, the AUCs from time zero to infinity were 2.6 ng · h/ml and 1,336 ng · h/ml, respectively, and the terminal half-lives were 5.6 h and 1.4 h, respectively. When the AUC values were normalized to a dose of 1.0 mg/kg, the AUC values were 277.5 ng · h/ml for the microdose and 418.2 ng · h/ml for the pharmacological dose. This 1.5-fold difference in AUC following a 300-fold difference in dose is considered linear across the dose range. On the basis of the results, the PKs from the microdosed animals were considered to be predictive of the PKs from the therapeutically dosed animals.

  14. A comparison of Bayesian and non-linear regression methods for robust estimation of pharmacokinetics in DCE-MRI and how it affects cancer diagnosis.

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    Dikaios, Nikolaos; Atkinson, David; Tudisca, Chiara; Purpura, Pierpaolo; Forster, Martin; Ahmed, Hashim; Beale, Timothy; Emberton, Mark; Punwani, Shonit

    2017-03-01

    The aim of this work is to compare Bayesian Inference for nonlinear models with commonly used traditional non-linear regression (NR) algorithms for estimating tracer kinetics in Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI). The algorithms are compared in terms of accuracy, and reproducibility under different initialization settings. Further it is investigated how a more robust estimation of tracer kinetics affects cancer diagnosis. The derived tracer kinetics from the Bayesian algorithm were validated against traditional NR algorithms (i.e. Levenberg-Marquardt, simplex) in terms of accuracy on a digital DCE phantom and in terms of goodness-of-fit (Kolmogorov-Smirnov test) on ROI-based concentration time courses from two different patient cohorts. The first cohort consisted of 76 men, 20 of whom had significant peripheral zone prostate cancer (any cancer-core-length (CCL) with Gleason>3+3 or any-grade with CCL>=4mm) following transperineal template prostate mapping biopsy. The second cohort consisted of 9 healthy volunteers and 24 patients with head and neck squamous cell carcinoma. The diagnostic ability of the derived tracer kinetics was assessed with receiver operating characteristic area under curve (ROC AUC) analysis. The Bayesian algorithm accurately recovered the ground-truth tracer kinetics for the digital DCE phantom consistently improving the Structural Similarity Index (SSIM) across the 50 different initializations compared to NR. For optimized initialization, Bayesian did not improve significantly the fitting accuracy on both patient cohorts, and it only significantly improved the ve ROC AUC on the HN population from ROC AUC=0.56 for the simplex to ROC AUC=0.76. For both cohorts, the values and the diagnostic ability of tracer kinetic parameters estimated with the Bayesian algorithm weren't affected by their initialization. To conclude, the Bayesian algorithm led to a more accurate and reproducible quantification of tracer kinetic

  15. Urinary Biomarker Panel to Improve Accuracy in Predicting Prostate Biopsy Result in Chinese Men with PSA 4–10 ng/mL

    Science.gov (United States)

    Zhou, Yongqiang; Li, Yun; Li, Xiangnan

    2017-01-01

    This study aims to evaluate the effectiveness and clinical performance of a panel of urinary biomarkers to diagnose prostate cancer (PCa) in Chinese men with PSA levels between 4 and 10 ng/mL. A total of 122 patients with PSA levels between 4 and 10 ng/mL who underwent consecutive prostate biopsy at three hospitals in China were recruited. First-catch urine samples were collected after an attentive prostate massage. Urinary mRNA levels were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The predictive accuracy of these biomarkers and prediction models was assessed by the area under the curve (AUC) of the receiver-operating characteristic (ROC) curve. The diagnostic accuracy of PCA3, PSGR, and MALAT-1 was superior to that of PSA. PCA3 performed best, with an AUC of 0.734 (95% CI: 0.641, 0.828) followed by MALAT-1 with an AUC of 0.727 (95% CI: 0.625, 0.829) and PSGR with an AUC of 0.666 (95% CI: 0.575, 0.749). The diagnostic panel with age, prostate volume, % fPSA, PCA3 score, PSGR score, and MALAT-1 score yielded an AUC of 0.857 (95% CI: 0.780, 0.933). At a threshold probability of 20%, 47.2% of unnecessary biopsies may be avoided whereas only 6.2% of PCa cases may be missed. This urinary panel may improve the current diagnostic modality in Chinese men with PSA levels between 4 and 10 ng/mL.

  16. A Comparative Pharmacokinetics Study of the Anti-Parkinsonian Drug Pramipexole

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    Ratih S. I. Putri

    2016-11-01

    Full Text Available The present study aimed to compare pharmacokinetic parameters of two pramipexole 0.25 mg formulations in order to show bioequivalence. The study was conducted in a randomized, open-label, two-period, two-sequence, and crossover design, involving 23 healthy volunteers. One of the 0.25 mg formulations of pramipexole evaluated in the study was manufactured by PT Dexa Medica, Palembang, Indonesia, the other, used as the reference, by Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany. All eligible subjects were required to fast before each drug administration period, which was separated by a one-week washout period. Pramipexole concentrations in plasma were assayed using a validated ultra performance liquid chromatography with mass spectrometry (UPLC-MS/MS detector. The evaluated pharmacokinetic parameters included the area under the plasma concentration curve from time zero to the last observed measurable concentration (AUC0-t, the area under the plasma concentration curve extrapolated to infinite time (AUC0-∞, the maximum plasma concentration (Cmax, the time to reach Cmax (tmax, and the plasma concentration half-life (t1/2. To evaluate the bioequivalence of those two pramipexole formulations, 90% confidence intervals (CIs for geometric mean ratios of both formulations were calculated for AUC and Cmax parameters, while tmax and t1/2 differences were analyzed on the non-transformed data using Wilcoxon matched-pairs and a Student’s paired t-test, respectively. The 90% CIs for the geometric mean ratios of the two pramipexole formulations were 95.89% (90.73%–101.34%, 95.53% (89.75%–101.68%, and 92.11% (84.35%–100.58% for AUC0-t, AUC0-∞, and Cmax, respectively. There were no statistically significant differences for tmax and t1/2 between the two pramipexole formulations. It is concluded that two pramipexole formulations in this study were bioequivalent.

  17. Effects of DPP-4 inhibitors on the heart in a rat model of uremic cardiomyopathy.

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    Lyubov Chaykovska

    Full Text Available BACKGROUND: Uremic cardiomyopathy contributes substantially to mortality in chronic kidney disease (CKD patients. Glucagon-like peptide-1 (GLP-1 may improve cardiac function, but is mainly degraded by dipeptidyl peptidase-4 (DPP-4. METHODOLOGY/PRINCIPAL FINDINGS: In a rat model of chronic renal failure, 5/6-nephrectomized [5/6N] rats were treated orally with DPP-4 inhibitors (linagliptin, sitagliptin, alogliptin or placebo once daily for 4 days from 8 weeks after surgery, to identify the most appropriate treatment for cardiac dysfunction associated with CKD. Linagliptin showed no significant change in blood level AUC(0-∞ in 5/6N rats, but sitagliptin and alogliptin had significantly higher AUC(0-∞ values; 41% and 28% (p = 0.0001 and p = 0.0324, respectively. No correlation of markers of renal tubular and glomerular function with AUC was observed for linagliptin, which required no dose adjustment in uremic rats. Linagliptin 7 µmol/kg caused a 2-fold increase in GLP-1 (AUC 201.0 ng/l*h in 5/6N rats compared with sham-treated rats (AUC 108.6 ng/l*h (p = 0.01. The mRNA levels of heart tissue fibrosis markers were all significantly increased in 5/6N vs control rats and reduced/normalized by linagliptin. CONCLUSIONS/SIGNIFICANCE: DPP-4 inhibition increases plasma GLP-1 levels, particularly in uremia, and reduces expression of cardiac mRNA levels of matrix proteins and B-type natriuretic peptides (BNP. Linagliptin may offer a unique approach for treating uremic cardiomyopathy in CKD patients, with no need for dose-adjustment.

  18. Effect of telaprevir on the pharmacokinetics of buprenorphine in volunteers on stable buprenorphine/naloxone maintenance therapy.

    Science.gov (United States)

    Luo, Xia; Trevejo, Jose; van Heeswijk, Rolf P G; Smith, Frances; Garg, Varun

    2012-07-01

    This was an open-label, single-sequence trial in hepatitis C virus-negative volunteers on stable, individualized, buprenorphine maintenance therapy. Telaprevir at 750 mg every 8 h was coadministered with buprenorphine/naloxone (4:1 ratio as sublingual tablets) for 7 days with food. Pharmacokinetic profiles of buprenorphine, norbuprenorphine, and naloxone were measured over the 24-hour dosing interval on day -1 (buprenorphine/naloxone alone, reference) and day 7 of telaprevir coadministration (test). Geometric least-squares mean ratios and associated 90% confidence intervals of treatment ratios (test/reference) were calculated using log-transformed pharmacokinetic parameters. Opioid withdrawal symptoms were evaluated throughout the study (via questionnaires and pupillometry). Pharmacokinetic data were available for 14 and 13 volunteers on day -1 and day 7, respectively. The area under the concentration-time curve (AUC) for buprenorphine was unchanged and the maximum concentration of drug in serum (C(max)) for buprenorphine, C(max) and AUC for norbuprenorphine, and C(max) naxolone were modestly decreased during coadministration with telaprevir. Geometric least-squares mean ratios (90% confidence intervals) for buprenorphine were 0.80 (0.69, 0.93) for the C(max) and 0.96 (0.84, 1.10) for the AUC from 0 to 24 h (AUC(0-24)); for norbuprenorphine, values were 0.85 (0.66, 1.09) for C(max) and 0.91 (0.71, 1.16) for AUC(0-24); for naloxone, the C(max) was 0.84 (0.62, 1.13). Coadministration of telaprevir did not increase withdrawal symptom frequency, and there were no serious adverse events reported during or after completion of telaprevir coadministration. Results suggest dose adjustment may not be necessary when telaprevir and buprenorphine/naloxone are coadministered.

  19. Machine Learning Principles Can Improve Hip Fracture Prediction.

    Science.gov (United States)

    Kruse, Christian; Eiken, Pia; Vestergaard, Peter

    2017-04-01

    Apply machine learning principles to predict hip fractures and estimate predictor importance in Dual-energy X-ray absorptiometry (DXA)-scanned men and women. Dual-energy X-ray absorptiometry data from two Danish regions between 1996 and 2006 were combined with national Danish patient data to comprise 4722 women and 717 men with 5 years of follow-up time (original cohort n = 6606 men and women). Twenty-four statistical models were built on 75% of data points through k-5, 5-repeat cross-validation, and then validated on the remaining 25% of data points to calculate area under the curve (AUC) and calibrate probability estimates. The best models were retrained with restricted predictor subsets to estimate the best subsets. For women, bootstrap aggregated flexible discriminant analysis ("bagFDA") performed best with a test AUC of 0.92 [0.89; 0.94] and well-calibrated probabilities following Naïve Bayes adjustments. A "bagFDA" model limited to 11 predictors (among them bone mineral densities (BMD), biochemical glucose measurements, general practitioner and dentist use) achieved a test AUC of 0.91 [0.88; 0.93]. For men, eXtreme Gradient Boosting ("xgbTree") performed best with a test AUC of 0.89 [0.82; 0.95], but with poor calibration in higher probabilities. A ten predictor subset (BMD, biochemical cholesterol and liver function tests, penicillin use and osteoarthritis diagnoses) achieved a test AUC of 0.86 [0.78; 0.94] using an "xgbTree" model. Machine learning can improve hip fracture prediction beyond logistic regression using ensemble models. Compiling data from international cohorts of longer follow-up and performing similar machine learning procedures has the potential to further improve discrimination and calibration.

  20. Effect of breast cancer phenotype on diagnostic performance of MRI in the prediction to response to neoadjuvant treatment

    Energy Technology Data Exchange (ETDEWEB)

    Bufi, Enida, E-mail: reagandus@alice.it [Department of Bioimaging and Radiological Sciences, Catholic University, Rome (Italy); Belli, Paolo; Di Matteo, Marialuisa [Department of Bioimaging and Radiological Sciences, Catholic University, Rome (Italy); Terribile, Daniela; Franceschini, Gianluca [Department of Surgery, Breast Unit, Catholic University, Rome (Italy); Nardone, Luigia [Department of Radiotherapy, Catholic University, Rome (Italy); Petrone, Gianluigi [Department of Pathology, Catholic University, Rome (Italy); Bonomo, Lorenzo [Department of Bioimaging and Radiological Sciences, Catholic University, Rome (Italy)

    2014-09-15

    Aim: The estimation of response to neoadjuvant chemotherapy (NAC) is useful in the surgical decision in breast cancer. We addressed the diagnostic reliability of conventional MRI, of diffusion weighted imaging (DWI) and of a merged criterion coupling morphological MRI and DWI. Diagnostic performance was analysed separately in different tumor subtypes, including HER2+ (human epidermal growth factor receptor 2)/HR+ (hormone receptor) (hybrid phenotype). Materials and methods: Two-hundred and twenty-five patients underwent MRI before and after NAC. The response to treatment was defined according to the RECIST classification and the evaluation of DWI with apparent diffusion coefficient (ADC). The complete pathological response – pCR was assessed (Mandard classification). Results: Tumor phenotypes were Luminal (63.6%), Triple Negative (16.4%), HER2+ (7.6%) or Hybrid (12.4%). After NAC, pCR was observed in 17.3% of cases. Average ADC was statistically higher after NAC (p < 0.001) among patients showing pCR vs. those who had not pCR. The RECIST classification showed adequate performance in predicting the pCR in Triple Negative (area under the receiver operating characteristic curve, ROC AUC = 0.9) and in the HER2+ subgroup (AUC = 0.826). Lower performance was found in the Luminal and Hybrid subgroups (AUC 0.693 and 0.611, respectively), where the ADC criterion yielded an improved performance (AUC = 0.787 and 0.722). The coupling of morphological and DWI criteria yielded maximally improved performance in the Luminal and Hybrid subgroups (AUC = 0.797 and 0.761). Conclusion: The diagnostic reliability of MRI in predicting the pCR to NAC depends on the tumor phenotype, particularly in the Luminal and Hybrid subgroups. In these cases, the coupling of morphological MRI evaluation and DWI assessment may facilitate the diagnosis.

  1. Relationship between the level of fasting plasma glucose and beta cell functions in Chinese with or without diabetes

    Institute of Scientific and Technical Information of China (English)

    PANG Can; BAO Yu-qian; WANG Chen; LU Jun-xi; JIA Wei-ping; XIANG Kun-san

    2008-01-01

    Background Type 2 diabetes is a chronic disease characterized by a progressive loss of beta cell functions.However,the evaluation of beta cell functions is either expensive or inconvenient for clinical practice.We aimed to elucidate the association between the changes of insulin responsiveness and the fasting plasma glucose (FPG) during the development of diabetes.Methods A total of 1192 Chinese individuals with normal blood glucose or hyperglycemia were enrolled for the analysis.The early insulinogenic index (△I30/△G30),the area under the curve of insulin (AUC-I),and homeostasis model assessment were applied to evaluate the early phase secretion,total insulin secretion,and insulin resistance respectively.Polynomial regression analysis was performed to estimate the fluctuation of beta cell functions.Results The △I30/△G30 decreased much more rapidly than the AUC-I accompanying with the elevation of FPG.At the FPG of 110 mg/dl (a pre-diabetic stage),the △I30/△G30 lost 50% of its maximum while the AUC-I was still at a compensated normal level.The AUC-I exhibited abnormal and decreased gradually at the FPG of from 130 mg/dl to higher (overt diabetes),while the △I30/△G30 almost remained at 25% of its maximum value.When hyperglycemia continuously existed at >180 mg/dl,beth the △I30/△G30 and AUC-I were totally lost.Conclusion The increased fasting plasma glucose reflects progressive decompensation of beta cell functions,and could be used to guide the strategy of clinical treatments.

  2. Comparison of partial volume effects in arterial and venous contrast curves in CT brain perfusion imaging.

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    Alan J Riordan

    Full Text Available PURPOSE: In brain CT perfusion (CTP, the arterial contrast bolus is scaled to have the same area under the curve (AUC as the venous outflow to correct for partial volume effects (PVE. This scaling is based on the assumption that large veins are unaffected by PVE. Measurement of the internal carotid artery (ICA, usually unaffected by PVE due to its large diameter, may avoid the need for partial volume correction. The aims of this work are to examine i the assumptions behind PVE correction and ii the potential of selecting the ICA obviating correction for PVE. METHODS: The AUC of the ICA and sagittal sinus were measured in CTP datasets from 52 patients. The AUCs were determined by i using commercial CTP software based on a Gaussian curve-fitting to the time attenuation curve, and ii by simple integration of the time attenuation curve over a time interval. In addition, frames acquired up to 3 minutes after first bolus passage were used to examine the ratio of arterial and venous enhancement. The impact of selecting the ICA without PVE correction was illustrated by reporting cerebral blood volume (CBV measurements. RESULTS: In 49 of 52 patients, the AUC of the ICA was significantly larger than that of the sagittal sinus (p = 0.017. Measured after the first pass bolus, contrast enhancement remained 50% higher in the ICA just after the first pass bolus, and 30% higher 3 minutes later. CBV measurements were significantly lowered when the ICA was used without PVE correction. CONCLUSIONS: Contradicting the assumptions underlying PVE correction, contrast in the ICA was significantly higher than in the sagittal sinus, even 3 minutes after the first pass of the contrast bolus. PVE correction might lead to overestimation of CBV if the CBV is calculated using the AUC of the time attenuation curves.

  3. Single-Dose Pharmacokinetic Study of Tramadol Extended-Release Tablets in Children and Adolescents.

    Science.gov (United States)

    Vandenbossche, Joris; Van Peer, Achiel; Richards, Henry

    2016-09-01

    Combined analyses from 2 open-label, phase-1 studies-the pharmacokinetic profile of tramadol and its metabolite (M1) following a single oral dose of tramadol extended release (ER) (25 to 100 mg) in children (7 to 11 years old; study 1: n = 37) and adolescents (12 to 17 years old; study 2: n = 38) with painful conditions-were historically compared with that of healthy adults following similar dosing. The dose-normalized area under the curve (DN AUC0-24h ) and maximum concentration (DN Cmax ) of tramadol and of M1 in children and in adolescents were lower than those in adults (children vs adults: tramadol, DN AUC0-24h 82.19%; DN Cmax 80.38%, P = .0031; M1, DN AUC0-24h 51.19%, DN Cmax 52.68%, P < .0001; adolescents vs adults: tramadol, DN AUC0-24h 89.56%, DN Cmax 84.01%; M1, DN AUC0-24h 85.28%, DN Cmax 83.03%, P = .0004). The arithmetic mean terminal elimination t1/2 of tramadol in children and adolescents was comparable to that in adults (children 8.4 hours; adolescents 8.5 hours; adults 7.9 hours). The most frequently reported (≥5% of participants) treatment-emergent adverse events in children included headache, upper abdominal pain and constipation, and in adolescents were headache, nausea, dizziness, and stomach discomfort. Multiple factors may have contributed to these observations, including a higher proportion of children (56%) who may have a lower activity of CYP2D6, resulting in reduced clearance of tramadol.

  4. Multi-reader multi-case studies using the area under the receiver operator characteristic curve as a measure of diagnostic accuracy: systematic review with a focus on quality of data reporting.

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    Thaworn Dendumrongsup

    Full Text Available We examined the design, analysis and reporting in multi-reader multi-case (MRMC research studies using the area under the receiver-operating curve (ROC AUC as a measure of diagnostic performance.We performed a systematic literature review from 2005 to 2013 inclusive to identify a minimum 50 studies. Articles of diagnostic test accuracy in humans were identified via their citation of key methodological articles dealing with MRMC ROC AUC. Two researchers in consensus then extracted information from primary articles relating to study characteristics and design, methods for reporting study outcomes, model fitting, model assumptions, presentation of results, and interpretation of findings. Results were summarized and presented with a descriptive analysis.Sixty-four full papers were retrieved from 475 identified citations and ultimately 49 articles describing 51 studies were reviewed and extracted. Radiological imaging was the index test in all. Most studies focused on lesion detection vs. characterization and used less than 10 readers. Only 6 (12% studies trained readers in advance to use the confidence scale used to build the ROC curve. Overall, description of confidence scores, the ROC curve and its analysis was often incomplete. For example, 21 (41% studies presented no ROC curve and only 3 (6% described the distribution of confidence scores. Of 30 studies presenting curves, only 4 (13% presented the data points underlying the curve, thereby allowing assessment of extrapolation. The mean change in AUC was 0.05 (-0.05 to 0.28. Non-significant change in AUC was attributed to underpowering rather than the diagnostic test failing to improve diagnostic accuracy.Data reporting in MRMC studies using ROC AUC as an outcome measure is frequently incomplete, hampering understanding of methods and the reliability of results and study conclusions. Authors using this analysis should be encouraged to provide a full description of their methods and results.

  5. Validity of Chinese Version of the Composite International Diagnostic Interview-3.0 in Psychiatric Settings

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    Jin Lu

    2015-01-01

    Full Text Available Background: The Composite International Diagnostic Interview-3.0 (CIDI-3.0 is a fully structured lay-administered diagnostic interview for the assessment of mental disorders according to ICD-10 and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV criteria. The aim of the study was to investigate the concurrent validity of the Chinese CIDI in diagnosing mental disorders in psychiatric settings. Methods: We recruited 208 participants, of whom 148 were patients from two psychiatric hospitals and 60 healthy people from communities. These participants were administered with CIDI by six trained lay interviewers and the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I, gold standard by two psychiatrists. Agreement between CIDI and SCID-I was assessed with sensitivity, specificity, positive predictive value and negative predictive value. Individual-level CIDI-SCID diagnostic concordance was evaluated using the area under the receiver operator characteristic curve and Cohen′s K. Results: Substantial to excellent CIDI to SCID concordance was found for any substance use disorder (area under the receiver operator characteristic curve [AUC] = 0.926, any anxiety disorder (AUC = 0.807 and any mood disorder (AUC = 0.806. The concordance between the CIDI and the SCID for psychotic and eating disorders is moderate. However, for individual mental disorders, the CIDI-SCID concordance for bipolar disorders (AUC = 0.55 and anorexia nervosa (AUC = 0.50 was insufficient. Conclusions: Overall, the Chinese version of CIDI-3.0 has acceptable validity in diagnosing the substance use disorder, anxiety disorder and mood disorder among Chinese adult population. However, we should be cautious when using it for bipolar disorders and anorexia nervosa.

  6. Effect of polymer type and drug dose on the in vitro and in vivo behavior of amorphous solid dispersions.

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    Knopp, Matthias Manne; Chourak, Nabil; Khan, Fauzan; Wendelboe, Johan; Langguth, Peter; Rades, Thomas; Holm, René

    2016-08-01

    This study investigated the non-sink in vitro dissolution behavior and in vivo performance in rats of celecoxib (CCX) amorphous solid dispersions with polyvinyl acetate (PVA), polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose (HPMC) at different drug doses. Both in vitro and in vivo, the amorphous solid dispersions with the hydrophilic polymers PVP and HPMC led to higher areas under both, the in vitro dissolution and the plasma concentration-time curves (AUC) compared to crystalline and amorphous CCX for all doses. In contrast, the amorphous solid dispersion with the hydrophobic polymer PVA showed a lower AUC both in vitro and in vivo than crystalline CCX. For crystalline CCX and CCX:PVA, the in vitro AUC was limited by the low solubility of the drug and the slow release of the drug from the hydrophobic polymer, respectively. For the supersaturating formulations, amorphous CCX, CCX:PVP and CCX:HPMC, the in vitro performance was mainly dependent on the dissolution rate and precipitation/crystallization inhibition of the polymer. As expected, the crystallization tendency increased with increasing dose, and therefore the in vitro AUCs did not increase proportionally with dose. Even though the in vivo AUC for all formulations increased with increasing dose, the relative bioavailability decreased significantly, indicating that the supersaturating formulations also crystallized in vivo and that the absorption of CCX was solubility-limited. These findings underline the importance of evaluating relevant in vitro doses, in order to rationally assess the performance of amorphous solid dispersions and avoid confusion in early in vivo studies.

  7. Measuring the Corticosteroid Responsiveness Endophenotype in Asthma

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    Clemmer, George L.; Wu, Ann Chen; Rosner, Bernard; McGeachie, Michael J.; Litonjua, Augusto A.; Tantisira, Kelan G.; Weiss, Scott T.

    2015-01-01

    Background Inhaled corticosteroids are the most commonly used controller therapies for asthma, producing treatment responses in six clinical phenotypes; lung function, bronchodilator response, airway responsiveness, symptoms, need for oral steroids and frequency of emergency department visits and hospitalizations. We hypothesize that treatment response in all of these phenotypes is modulated by a single, quantative corticosteroid responsiveness endophenotype. Objective To develop a composite phenotype that combines multiple clinical phenotypes to measure corticosteroid responsiveness with high accuracy, high stability across populations, and high robustness to missing data. Methods We employed principal component analysis (PCA) to determine a composite corticosteroid responsiveness phenotype that we tested in four replication populations. We evaluated the relative accuracy with which the composite and clinical phenotypes measure the endophenotype using treatment effect area under the receiver operating characteristic curve (AUC). Results In the study population, the composite phenotype measured the endophenotype with an AUC of 0.74, significantly exceeding the AUCs of the six individual clinical phenotypes, which ranged from 0.56 (p-value <.001) to 0.67 (p-value 0.015). In four replication populations with a total of 22 clinical phenotypes available, the composite phenotype AUC ranged from 0.69 to 0.73, significantly exceeded the AUCs of 14 phenotypes, and was not significantly exceeded by any single phenotype. Conclusion The composite phenotype measured the endophenotype with higher accuracy, higher stability across populations, and higher robustness to missing data than any clinical phenotype. This should provide the capability to model corticosteroid pharmacologic response and resistance with increased accuracy and reproducibility. PMID:25951964

  8. Mutant-prevention concentration and mechanism of resistance in clinical isolates and enrofloxacin/marbofloxacin-selected mutants of Escherichia coli of canine origin.

    Science.gov (United States)

    Gebru, Elias; Choi, Myung-Jin; Lee, Seung-Jin; Damte, Dereje; Park, Seung Chun

    2011-10-01

    The antibacterial activity and selection of resistant bacteria, along with mechanisms of fluoroquinolone resistance, were investigated by integrating the static [MIC or mutant-prevention concentration (MPC)] and in vitro dynamic model approaches using Escherichia coli isolates from diseased dogs. Using the dynamic models, selected E. coli strains and enrofloxacin and marbofloxacin at a range of simulated area under concentration-time curve over a 24 h interval (AUC(24 h))/MIC ratios were investigated. Our results indicated increasing losses in susceptibility of E. coli upon continuous exposure to enrofloxacin and marbofloxacin in vitro. This effect was transferable to other fluoroquinolones, as well as to structurally unrelated drugs. Our results also confirmed an AUC(24 h)/MIC (AUC(24 h)/MPC)-dependent antibacterial activity and selection of resistant E. coli mutants, in which maximum losses in fluoroquinolone susceptibility occurred at simulated AUC(24 h)/MIC ratios of 40-60. AUC(24 h)/MPC ratios of 39 (enrofloxacin) and 32 (marbofloxacin) were considered protective against the selection of resistant mutants of E. coli. Integrating our MIC and MPC data with published pharmacokinetic information in dogs revealed a better effect of the conventional dosing regimen of marbofloxacin than that of enrofloxacin in restricting the selection of resistant mutants of E. coli. Target mutations, especially at codon 83 (serine to leucine) of gyrA, and overexpression of efflux pumps contributed to resistance development in both clinically resistant and in vitro-selected mutants of E. coli. We also report here a previously undescribed mutation at codon 116 of parC in two laboratory-derived resistant mutants of E. coli. Additional studies would determine the exact role of this mutation in fluoroquinolone susceptibility, as well as establish the importance of our findings in the clinical setting.

  9. Validity of Chinese Version of the Composite International Diagnostic Interview-3.0 in Psychiatric Settings

    Institute of Scientific and Technical Information of China (English)

    Jin Lu; Yue-Qin Huang; Zhao-Rui Liu; Xiao-Lan Cao

    2015-01-01

    Background:The Composite International Diagnostic Interview-3.0 (CIDI-3.0) is a fully structured lay-administered diagnostic interview for the assessment of mental disorders according to ICD-10 and Diagnostic and Statistical Manual of Mental Disorders,Fourth Edition (DSM-Ⅳ) criteria.The aim of the study was to investigate the concurrent validity of the Chinese CIDI in diagnosing mental disorders in psychiatric settings.Methods:We recruited 208 participants,of whom 148 were patients from two psychiatric hospitals and 60 healthy people from communities.These participants were administered with CIDI by six trained lay interviewers and the Structured Clinical Interview for DSM-Ⅳ Axis I Disorders (SCID-I,gold standard) by two psychiatrists.Agreement between CIDI and SCID-I was assessed with sensitivity,specificity,positive predictive value and negative predictive value.Individual-level CIDI-SCID diagnostic concordance was evaluated using the area under the receiver operator characteristic curve and Cohen's K.Results:Substantial to excellent CIDI to SCID concordance was found for any substance use disorder (area under the receiver operator characteristic curve [AUC] =0.926),any anxiety disorder (AUC =0.807) and any mood disorder (AUC =0.806).The concordance between the CIDI and the SCID for psychotic and eating disorders is moderate.However,for individual mental disorders,the CIDI-SCID concordance for bipolar disorders (AUC =0.55) and anorexia nervosa (AUC =0.50) was insufficient.Conclusions:Overall,the Chinese version of CIDI-3.0 has acceptable validity in diagnosing the substance use disorder,anxiety disorder and mood disorder among Chinese adult population.However,we should be cautious when using it for bipolar disorders and anorexia nervosa.

  10. 3D-Printing for Analytical Ultracentrifugation

    Science.gov (United States)

    Desai, Abhiksha; Krynitsky, Jonathan; Pohida, Thomas J.; Zhao, Huaying

    2016-01-01

    Analytical ultracentrifugation (AUC) is a classical technique of physical biochemistry providing information on size, shape, and interactions of macromolecules from the analysis of their migration in centrifugal fields while free in solution. A key mechanical element in AUC is the centerpiece, a component of the sample cell assembly that is mounted between the optical windows to allow imaging and to seal the sample solution column against high vacuum while exposed to gravitational forces in excess of 300,000 g. For sedimentation velocity it needs to be precisely sector-shaped to allow unimpeded radial macromolecular migration. During the history of AUC a great variety of centerpiece designs have been developed for different types of experiments. Here, we report that centerpieces can now be readily fabricated by 3D printing at low cost, from a variety of materials, and with customized designs. The new centerpieces can exhibit sufficient mechanical stability to withstand the gravitational forces at the highest rotor speeds and be sufficiently precise for sedimentation equilibrium and sedimentation velocity experiments. Sedimentation velocity experiments with bovine serum albumin as a reference molecule in 3D printed centerpieces with standard double-sector design result in sedimentation boundaries virtually indistinguishable from those in commercial double-sector epoxy centerpieces, with sedimentation coefficients well within the range of published values. The statistical error of the measurement is slightly above that obtained with commercial epoxy, but still below 1%. Facilitated by modern open-source design and fabrication paradigms, we believe 3D printed centerpieces and AUC accessories can spawn a variety of improvements in AUC experimental design, efficiency and resource allocation. PMID:27525659

  11. Development of a simple LC-MS/MS method for the determination of febuxostat in human plasma and its application to a bioequivalence study.

    Science.gov (United States)

    Shi, Zheng; Liu, Jian; Hu, Xing-Jiang; ShenTu, Jian-Zhong

    2013-06-01

    The purpose of this study was to design a simple, sensitive and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for a febuxostat bioequivalence study in healthy Chinese male volunteers. In this method, febuxostat and etodolac (internal standard) were isolated from plasma samples by protein precipitation with acetonitrile. The supernatant was chromatographed on a Zorbax SB-C18 (150 x 3.0 mm, 3.5-microm particle size, Agilent) column with a SecurityGuard Inertsil Symmetry C18 column (12.5 x 4.6 mm, 5-microm particle size, Waters). The lower limit of quantification for febuxostat in 0.2 mL of human plasma was 13.40 ng x mL(-1), and the linearity was achieved over a concentration range from 13.40 to 21440 ng x mL(-1). Febuxostat tablets from Hengrui Medicine Co., Ltd (test, Jiangsu, China) and from Takeda pharmaceuticals america, Inc. (reference, Deerfield, IL) were evaluated following a single 80 mg oral dose to 18 healthy volunteers. Bioequivalence was determined by calculating 90% confidence intervals (90% CI) for the ratio of C(max), AUC(0-t), and AUC(0-infinity) values for the test and reference products, using logarithmic transformed data. The calculated 90% CIs for the ratio of C(max) (88.7-131.2%), AUC(0-t) (99.2-122.7%) and AUC(0-infinity) (99.5-123.1%) values for the test and reference products were all located within the bioequivalence criteria range (80-125% for AUC, and 70-143% for Ca(mzax)), proposed by State of Food and Drug Administration [SFDA, 2005. China]. It was concluded that the two febuxostat formulations (test and reference) analyzed were bioequivalent in terms of rate and extent of absorption and the method met the principle of quick and easy clinical analysis.

  12. The effect of mirabegron, a potent and selective β3-adrenoceptor agonist, on the pharmacokinetics of CYP2D6 substrates desipramine and metoprolol.

    Science.gov (United States)

    Krauwinkel, Walter; Dickinson, James; Schaddelee, Marloes; Meijer, John; Tretter, Reiner; van de Wetering, Jeroen; Strabach, Gregory; van Gelderen, Marcel

    2014-03-01

    Mirabegron is a potent and selective β3-adrenoceptor agonist developed for the treatment of overactive bladder. In vitro studies demonstrated that mirabegron partly acts as a (quasi-) irreversible, metabolism-dependent inhibitor of CYP2D6. The effect of steady-state mirabegron on single doses of the sensitive CYP2D6 substrates metoprolol (100 mg) and desipramine (50 mg) was assessed in two open-label, one-sequence crossover studies in healthy subjects (CYP2D6 extensive metabolizers). Mirabegron 160 mg/day increased metoprolol maximum plasma concentration (C max) 1.90-fold (90 % confidence interval [CI] 1.54; 2.33) and total exposure (AUC0-∞) 3.29-fold (90 % CI 2.70; 4.00) in 12 males (study 1). Mean metoprolol half-life increased from 2.96 to 4.11 h. α-Hydroxymetoprolol C max and AUC to last measurable concentration decreased 2.6-fold and 2.2-fold, respectively. In study 2, mirabegron 100 mg/day increased desipramine C max 1.79-fold (90 % CI 1.69; 1.90) and AUC0-∞ 3.41-fold (90 % CI 3.07; 3.80) in 14 males and 14 females. Mean desipramine half-life increased from 19.5 to 35.8 h. C max of 2-hydroxydesipramine decreased ~twofold, while AUC increased ~1.3-fold. Desipramine was administered again 2 weeks after the last mirabegron dose. Desipramine C max and AUC0-∞ were still ~1.13-fold increased; the 90 % CIs fell within the 0.80-1.25 interval. All treatments were well tolerated. In conclusion, mirabegron is a moderate CYP2D6 inhibitor (ratio and 90 % CI <5.0).

  13. Synergistic effect of double-shelled and sandwiched TiO₂@Au@C hollow spheres with enhanced visible-light-driven photocatalytic activity.

    Science.gov (United States)

    Cai, Jiabai; Wu, Xueqing; Li, Shunxing; Zheng, Fengying; Zhu, Licong; Lai, Zhanghua

    2015-02-18

    A novel approach for the fabrication of double-shelled, sandwiched, and nanostructured hollow spheres was proposed, using hydrotherm reaction and calcination. The negatively charged nanoparticles (e.g., Au, Ag, and Pt) could be adsorbed successively onto the positively charged hollow spheres (e.g., TiO2, ZnO, and ZrO2). The resulted nanocomposites (TiO2@Au, as a proof-of-concept) were dispersed in glucose solution under hydrothermal conditions. After calcination, uniform double-shelled and sandwiched TiO2@Au@C hollow spheres were obtained and Au nanoparticles were sandwiched between the shell wall of TiO2 and C. The samples were characterized by SEM, TEM, XRD, XPS, BET, and UV-vis DRS. The photocatalytic activity for the degradation of 4-nitroaniline was in the order of TiO2@Au@C > TiO2@C > TiO2/Au > P25. The visible-light photodegradation rate of 92.65% for 4-nitroaniline was achieved by TiO2@Au@C, which exhibited an increase of 75% compared to Degussa P25 TiO2. Furthermore, no deactivation occurred during catalytic reaction for three times, i.e., the TiO2@Au@C microspheres exhibited superior photocatalytic stability. TiO2@Au@C microspheres could also enhance the photocatalytic activity for hydrogen generation from methanol/water solutions. The synergistic effect of coupling TiO2 hollow spheres with Au nanoparticles and C shell on photocatalytic performance was proved by us. The photoexcited electrons from Au nanoparticles could be captured by the conduction band of TiO2 and then the electron-hole separation was improved. Moreover, both the visible light absorption and the affinity between TiO2 and pollutants could be improved by the coexistence of carbonaceous materials, which could facilitate the photocatalytic interface reaction.

  14. Environmental and socio-economic risk modelling for Chagas disease in Bolivia

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    Paula Mischler

    2012-09-01

    Full Text Available Accurately defining disease distributions and calculating disease risk is an important step in the control and prevention of diseases. Geographical information systems (GIS and remote sensing technologies, with maximum entropy (Maxent ecological niche modelling computer software, were used to create predictive risk maps for Chagas disease in Bolivia. Prevalence rates were calculated from 2007 to 2009 household infection survey data for Bolivia, while environmental data were compiled from the Worldclim database and MODIS satellite imagery. Socio-economic data were obtained from the Bolivian National Institute of Statistics. Disease models identified altitudes at 500-3,500 m above the mean sea level (MSL, low annual precipitation (45-250 mm, and higher diurnal range of temperature (10-19 °C; peak 16 °C as compatible with the biological requirements of the insect vectors. Socio-economic analyses demonstrated the importance of improved housing materials and water source. Home adobe wall materials and having to fetch drinking water from rivers or wells without pump were found to be highly related to distribution of the disease by the receiver operator characteristic (ROC area under the curve (AUC (0.69 AUC, 0.67 AUC and 0.62 AUC, respectively, while areas with hardwood floors demonstrated a direct negative relationship (-0.71 AUC. This study demonstrates that Maxent modelling can be used in disease prevalence and incidence studies to provide governmental agencies with an easily learned, understandable method to define areas as either high, moderate or low risk for the disease. This information may be used in resource planning, targeting and implementation. However, access to high-resolution, sub-municipality socio-economic data (e.g. census tracts would facilitate elucidation of the relative influence of poverty-related factors on regional disease dynamics.

  15. Exposure-Response Analyses for Tafenoquine after Administration to Patients with Plasmodium vivax Malaria.

    Science.gov (United States)

    Tenero, David; Green, Justin A; Goyal, Navin

    2015-10-01

    Tafenoquine (TQ), a new 8-aminoquinoline with activity against all stages of the Plasmodium vivax life cycle, is being developed for the radical cure of acute P. vivax malaria in combination with chloroquine. The efficacy and exposure data from a pivotal phase 2b dose-ranging study were used to conduct exposure-response analyses for TQ after administration to subjects with P. vivax malaria. TQ exposure (i.e., area under the concentration-time curve [AUC]) and region (Thailand compared to Peru and Brazil) were found to be statistically significant predictors of clinical response based on multivariate logistic regression analyses. After accounting for region/country, the odds of being relapse free at 6 months increased by approximately 51% (95% confidence intervals [CI], 25%, 82%) for each 25-U increase in AUC above the median value of 54.5 μg · h/ml. TQ exposure was also a significant predictor of the time to relapse of the infection. The final parametric, time-to-event model for the time to relapse, included a Weibull distribution hazard function, AUC, and country as covariates. Based on the model, the risk of relapse decreased by 30% (95% CI, 17% to 42%) for every 25-U increase in AUC. Monte Carlo simulations indicated that the 300-mg dose of TQ would provide an AUC greater than the clinically relevant breakpoint obtained in a classification and regression tree (CART) analysis (56.4 μg · h/ml) in more than 90% of subjects and consequently result in a high probability of being relapse free at 6 months. This model-based approach was critical in selecting an appropriate phase 3 dose. (This study has been registered at ClinicalTrials.gov under registration no. NCT01376167.).

  16. Ethanol Modulates the Spontaneous Complex Spike Waveform of Cerebellar Purkinje Cells Recorded in vivo in Mice

    Science.gov (United States)

    Zhang, Guang-Jian; Wu, Mao-Cheng; Shi, Jin-Di; Xu, Yin-Hua; Chu, Chun-Ping; Cui, Song-Biao; Qiu, De-Lai

    2017-01-01

    Cerebellar Purkinje cells (PCs) are sensitive to ethanol, but the effect of ethanol on spontaneous complex spike (CS) activity in these cells in vivo is currently unknown. Here, we investigated the effect of ethanol on spontaneous CS activity in PCs in urethane-anesthetized mice using in vivo patch-clamp recordings and pharmacological manipulation. Ethanol (300 mM) induced a decrease in the CS-evoked pause in simple spike (SS) firing and in the amplitude of the afterhyperpolarization (AHP) under current clamp conditions. Under voltage-clamp conditions, ethanol significantly decreased the area under the curve (AUC) and the number of CS spikelets, without changing the spontaneous frequency of the CSs or the instantaneous frequency of the CS spikelets. Ethanol-induced a decrease in the AUC of spontaneous CSs was concentration dependent. The EC50 of ethanol for decreasing the AUC of spontaneous CSs was 168.5 mM. Blocking N-methyl-D-aspartate receptors (NMDARs) failed to prevent the ethanol-induced decreases in the CS waveform parameters. However, blockade of cannabinoid receptor 1 (CB1) significantly suppressed the ethanol-induced effects on the CS-evoked pause in SS firing, amplitude of the AHP, spikelet number and the AUC of CSs. Moreover, a CB1 receptor agonist not only reduced the number of spikelets and the AUC of CSs, but also prevented the ethanol-induced inhibition of CS activity. Our results indicate that ethanol inhibits CS activity via activation of the CB1 receptor in vivo in mice, suggesting that excessive ethanol intake inhibits climbing fiber (CF)–PC synaptic transmission by modulating CB1 receptors in the cerebellar cortex. PMID:28293172

  17. Validation of HOMA-IR in a model of insulin-resistance induced by a high-fat diet in Wistar rats.

    Science.gov (United States)

    Antunes, Luciana C; Elkfury, Jessica L; Jornada, Manoela N; Foletto, Kelly C; Bertoluci, Marcello C

    2016-04-01

    Objective The present study aimed to validate homeostasis model assessment of insulin resistance (HOMA-IR) in relation to the insulin tolerance test (ITT) in a model of insulin-resistance in Wistar rats induced by a 19-week high-fat diet. Materials and methods A total of 30 male Wistar rats weighing 200-300 g were allocated into a high-fat diet group (HFD) (55% fat-enriched chow, ad lib, n = 15) and a standard-diet group (CD) standard chow, ad lib, n = 15), for 19 weeks. ITT was determined at baseline and in the 19th week. HOMA-IR was determined between the 18-19th week in three different days and the mean was considered for analysis. Area under the curve (AUC-ITT) of the blood glucose excursion along 120 minutes after intra-peritoneal insulin injection was determined and correlated with the corresponding fasting values for HOMA-IR. Results AUC-ITT and HOMA-IR were significantly greater after 19th week in HFD compared to CD (p < 0.001 for both). AUC-OGTT was also higher in HFD rats (p = 0.003). HOMA-IR was strongly correlated (Pearson's) with AUC-ITT r = 0.637; p < 0.0001. ROC curves of HOMA-IR and AUC-ITT showed similar sensitivity and specificity. Conclusion HOMA-IR is a valid measure to determine insulin-resistance in Wistar rats. Arch Endocrinol Metab. 2016;60(2):138-42.

  18. Implementation of a reference-scaled average bioequivalence approach for highly variable generic drug products of agomelatine in Chinese subjects

    Directory of Open Access Journals (Sweden)

    Fang Tang

    2016-01-01

    Full Text Available The aim of this study was to apply the reference-scaled average bioequivalence (RSABE approach to evaluate the bioequivalence of 2 formulations of agomelatine, and to investigate the pharmacokinetic properties of agomelatine in Chinese healthy male subjects. This was performed in a single-dose, randomized-sequence, open-label, four-way crossover study with a one-day washout period between doses. Healthy Chinese males were randomly assigned to receive 25 mg of either the test or reference formulation. The formulations were considered bioequivalent if 90% confidence intervals (CIs for the log-transformed ratios and ratio of geometric means (GMR of AUC and Cmax of agomelatine were within the predetermined bioequivalence range based on RSABE method. Results showed that both of the 90% CIs for the log-transformed ratios of AUC and Cmax of 7-desmethyl-agomelatine and 3-hydroxy-agomelatine were within the predetermined bioequivalence range. The 90% CIs for natural log-transformed ratios of Cmax, AUC0–t and AUC0–∞ of agomelatine (104.42–139.86, 101.33–123.83 and 97.90–117.94 were within the RSABE acceptance limits, and 3-hydroxy-agomelatine (105.55–123.03, 101.95–109.10 and 101.72–108.70 and 7-desmethyl-agomelatine (104.50–125.23, 102.36–111.50 and 101.62–110.64 were within the FDA bioequivalence definition intervals (0.80–1.25 for AUC and 0.75–1.33 for Cmax. The RSABE approach was successful in evaluating the bioequivalence of these two formulations.

  19. A Comparative Pharmacokinetics Study of the Anti-Parkinsonian Drug Pramipexole

    Science.gov (United States)

    Putri, Ratih S. I.; Setiawati, Effi; Aziswan, Syifa A.; Ong, Fenny; Tjandrawinata, Raymond R.; Susanto, Liana W.

    2016-01-01

    The present study aimed to compare pharmacokinetic parameters of two pramipexole 0.25 mg formulations in order to show bioequivalence. The study was conducted in a randomized, open-label, two-period, two-sequence, and crossover design, involving 23 healthy volunteers. One of the 0.25 mg formulations of pramipexole evaluated in the study was manufactured by PT Dexa Medica, Palembang, Indonesia, the other, used as the reference, by Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany. All eligible subjects were required to fast before each drug administration period, which was separated by a one-week washout period. Pramipexole concentrations in plasma were assayed using a validated ultra performance liquid chromatography with mass spectrometry (UPLC-MS/MS) detector. The evaluated pharmacokinetic parameters included the area under the plasma concentration curve from time zero to the last observed measurable concentration (AUC0-t), the area under the plasma concentration curve extrapolated to infinite time (AUC0-∞), the maximum plasma concentration (Cmax), the time to reach Cmax (tmax), and the plasma concentration half-life (t1/2). To evaluate the bioequivalence of those two pramipexole formulations, 90% confidence intervals (CIs) for geometric mean ratios of both formulations were calculated for AUC and Cmax parameters, while tmax and t1/2 differences were analyzed on the non-transformed data using Wilcoxon matched-pairs and a Student’s paired t-test, respectively. The 90% CIs for the geometric mean ratios of the two pramipexole formulations were 95.89% (90.73%–101.34%), 95.53% (89.75%–101.68%), and 92.11% (84.35%–100.58%) for AUC0-t, AUC0-∞, and Cmax, respectively. There were no statistically significant differences for tmax and t1/2 between the two pramipexole formulations. It is concluded that two pramipexole formulations in this study were bioequivalent. PMID:27869754

  20. Multiplicity adjustments in testing for bioequivalence.

    Science.gov (United States)

    Hua, Steven Y; Xu, Siyan; D'Agostino, Ralph B

    2015-01-30

    Bioequivalence of two drugs is usually demonstrated by rejecting two one-sided null hypotheses using the two one-sided tests for pharmacokinetic parameters: area under the concentration-time curve (AUC) and maximum concentration (Cmax). By virtue of the intersection-union test, there is no need for multiplicity adjustment in testing the two one-sided null hypotheses within each parameter. However, the decision rule for bioequivalence often requires equivalence to be achieved simultaneously on both parameters that contain four one-sided null hypotheses together; without adjusting for multiplicity, the family wise error rate (FWER) could fail to be controlled at the nominal type-I error rate α. The multiplicity issue for bioequivalence in this regard is scarcely discussed in the literature. To address this issue, we propose two approaches including a closed test procedure that controls FWER for the simultaneous AUC and Cmax bioequivalence and requires no adjustment of the type-I error, and an alpha-adaptive sequential testing (AAST) that controls FWER by pre-specifying the significance level on AUC (α1) and obtaining it for Cmax (α2) adaptively after testing of AUC. While both methods control FWER, the closed test requires testing of eight intersection null hypotheses each at α, and AAST is at times accomplished through a slight deduction in α1 and no deduction in α2 relative to α. The latter considers equivalence reached in AUC a higher importance than that in Cmax. Illustrated with published data, the two approaches, although operate differently, can lead to the same substantive conclusion and are better than a traditional method like Bonferroni adjustment.

  1. New serum biomarkers for prostate cancer diagnosis

    Science.gov (United States)

    Chadha, Kailash C.; Miller, Austin; Nair, Bindukumar B.; Schwartz, Stanley A.; Trump, Donald L.; Underwood, Willie

    2014-01-01

    Background Prostate-specific antigen (PSA) is currently used as a biomarker for diagnosis and management of prostate cancer (CaP). However, PSA typically lacks the sensitivity and specificity desired of a diagnostic marker. Objective The goal of this study was to identify an additional biomarker or a panel of biomarkers that is more sensitive and specific than PSA in differentiating benign versus malignant prostate disease and/or localized CaP versus metastatic CaP. Methods Concurrent measurements of circulating interleukin-8 (IL-8), Tumor necrosis factor-α (TNF-α) and soluble tumor necrosis factor-α receptors 1 (sTNFR1) were obtained from four groups of men: (1) Controls (2) with elevated prostate-specific antigen with a negative prostate biopsy (elPSA_negBx) (3) with clinically localized CaP and (4) with castration resistant prostate cancer. Results TNF-α Area under the receiver operating characteristic curve (AUC = 0.93) and sTNFR1 (AUC = 0.97) were strong predictors of elPSA_negBx (vs. CaP). The best predictor of elPSA_negBx vs CaP was sTNFR1 and IL-8 combined (AUC = 0.997). The strongest single predictors of localized versus metastatic CaP were TNF-α (AUC = 0.992) and PSA (AUC = 0.963) levels. Conclusions The specificity and sensitivity of a PSA-based CaP diagnosis can be significantly enhanced by concurrent serum measurements of IL-8, TNF-α and sTNFR1. In view of the concerns about the ability of PSA to distinguish clinically relevant CaP from indolent disease, assessment of these biomarkers in the larger cohort is warranted. PMID:25593898

  2. Pharmacokinetics/pharmacodynamics of antofloxacin hydrochloride in a neutropenic murine thigh model of Staphylococcus aureus infection

    Institute of Scientific and Technical Information of China (English)

    Xiu-mei XIAO; Yong-hong XIAO

    2008-01-01

    Aim:Antofloxacin hydrochloride is a new fluoroquinolone antibiotic with broad-spectrum in vitro activity.Using the neutropenic murine thigh infection model,we defined the pharmacodynamic profile and property of antofloxacin hydroehloride against Staphylococcus aureus.Methods:Single-dose pharmacokinetic studies of antofloxacin hydrochloride were carried out in thigh infected mice.Therapy was initiated at 2 h postinoculation with 5-640 mg/kg per d fractionated for different dosing regimens.The thighs were removed for bacterial measurement after 24 h of therapy,the best pharmacokinetic/ pharmacodynamic (PK/PD) index correlated with the efficacy was determined by nonlinear regression analysis.A sigmoid Emax dose-response model was used to estimate the daily dose and AUC24 h/MIC (minimal inhibitory concentration) required to achieve a static effect.Results:The PK was linear with similar elimination half-life over the dose range studied.The AUC24 h/MIC ratio was the PK/PD parameter that best correlated with efficacy (R2=92.3%,90.8% for the two organisms,compared with Cmax/MIC and T>MIC [%],respectively).The 24 h static dose ranged from 34.3 to 153.7 mg/kg per d for all S aureus strains,the total AUC24h/MIC ratio to achieve bacteriostatic effect varied from 31.7 to 122.5 (mean,65.7±30.6).Conclusion:Antofloxacin hydrochloride showed powerful antibacterial activity against the S aureus isolates used in our neutropenic infected mice model.Our data suggested that the AUC/MIC ratio appeared to be most closely linked to the bacterial outcome (R290%),and a total AUC24/MIC ratio of 65.7 appears to be the target value to achieve a net bactericidal activity against S aureus,similar to the results of other fluoroquinolones.

  3. Reducing HAuCl4 by the C60 dianion: C60-directed self-assembly of gold nanoparticles into novel fullerene bound gold nanoassemblies

    Science.gov (United States)

    Liu, Wei; Gao, Xiang

    2008-10-01

    The C60 dianion is used to reduce tetrachloroauric acid (HAuCl4) for the first time; three-dimensional C60 bound gold (Au-C60) nanoclusters are obtained from C60-directed self-assembly of gold nanoparticles due to the strong affinities of Au-C60 and C60-C60. The process was monitored in situ by UV-vis-NIR spectroscopy. The resulting Au-C60 nanoclusters were characterized using transmission electron microscopy (TEM), selected area electron diffraction (SAED), energy-dispersive spectroscopy (EDS), x-ray powder diffraction (XRD), x-ray photoelectron spectroscopy (XPS), and FT-IR and Raman spectroscopies. TEM demonstrates the formation of 3D nanonetwork aggregates, which are composed of discrete gold nanocores covered with a C60 monolayer. The SAED and XRD patterns indicate that the gold nanocores inside the capped C60 molecules belong to the face-centred cubic crystal structure, while the C60 molecules are amorphous. The EDS and XPS measurements validate that the Au-C60 nanoclusters contain only Au and C elements and Au3+ is reduced to Au0. FT-IR spectroscopy shows the chemiadsorption of C60 to the gold nanocores, while Raman spectroscopy demonstrates the electron transfer from the gold nanocores to the chemiadsorbed C60 molecules. Au-C60 nanoclusters embedded in tetraoctyl-n-ammonium bromide (TOAB) on glassy carbon electrodes (GCEs) have been fabricated and have shown stable and well-defined electrochemical responses in aqueous solution.

  4. A predictive model combining fecal calgranulin B and fecal occult blood tests can improve the diagnosis of colorectal cancer.

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    Byung Chang Kim

    Full Text Available AIM: Current fecal screening tools for colorectal cancer (CRC, such as fecal occult blood tests (FOBT, are limited by their low sensitivity. Calgranulin B (CALB was previously reported as a candidate fecal marker for CRC. This study investigated whether a combination of the FOBT and fecal CALB has increased sensitivity and specificity for a diagnosis of CRC. MATERIALS AND METHODS: Patients with CRC (n = 175, and healthy individuals (controls; n = 151 were enrolled into the development (81 cases and 51 controls and validation (94 cases and 100 controls sets. Stool samples were collected before bowel preparation. CALB levels were determined by western blotting. FOBT and fecal CALB results were used to develop a predictive model based on logistic regression analysis. The benefit of adding CALB to a model with only FOBT was evaluated as an increased area under the receiver operating curve (AUC, partial AUC, and reclassification improvement (RI in cases and controls, and net reclassification improvement (NRI. RESULTS: Mean CALB level was significantly higher in CRC patients than in controls (P<0.001. CALB was not associated with tumor stage or cancer site, but positivity on the FOBT was significantly higher in advanced than in earlier tumor stages. At a specificity of 90%, the cross-validated AUC and sensitivity were 89.81% and 82.72%, respectively, in the development set, and 92.74% and 79.79%, respectively, in the validation set. The incremental benefit of adding CALB to the model, as shown by the increase in AUC, had a p-value of 0.0499. RI in cases and controls and NRI all revealed that adding CALB significantly improved the prediction model. CONCLUSION: A predictive model using a combination of FOBT and CALB may have greater sensitivity and specificity and AUC for predicting CRC than models using a single marker.

  5. Diagnostic significance of haematological testing in patients presenting at the Emergency Department

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    Giuseppe Lippi

    2012-03-01

    Full Text Available The use of simple and economic tests to rule out diseases of sufficient clinical severity is appealing in emergency department (ED, since it would be effective for contrasting ED overcrowding and decreasing healthcare costs. The aim of this study was to assess the diagnostic performance of simple and economic haematological testing in a large sample of adult patients presenting at the ED of the Academic Hospital of Parma during the year 2010 with the five most frequent acute pathologies (i.e., acute myocardial infarction, renal colic, pneumonia, trauma and pancreatitis. Both leukocyte count and hemoglobin showed a good diagnostic performance (Area Under the Curve [AUC] of 0.85 for leukocyte count and 0.76 for hemoglobin; both p < 0.01. Although the platelet count was significantly increased in all patients groups except pancreatitis, the diagnostic performance did not achieve statistical significance (AUC 0.53; p = 0.07. We also observed an increased RDW in all groups, except in those with trauma and the diagnostic performance was acceptable (AUC 0.705; p < 0.01. The mean platelet volume (MPV was consistently lower in all patients groups and also characterized by an efficient diagnostic performance (AUC 0.76; p < 0.01. This evidence led us to design an arbitrary formula, whereby MPV and hemoglobin were multiplied, and further divided by the leukocyte count, obtaining a remarkable AUC (0.91; p < 0.01. We conclude that simple, rapid and cheap hematological tests might provide relevant clinical information for decision making to busy emergency physicians, and the their combination into an arbitrary formula might further increase the specific diagnostic potential of each of them.

  6. Comprehensive serum profiling for the discovery of epithelial ovarian cancer biomarkers.

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    Ping Yip

    Full Text Available FDA-cleared ovarian cancer biomarkers are limited to CA-125 and HE4 for monitoring and recurrence and OVA1, a multivariate panel consisting of CA-125 and four additional biomarkers, for referring patients to a specialist. Due to relatively poor performance of these tests, more accurate and broadly applicable biomarkers are needed. We evaluated the dysregulation of 259 candidate cancer markers in serum samples from 499 patients. Sera were collected prospectively at 11 monitored sites under a single well-defined protocol. All stages of ovarian cancer and common benign gynecological conditions were represented. To ensure consistency and comparability of biomarker comparisons, all measurements were performed on a single platform, at a single site, using a panel of rigorously calibrated, qualified, high-throughput, multiplexed immunoassays and all analyses were conducted using the same software. Each marker was evaluated independently for its ability to differentiate ovarian cancer from benign conditions. A total of 175 markers were dysregulated in the cancer samples. HE4 (AUC=0.933 and CA-125 (AUC=0.907 were the most informative biomarkers, followed by IL-2 receptor α, α1-antitrypsin, C-reactive protein, YKL-40, cellular fibronectin, CA-72-4 and prostasin (AUC>0.800. To improve the discrimination between cancer and benign conditions, a simple multivariate combination of markers was explored using logistic regression. When combined into a single panel, the nine most informative individual biomarkers yielded an AUC value of 0.950, significantly higher than obtained when combining the markers in the OVA1 panel (AUC 0.912. Additionally, at a threshold sensitivity of 90%, the combination of the top 9 markers gave 88.9% specificity compared to 63.4% specificity for the OVA1 markers. Although a blinded validation study has not yet been performed, these results indicate that alternative biomarker combinations might lead to significant improvements in the

  7. Upper tract urinary cytology to detect upper tract urothelial carcinoma: Using the Johns Hopkins Hospital template and evaluation of its feasibility

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    Longwen Chen

    2015-01-01

    Full Text Available Introduction: Primary upper urinary tract (UT urothelial carcinoma (UC is rare. UT washing cytology is often used during UT surveillance. The Johns Hopkins Hospital template (JHHT is primarily designed to use on lower tract urine cytology and the data on applying JHHT on UT cytology is limited. We herein study the value of UT cytology in detecting UTUC using JHHT in a cohort. Materials and Methods : One hundred UT cytologic specimens were retrieved from our database during a 10-year period (2001-2011. For each patient, the cytology specimen with the highest degree of abnormality was selected. Histologic sections of these cases were also studied. Results: Seventy-six cases of UT cytology had histologic follow-up by either serial (>2 endoscopic biopsies or nephroureterectomy or ureterectomy. Among them, the cytologic diagnosis of positive or suspicious for high-grade UC (HGUC was made in 15 cases; suspicious for low-grade UC (LGUC in 3 cases; atypical urothelial cells (AUCs of undetermined significance in 19 cases; and negative in 39 cases. Of the 15 cases with diagnosis of positive for HGUC or AUC-HGUC (AUC-H, 10 had histologically confirmed HGUC, 1 had LGUC, and 4 had benign histology. All 3 cases of cytologically suspicious for LGUC had LGUC on concomitant histology. Among the 19 washings with AUCs with unknown significance, 7 were LGUC, 1 was HGUC, and 11 were benign on histology. Six of 39 cases with negative cytology had UC (3 low-grade and 3 high-grade on histology. Combining positive and AUC-H for UC diagnoses, sensitivity, and specificity for detecting HGUC were 71.4% and 91.9%, while for LGUC were 21.4% and 100%, respectively. Conclusions: UT washing cytology has high specificity for detecting UC, especially HGUC. Using JHHT on UT washing cytology is feasible, but the category of LGUC may need modification.

  8. Commonly used surfactant, Tween 80, improves absorption of P-glycoprotein substrate, digoxin, in rats.

    Science.gov (United States)

    Zhang, Hongjian; Yao, Ming; Morrison, Richard A; Chong, Saeho

    2003-09-01

    Tween 80 (Polysorbate 80) is a hydrophilic nonionic surfactant commonly used as an ingredient in dosing vehicles for pre-clinical in vivo studies (e.g., pharmacokinetic studies, etc.). Tween 80 increased apical to basolateral permeability of digoxin in Caco-2 cells suggesting that Tween 80 is an in vitro inhibitor of P-gp. The overall objective of the present study was to investigate whether an inhibition of P-gp by Tween 80 can potentially influence in vivo absorption of P-gp substrates by evaluating the effect of Tween 80 on the disposition of digoxin (a model P-gp substrate with minimum metabolism) after oral administration in rats. Rats were dosed orally with digoxin (0.2 mg/kg) formulated in ethanol (40%, v/v) and saline mixture with and without Tween 80 (1 or 10%, v/v). Digoxin oral AUC increased 30 and 61% when dosed in 1% and 10% Tween 80, respectively, compared to control (P Tween 80 is due, in part, to a systemic inhibition of digoxin excretion in addition to an inhibition of P-gp in the GI tract, a separate group of rats received digoxin intravenously (0.2 mg/kg) and Tween 80 (10% v/v) orally. No significant changes in digoxin IV AUC was noted when Tween 80 was administered orally. In conclusion, Tween 80 significantly increased digoxin AUC and Cmax after oral administration, and the increased AUC is likely to be due to an inhibition of P-gp in the gut (i.e., improved absorption). Therefore, Tween 80 is likely to improve systemic exposure of P-gp substrates after oral administration. Comparing AUC after oral administration with and without Tween 80 may be a viable strategy in evaluating whether oral absorption of P-gp substrates is potentially limited by P-gp in the gut.

  9. Quantitative forecasting of PTSD from early trauma responses: a Machine Learning application.

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    Galatzer-Levy, Isaac R; Karstoft, Karen-Inge; Statnikov, Alexander; Shalev, Arieh Y

    2014-12-01

    There is broad interest in predicting the clinical course of mental disorders from early, multimodal clinical and biological information. Current computational models, however, constitute a significant barrier to realizing this goal. The early identification of trauma survivors at risk of post-traumatic stress disorder (PTSD) is plausible given the disorder's salient onset and the abundance of putative biological and clinical risk indicators. This work evaluates the ability of Machine Learning (ML) forecasting approaches to identify and integrate a panel of unique predictive characteristics and determine their accuracy in forecasting non-remitting PTSD from information collected within 10 days of a traumatic event. Data on event characteristics, emergency department observations, and early symptoms were collected in 957 trauma survivors, followed for fifteen months. An ML feature selection algorithm identified a set of predictors that rendered all others redundant. Support Vector Machines (SVMs) as well as other ML classification algorithms were used to evaluate the forecasting accuracy of i) ML selected features, ii) all available features without selection, and iii) Acute Stress Disorder (ASD) symptoms alone. SVM also compared the prediction of a) PTSD diagnostic status at 15 months to b) posterior probability of membership in an empirically derived non-remitting PTSD symptom trajectory. Results are expressed as mean Area Under Receiver Operating Characteristics Curve (AUC). The feature selection algorithm identified 16 predictors, present in ≥ 95% cross-validation trials. The accuracy of predicting non-remitting PTSD from that set (AUC = .77) did not differ from predicting from all available information (AUC = .78). Predicting from ASD symptoms was not better then chance (AUC = .60). The prediction of PTSD status was less accurate than that of membership in a non-remitting trajectory (AUC = .71). ML methods may fill a critical gap in forecasting PTSD. The

  10. Urinary Biomarker Panel to Improve Accuracy in Predicting Prostate Biopsy Result in Chinese Men with PSA 4–10 ng/mL

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    Yongqiang Zhou

    2017-01-01

    Full Text Available This study aims to evaluate the effectiveness and clinical performance of a panel of urinary biomarkers to diagnose prostate cancer (PCa in Chinese men with PSA levels between 4 and 10 ng/mL. A total of 122 patients with PSA levels between 4 and 10 ng/mL who underwent consecutive prostate biopsy at three hospitals in China were recruited. First-catch urine samples were collected after an attentive prostate massage. Urinary mRNA levels were measured by quantitative real-time polymerase chain reaction (qRT-PCR. The predictive accuracy of these biomarkers and prediction models was assessed by the area under the curve (AUC of the receiver-operating characteristic (ROC curve. The diagnostic accuracy of PCA3, PSGR, and MALAT-1 was superior to that of PSA. PCA3 performed best, with an AUC of 0.734 (95% CI: 0.641, 0.828 followed by MALAT-1 with an AUC of 0.727 (95% CI: 0.625, 0.829 and PSGR with an AUC of 0.666 (95% CI: 0.575, 0.749. The diagnostic panel with age, prostate volume, % fPSA, PCA3 score, PSGR score, and MALAT-1 score yielded an AUC of 0.857 (95% CI: 0.780, 0.933. At a threshold probability of 20%, 47.2% of unnecessary biopsies may be avoided whereas only 6.2% of PCa cases may be missed. This urinary panel may improve the current diagnostic modality in Chinese men with PSA levels between 4 and 10 ng/mL.

  11. New serum biomarkers for prostate cancer diagnosis

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    Kailash C Chadha

    2014-01-01

    Full Text Available Background: Prostate-specific antigen (PSA is currently used as a biomarker for diagnosis and management of prostate cancer (CaP. However, PSA typically lacks the sensitivity and specificity desired of a diagnostic marker. Objective: The goal of this study was to identify an additional biomarker or a panel of biomarkers that is more sensitive and specific than PSA in differentiating benign versus malignant prostate disease and/or localized CaP versus metastatic CaP. Methods: Concurrent measurements of circulating interleukin-8 (IL-8, Tumor necrosis factor-α (TNF-α and soluble tumor necrosis factor-α receptors 1 (sTNFR1 were obtained from four groups of men: (1 Controls (2 with elevated prostate-specific antigen with a negative prostate biopsy (elPSA_negBx (3 with clinically localized CaP and (4 with castration resistant prostate cancer. Results: TNF-α Area under the receiver operating characteristic curve (AUC = 0.93 and sTNFR1 (AUC = 0.97 were strong predictors of elPSA_negBx (vs. CaP. The best predictor of elPSA_negBx vs CaP was sTNFR1 and IL-8 combined (AUC = 0.997. The strongest single predictors of localized versus metastatic CaP were TNF-α (AUC = 0.992 and PSA (AUC = 0.963 levels. Conclusions: The specificity and sensitivity of a PSA-based CaP diagnosis can be significantly enhanced by concurrent serum measurements of IL-8, TNF-α and sTNFR1. In view of the concerns about the ability of PSA to distinguish clinically relevant CaP from indolent disease, assessment of these biomarkers in the larger cohort is warranted.

  12. Predicting hospital-acquired infections by scoring system with simple parameters.

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    Ying-Jui Chang

    Full Text Available BACKGROUND: Hospital-acquired infections (HAI are associated with increased attributable morbidity, mortality, prolonged hospitalization, and economic costs. A simple, reliable prediction model for HAI has great clinical relevance. The objective of this study is to develop a scoring system to predict HAI that was derived from Logistic Regression (LR and validated by Artificial Neural Networks (ANN simultaneously. METHODOLOGY/PRINCIPAL FINDINGS: A total of 476 patients from all the 806 HAI inpatients were included for the study between 2004 and 2005. A sample of 1,376 non-HAI inpatients was randomly drawn from all the admitted patients in the same period of time as the control group. External validation of 2,500 patients was abstracted from another academic teaching center. Sixteen variables were extracted from the Electronic Health Records (EHR and fed into ANN and LR models. With stepwise selection, the following seven variables were identified by LR models as statistically significant: Foley catheterization, central venous catheterization, arterial line, nasogastric tube, hemodialysis, stress ulcer prophylaxes and systemic glucocorticosteroids. Both ANN and LR models displayed excellent discrimination (area under the receiver operating characteristic curve [AUC]: 0.964 versus 0.969, p = 0.507 to identify infection in internal validation. During external validation, high AUC was obtained from both models (AUC: 0.850 versus 0.870, p = 0.447. The scoring system also performed extremely well in the internal (AUC: 0.965 and external (AUC: 0.871 validations. CONCLUSIONS: We developed a scoring system to predict HAI with simple parameters validated with ANN and LR models. Armed with this scoring system, infectious disease specialists can more efficiently identify patients at high risk for HAI during hospitalization. Further, using parameters either by observation of medical devices used or data obtained from EHR also provided good prediction

  13. Clarithromycin suspension: bioequivalence studies on two different strengths.

    Science.gov (United States)

    Koytchev, Rossen; Ozalp, Yildiz; Erenmemisoglu, Aydin; van der Meer, Mike John; Alpan, Recep Serdar

    2004-09-01

    Two studies were performed in different groups of volunteers, with the aim to prove the bioequivalence of test (Klaromin) and reference clarithromycin (CAS 81103-11-9) suspensions containing in 5 mL either 125 mg (study 1) or 250 mg (study 2) of the drug, administered as an oral dose of 10 mL. Each study was conducted according to an open, randomized, single-dose, two-period cross-over design in healthy volunteers with a wash-out period from 7 to 14 days. Blood samples were taken up to 24 h in both studies, and concentrations of clarithromycin and its principal active 14-hydroxy metabolite were determined by HPLC. In the first study, the 90% confidence interval for intra-individual ratios of AUC0-t and Cmax of clarithromycin were between 0.84 and 1.03 (AUC0-t) and between 0.89 and 1.03 (Cmax). In the second study, i.e. after administration of clarithromycin suspension 250mg/5mL, the 90% confidence interval for intra-individual ratios of AUC0-inf and Cmax of clarithromycin were between 1.01 and 1.17 (AUC0-inf) and between 1.01 and 1.16 (Cmax). All these values were within the acceptance ranges for bioequivalence studies. In both studies, the 90% confidence interval for intra-individual ratios of AUC0-inf and Cmax of 14-hydroxy-clarithromycin were also within the acceptance ranges. In the light of the results of the studies reported here it can be concluded that the clarithromycin test formulations are bioequivalent to the respective reference formulations, i.e. suspensions containing 125 mg/5 mL and 250 mg/5 mL of the drug.

  14. A rapid and sensitive HPLC method for the analysis of metronidazole in human plasma: application to single dose pharmacokinetic and bioequivalence studies

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    Jaber Emami

    2006-03-01

    Full Text Available A sensitive, accurate and rapid reverse phase HPLC method was developed to quantitate plasma levels of metronidazole in order to conduct a comparative bioavailability studies. The drug and internal standard were added to plasma samples, vortexed and then zinc sulfate solution was added in order to precipitate the plasma proteins. Samples were centrifuged at 3000 rpm for 10 min. The supernatant layer was separated and analyzed on a phenyl (300 × 4.6mm column, with 5% acetonitrile in 0.1 M KH2PO4 buffer (pH = 4.5 at 324 nm. The standard curve covering 0.15 – 30 μg/ml concentration range, was linear (r2 = 0.9999, relative errors were within 2.48 to 9.15 % and the CV% ranged from 2.999 to 10.796. The method is suitable for bioavailability, pharmacokinetic, and bioequivalent studies in human. The in-vivo study was carried out in 12 healthy volunteers according to a single dose, two-sequence, cross over randomized design. The bioavailability was compared using the total area under the plasma level versus time curve (AUC0-48, AUC0-, peak plasma concentration (Cmax and time to Cmax (Tmax. No statistically significant difference was found between the AUC0- , Cmax and Tmax values of the test and reference, Flagyl® (p > 0.05. The 90% CI for the ratio of the AUC0- (0.94-1.07 and Cmax (0.88-1.03 and the logarithmically transformed AUC0- (0.99-1.01 and Cmax (0.94-1.01 values of the generic product over those of Flagyl® was calculated to be within the acceptable limit of 0.80-1.20 and 0.80-1.25, respectively. It was, therefore, concluded that the generic metronidazole was bioequivalent with the innovator formulation.

  15. Can We Reduce Negative Blood Cultures With Clinical Scores and Blood Markers? Results From an Observational Cohort Study.

    Science.gov (United States)

    Laukemann, Svenja; Kasper, Nina; Kulkarni, Prasad; Steiner, Deborah; Rast, Anna Christina; Kutz, Alexander; Felder, Susan; Haubitz, Sebastian; Faessler, Lukas; Huber, Andreas; Fux, Christoph A; Mueller, Beat; Schuetz, Philipp

    2015-12-01

    Only a small proportion of blood cultures routinely performed in emergency department (ED) patients is positive. Multiple clinical scores and biomarkers have previously been examined for their ability to predict bacteremia. Conclusive clinical validation of these scores and biomarkers is essential.This observational cohort study included patients with suspected infection who had blood culture sampling at ED admission. We assessed 5 clinical scores and admission concentrations of procalcitonin (PCT), C-reactive protein (CRP), lymphocyte and white blood cell counts, the neutrophil-lymphocyte count ratio (NLCR), and the red blood cell distribution width (RDW). Two independent physicians assessed true blood culture positivity. We used logistic regression models with area under the curve (AUC) analysis.Of 1083 patients, 104 (9.6%) had positive blood cultures. Of the clinical scores, the Shapiro score performed best (AUC 0.729). The best biomarkers were PCT (AUC 0.803) and NLCR (AUC 0.700). Combining the Shapiro score with PCT levels significantly increased the AUC to 0.827. Limiting blood cultures only to patients with either a Shapiro score of ≥4 or PCT > 0.1 μg/L would reduce negative sampling by 20.2% while still identifying 100% of positive cultures. Similarly, a Shapiro score ≥3 or PCT >0.25 μg/L would reduce cultures by 41.7% and still identify 96.1% of positive blood cultures.Combination of the Shapiro score with admission levels of PCT can help reduce unnecessary blood cultures with minimal false negative rates.The study was registered on January 9, 2013 at the 'ClinicalTrials.gov' registration web site (NCT01768494).

  16. 3D-Printing for Analytical Ultracentrifugation.

    Science.gov (United States)

    Desai, Abhiksha; Krynitsky, Jonathan; Pohida, Thomas J; Zhao, Huaying; Schuck, Peter

    2016-01-01

    Analytical ultracentrifugation (AUC) is a classical technique of physical biochemistry providing information on size, shape, and interactions of macromolecules from the analysis of their migration in centrifugal fields while free in solution. A key mechanical element in AUC is the centerpiece, a component of the sample cell assembly that is mounted between the optical windows to allow imaging and to seal the sample solution column against high vacuum while exposed to gravitational forces in excess of 300,000 g. For sedimentation velocity it needs to be precisely sector-shaped to allow unimpeded radial macromolecular migration. During the history of AUC a great variety of centerpiece designs have been developed for different types of experiments. Here, we report that centerpieces can now be readily fabricated by 3D printing at low cost, from a variety of materials, and with customized designs. The new centerpieces can exhibit sufficient mechanical stability to withstand the gravitational forces at the highest rotor speeds and be sufficiently precise for sedimentation equilibrium and sedimentation velocity experiments. Sedimentation velocity experiments with bovine serum albumin as a reference molecule in 3D printed centerpieces with standard double-sector design result in sedimentation boundaries virtually indistinguishable from those in commercial double-sector epoxy centerpieces, with sedimentation coefficients well within the range of published values. The statistical error of the measurement is slightly above that obtained with commercial epoxy, but still below 1%. Facilitated by modern open-source design and fabrication paradigms, we believe 3D printed centerpieces and AUC accessories can spawn a variety of improvements in AUC experimental design, efficiency and resource allocation.

  17. Evaluation of Respiratory Motion Effect on Defect Detection in Myocardial Perfusion SPECT: A Simulation Study.

    Science.gov (United States)

    Yang, Yu-Wen; Chen, Jyh-Cheng; He, Xin; Wang, Shyh-Jen; Tsui, Benjamin M W

    2009-06-01

    The objective of this study is to investigate the effects of respiratory motion (RM) on defect detection in Tc-99m sestamibi myocardial perfusion SPECT (MPS) using a phantom population that includes patient variability. Three RM patterns are included, namely breath-hold, slightly enhanced normal breathing, and deep breathing. For each RM pattern, six 4-D NCAT phantoms were generated, each with anatomical variations. Anterior, lateral and inferior myocardial defects with different sizes and contrasts were inserted. Noise-free SPECT projections were simulated using an analytical projector. Poisson noise was then added to generate noisy realizations. The projection data were reconstructed using the OS-EM algorithm with 1 and 4 subsets/iteration and at 1, 2, 3, 5, 7, and 10 iterations. Short-axis images centered at the centroid of the myocardial defect were extracted, and the channelized Hotelling observer (CHO) was applied for the detection of the defect. The CHO results show that the value of the area under the receiver operating characteristics (ROC) curve (AUC) is affected by the RM amplitude. For all the defect sizes and contrasts studied, the highest or optimal AUC values indicate maximum detectability decrease with the increase of the RM amplitude. With no respiration, the ranking of the optimal AUC value in decreasing order is anterior then lateral, and finally inferior defects. The AUC value of the lateral defect drops more severely as the RM amplitude increases compared to other defect locations. Furthermore, as the RM amplitude increases, the AUC values of the smaller defects drop more quickly than the larger ones. We demonstrated that RM affects defect detectability of MPS imaging. The results indicate that developments of optimal data acquisition methods and RM correction methods are needed to improve the defect detectability in MPS.

  18. Soft-tissue penetration of ceftobiprole in healthy volunteers determined by in vivo microdialysis.

    Science.gov (United States)

    Barbour, April; Schmidt, Stephan; Sabarinath, Sreedharan Nair; Grant, Maria; Seubert, Christoph; Skee, Donna; Murthy, Bindu; Derendorf, Hartmut

    2009-07-01

    Ceftobiprole is a promising new broad-spectrum cephalosporin with activity against several multidrug-resistant gram-positive and gram-negative species, including methicillin-resistant Staphylococcus aureus. In order to make efficacy predications against these resistant bacteria in soft-tissue infections, i.e., skin and skin structure infections, ceftobiprole's ability to reach the site of action should be explored. Therefore, a microdialysis study was conducted in 12 healthy volunteers to determine the penetration of ceftobiprole into skeletal muscle and subcutaneous (s.c.) adipose tissue after a single intravenous dose of 500 mg. Plasma and tissue interstitial space fluid (ISF) drug concentrations were measured for 24 h from the start of the 2-h intravenous infusion. Pharmacokinetic parameters were determined using noncompartmental analysis. The penetration of ceftobiprole into the ISF of tissues was assessed by comparing the ratios between tissue and plasma of the free drug area under the concentration-time curve (fAUC). It was found that ceftobiprole distributes into the muscle (fAUC(muscle)/fAUC(plasma) of 0.69 +/- 0.13) and s.c. adipose tissue (fAUC(s.c.adipose)/fAUC(plasma) of 0.49 +/- 0.28). The concentrations in both skeletal muscle and s.c. adipose tissue met the efficacy breakpoint (percentage of the time that free drug concentrations remained above the MIC) for at least 40% of the 8-h dosing interval for organisms with a MIC of 2 mg/liter. Therefore, ceftobiprole qualifies as a potential agent with drug penetration capabilities to treat complicated skin and skin structure infections due to both gram-negative and gram-positive pathogens with MICs equal to or below 2 mg/liter.

  19. 多糖铁胶囊的人体生物等效性研究%Study on Bioequivalence of Polyferose Capsules

    Institute of Scientific and Technical Information of China (English)

    孙伟; 马霖; 刘雅丽

    2004-01-01

    目的:评价多糖铁胶囊与进口制剂力蜚能胶囊的生物等效性.方法: 20名男性健康受试者,采用单剂量、随机、自身交叉对照试验设计,空腹口服多糖铁胶囊与力蜚能胶囊 150mg,采集 12h内动态血标本,用原子吸收光谱法测定血清铁浓度并计算 Cmax、 Tmax、 AUC0~ t、 AUC0~∞等相关参数,以双单侧 t检验判断两制剂是否具有生物等效性.结果:多糖铁胶囊和力蜚能胶囊的 AUC0~ t均为 6. 58(μ g· h) /ml, Cmax分别为 1. 07、 1. 10μ g/ml, Tmax均为 3. 93h, T1/2均为 2. 33h, AUC0~∞分别为 6. 95、 6. 93(μ g· h) /ml.两组参数均无统计学差异( P>0. 05); AUC0~ t、 Tmax和 Cmax经双单侧 t检验证明亦无显著性差异.结论:多糖铁胶囊的相对生物利用度为 101. 02%,与力蜚能胶囊为生物等效制剂.

  20. Effect of postprandial hyperglycaemia in non-invasive measurement of cerebral metabolic rate of glucose in non-diabetic subjects

    Energy Technology Data Exchange (ETDEWEB)

    Tsuchida, Tatsuro; Itoh, Harumi [Department of Radiology, Fukui Medical University, Matsuoka (Japan); Sadato, Norihiro; Nishizawa, Sadahiko; Yonekura, Yoshiharu [Biomedical Imaging Research Center, Fukui Medical University (Japan)

    2002-02-01

    The aim of this study was to determine the effect of postprandial hyperglycaemia (HG) on the non-invasive measurement of cerebral metabolic rate of glucose (CMRGlc). Five patients who had a meal within an hour before a fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) examination were recruited in this study. They underwent intermittent arterial blood sampling (measured input function), and, based on this sampling, CMRGlc was calculated using an autoradiographic method (CMRGlc{sub real}). Simulated input functions were generated based on standardised input function, body surface area and net injected dose of FDG, and simulated CMRGlc (CMRGlc{sub sim}) was also calculated. Percent error of the area under the curve (AUC) between measured (AUC{sub real}) and simulated input function (AUC{sub IFsim}) and percent error between CMRGlc{sub real} and CMRGlc{sub sim} were calculated. These values were compared with those obtained from a previous study conducted under fasting conditions (F). The serum glucose level in the HG group was significantly higher than that in the F group (165{+-}69 vs 100{+-}9 mg/dl, P=0.0007). Percent errors of AUC and CMRGlc in grey matter and white matter in HG were significantly higher than those in F (12.9%{+-}1.3% vs 3.5%{+-}2.2% in AUC, P=0.0015; 18.2%{+-}2.2% vs 2.9%{+-}1.9% in CMRGlc in grey matter, P=0.0028; 24.0%{+-}4.6% vs 3.4%{+-}2.2% in CMRGlc in white matter, P=0.0028). It is concluded that a non-invasive method of measuring CMRGlc should be applied only in non-diabetic subjects under fasting conditions. (orig.)

  1. Pathway analysis of GWAS provides new insights into genetic susceptibility to 3 inflammatory diseases.

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    Hariklia Eleftherohorinou

    Full Text Available Although the introduction of genome-wide association studies (GWAS have greatly increased the number of genes associated with common diseases, only a small proportion of the predicted genetic contribution has so far been elucidated. Studying the cumulative variation of polymorphisms in multiple genes acting in functional pathways may provide a complementary approach to the more common single SNP association approach in understanding genetic determinants of common disease. We developed a novel pathway-based method to assess the combined contribution of multiple genetic variants acting within canonical biological pathways and applied it to data from 14,000 UK individuals with 7 common diseases. We tested inflammatory pathways for association with Crohn's disease (CD, rheumatoid arthritis (RA and type 1 diabetes (T1D with 4 non-inflammatory diseases as controls. Using a variable selection algorithm, we identified variants responsible for the pathway association and evaluated their use for disease prediction using a 10 fold cross-validation framework in order to calculate out-of-sample area under the Receiver Operating Curve (AUC. The generalisability of these predictive models was tested on an independent birth cohort from Northern Finland. Multiple canonical inflammatory pathways showed highly significant associations (p 10(-3-10(-20 with CD, T1D and RA. Variable selection identified on average a set of 205 SNPs (149 genes for T1D, 350 SNPs (189 genes for RA and 493 SNPs (277 genes for CD. The pattern of polymorphisms at these SNPS were found to be highly predictive of T1D (91% AUC and RA (85% AUC, and weakly predictive of CD (60% AUC. The predictive ability of the T1D model (without any parameter refitting had good predictive ability (79% AUC in the Finnish cohort. Our analysis suggests that genetic contribution to common inflammatory diseases operates through multiple genes interacting in functional pathways.

  2. Cocoa extract intake for 4 weeks reduces postprandial systolic blood pressure response of obese subjects, even after following an energy-restricted diet

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    Idoia Ibero-Baraibar

    2016-03-01

    Full Text Available Background: Cardiometabolic profile is usually altered in obesity. Interestingly, the consumption of flavanol-rich foods might be protective against those metabolic alterations. Objective: To evaluate the postprandial cardiometabolic effects after the acute consumption of cocoa extract before and after 4 weeks of its daily intake. Furthermore, the bioavailability of cocoa extract was investigated. Design: Twenty-four overweight/obese middle-aged subjects participated in a 4-week intervention study. Half of the volunteers consumed a test meal enriched with 1.4 g of cocoa extract (415 mg flavanols, while the rest of the volunteers consumed the same meal without the cocoa extract (control group. Glucose and lipid profile, as well as blood pressure and cocoa metabolites in plasma, were assessed before and at 60, 120, and 180 min post-consumption, at the beginning of the study (Postprandial 1 and after following a 4-week 15% energy-restricted diet including meals containing or not containing the cocoa extract (Postprandial 2. Results: In the Postprandial 1 test, the area under the curve (AUC of systolic blood pressure (SBP was significantly higher in the cocoa group compared with the control group (p=0.007, showing significant differences after 120 min of intake. However, no differences between groups were observed at Postprandial 2. Interestingly, the reduction of postprandial AUC of SBP (AUC_Postprandial 2-AUC_Postprandial 1 was higher in the cocoa group (p=0.016. Furthermore, cocoa-derived metabolites were detected in plasma of the cocoa group, while the absence or significantly lower amounts of metabolites were found in the control group. Conclusions: The daily consumption of cocoa extract within an energy-restricted diet for 4 weeks resulted in a greater reduction of postprandial AUC of SBP compared with the effect of energy-restricted diet alone and independently of body weight loss. These results suggest the role of cocoa flavanols on

  3. Can We Reduce Negative Blood Cultures With Clinical Scores and Blood Markers? Results From an Observational Cohort Study

    Science.gov (United States)

    Laukemann, Svenja; Kasper, Nina; Kulkarni, Prasad; Steiner, Deborah; Rast, Anna Christina; Kutz, Alexander; Felder, Susan; Haubitz, Sebastian; Faessler, Lukas; Huber, Andreas; Fux, Christoph A.; Mueller, Beat; Schuetz, Philipp

    2015-01-01

    Abstract Only a small proportion of blood cultures routinely performed in emergency department (ED) patients is positive. Multiple clinical scores and biomarkers have previously been examined for their ability to predict bacteremia. Conclusive clinical validation of these scores and biomarkers is essential. This observational cohort study included patients with suspected infection who had blood culture sampling at ED admission. We assessed 5 clinical scores and admission concentrations of procalcitonin (PCT), C-reactive protein (CRP), lymphocyte and white blood cell counts, the neutrophil-lymphocyte count ratio (NLCR), and the red blood cell distribution width (RDW). Two independent physicians assessed true blood culture positivity. We used logistic regression models with area under the curve (AUC) analysis. Of 1083 patients, 104 (9.6%) had positive blood cultures. Of the clinical scores, the Shapiro score performed best (AUC 0.729). The best biomarkers were PCT (AUC 0.803) and NLCR (AUC 0.700). Combining the Shapiro score with PCT levels significantly increased the AUC to 0.827. Limiting blood cultures only to patients with either a Shapiro score of ≥4 or PCT > 0.1 μg/L would reduce negative sampling by 20.2% while still identifying 100% of positive cultures. Similarly, a Shapiro score ≥3 or PCT >0.25 μg/L would reduce cultures by 41.7% and still identify 96.1% of positive blood cultures. Combination of the Shapiro score with admission levels of PCT can help reduce unnecessary blood cultures with minimal false negative rates. The study was registered on January 9, 2013 at the ‘ClinicalTrials.gov’ registration web site (NCT01768494). PMID:26656373

  4. Environmental and socio-economic risk modelling for Chagas disease in Bolivia.

    Science.gov (United States)

    Mischler, Paula; Kearney, Michael; McCarroll, Jennifer C; Scholte, Ronaldo G C; Vounatsou, Penelope; Malone, John B

    2012-09-01

    Accurately defining disease distributions and calculating disease risk is an important step in the control and prevention of diseases. Geographical information systems (GIS) and remote sensing technologies, with maximum entropy (Maxent) ecological niche modelling computer software, were used to create predictive risk maps for Chagas disease in Bolivia. Prevalence rates were calculated from 2007 to 2009 household infection survey data for Bolivia, while environmental data were compiled from the Worldclim database and MODIS satellite imagery. Socio-economic data were obtained from the Bolivian National Institute of Statistics. Disease models identified altitudes at 500-3,500 m above the mean sea level (MSL), low annual precipitation (45-250 mm), and higher diurnal range of temperature (10-19 °C; peak 16 °C) as compatible with the biological requirements of the insect vectors. Socio-economic analyses demonstrated the importance of improved housing materials and water source. Home adobe wall materials and having to fetch drinking water from rivers or wells without pump were found to be highly related to distribution of the disease by the receiver operator characteristic (ROC) area under the curve (AUC) (0.69 AUC, 0.67 AUC and 0.62 AUC, respectively), while areas with hardwood floors demonstrated a direct negative relationship (-0.71 AUC). This study demonstrates that Maxent modelling can be used in disease prevalence and incidence studies to provide governmental agencies with an easily learned, understandable method to define areas as either high, moderate or low risk for the disease. This information may be used in resource planning, targeting and implementation. However, access to high-resolution, sub-municipality socio-economic data (e.g. census tracts) would facilitate elucidation of the relative influence of poverty-related factors on regional disease dynamics.

  5. Cut-Offs and Response Criteria for the Hospital Universitario La Princesa Index (HUPI) and Their Comparison to Widely-Used Indices of Disease Activity in Rheumatoid Arthritis

    Science.gov (United States)

    Castrejón, Isabel; Ortiz, Ana M.; Toledano, Esther; Castañeda, Santos; García-Vadillo, Alberto; Carmona, Loreto

    2016-01-01

    Objective To estimate cut-off points and to establish response criteria for the Hospital Universitario La Princesa Index (HUPI) in patients with chronic polyarthritis. Methods Two cohorts, one of early arthritis (Princesa Early Arthritis Register Longitudinal [PEARL] study) and other of long-term rheumatoid arthritis (Estudio de la Morbilidad y Expresión Clínica de la Artritis Reumatoide [EMECAR]) including altogether 1200 patients were used to determine cut-off values for remission, and for low, moderate and high activity through receiver operating curve (ROC) analysis. The areas under ROC (AUC) were compared to those of validated indexes (SDAI, CDAI, DAS28). ROC analysis was also applied to establish minimal and relevant clinical improvement for HUPI. Results The best cut-off points for HUPI are 2, 5 and 9, classifying RA activity as remission if ≤2, low disease activity if >2 and ≤5), moderate if >5 and <9 and high if ≥9. HUPI’s AUC to discriminate between low-moderate activity was 0.909 and between moderate-high activity 0.887. DAS28’s AUCs were 0.887 and 0.846, respectively; both indices had higher accuracy than SDAI (AUCs: 0.832 and 0.756) and CDAI (AUCs: 0.789 and 0.728). HUPI discriminates remission better than DAS28-ESR in early arthritis, but similarly to SDAI. The HUPI cut-off for minimal clinical improvement was established at 2 and for relevant clinical improvement at 4. Response criteria were established based on these cut-off values. Conclusions The cut-offs proposed for HUPI perform adequately in patients with either early or long term arthritis. PMID:27603313

  6. [Endemic heteroresistant glycopeptide intermediate Staphylcoccus aureus (hGISA) comprising unrelated clonal types and not associated with vancomycin therapy].

    Science.gov (United States)

    Lecaillon, E; Gueudet, P; Wooton, M; Walsh, T R; Macgowan, A P; Jones, M E

    2002-11-01

    The detection of methicillin-resistant S. aureus (SA) (MRSA) refractory to glycopeptides is a serious clinical issue. The prevalence of hetero-resistant GISA (hGISA) strains at H. Maréchal Joffre, France is reported.858 non-repeat SA were isolated during 1999. 367 (43%) of these, from 257 patients, were MRSA (mean incidence 11.9/1000 admissions). All MSRA detected during 1999 were screened for vancomycin (VAN) resistance (BHI+4 mg/l VAN). Isolates recovered were retested using Etest strips (2 McFarland inoculum on BHI) and population analysis profile/area under the curve (PAP-AUC) analysis with hGISA SA Mu3 as a comparator. 58 selected strains were screened for teicoplanin resistance(TEI) using SFM recommended screen (2 McFarland inoculum on MH+5 mg/L TEI) and MIC (0.5 MF inoculum swabbed on MH agar) methods. 188 (51.3%) grew on VAN screen agar (6.1/1000 admissions). 58 strains (7.6%) possessed Etest VAN MIC > 8 mg/l all others being VAN 8 mg/l). PAP-AUC showed 12 strains to have PAP-AUC ratios > 0.95 but < 1.5 (ie. hGISA, not GISA). All 7 isolates defined as hGISA by both Etest and PAP-AUC comprised 1 PFGE clone (< 3 bands difference). Additionally 2 distinct PFGE types were detected among the other 5 hGISA identified PAP-AUC. The 12 hGISAs, were derived from 12 patients with severe underlying disease. None were on glycopeptide therapy prior to hGISA isolation. This is the first report of endemic hGISA, comprising 3 clonal types. The isolation of hVISA seems not to be associated with patient-specific glycopeptide therapies.

  7. Diagnostic significance of leptin/adiponectin ratio in metabolic syndrome of Chinese children and adolescents%瘦素脂联素比值在儿童青少年代谢综合征中的诊断价值

    Institute of Scientific and Technical Information of China (English)

    王颖; 黎明; 阴津华; 徐璐; 李路娇; 高珊; 米杰

    2015-01-01

    Objective To investigate the correlation between serum leptin(LEP)/adiponectin (APN) (L/A) ratio and metabolic syndrome (MS) in children and adolescents. Methods Total of 3 520 children and adolescents between 6 and 18 years of age were selected from the subjects that had been recruited for 2004 survey conducted by Beijing Children and Adolescent MS (BCAMS) study. Adjusted criteria issued by International Diabetes Federation (IDF) in 2007 were used to establish a diagnosis of MS. Enzyme-linked immunosorbent assay (ELISA) was used to determine serum leptin and adiponectin levels. Areas under the receiver operating characteristi c curve (ROC) were also examined to determine the diagnostic value of L/A in the diagnosis of MS in children.Multiple comparisons were made between groups using analysis of variance (ANOVA) and the chi-square test. Pearson correlation analysis was performed to determine the correlation between L/A values and various components of MS. Results (1) As the L/A value increased, body mass index (BMI), blood pressure (BP), central obesity (CO%) and insulin resistance (IR%) increased progressively, as did, MS detection rate (MS%) increased (χ2=male:108.63;female:94.30) (all P<0.01). (2) L/A ratio area under curve (AUC) of ROC (AUC=0.803) in boys was higher than leption (AUC=0.771) and adiponectin (AUC=0.703, all P<0.05).L/A ratio AUC of ROC (AUC=0.838) in girls was higher than leptin (AUC=0.817, P=0.0785). L/A ratio and leptin AUC of ROC are higher than adiponectin (AUC=0.717, all P<0.05). Conclusions L/A is a better marker for the diagnosis of MS in Children better than leptin and adiponectin alone. L/A could be used as an indicator for MS in children and adolescents, and played an auxiliary role in the diagnosis of obesity-related MS in children.%目的:探讨血清瘦素(LEP)/脂联素(APN)(L/A)比值对儿童代谢综合征(MS)的诊断价值。方法回顾性分析2004年北京市儿童青少年MS(BcAMs)调查总样本中3520例6~18

  8. 多剂量口服硝苯地平控释片的人体药动学及生物等效性研究%Pharmacokinetics and Bioequivalence Study of Nifedipine Controlled-release Tablets after Multiple Doses Administration in Healthy Volunteers

    Institute of Scientific and Technical Information of China (English)

    周新腾; 魏敏吉; 石晓东; 张明; 张朴; 姜斯博

    2009-01-01

    OBJECTIVE Povidone/Copovidone were used as the main osmopolymers instead of Poly (ethylene oxide) (PEO) to prepare nifedipine controlled-release tablets of new osmotic pump type. The pharmacokinetic properties of nifedipine controlled-release tablets after multiple doses in healthy volunteers were studied, and the relative bioavailability of the test preparation was calculated and the bioequivalence was evaluated. METHODS Twenty four male healthy volunteers were enrolled in a randomized two-way crossover design. 30 mg nifedipine was administered per day during consecutive 7 d. The drug concentration in blood was determined with LC-MS/MS method. The pharmacokinetic parameters, relative bioavailability and the bioequivalence were calculated by DAS program. RESULTS The main pharmacokinetic parameters after multiple doses of test preparation and reference preparation were as follows: T_(1/2β) (9.0±2.2)h and (9.5±3.8)h; T_(max) (8.1±7.4)h and (6.7±4.1)h; C_(ssmax) (52.7±28.2)μg.L~(-1) and (44.5±22.6)μg·L~(-1); C_(ssmin) (29.4±22.2)μg·L~(-1) and (28.7 15.8)μg·L~(-1); AUC_(0-60) (1 087.4±671.6)μg·L~(-1)·h and (1 040.2±518.4)μg·L~(-1)·h; AUC_(0-∞) (1 113.1±677.2)μg·L~(-1)·h and (1 074.5±519.8)μg·L~(-1)·h, AUC_(ss) (809.1±454.0)μg·L~(-1)·h and (713.9±382.2)μg·L~(-1)·h. The average relative bioavailability of the test preparation versus the reference preparation was as follows: F_(AUC_(ss)) (115.2±29.2)%, F_(AUC_(0-40)) (103.4±30.2)% and F_(AUC_(0-)) (102.2±29.7)%. DF was (77.84±52.09)% and (55.48±30.54)%. The 90% confidence interval of C_(max), AUC_(0-60), AUC_(0-∞) and AUC_(ss) after longarithmic transform was (100.9-126.0)%, (87.5-111.8)%,(86.8-110.3)% and (98.8-124.4)% respectively. There was no significant difference in T_(max) after non-parameter rank sum test. No adverse reaction was observed during the trial. CONCLUSION The test preparation was bioequivalent to the reference preparation. Povidone/Copovidone could

  9. Effect of CYP2C19 genetic polymorphism on pharmacokinetic characterstics and 5-hydroxyl metabolic pathway of lansoprazole in Chinese volunteers%CYP2C19基因多态性对中国人体内兰索拉唑药代动力学及其5-羟基代谢通路的影响

    Institute of Scientific and Technical Information of China (English)

    严非; 夏春华; 熊玉卿

    2011-01-01

    AIM: To investigate the effect of CYP2C19 polymorphism on pharmacokinetic characteristics and 5-hydroxyl metabolic pathway of lansoprazole in Chinese subjects. METH-ODS: Twelve healthy subjects were typed by u-sing RFLP-PCR method. After intravenous drip 30 mg lansoprazole, the plasma concentrations of lansoprazole in subjects were determined byLC-MS method. The pharmacokinetic parameters of lansoprazole and AUClpz/AUC5-Ohlpz were calculated and compared between different groups. RESULTS-. After all the subjects were given 30 mg lansoprazole, it found that the AUCo-,, AUCo-(x), CLz, ( AUCLpz/ AUC5-oh)0-t, and (AUCLpZ/AUC5-oh)0-∞ of the mutant types were equivalent to 2.381, 2.572, 0. 428, 3. 602 and 4. 083-fold as those of the wild types, respectively. CONCLUSION: The CYP2C19 genetic polymorphism, which has significant influence on the pharmacokinetic characteristics of the lansoprazole in Chinese volun-teers (P<0. 05), has very significant influence on the 5-hydroxyl metabolic pathway of the lansoprazole (P<0. 01). The result suggests that CYP2C19 genetic polymorphism is one of the important factors leading to individual concentration differences of the lansoprazole and has a better relevance with the 5-hydroxyl metabolic pathway.%目的:研究CYP2C19基因多态性对中国人体内兰索拉唑药代动力学及其5-羟基代谢通路的影响.方法:采用RFLP-PCR方法对12名健康受试者进行CYP2C19基因多态性检测,并采用液相色谱-质谱法(LC-MS)检测兰索拉唑体内血药浓度并计算相关的药代动力学参数,比较不同基因型受试者之间主要药代动力学参数以及AUCLpz/AUC5-oH LPZ 比 值(AUGansoprazole/AUC5-hydroxylansoprazole,此参数用以评价5-羟基代谢的标准)的差异.结果:12名健康受试者在给予30 mg兰索拉唑后,发现突变型个体AUC0-t、AUC0-∞、CLz、(AUCLPZ/AUC5-OHLPZ)0-t、(AUCLPZ/AUC5-OH LPZ)0-.∞分别相当于野生型个体的2.381、2.572、0.428、3.602、4.083

  10. Petrogenesis of Late Triassic ultramafic rocks from the Andong Ultramafic Complex, South Korea

    Science.gov (United States)

    Kim, Nak Kyu; Choi, Sung Hi

    2016-11-01

    To constrain the source and tectonomagmatic processes that gave rise to the Andong Ultramafic Complex (AUC) in South Korea, we determined the clinopyroxene Sr-Nd-Hf-Pb isotope and trace element compositions as well as the whole-rock and mineral compositions for the Late Triassic (ca. 222 Ma) ultramafic rocks from the complex. They are composed of dunites, wehrlites, pyroxene/hornblende peridotites, and pyroxenites. The constituent minerals are olivines, diopsides/augites, bronzites, calcic-amphiboles, and spinels. Clinopyroxenes exhibit a convex-upward rare earth element (REE) pattern, with an apex at Sm. The whole-rock compositions plot away from the residual mantle peridotite trends, with variable but lower Al2O3 and SiO2 contents, and higher CaO, FeO*, and TiO2 contents at a given value of MgO. Estimated equilibrium temperatures for the AUC rocks range from 420 to 780 °C. These observations, together with the absence of reaction or melt impregnation textures, indicate that the AUC ultramafic rocks are magmatic cumulates emplaced within the crust rather than residual mantle or mantle-melt reaction products. The AUC clinopyroxenes have compositions intermediate between the oceanic island basalt- and arc basalt-related cumulate clinopyroxenes. The AUC spinels have lower Cr#s than the arc-related magmatic cumulate spinels. They plot within the field for spinels from mid-ocean ridge basalts (MORB) on a TiO2 vs. Cr# diagram. However, the AUC clinopyroxenes have much more radiogenic Sr ([87Sr/86Sr]i = 0.70554 to 0.70596), unradiogenic Nd ([εNd]i = - 1.0 to - 0.3), and Hf ([εHf]i = + 4.4 to + 6.6) isotopic compositions than those of the MORB or fore-arc basalts (FAB). In the Sr-Nd isotopic correlation diagram, the AUC clinopyroxenes plot in the enriched extension of the "mantle array". They also have more elevated 207Pb/204Pb ratios at a given 206Pb/204Pb than those of the MORB or FAB. In the Nd-Hf isotope space, the AUC clinopyroxenes have somewhat elevated 176Hf

  11. Pharmacokinetic equivalence study of two formulations of the anticonvulsant pregabalin

    Directory of Open Access Journals (Sweden)

    Tjandrawinata RR

    2015-04-01

    Full Text Available Raymond R Tjandrawinata,1 Effi Setiawati,2 Ratih Sofia Ika Putri,2 Vincent Angga Gunawan,2 Fenny Ong,1 Liana W Susanto,1 Dwi Nofiarny11Dexa Laboratories of Biomolecular Sciences, Cikarang, West Java, Indonesia; 2PT Equilab International Bioavailability and Bioequivalence Laboratory, Jakarta, IndonesiaPurpose: The present study was conducted to evaluate whether the bioavailability of pregabalin capsules 150 mg manufactured by PT Dexa Medica was equivalent to the reference formulation.Methods: This was a randomized, open-label, two-period, two-sequence, and crossover study under fasting condition, with a 1-week washout period. Plasma concentrations of pregabalin from 20 subjects were determined by using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS detection method. Pharmacokinetic parameters assessed in this study were: area under the plasma concentration–time curve from time zero to last observed quantifiable concentration (AUC0–t, area under the plasma concentration–time curve from time zero to infinity (AUC0–∞, maximum plasma concentration (Cmax, time to maximum plasma concentration (tmax, and terminal half-life (t1/2. The 90% confidence intervals (CIs for the geometric mean ratios of test formulation/reference formulation were calculated for the AUC and Cmax parameters; while tmax difference was analyzed nonparametrically on the original data using the Wilcoxon matched-pairs test, and t1/2 difference was analyzed using Student's paired t-test.Results: The mean (standard deviation [SD] AUC0–t, AUC0–∞, Cmax, and t1/2 of pregabalin from the test formulation were 27,845.86 (4,508.27 ng·h/mL, 28,311.70 (4,790.55 ng·h/mL, 3,999.71 (801.52 ng/mL, and 5.66 (1.20 hours, respectively; while the mean (SD AUC0–t, AUC0–∞, Cmax, and t1/2 of pregabalin from the reference formulation were 27,398.12 (4,266.28 ng·h/mL, 27,904.24 (4,507.31 ng·h/mL, 3,849.50 (814.50 ng/mL, and 5.87 (1.25 hours, respectively

  12. Relationship between the temporal changes in positron-emission-tomography-imaging-based textural features and pathologic response and survival in esophageal cancer patients

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    Stephen ShingFan Yip

    2016-03-01

    Full Text Available Purpose: Although change in SUV measures and PET-based textural features during treatment have shown promise in tumor response prediction, it is unclear which quantitative measure is the most predictive. We compared the relationship between PET-based features and pathologic response and overall survival with the SUV measures in esophageal cancer. Methods: Fifty-four esophageal cancer patients received PET/CT scans before and after chemo-radiotherapy. Of these, 45 patients underwent surgery and were classified into complete, partial, and non-responders to the preoperative chemoradiation. SUVmax and SUVmean, two co-occurrence matrix (Entropy and Homogeneity, two run-length-matrix (High-gray-run-emphasis and Short-run-high-gray-run-emphasis, and two size-zone-matrix (High-gray-zone-emphasis and Short-zone-high-gray-emphasis textures were computed. The relationship between the relative difference of each measure at different treatment time points and the pathologic response and overall survival was assessed using the area under the receiver-operating-characteristic curve (AUC and Kaplan-Meier statistics respectively. Results: All Textures, except Homogeneity, were better related to pathologic response than SUVmax and SUVmean. Entropy was found to significantly distinguish non-responders from the complete (AUC=0.79, p=1.7x10^-4 and partial (AUC=0.71, p=0.01 responders. Non-responders can also be significantly differentiated from partial and complete responders by the change in the run length and size zone matrix textures (AUC=0.71‒0.76, p≤0.02. Homogeneity, SUVmax and SUVmean failed to differentiate between any of the responders (AUC=0.50‒0.57, p≥0.46. However, none of the measures were found to significantly distinguish between complete and partial responders with AUC0.25. Conclusions: For the patients studied, temporal change in Entropy and all Run length matrix were better correlated with pathological response and survival than the SUV

  13. In vivo pharmacokinetic comparisons of ferulic acid and puerarin after oral administration of monomer, medicinal substance aqueous extract and Nao-De-Sheng to rats

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    Zhen Ouyang

    2012-01-01

    Full Text Available Background: Nao-De-Sheng decoction (NDS, a traditional Chinese medicine (TCM prescription containing Radix puerariae lobatae, Floscarthami, Radix et Rhizoma Notoginseng, Rhizoma chuanxiong and Fructus crataegi, is effective in the treatment of cerebral arteriosclerosis, ischemic cerebral stroke and apoplexy linger effect. Ferulic acid and puerarin are the main absorbed effective ingredients of NDS. Objective: To assess the affection of other components in medical material and compound recipe compatibility on the pharmacokinetics of ferulaic acid and puerarin, of ferulic acid from the monomer Rhizoma chuanxiong aqueous extract and NDS were studied. And pharmacokinetics comparisons of puerarin from the monomer Radix puerariae extract and NDS decoction were investigated simultaneously. Materials and Methods: At respective different time points after oral administration of the monomer, medicinal substance aqueous extract and NDS at the same dose in rats, plasma concentrations of ferulic acid and puerarin in rats were determined by RP-HPLC, and the main pharmacokinetic parameters were estimated with 3P97 software. Results: The plasma concentration-time curves of ferulaic acid and puerarin were both best fitted with a two-compartment model. AUC 0−t, AUC 0→∞ , Tmax , and Cmax of ferulic acid in the monomer and NDS decoction were increased significantly (P < 0.05 compared with that in Rhizoma chuanxiong aqueous extract. And statistically significant increase (P < 0.05 in pharmacokinetic parameters of puerarin including AUC 0−t, AUC 0→∞ , CL, Tmax and Cmax were obtained after oral administration of puerarin monomer compared with Radix puerariae extract. Although the changes of AUC 0−t, AUC 0→∞ and CL had no statistically significant, Cmax of puerarin in NDS was increased remarkably (P < 0.05 compared with that in single puerarin. Conclusions: Some ingredients of Rhizoma chuanxiong and Radix puerariae may be suggested to remarkably

  14. Plasma Cystatin C and High-Density Lipoprotein Are Important Biomarkers of Alzheimer’s Disease and Vascular Dementia: A Cross-Sectional Study

    Science.gov (United States)

    Wang, Rui; Chen, Zhaoyu; Fu, Yongmei; Wei, Xiaobo; Liao, Jinchi; Liu, Xu; He, Bingjun; Xu, Yunqi; Zou, Jing; Yang, Xiaoyan; Weng, Ruihui; Tan, Sheng; McElroy, Christopher; Jin, Kunlin; Wang, Qing

    2017-01-01

    Objectives: Cystatin C (Cys C) and high-density lipoprotein (HDL) play critical roles in neurodegenerative diseases, such as dementia, Alzheimer’s disease (AD) and vascular dementia (VaD). However, whether they can be used as reliable biomarkers to distinguish patients with dementia from healthy subjects and to determine disease severity remain largely unknown. Methods: We conducted a cross-sectional study to determine plasma Cys C and HDL levels of 88 patients with dementia (43 AD patients, 45 VaD patients) and 45 healthy age-matched controls. The severity of dementia was determined based on the Schwab and England Activities of Daily Living (ADL) Scale, the Mini-mental State Examination (MMSE), the Global Deterioration Scale (GDS), the Lawton Instrumental ADL (IADL) Scale, and the Hachinski Ischemia Scale (Hachinski). Receiver operating characteristic (ROC) curves were calculated to determine the diagnostic accuracy of Cys C and HDL levels in distinguishing patients with dementia from healthy subjects. Results: We found that plasma Cys C levels were higher, but HDL levels were lower in AD and VaD patients respectively, compared to healthy control subjects. Yet, Cys C levels were highest among patients with VaD. Interestingly, plasma Cys C levels were significantly correlated with IADL Scale scores. In addition, the ROC curves for Cys C (area under the curve, AUC 0.816 for AD, AUC 0.841 for VaD) and HDL (AUC 0.800 for AD, AUC 0.731 for VaD) exhibited potential diagnostic value in distinguishing AD/VaD patients from healthy subjects. While the ROC curve for the combination of Cys C and HDL (AUC 0.873 for AD, AUC 0.897 for VaD) showed higher diagnostic accuracy in distinguishing AD/VaD patients from healthy subjects than the separate curves for each parameter. Conclusions: Our findings suggest that the inflammatory mediators Cys C and HDL may play important roles in the pathogenesis of dementia, and plasma Cys C and HDL levels may be useful screening tools for

  15. Effects of contrast-enhancement, reconstruction slice thickness and convolution kernel on the diagnostic performance of radiomics signature in solitary pulmonary nodule

    Science.gov (United States)

    He, Lan; Huang, Yanqi; Ma, Zelan; Liang, Cuishan; Liang, Changhong; Liu, Zaiyi

    2016-01-01

    The Effects of contrast-enhancement, reconstruction slice thickness and convolution kernel on the diagnostic performance of radiomics signature in solitary pulmonary nodule (SPN) remains unclear. 240 patients with SPNs (malignant, n = 180; benign, n = 60) underwent non-contrast CT (NECT) and contrast-enhanced CT (CECT) which were reconstructed with different slice thickness and convolution kernel. 150 radiomics features were extracted separately from each set of CT and diagnostic performance of each feature were assessed. After feature selection and radiomics signature construction, diagnostic performance of radiomics signature for discriminating benign and malignant SPN was also assessed with respect to the discrimination and classification and compared with net reclassification improvement (NRI). Our results showed NECT-based radiomics signature demonstrated better discrimination and classification capability than CECT in both primary (AUC: 0.862 vs. 0.829, p = 0.032; NRI = 0.578) and validation cohort (AUC: 0.750 vs. 0.735, p = 0.014; NRI = 0.023). Thin-slice (1.25 mm) CT-based radiomics signature had better diagnostic performance than thick-slice CT (5 mm) in both primary (AUC: 0.862 vs. 0.785, p = 0.015; NRI = 0.867) and validation cohort (AUC: 0.750 vs. 0.725, p = 0.025; NRI = 0.467). Standard convolution kernel-based radiomics signature had better diagnostic performance than lung convolution kernel-based CT in both primary (AUC: 0.785 vs. 0.770, p = 0.015; NRI = 0.156) and validation cohort (AUC: 0.725 vs.0.686, p = 0.039; NRI = 0.467). Therefore, this study indicates that the contrast-enhancement, reconstruction slice thickness and convolution kernel can affect the diagnostic performance of radiomics signature in SPN, of which non-contrast, thin-slice and standard convolution kernel-based CT is more informative. PMID:27721474

  16. Pharmacokinetics and bioavailability study of two ondansetron oral soluble film formulations in fasting healthy male Chinese volunteers

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    Zhu YB

    2015-08-01

    Full Text Available Yubing Zhu,1 Qian Zhang,1 Jianjun Zou,2 Meng Wan,1 Zheng Zhao,1 Junrong Zhu1 1Department of Pharmacy, 2Laboratory of Clinical Pharmacology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China Background: Ondansetron oral soluble film is designed to be applied on top of the tongue without requiring water to aid dissolution or swallowing, which is especially fitting for nausea and vomiting patients.Purpose: This study was conducted to compare the bioavailability of two 8 mg ondansetron oral soluble film formulations.Patients and methods: This randomized, open-label, two-period crossover study was performed under fasting conditions. A total of ten eligible subjects were randomly assigned at a 1:1 ratio to receive a single 8 mg dose of the test and reference ondansetron oral soluble film formulations, followed by a 1-week washout period and administration of the alternate formulation. The concentrations of ondansetron were assayed using an liquid chromatograph-mass spectrometer/mass spectrometer (LC-MS/MS method. For analysis of pharmacokinetic properties, including the peak concentration of Tmax (Cmax, AUC from time 0 (baseline to t hours (AUC0–t, and AUC from baseline to infinity (AUC0–∞, blood samples were obtained at intervals over the 24-hour period after studying drug administration. Tolerability was assessed by monitoring vital signs and laboratory tests (hematology, blood biochemistry, hepatic function, and urinalysis and by questioning subjects about adverse events.Results: The mean (standard derivation [SD] relative bioavailability was 96.5 (23.7%. The 90% confidence intervals (CIs for the log-transformed ratios of Cmax and AUC0–t were 84.71%–103.28% and 91.38%–108.60%, respectively (P>0.05. Similar results were found for the data without log-transformation. No statistically significant differences were found based on analysis of variance. No significant adverse events occurred

  17. Quantum dots-based quantitative and in situ multiple imaging on ki67 and cytokeratin to improve ki67 assessment in breast cancer.

    Directory of Open Access Journals (Sweden)

    Jing Ping Yuan

    Full Text Available As a marker for tumor cell proliferation, Ki67 has important impacts on breast cancer (BC prognosis. Although immunohistochemical staining is the current standard method, variations in analytical practice make it difficult for pathologists to manually measure Ki67 index. This study was to develop a fluorescent spectrum-based quantitative analysis of Ki67 expression by quantum-dots (QDs multiple imaging technique.A QDs-based in situ multiple fluorescent imaging method was developed, which stained nuclear Ki67 as red signal and cytoplasmic cytokeratin (CK as green signal. Both Ki67 and CK signals were automatically separated and quantified by professional spectrum analysis software. This technique was applied to tissue microarrays from 240 BC patients. Both Ki67 and CK values, and Ki67/CK ratio were obtained for each patient, and their prognostic value on 5-year disease free survival was assessed.This method simultaneously stains nuclear Ki67 and cytoplasmic CK with clear signal contrast, making it easy for signal separation and quantification. The total fluorescent signal intensities of both Ki67 sum and CK sum were obtained, and Ki67/CK ratio calculated. Ki67 sum and Ki67/CK ratio were each attributed into two grades by X-tile software based on the best P value principle. Multivariate analysis showed Ki67 grade (P = 0.047 and Ki67/CK grade (P = 0.004 were independent prognostic factors. Furthermore, area under curve (AUC of ROC analysis for Ki67/CK grade (AUC: 0.683, 95%CI: 0.613-0.752 was higher than Ki67 grade (AUC: 0.665, 95%CI: 0.596-0.734 and HER-2 gene (AUC: 0.586, 95%CI: 0.510-0.661, but lower than N stage (AUC: 0.760, 95%CI: 0.696-0.823 and histological grade (AUC: 0.756, 95%CI: 0.692-0.820 on predicting the risk for recurrence.A QDs-based quantitative and in situ multiple imaging on Ki67 and CK was developed to improve Ki67 assessment in BC, and Ki67/CK grade had better performance than Ki67 grade in predicting prognosis.

  18. AKT1 G205T Genotype Influences Obesity-Related Metabolic Phenotypes and Their Responses to Aerobic Exercise Training in Older Caucasians

    Science.gov (United States)

    McKenzie, Jennifer A.; Witkowski, Sarah; Ludlow, Andrew T.; Roth, Stephen M.; Hagberg, James M.

    2010-01-01

    As part of the insulin signaling pathway, AKT influences growth and metabolism. The AKT1 gene G205T (rs1130214) polymorphism has potential functional effects. Thus, we determined whether the G205T polymorphism influences metabolic variables and their responses to aerobic exercise training. Following dietary stabilization, healthy, sedentary, 50-75 yr old Caucasian men (n = 51) and women (n = 58) underwent 6 months of aerobic exercise training. Before and after completing the intervention, dual-energy x-ray absorptiometry measured percent body fat, computed tomography measured visceral and subcutaneous fat, and oral glucose tolerance testing measured glucose total area under the curve (AUC), insulin AUC, and insulin sensitivity. Taqman assay determined AKT1 G205T genotypes. At baseline, men with the GG genotype (n = 29) had lower VO2max values (p = 0.026), and higher percent body fat (p = 0.046), subcutaneous fat (p = 0.021), and insulin AUC (p = 0.003) values than T allele carriers (n = 22). Despite their rather disadvantageous starting values, men with the GG genotype seemed to respond to exercise training more robustly than men with the T allele, highlighted by significantly greater fold change improvements in insulin AUC (p = 0.012) and glucose AUC (p = 0.035). Although the GG group also significantly improved VO2max with training, the change in VO2max was not as great as that of the T allele carriers (p = 0.037). In contrast, after accounting for hormone replacement therapy use, none of the variables differed in the women at baseline. As a result of exercise training, women with the T allele (n = 20) had greater fold change improvements in fasting glucose (p = 0.011), glucose AUC (p = 0.017), and insulin sensitivity (p = 0.044) than GG genotype women (n = 38). Our results suggest that the AKT1 G205T polymorphism influences metabolic variables and their responses to aerobic exercise training in older previously sedentary individuals. PMID:21097644

  19. A Phase 1, randomized, open-label crossover study to evaluate the safety and pharmacokinetics of 400 mg albaconazole administered to healthy participants as a tablet formulation versus a capsule formulation

    Directory of Open Access Journals (Sweden)

    van Rossem K

    2013-01-01

    Full Text Available Koen van Rossem,1 Jenny A Lowe21Stiefel, Research Triangle Park, NC, USA; 2Stiefel, Stockley Park West, Uxbridge, UKBackground: Albaconazole is a novel triazole being developed for the oral treatment of fungal diseases. Once-weekly oral dosing with 400 mg albaconazole for 24 or 36 weeks resulted in high rates of clinical and mycological resolution for distal subungual onychomycosis, as well as a favorable safety and tolerability profile.Purpose: To compare four 100-mg albaconazole capsules to one 400-mg albaconazole tablet for bioavailability, bioequivalence, tolerability, and safety.Patients and methods: Forty participants were enrolled in this Phase I, open-label, two-sequence crossover study. Twenty participants were exposed to a single 400-mg tablet dose of albaconazole before being crossed over to a single dose of four 100-mg albaconazole capsules. The second group of 20 participants received the study products in reverse order. Blood samples were taken over 15 days post-dose to assess the plasma concentrations and pharmacokinetic parameters of albaconazole and its primary metabolite, 6-hydroxyalbaconazole. Safety was assessed throughout the study.Results: The area under the curve (AUC and maximum measured plasma concentration (Cmax of the albaconazole tablet were approximately 10% and 22% lower, respectively, than for the albaconazole capsules. Statistical significance was reached for the Cmax but not for the AUC measurements (AUC0-t and AUC0-inf. Because the 90% confidence intervals based on the differences between the tablet and capsule were outside the 80%–125% range for both the Cmax and AUC, we concluded that the formulations were not bioequivalent with respect to the rate or extent of absorption. Both formulations were safe and well-tolerated in this study. All adverse events (AEs were generally mild and were mainly gastrointestinal- or nervous system-related (eg, dizziness, headache. No electrocardiogram findings were reported as

  20. Effects of contrast-enhancement, reconstruction slice thickness and convolution kernel on the diagnostic performance of radiomics signature in solitary pulmonary nodule.

    Science.gov (United States)

    He, Lan; Huang, Yanqi; Ma, Zelan; Liang, Cuishan; Liang, Changhong; Liu, Zaiyi

    2016-10-10

    The Effects of contrast-enhancement, reconstruction slice thickness and convolution kernel on the diagnostic performance of radiomics signature in solitary pulmonary nodule (SPN) remains unclear. 240 patients with SPNs (malignant, n = 180; benign, n = 60) underwent non-contrast CT (NECT) and contrast-enhanced CT (CECT) which were reconstructed with different slice thickness and convolution kernel. 150 radiomics features were extracted separately from each set of CT and diagnostic performance of each feature were assessed. After feature selection and radiomics signature construction, diagnostic performance of radiomics signature for discriminating benign and malignant SPN was also assessed with respect to the discrimination and classification and compared with net reclassification improvement (NRI). Our results showed NECT-based radiomics signature demonstrated better discrimination and classification capability than CECT in both primary (AUC: 0.862 vs. 0.829, p = 0.032; NRI = 0.578) and validation cohort (AUC: 0.750 vs. 0.735, p = 0.014; NRI = 0.023). Thin-slice (1.25 mm) CT-based radiomics signature had better diagnostic performance than thick-slice CT (5 mm) in both primary (AUC: 0.862 vs. 0.785, p = 0.015; NRI = 0.867) and validation cohort (AUC: 0.750 vs. 0.725, p = 0.025; NRI = 0.467). Standard convolution kernel-based radiomics signature had better diagnostic performance than lung convolution kernel-based CT in both primary (AUC: 0.785 vs. 0.770, p = 0.015; NRI = 0.156) and validation cohort (AUC: 0.725 vs.0.686, p = 0.039; NRI = 0.467). Therefore, this study indicates that the contrast-enhancement, reconstruction slice thickness and convolution kernel can affect the diagnostic performance of radiomics signature in SPN, of which non-contrast, thin-slice and standard convolution kernel-based CT is more informative.

  1. Salivary Cortisol and Cortisone do not Appear to be Useful Biomarkers for Monitoring Hydrocortisone Replacement in Addison's Disease.

    Science.gov (United States)

    Ross, I L; Lacerda, M; Pillay, T S; Blom, D J; Johannsson, G; Dave, J A; Levitt, N S; Haarburger, D; van der Walt, J-S

    2016-12-01

    Salivary cortisol has been used to monitor hydrocortisone replacement in patients with Addison's disease (AD). Since salivary cortisol is metabolised to salivary cortisone, it may be an adjunctive analyte to assess adequacy of hydrocortisone replacement in patients with AD. We aimed to characterise the exposure of salivary cortisol and cortisone in patients and healthy controls. We measured salivary cortisol and cortisone by liquid chromatography-tandem mass spectrometry and constructed a day curve (08:00 until 24:00 h) with 16 time points in 25 AD patients taking their usual hydrocortisone dose and in 26 healthy controls. The median (interquartile range) area under the curve (AUC) for cortisol was not different for patients, compared with controls [55.63 (32.91-151.07) nmol*min*l(-1) vs. 37.49 (27.41-52.00) nmol*min*l(-1); p=0.098, respectively], whereas the peak cortisol Cmax was higher in patients [32.61 (5.75-146.19) nmol/l vs. 8.96 (6.96-12.23) nmol/l; p=0.013], compared with controls. The AUC for cortisone [23.65 (6.10-54.76) nmol*min*l(-1) vs. 227.73 (200.10-280.52) nmol*min*l(-1); p≤ 0.001, respectively], and peak cortisone Cmax was lower in patients than in controls [11.11 (2.91-35.85) nmol/l vs. 33.12 (25.97-39.95) nmol/l; p=0.002]. The AUC for salivary cortisol and salivary cortisone were not correlated with any measures of hydrocortisone dose. The time-course and AUC of salivary cortisol were similar between Addison's patients and healthy controls. Patients had substantially lower salivary cortisone AUC, compared to healthy controls. Salivary cortisol AUC and pharmacokinetics were not related to hydrocortisone dose and thus are not likely useful markers for the adequacy of hydrocortisone replacement.

  2. AKT1 G205T genotype influences obesity-related metabolic phenotypes and their responses to aerobic exercise training in older Caucasians.

    Science.gov (United States)

    McKenzie, Jennifer A; Witkowski, Sarah; Ludlow, Andrew T; Roth, Stephen M; Hagberg, James M

    2011-03-01

    As part of the insulin signalling pathway, Akt influences growth and metabolism. The AKT1 gene G205T (rs1130214) polymorphism has potential functional effects. Thus, we determined whether the G205T polymorphism influences metabolic variables and their responses to aerobic exercise training. Following dietary stabilization, healthy, sedentary, 50- to 75-year-old Caucasian men (n = 51) and women (n = 58) underwent 6 months of aerobic exercise training. Before and after completing the intervention, dual-energy X-ray absorptiometry was used to measure percentage body fat, computed tomography to measure visceral and subcutaneous fat, and oral glucose tolerance testing to measure glucose total area under the curve (AUC), insulin AUC and insulin sensitivity. Taqman assay was used to determine AKT1 G205T genotypes. At baseline, men with the GG genotype (n = 29) had lower maximal oxygen consumption (VO2 max) values (P = 0.026) and higher percentage body fat (P = 0.046), subcutaneous fat (P = 0.021) and insulin AUC (P = 0.003) values than T allele carriers (n = 22). Despite their rather disadvantageous starting values, men with the GG genotype seemed to respond to exercise training more robustly than men with the T allele, highlighted by significantly greater fold change improvements in insulin AUC (P = 0.012) and glucose AUC (P = 0.035). Although the GG group also significantly improved VO2 max with training, the change in VO2 max was not as great as that of the T allele carriers (P = 0.037). In contrast, after accounting for hormone replacement therapy use, none of the variables differed in the women at baseline. As a result of exercise training, women with the T allele (n = 20) had greater fold change improvements in fasting glucose (P = 0.011), glucose AUC (P = 0.017) and insulin sensitivity (P = 0.044) than GG genotype women (n = 38). Our results suggest that the AKT1 G205T polymorphism influences metabolic variables and their responses to aerobic exercise training in

  3. Pharmacokinetic and bioequivalence studies of trospium chloride after a single-dose administration in healthy Chinese volunteers.

    Science.gov (United States)

    Zhang, R; Yuan, G; Li, R; Liu, X; Wei, C; Wang, B; Gao, H; Guo, R

    2012-05-01

    The study aimed to compare and evaluate the bioequivalence of a new generic preparation of trospium chloride (CAS NO:10405-02-4) capsule (20 mg, test) and the available import tablet (20 mg , reference) for the requirement of state regulatory criteria in China. A randomized- sequence, 2-period crossover study was conducted in 20 healthy Chinese male volunteers in the fasted state. Blood samples were collected before and 1, 2, 3, 4, 5, 6, 7, 8, 12, 24, 36, 48, 60 h after administration of a single oral dose of 40 mg trospium chloride capsules or tablets, followed by a 7-day washout period. The concentration of trospium chloride was determined by a LC-MS/MS method. Drug And Statistical-Version 2.0 was used to calculate the pharmacokinetics parameters and assess bioequivalence of the two preparations. It was considered bioequivalent if the 90% CIs of the mean ratios (test: reference) for Cmax, AUC0-t and AUC0-∞ were within the range from 80% to 125%, respectively. The main pharmacokinetics parameters of test and reference were as follows: t1/2 was (15.11 ± 3.24) h and (16.00 ± 3.96) h; Tmax was (4.0 ± 1.2) h and (4.1 ± 0.9) h; Cmax was (3.76 ± 1.87) ng·mL - 1 and (3.70 ± 1.89) ng·mL - 1; AUC0-t was (33.51 ± 14.39) ng·mL - 1·h and (33.33 ± 14.88) ng·mL - 1·h, and the AUC0-∞ was (35.20 ± 14.88) ng·mL - 1·h and (35.16±15.17) ng·mL - 1·h. The ratios (test: reference) for Cmax, AUC0-t, and AUC0-∞ were 94.0%~111.7%, 96.4%~106.8%, and 96.1%~105.3%, respectively. No significant differences in pharmacokinetic parameters were found between preparations and periods (p>0.05). No obvious adverse events were monitored throughout the study based on clinical parameters and patient reports.

  4. Cortical porosity not superior to conventional densitometry in identifying hemodialysis patients with fragility fracture

    Science.gov (United States)

    Patsch, Janina M.; Fischer, Lukas; Bojic, Marija; Winnicki, Wolfgang; Weber, Michael; Cejka, Daniel

    2017-01-01

    Hemodialysis (HD) patients face increased fracture risk, which is further associated with elevated risk of hospitalization and mortality. High-resolution peripheral computed tomography (HR-pQCT) has advanced our understanding of bone disease in chronic kidney disease by characterizing distinct changes in both the cortical and trabecular compartments. Increased cortical porosity (Ct.Po) has been shown to be associated with fracture in patients with osteopenia or in postmenopausal diabetic women. We tested whether the degree of Ct.Po identifies hemodialysis patients with prevalent fragility fractures in comparison to bone mineral density (BMD) assessed by dual X-ray absorptiometry (DXA). We performed a post-hoc analysis of a cross-sectional study in 76 prevalent hemodialysis patients. Markers of mineral metabolism, coronary calcification score, DXA-, and HR-pQCT-data were analyzed, and Ct.Po determined at radius and tibia. Ct.Po was significantly higher in patients with fracture but association was lost after adjusting for age and gender (tibia p = 0.228, radius p = 0.5). Instead, femoral (F) BMD neck area (p = 0.03), F T-score neck area (p = 0.03), radius (R) BMD (p = 0.03), R T-score (p = 0.03), and cortical HR-pQCT indices such as cortical area (Ct.Ar) (tibia: p = 0.01; radius: p = 0.02) and cortical thickness (Ct.Th) (tibia: p = 0.03; radius: p = 0.02) correctly classified patients with fragility fractures. Area under receiver operating characteristic curves (AUC) for Ct.Po (tibia AUC: 0.711; p = 0.01; radius AUC: 0.666; p = 0.04), Ct.Ar (tibia AUC: 0.832; p<0.001; radius AUC: 0.796; p<0.001), and F neck BMD (AUC: 0.758; p = 0.002) did not differ significantly among each other. In conclusion, measuring Ct.Po is not superior to BMD determined by DXA for identification of HD patients with fragility fracture. PMID:28199411

  5. Comparison of the pharmacokinetics, safety, and immunogenicity of MSB11022, a biosimilar of adalimumab, with Humira® in healthy subjects

    Science.gov (United States)

    Mant, Tim; Vlachos, Pantelis; Attkins, Neil; Ullmann, Martin; Roy, Sanjeev; Wagner, Volker

    2016-01-01

    Aims The aim of the study was to compare the pharmacokinetics (PK), safety and tolerability of the proposed adalimumab biosimilar MSB11022 (Merck) with Humira® (AbbVie), sourced from both the US (US reference product [US‐RP]) and Europe (European reference medicinal product [EU‐RMP]). Methods In this phase 1 double‐blind, parallel group trial (EMR200588‐001), 213 healthy volunteers were randomized 1 : 1 : 1 to receive a single dose (40 mg) of MSB11022, US‐RP or EU‐RMP in order to achieve 80% power assuming a 5% difference among groups and a 10% dropout rate. Following a preplanned blinded sample size re‐assessment after more than 50% of the originally planned subjects had been observed, the sample size was increased to 237 (79 per arm) to ensure 213 completers. Primary PK endpoints analyzed by non‐compartmental methods, were area under the curve (AUC) from time 0 extrapolated to infinity (AUC(0,∞)), maximum observed concentration (C max), and AUC from time 0 to the last quantifiable concentration (AUC(0,t last)). PK equivalence was declared if the 90% CI for the test : reference ratio lay within the 80–125% equivalence margin. Bioequivalence was demonstrated if all three PK parameters met the PK equivalence criteria. Safety and tolerability were also evaluated. Results Mean serum concentration–time profiles for the three treatments were similar. MSB11022 demonstrated PK equivalence to US‐RP and EU‐RMP for all primary endpoints. The geometric means of AUC(0,∞), C max and AUC(0,t last) following a single dose of MSB11022 were 2276.05 μg ml–1 h, 3.44 μg ml–1  and 1983.90 μg ml–1 h, respectively. Adverse events (AEs) were similar across all groups, with treatment‐emergent AEs (TEAEs) reported by 62.8%, 56.3% and 62.0% of subjects within the MSB11022, US‐RP and EU‐RMP groups, respectively. Most of the TEAEs were considered mild and unrelated to study drug. No deaths or severe AEs related to the study drug were

  6. Study on Bioequivalence of Dioxopromethazine Hydrochloride Granules in Healthy Volunteers%盐酸二氧丙嗪颗粒的人体生物等效性研究

    Institute of Scientific and Technical Information of China (English)

    胡国新; 陈冰冰; 杨代正; 胡卢丰; 黄成坷; 徐鹏; 代宗顺

    2007-01-01

    目的 研究盐酸二氧丙嗪颗粒的人体相对生物利用度.方法 健康志愿者18名,随机双交叉单剂量口服盐酸二氧丙嗪实验和参比制剂,用高效液相色谱法测定血浆中盐酸二氧丙嗪的浓度.用DAS程序计算相对生物利用度和评价生物等效性.AUC0-60,AUC0-inf和ρmax经方差分析和双单侧;检验,tmax进行秩和检验.结果 单剂量口服实验制剂和参比制剂后血浆中的盐酸二氧丙嗪的ρmax分别为(30.548±5.373)和(29.670±4.970)μg·L-1;tmax分别为(2.833±1.225)和(2.593±1.798)h;AUC0-60分别为(436.722±95.713)和(433.668±83.881)μg·h·L-1;AUC0-inf分别为(455.990±105.688)和(448.718±84.741)μg·h·L-1.ρmax,AUC0-60,AUC0-inf的90%可信区间分别为98.0%~107.9%,95.7%~105.0%,95.1%~107.0%.结论 试验制刑对参比制剂的人体相对生物利用度为(101.3±15.2)%,试验制剂和参比制荆具有生物等效性.

  7. Study on bioequivalance of aceclofenae enteric capsules and tablet in healthy volunteers%醋氯芬酸肠溶胶囊的人体生物等效性

    Institute of Scientific and Technical Information of China (English)

    朱华; 柳晓泉; 谈恒山; 许建国

    2009-01-01

    目的:用高效液相色谱法评价醋氯芬酸肠溶胶囊(试验品)与醋氯芬酸片(对照品)在人体内的生物等效性.方法:20名受试者单剂量交叉口服2种制剂,采用HPLC法测定血中醋氯芬酸的经时血浓度,计算2种制剂的药动学参数和生物利用度,并对主要药动学参数进行生物等效性考察.结果:20名受试者口服单剂量醋氧芬酸的主要药动学参数:试验品的tmax为(3.3±0.6)h,Cmax为(7.7±1.4)mg·L-1,AUC0-24为(25.4±4.7)mg·h·L-1,AUC0-∞为(27.0±4.8)mg·h·L-1;对照品的tmax为(1.6±0.9)h,Cmax为(8.0±1.5)mg·L-1,AUC0-24为(24.3±4.2)mg·h·L-1,AUC0-∞为(25.3±4.4)mg·h·L-1.醋氯芬酸肠溶胶囊的相对生物利用度为(104.4±12.8)%.对Cmax和AUC0-24的对数转换值进行方差分析和双单侧t检验以及90%置信区间的统计分析,结果Cmax和AUC0-24的90%置信区间符合生物等效性研究要求.结论:根据醋氯芬酸肠溶胶囊与醋氯芬酸片在人体内研究结果,确认这两种制剂为生物等效.

  8. Enantiomer-selective pharmacokinetics, oral bioavailability, and sex effects of various alpha-lipoic acid dosage forms.

    Science.gov (United States)

    Hermann, Robert; Mungo, Julius; Cnota, Peter Jürgen; Ziegler, Dan

    2014-01-01

    The present study aimed to examine the enantiomer-selective pharmacokinetics (PK), relative bioavailability (Frel), and sex effects of various oral dosage forms of racemic alpha-lipoic acid (ALA). In an open-label, randomized, four-period, four-sequence crossover study, 24 healthy adult subjects (12 males and 12 females) received single doses of 600 mg of ALA in fasted state at four different occasions as follows: three 200 mg tablets (T 200); two 300 mg tablets (T 300); one 600 mg tablet (T 600); and a racemic ALA solution (OS). All tablet formulations (Thioctacid HR) were considered test treatments, while the OS (Thioctacid, 600 T) served as the reference treatment. Serial blood samples were collected over 8 hours postdose to quantify R-(+)- and S-(-)-ALA enantiomer plasma concentrations for the PK evaluation. The maximum observed plasma concentration (Cmax) and total exposure (area under the curve [AUC]0-t) were compared between treatments by analysis of variance. Weight-normalized Cmax and the AUC data of male and female study subjects were applied to examine the presence of sex effects. All treatments displayed rapid absorption of both enantiomers with median time to maximum concentration (tmax) values ranging from 0.33-0.5 hours. The Frel of all tablet formulations was comparable, with R-(+)-enantiomer Cmax test/reference ratios ranging from 36% (T 600) to 43% (T 200), and R-(+)-enantiomer AUC test/reference ratios ranging from 64% (T 600) to 79% (T 300), indicating a favorable Frel of all tablet formulations, especially in terms of the total extent of absorption (AUC). An examination of weight-normalized female/male Cmax and AUC sex ratios for both ALA enantiomers indicated the absence of a significant sex effect for Cmax, as well as 20%-26% and 25%-32% higher R-(+)- and S-(-)-ALA enantiomer AUC outcomes in females when compared to males. The observed modest sex effect was comparable for both ALA enantiomers and across all formulations, and it did not appear

  9. Enantiomer-selective pharmacokinetics, oral bioavailability, and sex effects of various alpha-lipoic acid dosage forms

    Directory of Open Access Journals (Sweden)

    Hermann R

    2014-11-01

    Full Text Available Robert Hermann,1 Julius Mungo,2 Peter Jürgen Cnota,2 Dan Ziegler3 1Clinical Research Appliance (cr appliance, Gelnhausen, Germany; 2MEDA Pharma GmbH & Co KG, Bad Homburg, Germany; 3Institute for Clinical Diabetology, German Diabetes Center, Heinrich Heine University, Düsseldorf, Germany Abstract: The present study aimed to examine the enantiomer-selective pharmacokinetics (PK, relative bioavailability (Frel, and sex effects of various oral dosage forms of racemic alpha-lipoic acid (ALA. In an open-label, randomized, four-period, four-sequence crossover study, 24 healthy adult subjects (12 males and 12 females received single doses of 600 mg of ALA in fasted state at four different occasions as follows: three 200 mg tablets (T 200; two 300 mg tablets (T 300; one 600 mg tablet (T 600; and a racemic ALA solution (OS. All tablet formulations (Thioctacid HR were considered test treatments, while the OS (Thioctacid, 600 T served as the reference treatment. Serial blood samples were collected over 8 hours postdose to quantify R-(+- and S-(–-ALA enantiomer plasma concentrations for the PK evaluation. The maximum observed plasma concentration (Cmax and total exposure (area under the curve [AUC]0–t were compared between treatments by analysis of variance. Weight-normalized Cmax and the AUC data of male and female study subjects were applied to examine the presence of sex effects. All treatments displayed rapid absorption of both enantiomers with median time to maximum concentration (tmax values ranging from 0.33–0.5 hours. The Frel of all tablet formulations was comparable, with R-(+-enantiomer Cmax test/reference ratios ranging from 36% (T 600 to 43% (T 200, and R-(+-enantiomer AUC test/reference ratios ranging from 64% (T 600 to 79% (T 300, indicating a favorable Frel of all tablet formulations, especially in terms of the total extent of absorption (AUC. An examination of weight-normalized female/male Cmax and AUC sex ratios for both ALA

  10. 超声造影对肝细胞癌与肝局灶性结节增生的定量对比分析%Quantification analysis of contrast enhanced ultrasonography on hepatocellular carcinoma and focal nodular hyperplasia

    Institute of Scientific and Technical Information of China (English)

    黄莺; 杜雅灵

    2012-01-01

    Objective To investigate the value of quantification analysis of contrast enhanced ultrasonography (CEUS)in differential diagnosis of hepatocellular carcinoma(HCC)and focal nodular hyperplasia(FNH). Methods 64 HCCs and 21 FNHs were off-line analyzed with dynamic images. Quantitative parameters such as derived peak intensity (DPI), time to peak(TTP), area under the curve(AUC), slop of rise, the absolute vslue for slop of down were acquired , and the standardized values (sDPI, sAUC) included the ratio of parameters from the focus to those from hepatic parenchyma. These quantitative parameters were analyzed by statistics. Results Quantitative parameters such as AUC, slop of rise, sDPI and sAUC in HCC group were smaller than those in FNH group(P0. 05). Conclusion TIC of contrast enhanced ultrasonography can provide quantitative analysis for HCC and FNH with preferable clinical application value.%目的 探讨超声造影(CEUS)对肝细胞癌(HCC)与肝局灶性结节增生(FNH)的声学定量对比价值.方法 回顾性分析64例HCC和21例FNH患者,对其CEUS检查结果进行定量分析,从时间-强度曲线(TIC)上得到下列定量参数:达峰绝对值(DPI)、达峰时间(TTP)、曲线下面积(AUC)、曲线上升支斜率、下降支斜率的绝对值以及病灶与肝实质相应参数相比所得的标化值sDPI、sAUC,进行统计学分析.结果 HCC组的AUC、曲线上升支斜率、sDPI及sAUC分别均小于FNH组(P<0.05),而TTP、曲线下降支斜率的绝对值大于FNH组(P<0.05),两组的DPI无显著差异(P>0.05).结论 超声造影技术结合时间-强度曲线定量分析对HCC和FNH的鉴别诊断有重要的临床应用价值.

  11. New Insights in Abdominal Pain in Paroxysmal Nocturnal Hemoglobinuria (PNH: A MRI Study.

    Directory of Open Access Journals (Sweden)

    Francesco De Cobelli

    Full Text Available Abdominal pain in PNH has never been investigated by in-vivo imaging studies. With MRI, we aimed to assess mesenteric vessels flow and small bowel wall perfusion to investigate the ischemic origin of abdominal pain.Six PNH patients with (AP and six without (NOP abdominal pain underwent MRI. In a blinded fashion, mean flow (MF, quantity of blood moving through a vessel within a second, in mL·s-1 and stroke volume (SV, volume of blood pumped out at each heart contraction, in mL of Superior Mesenteric Vein (SMV and Artery (SMA, areas under the curve at 60 (AUC60 and 90 seconds (AUC90 and Ktrans were assessed by two operators.Mean total perfusion and flow parameters were lower in AP than in NOP group. AUC60: 84.81 ± 11.75 vs. 131.73 ± 18.89 (P < 0.001; AUC90: 102.33 ± 14.16 vs. 152.58 ± 22.70 (P < 0.001; Ktrans: 0.0346 min-1 ± 0.0019 vs. 0.0521 ± 0.0015 (P = 0.093 duodenum, 0.009 jejunum/ileum. SMV: MF 4.67 ml/s ± 0.85 vs. 8.32 ± 2.14 (P = 0.002; SV 3.85 ml ± 0.76 vs. 6.55 ± 1.57 (P = 0.02. SMA: MF 6.95 ± 2.61 vs. 11.2 ± 2.32 (P = 0.07; SV 6.52 ± 2.19 vs. 8.78 ± 1.63 (P = 0.07. We found a significant correlation between MF and SV of SMV and AUC60 (MF:ρ = 0.88, P < 0.001; SV: ρ = 0.644, P = 0.024, AUC90 (MF: ρ = 0.874, P < 0.001; SV:ρ = 0.774, P = 0.003 and Ktrans (MF:ρ = 0.734, P = 0.007; SV:ρ = 0.581, P = 0.047.Perfusion and flow MRI findings suggest that the impairment of small bowel blood supply is significantly associated with abdominal pain in PNH.

  12. Pharmacokinetics and bioequivalence of self-assembly nanocapsules loaded with asparaginase%载天冬酰胺酶自组装纳米囊的药动学及生物等效性

    Institute of Scientific and Technical Information of China (English)

    谢江川; 胡雪原; 晏子俊; 周云莉; 张景勍

    2016-01-01

    目的 研究载天冬酰胺酶(Asp)自组装透明质酸-聚乙二醇(HA-g-PEG)/二甲基-β环糊精(DCD)纳米囊(AHDPs)在雄性SD大鼠体内的药代动力学和生物等效性.方法 考察了AHDPs的透射电镜、粒径、zeta电位、包封率,并分别测定大鼠静脉给予AHDPs和游离Asp后,不同时间点大鼠血浆样品中Asp的活性.采用DAS 2.1.1软件计算药动学参数,对AHDPs和游离Asp进行生物等效性评价.结果 AHDPs的平均粒径为(439.63±8.49) nm,zeta电位为(-20.43±2.20) mV,平均包封率为(55.75±4.11)%(n=3).AHDPs和游离Asp的主要药动学参数AUC0-48h分别为(138.93±0.89)U· mL-1·h和(46.38±1.98) U· mL-1·h,AUC0-∞分别为(175.22±13.59)U·mL-1·h和(51.44±3.01)U·mL-1·h,t1/2分别为(4.46±1.04)h和(1.86±0.38)h.与游离Asp比较,AHDPs的AUC0-48 h、AUC0-∞和t1/2分别提高至约游离ASP的3.00、3.40和2.40倍.AUC0-48 h、AUC0-∞和Cmax的90%置信区间分别为76.9%~78.3%、76.9%~78.3%、92.8%~94.4%.结论 AHDPs延长了Asp在大鼠体内的生物半衰期,提高了Asp在大鼠体内的生物利用度,且AHDPs与游离Asp不具有生物等效性.

  13. Wearable Sensor-Based In-Home Assessment of Gait, Balance, and Physical Activity for Discrimination of Frailty Status: Baseline Results of the Arizona Frailty Cohort Study

    Science.gov (United States)

    Schwenk, Michael; Mohler, Jane; Wendel, Christopher; D’Huyvetter, Karen; Fain, Mindy; Taylor-Piliae, Ruth; Najafi, Bijan

    2015-01-01

    BACKGROUND Frailty is a geriatric syndrome resulting from age-related cumulative decline across multiple physiologic systems, impaired homeostatic reserve, and reduced capacity to resist stress. Based on recent estimates, 10% of community-dwelling older persons are frail and another 41.6% are pre-frail. Frail elders account for the highest healthcare costs in industrialized nations. Impaired physical function is a major indicator of frailty and functional performance tests are useful for identification of frailty. Objective instrumented assessments of physical functioning that are feasible for home frailty screening have not been adequately developed. OBJECTIVE To examine the ability of wearable, sensor-based, in-home assessment of gait, balance, and physical activity (PA) to discriminate between frailty levels (non-frail, pre-frail, frail). METHODS In an observational cross-sectional study; in-home visits were completed in 125 older adults (non-frail n=44, pre-frail n=60, frail n=21) in Tucson, Arizona between September, 2012 and November, 2013. Temporal-spatial gait parameters (speed, stride length, stride time, double support, variability of stride velocity), postural balance (sway of hip, ankle, center of mass), and PA (percentage of walking, standing, sitting, lying; mean duration and variability of single walking, standing, sitting, and lying bouts) were measured in the participant’s home using validated wearable sensor-technology. Logistic regression was used to identify the most sensitive gait, balance, and PA variables for identifying pre-frail participants (vs. non-frail). Multinomial logistic regression was used to identify variables sensitive to discriminate three frailty levels. RESULTS Gait speed (area under the curve, AUC= .802), hip sway (AUC= .734), and steps/day (AUC= .736) were the most sensitive parameters for identification of pre-frailty. Multinomial regression revealed that stride length (AUC= .857) and double support (AUC= .841) were most

  14. Usefulness of the Waist Circumference-to-Height Ratio in Screening for Obesity and Metabolic Syndrome among Korean Children and Adolescents: Korea National Health and Nutrition Examination Survey, 2010-2014.

    Science.gov (United States)

    Choi, Dong-Hyun; Hur, Yang-Im; Kang, Jae-Heon; Kim, Kyoungwoo; Cho, Young Gyu; Hong, Soo-Min; Cho, Eun Byul

    2017-03-10

    The aims of this study were to assess the diagnostic value of the weight-to-height ratio (WHtR) for the detection of obesity and metabolic syndrome (MS) in Korean children and adolescents, and to determine the advantages of WHtR as a population-based screening tool in comparison with other obesity indicators, such as body mass index (BMI) and waist circumference (WC). We performed a cross-sectional analysis of data from 3057 children and adolescents (1625 boys, 1332 girls) aged 10-19 years who were included in the fifth Korean National Health and Nutrition Examination Survey (KNHANES, 2010-2012) up to the second year of the sixth KNHANES (2013-2014). Receiver operation characteristic (ROC) curves were generated to determine the optimal cutoff value and accuracy of WHtR for predicting individual obesity indicators or more than two non-WC components of MS. The area under the ROC curve (AUC) is a measure of the diagnostic power of a test. A perfect test will have an AUC of 1.0, and an AUC equal to 0.5 means that the test performs no better than chance. The optimal WHtR cutoff for the evaluation of general obesity and central obesity was 0.50 in boys and 0.47-0.48 in girls, and the AUC was 0.9. Regarding the assessment of each MS risk factor, the optimal WHtR cutoff was 0.43-0.50 in boys and 0.43-0.49 in girls, and these cutoffs were statistically significant only for the detection of high triglyceride and low High-density lipoprotein (HDL) cholesterol levels. When a pairwise comparison of the AUCs was conducted between WHtR and BMI/WC percentiles to quantify the differences in power for MS screening, the WHtR AUC values (boys, 0.691; girls, 0.684) were higher than those of other indices; however, these differences were not statistically significant (boys, p = 0.467; girls, p = 0.51). The WHtR cutoff value was 0.44 (sensitivity, 67.7%; specificity, 64.6%) for boys and 0.43 (sensitivity, 66.4%; specificity, 66.9%) for girls. There was no significant difference between

  15. Usefulness of the Waist Circumference-to-Height Ratio in Screening for Obesity and Metabolic Syndrome among Korean Children and Adolescents: Korea National Health and Nutrition Examination Survey, 2010–2014

    Science.gov (United States)

    Choi, Dong-Hyun; Hur, Yang-Im; Kang, Jae-Heon; Kim, Kyoungwoo; Cho, Young Gyu; Hong, Soo-Min; Cho, Eun Byul

    2017-01-01

    The aims of this study were to assess the diagnostic value of the weight-to-height ratio (WHtR) for the detection of obesity and metabolic syndrome (MS) in Korean children and adolescents, and to determine the advantages of WHtR as a population-based screening tool in comparison with other obesity indicators, such as body mass index (BMI) and waist circumference (WC). We performed a cross-sectional analysis of data from 3057 children and adolescents (1625 boys, 1332 girls) aged 10–19 years who were included in the fifth Korean National Health and Nutrition Examination Survey (KNHANES, 2010–2012) up to the second year of the sixth KNHANES (2013–2014). Receiver operation characteristic (ROC) curves were generated to determine the optimal cutoff value and accuracy of WHtR for predicting individual obesity indicators or more than two non-WC components of MS. The area under the ROC curve (AUC) is a measure of the diagnostic power of a test. A perfect test will have an AUC of 1.0, and an AUC equal to 0.5 means that the test performs no better than chance. The optimal WHtR cutoff for the evaluation of general obesity and central obesity was 0.50 in boys and 0.47–0.48 in girls, and the AUC was 0.9. Regarding the assessment of each MS risk factor, the optimal WHtR cutoff was 0.43–0.50 in boys and 0.43–0.49 in girls, and these cutoffs were statistically significant only for the detection of high triglyceride and low High-density lipoprotein (HDL) cholesterol levels. When a pairwise comparison of the AUCs was conducted between WHtR and BMI/WC percentiles to quantify the differences in power for MS screening, the WHtR AUC values (boys, 0.691; girls, 0.684) were higher than those of other indices; however, these differences were not statistically significant (boys, p = 0.467; girls, p = 0.51). The WHtR cutoff value was 0.44 (sensitivity, 67.7%; specificity, 64.6%) for boys and 0.43 (sensitivity, 66.4%; specificity, 66.9%) for girls. There was no significant

  16. Study on bioequivalence of domestic Itraconazole capsules before or after diet%空腹或餐后服用国产伊曲康唑胶囊的人体生物等效性研究

    Institute of Scientific and Technical Information of China (English)

    黄洁; 阳国平; 项玉霞; 杨柳; 谭鸿毅; 杨双

    2013-01-01

    目的:评价健康男性志愿者空腹或餐后单次口服国产伊曲康唑胶囊与进口伊曲康唑胶囊(商品名为斯皮仁诺胶囊)的生物等效性.方法:本研究包括两个随机、开放、双周期、单次口服给药试验,各入组24名健康中国男性受试者,分别在空腹和餐后服用200 mg试验制剂和200 mg参比制剂后,采用HPLC-MS/MS方法测定给药后伊曲康唑的血药浓度.计算主要药动学参数,分别对两种制剂的空腹或餐后给药进行生物等效性评价.结果:空腹给药试验制剂与参比制剂的主要药动学参数为.Cmax为(124±79)和(124±86) μg/L;tmax为(2.9±0.8)和(2.5±0.9)h;AUC0-t为 (1320±826) 和(1348±1095) μg·h·L-1; AUC0-∞为(1420±902)和(1444±1148) μg·h·L-1;AUC0-t/AUC0∞为(93.0±4.9)和(92.3±5.1)%;t1/2为(17.7±4.7)和(18.1±2.8)h.空腹给药试验制剂的相对生物利用度F为(106.5±35.4)%.餐后给药试验制剂和参比制剂的主要药动学参数为:Cmax为(202±107)和(218±109) μg/L;tmax为(4.2±0.8)和(3.9±0.8) h;AUC0-t为(2494±1163)和(2657±1424) μg·h·L-1;AUC0-∞为(2705±1290)和(2870±1578) μg·h·L-1;AUC0-t/AUC0∞为(92.3±5.2)和(93.6±4.1)%;t1/2为(19.3±5.5)和(18.0±5.1)h.餐后给药试验制剂的相对生物利用度F为(100.5±33.1)%.结论:两种制剂在空腹给药和餐后给药时都具有生物等效性.餐后给药组Cmax和AUC均明显高于空腹给药组,建议临床使用餐后服用药物,以提高药物的生物利用度,增强疗效.%AIM:To study the bioequivalence of domestic Itraconazole capsules in healthy Chinese volunteers before diet or after diet respectively.METHODS:There were two randomized,open-label,two-period clinical studies,and 24 healthy Chinese male volunteers were enrolled in each study.All the volunteers in each study had taken a single dose of 200 mg Itraconazole test capsules and 200 mg of its reference.The plasma Itraconazole concentration were determined by HPLC-MS/MS.The major

  17. Pharmacokinetics on tramadol/acetaminophen combination tablets in Chinese healthy volunteers%曲马氨酚片的人体药物动力学研究

    Institute of Scientific and Technical Information of China (English)

    戴维; 梁建英

    2009-01-01

    To stury the pharmacokinetie of tramadol and aeetaminophen in healthy volunteers. Methods Totally 20 healthy adult male volunteers participated in the study were randomly assigned to 2 treatment groups and were given respectively the dose of one and two pills by oral administration. Serum was separated and the concentrations of tramadol and acetaminophen in human serum were determined by HPLC using fluorescence and UV detector. The values of concentration were directly detected, and AUC was calculated by linear trapezoid method. Results The main pharmacokinetie parameters of tramadol and acetaminophen of 2 dosages groups were as follow: Tramadol: AUC_(0-24h)(ng · h· mL~(-1)) were 2 724. 89 ± 1 016.54 and 1 361.61 + 441. 79; AUC_(0-∞)(ng·h·mL~(-1)) were3 065.49±1 190.66 and 1 555.04±582.51; t_(max)(h) were 1.8±0.75 and 1.9±0.57; t_(t/2)(h) were 7.34±1.39and7.63±2.02; Kel(h~(-1)) were 0. 098±0. 019 and 0. 097± 0.027; Cl_r(mL · min~(-1)) were 31.84±13.65 and 30.03 ± 9.20; MRT(h) were 7.62 ± 1.07 and 7.77 ± 0.75. Acetaminophen. AUC_(0-24h)(μg · h · mL~(-1)) were 40.28 ± 10.36 and 18.37 ± 3.84 ; AUC_(0-∞)(μg · h · mL~(-1)) were 41.63 ± 10. 96 and 18. 81 ± 4.06; t_(max)(h) were 0. 9 ± 0.46 and 0. 9 ± 0. 39; t_(t/2)(h) were5.39 ± 1. 16 and 4. 96 ± 1.03; Kel(h~(-1)) were 0. 13 ± 0. 03 and 0. 15 ± 0. 03; Clr (mL · min~(-1)) were 17.17 ± 4.57 and 18.42 ± 3.89; MRT(h) were 4.86 ± 0.48 and 4.50 ± 0.53. Conclusions No significant difference in pharmacokinetic parameters, such as t_(max), t_(t/2), Ke,Cl, MRT,AUC_(0-t)/dose, AUC_(0-∞)/dose and C_(max)/dose are shown between these two dose groups and a linear pharmacokinetic is featured.%目的 测定曲马氨酚片中曲马多和对乙酰氨基酚的药动学参数.方法 采用高效液相色谱法分别测定20名健康志愿者口服曲马氨酚片(2个剂量组:1片和2片,每组10名)后血清中的药物浓度,进行药动学分析.结果 2组健康志愿者口服曲马氨酚片

  18. DPOAEs in infants developmentally exposed to PCBs show two differently time spaced exposure sensitive windows.

    Science.gov (United States)

    Koštiaková, Vladimíra; Moleti, Arturo; Wimmerová, Soňa; Jusko, Todd A; Palkovičová Murínová, Ľubica; Sisto, Renata; Richterová, Denisa; Kováč, Ján; Čonka, Kamil; Patayová, Henrieta; Tihányi, Juraj; Trnovec, Tomáš

    2016-10-01

    The study aim was to identify the timing of sensitive windows for ototoxicity related to perinatal exposure to PCBs. A total of 351 and 214 children from a birth cohort in eastern Slovakia underwent otoacoustic testing at 45 and 72 months, respectively, and distortion product otoacoustic emissions (DPOAEs) at 11 frequencies were recorded. Cord and child 6-, 16-, 45-, and 72- month blood samples were analyzed for PCB 153 concentration. The PCB 153 concentration-time profiles were approximated with a system model to calculate area under the PCB*time curves (AUCs) for specific time intervals (3 and 6 months for 45 and 72 months data, respectively). DPOAE amplitudes were correlated (Spearman) with cord serum PCB and AUCs, markers of prenatal and postnatal exposure, respectively. Two exposure critical windows were identified in infants, the first related to prenatal and early postnatal and the second to postnatal exposure to PCBs. Our data have shown tonotopicity, sexual dimorphism, and asymmetry in ototoxicity of PCBs.

  19. L-Arginine Pathway in COPD Patients with Acute Exacerbation

    DEFF Research Database (Denmark)

    Ruzsics, Istvan; Nagy, Lajos; Keki, Sandor

    2016-01-01

    (ADMA, SDMA) is related to hypoxia. In COPD, a rise in ADMA results in a shift of L-arginine breakdown, contributing to airway obstruction. We aimed to compare serum levels of ADMA, SDMA and L-arginine in patients with and without AECOPD. METHODS: L-arginine metabolites quantified by high......-performance liquid chromatography in venous blood samples and partial capillary oxygen pressure were prospectively investigated in 32 patients with COPD, 12 with AECOPD and 30 healthy subjects. RESULTS: Both ADMA and SDMA were significantly higher in AECOPD compared to stable COPD (p = 0.004 and p ....001, respectively). Oxygen content in capillaries correlated with serum ADMA concentration. However, the concentration of L-arginine was not different between AECOPD and stable COPD. Both ADMA and SDMA separated AECOPD with high sensitivity and specificity (AUC: 0.81, p = 0.001; AUC: 0.91, p

  20. Postprandial diabetic glucose tolerance is normalized by gastric bypass feeding as opposed to gastric feeding and is associated with exaggerated GLP-1 secretion: a case report

    DEFF Research Database (Denmark)

    Dirksen, Carsten; Hansen, Dorte L; Madsbad, Sten;

    2010-01-01

    OBJECTIVE: To examine after gastric bypass the effect of peroral versus gastroduodenal feeding on glucose metabolism. RESEARCH DESIGN AND METHODS: A type 2 diabetic patient was examined on 2 consecutive days 5 weeks after gastric bypass. A standard liquid meal was given on the first day...... into the bypassed gastric remnant and on the second day perorally. Plasma glucose, insulin, C-peptide, glucagon, incretin hormones, peptide YY, and free fatty acids were measured. RESULTS: Peroral feeding reduced 2-h postprandial plasma glucose (7.8 vs. 11.1 mmol/l) and incremental area under the glucose curve (i......AUC) (0.33 vs. 0.49 mmol . l(-1) . min(-1)) compared with gastroduodenal feeding. beta-Cell function (iAUC(Cpeptide/Glu)) was more than twofold improved during peroral feeding, and the glucagon-like peptide (GLP)-1 response increased nearly fivefold. CONCLUSIONS: Improvement in postprandial glucose...

  1. A comparative bioavailability study of two ibuprofen formulations after single-dose administration in healthy volunteers

    Directory of Open Access Journals (Sweden)

    Metta S.S. Wiria

    2007-09-01

    Full Text Available This study was aimed to investigate the bioequivalence of ibuprofen 125 mg suppository formulation (Ibukal®, test formulation from PT. Kalbe Farma, Tbk., Jakarta and the ibuprofen suppository comparative formulation (Proris®, from PT. Pharos Indonesia, Jakarta in 12 healthy volunteers. The pharmacokinetic parameters used in this study were the area under the concentration-time curve from time zero to hour 10 (AUC0-t, the area under the concentration-time curve from time zero to infinite (AUC0-inf, the maximum concentration (Cmax, and the time needed to reach the maximum concentration (tmax. The study was designed as a random cross-over fashion, single-blinded which included 12 healthy adult volunteers. The volunteers were fasted overnight and in the morning they received a suppository of the test drug (Ibukal® or a suppository of the comparative drug (Proris®. Blood samples were withdrawn on hour 0 (control, 20 min; 40 min; 1; 1.5; 2; 2.5; 3; 4; 6; 8; and 10 time points after the administration of the drug. Following a wash-out period of 1 week, this procedure was repeated using the other drug. The serum concentration of the drug was determined by means of high-performance liquid chromatography with ultraviolet detection. The results of the study showed that, the mean (SD of AUC0-t, AUC0-inf, Cmax and tmax of the test drug were, respectively, 28.59(3.37 μg.h.mL-1, 30.47(3.56 μg.h.mL-1, 8.24(1.44 μg/mL, and 1.33(0.44 h. The mean (SD of AUC0-t, AUC0-inf, Cmax and tmax of the comparative drug were, respectively, 28.13(8.14 μg.h.mL-1, 30.56(8.05 μg.h.mL-1, 8.27(2.88 μg/mL, and 1.79(0.33 h. The geometric means ratio of the test to the comparative drug were 104.38% (CI 90%: 90.38-120.54% for AUC0-t, 101.97% (CI 90%: 89.51-116.16% for AUC0-inf, and 104.02% (CI 90%: 85.73-126.16% for Cmax. There was no side effect of the drug detected in this study. From the results we can conclude that the 125 mg of ibuprofen suppository of PT Kalbe Farma

  2. An individual bioequivalence approach to compare the intrasubject variability of two ciclosporin formulations, SangCya and Neoral.

    Science.gov (United States)

    Canafax, D M; Irish, W D; Moran, H B; Squiers, E; Levy, R; Pouletty, P; First, M R; Christians, U

    1999-08-01

    A novel bioequivalence testing approach was used to determine intrasubject variability and switchability of two ciclosporin formulations, SangCya (test) and Neoral (reference). Twenty healthy volunteers were enrolled into a single-dose, randomized, open-label, 4-period, 2-sequence study with a crossover replicate design. Subject-by-formulation interaction variances were compared using a mixed effects linear model. Intrasubject variability for ln AUC(0-infinity) and ln C(max) of SangCya and Neoral were not significantly different. The 95% confidence intervals of the intrasubject variability of AUC(0-infinity) (0.94) and C(max) (1.28) as determined using the bootstrap nonparametric percentile method (n = 2,000) were below the individual bioequivalence limit estimated at 2.25. We concluded equivalent intrasubject variability of ciclosporin pharmacokinetics and switchability between SangCya and Neoral.

  3. Apparent diffusion coefficient ratio correlates significantly with prostate cancer gleason score at final pathology

    DEFF Research Database (Denmark)

    Boesen, Lars; Chabanova, Elizaveta; Løgager, Vibeke;

    2015-01-01

    PURPOSE: To evaluate the correlation between apparent diffusion coefficient measurements (ADCtumor and ADCratio ) and the Gleason score from radical prostatectomy specimens. MATERIALS AND METHODS: Seventy-one patients with clinically localized prostate cancer scheduled for radical prostatectomy...... correlated with the Gleason score from the prostatectomy specimens. RESULTS: The association between ADC measurements and Gleason score showed a significant negative correlation (P ... between ADC measurements and the Gleason score for all tumors (P = 0.001). Receiver operating characteristic curve analysis showed an overall area under the curve (AUC) of 0.73 (ADCtumor ) to 0.80 (ADCratio ) in discriminating Gleason score 6 from Gleason score ≥7 tumors. The AUC changed to 0.72 (ADCtumor...

  4. A predictive tool to estimate the risk of axillary metastases in breast cancer patients with negative axillary ultrasound

    DEFF Research Database (Denmark)

    Meretoja, T J; Heikkilä, P S; Mansfield, A S;

    2014-01-01

    risk factors for axillary metastases. Binary logistic regression analysis was conducted to form a predictive model based on the risk factors. The predictive model was first validated internally in a patient series of 566 further patients and then externally in a patient series of 2,463 patients from...... of this study was to evaluate the risk factors for axillary metastases in breast cancer patients with negative preoperative axillary ultrasound. METHODS: A total of 1,395 consecutive patients with invasive breast cancer and SNB formed the original patient series. A univariate analysis was conducted to assess...... of the primary tumor (P predictive model. Internal validation of the model produced an area under the receiver operating characteristics curve (AUC) of 0.731 and external validation an AUC of 0.79. CONCLUSIONS: We present a predictive model to assess the patient-specific probability...

  5. Procesos de desmovilización de las Autodefensas Unidas de Colombia y el Frente Farabundo Martí para la Liberación Nacional en el marco de la Ley de Justicia y Paz en Colombia y los Acuerdos de Paz de Chapultepec en El Salvador.

    Directory of Open Access Journals (Sweden)

    María Fernanda Molina Álvarez

    2016-01-01

    Full Text Available Este trabajo establece una comparación entre los procesos de reinserción de los desmovilizados de las Autodefensas Unidas de Colombia (AUC en Colombia durante el 2006 y el Frente Farabundo Martí para la Liberación Nacional (FMLN en El Salvador en 1992. Desde el enfoque histórico- hermenéutico, se realizó un análisis de las investigaciones empíricas y de los informes académicos, estatales y de organizaciones internacionales. Hay una concurrencia entre los artículos científicos y los informes hallados con respecto al gran alcance de la violencia política y la implementación de estrategias por parte de las AUC y el FMLN. Sin embargo, existen diferencias relevantes entre ambos procesos de cara al escenario del postconflicto.

  6. MicroRNA-223 and miR-143 are important systemic biomarkers for disease activity in psoriasis

    DEFF Research Database (Denmark)

    Løvendorf, Marianne B; Zibert, John R; Gyldenløve, Mette;

    2014-01-01

    including miR-223 and miR-143 which were found to be significantly upregulated in the PBMCs from patients with psoriasis compared with healthy controls (FCH=1.63, PmiR-223 and miR-143 significantly correlated with the PASIscore (r=0.46, P...miR-223 and -143 have the potential to distinguish between psoriasis and healthy controls (miR-223: area under the curve (AUC)=0.80, miR-143: AUC=0.75). Interestingly, after 3-5 weeks of treatment with methotrexate...... following a significant decrease in psoriasis severity, miR-223 and miR-143 were significantly downregulated in the PBMCs from patients with psoriasis. CONCLUSION: We suggest that changes in the miR-223 and miR-143 expressions in PBMCs from patients with psoriasis may serve as novel biomarkers for disease...

  7. The trigonometric responder approach: a new method for detecting responders to pharmacological or experimental challenges.

    Science.gov (United States)

    Reuter, M; Siegmund, A; Netter, P

    2002-09-01

    The paper presents a newly developed response measure that is particularly suitable for the evaluation of pharmacokinetic data. This method is based on trigonometric considerations, defining a hormone response as the difference between the angle of the slope of the curve before and after drug intake. In addition, the size of this difference is compared to the difference obtained in placebo conditions. In this way, the trigonometric response measure overcomes one of the most problematic shortcomings of the 'area under the curve' (AUC) approach, the problem of the initial value. We will present the mathematical background of the trigonometric method and demonstrate its usefulness by evaluating empirical data (a pharmacological challenge test using the dopamine agonist lisuride) and comparing it to classical AUC measures. This has been achieved by contrasting both approaches with responder definitions according to binary time series analysis and the peak value of the curve.

  8. Relative bioavailability of the flavonoids quercetin, hesperetin and naringenin given simultaneously through diet

    DEFF Research Database (Denmark)

    Krogholm, Kirstine Suszkiewicz; Bredsdorff, Lea; Knuthsen, Pia

    2010-01-01

    The bioavailability and urinary excretion of three dietary flavonoids, quercetin, hesperetin and naringenin, were investigated. Ten healthy men were asked to consume a 'juice mix' containing equal amounts of the three flavonoids, and their urine and plasma samples were collected. The resulting mean...... plasma area under the curve (AUC)(0-48h) and C-max values for quercetin and hesperetin were similar, whereas the AUC(0-48h) of naringenin and, thus, the relative bioavailability were higher after consumption of the same dose. The study consolidates a significantly lower urinary excretion of quercetin (1.......5 +/- 1%) compared with hesperetin (14.2 +/- 9.1%) and naringenin (22.6 +/- 11.5%) and shows that this is not due to a lower bioavailability of quercetin, but rather reflects different clearance mechanisms. European Journal of Clinical Nutrition (2010) 64, 432-435; doi: 10.1038/ejcn.2010.6; published...

  9. Pharmacokinetics of mycophenolic acid in Chinese kidney transplant patients

    Institute of Scientific and Technical Information of China (English)

    LU Xiao-yang; HUANG Hong-feng; SHENG-TU Jian-zhong; LIU Jian

    2005-01-01

    To assess the influence ofcyclosporin A (CsA) and tacrolimus (FK506) on mycophenolic acid (MPA) and correlation analysis of the pharmacokinetic parameters and patient characteristics, clinical outcome in Chinese kidney transplant recipients,the pharmacokinetics of 1000 mg mycophenolate mofetil (MMF) twice daily was measured by high-performance liquid chromatography (HPLC). PKS (Pharmaceutical Kinetics Software) 1.0.2 software package was used for the calculation of pharmarespectively. The level of AUC(0-12) in the FK506 group was significantly higher than that in the CsA group. MPA appeared not to be affected by renal function. MPA AUC(0-12) showed statistically significant difference according to the patient's gender.

  10. Immunity raised by recent European subtype 1 PRRSV strains allows better replication of East European subtype 3 PRRSV strain Lena than that raised by an older strain

    DEFF Research Database (Denmark)

    Trus, Ivan; Frydas, Ilias S.; Reddy, Vishwanatha R. A. P.

    2016-01-01

    Stable spatial distribution of porcine reproductive and respiratory syndrome (PRRSV)-1 subtypes in Europe is accompanied by a strong population immunity induced by local PRRSV strains. In the present study, it was examined if the immunity induced by three West European subtype 1 PRRSV strains (2007...... isolate 07V063 and 2013 isolates 13V091 and 13V117) offers protection against the highly virulent East European subtype 3 PRRSV strain Lena. The number of fever days was greater (p ...: 8.3). Reduction of respiratory disease, nasal shedding (mean AUC and mean peak values) and viremia (mean AUC and mean peak values) was more pronounced in 07V063-immune (p strains caused priming of the Lena...

  11. Influence of polymer molecular weight on in vitro dissolution behavior and in vivo performance of celecoxib:PVP amorphous solid dispersions

    DEFF Research Database (Denmark)

    Knopp, Matthias Manne; Nguyen, Julia Hoang; Becker, Christian;

    2016-01-01

    In this study, the influence of the molecular weight of polyvinylpyrrolidone (PVP) on the non-sink in vitro dissolution and in vivo performance of celecoxib (CCX):PVP amorphous solid dispersions were investigated. The dissolution rate of CCX from the amorphous solid dispersions increased...... weight where the crystallization inhibition was strongest. Consistent with the findings from the non-sink in vitro dissolution tests, the amorphous solid dispersions with the highest molecular weight PVPs (K30 and K60) resulted in significantly higher in vivo bioavailability (AUC0-24h) compared with pure...... amorphous and crystalline CCX. A linear relationship between the in vitro and in vivo parameter AUC0-24h indicated that the simple non-sink in vitro dissolution method used in this study could be used to predict the in vivo performance of amorphous solid dispersion with good precision, which enabled...

  12. The effect of transversus abdominis plane block or local anaesthetic infiltration in inguinal hernia repair

    DEFF Research Database (Denmark)

    Petersen, Pernille Lykke; Mathiesen, Ole; Stjernholm, Pia;

    2013-01-01

    measure was pain scores while coughing between group TAP and group placebo calculated as area under the curve for the first 24 h (AUC24 h). Secondary outcomes were pain scores while coughing and at rest, opioid consumption and side effects in groups TAP, infiltration and placebo. RESULTS: Visual analogue...... pain scores while coughing and at rest demonstrated no difference between groups. Pain scores in groups infiltration, TAP and placebo were 19 versus 22 versus 15 mm at rest (P = 1.00) and 37 versus 41 versus 37 mm while coughing (P = 1.00). Pain scores at 6 h (AUC6 h) were significantly lower in group...

  13. Palliative chemotherapy beyond three courses conveys no survival or consistent quality-of-life benefits in advanced non-small-cell lung cancer

    DEFF Research Database (Denmark)

    von Plessen, C; Bergman, B; Andresen, O;

    2006-01-01

    and 8 of a 3-week cycle. Key end points were QoL at 18 weeks, measured with EORTC Quality of Life Questionnaire (QLQ)-C30 and QLQ-LC13, and overall survival. Secondary end points were progression-free survival and need of palliative radiotherapy. Two hundred and ninety-seven patients were randomised (C3...... of life (QoL) and survival. Patients with stage IIIB or IV NSCLC and WHO performance status (PS) 0-2 were randomised to receive three (C3) or six (C6) courses of carboplatin (area under the curve (AUC) 4, Chatelut's formula, equivalent to Calvert's AUC 5) on day 1 and vinorelbine 25 mg m(-2) on days 1...

  14. Deferasirox pharmacokinetics evaluation in a woman with hereditary haemochromatosis and heterozygous β-thalassaemia.

    Science.gov (United States)

    Allegra, Sarah; De Francia, Silvia; Longo, Filomena; Massano, Davide; Cusato, Jessica; Arduino, Arianna; Pirro, Elisa; Piga, Antonio; D'Avolio, Antonio

    2016-12-01

    We present the deferasirox pharmacokinetics evaluation of a female patient on iron chelation, for the interesting findings from her genetic background (hereditary haemochromatosis and heterozygous β-thalassaemia) and clinical history (ileostomy; iron overload from transfusions). Drug plasma concentrations were measured by an HPLC-UV validated method, before and after ileum resection. Area under deferasirox concentration curve over 24h (AUC) values were determined by the mixed log-linear rule, using Kinetica software. AUC was low also with high deferasirox dose as well as tolerability. Non invasive tissue iron quantification by magnetic resonance imaging or superconducting quantum interference device were prevented by a metal hip replacement. Good efficacy and normalisation of iron markers was obtained on long term. Therapeutic drug monitoring in patient in critical conditions may help to understand reasons for non response and set individualised treatment.

  15. Determination of lisinopril in human plasma by HP LC-MS/MS and bioequivalence of lisinopril tablets%赖诺普利片人体生物等效性研究

    Institute of Scientific and Technical Information of China (English)

    周焕; 陈余清; 马涛; 霍强; 孙思雨; 张俊东

    2012-01-01

    Objective :To evaluate the bioequivalence of lisinopril tablets in healthy volunteers. Methods: A single oral dose of 10 mg test or reference formulations were given to 20 male healthy volunteers in a randomized crossover design. Three ml of blood was drawn out from the ulnar vein of the volunteers at 1,2,3 ,4 ,6,8 ,10,12,16,24,36,48 and 60 h before and after the administration. The plasma concentration of lisinopril was determined by LC-MS/MS method. The pharmacokinetic parameters and relative bioavailability were calculated with DAS program to evaluate the bioequivalence of the two formulations. Results: The pharmacokinetic parameters of lisinopril test formulation were obtained as follows-tmax was(6. 1 ±1.0) h,Cmax(64. 24 ±25.2) μg/L, AUC0_60 (942. 0 ±330) (μg ? T-1 ? h-1 and AUC0-∞ (969.6 ±327) μg ? L-1 ? h-1 ;for reference formulation:tmas(6. 1 ± 1. 2) h,Cmax (68. 19 ±26. 5 ) μg/L, AUC0-144(980.1 ±340) μg ? L-1 ? h-1 and AUC0-∞ (1002.3 ±337) μg ? L-1 ? h-1. Calculated with AUC0-144 ,the bioavailability of the two formulations was(98. 8 ±27. 5) %. Conclusions:The lisinopril tablet test formulation and reference formulation are bioequivalent.%目的:评价两种赖诺普利片的人体生物等效性.方法:20名男性健康志愿者随机交叉口服赖诺普利片试验制剂和参比制剂各10 mg,于给药前及给药后1、2、3、4、6、8、10、12、16、24、36、48、60 h从受试者肘静脉采血3 ml,采用液相-串联质谱法(LC-MS/MS)测定血药浓度.以DAS2.0软件计算其药动学参数,考察其生物等效性.结果:赖诺普利片试验制剂和参比制剂的tmax、Cmax、AUC0~60、AUC0~∞分别为(6.1±1.0)h和(6.1±1.2)h、(64.24±25.2)μg/L和(68.19±26.5)μg/L、(942.0±330)μg·L-1·h-1和(980.1±340)μg·L-1·h-1、(969.6±327)μg·L-1·h-1和(1002.3±337)μg·L-1·h-1.以AUC0~144计算,赖诺普利片试验制剂和参比制剂比较的人体相对生物利用度为(98.8±27.5)%.结论:试验制剂赖诺

  16. 尼美舒利颗粒在健康人体的生物等效性%Bioequivalence of Nimesulide Granules in Healthy Volunteers

    Institute of Scientific and Technical Information of China (English)

    曾东向; 李坤艳; 符一岚

    2014-01-01

    目的:评价2种国产尼美舒利颗粒在中国健康人体的生物等效性。方法:18名健康男性受试者随机交叉单剂量口服试验制药或参比制剂各200 mg。用高效液相色谱法测定血浆中尼美舒利的浓度;用DAS2.1软件计算主要药动学参数,并对2种药物进行生物等效性评价。结果:试验制药和参比制剂的主要药动学参数:Cmax分别为(9.28±2.05)和(9.41±2.31)μg·ml-1;Tmax分别为(3.50±1.86)和(3.56±1.65)h; T1/2分别为(3.43±0.85)和(3.38±0.68)h;AUC0-24分别为(77.78±18.42)和(81.69±23.50)μg·ml·h-1;AUC(0-∞)分别为(79.07±19.21)和(82.92±24.11)μg·ml·h-1。 ln(AUC0-24)、ln (AUC0-∞)、ln(Cmax)的90%可信区间分别为90.7%~107.9%、90.6%~111.2%和90.7%~103.0%。试验制药相对于参比制剂的生物利用度F为(96.7±37.6)%。结论:受试制剂和参比制剂生物等效。%Objective:To evaluate the bioequivalence of two kinds of domestic nimesulide granules in healthy volunteers. Meth-ods:In self-control and two-way crossover design, 18 healthy male volunteers were divided into two groups randomly. Each subject was given 100 mg test or reference nimesulide granules with single dose. The concentration of nimesulide in plasma was determined by HPLC. The concentration of nimesulide in plasma was calculated and compared statistically to evaluate the bioequivalence between the two kinds of granules by DAS 2. 1 software. Results:The main pharmacokinetic parameters of test and reference preparations were as follows:Cmax was(9. 28 ± 2. 05) and(9. 41 ± 2. 31)μg·ml-1;Tmax was(3. 50 ± 1. 86)and(3. 56 ± 1. 65)h;T1/2 was (3. 43 ± 0. 85) and(3.38 ±0.68)h;AUC0-24 was(77.78 ±18.42)and(81.69 ±23.50)μg·ml·h-1;AUC(0-∞) was (79.07 ±19.21)and(82.92 ± 24. 11)μg·ml·h-1, respectively. The 90% confidential interval of ln(AUC0-24), ln(AUC0-∞) and ln(Cmax) of the test preparation was 90. 7%-107. 9%,90. 6%-111. 2% and 90. 7%-103. 0%, respectively. The

  17. Lornoxicam Immediate-Release Tablets: Formulation and Bioequivalence Study in Healthy Mediterranean Volunteers Using a Validated LC-MS/MS Method.

    Science.gov (United States)

    Zaid, Abdel Naser; Mousa, Ayman; Jaradat, Nidal; Bustami, Rana

    2017-02-08

    This study aimed to demonstrate interchangeability between 2 lornoxicam tablet formulations under fasting conditions among Mediterranean Arabs by using a newly validated high-pressure liquid chromatography-tandem mass spectrometry method. A single-oral solid dosage form (8 mg/tablet), randomized, open-label, 2-way crossover study was conducted on 30 healthy male volunteers. Blood samples were collected prior to dosing and over a 24-hour period, and the washout period was 9 days. Statistical comparison of the main pharmacokinetic parameters showed no significant difference between generic and branded products. The point estimates (ratios of geometric mean %) were 90.91, 96.34, and 94.86 for Cmax, AUC0-last , and AUC0-∞ , respectively. The 90% confidence intervals were within the predefined limits of 80.00%-125.00%, as specified by the international guidelines. This study showed that both formulations met the regulatory criteria for bioequivalence.

  18. Bioequivalence study of 2 orodispersible formulations of zolmitriptan 5 mg in healthy volunteers.

    Science.gov (United States)

    Cánovas, M; Canals, M; Polonio, F; Cabré, F

    2012-10-01

    A bioequivalence study of 2 zolmitriptan (CAS 139264-17-8) orodispersible tablet formulations was carried out in 26 healthy volunteers according to an open label, randomized, 2-period, 2-sequence, crossover, single dose and fasting conditions design. The test and reference formulations were administered in 2 treatment days, separated by a washout period of 7 days. Plasma concentrations of zolmitriptan and its active metabolite (N-desmethyl-zolmitriptan) were obtained by LC/MS/MS method. Log-transformed AUCs and Cmax values were tested for bioequivalence based on the ratios of the geometric means (test/reference). Tmax was analysed nonparametrically. The 90% confidence intervals of the geometric mean values for the test/reference ratios for AUC0-t and Cmax were within the bioequivalence acceptance range of 80-125%. According to the European Guideline 1 it may be therefore concluded that test formulation of zolmitriptan 5 mg orodispersible tablet is bioequivalent to the reference formulation.

  19. Dose-dependent adsorptive capacity of activated charcoal for gastrointestinal decontamination of a simulated paracetamol overdose in human volunteers

    DEFF Research Database (Denmark)

    Gude, Anne-Bolette Jill; Hoegberg, Lotte Christine Groth; Riis Angelo, Helle

    2010-01-01

    The amount of activated charcoal needed to treat drug overdoses has arbitrarily been set at a charcoal-drug ratio of 10:1. Recent in vitro studies have shown a larger adsorptive capacity for activated charcoal when used in a model of paracetamol overdose. In the present study, we investigated...... whether this reserve capacity exists in vivo. This is clinically relevant in cases of large overdoses or if the full standard dose of 50 g activated charcoal cannot be administered. We performed a randomized, cross-over study (n = 16). One hour after a standard breakfast, 50 mg/kg paracetamol...... was administered, followed 1 hr later by an activated charcoal-Water slurry containing 50 (control), 25 or 5 g activated charcoal. The areas under the serum concentration-time curve (AUC) for paracetamol were used to estimate the efficacy of each activated charcoal dose. The AUC of the 25-g dose was found...

  20. Antimicrobial activity and a comparison of published pharmacodynamics of gemifloxacin and eight fluoroquinolones against Streptococcus pneumoniae.

    Science.gov (United States)

    Saravolatz, Louis; Manzor, Odette; Pawlak, Joan; Belian, Bradley

    2005-07-01

    Gemifloxacin was evaluated for its in vitro activity and was compared with eight fluoroquinolones. Pharmacodynamic comparisons were made based on published pharmacokinetic information. Gemifloxacin demonstrated excellent in vitro activity (minimum inhibitory concentration necessary to inhibit 90% of the strains tested, MIC90 = 0.03 mg/L (range 0.0019-0.03 mg/L)) against 199 strains of Streptococcus pneumoniae. Its activity was not influenced by penicillin or ciprofloxacin non-susceptibility. Gemifloxacin demonstrated excellent pharmacodynamic parameters, with a Cmax/MIC90 of 67 (where Cmax is the peak serum level) and an AUC/MIC90 of 297 (where AUC is the area under the curve). Compared with the other eight fluoroquinolones tested, gemifloxacin demonstrated the best in vitro activity and Cmax/MIC90.

  1. Bioequivalence of Two Different Ivermectin Injections in Rabbits%两种伊维菌素注射液在家兔体内的生物等效性研究

    Institute of Scientific and Technical Information of China (English)

    李朋朋; 张聪; 张晓会; 周德刚; 李召斌; 张晓东; 刘栓

    2016-01-01

    To evaluate the pharmacokinetics and bioequivalence of two kinds of ivermectin injections in rabbits,in a randomized two -way self -crossover study,16 healthy rabbits were randomly divided into two groups,and were given respectively a single dose of two kinds of ivermectin injection by subcutaneous injection (5 mg/kg).Plasma concentrations of ivermectin were measured by HPLC.The pharmacokinetic parameters were calculated by 3P97 pharmacokinetic software,and the bioequivalence were evaluated.The main pharmacokinetic parameters of the test and reference preparations were as follows:Tmax were (26.45 ±8.62)h,(22.33 ±11.72)h;Cmax were (182.73 ± 59.27)ng/mL,(166.77 ±65.25)ng/mL;AUC0 -t were (21122 ±9999)ng·h·L -1 ,(19475 ±7009)ng·h·L -1;AUC0 -∞were (27390 ±12197)ng·h·L -1 ,(31559 ±13412)ng·h·L -1 .The pharmacokinetic parameters (AUC0 -t、AUC0 -∞、Cmax、Tmax ) showed no significant difference between test and reference preparations of ivermectin injections.The test and reference formulations were bioequivalent after two one -side t -test.This study provided theoretical basis for making of veterinary clinical dosage regimen and clinical rational administration.%为评价两种伊维菌素注射液在家兔体内的生物等效性,采用双周期交叉给药方式,将16只健康家兔随机分成2组,按5 mg/kg 体重皮下单剂量注射两种伊维菌素注射液,使用 HPLC法测定血浆中的伊维菌素,利用3P97药动软件计算主要药动学参数。结果显示,受试制剂和参比制剂的 Tmax分别为(26.45±8.62)h,(22.33±11.72)h;Cmax 分别为(182.73±59.27)ng/mL,(166.77±65.25)ng/mL;AUC0-t 分别为(21122±9999)ng·h·L -1,(19475±7009)ng·h·L -1;AUC0-∞分别为(27390±12197)ng·h·L -1,(31559±13412)ng·h·L -1。伊维菌素注射液受试制剂与参比制剂的 AUC0-t、AUC0-∞、Cmax、Tmax均无显著性差异(P >0.05

  2. Pharmacokinetic and pharmacodynamic evaluation of AZD5847 in a mouse model of tuberculosis.

    Science.gov (United States)

    Balasubramanian, V; Solapure, Suresh; Shandil, Radha; Gaonkar, Sheshagiri; Mahesh, K N; Reddy, Jitender; Deshpande, Abhijeet; Bharath, Sowmya; Kumar, Naveen; Wright, Lindsay; Melnick, David; Butler, Scott L

    2014-07-01

    AZD5847, a novel oxazolidinone with an MIC of 1 μg/ml, exhibits exposure-dependent killing kinetics against extracellular and intracellular Mycobacterium tuberculosis. Oral administration of AZD5847 to mice infected with M. tuberculosis H37Rv in a chronic-infection model resulted in a 1.0-log10 reduction in the lung CFU count after 4 weeks of treatment at a daily area under the concentration-time curve (AUC) of 105 to 158 μg · h/ml. The pharmacokinetic-pharmacodynamic parameter that best predicted success in an acute-infection model was an AUC for the free, unbound fraction of the drug/MIC ratio of ≥ 20. The percentage of time above the MIC in all of the efficacious regimens was 25% or greater.

  3. 沙丁胺醇气雾剂在健康受试者体内的药物动力学和相对生物利用度%Pharmacokinetics and relative bioavailability of salbutamol metered-dose inhaler in healthy volunteers

    Institute of Scientific and Technical Information of China (English)

    杜小莉; 朱珠; 傅强; 李大魁; 许文兵

    2002-01-01

    目的:研究沙丁胺醇气雾剂在健康受试者的药物动力学和生物利用度.方法:十名健康男性志愿者单剂量吸入1.2 mg沙丁胺醇气雾剂或口服沙丁胺醇水溶液.用HPLC法测定人血浆中沙丁胺醇浓度.以非房室模型计算药物动力学参数,计算气雾剂相对水溶液的生物利用度.结果:气雾剂和口服溶液的药物动力学参数如下:Tmax(0.22±0.07)和(1.8±0.6)h,Cmax(3.4±1.1)和(3.9±1.4)μg@L-1,T1/2(4.5±1.5)和(4.6±1.1)h,AUC0-20min(0.9±0.3)和(0.16±0.10)μg@h@L-1.两种给药途径的Tmax和AUC0-20min之间差异显著(P<0.01).AUC0-20min(inhal)为AUC0-20min(po)的8倍.沙丁胺醇气雾剂相对口服溶液的生物利用度为57%±24%.结论:沙丁胺醇气雾剂在人体的吸收过程与口服溶液差异有显著性.%AIM: To study the pharmacokinetics and relative bioavailability of salbutamol metered-dose inhaler (MDI)in healthy volunteers. METHODS: An HPLC method for the determination of salbutamol in human plasma was improved. Ten healthy male Chinese volunteers were enrolled in a randomized crossover study. After the subjects inhaled or orally administered 1.2 mg salbutamol, fourteen blood samples were collected at predetermined time points. The concentrations of salbutamol in plasma were assessed with non-compartment model to obtain the pharmacokinetic parameters. The relative bioavailability of MDI versus water solution was calculated. RESULTS: The HPLC assay was sensitive, specific, accurate, and precise. The pharmacokinetics of salbutamol MDI was described well with twocompartment model. The parameters for salbutamol inhaled and orally administered were as following: Tmax (0.22±0.07) and (1.8±0.6) h, Cmax(3.4± 1.1) and (3.9±1.4) μg@L-1, T1/2(4.5±1.5) and (4.6±1.1)h, AUC0-20min(0.9±0.3) and (0.16±0.10) μg@h@L-1, respectively. There were significant differences in Tmax and AUC0-20 min between the two dosage forms.The AUC0-20min ( inhal ) was 8 times as high as the AUC0

  4. Six different fat tolerance tests in young, healthy subjects –gender dependent postprandial lipemia and glucose

    DEFF Research Database (Denmark)

    Rasmussen, Ole Winther; Lauszus, Finn Friis

    2016-01-01

    tolerenctes (OFTT) with varying amoun of saturated fat. Methods: With six different types of fatin random order to tomatoes we measured postprandial lipemia, lipoprotein, glucose and insulin increments for eight hours in 14 young lean healthy students, seven of each gender. The area under the curve (AUC......) was dtermined for the postprandial values. Results: The meals with six types of butters had similar postprandial response even if the saturated fat content varied with 50%.Gender significantly affected the TG responses, as time to pesk was 90 minutes in women and 180 min in men. Postprandial AUC was higherwith...... responses and postprandial lipemia was gender-specific. Replacement of saturated fat by mono- or polyunsaturated fat did not alter postprandial lipemia during single OFTT...

  5. The effect of metformin on glucose homeostasis during moderate exercise

    DEFF Research Database (Denmark)

    Hansen, Merethe; Palsøe, Marie K.; Helge, Jørn Wulff;

    2015-01-01

    OBJECTIVE: We investigated the role of metformin on glucose kinetics during moderate exercise. RESEARCH DESIGN AND METHODS: Before, during, and after a 45-min bout of exercise at 60% VO2max, glucose kinetics were determined by isotope tracer technique in patients with type 2 diabetes mellitus...... with metformin treatment (DM2+Met) or without metformin treatment (DM2) and in healthy control subjects (CON) matched for BMI and age. Glucoregulatory hormones and metabolites were measured throughout the study. RESULTS: Plasma glucose concentration was unchanged during exercise in CON but decreased in DM2....... No significant change was found in DM2+Met. Hormones and metabolites showed no differences among the groups except for elevated exercise-induced concentrations of lactate in DM2 (area under the curve [AUC] 31 ± 1% vs. CON) and glucagon in DM2 (AUC 5 ± 1% vs. DM2+Met). Free fatty acid levels were lower in DM2+Met...

  6. Involvement of Multiple Transporters-mediated Transports in Mizoribine and Methotrexate Pharmacokinetics

    Directory of Open Access Journals (Sweden)

    Teruo Murakami

    2012-08-01

    Full Text Available Mizoribine is administered orally and excreted into urine without being metabolized. Many research groups have reported a linear relationship between the dose and peak serum concentration, between the dose and AUC, and between AUC and cumulative urinary excretion of mizoribine. In contrast, a significant interindividual variability, with a small intraindividual variability, in oral bioavailability of mizoribine is also reported. The interindividual variability is mostly considered to be due to the polymophisms of transporter genes. Methotrexate (MTX is administered orally and/or by parenteral routes, depending on the dose. Metabolic enzymes and multiple transporters are involved in the pharmacokinetics of MTX. The oral bioavailability of MTX exhibits a marked interindividual variability and saturation with increase in the dose of MTX, with a small intraindividual variability, where the contribution of gene polymophisms of transporters and enzymes is suggested. Therapeutic drug monitoring of both mizoribine and MTX is expected to improve their clinical efficacy in the treatment of rheumatoid arthritis.

  7. Optical tomographic detection of rheumatoid arthritis with computer-aided classification schemes

    Science.gov (United States)

    Klose, Christian D.; Klose, Alexander D.; Netz, Uwe; Beuthan, Jürgen; Hielscher, Andreas H.

    2009-02-01

    A recent research study has shown that combining multiple parameters, drawn from optical tomographic images, leads to better classification results to identifying human finger joints that are affected or not affected by rheumatic arthritis RA. Building up on the research findings of the previous study, this article presents an advanced computer-aided classification approach for interpreting optical image data to detect RA in finger joints. Additional data are used including, for example, maximum and minimum values of the absorption coefficient as well as their ratios and image variances. Classification performances obtained by the proposed method were evaluated in terms of sensitivity, specificity, Youden index and area under the curve AUC. Results were compared to different benchmarks ("gold standard"): magnet resonance, ultrasound and clinical evaluation. Maximum accuracies (AUC=0.88) were reached when combining minimum/maximum-ratios and image variances and using ultrasound as gold standard.

  8. Optimal dose and timing of insulin Aspart to mimic first phase insulin response in patients with recently onset type 2 diabetes

    DEFF Research Database (Denmark)

    Gredal, C.; Rosenfalck, A.; Dejgaard, A.

    2008-01-01

    OBJECTIVE: To assess the optimal dose and timing of subcutaneous injection of insulin Aspart (IAsp) in relation to meal to mimic first phase insulin response in patients with recently diagnosed type 2 diabetes. DESIGN AND METHODS: Twenty patients were randomised in a double blind, double dummy...... design to four standard meal tests with pre-meal injection of insulin Aspart 0.08 IU/kg BW 30 min before the meal, insulin Aspart 0.04 IU/kg BW 30 or 15 min before the meal and placebo. RESULTS: All three insulin regimes significantly reduced postprandial glucose increment (area under the curve AUC(-30...... to 240 min)) and peak plasma glucose increment (DeltaC(max)) compared with placebo. Postprandial glucose increment AUC(-30 to 240 min) but not DeltaC(max) was significantly lower with IAsp 0.08 IU/kg BW as compared to IAsp 0.04IU/kg BW, (p

  9. Influence of isoniazid on the metabolism of rifampicin on rat hepatocytes

    Directory of Open Access Journals (Sweden)

    Fasich Fasich

    2000-06-01

    Full Text Available Research on the influence of isoniazid on rifampicin metabolism using rat hepatocytes has been done. As the system metabolism, hepatocytes suspension was prepared by perfusion in the calcium binding media containing EDTA, citrate and glycine was used. In the experiment, combination of rifampicin and INH on various doses was incubated in those metabolism system at 30oC from 0 and up to 180 minutes duration. Then, analysis was done by thin layer chromathography and densitomeric method for each incubation intervals. Result calculated on the base of variation of rifampicin AUC-value beginning from 0 up to 180 minutes showed that isoniazid with concentration 5 µl, 10 µl, 15 µl, and 20 µl did not influence the metabolism of rifampicin (10 µl/ml as showed by no significance changes of AUC value of rifampicin for α = 0.05.

  10. Alzheimer's Disease Diagnostic Performance of a Multi-Atlas Hippocampal Segmentation Method using the Harmonized Hippocampal Protocol

    DEFF Research Database (Denmark)

    Anker, Cecilie Benedicte; Sørensen, Lauge; Pai, Akshay

    baseline to month 12 was estimated for the three methods, and diagnostic performance was evaluated using the area under the receiver operating characteristic curve (AUC) of pairwise diagnostic group comparisons. RESULTS Mean (SD) atrophy rates were as follows (MRP / static FS / longitudinal FS): NC -0.86...... (2.46) / -1.39 (5.41) / -1.63 (2.54), MCI -2.38 (3.28) / -3.69 (5.48) / -3.25 (3.53), AD -4.23 (3.07) / -4.29 (5.32) / -4.83 (3.74). Diagnostic performances were as follows (AUC; MRP / static FS / longitudinal FS): NC vs. MCI 0.65 / 0.67 / 0.64, NC vs. AD 0.80 / 0.69 / 0.76, MCI vs. AD 0.66 / 0...

  11. Fusion of multi-parametric MRI and temporal ultrasound for characterization of prostate cancer: in vivo feasibility study

    Science.gov (United States)

    Imani, Farhad; Ghavidel, Sahar; Abolmaesumi, Purang; Khallaghi, Siavash; Gibson, Eli; Khojaste, Amir; Gaed, Mena; Moussa, Madeleine; Gomez, Jose A.; Romagnoli, Cesare; Cool, Derek W.; Bastian-Jordan, Matthew; Kassam, Zahra; Siemens, D. Robert; Leveridge, Michael; Chang, Silvia; Fenster, Aaron; Ward, Aaron D.; Mousavi, Parvin

    2016-03-01

    Recently, multi-parametric Magnetic Resonance Imaging (mp-MRI) has been used to improve the sensitivity of detecting high-risk prostate cancer (PCa). Prior to biopsy, primary and secondary cancer lesions are identified on mp-MRI. The lesions are then targeted using TRUS guidance. In this paper, for the first time, we present a fused mp-MRI-temporal-ultrasound framework for characterization of PCa, in vivo. Cancer classification results obtained using temporal ultrasound are fused with those achieved using consolidated mp-MRI maps determined by multiple observers. We verify the outcome of our study using histopathology following deformable registration of ultrasound and histology images. Fusion of temporal ultrasound and mp-MRI for characterization of the PCa results in an area under the receiver operating characteristic curve (AUC) of 0.86 for cancerous regions with Gleason scores (GSs)>=3+3, and AUC of 0.89 for those with GSs>=3+4.

  12. An in vivo microdialysis measurement of harpagoside in rat blood and bile for predicting hepatobiliary excretion and its interaction with cyclosporin A and verapamil.

    Science.gov (United States)

    Wu, Qian; Wen, Xiao-Dong; Qi, Lian-Wen; Wang, Wei; Yi, Ling; Bi, Zhi-Ming; Li, Ping

    2009-03-15

    Harpagoside, a major bioactive iridoid glucoside in genus Scrophularia, has been widely used in clinical practice for the treatment of pain in the joints and lower back for its neuroprotective and anti-inflammation activities. To investigate the pharmacokinetics and hepatobiliary excretion, an in vivo microdialysis method coupled with high performance liquid chromatography was developed to monitor the concentration of harpagoside in blood and bile. The harpagoside bile-to-blood distribution ratio (AUC(bile)/AUC(blood)) up to 986.28+/-78.46 significantly decreased to 6.41+/-0.56 or 221.20+/-18.92 after co-administration of cyclosporin A or verapamil. The results indicated that harpagoside went through concentrative elimination from the bile which was probably regulated by P-glucoprotein, providing possible clinical trials of co-administration of transporter inhibitors to decrease drug efflux, thus to enhance the curative effects.

  13. Comparison of circulating MMP-9, TIMP-1 and CA19-9 in the detection of pancreatic cancer

    DEFF Research Database (Denmark)

    Joergensen, Maiken Thyregod; Brünner, Nils; De Muckadell, Ove B Schaffalitzky

    2010-01-01

    Background/Aim: The performance of the circulating tumor markers carbohydrate antigen 19-9 (CA19-9), matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) were evaluated separately and in combination for their potential value in detecting pancreatic ductal...... adenocarcinoma. PATIENTS AND METHODS: The patients had symptoms of pancreatic cancer. The discriminative strength of MMP-9 and TIMP-1 were compared to that of CA19-9 using receiver operating characteristics curves, area under the curves (AUC), specificity and sensitivity. RESULTS: The sensitivities of MMP-9......, TIMP-1 and CA19-9 in detecting pancreatic ductal adenocarcinoma were 58.82%, 47.1% and 86%, respectively, with specificities of 34.6%, 69.2% and 73%. The AUCs of MMP-9, TIMP-1 and CA19-9 were 0.50, 0.64 and 0.84, respectively. Combining the three markers did not significantly improve detection...

  14. Variance of the SGK1 gene is associated with insulin secretion in different European populations: results from the TUEF, EUGENE2, and METSIM studies

    DEFF Research Database (Denmark)

    Friedrich, Björn; Weyrich, Peter; Stancáková, Alena

    2008-01-01

    gene (SGK) variations and insulin secretion traits. The German TUEF project provided the screening population (N = 725), and four tagging SNPs (rs1763527, rs1743966, rs1057293, rs9402571) were investigated. EUGENE2 (N = 827) served as a replication cohort for the detected associations. Finally...... secretion only remained significant in lean TUEF participants (BMIEUGENE2 rs9402571 minor allele carriers, who had a significantly higher AUC(Ins)/AUC(Glc) (TT: 226+/-7, XG: 246+/-9; p = 0.019). Accordingly, the METSIM trial revealed a lower prevalence of type...... 2 diabetes (OR: 0.85; 95%CI: 0.71-1.01; p = 0.065, dominant model) in rs9402571 minor allele carriers. CONCLUSIONS: The rs9402571 SGK genotype associates with increased insulin secretion in lean non-diabetic TUEF/EUGENE2 participants and with lower diabetes prevalence in METSIM. Our study in three...

  15. Seasonal Assessment of Habitat Suitability of the Wild Goat (Capra aegagrus in Mountainous Areas of Kolah-Qazi National Park using Maximum Entropy Approach

    Directory of Open Access Journals (Sweden)

    N. Ranjbar

    2016-09-01

    Full Text Available Knowledge of species’ habitat needs is considered as one of the requirements of wildlife management. We studied seasonal habitat suitability and habitat associations of wild goat (Capra aegagrus in Kolah-Qazi National Park, one of its typical habitats in central Asia, using Maximum Entropy approach. The study area was confined to mountainous areas as the potential habitat of the wild goat. Elevation, distance to water sources, distance to human settlements, and distance to guard patrol roads were recognised as the most important variables determining habitat suitability of the species. The extent of suitable habitats was maximum in spring (3882.25 ha and the least in summer (1362.5 ha. The AUC values of MaxEnt revealed acceptable to good efficiency (AUC ≥0.7. The obtained results may have implications for conservation of the wild goat in similar habitats across its distribution range.

  16. Pharmacokinetics of doxapram in Chinese Hui and Han healthy volunteers%多沙普仑在中国回族和汉族健康人体内的药动学

    Institute of Scientific and Technical Information of China (English)

    肖勇; 程佳; 郭涛; 夏东亚; 郑谊; 郭红亮

    2011-01-01

    Objective:To investigate the pharmacokinetics of doxapram in Chinese Hui and Han healthy volunteers. Methods:Ten Hui volunteers and ten Han volunteers were given a single dose of 50 mg doxapram by intravenous infusion. The concentration of doxapram in plasma was determined by HPLC method, and the pharmacokinetic parameters were calculated by DAS 2. 0 software. ResultS:The main pharmacokinetic parameters of Hui volunteers were as follows: cmax 48±0. 46) μg/ml, t1/2β(3. 91±2.05) h,Vd(l. 35±0.45) L/kg,AUC0-12 (3. 02±0. 56)μg · h · ml-1 ,AUC0-∞(3. 49 + 0. 73) μg · h · ml-1. The main pharmacokinetic parameters of Han volunteers were as follows: cmax( 55±0. 52) μg/ml,t1/2β(3. 87 + 2. 17) h,Vd(l. 35± 0. 96) L/kg,AUC0-12(3. 51±1. 26)μg· h · ml-1, AUC0-∞ (4. 06±l. 44) μg · h· ml-1. Conclusion:There were no significant differences in the pharmacokinetic parameters of doxapram between Chinese Hui and Han healthy volunteers.%目的:研究汉族和回族健康受试者单次静脉滴注盐酸多沙普仑后的药动学.方法:回族和汉族健康受试者各10名,单次静脉滴注盐酸多沙普仑50 mg,定时采血,用HPLC法测定多沙普仑血药浓度,DAS 2.0软件计算药动学参数.结果:回族受试者的主要药动学参数为:cmax(1.48±0.46) μg/ml、t1/2β(3.91±2.05) h、Vd(1.35±0.45) L/kg、AUC0~12(3.02±0.56) μg·h·ml-1、AUC0~∞(3.49±0.73) μg·h·ml-1.汉族受试者的主要药动学参数为:cmax(1.55±0.52) μg/ml、t1/2β(3.87±2.17) h、Vd(1.35±0.96) L/kg、AUC0~12(3.51±1.26) μg·h·ml-1、AUC0~∞(4.06±1.44) μg·h·ml-1.结论:经统计学分析,回族和汉族健康受试者单次静脉滴注盐酸多沙普仑后药动学参数的差异无统计学意义.

  17. Bioequivalence of oral candesartan cilexetil capsules in healthy volunteers%国产与进口坎地沙坦酯胶囊人体生物等效性评价

    Institute of Scientific and Technical Information of China (English)

    郭喆; 强烈应; 朱哲; 王惠; 毕京峰; 魏振满

    2015-01-01

    目的:评价坎地沙坦酯胶囊(受试制剂)与原研药品坎地沙坦酯片(商品名:必洛斯)(参比制剂)是否具有健康人体生物等效性。方法采取双交叉设计方法,22名健康男性志愿者随机口服国产坎地沙坦酯胶囊及进口坎地沙坦酯片8 mg后,采用高效液相色谱串联质谱法测定不同时刻血浆中坎地沙坦的浓度,用DAS2.1.1统计软件计算药代动力学参数,并评价其生物等效性。结果受试制剂和参比制剂的Cmax分别为(79.62±29.99) ng/ml 和(77.74±28.46) ng/ml,AUC0-t 分别为(850.17±249.52)ng/(ml· h)和(837.26±243.26)ng/(ml· h),AUC0-∞分别为(908.96±249.64)ng/(ml· h)和(896.94±241.53)ng/(ml· h)。 AUC0-t的90%的置信区间为88.9%~109.5%,AUC0-∞的90%的置信区间为89.2%~109.2%,Cmax 90%的置信区间为参比制剂的86.2%~112.0%,均拒绝生物不等效假设,且双单侧t检验均有统计学意义。结论国产坎地沙坦酯胶囊与进口坎地沙坦酯片在健康人体内具有生物等效性。%Objective To study the bioequivalence of the tested and reference oral candesartan Cilexetil in healthy male vol-unteers.Methods According to the crossover design,each volunteer was orally given 8 mg candesartan cilexetil capsules or tablets. Their plasma concentrations were determined by LC/MS/MS.Pharmacokinetic parameters were obtained using DAS program. Results Cmax were(79.62 ±29.99) ng/ml and (77.74 ±28.46) ng/ml,AUC0-t were (850.17 ±249.52) ng/(ml· h)and (837.26 ±243.26)ng/(ml· h),AUC0-∞ were (908.96 ±249.64) ng/(ml· h) and(896.94 ±241.53) ng/(ml· h),respec-tively.Two-way unilateral t-test results showed that the test preparation did not exceed the prescribed upper limit and lower limit of the reference preparation, rejected null hypothesis (P<0.05).The 90% confidence intervals of Cmax,AUC0-t

  18. Alpha-1 antitrypsin and granulocyte colony-stimulating factor as serum biomarkers of disease severity in ulcerative colitis

    DEFF Research Database (Denmark)

    Soendergaard, Christoffer; Nielsen, Ole Haagen; Seidelin, Jakob Benedict

    2015-01-01

    biomarkers are currently needed for identification of patients with mild or moderate disease activity. Using a commercially available platform, we aimed at identifying serum biomarkers that are able to grade the disease severity. METHODS: Serum samples from 65 patients with UC with varying disease activity......-stimulating factor produced a predictive model with an AUC of 0.72 when differentiating mild and moderate UC, and an AUC of 0.96 when differentiating moderate and severe UC, the latter being as reliable as CRP. CONCLUSIONS: Alpha-1 antitrypsin is identified as a potential serum biomarker of mild-to-moderate disease......BACKGROUND: Initial assessment of patients with ulcerative colitis (UC) is challenging and relies on apparent clinical symptoms and measurements of surrogate markers (e.g., C-reactive protein [CRP] or similar acute phase proteins). As CRP only reliably identifies patients with severe disease, novel...

  19. Pharmacokinetics of terazosin enantiomers in healthy Chinese male subjects.

    Science.gov (United States)

    Liu, Man; Zhang, Dan; Yang, Man; Zhao, Ting; Wang, Xiaolin; Zhang, Yanan; Han, Jing; Liu, Huichen

    2012-12-01

    The purpose of this study was to elucidate the pharmacokinetics of terazosin enantiomers in healthy Chinese male subjects. After a single oral dose of 2-mg terazosin, the plasma concentrations of terazosin enantiomers were measured over the course of 48 h in 12 healthy subjects. The plasma concentrations of (+)-(R)-terazosin at all time points were higher than those of (-)-(S)-terazosin. The area under the plasma concentration-time curve (AUC(0-∞) ) and maximum plasma concentration of (+)-(R)-terazosin were significantly greater than those of the (-)-(S)-terazosin (P < 0.01, respectively). The R/S ratio of AUC(0-∞) of terazosin was 1.68. For the first time, it was proven that the pharmacokinetics of terazosin was stereoselective in healthy Chinese male subjects.

  20. ¿Tiene utilidad el tratamiento preoperatorio con ácido ursodeoxicólico en la reducción de las recidivas en la pancreatitis aguda biliar? Is pre-operative treatment with ursodeoxycholic acid useful in reducing relapses in acute biliary pancreatitis?

    Directory of Open Access Journals (Sweden)

    F. Borda

    2003-08-01

    Full Text Available En el presente trabajo se ha valorado la posible reducción de la tasa de recidivas en la pancreatitis aguda biliar mediante el tratamiento con ácido ursodeoxicólico (AUC entre el episodio de pancreatitis y el momento de la colecistectomía. Se estudiaron 72 primeros episodios consecutivos de pancreatitis aguda biliar, en pacientes no colecistectomizados, seguidos hasta la cirugía. Los casos se dividieron en grupo A (n = 30, tratados al alta con AUC 10 mg/kg/día, hasta la cirugía, y grupo B o control (n = 42. Se evaluaron las diferencias entre ambos grupos en cuanto a características del paciente, gravedad de la pancreatitis, características de la litiasis y demora hasta la cirugía. Analizamos las recidivas de la pancreatitis entre los grupos con y sin AUC. En el grupo con AUC comparamos la duración del tratamiento entre los pacientes con y sin recidiva de la pancreatitis. Los dos grupos no mostraron diferencias significativas en cuanto a ninguno de los parámetros estudiados. Registramos 7/30 (23,3% recidivas en el grupo AUC, frente a 9/42 (21,4% recidivas en el control (p = 0,85. Dentro del grupo AUC, la duración del tratamiento fue similar entre los casos que recidivaron: 4,9±4,5 meses y los no recidivados: 4,4±1,9 meses (p = 0,78. En nuestra experiencia, el empleo de AUC hasta el momento de la colecistectomía no reduce la incidencia de recidiva en los pacientes tras un primer episodio de pancreatitis aguda biliar. La duración del tratamiento con AUC tampoco parece relacionarse con la aparición o no de recidivas.In the present paper, we evaluate the possible reduction in the rate of relapses in acute biliary pancreatitis through treatment with ursodeoxycholic acid (UCA, between the episode of pancreatitis and the moment of cholecystectomy. We studied 72 consecutive first episodes of acute biliary pancreatitis, in patients who had not yet undergone colecistectomy, followed up until surgery. The cases were divided into group A (n

  1. Prediction of outcome in patients with low back pain

    DEFF Research Database (Denmark)

    Kongsted, Alice; Andersen, Cathrine Hedegaard; Hansen, Martin Mørk;

    2016-01-01

    The clinical course of low back pain (LBP) cannot be accurately predicted by existing prediction tools. Therefore clinicians rely largely on their experience and clinical judgement. The objectives of this study were to investigate 1) which patient characteristics were associated with chiropractors...... at baseline and related to all outcomes. The accuracies of predictions made by clinicians (AUC .58-.63) and the SBT (AUC .50-.61) were comparable and low. No substantial increase in the predictive capability was achieved by combining clinicians' expectations and the SBT. In conclusion, chiropractors......' predictions were associated with well-established prognostic factors but not simply a product of these. Chiropractors were able to predict differences in outcome on a group level, but prediction of individual patients' outcomes were inaccurate and not substantially improved by the SBT. It is worth...

  2. Development and validation of a prediction model for long-term sickness absence based on occupational health survey variables

    DEFF Research Database (Denmark)

    Roelen, Corné; Thorsen, Sannie; Heymans, Martijn

    2016-01-01

    Purpose: The purpose of this study is to develop and validate a prediction model for identifying employees at increased risk of long-term sickness absence (LTSA), by using variables commonly measured in occupational health surveys. Materials and methods: Based on the literature, 15 predictor...... and then validated in a sample of 2524 DANES participants, not included in the development sample. Identification of employees at increased LTSA risk was investigated by receiver operating characteristic (ROC) analysis; the area-under-the-ROC-curve (AUC) reflected discrimination between employees with and without...... LTSA during follow-up. Results: The 15-predictor model was reduced to a 9-predictor model including age, gender, education, self-rated health, mental health, prior LTSA, work ability, emotional job demands, and recognition by the management. Discrimination by the 9-predictor model was significant (AUC...

  3. The impact of everolimus versus mycophenolate on blood and lymphocyte cyclosporine exposure in heart-transplant recipients

    DEFF Research Database (Denmark)

    Gustafsson, Finn; Barth, David; Delgado, Diego H

    2009-01-01

    . METHODS: Twelve-hour pharmacokinetic studies of whole-blood and intralymphocytic CsA concentrations were conducted in long-term heart-transplant recipients treated with mycophenolate mofetil (MMF) + CsA (n = 8) and everolimus + CsA (n = 9). RESULTS: There was a highly significant correlation between blood...... CsA C2 levels and blood CsA AUC(0-12) in groups of patients treated with MMF or everolimus (R(2) 0.93 and 0.96, respectively; P MMF (R(2) = 0.98), there was poor correlation...... between whole-blood C2 and lymphocyte AUC(0-12) in patients treated with everolimus (R(2) = 0.24). CONCLUSION: Standard blood CsA levels accurately predict intralymphocytic exposure to CsA in patients concomitantly treated with MMF but not in patients treated with everolimus....

  4. Kolliphor surfactants affect solubilization and bioavailability of fenofibrate. Studies of in vitro digestion and absorption in rats

    DEFF Research Database (Denmark)

    Berthelsen, Ragna; Holm, Rene; Jacobsen, Jette

    2015-01-01

    formulations only comprised an aqueous micellar solution of the model drug (fenofibrate) in varying concentrations (2–25% (w/v)) of the three tested surfactants. Increased concentrations of Kolliphor ELP and EL led to increased fenofibrate AUC0–24h values. For the Kolliphor RH40 formulations, an apparent...... fenofibrate absorption optimum was seen at 15% (w/v) surfactant, displaying both the highest AUC0–24h and Cmax. The reduced absorption of fenofibrate from the formulation containing the highest level of surfactant (25% w/v) was thought to be caused by some degree of trapping within Kolliphor RH40 micelles....... In vitro, Kolliphor ELP and EL were found to be more prone to digestion than Kolliphor RH40, though not affecting the in vivo results. The highest fenofibrate bioavailability was attained from formulations with high Kolliphor ELP/EL levels (25% (w/v)), indicating that these surfactants are the better...

  5. The effect of immobilization stress on the pharmacokinetics of omeprazole in rats.

    Directory of Open Access Journals (Sweden)

    Watanabe K

    2002-02-01

    Full Text Available The effects of immobilization stress on the pharmacokinetics of omeprazole were studied in rats. The immobilization stress for 30 or 60 min immediately after oral administration of the drug caused an increase in the time to reach the maximum concentration. However, such stress did not alter the area under the plasma concentration-time curve (AUC. When administered intravenously, the half-life during the elimination phase was significantly prolonged by 30 min of immobilization stress, but the AUC value remained unchanged. The intestinal propulsive activity was significantly decreased by immobilization stress. These findings suggest that immobilization stress reduces gastrointestinal motility. A resulting delay during the absorption phase of omeprazole occurs, although the degree of influence on overall pharmacokinetics is relatively insignificant.

  6. Bioequivalence of Enalapril Maleate Tablets in Healthy Volunteers%马来酸依那普利片的人体生物等效性研究

    Institute of Scientific and Technical Information of China (English)

    梁宇光; 李海燕; 高洪志; 王晓芳; 郝光涛; 刘泽源

    2009-01-01

    -48h)平均值分别为(59.22±20.46)、(64.43±23.42)mg · h · L-1;AUC(0-∞)平均值分别为(60.01±20.39)、(65.09±23.43)mg · h · L-1;以AUC(0-48h)计算,受试制剂的相对生物利用度为(97.8±34.1)%.结论 受试制剂和参比制剂具有生物等效性.

  7. Proteinuria as a Noninvasive Marker for Renal Allograft Histology and Failure: An Observational Cohort Study.

    Science.gov (United States)

    Naesens, Maarten; Lerut, Evelyne; Emonds, Marie-Paule; Herelixka, Albert; Evenepoel, Pieter; Claes, Kathleen; Bammens, Bert; Sprangers, Ben; Meijers, Björn; Jochmans, Ina; Monbaliu, Diethard; Pirenne, Jacques; Kuypers, Dirk R J

    2016-01-01

    Proteinuria is routinely measured to assess renal allograft status, but the diagnostic and prognostic values of this measurement for renal transplant pathology and outcome remain unclear. We included 1518 renal allograft recipients in this prospective, observational cohort study. All renal allograft biopsy samples with concomitant data on 24-hour proteinuria were included in the analyses (n=2274). Patients were followed for ≥7 years post-transplantation. Compared with proteinuria 3.0 g/24 h, independent of GFR and allograft histology. The predictive performance of proteinuria for graft failure was lower at 3 months after transplant (area under the receiver-operating characteristic curve [AUC] 0.64, P3 months after transplant (AUC 0.73, P1.0 g/24 h. These data support current clinical guidelines to routinely measure proteinuria after transplant, but illustrate the need for more sensitive biomarkers of allograft injury and prognosis.

  8. Assessment of Landslide Susceptibility by Decision Trees in the Metropolitan Area of Istanbul, Turkey

    Directory of Open Access Journals (Sweden)

    H. A. Nefeslioglu

    2010-01-01

    Full Text Available The main purpose of the present study is to investigate the possible application of decision tree in landslide susceptibility assessment. The study area having a surface area of 174.8 km2 locates at the northern coast of the Sea of Marmara and western part of Istanbul metropolitan area. When applying data mining and extracting decision tree, geological formations, altitude, slope, plan curvature, profile curvature, heat load and stream power index parameters are taken into consideration as landslide conditioning factors. Using the predicted values, the landslide susceptibility map of the study area is produced. The AUC value of the produced landslide susceptibility map has been obtained as 89.6%. According to the results of the AUC evaluation, the produced map has exhibited a good enough performance.

  9. The Effect of Silibinin on the Pharmacokinetics of Ivabradine and N-Desmethylivabradine in Rats.

    Science.gov (United States)

    Chen, Xing-Peng; Zheng, Hai-Tao; Cai, Wei-Wei; Li, Meng-Ke; Zhang, Jian-Wei; Hu, Jie

    2015-01-01

    The objective of this work was to investigate the effect of orally administered silibinin on the pharmacokinetics of ivabradine and its active metabolite N-desmethylivabradine in rats. Twelve healthy male Sprague-Dawley rats were randomly divided into 2 groups: the control group (received oral 1.0 mg/kg ivabradine alone) and the combination group (1.0 mg/kg ivabradine orally coadministered with 30 mg/kg silibinin). The plasma concentration of ivabradine and N-desmethylivabradine were estimated by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) and different pharmacokinetic parameters were calculated using the DAS 2.0 software. The pharmacokinetic parameters of t1/2, Cmax, AUC(0-t) and AUC(0-∞) of ivabradine in the combination group were significantly higher than those in the control group (p ivabradine. Henceforth, the pharmacodynamic influence of this interaction should be taken into consideration while prescribing ivabradine to patients already taking silibinin.

  10. Pharmacokinetics of oral and intravenous melatonin in healthy volunteers

    DEFF Research Database (Denmark)

    Andersen, Lars Peter Holst; Werner, Mads Utke; Rosenkilde, Mette Marie

    2016-01-01

    BACKGROUND: The aim was to investigate the pharmacokinetics of oral and iv melatonin in healthy volunteers. METHODS: The study was performed as a cohort crossover study. The volunteers received either 10 mg oral melatonin or 10 mg intravenous melatonin on two separate study days. Blood samples were...... collected at different time points following oral administration and short iv infusion, respectively. Plasma melatonin concentrations were determined by RIA technique. Pharmacokinetic analyses were performed by "the method of residuals" and compartmental analysis. The pharmacokinetic variables: k a, t 1....../2 absorption, t max, C max, t 1/2 elimination, AUC 0-∞, and bioavailability were determined for oral melatonin. C max, t 1/2 elimination, V d, CL and AUC 0-∞ were determined for intravenous melatonin. RESULTS: Twelve male volunteers completed the study. Baseline melatonin plasma levels did not differ...

  11. Single vs double antiplatelet therapy in acute coronary syndrome: Predictors of bleeding after coronary artery bypass grafting

    Institute of Scientific and Technical Information of China (English)

    Vincenzo; Tarzia; Giacomo; Bortolussi; Edward; Buratto; Carla; Paolini; Carlo; Dal; Lin; Giulio; Rizzoli; Tomaso; Bottio; Gino; Gerosa

    2015-01-01

    AIM:To investigate the contribution of anti-platelet therapy and derangements of pre-operative classical coagulation and thromboelastometry parameters to major bleeding post-coronary artery bypass grafting(CABG).METHODS:Two groups of CABG patients were studied:Group A,treated with aspirin alone(n=50),and Group B treated with aspirin and clopidogrel(n=50).Both had similar preoperative,clinical,biologic characteristics and operative management.Classic coagulation parameters and rotational thromboelastometry(ROTEM)profiles were determined preoperatively for both groups and the same heparin treatment was administered.ROTEM profiles(INTEM and EXTEM assays)were analyzed,both for traditional parameters,and thrombin generation potential,expressed by area-under-curve(AUC).RESULTS:There was no significant difference betweenrates of major bleeding between patients treated with aspirin alone,compared with those treated with aspirin and clopidogrel(12%vs 16%,P=0.77).In the 14 cases of major bleeding,pre-operative classic coagulation and traditional ROTEM parameters were comparable.Conversely we observed that the AUC in the EXTEM test was significantly lower in bleeders(5030±1115 Ohm*min)than non-bleeders(6568±548Ohm*min)(P<0.0001).CONCLUSION:We observed that patients with a low AUC value were at a significantly higher risk of bleeding compared to patients with higher AUC,regardless of antiplatelet treatment.This suggests that thrombin generation potential,irrespective of the degree of platelet inhibition,correlates with surgical bleeding.

  12. Association between body composition and frailty among prevalent hemodialysis patients: a US Renal Data System special study.

    Science.gov (United States)

    Johansen, Kirsten L; Dalrymple, Lorien S; Delgado, Cynthia; Kaysen, George A; Kornak, John; Grimes, Barbara; Chertow, Glenn M

    2014-02-01

    Studies of frailty among patients on hemodialysis have relied on definitions that substitute self-reported functioning for measures of physical performance and omit weight loss or substitute alternate criteria. We examined the association between body composition and a definition of frailty that includes measured physical performance and weight loss in a cross-sectional analysis of 638 adult patients receiving maintenance hemodialysis at 14 centers. Frailty was defined as having three of following characteristics: weight loss, weakness, exhaustion, low physical activity, and slow gait speed. We performed logistic regression with body mass index (BMI) and bioelectrical impedance spectroscopy (BIS)-derived estimates of intracellular water (ICW), fat mass, and extracellular water (ECW) as the main predictors, and age, sex, race, and comorbidity as covariates. Overall, 30% of participants were frail. Older age (odds ratio [OR], 1.31 per 10 years; 95% confidence interval [95% CI], 1.14 to 1.50), diabetes (OR, 1.65; 95% CI, 1.13 to 2.40), higher fat mass (OR, 1.18; 95% CI, 1.02 to 1.37), and higher ECW (OR, 1.33; 95% CI, 1.20 to 1.47) associated with higher odds of frailty. Higher ICW associated with lower odds of frailty (OR, 0.80 per kg; 95% CI, 0.73 to 0.87). The addition of BMI data did not change the area under the receiver operating characteristics curve (AUC; AUC=0.66 versus 0.66; P=0.71), but the addition of BIS data did change the AUC (AUC=0.72; Phemodialysis.

  13. Diagnostic criteria for sarcopenia relate differently to insulin resistance

    OpenAIRE

    Bijlsma, A. Y.; Meskers, C. G. M.; van Heemst, D.; Westendorp, R. G. J.; de Craen, A. J. M.; Maier, A. B.

    2013-01-01

    Skeletal muscle is important in insulin-stimulated glucose uptake. Sarcopenia is, therefore, a possible risk factor for insulin resistance. Currently, different diagnostic criteria for sarcopenia include low muscle mass, muscle strength, and walking speed. We assessed these muscle characteristics in relation to insulin resistance in nondiabetics. This cross-sectional study included 301 nondiabetics, mean age 65.9 years. Area under curve (AUC) calculations of insulin and glucose from a 2-h ora...

  14. Assessing liver function in patients with HBV-related HCC: a comparison of T{sub 1} mapping on Gd-EOB-DTPA-enhanced MR imaging with DWI

    Energy Technology Data Exchange (ETDEWEB)

    Ding, Ying; Rao, Sheng-Xiang; Chen, Caizhong; Li, Renchen; Zeng, Meng-Su [Zhongshan Hospital of Fudan University, Department of Radiology, 180 Fenglin Road, Xuhui District, Shanghai (China)

    2015-05-01

    To compare the potential of T{sub 1} mapping on gadoxetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) for assessing liver function in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). One hundred consecutive patients with known HBV-related HCCs were included. T{sub 1} relaxation time and apparent diffusion coefficient (ADC) of the liver were measured, and the reduction rate of T{sub 1} relaxation time (∇%) was calculated. T{sub 1} relaxation time measurements were compared with ADC values according to the Model for End-Stage Liver Disease (MELD) score. Hepatobiliary phase (HBP) and ∇% of T{sub 1} relaxation time measurements showed significant correlations with MELD score (rho = 0.571, p < 0.0001; rho = -0.573, p < 0.0001, respectively). HBP and ∇% of T{sub 1} relaxation time were significantly different between good (MELD ≤8) and poor liver function (MELD ≥9) (p < 0.0001 for both). Areas under the receiver operating characteristic curves (AUCs) of T{sub 1} relaxation time for HBP (AUC 0.84) and ∇% (AUC 0.82) were significantly better than for ADC (AUC 0.53; p < 0.0001). T{sub 1} mapping on Gd-EOB-DTPA-enhanced MRI showed promise for evaluating liver function in patients with HBV-related HCC, while DWI was not reliable. HBP T{sub 1} relaxation time measurement was equally accurate as ∇% measurement. (orig.)

  15. Preliminary observations indicate variable patterns of plasma 5-fluorouracil (5-FU) levels during dose optimization of infusional 5-FU in colorectal cancer patients.

    Science.gov (United States)

    Kline, Christina Leah; Sheikh, Hassan S; Scicchitano, Angelique; Gingrich, Rebecca; Beachler, Cheryl; Finnberg, Niklas K; Liao, Jason; Sivik, Jeffrey; El-Deiry, Wafik S

    2011-10-01

    Efforts to improve efficacy and minimize toxicity have led to pharmacokinetic monitoring of plasma 5-Fluorouracil (5-FU) levels in colorectal cancer patients undergoing chemotherapy. We observed variation in basal 5-FU levels in 21 patients and significant variation during subsequent dose optimization. Tumor KRAS, BRAF mutations and TS mRNA levels were determined. Regimens included FOLFOX6 + Avastin (N = 8), FOLFOX6 (N = 11), FOLFIRI (N = 1) and FOLFOX4 (N = 1). Mutations identified in tumors included G12V KRAS (N = 2), G12A KRAS (N = 1), and V600E BRAF (N = 3). Six-of-eleven patients with normalized tumor TS mRNA levels 5-FU AUC of 20 mg.h/L or greater, and 80% of patients (4 of 5) with TS levels > 4.0 had a plasma 5-FU AUC of less than or equal to 20 mg.h/L. Approximately 2/3 of patients achieved therapeutic 5-FU AUC levels with 0-2 dose adjustments while a sub-group of ~1/3 of patients slowly achieved therapeutic levels (> 3-4 dose increases leading to supra-therapeutic 5-FU and subsequent reductions to lesser than original doses). Liver metastases and tumor TS levels did not fully account for variable 5-FU AUC optimization patterns. The 5-FU level during continuous infusion was half-therapeutic in one patient who received FOLFOX4. The observed heterogeneous patterns at baseline and during dose optimization of 5-FU levels suggest variations in 5-FU metabolism among treated patients. Physiological and/or genetic differences underlying heterogeneity in 5-FU levels during dose optimization require further study of patient demographics, single nucleotide polymorphisms in Dihydropyrimidine Dehydrogenase (DPD), TS, or other genes that impact 5-FU metabolism and gene expression changes in liver after 5-FU therapy.

  16. Evaluation of 5-fluorouracil applicability by multi-point collagen gel droplet embedded drug sensitivity test.

    Science.gov (United States)

    Ochiai, Takumi; Nishimura, Kazuhiko; Noguchi, Hajime; Kitajima, Masayuki; Tsuruoka, Yuko; Takahashi, Yuka

    2005-07-01

    The drug sensitivity of tumor cells is one of key issues to explore individualized therapy for cancer patients. One of such methods is in vitro anticancer drug sensitivity test which is generally based on one drug concentration and contact time. In this study, 5-fluorouracil (5-FU) sensitivity of cancer cells from colorectal cancer patients was evaluated by collagen gel droplet embedded drug sensitivity test (CD-DST) under multiple drug concentrations and contact durations. Cancer cells from 19 patients were measured for 9 drug concentration/contact time conditions (cohort 1) and from 34 patients were measured for 2 drug concentration/contact time conditions (cohort 2) using CD-DST. There was not significant difference in growth inhibition rate for 1.0 microg/ml for 24 h and 0.2 microg/ml for 120 h, which gives the same area under the curve (AUC) (p=0.832) in all 53 patients (cohort 1 and 2). In cohort 1, 9 conditions were successfully measured in 18 of 19 cohort 1 patients (94.7%). The drug concentrations and growth inhibition rate approximated to logarithmic curve for all 3 contact times and 50% inhibitory concentration (IC50) values at 3 contact times could be calculated in these 18 patients. Growth inhibition rate and AUC also approximated to logarithmic curve. These values varied several orders of magnitude among patients. In vitro antitumor effect of 5-FU depended on AUC in colorectal tumor and it might support the use of continuous infusion or oral therapy which generates significant AUC with manageable toxicity. Some patients demonstrating low 5-FU sensitivity could not be indicated for 5-FU based therapy, and non-5-FU therapy should be explored for them.

  17. Virtual population pharmacokinetic using physiologically based pharmacokinetic model for evaluating bioequivalence of oral lacidipine formulations in dogs

    Directory of Open Access Journals (Sweden)

    Bin Yang

    2017-01-01

    Full Text Available The aim of the present study was to investigate virtual population pharmacokinetic using physiologically based pharmacokinetic (PBPK model for evaluating bioequivalence of oral lacidipine formulations in dogs. The dissolution behaviors of three lacidipine formulations including one commercial product and two self-made amorphous solid dispersions (ASDs capsules were determined in 0.07% Tween 80 media. A randomized 3-period crossover design in 6 healthy beagle dogs after oral administration of the three formulations at a single dose of 4 mg was conducted. The PBPK modeling was utilized for the virtual bioequivalence study. In vitro dissolution experiment showed that the dissolution behaviors of lacidipine amorphous solid dispersions (ASDs capsules, which was respectively prepared by HPMC-E5 or Soluplus, as polymer displayed similar curves compared with the reference formulation in 0.07% Tween 80 media. In vivo pharmacokinetics experiments showed that three formulations had comparable maximum plasma drug concentration (Cmax, and the time (Tmax to reach Cmax of lacidipine tablet, which was prepared by Soluplus, as polymer was slower than other two formulations in consistency with the in vitro dissolution rate. The 90% confidence interval (CI for the Cmax, AUC0–24 h and AUC0–∞ of the ratio of the test drug to the referencedrug exceeded the acceptable bioequivalence (BE limits (0.80–1.25. However, the 90% CI of the AUC0–24 h, AUC0–∞ and Cmax of the ratio of test to reference drug were within the BE limit, calculated using PBPK modeling when the virtual subjects reached 24 dogs. The results all demonstrated that virtual bioequivalence study can overcome the inequivalence caused by inter-subject variability of the 6 beagle dogs involved in in vivo experiments.

  18. Factor Analysis of Wildfire and Risk Area Estimation in Korean Peninsula Using Maximum Entropy

    Science.gov (United States)

    Kim, Teayeon; Lim, Chul-Hee; Lee, Woo-Kyun; Kim, YouSeung; Heo, Seongbong; Cha, Sung Eun; Kim, Seajin

    2016-04-01

    The number of wildfires and accompanying human injuries and physical damages has been increased by frequent drought. Especially, Korea experienced severe drought and numbers of wildfire took effect this year. We used MaxEnt model to figure out major environmental factors for wildfire and used RCP scenarios to predict future wildfire risk area. In this study, environmental variables including topographic, anthropogenic, meteorologic data was used to figure out contributing variables of wildfire in South and North Korea, and compared accordingly. As for occurrence data, we used MODIS fire data after verification. In North Korea, AUC(Area Under the ROC Curve) value was 0.890 which was high enough to explain the distribution of wildfires. South Korea had low AUC value than North Korea and high mean standard deviation which means there is low anticipation to predict fire with same environmental variables. It is expected to enhance AUC value in South Korea with environmental variables such as distance from trails, wildfire management systems. For instance, fire occurred within DMZ(demilitarized zone, 4kms boundary from 38th parallel) has decisive influence on fire risk area in South Korea, but not in North Korea. The contribution of each environmental variables was more distributed among variables in North Korea than in South Korea. This means South Korea is dependent on few certain variables, and North Korea can be explained as number of variables with evenly distributed portions. Although the AUC value and standard deviation of South Korea was not high enough to predict wildfire, the result carries an significant meaning to figure out scientific and social matters that certain environmental variables has great weight by understanding their response curves. We also made future wildfire risk area map in whole Korean peninsula using the same model. In four RCP scenarios, it was found that severe climate change would lead wildfire risk area move north. Especially North

  19. Comparison of inhibitory duration of grapefruit juice on organic anion-transporting polypeptide and cytochrome P450 3A4.

    Science.gov (United States)

    Tanaka, Shimako; Uchida, Shinya; Miyakawa, Sachiko; Inui, Naoki; Takeuchi, Kazuhiko; Watanabe, Hiroshi; Namiki, Noriyuki

    2013-01-01

    Recently, a new type of interaction has been reported in which fruit juices diminish oral drug bioavailability through inhibition of organic anion-transporting polypeptide (OATP). In this study, we aimed to clarify the duration of OATP inhibition by grapefruit juice (GFJ), and to compare it with the duration of GFJ-induced inhibition of cytochrome P450 (CYP) 3A4 activity. Seven healthy volunteers were enrolled in this open-label, single-sequence study. They were orally administered celiprolol (100 mg) and midazolam (15 µg/kg) with water on the control day. Three days later, they ingested GFJ (200 mL) 3 times a day for 3 d. On day 1, the same drugs were administered with GFJ. On days 3 and 7, the same drugs were administered with water. Pharmacokinetics of both drugs were evaluated on each trial day. The peak plasma concentration (Cmax) and the area under the plasma concentration-time curve from 0 to 8 h (AUC0-8) of celiprolol significantly decreased on day 1, and the mean ratios of these values and the corresponding control-day values were 0.18 and 0.25, respectively. The Cmax and AUC0-8 returned to the control levels on days 3 and 7. In contrast, AUC0-8 of midazolam were higher on days 1 and 3 than on the control day (mean ratio, 2.12 and 1.47, respectively). The AUC0-8 returned to the control level on day 7. In conclusion, results of this study indicated that the OATP inhibition caused by GFJ dissipated faster than GFJ-mediated alterations in CYP3A4 activity, which were sustained for at least 48 h.

  20. Circulating MicroRNAs as Non-Invasive Biomarkers for Early Detection of Non-Small-Cell Lung Cancer.

    Directory of Open Access Journals (Sweden)

    Magdalena B Wozniak

    Full Text Available Detection of lung cancer at an early stage by sensitive screening tests could be an important strategy to improving prognosis. Our objective was to identify a panel of circulating microRNAs in plasma that will contribute to early detection of lung cancer.Plasma samples from 100 early stage (I to IIIA non-small-cell lung cancer (NSCLC patients and 100 non-cancer controls were screened for 754 circulating microRNAs via qRT-PCR, using TaqMan MicroRNA Arrays. Logistic regression with a lasso penalty was used to select a panel of microRNAs that discriminate between cases and controls. Internal validation of model discrimination was conducted by calculating the bootstrap optimism-corrected AUC for the selected model.We identified a panel of 24 microRNAs with optimum classification performance. The combination of these 24 microRNAs alone could discriminate lung cancer cases from non-cancer controls with an AUC of 0.92 (95% CI: 0.87-0.95. This classification improved to an AUC of 0.94 (95% CI: 0.90-0.97 following addition of sex, age and smoking status to the model. Internal validation of the model suggests that the discriminatory power of the panel will be high when applied to independent samples with a corrected AUC of 0.78 for the 24-miRNA panel alone.Our 24-microRNA predictor improves lung cancer prediction beyond that of known risk factors.

  1. Topotecan and cisplatin in combination with concurrent twice-daily chemoradiation in limited disease small cell lung cancer-a Danish Oncological Lung Cancer Group (DOLG) phase II trial

    DEFF Research Database (Denmark)

    Sorensen, Morten; Lassen, Ulrik; Palshof, Torben;

    2007-01-01

    of topotecan with concurrent twice-daily radiochemotherapy in LD SCLC. PATIENT AND METHODS: Multicentre phase II study of three cycles of regimen A (topotecan i.v., 1.5mg/m(2), day 1-5; cisplatin 50mg/m(2), day 1) and three cycles of regimen B (etoposide i.v., 120mg/m(2), day 1-3; carboplatin, AUC=5, day 1...

  2. KAMIR评分与GRACE评分预测急性心肌梗死患者一年死亡率的临床研究%Clinical assessment of KAMIR and GRACE scores system on predicting one-year mortality of acute myocardial infarction patients

    Institute of Scientific and Technical Information of China (English)

    高戎; 钱骏; 徐建如

    2013-01-01

    目的 比较KAMIR评分与GRACE评分预测急性心肌梗死(AMI)患者一年死亡率的价值.方法 对收治128例AMI患者进行回顾性分析,计算KAMIR、GRACE评分,采用受试者工作特征曲线(ROC曲线),计算曲线下面积(AUC);KAMIR和GRACE的评分AUC比较采用Z检验.结果 KAMIR及GRACE评分预测AMI患者一年死亡率的AUC分别为0.880和0.792,两者比较差异有统计学意义(Z=2.524,P=0.0116).结论 KAMIR评分对预测AMI患者一年死亡率有较好的预测价值.%Objective To evaluate the predictive value of KAMIR and GRACE scores system score on predicting one - year mortality of acute myocardial infarction (AMI) patients. Methods One hundred and twenty - eight patients with AMI were retrospectively analyzed. The KAMIR and GRACE scores were calculated. The area under the receiver operating characteristic ( ROC ) curve ( AUC ) was evaluated using ROC curve. KAMIR, GRACE scores and AUC were analyzed by Z test. Results The AUCs of KAMIR and GRACE score for predicting one - year mortality of AMI patients were 0. 880 and 0. 792,respectively, which were significantly different between the two scores system(Z =2. 524,P = 0.0116). Conclusion KAMIR score is a better predictive factor of one - year mortality for AMI patients.

  3. Uptake and biodistribution of rizatriptan to blood and brain following different routes of administration in rats.

    Science.gov (United States)

    Wang, Chun; Quan, Li-Hui; Guo, Yi; Liu, Chun-Yu; Liao, Yong-Hong

    2007-06-07

    The objective of the present study was to investigate the biodistribution profiles of rizatriptan in the blood and brain of Wistar rats after peroral, subcutaneous, intranasal and intratracheal administration with a particular view to determining the applicability of inhalation delivery to achieve rapid and high availability of the drug in both blood and the brain. Following the intratracheal administration of the drug (4.0mg/kg) to the rats, the absolute bioavailability was found to be 91.2%, significantly higher than those from intranasal or peroral routes, and T(max) in plasma and brain was attained within 2 min, significantly shorter than the T(max) of intranasal ( approximately 10 min in both plasma and brain), subcutaneous (16.7 min in plasma and 22.5 min in brain) and peroral (30.0 min in plasma and 45.0 min in brain) administration. In addition, other pharmacokinetic parameters associated with rapid onset of action including AUC(plasma/brain) and C(max), of intratracheal instillated rizatriptan appeared also to be comparable or superior to those of other delivered routes. Although AUC(brain)/AUC(plasma) ratios after intranasal delivery (43.4%) differed significantly from the ratios shown after intratracheal instillation (23.2%), the AUC(brain 0-120 min) via the latter routes was slightly but not significantly higher than that from the former routes. The results in the present study indicated that pulmonary delivery of rizatriptan may achieve maximum plasma and brain concentrations significantly more rapidly compared with intranasal, subcutaneous and peroral administration and be a promising delivery method with extremely rapid onset of action in the pain relief of migraine.

  4. Accuracy of GastroPanel for the diagnosis of atrophic gastritis

    Science.gov (United States)

    Forné, Montserrat; Barrio, Jesus; De la Coba, Cristobal; González, Begoña; Rivera, Robin; Esteve, Maria; Fernandez-Bañares, Fernando; Madrigal, Beatriz; Gras-Miralles, Beatriz; Perez-Aisa, Angeles; Viver-Pi-Sunyer, Jose M.; Bory, Felipe; Rosinach, Merce; Loras, Carmen; Esteban, Carlos; Santolaria, Santos; Gomollon, Fernando; Valle, Julio; Gisbert, Javier P.

    2014-01-01

    Background It has been suggested that GastroPanel might be a useful tool for the diagnosis of chronic atrophic gastritis (CAG) measuring four biomarkers in blood: basal gastrin-17 (G17), pepsinogen I and II (PGI and PGII), and Helicobacter pylori antibodies. Aim To determine the accuracy of GastroPanel for the diagnosis of CAG. Methods This was a prospective, blinded, multicenter study that included dyspeptic patients. G17, PGI, and PGII were determined by enzyme immunoassays. Three antrum and two corpus biopsies were obtained for standard histological analysis and rapid urease test. Biopsies were analyzed by a single blinded expert pathologist. Results Ninety-one patients were included (77% women, mean age 44 years, 51% H. pylori positive, 17% with CAG). G17 was reduced in patients with antrum CAG (5.4 vs. 13.4 pmol/l; P<0.01) and increased in patients with corpus CAG (11 vs. 24 pmol/l; P<0.05), but its accuracy was only acceptable in the case of corpus localization [area under the receiver operating characteristic curve (AUC), 74%]; PGII difference was almost statistically significant only when testing for corpus atrophy (33 vs. 21 μg/l; P=0.05; AUC=72%). The PGI and PGI/PGII ratio showed no significant differences (AUCs were all unacceptably low). Helicobacter pylori antibody levels were higher in H. pylori-infected patients (251 vs. 109 EIU, P=0.01; AUC=70). The accuracy of GastroPanel for the diagnosis of CAG was as follows: sensitivity 50%; specificity 80%; positive 25% and negative 92% predictive values; and positive 2.4 and negative 0.6 likelihood ratios. Conclusion GastroPanel is not accurate enough for the diagnosis of CAG; thus, its systematic use in clinical practice cannot be recommended. PMID:25014624

  5. A Multilaboratory Comparison of Calibration Accuracy and the Performance of External References in Analytical Ultracentrifugation

    KAUST Repository

    Zhao, Huaying

    2015-05-21

    Analytical ultracentrifugation (AUC) is a first principles based method to determine absolute sedimentation coefficients and buoyant molar masses of macromolecules and their complexes, reporting on their size and shape in free solution. The purpose of this multi-laboratory study was to establish the precision and accuracy of basic data dimensions in AUC and validate previously proposed calibration techniques. Three kits of AUC cell assemblies containing radial and temperature calibration tools and a bovine serum albumin (BSA) reference sample were shared among 67 laboratories, generating 129 comprehensive data sets. These allowed for an assessment of many parameters of instrument performance, including accuracy of the reported scan time after the start of centrifugation, the accuracy of the temperature calibration, and the accuracy of the radial magnification. The range of sedimentation coefficients obtained for BSA monomer in different instruments and using different optical systems was from 3.655 S to 4.949 S, with a mean and standard deviation of (4.304 ± 0.188) S (4.4%). After the combined application of correction factors derived from the external calibration references for elapsed time, scan velocity, temperature, and radial magnification, the range of s-values was reduced 7-fold with a mean of 4.325 S and a 6-fold reduced standard deviation of ± 0.030 S (0.7%). In addition, the large data set provided an opportunity to determine the instrument-to-instrument variation of the absolute radial positions reported in the scan files, the precision of photometric or refractometric signal magnitudes, and the precision of the calculated apparent molar mass of BSA monomer and the fraction of BSA dimers. These results highlight the necessity and effectiveness of independent calibration of basic AUC data dimensions for reliable quantitative studies.

  6. Area-under-the-curve for peginterferon alpha-2a and peginterferon alpha-2b is not related to body weight in treatment-naive patients with chronic hepatitis C.

    Science.gov (United States)

    Bruno, Raffaele; Sacchi, Paolo; Maiocchi, Laura; Zocchetti, Cristina; Ciappina, Valentina; Patruno, Savino; Filice, Gaetano

    2005-01-01

    One reason for dosing a drug by body weight is to reduce interpatient variability in clinical response. This study evaluated the relationship between body weight and drug exposure for peginterferon alpha-2a and peginterferon alpha-2b used in combination with ribavirin for treating patients with chronic hepatitis C. These two products are dosed differently: peginterferon alpha-2a is flat-dosed at 180 microg regardless of body weight, whereas peginterferon alpha-2b is dosed by body weight at 0.5-1.5 microg/kg. Bodyweight dosing of peginterferon alpha-2b is purported to overcome the adverse effect of increased body weight on sustained virological response. To test this hypothesis, we measured the area-under-the-curve (AUC) for both drugs as part of a previously reported pharmacokinetics study. In total, 22 interferon-naive patients with chronic hepatitis C were treated for 12 weeks. Patients were randomly assigned in a 1:1 ratio to receive once-weekly peginterferon alpha-2a 180 microg (n=10) or peginterferon alpha-2b 1.0 microg/kg (n=12). Ribavirin was dosed by body weight at 1000 mg/day ( 75 kg). We found no correlation between body weight and AUC for either peginterferon alpha-2a or peginterferon alpha-2b. Considerable interpatient variability in AUC occurred for peginterferon alpha-2a [coefficient of variation (CV): 37.5%] and, despite dosing by body weight, for peginterferon alpha-2b (CV: 36.8%). Thus, there appears to be no rationale for a body-weight dosing regimen for peginterferon alpha-2a, and such dosing does not achieve more consistent AUC measurements in patients receiving peginterferon alpha-2b.

  7. A Multilaboratory Comparison of Calibration Accuracy and the Performance of External References in Analytical Ultracentrifugation

    Science.gov (United States)

    Zhao, Huaying; Ghirlando, Rodolfo; Alfonso, Carlos; Arisaka, Fumio; Attali, Ilan; Bain, David L.; Bakhtina, Marina M.; Becker, Donald F.; Bedwell, Gregory J.; Bekdemir, Ahmet; Besong, Tabot M. D.; Birck, Catherine; Brautigam, Chad A.; Brennerman, William; Byron, Olwyn; Bzowska, Agnieszka; Chaires, Jonathan B.; Chaton, Catherine T.; Cölfen, Helmut; Connaghan, Keith D.; Crowley, Kimberly A.; Curth, Ute; Daviter, Tina; Dean, William L.; Díez, Ana I.; Ebel, Christine; Eckert, Debra M.; Eisele, Leslie E.; Eisenstein, Edward; England, Patrick; Escalante, Carlos; Fagan, Jeffrey A.; Fairman, Robert; Finn, Ron M.; Fischle, Wolfgang; de la Torre, José García; Gor, Jayesh; Gustafsson, Henning; Hall, Damien; Harding, Stephen E.; Cifre, José G. Hernández; Herr, Andrew B.; Howell, Elizabeth E.; Isaac, Richard S.; Jao, Shu-Chuan; Jose, Davis; Kim, Soon-Jong; Kokona, Bashkim; Kornblatt, Jack A.; Kosek, Dalibor; Krayukhina, Elena; Krzizike, Daniel; Kusznir, Eric A.; Kwon, Hyewon; Larson, Adam; Laue, Thomas M.; Le Roy, Aline; Leech, Andrew P.; Lilie, Hauke; Luger, Karolin; Luque-Ortega, Juan R.; Ma, Jia; May, Carrie A.; Maynard, Ernest L.; Modrak-Wojcik, Anna; Mok, Yee-Foong; Mücke, Norbert; Nagel-Steger, Luitgard; Narlikar, Geeta J.; Noda, Masanori; Nourse, Amanda; Obsil, Tomas; Park, Chad K.; Park, Jin-Ku; Pawelek, Peter D.; Perdue, Erby E.; Perkins, Stephen J.; Perugini, Matthew A.; Peterson, Craig L.; Peverelli, Martin G.; Piszczek, Grzegorz; Prag, Gali; Prevelige, Peter E.; Raynal, Bertrand D. E.; Rezabkova, Lenka; Richter, Klaus; Ringel, Alison E.; Rosenberg, Rose; Rowe, Arthur J.; Rufer, Arne C.; Scott, David J.; Seravalli, Javier G.; Solovyova, Alexandra S.; Song, Renjie; Staunton, David; Stoddard, Caitlin; Stott, Katherine; Strauss, Holger M.; Streicher, Werner W.; Sumida, John P.; Swygert, Sarah G.; Szczepanowski, Roman H.; Tessmer, Ingrid; Toth, Ronald T.; Tripathy, Ashutosh; Uchiyama, Susumu; Uebel, Stephan F. W.; Unzai, Satoru; Gruber, Anna Vitlin; von Hippel, Peter H.; Wandrey, Christine; Wang, Szu-Huan; Weitzel, Steven E.; Wielgus-Kutrowska, Beata; Wolberger, Cynthia; Wolff, Martin; Wright, Edward; Wu, Yu-Sung; Wubben, Jacinta M.; Schuck, Peter

    2015-01-01

    Analytical ultracentrifugation (AUC) is a first principles based method to determine absolute sedimentation coefficients and buoyant molar masses of macromolecules and their complexes, reporting on their size and shape in free solution. The purpose of this multi-laboratory study was to establish the precision and accuracy of basic data dimensions in AUC and validate previously proposed calibration techniques. Three kits of AUC cell assemblies containing radial and temperature calibration tools and a bovine serum albumin (BSA) reference sample were shared among 67 laboratories, generating 129 comprehensive data sets. These allowed for an assessment of many parameters of instrument performance, including accuracy of the reported scan time after the start of centrifugation, the accuracy of the temperature calibration, and the accuracy of the radial magnification. The range of sedimentation coefficients obtained for BSA monomer in different instruments and using different optical systems was from 3.655 S to 4.949 S, with a mean and standard deviation of (4.304 ± 0.188) S (4.4%). After the combined application of correction factors derived from the external calibration references for elapsed time, scan velocity, temperature, and radial magnification, the range of s-values was reduced 7-fold with a mean of 4.325 S and a 6-fold reduced standard deviation of ± 0.030 S (0.7%). In addition, the large data set provided an opportunity to determine the instrument-to-instrument variation of the absolute radial positions reported in the scan files, the precision of photometric or refractometric signal magnitudes, and the precision of the calculated apparent molar mass of BSA monomer and the fraction of BSA dimers. These results highlight the necessity and effectiveness of independent calibration of basic AUC data dimensions for reliable quantitative studies. PMID:25997164

  8. Understanding Systems Theory for U.S. Marines

    Science.gov (United States)

    2007-01-01

    Sons, 2000. *Checkland, Peter and Porter, John. Learning for Action: A Short Definitive Account of Soft Systems Methodology and its use for...Practitioners, Teachers, and Students. West Sussex, England: John Wiley and Sons, 2006. *Checkland, Peter and Scholes, John. Soft Systems Methodology in...Metropolitan University, Department of BIT. Soft Systems Methodology . Undated. Available: http://www.cs.auc.dk/~jeremy/resources%20files

  9. HCC-DETECT: a combination of nuclear, cytoplasmic, and oncofetal proteins as biomarkers for hepatocellular carcinoma.

    Science.gov (United States)

    Attallah, Abdelfattah M; El-Far, Mohamed; Malak, Camelia A Abdel; Omran, Mohamed M; Shiha, Gamal E; Farid, Khaled; Barakat, Lamiaa A; Albannan, Mohamed S; Attallah, Ahmed A; Abdelrazek, Mohamed A; Elbendary, Mohamed S; Sabry, Refaat; Hamoda, Gehan A; Elshemy, Mohamed M; Ragab, Abdallah A; Foda, Basma M; Abdallah, Sanaa O

    2015-09-01

    Currently, the search for suitable hepatocellular carcinoma (HCC) biomarkers is very intensive. Besides, efficacy and cost/effectiveness of screening and surveillance of cirrhotics for the diagnosis of HCC is still debated. So, the present study is concerned with the evaluation of cytokeratin-1 (CK-1) and nuclear matrix protein-52 (NMP-52) for identifying HCC. Two-hundred and eighty individuals categorized into three groups [liver fibrosis (F1-F3), cirrhosis (F4), and HCC] constituted this study. Western blot was used for identifying CK-1 and NMP-52 in serum samples. As a result, a single immunoreactive band was shown at 67 and 52 kDa corresponding to CK-1 and NMP-52, respectively. Both CK-1 and NMP-52 bands were cut and electroeluted separately. These markers were quantified in sera using ELISA. Patients with HCC were associated with higher concentrations of CK-1 and NMP-52 than those without HCC with a significant difference (P < 0.0001). CK-1 showed an area under receiver-operating characteristic curve (AUC) of 0.83 with 75 % sensitivity and 82 % specificity while NMP-52 yielded 0.72 AUC with 62 % sensitivity and 70 % specificity for identifying HCC. HCC-DETECT comprising CK-1 and NMP-52 together with AFP was then constructed yielding 0.90 AUC for identifying HCC with 80 % sensitivity and 92 % specificity. HCC-DETECT was then tested for separating HCC from F1-F3 showing 0.94 AUC with 80 % sensitivity and 93 % specificity. In conclusion, CK-1 in conjunction with NMP-52 and AFP could have a potential role for improving the detection of HCC with a high degree of accuracy.

  10. How Fast Is Recovery of Impaired Glucose Tolerance after 21-Day Bed Rest (NUC Study in Healthy Adults?

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    Martina Heer

    2014-01-01

    Full Text Available Aim. We hypothesized that 4 days of normal daily activity after 21 days of experimental bed rest (BR will not reverse BR induced impaired glucose tolerance. Design. Glucose tolerance of seven male, healthy, untrained test subjects (age: 27.6 (3.3 years (mean (SD; body mass: 78.6 (6.4 kg; height: 1.81 (0.04 m; VO2 max: 39.5 (5.4 ml/kg body mass/min was studied. They stayed twice in the metabolic ward (crossover design, 21 days in bed and 7 days before and after BR each. Oral glucose tolerance tests were applied before, on day 21 of BR, and 5 and 14 days after BR. Results. On day 21 of BR, AUC120 min of glucose concentration was increased by 28.8 (5.2% and AUC120 min of insulin by 35.9 (10.2% (glucose: P<0.001; insulin: P=0.02. Fourteen days after BR, AUC120 min of serum insulin concentrations returned to pre-bed-rest concentrations (P=0.352 and AUC120 min of glucose was still higher (P=0.038. Insulin resistance did not change, but sensitivity index was reduced during BR (P=0.005. Conclusion. Four days of light physical workload does not compensate inactivity induced impaired glucose tolerance. An individually tailored and intensified training regime is mandatory in patients being in bed rest to get back to normal glucose metabolism in a reasonable time frame.

  11. Pharmacokinetic targeting of intravenous busulfan reduces conditioning regimen related toxicity following allogeneic hematopoietic cell transplantation for acute myelogenous leukemia

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    Nishihori Taiga

    2010-10-01

    Full Text Available Abstract Optimal conditioning therapy for hematopoietic cell transplantation (HCT in acute myelogenous leukemia (AML remains undefined. We retrospectively compared outcomes of a consecutive series of 51 AML patients treated with oral busulfan (1 mg/kg every 6 hours for 4 days and cyclophosphamide (60 mg/kg IV × 2 days - (Bu/Cy with 100 consecutive AML patients treated with pharmacokinetic targeted IV busulfan (AUC

  12. Low Potential of Basimglurant to Be Involved in Drug-Drug Interactions: Influence of Non-Michaelis-Menten P450 Kinetics on Fraction Metabolized.

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    Fowler, Stephen; Guerini, Elena; Qiu, NaHong; Cleary, Yumi; Parrott, Neil; Greig, Gerard; Mallalieu, Navita L

    2017-01-01

    Basimglurant, a novel mGlu5-negative allosteric modulator under development for the treatment of major depressive disorder, is cleared via cytochrome P450 (P450)-mediated oxidative metabolism. Initial enzyme phenotyping studies indicated that CYP3A4/5 dominates basimglurant metabolism and highlights a risk for drug-drug interactions when it is comedicated with strong CYP3A4/5 inhibitors or inactivators; however, a clinical drug-drug interaction (DDI) study using the potent and selective CYP3A4/5 inhibitor ketoconazole resulted in an area under the curve (AUC) AUCi/AUC ratio of only 1.24. A further study using the CYP3A4 inducer carbamazepine resulted in an AUCi/AUC ratio of 0.69. More detailed in vitro enzyme phenotyping and kinetics studies showed that, at the low concentrations attained clinically, basimglurant metabolic clearance is catalyzed mainly by CYP1A2. The relative contributions of the enzymes were estimated as 70:30 CYP1A2:CYP3A4/5. Using this information, a clinical study using the CYP1A2 inhibitor fluvoxamine was performed, resulting in an AUCi/AUC ratio of 1.60, confirming the role of CYP1A2 and indicating a balanced DDI risk profile. Basimglurant metabolism kinetics show enzyme dependency: CYP1A2-mediated metabolism follows Michaelis-Menten kinetics, whereas CYP3A4 and CYP3A5 follow sigmoidal kinetics [with similar constant (KM) and S50 values]. The interplay of the different enzyme kinetics leads to changing fractional enzyme contributions to metabolism with substrate concentration, even though none of the metabolic enzymes is saturated. This example demonstrates the relevance of non-Michaelis-Menten P450 enzyme kinetics and highlights the need for a thorough understanding of metabolism enzymology to make accurate predictions for human metabolism in vivo.

  13. A Population-Based Clinical Trial of Irinotecan and Carboplatin

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    Derick Lau

    2009-01-01

    Full Text Available Purpose. Phase I trials of anticancer drugs are commonly conducted using the method of modified Fibonacci. We have developed a population-based design for phase I trials of combining anticancer drugs such as irinotecan and carboplatin. Patients and Methods. Intrapatient dose escalation of irinotecan and carboplatin was performed according to a predetermined schema to reach individual dose-limiting toxicity (DLT in 50 patients with solid tumors refractory to previous chemotherapy. The individual toxicity-limiting dose levels were analyzed for normal distribution using the method of Ryan-Joiner and subsequently used to determine a population-based maximum tolerated dose (pMTD. For comparison, a simulation study was performed using the method of modified Fibonacci. Results. The most common dose-limiting toxicities (DLTs included neutropenia (58%, thrombocytopenia (16%, and diarrhea (8%. The frequency of individual toxicity-limiting dose levels of 50 patients approximated a normal distribution. The dose levels associated with individual limiting toxicities ranged from level 1 (irinotecan 100 mg/m2 and carboplatin AUC = 4 mg/mL x min to level 8 (irinotecan 350 mg/m2 and carboplatin AUC = 6. The pMTD was determined to be dose level 3 (150 mg/m2 for irinotecan and AUC = 5 for carboplatin. In contrast, the MTD was determined to be dose level 4 (200 mg/m2 for irinotecan and AUC 5 for carboplatin by modified-Fibonacci simulation. Conclusions. The population-based design of phase I trial allows optimization of dose intensity and derivation of a pMTD. The pMTD has been applied in phase II trial of irinotecan and carboplatin in patients with small-cell lung cancer.

  14. 2D analysis of polydisperse core-shell nanoparticles using analytical ultracentrifugation.

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    Walter, Johannes; Gorbet, Gary; Akdas, Tugce; Segets, Doris; Demeler, Borries; Peukert, Wolfgang

    2016-12-19

    Accurate knowledge of the size, density and composition of nanoparticles (NPs) is of major importance for their applications. In this work the hydrodynamic characterization of polydisperse core-shell NPs by means of analytical ultracentrifugation (AUC) is addressed. AUC is one of the most accurate techniques for the characterization of NPs in the liquid phase because it can resolve particle size distributions (PSDs) with unrivaled resolution and detail. Small NPs have to be considered as core-shell systems when dispersed in a liquid since a solvation layer and a stabilizer shell will significantly contribute to the particle's hydrodynamic diameter and effective density. AUC measures the sedimentation and diffusion transport of the analytes, which are affected by the core-shell compositional properties. This work demonstrates that polydisperse and thus widely distributed NPs pose significant challenges for current state-of-the-art data evaluation methods. The existing methods either have insufficient resolution or do not correctly reproduce the core-shell properties. First, we investigate the performance of different data evaluation models by means of simulated data. Then, we propose a new methodology to address the core-shell properties of NPs. This method is based on the parametrically constrained spectrum analysis and offers complete access to the size and effective density of polydisperse NPs. Our study is complemented using experimental data derived for ZnO and CuInS2 NPs, which do not have a monodisperse PSD. For the first time, the size and effective density of such structures could be resolved with high resolution by means of a two-dimensional AUC analysis approach.

  15. In vivo effect of Schisandrin B on cytochrome P450 enzyme activity.

    Science.gov (United States)

    Li, Wei-Liang; Xin, Hua-Wen; Yu, Ai-Rong; Wu, Xiao-Chun

    2013-06-15

    To investigate the possible drug interaction, this study is designed to evaluate the ability of Schisandrin B (Sch B) to modulate cytochrome P450 3A activity (CYP3A) in vivo and to alter the pharmacokinetic profiles of CYP3A substrate (midazolam) in treated rats. Rats were repeated administered with physiological saline (negative control group), ketoconazole (75 mg/kg, positive control group) or varied doses of Sch B (experimental groups) for three consecutive days. Subsequently, changes in hepatic microsomal CYP3A activity and the pharmacokinetic profiles of midazolam and 1'-hydroxy midazolam in plasma were studied to evaluate CYP3A activity. The results indicated that Sch B significantly dose-dependently inhibited rat hepatic microsomal CYP3A activity with Ki value of 16.64 mg/kg and showed the characteristic of a noncompetitive inhibitor. Oral administration of Sch B for 3 days in rats produced significant effect on the pharmacokinetics of oral midazolam. Sch B resulted in a significant, dose-dependent increase in midazolam AUC0-∞ except at the dose of 2 mg/kg, while AUC0-∞ increased by 26.1% (8 mg/kg) and 60.6% (16 mg/kg), respectively. In the pharmacokinetic profiles of 1'-hydroxy midazolam, the significant, dose-dependent decrease in AUC0-∞ was observed except at the dose of 2 mg/kg, while AUC0-∞ reduced by 44.5% (8 mg/kg) and 49.2% (16 mg/kg), respectively. These results suggested that 3-day treatment of Sch B could increase concentration and oral bioavailability of drug metabolized by CYP3A. When the drug, consisting of Sch B, is used in the clinic for more than 3 days, the possible drug-drug interactions should be taken into consideration.

  16. Accuracy and Calibration of Computational Approaches for Inpatient Mortality Predictive Modeling.

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    Christos T Nakas

    Full Text Available Electronic Health Record (EHR data can be a key resource for decision-making support in clinical practice in the "big data" era. The complete database from early 2012 to late 2015 involving hospital admissions to Inselspital Bern, the largest Swiss University Hospital, was used in this study, involving over 100,000 admissions. Age, sex, and initial laboratory test results were the features/variables of interest for each admission, the outcome being inpatient mortality. Computational decision support systems were utilized for the calculation of the risk of inpatient mortality. We assessed the recently proposed Acute Laboratory Risk of Mortality Score (ALaRMS model, and further built generalized linear models, generalized estimating equations, artificial neural networks, and decision tree systems for the predictive modeling of the risk of inpatient mortality. The Area Under the ROC Curve (AUC for ALaRMS marginally corresponded to the anticipated accuracy (AUC = 0.858. Penalized logistic regression methodology provided a better result (AUC = 0.872. Decision tree and neural network-based methodology provided even higher predictive performance (up to AUC = 0.912 and 0.906, respectively. Additionally, decision tree-based methods can efficiently handle Electronic Health Record (EHR data that have a significant amount of missing records (in up to >50% of the studied features eliminating the need for imputation in order to have complete data. In conclusion, we show that statistical learning methodology can provide superior predictive performance in comparison to existing methods and can also be production ready. Statistical modeling procedures provided unbiased, well-calibrated models that can be efficient decision support tools for predicting inpatient mortality and assigning preventive measures.

  17. Human pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) after repeated doses taken 4 h apart Human pharmacology of MDMA after repeated doses taken 4 h apart.

    Science.gov (United States)

    Farré, Magí; Tomillero, Angels; Pérez-Mañá, Clara; Yubero, Samanta; Papaseit, Esther; Roset, Pere-Nolasc; Pujadas, Mitona; Torrens, Marta; Camí, Jordi; de la Torre, Rafael

    2015-10-01

    3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a popular psychostimulant, frequently associated with multiple administrations over a short period of time. Repeated administration of MDMA in experimental settings induces tolerance and metabolic inhibition. The aim is to determine the acute pharmacological effects and pharmacokinetics resulting from two consecutive 100mg doses of MDMA separated by 4h. Ten male volunteers participated in a randomized, double-blind, crossover, placebo-controlled trial. The four conditions were placebo plus placebo, placebo plus MDMA, MDMA plus placebo, and MDMA plus MDMA. Outcome variables included pharmacological effects and pharmacokinetic parameters. After a second dose of MDMA, most effects were similar to those after a single dose, despite a doubling of MDMA concentrations (except for systolic blood pressure and reaction time). After repeated MDMA administration, a 2-fold increase was observed in MDMA plasma concentrations. For a simple dose accumulation MDMA and MDA concentrations were higher (+23.1% Cmax and +17.1% AUC for MDMA and +14.2% Cmax and +10.3% AUC for MDA) and HMMA and HMA concentrations lower (-43.3% Cmax and -39.9% AUC for HMMA and -33.2% Cmax and -35.1% AUC for HMA) than expected, probably related to MDMA metabolic autoinhibition. Although MDMA concentrations doubled after the second dose, most pharmacological effects were similar or slightly higher in comparison to the single administration, except for systolic blood pressure and reaction time which were greater than predicted. The pharmacokinetic-effects relationship suggests that when MDMA is administered at a 4h interval there exists a phenomenon of acute tolerance to its effects.

  18. Increased Insulin following an Oral Glucose Load, Genetic Variation near the Melatonin Receptor MTNR1B, but No Biochemical Evidence of Endothelial Dysfunction in Young Asian Men and Women.

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    Maria A Matuszek

    Full Text Available To identify biochemical and genetic variation relating to increased risk of developing type 2 diabetes mellitus and cardiovascular disease in young, lean male and female adults of different ethnicities.Fasting blood and urine and non-fasting blood following oral glucose intake were analysed in 90 Caucasians, South Asians and South East/East Asians.There were no differences in age, birthweight, blood pressure, body mass index, percent body fat, total energy, percentage of macronutrient intake, microalbumin, leptin, cortisol, adrenocorticotropic hormone, nitric oxide metabolites, C-reactive protein, homocysteine, tumor necrosis factor-α, interleukin-6, von Willebrand factor, vascular cell adhesion molecule-1, plasminogen activator inhibitor-1, and tissue plasminogen activator. Fasting total cholesterol (P = .000, triglycerides (P = .050, low density lipoprotein (P = .009 and non-fasting blood glucose (15 min (P = .024 were elevated in South Asians compared with Caucasians, but there was no significant difference in glucose area under curve (AUC. Non-fasting insulin in South Asians (15-120 min, in South East/East Asians (60-120 min, and insulin AUC in South Asians and South East/East Asians, were elevated compared with Caucasians (P≤0.006. The molar ratio of C-peptide AUC/Insulin AUC (P = .045 and adiponectin (P = .037 were lower in South Asians compared with Caucasians. A significant difference in allele frequency distributions in Caucasians and South Asians was found for rs2166706 (P = 0.022 and rs10830963 (P = 0.009, which are both near the melatonin receptor MTNR1B.Elevated non-fasting insulin exists in young South Asians of normal fasting glucose and insulin. Hepatic clearance of insulin may be reduced in South Asians. No current biochemical evidence exists of endothelial dysfunction at this stage of development. MTNR1B signalling may be a useful therapeutic target in Asian populations in the prevention of type 2 diabetes mellitus.

  19. Energy dense, protein restricted diet increases adiposity and perturbs metabolism in young, genetically lean pigs.

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    Kimberly D Fisher

    Full Text Available Animal models of obesity and metabolic dysregulation during growth (or childhood are lacking. Our objective was to increase adiposity and induce metabolic syndrome in young, genetically lean pigs. Pre-pubertal female pigs, age 35 d, were fed a high-energy diet (HED; n = 12, containing 15% tallow, 35% refined sugars and 9.1-12.9% crude protein, or a control corn-based diet (n = 11 with 12.2-19.2% crude protein for 16 wk. Initially, HED pigs self-regulated energy intake similar to controls, but by wk 5, consumed more (P<0.001 energy per kg body weight. At wk 15, pigs were subjected to an oral glucose tolerance test (OGTT; blood glucose increased (P<0.05 in control pigs and returned to baseline levels within 60 min. HED pigs were hyperglycemic at time 0, and blood glucose did not return to baseline (P = 0.01, even 4 h post-challenge. During OGTT, glucose area under the curve (AUC was higher and insulin AUC was lower in HED pigs compared to controls (P = 0.001. Chronic HED intake increased (P<0.05 subcutaneous, intramuscular, and perirenal fat deposition, and induced hyperglycemia, hypoinsulinemia, and low-density lipoprotein hypercholesterolemia. A subset of HED pigs (n = 7 was transitioned back to a control diet for an additional six weeks. These pigs were subjected to an additional OGTT at 22 wk. Glucose AUC and insulin AUC did not improve, supporting that dietary intervention was not sufficient to recover glucose tolerance or insulin production. These data suggest a HED may be used to increase adiposity and disrupt glucose homeostasis in young, growing pigs.

  20. Electrically contractile polymers augment right ventricular output in the heart.

    Science.gov (United States)

    Ruhparwar, Arjang; Piontek, Patricia; Ungerer, Matthias; Ghodsizad, Ali; Partovi, Sasan; Foroughi, Javad; Szabo, Gabor; Farag, Mina; Karck, Matthias; Spinks, Geoffrey M; Kim, Seon Jeong

    2014-12-01

    Research into the development of artificial heart muscle has been limited to assembly of stem cell-derived cardiomyocytes seeded around a matrix, while nonbiological approaches to tissue engineering have rarely been explored. The aim of the study was to apply electrically contractile polymer-based actuators as cardiomyoplasty for positive inotropic support of the right ventricle. Complex trilayer polypyrrole (PPy) bending polymers for high-speed applications were generated. Bending motion occurred directly as a result of electrochemically driven charging and discharging of the PPy layers. In a rat model (n = 5), strips of polymers (3 × 20 mm) were attached and wrapped around the right ventricle (RV). RV pressure was continuously monitored invasively by direct RV cannulation. Electrical activation occurred simultaneously with either diastole (in order to evaluate the polymer's stand-alone contraction capacity; group 1) or systole (group 2). In group 1, the pressure generation capacity of the polymers was measured by determining the area under the pressure curve (area under curve, AUC). In group 2, the RV pressure AUC was measured in complexes directly preceding those with polymer contraction and compared to RV pressure complexes with simultaneous polymer contraction. In group 1, the AUC generated by polymer contraction was 2768 ± 875 U. In group 2, concomitant polymer contraction significantly increased AUC compared with complexes without polymer support (5987 ± 1334 U vs. 4318 ± 691 U, P ≤ 0.01). Electrically contractile polymers are able to significantly augment right ventricular contraction. This approach may open new perspectives for myocardial tissue engineering, possibly in combination with fetal or embryonic stem cell-derived cardiomyocytes.

  1. Bladder Cancer Segmentation in CT for Treatment Response Assessment: Application of Deep-Learning Convolution Neural Network—A Pilot Study

    Science.gov (United States)

    Cha, Kenny H.; Hadjiiski, Lubomir M.; Samala, Ravi K.; Chan, Heang-Ping; Cohan, Richard H.; Caoili, Elaine M.; Paramagul, Chintana; Alva, Ajjai; Weizer, Alon Z.

    2017-01-01

    Assessing the response of bladder cancer to neoadjuvant chemotherapy is crucial for reducing morbidity and increasing quality of life of patients. Changes in tumor volume during treatment is generally used to predict treatment outcome. We are developing a method for bladder cancer segmentation in CT using a pilot data set of 62 cases. 65 000 regions of interests were extracted from pre-treatment CT images to train a deep-learning convolution neural network (DL-CNN) for tumor boundary detection using leave-one-case-out cross-validation. The results were compared to our previous AI-CALS method. For all lesions in the data set, the longest diameter and its perpendicular were measured by two radiologists, and 3D manual segmentation was obtained from one radiologist. The World Health Organization (WHO) criteria and the Response Evaluation Criteria In Solid Tumors (RECIST) were calculated, and the prediction accuracy of complete response to chemotherapy was estimated by the area under the receiver operating characteristic curve (AUC). The AUCs were 0.73 ± 0.06, 0.70 ± 0.07, and 0.70 ± 0.06, respectively, for the volume change calculated using DL-CNN segmentation, the AI-CALS and the manual contours. The differences did not achieve statistical significance. The AUCs using the WHO criteria were 0.63 ± 0.07 and 0.61 ± 0.06, while the AUCs using RECIST were 0.65 ± 007 and 0.63 ± 0.06 for the two radiologists, respectively. Our results indicate that DL-CNN can produce accurate bladder cancer segmentation for calculation of tumor size change in response to treatment. The volume change performed better than the estimations from the WHO criteria and RECIST for the prediction of complete response. PMID:28105470

  2. When Do Governments Concede to Terrorists

    Science.gov (United States)

    2014-06-01

    which started out as a civil war and has continued 9 until today’s conflict that involves terrorists, drug cartels , and self-defense groups. What...power between the government and terrorist groups (FARC), drug cartels , and paramilitary self-defense 10 groups (AUC). It is similar to La...http://www.nytimes.com/2013/07/22/world/americas/colombian- rebels-kill-19-soldiers.html Richardson, L. (2007). Britain and the IRA. In R. Art & L

  3. Predicting death from kala-azar: construction, development, and validation of a score set and accompanying software

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    Dorcas Lamounier Costa

    Full Text Available Abstract INTRODUCTION Early identification of patients at higher risk of progressing to severe disease and death is crucial for implementing therapeutic and preventive measures; this could reduce the morbidity and mortality from kala-azar. We describe a score set composed of four scales in addition to software for quick assessment of the probability of death from kala-azar at the point of care. METHODS: Data from 883 patients diagnosed between September 2005 and August 2008 were used to derive the score set, and data from 1,031 patients diagnosed between September 2008 and November 2013 were used to validate the models. Stepwise logistic regression analyses were used to derive the optimal multivariate prediction models. Model performance was assessed by its discriminatory accuracy. A computational specialist system (Kala-Cal(r was developed to speed up the calculation of the probability of death based on clinical scores. RESULTS: The clinical prediction score showed high discrimination (area under the curve [AUC] 0.90 for distinguishing death from survival for children ≤2 years old. Performance improved after adding laboratory variables (AUC 0.93. The clinical score showed equivalent discrimination (AUC 0.89 for older children and adults, which also improved after including laboratory data (AUC 0.92. The score set also showed a high, although lower, discrimination when applied to the validation cohort. CONCLUSIONS: This score set and Kala-Cal(r software may help identify individuals with the greatest probability of death. The associated software may speed up the calculation of the probability of death based on clinical scores and assist physicians in decision-making.

  4. A comparison of Child-Pugh, APACHE II and APACHE III scoring systems in predicting hospital mortality of patients with liver cirrhosis

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    Romanos John

    2003-05-01

    Full Text Available Abstract Background The aim of this study was to assess the prognostic accuracy of Child-Pugh and APACHE II and III scoring systems in predicting short-term, hospital mortality of patients with liver cirrhosis. Methods 200 admissions of 147 cirrhotic patients (44% viral-associated liver cirrhosis, 33% alcoholic, 18.5% cryptogenic, 4.5% both viral and alcoholic were studied prospectively. Clinical and laboratory data conforming to the Child-Pugh, APACHE II and III scores were recorded on day 1 for all patients. Discrimination was evaluated using receiver operating characteristic (ROC curves and area under a ROC curve (AUC. Calibration was estimated using the Hosmer-Lemeshow goodness-of-fit test. Results Overall mortality was 11.5%. The mean Child-Pugh, APACHE II and III scores for survivors were found to be significantly lower than those of nonsurvivors. Discrimination was excellent for Child-Pugh (ROC AUC: 0.859 and APACHE III (ROC AUC: 0.816 scores, and acceptable for APACHE II score (ROC AUC: 0.759. Although the Hosmer-Lemeshow statistic revealed adequate goodness-of-fit for Child-Pugh score (P = 0.192, this was not the case for APACHE II and III scores (P = 0.004 and 0.003 respectively Conclusion Our results indicate that, of the three models, Child-Pugh score had the least statistically significant discrepancy between predicted and observed mortality across the strata of increasing predicting mortality. This supports the hypothesis that APACHE scores do not work accurately outside ICU settings.

  5. Effects of Fuscoporia obliqua on Postprandial Glucose Excursion and Endothelial Dysfunction in Type 2 Diabetic Patients

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Postprandial hyperglycemia has been reported to elicit endothelial dysfunction and provoke future cardiovascular complications. A reduction of postprandial blood glucose levels by the glucosidase inhibitor Fuscoporia obliqua was associated with a risk reduction of cardiovascular complications, but the effects of Fuscoporia obliqua on endothelial function have never been elucidated. This study is aimed to assess the efficacy of Fuscoporia obliqua on postprandial metabolic parameters and endothelial function in type 2 diabetic patients. Postprandial peak glucose (14.47±1.27 vs. 8.50±0.53 mmol/liter), plasma glucose excursion (PPGE), and change in the area under the curve (AUC) glucose after a single loading of test meal (total 450 kcal; protein 15.3%; fat 32.3%; carbohydrate 51.4%) were significantly higher in the diet-treated type 2 diabetic patients (n=14) than the age- and sex-matched controls (n=12). The peak forearm blood flow response and total reactive hyperemic flow (flow debt repayment) during reactive hyperemia, indices of resistance artery endothelial function on strain-gauge plethysmography, were unchanged before and after meal loading in the controls. But those of the diabetics were significantly decreased 120 and 240 min after the test meal. A prior administration of Fuscoporia obliqua decreased postprandial peak glucose, PPGE, and AUC glucose. The peak forearm blood flow and flow debt repayment were inversely well correlated with peak glucose, PPGE, and AUC glucose, but not with AUC insulin or the other lipid parameters. Even a single loading of the test meal was shown to impair the endothelial function in type 2 diabetic patients, and the postprandial endothelial dysfunction was improved by a prior use of Fuscoporia obliqua. Fuscoporia obliqua might reduce macrovascular complication by avoiding endothelial injury in postprandial hyperglycemic status.

  6. Pharmacokinetics of CPU0213, a novel endothelin receptor antagonist, after intravenous administration in mice

    Institute of Scientific and Technical Information of China (English)

    Li GUAN; Yu FENG; Min JI; De-zai DAI

    2006-01-01

    Aim: To determine the pharmacokinetics associated with acute toxic doses of CPU0213, a novel endothelin receptor antagonist in mice after a single intravenous administration. Methods: Concentrations in serum and the pharmacokinetic parameters of CPU0213 were assayed by high pressure liquid chromatography (HPLC) following a single intravenous bolus of CPU0213 at concentrations of 25, 50, and 100 mg/kg in mice. The intravenous acute toxicity of CPU0213 was also assessed in mice. Results: A simple, sensitive and selective HPLC method was developed for quantitative determination of CPU0213 in mouse serum. The concentration-time data conform to a 2-compartment model after iv administration of CPU0213 at concentrations of 25, 50,100 mg/kg. The corresponding distribution half-lives (T1/2α) were 3.6, 4.2, 1.1 min and the elimination half-lives (T1/2β) were 39.4,70.3,61.9 min. There was a linear increase in C0 proportional to dose, and the same as AUC0-t and AUC0-∞. AUC0-t and AUC0-∞ were 4.511,13.070,23.666 g·min·L-1 and 4.596,13.679,24.115 g·min·L-1, respectively. The intravenous LD50 was 315.5 mg/kg. Conclusion: First order rate pharmacokinetics were observed for CPU0213 within the range of doses used, and the acute toxicity of CPU0213 is mild.

  7. Comparative bioequivalence study of leflunomide tablets in Indian healthy volunteers.

    Science.gov (United States)

    Agarwal, S; Das, A; Ghosh, D; Sarkar, A K; Chattaraj, T K; Pal, T K

    2012-03-01

    The pharmacokinetics of teriflunomide [CAS No. 163451-81-8], the metabolite of leflunomide [CAS No. 75706-12-6] has been evaluated in adult human volunteers after oral administration of tablet formulation. However, no published data is available regarding the bioavailability of this in the Indian population. In light of the above, a study was designed to carry out a bioequivalence study of 2 preparations of leflunomide 20 mg in healthy Indian male volunteers.24 healthy male volunteers (age, 25±4.1 years; weight, 57.58±7.01 kg) were enrolled in this study. Each subject received a test and reference formulation in a single dose, fasting 2 period, 2 way crossover study with a wash out period of 4 weeks. Analysis of teriflunomide from plasma samples was done by a simple and sensitive HPLC method using UV detection developed in our laboratory. An analysis of variance was performed on the pharmacokinetic parameters Cmax, AUC0-t, AUC0-∞ using GLM procedures in which sources of variation were subject, formulation, and period.The results indicated that there are no statistically significant differences between the 2 products in either the mean concentration-time profiles or in the obtained pharmacokinetic parameters. 90% confidence limits for the log transformed data of Cmax, AUC0-t, AUC0-∞. were within the acceptable range of 0.80-1.25.The results indicate that the 2 products are bioequivalent in terms of rate and extent of drug absorption. Both the preparations were well tolerated with no adverse reactions throughout the study.

  8. Simple and Robust Analysis of Cefuroxime in Human Plasma by LC-MS/MS: Application to a Bioequivalence Study

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    Xingjiang Hu

    2014-01-01

    Full Text Available A simple, robust LC-MS/MS assay for quantifying cefuroxime in human plasma was developed. Cefuroxime and tazobactam, as internal standard (IS, were extracted from human plasma by methanol to precipitate protein. Separation was achieved on a Zorbax SB-Aq (4.6×250 mm, 5 μm column under isocratic conditions. The calibration curve was linear in the concentration range of 0.0525–21.0 μg/mL (r=0.9998. The accuracy was higher than 90.92%, while the intra- and interday precision were less t