An Integrated Finite Element-based Simulation Framework: From Hole Piercing to Hole Expansion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hu, Xiaohua; Sun, Xin; Golovashchenko, Segey F.

An integrated finite element-based modeling framework is developed to predict the hole expansion ratio (HER) of AA6111-T4 sheet by considering the piercing-induced damages around the hole edge. Using damage models and parameters calibrated from previously reported tensile stretchability studies, the predicted HER correlates well with experimentally measured HER values for different hole piercing clearances. The hole piercing model shows burrs are not generated on the sheared surface for clearances less than 20%, which corresponds well with the experimental data on pierced holes cross-sections. Finite-element-calculated HER also is not especially sensitive to piercing clearances less than this value. However, as clearancesmore » increase to 30% and further to 40%, the HER values are predicted to be considerably smaller, also consistent with experimental measurements. Upon validation, the integrated modeling framework is used to examine the effects of different hole piercing and hole expansion conditions on the critical HERs for AA6111-T4.« less

Dexmedetomidine metabolic clearance is not affected by fat mass in obese patients.

PubMed

Rolle, A; Paredes, S; Cortínez, L I; Anderson, B J; Quezada, N; Solari, S; Allende, F; Torres, J; Cabrera, D; Contreras, V; Carmona, J; Ramírez, C; Oliveros, A M; Ibacache, M

2018-05-01

Obesity has been associated with reduced dexmedetomidine clearance, suggesting impaired hepatic function or reduced hepatic blood flow. The aim of this study was to clarify the effect of obesity in dexmedetomidine metabolic clearance. Forty patients, ASA I-III, 18-60 yr old, weighing 47-126 kg, scheduled for abdominal laparoscopic surgery, were enrolled. Anaesthetic agents (propofol, remifentanil, and dexmedetomidine) were dosed based on lean body weight measured by dual X-ray absorptiometry. Serial venous samples were drawn during and after dexmedetomidine infusion. A pharmacokinetic analysis was undertaken using non-linear mixed-effect models. In the modelling approach, the total body weight, lean body weight, and adjusted body weight were first tested as size descriptors for volumes and clearances. Hepatic blood flow, liver histopathology, liver enzymes, and gene expression of metabolic enzymes (UGT2B10 and UGT1A4) were tested as covariates of dexmedetomidine metabolic clearance. A decrease in NONMEM objective function value (ΔOFV) of 3.84 points, for an added parameter, was considered significant at the 0.05 level. A total of 637 dexmedetomidine serum samples were obtained. A two-compartmental model scaled to measured lean weight adequately described the dexmedetomidine pharmacokinetics. Liver blood flow was a covariate for dexmedetomidine clearance (ΔOFV=-5.878). Other factors, including fat mass, histopathological damage, and differential expression of enzymes, did not affect the dexmedetomidine clearance in the population studied (ΔOFV<3.84). We did not find a negative influence of obesity in dexmedetomidine clearance when doses were adjusted to lean body weight. Liver blood flow showed a significant effect on dexmedetomidine clearance. NCT02557867. Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

Predicting lung dosimetry of inhaled particleborne benzo[a]pyrene using physiologically based pharmacokinetic modeling

PubMed Central

Campbell, Jerry; Franzen, Allison; Van Landingham, Cynthia; Lumpkin, Michael; Crowell, Susan; Meredith, Clive; Loccisano, Anne; Gentry, Robinan; Clewell, Harvey

2016-01-01

Abstract Benzo[a]pyrene (BaP) is a by-product of incomplete combustion of fossil fuels and plant/wood products, including tobacco. A physiologically based pharmacokinetic (PBPK) model for BaP for the rat was extended to simulate inhalation exposures to BaP in rats and humans including particle deposition and dissolution of absorbed BaP and renal elimination of 3-hydroxy benzo[a]pyrene (3-OH BaP) in humans. The clearance of particle-associated BaP from lung based on existing data in rats and dogs suggest that the process is bi-phasic. An initial rapid clearance was represented by BaP released from particles followed by a slower first-order clearance that follows particle kinetics. Parameter values for BaP-particle dissociation were estimated using inhalation data from isolated/ventilated/perfused rat lungs and optimized in the extended inhalation model using available rat data. Simulations of acute inhalation exposures in rats identified specific data needs including systemic elimination of BaP metabolites, diffusion-limited transfer rates of BaP from lung tissue to blood and the quantitative role of macrophage-mediated and ciliated clearance mechanisms. The updated BaP model provides very good prediction of the urinary 3-OH BaP concentrations and the relative difference between measured 3-OH BaP in nonsmokers versus smokers. This PBPK model for inhaled BaP is a preliminary tool for quantifying lung BaP dosimetry in rat and humans and was used to prioritize data needs that would provide significant model refinement and robust internal dosimetry capabilities. PMID:27569524

Theoretic criteria for antibody penetration into solid tumors and micrometastases.

PubMed

Thurber, Greg M; Zajic, Stefan C; Wittrup, K Dane

2007-06-01

Targeting tumors with antibody-based therapeutics is a complex task presenting multiple kinetic barriers. Antibody internalization and clearance inhibit uptake both in solid tumors, limited by tumor vascular permeability, and in micrometastases, limited by diffusion. A modeling exercise is used to introduce 2 simple criteria that must be less than unity for saturation of both tumors and micrometastases. The clearance modulus and the Thiele modulus are ratios of the plasma clearance rate and antibody catabolism, respectively, to the tumor tissue penetration rate. Even low rates of antigen internalization from constitutive membrane turnover can significantly retard antibody penetration. Rapid clearance of single-chain variable fragments also hinders uptake, often more than counterbalancing their more rapid extravasation and diffusion. The model illustrates that with the large resistance from the tumor capillary, antibodies may be more suitable for targeting micrometastases than vascularized tumors.

Creatinine generation from kinetic modeling with or without postdialysis serum creatinine measurement: results from the HEMO study.

PubMed

Daugirdas, John T; Depner, Thomas A

2017-11-01

A convenient method to estimate the creatinine generation rate and measures of creatinine clearance in hemodialysis patients using formal kinetic modeling and standard pre- and postdialysis blood samples has not been described. We used data from 366 dialysis sessions characterized during follow-up month 4 of the HEMO study, during which cross-dialyzer clearances for both urea and creatinine were available. Blood samples taken at 1 h into dialysis and 30 min and 60 min after dialysis were used to determine how well a two-pool kinetic model could predict creatinine concentrations and other kinetic parameters, including the creatinine generation rate. An extrarenal creatinine clearance of 0.038 l/kg/24 h was included in the model. Diffusive cross-dialyzer clearances of urea [230 (SD 37 mL/min] correlated well (R2 = 0.78) with creatinine clearances [164 (SD 30) mL/min]. When the effective diffusion volume flow rate was set at 0.791 times the blood flow rate for the cross-dialyzer clearance measurements at 1 h into dialysis, the mean calculated volume of creatinine distribution averaged 29.6 (SD 7.2) L], compared with 31.6 (SD 7.0) L for urea (P < 0.01). The modeled creatinine generation rate [1183 (SD 463) mg/day] averaged 100.1 % (SD 29; median 99.3) of that predicted in nondialysis patients by an anthropometric equation. A simplified method for modeling the creatinine generation rate using the urea distribution volume and urea dialyzer clearance without use of the postdialysis serum creatinine measurement gave results for creatinine generation rate [1187 (SD 475) mg/day; that closely matched the value calculated using the formally modeled value, R2 = 0.971]. Our analysis confirms previous findings of similar distribution volumes for creatinine and urea. After taking extra-renal clearance into consideration, the creatinine generation rate in dialysis patients is similar to that in nondialysis patients. A simplified method based on urea clearance and urea distribution volume not requiring a postdialysis serum creatinine measurement can be used to yield creatinine generation rates that closely match those determined from standard modeling. © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Output Error Analysis of Planar 2-DOF Five-bar Mechanism

NASA Astrophysics Data System (ADS)

Niu, Kejia; Wang, Jun; Ting, Kwun-Lon; Tao, Fen; Cheng, Qunchao; Wang, Quan; Zhang, Kaiyang

2018-03-01

Aiming at the mechanism error caused by clearance of planar 2-DOF Five-bar motion pair, the method of equivalent joint clearance of kinematic pair to virtual link is applied. The structural error model of revolute joint clearance is established based on the N-bar rotation laws and the concept of joint rotation space, The influence of the clearance of the moving pair is studied on the output error of the mechanis. and the calculation method and basis of the maximum error are given. The error rotation space of the mechanism under the influence of joint clearance is obtained. The results show that this method can accurately calculate the joint space error rotation space, which provides a new way to analyze the planar parallel mechanism error caused by joint space.

Applications of minimal physiologically-based pharmacokinetic models

PubMed Central

Cao, Yanguang

2012-01-01

Conventional mammillary models are frequently used for pharmacokinetic (PK) analysis when only blood or plasma data are available. Such models depend on the quality of the drug disposition data and have vague biological features. An alternative minimal-physiologically-based PK (minimal-PBPK) modeling approach is proposed which inherits and lumps major physiologic attributes from whole-body PBPK models. The body and model are represented as actual blood and tissue usually total body weight) volumes, fractions (fd) of cardiac output with Fick’s Law of Perfusion, tissue/blood partitioning (Kp), and systemic or intrinsic clearance. Analyzing only blood or plasma concentrations versus time, the minimal-PBPK models parsimoniously generate physiologically-relevant PK parameters which are more easily interpreted than those from mam-millary models. The minimal-PBPK models were applied to four types of therapeutic agents and conditions. The models well captured the human PK profiles of 22 selected beta-lactam antibiotics allowing comparison of fitted and calculated Kp values. Adding a classical hepatic compartment with hepatic blood flow allowed joint fitting of oral and intravenous (IV) data for four hepatic elimination drugs (dihydrocodeine, verapamil, repaglinide, midazolam) providing separate estimates of hepatic intrinsic clearance, non-hepatic clearance, and pre-hepatic bioavailability. The basic model was integrated with allometric scaling principles to simultaneously describe moxifloxacin PK in five species with common Kp and fd values. A basic model assigning clearance to the tissue compartment well characterized plasma concentrations of six monoclonal antibodies in human subjects, providing good concordance of predictions with expected tissue kinetics. The proposed minimal-PBPK modeling approach offers an alternative and more rational basis for assessing PK than compartmental models. PMID:23179857

Prediction of paraquat exposure and toxicity in clinically ill poisoned patients: a model based approach.

PubMed

Wunnapuk, Klintean; Mohammed, Fahim; Gawarammana, Indika; Liu, Xin; Verbeeck, Roger K; Buckley, Nicholas A; Roberts, Michael S; Musuamba, Flora T

2014-10-01

Paraquat poisoning is a medical problem in many parts of Asia and the Pacific. The mortality rate is extremely high as there is no effective treatment. We analyzed data collected during an ongoing cohort study on self-poisoning and from a randomized controlled trial assessing the efficacy of immunosuppressive therapy in hospitalized paraquat-intoxicated patients. The aim of this analysis was to characterize the toxicokinetics and toxicodynamics of paraquat in this population. A non-linear mixed effects approach was used to perform a toxicokinetic/toxicodynamic population analysis in a cohort of 78 patients. The paraquat plasma concentrations were best fitted by a two compartment toxicokinetic structural model with first order absorption and first order elimination. Changes in renal function were used for the assessment of paraquat toxicodynamics. The estimates of toxicokinetic parameters for the apparent clearance, the apparent volume of distribution and elimination half-life were 1.17 l h(-1) , 2.4 l kg(-1) and 87 h, respectively. Renal function, namely creatinine clearance, was the most significant covariate to explain between patient variability in paraquat clearance.This model suggested that a reduction in paraquat clearance occurred within 24 to 48 h after poison ingestion, and afterwards the clearance was constant over time. The model estimated that a paraquat concentration of 429 μg l(-1) caused 50% of maximum renal toxicity. The immunosuppressive therapy tested during this study was associated with only 8% improvement of renal function. The developed models may be useful as prognostic tools to predict patient outcome based on patient characteristics on admission and to assess drug effectiveness during antidote drug development. © 2014 The British Pharmacological Society.

A physiologically based pharmacokinetic model to predict the pharmacokinetics of highly protein-bound drugs and the impact of errors in plasma protein binding.

PubMed

Ye, Min; Nagar, Swati; Korzekwa, Ken

2016-04-01

Predicting the pharmacokinetics of highly protein-bound drugs is difficult. Also, since historical plasma protein binding data were often collected using unbuffered plasma, the resulting inaccurate binding data could contribute to incorrect predictions. This study uses a generic physiologically based pharmacokinetic (PBPK) model to predict human plasma concentration-time profiles for 22 highly protein-bound drugs. Tissue distribution was estimated from in vitro drug lipophilicity data, plasma protein binding and the blood: plasma ratio. Clearance was predicted with a well-stirred liver model. Underestimated hepatic clearance for acidic and neutral compounds was corrected by an empirical scaling factor. Predicted values (pharmacokinetic parameters, plasma concentration-time profile) were compared with observed data to evaluate the model accuracy. Of the 22 drugs, less than a 2-fold error was obtained for the terminal elimination half-life (t1/2 , 100% of drugs), peak plasma concentration (Cmax , 100%), area under the plasma concentration-time curve (AUC0-t , 95.4%), clearance (CLh , 95.4%), mean residence time (MRT, 95.4%) and steady state volume (Vss , 90.9%). The impact of fup errors on CLh and Vss prediction was evaluated. Errors in fup resulted in proportional errors in clearance prediction for low-clearance compounds, and in Vss prediction for high-volume neutral drugs. For high-volume basic drugs, errors in fup did not propagate to errors in Vss prediction. This is due to the cancellation of errors in the calculations for tissue partitioning of basic drugs. Overall, plasma profiles were well simulated with the present PBPK model. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Mechanism-based pharmacokinetic modeling to evaluate transporter-enzyme interplay in drug interactions and pharmacogenetics of glyburide.

PubMed

Varma, Manthena V S; Scialis, Renato J; Lin, Jian; Bi, Yi-An; Rotter, Charles J; Goosen, Theunis C; Yang, Xin

2014-07-01

The purpose of this study is to characterize the involvement of hepato-biliary transport and cytochrome-P450 (CYP)-mediated metabolism in the disposition of glyburide and predict its pharmacokinetic variability due to drug interactions and genetic variations. Comprehensive in vitro studies suggested that glyburide is a highly permeable drug with substrate affinity to multiple efflux pumps and to organic anion transporting polypeptide (OATP)1B1 and OATP2B1. Active hepatic uptake was found to be significantly higher than the passive uptake clearance (15.8 versus 5.3 μL/min/10(6)-hepatocytes), using the sandwich-cultured hepatocyte model. In vitro, glyburide is metabolized (intrinsic clearance, 52.9 μL/min/mg-microsomal protein) by CYP3A4, CYP2C9, and CYP2C8 with fraction metabolism of 0.53, 0.36, and 0.11, respectively. Using these in vitro data, physiologically based pharmacokinetic models, assuming rapid-equilibrium between blood and liver compartments or permeability-limited hepatic disposition, were built to describe pharmacokinetics and evaluate drug interactions. Permeability-limited model successfully predicted glyburide interactions with rifampicin and other perpetrator drugs. Conversely, model assuming rapid-equilibrium mispredicted glyburide interactions, overall, suggesting hepatic uptake as the primary rate-determining process in the systemic clearance of glyburide. Further modeling and simulations indicated that the impairment of CYP2C9 function has a minimal effect on the systemic exposure, implying discrepancy in the contribution of CYP2C9 to glyburide clearance.

An enhanced flexible dynamic model and experimental verification for a valve train with clearance and multi-directional deformations

NASA Astrophysics Data System (ADS)

Zhou, Changjiang; Hu, Bo; Chen, Siyu; He, Liping

2017-12-01

An enhanced flexible dynamic model for a valve train with clearance and multi-directional deformations is proposed based on finite element method (FEM), and verified by experiment. According to the measured cam profile, the available internal excitations in numerical solution to the model are achieved by using piecewise cubic Hermite interpolating polynomial. The comparative analysis demonstrates that the bending deformation of the rocker arm is much larger than the radial deformation, signifying the necessities of multi-directional deformations in dynamic analysis for the valve train. The effects of valve clearance and cam rotation speed on contact force, acceleration and dynamic transmission error (DTE) are investigated. Both theoretical predictions and experimental measurements show that the amplitudes and fluctuations of contact force, acceleration and DTE become larger, when the valve clearance or cam speed increases. It is found that including the elasticity and the damping will weaken the impact between the rocker arm and the valve on the components (not adjacent to the valve) at either unseating or seating scenario. Additionally, as valve clearance or cam rotation speed becomes larger, the valve lift and the working phase decrease, which eventually leads to inlet air reduction. Furthermore, our study shows that the combustion rate improvement, input torque, and components durability can be improved by tuning valve clearance or adjustment the cam profile.

Predicting Human Clearance of OATP substrates using Cynomolgus monkey: In vitro-in vivo scaling of hepatic uptake clearance.

PubMed

de Bruyn, Tom; Ufuk, Ayse; Cantrill, Carina; Kosa, Rachel E; Bi, Yi-An; Niosi, Mark; Modi, Sweta; Rodrigues, A David; Tremaine, Larry M; Varma, Manthena Vs; Galetin, Aleksandra; Houston, J Brian

2018-05-02

This work explores the utility of the cynomolgus monkey as a preclinical model to predict hepatic uptake clearance mediated by organic anion transporting polypeptide (OATP) transporters. Nine OATP substrates (rosuvastatin, pravastatin, repaglinide, fexofenadine, cerivastatin, telmisartan, pitavastatin, bosentan and valsartan) were investigated in plated cynomolgus monkey and human hepatocytes. Total uptake clearance and passive diffusion were measured in vitro from initial rates in the absence and presence of the OATP inhibitor rifamycin SV, respectively. Total uptake clearance values in plated hepatocytes ranged over three orders of magnitude in both species with a similar rank order and good agreement in the relative contribution of active transport to total uptake between cynomolgus monkey and human. In vivo hepatic clearance for these nine drugs was determined in cynomolgus monkey after intravenous dosing. Hepatic clearances showed a similar range to human parameters and good predictions from respective hepatocyte parameters (with 2.7 and 3.8-fold bias on average, respectively). The use of cross species empirical scaling factors (based on either dataset average or individual drug scaling factor from cynomolgus monkey data) improved prediction (less bias, better concordance) of human hepatic clearance from human hepatocyte data alone. In vitro intracellular binding in hepatocytes also correlated well between species. It is concluded that the minimal species differences observed for the current dataset between cynomolgus monkey and human hepatocyte uptake, both in vitro and in vivo, support future use of this preclinical model to delineate drug hepatic uptake and enable prediction of human in vivo intrinsic hepatic clearance. The American Society for Pharmacology and Experimental Therapeutics.

A statistical model of diurnal variation in human growth hormone

NASA Technical Reports Server (NTRS)

Klerman, Elizabeth B.; Adler, Gail K.; Jin, Moonsoo; Maliszewski, Anne M.; Brown, Emery N.

2003-01-01

The diurnal pattern of growth hormone (GH) serum levels depends on the frequency and amplitude of GH secretory events, the kinetics of GH infusion into and clearance from the circulation, and the feedback of GH on its secretion. We present a two-dimensional linear differential equation model based on these physiological principles to describe GH diurnal patterns. The model characterizes the onset times of the secretory events, the secretory event amplitudes, as well as the infusion, clearance, and feedback half-lives of GH. We illustrate the model by using maximum likelihood methods to fit it to GH measurements collected in 12 normal, healthy women during 8 h of scheduled sleep and a 16-h circadian constant-routine protocol. We assess the importance of the model components by using parameter standard error estimates and Akaike's Information Criterion. During sleep, both the median infusion and clearance half-life estimates were 13.8 min, and the median number of secretory events was 2. During the constant routine, the median infusion half-life estimate was 12.6 min, the median clearance half-life estimate was 11.7 min, and the median number of secretory events was 5. The infusion and clearance half-life estimates and the number of secretory events are consistent with current published reports. Our model gave an excellent fit to each GH data series. Our analysis paradigm suggests an approach to decomposing GH diurnal patterns that can be used to characterize the physiological properties of this hormone under normal and pathological conditions.

Tip clearance effects on loads and performances of semi-open impeller centrifugal pumps at different specific speeds

NASA Astrophysics Data System (ADS)

Boitel, G.; Fedala, D.; Myon, N.

2016-11-01

Relevant industrial standards or customer's specifications could strictly forbid any device adjusting the axial rotor/stator position, so that tip clearance between semi-open impeller and casing might become a result of the pump machining tolerances and assembling process, leading to big tip clearance variations compared to its nominal value. Consequently, large disparities of global performances (head, power, efficiency) and axial loads are observed with high risk of both specifications noncompliance and bearing damages. This work aims at quantifying these variations by taking into account tip clearance value and pump specific speed. Computational Fluid Dynamics is used to investigate this phenomenon by means of steady simulations led on a semi-open centrifugal pump numerical model including secondary flows, based on a k-omega SST turbulence model. Four different specific speed pump sizes are simulated (from 8 to 50, SI units), with three tip clearances for each size on a wide flow range (from 40% to 120% of the best efficiency point). The numerical results clearly show that head, power and efficiency increase as the tip clearance decreases for the whole flow range. This effect is more significant when the specific speed is low. Meanwhile, the resulting axial thrust on the impeller is very sensitive to the tip clearance and can even lead to direction inversion.

Integrated Turbine Tip Clearance and Gas Turbine Engine Simulation

NASA Technical Reports Server (NTRS)

Chapman, Jeffryes W.; Kratz, Jonathan; Guo, Ten-Huei; Litt, Jonathan

2016-01-01

Gas turbine compressor and turbine blade tip clearance (i.e., the radial distance between the blade tip of an axial compressor or turbine and the containment structure) is a major contributing factor to gas path sealing, and can significantly affect engine efficiency and operational temperature. This paper details the creation of a generic but realistic high pressure turbine tip clearance model that may be used to facilitate active tip clearance control system research. This model uses a first principles approach to approximate thermal and mechanical deformations of the turbine system, taking into account the rotor, shroud, and blade tip components. Validation of the tip clearance model shows that the results are realistic and reflect values found in literature. In addition, this model has been integrated with a gas turbine engine simulation, creating a platform to explore engine performance as tip clearance is adjusted. Results from the integrated model explore the effects of tip clearance on engine operation and highlight advantages of tip clearance management.

On the influence of pseudoelastic material behaviour in planar shape-memory tubular continuum structures

NASA Astrophysics Data System (ADS)

Greiner-Petter, Christoph; Sattel, Thomas

2017-12-01

For planar tubular continuum structures based on precurved shape memory alloy tubes a beam model with respect to the pseudoelastic material behaviour of NiTi is derived. Thereunto a constitutive material law respecting tension-compression asymmetry as well as hysteresis is used. The beam model is then employed to calculate equilibrium curvatures of concentric tube assemblies without clearance between the tubes. In a second step, the influence of clearance is approximated to account for non-concentric tube assemblies. These elastokinematic results are integrated into a purely kinematic model to describe the cannula path under the presence of material hysteresis and clearance. Finally a photogrammetric measurement system is used to track the path of an exemplary two-tube continuum structure to examine the accuracy of the proposed model. It is shown that material hysteresis leads to a hysteresis phenomena in the path of the tubular continuum structure.

Modeling Immunization To Infliximab in Children With Crohn's Disease Using Population Pharmacokinetics: A Pilot Study.

PubMed

Petitcollin, Antoine; Leuret, Oriane; Tron, Camille; Lemaitre, Florian; Verdier, Marie-Clémence; Paintaud, Gilles; Bouguen, Guillaume; Willot, Stéphanie; Bellissant, Eric; Ternant, David

2018-05-18

Antidrug antibodies (ADAs) dramatically increase infliximab clearance and are responsible for underexposure to the drug, leading to treatment failure. This pilot study aimed at developing a population pharmacokinetic model to detect and describe an early increase in infliximab clearance due to ADA. Twenty children with Crohn's disease (CD) were followed for 1 year or until treatment failure. Infliximab trough concentration, ADA, C-reactive protein (CRP), and Paediatric Crohn's Disease Activity Index (PCDAI) were recorded at each visit. A time-varying clearance population pharmacokinetic model was built to detect and describe an increase in infliximab clearance, independent from ADA testing. Factors associated with clearance variation and the relationships between infliximab concentrations, clearance variation, and clinical response were investigated. The model detected important increases in clearance in 4 patients. These patients had suboptimal early response, with higher mean PCDAI (P = 0.0086) and CRP (P = 0.028) compared with other patients. Two of them had detectable ADA. Clearance increase as described by the model and lower infliximab trough concentration at week 2 were associated with poorer outcomes in a multivariate Cox model (P = 0.001 and P = 0.0048, respectively). Being able to detect an increase in infliximab clearance, this model could allow the early detection of immunization to infliximab and therefore could help with dose adjustment in patients with CD. Moreover, the results suggest that clearance variations could be used as a predictive marker of clinical response. These findings need to be confirmed in a larger cohort, however, and predictive factors of clearance increase have to be investigated.

Comparison of methods for the prediction of human clearance from hepatocyte intrinsic clearance for a set of reference compounds and an external evaluation set.

PubMed

Yamagata, Tetsuo; Zanelli, Ugo; Gallemann, Dieter; Perrin, Dominique; Dolgos, Hugues; Petersson, Carl

2017-09-01

1. We compared direct scaling, regression model equation and the so-called "Poulin et al." methods to scale clearance (CL) from in vitro intrinsic clearance (CL int ) measured in human hepatocytes using two sets of compounds. One reference set comprised of 20 compounds with known elimination pathways and one external evaluation set based on 17 compounds development in Merck (MS). 2. A 90% prospective confidence interval was calculated using the reference set. This interval was found relevant for the regression equation method. The three outliers identified were justified on the basis of their elimination mechanism. 3. The direct scaling method showed a systematic underestimation of clearance in both the reference and evaluation sets. The "Poulin et al." and the regression equation methods showed no obvious bias in either the reference or evaluation sets. 4. The regression model equation was slightly superior to the "Poulin et al." method in the reference set and showed a better absolute average fold error (AAFE) of value 1.3 compared to 1.6. A larger difference was observed in the evaluation set were the regression method and "Poulin et al." resulted in an AAFE of 1.7 and 2.6, respectively (removing the three compounds with known issues mentioned above). A similar pattern was observed for the correlation coefficient. Based on these data we suggest the regression equation method combined with a prospective confidence interval as the first choice for the extrapolation of human in vivo hepatic metabolic clearance from in vitro systems.

Combining 'Bottom-Up' and 'Top-Down' Methods to Assess Ethnic Difference in Clearance: Bitopertin as an Example.

PubMed

Feng, Sheng; Shi, Jun; Parrott, Neil; Hu, Pei; Weber, Cornelia; Martin-Facklam, Meret; Saito, Tomohisa; Peck, Richard

2016-07-01

We propose a strategy for studying ethnopharmacology by conducting sequential physiologically based pharmacokinetic (PBPK) prediction (a 'bottom-up' approach) and population pharmacokinetic (popPK) confirmation (a 'top-down' approach), or in reverse order, depending on whether the purpose is ethnic effect assessment for a new molecular entity under development or a tool for ethnic sensitivity prediction for a given pathway. The strategy is exemplified with bitopertin. A PBPK model was built using Simcyp(®) to simulate the pharmacokinetics of bitopertin and to predict the ethnic sensitivity in clearance, given pharmacokinetic data in just one ethnicity. Subsequently, a popPK model was built using NONMEM(®) to assess the effect of ethnicity on clearance, using human data from multiple ethnic groups. A comparison was made to confirm the PBPK-based ethnic sensitivity prediction, using the results of the popPK analysis. PBPK modelling predicted that the bitopertin geometric mean clearance values after 20 mg oral administration in Caucasians would be 1.32-fold and 1.27-fold higher than the values in Chinese and Japanese, respectively. The ratios of typical clearance in Caucasians to the values in Chinese and Japanese estimated by popPK analysis were 1.20 and 1.17, respectively. The popPK analysis results were similar to the PBPK modelling results. As a general framework, we propose that PBPK modelling should be considered to predict ethnic sensitivity of pharmacokinetics prior to any human data and/or with data in only one ethnicity. In some cases, this will be sufficient to guide initial dose selection in different ethnicities. After clinical trials in different ethnicities, popPK analysis can be used to confirm ethnic differences and to support dose justification and labelling. PBPK modelling prediction and popPK analysis confirmation can complement each other to assess ethnic differences in pharmacokinetics at different drug development stages.

Time-dependent pharmacokinetics of dexamethasone and its efficacy in human breast cancer xenograft mice: a semi-mechanism-based pharmacokinetic/pharmacodynamic model.

PubMed

Li, Jian; Chen, Rong; Yao, Qing-Yu; Liu, Sheng-Jun; Tian, Xiu-Yun; Hao, Chun-Yi; Lu, Wei; Zhou, Tian-Yan

2018-03-01

Dexamethasone (DEX) is the substrate of CYP3A. However, the activity of CYP3A could be induced by DEX when DEX was persistently administered, resulting in auto-induction and time-dependent pharmacokinetics (pharmacokinetics with time-dependent clearance) of DEX. In this study we investigated the pharmacokinetic profiles of DEX after single or multiple doses in human breast cancer xenograft nude mice and established a semi-mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model for characterizing the time-dependent PK of DEX as well as its anti-cancer effect. The mice were orally given a single or multiple doses (8 mg/kg) of DEX, and the plasma concentrations of DEX were assessed using LC-MS/MS. Tumor volumes were recorded daily. Based on the experimental data, a two-compartment model with first order absorption and time-dependent clearance was established, and the time-dependence of clearance was modeled by a sigmoid E max equation. Moreover, a semi-mechanism-based PK/PD model was developed, in which the auto-induction effect of DEX on its metabolizing enzyme CYP3A was integrated and drug potency was described using an E max equation. The PK/PD model was further used to predict the drug efficacy when the auto-induction effect was or was not considered, which further revealed the necessity of adding the auto-induction effect into the final PK/PD model. This study established a semi-mechanism-based PK/PD model for characterizing the time-dependent pharmacokinetics of DEX and its anti-cancer effect in breast cancer xenograft mice. The model may serve as a reference for DEX dose adjustments or optimization in future preclinical or clinical studies.

Disposition of pentachlorophenol in rainbow trout (Salmo gairdneri ): Effect of inhibition of metabolism

USGS Publications Warehouse

Stehly, G.R.; Hayton, W.L.

1989-01-01

The accumulation kinetics of pentachlorophenol (PCP) were investigated in rainbow trout (Salmo gairdneri ) in the absence and presence of 25 mg/l salicylamide, an inhibitor of PCP metabolism. After exposure to 5 mu g/l PCP over 1-96 h, the amount of PCP in the whole fish, its concentration in water and the total amount of metabolites (water, whole fish and bile) were measured. Equations for these variables, based on a two compartment pharmacokinetic model, were fitted simultaneously to the data using the computer program NONLIN, which uses an iterative nonlinear least squares technique. Salicylamide decreased the metabolic clearance of PCP, which resulted in an increase in the bioconcentration factor (BCF); this increase was partially offset by a salicylamide-induced decrease in the apparent volume of distribution of PCP. A clearance-volume compartment model permitted partitioning of the BCF in terms of the underlying physiologic and biochemical processes (uptake clearance, metabolic clearance and apparent volume of distribution).

Enhanced analysis and users manual for radial-inflow turbine conceptual design code RTD

NASA Technical Reports Server (NTRS)

Glassman, Arthur J.

1995-01-01

Modeling enhancements made to a radial-inflow turbine conceptual design code are documented in this report. A stator-endwall clearance-flow model was added for use with pivoting vanes. The rotor calculations were modified to account for swept blades and splitter blades. Stator and rotor trailing-edge losses and a vaneless-space loss were added to the loss model. Changes were made to the disk-friction and rotor-clearance loss calculations. The loss model was then calibrated based on experimental turbine performance. A complete description of code input and output along with sample cases are included in the report.

A Study on the Requirements for Fast Active Turbine Tip Clearance Control Systems

NASA Technical Reports Server (NTRS)

DeCastro, Jonathan A.; Melcher, Kevin J.

2004-01-01

This paper addresses the requirements of a control system for active turbine tip clearance control in a generic commercial turbofan engine through design and analysis. The control objective is to articulate the shroud in the high pressure turbine section in order to maintain a certain clearance set point given several possible engine transient events. The system must also exhibit reasonable robustness to modeling uncertainties and reasonable noise rejection properties. Two actuators were chosen to fulfill such a requirement, both of which possess different levels of technological readiness: electrohydraulic servovalves and piezoelectric stacks. Identification of design constraints, desired actuator parameters, and actuator limitations are addressed in depth; all of which are intimately tied with the hardware and controller design process. Analytical demonstrations of the performance and robustness characteristics of the two axisymmetric LQG clearance control systems are presented. Takeoff simulation results show that both actuators are capable of maintaining the clearance within acceptable bounds and demonstrate robustness to parameter uncertainty. The present model-based control strategy was employed to demonstrate the tradeoff between performance, control effort, and robustness and to implement optimal state estimation in a noisy engine environment with intent to eliminate ad hoc methods for designing reliable control systems.

Measurement method of rotation angle and clearance in intelligent spherical hinge

NASA Astrophysics Data System (ADS)

Hu, Penghao; Lu, Yichang; Chen, Shiyi; Hu, Yi; Zhu, Lianqing

2018-06-01

Precision ball hinges are widely applied in parallel mechanisms, robotics, and other areas, but their rotation orientation and angle cannot be obtained during passive motion. The simultaneous clearance error in a precision ball hinge’s motion also can not be determined. In this paper we propose an intelligent ball hinge (IBH) that can detect the rotation angle and moving clearance, based on our previous research results. The measurement model was optimized to promote measurement accuracy and resolution, and an optimal design for the IBH’s structure was determined. The experimental data showed that the measurement accuracy and resolution of the modified scheme were improved. Within  ±10° and  ±  20°, the average errors of the uniaxial measurements were 0.29° and 0.42°, respectively. The resolution of the measurements was 15″. The source of the measurement errors was analyzed through theory and experimental data and several key error sources were determined. A point capacitance model for measuring the clearance error is proposed, which is useful not only in compensating for the angle measurement error but also in realizing the motion clearance of an IBH in real-time.

Numerical investigation of tip clearance cavitation in Kaplan runners

NASA Astrophysics Data System (ADS)

Nikiforova, K.; Semenov, G.; Kuznetsov, I.; Spiridonov, E.

2016-11-01

There is a gap between the Kaplan runner blade and the shroud that makes for a special kind of cavitation: cavitation in the tip leakage flow. Two types of cavitation caused by the presence of clearance gap are known: tip vortex cavitation that appears at the core of the rolled up vortex on the blade suction side and tip clearance cavitation that appears precisely in the gap between the blade tip edge and the shroud. In the context of this work numerical investigation of the model Kaplan runner has been performed taking into account variable tip clearance for several cavitation regimes. The focus is put on investigation of structure and origination of mechanism of cavitation in the tip leakage flow. Calculations have been performed with the help of 3-D unsteady numerical model for two-phase medium. Modeling of turbulent flow in this work has been carried out using full equations of Navier-Stokes averaged by Reynolds with correction for streamline curvature and system rotation. For description of this medium (liquid-vapor) simplification of Euler approach is used; it is based on the model of interpenetrating continuums, within the bounds of this two- phase medium considered as a quasi-homogeneous mixture with the common velocity field and continuous distribution of density for both phases. As a result, engineering techniques for calculation of cavitation conditioned by existence of tip clearance in model turbine runner have been developed. The detailed visualization of the flow was carried out and vortex structure on the suction side of the blade was reproduced. The range of frequency with maximum value of pulsation was assigned and maximum energy frequency was defined; it is based on spectral analysis of the obtained data. Comparison between numerical computation results and experimental data has been also performed. The location of cavitation zone has a good agreement with experiment for all analyzed regimes.

Calculation of tip clearance effects in a transonic compressor rotor

NASA Technical Reports Server (NTRS)

Chima, R. V.

1996-01-01

The flow through the tip clearance region of a transonic compressor rotor (NASA rotor 37) was computed and compared to aerodynamic probe and laser anemometer data. Tip clearance effects were modeled both by gridding the clearance gap and by using a simple periodicity model across the ungridded gap. The simple model was run with both the full gap height, and with half the gap height to simulate a vena-contracta effect. Comparisons between computed and measured performance maps and downstream profiles were used to validate the models and to assess the effects of gap height on the simple clearance model. Recommendations were made concerning the use of the simple clearance model. Detailed comparisons were made between the gridded clearance gap solution and the laser anemometer data near the tip at two operating points. The computer results agreed fairly well with the data but overpredicted the extent of the casing separation and underpredicted the wake decay rate. The computations were then used to describe the interaction of the tip vortex, the passage shock, and the casing boundary layer.

Railway Tunnel Clearance Inspection Method Based on 3D Point Cloud from Mobile Laser Scanning

PubMed Central

Zhou, Yuhui; Wang, Shaohua; Mei, Xi; Yin, Wangling; Lin, Chunfeng; Mao, Qingzhou

2017-01-01

Railway tunnel clearance is directly related to the safe operation of trains and upgrading of freight capacity. As more and more railway are put into operation and the operation is continuously becoming faster, the railway tunnel clearance inspection should be more precise and efficient. In view of the problems existing in traditional tunnel clearance inspection methods, such as low density, slow speed and a lot of manual operations, this paper proposes a tunnel clearance inspection approach based on 3D point clouds obtained by a mobile laser scanning system (MLS). First, a dynamic coordinate system for railway tunnel clearance inspection has been proposed. A rail line extraction algorithm based on 3D linear fitting is implemented from the segmented point cloud to establish a dynamic clearance coordinate system. Second, a method to seamlessly connect all rail segments based on the railway clearance restrictions, and a seamless rail alignment is formed sequentially from the middle tunnel section to both ends. Finally, based on the rail alignment and the track clearance coordinate system, different types of clearance frames are introduced for intrusion operation with the tunnel section to realize the tunnel clearance inspection. By taking the Shuanghekou Tunnel of the Chengdu–Kunming Railway as an example, when the clearance inspection is carried out by the method mentioned herein, its precision can reach 0.03 m, and difference types of clearances can be effectively calculated. This method has a wide application prospects. PMID:28880232

Population Pharmacokinetics and Exposure Response Assessment of CC-292, a Potent BTK Inhibitor, in Patients With Chronic Lymphocytic Leukemia.

PubMed

Li, Yan; Ramírez-Valle, Francisco; Xue, Yongjun; Ventura, Judith I; Gouedard, Olivier; Mei, Jay; Takeshita, Kenichi; Palmisano, Maria; Zhou, Simon

2017-10-01

CC-292, a potent Bruton tyrosine kinase inhibitor, is under development for the treatment of B-cell malignancies. An analysis was performed to develop a population pharmacokinetic model of CC-292 and assess the influence of demographics and disease-related covariates on CC-292 exposure and to assess the exposure-response (overall response rate) relationship in patients with chronic lymphocytic leukemia. Population pharmacokinetic analysis was based on a 2-compartment base model conducted in NONMEM. Categorical exposure-response analysis was performed using logistic regression in SAS. The population pharmacokinetic analysis results indicated that CC-292 pharmacokinetic disposition is similar between healthy subjects and patients. CC-292 showed a larger central compartment volume of distribution than the peripheral compartment volume of distribution (158 L and 72 L, respectively) and a faster clearance than intercompartmental clearance (134 L/h and 18.7 L/h, respectively), indicating that for CC-292, clearance from blood occurs faster than distribution into deep tissues and organs. CC-292 clearance is not affected by demographics or baseline clinical lab factors, except for sex. Although sex significantly reduced variation of apparent clearance, the sex effect on apparent clearance is unlikely to be clinically relevant. The exposure-response analysis suggested that higher drug exposure is linearly correlated with higher overall response rate. A twice-daily dose regimen showed higher overall response rate as compared to once-daily dosing, consistent with a threshold concentration of approximately 300 ng/mL, above which the probability of overall response rate significantly increases. © 2017, The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Dynamic modelling and experimental study of cantilever beam with clearance

NASA Astrophysics Data System (ADS)

Li, B.; Jin, W.; Han, L.; He, Z.

2012-05-01

Clearances occur in almost all mechanical systems, typically such as the clearance between slide plate of gun barrel and guide. Therefore, to study the clearances of mechanisms can be very important to increase the working performance and lifetime of mechanisms. In this paper, rigid dynamic modelling of cantilever with clearance was done according to the subject investigated. In the rigid dynamic modelling, clearance is equivalent to the spring-dashpot model, the impact of beam and boundary face was also taken into consideration. In ADAMS software, the dynamic simulation was carried out according to the model above. The software simulated the movement of cantilever with clearance under external excitation. Research found: When the clearance is larger, the force of impact will become larger. In order to study how the stiffness of the cantilever's supporting part influences natural frequency of the system, A Euler beam which is restricted by a draught spring and a torsion spring at its end was raised. Through numerical calculation, the relationship between natural frequency and stiffness was found. When the value of the stiffness is close to the limit value, the corresponding boundary condition is illustrated. An ADAMS experiment was carried out to check the theory and the simulation.

Simultaneous Assessment of Clearance, Metabolism, Induction, and Drug-Drug Interaction Potential Using a Long-Term In Vitro Liver Model for a Novel Hepatitis B Virus Inhibitor.

PubMed

Kratochwil, Nicole A; Triyatni, Miriam; Mueller, Martina B; Klammers, Florian; Leonard, Brian; Turley, Dan; Schmaler, Josephine; Ekiciler, Aynur; Molitor, Birgit; Walter, Isabelle; Gonsard, Pierre-Alexis; Tournillac, Charles A; Durrwell, Alexandre; Marschmann, Michaela; Jones, Russell; Ullah, Mohammed; Boess, Franziska; Ottaviani, Giorgio; Jin, Yuyan; Parrott, Neil J; Fowler, Stephen

2018-05-01

Long-term in vitro liver models are now widely explored for human hepatic metabolic clearance prediction, enzyme phenotyping, cross-species metabolism, comparison of low clearance drugs, and induction studies. Here, we present studies using a long-term liver model, which show how metabolism and active transport, drug-drug interactions, and enzyme induction in healthy and diseased states, such as hepatitis B virus (HBV) infection, may be assessed in a single test system to enable effective data integration for physiologically based pharmacokinetic (PBPK) modeling. The approach is exemplified in the case of (3S)-4-[[(4R)-4-(2-Chloro-4-fluorophenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid RO6889678, a novel inhibitor of HBV with a complex absorption, distribution, metabolism, and excretion (ADME) profile. RO6889678 showed an intracellular enrichment of 78-fold in hepatocytes, with an apparent intrinsic clearance of 5.2 µ l/min per mg protein and uptake and biliary clearances of 2.6 and 1.6 µ l/min per mg protein, respectively. When apparent intrinsic clearance was incorporated into a PBPK model, the simulated oral human profiles were in good agreement with observed data at low doses but were underestimated at high doses due to unexpected overproportional increases in exposure with dose. In addition, the induction potential of RO6889678 on cytochrome P450 (P450) enzymes and transporters at steady state was assessed and cotreatment with ritonavir revealed a complex drug-drug interaction with concurrent P450 inhibition and moderate UDP-glucuronosyltransferase induction. Furthermore, we report on the first evaluation of in vitro pharmacokinetics studies using HBV-infected HepatoPac cocultures. Thus, long-term liver models have great potential as translational research tools exploring pharmacokinetics of novel drugs in vitro in health and disease. Copyright © 2018 The Author(s).

Parabolic quantitative structure-activity relationships and photodynamic therapy: application of a three-compartment model with clearance to the in vivo quantitative structure-activity relationships of a congeneric series of pyropheophorbide derivatives used as photosensitizers for photodynamic therapy.

PubMed

Potter, W R; Henderson, B W; Bellnier, D A; Pandey, R K; Vaughan, L A; Weishaupt, K R; Dougherty, T J

1999-11-01

An open three-compartment pharmacokinetic model was applied to the in vivo quantitative structure-activity relationship (QSAR) data of a homologous series of pyropheophorbide photosensitizers for photodynamic therapy (PDT). The physical model was a lipid compartment sandwiched between two identical aqueous compartments. The first compartment was assumed to clear irreversibly at a rate K0. The measured octanol-water partition coefficients, P(i) (where i is the number of carbons in the alkyl chain) and the clearance rate K0 determined the clearance kinetics of the drugs. Solving the coupled differential equations of the three-compartment model produced clearance kinetics for each of the sensitizers in each of the compartments. The third compartment was found to contain the target of PDT. This series of compounds is quite lipophilic. Therefore these drugs are found mainly in the second compartment. The drug level in the third compartment represents a small fraction of the tissue level and is thus not accessible to direct measurement by extraction. The second compartment of the model accurately predicted the clearance from the serum of mice of the hexyl ether of pyropheophorbide a, one member of this series of compounds. The diffusion and clearance rate constants were those found by fitting the pharmacokinetics of the third compartment to the QSAR data. This result validated the magnitude and mechanistic significance of the rate constants used to model the QSAR data. The PDT response to dose theory was applied to the kinetic behavior of the target compartment drug concentration. This produced a pharmacokinetic-based function connecting PDT response to dose as a function of time postinjection. This mechanistic dose-response function was fitted to published, single time point QSAR data for the pheophorbides. As a result, the PDT target threshold dose together with the predicted QSAR as a function of time postinjection was found.

10 CFR 1016.3 - Definitions.

Code of Federal Regulations, 2014 CFR

2014-01-01

... authorizations or clearances will be defined. (1) “Q” access authorizations or clearances are based upon full... quantities as required in the performance of duties. (2) “Q(X)” access authorizations or clearances are based...” access authorizations or clearances are based upon National Agency Checks and Inquiries (NACI) for...

10 CFR 1016.3 - Definitions.

Code of Federal Regulations, 2012 CFR

2012-01-01

... authorizations or clearances will be defined. (1) “Q” access authorizations or clearances are based upon full... quantities as required in the performance of duties. (2) “Q(X)” access authorizations or clearances are based...” access authorizations or clearances are based upon National Agency Checks and Inquiries (NACI) for...

Hepatobiliary Clearance Prediction: Species Scaling From Monkey, Dog, and Rat, and In Vitro-In Vivo Extrapolation of Sandwich-Cultured Human Hepatocytes Using 17 Drugs.

PubMed

Kimoto, Emi; Bi, Yi-An; Kosa, Rachel E; Tremaine, Larry M; Varma, Manthena V S

2017-09-01

Hepatobiliary elimination can be a major clearance pathway dictating the pharmacokinetics of drugs. Here, we first compared the dose eliminated in bile in preclinical species (monkey, dog, and rat) with that in human and further evaluated single-species scaling (SSS) to predict human hepatobiliary clearance. Six compounds dosed in bile duct-cannulated (BDC) monkeys showed biliary excretion comparable to human; and the SSS of hepatobiliary clearance with plasma fraction unbound correction yielded reasonable predictions (within 3-fold). Although dog SSS also showed reasonable predictions, rat overpredicted hepatobiliary clearance for 13 of 24 compounds. Second, we evaluated the translatability of in vitro sandwich-cultured human hepatocytes (SCHHs) to predict human hepatobiliary clearance for 17 drugs. For drugs with no significant active uptake in SCHH studies (i.e., with or without rifamycin SV), measured intrinsic biliary clearance was directly scalable with good predictability (absolute average fold error [AAFE] = 1.6). Drugs showing significant active uptake in SCHH, however, showed improved predictability when scaled based on extended clearance term (AAFE = 2.0), which incorporated sinusoidal uptake along with a global scaling factor for active uptake and the canalicular efflux clearance. In conclusion, SCHH is a useful tool to predict human hepatobiliary clearance, whereas BDC monkey model may provide further confidence in the prospective predictions. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Pharmacokinetics of Intravenous Sildenafil in Children with Palliated Single Ventricle Heart Defects: Effect of Elevated Hepatic Pressures

PubMed Central

Hill, Kevin D.; Sampson, Mario R.; Li, Jennifer S.; Tunks, Robert D.; Schulman, Scott R.; Cohen-Wolkowiez, Michael

2015-01-01

Aims Sildenafil is frequently prescribed to children with single ventricle heart defects. These children have unique hepatic physiology with elevated hepatic pressures which may alter drug pharmacokinetics. We sought to determine the impact of hepatic pressure on sildenafil pharmacokinetics in children with single ventricle heart defects. Methods A population pharmacokinetic model was developed using data from 20 single ventricle children receiving single dose intravenous sildenafil during cardiac catheterization. Nonlinear mixed effect modeling was used for model development and covariate effects were evaluated based on estimated precision and clinical significance. Results The analysis included a median (range) of 4 (2–5) pharmacokinetic samples per child. The final structural model was a two-compartment model for sildenafil with a one-compartment model for des-methyl-sildenafil (active metabolite), with assumed 100% sildenafil to des-methyl-sildenafil conversion. Sildenafil clearance was unaffected by hepatic pressure (clearance = 0.62 L/H/kg); however, clearance of des-methyl-sildenafil (1.94 × (hepatic pressure/9)−1.33 L/h/kg) was predicted to decrease ~7 fold as hepatic pressure increased from 4 to 18 mm Hg. Predicted drug exposure was increased by ~1.5 fold in subjects with hepatic pressures ≥ 10 mm Hg versus < 10 mm Hg (median area under the curve = 533 μg*h/L versus 792 μg*h/L). Discussion Elevated hepatic pressure delays clearance of the sildenafil metabolite, des-methyl-sildenafil and increases drug exposure. We speculate that this results from impaired biliary clearance. Hepatic pressure should be considered when prescribing sildenafil to children. These data demonstrate the importance of pharmacokinetic assessment in patients with unique cardiovascular physiology that may affect drug metabolism. PMID:26197839

An alternate metabolic hypothesis for a binary mixture of trichloroethylene and carbon tetrachloride: application of physiologically based pharmacokinetic (PBPK) modeling in rats.

EPA Science Inventory

Carbon tetrachloride (CC4) and trichloroethylene (TCE) are hepatotoxic volatile organic compounds (VOCs) and environmental contaminants. Previous physiologically based pharmacokinetic (PBPK) models describe the kinetics ofindividual chemical disposition and metabolic clearance fo...

Construction of a model for predicting creatinine clearance in Japanese patients treated with Cisplatin therapy.

PubMed

Yajima, Airi; Uesawa, Yoshihiro; Ogawa, Chiaki; Yatabe, Megumi; Kondo, Naoki; Saito, Shinichiro; Suzuki, Yoshihiko; Atsuda, Kouichiro; Kagaya, Hajime

2015-05-01

There exist various useful predictive models, such as the Cockcroft-Gault model, for estimating creatinine clearance (CLcr). However, the prediction of renal function is difficult in patients with cancer treated with cisplatin. Therefore, we attempted to construct a new model for predicting CLcr in such patients. Japanese patients with head and neck cancer who had received cisplatin-based chemotherapy were used as subjects. A multiple regression equation was constructed as a model for predicting CLcr values based on background and laboratory data. A model for predicting CLcr, which included body surface area, serum creatinine and albumin, was constructed. The model exhibited good performance prior to cisplatin therapy. In addition, it performed better than previously reported models after cisplatin therapy. The predictive model constructed in the present study displayed excellent potential and was useful for estimating the renal function of patients treated with cisplatin therapy. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Paracetamol pharmacokinetics and metabolism in young women.

PubMed

Allegaert, Karel; Peeters, Mariska Y; Beleyn, Bjorn; Smits, Anne; Kulo, Aida; van Calsteren, Kristel; Deprest, Jan; de Hoon, Jan; Knibbe, Catherijne A J

2015-11-13

There is relevant between individual variability in paracetamol clearance in young women. In this pooled study, we focused on the population pharmacokinetic profile of intravenous paracetamol metabolism and its covariates in young women. Population PK parameters using non-linear mixed effect modelling were estimated in a pooled dataset of plasma and urine PK studies in 69 young women [47 at delivery, 8/47 again 10-15 weeks after delivery (early postpartum), and 7/8 again 1 year after delivery (late postpartum), 22 healthy female volunteers with or without oral contraceptives]. Population PK parameters were estimated based on 815 plasma samples and 101 urine collections. Compared to healthy female volunteers (reference group) not on oral contraceptives, being at delivery was the most significant covariate for clearance to paracetamol glucuronide (Factor = 2.03), while women in early postpartum had decreased paracetamol glucuronidation clearance (Factor = 0.55). Women on contraceptives showed increased paracetamol glucuronidation clearance (Factor = 1.46). The oestradiol level did not further affect this model. Being at delivery did not prove significant for clearance to paracetamol sulphate, but was higher in pregnant women who delivered preterm (<37 weeks, Factor = 1.34) compared to term delivery and non-pregnant women. Finally, clearance of unchanged paracetamol was dependent on urine flow rate. Compared to healthy female volunteers not on oral contraceptives, urine paracetamol glucuronidation elimination in young women is affected by pregnancy (higher), early postpartum (lower) or exposure to oral contraceptives (higher), resulting in at least a two fold variability in paracetamol clearance in young women.

Influence of road network and population demand assumptions in evacuation modeling for distant tsunamis

USGS Publications Warehouse

Henry, Kevin; Wood, Nathan J.; Frazier, Tim G.

2017-01-01

Tsunami evacuation planning in coastal communities is typically focused on local events where at-risk individuals must move on foot in a matter of minutes to safety. Less attention has been placed on distant tsunamis, where evacuations unfold over several hours, are often dominated by vehicle use and are managed by public safety officials. Traditional traffic simulation models focus on estimating clearance times but often overlook the influence of varying population demand, alternative modes, background traffic, shadow evacuation, and traffic management alternatives. These factors are especially important for island communities with limited egress options to safety. We use the coastal community of Balboa Island, California (USA), as a case study to explore the range of potential clearance times prior to wave arrival for a distant tsunami scenario. We use a first-in–first-out queuing simulation environment to estimate variations in clearance times, given varying assumptions of the evacuating population (demand) and the road network over which they evacuate (supply). Results suggest clearance times are less than wave arrival times for a distant tsunami, except when we assume maximum vehicle usage for residents, employees, and tourists for a weekend scenario. A two-lane bridge to the mainland was the primary traffic bottleneck, thereby minimizing the effect of departure times, shadow evacuations, background traffic, boat-based evacuations, and traffic light timing on overall community clearance time. Reducing vehicular demand generally reduced clearance time, whereas improvements to road capacity had mixed results. Finally, failure to recognize non-residential employee and tourist populations in the vehicle demand substantially underestimated clearance time.

Clearance Rate and BP-ANN Model in Paraquat Poisoned Patients Treated with Hemoperfusion

PubMed Central

Hu, Lufeng; Hong, Guangliang; Ma, Jianshe; Wang, Xianqin; Lin, Guanyang; Zhang, Xiuhua; Lu, Zhongqiu

2015-01-01

In order to investigate the effect of hemoperfusion (HP) on the clearance rate of paraquat (PQ) and develop a clearance model, 41 PQ-poisoned patients who acquired acute PQ intoxication received HP treatment. PQ concentrations were determined by high performance liquid chromatography (HPLC). According to initial PQ concentration, study subjects were divided into two groups: Low-PQ group (0.05–1.0 μg/mL) and High-PQ group (1.0–10 μg/mL). After initial HP treatment, PQ concentrations decreased in both groups. However, in the High-PQ group, PQ levels remained in excess of 0.05 μg/mL and increased when the second HP treatment was initiated. Based on the PQ concentrations before and after HP treatment, the mean clearance rate of PQ calculated was 73 ± 15%. We also established a backpropagation artificial neural network (BP-ANN) model, which set PQ concentrations before HP treatment as input data and after HP treatment as output data. When it is used to predict PQ concentration after HP treatment, high prediction accuracy (R = 0.9977) can be obtained in this model. In conclusion, HP is an effective way to clear PQ from the blood, and the PQ concentration after HP treatment can be predicted by BP-ANN model. PMID:25695058

Differences in amyloid-β clearance across mouse and human blood-brain barrier models: kinetic analysis and mechanistic modeling.

PubMed

Qosa, Hisham; Abuasal, Bilal S; Romero, Ignacio A; Weksler, Babette; Couraud, Pierre-Oliver; Keller, Jeffrey N; Kaddoumi, Amal

2014-04-01

Alzheimer's disease (AD) has a characteristic hallmark of amyloid-β (Aβ) accumulation in the brain. This accumulation of Aβ has been related to its faulty cerebral clearance. Indeed, preclinical studies that used mice to investigate Aβ clearance showed that efflux across blood-brain barrier (BBB) and brain degradation mediate efficient Aβ clearance. However, the contribution of each process to Aβ clearance remains unclear. Moreover, it is still uncertain how species differences between mouse and human could affect Aβ clearance. Here, a modified form of the brain efflux index method was used to estimate the contribution of BBB and brain degradation to Aβ clearance from the brain of wild type mice. We estimated that 62% of intracerebrally injected (125)I-Aβ40 is cleared across BBB while 38% is cleared by brain degradation. Furthermore, in vitro and in silico studies were performed to compare Aβ clearance between mouse and human BBB models. Kinetic studies for Aβ40 disposition in bEnd3 and hCMEC/D3 cells, representative in vitro mouse and human BBB models, respectively, demonstrated 30-fold higher rate of (125)I-Aβ40 uptake and 15-fold higher rate of degradation by bEnd3 compared to hCMEC/D3 cells. Expression studies showed both cells to express different levels of P-glycoprotein and RAGE, while LRP1 levels were comparable. Finally, we established a mechanistic model, which could successfully predict cellular levels of (125)I-Aβ40 and the rate of each process. Established mechanistic model suggested significantly higher rates of Aβ uptake and degradation in bEnd3 cells as rationale for the observed differences in (125)I-Aβ40 disposition between mouse and human BBB models. In conclusion, current study demonstrates the important role of BBB in the clearance of Aβ from the brain. Moreover, it provides insight into the differences between mouse and human BBB with regards to Aβ clearance and offer, for the first time, a mathematical model that describes Aβ clearance across BBB. Copyright © 2014 Elsevier Ltd. All rights reserved.

Differences in amyloid-β clearance across mouse and human blood-brain barrier models: Kinetic analysis and mechanistic modeling

PubMed Central

Qosa, Hisham; Abuasal, Bilal S.; Romero, Ignacio A.; Weksler, Babette; Couraud, Pierre-Oliver; Keller, Jeffrey N.; Kaddoumi, Amal

2014-01-01

Alzheimer’s disease (AD) has a characteristic hallmark of amyloid-β (Aβ) accumulation in the brain. This accumulation of Aβ has been related to its faulty cerebral clearance. Indeed, preclinical studies that used mice to investigate Aβ clearance showed that efflux across blood-brain barrier (BBB) and brain degradation mediate efficient Aβ clearance. However, the contribution of each process to Aβ clearance remains unclear. Moreover, it is still uncertain how species differences between mouse and human could affect Aβ clearance. Here, a modified form of the brain efflux index method was used to estimate the contribution of BBB and brain degradation to Aβ clearance from the brain of wild type mice. We estimated that 62% of intracerebrally injected 125I-Aβ40 is cleared across BBB while 38% is cleared by brain degradation. Furthermore, in vitro and in silico studies were performed to compare Aβ clearance between mouse and human BBB models. Kinetic studies for Aβ40 disposition in bEnd3 and hCMEC/D3 cells, representative in vitro mouse and human BBB models, respectively, demonstrated 30-fold higher rate of 125I-Aβ40 uptake and 15-fold higher rate of degradation by bEnd3 compared to hCMEC/D3 cells. Expression studies showed both cells to express different levels of P-glycoprotein and RAGE, while LRP1 levels were comparable. Finally, we established a mechanistic model, which could successfully predict cellular levels of 125I-Aβ40 and the rate of each process. Established mechanistic model suggested significantly higher rates of Aβ uptake and degradation in bEnd3 cells as rationale for the observed differences in 125I-Aβ40 disposition between mouse and human BBB models. In conclusion, current study demonstrates the important role of BBB in the clearance of Aβ from the brain. Moreover, it provides insight into the differences between mouse and human BBB with regards to Aβ clearance and offer, for the first time, a mathematical model that describes Aβ clearance across BBB. PMID:24467845

Morphine Glucuronidation and Elimination in Intensive Care Patients: A Comparison with Healthy Volunteers.

PubMed

Ahlers, Sabine J G M; Välitalo, Pyry A J; Peeters, Mariska Y M; Gulik, Laura van; van Dongen, Eric P A; Dahan, Albert; Tibboel, Dick; Knibbe, Catherijne A J

2015-11-01

Although morphine is used frequently to treat pain in the intensive care unit, its pharmacokinetics has not been adequately quantified in critically ill patients. We evaluated the glucuronidation and elimination clearance of morphine in intensive care patients compared with healthy volunteers based on the morphine and morphine-3-glucuronide (M3G) concentrations. A population pharmacokinetic model with covariate analysis was developed with the nonlinear mixed-effects modeling software (NONMEM 7.3). The analysis included 3012 morphine and M3G concentrations from 135 intensive care patients (117 cardiothoracic surgery patients and 18 critically ill patients), who received continuous morphine infusions adapted to individual pain levels, and 622 morphine and M3G concentrations from a previously published study of 20 healthy volunteers, who received an IV bolus of morphine followed by a 1-hour infusion. For morphine, a 3-compartment model best described the data, whereas for M3G, a 1-compartment model fits best. In intensive care patients with a normal creatinine concentration, a decrease of 76% was estimated in M3G clearance compared with healthy subjects, conditional on the M3G volume of distribution being the same in intensive care patients and healthy volunteers. Furthermore, serum creatinine concentration was identified as a covariate for both elimination clearance of M3G in intensive care patients and unchanged morphine clearance in all patients and healthy volunteers. Under the assumptions in the model, M3G elimination was significantly decreased in intensive care patients when compared with healthy volunteers, which resulted in substantially increased M3G concentrations. Increased M3G levels were even more pronounced in patients with increased serum creatinine levels. Model-based simulations show that, because of the reduction in morphine clearance in intensive care patients with renal failure, a 33% reduction in the maintenance dose would result in morphine serum concentrations equal to those in healthy volunteers and intensive care patients with normal renal function, although M3G concentrations remain increased. Future pharmacodynamic investigations are needed to identify target concentrations in this population, after which final dosing recommendations can be made.

Lung-clearance classification of radionuclides in calcined phosphate rock dust

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kalkwarf, D.R.; Jackson, P.O.

1984-08-01

Lung-clearance classifications for /sup 210/Pb and /sup 210/Po in airborne dust from elemental phosphorus plants were estimated for use with the lung clearance model proposed by the ICRP Task Group on Lung Dynamics. Estimates were based on measurements of dissolution rates for these radionuclides from sized dust samples into simulated lung fluid at 37/sup 0/C. The estimates were expressed in the classification terms of the model, i.e., D, W and Y, indicating lung clearance half-times of 0 to 10 days, 11 to 100 days and more than 100 days. Dust samples were obtained from two plants in the western Unitedmore » States, and dissolution trials were conducted on fractions containing particles with aerodynamic equivalent diameters (AED) of 0 to 3 ..mu..m and of 3 to 10 ..mu..m. The /sup 210/Pb and /sup 210/Po in each of these fractions were classified 100% Class Y. The specific activities of both radionuclides increased with decreasing AED of the particles. 11 references, 1 figure, 4 tables.« less

Estimated Chemical Warfare Agent Surface Clearance Goals for Remediation Pre-Planning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dolislager, Frederick; Bansleben, Dr. Donald; Watson, Annetta Paule

2010-01-01

Health-based surface clearance goals, in units of mg/cm2, have been developed for the persistent chemical warfare agents sulfur mustard (HD) and nerve agent VX as well as their principal degradation products. Selection of model parameters and critical receptor (toddler child) allow calculation of surface residue estimates protective for the toddler child, the general population and adult employees of a facilty that has undergone chemical warfare agent attack.

Towards improved models for predicting bioconcentration of well-metabolized compounds by rainbow trout using measured rates of in vitro intrinsic clearance

EPA Science Inventory

Consensus models were developed to predict the bioconcentration of well-metabolized chemicals by rainbow trout. The models employ intrinsic clearance data from in vitro studies with liver S9 fractions or isolated hepatocytes to estimate a liver clearance rate which is extrapolat...

An Evaluation of the Venous Equilibrium Model for Hepatic Clearance using Isolated Perfused Rainbow Trout Livers

EPA Science Inventory

The venous equilibrium model is widely used to describe hepatic clearance (CLH) of chemicals metabolized by the liver. If chemical delivery to the tissue does not limit CLH, this model predicts that CLH will approximately equal the product of intrinsic metabolic clearance and a t...

ANSYS-MATLAB co-simulation of mucus flow distribution and clearance effectiveness of a new simulated cough device.

PubMed

Ren, Shuai; Shi, Yan; Cai, Maolin; Zhao, Hongmei; Zhang, Zhaozhi; Zhang, Xiaohua Douglas

2018-06-01

Coughing is an irritable reaction that protects the respiratory system from infection and improves mucus clearance. However, for the patients who cannot cough autonomously, an assisted cough device is essential for mucus clearance. Considering the low efficiency of current assisted cough devices, a new simulated cough device based on the pneumatic system is proposed in this paper. Given the uncertainty of airflow rates necessary to clear mucus from airways, the computational fluid dynamics Eulerian wall film model and cough efficiency (CE) were used in this study to simulate the cough process and evaluate cough effectiveness. The Ansys-Matlab co-simulation model was set up and verified through experimental studies using Newtonian fluids. Next, model simulations were performed using non-Newtonian fluids, and peak cough flow (PCF) and PCF duration time were analyzed to determine their influence on mucus clearance. CE growth rate (λ) was calculated to reflect the CE variation trend. From the numerical simulation results, we find that CE rises as PCF increases while the growth rate trends to slow as PCF increases; when PCF changes from 60 to 360 L/min, CE changes from 3.2% to 51.5% which is approximately 16 times the initial value. Meanwhile, keeping a long PCF duration time could greatly improve CE under the same cough expired volume and PCF. The results indicated that increasing the PCF and PCF duration time can improve the efficiency of mucus clearance. This paper provides a new approach and a research direction for control strategy in simulated cough devices for airway mucus clearance. Copyright © 2018 John Wiley & Sons, Ltd.

Pharmacokinetic modeling in aquatic animals. 1. Models and concepts

USGS Publications Warehouse

Barron, M.G.; Stehly, Guy R.; Hayton, W.L.

1990-01-01

While clinical and toxicological applications of pharmacokinetics have continued to evolve both conceptually and experimentally, pharmacokinetics modeling in aquatic animals has not progressed accordingly. In this paper we present methods and concepts of pharmacokinetic modeling in aquatic animals using multicompartmental, clearance-based, non-compartmental and physiologically-based pharmacokinetic models. These models should be considered as alternatives to traditional approaches, which assume that the animal acts as a single homogeneous compartment based on apparent monoexponential elimination.

Prediction of human pharmacokinetics using physiologically based modeling: a retrospective analysis of 26 clinically tested drugs.

PubMed

De Buck, Stefan S; Sinha, Vikash K; Fenu, Luca A; Nijsen, Marjoleen J; Mackie, Claire E; Gilissen, Ron A H J

2007-10-01

The aim of this study was to evaluate different physiologically based modeling strategies for the prediction of human pharmacokinetics. Plasma profiles after intravenous and oral dosing were simulated for 26 clinically tested drugs. Two mechanism-based predictions of human tissue-to-plasma partitioning (P(tp)) from physicochemical input (method Vd1) were evaluated for their ability to describe human volume of distribution at steady state (V(ss)). This method was compared with a strategy that combined predicted and experimentally determined in vivo rat P(tp) data (method Vd2). Best V(ss) predictions were obtained using method Vd2, providing that rat P(tp) input was corrected for interspecies differences in plasma protein binding (84% within 2-fold). V(ss) predictions from physicochemical input alone were poor (32% within 2-fold). Total body clearance (CL) was predicted as the sum of scaled rat renal clearance and hepatic clearance projected from in vitro metabolism data. Best CL predictions were obtained by disregarding both blood and microsomal or hepatocyte binding (method CL2, 74% within 2-fold), whereas strong bias was seen using both blood and microsomal or hepatocyte binding (method CL1, 53% within 2-fold). The physiologically based pharmacokinetics (PBPK) model, which combined methods Vd2 and CL2 yielded the most accurate predictions of in vivo terminal half-life (69% within 2-fold). The Gastroplus advanced compartmental absorption and transit model was used to construct an absorption-disposition model and provided accurate predictions of area under the plasma concentration-time profile, oral apparent volume of distribution, and maximum plasma concentration after oral dosing, with 74%, 70%, and 65% within 2-fold, respectively. This evaluation demonstrates that PBPK models can lead to reasonable predictions of human pharmacokinetics.

A Reduced Model for Prediction of Thermal and Rotational Effects on Turbine Tip Clearance

NASA Technical Reports Server (NTRS)

Kypuros, Javier A.; Melcher, Kevin J.

2003-01-01

This paper describes a dynamic model that was developed to predict changes in turbine tip clearance the radial distance between the end of a turbine blade and the abradable tip seal. The clearance is estimated by using a first principles approach to model the thermal and mechanical effects of engine operating conditions on the turbine sub-components. These effects are summed to determine the resulting clearance. The model is demonstrated via a ground idle to maximum power transient and a lapse-rate takeoff transient. Results show the model demonstrates the expected pinch point behavior. The paper concludes by identifying knowledge gaps and suggesting additional research to improve the model.

Design optimization of dual-axis driving mechanism for satellite antenna with two planar revolute clearance joints

NASA Astrophysics Data System (ADS)

Bai, Zheng Feng; Zhao, Ji Jun; Chen, Jun; Zhao, Yang

2018-03-01

In the dynamic analysis of satellite antenna dual-axis driving mechanism, it is usually assumed that the joints are ideal or perfect without clearances. However, in reality, clearances in joints are unavoidable due to assemblage, manufacturing errors and wear. When clearance is introduced to the mechanism, it will lead to poor dynamic performances and undesirable vibrations due to impact forces in clearance joint. In this paper, a design optimization method is presented to reduce the undesirable vibrations of satellite antenna considering clearance joints in dual-axis driving mechanism. The contact force model in clearance joint is established using a nonlinear spring-damper model and the friction effect is considered using a modified Coulomb friction model. Firstly, the effects of clearances on dynamic responses of satellite antenna are investigated. Then the optimization method for dynamic design of the dual-axis driving mechanism with clearance is presented. The objective of the optimization is to minimize the maximum absolute vibration peak of antenna acceleration by reducing the impact forces in clearance joint. The main consideration here is to optimize the contact parameters of the joint elements. The contact stiffness coefficient, damping coefficient and the dynamic friction coefficient for clearance joint elements are taken as the optimization variables. A Generalized Reduced Gradient (GRG) algorithm is used to solve this highly nonlinear optimization problem for dual-axis driving mechanism with clearance joints. The results show that the acceleration peaks of satellite antenna and contact forces in clearance joints are reduced obviously after design optimization, which contributes to a better performance of the satellite antenna. Also, the application and limitation of the proposed optimization method are discussed.

Application of a Pharmacokinetic Model of Metformin Clearance in a Population with Acute Myeloid Leukemia.

PubMed

Ceacareanu, Alice C; Brown, Geoffrey W; Moussa, Hoda A; Wintrob, Zachary A P

2018-01-01

We aimed to estimate the metformin-associated lactic acidosis (MALA) risk by assessing retrospectively the renal clearance variability and applying a pharmacokinetic (PK) model of metformin clearance in a population diagnosed with acute myeloid leukemia (AML) and diabetes mellitus (DM). All adults with preexisting DM and newly diagnosed AML at Roswell Park Cancer Institute were reviewed (January 2003-December 2010, n = 78). Creatinine clearance (CrCl) and total body weight distributions were used in a two-compartment PK model adapted for multiple dosing and modified to account for actual intra- and inter-individual variability. Based on this renal function variability evidence, 1000 PK profiles were simulated for multiple metformin regimens with the resultant PK profiles being assessed for safe CrCl thresholds. Metformin 500 mg up to three times daily was safe for all simulated profiles with CrCl ≥25 mL/min. Furthermore, the estimated overall MALA risk was below 10%, remaining under 5% for 500 mg given once daily. CrCl ≥65.25 mL/min was safe for administration in any of the tested regimens (500 mg or 850 mg up to three times daily or 1000 mg up to twice daily). PK simulation-guided prescribing can maximize metformin's beneficial effects on cancer outcomes while minimizing MALA risk.

Carbon Nanotubes in the Human Respiratory Tract-Clearance Modeling.

PubMed

Sturm, Robert

2017-03-01

Clearance of single-wall carbon nanotubes (SWCNT, diameter: 5 nm) and multi-wall carbon nanotubes (MWCNT, diameter: 50 nm) in the respiratory tract was predicted for various age groups (infants, children, adolescents, and adults). The model was founded on the assumption that lung clearance takes place in three distinct phases: (i) fast mucociliary clearance, (ii) slow bronchial clearance, and (iii) alveolar clearance. To each of these phases a specific fraction of deposited particles was attributed, the amount of which depended on particles' geometry and particles' deposition sites in the respiratory system. Clearance velocities were expressed by respective clearance half-times ranging from several hours in the case of fast clearance to tens of days in the case of slow clearance. Results of the simulations clearly demonstrate that for the specific deposition scenario (sitting, nasal breathing) considered here fast clearance fraction exhibits a slight decrease with increasing age, but total clearance times (i.e. time spans, within which 100% of the deposited particulate mass are removed) are rather constant among the age groups. Nanotubes deposited in the respiratory bronchioles and alveoli are usually subject to a long-term storage in these structures and, thus, may trigger malignant transformations in adjacent cells and tissues. © The Author 2017. Published by Oxford University Press on behalf of the British Occupational Hygiene Society.

Application of Markov chain Monte Carlo analysis to biomathematical modeling of respirable dust in US and UK coal miners

PubMed Central

Sweeney, Lisa M.; Parker, Ann; Haber, Lynne T.; Tran, C. Lang; Kuempel, Eileen D.

2015-01-01

A biomathematical model was previously developed to describe the long-term clearance and retention of particles in the lungs of coal miners. The model structure was evaluated and parameters were estimated in two data sets, one from the United States and one from the United Kingdom. The three-compartment model structure consists of deposition of inhaled particles in the alveolar region, competing processes of either clearance from the alveolar region or translocation to the lung interstitial region, and very slow, irreversible sequestration of interstitialized material in the lung-associated lymph nodes. Point estimates of model parameter values were estimated separately for the two data sets. In the current effort, Bayesian population analysis using Markov chain Monte Carlo simulation was used to recalibrate the model while improving assessments of parameter variability and uncertainty. When model parameters were calibrated simultaneously to the two data sets, agreement between the derived parameters for the two groups was very good, and the central tendency values were similar to those derived from the deterministic approach. These findings are relevant to the proposed update of the ICRP human respiratory tract model with revisions to the alveolar-interstitial region based on this long-term particle clearance and retention model. PMID:23454101

Semi-mechanistic autoinduction model of midazolam in critically ill patients: population pharmacokinetic analysis.

PubMed

Aoyama, T; Hirata, K; Yamamoto, Y; Yokota, H; Hayashi, H; Aoyama, Y; Matsumoto, Y

2016-08-01

Midazolam (MDZ) is commonly used for sedating critically ill patients. The daily dose required for adequate sedation increases in increments over 100 h after administration. The objectives of this study were to characterize the MDZ pharmacokinetics in critically ill patients and to describe the phenomenon of increasing daily dose by means of population pharmacokinetic analysis. Data were obtained from 30 patients treated in an intensive care unit. The patients received MDZ intravenously as a combination of bolus and continuous infusion. Serum MDZ concentration was assayed by high-performance liquid chromatography. Population pharmacokinetic analysis was performed using the NONMEM software package. The alteration of clearance unexplained by demographic factors and clinical laboratory data was described as an autoinduction of MDZ clearance using a semi-mechanistic pharmacokinetic-enzyme turnover model. The final population pharmacokinetic model was a one-compartment model estimated by incorporating a semi-mechanistic pharmacokinetic-enzyme turnover model for clearance, taking autoinduction into account. A significant covariate for MDZ clearance was total bilirubin. An increase in total bilirubin indicated a reduction in MDZ clearance. From simulation using the population pharmacokinetic parameters obtained in this study, MDZ clearance increased 2·3 times compared with pre-induced clearance 100 h after the start of 12·5 mg/h continuous infusion. Autoinduction and total bilirubin were significant predictors of the clearance of MDZ in this population. Step-by-step dosage adjustment using this population pharmacokinetic model may be useful for establishing a MDZ dosage regimen in critically ill patients. © 2016 John Wiley & Sons Ltd.

Oleocanthal Enhances Amyloid-β Clearance from the Brains of TgSwDI Mice and in Vitro across a Human Blood-Brain Barrier Model

PubMed Central

2015-01-01

Numerous clinical and preclinical studies have suggested several health promoting effects for the dietary consumption of extra-virgin olive oil (EVOO) that could protect and decrease the risk of developing Alzheimer’s disease (AD). Moreover, recent studies have linked this protective effect to oleocanthal, a phenolic secoiridoid component of EVOO. This protective effect of oleocanthal against AD has been related to its ability to prevent amyloid-β (Aβ) and tau aggregation in vitro, and enhance Aβ clearance from the brains of wild type mice in vivo; however, its effect in a mouse model of AD is not known. In the current study, we investigated the effect of oleocanthal on pathological hallmarks of AD in TgSwDI, an animal model of AD. Mice treatment for 4 weeks with oleocanthal significantly decreased amyloid load in the hippocampal parenchyma and microvessels. This reduction was associated with enhanced cerebral clearance of Aβ across the blood-brain barrier (BBB). Further mechanistic studies demonstrated oleocanthal to increase the expression of important amyloid clearance proteins at the BBB including P-glycoprotein and LRP1, and to activate the ApoE-dependent amyloid clearance pathway in the mice brains. The anti-inflammatory effect of oleocanthal in the brains of these mice was also obvious where it was able to reduce astrocytes activation and IL-1β levels. Finally, we could recapitulate the observed protective effect of oleocanthal in an in vitro human-based model, which could argue against species difference in response to oleocanthal. In conclusion, findings from in vivo and in vitro studies provide further support for the protective effect of oleocanthal against the progression of AD. PMID:26348065

Effects of body size and gender on the population pharmacokinetics of artesunate and its active metabolite dihydroartemisinin in pediatric malaria patients.

PubMed

Morris, Carrie A; Tan, Beesan; Duparc, Stephan; Borghini-Fuhrer, Isabelle; Jung, Donald; Shin, Chang-Sik; Fleckenstein, Lawrence

2013-12-01

Despite the important role of the antimalarial artesunate and its active metabolite dihydroartemisinin (DHA) in malaria treatment efforts, there are limited data on the pharmacokinetics of these agents in pediatric patients. This study evaluated the effects of body size and gender on the pharmacokinetics of artesunate-DHA using data from pediatric and adult malaria patients. Nonlinear mixed-effects modeling was used to obtain a base model consisting of first-order artesunate absorption and one-compartment models for artesunate and for DHA. Various methods of incorporating effects of body size descriptors on clearance and volume parameters were tested. An allometric scaling model for weight and a linear body surface area (BSA) model were deemed optimal. The apparent clearance and volume of distribution of DHA obtained with the allometric scaling model, normalized to a 38-kg patient, were 63.5 liters/h and 65.1 liters, respectively. Estimates for the linear BSA model were similar. The 95% confidence intervals for the estimated gender effects on clearance and volume parameters for artesunate fell outside the predefined no-relevant-clinical-effect interval of 0.75 to 1.25. However, the effect of gender on apparent DHA clearance was almost entirely contained within this interval, suggesting a lack of an influence of gender on this parameter. Overall, the pharmacokinetics of artesunate and DHA following oral artesunate administration can be described for pediatric patients using either an allometric scaling or linear BSA model. Both models predict that, for a given artesunate dose in mg/kg of body weight, younger children are expected to have lower DHA exposure than older children or adults.

Methodological uncertainty in quantitative prediction of human hepatic clearance from in vitro experimental systems.

PubMed

Hallifax, D; Houston, J B

2009-03-01

Mechanistic prediction of unbound drug clearance from human hepatic microsomes and hepatocytes correlates with in vivo clearance but is both systematically low (10 - 20 % of in vivo clearance) and highly variable, based on detailed assessments of published studies. Metabolic capacity (Vmax) of commercially available human hepatic microsomes and cryopreserved hepatocytes is log-normally distributed within wide (30 - 150-fold) ranges; Km is also log-normally distributed and effectively independent of Vmax, implying considerable variability in intrinsic clearance. Despite wide overlap, average capacity is 2 - 20-fold (dependent on P450 enzyme) greater in microsomes than hepatocytes, when both are normalised (scaled to whole liver). The in vitro ranges contrast with relatively narrow ranges of clearance among clinical studies. The high in vitro variation probably reflects unresolved phenotypical variability among liver donors and practicalities in processing of human liver into in vitro systems. A significant contribution from the latter is supported by evidence of low reproducibility (several fold) of activity in cryopreserved hepatocytes and microsomes prepared from the same cells, between separate occasions of thawing of cells from the same liver. The large uncertainty which exists in human hepatic in vitro systems appears to dominate the overall uncertainty of in vitro-in vivo extrapolation, including uncertainties within scaling, modelling and drug dependent effects. As such, any notion of quantitative prediction of clearance appears severely challenged.

Population pharmacokinetics of rifampicin, pyrazinamide and isoniazid in children with tuberculosis: in silico evaluation of currently recommended doses.

PubMed

Zvada, Simbarashe P; Denti, Paolo; Donald, Peter R; Schaaf, H Simon; Thee, Stephanie; Seddon, James A; Seifart, Heiner I; Smith, Peter J; McIlleron, Helen M; Simonsson, Ulrika S H

2014-05-01

To describe the population pharmacokinetics of rifampicin, pyrazinamide and isoniazid in children and evaluate the adequacy of steady-state exposures. We used previously published data for 76 South African children with tuberculosis to describe the population pharmacokinetics of rifampicin, pyrazinamide and isoniazid. Monte Carlo simulations were used to predict steady-state exposures in children following doses in fixed-dose combination tablets in accordance with the revised guidelines. Reference exposures were derived from an ethnically similar adult population with tuberculosis taking currently recommended doses. The final models included allometric scaling of clearance and volume of distribution using body weight. Maturation was included for clearance of isoniazid and clearance and absorption transit time of rifampicin. For a 2-year-old child weighing 12.5 kg, the estimated typical oral clearances of rifampicin and pyrazinamide were 8.15 and 1.08 L/h, respectively. Isoniazid typical oral clearance (adjusted for bioavailability) was predicted to be 4.44, 11.6 and 14.6 L/h for slow, intermediate and fast acetylators, respectively. Higher oral clearance values in intermediate and fast acetylators also resulted from 23% lower bioavailability compared with slow acetylators. Simulations based on our models suggest that with the new WHO dosing guidelines and utilizing available paediatric fixed-dose combinations, children will receive adequate rifampicin exposures when compared with adults, but with a larger degree of variability. However, pyrazinamide and isoniazid exposures in many children will be lower than in adults. Further studies are needed to confirm these findings in children administered the revised dosages and to optimize pragmatic approaches to dosing.

Unsolved homicides in Sweden: A population-based study of 264 homicides.

PubMed

Sturup, Joakim; Karlberg, Daniel; Kristiansson, Marianne

2015-12-01

The clearance rates for homicides have decreased internationally. This retrospective population-based study of all Swedish homicide incidents between 2007 and 2009 (n=264) aims to investigate factors associated with solvability in homicides. Victims were identified in an autopsy registry and offenders in a criminal-conviction registry. Autopsy reports, police files, court verdicts and criminal records were systematically collected and linked. The clearance rate was 86.4% (n=228), and almost three quarters of cases (71.9%) were solved within the first week. Nine factors were significantly associated with the case status; however, only four factors remained significant in the multivariate logistic-regression model. Cases were more likely to be solved if there was an eyewitness and if the victim was intoxicated with alcohol. Moreover, cases were less likely to be solved if the victim had a criminal record in the past five years and was killed by a firearm. In the final model, a Cox proportional-hazards model, where time to arrest was taken into account, only alcohol intoxication were positively and firearms negatively significantly associated with clearance status. The study concludes that cases involving these factors should be granted extra, intensive and lasting resources. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Glottis effects on the cough clearance process simulated with a CFD dynamic mesh and Eulerian wall film model.

PubMed

Paz, Concepción; Suárez, Eduardo; Parga, Oscar; Vence, Jesús

2017-09-01

In this study, we have reproduced the cough clearance process with an Eulerian wall film model. The simulated domain is based on realistic geometry from the literature, which has been improved by adding the glottis and epiglottis. The vocal fold movement has been included due to the dynamic mesh method, considering different abduction and adduction angles and velocities. The proposed methodology captures the deformation of the flexible tissue, considers non-Newtonian properties for the mucus, and enables us to reproduce a single cough or a cough epoch. The cough efficiency (CE) has been used to quantify the overall performance of the cough, considering many different boundary conditions, for the analysis of the glottis effect. It was observed that a viscous shear force is the main mechanism in the cough clearance process, while the glottis closure time and the epiglottis position do not have a significant effect on the CE. The cough assistance devices improve the CE, and the enhancement rate grows logarithmically with the operating pressure. The cough can achieve an effective mucus clearance process, even with a fixed glottis. Nevertheless, the glottis closure substantially improves the CE results.

Urea clearance: a new technique based on microdialysis to assess liver blood flow studied in a pig model of ischemia/reperfusion.

PubMed

Farnebo, S; Winbladh, A; Zettersten, E K; Sandström, P; Gullstrand, P; Samuelsson, A; Theodorson, E; Sjöberg, F

2010-01-01

Delayed detection of ischemia is one of the most feared postoperative complications. Early detection of impaired blood flow and close monitoring of the organ-specific metabolic status may therefore be critical for the surgical outcome. Urea clearance is a new technique for continuous monitoring of alterations in blood flow and metabolic markers with acceptable temporal characteristics. We compare this new microdialysis technique with the established microdialysis ethanol technique to assess hepatic blood flow. Six pigs were used in a liver ischemia/reperfusion injury model. Microdialysis catheters were placed in liver segment IV and all circulation was stopped for 80 min, followed by reperfusion for 220 min. Urea and ethanol clearance was calculated from the dialysate and correlated with metabolic changes. A laser Doppler probe was used as reference of restoration of blood flow. Both urea and ethanol clearance reproducibly depicted changes in liver blood flow in relation to metabolic changes and laser Doppler measurements. The two techniques highly correlated both overall and during the reperfusion phase (r = 0.8) and the changes were paralleled by altered perfusion as recorded by laser Doppler. Copyright © 2010 S. Karger AG, Basel.

Retrospective Evaluation of Milrinone Pharmacokinetics in Children With Kidney Injury.

PubMed

Gist, Katja M; Mizuno, Tomoyuki; Goldstein, Stuart L; Vinks, Alexander

2015-12-01

Milrinone is an inotropic agent with vasodilating properties used in the treatment of ventricular dysfunction. Milrinone is predominantly eliminated by the kidneys and accumulates in the setting of acute kidney injury (AKI). The purpose of this study was to evaluate milrinone pharmacokinetics in children with AKI with or without continuous renal replacement therapy (CRRT). Retrospective collection of milrinone therapeutic drug monitoring data in patients with AKI, including those requiring CRRT, through chart review from January 2008 to March 2014. Pharmacokinetic (PK) data were analyzed by Bayesian estimation using a pediatric population PK model (MW/Pharm). Clearance estimates were allometrically scaled to body weight. Data on 11 patients were available for analysis. Three patients required CRRT. Milrinone concentrations during continuous infusion varied 30-fold and ranged from 44 to 1343 ng/mL. Of the 33 samples obtained in 11 patients, 24 were outside the target range (72.7%), with 16 (48.5%) above and 8 (24.2%) below. Patients with AKI had significantly lower milrinone clearance (4.72 ± 2.26 L/h per 70 kg) compared with published data in patients without AKI. There was large between-patient variability in milrinone clearance (range: 2.91-13.6 L/h per 70 kg). Clearance in patients on CRRT ranged from 2.8 to 7.19 L/h per 70 kg. A significant correlation between milrinone clearance and estimated creatinine clearance was observed (r = 0.70, P = 0.0097). Allometrically scaled milrinone clearance was lower in the youngest patients (younger than 2 years), suggestive of ongoing renal maturation and existing AKI. Pediatric patients with AKI have significantly lower milrinone clearance compared with published data in patients without AKI. Large variability was noted in milrinone concentrations, and they were frequently outside the target range. The large between-patient variability in milrinone concentrations suggests that dosing regimens should be individualized in this population of critically ill patients. Evaluation of PK model-based milrinone dose optimization and the use of biomarkers as predictors of changes in clearance warrant further study.

Pharmacoepidemiologic investigation of clonazepam relative clearance by mixed-effect modeling using routine clinical pharmacokinetic data in Japanese patients.

PubMed

Yukawa, Eiji; Satou, Masayasu; Nonaka, Toshiharu; Yukawa, Miho; Ohdo, Shigehiro; Higuchi, Shun; Kuroda, Takeshi; Goto, Yoshinobu

2002-01-01

The effects of drug-drug interactions on clonazepam clearance were examined through a retrospective analysis of serum concentration data from pediatric and adult epileptic patients. Patients received clonazepam as monotherapy or in combination with other antiepileptic drugs. A total of 259 serum clonazepam concentrations gathered from 137 patients were used in a population analysis of drug-drug interactions on clonazepam clearance. Data were analyzed using a nonlinear mixed-effects modeling (NONMEM) technique. The final model describing clonazepam clearance was CL = 152 x TBW(-0.181) x DIF, where CL is clearance (ml/kg/h), TBWis total body weight (kg), and DIF (drug interaction factor) is a scaling factor for concomitant medication with a value of 1 for patients on clonazepam monotherapy, 1.18 for those patients receiving concomitant administration of clonazepam and one antiepileptic drug (carbamazepine or valproic acid), and 2.12 x TBW(-0.119) for those patients receiving concomitant administration of clonazepam and more than two antiepileptic drugs. Clonazepam clearance decreased in a weight-related fashion in children, with minimal changes observed in adults. Concomitant administration of clonazepam and carbamazepine resulted in a 22% increase in clonazepam clearance. Concomitant administration of clonazepam and valproic acid resulted in a 12% increase in clonazepam clearance. Concomitant administration of clonazepam with two or more antiepileptic drugs resulted in a 23% to 75% increase in clonazepam clearance.

Use of mouse models to study the mechanisms and consequences of RBC clearance

PubMed Central

Hod, E. A.; Arinsburg, S. A.; Francis, R. O.; Hendrickson, J. E.; Zimring, J. C.; Spitalnik, S. L.

2013-01-01

Mice provide tractable animal models for studying the pathophysiology of various human disorders. This review discusses the use of mouse models for understanding red-blood-cell (RBC) clearance. These models provide important insights into the pathophysiology of various clinically relevant entities, such as autoimmune haemolytic anaemia, haemolytic transfusion reactions, other complications of RBC transfusions and immunomodulation by Rh immune globulin therapy. Mouse models of both antibody- and non-antibody-mediated RBC clearance are reviewed. Approaches for exploring unanswered questions in transfusion medicine using these models are also discussed. PMID:20345515

24 CFR 3285.305 - Clearance under homes.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 24 Housing and Urban Development 5 2011-04-01 2011-04-01 false Clearance under homes. 3285.305... URBAN DEVELOPMENT MODEL MANUFACTURED HOME INSTALLATION STANDARDS Foundations § 3285.305 Clearance under homes. A minimum clearance of 12 inches must be maintained between the lowest member of the main frame...

24 CFR 3285.305 - Clearance under homes.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 24 Housing and Urban Development 5 2010-04-01 2010-04-01 false Clearance under homes. 3285.305... URBAN DEVELOPMENT MODEL MANUFACTURED HOME INSTALLATION STANDARDS Foundations § 3285.305 Clearance under homes. A minimum clearance of 12 inches must be maintained between the lowest member of the main frame...

24 CFR 3285.305 - Clearance under homes.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 24 Housing and Urban Development 5 2012-04-01 2012-04-01 false Clearance under homes. 3285.305... URBAN DEVELOPMENT MODEL MANUFACTURED HOME INSTALLATION STANDARDS Foundations § 3285.305 Clearance under homes. A minimum clearance of 12 inches must be maintained between the lowest member of the main frame...

24 CFR 3285.305 - Clearance under homes.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 24 Housing and Urban Development 5 2014-04-01 2014-04-01 false Clearance under homes. 3285.305... URBAN DEVELOPMENT MODEL MANUFACTURED HOME INSTALLATION STANDARDS Foundations § 3285.305 Clearance under homes. A minimum clearance of 12 inches must be maintained between the lowest member of the main frame...

24 CFR 3285.305 - Clearance under homes.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 24 Housing and Urban Development 5 2013-04-01 2013-04-01 false Clearance under homes. 3285.305... URBAN DEVELOPMENT MODEL MANUFACTURED HOME INSTALLATION STANDARDS Foundations § 3285.305 Clearance under homes. A minimum clearance of 12 inches must be maintained between the lowest member of the main frame...

Estimation of end point foot clearance points from inertial sensor data.

PubMed

Santhiranayagam, Braveena K; Lai, Daniel T H; Begg, Rezaul K; Palaniswami, Marimuthu

2011-01-01

Foot clearance parameters provide useful insight into tripping risks during walking. This paper proposes a technique for the estimate of key foot clearance parameters using inertial sensor (accelerometers and gyroscopes) data. Fifteen features were extracted from raw inertial sensor measurements, and a regression model was used to estimate two key foot clearance parameters: First maximum vertical clearance (m x 1) after toe-off and the Minimum Toe Clearance (MTC) of the swing foot. Comparisons are made against measurements obtained using an optoelectronic motion capture system (Optotrak), at 4 different walking speeds. General Regression Neural Networks (GRNN) were used to estimate the desired parameters from the sensor features. Eight subjects foot clearance data were examined and a Leave-one-subject-out (LOSO) method was used to select the best model. The best average Root Mean Square Errors (RMSE) across all subjects obtained using all sensor features at the maximum speed for m x 1 was 5.32 mm and for MTC was 4.04 mm. Further application of a hill-climbing feature selection technique resulted in 0.54-21.93% improvement in RMSE and required fewer input features. The results demonstrated that using raw inertial sensor data with regression models and feature selection could accurately estimate key foot clearance parameters.

Axial compressor blade design for desensitization of aerodynamic performance and stability to tip clearance

NASA Astrophysics Data System (ADS)

Erler, Engin

Tip clearance flow is the flow through the clearance between the rotor blade tip and the shroud of a turbomachine, such as compressors and turbines. This flow is driven by the pressure difference across the blade (aerodynamic loading) in the tip region and is a major source of loss in performance and aerodynamic stability in axial compressors of modern aircraft engines. An increase in tip clearance, either temporary due to differential radial expansion between the blade and the shroud during transient operation or permanent due to engine wear or manufacturing tolerances on small blades, increases tip clearance flow and results in higher fuel consumption and higher risk of engine surge. A compressor design that can reduce the sensitivity of its performance and aerodynamic stability to tip clearance increase would have a major impact on short and long-term engine performance and operating envelope. While much research has been carried out on improving nominal compressor performance, little had been done on desensitization to tip clearance increase beyond isolated observations that certain blade designs such as forward chordwise sweep, seem to be less sensitive to tip clearance size increase. The current project aims to identify through a computational study the flow features and associated mechanisms that reduces sensitivity of axial compressor rotors to tip clearance size and propose blade design strategies that can exploit these results. The methodology starts with the design of a reference conventional axial compressor rotor followed by a parametric study with variations of this reference design through modification of the camber line and of the stacking line of blade profiles along the span. It is noted that a simple desensitization method would be to reduce the aerodynamic loading of the blade tip which would reduce the tip clearance flow and its proportional contribution to performance loss. However, with the larger part of the work on the flow done in this region, this approach would entail a nominal performance penalty. Therefore, the chosen rotor design philosophy aims to keep the spanwise loading constant to avoid trading performance for desensitization. The rotor designs that resulted from this exercise are simulated in ANSYS CFX at different tip clearance sizes. The change in their performance with respect to tip clearance size (sensitivity) is compared both on an integral level in terms of pressure ratio and adiabatic efficiency, as well as on a detailed level in terms of aerodynamic losses and blockage associated with tip clearance flow. The sensitivity of aerodynamic stability is evaluated either directly through the simulations of the rotor characteristics up to the stall point (expensive in time and resources) for a few designs or indirectly through the position of the interface between the incoming and tip clearance flow with respect to the rotor leading edge plane. The latter approach is based on a generally observed stall criteria in modern axial compressors. The rotor designs are then assessed according to their sensitivity in comparison to that of the reference rotor design to detect features that can explain the trend in sensitivity to tip clearance size. These features can then be validated and the associated flow mechanisms explained through numerical simulations and modelling. Analysis of the database from the rotor parametric study shows that the observed trend in sensitivity cannot be explained by the shifting of the aerodynamic loading along the blade chord, as initially hypothesized based on the literature review. Instead, two flow features are found to reduce sensitivity of performance and stability to tip clearance, namely an increase in incoming meridional momentum in the tip region and a reduction/elimination of double leakage flow. Double leakage flow is the flow that exits the tip clearance of one blade and proceeds into the clearance of the adjacent blade rather than convecting downstream out of the local blade passage. These flow features are isolated and validated based on the reference rotor design through changes in the inlet total pressure condition to alter incoming flow momentum and blade number count to change double leakage rate. In terms of flow mechanism, double leakage is shown to be detrimental to performance and stability, and its proportional increase with tip clearance size explains the sensitivity increase in the presence of double leakage and, conversely, the desensitization effect of reducing or eliminating double leakage. The increase in incoming meridional momentum in the tip region reduces sensitivity to tip clearance through its reduction of double leakage as well as through improved mixing with tip clearance flow, as demonstrated by an analytical model without double leakage flow. The above results imply that any blade design strategy that exploits the two desensitizing flow features would reduce the performance and stability sensitivity to tip clearance size. The increase of the incoming meridional momentum can be achieved through forward chordwise sweep of the blade. The reduction of double leakage without changing blade pitch can be obtained by decreasing the blade stagger angle in the tip region. Examples of blade designs associated with these strategies are shown through CFX simulations to be successful in reducing sensitivity to tip clearance size.

Pharmacokinetics of paracetamol and its metabolites in women at delivery and post‐partum

PubMed Central

Kulo, Aida; Peeters, Mariska Y.; Allegaert, Karel; Smits, Anne; de Hoon, Jan; Verbesselt, Rene; Lewi, Liesbeth; van de Velde, Marc; Knibbe, Catherijne A. J.

2013-01-01

Aim A recent report on intravenous (i.v.) paracetamol pharmacokinetics (PK) showed a higher total clearance in women at delivery compared with non‐pregnant women. To describe the paracetamol metabolic and elimination routes involved in this increase in clearance, we performed a population PK analysis in women at delivery and post‐partum in which the different pathways were considered. Methods Population PK parameters using non‐linear mixed effect modelling were estimated in a two‐period PK study in women to whom i.v. paracetamol (2 g loading dose followed by 1 g every 6 h up to 24 h) was administered immediately following Caesarean delivery and in a subgroup of the same women to whom single 2 g i.v.loading dose was administered 10–15 weeks post‐partum. Results Population PK analysis was performed based on 255 plasma and 71 urine samples collected in 39 women at delivery and in eight of these 39 women 12 weeks post‐partum. Total clearance was higher in women at delivery compared with 12th post‐partum week (21.1 vs. 11.7 l h−1) due to higher clearances to paracetamol glucuronide (11.6 vs. 4.76 l h−1), to oxidative metabolites (4.95 vs. 2.77 l h−1) and of unchanged paracetamol (1.15 vs. 0.75 l h−1). In contrast, there was no difference in clearance to paracetamol sulphate. Conclusion The increased total paracetamol clearance at delivery is caused by a disproportional increase in glucuronidation clearance and a proportional increase in clearance of unchanged paracetamol and in oxidation clearance, of which the latter may potentially limit further dose increase in this patient group. PMID:22845052

Improved prediction of tacrolimus concentrations early after kidney transplantation using theory-based pharmacokinetic modelling.

PubMed

Størset, Elisabet; Holford, Nick; Hennig, Stefanie; Bergmann, Troels K; Bergan, Stein; Bremer, Sara; Åsberg, Anders; Midtvedt, Karsten; Staatz, Christine E

2014-09-01

The aim was to develop a theory-based population pharmacokinetic model of tacrolimus in adult kidney transplant recipients and to externally evaluate this model and two previous empirical models. Data were obtained from 242 patients with 3100 tacrolimus whole blood concentrations. External evaluation was performed by examining model predictive performance using Bayesian forecasting. Pharmacokinetic disposition parameters were estimated based on tacrolimus plasma concentrations, predicted from whole blood concentrations, haematocrit and literature values for tacrolimus binding to red blood cells. Disposition parameters were allometrically scaled to fat free mass. Tacrolimus whole blood clearance/bioavailability standardized to haematocrit of 45% and fat free mass of 60 kg was estimated to be 16.1 l h−1 [95% CI 12.6, 18.0 l h−1]. Tacrolimus clearance was 30% higher (95% CI 13, 46%) and bioavailability 18% lower (95% CI 2, 29%) in CYP3A5 expressers compared with non-expressers. An Emax model described decreasing tacrolimus bioavailability with increasing prednisolone dose. The theory-based model was superior to the empirical models during external evaluation displaying a median prediction error of −1.2% (95% CI −3.0, 0.1%). Based on simulation, Bayesian forecasting led to 65% (95% CI 62, 68%) of patients achieving a tacrolimus average steady-state concentration within a suggested acceptable range. A theory-based population pharmacokinetic model was superior to two empirical models for prediction of tacrolimus concentrations and seemed suitable for Bayesian prediction of tacrolimus doses early after kidney transplantation.

Inert gas clearance from tissue by co-currently and counter-currently arranged microvessels

PubMed Central

Lu, Y.; Michel, C. C.

2012-01-01

To elucidate the clearance of dissolved inert gas from tissues, we have developed numerical models of gas transport in a cylindrical block of tissue supplied by one or two capillaries. With two capillaries, attention is given to the effects of co-current and counter-current flow on tissue gas clearance. Clearance by counter-current flow is compared with clearance by a single capillary or by two co-currently arranged capillaries. Effects of the blood velocity, solubility, and diffusivity of the gas in the tissue are investigated using parameters with physiological values. It is found that under the conditions investigated, almost identical clearances are achieved by a single capillary as by a co-current pair when the total flow per tissue volume in each unit is the same (i.e., flow velocity in the single capillary is twice that in each co-current vessel). For both co-current and counter-current arrangements, approximate linear relations exist between the tissue gas clearance rate and tissue blood perfusion rate. However, the counter-current arrangement of capillaries results in less-efficient clearance of the inert gas from tissues. Furthermore, this difference in efficiency increases at higher blood flow rates. At a given blood flow, the simple conduction-capacitance model, which has been used to estimate tissue blood perfusion rate from inert gas clearance, underestimates gas clearance rates predicted by the numerical models for single vessel or for two vessels with co-current flow. This difference is accounted for in discussion, which also considers the choice of parameters and possible effects of microvascular architecture on the interpretation of tissue inert gas clearance. PMID:22604885

3-D Model of the Human Respiratory System

EPA Science Inventory

The U.S. EPA’s Office of Research and Development (ORD) has developed a 3-D computational fluid dynamics (CFD) model of the human respiratory system that allows for the simulation of particulate based contaminant deposition and clearance, while being adaptable for age, ethnicity,...

Prediction of Fetal Darunavir Exposure by Integrating Human Ex-Vivo Placental Transfer and Physiologically Based Pharmacokinetic Modeling.

PubMed

Schalkwijk, Stein; Buaben, Aaron O; Freriksen, Jolien J M; Colbers, Angela P; Burger, David M; Greupink, Rick; Russel, Frans G M

2017-07-25

Fetal antiretroviral exposure is usually derived from the cord-to-maternal concentration ratio. This static parameter does not provide information on the pharmacokinetics in utero, limiting the assessment of a fetal exposure-effect relationship. The aim of this study was to incorporate placental transfer into a pregnancy physiologically based pharmacokinetic model to simulate and evaluate fetal darunavir exposure at term. An existing and validated pregnancy physiologically based pharmacokinetic model of maternal darunavir/ritonavir exposure was extended with a feto-placental unit. To parameterize the model, we determined maternal-to-fetal and fetal-to-maternal darunavir/ritonavir placental clearance with an ex-vivo human cotyledon perfusion model. Simulated maternal and fetal pharmacokinetic profiles were compared with observed clinical data to qualify the model for simulation. Next, population fetal pharmacokinetic profiles were simulated for different maternal darunavir/ritonavir dosing regimens. An average (±standard deviation) maternal-to-fetal cotyledon clearance of 0.91 ± 0.11 mL/min and fetal-to-maternal clearance of 1.6 ± 0.3 mL/min was determined (n = 6 perfusions). Scaled placental transfer was integrated into the pregnancy physiologically based pharmacokinetic model. For darunavir 600/100 mg twice a day, the predicted fetal maximum plasma concentration, trough concentration, time to maximum plasma concentration, and half-life were 1.1, 0.57 mg/L, 3, and 21 h, respectively. This indicates that the fetal population trough concentration is higher or around the half-maximal effective darunavir concentration for a resistant virus (0.55 mg/L). The results indicate that the population fetal exposure after oral maternal darunavir dosing is therapeutic and this may provide benefits to the prevention of mother-to-child transmission of human immunodeficiency virus. Moreover, this integrated approach provides a tool to prevent fetal toxicity or enhance the development of more selectively targeted fetal drug treatments.

Evaluation of Aztreonam Dosing Regimens in Patients With Normal and Impaired Renal Function: A Population Pharmacokinetic Modeling and Monte Carlo Simulation Analysis.

PubMed

Xu, Hongmei; Zhou, Wangda; Zhou, Diansong; Li, Jianguo; Al-Huniti, Nidal

2017-03-01

Aztreonam is a monocyclic β-lactam antibiotic often used to treat infections caused by Enterobacteriaceae or Pseudomonas aeruginosa. Despite the long history of clinical use, population pharmacokinetic modeling of aztreonam in renally impaired patients is not yet available. The aims of this study were to assess the impact of renal impairment on aztreonam exposure and to evaluate dosing regimens for patients with renal impairment. A population model describing aztreonam pharmacokinetics following intravenous administration was developed using plasma concentrations from 42 healthy volunteers and renally impaired patients from 2 clinical studies. The final pharmacokinetic model was used to predict aztreonam plasma concentrations and evaluate the probability of pharmacodynamic target attainment (PTA) in patients with different levels of renal function. A 2-compartment model with first-order elimination adequately described aztreonam pharmacokinetics. The population mean estimates of aztreonam clearance, intercompartmental clearance, volume of distribution of the central compartment, and volume of distribution of the peripheral compartment were 4.93 L/h, 9.26 L/h, 7.43 L, and 6.44 L, respectively. Creatinine clearance and body weight were the most significant variables to explain patient variability in aztreonam clearance and volume of distribution, respectively. Simulations using the final pharmacokinetic model resulted in a clinical susceptibility break point of 4 and 8 mg/L, respectively, based on the clinical use of 1- and 2-g loading doses with the same or reduced maintenance dose every 8 hours for various renal deficiency patients. The population pharmacokinetic modeling and PTA estimation support adequate PTAs (>90% PTA) from the aztreonam label for dose adjustment of aztreonam in patients with moderate and severe renal impairment. © 2016, The American College of Clinical Pharmacology.

Application of a Pharmacokinetic Model of Metformin Clearance in a Population with Acute Myeloid Leukemia

PubMed Central

Ceacareanu, Alice C.; Brown, Geoffrey W.; Moussa, Hoda A.; Wintrob, Zachary A. P.

2018-01-01

Objective: We aimed to estimate the metformin-associated lactic acidosis (MALA) risk by assessing retrospectively the renal clearance variability and applying a pharmacokinetic (PK) model of metformin clearance in a population diagnosed with acute myeloid leukemia (AML) and diabetes mellitus (DM). Methods: All adults with preexisting DM and newly diagnosed AML at Roswell Park Cancer Institute were reviewed (January 2003–December 2010, n = 78). Creatinine clearance (CrCl) and total body weight distributions were used in a two-compartment PK model adapted for multiple dosing and modified to account for actual intra- and inter-individual variability. Based on this renal function variability evidence, 1000 PK profiles were simulated for multiple metformin regimens with the resultant PK profiles being assessed for safe CrCl thresholds. Findings: Metformin 500 mg up to three times daily was safe for all simulated profiles with CrCl ≥25 mL/min. Furthermore, the estimated overall MALA risk was below 10%, remaining under 5% for 500 mg given once daily. CrCl ≥65.25 mL/min was safe for administration in any of the tested regimens (500 mg or 850 mg up to three times daily or 1000 mg up to twice daily). Conclusion: PK simulation-guided prescribing can maximize metformin's beneficial effects on cancer outcomes while minimizing MALA risk. PMID:29755998

Distributed collaborative probabilistic design for turbine blade-tip radial running clearance using support vector machine of regression

NASA Astrophysics Data System (ADS)

Fei, Cheng-Wei; Bai, Guang-Chen

2014-12-01

To improve the computational precision and efficiency of probabilistic design for mechanical dynamic assembly like the blade-tip radial running clearance (BTRRC) of gas turbine, a distribution collaborative probabilistic design method-based support vector machine of regression (SR)(called as DCSRM) is proposed by integrating distribution collaborative response surface method and support vector machine regression model. The mathematical model of DCSRM is established and the probabilistic design idea of DCSRM is introduced. The dynamic assembly probabilistic design of aeroengine high-pressure turbine (HPT) BTRRC is accomplished to verify the proposed DCSRM. The analysis results reveal that the optimal static blade-tip clearance of HPT is gained for designing BTRRC, and improving the performance and reliability of aeroengine. The comparison of methods shows that the DCSRM has high computational accuracy and high computational efficiency in BTRRC probabilistic analysis. The present research offers an effective way for the reliability design of mechanical dynamic assembly and enriches mechanical reliability theory and method.

Loss model for off-design performance analysis of radial turbines with pivoting-vane, variable-area stators

NASA Technical Reports Server (NTRS)

Meitner, P. L.; Glassman, A. J.

1980-01-01

An off-design performance loss model for a radial turbine with pivoting, variable-area stators is developed through a combination of analytical modeling and experimental data analysis. A viscous loss model is used for the variation in stator loss with setting angle, and stator vane end-clearance leakage effects are predicted by a clearance flow model. The variation of rotor loss coefficient with stator setting angle is obtained by means of an analytical matching of experimental data for a rotor that was tested with six stators, having throat areas from 20 to 144% of the design area. An incidence loss model is selected to obtain best agreement with experimental data. The stator vane end-clearance leakage model predicts increasing mass flow and decreasing efficiency as a result of end-clearances, with changes becoming significantly larger with decreasing stator area.

Developmental changes rather than repeated administration drive paracetamol glucuronidation in neonates and infants.

PubMed

Krekels, Elke H J; van Ham, Saskia; Allegaert, Karel; de Hoon, Jan; Tibboel, Dick; Danhof, Meindert; Knibbe, Catherijne A J

2015-09-01

Based on recovered metabolite ratios in urine, it has been concluded that paracetamol glucuronidation may be up-regulated upon multiple dosing. This study investigates paracetamol clearance in neonates and infants after single and multiple dosing using a population modelling approach. A population pharmacokinetic model was developed in NONMEM VI, based on paracetamol plasma concentrations from 54 preterm and term neonates and infants, and on paracetamol, paracetamol-glucuronide and paracetamol-sulphate amounts in urine from 22 of these patients. Patients received either a single intravenous propacetamol dose or up to 12 repeated doses. Paracetamol and metabolite disposition was best described with one-compartment models. The formation clearance of paracetamol-sulphate was 1.46 mL/min/kg(1.4), which was about 5.5 times higher than the formation clearance of the glucuronide of 0.266 mL/min/kg. The renal excretion rate constants of both metabolites was estimated to be 11.4 times higher than the excretion rate constant of unchanged paracetamol, yielding values of 0.580 mL/min/kg. Developmental changes were best described by bodyweight in linear relationships on the distribution volumes, the formation of paracetamol-glucuronide and the unchanged excretion of paracetamol, and in an exponential relationship on the formation of paracetamol-sulphate. There was no evidence for up-regulation or other time-varying changes in any of the model parameters. Simulations with this model illustrate how paracetamol-glucuronide recovery in urine increases over time due to the slower formation of this metabolite and in the absence of up-regulation. Developmental changes, described by bodyweight-based functions, rather than up-regulation, explain developmental changes in paracetamol disposition in neonates and infants.

First pass intestinal and liver metabolism of paracetamol in a microfluidic platform coupled with a mathematical modeling as a means of evaluating ADME processes in humans.

PubMed

Prot, Jean Matthieu; Maciel, Luis; Bricks, Thibault; Merlier, Franck; Cotton, Jérôme; Paullier, Patrick; Bois, Fréderic Yves; Leclerc, Eric

2014-10-01

We developed a microfluidic platform to investigate paracetamol intestinal and liver first pass metabolism. This approach was coupled with a mathematical model to estimate intrinsic in vitro parameters and to predict in vivo processes. The kinetic modeling estimated the paracetamol and paracetamol sulfate permeabilities, the sulfate and glucuronide effluxes in the intestine compartment. Based on a gut model, we estimated intrinsic intestinal clearance of between 26 and 77 L/h for paracetamol in humans, a permeability of 10 L/h, and a gut availability between 0.17 and 0.53 (compared to 0.95-1 in vivo). The role played by the liver in paracetamol metabolism was estimated via in vitro intrinsic clearances of 7.6, 13.6, and 11.5 µL/min/10(6) cells for HepG2/C3a, rat primary hepatocytes, and human primary hepatocytes, respectively. Based on a parallel tube model to describe the liver, the paracetamol hepatic clearance, and the paracetamol hepatic availability in humans were estimated at 6.5 mL/min/kg of bodyweight (BDW) and 0.7, respectively (when compared to 5 mL/min/kg of BDW and 0.77 to 0.88 for in vivo values, respectively). The drug availability was predicted ranging between 0.24 and 0.41 (0.88 in vivo). The overall approach provided a first step in an integrated strategy combining in silico/in vitro methods based on microfluidic for evaluating drug absorption, distribution and metabolism processes. © 2014 Wiley Periodicals, Inc.

Population pharmacokinetics of rifampicin, pyrazinamide and isoniazid in children with tuberculosis: in silico evaluation of currently recommended doses

PubMed Central

Zvada, Simbarashe P.; Denti, Paolo; Donald, Peter R.; Schaaf, H. Simon; Thee, Stephanie; Seddon, James A.; Seifart, Heiner I.; Smith, Peter J.; McIlleron, Helen M.; Simonsson, Ulrika S. H.

2014-01-01

Objectives To describe the population pharmacokinetics of rifampicin, pyrazinamide and isoniazid in children and evaluate the adequacy of steady-state exposures. Patients and methods We used previously published data for 76 South African children with tuberculosis to describe the population pharmacokinetics of rifampicin, pyrazinamide and isoniazid. Monte Carlo simulations were used to predict steady-state exposures in children following doses in fixed-dose combination tablets in accordance with the revised guidelines. Reference exposures were derived from an ethnically similar adult population with tuberculosis taking currently recommended doses. Results The final models included allometric scaling of clearance and volume of distribution using body weight. Maturation was included for clearance of isoniazid and clearance and absorption transit time of rifampicin. For a 2-year-old child weighing 12.5 kg, the estimated typical oral clearances of rifampicin and pyrazinamide were 8.15 and 1.08 L/h, respectively. Isoniazid typical oral clearance (adjusted for bioavailability) was predicted to be 4.44, 11.6 and 14.6 L/h for slow, intermediate and fast acetylators, respectively. Higher oral clearance values in intermediate and fast acetylators also resulted from 23% lower bioavailability compared with slow acetylators. Conclusions Simulations based on our models suggest that with the new WHO dosing guidelines and utilizing available paediatric fixed-dose combinations, children will receive adequate rifampicin exposures when compared with adults, but with a larger degree of variability. However, pyrazinamide and isoniazid exposures in many children will be lower than in adults. Further studies are needed to confirm these findings in children administered the revised dosages and to optimize pragmatic approaches to dosing. PMID:24486870

Steady-State Dynamic Behavior of a Flexible Rotor With Auxiliary Support From a Clearance Bearing

NASA Technical Reports Server (NTRS)

Xie, Huajun; Flowers, George T.; Feng, Li; Lawrence, Charles T.

1996-01-01

This paper investigates the steady-state responses of a rotor system supported by auxiliary bearings in which there is a clearance between the rotor and the inner race of the bearing. A simulation model based upon the rotor of a production jet engine is developed and its steady-state behavior is explored over a wide range of operating conditions for various parametric configurations. Specifically, the influence of rotor imbalance, clearance, support stiffness and damping is studied. Bifurcation diagrams are used as a tool to examine the dynamic behavior of this system as a function of the afore mentioned parameters. The harmonic balance method is also employed for synchronous response cases. The observed dynamical responses is discussed and some insights into the behavior of such systems are presented.

Pharmacoepidemiologic investigation of a clonazepam-valproic acid interaction by mixed effect modeling using routine clinical pharmacokinetic data in Japanese patients.

PubMed

Yukawa, E; Nonaka, T; Yukawa, M; Higuchi, S; Kuroda, T; Goto, Y

2003-12-01

Non-linear Mixed Effects Modeling (NONMEM) was used to estimate the effects of clonazepam-valproic acid interaction on clearance values using 576 serum levels collected from 317 pediatric and adult epileptic patients (age range, 0.3-32.6 years) during their clinical routine care. Patients received the administration of clonazepam and/or valproic acid. The final model describing clonazepam clearance was CL = 144.0 TBW-0.172 1.14VPA, where CL is total body clearance (mL/kg/h); TBW is total body weight (kg); VPA = 1 for concomitant administration of valproic acid and VPA = zero otherwise. The final model describing valproic acid clearance was CL (mL/kg/h) = 17.2 TBW-0.264 DOSE0.159 0.821CZP 0.896GEN, where DOSE is the daily dose of valproic acid (mg/kg/day); CZP = 1 for concomitant administration of clonazepam and CZP = zero otherwise; GEN = 1 for female and GEN = zero otherwise. Concomitant administration of clonazepam and valproic acid resulted in a 14% increase in clonazepam clearance, and a 17.9% decrease in valproic acid clearance.

Physiologically Based Pharmacokinetic Modeling in Lead Optimization. 1. Evaluation and Adaptation of GastroPlus To Predict Bioavailability of Medchem Series.

PubMed

Daga, Pankaj R; Bolger, Michael B; Haworth, Ian S; Clark, Robert D; Martin, Eric J

2018-03-05

When medicinal chemists need to improve bioavailability (%F) within a chemical series during lead optimization, they synthesize new series members with systematically modified properties mainly by following experience and general rules of thumb. More quantitative models that predict %F of proposed compounds from chemical structure alone have proven elusive. Global empirical %F quantitative structure-property (QSPR) models perform poorly, and projects have too little data to train local %F QSPR models. Mechanistic oral absorption and physiologically based pharmacokinetic (PBPK) models simulate the dissolution, absorption, systemic distribution, and clearance of a drug in preclinical species and humans. Attempts to build global PBPK models based purely on calculated inputs have not achieved the <2-fold average error needed to guide lead optimization. In this work, local GastroPlus PBPK models are instead customized for individual medchem series. The key innovation was building a local QSPR for a numerically fitted effective intrinsic clearance (CL loc ). All inputs are subsequently computed from structure alone, so the models can be applied in advance of synthesis. Training CL loc on the first 15-18 rat %F measurements gave adequate predictions, with clear improvements up to about 30 measurements, and incremental improvements beyond that.

Covariates of intravenous paracetamol pharmacokinetics in adults

PubMed Central

2014-01-01

Background Pharmacokinetic estimates for intravenous paracetamol in individual adult cohorts are different to a certain extent, and understanding the covariates of these differences may guide dose individualization. In order to assess covariate effects of intravenous paracetamol disposition in adults, pharmacokinetic data on discrete studies were pooled. Methods This pooled analysis was based on 7 studies, resulting in 2755 time-concentration observations in 189 adults (mean age 46 SD 23 years; weight 73 SD 13 kg) given intravenous paracetamol. The effects of size, age, pregnancy and other clinical settings (intensive care, high dependency, orthopaedic or abdominal surgery) on clearance and volume of distribution were explored using non-linear mixed effects models. Results Paracetamol disposition was best described using normal fat mass (NFM) with allometric scaling as a size descriptor. A three-compartment linear disposition model revealed that the population parameter estimates (between subject variability,%) were central volume (V1) 24.6 (55.5%) L/70 kg with peripheral volumes of distribution V2 23.1 (49.6%) L/70 kg and V3 30.6 (78.9%) L/70 kg. Clearance (CL) was 16.7 (24.6%) L/h/70 kg and inter-compartment clearances were Q2 67.3 (25.7%) L/h/70 kg and Q3 2.04 (71.3%) L/h/70 kg. Clearance and V2 decreased only slightly with age. Sex differences in clearance were minor and of no significance. Clearance, relative to median values, was increased during pregnancy (FPREG = 1.14) and decreased during abdominal surgery (FABDCL = 0.715). Patients undergoing orthopaedic surgery had a reduced V2 (FORTHOV = 0.649), while those in intensive care had increased V2 (FICV = 1.51). Conclusions Size and age are important covariates for paracetamol pharmacokinetics explaining approximately 40% of clearance and V2 variability. Dose individualization in adult subpopulations would achieve little benefit in the scenarios explored. PMID:25342929

Population Pharmacokinetic Analysis of Isoniazid, Acetylisoniazid, and Isonicotinic Acid in Healthy Volunteers

PubMed Central

Seng, Kok-Yong; Hee, Kim-Hor; Soon, Gaik-Hong; Chew, Nicholas; Khoo, Saye H.

2015-01-01

In this study, we aimed to quantify the effects of the N-acetyltransferase 2 (NAT2) phenotype on isoniazid (INH) metabolism in vivo and identify other sources of pharmacokinetic variability following single-dose administration in healthy Asian adults. The concentrations of INH and its metabolites acetylisoniazid (AcINH) and isonicotinic acid (INA) in plasma were evaluated in 33 healthy Asians who were also given efavirenz and rifampin. The pharmacokinetics of INH, AcINH, and INA were analyzed using nonlinear mixed-effects modeling (NONMEM) to estimate the population pharmacokinetic parameters and evaluate the relationships between the parameters and the elimination status (fast, intermediate, and slow acetylators), demographic status, and measures of renal and hepatic function. A two-compartment model with first-order absorption best described the INH pharmacokinetics. AcINH and INA data were best described by a two- and a one-compartment model, respectively, linked to the INH model. In the final model for INH, the derived metabolic phenotypes for NAT2 were identified as a significant covariate in the INH clearance, reducing its interindividual variability from 86% to 14%. The INH clearance in fast eliminators was 1.9- and 7.7-fold higher than in intermediate and slow eliminators, respectively (65 versus 35 and 8 liters/h). Creatinine clearance was confirmed as a significant covariate for AcINH clearance. Simulations suggested that the current dosing guidelines (200 mg for 30 to 45 kg and 300 mg for >45 kg) may be suboptimal (3 mg/liter ≤ Cmax ≤ 6 mg/liter) irrespective of the acetylator class. The analysis established a model that adequately characterizes INH, AcINH, and INA pharmacokinetics in healthy Asians. Our results refine the NAT2 phenotype-based predictions of the pharmacokinetics for INH. PMID:26282412

Limitations of the hCMEC/D3 cell line as a model for Aβ clearance by the human blood-brain barrier.

PubMed

Biemans, Elisanne A L M; Jäkel, Lieke; de Waal, Robert M W; Kuiperij, H Bea; Verbeek, Marcel M

2017-07-01

Alzheimer's disease and cerebral amyloid angiopathy are characterized by accumulation of amyloid-β (Aβ) at the cerebrovasculature due to decreased clearance at the blood-brain barrier (BBB). However, the exact mechanism of Aβ clearance across this barrier has not been fully elucidated. The hCMEC/D3 cell line has been characterized as a valid model for the BBB. In this study we evaluated the use of this model to study Aβ clearance across the BBB, with an emphasis on brain-to-blood directional permeability. Barrier integrity of hCMEC/D3 monolayers was confirmed for large molecules in both the apical to basolateral and the reverse direction. However, permeability for smaller molecules was substantially higher, especially in basolateral to apical direction, and barrier formation for Aβ was completely absent in this direction. In addition, hCMEC/D3 cells failed to develop a high TEER, possibly caused by incomplete formation of tight junctions. We conclude that the hCMEC/D3 model has several limitations to study the cerebral clearance of Aβ. Therefore, the model needs further characterization before this cell system can be generally applied as a model to study cerebral Aβ clearance. © 2016 The Authors Journal of Neuroscience Research Published by Wiley Periodicals, Inc. © 2016 The Authors Journal of Neuroscience Research Published by Wiley Periodicals, Inc.

Role of genetic variation in docetaxel-induced neutropenia and pharmacokinetics.

PubMed

Nieuweboer, A J M; Smid, M; de Graan, A-J M; Elbouazzaoui, S; de Bruijn, P; Eskens, F A L M; Hamberg, P; Martens, J W M; Sparreboom, A; de Wit, R; van Schaik, R H N; Mathijssen, R H J

2016-11-01

Docetaxel is used for treatment of several solid malignancies. In this study, we aimed for predicting docetaxel clearance and docetaxel-induced neutropenia by developing several genetic models. Therefore, pharmacokinetic data and absolute neutrophil counts (ANCs) of 213 docetaxel-treated cancer patients were collected. Next, patients were genotyped for 1936 single nucleotide polymorphisms (SNPs) in 225 genes using the drug-metabolizing enzymes and transporters platform and thereafter split into two cohorts. The combination of SNPs that best predicted severe neutropenia or low clearance was selected in one cohort and validated in the other. Patients with severe neutropenia had lower docetaxel clearance than patients with ANCs in the normal range (P=0.01). Severe neutropenia was predicted with 70% sensitivity. True low clearance (1 s.d.

Deterministic Models of Inhalational Anthrax in New Zealand White Rabbits

PubMed Central

2014-01-01

Computational models describing bacterial kinetics were developed for inhalational anthrax in New Zealand white (NZW) rabbits following inhalation of Ames strain B. anthracis. The data used to parameterize the models included bacterial numbers in the airways, lung tissue, draining lymph nodes, and blood. Initial bacterial numbers were deposited spore dose. The first model was a single exponential ordinary differential equation (ODE) with 3 rate parameters that described mucociliated (physical) clearance, immune clearance (bacterial killing), and bacterial growth. At 36 hours postexposure, the ODE model predicted 1.7×107 bacteria in the rabbit, which agreed well with data from actual experiments (4.0×107 bacteria at 36 hours). Next, building on the single ODE model, a physiological-based biokinetic (PBBK) compartmentalized model was developed in which 1 physiological compartment was the lumen of the airways and the other was the rabbit body (lung tissue, lymph nodes, blood). The 2 compartments were connected with a parameter describing transport of bacteria from the airways into the body. The PBBK model predicted 4.9×107 bacteria in the body at 36 hours, and by 45 hours the model showed all clearance mechanisms were saturated, suggesting the rabbit would quickly succumb to the infection. As with the ODE model, the PBBK model results agreed well with laboratory observations. These data are discussed along with the need for and potential application of the models in risk assessment, drug development, and as a general aid to the experimentalist studying inhalational anthrax. PMID:24527843

Research Summary 3-D Computational Fluid Dynamics (CFD) Model Of The Human Respiratory System

EPA Science Inventory

The U.S. EPA’s Office of Research and Development (ORD) has developed a 3-D computational fluid dynamics (CFD) model of the human respiratory system that allows for the simulation of particulate based contaminant deposition and clearance, while being adaptable for age, ethnicity,...

Assessment of the operating characteristics of the SSME LOX turbopump pump-end bearing

NASA Technical Reports Server (NTRS)

New, L. S.; Tiller, B. K.

1984-01-01

A bearing/shaft model of the SSME LOX turbopump was developed using the SHABERTH bearing/shaft math modeling computer code. A previously developed bearing/shaft thermal model of the SSME LOX turbopump turbine and bearing was used in conjunction with SHABERTH to evaluate the thermomechanical operating characteristics of the LOX turbopump end bearings. Results show that for the two unmounted diametrical clearances evaluated (4.0 mils and 6.3 mils), the inboard pump end bearing supports about 81% of the isolator load for the small clearance and 77% of the isolator load for the larger clearance. Bearing clearance changes due to thermal effects were 40% for the 4.0 mil diametrical clearance case and 19% for the 6.3 mil clearance case evaluated. The thermal analysis included evaluation of bearing temperatures for a subcooled case and a saturated case. Results indicate that no drastic temperature change occurred between the two cases. Since the rolling element and race surfaces of the subcooled case were at temperatures sufficiently high enough to be vapor blanketed, exceeding saturation temperature at the bearing inlet did not increase surface temperatures greatly.

Circadian Clearance of a Fungal Pathogen from the Lung Is Not Based on Cell-intrinsic Macrophage Rhythms.

PubMed

Chen, Shan; Fuller, Kevin K; Dunlap, Jay C; Loros, Jennifer J

2018-02-01

Circadian rhythms govern immune cell function, giving rise to time-of-day variation in the recognition and clearance of bacterial or viral pathogens; to date, however, no such regulation of the host-fungal interaction has been described. In this report, we use murine models to explore circadian control of either fungal-macrophage interactions in vitro or pathogen clearance from the lung in vivo. First, we show that expression of the important fungal pattern recognition receptor Dectin-1 ( clec7a), from either bone marrow-derived or peritoneum-derived macrophages, is not under circadian regulation at either the level of transcript or cell surface protein expression. Consistent with this finding, the phagocytic activity of macrophages in culture against spores of the pathogen Aspergillus fumigatus also did not vary over time. To account for the multiple cell types and processes that may be coordinated in a circadian fashion in vivo, we examined the clearance of A. fumigatus from the lungs of immunocompetent mice. Interestingly, animals inoculated at night demonstrated a 2-fold enhancement in clearance compared with animals inoculated in the morning. Taken together, our data suggest that while molecular recognition of fungi by immune cells may not be circadian, other processes in vivo may still allow for time-of-day differences in fungal clearance from the lung.

Pharmacokinetic-Pharmacodynamic Modeling in Pediatric Drug Development, and the Importance of Standardized Scaling of Clearance.

PubMed

Germovsek, Eva; Barker, Charlotte I S; Sharland, Mike; Standing, Joseph F

2018-04-19

Pharmacokinetic/pharmacodynamic (PKPD) modeling is important in the design and conduct of clinical pharmacology research in children. During drug development, PKPD modeling and simulation should underpin rational trial design and facilitate extrapolation to investigate efficacy and safety. The application of PKPD modeling to optimize dosing recommendations and therapeutic drug monitoring is also increasing, and PKPD model-based dose individualization will become a core feature of personalized medicine. Following extensive progress on pediatric PK modeling, a greater emphasis now needs to be placed on PD modeling to understand age-related changes in drug effects. This paper discusses the principles of PKPD modeling in the context of pediatric drug development, summarizing how important PK parameters, such as clearance (CL), are scaled with size and age, and highlights a standardized method for CL scaling in children. One standard scaling method would facilitate comparison of PK parameters across multiple studies, thus increasing the utility of existing PK models and facilitating optimal design of new studies.

A similitude method and the corresponding blade design of a low-speed large-scale axial compressor rotor

NASA Astrophysics Data System (ADS)

Yu, Chenghai; Ma, Ning; Wang, Kai; Du, Juan; Van den Braembussche, R. A.; Lin, Feng

2014-04-01

A similitude method to model the tip clearance flow in a high-speed compressor with a low-speed model is presented in this paper. The first step of this method is the derivation of similarity criteria for tip clearance flow, on the basis of an inviscid model of tip clearance flow. The aerodynamic parameters needed for the model design are then obtained from a numerical simulation of the target high-speed compressor rotor. According to the aerodynamic and geometric parameters of the target compressor rotor, a large-scale low-speed rotor blade is designed with an inverse blade design program. In order to validate the similitude method, the features of tip clearance flow in the low-speed model compressor are compared with the ones in the high-speed compressor at both design and small flow rate points. It is found that not only the trajectory of the tip leakage vortex but also the interface between the tip leakage flow and the incoming main flow in the high-speed compressor match well with that of its low speed model. These results validate the effectiveness of the similitude method for the tip clearance flow proposed in this paper.

Population pharmacokinetics of busulfan in pediatric and young adult patients undergoing hematopoietic cell transplant: a model-based dosing algorithm for personalized therapy and implementation into routine clinical use.

PubMed

Long-Boyle, Janel R; Savic, Rada; Yan, Shirley; Bartelink, Imke; Musick, Lisa; French, Deborah; Law, Jason; Horn, Biljana; Cowan, Morton J; Dvorak, Christopher C

2015-04-01

Population pharmacokinetic (PK) studies of busulfan in children have shown that individualized model-based algorithms provide improved targeted busulfan therapy when compared with conventional dose guidelines. The adoption of population PK models into routine clinical practice has been hampered by the tendency of pharmacologists to develop complex models too impractical for clinicians to use. The authors aimed to develop a population PK model for busulfan in children that can reliably achieve therapeutic exposure (concentration at steady state) and implement a simple model-based tool for the initial dosing of busulfan in children undergoing hematopoietic cell transplantation. Model development was conducted using retrospective data available in 90 pediatric and young adult patients who had undergone hematopoietic cell transplantation with busulfan conditioning. Busulfan drug levels and potential covariates influencing drug exposure were analyzed using the nonlinear mixed effects modeling software, NONMEM. The final population PK model was implemented into a clinician-friendly Microsoft Excel-based tool and used to recommend initial doses of busulfan in a group of 21 pediatric patients prospectively dosed based on the population PK model. Modeling of busulfan time-concentration data indicates that busulfan clearance displays nonlinearity in children, decreasing up to approximately 20% between the concentrations of 250-2000 ng/mL. Important patient-specific covariates found to significantly impact busulfan clearance were actual body weight and age. The percentage of individuals achieving a therapeutic concentration at steady state was significantly higher in subjects receiving initial doses based on the population PK model (81%) than in historical controls dosed on conventional guidelines (52%) (P = 0.02). When compared with the conventional dosing guidelines, the model-based algorithm demonstrates significant improvement for providing targeted busulfan therapy in children and young adults.

A conceptual framework for dynamic extension of the red clearance interval as a countermeasure for red-light-running.

PubMed

Gates, Timothy J; Noyce, David A

2016-11-01

This manuscript describes the development and evaluation of a conceptual framework for real-time operation of dynamic on-demand extension of the red clearance interval as a countermeasure for red-light-running. The framework includes a decision process for determining, based on the real-time status of vehicles arriving at the intersection, when extension of the red clearance interval should occur and the duration of each extension. A zonal classification scheme was devised to assess whether an approaching vehicle requires additional time to safely clear the intersection based on the remaining phase time, type of vehicle, current speed, and current distance from the intersection. Expected performance of the conceptual framework was evaluated through modeling of replicated field operations using vehicular event data collected as part of this research. The results showed highly accurate classification of red-light-running vehicles needing additional clearance time and relatively few false extension calls from stopping vehicles, thereby minimizing the expected impacts to signal and traffic operations. Based on the recommended parameters, extension calls were predicted to occur once every 26.5cycles. Assuming a 90scycle, 1.5 extensions per hour were expected per approach, with an estimated extension time of 2.30s/h. Although field implementation was not performed, it is anticipated that long-term reductions in targeted red-light-running conflicts and crashes will likely occur if red clearance interval extension systems are implemented at locations where start-up delay on the conflicting approach is generally minimal, such as intersections with lag left-turn phasing. Copyright © 2015 Elsevier Ltd. All rights reserved.

Accelerated autoantibody clearance by intravenous immunoglobulin therapy: studies in experimental models to determine the magnitude and time course of the effect.

PubMed

Bleeker, W K; Teeling, J L; Hack, C E

2001-11-15

Recently, it has been postulated that the beneficial effect of intravenous immunoglobulins (IVIGs) in antibody-mediated autoimmune disorders is based on accelerated catabolism of autoantibodies. In the current study, in vivo experiments were performed with mice in which autoantibody production was mimicked by continuous infusion of monoclonal antibodies. In this model, a single dose of IVIG reduced the plasma concentrations of the infused immunoglobulin (Ig)G1 monoclonal antibody (mAb) by approximately 40% after 3 days, whereas the concentration of an IgA mAb was not affected. To extrapolate these findings to humans, a computational model for IgG clearance was established that accurately predicted the time course and magnitude of the decrease in IgG plasma levels observed in mice. Adapted for humans, this model predicted a gradually occurring decrease in autoantibody levels after IVIG administration (2 g/kg), with a maximum reduction of approximately 25% after 3 to 4 weeks and a continued decrease of several months. In conclusion, a single high dose of IVIG induces a relatively small but long-lasting reduction of autoantibody levels by accelerated IgG clearance. This mechanism has clinical relevance in the sense that it can fully explain, as the sole mechanism, the gradual decrease in autoantibody levels observed in several patient studies. However, in some clinical studies, larger or more rapid effects have been observed that cannot be explained by accelerated clearance. Hence, IVIG can also reduce autoantibody levels through mechanisms such as down-regulation of antibody production or neutralization by anti-idiotypic antibodies.

Model-based meta-analysis for comparing Vitamin D2 and D3 parent-metabolite pharmacokinetics.

PubMed

Ocampo-Pelland, Alanna S; Gastonguay, Marc R; Riggs, Matthew M

2017-08-01

Association of Vitamin D (D3 & D2) and its 25OHD metabolite (25OHD3 & 25OHD2) exposures with various diseases is an active research area. D3 and D2 dose-equivalency and each form's ability to raise 25OHD concentrations are not well-defined. The current work describes a population pharmacokinetic (PK) model for D2 and 25OHD2 and the use of a previously developed D3-25OHD3 PK model [1] for comparing D3 and D2-related exposures. Public-source D2 and 25OHD2 PK data in healthy or osteoporotic populations, including 17 studies representing 278 individuals (15 individual-level and 18 arm-level units), were selected using search criteria in PUBMED. Data included oral, single and multiple D2 doses (400-100,000 IU/d). Nonlinear mixed effects models were developed simultaneously for D2 and 25OHD2 PK (NONMEM v7.2) by considering 1- and 2-compartment models with linear or nonlinear clearance. Unit-level random effects and residual errors were weighted by arm sample size. Model simulations compared 25OHD exposures, following repeated D2 and D3 oral administration across typical dosing and baseline ranges. D2 parent and metabolite were each described by 2-compartment models with numerous parameter estimates shared with the D3-25OHD3 model [1]. Notably, parent D2 was eliminated (converted to 25OHD) through a first-order clearance whereas the previously published D3 model [1] included a saturable non-linear clearance. Similar to 25OHD3 PK model results [1], 25OHD2 was eliminated by a first-order clearance, which was almost twice as fast as the former. Simulations at lower baselines, following lower equivalent doses, indicated that D3 was more effective than D2 at raising 25OHD concentrations. Due to saturation of D3 clearance, however, at higher doses or baselines, the probability of D2 surpassing D3's ability to raise 25OHD concentrations increased substantially. Since 25OHD concentrations generally surpassed 75 nmol/L at these higher baselines by 3 months, there would be no expected clinical difference in the two forms.

Controls Considerations for Turbine Active Clearance Control

NASA Technical Reports Server (NTRS)

Melcher, Kevin J.

2004-01-01

This presentation discusses active control of turbine tip clearance from a control systems perspective. It is a subset of charts that were presented at the 2003 meeting of the International Society of Air Breathing Engines which was held August 31 through September 5 in Cleveland, Ohio. The associated reference paper is cited at the end of the presentation. The presentation describes active tip clearance control research being conducted by NASA to improve turbine engine systems. The target application for this effort is commercial aircraft engines. However, it is believed that the technologies developed as part of this research will benefit a broad spectrum of current and future turbomachinery. The first part of the presentation discusses the concept of tip clearance, problems associated with it, and the benefits of controlling it. It lays out a framework for implementing tip clearance controls that enables the implementation to progress from purely analytical to hardware-in-the-loop to fully experimental. And it briefly discusses how the technologies developed will be married to the previously described ACC Test Rig for hardware-in-the-loop demonstrations. The final portion of the presentation, describes one of the key technologies in some detail by presenting equations and results for a functional dynamic model of the tip clearance phenomena. As shown, the model exhibits many of the clearance dynamics found in commercial gas turbine engines. However, initial attempts to validate the model identified limitations that are being addressed to make the model more realistic.

Caffeine Citrate Dosing Adjustments to Assure Stable Caffeine Concentrations in Preterm Neonates.

PubMed

Koch, Gilbert; Datta, Alexandre N; Jost, Kerstin; Schulzke, Sven M; van den Anker, John; Pfister, Marc

2017-12-01

To identify dosing strategies that will assure stable caffeine concentrations in preterm neonates despite changing caffeine clearance during the first 8 weeks of life. A 3-step simulation approach was used to compute caffeine doses that would achieve stable caffeine concentrations in the first 8 weeks after birth: (1) a mathematical weight change model was developed based on published weight distribution data; (2) a pharmacokinetic model was developed based on published models that accounts for individual body weight, postnatal, and gestational age on caffeine clearance and volume of distribution; and (3) caffeine concentrations were simulated for different dosing regimens. A standard dosing regimen of caffeine citrate (using a 20 mg/kg loading dose and 5 mg/kg/day maintenance dose) is associated with a maximal trough caffeine concentration of 15 mg/L after 1 week of treatment. However, trough concentrations subsequently exhibit a clinically relevant decrease because of increasing clearance. Model-based simulations indicate that an adjusted maintenance dose of 6 mg/kg/day in the second week, 7 mg/kg/day in the third to fourth week and 8 mg/kg/day in the fifth to eighth week assures stable caffeine concentrations with a target trough concentration of 15 mg/L. To assure stable caffeine concentrations during the first 8 weeks of life, the caffeine citrate maintenance dose needs to be increased by 1 mg/kg every 1-2 weeks. These simple adjustments are expected to maintain exposure to stable caffeine concentrations throughout this important developmental period and might enhance both the short- and long-term beneficial effects of caffeine treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

Population pharmacokinetics of epsilon-aminocaproic acid in infants undergoing craniofacial reconstruction surgery

PubMed Central

Stricker, P. A.; Zuppa, A. F.; Fiadjoe, J. E.; Maxwell, L. G.; Sussman, E. M.; Pruitt, E. Y.; Goebel, T. K.; Gastonguay, M. R.; Taylor, J. A.; Bartlett, S. P.; Schreiner, M. S.

2013-01-01

Background Understanding the clinical pharmacology of the antifibrinolytic epsilon-aminocaproic acid (EACA) is necessary for rational drug administration in children. The aim of this study is to determine the pharmacokinetics (PKs) of EACA in infants aged 6–24 months undergoing craniofacial reconstruction surgery. Methods Cohorts of six infants were enrolled sequentially to one of the three escalating loading dose–continuous i.v. infusion (CIVI) regimens: 25 mg kg−1, 10 mg kg−1 h−1; 50 mg kg−1, 20 mg kg−1 h−1; 100 mg kg−1, 40 mg kg−1 h−1. Plasma EACA concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry assay. A population non-linear mixed effects modelling approach was used to characterize EACA PKs. Results Population PK parameters of EACA were estimated using a two-compartment disposition model with weight expressed as an allometric covariate and an age effect. The typical patient in this study had an age of 38.71 weeks and a weight of 8.82 kg. PK parameters for this typical patient were: pre-/postoperative plasma drug clearance of 32 ml min−1 (3.6 ml kg−1 min−1), inter-compartmental clearance of 42.4 ml min−1 (4.8 ml min−1 kg−1), central volume of distribution of 1.27 litre (0.14 litre kg−1), and peripheral volume of distribution of 2.53 litre (0.29 litre kg−1). Intra-operative clearance and central volume of distribution were 89% and 80% of the pre-/postoperative value, respectively. Conclusions EACA clearance increased with weight and age. The dependence of clearance on body weight supports weight-based dosing. Based on this study, a loading dose of 100 mg kg−1 followed by a CIVI of 40 mg kg−1 h−1 is appropriate to maintain target plasma EACA concentrations in children aged 6–24 months undergoing these procedures. PMID:23353035

Population pharmacokinetics of epsilon-aminocaproic acid in infants undergoing craniofacial reconstruction surgery.

PubMed

Stricker, P A; Zuppa, A F; Fiadjoe, J E; Maxwell, L G; Sussman, E M; Pruitt, E Y; Goebel, T K; Gastonguay, M R; Taylor, J A; Bartlett, S P; Schreiner, M S

2013-05-01

Understanding the clinical pharmacology of the antifibrinolytic epsilon-aminocaproic acid (EACA) is necessary for rational drug administration in children. The aim of this study is to determine the pharmacokinetics (PKs) of EACA in infants aged 6-24 months undergoing craniofacial reconstruction surgery. Cohorts of six infants were enrolled sequentially to one of the three escalating loading dose-continuous i.v. infusion (CIVI) regimens: 25 mg kg(-1), 10 mg kg(-1) h(-1); 50 mg kg(-1), 20 mg kg(-1) h(-1); 100 mg kg(-1), 40 mg kg(-1) h(-1). Plasma EACA concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry assay. A population non-linear mixed effects modelling approach was used to characterize EACA PKs. Population PK parameters of EACA were estimated using a two-compartment disposition model with weight expressed as an allometric covariate and an age effect. The typical patient in this study had an age of 38.71 weeks and a weight of 8.82 kg. PK parameters for this typical patient were: pre-/postoperative plasma drug clearance of 32 ml min(-1) (3.6 ml kg(-1) min(-1)), inter-compartmental clearance of 42.4 ml min(-1) (4.8 ml min(-1) kg(-1)), central volume of distribution of 1.27 litre (0.14 litre kg(-1)), and peripheral volume of distribution of 2.53 litre (0.29 litre kg(-1)). Intra-operative clearance and central volume of distribution were 89% and 80% of the pre-/postoperative value, respectively. EACA clearance increased with weight and age. The dependence of clearance on body weight supports weight-based dosing. Based on this study, a loading dose of 100 mg kg(-1) followed by a CIVI of 40 mg kg(-1) h(-1) is appropriate to maintain target plasma EACA concentrations in children aged 6-24 months undergoing these procedures.

Improved Temperature Dynamic Model of Turbine Subcomponents for Facilitation of Generalized Tip Clearance Control

NASA Technical Reports Server (NTRS)

Kypuros, Javier A.; Colson, Rodrigo; Munoz, Afredo

2004-01-01

This paper describes efforts conducted to improve dynamic temperature estimations of a turbine tip clearance system to facilitate design of a generalized tip clearance controller. This work builds upon research previously conducted and presented in and focuses primarily on improving dynamic temperature estimations of the primary components affecting tip clearance (i.e. the rotor, blades, and casing/shroud). The temperature profiles estimated by the previous model iteration, specifically for the rotor and blades, were found to be inaccurate and, more importantly, insufficient to facilitate controller design. Some assumptions made to facilitate the previous results were not valid, and thus improvements are presented here to better match the physical reality. As will be shown, the improved temperature sub- models, match a commercially validated model and are sufficiently simplified to aid in controller design.

Interplay of drug metabolism and transport: a real phenomenon or an artifact of the site of measurement?

PubMed

Endres, Christopher J; Endres, Michael G; Unadkat, Jashvant D

2009-01-01

The interdependence of both transport and metabolism on the disposition of drugs has recently gained heightened attention in the literature, and has been termed the "interplay of transport and metabolism". Such "interplay" is observed when inhibition of biliary clearance of a drug results in an "apparent" increase in the metabolic clearance of the drug or vice versa. In this manuscript, we derived and explored through simulations a physiological-based pharmacokinetic model that integrates both transport and metabolism and explains the "apparent" dependence of hepatic clearance on both these processes. In addition, we show that the phenomenon of hepatic "transport-metabolism interplay" is a result of using the plasma concentration as a point of reference when calculating metabolic or biliary clearance, and this interplay is maximal when the drug is actively transported into the hepatocytes (i.e., hepatocyte sinusoidal influx clearance is greater than the sinusoidal efflux clearance). When the hepatic drug concentration is used as a reference point to calculate metabolic or biliary clearance, this interplay ceases to exist. A mechanistic understanding of this interplay phenomenon can be used to explain the somewhat paradoxical results that may be observed in drug-drug interaction studies when a drug is cleared by both metabolism and biliary excretion. That is, when one of these two pathways is inhibited, the other pathway appears to be induced or activated. This interplay results in an increase in hepatic drug concentrations and therefore has implications for the hepatic efficacy and toxicity of a drug.

Computational Fluid Dynamics of Choanoflagellate Filter-Feeding

NASA Astrophysics Data System (ADS)

Asadzadeh, Seyed Saeed; Walther, Jens; Nielsen, Lasse Tore; Kiorboe, Thomas; Dolger, Julia; Andersen, Anders

2017-11-01

Choanoflagellates are unicellular aquatic organisms with a single flagellum that drives a feeding current through a funnel-shaped collar filter on which bacteria-sized prey are caught. Using computational fluid dynamics (CFD) we model the beating flagellum and the complex filter flow of the choanoflagellate Diaphanoeca grandis. Our CFD simulations based on the current understanding of the morphology underestimate the experimentally observed clearance rate by more than an order of magnitude: The beating flagellum is simply unable to draw enough water through the fine filter. Our observations motivate us to suggest a radically different filtration mechanism that requires a flagellar vane (sheet), and addition of a wide vane in our CFD model allows us to correctly predict the observed clearance rate.

Theophylline Population Pharmacokinetics and Dosing in Children Following Congenital Heart Surgery With Cardiopulmonary Bypass.

PubMed

Frymoyer, Adam; Su, Felice; Grimm, Paul C; Sutherland, Scott M; Axelrod, David M

2016-09-01

Children undergoing cardiac surgery requiring cardiopulmonary bypass (CPB) frequently develop acute kidney injury due to renal ischemia. Theophylline, which improves renal perfusion via adenosine receptor inhibition, is a potential targeted therapy. However, children undergoing cardiac surgery and CPB commonly have alterations in drug pharmacokinetics. To help understand optimal aminophylline (salt formulation of theophylline) dosing strategies in this population, a population-based pharmacokinetic model was developed using nonlinear mixed-effects modeling (NONMEM) from 71 children (median age 5 months; 90% range 1 week to 10 years) who underwent cardiac surgery requiring CPB and received aminophylline as part of a previous randomized controlled trial. A 1-compartment model with linear elimination adequately described the pharmacokinetics of theophylline. Weight scaled via allometry was a significant predictor of clearance and volume. In addition, allometric scaled clearance increased with age implemented as a power maturation function. Compared to prior reports in noncardiac children, theophylline clearance was markedly reduced across age. In the final population pharmacokinetic model, optimized empiric dosing regimens were developed via Monte Carlo simulations. Doses 50% to 75% lower than those recommended in noncardiac children were needed to achieve target serum concentrations of 5 to 10 mg/L. © 2016, The American College of Clinical Pharmacology.

The population pharmacokinetics of R- and S-warfarin: effect of genetic and clinical factors.

PubMed

Lane, Steven; Al-Zubiedi, Sameh; Hatch, Ellen; Matthews, Ivan; Jorgensen, Andrea L; Deloukas, Panos; Daly, Ann K; Park, B Kevin; Aarons, Leon; Ogungbenro, Kayode; Kamali, Farhad; Hughes, Dyfrig; Pirmohamed, Munir

2012-01-01

Warfarin is a drug with a narrow therapeutic index and large interindividual variability in daily dosing requirements. Patients commencing warfarin treatment are at risk of bleeding due to excessive anticoagulation caused by overdosing. The interindividual variability in dose requirements is influenced by a number of factors, including polymorphisms in genes mediating warfarin pharmacology, co-medication, age, sex, body size and diet. To develop population pharmacokinetic models of both R- and S-warfarin using clinical and genetic factors and to identify the covariates which influence the interindividual variability in the pharmacokinetic parameters of clearance and volume of distribution in patients on long-term warfarin therapy. Patients commencing warfarin therapy were followed up for 26 weeks. Plasma warfarin enantiomer concentrations were determined in 306 patients for S-warfarin and in 309 patients for R-warfarin at 1, 8 and 26 weeks. Patients were also genotyped for CYP2C9 variants (CYP2C9*1,*2 and *3), two single-nucleotide polymorphisms (SNPs) in CYP1A2, one SNP in CYP3A4 and six SNPs in CYP2C19. A base pharmacokinetic model was developed using NONMEM software to determine the warfarin clearance and volume of distribution. The model was extended to include covariates that influenced the between-subject variability. Bodyweight, age, sex and CYP2C9 genotype significantly influenced S-warfarin clearance. The S-warfarin clearance was estimated to be 0.144 l h⁻¹ (95% confidence interval 0.131, 0.157) in a 70 kg woman aged 69.8 years with the wild-type CYP2C9 genotype, and the volume of distribution was 16.6 l (95% confidence interval 13.5, 19.7). Bodyweight and age, along with the SNPs rs3814637 (in CYP2C19) and rs2242480 (in CYP3A4), significantly influenced R-warfarin clearance. The R-warfarin clearance was estimated to be 0.125 l h⁻¹ (95% confidence interval 0.115, 0.135) in a 70 kg individual aged 69.8 years with the wild-type CYP2C19 and CYP3A4 genotypes, and the volume of distribution was 10.9 l (95% confidence interval 8.63, 13.2). Our analysis, based on exposure rather than dose, provides quantitative estimates of the clinical and genetic factors impacting on the clearance of both the S- and R-enantiomers of warfarin, which can be used in developing improved dosing algorithms. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

Evaluating the Use of Antibody Variable Region (Fv) Charge as a Risk Assessment Tool for Predicting Typical Cynomolgus Monkey Pharmacokinetics*

PubMed Central

Bumbaca Yadav, Daniela; Sharma, Vikas K.; Boswell, Charles Andrew; Hotzel, Isidro; Tesar, Devin; Shang, Yonglei; Ying, Yong; Fischer, Saloumeh K.; Grogan, Jane L.; Chiang, Eugene Y.; Urban, Konnie; Ulufatu, Sheila; Khawli, Leslie A.; Prabhu, Saileta; Joseph, Sean; Kelley, Robert F.

2015-01-01

The pharmacokinetic (PK) behavior of monoclonal antibodies in cynomolgus monkeys (cynos) is generally translatable to that in humans. Unfortunately, about 39% of the antibodies evaluated for PKs in cynos have fast nonspecific (or non-target-mediated) clearance (in-house data). An empirical model relating variable region (Fv) charge and hydrophobicity to cyno nonspecific clearance was developed to gauge the risk an antibody would have for fast nonspecific clearance in the monkey. The purpose of this study was to evaluate the predictability of this empirical model on cyno nonspecific clearance with antibodies specifically engineered to have either high or low Fv charge. These amino acid changes were made in the Fv region of two test antibodies, humAb4D5-8 and anti-lymphotoxin α. The humAb4D5-8 has a typical nonspecific clearance in cynos, and by making it more positively charged, the antibody acquires fast nonspecific clearance, and making it less positively charged did not impact its clearance. Anti-lymphotoxin α has fast nonspecific clearance in cynos, and making it more positively charged caused it to clear even faster, whereas making it less positively charged caused it to clear slower and within the typical range. These trends in clearance were also observed in two other preclinical species, mice and rats. The effect of modifying Fv charge on subcutaneous bioavailability was also examined, and in general bioavailability was inversely related to the direction of the Fv charge change. Thus, modifying Fv charge appears to impact antibody PKs, and the changes tended to correlate with those predicted by the empirical model. PMID:26491012

Navier-Stokes analysis of radial turbine rotor performance

NASA Technical Reports Server (NTRS)

Larosiliere, L. M.

1993-01-01

An analysis of flow through a radial turbine rotor using the three-dimensional, thin-layer Navier-Stokes code RVC3D is described. The rotor is a solid version of an air-cooled metallic radial turbine having thick trailing edges, shroud clearance, and scalloped-backface clearance. Results are presented at the nominal operating condition using both a zero-clearance model and a model simulating the effects of the shroud and scalloped-backface clearance flows. A comparison with the available test data is made and details of the internal flow physics are discussed, allowing a better understanding of the complex flow distribution within the rotor.

Recommendations for Achieving Accurate Numerical Simulation of Tip Clearance Flows in Transonic Compressor Rotors

NASA Technical Reports Server (NTRS)

VanZante, Dale E.; Strazisar, Anthony J.; Wood, Jerry R,; Hathaway, Michael D.; Okiishi, Theodore H.

2000-01-01

The tip clearance flows of transonic compressor rotors are important because they have a significant impact on rotor and stage performance. While numerical simulations of these flows are quite sophisticated. they are seldom verified through rigorous comparisons of numerical and measured data because these kinds of measurements are rare in the detail necessary to be useful in high-speed machines. In this paper we compare measured tip clearance flow details (e.g. trajectory and radial extent) with corresponding data obtained from a numerical simulation. Recommendations for achieving accurate numerical simulation of tip clearance flows are presented based on this comparison. Laser Doppler Velocimeter (LDV) measurements acquired in a transonic compressor rotor, NASA Rotor 35, are used. The tip clearance flow field of this transonic rotor was simulated using a Navier-Stokes turbomachinery solver that incorporates an advanced k-epsilon turbulence model derived for flows that are not in local equilibrium. Comparison between measured and simulated results indicates that simulation accuracy is primarily dependent upon the ability of the numerical code to resolve important details of a wall-bounded shear layer formed by the relative motion between the over-tip leakage flow and the shroud wall. A simple method is presented for determining the strength of this shear layer.

Influence of blade tip rounding on tip leakage vortex cavitation of axial flow pump

NASA Astrophysics Data System (ADS)

Wu, S. Q.; Shi, W. D.; Zhang, D. S.; Yao, J.; Cheng, C.

2013-12-01

Tip leakage flow in axial flow pumps is mainly caused by the tip clearance, which is the main cause of tip leakage vortex cavitation and blade tip cavitation erosion. In order to improve tip clearance flow and reduce TLV cavitation, four schemes were adopted to the round blade tip. These are: no tip rounding, one time tip clearance tip rounding, two times tip clearance tip rounding, four times tip clearance tip rounding. Using SST k-ω turbulence model and Zwart cavitation model in CFX software, this simulation obtained four kinds of inner flow field results. The numerical results indicated that with the increase of r*, NPSHc gradually increased and the cavitation performance reduced. However, corner vortex was eliminated so that cavitation in gap was restrained. But TLV vorticity increased and cavitation's range here had a little expansion. Combined with the research of this paper and the different analyses of four schemes, we recommend adopting the two times of the tip clearance rounding.

A comparison of experimental and theoretical results for labyrinth gas seals with honeycomb stators. M.S. Thesis

NASA Technical Reports Server (NTRS)

Hawkins, Lawrence Allen

1988-01-01

Experimental results for the rotordynamic stiffness and damping coefficients of a labyrinth -rotor honeycomb-stator seal are presented. The coefficients are compared to the coefficients of a labyrinth-rotor smooth-stator seal having the same geometry. The coefficients are compared to analytical results from a two-control-volume compressible flow model. The experimental results show that the honeycomb stator configuration is more stable than the smooth stator configuration at low rotor speeds. At high rotor speeds and low clearance, the smooth stator seal is more stable. The theoretical model predicts the cross-coupled stiffness of the honeycomb stator seal correctly within 25 percent of measured values. The model provides accurate predictions of direct damping for large clearance seals. Overall, the model does not perform as well for low clearance seals as for high clearance seals.

Robust Optimization Design for Turbine Blade-Tip Radial Running Clearance using Hierarchically Response Surface Method

NASA Astrophysics Data System (ADS)

Zhiying, Chen; Ping, Zhou

2017-11-01

Considering the robust optimization computational precision and efficiency for complex mechanical assembly relationship like turbine blade-tip radial running clearance, a hierarchically response surface robust optimization algorithm is proposed. The distribute collaborative response surface method is used to generate assembly system level approximation model of overall parameters and blade-tip clearance, and then a set samples of design parameters and objective response mean and/or standard deviation is generated by using system approximation model and design of experiment method. Finally, a new response surface approximation model is constructed by using those samples, and this approximation model is used for robust optimization process. The analyses results demonstrate the proposed method can dramatic reduce the computational cost and ensure the computational precision. The presented research offers an effective way for the robust optimization design of turbine blade-tip radial running clearance.

Pharmacokinetic modelling of intravenous tobramycin in adolescent and adult patients with cystic fibrosis using the nonparametric expectation maximization (NPEM) algorithm.

PubMed

Touw, D J; Vinks, A A; Neef, C

1997-06-01

The availability of personal computer programs for individualizing drug dosage regimens has stimulated the interest in modelling population pharmacokinetics. Data from 82 adolescent and adult patients with cystic fibrosis (CF) who were treated with intravenous tobramycin because of an exacerbation of their pulmonary infection were analysed with a non-parametric expectation maximization (NPEM) algorithm. This algorithm estimates the entire discrete joint probability density of the pharmacokinetic parameters. It also provides traditional parametric statistics such as the means, standard deviation, median, covariances and correlations among the various parameters. It also provides graphic-2- and 3-dimensional representations of the marginal densities of the parameters investigated. Several models for intravenous tobramycin in adolescent and adult patients with CF were compared. Covariates were total body weight (for the volume of distribution) and creatinine clearance (for the total body clearance and elimination rate). Because of lack of data on patients with poor renal function, restricted models with non-renal clearance and the non-renal elimination rate constant fixed at literature values of 0.15 L/h and 0.01 h-1 were also included. In this population, intravenous tobramycin could be best described by median (+/-dispersion factor) volume of distribution per unit of total body weight of 0.28 +/- 0.05 L/kg, elimination rate constant of 0.25 +/- 0.10 h-1 and elimination rate constant per unit of creatinine clearance of 0.0008 +/- 0.0009 h-1/(ml/min/1.73 m2). Analysis of populations of increasing size showed that using a restricted model with a non-renal elimination rate constant fixed at 0.01 h-1, a model based on a population of only 10 to 20 patients, contained parameter values similar to those of the entire population and, using the full model, a larger population (at least 40 patients) was needed.

Population Pharmacokinetic Analyses of Lithium: A Systematic Review.

PubMed

Methaneethorn, Janthima

2018-02-01

Even though lithium has been used for the treatment of bipolar disorder for several decades, its toxicities are still being reported. The major limitation in the use of lithium is its narrow therapeutic window. Several methods have been proposed to predict lithium doses essential to attain therapeutic levels. One of the methods used to guide lithium therapy is population pharmacokinetic approach which accounts for inter- and intra-individual variability in predicting lithium doses. Several population pharmacokinetic studies of lithium have been conducted. The objective of this review is to provide information on population pharmacokinetics of lithium focusing on nonlinear mixed effect modeling approach and to summarize significant factors affecting lithium pharmacokinetics. A literature search was conducted from PubMed database from inception to December, 2016. Studies conducted in humans, using lithium as a study drug, providing population pharmacokinetic analyses of lithium by means of nonlinear mixed effect modeling, were included in this review. Twenty-four articles were identified from the database. Seventeen articles were excluded based on the inclusion and exclusion criteria. A total of seven articles were included in this review. Of these, only one study reported a combined population pharmacokinetic-pharmacodynamic model of lithium. Lithium pharmacokinetics were explained using both one- and two-compartment models. The significant predictors of lithium clearance identified in most studies were renal function and body size. One study reported a significant effect of age on lithium clearance. The typical values of lithium clearance ranged from 0.41 to 9.39 L/h. The magnitude of inter-individual variability on lithium clearance ranged from 12.7 to 25.1%. Only two studies evaluated the models using external data sets. Model methodologies in each study are summarized and discussed in this review. For future perspective, a population pharmacokinetic-pharmacodynamic study of lithium is recommended. Moreover, external validation of previously published models should be performed.

Deformation Analysis of the Main Components in a Single Screw Compressor

NASA Astrophysics Data System (ADS)

Liu, Feilong; Liao, Xueli; Feng, Quanke; Van Den Broek, Martijn; De Paepe, Michel

2015-08-01

The single screw compressor is used in many fields such as air compression, chemical industry and refrigeration. During operation, different gas pressures and temperatures applied on the components can cause different degrees of deformation, which leads to a difference between the thermally induced clearance and the designed clearance. However, limited research about clearance design is reported. In this paper, a temperature measurement instrument and a convective heat transfer model were described and used to establish the temperature of a single screw air compressor's casing, screw rotor and star wheel. 3-D models of these three main components were built. The gas force deformation, thermal- structure deformation and thermal-force coupling deformation were carried out by using a finite element simulation method. Results show that the clearance between the bottom of the groove and the top of star wheel is reduced by 0.066 mm, the clearance between the side of groove and the star wheel is reduced by 0.015 mm, and the clearance between the cylinder and the rotor is reduced by 0.01 mm. It is suggested that these deformations should be taken into account during the design of these clearances.

Levitation force of small clearance superconductor-magnet system under non-coaxial condition

NASA Astrophysics Data System (ADS)

Xu, Jimin; Jin, Yingze; Yuan, Xiaoyang; Miao, Xusheng

2017-03-01

A novel superconducting tilting-pad bearing was proposed for the advanced research of reusable liquid hydrogen turbopump in liquid rocket. The bearing is a combination of superconducting magnetic bearing and hydrodynamic fluid-film bearing. Since the viscosity of cryogenic fuel to activate superconducting state and form hydrodynamic fluid-film is very low, bearing clearance will be very small. This study focuses on the investigation of superconducting levitation force in this kind of small clearance superconductor-magnet system. Based on Bean critical state model and three-dimensional finite element method, an analysis method is presented to obtain the levitation force under such situation. Since the complicated operational conditions and structural arrangement for application in liquid rocket, center lines of bulk superconductor and magnet rotor will usually be in non-coaxial state. Superconducting levitation forces in axial direction and radial direction under non-coaxial situation are also analyzed by the presented method.

Quality by design approach for viral clearance by protein a chromatography

PubMed Central

Zhang, Min; Miesegaes, George R; Lee, Michael; Coleman, Daniel; Yang, Bin; Trexler-Schmidt, Melody; Norling, Lenore; Lester, Philip; Brorson, Kurt A; Chen, Qi

2014-01-01

Protein A chromatography is widely used as a capture step in monoclonal antibody (mAb) purification processes. Antibodies and Fc fusion proteins can be efficiently purified from the majority of other complex components in harvested cell culture fluid (HCCF). Protein A chromatography is also capable of removing modest levels of viruses and is often validated for viral clearance. Historical data mining of Genentech and FDA/CDER databases systematically evaluated the removal of model viruses by Protein A chromatography. First, we found that for each model virus, removal by Protein A chromatography varies significantly across mAbs, while remains consistent within a specific mAb product, even across the acceptable ranges of the process parameters. In addition, our analysis revealed a correlation between retrovirus and parvovirus removal, with retrovirus data generally possessing a greater clearance factor. Finally, we describe a multivariate approach used to evaluate process parameter impacts on viral clearance, based on the levels of retrovirus-like particles (RVLP) present among process characterization study samples. It was shown that RVLP removal by Protein A is robust, that is, parameter effects were not observed across the ranges tested. Robustness of RVLP removal by Protein A also correlates with that for other model viruses such as X-MuLV, MMV, and SV40. The data supports that evaluating RVLP removal using process characterization study samples can establish multivariate acceptable ranges for virus removal by the protein A step for QbD. By measuring RVLP instead of a model retrovirus, it may alleviate some of the technical and economic challenges associated with performing large, design-of-experiment (DoE)—type virus spiking studies. This approach could also serve to provide useful insight when designing strategies to ensure viral safety in the manufacturing of a biopharmaceutical product. PMID:23860745

Pooled population pharmacokinetic model of imipenem in plasma and the lung epithelial lining fluid

PubMed Central

Rizk, Matthew L.; Lala, Mallika; Chavez‐Eng, Cynthia; Visser, Sandra A. G.; Kerbusch, Thomas; Danhof, Meindert; Rao, Gauri; van der Graaf, Piet H.

2016-01-01

Aims Several clinical trials have confirmed the therapeutic benefit of imipenem for treatment of lung infections. There is however no knowledge of the penetration of imipenem into the lung epithelial lining fluid (ELF), the site of action relevant for lung infections. Furthermore, although the plasma pharmacokinetics (PK) of imipenem has been widely studied, most studies have been based on selected patient groups. The aim of this analysis was to characterize imipenem plasma PK across populations and to quantify imipenem ELF penetration. Methods A population model for imipenem plasma PK was developed using data obtained from healthy volunteers, elderly subjects and subjects with renal impairment, in order to identify predictors for inter‐individual variability (IIV) of imipenem PK. Subsequently, a clinical study which measured plasma and ELF concentrations of imipenem was included in order to quantify lung penetration. Results A two compartmental model best described the plasma PK of imipenem. Creatinine clearance and body weight were included as subject characteristics predictive for IIV on clearance. Typical estimates for clearance, central and peripheral volume, and inter‐compartmental clearance were 11.5 l h–1, 9.37 l, 6.41 l, 13.7 l h–1, respectively (relative standard error (RSE) <8%). The distribution of imipenem into ELF was described using a time‐independent penetration coefficient of 0.44 (RSE 14%). Conclusion The identified lung penetration coefficient confirms the clinical relevance of imipenem for treatment of lung infections, while the population PK model provided insights into predictors of IIV for imipenem PK and may be of relevance to support dose optimization in various subject groups. PMID:26852277

Pooled population pharmacokinetic model of imipenem in plasma and the lung epithelial lining fluid.

PubMed

van Hasselt, J G Coen; Rizk, Matthew L; Lala, Mallika; Chavez-Eng, Cynthia; Visser, Sandra A G; Kerbusch, Thomas; Danhof, Meindert; Rao, Gauri; van der Graaf, Piet H

2016-06-01

Several clinical trials have confirmed the therapeutic benefit of imipenem for treatment of lung infections. There is however no knowledge of the penetration of imipenem into the lung epithelial lining fluid (ELF), the site of action relevant for lung infections. Furthermore, although the plasma pharmacokinetics (PK) of imipenem has been widely studied, most studies have been based on selected patient groups. The aim of this analysis was to characterize imipenem plasma PK across populations and to quantify imipenem ELF penetration. A population model for imipenem plasma PK was developed using data obtained from healthy volunteers, elderly subjects and subjects with renal impairment, in order to identify predictors for inter-individual variability (IIV) of imipenem PK. Subsequently, a clinical study which measured plasma and ELF concentrations of imipenem was included in order to quantify lung penetration. A two compartmental model best described the plasma PK of imipenem. Creatinine clearance and body weight were included as subject characteristics predictive for IIV on clearance. Typical estimates for clearance, central and peripheral volume, and inter-compartmental clearance were 11.5 l h(-1) , 9.37 l, 6.41 l, 13.7 l h(-1) , respectively (relative standard error (RSE) <8%). The distribution of imipenem into ELF was described using a time-independent penetration coefficient of 0.44 (RSE 14%). The identified lung penetration coefficient confirms the clinical relevance of imipenem for treatment of lung infections, while the population PK model provided insights into predictors of IIV for imipenem PK and may be of relevance to support dose optimization in various subject groups. © 2016 The British Pharmacological Society.

Population Pharmacokinetics of Rifapentine and Desacetyl Rifapentine in Healthy Volunteers: Nonlinearities in Clearance and Bioavailability

PubMed Central

Lu, Yanhui; Bliven-Sizemore, Erin; Weiner, Marc; Nuermberger, Eric; Burman, William; Dorman, Susan E.; Dooley, Kelly E.

2014-01-01

Rifapentine is under active investigation as a potent drug that may help shorten the tuberculosis (TB) treatment duration. A previous rifapentine dose escalation study with daily dosing indicated a possible decrease in bioavailability as the dose increased and an increase in clearance over time for rifapentine and its active metabolite, desacetyl rifapentine. This study aimed to assess the effects of increasing doses on rifapentine absorption and bioavailability and to evaluate the clearance changes over 14 days. A population analysis was performed with nonlinear mixed-effects modeling. Absorption, time-varying clearance, bioavailability, and empirical and semimechanistic autoinduction models were investigated. A one-compartment model linked to a transit compartment absorption model best described the data. The bioavailability of rifapentine decreased linearly by 2.5% for each 100-mg increase in dose. The autoinduction model suggested a dose-independent linear increase in clearance of the parent drug and metabolite over time from 1.2 and 3.1 liters · h−1, respectively, after a single dose to 2.2 and 5.0 liters · h−1, respectively, after 14 once-daily doses, with no plateau being reached by day 14. In clinical trial simulations using the final model, rifapentine demonstrated less-than-dose-proportional pharmacokinetics, but there was no plateau in exposures over the dose range tested (450 to 1,800 mg), and divided dosing increased exposures significantly. Thus, the proposed compartmental model incorporating daily dosing of rifapentine over a wide range of doses and time-related changes in bioavailability and clearance provides a useful tool for estimation of drug exposure that can be used to optimize rifapentine dosing for TB treatment. (This study has been registered at ClinicalTrials.gov under registration no. NCT01162486.) PMID:24614383

Low but inducible contribution of renal elimination to clearance of propylene glycol in preterm and term neonates.

PubMed

De Cock, Roosmarijn F W; Allegaert, Karel; Vanhaesebrouck, Sophie; de Hoon, Jan; Verbesselt, Rene; Danhof, Meindert; Knibbe, Catherijne A J

2014-06-01

Despite limited information being available on the pharmacokinetics of excipients, propylene glycol (PG) is often used as an excipient in both adults and children. The aim of this study is to characterize the renal and hepatic elimination of PG in preterm and term neonates. The pharmacokinetic analysis of PG was performed in NONMEM 6.2. on the basis of PG concentrations in plasma and/or urine samples for a total of 69 (pre)term neonates (birth weight 630-3980 g, gestational age 24-41 weeks, postnatal age 1-29 days) who received PG coadministered with intravenous paracetamol (5-10 mg/kg per 6 hours), phenobarbital (5 mg·kg(-1)·d(-1)), or both. To capture the time-dependent trend in the renal excretion of PG, different models based on time after the first dose, urine volume, and creatinine amount in urine were tested. A one-compartment model parameterized in terms of renal clearance, hepatic clearance, and volume of distribution was found to adequately describe the observations in both plasma and urine. After the first dose was administered, the renal elimination of PG was 15% of total clearance, which increased over time to 25% at 24 hours after the first dose of PG. This increase was best described using a hyperbolic function based on time after the first dose. Renal elimination of PG in (pre)term neonates is low, particularly compared with the reported percentage of 45% in adults, but it may increase with time after the first dose of PG. To study whether this increase is caused by an autoinduced increase in the renal secretion or a reduction of tubular reabsorption of PG, further research is needed.

How to report and discuss ADME data in medicinal chemistry publications: in vitro data or in vivo extrapolations?

PubMed

Svennebring, Andreas M

2015-01-01

Early drug discovery projects often utilize data from ADME (absorption, distribution, metabolism, elimination) assays to benchmark data and guide discussion, rather than the predicted in vivo consequences of these data. Here, the two paradigms are compared, using evaluations of metabolic stability based on either microsomal clearance assay data or from the predicted in vivo hepatic clearance and half-life calculated through the combination of the venous well-stirred model and Øie-Tozer's model. The need for a shift in paradigm is presented, and its implications discussed. It is suggested that discussions about ADME data should revolve around potential clinical problems that are most likely to surface during the development phase, each benchmarked with a suitable variable derived from the assay data.

Bioconcentration of 5,5',6-trichlorobiphenyl and pentachlorophenol in the midge, Chironomus riparius, as measured by a pharmacokinetic model

USGS Publications Warehouse

Lydy, M.J.; Hayton, W.L.; Staubus, A.E.; Fisher, S.W.

1994-01-01

A two compartment pharmacokinetic model was developed which describes the uptake and elimination of 5,5',6-trichlorobiphenyl (TCB) and pentachlorophenol (PCP) in the midge, Chironomus riparius. C. riparius were exposed to nominal TCB (2 ??g L-1) and PCP (9 ??g L-1) concentrations during a 16 h static uptake phase. Depuration was determined over approximately 45 h using a flowthrough system without feeding. The uptake clearance (P) was 330 ?? 61 ml g-1 midge h-1 for TCB and 55 ?? 4 ml g-1 midge h-1 for PCP, while measured bioconcentration factors (BCF) were 35,900 and 458 for TCB and PCP, respectively. Overall, the clearance-volume- based pharmacokinetic model predicted BCF values that were consistent with published values as well as with BCF values obtained from the octanol-water partition coefficient (K(ow)).

Study of blade clearance effects on centrifugal pumps

NASA Technical Reports Server (NTRS)

Hoshide, R. K.; Nielson, C. E.

1972-01-01

A program of analysis, design, fabrication, and testing has been conducted to develop and experimentally verify analytical models to predict the effects of impeller blade clearance on centrifugal pumps. The effect of tip clearance on pump efficiency, and the relationship between the head coefficient and torque loss with tip clearance was established. Analysis were performed to determine the cost variation in design, manufacture, and test that would occur between unshrouded and shrouded impellers. An impeller, representative of typical rocket engine impellers, was modified by removing its front shroud to permit variation of its blade clearances. It was tested in water with special instrumentation to provide measurements of blade surface pressures during operation. Pump performance data were obtained from tests at various impeller tip clearances. Blade pressure data were obtained at the nominal tip clearance. Comparisons of predicted and measured data are given.

Population pharmacokinetics of telapristone (CDB-4124) and its active monodemethylated metabolite CDB-4453, with a mixture model for total clearance.

PubMed

Morris, Denise; Podolski, Joseph; Kirsch, Alan; Wiehle, Ronald; Fleckenstein, Lawrence

2011-12-01

Telapristone is a selective progesterone antagonist that is being developed for the long-term treatment of symptoms associated with endometriosis and uterine fibroids. The population pharmacokinetics of telapristone (CDB-4124) and CDB-4453 was investigated using nonlinear mixed-effects modeling. Data from two clinical studies (n = 32) were included in the analysis. A two-compartment (parent) one compartment (metabolite) mixture model (with two populations for apparent clearance) with first-order absorption and elimination adequately described the pharmacokinetics of telapristone and CDB-4453. Telapristone was rapidly absorbed with an absorption rate constant (Ka) of 1.26 h(-1). Moderate renal impairment resulted in a 74% decrease in Ka. The population estimates for oral clearance (CL/F) for the two populations were 11.6 and 3.34 L/h, respectively, with 25% of the subjects being allocated to the high-clearance group. Apparent volume of distribution for the central compartment (V2/F) was 37.4 L, apparent inter-compartmental clearance (Q/F) was 21.9 L/h, and apparent peripheral volume of distribution for the parent (V4/F) was 120 L. The ratio of the fraction of telapristone converted to CDB-4453 to the distribution volume of CDB-4453 (Fmet(est)) was 0.20/L. Apparent volume of distribution of the metabolite compartment (V3/F) was fixed to 1 L and apparent clearance of the metabolite (CLM/F) was 2.43 L/h. A two-compartment parent-metabolite model adequately described the pharmacokinetics of telapristone and CDB-4453. The clearance of telapristone was separated into two populations and could be the result of metabolism via polymorphic CYP3A5.

Dynamic analysis of nonlinear rotor-housing systems

NASA Technical Reports Server (NTRS)

Noah, Sherif T.

1988-01-01

Nonlinear analysis methods are developed which will enable the reliable prediction of the dynamic behavior of the space shuttle main engine (SSME) turbopumps in the presence of bearing clearances and other local nonlinearities. A computationally efficient convolution method, based on discretized Duhamel and transition matrix integral formulations, is developed for the transient analysis. In the formulation, the coupling forces due to the nonlinearities are treated as external forces acting on the coupled subsystems. Iteration is utilized to determine their magnitudes at each time increment. The method is applied to a nonlinear generic model of the high pressure oxygen turbopump (HPOTP). As compared to the fourth order Runge-Kutta numerical integration methods, the convolution approach proved to be more accurate and more highly efficient. For determining the nonlinear, steady-state periodic responses, an incremental harmonic balance method was also developed. The method was successfully used to determine dominantly harmonic and subharmonic responses fo the HPOTP generic model with bearing clearances. A reduction method similar to the impedance formulation utilized with linear systems is used to reduce the housing-rotor models to their coordinates at the bearing clearances. Recommendations are included for further development of the method, for extending the analysis to aperiodic and chaotic regimes and for conducting critical parameteric studies of the nonlinear response of the current SSME turbopumps.

Environmental Assessment: 2005 Base Realignment and Closure Seymour Johnson Air Force Base Goldsboro, North Carolina

DTIC Science & Technology

2007-07-01

clearance criteria is being prepared. Expected completion date: __ _ A temporary waiver for construction activity in the airfield vacinity was approved on...space clearance criteria is being prepared. Expected completion date: __ _ A temporary waiver for construction activity in the airfield vacinity was...construction activity in the airfield vacinity was approved on ____ (date). A permanent waiver of airfield/airspace clearance criteria was obtained on

Abnormal oral glucose tolerance and glucose malabsorption after vagotomy and pyloroplasty. A tracer method for measuring glucose absorption rates

DOE Office of Scientific and Technical Information (OSTI.GOV)

Radziuk, J.; Bondy, D.C.

1982-11-01

The mechanisms underlying the abnormal glucose tolerance in patients who had undergone vagotomy and pyloroplasty were investigated by measuring the rates of absorption of ingested glucose and the clearance rate of glucose using tracer methods. These methods are based on labeling a 100-g oral glucose load with (1-/sup 14/C)glucose and measuring glucose clearance using plasma levels of infused (3-/sup 3/H)glucose. The rate of appearance of both ingested and total glucose is then calculated continuously using a two-compartment model of glucose kinetics. It was found that about 30% of the ingested glucose (100 g) failed to appear in the systemic circulation.more » That this was due to malabsorption was confirmed using breath-hydrogen analysis. The absorption period is short (101 +/- 11 min) compared with normal values but the clearance of glucose is identical to that in control subjects, and it peaks 132 +/- 7 min after glucose loading. The peak plasma insulin values were more than four times higher in patients than in normal subjects, and this may afford an explanation of rates of glucose clearance that are inappropriate for the short absorption period. The combination of glucose malabsorption and this clearance pattern could yield the hypoglycemia that may be observed in patients after gastric surgery.« less

Application of an in vitro OAT assay in drug design and optimization of renal clearance.

PubMed

Soars, Matthew G; Barton, Patrick; Elkin, Lisa L; Mosure, Kathleen W; Sproston, Joanne L; Riley, Robert J

2014-07-01

1. Optimization of renal clearance is a complex balance between passive and active processes mediated by renal transporters. This work aimed to characterize the interaction of a series of compounds with rat and human organic anion transporters (OATs) and develop quantitative structure-activity relationships (QSARs) to optimize renal clearance. 2. In vitro inhibition assays were established for human OAT1 and rat Oat3 and rat in vivo renal clearance was obtained. Statistically significant quantitative relationships were explored between the compounds' physical properties, their affinity for OAT1 and oat3 and the inter-relationship with unbound renal clearance (URC) in rat. 3. Many of the compounds were actively secreted and in vitro analysis demonstrated that these were ligands for rat and human OAT transporters (IC50 values ranging from <1 to >100 µM). Application of resultant QSAR models reduced renal clearance in the rat from 24 to <0.1 ml/min/kg. Data analysis indicated that the properties associated with increasing affinity at OATs are the same as those associated with reducing URC but orthogonal in nature. 4. This study has demonstrated that OAT inhibition data and QSAR models can be successfully used to optimize rat renal clearance in vivo and provide confidence of translation to humans.

Population pharmacokinetics of teicoplanin in hospitalized elderly patients using cystatin C as an indicator of renal function.

PubMed

Kasai, Hidefumi; Tsuji, Yasuhiro; Hiraki, Yoichi; Tsuruyama, Moeko; To, Hideto; Yamamoto, Yoshihiro

2018-04-01

Serum cystatin C (CysC) has recently been proposed as an alternative marker to serum creatinine (SCR) for estimating renal clearance. In the present study, we performed a population pharmacokinetic analysis of teicoplanin (TEIC), which is mainly eliminated through the kidneys, using CysC as a predictor for renal clearance. Thirty-six patients with MRSA infections who were administrated to the National Hospital Organization Beppu Medical Center between January 2012 and December 2013 were enrolled and gave 123 sets of blood TEIC concentration data. Renal clearance was estimated by the Hoek equation using CysC, by creatinine clearance predicted by the Cockcroft-Gault equation using SCR, or directly by CysC. One compartment open model with inter-individual variabilities for renal clearance and the volume of distribution as well as an additional residual error model was used to estimate population pharmacokinetic parameters for TEIC. The model with the best predictability was that with CysC as a predictor for renal clearance; it showed better significance than the models using estimated the glomerular filtration rate by the Hoek equation or CLcr. The final model was as follows: CL (L/hr) = 0.510 × (CysC/1.4) -0.68  × Total body weight/60 0.81 , omega (CL) = 19.8% CV, VC (L) = 78.1, omega (V) = 42.7% CV. The present results show the usefulness of CysC to more accurately predict the pharmacokinetics of drugs mainly eliminated through the kidneys, such as TEIC. However, since the sample size in this study was relatively small, further investigations on renal clearance predictability using CysC are needed. Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Dynamic microvesicle release and clearance within the cardiovascular system: triggers and mechanisms.

PubMed

Ayers, Lisa; Nieuwland, Rienk; Kohler, Malcolm; Kraenkel, Nicolle; Ferry, Berne; Leeson, Paul

2015-12-01

Interest in cell-derived microvesicles (or microparticles) within cardiovascular diagnostics and therapeutics is rapidly growing. Microvesicles are often measured in the circulation at a single time point. However, it is becoming clear that microvesicle levels both increase and decrease rapidly in response to certain stimuli such as hypoxia, acute cardiac stress, shear stress, hypertriglyceridaemia and inflammation. Consequently, the levels of circulating microvesicles will reflect the balance between dynamic mechanisms for release and clearance. The present review describes the range of triggers currently known to lead to microvesicle release from different cellular origins into the circulation. Specifically, the published data are used to summarize the dynamic impact of these triggers on the degree and rate of microvesicle release. Secondly, a summary of the current understanding of microvesicle clearance via different cellular systems, including the endothelial cell and macrophage, is presented, based on reported studies of clearance in experimental models and clinical scenarios, such as transfusion or cardiac stress. Together, this information can be used to provide insights into potential underlying biological mechanisms that might explain the increases or decreases in circulating microvesicle levels that have been reported and help to design future clinical studies. © 2015 Authors; published by Portland Press Limited.

Dimerization of glycoprotein Ibα is not sufficient to induce platelet clearance.

PubMed

Liang, X; Syed, A K; Russell, S R; Ware, J; Li, R

2016-02-01

ESSENTIALS: Many anti-glycoprotein (GP)Ibα antibodies induce platelet clearance in a dimer-dependent manner. Characterization of monoclonal antibodies that bind the mechanosensitive domain (MSD) of GPIbα. An anti-MSD antibody binds two copies of GPIbα in platelets but does not induce platelet clearance. The prevailing clustering model of GPIbα signaling is incorrect or needs revision. The mechanism of platelet clearance is not clear. Many antibodies binding the membrane-distal ligand-binding domain of glycoprotein (GP)Ibα induce rapid clearance of platelets and acute thrombocytopenia, which requires the bifurcated antibody structure. It was thought that binding of these antibodies induced lateral dimerization or clustering of GPIbα in the plasma membrane, which leads to downstream signaling and platelet clearance. However, many antibodies targeting GPIbβ and GPIX, which are associated with GPIbα in the GPIb-IX complex, do not induce platelet clearance, which is in contradiction to the clustering model. To test whether dimerization or clustering of GPIbα is sufficient to transmit the signal that leads to platelet clearance. We have recently raised several mAbs targeting the mechanosensitive domain (MSD) of GPIbα. Binding of these anti-MSD antibodies was characterized with biochemical methods. Their ability to stimulate platelets and induce platelet clearance in mice was assessed. Infusion of anti-MSD antibodies does not cause thrombocytopenia in mice. These antibodies show no detectable effects on platelet activation and aggregation in vitro. Further biochemical investigation showed that the anti-MSD antibody 3D1 binds two copies of GPIbα on the platelet surface. Therefore, lateral dimerization of GPIbα induced by antibody binding is not sufficient to initiate GPIb-IX signaling and induce platelet clearance. Our results suggest that a factor other than or in addition to clustering of GPIbα is required to induce platelet clearance. © 2015 International Society on Thrombosis and Haemostasis.

Clinical review: Drug metabolism and nonrenal clearance in acute kidney injury

PubMed Central

Vilay, A Mary; Churchwell, Mariann D; Mueller, Bruce A

2008-01-01

Decreased renal drug clearance is an obvious consequence of acute kidney injury (AKI). However, there is growing evidence to suggest that nonrenal drug clearance is also affected. Data derived from human and animal studies suggest that hepatic drug metabolism and transporter function are components of nonrenal clearance affected by AKI. Acute kidney injury may also impair the clearance of formed metabolites. The fact that AKI does not solely influence kidney function may have important implications for drug dosing, not only of renally eliminated drugs but also of those that are hepatically cleared. A review of the literature addressing the topic of drug metabolism and clearance alterations in AKI reveals that changes in nonrenal clearance are highly complicated and poorly studied, but they may be quite common. At present, our understanding of how AKI affects drug metabolism and nonrenal clearance is limited. However, based on the available evidence, clinicians should be cognizant that even hepatically eliminated drugs and formed drug metabolites may accumulate during AKI, and renal replacement therapy may affect nonrenal clearance as well as drug metabolite clearance. PMID:19040780

Comparison of mathematic models for assessment of glomerular filtration rate with electron-beam CT in pigs.

PubMed

Daghini, Elena; Juillard, Laurent; Haas, John A; Krier, James D; Romero, Juan C; Lerman, Lilach O

2007-02-01

To prospectively compare in pigs three mathematic models for assessment of glomerular filtration rate (GFR) on electron-beam (EB) computed tomographic (CT) images, with concurrent inulin clearance serving as the reference standard. This study was approved by the institutional animal care and use committee. Inulin clearance was measured in nine pigs (18 kidneys) and compared with single-kidney GFR assessed from renal time-attenuation curves (TACs) obtained with EB CT before and after infusion of the vasodilator acetylcholine. CT-derived GFR was calculated with the original and modified Patlak methods and with previously validated extended gamma variate modeling of first-pass cortical TACs. Statistical analysis was performed to assess correlation between CT methods and inulin clearance for estimation of GFR with least-squares regression analysis and Bland-Altman graphical representation. Comparisons within groups were performed with a paired t test. GFR assessed with the original Patlak method indicated poor correlation with inulin clearance, whereas GFR assessed with the modified Patlak method (P < .001, r = 0.75) and with gamma variate modeling (P < .001, r = 0.79) correlated significantly with inulin clearance and indicated an increase in response to acetylcholine. CT-derived estimates of GFR can be significantly improved by modifications in image analysis methods (eg, use of a cortical region of interest). (c) RSNA, 2007.

Population pharmacokinetic and pharmacogenetic analysis of tacrolimus in paediatric liver transplant patients

PubMed Central

Abdel Jalil, Mariam H; Hawwa, Ahmed F; McKiernan, Patrick J; Shields, Michael D; McElnay, James C

2014-01-01

Aims To build a population pharmacokinetic model that describes the apparent clearance of tacrolimus and the potential demographic, clinical and genetically controlled factors that could lead to inter-patient pharmacokinetic variability within children following liver transplantation. Methods The present study retrospectively examined tacrolimus whole blood pre-dose concentrations (n = 628) of 43 children during their first year post-liver transplantation. Population pharmacokinetic analysis was performed using the non-linear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance and influential covariates. Results The final model identified time post-transplantation and CYP3A5*1 allele as influential covariates on tacrolimus apparent clearance according to the following equation: where TVCL is the typical value for apparent clearance, TPT is time post-transplantation in days and the CYP3A5 is 1 where *1 allele is present and 0 otherwise. The population estimate and inter-individual variability (%CV) of tacrolimus apparent clearance were found to be 0.977 l h−1 kg−1 (95% CI 0.958, 0.996) and 40.0%, respectively, while the residual variability between the observed and predicted concentrations was 35.4%. Conclusion Tacrolimus apparent clearance was influenced by time post-transplantation and CYP3A5 genotypes. The results of this study, once confirmed by a large scale prospective study, can be used in conjunction with therapeutic drug monitoring to recommend tacrolimus dose adjustments that take into account not only body weight but also genetic and time-related changes in tacrolimus clearance. PMID:23738951

Population pharmacokinetics of intravenous Erwinia asparaginase in pediatric acute lymphoblastic leukemia patients.

PubMed

Sassen, Sebastiaan D T; Mathôt, Ron A A; Pieters, Rob; Kloos, Robin Q H; de Haas, Valérie; Kaspers, Gertjan J L; van den Bos, Cor; Tissing, Wim J E; Te Loo, Maroeska; Bierings, Marc B; Kollen, Wouter J W; Zwaan, Christian M; van der Sluis, Inge M

2017-03-01

Erwinia asparaginase is an important component in the treatment of pediatric acute lymphoblastic leukemia. A large variability in serum concentrations has been observed after intravenous Erwinia asparaginase. Currently, Dutch Childhood Oncology Group protocols dose alterations are based on trough concentrations to ensure adequate asparaginase activity (≥100 IU/L). The aim of this study was to describe the population pharmacokinetics of intravenous Erwinia asparaginase to quantify and gather insight into inter-individual and inter-occasion variability. The starting dose was evaluated on the basis of the derived population pharmacokinetic parameters. In a multicenter prospective observational study, a total of 714 blood samples were collected from 51 children (age 1-17 years) with acute lymphoblastic leukemia. The starting dose was 20,000 IU/m 2 three times a week and adjusted according to trough levels from week three onwards. A population pharmacokinetic model was developed using NONMEM ® A 2-compartment linear model with allometric scaling best described the data. Inter-individual and inter-occasion variability of clearance were 33% and 13%, respectively. Clearance in the first month of treatment was 14% higher ( P <0.01). Monte Carlo simulations with our pharmacokinetic model demonstrated that patients with a low weight might require higher doses to achieve similar concentrations compared to patients with high weight. The current starting dose of 20,000 IU/m 2 might result in inadequate concentrations, especially for smaller, lower weight patients, hence dose adjustments based on individual clearance are recommended. The protocols were approved by the institutional review boards. (Registered at NTR 3379 Dutch Trial Register; www.trialregister.nl). Copyright© Ferrata Storti Foundation.

Schwann cells use TAM receptor-mediated phagocytosis in addition to autophagy to clear myelin in a mouse model of nerve injury.

PubMed

Brosius Lutz, Amanda; Chung, Won-Suk; Sloan, Steven A; Carson, Glenn A; Zhou, Lu; Lovelett, Emilie; Posada, Sean; Zuchero, J Bradley; Barres, Ben A

2017-09-19

Ineffective myelin debris clearance is a major factor contributing to the poor regenerative ability of the central nervous system. In stark contrast, rapid clearance of myelin debris from the injured peripheral nervous system (PNS) is one of the keys to this system's remarkable regenerative capacity, but the molecular mechanisms driving PNS myelin clearance are incompletely understood. We set out to discover new pathways of PNS myelin clearance to identify novel strategies for activating myelin clearance in the injured central nervous system, where myelin debris is not cleared efficiently. Here we show that Schwann cells, the myelinating glia of the PNS, collaborate with hematogenous macrophages to clear myelin debris using TAM (Tyro3, Axl, Mer) receptor-mediated phagocytosis as well as autophagy. In a mouse model of PNS nerve crush injury, Schwann cells up-regulate TAM phagocytic receptors Axl and Mertk following PNS injury, and Schwann cells lacking both of these phagocytic receptors exhibit significantly impaired myelin phagocytosis both in vitro and in vivo. Autophagy-deficient Schwann cells also display reductions in myelin clearance after mouse nerve crush injury, as has been recently shown following nerve transection. These findings add a mechanism, Axl/Mertk-mediated myelin clearance, to the repertoire of cellular machinery used to clear myelin in the injured PNS. Given recent evidence that astrocytes express Axl and Mertk and have previously unrecognized phagocytic potential, this pathway may be a promising avenue for activating myelin clearance after CNS injury.

Human health and the environment: Predicting plasma protein binding and metabolic clearance rates of environmentally relevant chemicals.

EPA Science Inventory

In silico methods provide a rapid, inexpensive means of screening a wide array of environmentally relevant pollutants, pesticides, fungicides and consumer products for further toxicity testing. Physiologically based pharmacokinetic (PBPK) models bridge the gap between in vitro as...

In Silico Prediction of Toxicokinetic Parameters for Environmentally Relevant Chemicals for Risk-Based Prioritization

EPA Science Inventory

Toxicokinetic (TK) models can address an important component of chemical risk assessments by helping bridge the gap between chemical exposure and measured toxicity endpoints. The metabolic clearance rate (CLint) and fraction of a chemical unbound by plasma proteins (Fub) are crit...

Lung dosimetry for inhaled long-lived radionuclides and radon progeny.

PubMed

Hussain, M; Winkler-Heil, R; Hofmann, W

2011-05-01

The current version of the stochastic lung dosimetry model IDEAL-DOSE considers deposition in the whole tracheobronchial (TB) and alveolar airway system, while clearance is restricted to TB airways. For the investigation of doses produced by inhaled long-lived radionuclides (LLR) together with short-lived radon progeny, alveolar clearance has to be considered. Thus, present dose calculations are based on the average transport rates proposed for the revision of the ICRP human respiratory tract model. The results obtained indicate that LLR cleared from the alveolar region can deliver up to two to six times higher doses to the TB region when compared with the doses from directly deposited particles. Comparison of LLR doses with those of short-lived radon progeny indicates that LLR in uranium mines can deliver up to 5 % of the doses predicted for the short-lived radon daughters.

48 CFR 832.502-2 - Contract finance office clearance.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Contract finance office clearance. 832.502-2 Section 832.502-2 Federal Acquisition Regulations System DEPARTMENT OF VETERANS AFFAIRS GENERAL CONTRACTING REQUIREMENTS CONTRACT FINANCING Progress Payments Based on Costs 832.502-2 Contract finance office clearance. Contracting...

48 CFR 32.502-2 - Contract finance office clearance.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Contract finance office clearance. 32.502-2 Section 32.502-2 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION GENERAL CONTRACTING REQUIREMENTS CONTRACT FINANCING Progress Payments Based on Costs 32.502-2 Contract finance office clearance. The contracting...

Test of Cure for Anogenital Gonorrhoea Using Modern RNA-Based and DNA-Based Nucleic Acid Amplification Tests: A Prospective Cohort Study.

PubMed

Wind, Carolien M; Schim van der Loeff, Maarten F; Unemo, Magnus; Schuurman, Rob; van Dam, Alje P; de Vries, Henry J C

2016-06-01

The use of nucleic acid amplification tests (NAATs) to diagnose Neisseria gonorrhoeae infections complicates the performance of a test of cure (TOC) to monitor treatment failure, if this is indicated. As evidence for the timing of TOC using modern NAATs is limited, we performed a prospective cohort study to assess time to clearance when using modern RNA- and DNA-based NAATs. We included patients with anogenital gonorrhoea visiting the Sexually Transmitted Infection Clinic Amsterdam from March through October 2014. After treatment with ceftriaxone mono- or dual therapy (with azithromycin or doxycycline), anal, vaginal, or urine samples were self-collected during 28 consecutive days, and analyzed using an RNA-based NAAT (Aptima Combo 2) and a DNA-based NAAT (Cobas 4800). Clearance was defined as 3 consecutive negative results, and blips as isolated positive results following clearance. We included 77 patients; 5 self-cleared gonorrhoea before treatment and 10 were lost to follow-up. Clearance rate of the remaining 62 patients was 100%. Median time to clearance was 2 days, with a range of 1-7 days for RNA-based NAAT and 1-15 days for DNA-based NAAT. The risk of finding a blip after clearance was 0.8% and 1.5%, respectively. One patient had a reinfection. If indicated, we recommend that TOC be performed for anogenital gonorrhoea at least 7 or 14 days after administering therapy, when using modern RNA- or DNA-based NAATs, respectively. When interpreting TOC results for possible treatment failure, both the occurrence of blips and a possible reinfection need to be taken into account. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Adaptation of the ICRP publication 66 respiratory tract model to data on plutonium biokinetics for Mayak workers.

PubMed

Khokhryakov, V F; Suslova, K G; Vostrotin, V V; Romanov, S A; Eckerman, K F; Krahenbuhl, M P; Miller, S C

2005-02-01

The biokinetics of inhaled plutonium were analyzed using compartment models representing their behavior within the respiratory tract, the gastrointestinal tract, and in systemic tissues. The processes of aerosol deposition, particle transport, absorption, and formation of a fixed deposit in the respiratory tract were formulated in the framework of the Human Respiratory Tract Model described in ICRP Publication 66. The values of parameters governing absorption and formation of the fixed deposit were established by fitting the model to the observations in 530 autopsy cases. The influence of smoking on mechanical clearance of deposited plutonium activity was considered. The dependence of absorption on the aerosol transportability, as estimated by in vitro methods (dialysis), was demonstrated. The results of this study were compared to those obtained from an earlier model of plutonium behavior in the respiratory tract, which was based on the same set of autopsy data. That model did not address the early phases of respiratory clearance and hence underestimated the committed lung dose by about 25% for plutonium oxides. Little difference in lung dose was found for nitrate forms.

Population Pharmacokinetics of Cladribine in Patients with Multiple Sclerosis.

PubMed

Savic, Radojka M; Novakovic, Ana M; Ekblom, Marianne; Munafo, Alain; Karlsson, Mats O

2017-10-01

The aims of this study were to characterize the concentration-time course of cladribine (CdA) and its main metabolite 2-chloroadenine (CAde), estimate interindividual variability in pharmacokinetics (PK), and identify covariates explaining variability in the PK of CdA. This population PK analysis was based on the combined dataset from four clinical studies in patients with multiple sclerosis (MS): three phase I studies, including one food and one drug-drug interaction study, and one phase III clinical study. Plasma and urine concentration data of CdA and CAde were modeled simultaneously. The analysis comprised a total of 2619 CdA and CAde plasma and urine concentration observations from 173 patients with MS who received an intravenous infusion or oral tablet doses of CdA as a single agent or in combination with interferon (IFN) β-1a. CdA PK data were best described by a three-compartment model, while a one-compartment model best described the PK of CAde. CdA renal clearance (CL R ) was correlated with creatinine clearance (CL CR ), predicting a decrease in the total clearance of 19%, 30% and 40% for patients with mild (CL CR  = 65 ml/min), moderate (CL CR  = 40 ml/min) and severe (CL CR  = 20 ml/min) renal impairment, respectively. Food decreased the extent of CdA absorption by 11.2% and caused an absorption delay. Coadministration with IFNβ-1a was found to increase non-CL R (CL NR ) by 21%, resulting in an increase of 11% in total clearance. Both CdA and CAde displayed linear PK after intravenous and oral administration of CdA, with CdA renal function depending on CL CR . Trial registration number for study 25643: NCT00213135.

Off-design performance loss model for radial turbines with pivoting, variable-area stators

NASA Technical Reports Server (NTRS)

Meitner, P. L.; Glassman, A. J.

1980-01-01

An off-design performance loss model was developed for variable stator (pivoted vane), radial turbines through analytical modeling and experimental data analysis. Stator loss is determined by a viscous loss model; stator vane end-clearance leakage effects are determined by a clearance flow model. Rotor loss coefficient were obtained by analyzing the experimental data from a turbine rotor previously tested with six stators having throat areas from 20 to 144 percent of design area and were correlated with stator-to-rotor throat area ratio. An incidence loss model was selected to obtain best agreement with experimental results. Predicted turbine performance is compared with experimental results for the design rotor as well as with results for extended and cutback versions of the rotor. Sample calculations were made to show the effects of stator vane end-clearance leakage.

Combined Effects of Gravity, Bending Moment, Bearing Clearance, and Input Torque on Wind Turbine Planetary Gear Load Sharing: Preprint

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guo, Y.; Keller, J.; LaCava, W.

2012-09-01

This computational work investigates planetary gear load sharing of three-mount suspension wind turbine gearboxes. A three dimensional multibody dynamic model is established, including gravity, bending moments, fluctuating mesh stiffness, nonlinear tooth contact, and bearing clearance. A flexible main shaft, planetary carrier, housing, and gear shafts are modeled using reduced degrees-of-freedom through modal compensation. This drivetrain model is validated against the experimental data of Gearbox Reliability Collaborative for gearbox internal loads. Planet load sharing is a combined effect of gravity, bending moment, bearing clearance, and input torque. Influences of each of these parameters and their combined effects on the resulting planetmore » load sharing are investigated. Bending moments and gravity induce fundamental excitations in the rotating carrier frame, which can increase gearbox internal loads and disturb load sharing. Clearance in carrier bearings reduces the bearing load carrying capacity and thus the bending moment from the rotor can be transmitted into gear meshes. With bearing clearance, the bending moment can cause tooth micropitting and can induce planet bearing fatigue, leading to reduced gearbox life. Planet bearings are susceptible to skidding at low input torque.« less

Impeller leakage flow modeling for mechanical vibration control

NASA Technical Reports Server (NTRS)

Palazzolo, Alan B.

1996-01-01

HPOTP and HPFTP vibration test results have exhibited transient and steady characteristics which may be due to impeller leakage path (ILP) related forces. For example, an axial shift in the rotor could suddenly change the ILP clearances and lengths yielding dynamic coefficient and subsequent vibration changes. ILP models are more complicated than conventional-single component-annular seal models due to their radial flow component (coriolis and centrifugal acceleration), complex geometry (axial/radial clearance coupling), internal boundary (transition) flow conditions between mechanical components along the ILP and longer length, requiring moment as well as force coefficients. Flow coupling between mechanical components results from mass and energy conservation applied at their interfaces. Typical components along the ILP include an inlet seal, curved shroud, and an exit seal, which may be a stepped labyrinth type. Von Pragenau (MSFC) has modeled labyrinth seals as a series of plain annular seals for leakage and dynamic coefficient prediction. These multi-tooth components increase the total number of 'flow coupled' components in the ILP. Childs developed an analysis for an ILP consisting of a single, constant clearance shroud with an exit seal represented by a lumped flow-loss coefficient. This same geometry was later extended to include compressible flow. The objective of the current work is to: supply ILP leakage-force impedance-dynamic coefficient modeling software to MSFC engineers, base on incompressible/compressible bulk flow theory; design the software to model a generic geometry ILP described by a series of components lying along an arbitrarily directed path; validate the software by comparison to available test data, CFD and bulk models; and develop a hybrid CFD-bulk flow model of an ILP to improve modeling accuracy within practical run time constraints.

The Constraints, Construction, and Verification of a Strain-Specific Physiologically Based Pharmacokinetic Rat Model.

PubMed

Musther, Helen; Harwood, Matthew D; Yang, Jiansong; Turner, David B; Rostami-Hodjegan, Amin; Jamei, Masoud

2017-09-01

The use of in vitro-in vivo extrapolation (IVIVE) techniques, mechanistically incorporated within physiologically based pharmacokinetic (PBPK) models, can harness in vitro drug data and enhance understanding of in vivo pharmacokinetics. This study's objective was to develop a user-friendly rat (250 g, male Sprague-Dawley) IVIVE-linked PBPK model. A 13-compartment PBPK model including mechanistic absorption models was developed, with required system data (anatomical, physiological, and relevant IVIVE scaling factors) collated from literature and analyzed. Overall, 178 system parameter values for the model are provided. This study also highlights gaps in available system data required for strain-specific rat PBPK model development. The model's functionality and performance were assessed using previous literature-sourced in vitro properties for diazepam, metoprolol, and midazolam. The results of simulations were compared against observed pharmacokinetic rat data. Predicted and observed concentration profiles in 10 tissues for diazepam after a single intravenous (i.v.) dose making use of either observed i.v. clearance (CL iv ) or in vitro hepatocyte intrinsic clearance (CL int ) for simulations generally led to good predictions in various tissue compartments. Overall, all i.v. plasma concentration profiles were successfully predicted. However, there were challenges in predicting oral plasma concentration profiles for metoprolol and midazolam, and the potential reasons and according solutions are discussed. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Higher serum levels of uric acid are associated with a reduced insulin clearance in non-diabetic individuals.

PubMed

Fiorentino, Teresa Vanessa; Sesti, Franz; Succurro, Elena; Pedace, Elisabetta; Andreozzi, Francesco; Sciacqua, Angela; Hribal, Marta Letizia; Perticone, Francesco; Sesti, Giorgio

2018-05-17

Decreased insulin clearance has been reported to be associated with insulin resistance-related disorders and incident type 2 diabetes. The aim of this study was to evaluate whether higher levels of uric acid (UA), a known risk factor of type 2 diabetes, are associated with a reduced insulin clearance. 440 non-diabetic individuals were stratified in tertiles according to serum UA levels. Insulin clearance and skeletal muscle insulin sensitivity were assessed by euglycemic hyperinsulinemic clamp. Hepatic insulin resistance was estimated by the liver IR index. Subjects with higher levels of UA displayed an unfavorable metabolic phenotype with a worse lipid profile, increased levels of 2-h post-load glucose levels, fasting, and 2-h post-load insulin levels, hsCRP, liver IR index, and lower levels of eGFR and skeletal muscle insulin sensitivity, in comparison to individuals with lower UA levels. Moreover, subjects with higher UA concentrations exhibited decreased levels of insulin clearance even after adjustment for age, gender, BMI, eGFR, and skeletal muscle insulin sensitivity. In a multivariate regression analysis model including several confounding factors, UA concentration was an independent predictor of insulin clearance (β = - 0.145; P = 0.03). However, when liver IR index was included in the model, the independent association between UA levels and insulin clearance was not retained. Accordingly, in a mediation analysis, liver IR index was a mediator of the negative effects of UA levels on insulin clearance (t = - 2.55, P = 0.01). Higher serum levels of UA may affect insulin clearance by impairing hepatic insulin sensitivity.

Modeling of thermal processes arising during shaping gears with internal non-involute teeth

NASA Astrophysics Data System (ADS)

Kanatnikov, N. V.; Kanatnikova, P. A.; Vlasov, V. V.; Pashmentova, A. S.

2018-03-01

The paper presents a model for predicting the thermal processes arising during shaping gears with internal non-involute teeth. The kinematics of cutting is modeled due to the analytical model. Chipping is modeled using the finite element method. The experiment is based on the method of infrared photography of the cutting process. The simulation results showed that the maximum temperatures and heat flows in the tool vary by more than 10% when the rake and clearance angels of the cutting are changed.

Structure-activity models of oral clearance, cytotoxicity, and LD50: a screen for promising anticancer compounds

PubMed Central

Boik, John C; Newman, Robert A

2008-01-01

Background Quantitative structure-activity relationship (QSAR) models have become popular tools to help identify promising lead compounds in anticancer drug development. Few QSAR studies have investigated multitask learning, however. Multitask learning is an approach that allows distinct but related data sets to be used in training. In this paper, a suite of three QSAR models is developed to identify compounds that are likely to (a) exhibit cytotoxic behavior against cancer cells, (b) exhibit high rat LD50 values (low systemic toxicity), and (c) exhibit low to modest human oral clearance (favorable pharmacokinetic characteristics). Models were constructed using Kernel Multitask Latent Analysis (KMLA), an approach that can effectively handle a large number of correlated data features, nonlinear relationships between features and responses, and multitask learning. Multitask learning is particularly useful when the number of available training records is small relative to the number of features, as was the case with the oral clearance data. Results Multitask learning modestly but significantly improved the classification precision for the oral clearance model. For the cytotoxicity model, which was constructed using a large number of records, multitask learning did not affect precision but did reduce computation time. The models developed here were used to predict activities for 115,000 natural compounds. Hundreds of natural compounds, particularly in the anthraquinone and flavonoids groups, were predicted to be cytotoxic, have high LD50 values, and have low to moderate oral clearance. Conclusion Multitask learning can be useful in some QSAR models. A suite of QSAR models was constructed and used to screen a large drug library for compounds likely to be cytotoxic to multiple cancer cell lines in vitro, have low systemic toxicity in rats, and have favorable pharmacokinetic properties in humans. PMID:18554402

Structure-activity models of oral clearance, cytotoxicity, and LD50: a screen for promising anticancer compounds.

PubMed

Boik, John C; Newman, Robert A

2008-06-13

Quantitative structure-activity relationship (QSAR) models have become popular tools to help identify promising lead compounds in anticancer drug development. Few QSAR studies have investigated multitask learning, however. Multitask learning is an approach that allows distinct but related data sets to be used in training. In this paper, a suite of three QSAR models is developed to identify compounds that are likely to (a) exhibit cytotoxic behavior against cancer cells, (b) exhibit high rat LD50 values (low systemic toxicity), and (c) exhibit low to modest human oral clearance (favorable pharmacokinetic characteristics). Models were constructed using Kernel Multitask Latent Analysis (KMLA), an approach that can effectively handle a large number of correlated data features, nonlinear relationships between features and responses, and multitask learning. Multitask learning is particularly useful when the number of available training records is small relative to the number of features, as was the case with the oral clearance data. Multitask learning modestly but significantly improved the classification precision for the oral clearance model. For the cytotoxicity model, which was constructed using a large number of records, multitask learning did not affect precision but did reduce computation time. The models developed here were used to predict activities for 115,000 natural compounds. Hundreds of natural compounds, particularly in the anthraquinone and flavonoids groups, were predicted to be cytotoxic, have high LD50 values, and have low to moderate oral clearance. Multitask learning can be useful in some QSAR models. A suite of QSAR models was constructed and used to screen a large drug library for compounds likely to be cytotoxic to multiple cancer cell lines in vitro, have low systemic toxicity in rats, and have favorable pharmacokinetic properties in humans.

In Silico Prediction of Toxicokinetic Parameters for Environmentally Relevant Chemicals with Application to Risk-Based Prioritization

EPA Science Inventory

Toxicokinetic (TK) models can help bridge the gap between chemical exposure and measured toxicity endpoints, thereby addressing an important component of chemical risk assessments. The fraction of a chemical unbound by plasma proteins (Fub) and metabolic clearance rate (CLint) ar...

Comparison of trout hepatocytes and liver S9 fractions as in ...

EPA Pesticide Factsheets

Isolated hepatocytes and liver S9 fractions have been used to collect in vitro biotransformation data for fish as a means of improving modeled estimates of chemical bioaccumulation. To date, however, there have been few direct comparisons of these two methods. In the present study, cryopreserved trout hepatocytes were used to measure in vitro intrinsic clearance rates for 6 polycyclic aromatic hydrocarbons (PAHs). These rates were extrapolated to estimates of in vivo intrinsic clearance and used as inputs to a well-stirred liver model to predict hepatic clearance. Predicted rates of hepatic clearance were then evaluated by comparison to measured rates determined previously using isolated perfused livers. Hepatic clearance rates predicted using hepatocytes were in good agreement with measured values (< 2.1 fold difference for 5 of 6 compounds) under two competing binding assumptions. These findings, which may be attributed in part to high rates of PAH metabolism, are similar to those obtained previously using data from liver S9 fractions. For one compound (benzo[a]pyrene), the in vivo intrinsic clearance rate calculated using S9 data was 10-fold higher than that determined using hepatocytes, possibly due to a diffusion limitation on cellular uptake. Generally, however, there was good agreement between calculated in vivo intrinsic clearance rates obtained using either in vitro test system. These results suggest that both systems can be used to improve

Wear in ceramic on ceramic type lumbar total disc replacement: effect of radial clearance.

PubMed

Shankar, S; Kesavan, D

2015-01-01

The wear of the bearing surfaces of total disc replacement (TDR) is a key problem leads to reduction in the lifetime of the prosthesis and it mainly occurs due to the range of clearances of the articulating surface between the superior plate and core. The objective of this paper is to estimate the wear using finite element concepts considering the different radial clearances between the articulating surfaces of ceramic on ceramic type Lumbar Total Disc Replacement (LTDR). The finite element (FE) model was subjected to wear testing protocols according to loading profile of International Standards Organization (ISO) 18192 standards through 10 million cycles. The radial clearance value of 0.05 mm showed less volumetric wear when compared with other radial clearance values. Hence, low radial clearance values are suitable for LTDR to minimize the wear.

Blade tip clearance measurement of the turbine engines based on a multi-mode fiber coupled laser ranging system

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guo, Haotian; Duan, Fajie; Wu, Guoxiu

2014-11-15

The blade tip clearance is a parameter of great importance to guarantee the efficiency and safety of the turbine engines. In this article, a laser ranging system designed for blade tip clearance measurement is presented. Multi-mode fiber is utilized for optical transmission to guarantee that enough optical power is received by the sensor probe. The model of the tiny sensor probe is presented. The error brought by the optical path difference of different modes of the fiber is estimated and the length of the fiber is limited to reduce this error. The measurement range in which the optical power receivedmore » by the probe remains essentially unchanged is analyzed. Calibration experiments and dynamic experiments are conducted. The results of the calibration experiments indicate that the resolution of the system is about 0.02 mm and the range of the system is about 9 mm.« less

Gram-scale synthesis of coordination polymer nanodots with renal clearance properties for cancer theranostic applications

NASA Astrophysics Data System (ADS)

Liu, Fuyao; He, Xiuxia; Chen, Hongda; Zhang, Junping; Zhang, Huimao; Wang, Zhenxin

2015-08-01

An ultrasmall hydrodynamic diameter is a critical factor for the renal clearance of nanoparticles from the body within a reasonable timescale. However, the integration of diagnostic and therapeutic components into a single ultrasmall nanoparticle remains challenging. In this study, pH-activated nanodots (termed Fe-CPNDs) composed of coordination polymers were synthesized via a simple and scalable method based on coordination reactions among Fe3+, gallic acid and poly(vinylpyrrolidone) at ambient conditions. The Fe-CPNDs exhibited ultrasmall (5.3 nm) hydrodynamic diameters and electrically neutral surfaces. The Fe-CPNDs also exhibited pH-activatable magnetic resonance imaging contrast and outstanding photothermal performance. The features of Fe-CPNDs greatly increased the tumour-imaging sensitivity and facilitated renal clearance after injection in animal models in vivo. Magnetic resonance imaging-guided photothermal therapy using Fe-CPNDs completely suppressed tumour growth. These findings demonstrate that Fe-CPNDs constitute a new class of renal clearable nanomedicine for photothermal therapy and molecular imaging.

Friction factor data for flat plate tests of smooth and honeycomb surfaces. M.S. Thesis

NASA Technical Reports Server (NTRS)

Ha, Tae Woong

1989-01-01

Friction factors for honeycomb surfaces were measured with a flat plate tester. The flat plate test apparatus was described and a method was discussed for determining the friction factor experimentally. The friction factor model was developed for the flat plate test based on the Fanno Line Flow. The comparisons of the friction factor were plotted for smooth surfaces and six-honeycomb surfaces with three-clearances, 6.9 bar to 17.9 bar range of inlet pressures, and 5,000 to 100,000 range of the Reynolds number. The optimum geometries for the maximum friction factor were found as a function of cell width to cell depth and cell width to clearance ratios.

48 CFR 1432.502-2 - Contract finance office clearance.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Contract finance office clearance. 1432.502-2 Section 1432.502-2 Federal Acquisition Regulations System DEPARTMENT OF THE INTERIOR GENERAL CONTRACTING REQUIREMENTS CONTRACT FINANCING Progress Payments Based on Costs 1432.502-2 Contract finance office clearance. The CO shall...

Impulsive response of an automatic transmission system with multiple clearances: Formulation, simulation and experiment

NASA Astrophysics Data System (ADS)

Crowther, Ashley R.; Singh, Rajendra; Zhang, Nong; Chapman, Chris

2007-10-01

Impulsive responses in geared systems with multiple clearances are studied when the mean torque excitation and system load change abruptly, with application to a vehicle driveline with an automatic transmission. First, torsional lumped-mass models of the planetary and differential gear sets are formulated using matrix elements. The model is then reduced to address tractable nonlinear problems while successfully retaining the main modes of interest. Second, numerical simulations for the nonlinear model are performed for transient conditions and a typical driving situation that induces an impulsive behaviour simulated. However, initial conditions and excitation and load profiles have to be carefully defined before the model can be numerically solved. It is shown that the impacts within the planetary or differential gears may occur under combinations of engine, braking and vehicle load transients. Our analysis shows that the shaping of the engine transient by the torque converter before reaching the clearance locations is more critical. Third, a free vibration experiment is developed for an analogous driveline with multiple clearances and three experiments that excite different response regimes have been carried out. Good correlations validate the proposed methodology.

Errors in Computing the Normalized Protein Catabolic Rate due to Use of Single-pool Urea Kinetic Modeling or to Omission of the Residual Kidney Urea Clearance.

PubMed

Daugirdas, John T

2017-07-01

The protein catabolic rate normalized to body size (PCRn) often is computed in dialysis units to obtain information about protein ingestion. However, errors can manifest when inappropriate modeling methods are used. We used a variable volume 2-pool urea kinetic model to examine the percent errors in PCRn due to use of a 1-pool urea kinetic model or after omission of residual urea clearance (Kru). When a single-pool model was used, 2 sources of errors were identified. The first, dependent on the ratio of dialyzer urea clearance to urea distribution volume (K/V), resulted in a 7% inflation of the PCRn when K/V was in the range of 6 mL/min per L. A second, larger error appeared when Kt/V values were below 1.0 and was related to underestimation of urea distribution volume (due to overestimation of effective clearance) by the single-pool model. A previously reported prediction equation for PCRn was valid, but data suggest that it should be modified using 2-pool eKt/V and V coefficients instead of single-pool values. A third source of error, this one unrelated to use of a single-pool model, namely omission of Kru, was shown to result in an underestimation of PCRn, such that each ml/minute Kru per 35 L of V caused a 5.6% underestimate in PCRn. Marked overestimation of PCRn can result due to inappropriate use of a single-pool urea kinetic model, particularly when Kt/V <1.0 (as in short daily dialysis), or after omission of residual native kidney clearance. Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, H.B.; Blaufox, M.D.

Rats with one kidney clamped (2K1C), both kidneys clamped (2K2C), unilaterally nephrectomized with remaining kidney clamped (1K1C), and normals, were studied using /sup 99m/Tc mercaptoacetyltriglycine ((/sup 99m/Tc)MAG-3) and /sup 131/I orthoiodohippurate ((/sup 131/I)OIH). Clearances of (/sup 99m/Tc)MAG-3 and (/sup 131/I)OIH were performed after constricted rats became hypertensive. Clearances were repeated after i.v. Captopril. Clearances of (/sup 99m/Tc)MAG-3 and (/sup 131/I)OIH in normals didn't change significantly after Captopril. Clearances of (/sup 99m/Tc)MAG-3 and (/sup 131/I)OIH decreased insignificantly after Captopril in the 2K2C model. in the 2K1C group, normal kidney clearance increased ((/sup 99m/Tc)MAG-3 p less than 0.01 and (/sup 131/I)OIH pmore » less than 0.025) and clamped kidney clearance decreased after inhibition ((/sup 99m/Tc)MAG-3, p less than 0.01, (/sup 131/I)OIH p less than 0.02). Clearances increased in the 1K1C group after Captopril ((/sup 99m/Tc)MAG-3 p less than 0.0025 and (/sup 131/I)OIH, p less than 0.001). The ratio of (/sup 99m/Tc)MAG-3 to (/sup 131/I)OIH before Captopril was 0.81 and 0.84 after Captopril. Changes in renal function after Captopril depend on the model of renovascular hypertension and possibly the dose administered. Technetium-99m MAG-3 clearance parallels (/sup 131/I)orthoiodohippurate in renovascular hypertension.« less

A new paradigm in respiratory hygiene: modulating respiratory secretions to contain cough bioaerosol without affecting mucus clearance.

PubMed

Zayas, Gustavo; Valle, Juan C; Alonso, Mauricio; Alfaro, Henry; Vega, Daniel; Bonilla, Gloria; Reyes, Miguel; King, Malcolm

2007-08-13

Several strategies and devices have been designed to protect health care providers from acquiring transmissible respiratory diseases while providing care. In modulating the physical characteristics of the respiratory secretions to minimize the aerosolization that facilitates transmission of airborne diseases, a fundamental premise is that the prototype drugs have no adverse effect on the first line of respiratory defense, clearance of mucus by ciliary action. To assess and demonstrate the primary mechanism of our mucomodulators (XLs), we have built our evidence moving from basic laboratory studies to an ex-vivo model and then to an in-vivo large animal model. We exposed anesthetized dogs without hypersecretion to different dose concentrations of aerosolized XL "B", XL "D" and XL "S". We assessed: cardio-respiratory pattern, tracheal mucus clearance, airway patency, and mucus viscoelastic changes. Exposure of frog palate mucus to XLs did not affect the clearance of mucus by ciliary action. Dogs maintained normal cardio-respiratory pattern with XL administration. Tracheal mucociliary clearance in anesthetized dogs indicated a sustained 40% mean increase. Tracheal mucus showed increased filance, and there was no mucus retention in the airways. The ex-vivo frog palate and the in-vivo mammalian models used in this study, appear to be appropriate and complement each other to better assess the effects that our mucomodulators exert on the mucociliary clearance defence mechanism. The physiological function of the mucociliary apparatus was not negatively affected in any of the two epithelial models. Airway mucus crosslinked by mucomodulators is better cleared from an intact airway and normally functioning respiratory system, either due to enhanced interaction with cilia or airflow-dependent mechanisms. Data obtained in this study allow us to assure that we have complied with the fundamental requirement criteria established in the initial phase of developing the concept of mucomodulation: Can we modulate the physical characteristics of the respiratory secretions to reduce aerosolization without affecting normal mucociliary clearance function, or even better improving it?

Pharmacokinetic modeling of gentamicin in treatment of infective endocarditis: Model development and validation of existing models.

PubMed

Gomes, Anna; van der Wijk, Lars; Proost, Johannes H; Sinha, Bhanu; Touw, Daan J

2017-01-01

Gentamicin shows large variations in half-life and volume of distribution (Vd) within and between individuals. Thus, monitoring and accurately predicting serum levels are required to optimize effectiveness and minimize toxicity. Currently, two population pharmacokinetic models are applied for predicting gentamicin doses in adults. For endocarditis patients the optimal model is unknown. We aimed at: 1) creating an optimal model for endocarditis patients; and 2) assessing whether the endocarditis and existing models can accurately predict serum levels. We performed a retrospective observational two-cohort study: one cohort to parameterize the endocarditis model by iterative two-stage Bayesian analysis, and a second cohort to validate and compare all three models. The Akaike Information Criterion and the weighted sum of squares of the residuals divided by the degrees of freedom were used to select the endocarditis model. Median Prediction Error (MDPE) and Median Absolute Prediction Error (MDAPE) were used to test all models with the validation dataset. We built the endocarditis model based on data from the modeling cohort (65 patients) with a fixed 0.277 L/h/70kg metabolic clearance, 0.698 (±0.358) renal clearance as fraction of creatinine clearance, and Vd 0.312 (±0.076) L/kg corrected lean body mass. External validation with data from 14 validation cohort patients showed a similar predictive power of the endocarditis model (MDPE -1.77%, MDAPE 4.68%) as compared to the intensive-care (MDPE -1.33%, MDAPE 4.37%) and standard (MDPE -0.90%, MDAPE 4.82%) models. All models acceptably predicted pharmacokinetic parameters for gentamicin in endocarditis patients. However, these patients appear to have an increased Vd, similar to intensive care patients. Vd mainly determines the height of peak serum levels, which in turn correlate with bactericidal activity. In order to maintain simplicity, we advise to use the existing intensive-care model in clinical practice to avoid potential underdosing of gentamicin in endocarditis patients.

Pharmacokinetic modeling of gentamicin in treatment of infective endocarditis: Model development and validation of existing models

PubMed Central

van der Wijk, Lars; Proost, Johannes H.; Sinha, Bhanu; Touw, Daan J.

2017-01-01

Gentamicin shows large variations in half-life and volume of distribution (Vd) within and between individuals. Thus, monitoring and accurately predicting serum levels are required to optimize effectiveness and minimize toxicity. Currently, two population pharmacokinetic models are applied for predicting gentamicin doses in adults. For endocarditis patients the optimal model is unknown. We aimed at: 1) creating an optimal model for endocarditis patients; and 2) assessing whether the endocarditis and existing models can accurately predict serum levels. We performed a retrospective observational two-cohort study: one cohort to parameterize the endocarditis model by iterative two-stage Bayesian analysis, and a second cohort to validate and compare all three models. The Akaike Information Criterion and the weighted sum of squares of the residuals divided by the degrees of freedom were used to select the endocarditis model. Median Prediction Error (MDPE) and Median Absolute Prediction Error (MDAPE) were used to test all models with the validation dataset. We built the endocarditis model based on data from the modeling cohort (65 patients) with a fixed 0.277 L/h/70kg metabolic clearance, 0.698 (±0.358) renal clearance as fraction of creatinine clearance, and Vd 0.312 (±0.076) L/kg corrected lean body mass. External validation with data from 14 validation cohort patients showed a similar predictive power of the endocarditis model (MDPE -1.77%, MDAPE 4.68%) as compared to the intensive-care (MDPE -1.33%, MDAPE 4.37%) and standard (MDPE -0.90%, MDAPE 4.82%) models. All models acceptably predicted pharmacokinetic parameters for gentamicin in endocarditis patients. However, these patients appear to have an increased Vd, similar to intensive care patients. Vd mainly determines the height of peak serum levels, which in turn correlate with bactericidal activity. In order to maintain simplicity, we advise to use the existing intensive-care model in clinical practice to avoid potential underdosing of gentamicin in endocarditis patients. PMID:28475651

Processing Impact on Monoclonal Antibody Drug Products: Protein Subvisible Particulate Formation Induced by Grinding Stress.

PubMed

Gikanga, Benson; Eisner, Devon Roshan; Ovadia, Robert; Day, Eric S; Stauch, Oliver B; Maa, Yuh-Fun

2017-01-01

Subvisible particle formation in monoclonal antibody drug product resulting from mixing and filling operations represents a significant processing risk that can lead to filter fouling and thereby lead to process delays or failures. Several previous studies from our lab and others demonstrated the formation of subvisible particulates in mAb formulations resulting from mixing operations using some bottom-mounted mixers or stirrer bars. It was hypothesized that the stress (e.g., shear/cavitation) derived from tight clearance and/or close contact between the impeller and shaft was responsible for protein subvisible particulate generation. These studies, however, could not distinguish between the two surfaces without contact (tight clearance) or between two contacting surfaces (close contact). In the present study we expand on those findings and utilize small-scale mixing models that are able to, for the first time, distinguish between tight clearances and tight contact. In this study we evaluated different mixer types including a top-mounted mixer, several impeller-based bottom-mounted mixers, and a rotary piston pump. The impact of tight clearance/close contact on subvisible particle formation in at-scale mixing platforms was demonstrated in the gap between the impeller and drive unit as well as between the piston and the housing of the pump. Furthermore, small-scale mixing models based on different designs of magnetic stir bars that mimic the tight clearance/close contact of the manufacturing-scale mixers also induced subvisible particles in mAb formulations. Additional small-scale models that feature tight clearance but no close contact (grinding) suggested that it is the repeated grinding/contacting of the moving parts and not the presence of tight clearance in the processing equipment that is the root cause of protein subvisible particulate formation. When multiple mAbs, Fabs (fragment antigen binding), or non-antibody related proteins were mixed in the small-scale mixing model, for molecules investigated, it was observed that mAbs and Fabs appear to be more susceptible to particle formation than non-antibody-related proteins. In the grinding zone, mAb/Fab molecules aggregated into insoluble particles with neither detectable soluble aggregates nor fragmented species. This investigation represents a step closer to the understanding of the underlying stress mechanism leading to mAb subvisible particulate formation as the result of drug product processing. LAY ABSTRACT: Mixing and fill finish are important unit operations in drug product manufacturing for compounding (dilution, pooling, homogenization, etc.) and filling into primary packaging containers (vials, pre-filled syringes, etc.), respectively. The current trend in adopting bottom-mounted mixers as well as low fill-volume filling systems has raised concerns about their impact on drug product quality and process performance. However, investigations into the effects of their use for biopharmaceutical products, particularly monoclonal antibody formulations, are rarely published. The purpose of this study is three-fold: (1) to revisit the impact of bottom-mounted mixer design on monoclonal antibody subvisible particle formation; (2) to identify the root cause for subvisible particle formation; and (3) to fully utilize available particle analysis tools to demonstrate the correlation between particle count in the solution and filter fouling during sterile filtration. The outcomes of this study will benefit scientists and engineers who develop biologic product manufacturing processes by providing a better understanding of drug product process challenges. © PDA, Inc. 2017.

Design highwater clearances for highway pavements appendix : volume II, appendix, August 2008.

DOT National Transportation Integrated Search

2008-08-01

High groundwater table exerts detrimental effects on the roadway base and the whole pavement. Base clearance guidelines have been developed to prevent water from entering the pavement system in order to reduce its detrimental effects. In these guidel...

Design highwater clearances for highway pavements : volume I, final report, August 2008.

DOT National Transportation Integrated Search

2008-08-01

High groundwater table exerts detrimental effects on the roadway base and the whole pavement. Base : clearance guidelines have been developed to prevent water from entering the pavement system in order to : reduce its detrimental effects. In these gu...

Rotor tip clearance effects on overall and blade-element performance of axial-flow transonic fan stage

NASA Technical Reports Server (NTRS)

Moore, R. D.

1982-01-01

The effects of tip clearance on the overall and blade-element performance of an axial-flow transonic fan stage are presented. The 50-centimeter-diameter fan was tested at four tip clearances (nonrotating) from 0.061 to 0.178 centimeter. The calculated radial growth of the blades was 0.040 centimeter at design conditions. The decrease in overall stage performance with increasing clearance is attributed to the loss in rotor performance. For the rotor the effects of clearance on performance parameters extended to about 70 percent of blade span from the tip. The stage still margin based on an assumed operating line decreased from 15.3 to 0 percent as the clearance increased from 0.061 to 0.178 centimeter.

Theory-based pharmacokinetics and pharmacodynamics of S- and R-warfarin and effects on international normalized ratio: influence of body size, composition and genotype in cardiac surgery patients.

PubMed

Xue, Ling; Holford, Nick; Ding, Xiao-Liang; Shen, Zhen-Ya; Huang, Chen-Rong; Zhang, Hua; Zhang, Jing-Jing; Guo, Zhe-Ning; Xie, Cheng; Zhou, Ling; Chen, Zhi-Yao; Liu, Lin-Sheng; Miao, Li-Yan

2017-04-01

The aims of this study are to apply a theory-based mechanistic model to describe the pharmacokinetics (PK) and pharmacodynamics (PD) of S- and R-warfarin. Clinical data were obtained from 264 patients. Total concentrations for S- and R-warfarin were measured by ultra-high performance liquid tandem mass spectrometry. Genotypes were measured using pyrosequencing. A sequential population PK parameter with data method was used to describe the international normalized ratio (INR) time course. Data were analyzed with NONMEM. Model evaluation was based on parameter plausibility and prediction-corrected visual predictive checks. Warfarin PK was described using a one-compartment model. CYP2C9 *1/*3 genotype had reduced clearance for S-warfarin, but increased clearance for R-warfarin. The in vitro parameters for the relationship between prothrombin complex activity (PCA) and INR were markedly different (A = 0.560, B = 0.386) from the theory-based values (A = 1, B = 0). There was a small difference between healthy subjects and patients. A sigmoid E max PD model inhibiting PCA synthesis as a function of S-warfarin concentration predicted INR. Small R-warfarin effects was described by competitive antagonism of S-warfarin inhibition. Patients with VKORC1 AA and CYP4F2 CC or CT genotypes had lower C50 for S-warfarin. A theory-based PKPD model describes warfarin concentrations and clinical response. Expected PK and PD genotype effects were confirmed. The role of predicted fat free mass with theory-based allometric scaling of PK parameters was identified. R-warfarin had a minor effect compared with S-warfarin on PCA synthesis. INR is predictable from 1/PCA in vivo. © 2016 The British Pharmacological Society.

Theory‐based pharmacokinetics and pharmacodynamics of S‐ and R‐warfarin and effects on international normalized ratio: influence of body size, composition and genotype in cardiac surgery patients

PubMed Central

Xue, Ling; Holford, Nick; Ding, Xiao‐liang; Shen, Zhen‐ya; Huang, Chen‐rong; Zhang, Hua; Zhang, Jing‐jing; Guo, Zhe‐ning; Xie, Cheng; Zhou, Ling; Chen, Zhi‐yao; Liu, Lin‐sheng

2016-01-01

Aims The aims of this study are to apply a theory‐based mechanistic model to describe the pharmacokinetics (PK) and pharmacodynamics (PD) of S‐ and R‐warfarin. Methods Clinical data were obtained from 264 patients. Total concentrations for S‐ and R‐warfarin were measured by ultra‐high performance liquid tandem mass spectrometry. Genotypes were measured using pyrosequencing. A sequential population PK parameter with data method was used to describe the international normalized ratio (INR) time course. Data were analyzed with NONMEM. Model evaluation was based on parameter plausibility and prediction‐corrected visual predictive checks. Results Warfarin PK was described using a one‐compartment model. CYP2C9 *1/*3 genotype had reduced clearance for S‐warfarin, but increased clearance for R‐warfarin. The in vitro parameters for the relationship between prothrombin complex activity (PCA) and INR were markedly different (A = 0.560, B = 0.386) from the theory‐based values (A = 1, B = 0). There was a small difference between healthy subjects and patients. A sigmoid Emax PD model inhibiting PCA synthesis as a function of S‐warfarin concentration predicted INR. Small R‐warfarin effects was described by competitive antagonism of S‐warfarin inhibition. Patients with VKORC1 AA and CYP4F2 CC or CT genotypes had lower C50 for S‐warfarin. Conclusion A theory‐based PKPD model describes warfarin concentrations and clinical response. Expected PK and PD genotype effects were confirmed. The role of predicted fat free mass with theory‐based allometric scaling of PK parameters was identified. R‐warfarin had a minor effect compared with S‐warfarin on PCA synthesis. INR is predictable from 1/PCA in vivo. PMID:27763679

Prognostic Value of Procalcitonin in Adult Patients with Sepsis: A Systematic Review and Meta-Analysis.

PubMed

Liu, Dan; Su, Longxiang; Han, Gencheng; Yan, Peng; Xie, Lixin

2015-01-01

Procalcitonin (PCT) has been widely investigated for its prognostic value in septic patients. However, studies have produced conflicting results. The purpose of the present meta-analysis is to explore the diagnostic accuracy of a single PCT concentration and PCT non-clearance in predicting all-cause sepsis mortality. We searched PubMed, Embase, Web of Knowledge and the Cochrane Library. Articles written in English were included. A 2 × 2 contingency table was constructed based on all-cause mortality and PCT level or PCT non-clearance in septic patients. Two authors independently evaluated study eligibility and extracted data. The diagnostic value of PCT in predicting prognosis was determined using a bivariate meta-analysis model. We used the Q-test and I2 index to test heterogeneity. Twenty-three studies with 3,994 patients were included. An elevated PCT level was associated with a higher risk of death. The pooled relative risk (RR) was 2.60 (95% confidence interval (CI), 2.05-3.30) using a random-effects model (I(2) = 63.5%). The overall area under the summary receiver operator characteristic (SROC) curve was 0.77 (95% CI, 0.73-0.80), with a sensitivity and specificity of 0.76 (95% CI, 0.67-0.82) and 0.64 (95% CI, 0.52-0.74), respectively. There was significant evidence of heterogeneity for the PCT testing time (P = 0.020). Initial PCT values were of limited prognostic value in patients with sepsis. PCT non-clearance was a prognostic factor of death in patients with sepsis. The pooled RR was 3.05 (95% CI, 2.35-3.95) using a fixed-effects model (I(2) = 37.9%). The overall area under the SROC curve was 0.79 (95% CI, 0.75-0.83), with a sensitivity and specificity of 0.72 (95% CI, 0.58-0.82) and 0.77 (95% CI, 0.55-0.90), respectively. Elevated PCT concentrations and PCT non-clearance are strongly associated with all-cause mortality in septic patients. Further studies are needed to define the optimal cut-off point and the optimal definition of PCT non-clearance for accurate risk assessment.

PAH clearance after renal ischemia and reperfusion is a function of impaired expression of basolateral Oat1 and Oat3.

PubMed

Bischoff, Ariane; Bucher, Michael; Gekle, Michael; Sauvant, Christoph

2014-02-01

Determination of renal plasma flow (RPF) by para-aminohippurate (PAH) clearance leads to gross underestimation of this respective parameter due to impaired renal extraction of PAH after renal ischemia and reperfusion injury. However, no mechanistic explanation for this phenomenon is available. Based on our own previous studies we hypothesized that this may be due to impairment of expression of the basolateral rate limiting organic anion transporters Oat1 and Oat3. Thus, we investigated this phenomenon in a rat model of renal ischemia and reperfusion by determining PAH clearance, PAH extraction, PAH net secretion, and the expression of rOat1 and rOat3. PAH extraction was seriously impaired after ischemia and reperfusion which led to a threefold underestimation of RPF when PAH extraction ratio was not considered. PAH extraction directly correlated with the expression of basolateral Oat1 and Oat3. Tubular PAH secretion directly correlated with PAH extraction. Consequently, our data offer an explanation for impaired renal PAH extraction by reduced expression of the rate limiting basolateral organic anion transporters Oat1 and Oat3. Moreover, we show that determination of PAH net secretion is suitable to correct PAH clearance for impaired extraction after ischemia and reperfusion in order to get valid results for RPF.

Development of a physiologically based pharmacokinetic model of actinomycin D in children with cancer

PubMed Central

Walsh, Christopher; Bonner, Jennifer J.; Johnson, Trevor N.; Neuhoff, Sibylle; Ghazaly, Essam A.; Gribben, John G.; Boddy, Alan V.

2016-01-01

Aims Use of the anti‐tumour antibiotic actinomycin D is associated with development of hepatotoxicity, particularly in young children. A paucity of actinomycin D pharmacokinetic data make it challenging to develop a sound rationale for defining dosing regimens in younger patients. The study aim was to develop a physiologically based pharmacokinetic (PBPK) model using a combination of data from the literature and generated from experimental analyses. Methods Assays to determine actinomycin D Log P, blood:plasma partition ratio and ABCB1 kinetics were conducted. These data were combined with physiochemical properties sourced from the literature to generate a compound file for use within the modelling‐simulation software Simcyp (version 14 release 1). For simulation, information was taken from two datasets, one from 117 patients under the age of 21 and one from 20 patients aged 16–48. Results The final model incorporated clinical renal and biliary clearance data and an additional systemic clearance value. The mean AUC0‐26h of simulated subjects was within 1.25‐fold of the observed AUC0‐26h (84 ng h ml−1 simulated vs. 93 ng h ml−1 observed). For the younger age ranges, AUC predictions were within two‐fold of observed values, with simulated data from six of the eight age/dose ranges falling within 15% of observed data. Simulated values for actinomycin D AUC0‐26h and clearance in infants aged 0–12 months ranged from 104 to 115 ng h ml−1 and 3.5–3.8 l h−1, respectively. Conclusions The model has potential utility for prediction of actinomycin D exposure in younger patients and may help guide future dosing. However, additional independent data from neonates and infants is needed for further validation. Physiological differences between paediatric cancer patients and healthy children also need to be further characterized and incorporated into PBPK models. PMID:26727248

Adaptation of time line analysis program to single pilot instrument flight research

NASA Technical Reports Server (NTRS)

Hinton, D. A.; Shaughnessy, J. D.

1978-01-01

A data base was developed for SPIFR operation and the program was run. The outputs indicated that further work was necessary on the workload models. In particular, the workload model for the cognitive channel should be modified as the output workload appears to be too small. Included in the needed refinements are models to show the workload when in turbulence, when overshooting a radial or glideslope, and when copying air traffic control clearances.

Transporter-Enzyme Interplay: Deconvoluting Effects of Hepatic Transporters and Enzymes on Drug Disposition Using Static and Dynamic Mechanistic Models.

PubMed

Varma, Manthena V; El-Kattan, Ayman F

2016-07-01

A large body of evidence suggests hepatic uptake transporters, organic anion-transporting polypeptides (OATPs), are of high clinical relevance in determining the pharmacokinetics of substrate drugs, based on which recent regulatory guidances to industry recommend appropriate assessment of investigational drugs for the potential drug interactions. We recently proposed an extended clearance classification system (ECCS) framework in which the systemic clearance of class 1B and 3B drugs is likely determined by hepatic uptake. The ECCS framework therefore predicts the possibility of drug-drug interactions (DDIs) involving OATPs and the effects of genetic variants of SLCO1B1 early in the discovery and facilitates decision making in the candidate selection and progression. Although OATP-mediated uptake is often the rate-determining process in the hepatic clearance of substrate drugs, metabolic and/or biliary components also contribute to the overall hepatic disposition and, more importantly, to liver exposure. Clinical evidence suggests that alteration in biliary efflux transport or metabolic enzymes associated with genetic polymorphism leads to change in the pharmacodynamic response of statins, for which the pharmacological target resides in the liver. Perpetrator drugs may show inhibitory and/or induction effects on transporters and enzymes simultaneously. It is therefore important to adopt models that frame these multiple processes in a mechanistic sense for quantitative DDI predictions and to deconvolute the effects of individual processes on the plasma and hepatic exposure. In vitro data-informed mechanistic static and physiologically based pharmacokinetic models are proven useful in rationalizing and predicting transporter-mediated DDIs and the complex DDIs involving transporter-enzyme interplay. © 2016, The American College of Clinical Pharmacology.

Antibody to endotoxin core glycolipid reverses reticuloendothelial system depression in an animal model of severe sepsis and surgical injury

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aldridge, M.C.; Chadwick, S.J.; Cheslyn-Curtis, S.

To study the effect of severe sepsis on the function of the reticuloendothelial system (RES) we have measured the clearance kinetics and organ distribution of both low-dose technetium tin colloid (TTC) and /sup 75/selenomethionine-labelled E. coli in rabbits 24 hours after either sham laparotomy or appendix devascularization. Sepsis resulted in similar delayed blood clearance and reduced liver (Kupffer cell) uptake of both TTC and E. coli. To investigate the ability of polyclonal antibody to E. coli-J-5 (core glycolipid) to improve RES function in the same model of sepsis, further animals were pretreated with either core glycolipid antibody or control serummore » (10 ml IV) 2 hours before induction of sepsis. TTC clearance kinetics were determined 24 hours later. Antibody pretreated animals showed: a reduced incidence of bacteremia; normalization of the rate of blood clearance and liver uptake of TTC; and a 'rebound' increase in splenic uptake of TTC. We conclude that antibody to E. coli-J-5 enhances bacterial clearance by the RES.« less

Quantification and Formalization of Security

DTIC Science & Technology

2010-02-01

Quantification of Information Flow . . . . . . . . . . . . . . . . . . 30 2.4 Language Semantics . . . . . . . . . . . . . . . . . . . . . . . . . . 46...system behavior observed by users holding low clearances. This policy, or a variant of it, is enforced by many pro- gramming language -based mechanisms...illustrates with a particular programming language (while-programs plus probabilistic choice). The model is extended in §2.5 to programs in which

Small molecule LX2343 ameliorates cognitive deficits in AD model mice by targeting both amyloid β production and clearance.

PubMed

Guo, Xiao-Dan; Sun, Guang-Long; Zhou, Ting-Ting; Xu, Xin; Zhu, Zhi-Yuan; Rukachaisirikul, Vatcharin; Hu, Li-Hong; Shen, Xu

2016-09-01

Streptozotocin (STZ) is widely used to induce oxidative damage and to impair glucose metabolism, apoptosis, and tau/Aβ pathology, eventually leading to cognitive deficits in both in vitro and in vivo models of Alzheimer's disease (AD). In this study, we constructed a cell-based platform using STZ to induce stress conditions mimicking the complicated pathologies of AD in vitro, and evaluated the anti-amyloid effects of a small molecule, N-(1,3-benzodioxol-5-yl)-2-[5-chloro-2-methoxy(phenylsulfonyl)anilino]acetamide (LX2343) in the amelioration of cognitive deficits in AD model mice. Cell-based assays for screening anti-amyloid compounds were established by assessing Aβ accumulation in HEK293-APP sw and CHO-APP cells, and Aβ clearance in primary astrocytes and SH-SY5Y cells after the cells were treated with STZ in the presence of the test compounds. Autophagic flux was observed using confocal laser scanning microscopy. APP/PS1 transgenic mice were administered LX2343 (10 mg·kg -1 ·d -1 , ip) for 100 d. After LX2343 administration, cognitive ability of the mice was evaluated using Morris water maze test, and senile plaques in the brains were detected using Thioflavine S staining. ELISA assay was used to evaluate Aβ and sAPPβ levels, while Western blot analysis was used to measure the signaling proteins in both cell and animal brains. LX2343 (5-20 μmol/L) dose-dependently decreased Aβ accumulation in HEK293-APP sw and CHO-APP cells, and promoted Aβ clearance in SH-SY5Y cells and primary astrocytes. The anti-amyloid effects of LX2343 were attributed to suppressing JNK-mediated APP Thr668 phosphorylation, thus inhibiting APP cleavage on one hand, and inhibiting BACE1 enzymatic activity with an IC 50 value of 11.43±0.36 μmol/L, on the other hand. Furthermore, LX2343 acted as a non-ATP competitive PI3K inhibitor to negatively regulate AKT/mTOR signaling, thus promoting autophagy, and increasing Aβ clearance. Administration of LX2343 in APP/PS1 transgenic mice significantly ameliorated cognitive deficits and markedly ameliorated the Aβ pathology in their brains. LX2343 ameliorates cognitive dysfunction in APP/PS1 transgenic mice via both Aβ production inhibition and clearance promotion, which highlights the potential of LX2343 in the treatment of AD.

Pharmacokinetic-Pharmacodynamic-Model-Guided Doripenem Dosing in Critically Ill Patients▿ †

PubMed Central

Samtani, Mahesh N.; Flamm, Robert; Kaniga, Koné; Nandy, Partha

2010-01-01

The growing number of infections caused by multidrug-resistant pathogens has prompted a more rational use of available antibiotics given the paucity of new, effective agents. Monte Carlo simulations were utilized to determine the appropriateness of several doripenem dosing regimens based on the probability of attaining the critical drug exposure metric of time that drug concentrations remain above the drug MIC (T>MIC) for 35% (and lower thresholds) of the dosing interval in >80 to 90% of the population (T>MIC 35% target). This exposure level generally correlates with in vivo efficacy for carbapenems. In patients with creatinine clearance of >50 ml/min, a 500-mg dose of doripenem infused over 1 h every 8 h is expected to be effective against bacilli with doripenem MICs of ≤1 μg/ml based on a T>MIC 35% target and MICs of ≤2 μg/ml based on lower targets. A longer, 4-hour infusion time improved target attainment in most cases, such that the T>MIC was adequate for pathogens with doripenem MICs as high as 4 μg/ml. Efficacy is expected for infections caused by pathogens with doripenem MICs of ≤2 μg/ml in patients with moderate renal impairment (creatinine clearance, 30 to 50 ml/min) who receive doripenem at 250 mg infused over 1 h every 8 h and in patients with severe impairment (creatinine clearance between 10 and 29 ml/min) who receive doripenem at 250 mg, infused over 1 h or 4 h, every 12 h. Results of pharmacokinetics/pharmacodynamics (PK/PD) modeling can guide dose optimization, thereby potentially increasing the clinical efficacy of doripenem against serious Gram-negative bacterial infections. PMID:20385857

Population pharmacokinetics of intravenous acyclovir in preterm and term infants.

PubMed

Sampson, Mario R; Bloom, Barry T; Lenfestey, Robert W; Harper, Barrie; Kashuba, Angela D; Anand, Ravinder; Benjamin, Daniel K; Capparelli, Edmund; Cohen-Wolkowiez, Michael; Smith, P Brian

2014-01-01

Acyclovir is used to treat herpes infections in preterm and term infants; however, the influence of maturation on drug disposition and dosing requirements is poorly characterized in this population. We administered intravenous acyclovir to preterm and term infants <31 days postnatal age and collected plasma samples. We performed a population pharmacokinetic analysis. The primary pharmacodynamic target was acyclovir concentration ≥3 mg/L for ≥50% of the dosing interval. The final model was simulated using infant data from a clinical database. The analysis included 28 infants (median 30 weeks gestation). Acyclovir pharmacokinetics was described by a 1-compartment model: clearance (L/h/kg) = 0.305 × [postmenstrual age (PMA)/31.3 weeks]. This equation predicts a 4.5-fold increase in clearance from 25 to 41 weeks PMA. With proposed dosing, the pharmacodynamic target was achieved in 91% of infants: 20 mg/kg every 12 hours in infants <30 weeks PMA; 20 mg/kg every 8 hours in infants 30 to <36 weeks PMA and 20 mg/kg every 6 hours in infants 36-41 weeks PMA. Acyclovir clearance increased with infant maturation. A dosing strategy based on PMA accounted for developmental changes in acyclovir disposition to achieve the surrogate pharmacodynamic target in many infants.

Contribution of Antibody Hydrodynamic Size to Vitreal Clearance Revealed through Rabbit Studies Using a Species-Matched Fab.

PubMed

Shatz, Whitney; Hass, Philip E; Mathieu, Mary; Kim, Hok Seon; Leach, Kim; Zhou, Michelle; Crawford, Yongping; Shen, Amy; Wang, Kathryn; Chang, Debby P; Maia, Mauricio; Crowell, Susan R; Dickmann, Leslie; Scheer, Justin M; Kelley, Robert F

2016-09-06

We have developed a tool Fab fragment of a rabbit monoclonal antibody that is useful for early evaluation in rabbit models of technologies for long acting delivery (LAD) of proteins to the eye. Using this Fab we show that vitreal clearance can be slowed through increased hydrodynamic size. Fab (G10rabFab) and Fab' (G10rabFab') fragments of a rabbit monoclonal antibody (G10rabIgG) were expressed in Chinese hamster ovary (CHO) cells and purified using antigen-based affinity chromatography. G10rabFab retains antigen-binding upon thermal stress (37 °C) for 8 weeks in phosphate-buffered saline (PBS) and can be detected in rabbit tissues using an antigen-based ELISA. Hydrodynamic radius, measured using quasi-elastic light scattering (QELS), was increased through site-specific modification of the G10rabFab' free cysteine with linear methoxy-polyethylene glycol(PEG)-maleimide of 20000 or 40000 molecular weight. Pharmacokinetic studies upon intravitreal dosing in New Zealand white rabbits were conducted on the G10rabFab and PEGylated G10rabFab'. Results of single and multidose pharmacokinetic experiments yield reproducible results and a vitreal half-life for G10rabFab of 3.2 days. Clearance from the eye is slowed through increased hydrodynamic size, with vitreal half-life showing a linear dependence on hydrodynamic radius (RH). A linear dependence of vitreal half-life on RH suggests that molecule diffusivity makes an important contribution to vitreal clearance. A method for prediction of vitreal half-life from RH measurements is proposed.

Population pharmacokinetic and pharmacogenetic analysis of 6-mercaptopurine in paediatric patients with acute lymphoblastic leukaemia.

PubMed

Hawwa, Ahmed F; Collier, Paul S; Millership, Jeff S; McCarthy, Anthony; Dempsey, Sid; Cairns, Carole; McElnay, James C

2008-12-01

To investigate the population pharmacokinetics of 6-mercaptopurine (6-MP) active metabolites in paediatric patients with acute lymphoblastic leukaemia (ALL) and examine the effects of various genetic polymorphisms on the disposition of these metabolites. Data were collected prospectively from 19 paediatric patients with ALL (n = 75 samples, 150 concentrations) who received 6-MP maintenance chemotherapy (titrated to a target dose of 75 mg m(-2) day(-1)). All patients were genotyped for polymorphisms in three enzymes involved in 6-MP metabolism. Population pharmacokinetic analysis was performed with the nonlinear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance for the active metabolites. The developed model revealed considerable interindividual variability (IIV) in the clearance of 6-MP active metabolites [6-thioguanine nucleotides (6-TGNs) and 6-methylmercaptopurine nucleotides (6-mMPNs)]. Body surface area explained a significant part of 6-TGNs clearance IIV when incorporated in the model (IIV reduced from 69.9 to 29.3%). The most influential covariate examined, however, was thiopurine methyltransferase (TPMT) genotype, which resulted in the greatest reduction in the model's objective function (P < 0.005) when incorporated as a covariate affecting the fractional metabolic transformation of 6-MP into 6-TGNs. The other genetic covariates tested were not statistically significant and therefore were not included in the final model. The developed pharmacokinetic model (if successful at external validation) would offer a more rational dosing approach for 6-MP than the traditional empirical method since it combines the current practice of using body surface area in 6-MP dosing with a pharmacogenetically guided dosing based on TPMT genotype.

Population pharmacokinetics and maximum a posteriori probability Bayesian estimator of abacavir: application of individualized therapy in HIV-infected infants and toddlers

PubMed Central

Zhao, Wei; Cella, Massimo; Della Pasqua, Oscar; Burger, David; Jacqz-Aigrain, Evelyne

2012-01-01

AIMS To develop a population pharmacokinetic model for abacavir in HIV-infected infants and toddlers, which will be used to describe both once and twice daily pharmacokinetic profiles, identify covariates that explain variability and propose optimal time points to optimize the area under the concentration–time curve (AUC) targeted dosage and individualize therapy. METHODS The pharmacokinetics of abacavir was described with plasma concentrations from 23 patients using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment model with first-order absorption and elimination was developed. The final model was validated using bootstrap, visual predictive check and normalized prediction distribution errors. The Bayesian estimator was validated using the cross-validation and simulation–estimation method. RESULTS The typical population pharmacokinetic parameters and relative standard errors (RSE) were apparent systemic clearance (CL) 13.4 l h−1 (RSE 6.3%), apparent central volume of distribution 4.94 l (RSE 28.7%), apparent peripheral volume of distribution 8.12 l (RSE14.2%), apparent intercompartment clearance 1.25 l h−1 (RSE 16.9%) and absorption rate constant 0.758 h−1 (RSE 5.8%). The covariate analysis identified weight as the individual factor influencing the apparent oral clearance: CL = 13.4 × (weight/12)1.14. The maximum a posteriori probability Bayesian estimator, based on three concentrations measured at 0, 1 or 2, and 3 h after drug intake allowed predicting individual AUC0–t. CONCLUSIONS The population pharmacokinetic model developed for abacavir in HIV-infected infants and toddlers accurately described both once and twice daily pharmacokinetic profiles. The maximum a posteriori probability Bayesian estimator of AUC0–t was developed from the final model and can be used routinely to optimize individual dosing. PMID:21988586

Fiber-optic laser Doppler turbine tip clearance probe

NASA Astrophysics Data System (ADS)

Büttner, Lars; Pfister, Thorsten; Czarske, Jürgen

2006-05-01

A laser Doppler based method for in situ single blade tip clearance measurements of turbomachines with high precision is presented for what we believe is the first time. The sensor is based on two superposed fanlike interference fringe systems generated by two laser wavelengths from a fiber-coupled, passive, and therefore compact measurement head employing diffractive optics. Tip clearance measurements at a transonic centrifugal compressor performed during operation at 50,000 rpm (833 Hz, 586 m/s tip speed) are reported. At these speeds the measured uncertainty of the tip position was less than 20 μm, a factor of 2 more accurate than that of capacitive probes. The sensor offers great potential for in situ and online high-precision tip clearance measurements of metallic and nonmetallic turbine blades.

Fiber-optic laser Doppler turbine tip clearance probe.

PubMed

Büttner, Lars; Pfister, Thorsten; Czarske, Jürgen

2006-05-01

A laser Doppler based method for in situ single blade tip clearance measurements of turbomachines with high precision is presented for what we believe is the first time. The sensor is based on two superposed fanlike interference fringe systems generated by two laser wavelengths from a fiber-coupled, passive, and therefore compact measurement head employing diffractive optics. Tip clearance measurements at a transonic centrifugal compressor performed during operation at 50,000 rpm (833 Hz, 586 m/s tip speed) are reported. At these speeds the measured uncertainty of the tip position was less than 20 microm, a factor of 2 more accurate than that of capacitive probes. The sensor offers great potential for in situ and online high-precision tip clearance measurements of metallic and nonmetallic turbine blades.

The Impact of the Hepatocyte-to-Plasma pH Gradient on the Prediction of Hepatic Clearance and Drug-Drug Interactions for CYP2C9 and CYP3A4 Substrates.

PubMed

Rougée, Luc R A; Mohutsky, Michael A; Bedwell, David W; Ruterbories, Kenneth J; Hall, Stephen D

2017-09-01

Surrogate assays for drug metabolism and inhibition are traditionally performed in buffer systems at pH 7.4, despite evidence that hepatocyte intracellular pH is 7.0. This pH gradient can result in a pK a -dependent change in intracellular/extracellular concentrations for ionizable drugs that could affect predictions of clearance and P450 inhibition. The effect of microsomal incubation pH on in vitro enzyme kinetic parameters for CYP2C9 (diclofenac, (S)-warfarin) and CYP3A4 (midazolam, dextromethorphan, testosterone) substrates, enzyme specific reversible inhibitors (amiodarone, desethylamiodarone, clozapine, nicardipine, fluconazole, fluvoxamine, itraconazole) and a mechanism-based inhibitor (amiodarone) was investigated. Intrinsic clearance through CYP2C9 significantly increased (25% and 50% for diclofenac and (S)-warfarin respectively) at intracellular pH 7.0 compared with traditional pH 7.4. The CYP3A4 substrate dextromethorphan intrinsic clearance was decreased by 320% at pH 7.0, while midazolam and testosterone remained unchanged. Reversible inhibition of CYP2C9 was less potent at pH 7.0 compared with 7.4, while CYP3A4 inhibition potency was variably affected. Maximum enzyme inactivation rate of amiodarone toward CYP2C9 and CYP3A4 decreased at pH 7.0, while the irreversible inhibition constant remained unchanged for CYP2C9, but decreased for CYP3A4 at pH 7.0. Predictions of clearance and drug-drug interactions made through physiologically based pharmacokinetic models were improved with the inclusion of predicted intracellular concentrations based at pH 7.0 and in vitro parameters determined at pH 7.0. No general conclusion on the impact of pH could be made and therefore a recommendation to change buffer pH to 7.0 cannot be made at this time. It is recommended that the appropriate hepatocyte intracellular pH 7.0 be used for in vitro determinations when in vivo predictions are made. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Effect of increased surface hydrophobicity via drug conjugation on the clearance of inhaled PEGylated polylysine dendrimers.

PubMed

Haque, Shadabul; McLeod, Victoria M; Jones, Seth; Fung, Sandy; Whittaker, Michael; McIntosh, Michelle; Pouton, Colin; Owen, David J; Porter, Christopher J H; Kaminskas, Lisa M

2017-10-01

PEGylated polylysine dendrimers are attractive and well tolerated inhalable drug delivery platforms that have the potential to control the release, absorption kinetics and lung retention time of conjugated drugs. The clinical application of these systems though, would likely require partial substitution of surface PEG groups with drug molecules that are anticipated to alter their lung clearance kinetics and clearance pathways. In the current study, we therefore evaluated the impact of increased surface hydrophobicity via substitution of 50% surface PEG groups with a model hydrophobic drug (α-carboxyl OtButylated methotrexate) on the lung clearance of a Generation 5 PEGylated polylysine dendrimer in rats. PEG substitution with OtBu-methotrexate accelerated lung clearance of the dendrimer by increasing polylysine scaffold catabolism, improving systemic absorption of the intact dendrimer and low molecular weight products of scaffold catabolism, and enhancing mucociliary clearance. These results suggest that the conjugation of hydrophobic drug on the surface of a PEGylated dendrimer is likely to accelerate lung clearance when compared to a fully PEGylated dendrimer. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

Hepatic drug clearance following traumatic injury.

PubMed

Slaughter, R L; Hassett, J M

1985-11-01

Trauma is a complex disease state associated with physiologic changes that have the potential to alter hepatic drug clearance mechanisms. These responses include alterations in hepatic blood flow, reduction in hepatic microsomal activity, reduction in hepatic excretion processes, and changes in protein binding. Hepatic blood flow is influenced by sympathomimetic activity. Both animal and human studies demonstrate an initial reduction and subsequent increase in hepatic blood flow, which coincides with an observed increase and subsequent return to normal in serum catecholamine concentrations. Unfortunately, there are no human studies that address the importance these findings may have to the clearance processes of high intrinsic clearance compounds. Animal studies of trauma indicate that hepatic microsomal activity is depressed during the post-traumatic period. Reduction in the hepatic clearance of antipyrine, a model low intrinsic compound, has also been demonstrated in animal models of trauma. In addition to these effects, hepatic excretion of substances such as indocyanine green and bilirubin have been demonstrated to be impaired in both traumatized animals and humans. Finally, substantial increases in the serum concentration of the binding protein alpha 1-acid glycoprotein occur in trauma patients. This has been reported to be associated with subsequent decreases in the free fraction of lidocaine and quinidine. In addition to changing serum drug concentration/response relationships, the pharmacokinetic behavior of drugs bound to alpha 1-acid glycoprotein should also change. Preliminary observations in our laboratory in a dog model of surgically-induced trauma have shown a reduction in the total clearance of lidocaine and reduction in free lidocaine concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Interfacial distribution of mucus under forced expiration in a double bifurcation model

NASA Astrophysics Data System (ADS)

Rajendran, Rahul; Banerjee, Arindam

2017-11-01

Mucus is removed from the lung airways by the rhythmic beating of cilia and the mucus interaction with the turbulent core airflow generated during a cough or forced expiration. The quantity and quality of mucus are adversely altered, impairing mucociliary clearance under chronic pulmonary conditions. Existing studies on airflow induced mucus clearance have established a functional relationship between the airflow rate, mucus properties, flow bias, breathing frequency and clearance; however, the impact of airway branching, gravity, and characterization of primary and secondary flows have not been studied. The focus of the current investigation is the detailed understanding of air-mucus two-phase flow mechanism under steady expiratory airflow in a double bifurcation model. The effect of different airflow rates and mucus viscosities on the flow morphology, mucus layer thickness, mucus clearance and pressure drop across the model will be discussed. The impact of in-plane and out-of-plane configurations of the bifurcation model on the primary and secondary flow structures as well as the mucus distribution will be addressed. In addition, a detailed comparison of the flow structures in the mucus-lined airways, and its corresponding dry wall (no mucus lining) case will be presented.

Cerebrospinal Fluid Clearance in Alzheimer Disease Measured with Dynamic PET.

PubMed

de Leon, Mony J; Li, Yi; Okamura, Nobuyuki; Tsui, Wai H; Saint-Louis, Les A; Glodzik, Lidia; Osorio, Ricardo S; Fortea, Juan; Butler, Tracy; Pirraglia, Elizabeth; Fossati, Silvia; Kim, Hee-Jin; Carare, Roxana O; Nedergaard, Maiken; Benveniste, Helene; Rusinek, Henry

2017-09-01

Evidence supporting the hypothesis that reduced cerebrospinal fluid (CSF) clearance is involved in the pathophysiology of Alzheimer disease (AD) comes primarily from rodent models. However, unlike rodents, in which predominant extracranial CSF egress is via olfactory nerves traversing the cribriform plate, human CSF clearance pathways are not well characterized. Dynamic PET with 18 F-THK5117, a tracer for tau pathology, was used to estimate the ventricular CSF time-activity as a biomarker for CSF clearance. We tested 3 hypotheses: extracranial CSF is detected at the superior turbinates; CSF clearance is reduced in AD; and CSF clearance is inversely associated with amyloid deposition. Methods: Fifteen subjects, 8 with AD and 7 normal control volunteers, were examined with 18 F-THK5117. Ten subjects additionally underwent 11 C-Pittsburgh compound B ( 11 C-PiB) PET scanning, and 8 were 11 C-PiB-positive. Ventricular time-activity curves of 18 F-THK5117 were used to identify highly correlated time-activity curves from extracranial voxels. Results: For all subjects, the greatest density of CSF-positive extracranial voxels was in the nasal turbinates. Tracer concentration analyses validated the superior nasal turbinate CSF signal intensity. AD patients showed ventricular tracer clearance reduced by 23% and 66% fewer superior turbinate CSF egress sites. Ventricular CSF clearance was inversely associated with amyloid deposition. Conclusion: The human nasal turbinate is part of the CSF clearance system. Lateral ventricle and superior nasal turbinate CSF clearance abnormalities are found in AD. Ventricular CSF clearance reductions are associated with increased brain amyloid depositions. These data suggest that PET-measured CSF clearance is a biomarker of potential interest in AD and other neurodegenerative diseases. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

20 CFR 655.103 - Overview of this subpart and definition of terms.

Code of Federal Regulations, 2010 CFR

2010-04-01

... (combined) in the States or regions as published annually by the U.S. Department of Agriculture (USDA) based... intra-state job clearance systems based on the employer's Agricultural and Food Processing Clearance... Employment Certification. Office of Foreign Labor Certification (OFLC). OFLC means the organizational...

Iohexol clearance is superior to creatinine-based renal function estimating equations in detecting short-term renal function decline in chronic heart failure.

PubMed

Cvan Trobec, Katja; Kerec Kos, Mojca; von Haehling, Stephan; Anker, Stefan D; Macdougall, Iain C; Ponikowski, Piotr; Lainscak, Mitja

2015-12-01

To compare the performance of iohexol plasma clearance and creatinine-based renal function estimating equations in monitoring longitudinal renal function changes in chronic heart failure (CHF) patients, and to assess the effects of body composition on the equation performance. Iohexol plasma clearance was measured in 43 CHF patients at baseline and after at least 6 months. Simultaneously, renal function was estimated with five creatinine-based equations (four- and six-variable Modification of Diet in Renal Disease, Cockcroft-Gault, Cockcroft-Gault adjusted for lean body mass, Chronic Kidney Disease Epidemiology Collaboration equation) and body composition was assessed using bioimpedance and dual-energy x-ray absorptiometry. Over a median follow-up of 7.5 months (range 6-17 months), iohexol clearance significantly declined (52.8 vs 44.4 mL/[min ×1.73 m2], P=0.001). This decline was significantly higher in patients receiving mineralocorticoid receptor antagonists at baseline (mean decline -22% of baseline value vs -3%, P=0.037). Mean serum creatinine concentration did not change significantly during follow-up and no creatinine-based renal function estimating equation was able to detect the significant longitudinal decline of renal function determined by iohexol clearance. After accounting for body composition, the accuracy of the equations improved, but not their ability to detect renal function decline. Renal function measured with iohexol plasma clearance showed relevant decline in CHF patients, particularly in those treated with mineralocorticoid receptor antagonists. None of the equations for renal function estimation was able to detect these changes. ClinicalTrials.gov registration number: NCT01829880.

The influences of tip clearance on the performance of nozzle blades of radial turbines - Experiment and performance prediction at three nozzle angles

NASA Astrophysics Data System (ADS)

Hyun, Yong-Ik; Yamaguchi, Michiteru; Hayami, Hiroshi; Senoo, Yasutoshi

1988-05-01

In order to study the influence of tip clearance on the turning angle and pressure loss of turbine nozzles, experimental results were obtained for nozzle angles at which the throat area was 0.8 and 1.4 times the rated condition. Contour maps of the total pressure loss and of the spanwise distributions of the mean exit-flow angle have been obtained. Although the two-layer flow model of Senoo et al., (1987) is shown to accurately predict the effects of tip clearance, it underestimates the clearance effect for a lightly loaded condition.

Toward a Fast-Response Active Turbine Tip Clearance Control

NASA Technical Reports Server (NTRS)

Melcher, Kevin J.; Kypuros, Javier A.

2003-01-01

This paper describes active tip clearance control research being conducted by NASA to improve turbine engine systems. The target application for this effort is commercial aircraft engines. However, technologies developed for clearance control can benefit a broad spectrum of current and future turbomachinery. The first portion of the paper addresses the research from a programmatic viewpoint. Recent studies that provide motivation for the work, identification of key technologies, and NASA's plan for addressing deficiencies in the technologies are discussed. The later portion of the paper drills down into one of the key technologies by presenting equations and results for a preliminary dynamic model of the tip clearance phenomena.

The Role of Radial Clearance on the Performance of Foil Air Bearings

NASA Technical Reports Server (NTRS)

Radil, Kevin; Howard, Samuel; Dykas, Brian

2002-01-01

Load capacity tests were conducted to determine how radial clearance variations affect the load capacity coefficient of foil air bearings. Two Generation III foil air bearings with the same design but possessing different initial radial clearances were tested at room temperature against an as-ground PS304 coated journal operating at 30,000 rpm. Increases in radial clearance were accomplished by reducing the journal's outside diameter via an in-place grinding system. From each load capacity test the bearing load capacity coefficient was calculated from the rule-of-thumb (ROT) model developed for foil air bearings. The test results indicate that, in terms of the load capacity coefficient, radial clearance has a direct impact on the performance of the foil air bearing. Each test bearing exhibited an optimum radial clearance that resulted in a maximum load capacity coefficient. Relative to this optimum value are two separate operating regimes that are governed by different modes of failure. Bearings operating with radial clearances less than the optimum exhibit load capacity coefficients that are a strong function of radial clearance and are prone to a thermal runaway failure mechanism and bearing seizure. Conversely, a bearing operating with a radial clearance twice the optimum suffered only a 20 percent decline in its maximum load capacity coefficient and did not experience any thermal management problems. However, it is unknown to what degree these changes in radial clearance had on other performance parameters, such as the stiffness and damping properties of the bearings.

Effects of CYP2D6 Status on Harmaline Metabolism, Pharmacokinetics and Pharmacodynamics, and a Pharmacogenetics-Based Pharmacokinetic Model

PubMed Central

Wu, Chao; Jiang, Xi-Ling; Shen, Hong-Wu; Yu, Ai-Ming

2009-01-01

Harmaline is a β-carboline alkaloid showing neuroprotective and neurotoxic properties. Our recent studies have revealed an important role for cytochrome P450 2D6 (CYP2D6) in harmaline O-demethylation. This study, therefore, aimed to delineate the effects of CYP2D6 phenotype/genotype on harmaline metabolism, pharmacokinetics (PK) and pharmacodynamics (PD), and to develop a pharmacogenetics mechanism-based compartmental PK model. In vitro kinetic studies on metabolite formation in human CYP2D6 extensive metabolizer (EM) and poor metabolizer (PM) hepatocytes indicated that harmaline O-demethylase activity (Vmax/Km) was about 9-fold higher in EM hepatocytes. Substrate depletion showed mono-exponential decay trait, and estimated in vitro harmaline clearance (CLint, μL/min/106 cells) was significantly lower in PM hepatocytes (28.5) than EM hepatocytes (71.1). In vivo studies in CYP2D6-humanized and wild-type mouse models showed that wild-type mice were subjected to higher and longer exposure to harmaline (5 and 15 mg/kg; i.v. and i.p.), and more severe hypothermic responses. The PK/PD data were nicely described by our pharmacogenetics-based PK model involving the clearance of drug by CYP2D6 (CLCYP2D6) and other mechanisms (CLother), and an indirect response PD model, respectively. Wild-type mice were also more sensitive to harmaline in marble-burying tests, as manifested by significantly lower ED50 and steeper Hill slope. These findings suggest that distinct CYP2D6 status may cause considerable variations in harmaline metabolism, PK and PD. In addition, the pharmacogenetics-based PK model may be extended to define PK difference caused by other polymorphic drug-metabolizing enzyme in different populations. PMID:19445902

High-dose methotrexate therapy of childhood acute lymphoblastic leukemia: lack of relation between serum methotrexate concentration and creatinine clearance.

PubMed

Joannon, Pilar; Oviedo, Iris; Campbell, Myriam; Tordecilla, Juan

2004-07-01

The objectives of this study were: (1) to analyze the relation of serum methotrexate (MTX) concentration with creatinine clearance, (2) to compare the leucovorin rescue dose administered to the patients based on creatinine clearance, with the one calculated according to serum MTX levels, and (3) to determine MTX-related toxicity. Thirty children with high-risk non-B acute lymphoblastic leukemia (ALL) treated according to the national protocol (PINDA 92) based on ALL BFM 90, were randomized to receive consolidation with four doses of either 1 or 2 g/m(2) MTX as a 24-hr infusion, at 2-week intervals (group M1 and M2, respectively). Serum MTX concentrations were measured at 24, 42, and 48 hr after beginning the infusion and were analyzed retrospectively. The creatinine clearance was calculated after 12-hr intravenous hydration prior to each MTX dose. Leucovorin dosage was adjusted according to creatinine clearance. Serum MTX concentrations at 24, 42, and 48 hr after starting the infusion were not related to creatinine clearance in both treatment groups. Leucovorin rescue administered according to creatinine clearance was excessive in 43% in group M1 and in 51% in group M2, as compared to the dose calculated according to serum MTX levels. No serious clinical complications were observed. These results suggest that creatinine clearance is not a good parameter to calculate leucovorin rescue. MTX-related toxicity in this group of patients receiving a dose of 1 or 2 g/m(2) and rescued with leucovorin without monitoring serum MTX levels was acceptable. Copyright 2004 Wiley-Liss, Inc.

Comparative study of three methods of estimation of creatinine clearance in critically ill patients.

PubMed

Blasco, V; Antonini, F; Zieleskiewicz, L; Hammad, E; Albanèse, J; Martin, C; Leone, M

2014-05-01

At the bedside, the reference method for creatinine clearance determination is based on the measurement of creatinine concentrations in urine and serum (mCrCl). Several models are available to calculate the creatinine clearance from the serum creatinine concentration. This observational survey aimed at testing the hypothesis that the proposed equations are unreliable to determine accurate creatinine clearance in patients admitted to intensive care unit (ICU). Creatinine clearance was determined by the use of mCrCl. Then, we compared three equations: Cockcroft-Gault (CG), Simplified Modification of Diet in Renal Disease (MDRDs), and Chronic Kidney Disease Epidemiology (CKD-EPI) in 156 consecutive patients within the first 24hours after ICU admission. We tested the hypothesis that the three equations were equivalent. The agreement between the three equations was evaluated by linear regression and Bland and Altman analysis. Bland and Altman analysis showed similar agreement between the three equations. The biases and precisions were -4.8±51, -1.3±50, and 8.2±44 for CG, MDRDs, and CKD-EPI equations, respectively (P>0.05). The precisions were similar for the three equations (P>0.05). The percentages of outliers at ±30% were 44%, 45%, and 49% for CG, MDRDs, and CKD-EPI, respectively (P>0.05). Regarding the high percentage of outliers, the use of these equations cannot be recommended in ICU patients. Copyright © 2014 Société française d’anesthésie et de réanimation (Sfar). Published by Elsevier SAS. All rights reserved.

Risk-based Strategy to Determine Testing Requirement for the Removal of Residual Process Reagents as Process-related Impurities in Bioprocesses.

PubMed

Qiu, Jinshu; Li, Kim; Miller, Karen; Raghani, Anil

2015-01-01

The purpose of this article is to recommend a risk-based strategy for determining clearance testing requirements of the process reagents used in manufacturing biopharmaceutical products. The strategy takes account of four risk factors. Firstly, the process reagents are classified into two categories according to their safety profile and history of use: generally recognized as safe (GRAS) and potential safety concern (PSC) reagents. The clearance testing of GRAS reagents can be eliminated because of their safe use historically and process capability to remove these reagents. An estimated safety margin (Se) value, a ratio of the exposure limit to the estimated maximum reagent amount, is then used to evaluate the necessity for testing the PSC reagents at an early development stage. The Se value is calculated from two risk factors, the starting PSC reagent amount per maximum product dose (Me), and the exposure limit (Le). A worst-case scenario is assumed to estimate the Me value, that is common. The PSC reagent of interest is co-purified with the product and no clearance occurs throughout the entire purification process. No clearance testing is required for this PSC reagent if its Se value is ≥1; otherwise clearance testing is needed. Finally, the point of the process reagent introduction to the process is also considered in determining the necessity of the clearance testing for process reagents. How to use the measured safety margin as a criterion for determining PSC reagent testing at process characterization, process validation, and commercial production stages are also described. A large number of process reagents are used in the biopharmaceutical manufacturing to control the process performance. Clearance testing for all of the process reagents will be an enormous analytical task. In this article, a risk-based strategy is described to eliminate unnecessary clearance testing for majority of the process reagents using four risk factors. The risk factors included in the strategy are (i) safety profile of the reagents, (ii) the starting amount of the process reagents used in the manufacturing process, (iii) the maximum dose of the product, and (iv) the point of introduction of the process reagents in the process. The implementation of the risk-based strategy can eliminate clearance testing for approximately 90% of the process reagents used in the manufacturing processes. This science-based strategy allows us to ensure patient safety and meet regulatory agency expectations throughout the product development life cycle. © PDA, Inc. 2015.

Impact of mechanism vibration characteristics by joint clearance and optimization design of its multi-objective robustness

NASA Astrophysics Data System (ADS)

Zeng, Baoping; Wang, Chao; Zhang, Yu; Gong, Yajun; Hu, Sanbao

2017-12-01

Joint clearances and friction characteristics significantly influence the mechanism vibration characteristics; for example: as for joint clearances, the shaft and bearing of its clearance joint collide to bring about the dynamic normal contact force and tangential coulomb friction force while the mechanism works; thus, the whole system may vibrate; moreover, the mechanism is under contact-impact with impact force constraint from free movement under action of the above dynamic forces; in addition, the mechanism topology structure also changes. The constraint relationship between joints may be established by a repeated complex nonlinear dynamic process (idle stroke - contact-impact - elastic compression - rebound - impact relief - idle stroke movement - contact-impact). Analysis of vibration characteristics of joint parts is still a challenging open task by far. The dynamic equations for any mechanism with clearance is often a set of strong coupling, high-dimensional and complex time-varying nonlinear differential equations which are solved very difficultly. Moreover, complicated chaotic motions very sensitive to initial values in impact and vibration due to clearance let high-precision simulation and prediction of their dynamic behaviors be more difficult; on the other hand, their subsequent wearing necessarily leads to some certain fluctuation of structure clearance parameters, which acts as one primary factor for vibration of the mechanical system. A dynamic model was established to the device for opening the deepwater robot cabin door with joint clearance by utilizing the finite element method and analysis was carried out to its vibration characteristics in this study. Moreover, its response model was carried out by utilizing the DOE method and then the robust optimization design was performed to sizes of the joint clearance and the friction coefficient change range so that the optimization design results may be regarded as reference data for selecting bearings and controlling manufacturing process parameters for the opening mechanism. Several optimization objectives such as x/y/z accelerations for various measuring points and dynamic reaction forces of mounting brackets, and a few constraints including manufacturing process were taken into account in the optimization models, which were solved by utilizing the multi-objective genetic algorithm (NSGA-II). The vibration characteristics of the optimized opening mechanism are superior to those of the original design. In addition, the numerical forecast results are in good agreement with the test results of the prototype.

MATILDA Version 2: Rough Earth TIALD Model for Laser Probabilistic Risk Assessment in Hilly Terrain - Part I

DTIC Science & Technology

2017-03-13

support of airborne laser designator use during test and training exercises on military ranges. The initial MATILDA tool, MATILDA PRO Version-1.6.1...was based on the 2007 PRA model developed to perform range safety clearances for the UK Thermal Imaging Airborne Laser Designator (TIALD) system...AFRL Technical Reports. This Technical Report, designated Part I, con- tains documentation of the computational procedures for probabilistic fault

Delayed clearance of triglyceride‐rich lipoproteins in young, healthy obese subjects†

PubMed Central

Goll, R.; Lekahl, S.; Moen, O. S.; Florholmen, J.

2015-01-01

Summary Obesity is associated with the metabolic syndrome. The aims were, first, to study the postprandial triglyceride clearance in young, healthy obese subjects and, second, to investigate if fasting triglycerides can predict delayed postprandial triglyceride clearance. Eighteen apparently healthy, obese subjects with no clinical signs of metabolic disturbances participated. Controls were age‐ and sex‐matched, healthy, normal weight subjects. Subclinical markers of metabolic disturbances were assessed by measuring postprandial triglycerides in serum and in chylomicrons by oral fat tolerance test. Postprandial triglyceride clearance for 8 h was assessed indirectly as removal of the lipid from serum during the oral fat tolerance test. Insulin resistance was measured by the homeostasis model assessment of insulin resistance (HOMA‐IR). Twelve (66%) of the apparently healthy obese individuals had insulin resistance measured by HOMA‐IR. There was a delayed clearance of serum triglycerides and chylomicron triglycerides at 6 h when compared with the control group, while, at 8 h, the differences were only detected for the chylomicron triglyceride clearance. Triglyceride response was significantly greater in the obese subjects. Fasting triglycerides in upper normal level predicted a delayed postprandial triglyceride clearance and insulin resistance. In young, apparently healthy obese subjects early metabolic disturbances including insulin resistance and delayed postprandial triglyceride clearance can be detected. Fasting serum triglyceride in upper normal level predicted delayed postprandial triglyceride clearance and insulin resistance. PMID:26469529

A novel model to explain dietary factors affecting hypocalcaemia in dairy cattle.

PubMed

Martín-Tereso, Javier; Verstegen, Martin W A

2011-12-01

Most dairy cows exhibit different degrees of hypocalcaemia around calving because the gestational Ca requirements shift to the disproportionately high Ca requirements of lactation. Ca homeostasis is a robust system that effectively adapts to changes in Ca demand or supply. However, these adaptations often are not rapid enough to avoid hypocalcaemia. A delay in the reconfiguration of intestinal Ca absorption and bone resorption is probably the underlying cause of this transient hypocalcaemia. Several dietary factors that affect different aspects of Ca metabolism are known to reduce the incidence of milk fever. The present review describes the interactions between nutrition and Ca homeostasis using observations from cattle and extrapolations from other species and aims to quantitatively model the effects of the nutritional approaches that are used to induce dry cows into an early adaptation of Ca metabolism. The present model suggests that reducing dietary cation-anion difference (DCAD) increases Ca clearance from the blood by dietary induction of systemic acidosis, which results in hypercalciuria due to the loss of function of the renal Ca transient receptor potential vanilloid channel TRPV5. Alternatively, reducing the gastrointestinal availability of Ca by reducing dietary Ca or its nutritional availability will also induce the activation of Ca metabolism to compensate for basal blood Ca clearance. Our model of gastrointestinal Ca availability as well as blood Ca clearance in the transition dairy cow allowed us to conclude that the most common dietary strategies for milk fever prevention may have analogous modes of action that are based on the principle of metabolic adaptation before calving.

75 FR 35622 - Airworthiness Directives; Bombardier, Inc. Model DHC-8-400 Series Airplanes

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-23

... and a rework of the weight on wheel (WOW) proximity sensor cover to provide clearance for the re... and a rework of the weight on wheel (WOW) proximity sensor cover to provide clearance for the re...

Measurement of Rotating Blade Tip Clearance with Fibre-Optic Probe

NASA Astrophysics Data System (ADS)

Cao, S. Z.; Duan, F. J.; Zhang, Y. G.

2006-10-01

This paper described a tip clearance measuring system with fibre-optic probe. The system is based on a novel tip clearance sensor of optical fibre-bundle mounted on the casing, rotating speed synchronization sensor mounted on the rotating shaft, the tip clearance preamplification processing circuit followed by high speed data-acquisition unit. A novel tip clearance sensor of trifurcated optical fibre bundle was proposed and demonstrated. It is independent of material of measured surface but capacitive probe demands target conductive. Measurements can be taken under severe conditions such as ionization. Sensor circuitry and data acquisition circuit were successfully designed. With the help of Rotation synchronized sensor, all the blades can be detected in real-time. Because of fibre-optic sensor, the measuring system has commendably frequency response, which can work well in high rotating speed from 0-15000rpm.The measurement range of tip clearance is 0-3mm with 25um precision.

B747/JT9D flight loads and their effect on engine running clearances and performance deterioration; BCAC NAIL/P and WA JT9D engine diagnostics programs

NASA Technical Reports Server (NTRS)

Olsson, W. J.; Martin, R. L.

1982-01-01

Flight loads on the 747 propulsion system and resulting JT9D blade to outer airseal running clearances during representative acceptance flight and revenue flight sequences were measured. The resulting rub induced clearance changes, and engine performance changes were then analyzed to validate and refine the JT9D-7A short term performance deterioration model.

Intra-articular clearance of labeled dextrans from naive and arthritic rat knee joints.

PubMed

Mwangi, Timothy K; Berke, Ian M; Nieves, Eduardo H; Bell, Richard D; Adams, Samuel B; Setton, Lori A

2018-05-26

Determine the effects of arthritis on the trans-synovial clearance of small and large model compounds following local delivery to the knee joint in a rat model. Intra-articular delivery was studied in rat knee joints in an osteoarthritis model of joint instability (medial collateral ligament and meniscus transection model or MMT). Fluorescently-labeled 10 kDa or 500 kDa dextran was injected in the arthritic or unoperated control (naive) joints 3 weeks after surgical destabilization, and the temporal clearance pattern was evaluated via in vivo regional fluorescence imaging, dextran concentrations in plasma and draining lymph nodes, and by quantification of fluorescence in histological synovium sections. Together these data were used to evaluate the effect of osteoarthritis and solute size on the rate of drug clearance from the joint. Clearance of 10 kDa dextran from the joint space quantified using in vivo fluorescence imaging of the knee joint region was not significantly different between naive and MMT joints. In contrast, clearance of 500 kDa dextran was significantly reduced for MMT joints when compared to naive joints by fluorescence in vivo imaging. Drug accumulation in lymph nodes and plasma were lower for the 500 kDa dextran as compared to 10 kDa dextran, and lymph node levels were further reduced with the presence of osteoarthritis. Furthermore, synovium was significantly thicker in MMT joints than in naive joints and image analysis of joint tissue sections revealed different trans-synovial distributions of 10 and 500 kDa dextran. Large macromolecules were retained in the arthritic joint longer than in the healthy joint, while smaller molecules were cleared similarly in healthy and arthritic joints. In vivo fluorescence imaging, plasma and lymph node concentrations, and spatial distributions of drug fluorescence identified differences in higher molecular weight clearance between naive and arthritic disease states. Findings may relate to a thickening of synovium for joints with induced arthritis, and support the concept that intra-articular drug delivery effectiveness may vary with the state of joint pathology. Copyright © 2018 Elsevier B.V. All rights reserved.

A new paradigm in respiratory hygiene: modulating respiratory secretions to contain cough bioaerosol without affecting mucus clearance

PubMed Central

Zayas, Gustavo; Valle, Juan C; Alonso, Mauricio; Alfaro, Henry; Vega, Daniel; Bonilla, Gloria; Reyes, Miguel; King, Malcolm

2007-01-01

Background Several strategies and devices have been designed to protect health care providers from acquiring transmissible respiratory diseases while providing care. In modulating the physical characteristics of the respiratory secretions to minimize the aerosolization that facilitates transmission of airborne diseases, a fundamental premise is that the prototype drugs have no adverse effect on the first line of respiratory defense, clearance of mucus by ciliary action. Methods To assess and demonstrate the primary mechanism of our mucomodulators (XLs), we have built our evidence moving from basic laboratory studies to an ex-vivo model and then to an in-vivo large animal model. We exposed anesthetized dogs without hypersecretion to different dose concentrations of aerosolized XL "B", XL "D" and XL "S". We assessed: cardio-respiratory pattern, tracheal mucus clearance, airway patency, and mucus viscoelastic changes. Results Exposure of frog palate mucus to XLs did not affect the clearance of mucus by ciliary action. Dogs maintained normal cardio-respiratory pattern with XL administration. Tracheal mucociliary clearance in anesthetized dogs indicated a sustained 40% mean increase. Tracheal mucus showed increased filance, and there was no mucus retention in the airways. Conclusion The ex-vivo frog palate and the in-vivo mammalian models used in this study, appear to be appropriate and complement each other to better assess the effects that our mucomodulators exert on the mucociliary clearance defence mechanism. The physiological function of the mucociliary apparatus was not negatively affected in any of the two epithelial models. Airway mucus crosslinked by mucomodulators is better cleared from an intact airway and normally functioning respiratory system, either due to enhanced interaction with cilia or airflow-dependent mechanisms. Data obtained in this study allow us to assure that we have complied with the fundamental requirement criteria established in the initial phase of developing the concept of mucomodulation: Can we modulate the physical characteristics of the respiratory secretions to reduce aerosolization without affecting normal mucociliary clearance function, or even better improving it? PMID:17697323

Implications of intercorrelation between hepatic CYP3A4-CYP2C8 enzymes for the evaluation of drug-drug interactions: a case study with repaglinide.

PubMed

Doki, Kosuke; Darwich, Adam S; Achour, Brahim; Tornio, Aleksi; Backman, Janne T; Rostami-Hodjegan, Amin

2018-05-01

Statistically significant positive correlations are reported for the abundance of hepatic drug-metabolizing enzymes. We investigate, as an example, the impact of CYP3A4-CYP2C8 intercorrelation on the predicted interindividual variabilities of clearance and drug-drug interactions (DDIs) for repaglinide using physiologically based pharmacokinetic (PBPK) modelling. PBPK modelling and simulation were employed using Simcyp Simulator (v15.1). Virtual populations were generated assuming intercorrelations between hepatic CYP3A4-CYP2C8 abundances derived from observed values in 24 human livers. A repaglinide PBPK model was used to predict PK parameters in the presence and absence of gemfibrozil in virtual populations, and the results were compared with a clinical DDI study. Coefficient of variation (CV) of oral clearance was 52.5% in the absence of intercorrelation between CYP3A4-CYP2C8 abundances, which increased to 54.2% when incorporating intercorrelation. In contrast, CV for predicted DDI (as measured by AUC ratio before and after inhibition) was reduced from 46.0% in the absence of intercorrelation between enzymes to 43.8% when incorporating intercorrelation: these CVs were associated with 5th/95th percentiles (2.48-11.29 vs. 2.49-9.69). The range of predicted DDI was larger in the absence of intercorrelation (1.55-77.06) than when incorporating intercorrelation (1.79-25.15), which was closer to clinical observations (2.6-12). The present study demonstrates via a systematic investigation that population-based PBPK modelling incorporating intercorrelation led to more consistent estimation of extreme values than those observed in interindividual variabilities of clearance and DDI. As the intercorrelations more realistically reflect enzyme abundances, virtual population studies involving PBPK and DDI should avoid using Monte Carlo assignment of enzyme abundance. © 2018 The British Pharmacological Society.

Partitioning of human and sheep forms of the pathogenic prion protein during the purification of therapeutic proteins from human plasma.

PubMed

Stenland, Christopher J; Lee, Douglas C; Brown, Paul; Petteway, Stephen R; Rubenstein, Richard

2002-11-01

Therapeutic proteins derived from human plasma and other biologic sources have demonstrated an excellent safety record relative to the potential threat of transmissible spongiform encephalopathy (TSE) transmission. Previously, hamster-adapted scrapie was used as a model agent to assess TSE clearance in purification steps leading to the isolation of biopharmaceutical proteins. The current study investigated the validity of hamster scrapie as a model for human TSE clearance studies. The partitioning of the pathogenic forms of the prion protein associated with human variant CJD (PrP(vCJD)), human sporadic CJD (PrP(sCJD)) and Gerstmann-Sträussler-Scheinker (PrP(GSS)) syndrome was compared to the partitioning of hamster scrapie (PrP(Sc)) in three plasma protein purification steps. Sheep scrapie (PrP(Sc)) was similarly evaluated. The starting materials for three plasma protein purification steps, cryoseparation, 3 percent PEG separation, and 11.5 percent PEG separation, were spiked with brain homogenates containing human PrP(vCJD), human PrP(sCJD), human PrP(GSS), sheep PrP(Sc), and hamster 263K PrP(Sc). The partitioning of the pathogenic form of the PrP was analyzed. Clearance of the pathogenic form of the PrP was measured relative to the effluent fraction. Regardless of the source of the pathogenic prion, clearance was similar to hamster PrP(Sc). A nominal amount of clearance (approx., 1 log), an intermediate amount of clearance (approx., 2 log), and a substantial amount of clearance (> or = 3 log) were observed for the cryoseparation, 3 percent PEG separation, and 11.5 percent PEG separation steps, respectively. In the latter step, no PrP was detected in the effluents. These data demonstrate that human prions, including vCJD prions, can be removed during the purification of human therapeutic proteins and indicate that partitioning of human prions is similar to that observed in the hamster scrapie model.

Modeling accumulations of particles in lung during chronic inhalation exposures that lead to impaired clearance

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wolff, R.K.; Griffith, W.C. Jr.; Cuddihy, R.G.

Chronic inhalation of insoluble particles of low toxicity that produce substantial lung burdens of particles, or inhalation of particles that are highly toxic to the lung, can impair clearance. This report describes model calculations of accumulations in lung of inhaled low-toxicity diesel exhaust soot and high-toxicity Ga2O3 particles. Lung burdens of diesel soot were measured periodically during a 24-mo exposure to inhaled diesel exhaust at soot concentrations of 0, 0.35, 3.5, and 7 mg m-3, 7 h d-1, 5 d wk-1. Lung burdens of Ga2O3 were measured for 1 y after a 4-wk exposure to 23 mg Ga2O3 m-3, 2more » h d-1, 5 d wk-1. Lung burdens of Ga2O3 were measured for 1 y both studies using inhaled radiolabeled tracer particles. Simulation models fit the observed lung burdens of diesel soot in rats exposed to the 3.5- and 7-mg m-3 concentrations of soot only if it was assumed that clearance remained normal for several months, then virtually stopped. Impaired clearance from high-toxicity particles occurred early after accumulations of a low burden, but that from low-toxicity particles was evident only after months of exposure, when high burdens had accumulated in lung. The impairment in clearances of Ga2O3 particles and radiolabeled tracers was similar, but the impairment in clearance of diesel soot and radiolabeled tracers differed in magnitude. This might have been related to differences in particle size and composition between the tracers and diesel soot. Particle clearance impairment should be considered both in the design of chronic exposures of laboratory animals to inhaled particles and in extrapolating the results to people.« less

Automatic Rail Extraction and Celarance Check with a Point Cloud Captured by Mls in a Railway

NASA Astrophysics Data System (ADS)

Niina, Y.; Honma, R.; Honma, Y.; Kondo, K.; Tsuji, K.; Hiramatsu, T.; Oketani, E.

2018-05-01

Recently, MLS (Mobile Laser Scanning) has been successfully used in a road maintenance. In this paper, we present the application of MLS for the inspection of clearance along railway tracks of West Japan Railway Company. Point clouds around the track are captured by MLS mounted on a bogie and rail position can be determined by matching the shape of the ideal rail head with respect to the point cloud by ICP algorithm. A clearance check is executed automatically with virtual clearance model laid along the extracted rail. As a result of evaluation, the accuracy of extracting rail positions is less than 3 mm. With respect to the automatic clearance check, the objects inside the clearance and the ones related to a contact line is successfully detected by visual confirmation.

Population pharmacokinetic study of isepamicin with intensive care unit patients.

PubMed Central

Tod, M; Padoin, C; Minozzi, C; Cougnard, J; Petitjean, O

1996-01-01

The pharmacokinetics (PK) of isepamicin, a new aminoglycoside, were studied in 85 intensive care unit (ICU) patients and were compared with those observed in 10 healthy volunteers. A parametric method based on a nonlinear mixed-effect model was used to assess population PK. Isepamicin was given intravenously over 0.5 h at dosages of 15 mg/kg once daily or 7.5 mg/kg twice daily. The data were fitted to a bicompartmental open model. Compared with healthy volunteers, the mean values of the PK parameters were profoundly modified in ICU patients: elimination clearance was reduced by 48%, the volume of distribution in the central compartment (Vc) was increased by 50%, the peripheral volume of distribution was 70% higher, the distribution clearance was 146% lower, and the elimination half-life was ca. 3.4 times higher. The interindividual variability in PK parameters was about 50% in ICU patients. Five covariates (body weight [BW], simplified acute physiology score [SAPS], temperature, serum creatinine level, and creatinine clearance [CLCR]) were tentatively correlated with PK parameters by multivariate linear regression analysis with stepwise addition and deletion. The variability of isepamicin clearance was explained by three covariates (BW, SAPS, and CLCR), that of Vc was explained by BW and SAPS, and that of the elimination half-life was explained by CLCR and SAPS. Simulation of the concentration-versus-time profile for 500 individuals showed that the mean peak (0.75 h) concentration was 18% lower in ICU patients than in healthy volunteers and that the range in ICU patients was very broad (28.4 to 95.4 mg/liter). Therefore, monitoring of the isepamicin concentration is in ICU patients is mandatory. PMID:8849264

Gentamicin Nephrotoxicity in Subclinical Renal Disease.

NASA Astrophysics Data System (ADS)

Frazier, Donita L.

The purpose of the present study was to examine the pharmacokinetic disposition of gentamicin and to define the mechanisms which predispose to nephrotoxicity in subclinical renal disease. Subtotally nephrectomized beagle dogs were used as a model for human beings with compromised renal function secondary to a reduced number of functional nephrons. Using ultrastructural morphometry, light microscopy and clinical chemistry data, the model was defined and the nephrotoxic responses of intact dogs administered recommended doses of drug were compared to the response of subtotally nephrectomized dogs administered reduced doses based on each animal's clearance of drug. Lysosomal and mitochondrial morphometric changes suggested mechanisms for increased sensitivity. To determine if increased sensitivity in this model was dependent on altered serum concentrations, variable rate infusions based on individual pharmacokinetic disposition of drug were administered using computer-driven infusion pumps. Identical serum concentration-time profiles were achieved in normal dogs and subtotally nephrectomized dogs, however, toxicity was significantly greater in nephrectomized dogs. The difference in the nephrotoxic response was characterized by administering supratherapeutic doses of drug to dogs. Nephrectomized dogs given a recommended dose of gentamicin became oliguric during the second week of treatment and increasingly uremic after withdrawal of drug. In contrast, intact dogs administered 2 times the recommended dose of gentamicin become only slightly polyuric during week 4 of treatment. The need to individualize dosage regimens based on drug clearance and not serum creatinine nor creatinine clearance alone was substantiated by describing the pharmacokinetic disposition of gentamicin in spontaneously occurring disease states. Four individualized dosage regimens with differing predicted efficacy were then administered to nephrectomized dogs to determine their relative nephrotoxic potential. Conclusions from these studies include (1) nephrectomized dogs are more susceptible to gentamicin-induced nephrotoxicity than intact dogs, (2) sensitivity is not totally dependent on serum drug concentrations, (3) nephrectomized dogs have hypertrophied nephrons with subcellular alterations in proximal tubule cells, (4) unlike intact dogs, the toxic response in nephrectomized dogs is characterized by oliguria and irreversibility, (5) dosage regimens of aminoglycosides should be based on individual drug disposition since it varies greatly in spontaneous disease states and (6) altered dosage regimens may decrease toxicity and increase efficacy.

Preliminary Diffusive Clearance of Silicon Nanopore Membranes in a Parallel Plate Configuration for Renal Replacement Therapy

PubMed Central

Kim, Steven; Heller, James; Iqbal, Zohora; Kant, Rishi; Kim, Eun Jung; Durack, Jeremy; Saeed, Maythem; Do, Loi; Hetts, Steven; Wilson, Mark; Brakeman, Paul; Fissell, William H.; Roy, Shuvo

2015-01-01

Silicon nanopore membranes (SNM) with compact geometry and uniform pore size distribution have demonstrated a remarkable capacity for hemofiltration. These advantages could potentially be used for hemodialysis. Here we present an initial evaluation of the SNM’s mechanical robustness, diffusive clearance, and hemocompatibility in a parallel plate configuration. Mechanical robustness of the SNM was demonstrated by exposing membranes to high flows (200ml/min) and pressures (1,448mmHg). Diffusive clearance was performed in an albumin solution and whole blood with blood and dialysate flow rates of 25ml/min. Hemocompatibility was evaluated using scanning electron microscopy and immunohistochemistry after 4-hours in an extra-corporeal porcine model. The pressure drop across the flow cell was 4.6mmHg at 200ml/min. Mechanical testing showed that SNM could withstand up to 775.7mmHg without fracture. Urea clearance did not show an appreciable decline in blood versus albumin solution. Extra-corporeal studies showed blood was successfully driven via the arterial-venous pressure differential without thrombus formation. Bare silicon showed increased cell adhesion with a 4.1 fold increase and 1.8 fold increase over polyethylene-glycol (PEG)-coated surfaces for tissue plasminogen factor (t-PA) and platelet adhesion (CD-41), respectively. These initial results warrant further design and development of a fully scaled SNM-based parallel plate dialyzer for renal replacement therapy. PMID:26692401

Numerical simulation of steady three-dimensional flows in axial turbomachinery bladerows

NASA Astrophysics Data System (ADS)

Basson, Anton Herman

The formulation for and application of a numerical model for low Mach number steady three-dimensional flows in axial turbomachinery blade rows is presented. The formulation considered here includes an efficient grid generation scheme (particularly suited to computational grids for the analysis of turbulent turbomachinery flows) and a semi-implicit, pressure-based computational fluid dynamics scheme that directly includes artificial dissipation, applicable to viscous and inviscid flows. The grid generation technique uses a combination of algebraic and elliptic methods, in conjunction with the Minimal Residual Method, to economically generate smooth structured grids. For typical H-grids in turbomachinery bladerows, when compared to a purely elliptic grid generation scheme, the presented grid generation scheme produces grids with much improved smoothness near the leading and trailing edges, allows the use of small near wall grid spacing required by low Reynolds number turbulence models, and maintains orthogonality of the grid near the solid boundaries even for high flow angle cascades. A specialized embedded H-grid for application particularly to tip clearance flows is presented. This topology smoothly discretizes the domain without modifying the tip shape, while requiring only minor modifications to H-grid flow solvers. Better quantitative modeling of the tip clearance vortex structure than that obtained with a pinched tip approximation is demonstrated. The formulation of artificial dissipation terms for a semi-implicit, pressure-based (SIMPLE type) flow solver, is presented. It is applied to both the Euler and the Navier-Stokes equations, expressed in generalized coordinates using a non-staggered grid. This formulation is compared to some SIMPLE and time marching formulations, revealing the artificial dissipation inherent in some commonly used semi-implicit formulations. The effect of the amount of dissipation on the accuracy of the solution and the convergence rate is quantitatively demonstrated for a number of flow cases. The ability of the formulation to model complex steady turbomachinery flows is demonstrated, e.g. for pressure driven secondary flows, turbine nozzle wakes, turbulent boundary layers. The formulation's modeling of blade surface heat transfer is assessed. The numerical model is used to investigate the structure of phenomena associated with tip clearance flows in a turbine nozzle.

Comparison of Bite Registration Material Accuracy on in office Laser Scanned Digital Model Occlusion

DTIC Science & Technology

2014-05-20

School/Department/Center: Two Year Advanced Education in General Dentistry . Fort Bragg,NC 4. Phone:910-429-6626 5. Type of clearance: _X_Paper...Date: 11.~ l~ 4. Higher approval clearance required (for University-, DoD- or US Gov’t-level policy, communication systems or weapons issues review...or US Gov’t-level policy, communications systems or weapons issues review). *Note: It is DoD policy that clearance of information or material

Interstitial fluid drainage is impaired in ischemic stroke and Alzheimer’s disease mouse models

PubMed Central

Arbel-Ornath, Michal; Hudry, Eloise; Eikermann-Haerter, Katharina; Hou, Steven; Gregory, Julia L.; Zhao, Lingzhi; Betensky, Rebecca A.; Frosch, Matthew P.; Greenberg, Steven M.; Bacskai, Brian J.

2013-01-01

The interstitial fluid (ISF) drainage pathway has been hypothesized to underlie the clearance of solutes and metabolites from the brain. Previous work has implicated the perivascular spaces along arteries as the likely route for ISF clearance, however it has never been demonstrated directly. The accumulation of amyloid β (Aβ) peptides in brain parenchyma is one of the pathological hallmarks of Alzheimer disease (AD), and it is likely related to an imbalance between production and clearance of the peptide. Aβ drainage along perivascular spaces has been postulated to be one of the mechanisms that mediates the peptide clearance from the brain. We therefore devised a novel method to visualize solute clearance in real time in the living mouse brain using laser guided bolus dye injections and multiphoton imaging. This methodology allows high spatial and temporal resolution and revealed the kinetics of ISF clearance. We found that the ISF drains along perivascular spaces of arteries and capillaries but not veins, and its clearance exhibits a bi-exponential profile. ISF drainage requires a functional vasculature, as solute clearance decreased when perfusion was impaired. In addition, reduced solute clearance was observed in transgenic mice with significant vascular amyloid deposition; we suggest the existence of a feed-forward mechanism, by which amyloid deposition promotes further amyloid deposition. This important finding provides a mechanistic link between cerebrovascular disease and Alzheimer disease and suggests that facilitation of Aβ clearance along the perivascular pathway should be considered as a new target for therapeutic approaches to AD and CAA. PMID:23818064

The influence of size, clearance, cartilage properties, thickness and hemiarthroplasty on the contact mechanics of the hip joint with biphasic layers☆

PubMed Central

Li, Junyan; Stewart, Todd D.; Jin, Zhongmin; Wilcox, Ruth K.; Fisher, John

2013-01-01

Computational models of the natural hip joint are needed to examine and optimise tissue sparing interventions where the natural cartilage remains part of the bearing surfaces. Although the importance of interstitial fluid pressurisation in the performance of cartilage has long been recognized, few studies have investigated the time dependent interstitial fluid pressurisation in a three dimensional natural hip joint model. The primary aim of this study was to develop a finite element model of the natural hip incorporating the biphasic cartilage layers that was capable of simulating the joint response over a prolonged physiological loading period. An initial set of sensitivity studies were also undertaken to investigate the influence of hip size, clearance, cartilage properties, thickness and hemiarthroplasty on the contact mechanics of the joint. The contact stress, contact area, fluid pressure and fluid support ratio were calculated and cross-compared between models with different parameters to evaluate their influence. It was found that the model predictions for the period soon after loading were sensitive to the hip size, clearance, cartilage aggregate modulus, thickness and hemiarthroplasty, while the time dependent behaviour over 3000 s was influenced by the hip clearance and cartilage aggregate modulus, permeability, thickness and hemiarthroplasty. The modelling methods developed in this study provide a basic platform for biphasic simulation of the whole hip joint onto which more sophisticated material models or other input parameters could be added in the future. PMID:23664238

An analysis of the viscous flow through a compact radial turbine by the average passage approach

NASA Technical Reports Server (NTRS)

Heidmann, James D.; Beach, Timothy A.

1990-01-01

A steady, three-dimensional viscous average passage computer code is used to analyze the flow through a compact radial turbine rotor. The code models the flow as spatially periodic from blade passage to blade passage. Results from the code using varying computational models are compared with each other and with experimental data. These results include blade surface velocities and pressures, exit vorticity and entropy contour plots, shroud pressures, and spanwise exit total temperature, total pressure, and swirl distributions. The three computational models used are inviscid, viscous with no blade clearance, and viscous with blade clearance. It is found that modeling viscous effects improves correlation with experimental data, while modeling hub and tip clearances further improves some comparisons. Experimental results such as a local maximum of exit swirl, reduced exit total pressures at the walls, and exit total temperature magnitudes are explained by interpretation of the flow physics and computed secondary flows. Trends in the computed blade loading diagrams are similarly explained.

Iohexol clearance is superior to creatinine-based renal function estimating equations in detecting short-term renal function decline in chronic heart failure

PubMed Central

Cvan Trobec, Katja; Kerec Kos, Mojca; von Haehling, Stephan; Anker, Stefan D.; Macdougall, Iain C.; Ponikowski, Piotr; Lainscak, Mitja

2015-01-01

Aim To compare the performance of iohexol plasma clearance and creatinine-based renal function estimating equations in monitoring longitudinal renal function changes in chronic heart failure (CHF) patients, and to assess the effects of body composition on the equation performance. Methods Iohexol plasma clearance was measured in 43 CHF patients at baseline and after at least 6 months. Simultaneously, renal function was estimated with five creatinine-based equations (four- and six-variable Modification of Diet in Renal Disease, Cockcroft-Gault, Cockcroft-Gault adjusted for lean body mass, Chronic Kidney Disease Epidemiology Collaboration equation) and body composition was assessed using bioimpedance and dual-energy x-ray absorptiometry. Results Over a median follow-up of 7.5 months (range 6-17 months), iohexol clearance significantly declined (52.8 vs 44.4 mL/[min ×1.73 m2], P = 0.001). This decline was significantly higher in patients receiving mineralocorticoid receptor antagonists at baseline (mean decline -22% of baseline value vs -3%, P = 0.037). Mean serum creatinine concentration did not change significantly during follow-up and no creatinine-based renal function estimating equation was able to detect the significant longitudinal decline of renal function determined by iohexol clearance. After accounting for body composition, the accuracy of the equations improved, but not their ability to detect renal function decline. Conclusions Renal function measured with iohexol plasma clearance showed relevant decline in CHF patients, particularly in those treated with mineralocorticoid receptor antagonists. None of the equations for renal function estimation was able to detect these changes. ClinicalTrials.gov registration number NCT01829880 PMID:26718759

Inter-laboratory comparison of xenobiotic clearance rates determined using cryopreserved trout hepatocytes for improving bioaccumulation predictions

EPA Science Inventory

Hepatic biotransformation is an important determinant of chemical bioaccumulation in fish. Consequently, bioaccumulation models can be improved using estimates of chemical biotransformation rates. Cryopreserved trout hepatocytes have been used to measure the clearance rates of so...

An investigation of rotor tip leakage flows in the rear-block of a multistage compressor

NASA Astrophysics Data System (ADS)

Brossman, John Richard

An effective method to improve gas turbine propulsive efficiency is to increase the bypass ratio. With fan diameter reaching a practical limit, increases in bypass ratio can be obtained from reduced core engine size. Decreasing the engine core, results in small, high pressure compressor blading, and large relative tip clearances. At general rule of 1% reduction in compressor efficiency with a 1% increase in tip clearance, a 0.66% change in SFC indicates the entire engine is sensitive to high pressure compressor tip leakage flows. Therefore, further investigations and understanding of the rotor tip leakage flows can help to improve gas turbine engine efficiency. The objectives of this research were to investigate tip leakage flows through computational modeling, examine the baseline experimental steady-stage performance, and acquire unsteady static pressure, over-the rotor to observe the tip leakage flow structure. While tip leakage flows have been investigated in the past, there have been no facilities capable of matching engine representative Reynolds number and Mach number while maintaining blade row interactions, presenting a unique and original flow field to investigate at the Purdue 3-stage axial compressor facility. To aid the design of experimental hardware and determine the influence of clearance geometry on compressor performance, a computational model of the Purdue 3-stage compressor was investigated using a steady RANS CFD analysis. A cropped rotor and casing recess design was investigated to increase the rotor tip clearance. While there were small performance differences between the geometries, the tip leakage flow field was found independent of the design therefore designing future experimental hardware around a casing recess is valid. The largest clearance with flow margin past the design point was 4% tip clearance based on the computational model. The Purdue 3-stage axial compressor facility was rebuilt and setup for high quality, detailed flow measurements during this investigation. A detailed investigation and sensitivity analysis of the inlet flow field found the influence by the inlet total temperature profile was important to performance calculations. This finding was significant and original as previous investigations have been conducted on low-speed machines where there is minimal temperature rise. The steady state performance of the baseline 1.5% tip clearance case was outlined at design speed and three off-design speeds. The leakage flow from the rear seal, the inlet flow field and a thermal boundary condition over the casing was recorded at each operating point. Stage 1 was found to be the limiting stage independent of speed. Few datasets exist on multistage compressor performance with full boundary condition definitions, especially with off-design operating points presenting this as a unique dataset for CFD comparison. The detailed unsteady pressure measurements were conducted over Rotor 1 at design and a near-stall operating condition to characterize the leakage trajectory and position. The leakage flow initial point closer to the leading edge and trajectory angle increased at the higher loading condition. The over-the-rotor static pressure field on Rotor 1 indicated similar trends between the computational model and the leakage trajectory.

A population pharmacokinetic model of valproic acid in pediatric patients with epilepsy: a non-linear pharmacokinetic model based on protein-binding saturation.

PubMed

Ding, Junjie; Wang, Yi; Lin, Weiwei; Wang, Changlian; Zhao, Limei; Li, Xingang; Zhao, Zhigang; Miao, Liyan; Jiao, Zheng

2015-03-01

Valproic acid (VPA) follows a non-linear pharmacokinetic profile in terms of protein-binding saturation. The total daily dose regarding VPA clearance is a simple power function, which may partially explain the non-linearity of the pharmacokinetic profile; however, it may be confounded by the therapeutic drug monitoring effect. The aim of this study was to develop a population pharmacokinetic model for VPA based on protein-binding saturation in pediatric patients with epilepsy. A total of 1,107 VPA serum trough concentrations at steady state were collected from 902 epileptic pediatric patients aged from 3 weeks to 14 years at three hospitals. The population pharmacokinetic model was developed using NONMEM(®) software. The ability of three candidate models (the simple power exponent model, the dose-dependent maximum effect [DDE] model, and the protein-binding model) to describe the non-linear pharmacokinetic profile of VPA was investigated, and potential covariates were screened using a stepwise approach. Bootstrap, normalized prediction distribution errors and external evaluations from two independent studies were performed to determine the stability and predictive performance of the candidate models. The age-dependent exponent model described the effects of body weight and age on the clearance well. Co-medication with carbamazepine was identified as a significant covariate. The DDE model best fitted the aim of this study, although there were no obvious differences in the predictive performances. The condition number was less than 500, and the precision of the parameter estimates was less than 30 %, indicating stability and validity of the final model. The DDE model successfully described the non-linear pharmacokinetics of VPA. Furthermore, the proposed population pharmacokinetic model of VPA can be used to design rational dosage regimens to achieve desirable serum concentrations.

Population pharmacokinetic modelling of the changes in atazanavir plasma clearance caused by ritonavir plasma concentrations in HIV‐1 infected patients

PubMed Central

Moltó, José; Estévez, Javier A.; Miranda, Cristina; Cedeño, Samandhy; Clotet, Bonaventura

2016-01-01

Aims The aim of the present study was to develop a simultaneous population pharmacokinetic model for atazanavir (ATV) incorporating the effect of ritonavir (RTV) on clearance to predict ATV concentrations under different dosing regimens in HIV‐1‐infected patients. Methods A Cross‐sectional study was carried out in 83 HIV‐1‐infected adults taking ATV 400 mg or ATV 300 mg/RTV 100 mg once daily. Demographic and clinical characteristics were registered and blood samples collected to measure drug concentrations. A population pharmacokinetic model was constructed using nonlinear mixed‐effects modelling and used to simulate six dosing scenarios. Results The selected one‐compartmental model described the pharmacokinetics of RTV and ATV simultaneously, showing exponential, direct inhibition of ATV clearance according to the RTV plasma concentration, which explained 17.5% of the variability. A mean RTV plasma concentration of 0.63 mg l–1 predicted an 18% decrease in ATV clearance. The percentages of patients with an end‐of‐dose‐interval concentration of ATV below or above the minimum and maximum target concentrations of 0.15 mg l–1 and 0.85 mg l–1 favoured the selection of the simulated ATV/RTV once‐daily regimens (ATV 400 mg, ATV 300 mg/RTV 100 mg, ATV 300 mg/RTV 50 mg, ATV 200/RTV 100 mg) over the unboosted twice‐daily regimens (ATV 300 mg, ATV 200 mg). Conclusions A one‐compartment simultaneous model can describe the pharmacokinetics of RTV and ATV, including the effect of RTV plasma concentrations on ATV clearance. This model is promising for predicting individuals' ATV concentrations in clinical scenarios, and supports further clinical trials of once‐daily doses of ATV 300 mg/RTV 50 mg or ATV 200 mg/RTV 100 mg to confirm efficacy and safety. PMID:27447851

Determination of a quantitative relationship between hepatic CYP3A5*1/*3 and CYP3A4 expression for use in the prediction of metabolic clearance in virtual populations.

PubMed

Barter, Z E; Perrett, H F; Yeo, K Rowland; Allorge, D; Lennard, M S; Rostami-Hodjegan, A

2010-11-01

The creation of virtual populations allows the estimation of pharmacokinetic parameters, such as metabolic clearance in extreme individuals rather than the 'average human'. Prediction of variability in metabolic clearance within genetically diverse populations relies on understanding the covariation in the expression of enzymes. A number of statistically significant positive correlations have been observed in the hepatic expression of cytochrome P450 drug metabolising enzymes. However, these rarely provided a quantitative description of the relationships which is required in creating virtual populations. Collation of data from 40 human liver microsomal samples in the current study indicated a significant positive relationship between hepatic microsomal CYP3A5*1/*3 and CYP3A4 content. Having developed a model describing the relationship between hepatic CYP3A4 and CYP3A5*1/*3, the Simcyp Population-based Simulator(®) was used to investigate the consequences of either incorporating or ignoring the relationship between the two enzymes on estimates of drug clearance. Simulations indicated that for a compound with greater metabolism by CYP3A5 than CYP3A4, such as tacrolimus, incorporation of the correlation between CYP3A4 and CYP3A5 does have an impact on the prediction of oral clearance. Failure to consider the relationship between CYP3A4 and CYP3A5 when creating the virtual population led to a 32% lower estimate of oral clearance in individuals possessing both the CYP3A5*1/*3 genotype and high basal concentrations of CYP3A4. Potential clinical implications may include an inadequate dose estimation during clinical study design, the consequences of which may include organ rejection in transplant recipients using immunosuppressants such as tacrolimus or toxicity due to elevated concentrations of circulating metabolites. Copyright © 2010 John Wiley & Sons, Ltd.

Population pharmacokinetics of perphenazine in schizophrenia patients from CATIE: impact of race and smoking.

PubMed

Jin, Yuyan; Pollock, Bruce G; Coley, Kim; Miller, Del; Marder, Stephen R; Florian, Jeff; Schneider, Lon; Lieberman, Jeffrey; Kirshner, Margaret; Bies, Robert R

2010-01-01

The goal of the study was to characterize population pharmacokinetics (PPK) for perphenazine in patients with schizophrenia from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Patients (n = 156) received 8 to 32 mg of perphenazine daily for 14 to 600 days for a total of 421 plasma concentrations measurements. Nonlinear mixed-effects modeling was used to determine PPK characteristics of perphenazine. One- and 2-compartment models with various random effect implementations and mixture distributions were evaluated. Objective function values and goodness-of-fit plots were used as model selection criteria. Age, weight, sex, race, smoking, and concomitant medications were evaluated as covariates. A 1-compartment linear model with proportional error best described the data. The population mean clearance and volume of distribution for perphenazine were 483 L/h and 18 200 L, respectively. Race and smoking status had significant impacts on perphenazine clearance estimates. In addition, the estimated population mean clearance was 48% higher in nonsmoking African Americans than in nonsmoking other races (512 L/h vs 346 L/h). Active smokers eliminated perphenazine 159 L/h faster than nonsmokers in each race. Clearances for smoking African Americans versus smokers in other races were 671 L/h versus 505 L/h, respectively.

A Parametric Study of Actuator Requirements for Active Turbine Tip Clearance Control of a Modern High Bypass Turbofan Engine

NASA Technical Reports Server (NTRS)

Kratz, Jonathan L.; Chapman, Jeffryes W.; Guo, Ten-Huei

2017-01-01

The efficiency of aircraft gas turbine engines is sensitive to the distance between the tips of its turbine blades and its shroud, which serves as its containment structure. Maintaining tighter clearance between these components has been shown to increase turbine efficiency, increase fuel efficiency, and reduce the turbine inlet temperature, and this correlates to a longer time-on-wing for the engine. Therefore, there is a desire to maintain a tight clearance in the turbine, which requires fast response active clearance control. Fast response active tip clearance control will require an actuator to modify the physical or effective tip clearance in the turbine. This paper evaluates the requirements of a generic active turbine tip clearance actuator for a modern commercial aircraft engine using the Commercial Modular Aero-Propulsion System Simulation 40k (C-MAPSS40k) software that has previously been integrated with a dynamic tip clearance model. A parametric study was performed in an attempt to evaluate requirements for control actuators in terms of bandwidth, rate limits, saturation limits, and deadband. Constraints on the weight of the actuation system and some considerations as to the force which the actuator must be capable of exerting and maintaining are also investigated. From the results, the relevant range of the evaluated actuator parameters can be extracted. Some additional discussion is provided on the challenges posed by the tip clearance control problem and the implications for future small core aircraft engines.

Erosion estimation of guide vane end clearance in hydraulic turbines with sediment water flow

NASA Astrophysics Data System (ADS)

Han, Wei; Kang, Jingbo; Wang, Jie; Peng, Guoyi; Li, Lianyuan; Su, Min

2018-04-01

The end surface of guide vane or head cover is one of the most serious parts of sediment erosion for high-head hydraulic turbines. In order to investigate the relationship between erosion depth of wall surface and the characteristic parameter of erosion, an estimative method including a simplified flow model and a modificatory erosion calculative function is proposed in this paper. The flow between the end surfaces of guide vane and head cover is simplified as a clearance flow around a circular cylinder with a backward facing step. Erosion characteristic parameter of csws3 is calculated with the mixture model for multiphase flow and the renormalization group (RNG) k-𝜀 turbulence model under the actual working conditions, based on which, erosion depths of guide vane and head cover end surfaces are estimated with a modification of erosion coefficient K. The estimation results agree well with the actual situation. It is shown that the estimative method is reasonable for erosion prediction of guide vane and can provide a significant reference to determine the optimal maintenance cycle for hydraulic turbine in the future.

Influence of backup bearings and support structure dynamics on the behavior of rotors with active supports

NASA Technical Reports Server (NTRS)

Flowers, George T.

1994-01-01

Substantial progress has been made toward the goals of this research effort in the past six months. A simplified rotor model with a flexible shaft and backup bearings has been developed. The model is based upon the work of Ishii and Kirk. Parameter studies of the behavior of this model are currently being conducted. A simple rotor model which includes a flexible disk and bearings with clearance has been developed and the dynamics of the model investigated. The study consists of simulation work coupled with experimental verification. The work is documented in the attached paper. A rotor model based upon the T-501 engine has been developed which includes backup bearing effects. The dynamics of this model are currently being studied with the objective of verifying the conclusions obtained from the simpler models. Parallel simulation runs are being conducted using an ANSYS based finite element model of the T-501.

Application of physiologically-based pharmacokinetic modeling to explore the role of kidney transporters in renal reabsorption of perfluorooctanoic acid in the rat

DOE Office of Scientific and Technical Information (OSTI.GOV)

Worley, Rachel Rogers, E-mail: idz7@cdc.gov; Interdisciplinary Toxicology Program, University of Georgia, 341 Pharmacy South, Athens, GA 30602; Fisher, Jeffrey

ABSTRACT: Renal elimination and the resulting clearance of perfluorooctanoic acid (PFOA) from the serum exhibit pronounced sex differences in the adult rat. The literature suggests that this is largely due to hormonally regulated expression of organic anion transporters (OATs) on the apical and basolateral membranes of the proximal tubule cells that facilitate excretion and reabsorption of PFOA from the filtrate into the blood. Previously developed PBPK models of PFOA exposure in the rat have not been parameterized to specifically account for transporter-mediated renal elimination. We developed a PBPK model for PFOA in male and female rats to explore the rolemore » of Oat1, Oat3, and Oatp1a1 in sex-specific renal reabsorption and excretion of PFOA. Descriptions of the kinetic behavior of these transporters were extrapolated from in vitro studies and the model was used to simulate time-course serum, liver, and urine data for intravenous (IV) and oral exposures in both sexes. Model predicted concentrations of PFOA in the liver, serum, and urine showed good agreement with experimental data for both male and female rats indicating that in vitro derived physiological descriptions of transporter-mediated renal reabsorption can successfully predict sex-dependent excretion of PFOA in the rat. This study supports the hypothesis that sex-specific serum half-lives for PFOA are largely driven by expression of transporters in the kidney and contribute to the development of PBPK modeling as a tool for evaluating the role of transporters in renal clearance. - Highlights: • The PBPK model for PFOA in the rat explores the role of OATs in sex-specific clearance. • Descriptions of OAT kinetics were extrapolated from in vitro studies. • Model predictions showed good fit with experimental data for male and female rats.« less

A high-fidelity airbus benchmark for system fault detection and isolation and flight control law clearance

NASA Astrophysics Data System (ADS)

Goupil, Ph.; Puyou, G.

2013-12-01

This paper presents a high-fidelity generic twin engine civil aircraft model developed by Airbus for advanced flight control system research. The main features of this benchmark are described to make the reader aware of the model complexity and representativeness. It is a complete representation including the nonlinear rigid-body aircraft model with a full set of control surfaces, actuator models, sensor models, flight control laws (FCL), and pilot inputs. Two applications of this benchmark in the framework of European projects are presented: FCL clearance using optimization and advanced fault detection and diagnosis (FDD).

Method to improve the blade tip-timing accuracy of fiber bundle sensor under varying tip clearance

NASA Astrophysics Data System (ADS)

Duan, Fajie; Zhang, Jilong; Jiang, Jiajia; Guo, Haotian; Ye, Dechao

2016-01-01

Blade vibration measurement based on the blade tip-timing method has become an industry-standard procedure. Fiber bundle sensors are widely used for tip-timing measurement. However, the variation of clearance between the sensor and the blade will bring a tip-timing error to fiber bundle sensors due to the change in signal amplitude. This article presents methods based on software and hardware to reduce the error caused by the tip clearance change. The software method utilizes both the rising and falling edges of the tip-timing signal to determine the blade arrival time, and a calibration process suitable for asymmetric tip-timing signals is presented. The hardware method uses an automatic gain control circuit to stabilize the signal amplitude. Experiments are conducted and the results prove that both methods can effectively reduce the impact of tip clearance variation on the blade tip-timing and improve the accuracy of measurements.

Contributions of SERCA pump and ryanodine-sensitive stores to presynaptic residual Ca2+

PubMed Central

Scullin, Chessa S.; Partridge, L. Donald

2010-01-01

The presynaptic Ca2+ signal, which triggers vesicle release, disperses to a broadly distributed residual [Ca2+] ([Ca2+]res) that plays an important role in synaptic plasticity. We have previously reported a slowing in the decay timecourse of [Ca2+]res during the second of paired pulses. In this study, we investigated the contributions of organelle and plasma membrane Ca2+ flux pathways to the reduction of effectiveness of [Ca2+]res clearance during short-term plasticity in Schaffer collateral terminals in the CA1 field of the hippocampus. We show that the slowed decay timecourse is mainly the result of a transport-dependent Ca2+ clearance process; that presynaptic caffeine-sensitive Ca2+ stores are not functionally loaded in the unstimulated terminal, but that these stores can effectively take up Ca2+ even during high frequency trains of stimuli; and that a rate limiting step of sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) kinetics following the first pulse is responsible for a large portion of the observed slowing of [Ca2+]res clearance during the second pulse. We were able to accurately fit our [Ca2+]res data with a kinetic model based on these observations and this model predicted a reduction in availability of unbound SERCA during paired pulses, but no saturation of Ca2+ buffer in the endoplasmic reticulum. PMID:20153896

[Development of Markov models for economics evaluation of strategies on hepatitis B vaccination and population-based antiviral treatment in China].

PubMed

Yang, P C; Zhang, S X; Sun, P P; Cai, Y L; Lin, Y; Zou, Y H

2017-07-10

Objective: To construct the Markov models to reflect the reality of prevention and treatment interventions against hepatitis B virus (HBV) infection, simulate the natural history of HBV infection in different age groups and provide evidence for the economics evaluations of hepatitis B vaccination and population-based antiviral treatment in China. Methods: According to the theory and techniques of Markov chain, the Markov models of Chinese HBV epidemic were developed based on the national data and related literature both at home and abroad, including the settings of Markov model states, allowable transitions and initial and transition probabilities. The model construction, operation and verification were conducted by using software TreeAge Pro 2015. Results: Several types of Markov models were constructed to describe the disease progression of HBV infection in neonatal period, perinatal period or adulthood, the progression of chronic hepatitis B after antiviral therapy, hepatitis B prevention and control in adults, chronic hepatitis B antiviral treatment and the natural progression of chronic hepatitis B in general population. The model for the newborn was fundamental which included ten states, i.e . susceptiblity to HBV, HBsAg clearance, immune tolerance, immune clearance, low replication, HBeAg negative CHB, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma (HCC) and death. The susceptible state to HBV was excluded in the perinatal period model, and the immune tolerance state was excluded in the adulthood model. The model for general population only included two states, survive and death. Among the 5 types of models, there were 9 initial states assigned with initial probabilities, and 27 states for transition probabilities. The results of model verifications showed that the probability curves were basically consistent with the situation of HBV epidemic in China. Conclusion: The Markov models developed can be used in economics evaluation of hepatitis B vaccination and treatment for the elimination of HBV infection in China though the structures and parameters in the model have uncertainty with dynamic natures.

A model for size and age changes in the pharmacokinetics of paracetamol in neonates, infants and children

PubMed Central

Anderson, Brian J; Woollard, Gerald A; Holford, Nicholas H G

2000-01-01

Aims The aims of this study were to describe paracetamol pharmacokinetics in neonates and infants. Methods Infants in their first 3 months of life (n = 30) were randomised to sequentially receive one of three paracetamol formulations (dose 30–40 mg kg−1) over a 2 day period. The formulations were (a) elixir, (b) glycogelatin capsule suppository and (c) triglyceride base suppository. Approximately six blood samples were taken after each dose over the subsequent 10–16 h. Data were analysed using a nonlinear mixed effect model. These neonatal and infant data were then included with data from four published studies of paracetamol pharmacokinetics (n = 221) and age-related pharmacokinetic changes investigated. Results Population pharmacokinetic parameter estimates and their coefficients of variation (CV%) for a one compartment model with first order input, lag time and first order elimination were volume of distribution 69.9 (18%) l and clearance 13.0 (41%) l h−1 (standardized to a 70 kg person). The volume of distribution decreased exponentially with a half-life of 1.9 days from 120 l 70 kg−1 at birth to 69.9 l 70 kg−1 by 14 days. Clearance increased from birth (4.9 l h−1 70 kg−1) with a half-life of 3.25 months to reach 12.4 l h−1 70 kg−1 by 12 months. The absorption half-life (tabs) for the oral preparation was 0.13 (154%) h with a lag time (tlag) of 0.39 h (31%). Absorption parameters for the triglyceride base and capsule suppositories were tabs 1.34 (90%) h, tlag 0.14 h (31%) and tabs 0.65 (63%) h, tlag 0.54 h (31%), respectively. The tabs for elixir and capsule suppository in children under 3 months were 3.68 and 1.51 times greater than children over 3 months. The relative bioavailability of rectal formulations compared with elixir were 0.67 (30%) and 0.61 (23%) for the triglyceride base and capsule suppositories, respectively. Conclusions Total body clearance of paracetamol at birth is 62% and volume of distribution 174% that of older children. A target concentration above 10 mg l−1 in approximately 50% subjects can be achieved by a dose from 45 mg kg−1 day−1 at birth and up to 90 mg kg−1 day−1 in 5-year-old children. A reduced dose of 75 mg kg−1 day−1 in an 8-year-old child is sufficient because clearance is a nonlinear function of weight. PMID:10930964

Apoptotic Cell Clearance in Development.

PubMed

Shklover, Jeny; Levy-Adam, Flonia; Kurant, Estee

2015-01-01

Programmed cell death and its specific form apoptosis play an important role during development of multicellular organisms. They are crucial for morphogenesis and organ sculpting as well as for adjusting cell number in different systems. Removal of apoptotic cells is the last critical step of apoptosis. Apoptotic cells are properly and efficiently recognized and eliminated through phagocytosis, which is performed by professional and nonprofessional phagocytes. Phagocytosis of apoptotic cells or apoptotic cell clearance is a dynamic multistep process, involving interactions between phagocytic receptors and ligands on apoptotic cells, which are highly conserved in evolution. However, this process is extremely redundant in mammals, containing multiple factors playing similar roles in the process. Using model organisms such as Caenorhabditis elegans, Drosophila melanogaster, zebrafish, and mouse permits addressing fundamental questions in developmental cell clearance by a comprehensive approach including powerful genetics and cell biological tools enriched by live imaging. Recent studies in model organisms have enhanced significantly our understanding of the molecular and cellular basis of apoptotic cell clearance during development. Here, we review the current knowledge and illuminate the great potential of the research performed in genetic models, which opens new directions in developmental biology. © 2015 Elsevier Inc. All rights reserved.

Designing a Quantitative Structure-Activity Relationship for the Intrinsic Metabolic Clearance of Environmentally Relevant Chemicals

EPA Science Inventory

Toxicokinetic models serve a vital role in risk assessment by bridging the gap between chemical exposure and potentially toxic endpoints. While intrinsic metabolic clearance rates have a strong impact on toxicokinetics, limited data is available for environmentally relevant chemi...

The impact of age on lamotrigine and oxcarbazepine kinetics: a historical cohort study.

PubMed

Wegner, Ilse; Wilhelm, Abraham J; Sander, Josemir W; Lindhout, Dick

2013-10-01

Age as well as estrogen levels may have an impact on the pharmacokinetics of lamotrigine (LTG) and monohydroxycarbazepine (MHD), the active metabolite of oxcarbazepine (OXC). To assess the effects of age and menopause, we evaluated retrospectively a therapeutic drug-monitoring database. Samples from 507 women and 302 men taking LTG and 464 women and 319 men taking OXC were used to develop a population pharmacokinetic model. Data were analyzed using NONMEM software and were compared with a population pharmacokinetic model based on samples of 1705 women and 1771 men taking carbamazepine (CBZ). Age was a significant factor contributing to pharmacokinetic variability in individuals using LTG, OXC, and CBZ with increasing clearance as a function of bioavailability (Cl/F) over age 18, a maximum Cl/F at 33years (CBZ) and 36 years (LTG and OXC), and a gradual decrease of Cl/F towards older age. We found no effect of perimenopausal age range on LTG and MHD clearance. © 2013.

IN VITRO ESTIMATES OF METABOLIC PARAMETERS AND THEIR USE IN PREDICTIVE PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING (PBPK) OF THE TYPE I PYRETHROIDS PERMETHRIN AND BIFENTHRIN

EPA Science Inventory

Pyrethroids are a class of neurotoxic insecticides that are used in a variety of agricultural and household activities. Hepatic clearance of the Type I pyrethroids permethrin and bifenthrin may be a critical determinant of their toxic effect. Rat LD50s reported in the literatur...

Dynamic alteration in splenic function during acute falciparum malaria

DOE Office of Scientific and Technical Information (OSTI.GOV)

Looareesuwan, S.; Ho, M.; Wattanagoon, Y.

Plasmodium-infected erythrocytes lose their normal deformability and become susceptible to splenic filtration. In animal models, this is one mechanism of antimalarial defense. To assess the effect of acute falciparum malaria on splenic filtration, we measured the clearance of heated /sup 51/Cr-labeled autologous erythrocytes in 25 patients with acute falciparum malaria and in 10 uninfected controls. Two groups of patients could be distinguished. Sixteen patients had splenomegaly, markedly accelerated clearance of the labeled erythrocytes (clearance half-time, 8.4 +/- 4.4 minutes (mean +/- SD) vs. 62.5 +/- 36.5 minutes in controls; P less than 0.001), and a lower mean hematocrit than didmore » the patients without splenomegaly (P less than 0.001). In the nine patients without splenomegaly, clearance was normal. After institution of antimalarial chemotherapy, however, the clearance in this group accelerated to supernormal rates similar to those in the patients with splenomegaly, but without the development of detectable splenomegaly. Clearance was not significantly altered by treatment in the group with splenomegaly. Six weeks later, normal clearance rates were reestablished in most patients in both groups. We conclude that splenic clearance of labeled erythrocytes is enhanced in patients with malaria if splenomegaly is present and is enhanced only after treatment if splenomegaly is absent. Whether this enhanced splenic function applies to parasite-infected erythrocytes in patients with malaria and has any clinical benefit will require further studies.« less

Clearance Properties of Nano-sized Particles and Molecules as Imaging Agents: Considerations and Caveats

PubMed Central

Longmire, Michelle; Choyke, Peter L.; Kobayashi, Hisataka

2009-01-01

Summary Nanoparticles possess enormous potential as diagnostic imaging agents and hold promise for the development of multimodality agents with both imaging and therapeutic capabilities. Yet, some of the most promising nanoparticles demonstrate prolonged tissue retention and contain heavy metals. This presents serious concerns for toxicity. The creation of nanoparticles with optimal clearance characteristics will minimize toxicity risks by reducing the duration of exposure to these agents. Given that many nanoparticles possess easily modifiable surface and interior chemistry, if nanoparticle characteristics associated with optimal clearance from the body were well established, it would be feasible to design and create agents with more favorable clearance properties. This paper presents a thorough discussion of the physiologic aspects of nanoparticle clearance, focusing on renal mechanisms, as well as provides an overview of current research investigating clearance of specific types of nanoparticles and nano-sized macromolecules, including dendrimers, quantum dots, liposomes and carbon, gold, and silica-based nanoparticles. PMID:18817471

Aerodynamic analysis of Audi A4 Sedan using CFD

NASA Astrophysics Data System (ADS)

Birwa, S. K.; Rathi, N.; Gupta, R.

2013-04-01

This paper presents the aerodynamic influence of velocity and ground clearance for Audi A4 Sedan. The topology of the test vehicle was modeled using CATIA P3 V5 R17. ANSYS FLUENT 12 was the CFD solver employed in this study. The distribution of pressure and velocity was obtained. The velocities were 30, 40, 50 and 60 m/s and ground clearances were 76.2 mm,101.6 mm,127 mm and 152.4 mm. The simulation results were compared with the available resources. It was found that the drag coefficient decreases with the velocity increasing from 30 to 60 m/s and increases with the ground clearance from 101.6 mm to 152.4 mm. Further decrease in ground clearance showed no effect on the value of coefficient of drag. The lift coefficient was found to decrease firstly with ground clearance from 152.4 mm to 101.6 mm, and then increase from 101.6 mm to 76.2 mm. Both the lift coefficient and drag coefficient was found to be minimum for the ground clearance of 101.6 mm as designed by the company.

Nano-Advantage in Enhanced Drug Delivery with Biodegradable Nanoparticles: Contribution of Reduced Clearance

PubMed Central

Kadam, Rajendra S.; Bourne, David W. A.

2012-01-01

The aim of this study was to investigate the contribution of reduced apparent clearance to the enhanced exposure reported for biodegradable nanoparticles after extravascular and intravascular routes of administration. Plasma concentration profiles for drug and nanoparticle formulations after administration by intravenous, intraduodenal, and oral routes were extracted from the literature. Data were fit to pharmacokinetic models using BOOMER. The compartmental pharmacokinetic analysis of literature data for six drugs (camptothecin, 9-nitrocamptothecin, epirubicin, vinpocetine, clozapine, and cyclosporine) showed that the encapsulation of drug molecules in nanoparticles significantly reduced the apparent clearance and prolonged the apparent circulation half-life compared with those for the plain drug. Positively charged nanoparticles assessed in this study had lower apparent clearance, lower elimination rate constant values, and longer apparent circulation half-life than neutral and negatively charged nanoparticles. After oral administration, a reduction in apparent clearance contributed substantially to elevations in plasma drug exposure with nanoparticles. For the drugs and delivery systems examined, the nano-advantage in drug delivery enhancement can be explained, in part, by reduced clearance. PMID:22498894

Cervical Spine Clearance in Pediatric Trauma Centers: The Need for Standardization and an Evidence-based Protocol.

PubMed

Pannu, Gurpal S; Shah, Mitesh P; Herman, Marty J

Cervical spine clearance in the pediatric trauma patient represents a particularly challenging task. Unfortunately, standardized clearance protocols for pediatric cervical clearance are poorly reported in the literature and imaging recommendations demonstrate considerable variability. With the use of a web-based survey, this study aims to define the methods utilized by pediatric trauma centers throughout North America. Specific attention was given to the identification of personnel responsible for cervical spine care, diagnostic imaging modalities used, and the presence or absence of a written pediatric cervical spine clearance protocol. A 10-question electronic survey was given to members of the newly formed Pediatric Cervical Spine Study Group, all of whom are active POSNA members. The survey was submitted via the online service SurveyMonkey (https://www.surveymonkey.com/r/7NVVQZR). The survey assessed the respondent's institution demographics, such as trauma level and services primarily responsible for consultation and operative management of cervical spine injuries. In addition, respondents were asked to identify the protocols and primary imaging modality used for cervical spine clearance. Finally, respondents were asked if their institution had a documented cervical spine clearance protocol. Of the 25 separate institutions evaluated, 21 were designated as level 1 trauma centers. Considerable variation was reported with regards to the primary service responsible for cervical spine clearance. General Surgery/Trauma (44%) is most commonly the primary service, followed by a rotating schedule (33%), Neurosugery (11%), and Orthopaedic Surgery (8%). Spine consults tend to be seen most commonly by a rotating schedule of Orthopaedic Surgery and Neurosurgery. The majority of responding institutions utilize computed tomographic imaging (46%) as the primary imaging modality, whereas 42% of hospitals used x-ray primarily. The remaining institutions reported using a combination of x-ray and computed tomographic imaging. Only 46% of institutions utilize a written, standardized pediatric cervical spine clearance protocol. This study demonstrates a striking variability in the use of personnel, imaging modalities and, most importantly, standardized protocol in the evaluation of the pediatric trauma patient with a potential cervical spine injury. Cervical spine clearance protocols have been shown to decrease the incidence of missed injuries, minimize excessive radiation exposure, decrease the time to collar removal, and lower overall associated costs. It is our opinion that development of a task force or multicenter research protocol that incorporates existing evidence-based literature is the next best step in improving the care of children with cervical spine injuries. Level 4-economic and decision analyses.

Mechanistic modeling to predict the transporter- and enzyme-mediated drug-drug interactions of repaglinide.

PubMed

Varma, Manthena V S; Lai, Yurong; Kimoto, Emi; Goosen, Theunis C; El-Kattan, Ayman F; Kumar, Vikas

2013-04-01

Quantitative prediction of complex drug-drug interactions (DDIs) is challenging. Repaglinide is mainly metabolized by cytochrome-P-450 (CYP)2C8 and CYP3A4, and is also a substrate of organic anion transporting polypeptide (OATP)1B1. The purpose is to develop a physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics and DDIs of repaglinide. In vitro hepatic transport of repaglinide, gemfibrozil and gemfibrozil 1-O-β-glucuronide was characterized using sandwich-culture human hepatocytes. A PBPK model, implemented in Simcyp (Sheffield, UK), was developed utilizing in vitro transport and metabolic clearance data. In vitro studies suggested significant active hepatic uptake of repaglinide. Mechanistic model adequately described repaglinide pharmacokinetics, and successfully predicted DDIs with several OATP1B1 and CYP3A4 inhibitors (<10% error). Furthermore, repaglinide-gemfibrozil interaction at therapeutic dose was closely predicted using in vitro fraction metabolism for CYP2C8 (0.71), when primarily considering reversible inhibition of OATP1B1 and mechanism-based inactivation of CYP2C8 by gemfibrozil and gemfibrozil 1-O-β-glucuronide. This study demonstrated that hepatic uptake is rate-determining in the systemic clearance of repaglinide. The model quantitatively predicted several repaglinide DDIs, including the complex interactions with gemfibrozil. Both OATP1B1 and CYP2C8 inhibition contribute significantly to repaglinide-gemfibrozil interaction, and need to be considered for quantitative rationalization of DDIs with either drug.

The Role of Infected Cell Proliferation in the Clearance of Acute HBV Infection in Humans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goyal, Ashish; Ribeiro, Ruy Miguel; Perelson, Alan S.

Around 90–95% of hepatitis B virus (HBV) infected adults do not progress to the chronic phase and, instead, recover naturally. The strengths of the cytolytic and non-cytolytic immune responses are key players that decide the fate of acute HBV infection. In addition, it has been hypothesized that proliferation of infected cells resulting in uninfected progeny and/or cytokine-mediated degradation of covalently closed circular DNA (cccDNA) leading to the cure of infected cells are two major mechanisms assisting the adaptive immune response in the clearance of acute HBV infection in humans. We employed fitting of mathematical models to human acute infection datamore » together with physiological constraints to investigate the role of these hypothesized mechanisms in the clearance of infection. Results suggest that cellular proliferation of infected cells resulting in two uninfected cells is required to minimize the destruction of the liver during the clearance of acute HBV infection. In contrast, we find that a cytokine-mediated cure of infected cells alone is insufficient to clear acute HBV infection. Lastly, our modeling indicates that HBV clearance without lethal loss of liver mass is associated with the production of two uninfected cells upon proliferation of an infected cell.« less

The Role of Infected Cell Proliferation in the Clearance of Acute HBV Infection in Humans

DOE PAGES

Goyal, Ashish; Ribeiro, Ruy Miguel; Perelson, Alan S.

2017-11-18

Around 90–95% of hepatitis B virus (HBV) infected adults do not progress to the chronic phase and, instead, recover naturally. The strengths of the cytolytic and non-cytolytic immune responses are key players that decide the fate of acute HBV infection. In addition, it has been hypothesized that proliferation of infected cells resulting in uninfected progeny and/or cytokine-mediated degradation of covalently closed circular DNA (cccDNA) leading to the cure of infected cells are two major mechanisms assisting the adaptive immune response in the clearance of acute HBV infection in humans. We employed fitting of mathematical models to human acute infection datamore » together with physiological constraints to investigate the role of these hypothesized mechanisms in the clearance of infection. Results suggest that cellular proliferation of infected cells resulting in two uninfected cells is required to minimize the destruction of the liver during the clearance of acute HBV infection. In contrast, we find that a cytokine-mediated cure of infected cells alone is insufficient to clear acute HBV infection. Lastly, our modeling indicates that HBV clearance without lethal loss of liver mass is associated with the production of two uninfected cells upon proliferation of an infected cell.« less

Population Pharmacokinetics of Darbepoetin Alfa in Conjunction with Hypothermia for the Treatment of Neonatal Hypoxic-Ischemic Encephalopathy.

PubMed

Roberts, Jessica K; Stockmann, Chris; Ward, Robert M; Beachy, Joanna; Baserga, Mariana C; Spigarelli, Michael G; Sherwin, Catherine M T

2015-12-01

The aim of this study was to determine the population pharmacokinetics of darbepoetin alfa in hypothermic neonates with hypoxic-ischemic encephalopathy treated with hypothermia. Neonates ≥36 weeks gestation and <12 h postpartum with moderate to severe hypoxic-ischemic encephalopathy who were undergoing hypothermia treatment were recruited in this randomized, multicenter, investigational, new drug pharmacokinetic study. Two intravenous darbepoetin alfa treatment groups were evaluated: 2 and 10 µg/kg. Serum erythropoietin concentrations were measured using an enzyme-linked immunosorbent assay. Monolix 4.3.1 was used to estimate darbepoetin alfa clearance and volume of distribution. Covariates tested included: birthweight, gestational age, postnatal age, postmenstrual age, sex, Sarnat score, and study site. Darbepoetin alfa pharmacokinetics were well described by a one-compartment model with exponential error. Clearance and the volume of distribution were scaled by birthweight (centered on the mean) a priori. Additionally, gestational age (also centered on the mean) significantly affected darbepoetin alfa clearance. Clearance and volume of distribution were estimated as 0.0465 L/h (95% confidence interval 0.0392-0.0537) and 1.58 L (95% confidence interval 1.29-1.87), respectively. A one-compartment model successfully described the pharmacokinetics of darbepoetin alfa among hypothermic neonates treated for hypoxic-ischemic encephalopathy. Clearance decreased with increasing gestational age.

Intra- and inter-laboratory reliability of a cryopreserved trout hepatocyte assay for the prediction of chemical bioaccumulation potential

EPA Science Inventory

Cryopreserved trout hepatocytes provide a convenient in vitro system for measuring the intrinsic clearance of xenobiotics. Measured clearance rates can then be extrapolated to the whole animal as a means of improving modeled bioaccumulation predictions. To date, however, the in...

Use of isolated hepatocytes to predict measured hepatic clearance of five polyaromatic hydrocarbons by perfused trout livers

EPA Science Inventory

Measured rates of in vitro hepatic clearance by fish have been used by several authors as inputs to predictive models for chemical accumulation. The resulting predictions are consistent with observed trends in bioaccumulation and provide a proof of principal for the approach. ...

Is there a rationale to use a dual mobility poly insert for failed Birmingham metal-on-metal hip replacements? A retrieval analysis.

PubMed

Renner, Lisa; Faschingbauer, Martin; Boettner, Friedrich

2015-08-01

Previous studies showed poor outcomes for patients undergoing revision of failed metal-on-metal total hip arthroplasty (MoM-THA) and resurfacing (RS) with an increased risk of dislocation. Dual mobility inserts are an option to retain the acetabular component and change the metal-on-metal bearing to plastic-on-metal. The current study analyzes the rationale for the off-label use of a dual mobility poly insert (MDM X3, Stryker, Mahwah, NJ) in a Birmingham metal shell (Smith & Nephew, Memphis, TN). Based on retrievals from the implant database the study compared the clearance between 20 BHR shells, 31 MDM poly inserts and 24 ADM acetabular components of different sizes. The radial clearance was calculated for each possible combination of implants [n = 81 (MDM/BHR) and n = 119 (MDM/ADM)]. An MDM mobile bearing poly insert in an ADM shell has an average clearance of 0.314 mm (SD 0.031) compared to 0.234 mm (SD 0.030) in a BHR shell (p < 0.01). The minimal clearance is 0.246 and 0.163 mm, respectively. 30.9 % of the MDM/BHR clearances were within the range of the MDM/ADM bearing and 88.9 % had a clearance of more than 0.2 mm. Clearances of the MDM poly insert in a BHR shell are reduced, and although the majority of combinations appear safe, the indication needs to be made on an individual base carefully considering alternative treatment options.

A Novel Strategy for Development of Recombinant Antitoxin Therapeutics Tested in a Mouse Botulism Model

PubMed Central

Leysath, Clinton E.; Ofori, Kwasi; Baldwin, Karen; Feng, Xiaochuan; Bedenice, Daniela; Webb, Robert P.; Wright, Patrick M.; Smith, Leonard A.; Tzipori, Saul; Shoemaker, Charles B.

2012-01-01

Antitoxins are needed that can be produced economically with improved safety and shelf life compared to conventional antisera-based therapeutics. Here we report a practical strategy for development of simple antitoxin therapeutics with substantial advantages over currently available treatments. The therapeutic strategy employs a single recombinant ‘targeting agent’ that binds a toxin at two unique sites and a ‘clearing Ab’ that binds two epitopes present on each targeting agent. Co-administration of the targeting agent and the clearing Ab results in decoration of the toxin with up to four Abs to promote accelerated clearance. The therapeutic strategy was applied to two Botulinum neurotoxin (BoNT) serotypes and protected mice from lethality in two different intoxication models with an efficacy equivalent to conventional antitoxin serum. Targeting agents were a single recombinant protein consisting of a heterodimer of two camelid anti-BoNT heavy-chain-only Ab VH (VHH) binding domains and two E-tag epitopes. The clearing mAb was an anti-E-tag mAb. By comparing the in vivo efficacy of treatments that employed neutralizing vs. non-neutralizing agents or the presence vs. absence of clearing Ab permitted unprecedented insight into the roles of toxin neutralization and clearance in antitoxin efficacy. Surprisingly, when a post-intoxication treatment model was used, a toxin-neutralizing heterodimer agent fully protected mice from intoxication even in the absence of clearing Ab. Thus a single, easy-to-produce recombinant protein was as efficacious as polyclonal antiserum in a clinically-relevant mouse model of botulism. This strategy should have widespread application in antitoxin development and other therapies in which neutralization and/or accelerated clearance of a serum biomolecule can offer therapeutic benefit. PMID:22238680

A novel strategy for development of recombinant antitoxin therapeutics tested in a mouse botulism model.

PubMed

Mukherjee, Jean; Tremblay, Jacqueline M; Leysath, Clinton E; Ofori, Kwasi; Baldwin, Karen; Feng, Xiaochuan; Bedenice, Daniela; Webb, Robert P; Wright, Patrick M; Smith, Leonard A; Tzipori, Saul; Shoemaker, Charles B

2012-01-01

Antitoxins are needed that can be produced economically with improved safety and shelf life compared to conventional antisera-based therapeutics. Here we report a practical strategy for development of simple antitoxin therapeutics with substantial advantages over currently available treatments. The therapeutic strategy employs a single recombinant 'targeting agent' that binds a toxin at two unique sites and a 'clearing Ab' that binds two epitopes present on each targeting agent. Co-administration of the targeting agent and the clearing Ab results in decoration of the toxin with up to four Abs to promote accelerated clearance. The therapeutic strategy was applied to two Botulinum neurotoxin (BoNT) serotypes and protected mice from lethality in two different intoxication models with an efficacy equivalent to conventional antitoxin serum. Targeting agents were a single recombinant protein consisting of a heterodimer of two camelid anti-BoNT heavy-chain-only Ab V(H) (VHH) binding domains and two E-tag epitopes. The clearing mAb was an anti-E-tag mAb. By comparing the in vivo efficacy of treatments that employed neutralizing vs. non-neutralizing agents or the presence vs. absence of clearing Ab permitted unprecedented insight into the roles of toxin neutralization and clearance in antitoxin efficacy. Surprisingly, when a post-intoxication treatment model was used, a toxin-neutralizing heterodimer agent fully protected mice from intoxication even in the absence of clearing Ab. Thus a single, easy-to-produce recombinant protein was as efficacious as polyclonal antiserum in a clinically-relevant mouse model of botulism. This strategy should have widespread application in antitoxin development and other therapies in which neutralization and/or accelerated clearance of a serum biomolecule can offer therapeutic benefit.

Augmented renal clearance in the ICU: results of a multicenter observational study of renal function in critically ill patients with normal plasma creatinine concentrations*.

PubMed

Udy, Andrew A; Baptista, João P; Lim, Noelle L; Joynt, Gavin M; Jarrett, Paul; Wockner, Leesa; Boots, Robert J; Lipman, Jeffrey

2014-03-01

To describe the prevalence and natural history of augmented renal clearance in a cohort of recently admitted critically ill patients with normal plasma creatinine concentrations. Multicenter, prospective, observational study. Four, tertiary-level, university-affiliated, ICUs in Australia, Singapore, Hong Kong, and Portugal. Study participants had to have an expected ICU length of stay more than 24 hours, no evidence of absolute renal impairment (admission plasma creatinine < 120 µmol/L), and no history of prior renal replacement therapy or chronic kidney disease. Convenience sampling was used at each participating site. Eight-hour urinary creatinine clearances were collected daily, as the primary method of measuring renal function. Augmented renal clearance was defined by a creatinine clearance more than or equal to 130 mL/min/1.73 m. Additional demographic, physiological, therapeutic, and outcome data were recorded prospectively. Nine hundred thirty-two patients were admitted to the participating ICUs over the study period, and 281 of which were recruited into the study, contributing 1,660 individual creatinine clearance measures. The mean age (95% CI) was 54.4 years (52.5-56.4 yr), Acute Physiology and Chronic Health Evaluation II score was 16 (15.2-16.7), and ICU mortality was 8.5%. Overall, 65.1% manifested augmented renal clearance on at least one occasion during the first seven study days; the majority (74%) of whom did so on more than or equal to 50% of their creatinine clearance measures. Using a mixed-effects model, the presence of augmented renal clearance on study day 1 strongly predicted (p = 0.019) sustained elevation of creatinine clearance in these patients over the first week in ICU. Augmented renal clearance appears to be a common finding in this patient group, with sustained elevation of creatinine clearance throughout the first week in ICU. Future studies should focus on the implications for accurate dosing of renally eliminated pharmaceuticals in patients with augmented renal clearance, in addition to the potential impact on individual clinical outcomes.

High-Speed, capacitance-based tip clearance sensing

NASA Astrophysics Data System (ADS)

Haase, W. C.; Haase, Z. S.

This paper discusses recent advances in tip clearance measurement systems for turbine engines using capacitive probes. Real time measurements of individual blade pulses are generated using wideband signal processing providing 3 dB bandwidths of typically 5 MHz. Subsequent mixed-signal processing circuitry provide real-time measurements of maximum, minimum, and average clearance with latencies of one blade-to-blade time interval. Both guarded and unguarded probe configurations are possible with the system. Calibration techniques provide high accuracy measurements.

Novel hits for acetylcholinesterase inhibition derived by docking-based screening on ZINC database.

PubMed

Doytchinova, Irini; Atanasova, Mariyana; Valkova, Iva; Stavrakov, Georgi; Philipova, Irena; Zhivkova, Zvetanka; Zheleva-Dimitrova, Dimitrina; Konstantinov, Spiro; Dimitrov, Ivan

2018-12-01

The inhibition of the enzyme acetylcholinesterase (AChE) increases the levels of the neurotransmitter acetylcholine and symptomatically improves the affected cognitive function. In the present study, we searched for novel AChE inhibitors by docking-based virtual screening of the standard lead-like set of ZINC database containing more than 6 million small molecules using GOLD software. The top 10 best-scored hits were tested in vitro for AChE affinity, neurotoxicity, GIT and BBB permeability. The main pharmacokinetic parameters like volume of distribution, free fraction in plasma, total clearance, and half-life were predicted by previously derived models. Nine of the compounds bind to the enzyme with affinities from 0.517 to 0.735 µM, eight of them are non-toxic. All hits permeate GIT and BBB and bind extensively to plasma proteins. Most of them are low-clearance compounds. In total, seven of the 10 hits are promising for further lead optimisation. These are structures with ZINC IDs: 00220177, 44455618, 66142300, 71804814, 72065926, 96007907, and 97159977.

Population Pharmacokinetics of Vancomycin in Patients Undergoing Allogeneic Hematopoietic Stem-Cell Transplantation.

PubMed

Okada, Akira; Kariya, Misato; Irie, Kei; Okada, Yutaka; Hiramoto, Nobuhiro; Hashimoto, Hisako; Kajioka, Ryosuke; Maruyama, Chika; Kasai, Hidefumi; Hamori, Mami; Nishimura, Asako; Shibata, Nobuhito; Fukushima, Keizo; Sugioka, Nobuyuki

2018-05-15

Vancomycin is a commonly used antimicrobial agent for patients undergoing allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Vancomycin has large inter- and intraindividual pharmacokinetic variability, which is mainly described by renal function; various studies have indicated that vancomycin pharmacokinetics are altered in special populations. However, little is known regarding vancomycin pharmacokinetics in patients undergoing allo-HSCT. Therefore, we aimed to develop a population pharmacokinetic (PopPK) model of vancomycin in patients undergoing allo-HSCT for effective and safe antimicrobial therapy and to develop a vancomycin dosing nomogram for a vancomycin optimal-dosing strategy. In total, 285 observations from 95 patients undergoing allo-HSCT were available. The final PopPK parameter estimates were central volume of distribution (V1, L), 39.2; clearance (L/h), 4.25; peripheral volume of distribution (V2, L), 56.1; and intercompartmental clearance (L/h), 1.95. The developed vancomycin model revealed an increase in V1 and V2 compared with those in the general population that consisted of patients with methicillin-resistant Staphylococcus aureus. Moreover, serum creatinine was reduced because of an increase in the plasma fraction because of destruction of hematopoietic stem cells accompanying allo-HSCT pretreatment, suggesting that the Cockcroft-Gault equation-based creatinine clearance value was overestimated. To our knowledge, this is the first PopPK study to develop a dosing nomogram for vancomycin in patients undergoing allo-HSCT and was proven to be useful in optimizing the dosage and dosing interval of vancomycin in these patients. This strategy will provide more useful information for vancomycin therapy with an evidence-based dose adjustment. © 2018, The American College of Clinical Pharmacology.

Rate of hepatitis C viral clearance by human livers in human patients: Liver transplantation modeling primary infection and implications for studying entry inhibition.

PubMed

Hughes, Michael G; Tucker, William W; Reddy, Sreelatha; Brier, Michael E; Koch, David; McClain, Craig J; Jonsson, Colleen B; Matoba, Nobuyuki; Chung, Donghoon

2017-01-01

To better understand the dynamics of early hepatitis C virus (HCV) infection, we determined how rapidly non-cirrhotic HCV-uninfected liver allografts clear HCV from the circulation of cirrhotic HCV-infected patients at the time of transplantation but before administration of immunosuppression. Specifically, we characterized serum HCV kinetics during the first 90 min of reperfusion for 19 chronically HCV-infected patients transplanted with an HCV-uninfected liver by measuring serum viral load immediately prior to reperfusion (t = 0) and then every 15 min for a total of 90 min (t = 90). Immunosuppression was withheld until all samples were taken to better model primary infection. During this period, rates of viral clearance varied more than 20-fold with a median rate constant of 0.0357 1/min, range 0.0089-0.2169; half-life (minutes) median 19.4, range 3.2-77.8. The majority of viral clearance occurred within the first 60 min. The amount of blood transfused during this 90-min period (a potential confounding variable of this human liver transplant model of primary infection) accounted for 53% and 59% of k (r = 0.53, p = 0.05) and half-life (r = 0.59, p = 0.03) variability, respectively. No other clinical variables tested (age, allograft weight, and degree of reperfusion injury as assessed by peak postoperative ALT or AST) accounted for the remaining variability (p>0.05). In a human liver transplant model of primary infection, HCV rapidly clears the bloodstream. With approximately 90% of clearance occurring in the first 90 minutes of reperfusion, studies of HCV entry inhibition could utilize rate of clearance during this early period as an outcome measure.

The influence of size, clearance, cartilage properties, thickness and hemiarthroplasty on the contact mechanics of the hip joint with biphasic layers.

PubMed

Li, Junyan; Stewart, Todd D; Jin, Zhongmin; Wilcox, Ruth K; Fisher, John

2013-06-21

Computational models of the natural hip joint are needed to examine and optimise tissue sparing interventions where the natural cartilage remains part of the bearing surfaces. Although the importance of interstitial fluid pressurisation in the performance of cartilage has long been recognized, few studies have investigated the time dependent interstitial fluid pressurisation in a three dimensional natural hip joint model. The primary aim of this study was to develop a finite element model of the natural hip incorporating the biphasic cartilage layers that was capable of simulating the joint response over a prolonged physiological loading period. An initial set of sensitivity studies were also undertaken to investigate the influence of hip size, clearance, cartilage properties, thickness and hemiarthroplasty on the contact mechanics of the joint. The contact stress, contact area, fluid pressure and fluid support ratio were calculated and cross-compared between models with different parameters to evaluate their influence. It was found that the model predictions for the period soon after loading were sensitive to the hip size, clearance, cartilage aggregate modulus, thickness and hemiarthroplasty, while the time dependent behaviour over 3000s was influenced by the hip clearance and cartilage aggregate modulus, permeability, thickness and hemiarthroplasty. The modelling methods developed in this study provide a basic platform for biphasic simulation of the whole hip joint onto which more sophisticated material models or other input parameters could be added in the future. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

ADAPTIVE CLEARANCE CONTROL SYSTEMS FOR TURBINE ENGINES

NASA Technical Reports Server (NTRS)

Blackwell, Keith M.

2004-01-01

The Controls and Dynamics Technology Branch at NASA Glenn Research Center primarily deals in developing controls, dynamic models, and health management technologies for air and space propulsion systems. During the summer of 2004 I was granted the privilege of working alongside professionals who were developing an active clearance control system for commercial jet engines. Clearance, the gap between the turbine blade tip and the encompassing shroud, increases as a result of wear mechanisms and rubbing of the turbine blades on shroud. Increases in clearance cause larger specific fuel consumption (SFC) and loss of efficient air flow. This occurs because, as clearances increase, the engine must run hotter and bum more fuel to achieve the same thrust. In order to maintain efficiency, reduce fuel bum, and reduce exhaust gas temperature (EGT), the clearance must be accurately controlled to gap sizes no greater than a few hundredths of an inch. To address this problem, NASA Glenn researchers have developed a basic control system with actuators and sensors on each section of the shroud. Instead of having a large uniform metal casing, there would be sections of the shroud with individual sensors attached internally that would move slightly to reform and maintain clearance. The proposed method would ultimately save the airline industry millions of dollars.

Factors effective on peritoneal phosphorus transport and clearance in peritoneal dialysis patients
.

PubMed

Cebeci, Egemen; Gursu, Meltem; Uzun, Sami; Karadag, Serhat; Kazancioglu, Rumeyza; Ozturk, Savas

2017-02-01

Transport characteristics of phosphorus are different from other small solutes that are evaluated in routine peritoneal equilibration test (PET) in peritoneal dialysis (PD) patients. We aimed to evaluate peritoneal phosphorus clearance and permeability, and their relationship with peritoneal membrane transport type and creatinine clearance as well as factors affecting peritoneal phosphorus clearance. 70 adult patients on a PD program were included in our study. Phosphorus transport status was classified according to dialysate/plasma (D/P) phosphorus at the 4^th hour of PET as slow transporter (< 0.47), slow-average transporter (0.47 - 0.56), fast-average transporter (0.57 - 0.67), and fast transporter (> 0.67). We evaluated the relationship of peritoneal phosphorus clearance and transport type with PD regime, phosphorus level, and presence of residual renal function in addition to investigating factors that are effective on peritoneal phosphorus clearance. D/P phosphorus and peritoneal phosphorus clearance were positively correlated with D/P creatinine and peritoneal creatinine clearance, respectively. Automated PD and continuous ambulatory PD patients were similar regarding phosphorus and creatinine clearances and transport status based on D/P phosphorus. The major determinant of peritoneal phosphorus clearance was anuria status. Anuric patients had higher dialysate volume (11.6 ± 3.0 L vs. 8.4 ± 2.1 L, p < 0.001) and therefore higher peritoneal phosphorus clearance (61.7 ± 15.1 L/week/1.73 m² vs. 48.4 ± 14.0 L/week/1.73 m², p = 0.001). Hyperphosphatemia was present in 40% and 11% of anuric patients and those with residual renal function, respectively (p = 0.005). Peritoneal phosphorus transport characteristics are similar to that of creatinine. Although increased dialysis dose may increase peritoneal phosphorus clearance, it may be insufficient to prevent hyperphosphatemia in anuric patients.
.

Shape memory alloy adaptive control of gas turbine engine compressor blade tip clearance

NASA Astrophysics Data System (ADS)

Schetky, Lawrence M.; Steinetz, Bruce M.

1998-06-01

The ambient air ingested through the inlet of a gas turbine is first compressed by an axial compressor followed by further compression in a centrifugal compressor and then fed into the combustion chamber where ignition and expansion take place to produce the engine thrust. The axial compressor typically has five or more stages which consist of revolving blades and stators and the overall performance of the turbine is strongly affected by the compressor efficiency. When the turbine is turned on, to accommodate the rapid initial increase in the compressor blade length due to centrifugal force, the cold turbine has a built in clearance between the turbine blade tip and the casing. As the turbine reached its operating temperature there is a further increase in the blade length due to thermal expansion and, at the same time, the diameter of the casing increases. The net result is that when these various components have reached their equilibrium temperatures, the initial cold build clearance is reduced, but there remains a residual clearance. The magnitude of this clearance has a direct effect on the compressor efficiency and can be stated as: Δη/Δ CLR equals 0.5 where η is efficiency and CLR is the tip clearance. The concept of adaptive tip clearance control is based on the ability of a shape memory alloy ring to shrink to a predetermined diameter when heated to the temperature of a particular stage, and thus reducing the tip clearance. The ring is fabricated from a CuAlNi shape memory alloy and is mounted in the casing so as to be coaxial with the rotating blades of the particular stage. When cold, the ring dimensions are such as to provide the required cold build clearance, but when at operating temperature the reduced diameter creates a very small tip clearance. The clearance provided by this concept is much smaller than the clearance normally obtained for a turbine of the size being studied.

Propofol Pharmacokinetics and Estimation of Fetal Propofol Exposure during Mid-Gestational Fetal Surgery: A Maternal-Fetal Sheep Model

PubMed Central

Niu, Jing; Venkatasubramanian, Raja; Vinks, Alexander A.; Sadhasivam, Senthilkumar

2016-01-01

Background Measuring fetal drug concentrations is extremely difficult in humans. We conducted a study in pregnant sheep to simultaneously describe maternal and fetal concentrations of propofol, a common intravenous anesthetic agent used in humans. Compared to inhalational anesthesia, propofol supplemented anesthesia lowered the dose of desflurane required to provide adequate uterine relaxation during open fetal surgery. This resulted in better intraoperative fetal cardiac outcome. This study describes maternal and fetal propofol pharmacokinetics (PK) using a chronically instrumented maternal-fetal sheep model. Methods Fetal and maternal blood samples were simultaneously collected from eight mid-gestational pregnant ewes during general anesthesia with propofol, remifentanil and desflurane. Nonlinear mixed-effects modeling was performed by using NONMEM software. Total body weight, gestational age and hemodynamic parameters were tested in the covariate analysis. The final model was validated by bootstrapping and visual predictive check. Results A total of 160 propofol samples were collected. A 2-compartment maternal PK model with a third fetal compartment appropriately described the data. Mean population parameter estimates for maternal propofol clearance and central volume of distribution were 4.17 L/min and 37.7 L, respectively, in a typical ewe with a median heart rate of 135 beats/min. Increase in maternal heart rate significantly correlated with increase in propofol clearance. The estimated population maternal-fetal inter-compartment clearance was 0.0138 L/min and the volume of distribution of propofol in the fetus was 0.144 L. Fetal propofol clearance was found to be almost negligible compared to maternal clearance and could not be robustly estimated. Conclusions For the first time, a maternal-fetal PK model of propofol in pregnant ewes was successfully developed. This study narrows the gap in our knowledge in maternal-fetal PK model in human. Our study confirms that maternal heart rate has an important influence on the pharmacokinetics of propofol during pregnancy. Much lower propofol concentration in the fetus compared to maternal concentrations explain limited placental transfer in in-vivo paired model, and less direct fetal cardiac depression we observed earlier with propofol supplemented inhalational anesthesia compared to higher dose inhalational anesthesia in humans and sheep. PMID:26752560

Numerical simulation of steady and unsteady viscous flow in turbomachinery using pressure based algorithm

NASA Astrophysics Data System (ADS)

Lakshminarayana, B.; Ho, Y.; Basson, A.

1993-07-01

The objective of this research is to simulate steady and unsteady viscous flows, including rotor/stator interaction and tip clearance effects in turbomachinery. The numerical formulation for steady flow developed here includes an efficient grid generation scheme, particularly suited to computational grids for the analysis of turbulent turbomachinery flows and tip clearance flows, and a semi-implicit, pressure-based computational fluid dynamics scheme that directly includes artificial dissipation, and is applicable to both viscous and inviscid flows. The values of these artificial dissipation is optimized to achieve accuracy and convergency in the solution. The numerical model is used to investigate the structure of tip clearance flows in a turbine nozzle. The structure of leakage flow is captured accurately, including blade-to-blade variation of all three velocity components, pitch and yaw angles, losses and blade static pressures in the tip clearance region. The simulation also includes evaluation of such quantities of leakage mass flow, vortex strength, losses, dominant leakage flow regions and the spanwise extent affected by the leakage flow. It is demonstrated, through optimization of grid size and artificial dissipation, that the tip clearance flow field can be captured accurately. The above numerical formulation was modified to incorporate time accurate solutions. An inner loop iteration scheme is used at each time step to account for the non-linear effects. The computation of unsteady flow through a flat plate cascade subjected to a transverse gust reveals that the choice of grid spacing and the amount of artificial dissipation is critical for accurate prediction of unsteady phenomena. The rotor-stator interaction problem is simulated by starting the computation upstream of the stator, and the upstream rotor wake is specified from the experimental data. The results show that the stator potential effects have appreciable influence on the upstream rotor wake. The predicted unsteady wake profiles are compared with the available experimental data and the agreement is good. The numerical results are interpreted to draw conclusions on the unsteady wake transport mechanism in the blade passage.

Robust Foot Clearance Estimation Based on the Integration of Foot-Mounted IMU Acceleration Data

PubMed Central

Benoussaad, Mourad; Sijobert, Benoît; Mombaur, Katja; Azevedo Coste, Christine

2015-01-01

This paper introduces a method for the robust estimation of foot clearance during walking, using a single inertial measurement unit (IMU) placed on the subject’s foot. The proposed solution is based on double integration and drift cancellation of foot acceleration signals. The method is insensitive to misalignment of IMU axes with respect to foot axes. Details are provided regarding calibration and signal processing procedures. Experimental validation was performed on 10 healthy subjects under three walking conditions: normal, fast and with obstacles. Foot clearance estimation results were compared to measurements from an optical motion capture system. The mean error between them is significantly less than 15% under the various walking conditions. PMID:26703622

Role of Prolactin in the Regulation of Bicarbonates Biodynamics in Female Rat Model of Cholestasis of Pregnancy.

PubMed

Bulaeva, O A; Abramicheva, P A; Balakina, T A; Smirnova, O V

2017-03-01

We studied possible involvement of prolactin in the regulation of bicarbonate biodynamics using female rat model of cholestasis of pregnancy induced by transplantation of the donor pituitary under the renal capsule of a recipient (hyperprolactinemia) and bile duct ligation (cholestasis). The concentration of bicarbonates in the bile and blood, their excretion, clearance, and reabsorption, as well as glomerular filtration rate and excretion of sodium ions were assessed. It was found that the main effect of prolactin was directed to the kidney-regulated pool of bicarbonates and consisted in stimulation of their clearance and inhibition of reabsorption, which led to a decrease in bicarbonate blood concentration. Parallel influence of prolactin on the clearance of bicarbonates and sodium ions was observed.

Role of Na+/K+-ATPase in Natriuretic Effect of Prolactin in a Model of Cholestasis of Pregnancy.

PubMed

Abramicheva, P A; Balakina, T A; Bulaeva, O A; Guseva, A A; Lopina, O D; Smirnova, O V

2017-05-01

Participation of Na+/K+-ATPase in the natriuretic effect of prolactin in a cholestasis of pregnancy model was investigated. The Na+/K+-ATPase activity in rat kidney medulla, where active sodium reabsorption occurs, decreased in the model of cholestasis of pregnancy and other hyperprolactinemia types compared with intact animals. This effect was not connected with the protein level of α1- and β-subunits of Na+/K+-ATPase measured by Western blotting in the kidney medulla. Decrease in Na+/K+-ATPase activity in the kidney cortex was not significant, as well as decrease in the quantity of mRNA and proteins of the α1- and β-subunits of Na+/K+-ATPase. There were no correlations between the Na+/K+-ATPase activity and sodium clearance, although sodium clearance increased significantly in the model of cholestasis of pregnancy and other hyperprolactinemia groups under conditions of stable glomerular filtration rate measured by creatinine clearance. We conclude that the Na+/K+-ATPase is not the only mediator of the natriuretic effect of prolactin in the model of cholestasis of pregnancy.

Close Range Photogrammetry in Space - Measuring the On-Orbit Clearance between Hardware on the International Space Station

NASA Technical Reports Server (NTRS)

Liddle, Donn

2017-01-01

When photogrammetrists read an article entitled "Photogrammetry in Space" they immediately think of terrestrial mapping using satellite imagery. However in the last 19 years the roll of close range photogrammetry in support of the manned space flight program has grown exponentially. Management and engineers have repeatedly entrusted the safety of the vehicles and their crews to the results of photogrammetric analysis. In February 2010, the Node 3 module was attached to the port side Common Berthing Mechanism (CBM) of the International Space Station (ISS). Since this was not the location at which the module was originally designed to be located on the ISS, coolant lines containing liquid ammonia, were installed externally from the US Lab to Node 3 during a spacewalk. During mission preparation I had developed a plan and a set of procedures to have the astronauts acquire stereo imagery of these coolant lines at the conclusion of the spacewalk to enable us to map their as-installed location relative to the rest of the space station. Unfortunately, the actual installation of the coolant lines took longer than expected and in an effort to wrap up the spacewalk on time, the mission director made a real-time call to drop the photography. My efforts to reschedule the photography on a later spacewalk never materialized, so rather than having an as-installed model for the location of coolant lines, the master ISS CAD database continued to display an as-designed model of the coolant lines. Fast forward to the summer of 2015, the ISS program planned to berth a Japanese cargo module to the nadir Common Berthing Mechanism (CBM), immediately adjacent to the Node 3 module. A CAD based clearance analysis revealed a negative four inch clearance between the ammonia lines and a thruster nozzle on the port side of the cargo vehicle. Recognizing that the model of the ammonia line used in the clearance analysis was "as-designed" rather than "as-installed", I was asked to determine the real clearance between the ammonia lines and expected position of the thruster bell using existing on-orbit imagery. Imagery of the area of interest, taken several years earlier from the Space Shuttle during a fly-around of the ISS, was found and used to set a stereo pair. Space Vision System Targets and Handrail bolts measured in the ISS analytical coordinate system (ISSACS) prior to launch, were used to obtain an absolute orientation so all photogrammetric measurement's would be in the ISSACS coordinate system. Coordinates for the design location of the edges of the thruster bell, when the cargo vehicle was fully berthed to the ISS, were displayed in 3-D relative to the as-installed ammonia lines. This immediately revealed a positive clearance, which was later quantified to be a minimum of 10" +/0.5". The analysis was completed over a single weekend by a single analyst. Using updated imagery, acquired from the station's robotic arm, a complete as-installed model of the coolant lines was generated from stereo photography and replaced the design model in the master ISS CAD database.

Effect of antiorthostatic bed rest on hepatic blood flow in man.

PubMed

Putcha, L; Cintron, N M; Vanderploeg, J M; Chen, Y; Habis, J; Adler, J

1988-04-01

Physiological changes that occur during exposure to weightlessness may induce alterations in blood flow to the liver. Estimation of hepatic blood flow (HBF) using ground-based weightlessness simulation models may provide insight into functional changes of the liver in crewmembers during flight. In the present study HBF, indirectly estimated by indocyanine green (ICG) clearance, is compared in 10 subjects during the normal ambulatory condition and antiorthostatic (-6 degrees) bed rest. Plasma clearance of ICG was determined following intravenous administration of a 0.5-mg.kg-1 dose of ICG to each subject on two separate occasions, once after being seated for 1 h and once after 24 h of head-down bed rest. After 24 h of head-down bed rest, hepatic blood flow did not change significantly from the respective control value.

Clearance detector and method for motion and distance

DOEpatents

Xavier, Patrick G [Albuquerque, NM

2011-08-09

A method for correct and efficient detection of clearances between three-dimensional bodies in computer-based simulations, where one or both of the volumes is subject to translation and/or rotations. The method conservatively determines of the size of such clearances and whether there is a collision between the bodies. Given two bodies, each of which is undergoing separate motions, the method utilizes bounding-volume hierarchy representations for the two bodies and, mappings and inverse mappings for the motions of the two bodies. The method uses the representations, mappings and direction vectors to determine the directionally furthest locations of points on the convex hulls of the volumes virtually swept by the bodies and hence the clearance between the bodies, without having to calculate the convex hulls of the bodies. The method includes clearance detection for bodies comprising convex geometrical primitives and more specific techniques for bodies comprising convex polyhedra.

Use of isolated hepatocytes to predict measured hepatic clearance of five polyaromatic hydrocarbons by perfused trout livers, invited presentation

EPA Science Inventory

Measured rates of in vitro hepatic clearance by fish have been used by several authors as inputs to predictive models for chemical accumulation. The resulting predictions are consistent with observed trends in bioaccumulation and provide a proof of principal for the approach. ...

75 FR 11433 - Airworthiness Directives; Hawker Beechcraft Corporation Model G58 Airplanes

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-11

... brake reservoir tubing and the heater fuel pump wiring for minimum clearance and installing acceptable... of a power wire shorting out on the brake reservoir tube. We are issuing this AD to detect and correct inadequate clearance of the brake reservoir tubing and the heater fuel pump wiring, which could...

Prophylactic ranitidine treatment in critically ill children – a population pharmacokinetic study

PubMed Central

Hawwa, Ahmed F; Westwood, Paul M; Collier, Paul S; Millership, Jeffrey S; Yakkundi, Shirish; Thurley, Gillian; Shields, Mike D; Nunn, Anthony J; Halliday, Henry L; McElnay, James C

2013-01-01

Aims To characterize the population pharmacokinetics of ranitidine in critically ill children and to determine the influence of various clinical and demographic factors on its disposition. Methods Data were collected prospectively from 78 paediatric patients (n = 248 plasma samples) who received oral or intravenous ranitidine for prophylaxis against stress ulcers, gastrointestinal bleeding or the treatment of gastro-oesophageal reflux. Plasma samples were analysed using high-performance liquid chromatography, and the data were subjected to population pharmacokinetic analysis using nonlinear mixed-effects modelling. Results A one-compartment model best described the plasma concentration profile, with an exponential structure for interindividual errors and a proportional structure for intra-individual error. After backward stepwise elimination, the final model showed a significant decrease in objective function value (−12.618; P < 0.001) compared with the weight-corrected base model. Final parameter estimates for the population were 32.1 l h−1 for total clearance and 285 l for volume of distribution, both allometrically modelled for a 70 kg adult. Final estimates for absorption rate constant and bioavailability were 1.31 h−1 and 27.5%, respectively. No significant relationship was found between age and weight-corrected ranitidine pharmacokinetic parameters in the final model, with the covariate for cardiac failure or surgery being shown to reduce clearance significantly by a factor of 0.46. Conclusions Currently, ranitidine dose recommendations are based on children's weights. However, our findings suggest that a dosing scheme that takes into consideration both weight and cardiac failure/surgery would be more appropriate in order to avoid administration of higher or more frequent doses than necessary. PMID:23016949

Study on the leakage flow through a clearance gap between two stationary walls

NASA Astrophysics Data System (ADS)

Zhao, W.; Billdal, J. T.; Nielsen, T. K.; Brekke, H.

2012-11-01

In the present paper, the leakage flow in the clearance gap between stationary walls was studied experimentally, theoretically and numerically by the computational fluid dynamics (CFD) in order to find the relationship between leakage flow, pressure difference and clearance gap. The experimental set-up of the clearance gap between two stationary walls is the simplification of the gap between the guide vane faces and facing plates in Francis turbines. This model was built in the Waterpower laboratory at Norwegian University of Science and Technology (NTNU). The empirical formula for calculating the leakage flow rate between the two stationary walls was derived from the empirical study. The experimental model is simulated by computational fluid dynamics employing the ANSYS CFX commercial software in order to study the flow structure. Both numerical simulation results and empirical formula results are in good agreement with the experimental results. The correction of the empirical formula is verified by experimental data and has been proven to be very useful in terms of quickly predicting the leakage flow rate in the guide vanes for hydraulic turbines.

Dynamic clearance measure to evaluate locomotor and perceptuo-motor strategies used for obstacle circumvention in a virtual environment.

PubMed

Darekar, Anuja; Lamontagne, Anouk; Fung, Joyce

2015-04-01

Circumvention around an obstacle entails a dynamic interaction with the obstacle to maintain a safe clearance. We used a novel mathematical interpolation method based on the modified Shepard's method of Inverse Distance Weighting to compute dynamic clearance that reflected this interaction as well as minimal clearance. This proof-of-principle study included seven young healthy, four post-stroke and four healthy age-matched individuals. A virtual environment designed to assess obstacle circumvention was used to administer a locomotor (walking) and a perceptuo-motor (navigation with a joystick) task. In both tasks, participants were asked to navigate towards a target while avoiding collision with a moving obstacle that approached from either head-on, or 30° left or right. Among young individuals, dynamic clearance did not differ significantly between obstacle approach directions in both tasks. Post-stroke individuals maintained larger and smaller dynamic clearance during the locomotor and the perceptuo-motor task respectively as compared to age-matched controls. Dynamic clearance was larger than minimal distance from the obstacle irrespective of the group, task and obstacle approach direction. Also, in contrast to minimal distance, dynamic clearance can respond differently to different avoidance behaviors. Such a measure can be beneficial in contrasting obstacle avoidance behaviors in different populations with mobility problems. Copyright © 2015 Elsevier B.V. All rights reserved.

CF6 jet engine diagnostics program. High pressure turbine roundness/clearance investigation

NASA Technical Reports Server (NTRS)

Howard, W. D.; Fasching, W. A.

1982-01-01

The effects of high pressure turbine clearance changes on engine and module performance was evaluated in addition to the measurement of CF6-50C high pressure turbine Stage 1 tip clearance and stator out-of-roundness during steady-state and transient operation. The results indicated a good correlation of the analytical model of round engine clearance response with measured data. The stator out-of-roundness measurements verified that the analytical technique for predicting the distortion effects of mechanical loads is accurate, whereas the technique for calculating the effects of certain circumferential thermal gradients requires some modifications. A potential for improvement in roundness was established in the order of 0.38 mm (0.015 in.), equivalent to 0.86 percent turbine efficiency which translates to a cruise SFC improvement of 0.36 percent. The HP turbine Stage 1 tip clearance performance derivative was established as 0.44 mm (17 mils) per percent of turbine efficiency at take-off power, somewhat smaller, therefore, more sensitive than predicted from previous investigations.

Mechanisms of astrocytic K(+) clearance and swelling under high extracellular K(+) concentrations.

PubMed

Murakami, Shingo; Kurachi, Yoshihisa

2016-03-01

In response to the elevation of extracellular K(+) concentration ([K(+)]out), astrocytes clear excessive K(+) to maintain conditions necessary for neural activity. K(+) clearance in astrocytes occurs via two processes: K(+) uptake and K(+) spatial buffering. High [K(+)]out also induces swelling in astrocytes, leading to edema and cell death in the brain. Despite the importance of astrocytic K(+) clearance and swelling, the underlying mechanisms remain unclear. Here, we report results from a simulation analysis of astrocytic K(+) clearance and swelling. Astrocyte models were constructed by incorporating various mechanisms such as intra/extracellular ion concentrations of Na(+), K(+), and Cl(-), cell volume, and models of Na,K-ATPase, Na-K-Cl cotransporter (NKCC), K-Cl cotransporter, inwardly-rectifying K(+) (KIR) channel, passive Cl(-) current, and aquaporin channel. The simulated response of astrocyte models under the uniform distribution of high [K(+)]out revealed significant contributions of NKCC and Na,K-ATPase to increases of intracellular K(+) and Cl(-) concentrations, and swelling. Moreover, we found that, under the non-uniform distribution of high [K(+)]out, KIR channels localized at synaptic clefts absorbed excess K(+) by depolarizing the equivalent potential of K(+) (E K) above membrane potential, while K(+) released through perivascular KIR channels was enhanced by hyperpolarizing E K and depolarizing membrane potential. Further analysis of simulated drug effects revealed that astrocyte swelling was modulated by blocking each of the ion channels and transporters. Our simulation analysis revealed controversial mechanisms of astrocytic K(+) clearance and swelling resulting from complex interactions among ion channels and transporters.

Population pharmacokinetics of oseltamivir and oseltamivir carboxylate in obese and non‐obese volunteers

PubMed Central

Chairat, Kalayanee; Jittamala, Podjanee; Hanpithakpong, Warunee; Day, Nicholas P. J.; White, Nicholas J.; Pukrittayakamee, Sasithon

2016-01-01

Aims The aims of the present study were to compare the pharmacokinetics of oseltamivir and its active antiviral metabolite oseltamivir carboxylate in obese and non‐obese individuals and to determine the effect of obesity on the pharmacokinetic properties of oseltamivir and oseltamivir carboxylate. Methods The population pharmacokinetic properties of oseltamivir and oseltamivir carboxylate were evaluated in 12 obese [body mass index (BMI) ≥30 kg m−2) and 12 non‐obese (BMI <30 kg m−2) Thai adult volunteers receiving a standard dose of 75 mg and a double dose of 150 mg in a randomized sequence. Concentration–time data were collected and analysed using nonlinear mixed‐effects modelling. Results The pharmacokinetics of oseltamivir and oseltamivir carboxylate were described simultaneously by first‐order absorption, with a one‐compartment disposition model for oseltamivir, followed by a metabolism compartment and a one‐compartment disposition model for oseltamivir carboxylate. Creatinine clearance was a significant predictor of oseltamivir carboxylate clearance {3.84% increase for each 10 ml min−1 increase in creatinine clearance [95% confidence interval (CI) 0.178%, 8.02%]}. Obese individuals had an approximately 25% (95% CI 24%, 28%) higher oseltamivir clearance, 20% higher oseltamivir volume of distribution (95% CI 19%, 23%) and 10% higher oseltamivir carboxylate clearance (95% CI 9%, 11%) compared with non‐obese individuals. However, these altered pharmacokinetic properties were small and did not change the overall exposure to oseltamivir carboxylate. Conclusions The results confirmed that a dose adjustment for oseltamivir in obese individuals is not necessary on the basis of its pharmacokinetics. PMID:26810861

Population Pharmacokinetics of Combined Intravenous and Local Intrathecal Administration of Meropenem in Aneurysm Patients with Suspected Intracranial Infections After Craniotomy.

PubMed

Li, Xingang; Sun, Shusen; Wang, Qiang; Zhao, Zhigang

2018-02-01

For patients with intracranial infection, local intrathecal administration of meropenem may be a useful method to obtain a sufficient drug concentration in the cerebral spinal fluid (CSF). However, a large inter-individual variability may pose treatment efficacy at risk. This study aimed to identify factors affecting drug concentration in the CSF using population pharmacokinetics method. After craniotomy, aneurysm patients with an indwelling lumbar cistern drainage tube who received a combined intravenous and intrathecal administration of meropenem for the treatment of suspected intracranial infection were enrolled. Venous blood and CSF specimens were collected for determining meropenem concentrations. Nonlinear mixed-effects modeling method was used to fit blood and CSF concentrations simultaneously and to develop the population pharmacokinetic model. The proposed model was applied to simulate dosage regimens. A three-compartmental model was established to describe meropenem in vivo behavior. Lumbar CSF drainage resulted in a drug loss, and drug clearance in CSF (CL CSF ) was employed to describe this. The covariate analysis found that the drainage volume (mL/day) was strongly associated with CL CSF , and the effect of creatinine clearance was significant on the clearance of meropenem in blood (CL). Visual predictive check suggested that the proposed pharmacokinetic model agreed well with the observations. Simulation showed that both intravenous and intrathecal doses should be increased with the increases of minimum inhibitory concentration and daily CSF drainage volume. This model incorporates covariates of the creatinine clearance and the drainage volume, and a simple to use dosage regimen table was created to guide clinicians with meropenem dosing.

Reliability of ⁵¹Cr-EDTA plasma and urinary clearance as a measure of residual renal function in dialysis patients.

PubMed

Kjaergaard, Krista D; Jensen, Jens D; Jespersen, Bente; Rehling, Michael

2011-12-01

In dialysis patients, longer survival is associated with a higher residual renal function. Randomized controlled trials are conducted to clarify how residual renal function can be preserved. However, existing methods for measuring residual renal function are uncertain and there is a need for establishing a standard for measurements of glomerular filtration rate (GFR) in dialysis patients. ⁵¹Cr-EDTA clearances in plasma, urine, and dialysate were evaluated in a sample of 12 hemodialysis and 12 peritoneal dialysis patients. The patients' condition was generally stable, and all patients were investigated twice within 4-10 days. Plasma clearances of ⁵¹Cr-EDTA for all patients ranged between 2.1 and 30.8 mL/min/1.73 m², whereas urinary ⁵¹Cr-EDTA clearances ranged from 0.7-20.0 mL/min/1.73 m². This difference was statistically significant (p < 0.001). Week-to-week reproducibility expressed as coefficients of variation were below or equal to 10% for plasma clearances and 13% for urinary clearances in hemodialysis patients and 14% in peritoneal dialysis patients. This study demonstrated a difference between ⁵¹Cr-EDTA plasma and urinary clearances in dialysis patients. Plasma clearance of ⁵¹Cr-EDTA had the best reproducibility. For repeated measurements as in clinical prospective trials, we recommend ⁵¹Cr-EDTA plasma clearance based on blood sampling at 5 + 24 hours with subtraction of ⁵¹Cr-EDTA dialysate clearance in peritoneal dialysis patients. Further studies are needed to corroborate our findings.

Four hour creatinine clearance is better than plasma creatinine for monitoring renal function in critically ill patients

PubMed Central

2012-01-01

Introduction Acute kidney injury (AKI) diagnosis is based on an increase in plasma creatinine, which is a slowly changing surrogate of decreased glomerular filtration rate. We investigated whether serial creatinine clearance, a direct measure of the glomerular filtration rate, provided more timely and accurate information on renal function than serial plasma creatinine in critically ill patients. Methods Serial plasma creatinine and 4-hour creatinine clearance were measured 12-hourly for 24 hours and then daily in 484 patients. AKI was defined either as > 50% increase in plasma creatinine from baseline, or > 33.3% decrease in creatinine clearance. The diagnostic and predictive performance of the two AKI definitions were compared. Results Creatinine clearance decrease diagnosed AKI in 24% of those not diagnosed by plasma creatinine increase on entry. These patients entered the ICU sooner after insult than those diagnosed with AKI by plasma creatinine elevation (P = 0.0041). Mortality and dialysis requirement increased with the change in creatinine clearance-acute kidney injury severity class (P = 0.0021). Amongst patients with plasma creatinine < 1.24 mg/dl on entry, creatinine clearance improved the prediction of AKI considerably (Net Reclassification Improvement 83%, Integrated Discrimination Improvement 0.29). On-entry, creatinine clearance associated with AKI severity and duration (P < 0.0001) predicted dialysis need (area under the curve: 0.75) and death (0.61). A > 33.3% decrease in creatinine clearance over the first 12 hours was associated with a 2.0-fold increased relative risk of dialysis or death. Conclusions Repeated 4-hour creatinine clearance measurements in critically ill patients allow earlier detection of AKI, as well as progression and recovery compared to plasma creatinine. Trial Registration Australian New Zealand Clinical Trials Registry ACTRN012606000032550. PMID:22713519

Absorption and Clearance of Pharmaceutical Aerosols in the Human Nose: Effects of Nasal Spray Suspension Particle Size and Properties.

PubMed

Rygg, Alex; Hindle, Michael; Longest, P Worth

2016-04-01

The objective of this study was to use a recently developed nasal dissolution, absorption, and clearance (DAC) model to evaluate the extent to which suspended drug particle size influences nasal epithelial drug absorption for a spray product. Computational fluid dynamics (CFD) simulations of mucociliary clearance and drug dissolution were used to calculate total and microscale epithelial absorption of drug delivered with a nasal spray pump. Ranges of suspended particle sizes, drug solubilities, and partition coefficients were evaluated. Considering mometasone furoate as an example, suspended drug particle sizes in the range of 1-5 μm did not affect the total nasal epithelial uptake. However, the microscale absorption of suspended drug particles with low solubilities was affected by particle size and this controlled the extent to which the drug penetrated into the distal nasal regions. The nasal-DAC model was demonstrated to be a useful tool in determining the nasal exposure of spray formulations with different drug particle sizes and solubilities. Furthermore, the model illustrated a new strategy for topical nasal drug delivery in which drug particle size is selected to increase the region of epithelial surface exposure using mucociliary clearance while minimizing the drug dose exiting the nasopharynx.

Hepatitis B and C coinfection in a real-life setting: viral interactions and treatment issues.

PubMed

Papadopoulos, Nikolaos; Papavdi, Maria; Pavlidou, Anna; Konstantinou, Dimitris; Kranidioti, Hariklia; Kontos, George; Koskinas, John; Papatheodoridis, George V; Manolakopoulos, Spilios; Deutsch, Melanie

2018-01-01

Only limited data concerning hepatitis B (HBV) and C viruses (HCV) coinfection are available. Direct-acting antivirals (DAAs) may be more effective for HCV clearance than interferon (IFN)-based regimens with a risk of HBV reactivation. We retrospectively enrolled 40 HBV/HCV-coinfected patients to evaluate their clinical profile and treatment outcomes. Chronic dual infection was present in 25/40 (62.5%) patients, acute HCV superinfection in 5/40 (12.5%) patients and acute HBV superinfection in 10/40 (25%). Twenty-five patients (62.5%) were treated: 16/25 (64%) with IFN, 4/25 (16%) with nucleot(s)ide analogs (NUCs) and 5/25 (20%) with DAAs. Of the 16 patients treated with IFN-based therapy, 6 (37.5%) achieved both sustained virological response (SVR) and HBsAg clearance. Of the 4 patients treated with NUCs, one (25%) achieved both SVR and HBsAg clearance. All five patients treated with DAAs (100%) achieved SVR, while one case of HBV reactivation was recorded. Fifteen of the 40 patients (37.5%) did not receive any treatment. Eight of them (53.5%) presented with acute HBV superinfection: spontaneous HCV clearance was recorded in 5/8 (62.5%), while HBsAg clearance occurred in 6/8 (75%). Three of them (20%) presented with acute HCV superinfection; spontaneous HCV clearance was recorded in one of the three (33.5%). The other four patients (26.5%) presented with dual HBV/HCV infection. A significant proportion of patients presented with active HBV replication. Treatment with DAAs seems to be efficacious for HCV eradication. However, clinicians should be aware of HBV reactivation. HBV superinfection may lead to both HBsAg and HCV clearance.

Quantitative Impact of Plasma Clearance and Down-regulation on GLP-1 Receptor Molecular Imaging.

PubMed

Zhang, Liang; Thurber, Greg M

2016-02-01

Quantitative molecular imaging of beta cell mass (BCM) would enable early detection and treatment monitoring of type 1 diabetes. The glucagon-like peptide-1 (GLP-1) receptor is an attractive target due to its beta cell specificity and cell surface location. We quantitatively investigated the impact of plasma clearance and receptor internalization on targeting efficiency in healthy B6 mice. Four exenatide-based probes were synthesized that varied in molecular weight, binding affinity, and plasma clearance. The GLP-1 receptor internalization rate and in vivo receptor expression were quantified. Receptor internalization (54,000 receptors/cell in vivo) decreased significantly within minutes, reducing the benefit of a slower-clearing agent. The multimers and albumin binding probes had higher kidney and liver uptake, respectively. Slow plasma clearance is beneficial for GLP-1 receptor peptide therapeutics. However, for exendin-based imaging of islets, down-regulation of the GLP-1 receptor and non-specific background uptake result in a higher target-to-background ratio for fast-clearing agents.

Quantitative Impact of Plasma Clearance and Down-regulation on GLP-1 Receptor Molecular Imaging

PubMed Central

Zhang, Liang; Thurber, Greg M.

2016-01-01

Purpose Quantitative molecular imaging of beta cell mass (BCM) would enable early detection and treatment monitoring of type-1 diabetes. The glucagon like peptide-1 (GLP-1) receptor is an attractive target due to its beta cell specificity and cell surface location. We quantitatively investigated the impact of plasma clearance and receptor internalization on targeting efficiency in healthy B6 mice. Procedures Four exenatide-based probes were synthesized that varied in molecular weight, binding affinity, and plasma clearance. The GLP-1 receptor internalization rate and in vivo receptor expression were quantified. Results Receptor internalization (54,000 receptors/cell in vivo) decreased significantly within minutes, reducing the benefit of a slower clearing agent. The multimers and albumin binding probes had higher kidney and liver uptake, respectively. Conclusions Slow plasma clearance is beneficial for GLP-1 receptor peptide therapeutics. However, for exendin-based imaging of islets, downregulation of the GLP-1 receptor and non-specific background uptake result in a higher TBR for fast-clearing agents. PMID:26194012

Population pharmacokinetics of olmesartan following oral administration of its prodrug, olmesartan medoxomil: in healthy volunteers and hypertensive patients.

PubMed

Yoshihara, Kazutaka; Gao, Yuying; Shiga, Hiroshi; Wada, D Russell; Hisaoka, Masafumi

2005-01-01

Olmesartan medoxomil (CS-866) is a new orally active angiotensin II receptor antagonist that is highly selective for the AT1 receptor subtype. To develop a population pharmacokinetic model for olmesartan (RNH-6270), the active metabolite of olmesartan medoxomil, in healthy volunteers and hypertensive patients, and to evaluate effects of covariates on the apparent oral clearance (CL/F), with particular emphasis on the effect of race. Retrospective analysis of data from 12 phase I-III trials in the US, Europe and Japan. Eighty-nine healthy volunteers and 383 hypertensive patients. Nonlinear mixed-effects modelling was used to evaluate 7911 olmesartan plasma sample concentrations. The covariates included age, bodyweight, sex, race (Westerners [including Caucasians and Hispanics] versus Japanese), patient status (hypertensive patients versus healthy volunteers), serum creatinine level as an index of renal function and serum chemistry data as indices of hepatic function. The pharmacokinetic data of olmesartan were well described by a two-compartment linear model with first-order absorption and an absorption lag-time, parameterised in terms of CL/F (6.66 L/h for a typical male Western hypertensive patient), absorption rate constant (1.46h-1), elimination rate constant (0.193h-1), rate constant from the central to peripheral compartment (0.061h-1), rate constant from the peripheral to central compartment (0.079h-1) and absorption lag-time (0.427h). Analysis of covariates showed that age, bodyweight, sex, patient status and renal function were factors influencing the clearance of olmesartan. The population pharmacokinetic analysis of olmesartan showed that: (i) severe renal impairment (serum creatinine >265 micromol/L [approximately 3 mg/dL]) could cause a clearance decrease of > or =30%; (ii) older age, lower bodyweight and being female were determinants of lower clearance but their effects on olmesartan clearance were within 20%; (iii) no statistically significant difference in clearance was found between Westerners and Japanese.

Uranium Associations with Kidney Outcomes Vary by Urine Concentration Adjustment Method

PubMed Central

Shelley, Rebecca; Kim, Nam-Soo; Parsons, Patrick J.; Lee, Byung-Kook; Agnew, Jacqueline; Jaar, Bernard G.; Steuerwald, Amy J.; Matanoski, Genevieve; Fadrowski, Jeffrey; Schwartz, Brian S.; Todd, Andrew C.; Simon, David; Weaver, Virginia M.

2017-01-01

Uranium is a ubiquitous metal that is nephrotoxic at high doses. Few epidemiologic studies have examined the kidney filtration impact of chronic environmental exposure. In 684 lead workers environmentally exposed to uranium, multiple linear regression was used to examine associations of uranium measured in a four-hour urine collection with measured creatinine clearance, serum creatinine- and cystatin-C-based estimated glomerular filtration rates, and N-acetyl-β-D-glucosaminidase (NAG). Three methods were utilized, in separate models, to adjust uranium levels for urine concentration - μg uranium/g creatinine; μg uranium/L and urine creatinine as separate covariates; and μg uranium/4 hr. Median urine uranium levels were 0.07 μg/g creatinine and 0.02 μg/4 hr and were highly correlated (rs =0.95). After adjustment, higher ln-urine uranium was associated with lower measured creatinine clearance and higher NAG in models that used urine creatinine to adjust for urine concentration but not in models that used total uranium excreted (μg/4 hr). These results suggest that, in some instances, associations between urine toxicants and kidney outcomes may be statistical, due to the use of urine creatinine in both exposure and outcome metrics, rather than nephrotoxic. These findings support consideration of non-creatinine-based methods of adjustment for urine concentration in nephrotoxicant research. PMID:23591699

Population pharmacokinetic and pharmacogenetic analysis of 6-mercaptopurine in paediatric patients with acute lymphoblastic leukaemia

PubMed Central

Hawwa, Ahmed F; Collier, Paul S; Millership, Jeff S; McCarthy, Anthony; Dempsey, Sid; Cairns, Carole; McElnay, James C

2008-01-01

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECTThe cytotoxic effects of 6-mercaptopurine (6-MP) were found to be due to drug-derived intracellular metabolites (mainly 6-thioguanine nucleotides and to some extent 6-methylmercaptopurine nucleotides) rather than the drug itself.Current empirical dosing methods for oral 6-MP result in highly variable drug and metabolite concentrations and hence variability in treatment outcome. WHAT THIS STUDY ADDSThe first population pharmacokinetic model has been developed for 6-MP active metabolites in paediatric patients with acute lymphoblastic leukaemia and the potential demographic and genetically controlled factors that could lead to interpatient pharmacokinetic variability among this population have been assessed.The model shows a large reduction in interindividual variability of pharmacokinetic parameters when body surface area and thiopurine methyltransferase polymorphism are incorporated into the model as covariates.The developed model offers a more rational dosing approach for 6-MP than the traditional empirical method (based on body surface area) through combining it with pharmacogenetically guided dosing based on thiopurine methyltransferase genotype. AIMS To investigate the population pharmacokinetics of 6-mercaptopurine (6-MP) active metabolites in paediatric patients with acute lymphoblastic leukaemia (ALL) and examine the effects of various genetic polymorphisms on the disposition of these metabolites. METHODS Data were collected prospectively from 19 paediatric patients with ALL (n = 75 samples, 150 concentrations) who received 6-MP maintenance chemotherapy (titrated to a target dose of 75 mg m−2 day−1). All patients were genotyped for polymorphisms in three enzymes involved in 6-MP metabolism. Population pharmacokinetic analysis was performed with the nonlinear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance for the active metabolites. RESULTS The developed model revealed considerable interindividual variability (IIV) in the clearance of 6-MP active metabolites [6-thioguanine nucleotides (6-TGNs) and 6-methylmercaptopurine nucleotides (6-mMPNs)]. Body surface area explained a significant part of 6-TGNs clearance IIV when incorporated in the model (IIV reduced from 69.9 to 29.3%). The most influential covariate examined, however, was thiopurine methyltransferase (TPMT) genotype, which resulted in the greatest reduction in the model's objective function (P < 0.005) when incorporated as a covariate affecting the fractional metabolic transformation of 6-MP into 6-TGNs. The other genetic covariates tested were not statistically significant and therefore were not included in the final model. CONCLUSIONS The developed pharmacokinetic model (if successful at external validation) would offer a more rational dosing approach for 6-MP than the traditional empirical method since it combines the current practice of using body surface area in 6-MP dosing with a pharmacogenetically guided dosing based on TPMT genotype. PMID:18823306

Population Pharmacokinetics and Optimal Sampling Strategy for Model-Based Precision Dosing of Melphalan in Patients Undergoing Hematopoietic Stem Cell Transplantation.

PubMed

Mizuno, Kana; Dong, Min; Fukuda, Tsuyoshi; Chandra, Sharat; Mehta, Parinda A; McConnell, Scott; Anaissie, Elias J; Vinks, Alexander A

2018-05-01

High-dose melphalan is an important component of conditioning regimens for patients undergoing hematopoietic stem cell transplantation. The current dosing strategy based on body surface area results in a high incidence of oral mucositis and gastrointestinal and liver toxicity. Pharmacokinetically guided dosing will individualize exposure and help minimize overexposure-related toxicity. The purpose of this study was to develop a population pharmacokinetic model and optimal sampling strategy. A population pharmacokinetic model was developed with NONMEM using 98 observations collected from 15 adult patients given the standard dose of 140 or 200 mg/m 2 by intravenous infusion. The determinant-optimal sampling strategy was explored with PopED software. Individual area under the curve estimates were generated by Bayesian estimation using full and the proposed sparse sampling data. The predictive performance of the optimal sampling strategy was evaluated based on bias and precision estimates. The feasibility of the optimal sampling strategy was tested using pharmacokinetic data from five pediatric patients. A two-compartment model best described the data. The final model included body weight and creatinine clearance as predictors of clearance. The determinant-optimal sampling strategies (and windows) were identified at 0.08 (0.08-0.19), 0.61 (0.33-0.90), 2.0 (1.3-2.7), and 4.0 (3.6-4.0) h post-infusion. An excellent correlation was observed between area under the curve estimates obtained with the full and the proposed four-sample strategy (R 2  = 0.98; p < 0.01) with a mean bias of -2.2% and precision of 9.4%. A similar relationship was observed in children (R 2  = 0.99; p < 0.01). The developed pharmacokinetic model-based sparse sampling strategy promises to achieve the target area under the curve as part of precision dosing.

Longitudinal Associations among Renal Urea Clearance-Corrected Normalized Protein Catabolic Rate, Serum Albumin, and Mortality in Patients on Hemodialysis.

PubMed

Eriguchi, Rieko; Obi, Yoshitsugu; Streja, Elani; Tortorici, Amanda R; Rhee, Connie M; Soohoo, Melissa; Kim, Taehee; Kovesdy, Csaba P; Kalantar-Zadeh, Kamyar

2017-07-07

There are inconsistent reports on the association of dietary protein intake with serum albumin and outcomes among patients on hemodialysis. Using a new normalized protein catabolic rate (nPCR) variable accounting for residual renal urea clearance, we hypothesized that higher baseline nPCR and rise in nPCR would be associated with higher serum albumin and better survival among incident hemodialysis patients. Among 36,757 incident hemodialysis patients in a large United States dialysis organization, we examined baseline and change in renal urea clearance-corrected nPCR as a protein intake surrogate and modeled their associations with serum albumin and mortality over 5 years (1/2007-12/2011). Median nPCRs with and without accounting for renal urea clearance at baseline were 0.94 and 0.78 g/kg per day, respectively (median within-patient difference, 0.14 [interquartile range, 0.07-0.23] g/kg per day). During a median follow-up period of 1.4 years, 8481 deaths were observed. Baseline renal urea clearance-corrected nPCR was associated with higher serum albumin and lower mortality in the fully adjusted model ( P trend <0.001). Among 13,895 patients with available data, greater rise in renal urea clearance-corrected nPCR during the first 6 months was also associated with attaining high serum albumin (≥3.8 g/dl) and lower mortality ( P trend <0.001); compared with the reference group (a change of 0.1-0.2 g/kg per day), odds and hazard ratios were 0.53 (95% confidence interval, 0.44 to 0.63) and 1.32 (95% confidence interval, 1.14 to 1.54), respectively, among patients with a change of <-0.2 g/kg per day and 1.62 (95% confidence interval, 1.35 to 1.96) and 0.76 (95% confidence interval, 0.64 to 0.90), respectively, among those with a change of ≥0.5 g/kg per day. Within a given category of nPCR without accounting for renal urea clearance, higher levels of renal urea clearance-corrected nPCR consistently showed lower mortality risk. Among incident hemodialysis patients, higher dietary protein intake represented by nPCR and its changes over time appear to be associated with increased serum albumin levels and greater survival. nPCR may be underestimated when not accounting for renal urea clearance. Compared with the conventional nPCR, renal urea clearance-corrected nPCR may be a better marker of mortality. Copyright © 2017 by the American Society of Nephrology.

Genital Chlamydia trachomatis Infections Clear More Slowly in Men Than Women, but Are Less Likely to Become Established.

PubMed

Lewis, Joanna; Price, Malcolm J; Horner, Paddy J; White, Peter J

2017-07-15

Rigorous estimates for clearance rates of untreated chlamydia infections are important for understanding chlamydia epidemiology and designing control interventions, but were previously only available for women. We used data from published studies of chlamydia-infected men who were retested at a later date without having received treatment. Our analysis allowed new infections to take one of 1, 2, or 3 courses, each clearing at a different rate. We determined which of these 3 models had the most empirical support. The best-fitting model had 2 courses of infection in men, as was previously found for women: "slow-clearing" and "fast-clearing." Only 68% (57%-78%) (posterior median and 95% credible interval [CrI]) of incident infections in men were slow-clearing, vs 77% (69%-84%) in women. The slow clearance rate in men (based on 6 months' follow-up) was 0.35 (.05-1.15) year-1 (posterior median and 95% CrI), corresponding to mean infection duration 2.84 (.87-18.79) years. This compares to 1.35 (1.13-1.63) years in women. Our estimated clearance rate is slower than previously assumed. Fewer infections become established in men than women but once established, they clear more slowly. This study provides an improved description of chlamydia's natural history to inform public health decision making. We describe how further data collection could reduce uncertainty in estimates. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

Comparing taxi clearance input layouts for advancements in flight deck automation for surface operations

NASA Astrophysics Data System (ADS)

Cheng, Lara W. S.

Airport moving maps (AMMs) have been shown to decrease navigation errors, increase taxiing speed, and reduce workload when they depict airport layout, current aircraft position, and the cleared taxi route. However, current technologies are limited in their ability to depict the cleared taxi route due to the unavailability of datacomm or other means of electronically transmitting clearances from ATC to the flight deck. This study examined methods by which pilots can input ATC-issued taxi clearances to support taxi route depictions on the AMM. Sixteen general aviation (GA) pilots used a touchscreen monitor to input taxi clearances using two input layouts, softkeys and QWERTY, each with and without feedforward (graying out invalid inputs). QWERTY yielded more taxi route input errors than the softkeys layout. The presence of feedforward did not produce fewer taxi route input errors than in the non-feedforward condition. The QWERTY layout did reduce taxi clearance input times relative to the softkeys layout, but when feedforward was present this effect was observed only for the longer, 6-segment taxi clearances. It was observed that with the softkeys layout, feedforward reduced input times compared to non-feedforward but only for the 4-segment clearances. Feedforward did not support faster taxi clearance input times for the QWERTY layout. Based on the results and analyses of the present study, it is concluded that for taxi clearance inputs, (1) QWERTY remain the standard for alphanumeric inputs, and (2) feedforward be investigated further, with a focus on participant preference and performance of black-gray contrast of keys.

Effect of neurotrauma on hepatic drug clearance.

PubMed

Boucher, B A; Kuhl, D A; Fabian, T C; Robertson, J T

1991-11-01

Lorazepam, antipyrine, and indocyanine green were administered to 10 patients with severe head injuries as marker substrates of hepatic glucuronidation, oxidation, and hepatic blood flow, respectively. Pharmacokinetic parameter estimates were determined at baseline (20 to 80 hours after injury) and up to three additional times thereafter (study days 4, 7, and 14). Antipyrine clearance was increased significantly from baseline (0.50 +/- 0.31 ml/min/kg) on study days 4, 7, and 14 (p less than 0.0001). Increases in antipyrine clearance from baseline to the last study day were observed in all study patients ranging from 14% to 207%. A significant increase was also observed in lorazepam clearance on study day 14 relative to baseline (1.39 +/- 0.56 ml/min/kg) (p less than 0.005). Increases in lorazepam clearance occurred in seven of nine patients over time ranging from 9% to 130%. The unbound fraction of lorazepam did not change significantly over the study period. Likewise, no significant change was observed in the clearance of indocyanine green over time. Antipyrine clearance and alpha 1-acid glycoprotein (r = 0.41), and lorazepam clearance and C-reactive protein (r = -0.38) were significantly correlated (p less than 0.05). Similarly, antipyrine and lorazepam clearances were significantly correlated with injury severity based on the Acute Physiologic and Chronic Health Evaluation (APACHE II) score (r = -0.43 and r = -0.37, respectively). These findings suggest that hepatic oxidative and conjugative metabolism increase significantly over time in patients after acute head injury. An awareness of the potential for pharmacokinetic alterations in similarly metabolized drugs used for patients with severe head injuries is recommended.

Rectenna System Design. [energy conversion solar power satellites

NASA Technical Reports Server (NTRS)

Woodcock, G. R.; Andryczyk, R. W.

1980-01-01

The fundamental processes involved in the operation of the rectenna system designed for the solar power satellite system are described. The basic design choices are presented based on the desired microwave rf field concentration prior to rectification and based on the ground clearance requirements for the rectenna structure. A nonconcentrating inclined planar panel with a 2 meter minimum clearance configuration is selected as a representative of the typical rectenna.

Robotic Range Clearance Competition (R2C2)

DTIC Science & Technology

2011-10-01

unexploded ordnance (UXO). A large part of the debris field consists of ferrous metal objects that magnetic 39 Distribution A: Approved for public...was set at 7 degrees above horizontal based on terrain around the Base station. We used the BSUBR file for all fields except the Subsurface...and subsurface clearance test areas had numerous pieces of simulated unexploded ordinance (SUXO) buried at random locations around the field . These

78 FR 5780 - Agency Information Collection Activities: Proposed Collection, Comment Request: Generic Clearance...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-28

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24 CFR 200.213 - Applicability of procedure.

Code of Federal Regulations, 2010 CFR

2010-04-01

... Previous Participation Review and Clearance Procedure § 200.213 Applicability of procedure. The Previous Participation Review and Clearance procedure set forth in this part is administered by the Assistant Secretary... 887, which are tenant-based programs); (d) Sales of projects by the Secretary, including “all cash...

77 FR 75110 - Agency Information Collection Activities: Proposed Collection; Comment Request-Generic Clearance...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-19

...: Proposed Collection; Comment Request--Generic Clearance To Conduct Formative Research AGENCY: Food and.... This information collection will conduct research in support of FNS' goal of delivering science-based... target audience, FNS plans to conduct data collections that involve formative research including focus...

Investigation of the flow in the impeller side clearances of a centrifugal pump with volute casing

NASA Astrophysics Data System (ADS)

Will, Björn-Christian; Benra, Friedrich-Karl; Dohmen, Hans-Josef

2012-06-01

The paper is concerned with the fluid flow in the impeller side clearances of a centrifugal pump with volute casing. The flow conditions in these small axial gaps are of significant importance for a number of effects such as disk friction, leakage losses or hydraulic axial thrust to name but a few. In the investigated single stage pump, the flow pattern in the volute turns out to be asymmetric even at design flow rate. To gain a detailed insight into the flow structure, numerical simulations of the complete pump including the impeller side clearances are accomplished. Additionally, the hydraulic head and the radial pressure distributions in the impeller side clearances are measured and compared with the numerical results. Two configurations of the impeller, either with or without balancing holes, are examined. Moreover, three different operating points, i.e.: design point, part load or overload conditions are considered. In addition, analytical calculations are accomplished to determine the pressure distributions in the impeller side clearances. If accurate boundary conditions are available, the 1D flow models used in this paper can provide reasonable results for the radial static pressure distribution in the impeller side clearances. Furthermore, a counter rotating wake region develops in the rear impeller side clearances in absence of balancing holes which severely affects the inflow and outflow conditions of the cavity in circumferential direction.

Effects of Double-Leakage Tip Clearance Flow on the Performance of a Compressor Stage with a Large Rotor Tip Gap

NASA Technical Reports Server (NTRS)

Hah, Chunill

2016-01-01

Effects of a large rotor tip gap on the performance of a one and half stage axial compressor are investigated in detail with a numerical simulation based on LES and available PIV data. The current paper studies the main flow physics, including why and how the loss generation is increased with the large rotor tip gap. The present study reveals that when the tip gap becomes large, tip clearance fluid goes over the tip clearance core vortex and enters into the next blade's tip gap, which is called double-leakage tip clearance flow. As the tip clearance flow enters into the adjacent blade's tip gap, a vortex rope with a lower pressure core is generated. This vortex rope breaks up the tip clearance core vortex of the adjacent blade, resulting in a large additional mixing. This double-leakage tip clearance flow occurs at all operating conditions, from design flow to near stall condition, with the large tip gap for the current compressor stage. The double-leakage tip clearance flow, its interaction with the tip clearance core vortex of the adjacent blade, and the resulting large mixing loss are the main flow mechanism of the large rotor tip gap in the compressor. When the tip clearance is smaller, flow near the end wall follows more closely with the main passage flow and this double-leakage tip clearance flow does not happen near the design flow condition for the current compressor stage. When the compressor with a large tip gap operates at near stall operation, a strong vortex rope is generated near the leading edge due to the double-leakage flow. Part of this vortex separates from the path of the tip clearance core vortex and travels from the suction side of the blade toward the pressure side of the blade. This vortex is generated periodically at near stall operation with a large tip gap. As the vortex travels from the suction side to the pressure side of the blade, a large fluctuation of local pressure forces blade vibration. Nonsynchronous blade vibration occurs due to this vortex as the frequency of this vortex generation is not the same as the rotor. The present investigation confirms that this vortex is a part of separated tip clearance vortex, which is caused by the double-leakage tip clearance flow.

Development and gamma-scintigraphy study of Hibiscus rosasinensis polysaccharide-based microspheres for nasal drug delivery.

PubMed

Sharma, Nitin; Tyagi, Shanu; Gupta, Satish Kumar; Kulkarni, Giriraj Thirupathirao; Bhatnagar, Aseem; Kumar, Neeraj

2016-11-01

This work describes the application of natural plant polysaccharide as pharmaceutical mucoadhesive excipients in delivery systems to reduce the clearance rate through nasal cavity. Novel natural polysaccharide (Hibiscus rosasinensis)-based mucoadhesive microspheres were prepared by using emulsion crosslinking method for the delivery of rizatriptan benzoate (RB) through nasal route. Mucoadhesive microspheres were characterized for different parameters and nasal clearance of technetium-99m ((99m)Tc)-radiolabeled microspheres was determined by using gamma-scintigraphy. Their Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) studies showed that the drug was stable during preparation of microspheres. Aerodynamic diameter of microspheres was in the range 13.23 ± 1.83-33.57 ± 3.69 µm. Change in drug and polysaccharide ratio influenced the mucoadhesion, encapsulation efficiency and in-vitro release property. Scintigraphs taken at regular interval indicate that control solution was cleared rapidly from nasal cavity, whereas microspheres showed slower clearance (p < 0.005) with half-life of 160 min. Natural polysaccharide-based microspheres achieved extended residence by minimizing effect of mucociliary clearance with opportunity of sustained delivery for longer duration.

A mechanism-based pharmacokinetic-enzyme model for cyclophosphamide autoinduction in breast cancer patients

PubMed Central

Hassan, M; Svensson, U S H; Ljungman, P; Björkstrand, B; Olsson, H; Bielenstein, M; Abdel-Rehim, M; Nilsson, C; Johansson, M; Karlsson, M O

1999-01-01

Aims This study investigated the pharmacokinetics of cyclophosphamide (CP) and its main metabolite 4-hydroxycyclophosphamide (4-OH-CP) in patients with breast cancer undergoing high dose chemotherapy prior to autologous stem cell transplantation. An enzyme turn-over model was also developed to study the time course of cyclophosphamide induction. Methods Fourteen patients received a combination of CP (6 g m−2), thiotepum (500 mg m−2) and carboplatin (800 mg m−2) as a 96 h infusion. Plasma concentrations of CP and 4-OH-CP were determined with h.p.l.c. and a pharmacokinetic and enzyme turn-over model applied to data using NONMEM. Results CP plasma concentrations were described by a two-compartment model with a noninducible and an inducible pathway, the latter forming 4-OH-CP. In the final enzyme model, CP affects the amount of enzymes by increasing the enzyme production rate. CP concentrations decreased during the infusion with no subsequent change in 4-OH-CP concentrations. CP inducible and noninducible clearance were estimated to 1.76 l h−1 (90% C.I. 0.92–2.58) and 1.14 l h−1 (0.31–1.85), respectively. The induction resulted in an approximately doubled CP clearance through the inducible pathway at the end of treatment. The model predicted the enzyme turn-over half-life to be 24 h. Conclusions The presented mechanism-based enzyme induction model where the pharmacokinetics of the inducer and the enzyme pool counterbalance each other successfully described CP autoinduction. It is reasonable to believe that CP affects its own elimination by increasing the enzyme production rate and thereby increasing the amount of enzyme by which CP is eliminated. PMID:10594468

Population pharmacokinetics-pharmacodynamics of vedolizumab in patients with ulcerative colitis and Crohn's disease.

PubMed

Rosario, M; Dirks, N L; Gastonguay, M R; Fasanmade, A A; Wyant, T; Parikh, A; Sandborn, W J; Feagan, B G; Reinisch, W; Fox, I

2015-07-01

Vedolizumab, an anti-α(4)β(7) integrin monoclonal antibody (mAb), is indicated for treating patients with moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD). As higher therapeutic mAb concentrations have been associated with greater efficacy in inflammatory bowel disease, understanding determinants of vedolizumab clearance may help to optimise dosing. To characterise vedolizumab pharmacokinetics in patients with UC and CD, to identify clinically relevant determinants of vedolizumab clearance, and to describe the pharmacokinetic-pharmacodynamic relationship using population modelling. Data from a phase 1 healthy volunteer study, a phase 2 UC study, and 3 phase 3 UC/CD studies were included. Population pharmacokinetic analysis for repeated measures was conducted using nonlinear mixed effects modelling. Results from the base model, developed using extensive phase 1 and 2 data, were used to develop the full covariate model, which was fit to sparse phase 3 data. Vedolizumab pharmacokinetics was described by a 2-compartment model with parallel linear and nonlinear elimination. Using reference covariate values, linear elimination half-life of vedolizumab was 25.5 days; linear clearance (CL(L)) was 0.159 L/day for UC and 0.155 L/day for CD; central compartment volume of distribution (V(c)) was 3.19 L; and peripheral compartment volume of distribution was 1.66 L. Interindividual variabilities (%CV) were 35% for CLL and 19% for V(c); residual variance was 24%. Only extreme albumin and body weight values were identified as potential clinically important predictors of CL(L). Population pharmacokinetic parameters were similar in patients with moderately to severely active UC and CD. This analysis supports use of vedolizumab fixed dosing in these patients. Clinicaltrials.gov Identifiers: NCT01177228; NCT00783718 (GEMINI 1); NCT00783692 (GEMINI 2); NCT01224171 (GEMINI 3). © 2015 Takeda Pharmaceuticals International Co published by John Wiley & Sons Ltd.

Analytical formulation of 2-D aeroelastic model in weak ground effect

NASA Astrophysics Data System (ADS)

Dessi, Daniele; Mastroddi, Franco; Mancini, Simone

2013-10-01

This paper deals with the aeroelastic modeling and analysis of a 2-D oscillating airfoil in ground effect, elastically constrained by linear and torsional springs and immersed in an incompressible potential flow (typical section) at a finite distance from the ground. This work aims to extend Theodorsen theory, valid in an unbounded flow domain, to the case of weak ground effect, i.e., for clearances above half the airfoil chord. The key point is the determination of the aerodynamic loads, first in the frequency domain and then in the time domain, accounting for their dependence on the ground distance. The method of images is exploited in order to comply with the impermeability condition on the ground. The new integral equation in the unknown vortex distribution along the chord and the wake is solved using asymptotic expansions in the perturbation parameter defined as the inverse of the non-dimensional ground clearance of the airfoil. The mathematical model describing the aeroelastic system is transformed from the frequency domain into the time domain and then in a pure differential form using a finite-state aerodynamic approximation (augmented states). The typical section, which the developed theory is applied to, is obtained as a reduced model of a wing box finite element representation, thus allowing comparison with the corresponding aeroelastic analysis carried out by a commercial solver based on a 3-D lifting surface aerodynamic model. Stability (flutter margins) and response of the airfoil both in frequency and time domains are then investigated. In particular, within the developed theory, the solution of the Wagner problem can be directly achieved confirming an asymptotic trend of the aerodynamic coefficients toward the steady-state conditions different from that relative to the unbounded domain case. The dependence of flutter speed and the frequency response functions on ground clearance is highlighted, showing the usefulness of this approach in efficiently and robustly accounting for the presence of the ground when unsteady analysis of elastic lifting surfaces in weak ground effect is required.

Air-Traffic Controllers Evaluate The Descent Advisor

NASA Technical Reports Server (NTRS)

Tobias, Leonard; Volckers, Uwe; Erzberger, Heinz

1992-01-01

Report describes study of Descent Advisor algorithm: software automation aid intended to assist air-traffic controllers in spacing traffic and meeting specified times or arrival. Based partly on mathematical models of weather conditions and performances of aircraft, it generates suggested clearances, including top-of-descent points and speed-profile data to attain objectives. Study focused on operational characteristics with specific attention to how it can be used for prediction, spacing, and metering.

Liquid Annular Seal Research

NASA Technical Reports Server (NTRS)

Palazzolo, Alan B.; Venkataraman, Balaji; Padavala, Sathya S.; Ryan, Steve; Vallely, Pat; Funston, Kerry

1996-01-01

This paper highlights the accomplishments on a joint effort between NASA - Marshall Space Flight Center and Texas A and M University to develop accurate seal analysis software for use in rocket turbopump design, design audits and trouble shooting. Results for arbitrary clearance profile, transient simulation, thermal effects solution and flexible seal wall model are presented. A new solution for eccentric seals based on cubic spline interpolation and ordinary differential equation integration is also presented.

Factors influencing spatial pattern in tropical forest clearance and stand age: Implications for carbon storage and species diversity.

Treesearch

E. H. Helmer; Thomas J. Brandeis; Ariel E. Lugo; Todd Kennaway

2008-01-01

Little is known about the tropical forests that undergo clearing as urban/built-up and other developed lands spread. This study uses remote sensing-based maps of Puerto Rico, multinomial logit models and forest inventory data to explain patterns of forest age and the age of forests cleared for land development and assess their implications for forest carbon storage and...

A dosing algorithm for metformin based on the relationships between exposure and renal clearance of metformin in patients with varying degrees of kidney function.

PubMed

Duong, Janna K; Kroonen, M Y A M; Kumar, S S; Heerspink, H L; Kirkpatrick, C M; Graham, G G; Williams, K M; Day, R O

2017-08-01

The aims of this study were to investigate the relationship between metformin exposure, renal clearance (CL R ), and apparent non-renal clearance of metformin (CL NR /F) in patients with varying degrees of kidney function and to develop dosing recommendations. Plasma and urine samples were collected from three studies consisting of patients with varying degrees of kidney function (creatinine clearance, CL CR ; range, 14-112 mL/min). A population pharmacokinetic model was built (NONMEM) in which the oral availability (F) was fixed to 0.55 with an estimated inter-individual variability (IIV). Simulations were performed to estimate AUC 0-τ , CL R , and CL NR /F. The data (66 patients, 327 observations) were best described by a two-compartment model, and CL CR was a covariate for CL R . Mean CL R was 17 L/h (CV 22%) and mean CL NR /F was 1.6 L/h (69%).The median recovery of metformin in urine was 49% (range 19-75%) over a dosage interval. When CL R increased due to improved renal function, AUC 0-τ decreased proportionally, while CL NR /F did not change with kidney function. Target doses (mg/day) of metformin can be reached using CL CR /3 × 100 to obtain median AUC 0-12 of 18-26 mg/L/h for metformin IR and AUC 0-24 of 38-51 mg/L/h for metformin XR, with C max  < 5 mg/L. The proposed dosing algorithm can be used to dose metformin in patients with various degrees of kidney function to maintain consistent drug exposure. However, there is still marked IIV and therapeutic drug monitoring of metformin plasma concentrations is recommended.

In vitro metabolism of benzo[a]pyrene-7,8-dihydrodiol and dibenzo[def,p]chrysene-11,12 diol in rodent and human hepatic microsomes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smith, Jordan N.; Mehinagic, Denis; Nag, Subhasree

Polycyclic aromatic hydrocarbons (PAHs) are contaminants that are ubiquitously found in the environment, produced through combustion of organic matter or petrochemicals, and many of which are procarcinogens. The prototypic PAH, benzo[a]pyrene (B[a]P) and the highly carcinogenic dibenzo[def,p]chrysene (DBC) are metabolically activated by isoforms of the P450 enzyme superfamily producing benzo[a]pyrene-7,8-dihydrodiol (B[a]P diol), dibenzo[def,p]chrysene-11,12 diol (DBC diol). Each of these diols can be further metabolized by cytochrome P450 enzymes to highly reactive diol-epoxide metabolites that readily react with DNA or by phase II conjugation facilitating excretion. To complement prior in vitro metabolism studies with parent B[a]P and DBC, both phase Imore » metabolism and phase II glucuronidation of B[a]P diol and DBC diol were measured in hepatic microsomes from female B6129SF1/J mice, male Sprague-Dawley rats, and female humans. Metabolic parameters, including intrinsic clearance and Michaelis-Menten kinetics were calculated from substrate depletion data. Mice and rats demonstrated similar B[a]P diol phase I metabolic rates. Compared to rodents, human phase I metabolism of B[a]P diol demonstrated lower overall metabolic capacity, lower intrinsic clearance at higher substrate concentrations (>0.14 µM), and higher intrinsic clearance at lower substrate concentrations (<0.07 µM). Rates of DBC diol metabolism did not saturate in mice or humans and were highest overall in mice. Higher affinity constants and lower capacities were observed for DBC diol glucuronidation compared to B[a]P diol glucuronidation; however, intrinsic clearance values for these compounds were consistent within each species. Kinetic parameters reported here will be used to extend physiologically based pharmacokinetic (PBPK) models to include the disposition of B[a]P and DBC metabolites in animal models and humans to support future human health risk assessments.« less

Glucagon sensitivity and clearance in type 1 diabetes: insights from in vivo and in silico experiments.

PubMed

Hinshaw, Ling; Mallad, Ashwini; Dalla Man, Chiara; Basu, Rita; Cobelli, Claudio; Carter, Rickey E; Kudva, Yogish C; Basu, Ananda

2015-09-01

Glucagon use in artificial pancreas for type 1 diabetes (T1D) is being explored for prevention and rescue from hypoglycemia. However, the relationship between glucagon stimulation of endogenous glucose production (EGP) viz., hepatic glucagon sensitivity, and prevailing glucose concentrations has not been examined. To test the hypothesis that glucagon sensitivity is increased at hypoglycemia vs. euglycemia, we studied 29 subjects with T1D randomized to a hypoglycemia or euglycemia clamp. Each subject was studied at three glucagon doses at euglycemia or hypoglycemia, with EGP measured by isotope dilution technique. The peak EGP increments and the integrated EGP response increased with increasing glucagon dose during euglycemia and hypoglycemia. However, the difference in dose response based on glycemia was not significant despite higher catecholamine concentrations in the hypoglycemia group. Knowledge of glucagon's effects on EGP was used to develop an in silico glucagon action model. The model-derived output fitted the obtained data at both euglycemia and hypoglycemia for all glucagon doses tested. Glucagon clearance did not differ between glucagon doses studied in both groups. Therefore, the glucagon controller of a dual hormone control system may not need to adjust glucagon sensitivity, and hence glucagon dosing, based on glucose concentrations during euglycemia and hypoglycemia. Copyright © 2015 the American Physiological Society.

Roles of neutrophils in the regulation of the extent of human inflammation through delivery of IL-1 and clearance of chemokines

PubMed Central

Basran, Alexander; Jabeen, Maisha; Bingle, Lynne; Stokes, Clare A.; Dockrell, David H.; Whyte, Moira K. B.; Walmsley, Sarah R.; Higgins, Kathryn R.; Vogel, Stefanie N.; Wilson, Heather L.; Prince, Lynne R.; Prestwich, Elizabeth C.; Sabroe, Ruth A.; Parker, Lisa C.; Sabroe, Ian

2013-01-01

This study examined the establishment of neutrophilic inflammation in humans. We tested the hypotheses that neutrophil recruitment was associated with local CXCL8 production and that neutrophils themselves might contribute to the regulation of the size of the inflammatory response. Humans were challenged i.d. with endotoxin. Biopsies of these sites were examined for cytokine production and leukocyte recruitment by qPCR and IHC. Additional in vitro models of inflammation examined the ability of neutrophils to produce and sequester cytokines relevant to neutrophilic inflammation. i.d. challenge with 15 ng of a TLR4-selective endotoxin caused a local inflammatory response, in which 1% of the total biopsy area stained positive for neutrophils at 6 h, correlating with 100-fold up-regulation in local CXCL8 mRNA generation. Neutrophils themselves were the major source of the early cytokine IL-1β. In vitro, neutrophils mediated CXCL8 but not IL-1β clearance (>90% clearance of ≤2 nM CXCL8 over 24 h). CXCL8 clearance was at least partially receptor-dependent and modified by inflammatory context, preserved in models of viral infection but reduced in models of bacterial infection. In conclusion, in a human inflammatory model, neutrophils are rapidly recruited and may regulate the size and outcome of the inflammatory response through the uptake and release of cytokines and chemokines in patterns dependent on the underlying inflammatory stimulus. PMID:22904343

Step responses of a torsional system with multiple clearances: Study of vibro-impact phenomenon using experimental and computational methods

NASA Astrophysics Data System (ADS)

Oruganti, Pradeep Sharma; Krak, Michael D.; Singh, Rajendra

2018-01-01

Recently Krak and Singh (2017) proposed a scientific experiment that examined vibro-impacts in a torsional system under a step down excitation and provided preliminary measurements and limited non-linear model studies. A major goal of this article is to extend the prior work with a focus on the examination of vibro-impact phenomena observed under step responses in a torsional system with one, two or three controlled clearances. First, new measurements are made at several locations with a higher sampling frequency. Measured angular accelerations are examined in both time and time-frequency domains. Minimal order non-linear models of the experiment are successfully constructed, using piecewise linear stiffness and Coulomb friction elements; eight cases of the generic system are examined though only three are experimentally studied. Measured and predicted responses for single and dual clearance configurations exhibit double sided impacts and time varying periods suggest softening trends under the step down torque. Non-linear models are experimentally validated by comparing results with new measurements and with those previously reported. Several metrics are utilized to quantify and compare the measured and predicted responses (including peak to peak accelerations). Eigensolutions and step responses of the corresponding linearized models are utilized to better understand the nature of the non-linear dynamic system. Finally, the effect of step amplitude on the non-linear responses is examined for several configurations, and hardening trends are observed in the torsional system with three clearances.

The pharmacokinetics of dexmedetomidine during long-term infusion in critically ill pediatric patients. A Bayesian approach with informative priors.

PubMed

Wiczling, Paweł; Bartkowska-Śniatkowska, Alicja; Szerkus, Oliwia; Siluk, Danuta; Rosada-Kurasińska, Jowita; Warzybok, Justyna; Borsuk, Agnieszka; Kaliszan, Roman; Grześkowiak, Edmund; Bienert, Agnieszka

2016-06-01

The purpose of this study was to assess the pharmacokinetics of dexmedetomidine in the ICU settings during the prolonged infusion and to compare it with the existing literature data using the Bayesian population modeling with literature-based informative priors. Thirty-eight patients were included in the analysis with concentration measurements obtained at two occasions: first from 0 to 24 h after infusion initiation and second from 0 to 8 h after infusion end. Data analysis was conducted using WinBUGS software. The prior information on dexmedetomidine pharmacokinetics was elicited from the literature study pooling results from a relatively large group of 95 children. A two compartment PK model, with allometrically scaled parameters, maturation of clearance and t-student residual distribution on a log-scale was used to describe the data. The incorporation of time-dependent (different between two occasions) PK parameters improved the model. It was observed that volume of distribution is 1.5-fold higher during the second occasion. There was also an evidence of increased (1.3-fold) clearance for the second occasion with posterior probability equal to 62 %. This work demonstrated the usefulness of Bayesian modeling with informative priors in analyzing pharmacokinetic data and comparing it with existing literature knowledge.

A retrospective review of the carcinogenicity of refractory ceramic fiber in two chronic fischer 344 rat inhalation studies: an assessment of the MTD and implications for risk assessment.

PubMed

Mast, R W; Yu, C P; Oberdörster, G; McConnell, E E; Utell, M J

2000-12-01

The purpose of this article is to review previous chronic inhalation studies in rats with refractory ceramic fiber (RCF), the mathematical modeling efforts to describe the deposition, clearance, and retention of RCF fiber in the rat and human, and the concept of "overload," and to assess the possibility that the maximum tolerated dose (MTD) was exceeded. Lastly, based on recent biopersistence and pulmonary clearance studies of several investigators with a particulate-free RCF, we examine the potential impact on the chronic RCF rat bioassay of coexposure to both RCF particulate and RCF fibers. The review concludes, inter alia, that RCF particulate coexposure probably had a major impact on the observed chronic adverse effects, that the MTD was probably exceeded at the highest exposure concentration of 30 mg/m(3) in the rat bioassay, and that inclusion of the highest dose in the risk assessment process may overstate human health risk if a linear rather than nonlinear model is used.

Relationship of glomerular filtration rate based on serum iodixanol clearance to IRIS staging in cats with chronic kidney disease.

PubMed

Iwama, Ryosuke; Sato, Tsubasa; Katayama, Masaaki; Shimamura, Shunsuke; Satoh, Hiroshi; Ichijo, Toshihiro; Furuhama, Kazuhisa

2015-08-01

We examined the correlation between the glomerular filtration rate (GFR) estimated from an equation based on the serum iodixanol clearance technique and International Renal Interest Society (IRIS) stages of chronic kidney disease (CKD) in cats. The equation included the injection dose, sampling time, serum concentration and estimated volume of distribution (Vd) of the isotonic, nonionic, contrast medium iodixanol as a test tracer. The percent changes in the median basal GFR values calculated from the equation in CKD cats resembled those of IRIS stages 1-3. These data validate the association between the GFR derived from the simplified equation and IRIS stages based on the serum creatinine concentration in cats with CKD. They describe the GFR ranges determined using single-sample iodixanol clearance for healthy cats and cats with various IRIS stages of CKD.

Evaluation of methylene blue, pyrimethamine and its combination on an in vitro Neospora caninum model.

PubMed

Pereira, Luiz Miguel; Vigato-Ferreira, Isabel Cristina; DE Luca, Gabriela; Bronzon DA Costa, Cássia Mariana; Yatsuda, Ana Patrícia

2017-05-01

Neospora caninum is an apicomplexan parasite strongly related to reproductive problems in cattle. The neosporosis control is not well established and several fronts are under development, predominantly based on immune protection, immunomodulation and chemotherapy. The use of anti-malarial drugs as therapeutic sources has, in theory, considerable potential for any apicomplexan. Drugs such as methylene blue (MB) and pyrimethamine (Pyr) represent therapeutic options for malaria; thus, their use for neosporosis should be assessed. In this work, we tested the effects of MB and Pyr on N. caninum proliferation and clearance, using LacZ-tagged tachyzoites. The drugs inhibited at nanomolar dosages and its combination demonstrated an antagonistic interaction in proliferation assays, according to the Chou and Talalay method for drug combination index. However, the drug combination significantly improved the parasite in vitro clearance. The repositioning of well-established drugs opens a short-term strategy to obtain low-cost therapeutics approaches against neosporosis.

Convection-Enhanced Delivery of Carboplatin PLGA Nanoparticles for the Treatment of Glioblastoma.

PubMed

Arshad, Azeem; Yang, Bin; Bienemann, Alison S; Barua, Neil U; Wyatt, Marcella J; Woolley, Max; Johnson, Dave E; Edler, Karen J; Gill, Steven S

2015-01-01

We currently use Convection-Enhanced Delivery (CED) of the platinum-based drug, carboplatin as a novel treatment strategy for high grade glioblastoma in adults and children. Although initial results show promise, carboplatin is not specifically toxic to tumour cells and has been associated with neurotoxicity at high infused concentrations in pre-clinical studies. Our treatment strategy requires intermittent infusions due to rapid clearance of carboplatin from the brain. In this study, carboplatin was encapsulated in lactic acid-glycolic acid copolymer (PLGA) to develop a novel drug delivery system. Neuronal and tumour cytotoxicity were assessed in primary neuronal and glioblastoma cell cultures. Distribution, tissue clearance and toxicity of carboplatin nanoparticles following CED was assessed in rat and porcine models. Carboplatin nanoparticles conferred greater tumour cytotoxicity, reduced neuronal toxicity and prolonged tissue half-life. In conclusion, this drug delivery system has the potential to improve the prognosis for patients with glioblastomas.

Convection-Enhanced Delivery of Carboplatin PLGA Nanoparticles for the Treatment of Glioblastoma

PubMed Central

Arshad, Azeem; Yang, Bin; Bienemann, Alison S.; Barua, Neil U.; Wyatt, Marcella J.; Woolley, Max; Johnson, Dave E.; Edler, Karen J.; Gill, Steven S.

2015-01-01

We currently use Convection-Enhanced Delivery (CED) of the platinum-based drug, carboplatin as a novel treatment strategy for high grade glioblastoma in adults and children. Although initial results show promise, carboplatin is not specifically toxic to tumour cells and has been associated with neurotoxicity at high infused concentrations in pre-clinical studies. Our treatment strategy requires intermittent infusions due to rapid clearance of carboplatin from the brain. In this study, carboplatin was encapsulated in lactic acid-glycolic acid copolymer (PLGA) to develop a novel drug delivery system. Neuronal and tumour cytotoxicity were assessed in primary neuronal and glioblastoma cell cultures. Distribution, tissue clearance and toxicity of carboplatin nanoparticles following CED was assessed in rat and porcine models. Carboplatin nanoparticles conferred greater tumour cytotoxicity, reduced neuronal toxicity and prolonged tissue half-life. In conclusion, this drug delivery system has the potential to improve the prognosis for patients with glioblastomas. PMID:26186224

Identification of intestinal loss of a drug through physiologically based pharmacokinetic simulation of plasma concentration-time profiles.

PubMed

Peters, Sheila Annie

2008-01-01

Despite recent advances in understanding of the role of the gut as a metabolizing organ, recognition of gut wall metabolism and/or other factors contributing to intestinal loss of a compound has been a challenging task due to the lack of well characterized methods to distinguish it from first-pass hepatic extraction. The implications of identifying intestinal loss of a compound in drug discovery and development can be enormous. Physiologically based pharmacokinetic (PBPK) simulations of pharmacokinetic profiles provide a simple, reliable and cost-effective way to understand the mechanisms underlying pharmacokinetic processes. The purpose of this article is to demonstrate the application of PBPK simulations in bringing to light intestinal loss of orally administered drugs, using two example compounds: verapamil and an in-house compound that is no longer in development (referred to as compound A in this article). A generic PBPK model, built in-house using MATLAB software and incorporating absorption, metabolism, distribution, biliary and renal elimination models, was employed for simulation of concentration-time profiles. Modulation of intrinsic hepatic clearance and tissue distribution parameters in the generic PBPK model was done to achieve a good fit to the observed intravenous pharmacokinetic profiles of the compounds studied. These optimized clearance and distribution parameters are expected to be invariant across different routes of administration, as long as the kinetics are linear, and were therefore employed to simulate the oral profiles of the compounds. For compounds with reasonably good solubility and permeability, an area under the concentration-time curve for the simulated oral profile that far exceeded the observed would indicate some kind of loss in the intestine. PBPK simulations applied to compound A showed substantial loss of the compound in the gastrointestinal tract in humans but not in rats. This accounted for the lower bioavailability of the compound in humans than in rats. PBPK simulations of verapamil identified gut wall metabolism, well established in the literature, and showed large interspecies differences with respect to both gut wall metabolism and drug-induced delays in gastric emptying. Mechanistic insights provided by PBPK simulations can be very valuable in answering vital questions in drug discovery and development. However, such applications of PBPK models are limited by the lack of accurate inputs for clearance and distribution. This article demonstrates a successful application of PBPK simulations to identify and quantify intestinal loss of two model compounds in rats and humans. The limitation of inaccurate inputs for the clearance and distribution parameters was overcome by optimizing these parameters through fitting intravenous profiles. The study also demonstrated that the large interspecies differences associated with gut wall metabolism and gastric emptying, evident for the compounds studied, make animal model extrapolations to humans unreliable. It is therefore important to do PBPK simulations of human pharmacokinetic profiles to understand the relevance of intestinal loss of a compound in humans.

Particle deposition and clearance of atmospheric particles in the human respiratory tract during LACE 98

NASA Astrophysics Data System (ADS)

Bundke, U.; Hänel, G.

2003-04-01

During the LACE 98footnote{Lindenberg Aerosol Characterization Experiment, (Germany) 1998} experiment microphysical, chemical and optical properties of atmospheric particles were measured by several groups. (Bundke et al.). The particle deposition and clearance of the particles in the human respiratory tract was calculated using the ICRP (International Commission on Radiological Protection) deposition and clearance model (ICRP 1994). Particle growth as function of relative humidity outside the body was calculated from measurement data using the model introduced by Bundke et al.. Particle growth inside the body was added using a non-equilibrium particle growth model. As a result of the calculations, time series of the total dry particle mass and -size distribution were obtained for all compartments of the human respiratory tract defined by ICRP 1994. The combined ICRP deposition and clearance model was initialized for different probationers like man, woman, children of different ages and several circumstances like light work, sitting, sleeping etc. Keeping the conditions observed during LACE 98 constant a approximation of the aerosol burdens of the different compartments was calculated up to 4 years of exposure and compared to the results from Snipes et al. for the "Phoenix" and "Philadelphia" aerosol. References: footnotesize{ Bundke, U. et al.,it{Aerosol Optical Properties during the Lindenberg Aerosol Characterization Experiment (LACE 98)} ,10.1029/2000JD000188, JGR, 2002 ICRP,it{Human Respiratory Tract Model for Radiological Protection, Bd. ICRP Publication 66}, Annals of the ICRP, 24,1-3, Elsevier Science, Ocford, 1994 Snipes et al. ,it{The 1994 ICRP66 Human Respiratory Tract Model as a Tool for predicting Lung Burdens from Exposure to Environmental Aerosols}, Appl. Occup. Environ. Hyg., 12, 547-553,1997}

Diclofenac and metabolite pharmacokinetics in children.

PubMed

van der Marel, Caroline D; Anderson, Brian J; Rømsing, Janne; Jacqz-Aigrain, Evelyne; Tibboel, Dick

2004-06-01

Data concerning metabolism of diclofenac in children are limited to intravenous and enteric coated oral formulations. There are no data examining diclofenac or its hydroxyl metabolite pharmacokinetics after rectal administration in children. Infants (n = 26) undergoing tonsillectomy were given diclofenac 2 mg.kg(-1) followed by 1 mg.kg(-1) 8 h as suppository formulation for postoperative analgesia. Serum was assayed for diclofenac, 4'-hydroxydiclofenac and 5'-hydroxydiclofenac concentrations during the procedure and 1, 2 and 4 h postoperatively. The formation clearances of diclofenac to hydroxyl metabolites were estimated using nonlinear mixed effects models. A single compartment, first order absorption and first order elimination model was used to describe diclofenac pharmacokinetics. Published data from 11 children given enteric-coated diclofenac tablets were used to assess relative bioavailability. Mean (sd) age and weight of the patients were 4.5 (1.5) years and 20.5 (4.1) kg. The formation clearance to 4'-hydroxydiclofenac (% CV) and to 5'-hydroxydiclofenac were 8.41 (8.1) and 3.41 (113) l.h(-1) respectively, standardized to a 70 kg person using allometric '1/4 power' models. Clearance by other routes contributed 33.0 (64) l.h(-1) 70 kg(-1). Elimination clearance of hydroxyl metabolites was fixed at 27.5 l.h(-1) 70 kg(-1). The volumes of distribution of parent diclofenac and its hydroxyl metabolite were 22.8 (19.0) and 45.3 (l.70) kg(-1). The suppository formulation had an absorption half-life of 0.613 (33.2) h with a lag time of 0.188 (24.9) h. Interoccasion variability of formation clearance to 4'-hydroxydiclofenac, diclofenac volume of distribution, absorption half-time and lag time for the suppository was 36%, 55%, 14% and 119%, respectively. The relative bioavailability of the suppository compared with an enteric-coated tablet was 1.26. The formation clearance of the active metabolite 4'-hydroxydiclofenac contributed 19% of total clearance (44.82 l.h(-1) 70 kg(-1)). The rectum is a suitable route for administration of diclofenac in children 2-8 year of age and was associated with a higher relative bioavailabilty than enteric-coated tablets and an earlier maximum concentration (50 vs. 108 min). This pharmacokinetic profile renders diclofenac suppository a suitable formulation for short duration surgery.

Active control of surge in centrifugal compressors using magnetic thrust bearing actuation

NASA Astrophysics Data System (ADS)

Sanadgol, Dorsa

This research presents a new method for active surge control in centrifugal compressors with unshrouded impellers using a magnetic thrust bearing to modulate the impeller tip clearance. Magnetic bearings offer the potential for active control of flow instabilities. This capability is highly dependent on the sensitivity of the compressor characteristics to blade tip clearance. If the position of the shaft can be actuated with sufficient authority and speed, the induced pressure modulation makes control of surge promising. The active nature of the magnetic bearing system makes the real-time static and dynamic positioning of the rotor and therefore modulation of the impeller tip clearance possible. A theoretical model is first established that describes the sensitivity of the centrifugal compressor characteristic curve to tip clearance variations induced by axial motion of the rotor. Results from simulation of the nonlinear model for a single stage high-speed centrifugal compressor show that using the proposed control method, mass flow and pressure oscillations associated with compressor surge are quickly suppressed with acceptable tip clearance excursions, typically less than 20% of the available clearance. It is shown that it is possible to produce adequate axial excursions in the clearance between the impeller blades and the adjacent stationary shroud using a magnetic thrust bearing with practical levels of drive voltage. This surge control method would allow centrifugal compressors to reliably and safely operate with a wider range than is currently done in the field. The principal advantage of the proposed approach over conventional surge control methods lies in that, in machines already equipped with magnetic bearing, the method can potentially be implemented by simply modifying controller software. This dispenses with the need to introduce additional hardware, permitting adaptation of existing machinery at virtually no cost. In addition, since the controller is designed with the objective of keeping the trajectories on the compressor characteristic curve, the compressor performance and efficiency are no longer sacrificed by excessive recycling to achieve stability. In order to explore these conjectures experimentally, a high speed centrifugal compressor test facility with active magnetic bearings is developed. The test facility can be used for implementing the proposed surge control method and also for assessing the impeller and bearing loads at off-design conditions. This data can then be used to verify and refine analytical models used in compressor design. (Abstract shortened by UMI.)

Optimal antimalarial dose regimens for chloroquine in pregnancy based on population pharmacokinetic modelling.

PubMed

Salman, Sam; Baiwog, Francesca; Page-Sharp, Madhu; Kose, Kay; Karunajeewa, Harin A; Mueller, Ivo; Rogerson, Stephen J; Siba, Peter M; Ilett, Kenneth F; Davis, Timothy M E

2017-10-01

Despite extensive use and accumulated evidence of safety, there have been few pharmacokinetic studies from which appropriate chloroquine (CQ) dosing regimens could be developed specifically for pregnant women. Such optimised CQ-based regimens, used as treatment for acute malaria or as intermittent preventive treatment in pregnancy (IPTp), may have a valuable role if parasite CQ sensitivity returns following reduced drug pressure. In this study, population pharmacokinetic/pharmacodynamic modelling was used to simultaneously analyse plasma concentration-time data for CQ and its active metabolite desethylchloroquine (DCQ) in 44 non-pregnant and 45 pregnant Papua New Guinean women treated with CQ and sulfadoxine/pyrimethamine or azithromycin (AZM). Pregnancy was associated with 16% and 49% increases in CQ and DCQ clearance, respectively, as well as a 24% reduction in CQ relative bioavailability. Clearance of DCQ was 22% lower in those who received AZM in both groups. Simulations based on the final multicompartmental model demonstrated that a 33% CQ dose increase may be suitable for acute treatment for malaria in pregnancy as it resulted in equivalent exposure to that in non-pregnant women receiving recommended doses, whilst a double dose would likely be required for an effective duration of post-treatment prophylaxis when used as IPTp especially in areas of CQ resistance. The impact of co-administered AZM was clinically insignificant in simulations. The results of past/ongoing trials employing recommended adult doses of CQ-based regimens in pregnant women should be interpreted in light of these findings, and consideration should be given to using increased doses in future trials. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

76 FR 482 - Airworthiness Directives; Fokker Services B.V. Model F.28 Mark 1000, 2000, 3000, and 4000 Airplanes

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-05

...: * * * under certain conditions, an ignition source may develop in the wing tank vapour space, due to... tank vapour space, due to insufficient clearance between the wiring along the Fuel Quantity Tank Units... develop in the wing tank vapour space, due to insufficient clearance between the wiring along the Fuel...

Underkeel Clearance Study.

DTIC Science & Technology

1981-09-01

EnterewJ N00014-80-C-0395 CONTENTS Page EXECUTIVE SUMMARY 1.0 INTRODUCTION 1.1 The Underlying Problem ................. 1-1 1.2 The Current Study...3-4 3.2.4 CVN Berthinq Facilities .................... 3-4 ii! JI N00014-80-C-0395 CONTENTS (continued) 3.3 Hydrologic Conditions...Drafts ...................... 3-10 3.8.3 Underkeel Clearance ........ .............. 3-10 4.0 THE ANALYSIS 4.1 The Physical Model

76 FR 61561 - Airworthiness Directives; The Boeing Company Model 737-600, -700, -700C, -800, -900, and -900ER...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-05

... AGENCY: Federal Aviation Administration (FAA), DOT. ACTION: Final rule. SUMMARY: We are adopting a new... clearance and any wire bundle damage between wire bundle W443 and the left forward rudder quadrant, followed by adjusting the minimum clearance between the wire bundle and the left forward rudder quadrant, and...

Kinematics Simulation Analysis of Packaging Robot with Joint Clearance

NASA Astrophysics Data System (ADS)

Zhang, Y. W.; Meng, W. J.; Wang, L. Q.; Cui, G. H.

2018-03-01

Considering the influence of joint clearance on the motion error, repeated positioning accuracy and overall position of the machine, this paper presents simulation analysis of a packaging robot — 2 degrees of freedom(DOF) planar parallel robot based on the characteristics of high precision and fast speed of packaging equipment. The motion constraint equation of the mechanism is established, and the analysis and simulation of the motion error are carried out in the case of turning the revolute clearance. The simulation results show that the size of the joint clearance will affect the movement accuracy and packaging efficiency of the packaging robot. The analysis provides a reference point of view for the packaging equipment design and selection criteria and has a great significance on the packaging industry automation.

Event Classification and Identification Based on the Characteristic Ellipsoid of Phasor Measurement

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ma, Jian; Diao, Ruisheng; Makarov, Yuri V.

2011-09-23

In this paper, a method to classify and identify power system events based on the characteristic ellipsoid of phasor measurement is presented. The decision tree technique is used to perform the event classification and identification. Event types, event locations and clearance times are identified by decision trees based on the indices of the characteristic ellipsoid. A sufficiently large number of transient events were simulated on the New England 10-machine 39-bus system based on different system configurations. Transient simulations taking into account different event types, clearance times and various locations are conducted to simulate phasor measurement. Bus voltage magnitudes and recordedmore » reactive and active power flows are used to build the characteristic ellipsoid. The volume, eccentricity, center and projection of the longest axis in the parameter space coordinates of the characteristic ellipsoids are used to classify and identify events. Results demonstrate that the characteristic ellipsoid and the decision tree are capable to detect the event type, location, and clearance time with very high accuracy.« less

Turbo machine tip clearance and vibration measurements using a fibre optic laser Doppler position sensor

NASA Astrophysics Data System (ADS)

Pfister, T.; Büttner, L.; Czarske, J.; Krain, H.; Schodl, R.

2006-07-01

This paper presents a novel fibre optic laser Doppler position sensor for single blade tip clearance and vibration measurements at turbo machines, which offers high temporal resolution and high position resolution simultaneously. The sensor principle is based on the generation of a measurement volume consisting of two superposed fan-like interference fringe systems with contrary fringe spacing gradients using wavelength division multiplexing. A flexible and robust measurement system with an all-passive fibre coupled measurement head has been realized employing diffractive and refractive optics. Measurements of tip clearance and rotor vibrations at a transonic centrifugal compressor performed during operation at up to 50 000 rpm (833 Hz) corresponding to 21.7 kHz blade frequency and 586 m s-1 blade tip velocity are presented. The results are in excellent agreement with those of capacitive probes. The mean uncertainty of the position measurement was around 20 µm and, thus, considerably better than for conventional tip clearance probes. Consequently, this sensor is capable of fulfilling the requirements for future active clearance control systems and has great potential for in situ and online tip clearance and vibration measurements at metallic and non-metallic turbine blades with high precision.

Fault Diagnosis of Internal Combustion Engine Valve Clearance Using the Impact Commencement Detection Method.

PubMed

Jiang, Zhinong; Mao, Zhiwei; Wang, Zijia; Zhang, Jinjie

2017-12-15

Internal combustion engines (ICEs) are widely used in many important fields. The valve train clearance of an ICE usually exceeds the normal value due to wear or faulty adjustment. This work aims at diagnosing the valve clearance fault based on the vibration signals measured on the engine cylinder heads. The non-stationarity of the ICE operating condition makes it difficult to obtain the nominal baseline, which is always an awkward problem for fault diagnosis. This paper overcomes the problem by inspecting the timing of valve closing impacts, of which the referenced baseline can be obtained by referencing design parameters rather than extraction during healthy conditions. To accurately detect the timing of valve closing impact from vibration signals, we carry out a new method to detect and extract the commencement of the impacts. The results of experiments conducted on a twelve-cylinder ICE test rig show that the approach is capable of extracting the commencement of valve closing impact accurately and using only one feature can give a superior monitoring of valve clearance. With the help of this technique, the valve clearance fault becomes detectable even without the comparison to the baseline, and the changing trend of the clearance could be trackable.

Bayesian modelling of lung function data from multiple-breath washout tests.

PubMed

Mahar, Robert K; Carlin, John B; Ranganathan, Sarath; Ponsonby, Anne-Louise; Vuillermin, Peter; Vukcevic, Damjan

2018-05-30

Paediatric respiratory researchers have widely adopted the multiple-breath washout (MBW) test because it allows assessment of lung function in unsedated infants and is well suited to longitudinal studies of lung development and disease. However, a substantial proportion of MBW tests in infants fail current acceptability criteria. We hypothesised that a model-based approach to analysing the data, in place of traditional simple empirical summaries, would enable more efficient use of these tests. We therefore developed a novel statistical model for infant MBW data and applied it to 1197 tests from 432 individuals from a large birth cohort study. We focus on Bayesian estimation of the lung clearance index, the most commonly used summary of lung function from MBW tests. Our results show that the model provides an excellent fit to the data and shed further light on statistical properties of the standard empirical approach. Furthermore, the modelling approach enables the lung clearance index to be estimated by using tests with different degrees of completeness, something not possible with the standard approach. Our model therefore allows previously unused data to be used rather than discarded, as well as routine use of shorter tests without significant loss of precision. Beyond our specific application, our work illustrates a number of important aspects of Bayesian modelling in practice, such as the importance of hierarchical specifications to account for repeated measurements and the value of model checking via posterior predictive distributions. Copyright © 2018 John Wiley & Sons, Ltd.

Antibiotic-induced population fluctuations and stochastic clearance of bacteria

PubMed Central

Le, Dai; Şimşek, Emrah; Chaudhry, Waqas

2018-01-01

Effective antibiotic use that minimizes treatment failures remains a challenge. A better understanding of how bacterial populations respond to antibiotics is necessary. Previous studies of large bacterial populations established the deterministic framework of pharmacodynamics. Here, characterizing the dynamics of population extinction, we demonstrated the stochastic nature of eradicating bacteria with antibiotics. Antibiotics known to kill bacteria (bactericidal) induced population fluctuations. Thus, at high antibiotic concentrations, the dynamics of bacterial clearance were heterogeneous. At low concentrations, clearance still occurred with a non-zero probability. These striking outcomes of population fluctuations were well captured by our probabilistic model. Our model further suggested a strategy to facilitate eradication by increasing extinction probability. We experimentally tested this prediction for antibiotic-susceptible and clinically-isolated resistant bacteria. This new knowledge exposes fundamental limits in our ability to predict bacterial eradication. Additionally, it demonstrates the potential of using antibiotic concentrations that were previously deemed inefficacious to eradicate bacteria. PMID:29508699

Arctigenin effectively ameliorates memory impairment in Alzheimer's disease model mice targeting both β-amyloid production and clearance.

PubMed

Zhu, Zhiyuan; Yan, Jianming; Jiang, Wei; Yao, Xin-gang; Chen, Jing; Chen, Lili; Li, Chenjing; Hu, Lihong; Jiang, Hualiang; Shen, Xu

2013-08-07

Alzheimer's disease (AD) chiefly characterizes a progressively neurodegenerative disorder of the brain, and eventually leads to irreversible loss of intellectual abilities. The β-amyloid (Aβ)-induced neurodegeneration is believed to be the main pathological mechanism of AD, and Aβ production inhibition or its clearance promotion is one of the promising therapeutic strategies for anti-AD research. Here, we report that the natural product arctigenin from Arctium lappa (L.) can both inhibit Aβ production by suppressing β-site amyloid precursor protein cleavage enzyme 1 expression and promote Aβ clearance by enhancing autophagy through AKT/mTOR signaling inhibition and AMPK/Raptor pathway activation as investigated in cells and APP/PS1 transgenic AD model mice. Moreover, the results showing that treatment of arctigenin in mice highly decreased Aβ formation and senile plaques and efficiently ameliorated AD mouse memory impairment strongly highlight the potential of arctigenin in anti-AD drug discovery.

Prophylactic ranitidine treatment in critically ill children--a population pharmacokinetic study.

PubMed

Hawwa, Ahmed F; Westwood, Paul M; Collier, Paul S; Millership, Jeffrey S; Yakkundi, Shirish; Thurley, Gillian; Shields, Mike D; Nunn, Anthony J; Halliday, Henry L; McElnay, James C

2013-05-01

To characterize the population pharmacokinetics of ranitidine in critically ill children and to determine the influence of various clinical and demographic factors on its disposition. Data were collected prospectively from 78 paediatric patients (n = 248 plasma samples) who received oral or intravenous ranitidine for prophylaxis against stress ulcers, gastrointestinal bleeding or the treatment of gastro-oesophageal reflux. Plasma samples were analysed using high-performance liquid chromatography, and the data were subjected to population pharmacokinetic analysis using nonlinear mixed-effects modelling. A one-compartment model best described the plasma concentration profile, with an exponential structure for interindividual errors and a proportional structure for intra-individual error. After backward stepwise elimination, the final model showed a significant decrease in objective function value (-12.618; P < 0.001) compared with the weight-corrected base model. Final parameter estimates for the population were 32.1 l h(-1) for total clearance and 285 l for volume of distribution, both allometrically modelled for a 70 kg adult. Final estimates for absorption rate constant and bioavailability were 1.31 h(-1) and 27.5%, respectively. No significant relationship was found between age and weight-corrected ranitidine pharmacokinetic parameters in the final model, with the covariate for cardiac failure or surgery being shown to reduce clearance significantly by a factor of 0.46. Currently, ranitidine dose recommendations are based on children's weights. However, our findings suggest that a dosing scheme that takes into consideration both weight and cardiac failure/surgery would be more appropriate in order to avoid administration of higher or more frequent doses than necessary. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Increased Glyburide Clearance in the Pregnant Mouse Model

PubMed Central

Zhou, Lin; Zhang, Yi; Hebert, Mary F.; Unadkat, Jashvant D.

2010-01-01

Glyburide (GLB) is an oral sulfonylurea, commonly used for the treatment of gestational diabetes mellitus. It has been reported that the clearance of GLB in pregnant women is significantly higher than that in nonpregnant women. The molecular mechanism by which pregnancy increases the clearance of GLB is not known, but it may be caused by increased CYP3A activity. Because liver tissue from pregnant women is not readily available, in the present study, we investigated the mechanism of such pregnancy-related changes in GLB disposition in a mouse model. We demonstrated that the systemic clearance of GLB in pregnant mice was increased approximately 2-fold (p < 0.01) compared with nonpregnant mice, a magnitude of change similar to that observed in the clinical study. Plasma protein binding of GLB in mice was not altered by pregnancy. The half-life of GLB depletion in hepatic S-9 fractions of pregnant mice was significantly shorter than that of nonpregnant mice. Moreover, GLB depletion was markedly inhibited by ketoconazole, a potent inhibitor of mouse Cyp3a, suggesting that GLB metabolism in mice is primarily mediated by hepatic Cyp3a. These data suggest that the increased systemic clearance of GLB in pregnant mice is likely caused by an increase in hepatic Cyp3a activity during pregnancy, and they provide a basis for further mechanistic understanding and analysis of pregnancy-induced alterations in the disposition of GLB and drugs that are predominantly and extensively metabolized by CYP3A/Cyp3a. PMID:20558597

Measuring Clearance Mechanics Based on Dynamic Leg Length

ERIC Educational Resources Information Center

Khamis, Sam; Danino, Barry; Hayek, Shlomo; Carmeli, Eli

2018-01-01

The aim of this study was to quantify clearance mechanics during gait. Seventeen children diagnosed with hemiplegic cerebral palsy underwent a three-dimensional gait analysis evaluation. Dynamic leg lengths were measured from the hip joint center to the heel, to the ankle joint center and to the forefoot throughout the gait cycle. Significant…

Deriving an explicit hepatic clearance equation accounting for plasma protein binding and hepatocellular uptake.

PubMed

Yoon, Miyoung; Clewell, Harvey J; Andersen, Melvin E

2013-02-01

High throughput in vitro biochemical and cell-based assays have the promise to provide more mechanism-based assessments of the adverse effects of large numbers of chemicals. One of the most challenging hurdles for interpreting in vitro toxicity findings is the need for reverse dosimetry tools that estimate the exposures that will give concentrations in vivo similar to the active concentrations in vitro. Recent experience using IVIVE approaches to estimate in vivo pharmacokinetics (Wetmore et al., 2012) identified the need to develop a hepatic clearance equation that explicitly accounted for a broader set of protein binding and membrane transport processes and did not depend on a well-mixed description of the liver compartment. Here we derive an explicit steady-state hepatic clearance equation that includes these factors. In addition to the derivation, we provide simple computer code to calculate steady-state extraction for any combination of blood flow, membrane transport processes and plasma protein-chemical binding rates. This expanded equation provides a tool to estimate hepatic clearance for a more diverse array of compounds. Copyright © 2012 Elsevier Ltd. All rights reserved.

A practical method of I-131 thyroid cancer therapy dose optimization using estimated effective renal clearance.

PubMed

Howard, Brandon A; James, Olga G; Perkins, Jennifer M; Pagnanelli, Robert A; Borges-Neto, Salvador; Reiman, Robert E

2017-01-01

In thyroid cancer patients with renal impairment or other complicating factors, it is important to maximize I-131 therapy efficacy while minimizing bone marrow and lung damage. We developed a web-based calculator based on a modified Benua and Leeper method to calculate the maximum I-131 dose to reduce the risk of these toxicities, based on the effective renal clearance of I-123 as measured from two whole-body I-123 scans, performed at 0 and 24 h post-administration.

Nonlinear analysis of a rotor-bearing system using describing functions

NASA Astrophysics Data System (ADS)

Maraini, Daniel; Nataraj, C.

2018-04-01

This paper presents a technique for modelling the nonlinear behavior of a rotor-bearing system with Hertzian contact, clearance, and rotating unbalance. The rotor-bearing system is separated into linear and nonlinear components, and the nonlinear bearing force is replaced with an equivalent describing function gain. The describing function captures the relationship between the amplitude of the fundamental input to the nonlinearity and the fundamental output. The frequency response is constructed for various values of the clearance parameter, and the results show the presence of a jump resonance in bearings with both clearance and preload. Nonlinear hardening type behavior is observed in the case with clearance and softening behavior is observed for the case with preload. Numerical integration is also carried out on the nonlinear equations of motion showing strong agreement with the approximate solution. This work could easily be extended to include additional nonlinearities that arise from defects, providing a powerful diagnostic tool.

Simultaneous pharmacogenetics-based population pharmacokinetic analysis of darunavir and ritonavir in HIV-infected patients.

PubMed

Moltó, José; Xinarianos, George; Miranda, Cristina; Pushpakom, Sudeep; Cedeño, Samandhy; Clotet, Bonaventura; Owen, Andrew; Valle, Marta

2013-07-01

Darunavir is a potent protease inhibitor of HIV. To enhance its pharmacokinetic profile, darunavir must be co-administered with ritonavir. There is wide inter-patient variability in darunavir pharmacokinetics among HIV-infected individuals, however. Darunavir is a known substrate for influx transporters, such as the 1A2 and the 1B1 members of the solute carrier organic anion transporter family (SLCO1A2, SLCO1B1), as well as for efflux transporters such as the multi-drug resistance protein 1 (MRP1). The aim of this study was to develop a semi-mechanistic population pharmacokinetic model for darunavir and ritonavir administered in HIV-infected adults. The desired model would incorporate patient characteristics and pharmacogenetic data contributing to variability in drug concentrations and also take into account the interaction between the two compounds. A population pharmacokinetic analysis was performed with 705 plasma samples from 75 Caucasian individuals receiving darunavir/ritonavir (600/100 mg twice daily) for at least 4 weeks. At least one full pharmacokinetic profile was obtained for each participant, and darunavir and ritonavir concentrations in plasma were determined by high performance liquid chromatography. Genotyping for 148 polymorphisms in genes coding for transporters or metabolizing enzymes was conducted by two methods: MALDI-TOF mass spectrometry and real-time polymerase chain reaction-based allelic discrimination. A population pharmacokinetic model was developed for darunavir and for ritonavir. The effect of single nucleotide polymorphisms on the post hoc individual pharmacokinetic parameters was first explored using graphic methods and regression analysis. Those covariates related to changes in darunavir or ritonavir pharmacokinetic parameters were then further evaluated using non-linear mixed effects modeling (NONMEM version VII). Darunavir and ritonavir pharmacokinetics were best described by a two- and one-compartment model, respectively, both with first-order absorption and elimination. The darunavir peripheral volume of distribution decreased as α1-acid glycoprotein concentrations increased. Darunavir clearance was 12 % lower in patients with SLCO3A1 rs8027174 GT/TT genotypes, while homozygosity for the rs4294800 A allele was associated with 2.5-fold higher central volume of distribution. Body weight influenced ritonavir clearance. Ritonavir inhibited darunavir clearance following a maximum-effect model. A population pharmacokinetic model to simultaneously describe the pharmacokinetics of darunavir and ritonavir was developed in HIV-infected patients. The model provides better understanding of the interaction between darunavir and ritonavir and suggests an association between SLCO3A1 polymorphisms and darunavir pharmacokinetics. Bayesian estimates of individual darunavir parameters and ritonavir may be useful to predict darunavir exposure.

A Helix-Stabilizing Linker Improves Subcutaneous Bioavailability of a Helical Peptide Independent of Linker Lipophilicity.

PubMed

Zhang, Liang; Navaratna, Tejas; Thurber, Greg M

2016-07-20

Stabilized peptides address several limitations to peptide-based imaging agents and therapeutics such as poor stability and low affinity due to conformational flexibility. There is also active research in developing these compounds for intracellular drug targeting, and significant efforts have been invested to determine the effects of helix stabilization on intracellular delivery. However, much less is known about the impact on other pharmacokinetic parameters such as plasma clearance and bioavailability. We investigated the effect of different fluorescent helix-stabilizing linkers with varying lipophilicity on subcutaneous (sc) bioavailability using the glucagon-like peptide-1 (GLP-1) receptor ligand exendin as a model system. The stabilized peptides showed significantly higher protease resistance and increased bioavailability independent of linker hydrophilicity, and all subcutaneously delivered conjugates were able to successfully target the islets of Langerhans with high specificity. The lipophilic peptide variants had slower absorption and plasma clearance than their respective hydrophilic conjugates, and the absolute bioavailability was also lower likely due to the longer residence times in the skin. Their ease and efficiency make double-click helix stabilization chemistries a useful tool for increasing the bioavailability of peptide therapeutics, many of which suffer from rapid in vivo protease degradation. Helix stabilization using linkers of varying lipophilicity can further control sc absorption and clearance rates to customize plasma pharmacokinetics.

The effects of alcohol on spontaneous clearance of acute hepatitis C virus infection in females versus males.

PubMed

Tsui, Judith I; Mirzazadeh, Ali; Hahn, Judith A; Maher, Lisa; Bruneau, Julie; Grebely, Jason; Hellard, Margaret; Kim, Arthur Y; Shoukry, Naglaa H; Cox, Andrea L; Prins, Maria; Dore, Gregory J; Lauer, Georg; Lloyd, Andrew R; Page, Kimberly

2016-12-01

Approximately one quarter of persons exposed to hepatitis C virus (HCV) will spontaneously clear infection. We undertook this study to investigate the impact of alcohol on likelihood of HCV spontaneous viral clearance stratified by sex groups. Pooled data from an international collaboration of prospective observational studies of incident HIV and HCV infection in high-risk cohorts (the InC3 Study) was restricted to 411 persons (or 560.7 person-years of observation) with documented acute HCV infection and data regarding alcohol use. The predictor of interest was self-reported alcohol use at or after estimated date of incident HCV infection and the outcome was HCV spontaneous clearance. Sex stratified Cox proportional hazards models were used to evaluate the association between alcohol and spontaneous clearance, adjusting for age, race/ethnicity, and IFNL4 genotype. The median age was 28.5 years, 30.4% were women, 87.2% were white, and 71.8% reported alcohol use at or after incident infection. There were 89 (21.6%) cases of spontaneous clearance observed, 39 (31.2%) among women and 50 (17.5%) in men (p<0.01). Overall, spontaneous clearance occurred less frequently among participants who drank alcohol compared to those who did not drink (18.9% v. 28.5%, p=0.03). After adjustment for other covariates, alcohol was significantly and independently associated with lower relative hazards for spontaneous clearance of HCV in women (AHR=0.35; 95% CI: 0.19-0.66; p=0.001) but not in men (AHR=0.63; 95% CI: 0.36-1.09; p=0.10). Results indicate that abstaining from drinking alcohol may increase the likelihood of spontaneous clearance among women. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The Effects of Alcohol on Spontaneous Clearance of Acute Hepatitis C Virus Infection in Females versus Males

PubMed Central

Tsui, Judith I.; Mirzazadeh, Ali; Hahn, Judith A.; Maher, Lisa; Bruneau, Julie; Grebely, Jason; Hellard, Margaret; Kim, Arthur Y.; Shoukry, Naglaa H.; Cox, Andrea L.; Prins, Maria; Dore, Gregory; Lauer, Georg; Lloyd, Andrew; Page, Kimberly

2016-01-01

Background Approximately one quarter of persons exposed to hepatitis C virus (HCV) will spontaneously clear infection. We undertook this study to investigate the impact of alcohol on likelihood of HCV spontaneous viral clearance stratified by sex groups. Methods Pooled data from an international collaboration of prospective observational studies of incident HIV and HCV infection in high-risk cohorts (the InC3 Study) was restricted to 411 persons (or 560.7 person-years of observation) with documented acute HCV infection and data regarding alcohol use. The predictor of interest was self-reported alcohol use at or after estimated date of incident HCV infection and the outcome was HCV spontaneous clearance. Sex stratified Cox proportional hazards models were used to evaluate the association between alcohol and spontaneous clearance, adjusting for age, race/ethnicity, and IFNL4 genotype. Results The median age was 28.5 years, 30.4% were women, 87.2% were white, and 71.8% reported alcohol use at or after incident infection. There were 89 (21.6%) cases of spontaneous clearance observed, 39 (31.2%) among women and 50 (17.5%) in men (p<0.01). Overall, spontaneous clearance occurred less frequently among participants who drank alcohol compared to those who did not drink (18.9% v. 28.5%, p=0.03). After adjustment for other covariates, alcohol was significantly and independently associated with lower relative hazards for spontaneous clearance of HCV in women (AHR=0.35; 95% CI: 0.19-0.66; p=0.001) but not in men (AHR=0.63; 95% CI: 0.36-1.09; p=0.10). Conclusion Results indicate that abstaining from drinking alcohol may increase the likelihood of spontaneous clearance among women. PMID:27816863

Inhibition of cytochrome P450 enzymes by saturated and unsaturated fatty acids in human liver microsomes, characterization of enzyme kinetics in the presence of bovine serum albumin (0.1 and 1.0% w/v) and in vitro - in vivo extrapolation of hepatic clearance.

PubMed

Palacharla, Raghava Choudary; Uthukam, Venkatesham; Manoharan, Arunkumar; Ponnamaneni, Ranjith Kumar; Padala, Nagasurya Prakash; Boggavarapu, Rajesh Kumar; Bhyrapuneni, Gopinadh; Ajjala, Devender Reddy; Nirogi, Ramakrishna

2017-04-01

The objective of the study was to determine the effect of fatty acids on CYP enzymes and the effect of BSA on intrinsic clearance of probe substrates. The inhibitory effect of thirteen fatty acids including saturated, mono-unsaturated and polyunsaturated fatty acids on CYP enzymes, kinetic parameters and intrinsic clearance values of nine CYP marker probe substrate reactions in the absence and presence of BSA (0.1 and 1.0% w/v) were characterized in human liver microsomes. The results demonstrate that most of the unsaturated fatty acids showed marked inhibition towards CYP2C8 mediated amodiaquine N-deethylation followed by inhibition of CYP2C9 and CYP2B6 mediated activities. The addition of 0.1% BSA in the incubation markedly improved the unbound intrinsic clearance values of probe substrates by reducing the K m values with little or no effect on maximal velocity. The addition of BSA (0.1 and 1.0% w/v) did not influence the unbound intrinsic clearance of marker reactions for CYP2A6, and CYP3A4 enzymes. The addition of 0.1% w/v BSA is sufficient to determine the intrinsic clearance of marker probe reactions by metabolite formation approach. The predicted hepatic clearance values for the substrates using the well-stirred model, in the presence of BSA (0.1% BSA), are comparable to the in vivo hepatic clearance values. Copyright © 2017 Elsevier B.V. All rights reserved.

Depression of in vivo clearance function of hepatic macrophage complement receptors following thermal injury.

PubMed

Cuddy, B G; Loegering, D J; Blumenstock, F A

1984-09-01

Previous studies have implicated a role for impaired hepatic macrophage blood clearance function in the increased susceptibility to infection caused by experimental thermal injury. The present study evaluated in vivo hepatic macrophage complement receptor clearance function as a possible factor contributing to impaired hepatic clearance after thermal injury. Rat erythrocytes treated with anti-erythrocyte serum (EA) were used as the test particle in rats. EA were rapidly removed from the circulation primarily by the liver and hepatic uptake of EA was greatly depressed in animals rendered C3 deficient by treatment with cobra venom factor. Thermal injury caused a large depression in the hepatic uptake of EA. It was shown that the depression in the binding of EA to hepatic macrophages was not due to decreased hepatic blood flow, decreased serum complement levels, or increased fluid phase C3b. Also, the depression of the hepatic uptake of EA incubated with serum prior to injection (EAC) was not different from that of EA after thermal injury. On this basis it was concluded that the impairment in binding of EA to the macrophages was at the cellular level and represented a depression in complement receptor clearance function. Additional studies showed that the injection of erythrocyte stroma, as a model of intravascular hemolysis, also depressed in vivo hepatic macrophage complement receptor clearance function. This latter finding suggests that the intravascular hemolysis caused by thermal injury may contribute to the depression of macrophage receptor function. The depression of hepatic macrophage complement receptor clearance function may contribute to the impaired bacterial clearance and increased susceptibility to infection following experimental thermal injury.

A novel technique of contrast-enhanced optical coherence tomography imaging in evaluation of clearance of lipids in human tears.

PubMed

Napoli, Pietro Emanuele; Coronella, Franco; Satta, Giovanni Maria; Fossarello, Maurizio

2014-01-01

The aim of this work was to gather preliminary data in different conditions of healthy eyes, aqueous tear deficient dry eyes, obstructive meibomian gland disease (MGD) and non-obvious obstructive MGD (NOMGD) individuals, using a new, contrast-enhanced optical coherence tomography (OCT) imaging method to evaluate the clearance of lipids in human tears. Eighty-two adult patients presenting with complaints of ocular irritation were studied for abnormalities of the ocular surface and classified as healthy (n = 21), aqueous tear deficient dry eyes (n = 20), obstructive MGD (n = 15) and NOMGD (n = 26) individuals. A lipid-based tracer, containing an oil-in-water emulsion, was used to obtain an enhanced OCT imaging of the lower tear meniscus. After instillation, a dramatic initial increase of reflectivity of the lower tear meniscus was detected by OCT, followed by a decay back to baseline values over time. Based on this finding, the clearance of lipids was measured in real-time by Fourier-domain anterior segment OCT. The differences in the clearance of lipids among the four groups as well as the correlations between symptom questionnaire score, standardized visual scale test, fluorescein break-up time, ocular surface fluorescein staining score, Schirmer I test scores were found to be statistically significant. The individual areas under the curve of the clearance of lipids calculated by the receiver operating characteristic curve technique ranged from 0.66 to 0.98, suggesting reliable sensitivity and specificity of lipid-enhanced OCT imaging. This new technique of contrast-enhanced OCT imaging of the tear film following lipid-based tracer instillation provides a measure of the clearance of lipids. The quantitative values found are in agreement with other methods of evaluation of the lacrimal system. An improvement of the clinician's ability in the diagnosis and understanding of abnormalities of the ocular surface may be achieved by this simple approach.

Electronic Structure Methods Based on Density Functional Theory

DTIC Science & Technology

2010-01-01

0188 The public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing...chapter in the ASM Handbook , Volume 22A: Fundamentals of Modeling for Metals Processing, 2010. PAO Case Number: 88ABW-2009-3258; Clearance Date: 16 Jul...are represented using a linear combination, or basis, of plane waves. Over time several methods were developed to avoid the large number of planewaves

Generation of a new cystatin C-based estimating equation for glomerular filtration rate by use of 7 assays standardized to the international calibrator.

PubMed

Grubb, Anders; Horio, Masaru; Hansson, Lars-Olof; Björk, Jonas; Nyman, Ulf; Flodin, Mats; Larsson, Anders; Bökenkamp, Arend; Yasuda, Yoshinari; Blufpand, Hester; Lindström, Veronica; Zegers, Ingrid; Althaus, Harald; Blirup-Jensen, Søren; Itoh, Yoshi; Sjöström, Per; Nordin, Gunnar; Christensson, Anders; Klima, Horst; Sunde, Kathrin; Hjort-Christensen, Per; Armbruster, David; Ferrero, Carlo

2014-07-01

Many different cystatin C-based equations exist for estimating glomerular filtration rate. Major reasons for this are the previous lack of an international cystatin C calibrator and the nonequivalence of results from different cystatin C assays. Use of the recently introduced certified reference material, ERM-DA471/IFCC, and further work to achieve high agreement and equivalence of 7 commercially available cystatin C assays allowed a substantial decrease of the CV of the assays, as defined by their performance in an external quality assessment for clinical laboratory investigations. By use of 2 of these assays and a population of 4690 subjects, with large subpopulations of children and Asian and Caucasian adults, with their GFR determined by either renal or plasma inulin clearance or plasma iohexol clearance, we attempted to produce a virtually assay-independent simple cystatin C-based equation for estimation of GFR. We developed a simple cystatin C-based equation for estimation of GFR comprising only 2 variables, cystatin C concentration and age. No terms for race and sex are required for optimal diagnostic performance. The equation, [Formula: see text] is also biologically oriented, with 1 term for the theoretical renal clearance of small molecules and 1 constant for extrarenal clearance of cystatin C. A virtually assay-independent simple cystatin C-based and biologically oriented equation for estimation of GFR, without terms for sex and race, was produced. © 2014 The American Association for Clinical Chemistry.

Controversies in "clearing" trauma to the cervical spine.

PubMed

Tins, Bernhard; Cassar-Pullicino, Victor

2007-04-01

Clearance of the traumatic cervical spine is a subject affecting most healthcare professionals dealing with trauma patients. There is a host of often contradictory literature making it hard for an interested reader to come to their own informed opinion based on the current evidence. This review aims to outline the relevant literature for the clearance of the traumatic cervical spine with the particular aim of highlighting the contradictions, controversies and unanswered questions still besetting this important subject. A brief, subjective opinion for a combined clinical and imaging protocol for clearance of the traumatic cervical spine is given.

DataComm in Flight Deck Surface Trajectory-Based Operations

NASA Technical Reports Server (NTRS)

Bakowski, Deborah L.; Foyle, David C.; Hooey, Becky L.; Meyer, Glenn R.; Wolter, Cynthia A.

2012-01-01

The purpose of this pilot-in-the-loop aircraft taxi simulation was to evaluate a NextGen concept for surface trajectory-based operations (STBO) in which air traffic control (ATC) issued taxi clearances with a required time of arrival (RTA) by Data Communications (DataComm). Flight deck avionics, driven by an error-nulling algorithm, displayed the speed needed to meet the RTA. To ensure robustness of the algorithm, the ability of 10 two-pilot crews to meet the RTA was tested in nine experimental trials representing a range of realistic conditions including a taxi route change, an RTA change, a departure clearance change, and a crossing traffic hold scenario. In some trials, these DataComm taxi clearances or clearance modifications were accompanied by 'preview' information, in which the airport map display showed a preview of the proposed route changes, including the necessary speed to meet the RTA. Overall, the results of this study show that with the aid of the RTA speed algorithm, pilots were able to meet their RTAs with very little time error in all of the robustness-testing scenarios. Results indicated that when taxi clearance changes were issued by DataComm only, pilots required longer notification distances than with voice communication. However, when the DataComm was accompanied by graphical preview, the notification distance required by pilots was equivalent to that for voice.

DataComm in Flight Deck Surface Trajectory-Based Operations. Chapter 20

NASA Technical Reports Server (NTRS)

Bakowski, Deborah L.; Foyle, David C.; Hooey, Becky L.; Meyer, Glenn R.; Wolter, Cynthia A.

2012-01-01

The purpose of this pilot-in-the-loop aircraft taxi simulation was to evaluate a NextGen concept for surface trajectory-based operations (STBO) in which air traffic control (ATC) issued taxi clearances with a required time of arrival (RTA) by Data Communications (DataComm). Flight deck avionics, driven by an error-nulling algorithm, displayed the speed needed to meet the RTA. To ensure robustness of the algorithm, the ability of 10 two-pilot crews to meet the RTA was tested in nine experimental trials representing a range of realistic conditions including a taxi route change, an RTA change, a departure clearance change, and a crossing traffic hold scenario. In some trials, these DataComm taxi clearances or clearance modifications were accompanied by preview information, in which the airport map display showed a preview of the proposed route changes, including the necessary speed to meet the RTA. Overall, the results of this study show that with the aid of the RTA speed algorithm, pilots were able to meet their RTAs with very little time error in all of the robustness-testing scenarios. Results indicated that when taxi clearance changes were issued by DataComm only, pilots required longer notification distances than with voice communication. However, when the DataComm was accompanied by graphical preview, the notification distance required by pilots was equivalent to that for voice.

High-speed blanking of copper alloy sheets: Material modeling and simulation

NASA Astrophysics Data System (ADS)

Husson, Ch.; Ahzi, S.; Daridon, L.

2006-08-01

To optimize the blanking process of thin copper sheets ( ≈ 1. mm thickness), it is necessary to study the influence of the process parameters such as the punch-die clearance and the wear of the punch and the die. For high stroke rates, the strain rate developed in the work-piece can be very high. Therefore, the material modeling must include the dynamic effects.For the modeling part, we propose an elastic-viscoplastic material model combined with a non-linear isotropic damage evolution law based on the theory of the continuum damage mechanics. Our proposed modeling is valid for a wide range of strain rates and temperatures. Finite Element simulations, using the commercial code ABAQUS/Explicit, of the blanking process are then conducted and the results are compared to the experimental investigations. The predicted cut edge of the blanked part and the punch-force displacement curves are discussed as function of the process parameters. The evolution of the shape errors (roll-over depth, fracture depth, shearing depth, and burr formation) as function of the punch-die clearance, the punch and the die wear, and the contact punch/die/blank-holder are presented. A discussion on the different stages of the blanking process as function of the processing parameters is given. The predicted results of the blanking dependence on strain-rate and temperature using our modeling are presented (for the plasticity and damage). The comparison our model results with the experimental ones shows a good agreement.

Facilitating higher-fidelity simulations of axial compressor instability and other turbomachinery flow conditions

NASA Astrophysics Data System (ADS)

Herrick, Gregory Paul

The quest to accurately capture flow phenomena with length-scales both short and long and to accurately represent complex flow phenomena within disparately sized geometry inspires a need for an efficient, high-fidelity, multi-block structured computational fluid dynamics (CFD) parallel computational scheme. This research presents and demonstrates a more efficient computational method by which to perform multi-block structured CFD parallel computational simulations, thus facilitating higher-fidelity solutions of complicated geometries (due to the inclusion of grids for "small'' flow areas which are often merely modeled) and their associated flows. This computational framework offers greater flexibility and user-control in allocating the resource balance between process count and wall-clock computation time. The principal modifications implemented in this revision consist of a "multiple grid block per processing core'' software infrastructure and an analytic computation of viscous flux Jacobians. The development of this scheme is largely motivated by the desire to simulate axial compressor stall inception with more complete gridding of the flow passages (including rotor tip clearance regions) than has been previously done while maintaining high computational efficiency (i.e., minimal consumption of computational resources), and thus this paradigm shall be demonstrated with an examination of instability in a transonic axial compressor. However, the paradigm presented herein facilitates CFD simulation of myriad previously impractical geometries and flows and is not limited to detailed analyses of axial compressor flows. While the simulations presented herein were technically possible under the previous structure of the subject software, they were much less computationally efficient and thus not pragmatically feasible; the previous research using this software to perform three-dimensional, full-annulus, time-accurate, unsteady, full-stage (with sliding-interface) simulations of rotating stall inception in axial compressors utilized tip clearance periodic models, while the scheme here is demonstrated by a simulation of axial compressor stall inception utilizing gridded rotor tip clearance regions. As will be discussed, much previous research---experimental, theoretical, and computational---has suggested that understanding clearance flow behavior is critical to understanding stall inception, and previous computational research efforts which have used tip clearance models have begged the question, "What about the clearance flows?''. This research begins to address that question.

HPT Clearance Control: Intelligent Engine Systems-Phase 1

NASA Technical Reports Server (NTRS)

2005-01-01

The following work has been completed to satisfy the Phase I Deliverables for the "HPT Clearance Control" project under NASA GRC's "Intelligent Engine Systems" program: (1) Need for the development of an advanced HPT ACC system has been very clearly laid out, (2) Several existing and potential clearance control systems have been reviewed, (3) A scorecard has been developed to document the system, performance (fuel burn, range, payload, etc.), thermal, and mechanical characteristics of the existing clearance control systems, (4) Engine size and flight cycle selection for the advanced HPT ACC system has been reviewed with "large engine"/"long range mission" combination showing the most benefit, (5) A scoring criteria has been developed to tie together performance parameters for an objective, data driven comparison of competing systems, and (6) The existing HPT ACC systems have been scored based on this scoring system.

Design and Characterization of a Microfabricated Hydrogen Clearance Blood Flow Sensor

PubMed Central

Walton, Lindsay R.; Edwards, Martin A.; McCarty, Gregory S.; Wightman, R. Mark

2016-01-01

Background Modern cerebral blood flow (CBF) detection favors the use of either optical technologies that are limited to cortical brain regions, or expensive magnetic resonance. Decades ago, inhalation gas clearance was the choice method of quantifying CBF, but this suffered from poor temporal resolution. Electrolytic H2 clearance (EHC) generates and collects gas in situ at an electrode pair, which improves temporal resolution, but the probe size has prohibited meaningful subcortical use. New Method We microfabricated EHC electrodes to an order of magnitude smaller than those existing, on the scale of 100 µm, to permit use deep within the brain. Results Novel EHC probes were fabricated. The devices offered exceptional signal-to-noise, achieved high collection efficiencies (40 – 50%) in vitro, and agreed with theoretical modeling. An in vitro chemical reaction model was used to confirm that our devices detected flow rates higher than those expected physiologically. Computational modeling that incorporated realistic noise levels demonstrated devices would be sensitive to physiological CBF rates. Comparison with Existing Method The reduced size of our arrays makes them suitable for subcortical EHC measurements, as opposed to the larger, existing EHC electrodes that would cause substantial tissue damage. Our array can collect multiple CBF measurements per minute, and can thus resolve physiological changes occurring on a shorter timescale than existing gas clearance measurements. Conclusion We present and characterize microfabricated EHC electrodes and an accompanying theoretical model to interpret acquired data. Microfabrication allows for the high-throughput production of reproducible devices that are capable of monitoring deep brain CBF with sub-minute resolution. PMID:27102042

Population pharmacokinetics and maximum a posteriori probability Bayesian estimator of abacavir: application of individualized therapy in HIV-infected infants and toddlers.

PubMed

Zhao, Wei; Cella, Massimo; Della Pasqua, Oscar; Burger, David; Jacqz-Aigrain, Evelyne

2012-04-01

Abacavir is used to treat HIV infection in both adults and children. The recommended paediatric dose is 8 mg kg(-1) twice daily up to a maximum of 300 mg twice daily. Weight was identified as the central covariate influencing pharmacokinetics of abacavir in children. A population pharmacokinetic model was developed to describe both once and twice daily pharmacokinetic profiles of abacavir in infants and toddlers. Standard dosage regimen is associated with large interindividual variability in abacavir concentrations. A maximum a posteriori probability Bayesian estimator of AUC(0-) (t) based on three time points (0, 1 or 2, and 3 h) is proposed to support area under the concentration-time curve (AUC) targeted individualized therapy in infants and toddlers. To develop a population pharmacokinetic model for abacavir in HIV-infected infants and toddlers, which will be used to describe both once and twice daily pharmacokinetic profiles, identify covariates that explain variability and propose optimal time points to optimize the area under the concentration-time curve (AUC) targeted dosage and individualize therapy. The pharmacokinetics of abacavir was described with plasma concentrations from 23 patients using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment model with first-order absorption and elimination was developed. The final model was validated using bootstrap, visual predictive check and normalized prediction distribution errors. The Bayesian estimator was validated using the cross-validation and simulation-estimation method. The typical population pharmacokinetic parameters and relative standard errors (RSE) were apparent systemic clearance (CL) 13.4 () h−1 (RSE 6.3%), apparent central volume of distribution 4.94 () (RSE 28.7%), apparent peripheral volume of distribution 8.12 () (RSE14.2%), apparent intercompartment clearance 1.25 () h−1 (RSE 16.9%) and absorption rate constant 0.758 h−1 (RSE 5.8%). The covariate analysis identified weight as the individual factor influencing the apparent oral clearance: CL = 13.4 × (weight/12)1.14. The maximum a posteriori probability Bayesian estimator, based on three concentrations measured at 0, 1 or 2, and 3 h after drug intake allowed predicting individual AUC0–t. The population pharmacokinetic model developed for abacavir in HIV-infected infants and toddlers accurately described both once and twice daily pharmacokinetic profiles. The maximum a posteriori probability Bayesian estimator of AUC(0-) (t) was developed from the final model and can be used routinely to optimize individual dosing. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

Relative importance of magnetic moments in UXO clearance applications

USGS Publications Warehouse

Sanchez, V.; Li, Y.; Nabighian, M.; Wright, D.

2006-01-01

Surface magnetic anomaly observed in UXO clearance is mainly dipolar and, as a result, the dipole is the only moment used regularly in UXO applications. The dipole moment contains intensity of magnetization information but lacks shape information. Unlike dipole, higher-order moments, such as quadrupole and octupole, encode asymmetry properties of magnetization distribution within buried targets. In order to improve our understanding of magnetization distribution within UXO and non-UXO objects and its potential utility in UXO clearance, we present results of a 3D numerical modeling study for highly susceptible metallic objects. The basis for modeling is the solution of a nonlinear integral equation, describing magnetization within isolated objects, allowing us to compute magnetic moments of the object, analyze their relationships, and provide a depiction of the surface anomaly produced by the different moments within the object. Our modeling results show significant high-order moments for more asymmetric objects situated at typical UXO burial depths, and suggest that the increased relative contribution to magnetic gradient data from these higher-order moments may provide a practical tool for improved UXO discrimination. ?? 2005 Society of Exploration Geophysicists.

Plasmodium falciparum malaria: Convergent evolutionary trajectories towards delayed clearance following artemisinin treatment.

PubMed

Wilairat, Prapon; Kümpornsin, Krittikorn; Chookajorn, Thanat

2016-05-01

Malaria is a major global health challenge with 300million new cases every year. The most effective regimen for treating Plasmodium falciparum malaria is based on artemisinin and its derivatives. The drugs are highly effective, resulting in rapid clearance of parasites even in severe P. falciparum malaria patients. During the last five years, artemisinin-resistant parasites have begun to emerge first in Cambodia and now in Thailand and Myanmar. At present, the level of artemisinin resistance is relatively low with clinical presentation of delayed artemisinin clearance (a longer time to reduce parasite load) and a small decrease in artemisinin sensitivity in cultured isolates. Nevertheless, multiple genetic loci associated with delayed parasite clearance have been reported, but they cannot account for a large portion of cases. Even the most well-studied kelch 13 propeller mutations cannot always predict the outcome of artemisinin treatment in vitro and in vivo. Here we propose that delayed clearance by artemisinin could be the result of convergent evolution, driven by multiple trajectories to overcome artemisinin-induced stress, but precluded to become full blown resistance by high fitness cost. Genetic association studies by several genome-wide approaches reveal linkage disequilibrium between multiple loci and delayed parasite clearance. Genetic manipulations at some of these loci already have resulted in loss in artemisinin sensitivity. The notion presented here is by itself consistent with existing evidence on artemisinin resistance and has the potential to be explored using available genomic data. Most important of all, molecular surveillance of artemisinin resistance based on multi-genic markers could be more informative than relying on any one particular molecular marker. Copyright © 2016 Elsevier Ltd. All rights reserved.

Hawaii cohort study of serum micronutrient concentrations and clearance of incident oncogenic human papillomavirus infection of the cervix.

PubMed

Goodman, Marc T; Shvetsov, Yurii B; McDuffie, Katharine; Wilkens, Lynne R; Zhu, Xuemei; Franke, Adrian A; Bertram, Cathy Cramer; Kessel, Bruce; Bernice, Marge; Sunoo, Christian; Ning, Lily; Easa, David; Killeen, Jeffrey; Kamemoto, Lori; Hernandez, Brenda Y

2007-06-15

The degree to which the resolution of human papillomavirus (HPV) infection parallels exposure to other factors, particularly those related to nutritional status, is a relatively unexplored area of research. We established a cohort of women for long-term follow-up to examine the association of serum retinol, carotenoid, and tocopherol concentrations with the clearance of incident cervical HPV infection. Interviews and biological specimens were obtained at baseline and at 4-month intervals. At each visit, a cervical cell specimen for HPV DNA analysis and cytology and a fasting blood sample to measure micronutrient levels were collected. A Cox proportional hazards model was used to study the relationship between clearance of 189 incident (type-specific) oncogenic HPV infections and the levels of 20 serum micronutrients among 122 women. Higher circulating levels of trans-zeaxanthin, total trans-lutein/zeaxanthin, cryptoxanthin (total and beta), total trans-lycopene and cis-lycopene, carotene (alpha, beta, and total), and total carotenoids were associated with a significant decrease in the clearance time of type-specific HPV infection, particularly during the early stages of infection (120 days) was not significantly associated with circulating levels of carotenoids or tocopherols. Results from this investigation support an association of micronutrients with the rapid clearance of incident oncogenic HPV infection of the uterine cervix.

A Single Mutation in K13 Predominates in Southern China and Is Associated With Delayed Clearance of Plasmodium falciparum Following Artemisinin Treatment.

PubMed

Huang, Fang; Takala-Harrison, Shannon; Jacob, Christopher G; Liu, Hui; Sun, Xiaodong; Yang, Henglin; Nyunt, Myaing M; Adams, Matthew; Zhou, Shuisen; Xia, Zhigui; Ringwald, Pascal; Bustos, Maria Dorina; Tang, Linhua; Plowe, Christopher V

2015-11-15

Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and poses a threat to malaria control and elimination. Mutations in a P. falciparum gene encoding a kelch protein on chromosome 13 have been associated with delayed parasite clearance following artemisinin treatment elsewhere in the region, but not yet in China. Therapeutic efficacy studies of artesunate and dihydroartemisinin-piperaquine were conducted from 2009 to 2012 in the Yunnan Province of China near the border with Myanmar. K13 mutations were genotyped by capillary sequencing of DNA extracted from dried blood spots collected in these clinical trials and in routine surveillance. Associations between K13 mutations and delayed parasite clearance were tested using regression models. Parasite clearance half-lives were prolonged after artemisinin treatment, with 44% of infections having half-lives >5 hours (n = 109). Fourteen mutations in K13 were observed, with an overall prevalence of 47.7% (n = 329). A single mutation, F446I, predominated, with a prevalence of 36.5%. Infections with F446I were significantly associated with parasitemia on day 3 following artemisinin treatment and with longer clearance half-lives. Plasmodium falciparum infections in southern China displayed markedly delayed clearance following artemisinin treatment. F446I was the predominant K13 mutation and was associated with delayed parasite clearance. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Clearance of the cervical spine in clinically unevaluable trauma patients.

PubMed

Halpern, Casey H; Milby, Andrew H; Guo, Wensheng; Schuster, James M; Gracias, Vicente H; Stein, Sherman C

2010-08-15

Meta-analytic costeffectiveness analysis. Our goal was to compare the results of different management strategies for trauma patients in whom the cervical spine was not clinically evaluable due to impaired consciousness, endotracheal intubation, or painful distracting injuries. We performed a structured literature review related to cervical spine trauma, radiographic clearance techniques (plain radiography, flexion/extension, CT, and MRI), and complications associated with semirigid collar use. Meta-analytic techniques were used to pool data from multiple sources to calculate pooled mean estimates of sensitivities and specificities of imaging techniques for cervical spinal clearance, rates of complications from various clearance strategies and from empirical use of semirigid collars. A decision analysis model was used to compare outcomes and costs among these strategies. Slightly more than 7.5% of patients who are clinically unevaluable have cervical spine injuries, and 42% of these injuries are associated with spinal instability. Sensitivity of plain radiography or fluoroscopy for spinal clearance was 57% (95% CI: 57%-60%). Sensitivities for CT and MRI alone were 83% (82%-84%) and 87% (84%-89%), respectively. Complications associated with collar use ranged from 1.3% (2 days) to 7.1% (10 days) but were usually minor and short-lived. Quadriplegia resulting from spinal instability missed by a clearance test had enormous impacts on longevity, quality of life, and costs. These impacts overshadowed the effects of prolonged collar application, even when the incidence of quadriplegia was extremely low. As currently used, neuroimaging studies for cervical spinal clearance in clinically unevaluable patients are not cost-effective compared with empirical immobilization in a semirigid collar.

Mechanisms of failed apoptotic cell clearance by phagocyte subsets in cardiovascular disease

PubMed Central

2013-01-01

Recent evidence in humans indicate that defective phagocytic clearance of dying cells is linked to progression of advanced atherosclerotic lesions, the precursor to atherothrombosis, ischemic heart disease, and leading cause of death in the industrialized world. During atherogenesis, apoptotic cell turnover in the vascular wall is counterbalanced by neighboring phagocytes with high clearance efficiency, thereby limiting cellularity and maintaining lesion integrity. However, as lesions mature, phagocytic removal of apoptotic cells (efferocytosis) becomes defective, leading to secondary necrosis, expansion of plaque necrotic cores, and susceptibility to rupture. Recent genetic causation studies in experimental rodents have implicated key molecular regulators of efferocytosis in atherosclerotic progression. These include MER tyrosine kinase (MERTK), milk fat globule-EGF factor 8 (MFGE8), and complement C1q. At the cellular level, atheromata are infiltrated by a heterogenous population of professional phagocytes, comprised of monocytes, differentiated macrophages, and CD11c+ dendritic-like cells. Each cell type is characterized by disparate clearance efficiencies and varying activities of key phagocytic signaling molecules. It is in this context that we outline a working model whereby plaque necrosis and destabilization is jointly promoted by (1) direct inhibition of core phagocytic signaling pathways and (2) expansion of phagocyte subsets with poor clearance capacity. Towards identifying targets for promoting efficient apoptotic cell clearance and resolving inflammation in atherosclerosis and during ischemic heart disease and post myocardial infarction, this review will discuss potential in vivo suppressors of efferocytosis at each stage of clearance and how these putative interventional targets may differentially affect uptake at the level of vascular phagocyte subsets. PMID:20552278

Stable isotope labeling tandem mass spectrometry (SILT) to quantify protein production and clearance rates

PubMed Central

Bateman, Randall J.; Munsell, Ling Y.; Chen, Xianghong; Holtzman, David M.; Yarasheski, Kevin E.

2007-01-01

In all biological systems, protein amount is a function of the rate of production and clearance. The speed of a response to a disturbance in protein homeostasis is determined by turnover rate. Quantifying alterations in protein synthesis and clearance rates is vital to understanding disease pathogenesis (e.g., aging, inflammation). No methods exist for quantifying production and clearance rates of low abundance (femtomole) proteins in vivo. We describe a novel, mass spectrometry-based method for quantitating low abundance protein synthesis and clearance rates in vitro and in vivo in animals and humans. The utility of this method is demonstrated with amyloid-beta (Aß), an important low abundance protein involved in Alzheimer's disease pathogenesis. We used in vivo stable isotope labeling, immunoprecipitation of Aß from cerebrospinal fluid, and quantitative liquid chromatography electrospray-ionization tandem mass spectrometry (LC-ESI-tandem MS) to quantify human Aß protein production and clearance rates. The method is sensitive and specific for stable isotope labeled amino acid incorporation into CNS (± 1% accuracy). This in vivo method can be used to identify pathophysiologic changes in protein metabolism; and may serve as a biomarker for monitoring disease risk, progression, or response to novel therapeutic agents. The technique is adaptable to other macromolecules, such as carbohydrates or lipids. PMID:17383190

Fault Diagnosis of Internal Combustion Engine Valve Clearance Using the Impact Commencement Detection Method

PubMed Central

Jiang, Zhinong; Wang, Zijia; Zhang, Jinjie

2017-01-01

Internal combustion engines (ICEs) are widely used in many important fields. The valve train clearance of an ICE usually exceeds the normal value due to wear or faulty adjustment. This work aims at diagnosing the valve clearance fault based on the vibration signals measured on the engine cylinder heads. The non-stationarity of the ICE operating condition makes it difficult to obtain the nominal baseline, which is always an awkward problem for fault diagnosis. This paper overcomes the problem by inspecting the timing of valve closing impacts, of which the referenced baseline can be obtained by referencing design parameters rather than extraction during healthy conditions. To accurately detect the timing of valve closing impact from vibration signals, we carry out a new method to detect and extract the commencement of the impacts. The results of experiments conducted on a twelve-cylinder ICE test rig show that the approach is capable of extracting the commencement of valve closing impact accurately and using only one feature can give a superior monitoring of valve clearance. With the help of this technique, the valve clearance fault becomes detectable even without the comparison to the baseline, and the changing trend of the clearance could be trackable. PMID:29244722

Inhaled nano- and microparticles for drug delivery

PubMed Central

El-Sherbiny, Ibrahim M.; El-Baz, Nancy M.; Yacoub, Magdi H.

2015-01-01

The 21st century has seen a paradigm shift to inhaled therapy, for both systemic and local drug delivery, due to the lung's favourable properties of a large surface area and high permeability. Pulmonary drug delivery possesses many advantages, including non-invasive route of administration, low metabolic activity, control environment for systemic absorption and avoids first bypass metabolism. However, because the lung is one of the major ports of entry, it has multiple clearance mechanisms, which prevent foreign particles from entering the body. Although these clearance mechanisms maintain the sterility of the lung, clearance mechanisms can also act as barriers to the therapeutic effectiveness of inhaled drugs. This effectiveness is also influenced by the deposition site and delivered dose. Particulate-based drug delivery systems have emerged as an innovative and promising alternative to conventional inhaled drugs to circumvent pulmonary clearance mechanisms and provide enhanced therapeutic efficiency and controlled drug release. The principle of multiple pulmonary clearance mechanisms is reviewed, including mucociliary, alveolar macrophages, absorptive, and metabolic degradation. This review also discusses the current approaches and formulations developed to achieve optimal pulmonary drug delivery systems. PMID:26779496

Amylin Enhances Amyloid-β Peptide Brain to Blood Efflux Across the Blood-Brain Barrier

PubMed Central

Mohamed, Loqman A.; Zhu, Haihao; Mousa, Youssef M.; Wang, Erming; Qiu, Wei Qiao; Kaddoumi, Amal

2017-01-01

Findings from Alzheimer’s disease (AD) mouse models showed that amylin treatment improved AD pathology and enhanced amyloid-β (Aβ) brain to blood clearance; however, the mechanism was not investigated. Using the Tg2576 AD mouse model, a single intraperitoneal injection of amylin significantly increased Aβ serum levels, and the effect was abolished by AC253, an amylin receptor antagonist, suggesting that amylin effect could be mediated by its receptor. Subsequent mechanistic studies showed amylin enhanced Aβ transport across a cell-based model of the blood-brain barrier (BBB), an effect that was abolished when the amylin receptor was inhibited by two amylin antagonists and by siRNA knockdown of amylin receptor Ramp3. To explain this finding, amylin effect on Aβ transport proteins expressed at the BBB was evaluated. Findings indicated that cells treated with amylin induced LRP1 expression, a major receptor involved in brain Aβ efflux, in plasma membrane fraction, suggesting intracellular translocation of LRP1 from the cytoplasmic pool. Increased LRP1 in membrane fraction could explain, at least in part, the enhanced uptake and transport of Aβ across the BBB. Collectively, our findings indicated that amylin induced Aβ brain to blood clearance through amylin receptor by inducing LRP1 subcellular translocation to the plasma membrane of the BBB endothelium. PMID:28059785

Whirling Arm Tests on the Effect of Ground Proximity to an Airplane Wing

NASA Technical Reports Server (NTRS)

Long, M. E.

1944-01-01

This report gives the results of tests on a rectangular wing model with a 20% full spun split flap, conducted on the whirling arm at the Daniel Guggenheim Airship Institute in Akron, Ohio. The effect of a ground board on the lift and pitching moment was measured. The ground board consisted of an inclined ramp rising up in the test channel to a level floor extending for some distance parallel to the model path. The path of the wing model with respect to the ground board accordingly represented with comparative exactness an airplane coming in for a landing. The ground clearances over the level portion of the board varied from 0 6 to 1,6 chord lengths. Results are given in the standard dimensionless coefficients plotted versus angle of attack for a particular ground clearance. The effect of the ground board is to increase the lift coefficient for a given angle of attack all the way up the stall. The magnitude of the increase varies both with the ground clearance and the angle of attack. The effect on the pitching moment coefficient is not so readily apparent due to experimental difficulties but, in general, the diving moment increases over the ground board. This effect is apparent principally at the high angles of attack. An exception to this effect occurs with flaps deflected at the lowest ground clearance (0.6 chords). Here the diving moment decreases over the ground board.

Disk/Shaft Vibration Induced by Bearing Clearance Effects: Analysis and Experiment

NASA Technical Reports Server (NTRS)

Flowers, George T.; Wu, Fangsheng

1996-01-01

This study presents an investigation of the dynamics of a rotor system with bearing clearance. Of particular interest is the influence of such effects on coupled disk/shaft vibration. Experimental results for a rotor system with a flexible disk are presented and compared to predictions from a simulation model. Some insights and conclusions are obtained with regard to the conditions under which such vibration may be significant.

Mucus clearance from the pulmonary system by mechanical means: a dual-excitation approach.

PubMed

Ignagni, Mario; O'Dea, Thomas

2013-01-01

A dual-excitation approach to mechanical clearance of mucus from the pulmonary system is described. The approach employs independently controlled vibratory and constrictive pressure stimulations to the thorax. Patient cooperative efforts are integrated into the therapy regimen as a means of enhancing the efficacy of the treatment. An engineering model that demonstrates the capability to generate vibratory and constrictive pressure variations at specified levels is described.

Increased terrestrial to ocean sediment and carbon fluxes in the northern Chesapeake Bay associated with twentieth century land alteration

USGS Publications Warehouse

Saenger, C.; Cronin, T. M.; Willard, D.; Halka, J.; Kerhin, R.

2008-01-01

We calculated Chesapeake Bay (CB) sediment and carbon fluxes before and after major anthropogenic land clearance using robust monitoring, modeling and sedimentary data. Four distinct fluxes in the estuarine system were considered including (1) the flux of eroded material from the watershed to streams, (2) the flux of suspended sediment at river fall lines, (3) the burial flux in tributary sediments, and (4) the burial flux in main CB sediments. The sedimentary maximum in Ambrosia (ragweed) pollen marked peak land clearance (~1900 a.d.). Rivers feeding CB had a total organic carbon (TOC)/total suspended solids of 0.24??0.12, and we used this observation to calculate TOC fluxes from sediment fluxes. Sediment and carbon fluxes increased by 138-269% across all four regions after land clearance. Our results demonstrate that sediment delivery to CB is subject to significant lags and that excess post-land clearance sediment loads have not reached the ocean. Post-land clearance increases in erosional flux from watersheds, and burial in estuaries are important processes that must be considered to calculate accurate global sediment and carbon budgets. ?? 2008 Coastal and Estuarine Research Federation.

Acupuncture promotes mTOR-independent autophagic clearance of aggregation-prone proteins in mouse brain.

PubMed

Tian, Tian; Sun, Yanhong; Wu, Huangan; Pei, Jian; Zhang, Jing; Zhang, Yi; Wang, Lu; Li, Bin; Wang, Lihua; Shi, Jiye; Hu, Jun; Fan, Chunhai

2016-01-21

Acupuncture has historically been practiced to treat medical disorders by mechanically stimulating specific acupoints with fine needles. Despite its well-documented efficacy, its biological basis remains largely elusive. In this study, we found that mechanical stimulation at the acupoint of Yanglingquan (GB34) promoted the autophagic clearance of α-synuclein (α-syn), a well known aggregation-prone protein closely related to Parkinson's disease (PD), in the substantia nigra par compacta (SNpc) of the brain in a PD mouse model. We found the protein clearance arose from the activation of the autophagy-lysosome pathway (ALP) in a mammalian target of rapamycin (mTOR)-independent approach. Further, we observed the recovery in the activity of dopaminergic neurons in SNpc, and improvement in the motor function at the behavior level of PD mice. Whereas acupuncture and rapamycin, a chemical mTOR inhibitor, show comparable α-syn clearance and therapeutic effects in the PD mouse model, the latter adopts a distinctly different, mTOR-dependent, autophagy induction process. Due to this fundamental difference, acupuncture may circumvent adverse effects of the rapamycin treatment. The newly discovered connection between acupuncture and autophagy not only provides a new route to understanding the molecular mechanism of acupuncture but also sheds new light on cost-effective and safe therapy of neurodegenerative diseases.

Prediction of Relative In Vivo Metabolite Exposure from In Vitro Data Using Two Model Drugs: Dextromethorphan and Omeprazole

PubMed Central

Lutz, Justin D.

2012-01-01

Metabolites can have pharmacological or toxicological effects, inhibit metabolic enzymes, and be used as probes of drug-drug interactions or specific cytochrome P450 (P450) phenotypes. Thus, better understanding and prediction methods are needed to characterize metabolite exposures in vivo. This study aimed to test whether in vitro data could be used to predict and rationalize in vivo metabolite exposures using two model drugs and P450 probes: dextromethorphan and omeprazole with their primary metabolites dextrorphan, 5-hydroxyomeprazole (5OH-omeprazole), and omeprazole sulfone. Relative metabolite exposures were predicted using metabolite formation and elimination clearances. For dextrorphan, the formation clearances of dextrorphan glucuronide and 3-hydroxymorphinan from dextrorphan in human liver microsomes were used to predict metabolite (dextrorphan) clearance. For 5OH-omeprazole and omeprazole sulfone, the depletion rates of the metabolites in human hepatocytes were used to predict metabolite clearance. Dextrorphan/dextromethorphan in vivo metabolite/parent area under the plasma concentration versus time curve ratio (AUCm/AUCp) was overpredicted by 2.1-fold, whereas 5OH-omeprazole/omeprazole and omeprazole sulfone/omeprazole were predicted within 0.75- and 1.1-fold, respectively. The effect of inhibition or induction of the metabolite's formation and elimination on the AUCm/AUCp ratio was simulated. The simulations showed that unless metabolite clearance pathways are characterized, interpretation of the metabolic ratios is exceedingly difficult. This study shows that relative in vivo metabolite exposure can be predicted from in vitro data and characterization of secondary metabolism of probe metabolites is critical for interpretation of phenotypic data. PMID:22010218

Zone clearance in an infinite TASEP with a step initial condition

NASA Astrophysics Data System (ADS)

Cividini, Julien; Appert-Rolland, Cécile

2017-06-01

The TASEP is a paradigmatic model of out-of-equilibrium statistical physics, for which many quantities have been computed, either exactly or by approximate methods. In this work we study two new kinds of observables that have some relevance in biological or traffic models. They represent the probability for a given clearance zone of the lattice to be empty (for the first time) at a given time, starting from a step density profile. Exact expressions are obtained for single-time quantities, while more involved history-dependent observables are studied by Monte Carlo simulation, and partially predicted by a phenomenological approach.

Modeling Relationships Between Flight Crew Demographics and Perceptions of Interval Management

NASA Technical Reports Server (NTRS)

Remy, Benjamin; Wilson, Sara R.

2016-01-01

The Interval Management Alternative Clearances (IMAC) human-in-the-loop simulation experiment was conducted to assess interval management system performance and participants' acceptability and workload while performing three interval management clearance types. Twenty-four subject pilots and eight subject controllers flew ten high-density arrival scenarios into Denver International Airport during two weeks of data collection. This analysis examined the possible relationships between subject pilot demographics on reported perceptions of interval management in IMAC. Multiple linear regression models were created with a new software tool to predict subject pilot questionnaire item responses from demographic information. General patterns were noted across models that may indicate flight crew demographics influence perceptions of interval management.

Advanced diagnostic system for piston slap faults in IC engines, based on the non-stationary characteristics of the vibration signals

NASA Astrophysics Data System (ADS)

Chen, Jian; Randall, Robert Bond; Peeters, Bart

2016-06-01

Artificial Neural Networks (ANNs) have the potential to solve the problem of automated diagnostics of piston slap faults, but the critical issue for the successful application of ANN is the training of the network by a large amount of data in various engine conditions (different speed/load conditions in normal condition, and with different locations/levels of faults). On the other hand, the latest simulation technology provides a useful alternative in that the effect of clearance changes may readily be explored without recourse to cutting metal, in order to create enough training data for the ANNs. In this paper, based on some existing simplified models of piston slap, an advanced multi-body dynamic simulation software was used to simulate piston slap faults with different speeds/loads and clearance conditions. Meanwhile, the simulation models were validated and updated by a series of experiments. Three-stage network systems are proposed to diagnose piston faults: fault detection, fault localisation and fault severity identification. Multi Layer Perceptron (MLP) networks were used in the detection stage and severity/prognosis stage and a Probabilistic Neural Network (PNN) was used to identify which cylinder has faults. Finally, it was demonstrated that the networks trained purely on simulated data can efficiently detect piston slap faults in real tests and identify the location and severity of the faults as well.

Examining Plasmodium falciparum and P. vivax clearance subsequent to antimalarial drug treatment in the Myanmar-China border area based on quantitative real-time polymerase chain reaction.

PubMed

Lo, Eugenia; Nguyen, Jennifer; Oo, Winny; Hemming-Schroeder, Elizabeth; Zhou, Guofa; Yang, Zhaoqing; Cui, Liwang; Yan, Guiyun

2016-04-16

Recent emergence of artemisinin-resistant P. falciparum has posed a serious hindrance to the elimination of malaria in the Greater Mekong Subregion. Parasite clearance time, a measure of change in peripheral parasitaemia in a sequence of samples taken after treatment, can be used to reflect the susceptibility of parasites or the efficiency of antimalarials. The association of genetic polymorphisms and artemisinin resistance has been documented. This study aims to examine clearance time of P. falciparum and P. vivax parasitemia as well as putative gene mutations associated with residual or recurred parasitemia in Myanmar. A total of 63 P. falciparum and 130 P. vivax samples collected from two internally-displaced populations and one surrounding village were examined for parasitemia changes. At least four samples were taken from each patient, at the first day of diagnosis up to 3 months following the initial treatment. The amount of parasite gene copy number was estimated using quantitative real-time PCR based on a species-specific region of the 18S rRNA gene. For samples that showed residual or recurred parasitemia after treatment, microsatellites were used to identify the 'post-treatment' parasite genotype and compared such with the 'pre-treatment' genotype. Mutations in genes pfcrt, pfmdr1, pfatp6, pfmrp1 and pfK13 that are potentially associated with ACT resistance were examined to identify if mutation is a factor for residual or persistent parasitemia. Over 30% of the P. falciprium infections showed delayed clearance of parasitemia after 2-3 days of treatment and 9.5% showed recurred parasitemia. Mutations in codon 876 of the pfmrp1 corroborated significance association with slow clearance time. However, no association was observed in the variation in pfmdr1 gene copy number as well as mutations of various codonsinpfatp6, pfcrt, and pfK13 with clearance time. For P. vivax, over 95% of the infections indicated cleared parasitemia at days 2-3 of treatment. Four samples were found to be re-infected with new parasite strains based on microsatellite genotypes after initial treatment. The appearance of P.falciparum infected samples showing delayed clearance or recurred parasitemia after treatment raises concerns on current treatment and ACT drug resistance.

Population Pharmacokinetics of Topiramate in Japanese Pediatric and Adult Patients With Epilepsy Using Routinely Monitored Data.

PubMed

Takeuchi, Masato; Yano, Ikuko; Ito, Satoko; Sugimoto, Mitsuhiro; Yamamoto, Shota; Yonezawa, Atsushi; Ikeda, Akio; Matsubara, Kazuo

2017-04-01

Topiramate is a second-generation antiepileptic drug used as monotherapy and adjunctive therapy in adults and children with partial seizures. A population pharmacokinetic (PPK) analysis was performed to improve the topiramate dosage adjustment for individualized treatment. Patients whose steady-state serum concentration of topiramate was routinely monitored at Kyoto University Hospital from April 2012 to March 2013 were included in the model-building data. A nonlinear mixed effects modeling program was used to evaluate the influence of covariates on topiramate pharmacokinetics. The obtained PPK model was evaluated by internal model validations, including goodness-of-fit plots and prediction-corrected visual predictive checks, and was externally confirmed using the validation data from January 2015 to December 2015. A total of 177 steady-state serum concentrations from 93 patients were used for the model-building analysis. The patients' age ranged from 2 to 68 years, and body weight ranged from 8.6 to 105 kg. The median serum concentration of topiramate was 1.7 mcg/mL, and half of the patients received carbamazepine coadministration. Based on a one-compartment model with first order absorption and elimination, the apparent volume of distribution was 105 L/70 kg, and the apparent clearance was allometrically related to the body weight as 2.25 L·h·70 kg without carbamazepine or phenytoin. Combination treatment with carbamazepine or phenytoin increased the apparent clearance to 3.51 L·h·70 kg. Goodness-of-fit plots, prediction-corrected visual predictive check, and external validation using the validation data from 43 patients confirmed an appropriateness of the final model. Simulations based on the final model showed that dosage adjustments allometrically scaling to body weight can equalize the serum concentrations in children of various ages and adults. The PPK model, using the power scaling of body weight, effectively elucidated the topiramate serum concentration profile ranging from pediatric to adult patients. Dosage adjustments based on body weight and concomitant antiepileptic drug help obtain the dosage of topiramate necessary to reach an effective concentration in each individual.

Solute clearance measurement in the assessment of dialysis adequacy among African continuous ambulatory peritoneal dialysis patients.

PubMed

Abdu, Aliyu; Naidoo, Sagren; Malgas, Shirin; Naicker, Jocelyn T; Paget, Graham; Naicker, Saraladevi

2015-01-01

Solute clearance measurement is an objective means of quantifying the dose of peritoneal dialysis (PD). Despite continued debate on the interpretation and precise prognostic value of small solute clearance in PD patients, guidelines based on solute clearance values are common in clinical practice. There is limited information on the solute clearance indices and PD adequacy parameters among this predominantly low socioeconomic status PD population. We investigated the solute clearance among continuous ambulatory peritoneal dialysis (CAPD) patients at the Charlotte Maxeke Johannesburg Academic Hospital and its relationship with other parameters of PD adequacy. Seventy patients on CAPD were studied in this cross-sectional study. Solute clearance was assessed using urea clearance (Kt/V). Linear regression analysis was used to determine factors associated with solute clearance, while analysis of variance was used to test the influence of weekly Kt/V on blood pressure (BP), hemoglobin (Hb) and other biochemical parameters. The mean age of the study population was 37.9 ± 12.4 years, 43% were females and 86% were black Africans. The mean duration on CAPD was 19.7 ± 20.8 months. Mean systolic and diastolic BP were 144 ± 28 and 92 ± 17 mm Hg, respectively. The mean Hb was 11.1 ± 2.2 g/dL and the mean weekly Kt/V was 1.7 ± 0.3. Factors like systolic BP, Hb level, serum levels of cholesterol, calcium, phosphate, parathyroid hormone and albumin were not significantly associated with the weekly Kt/V. We conclude that the dose of PD received by the majority of our patients in terms of the weekly Kt/V is within the recommended values and that this finding is significant considering the low socioeconomic background of our patients. There is no significant association between Kt/V and other indices of dialysis adequacy.

Population pharmacokinetics of unbound hydrocortisone in critically ill neonates and infants with vasopressor-resistant hypotension.

PubMed

Vezina, Heather E; Ng, Chee M; Vazquez, Delia M; Barks, John D; Bhatt-Mehta, Varsha

2014-07-01

To determine the population pharmacokinetics of unbound hydrocortisone in critically ill neonates and infants receiving IV hydrocortisone for treatment of vasopressor-resistant hypotension and to identify patient-specific sources of pharmacokinetic variability. Prospective observational cohort study. Level 3 neonatal ICU. Sixty-two critically ill neonates and infants receiving IV hydrocortisone as part of standard of care for the treatment of vasopressor-resistant hypotension: median gestational age 28 weeks (range, 23-41), median weight 1.2 kg (range, 0.5-4.4), and 29 females. None. Unbound baseline cortisol and postdose hydrocortisone concentrations measured from blood samples being drawn for routine laboratory tests. A one-compartment model best described the data. Allometric weight and postmenstrual age were significant covariates on unbound hydrocortisone clearance and volume of distribution. Final population estimates for clearance, volume of distribution, and baseline cortisol concentration were 20.2 L/hr, 244 L, and 1.37 ng/mL, respectively. Using the median weight and postmenstrual age of our subjects (i.e., 1.2 kg and 28 wk) in the final model, the typical unbound hydrocortisone clearance and volume of distribution were 1.0 L/hr and 4.2 L, respectively. The typical half-life for unbound hydrocortisone was 2.9 hours. A sharp and continuous increase in unbound hydrocortisone clearance was observed at 35 weeks postmenstrual age. We report the first pharmacokinetic data for unbound hydrocortisone, the pharmacologically active moiety, in critically ill neonates and infants with vasopressor-resistant hypotension. Unbound hydrocortisone clearance increased with body weight and was faster in children with an older postmenstrual age. Unbound hydrocortisone clearance increased sharply at 35 weeks postmenstrual age and continued to mature thereafter. This study lays the groundwork for evaluating unbound hydrocortisone exposure-response relationships and drawing definitive conclusions about the dosing of IV hydrocortisone in critically ill neonates and infants with vasopressor-resistant hypotension.

Spine concerns in the Special Olympian with Down syndrome.

PubMed

Tassone, James Channing; Duey-Holtz, Allison

2008-03-01

As with any child participating in sports, the safety of The Special Olympian participating in athletics is paramount. The preparticipation medical clearance is necessary to ensure these athletes' safety. In response to evidence that 15% of all individuals with Down syndrome have atlanto-occipital and/or atlanto-axial instability or subluxation, the Special Olympics Inc have additionally mandated preparticipation spine clearance for all individuals with Down syndrome. Spine clearance for the Special Olympian is challenging for the healthcare provider. In addition, controversy has arisen surrounding The Special Olympics Inc policy statement. The purposes of this article are to provide healthcare providers with a review of atlanto-occipital and atlanto-axial instability and subluxation, review spine clearance guidelines, discuss the details and controversy surrounding The Special Olympics Inc mandate, and provide recommendations on how to improve screening and ensure safety of the participants based on the current medical literature.

Tracking short-term biodistribution and long-term clearance of SPIO tracers in magnetic particle imaging

NASA Astrophysics Data System (ADS)

Keselman, Paul; Yu, Elaine Y.; Zhou, Xinyi Y.; Goodwill, Patrick W.; Chandrasekharan, Prashant; Ferguson, R. Matthew; Khandhar, Amit P.; Kemp, Scott J.; Krishnan, Kannan M.; Zheng, Bo; Conolly, Steven M.

2017-05-01

Magnetic particle imaging (MPI) is an emerging tracer-based medical imaging modality that images non-radioactive, kidney-safe superparamagnetic iron oxide (SPIO) tracers. MPI offers quantitative, high-contrast and high-SNR images, so MPI has exceptional promise for applications such as cell tracking, angiography, brain perfusion, cancer detection, traumatic brain injury and pulmonary imaging. In assessing MPI’s utility for applications mentioned above, it is important to be able to assess tracer short-term biodistribution as well as long-term clearance from the body. Here, we describe the biodistribution and clearance for two commonly used tracers in MPI: Ferucarbotran (Meito Sangyo Co., Japan) and LS-oo8 (LodeSpin Labs, Seattle, WA). We successfully demonstrate that 3D MPI is able to quantitatively assess short-term biodistribution, as well as long-term tracking and clearance of these tracers in vivo.

Influence of backup bearings and support structure dynamics on the behavior of rotors with active supports

NASA Technical Reports Server (NTRS)

Flowers, George T.

1994-01-01

Progress over the past year includes the following: A simplified rotor model with a flexible shaft and backup bearings has been developed. A simple rotor model which includes a flexible disk and bearings with clearance has been developed and the dynamics of the model investigated. A rotor model based upon the T-501 engine has been developed which includes backup bearing effects. Parallel simulation runs are being conducted using an ANSYS based finite element model of the T-501. The magnetic bearing test rig is currently floating and dynamics/control tests are being conducted. A paper has been written that documents the work using the T-501 engine model. Work has continued with the simplified model. The finite element model is currently being modified to include the effects of foundation dynamics. A literature search for material on foil bearings has been conducted. A finite element model is being developed for a magnetic bearing in series with a foil backup bearing.

Flow Instability and Flow Control Scaling Laws

NASA Astrophysics Data System (ADS)

van Ness, Daniel; Corke, Thomas; Morris, Scott

2006-11-01

A flow instability that is receptive to perturbations is present in the tip clearance leakage flow over the tip of a turbine blade. This instability was investigated through the introduction of active flow control in the viscous flow field. Control was implemented in the form of a dielectric barrier discharge created by a weakly-ionized plasma actuation arrangement. The experimental setup consisted of a low-speed linear turbine cascade made up of an array of nine Pratt & Whitney ``PakB'' turbine blades. This idealized cascade configuration was used to examine the tip clearance leakage flow that exists within the low pressure turbine stage of a gas-turbine engine. The center blade of the cascade array had a variable tip clearance up to five percent chord. Reynolds numbers based on axial blade chord varied from 10^4 to 10^5. Multi-port pressure probe measurements, as well as Stereo Particle Image Velocimetry were used to document the dependence of the instability on the frequency and amplitude of flow control perturbations. Scaling laws based on the variation of blade tip clearance height and inflow conditions were investigated. These results permitted an improved understanding of the mechanism of flow instability.

An optical fiber bundle sensor for tip clearance and tip timing measurements in a turbine rig.

PubMed

García, Iker; Beloki, Josu; Zubia, Joseba; Aldabaldetreku, Gotzon; Illarramendi, María Asunción; Jiménez, Felipe

2013-06-05

When it comes to measuring blade-tip clearance or blade-tip timing in turbines, reflective intensity-modulated optical fiber sensors overcome several traditional limitations of capacitive, inductive or discharging probe sensors. This paper presents the signals and results corresponding to the third stage of a multistage turbine rig, obtained from a transonic wind-tunnel test. The probe is based on a trifurcated bundle of optical fibers that is mounted on the turbine casing. To eliminate the influence of light source intensity variations and blade surface reflectivity, the sensing principle is based on the quotient of the voltages obtained from the two receiving bundle legs. A discrepancy lower than 3% with respect to a commercial sensor was observed in tip clearance measurements. Regarding tip timing measurements, the travel wave spectrum was obtained, which provides the average vibration amplitude for all blades at a particular nodal diameter. With this approach, both blade-tip timing and tip clearance measurements can be carried out simultaneously. The results obtained on the test turbine rig demonstrate the suitability and reliability of the type of sensor used, and suggest the possibility of performing these measurements in real turbines under real working conditions.

An Optical Fiber Bundle Sensor for Tip Clearance and Tip Timing Measurements in a Turbine Rig

PubMed Central

García, Iker; Beloki, Josu; Zubia, Joseba; Aldabaldetreku, Gotzon; Illarramendi, María Asunción; Jiménez, Felipe

2013-01-01

When it comes to measuring blade-tip clearance or blade-tip timing in turbines, reflective intensity-modulated optical fiber sensors overcome several traditional limitations of capacitive, inductive or discharging probe sensors. This paper presents the signals and results corresponding to the third stage of a multistage turbine rig, obtained from a transonic wind-tunnel test. The probe is based on a trifurcated bundle of optical fibers that is mounted on the turbine casing. To eliminate the influence of light source intensity variations and blade surface reflectivity, the sensing principle is based on the quotient of the voltages obtained from the two receiving bundle legs. A discrepancy lower than 3% with respect to a commercial sensor was observed in tip clearance measurements. Regarding tip timing measurements, the travel wave spectrum was obtained, which provides the average vibration amplitude for all blades at a particular nodal diameter. With this approach, both blade-tip timing and tip clearance measurements can be carried out simultaneously. The results obtained on the test turbine rig demonstrate the suitability and reliability of the type of sensor used, and suggest the possibility of performing these measurements in real turbines under real working conditions. PMID:23739163

Optimization of protein and peptide drugs based on the mechanisms of kidney clearance.

PubMed

Huang, Jiaguo; Wu, Huizi

2018-05-30

Development of proteins and peptides into drugs has been considered as a promising strategy to target certain diseases. However, only few proteins and peptides has been approved as new drugs into the market each year. One major problem is that proteins and peptides often exhibit short plasma half-life times, which limits the application for their clinical use. In most cases a short half-life time is not effective to deliver sufficient amount of drugs to the target organs and tissues, which is generally caused by fast renal clearance and low plasma stability due to proteolytic degradation during systemic circulation, because the most common clearance pathway of small proteins and peptides is through glomerular filtration by the kidneys. In this review, enzymatic degradation of proteins and peptides were discussed. Furthermore, several approaches to lengthen the half-life of peptides and proteins drugs based on the unique structures of glomerular capillary wall and the mechanisms of glomerular filtration were summarized, such as increasing the size and hydrodynamic diameter; increasing the negative charge to delay the filtration; increasing plasma protein binding to decrease plasma clearance. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Diverse Data Sets Can Yield Reliable Information through Mechanistic Modeling: Salicylic Acid Clearance.

PubMed

Raymond, G M; Bassingthwaighte, J B

This is a practical example of a powerful research strategy: putting together data from studies covering a diversity of conditions can yield a scientifically sound grasp of the phenomenon when the individual observations failed to provide definitive understanding. The rationale is that defining a realistic, quantitative, explanatory hypothesis for the whole set of studies, brings about a "consilience" of the often competing hypotheses considered for individual data sets. An internally consistent conjecture linking multiple data sets simultaneously provides stronger evidence on the characteristics of a system than does analysis of individual data sets limited to narrow ranges of conditions. Our example examines three very different data sets on the clearance of salicylic acid from humans: a high concentration set from aspirin overdoses; a set with medium concentrations from a research study on the influences of the route of administration and of sex on the clearance kinetics, and a set on low dose aspirin for cardiovascular health. Three models were tested: (1) a first order reaction, (2) a Michaelis-Menten (M-M) approach, and (3) an enzyme kinetic model with forward and backward reactions. The reaction rates found from model 1 were distinctly different for the three data sets, having no commonality. The M-M model 2 fitted each of the three data sets but gave a reliable estimates of the Michaelis constant only for the medium level data (K m = 24±5.4 mg/L); analyzing the three data sets together with model 2 gave K m = 18±2.6 mg/L. (Estimating parameters using larger numbers of data points in an optimization increases the degrees of freedom, constraining the range of the estimates). Using the enzyme kinetic model (3) increased the number of free parameters but nevertheless improved the goodness of fit to the combined data sets, giving tighter constraints, and a lower estimated K m = 14.6±2.9 mg/L, demonstrating that fitting diverse data sets with a single model improves confidence in the results. This modeling effort is also an example of reproducible science available at html://www.physiome.org/jsim/models/webmodel/NSR/SalicylicAcidClearance.

Renal dysfunction as a predictor of stroke and systemic embolism in patients with nonvalvular atrial fibrillation: validation of the R(2)CHADS(2) index in the ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) and ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation) study cohorts.

PubMed

Piccini, Jonathan P; Stevens, Susanna R; Chang, YuChiao; Singer, Daniel E; Lokhnygina, Yuliya; Go, Alan S; Patel, Manesh R; Mahaffey, Kenneth W; Halperin, Jonathan L; Breithardt, Günter; Hankey, Graeme J; Hacke, Werner; Becker, Richard C; Nessel, Christopher C; Fox, Keith A A; Califf, Robert M

2013-01-15

We sought to define the factors associated with the occurrence of stroke and systemic embolism in a large, international atrial fibrillation (AF) trial. In ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation), 14 264 patients with nonvalvular AF and creatinine clearance ≥30 mL/min were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards modeling was used to identify factors at randomization independently associated with the occurrence of stroke or non-central nervous system embolism based on intention-to-treat analysis. A risk score was developed in ROCKET AF and validated in ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation), an independent AF patient cohort. Over a median follow-up of 1.94 years, 575 patients (4.0%) experienced primary end-point events. Reduced creatinine clearance was a strong, independent predictor of stroke and systemic embolism, second only to prior stroke or transient ischemic attack. Additional factors associated with stroke and systemic embolism included elevated diastolic blood pressure and heart rate, as well as vascular disease of the heart and limbs (C-index 0.635). A model that included creatinine clearance (R(2)CHADS(2)) improved net reclassification index by 6.2% compared with CHA(2)DS(2)VASc (C statistic=0.578) and by 8.2% compared with CHADS(2) (C statistic=0.575). The inclusion of creatinine clearance <60 mL/min and prior stroke or transient ischemic attack in a model with no other covariates led to a C statistic of 0.590.Validation of R(2)CHADS(2) in an external, separate population improved net reclassification index by 17.4% (95% confidence interval, 12.1%-22.5%) relative to CHADS(2). In patients with nonvalvular AF at moderate to high risk of stroke, impaired renal function is a potent predictor of stroke and systemic embolism. Stroke risk stratification in patients with AF should include renal function. URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00403767.

A novel mouse model for sudden unexpected death in epilepsy (SUDEP): role of impaired adenosine clearance.

PubMed

Shen, Hai-Ying; Li, Tianfu; Boison, Detlev

2010-03-01

Sudden unexpected death in epilepsy (SUDEP) is a significant cause of mortality in people with epilepsy. Two postulated causes for SUDEP, cardiac and respiratory depression, can both be explained by overstimulation of adenosine receptors. We hypothesized that SUDEP is a consequence of a surge in adenosine as a result of prolonged seizures combined with deficient adenosine clearance; consequently, blockade of adenosine receptors should prevent SUDEP. Here we induced impaired adenosine clearance in adult mice by pharmacologic inhibition of the adenosine-removing enzymes, adenosine kinase and deaminase. Combination of impaired adenosine clearance with kainic acid-induced seizures triggered sudden death in all animals. Most importantly, the adenosine receptor antagonist caffeine, when given after seizure onset, increased survival from 23.75 +/- 1.35 min to 54.86 +/- 6.59 min (p < 0.01). Our data indicate that SUDEP is due to overactivation of adenosine receptors and that caffeine treatment after seizure onset might be beneficial.

Numerical analysis of the blade tip-timing signal of a fiber bundle sensor probe

NASA Astrophysics Data System (ADS)

Guo, Haotian; Duan, Fajie; Cheng, Zhonghai

2015-03-01

Blade tip-timing is the most effective method for online blade vibration measurement of large rotating machines like turbine engines. Fiber bundle sensors are utilized in tip-timing system to measure the arrival time of the blade. The model of the tip-timing signal of the fiber bundle sensor is established. Experiments are conducted and the results are in concordance with the model established. The rising speed of the tip-timing signal is analyzed. To minimize the tip-timing error, the effects of the clearance change between the sensor and the blade and the deflection of the tip surface are analyzed. Simulation results indicate that the variable gain amplifier, which amplifies the signals to a similar level, can eliminate the measurement error caused by the variation of the clearance between the sensor and blade. Increasing the clearance between the sensor and blade can reduce the measurement error introduced by deflection of the tip surface.

High-resolution IKONOS satellite imagery for normalized difference vegetative index-related assessment applied to land clearance studies

NASA Astrophysics Data System (ADS)

Lavers, Chris R.; Mason, Travis

2017-07-01

High-resolution satellite imagery permits verification of human rights land clearance violations across international borders as a result of unstable regimes or socio-economic upheaval. Without direct access to these areas to validate allegations of human rights abuse, the use of remote sensing tools, techniques, and data is extremely important. Humanitarian assessment can benefit from software-based solutions, involving radiometrically calibrated normalized difference vegetation index and temporal change imagery. We discuss the introduction of a matrix filter approach for change detection studies to help assist rapid building detection over large search areas against a bright background to evaluate internally displaced people in the 2005 Porta Farm Zimbabwe clearances. Future wide-scale near real-time space-based monitoring with a range of digital filters would be of great benefit to international human rights observers and human rights networks.

Constitutive androstane receptor activation promotes bilirubin clearance in a murine model of alcoholic liver disease.

PubMed

Wang, Xiuyan; Zheng, Liyu; Wu, Jinming; Tang, Binbin; Zhang, Mengqin; Zhu, Debin; Lin, Xianfan

2017-06-01

Increased plasma levels of bilirubin have been reported in rat models and patients with alcoholic liver disease (ALD). The constitutive androstane receptor (CAR) is a known xenobiotic receptor, which induces the detoxification and transport of bilirubin. In the present study, the bilirubin transport regulatory mechanisms, and the role of CAR activation in hepatic and extrahepatic bilirubin clearance were investigated in a murine model of ALD. The mice were fed a Lieber-DeCarli ethanol diet or an isocaloric control diet for 4 weeks, followed by the administration of CAR agonists, 1,4-bis-[2‑(3,5-dichlorpyridyloxy)]benzene (TCPOBOP) and phenobarbital (PB), and their vehicles to examine the effect of the pharmacological activation of CAR on serum levels of bilirubin and on the bilirubin clearance pathway in ALD by serological survey, western blotting and reverse transcription‑quantitative polymerase chain reaction. The results showed that chronic ethanol ingestion impaired the nuclear translocation of CAR, which was accompanied by elevated serum levels of bilirubin, suppression of the expression of hepatic and renal organic anion transporting polypeptide (OATP) 1A1 and hepatic multidrug resistance‑associated protein 2 (MRP2), and induction of the expression of UDP-glucuronosyltransferase (UGT) 1A1. The activation of CAR by TCPOBOP and PB resulted in downregulation of the serum levels of bilirubin followed by selective upregulation of the expression levels of OATP1A1, OATP1A4, UGT1A1 and MRP2 in ALD. These results revealed the bilirubin transport regulatory mechanisms and highlighted the importance of CAR in modulating the bilirubin clearance pathway in the ALD mouse model.

Physiologic volume of phosphorus during hemodialysis: predictions from a pseudo one-compartment model.

PubMed

Leypoldt, John K; Akonur, Alp; Agar, Baris U; Culleton, Bruce F

2012-10-01

The kinetics of plasma phosphorus concentrations during hemodialysis (HD) are complex and cannot be described by conventional one- or two-compartment kinetic models. It has recently been shown by others that the physiologic (or apparent distribution) volume for phosphorus (Vr-P) increases with increasing treatment time and shows a large variation among patients treated by thrice weekly and daily HD. Here, we describe the dependence of Vr-P on treatment time and predialysis plasma phosphorus concentration as predicted by a novel pseudo one-compartment model. The kinetics of plasma phosphorus during conventional and six times per week daily HD were simulated as a function of treatment time per session for various dialyzer phosphate clearances and patient-specific phosphorus mobilization clearances (K(M)). Vr-P normalized to extracellular volume from these simulations were reported and compared with previously published empirical findings. Simulated results were relatively independent of dialyzer phosphate clearance and treatment frequency. In contrast, Vr-P was strongly dependent on treatment time per session; the increase in Vr-P with treatment time was larger for higher values of K(M). Vr-P was inversely dependent on predialysis plasma phosphorus concentration. There was significant variation among predicted Vr-P values, depending largely on the value of K(M). We conclude that a pseudo one-compartment model can describe the empirical dependence of the physiologic volume of phosphorus on treatment time and predialysis plasma phosphorus concentration. Further, the variation in physiologic volume of phosphorus among HD patients is largely due to differences in patient-specific phosphorus mobilization clearance. © 2012 The Authors. Hemodialysis International © 2012 International Society for Hemodialysis.

Pharmacokinetic Model of the Transport of Fast-Acting Insulin From the Subcutaneous and Intradermal Spaces to Blood.

PubMed

Lv, Dayu; Kulkarni, Sandip D; Chan, Alice; Keith, Stephen; Pettis, Ron; Kovatchev, Boris P; Farhi, Leon S; Breton, Marc D

2015-07-01

Pharmacokinetic (PK) models describing the transport of insulin from the injection site to blood assist clinical decision making and are part of in silico platforms for developing and testing of insulin delivery strategies for treatment of patients with diabetes. The ability of these models to accurately describe all facets of the in vivo insulin transport is therefore critical for their application. Here, we propose a new model of fast-acting insulin analogs transport from the subcutaneous and intradermal spaces to blood that can accommodate clinically observed biphasic appearance and delayed clearance of injected insulin, 2 phenomena that are not captured by existing PK models. To develop the model we compare 9 insulin transport PK models which describe hypothetical insulin delivery pathways potentially capable of approximating biphasic appearance of exogenous insulin. The models are tested with respect to their ability to describe clinical data from 10 healthy volunteers which received 1 subcutaneous and 2 intradermal insulin injections on 3 different occasions. The optimal model, selected based on information and posterior identifiability criteria, assumes that insulin is delivered at the administrative site and is then transported to the bloodstream via 2 independent routes (1) diffusion-like process to the blood and (2) combination of diffusion-like processes followed by an additional compartment before entering the blood. This optimal model accounts for biphasic appearance and delayed clearance of exogenous insulin. It agrees better with the clinical data as compared to commonly used models and is expected to improve the in silico development and testing of insulin treatment strategies, including artificial pancreas systems. © 2015 Diabetes Technology Society.

Apparently-Different Clearance Rates from Cohort Studies of Mycoplasma genitalium Are Consistent after Accounting for Incidence of Infection, Recurrent Infection, and Study Design.

PubMed

Smieszek, Timo; White, Peter J

2016-01-01

Mycoplasma genitalium is a potentially major cause of urethritis, cervicitis, pelvic inflammatory disease, infertility, and increased HIV risk. A better understanding of its natural history is crucial to informing control policy. Two extensive cohort studies (students in London, UK; Ugandan sex workers) suggest very different clearance rates; we aimed to understand the reasons and obtain improved estimates by making maximal use of the data from the studies. As M. genitalium is a sexually-transmitted infectious disease, we developed a model for time-to-event analysis that incorporates the processes of (re)infection and clearance, and fitted to data from the two cohort studies to estimate incidence and clearance rates under different scenarios of sexual partnership dynamics and study design (including sample handling and associated test sensitivity). In the London students, the estimated clearance rate is 0.80 p.a. (mean duration 15 months), with incidence 1.31%-3.93% p.a. Without adjusting for study design, corresponding estimates from the Ugandan data are 3.44 p.a. (mean duration 3.5 months) and 58% p.a. Apparent differences in clearance rates are probably mostly due to lower testing sensitivity in the Uganda study due to differences in sample handling, with 'true' clearance rates being similar, and adjusted incidence in Uganda being 28% p.a. Some differences are perhaps due to the sex workers having more-frequent antibiotic treatment, whilst reinfection within ongoing sexual partnerships might have caused some of the apparently-persistent infection in the London students. More information on partnership dynamics would inform more accurate estimates of natural-history parameters. Detailed studies in men are also required.

In vitro metabolism of benzo[a]pyrene-7,8-dihydrodiol and dibenzo[def,p]chrysene-11,12 diol in rodent and human hepatic microsomes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smith, Jordan N.; Mehinagic, Denis; Nag, Subhasree

Polycyclic aromatic hydrocarbons (PAHs) are contaminants that are ubiquitously found in the environment, produced through combustion of organic matter or petrochemicals, and many of which are procarcinogens. The prototypic PAH, benzo[a]pyrene (B[a]P) and the highly carcinogenic dibenzo[def,p]chrysene (DBC) are metabolically activated by isoforms of the P450 enzyme superfamily producing benzo[a]pyrene-7,8-dihydrodiol (B[a]P diol), dibenzo[def,p]chrysene-11,12 diol (DBC diol). Each of these diols can be further metabolized by cytochrome P450 enzymes to highly reactive diol-epoxide metabolites that readily react with DNA or by phase II conjugation facilitating excretion. To complement prior in vitro metabolism studies with parent B[a]P and DBC, both phase Imore » metabolism and phase II glucuronidation of B[a]P diol and DBC diol were measured in this paper in hepatic microsomes from female B6129SF1/J mice, male Sprague-Dawley rats, and female humans. Metabolic parameters, including intrinsic clearance and Michaelis-Menten kinetics were calculated from substrate depletion data. Mice and rats demonstrated similar B[a]P diol phase I metabolic rates. Compared to rodents, human phase I metabolism of B[a]P diol demonstrated lower overall metabolic capacity, lower intrinsic clearance at higher substrate concentrations (>0.14 μM), and higher intrinsic clearance at lower substrate concentrations (<0.07 μM). Rates of DBC diol metabolism did not saturate in mice or humans and were highest overall in mice. Higher affinity constants and lower capacities were observed for DBC diol glucuronidation compared to B[a]P diol glucuronidation; however, intrinsic clearance values for these compounds were consistent within each species. Finally, kinetic parameters reported here will be used to extend physiologically based pharmacokinetic (PBPK) models to include the disposition of B[a]P and DBC metabolites in animal models and humans to support future human health risk assessments.« less

In vitro metabolism of benzo[a]pyrene-7,8-dihydrodiol and dibenzo[def,p]chrysene-11,12 diol in rodent and human hepatic microsomes

DOE PAGES

Smith, Jordan N.; Mehinagic, Denis; Nag, Subhasree; ...

2017-01-21

Polycyclic aromatic hydrocarbons (PAHs) are contaminants that are ubiquitously found in the environment, produced through combustion of organic matter or petrochemicals, and many of which are procarcinogens. The prototypic PAH, benzo[a]pyrene (B[a]P) and the highly carcinogenic dibenzo[def,p]chrysene (DBC) are metabolically activated by isoforms of the P450 enzyme superfamily producing benzo[a]pyrene-7,8-dihydrodiol (B[a]P diol), dibenzo[def,p]chrysene-11,12 diol (DBC diol). Each of these diols can be further metabolized by cytochrome P450 enzymes to highly reactive diol-epoxide metabolites that readily react with DNA or by phase II conjugation facilitating excretion. To complement prior in vitro metabolism studies with parent B[a]P and DBC, both phase Imore » metabolism and phase II glucuronidation of B[a]P diol and DBC diol were measured in this paper in hepatic microsomes from female B6129SF1/J mice, male Sprague-Dawley rats, and female humans. Metabolic parameters, including intrinsic clearance and Michaelis-Menten kinetics were calculated from substrate depletion data. Mice and rats demonstrated similar B[a]P diol phase I metabolic rates. Compared to rodents, human phase I metabolism of B[a]P diol demonstrated lower overall metabolic capacity, lower intrinsic clearance at higher substrate concentrations (>0.14 μM), and higher intrinsic clearance at lower substrate concentrations (<0.07 μM). Rates of DBC diol metabolism did not saturate in mice or humans and were highest overall in mice. Higher affinity constants and lower capacities were observed for DBC diol glucuronidation compared to B[a]P diol glucuronidation; however, intrinsic clearance values for these compounds were consistent within each species. Finally, kinetic parameters reported here will be used to extend physiologically based pharmacokinetic (PBPK) models to include the disposition of B[a]P and DBC metabolites in animal models and humans to support future human health risk assessments.« less

A Helix-Stabilizing Linker Improves Subcutaneous Bioavailability of a Helical Peptide Independent of Linker Lipophilicity

PubMed Central

Zhang, Liang; Navaratna, Tejas; Thurber, Greg M.

2016-01-01

Stabilized peptides address several limitations to peptide-based imaging agents and therapeutics such as poor stability and low affinity due to conformational flexibility. There is also active research in developing these compounds for intracellular drug targeting, and significant efforts have been invested to determine the effects of helix stabilization on intracellular delivery. However, much less is known about the impact on other pharmacokinetic parameters such as plasma clearance and bioavailability. We investigated the effect of different fluorescent helix-stabilizing linkers with varying lipophilicity on subcutaneous (SC) bioavailability using the glucagon-like peptide-1 (GLP-1) receptor ligand exendin as a model system. The stabilized peptides showed significantly higher protease resistance and increased bioavailability independent of linker hydrophilicity, and all subcutaneously delivered conjugates were able to successfully target the islets of Langerhans with high specificity. The lipophilic peptide variants had slower absorption and plasma clearance than their respective hydrophilic conjugates, and the absolute bioavailability was also lower likely due to the longer residence times in the skin. The ease and efficiency of double-click helix stabilization chemistries is a useful tool for increasing the bioavailability of peptide therapeutics, many of which suffer from rapid in vivo protease degradation. Helix stabilization using linkers of varying lipophilicity can further control SC absorption and clearance rates to customize plasma pharmacokinetics. PMID:27327034

Influence of Cremophor EL and genetic polymorphisms on the pharmacokinetics of paclitaxel and its metabolites using a mechanism-based model.

PubMed

Fransson, Martin N; Gréen, Henrik; Litton, Jan-Eric; Friberg, Lena E

2011-02-01

The formulation vehicle Cremophor EL has previously been shown to affect paclitaxel kinetics, but it is not known whether it also affects the kinetics of paclitaxel metabolites. This information may be important for understanding paclitaxel metabolism in vivo and in the investigation of the role of genetic polymorphisms in the metabolizing enzymes CYP2C8 and CYP3A4/CYP3A5 and the ABCB1 transporter. In this study we used the population pharmacokinetic approach to explore the influence of predicted Cremophor EL concentrations on paclitaxel (Taxol) metabolites. In addition, correlations between genetic polymorphisms and enzyme activity with clearance of paclitaxel, its two primary metabolites, 6α-hydroxypaclitaxel and p-3'-hydroxypaclitaxel, and its secondary metabolite, 6α-p-3'-dihydroxypaclitaxel were investigated. Model building was based on 1156 samples from a study with 33 women undergoing paclitaxel treatment for gynecological cancer. Total concentrations of paclitaxel were fitted to a model described previously. One-compartment models characterized unbound metabolite concentrations. Total concentrations of 6α-hydroxypaclitaxel and p-3'-hydroxypaclitaxel were strongly dependent on predicted Cremophor EL concentrations, but this association was not found for 6α-p-3'-dihydroxypaclitaxel. Clearance of 6α-hydroxypaclitaxel (fraction metabolized) was significantly correlated (p < 0.05) to the ABCB1 allele G2677T/A. Individuals carrying the polymorphisms G/A (n = 3) or G/G (n = 5) showed a 30% increase, whereas individuals with polymorphism T/T (n = 8) showed a 27% decrease relative to those with the polymorphism G/T (n = 17). The correlation of G2677T/A with 6α-hydroxypaclitaxel has not been described previously but supports other findings of the ABCB1 transporter playing a part in paclitaxel metabolism.

Proposal of a pharmacokinetically optimized dosage regimen of antibiotics in patients receiving continuous hemodiafiltration.

PubMed

Yamamoto, Takehito; Yasuno, Nobuhiro; Katada, Shoichi; Hisaka, Akihiro; Hanafusa, Norio; Noiri, Eisei; Yahagi, Naoki; Fujita, Toshiro; Suzuki, Hiroshi

2011-12-01

The aim of the study was to quantitatively predict the clearance of three antibiotics, amikacin, vancomycin, and teicoplanin, during continuous hemodiafiltration (CHDF) and to propose their optimal dosage in patients receiving CHDF. For this goal, in vitro CHDF experiments with a polyacrylonitrile (PAN) membrane were first performed using these antibiotics, and then the clearances were compared with in vivo CHDF situations determined in 16 critically ill patients. The in vitro CHDF clearances were described as the product of the outflow rate of a drain (Q(outflow)) and the drug unbound fraction in artificial plasma, indicating that drug adsorption to the PAN membrane has minor effect on drug clearance in our settings. The observed in vivo clearances also agreed very well with the predicted values, with a product of Q(outflow) and plasma unbound fraction, when residual creatinine clearance (CL(CR)) was taken into account (within a range of 0.67- to 1.5-fold for 15 of 16 patients). Based on these results, a nomogram of the optimized dosages of amikacin, vancomycin, and teicoplanin was proposed, and it was evident that Q(outflow) and residual CL(CR) are major determinants of the dosage and dosing interval for these antibiotics. Although the applicability needs to be confirmed with another type of membrane or higher Q(outflow), our nomogram can help determine the dosage setting in critically ill patients receiving CHDF.

An Investigation of Flight Deck Data Link in the Terminal Area

NASA Technical Reports Server (NTRS)

Martin, Lynne; Lozito, Sandra; Kaneshige, John; Dulchinos, Vicki; Sharma, Shivanjli

2013-01-01

The Next Generation Air Transportation System (NextGen) and Europe's Single European Sky ATM Research (SESAR) concepts require an increased use of trajectory-based operations, including extensive strategic air traffic control clearances. The clearances are lengthy and complex, which necessitate data link communications to allow for message permanence and integration into the autoflight systems (i.e., autoload capability). This paper examines the use of flight deck data link communications for strategic and tactical clearance usage in the terminal area. A human-in-the-loop simulation was conducted using a high-fidelity flight deck simulator, with ten commercial flight crews as participants. Data were collected from six flight scenarios in the San Francisco terminal airspace. The variables of interest were ATC message modality (voice v. data link), temporal quality of the message (tactical v. strategic) and message length. Dependent variables were message response times, communication clarifications, communication-related errors, and pilot workload. Response time results were longer in data link compared to voice, a finding that has been consistently revealed in a number of other simulations [1]. In addition, strategic clearances and longer messages resulted in a greater number of clarifications and errors, suggesting an increase in uncertainty of message interpretation for the flight crews when compared to tactical clearances. The implications for strategic and compound clearance usage in NextGen and SESAR are discussed

Lactate clearance as a useful biomarker for the prediction of all-cause mortality in critically ill patients: a systematic review study protocol

PubMed Central

Zhang, Zhongheng; Xu, Xiao; Chen, Kun

2014-01-01

Introduction Arterial lactate is a reflection of balance between lactate production and clearance. Accumulating lactate may be a marker of global hypoxia or hypoperfusion. Lactate clearance is the reduction of lactate concentrations with interventional strategies, and it has been associated with increased risk of death in critically ill patients. However, conflicting results exist, which mandates a systematic review to clarify the association between lactate clearance and clinical outcome. Methods and analysis Critically ill adult patients will be included in our analysis. This population will include heterogeneous study participants, including patients with sepsis or severe sepsis, trauma, surgical intensive care unit (ICU) patients, and so on. We will search four databases including EBSCO, PubMed, Scopus and ISI Web of knowledge from inception to February 2014. There will be no language restrictions in the electronic search for studies. Newcastle Ottawa Scale for cohort study will be employed to assess the reporting quality of included original studies. We will report pooled relative risk of death for those with lactate clearance and those without. The diagnostic performance of lactate clearance in predicting mortality will be explored by using the hierarchical summary receiver operating characteristic model. Ethics and dissemination The protocol for the systematic review has been registered in PROSPERO. The study will be disseminated electronically and in print. It will also be presented to conferences related to critical care medicine. Trial registration number: CRD42013006511. PMID:24860001

Multiple-Breath Washout Outcomes Are Sensitive to Inflammation and Infection in Children with Cystic Fibrosis.

PubMed

Ramsey, Kathryn A; Foong, Rachel E; Grdosic, Jasmine; Harper, Alana; Skoric, Billy; Clem, Charles; Davis, Miriam; Turkovic, Lidija; Stick, Stephen M; Davis, Stephanie D; Ranganathan, Sarath C; Hall, Graham L

2017-09-01

The lung clearance index is a measure of ventilation distribution derived from the multiple-breath washout technique. The lung clearance index is increased in the presence of lower respiratory tract inflammation and infection in infants with cystic fibrosis; however, the associations during the preschool years are unknown. We assessed the ability of the lung clearance index to detect the presence and extent of lower respiratory tract inflammation and infection in preschool children with cystic fibrosis. Ventilation distribution outcomes were assessed at 82 visits with 58 children with cystic fibrosis and at 38 visits with 31 healthy children aged 3-6 years. Children with cystic fibrosis also underwent bronchoalveolar lavage fluid collection for detection of lower respiratory tract inflammation and infection. Associations between multiple-breath washout indices and the presence and extent of airway inflammation and infection were assessed using linear mixed effects models. Lung clearance index was elevated in children with cystic fibrosis (mean [SD], 8.00 [1.45]) compared with healthy control subjects (6.67 [0.56]). In cystic fibrosis, the lung clearance index was elevated in individuals with lower respiratory tract infections (difference compared with uninfected [95% confidence interval], 0.62 [0.06, 1.18]) and correlated with the extent of airway inflammation. These data suggest that the lung clearance index may be a useful surveillance tool for monitoring the presence and extent of lower airway inflammation and infection in preschool children with cystic fibrosis.

A Blade Tip Timing Method Based on a Microwave Sensor

PubMed Central

Zhang, Jilong; Duan, Fajie; Niu, Guangyue; Jiang, Jiajia; Li, Jie

2017-01-01

Blade tip timing is an effective method for blade vibration measurements in turbomachinery. This method is increasing in popularity because it is non-intrusive and has several advantages over the conventional strain gauge method. Different kinds of sensors have been developed for blade tip timing, including optical, eddy current and capacitance sensors. However, these sensors are unsuitable in environments with contaminants or high temperatures. Microwave sensors offer a promising potential solution to overcome these limitations. In this article, a microwave sensor-based blade tip timing measurement system is proposed. A patch antenna probe is used to transmit and receive the microwave signals. The signal model and process method is analyzed. Zero intermediate frequency structure is employed to maintain timing accuracy and dynamic performance, and the received signal can also be used to measure tip clearance. The timing method uses the rising and falling edges of the signal and an auto-gain control circuit to reduce the effect of tip clearance change. To validate the accuracy of the system, it is compared experimentally with a fiber optic tip timing system. The results show that the microwave tip timing system achieves good accuracy. PMID:28492469

A Blade Tip Timing Method Based on a Microwave Sensor.

PubMed

Zhang, Jilong; Duan, Fajie; Niu, Guangyue; Jiang, Jiajia; Li, Jie

2017-05-11

Blade tip timing is an effective method for blade vibration measurements in turbomachinery. This method is increasing in popularity because it is non-intrusive and has several advantages over the conventional strain gauge method. Different kinds of sensors have been developed for blade tip timing, including optical, eddy current and capacitance sensors. However, these sensors are unsuitable in environments with contaminants or high temperatures. Microwave sensors offer a promising potential solution to overcome these limitations. In this article, a microwave sensor-based blade tip timing measurement system is proposed. A patch antenna probe is used to transmit and receive the microwave signals. The signal model and process method is analyzed. Zero intermediate frequency structure is employed to maintain timing accuracy and dynamic performance, and the received signal can also be used to measure tip clearance. The timing method uses the rising and falling edges of the signal and an auto-gain control circuit to reduce the effect of tip clearance change. To validate the accuracy of the system, it is compared experimentally with a fiber optic tip timing system. The results show that the microwave tip timing system achieves good accuracy.

Crocus sativus Extract Tightens the Blood-Brain Barrier, Reduces Amyloid β Load and Related Toxicity in 5XFAD Mice.

PubMed

Batarseh, Yazan S; Bharate, Sonali S; Kumar, Vikas; Kumar, Ajay; Vishwakarma, Ram A; Bharate, Sandip B; Kaddoumi, Amal

2017-08-16

Crocus sativus, commonly known as saffron or Kesar, is used in Ayurveda and other folk medicines for various purposes as an aphrodisiac, antispasmodic, and expectorant. Previous evidence suggested that Crocus sativus is linked to improving cognitive function in Alzheimer's disease (AD) patients. The aim of this study was to in vitro and in vivo investigate the mechanism(s) by which Crocus sativus exerts its positive effect against AD. The effect of Crocus sativus extract on Aβ load and related toxicity was evaluated. In vitro results showed that Crocus sativus extract increases the tightness of a cell-based blood-brain barrier (BBB) model and enhances transport of Aβ. Further in vivo studies confirmed the effect of Crocus sativus extract (50 mg/kg/day, added to mice diet) on the BBB tightness and function that was associated with reduced Aβ load and related pathological changes in 5XFAD mice used as an AD model. Reduced Aβ load could be explained, at least in part, by Crocus sativus extract effect to enhance Aβ clearance pathways including BBB clearance, enzymatic degradation and ApoE clearance pathway. Furthermore, Crocus sativus extract upregulated synaptic proteins and reduced neuroinflammation associated with Aβ pathology in the brains of 5XFAD mice. Crocin, a major active constituent of Crocus sativus and known for its antioxidant and anti-inflammatory effect, was also tested separately in vivo in 5XFAD mice. Crocin (10 mg/kg/day) was able to reduce Aβ load but to a lesser extent when compared to Crocus sativus extract. Collectively, findings from this study support the positive effect of Crocus sativus against AD by reducing Aβ pathological manifestations.

Simulation of Controller Pilot Data Link Communications over VHF Digital Link Mode 3

NASA Technical Reports Server (NTRS)

Bretmersky, Steven C.; Murawski, Robert; Nguyen, Thanh C.; Raghavan, Rajesh S.

2004-01-01

The Federal Aviation Administration (FAA) has established an operational plan for the future Air Traffic Management (ATM) system, in which the Controller Pilot Data Link Communications (CPDLC) is envisioned to evolve into digital messaging that will take on an ever increasing role in controller to pilot communications, significantly changing the way the National Airspace System (NAS) is operating. According to FAA, CPDLC represents the first phase of the transition from the current analog voice system to an International Civil Aviation Organization (ICAO) compliant system in which digital communication becomes the alternate and perhaps primary method of routine communication. The CPDLC application is an Air Traffic Service (ATS) application in which pilots and controllers exchange messages via an addressed data link. CPDLC includes a set of clearance, information, and request message elements that correspond to existing phraseology employed by current Air Traffic Control (ATC) procedures. These message elements encompass altitude assignments, crossing constraints, lateral deviations, route changes and clearances, speed assignments, radio frequency assignments, and various requests for information. The pilot is provided with the capability to respond to messages, to request clearances and information, to report information, and to declare/rescind an emergency. A 'free text' capability is also provided to exchange information not conforming to defined formats. This paper presents simulated results of the aeronautical telecommunication application Controller Pilot Data Link Communications over VHF Digital Link Mode 3 (VDL Mode 3). The objective of this simulation study was to determine the impact of CPDLC traffic loads, in terms of timely message delivery and capacity of the VDL Mode 3 subnetwork. The traffic model is based on and is used for generating air/ground messages with different priorities. Communication is modeled for the en route domain of the Cleveland Center air traffic (ZOB ARTCC).

Modeling the Role of the Glymphatic Pathway and Cerebral Blood Vessel Properties in Alzheimer's Disease Pathogenesis.

PubMed

Kyrtsos, Christina Rose; Baras, John S

2015-01-01

Alzheimer's disease (AD) is the most common cause of dementia in the elderly, affecting over 10% population over the age of 65 years. Clinically, AD is described by the symptom set of short term memory loss and cognitive decline, changes in mentation and behavior, and eventually long-term memory deficit as the disease progresses. On imaging studies, significant atrophy with subsequent increase in ventricular volume have been observed. Pathology on post-mortem brain specimens demonstrates the classic findings of increased beta amyloid (Aβ) deposition and the presence of neurofibrillary tangles (NFTs) within affected neurons. Neuroinflammation, dysregulation of blood-brain barrier transport and clearance, deposition of Aβ in cerebral blood vessels, vascular risk factors such as atherosclerosis and diabetes, and the presence of the apolipoprotein E4 allele have all been identified as playing possible roles in AD pathogenesis. Recent research has demonstrated the importance of the glymphatic system in the clearance of Aβ from the brain via the perivascular space surrounding cerebral blood vessels. Given the variety of hypotheses that have been proposed for AD pathogenesis, an interconnected, multilayer model offers a unique opportunity to combine these ideas into a single unifying model. Results of this model demonstrate the importance of vessel stiffness and heart rate in maintaining adequate clearance of Aβ from the brain.

Validation of Non-Invasive Tracer Kinetic Analysis of 18F-Florbetaben PET Using a Dual Time-Window Acquisition Protocol.

PubMed

Bullich, Santiago; Barthel, Henryk; Koglin, Norman; Becker, Georg A; De Santi, Susan; Jovalekic, Aleksandar; Stephens, Andrew W; Sabri, Osama

2017-11-24

Accurate amyloid PET quantification is necessary for monitoring amyloid-beta accumulation and response to therapy. Currently, most of the studies are analyzed using the static standardized uptake value ratio (SUVR) approach because of its simplicity. However, this approach may be influenced by changes in cerebral blood flow (CBF) or radiotracer clearance. Full tracer kinetic models require arterial blood sampling and dynamic image acquisition. The objectives of this work were: (1) to validate a non-invasive kinetic modeling approach for 18 F-florbetaben PET using an acquisition protocol with the best compromise between quantification accuracy and simplicity and (2) to assess the impact of CBF changes and radiotracer clearance on SUVRs and non-invasive kinetic modeling data in 18 F-florbetaben PET. Methods: Data from twenty subjects (10 patients with probable Alzheimer's dementia/ 10 healthy volunteers) were used to compare the binding potential (BP ND ) obtained from the full kinetic analysis to the SUVR and to non-invasive tracer kinetic methods (simplified reference tissue model (SRTM), and multilinear reference tissue model 2 (MRTM2)). Different approaches using shortened or interrupted acquisitions were compared to the results of the full acquisition (0-140 min). Simulations were carried out to assess the effect of CBF and radiotracer clearance changes on SUVRs and non-invasive kinetic modeling outputs. Results: A 0-30 and 120-140 min dual time-window acquisition protocol using appropriate interpolation of the missing time points provided the best compromise between patient comfort and quantification accuracy. Excellent agreement was found between BP ND obtained using full and dual time-window (2TW) acquisition protocols (BP ND,2TW =0.01+ 1.00 BP ND,FULL , R2=0.97 (MRTM2); BP ND,2TW = 0.05+ 0.92·BP ND,FULL , R2=0.93 (SRTM)). Simulations showed a limited impact of CBF and radiotracer clearance changes on MRTM parameters and SUVRs. Conclusion: This study demonstrates accurate non-invasive kinetic modeling of 18 F-florbetaben PET data using a dual time-window acquisition protocol, thus providing a good compromise between quantification accuracy, scan duration and patient burden. The influence of CBF and radiotracer clearance changes on amyloid-beta load estimates was small. For most clinical research applications, the SUVR approach is appropriate. However, for longitudinal studies in which a maximum quantification accuracy is desired, this non-invasive dual time-window acquisition protocol and kinetic analysis is recommended. Copyright © 2017 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Tip-leakage cavitation in the clearance of a 2D hydrofoil with fillets: high-speed visualization and PIV/PTV measurements

NASA Astrophysics Data System (ADS)

Zapryagaev, Ivan I.; Timoshevskiy, Mikhail V.; Pervunin, Konstantin S.

2017-09-01

Tip-clearance cavitation is one of the most aggressive forms of cavitation as it can cause surface erosion of hydraulic machinery elements and, as a result, their fatigue damage and disturb designed operating conditions. At present, the literature lacks for detailed experimental data on the inception and development of this type of cavitation at various flow conditions. In the paper, a tip-leakage cavitation occurring in the clearance between an end face of a 2D hydrofoil (a scaled-down model of guide vanes (GV) of a Francis turbine) and a transparent wall of the test section was studied. The experiments were carried out for different cavitating regimes on the cavitation number and two attack angles of 3° and 9°, with the gap size (tip clearance width) varied in the range from 0.4 to 0.8 mm. In order to determine the cavitation inception conditions and investigate the dynamics of the tip-leakage cavitation, a high-speed visualization was applied. A modified PIV/PTV technique with a diverging laser beam instead of a laser light sheet was used to measure the mean velocity distributions within the gap. It was shown that the cavitation pattern on the suction side of the GV model impacts the dynamics of the leakage flow in the gap but does not affect the sheet cavity formed close to the foil leading edge in the clearance as well as its size and dynamics. When the gap size is increased, the tip-leakage cavitation initiates at higher cavitation numbers or, in other words, conditions for the cavitation occurrence become more favorable.

Population pharmacokinetics of rituximab in patients with diffuse large B-cell lymphoma and association with clinical outcome.

PubMed

Rozman, Samo; Grabnar, Iztok; Novaković, Srdjan; Mrhar, Ales; Jezeršek Novaković, Barbara

2017-08-01

Pharmacokinetic (PK) studies suggest that there is a room for improvement in clinical use of rituximab through more individualized treatment. The objective of this study was to characterize rituximab PK in 29 newly diagnosed patients with diffuse large B-cell lymphoma treated with rituximab in combination with cyclophosphamide, doxorubicin, vincristine and methylprednisolone every 3 weeks. We also evaluated the association of rituximab PK with clinical outcome. Rituximab serum levels were determined by enzyme-linked immunosorbent assay and evaluated by a population PK analysis applying nonlinear mixed effects modelling. The data were best described by a two-compartment model comprising linear nonspecific clearance of 0.252 [95% confidence interval (CI): 0.227-0.279] l day -1 and time-varying specific clearance of 0.278 (95% CI: 0.181-0.390) l day -1 , corresponding to target-mediated drug disposition of rituximab. Nonspecific clearance was lower in older patients and those with lower body weight. Additionally, volume of the central compartment was higher in males. A clear association of clinical response with rituximab PK has been observed. Rate constant of specific clearance decay was 0.143 day -1 (95% CI: 0.0478-0.418) in patients with no disease progression, while in patients with disease progression it was 82.2% lower (95% CI: 33.4-95.0). This finding indicates that time-changes in clearance could serve as a predictive marker of response to rituximab. Our report demonstrates the rationale for studies evaluating higher doses of rituximab in selected patients. © 2017 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Population pharmacokinetics of methadone hydrochloride after a single intramuscular administration in adult Japanese sika deer (Cervus nippon nippon).

PubMed

Scala, Christopher; Marsot, Amélie; Limoges, Marie-Josée; Locatelli, Yann; Simon, Nicolas; Alvarez, Jean-Claude

2015-03-01

To assess the population pharmacokinetics of methadone in deer. Prospective non-randomized experimental trial. Twelve healthy adult sika deer (nine males and three females). Deer received intramuscular administration of racemic methadone hydrochloride at 0.5 mg kg(-1) or 1 mg kg(-1) . Plasma methadone and its metabolite 2-Ethylidene-1,5-Dimethyl-3,3-Diphenyl-Pyrolidine (EDDP) concentrations were determined by validated liquid chromatography coupled to tandem mass spectrometry methods, at times 0, 30 minutes, 1, 2, 3, 4, 5, 6, 8, 12 and 24 hours. Population pharmacokinetics analysis was undertaken using a non-linear mixed effects modelling (NONMEM). A two-compartment linear disposition model best described observed time-concentration profiles of methadone and EDDP. Population parameter estimates of methadone were elimination clearance (17.3 L hour(-1) ), metabolic clearance (34.6 L hour(-1) ), volume of distribution of compartment 1 (216.0 L) and volume of distribution of compartment 2 (384.0 L). Population parameter estimates of EDDP were elimination clearance (121.0 L hour(-1) ), volume of distribution of compartment 3 (1.08 L) and volume of distribution of compartment 4 (499.5 L). The total clearance and total volume of distribution of methadone and EDDP were 51.9 L hour(-1) , 121.0 L hour (-1) , 600.0 L and 500.6 L, respectively. The methadone terminal elimination half-life was 8.19 hours. No adverse effects were observed after methadone administration. Following intramuscular injection, methadone was characterized by a large total volume of distribution, high systemic clearance and intermediate terminal half-life in sika deer. © 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

Comparative Analysis of Amphotericin B Lipid Complex and Liposomal Amphotericin B Kinetics of Lung Accumulation and Fungal Clearance in a Murine Model of Acute Invasive Pulmonary Aspergillosis▿

PubMed Central

Lewis, Russell E.; Liao, Guangling; Hou, Jinggou; Chamilos, Georgios; Prince, Randall A.; Kontoyiannis, Dimitrios P.

2007-01-01

The reformulation of amphotericin B (AMB) into a lipid complex (AMB lipid complex [ABLC]) or liposomal carrier (liposomal AMB [L-AMB]) changes the rate and extent of drug distribution to the lung. The importance of pharmacokinetic differences among the various lipid AMB formulations in the treatment of invasive pulmonary aspergillosis (IPA) remains unknown. We compared the kinetics of AMB lung accumulation and fungal clearance of ABLC- and L-AMB-treated mice with acute IPA. BALB/c mice were immunosuppressed with cyclophosphamide and cortisone before intranasal inoculation with 1.5 × 106 Aspergillus fumigatus 293 conidia. ABLC or L-AMB was administered in daily intravenous doses (1, 5, or 10 mg/kg of body weight), starting 12 h after infection and continuing until day 5. At predetermined times (0, 24, 72, and 120 h), mice were euthanized, and lungs were harvested for determinations of lung fungal burdens (quantitative PCR) and total AMB lung tissue concentrations. Both ABLC and L-AMB were effective at reducing lung fungal burdens at doses of ≥5 mg/kg/day. Clearance of A. fumigatus during the first 24 h was associated with AMB tissue concentrations of >4 μg/g. At 5 mg/kg/day, ABLC produced a more rapid fungal clearance than did L-AMB, but at the end of therapy, fungal burden reductions were similar for both formulations and were not improved with higher dosages. These data suggest that ABLC delivers active AMB to the lung more rapidly than does L-AMB, resulting in faster Aspergillus clearance in an experimental model of IPA. However, pharmacodynamic differences between the two formulations were less apparent when mice were dosed at 10 mg/kg/day. PMID:17261624

The choice of speed and clearance for RAS on 3D method

NASA Astrophysics Data System (ADS)

Wang, Jian-Fang; Li, Ji-De; Cai, Xin-Gong

2003-12-01

In this paper, a 3D source distribution technique is used to calculate the coupled motions between two ships which advance in the wave with the same speed. The numerical results of coupled motions for a frigate and a supply ship have a good agreement with the experimental results. Based on the 3D coupled motions of two ships, a spectral analysis is employed to clearly observe the effect of speed, clearance and wave heading on the significant relative motion amplitude (SRMA) of two ships. The method presented in this paper will be helpful to select suitable clearance, speed and wave heading for underway replenishment at sea(RAS).

Analysis of hepatitis C viral dynamics using Latin hypercube sampling

NASA Astrophysics Data System (ADS)

Pachpute, Gaurav; Chakrabarty, Siddhartha P.

2012-12-01

We consider a mathematical model comprising four coupled ordinary differential equations (ODEs) to study hepatitis C viral dynamics. The model includes the efficacies of a combination therapy of interferon and ribavirin. There are two main objectives of this paper. The first one is to approximate the percentage of cases in which there is a viral clearance in absence of treatment as well as percentage of response to treatment for various efficacy levels. The other is to better understand and identify the parameters that play a key role in the decline of viral load and can be estimated in a clinical setting. A condition for the stability of the uninfected and the infected steady states is presented. A large number of sample points for the model parameters (which are physiologically feasible) are generated using Latin hypercube sampling. An analysis of the simulated values identifies that, approximately 29.85% cases result in clearance of the virus during the early phase of the infection. Results from the χ2 and the Spearman's tests done on the samples, indicate a distinctly different distribution for certain parameters for the cases exhibiting viral clearance under the combination therapy.

A Preclinical Population Pharmacokinetic Model for Anti‐CD20/CD3 T‐Cell‐Dependent Bispecific Antibodies

PubMed Central

Reyes, Arthur; Sun, Liping L.; Cheu, Melissa; Oldendorp, Amy; Ramanujan, Saroja; Stefanich, Eric G.

2018-01-01

Abstract CD20 is a cell‐surface receptor expressed by healthy and neoplastic B cells and is a well‐established target for biologics used to treat B‐cell malignancies. Pharmacokinetic (PK) and pharmacodynamic (PD) data for the anti‐CD20/CD3 T‐cell‐dependent bispecific antibody BTCT4465A were collected in transgenic mouse and nonhuman primate (NHP) studies. Pronounced nonlinearity in drug elimination was observed in the murine studies, and time‐varying, nonlinear PK was observed in NHPs, where three empirical drug elimination terms were identified using a mixed‐effects modeling approach: i) a constant nonsaturable linear clearance term (7 mL/day/kg); ii) a rapidly decaying time‐varying, linear clearance term (t½ = 1.6 h); and iii) a slowly decaying time‐varying, nonlinear clearance term (t½ = 4.8 days). The two time‐varying drug elimination terms approximately track with time scales of B‐cell depletion and T‐cell migration/expansion within the central blood compartment. The mixed‐effects NHP model was scaled to human and prospective clinical simulations were generated. PMID:29351372

Reynolds-averaged Navier-Stokes computation on tip clearance flow in a compressor cascade using an unstructured grid

NASA Astrophysics Data System (ADS)

Shin, Sangmook

2001-07-01

A three-dimensional unstructured incompressible RANS code has been developed using artificial compressibility and Spalart-Allmaras eddy viscosity model. A node-based finite volume method is used in which all flow variables are defined at the vertices of tetrahedrons in an unstructured grid. The inviscid fluxes are computed by using the Roe's flux difference splitting method, and higher order accuracy is attained by data reconstruction based on Taylor series expansion. Gauss theorem is used to formulate necessary gradients. For time integration, an implicit scheme based on linearized Euler backward method is used. A tetrahedral unstructured grid generation code has been also developed and applied to the tip clearance flow in a highly staggered cascade. Surface grids are first generated in the flow passage and blade tip by using several triangulation methods including Delaunay triangulation, advancing front method and advancing layer method. Then the whole computational domain including tip gap region is filled with prisms using the surface grids. The code has been validated by comparisons with available computational and experimental results for several test cases: inviscid flow around NACA section, laminar and turbulent flow over a flat plate, turbulent flow through double-circular arc cascade and laminar flow through a square duct with 90° bend. Finally the code is applied to a linear cascade that has GE rotor B section with tip clearance and a high stagger angle of 56.9°. The overall structure of the tip clearance flow is well predicted. Loss of loading due to tip leakage flow and reloading due to tip leakage vortex are presented. On the end wall, separation line of the tip leakage vortex and reattachment line of passage vortex are identified. Prediction of such an interaction presents a challenge to RANS computations. The effects of blade span on the flow structure have been also investigated. Two cascades with blades of aspect ratios of 0.5 and 1.0 are considered. By comparing pressure distributions on the blade, it is shown that the aspect ratio has strong effects on loading distribution on the blade although the tip gap height is very small (0.016 chord). Grid convergence study has been carried out with three different grids for pressure distributions and limiting streamlines on the end wall. (Abstract shortened by UMI.)

Novel approaches for immunotherapeutic intervention in Alzheimer's disease.

PubMed

Vasilevko, Vitaly; Cribbs, David H

2006-07-01

Immunotherapy can attenuate amyloid neuropathology and improve cognitive function in transgenic models of Alzheimer's disease. However, the first clinical trial was halted when 6% of the Alzheimer's patients developed aseptic meningoencephalitis. Postmortem analysis of two cases with meningoencephalitis showed robust glial activation, T-cell infiltration and sporadic clearance of Abeta. Interestingly, transgenic mouse models of Alzheimer's disease failed as predictors of these adverse inflammatory events. However there are now several studies with amyloid precursor protein transgenic mice that have reported an increased risk of microhemorrhages at sites of cerebrovascular amyloid deposits and because approximately 80% of Alzheimer's patient's have cerebrovascular pathology, there is concern regarding clinical trials using passive administration of humanized anti-Abeta antibodies. Although many studies have now been published on immunotherapy in mouse models, the mechanism(s) of antibody-mediated clearance of beta-amyloid from the brain, and the cause of the antibody-induced microhemorrhages remain unclear. In this review, we will discuss the most recent results from the first clinical trial, offer speculation on possible causes for the failure of the trial, review data on antibody-mediated clearance mechanisms, explore the role of complement and inflammation in the clearance of beta-amyloid, and suggest novel strategies for avoiding problems in future clinical trials. The central hypothesis being proposed in this review is that anti-Abeta antibodies delivered directly to the CNS at the sites of amyloid deposits will be far more effective at clearing Abeta and safer than active or passive immunization strategies where the majority of the antibodies are in the periphery.

The impact of desorption kinetics from albumin on hepatic extraction efficiency and hepatic clearance: a model study.

PubMed

Krause, Sophia; Goss, Kai-Uwe

2018-05-23

Until now, the question whether slow desorption of compounds from transport proteins like the plasma protein albumin can affect hepatic uptake and thereby hepatic metabolism of these compounds has not yet been answered conclusively. This work now combines recently published experimental desorption rate constants with a liver model to address this question. For doing so, the used liver model differentiates the bound compound in blood, the unbound compound in blood and the compound within the hepatocytes as three well-stirred compartments. Our calculations show that slow desorption kinetics from albumin can indeed limit hepatic metabolism of a compound by decreasing hepatic extraction efficiency and hepatic clearance. The extent of this decrease, however, depends not only on the value of the desorption rate constant but also on how much of the compound is bound to albumin in blood and how fast intrinsic metabolism of the compound in the hepatocytes is. For strongly sorbing and sufficiently fast metabolized compounds, our calculations revealed a twentyfold lower hepatic extraction efficiency and hepatic clearance for the slowest known desorption rate constant compared to the case when instantaneous equilibrium between bound and unbound compound is assumed. The same desorption rate constant, however, has nearly no effect on hepatic extraction efficiency and hepatic clearance of weakly sorbing and slowly metabolized compounds. This work examines the relevance of desorption kinetics in various example scenarios and provides the general approach needed to quantify the effect of flow limitation, membrane permeability and desorption kinetics on hepatic metabolism at the same time.

Bacteria meets influenza A virus: A bioluminescence mouse model of Escherichia coli O157:H7 following influenza A virus/Puerto Rico/8/34 (H1N1) strain infection.

PubMed

Wang, Zhongyi; Chi, Hang; Wang, Xiwen; Li, Wenliang; Li, Zhiping; Li, Jiaming; Fu, Yingying; Lu, Bing; Xia, Zhiping; Qian, Jun; Liu, Linna

2018-01-01

Objective To develop a bioluminescence-labelled bacterial infection model to monitor the colonization and clearance process of Escherichia coli O157:H7 in the lungs of mice following influenza A virus/Puerto Rico/8/34 (H1N1) strain (IAV/PR8) infection. Methods BALB/c mice were administered IAV/PR8 or 0.01 M phosphate-buffered saline (PBS; pH 7.4) intranasally 4 days prior to intranasal administration of 1 × 10 7 colony-forming units (CFU) of E. coli O157:H7-lux. Whole-body bioluminescent signals were monitored at 10 min, 4 h, 8 h, 12 h, 16 h and 24 h post-bacterial infection. Lung bioluminescent signals and bacterial load (CFU/g) were monitored at 4 h, 8 h, 12 h, 16 h and 24 h post-bacterial infection. Results Prior IAV/PR8 infection of mice resulted in a higher level of bacterial colonization and a lower rate of bacterial clearance from the lungs compared with mice treated with PBS. There were also consistent findings between the bioluminescence imaging and the CFU measurements in terms of identifying bacterial colonization and monitoring the clearance dynamics of E. coli O157:H7-lux in mouse lungs. Conclusion This novel bioluminescence-labelled bacterial infection model rapidly detected bacterial colonization of the lungs and monitored the clearance dynamics of E. coli O157:H7-lux following IAV/PR8 infection.

Hyperglycemia impedes lung bacterial clearance in a murine model of cystic fibrosis-related diabetes

PubMed Central

Hunt, William R.; Zughaier, Susu M.; Guentert, Dana E.; Shenep, Melissa A.; Koval, Michael; McCarty, Nael A.

2013-01-01

Cystic fibrosis-related diabetes (CFRD) is the most common comorbidity associated with cystic fibrosis (CF), impacting more than half of patients over age 30. CFRD is clinically significant, portending accelerated decline in lung function, more frequent pulmonary exacerbations, and increased mortality. Despite the profound morbidity associated with CFRD, little is known about the underlying CFRD-related pulmonary pathology. Our aim was to develop a murine model of CFRD to explore the hypothesis that elevated glucose in CFRD is associated with reduced lung bacterial clearance. A diabetic phenotype was induced in gut-corrected CF transmembrane conductance regulator (CFTR) knockout mice (CFKO) and their CFTR-expressing wild-type littermates (WT) utilizing streptozotocin. Mice were subsequently challenged with an intratracheal inoculation of Pseudomonas aeruginosa (PAO1) (75 μl of 1–5 × 106 cfu/ml) for 18 h. Bronchoalveolar lavage fluid was collected for glucose concentration and cell counts. A portion of the lung was homogenized and cultured as a measure of the remaining viable PAO1 inoculum. Diabetic mice had increased airway glucose compared with nondiabetic mice. The ability to clear bacteria from the lung was significantly reduced in diabetic WT mice and control CFKO mice. Critically, bacterial clearance by diabetic CFKO mice was significantly more diminished compared with nondiabetic CFKO mice, despite an even more robust recruitment of neutrophils to the airways. This finding that CFRD mice boast an exaggerated, but less effective, inflammatory cell response to intratracheal PAO1 challenge presents a novel and useful murine model to help identify therapeutic strategies that promote bacterial clearance in CFRD. PMID:24097557

Highly fluorescent resorcinarene cavitand nanocapsules with efficient renal clearance

NASA Astrophysics Data System (ADS)

Mahadevan, Kalpana; Patthipati, Venkata Suresh; Han, Sangbum; Swanson, R. James; Whelan, Eoin C.; Osgood, Christopher; Balasubramanian, Ramjee

2016-08-01

Nanomaterial based imaging approaches hold substantial promise in addressing current diagnostic and therapeutic challenges. One of the key requirements for the successful clinical translation of nanomaterials is their complete clearance from the body within a reasonable time period preferably via the renal filtration route. This article describes the synthesis of highly fluorescent, water soluble, resorcinarene cavitand nanocapsules and demonstrates their effective renal clearance in mice. The synthesis and functionalization of nanocapsules was accomplished in a one-pot operation via thiol-ene reactions without involving self-assembly, sacrificial templates or emulsions. Water soluble resorcinarene cavitand nanocapsules obtained by this approach were covalently functionalized with Alexa Fluor 750. Highly fluorescent nanocapsules with hydrodynamic diameters of 122 nm and 68 nm and extinction coefficients of 1.3 × 109 M-1 cm-1 and 1.5 × 108 M-1 cm-1 respectively were prepared by varying the reaction conditions. The in vivo biodistribution and clearance of these nanocapsules in mice followed by whole-body fluorescence imaging showed that they were both cleared renally within a few hours. Given the inherent encapsulation capabilities of nanocapsules, the renal clearance demonstrated in this work opens up new opportunities for their theranostic applications especially for targeting and treating the urinary tract.

Population Pharmacokinetic Model-Based Evaluation of Standard Dosing Regimens for Cefuroxime Used in Coronary Artery Bypass Graft Surgery with Cardiopulmonary Bypass.

PubMed

Alqahtani, Saeed A; Alsultan, Abdullah S; Alqattan, Hussain M; Eldemerdash, Ahmed; Albacker, Turki B

2018-04-01

The purpose of this study was to investigate the population pharmacokinetics (PK) of cefuroxime in patients undergoing coronary artery bypass graft (CABG) surgery. In this observational pharmacokinetic study, multiple blood samples were collected over a 48-h interval of intravenous cefuroxime administration. The samples were analyzed by using a validated high-performance liquid chromatography (HPLC) method. Population pharmacokinetic models were developed using Monolix (version 4.4) software. Pharmacokinetic-pharmacodynamic (PD) simulations were performed to explore the ability of different dosage regimens to achieve the pharmacodynamic targets. A total of 468 blood samples from 78 patients were analyzed. The PK for cefuroxime were best described by a two-compartment model with between-subject variability on clearance, the volume of distribution of the central compartment, and the volume of distribution of the peripheral compartment. The clearance of cefuroxime was related to creatinine clearance (CL CR ). Dosing simulations showed that standard dosing regimens of 1.5 g could achieve the PK-PD target of the percentage of the time that the free concentration is maintained above the MIC during a dosing interval ( fT MIC ) of 65% for an MIC of 8 mg/liter in patients with a CL CR of 30, 60, or 90 ml/min, whereas this dosing regimen failed to achieve the PK-PD target in patients with a CL CR of ≥125 ml/min. In conclusion, administration of standard doses of 1.5 g three times daily provided adequate antibiotic prophylaxis in patients undergoing CABG surgery. Lower doses failed to achieve the PK-PD target. Patients with high CL CR values required either higher doses or shorter intervals of cefuroxime dosing. On the other hand, lower doses (1 g three times daily) produced adequate target attainment for patients with low CL CR values (≤30 ml/min). Copyright © 2018 American Society for Microbiology.

Population pharmacokinetics of ϵ-aminocaproic acid in adolescents undergoing posterior spinal fusion surgery.

PubMed

Stricker, P A; Gastonguay, M R; Singh, D; Fiadjoe, J E; Sussman, E M; Pruitt, E Y; Goebel, T K; Zuppa, A F

2015-04-01

Despite demonstrated efficacy of ϵ-aminocaproic acid (EACA) in reducing blood loss in adolescents undergoing spinal fusion, there are no population-specific pharmacokinetic data to guide dosing. The aim of this study was to determine the pharmacokinetics of EACA in adolescents undergoing spinal fusion surgery and make dosing recommendations. Twenty children ages 12-17 years were enrolled, with 10 children in each of two groups based on diagnosis (idiopathic scoliosis or non-idiopathic scoliosis). Previously reported data from infants undergoing craniofacial surgery were included in the model to enable dosing recommendations over a wide range of weights, ages, and diagnoses. A population non-linear mixed effects modelling approach was used to characterize EACA pharmacokinetics. Population pharmacokinetic parameters were estimated using a two-compartment disposition model with allometrically scaled weight and an age effect on clearance. Pharmacokinetic parameters for the typical patient were a plasma clearance of 153 ml min(-1) 70 kg(-1) (6.32 ml min(-1) kg(-0.75)), intercompartmental clearance of 200 ml min(-1) 70 kg(-1) (8.26 ml min(-1) kg(-0.75)), central volume of distribution of 8.78 litre 70 kg(-1) (0.13 litre kg(-1)), and peripheral volume of distribution of 15.8 litre 70 kg(-1) (0.23 litre kg(-1)). Scoliosis aetiology did not have a clinically significant effect on drug pharmacokinetics. The following dosing schemes are recommended according to patient weight: weight <25 kg, 100 mg kg(-1) loading dose and 40 mg kg(-1) h(-1) infusion; weight ≤25 kg-<50 kg, 100 mg kg(-1) loading dose and 35 mg kg(-1) h(-1) infusion; and weight ≥50 kg, 100 mg kg(-1) loading dose and 30 mg kg(-1) h(-1) infusion. An efficacy trial employing this dosing strategy is warranted. NCT01408823. © The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Population pharmacokinetics of ϵ-aminocaproic acid in adolescents undergoing posterior spinal fusion surgery

PubMed Central

Stricker, P. A.; Gastonguay, M. R.; Singh, D.; Fiadjoe, J. E.; Sussman, E. M.; Pruitt, E. Y.; Goebel, T. K.; Zuppa, A. F.

2015-01-01

Background Despite demonstrated efficacy of ϵ-aminocaproic acid (EACA) in reducing blood loss in adolescents undergoing spinal fusion, there are no population-specific pharmacokinetic data to guide dosing. The aim of this study was to determine the pharmacokinetics of EACA in adolescents undergoing spinal fusion surgery and make dosing recommendations. Methods Twenty children ages 12–17 years were enrolled, with 10 children in each of two groups based on diagnosis (idiopathic scoliosis or non-idiopathic scoliosis). Previously reported data from infants undergoing craniofacial surgery were included in the model to enable dosing recommendations over a wide range of weights, ages, and diagnoses. A population non-linear mixed effects modelling approach was used to characterize EACA pharmacokinetics. Results Population pharmacokinetic parameters were estimated using a two-compartment disposition model with allometrically scaled weight and an age effect on clearance. Pharmacokinetic parameters for the typical patient were a plasma clearance of 153 ml min−1 70 kg−1 (6.32 ml min−1 kg−0.75), intercompartmental clearance of 200 ml min−1 70 kg−1 (8.26 ml min−1 kg−0.75), central volume of distribution of 8.78 litre 70 kg−1 (0.13 litre kg−1), and peripheral volume of distribution of 15.8 litre 70 kg−1 (0.23 litre kg−1). Scoliosis aetiology did not have a clinically significant effect on drug pharmacokinetics. Conclusions The following dosing schemes are recommended according to patient weight: weight <25 kg, 100 mg kg−1 loading dose and 40 mg kg−1 h−1 infusion; weight ≤25 kg–<50 kg, 100 mg kg−1 loading dose and 35 mg kg−1 h−1 infusion; and weight ≥50 kg, 100 mg kg−1 loading dose and 30 mg kg−1 h−1 infusion. An efficacy trial employing this dosing strategy is warranted. Clinical trial registration NCT01408823. PMID:25586726

A comparison of the effect of convection against diffusion in hemodynamics and cytokines clearance in an experimental model of septic shock.

PubMed

Herrera-Gutiérrez, Manuel E; Seller-Pérez, Gemma; Arias-Verdú, Dolores; Granados, Maria M; Dominguez, Juan M; Navarrete, Rocío; Morgaz, Juán; Gómez-Villamandos, Rafael

2012-10-01

Replacement therapies based on the use of convection have value for the removal of inflammatory mediators. Such therapies have been proposed for the management of septic shock, but diffusion has not proved useful in this scenario, unless high-flow membranes are used. The exact role of diffusion in these cases remains to be clarified because continuous replacement therapies are usually delivered with low-flow membranes and mixed convection-diffusion modalities. However, studies specifically addressing this problem have not been performed. Our aim was to define the efficacy of hemofiltration (convection) and hemodialysis (diffusion) in cytokine clearance and hemodynamic improvement in an experimental model of septic shock. Shock was induced in 15 beagle dogs (weight 10-15 kg) by infusion of 1 mg/kg of ultrapure Escherichia coli lipopolysaccharide diluted in 20 mL saline for 10 minutes. Five animals were followed without interventions (controls), five animals were treated with convection (100 mL kg h) for 6 hours, and five animals were treated with diffusion (100 mL kg h) for 6 hours. All subjects in the control group died during the study, whereas all treated subjects survived. Mean arterial pressure, cardiac output, systolic variability volume, systemic vascular resistances, dPMax, and pulmonary compliance improved in treated subjects. However, the differences in mean arterial pressure and cardiac output were significant only in the convection group and not in the diffusion-treated group.Tumor necrosis factor α rose equally in all groups and decreased only in treated subjects. Interleukin 6 rose in the three groups but decreased only in the convection group and remained unchanged in the control and diffusion groups. Convection and diffusion improved survival and hemodynamic parameters in a septic shock model. Improvement was more pronounced with convection, a difference that may be explained by convective clearance of cytokines.

The influence of hepatic transport on the distribution volumes and mean residence time of drug in the body and the accuracy of estimating these parameters by the traditional pharmacokinetic calculations.

PubMed

Berezhkovskiy, Leonid M

2011-11-01

The influence of hepatic uptake and efflux, which includes passive diffusion and transporter-mediated component, on drug distribution volumes [steady-state volume of distribution (V(ss)) and terminal volume of distribution (V(β))], mean residence time (MRT), clearance, and terminal half-life is considered using a simplified physiologically based pharmacokinetic model. To account for hepatic uptake, liver is treated as two-compartmental unit with drug transfer from extracellular water into hepatocytes. The exactly calculated distribution volumes and MRT are compared with that obtained by the traditional equations based on the assumption of central elimination. It was found that V(ss) may increase more than 10-fold and V(β) more than 100-fold due to the contribution of transporter-mediated uptake. The terminal half-life may be substantially shortened (more than 100-fold) due to transporters. It may also decrease significantly due to the increase of intrinsic hepatic clearance (CL(int)), whereas hepatic clearance has already reached saturation (and stays close to the possible maximum value). It is shown that in case of transporter-mediated uptake of compound into hepatocytes, in the absence of efflux and passive diffusion (unidirectional uptake), hepatic clearance is independent of CL(int) and is determined by hepatic blood flow and uptake rate constant. The effects of transporter-mediated uptake are mostly pronounced for hydrophilic acidic compounds and moderately lipophilic neutral compounds. For basic compounds and lipophilic neutral compounds the change of distribution volumes due to transporters is rather unlikely. It was found that the traditional equations provide very accurate values of V(ss), V(β), and MRT in the absence of transporter action even for very low rates of passive diffusion. On the other hand, the traditional equations fail to provide the correct values of these parameters when the increase of distribution volumes due to transporters takes place, and actually yield the values substantially smaller than the true ones (up to an order of magnitude for V(ss) and MRT, and three orders of magnitude for V(β)). Copyright © 2011 Wiley-Liss, Inc.

Population pharmacokinetic modeling of furosemide in patients with hypertension and fluid overload conditions.

PubMed

Kodati, Devender; Yellu, Narsimhareddy

2017-06-01

Furosemide is a loop diuretic drug frequently indicated in hypertension and fluid overload conditions such as congestive heart failure and hepatic cirrhosis. The purpose of the study was to establish a population pharmacokinetic model for furosemide in Indian hypertensive and fluid overload patients, and to evaluate effects of covariates on the volume of distribution (V/F) and oral clearance (CL/F) of furosemide. A total of 188 furosemide plasma sample concentrations from 63 patients with hypertension or fluid overload conditions were collected in this study. The population pharmacokinetic model for furosemide was built using Phoenix NLME 1.3 software. The covariates included age, sex, body surface area, bodyweight, height and creatinine clearance (CRCL). The pharmacokinetic data of furosemide was adequately explained by a two-compartment linear pharmacokinetic model with first-order absorption and an absorption lag-time. The mean values of CL/F and Vd/F of furosemide in the patients were 15.054Lh -1 and 4.419L, respectively. Analysis of covariates showed that CRCL was significantly influencing the clearance of furosemide. The final population pharmacokinetic model was demonstrated to be appropriate and effective and it can be used to assess the pharmacokinetic parameters of furosemide in Indian patients with hypertension and fluid overload conditions. Copyright © 2017. Published by Elsevier Urban & Partner Sp. z o.o.

JT9D performance deterioration results from a simulated aerodynamic load test

NASA Technical Reports Server (NTRS)

Stakolich, E. G.; Stromberg, W. J.

1981-01-01

The results of testing to identify the effects of simulated aerodynamic flight loads on JT9D engine performance are presented. The test results were also used to refine previous analytical studies on the impact of aerodynamic flight loads on performance losses. To accomplish these objectives, a JT9D-7AH engine was assembled with average production clearances and new seals as well as extensive instrumentation to monitor engine performance, case temperatures, and blade tip clearance changes. A special loading device was designed and constructed to permit application of known moments and shear forces to the engine by the use of cables placed around the flight inlet. The test was conducted in the Pratt & Whitney Aircraft X-Ray Test Facility to permit the use of X-ray techniques in conjunction with laser blade tip proximity probes to monitor important engine clearance changes. Upon completion of the test program, the test engine was disassembled, and the condition of gas path parts and final clearances were documented. The test results indicate that the engine lost 1.1 percent in thrust specific fuel consumption (TSFC), as measured under sea level static conditions, due to increased operating clearances caused by simulated flight loads. This compares with 0.9 percent predicted by the analytical model and previous study efforts.

The detailed measurement of foot clearance by young adults during stair descent.

PubMed

Telonio, A; Blanchet, S; Maganaris, C N; Baltzopoulos, V; McFadyen, B J

2013-04-26

Foot clearance is an important variable for understanding safe stair negotiation, but few studies have provided detailed measures of it. This paper presents a new method to calculate minimal shoe clearance during stair descent and compares it to previous literature. Seventeen healthy young subjects descended a five step staircase with step treads of 300 mm and step heights of 188 mm. Kinematic data were collected with an Optotrak system (model 3020) and three non-colinear infrared markers on the feet. Ninety points were digitized on the foot sole prior to data collection using a 6 marker probe and related to the triad of markers on the foot. The foot sole was reconstructed using the Matlab (version 7.0) "meshgrid" function and minimal distance to each step edge was calculated for the heel, toe and foot sole. Results showed significant differences in minimum clearance between sole, heel and toe, with the shoe sole being the closest and the toe the furthest. While the hind foot sole was closest for 69% of the time, the actual minimum clearance point on the sole did vary across subjects and staircase steps. This new method, and the findings on healthy young subjects, can be applied to future studies of other populations and staircase dimensions. Copyright © 2013 Elsevier Ltd. All rights reserved.

The Paravascular Pathway for Brain Waste Clearance: Current Understanding, Significance and Controversy.

PubMed

Bacyinski, Andrew; Xu, Maosheng; Wang, Wei; Hu, Jiani

2017-01-01

The paravascular pathway, also known as the "glymphatic" pathway, is a recently described system for waste clearance in the brain. According to this model, cerebrospinal fluid (CSF) enters the paravascular spaces surrounding penetrating arteries of the brain, mixes with interstitial fluid (ISF) and solutes in the parenchyma, and exits along paravascular spaces of draining veins. Studies have shown that metabolic waste products and solutes, including proteins involved in the pathogenesis of neurodegenerative diseases such as amyloid-beta, may be cleared by this pathway. Consequently, a growing body of research has begun to explore the association between glymphatic dysfunction and various disease states. However, significant controversy exists in the literature regarding both the direction of waste clearance as well as the anatomical space in which the waste-fluid mixture is contained. Some studies have found no evidence of interstitial solute clearance along the paravascular space of veins. Rather, they demonstrate a perivascular pathway in which waste is cleared from the brain along an anatomically distinct perivascular space in a direction opposite to that of paravascular flow. Although possible explanations have been offered, none have been able to fully reconcile the discrepancies in the literature, and many questions remain. Given the therapeutic potential that a comprehensive understanding of brain waste clearance pathways might offer, further research and clarification is highly warranted.

Effect of Short-Term Fasting on Systemic Cytochrome P450-Mediated Drug Metabolism in Healthy Subjects: A Randomized, Controlled, Crossover Study Using a Cocktail Approach.

PubMed

Lammers, Laureen A; Achterbergh, Roos; van Schaik, Ron H N; Romijn, Johannes A; Mathôt, Ron A A

2017-10-01

Short-term fasting can alter drug exposure but it is unknown whether this is an effect of altered oral bioavailability and/or systemic clearance. Therefore, the aim of our study was to assess the effect of short-term fasting on oral bioavailability and systemic clearance of different drugs. In a randomized, controlled, crossover trial, 12 healthy subjects received a single administration of a cytochrome P450 (CYP) probe cocktail, consisting of caffeine (CYP1A2), metoprolol (CYP2D6), midazolam (CYP3A4), omeprazole (CYP2C19) and warfarin (CYP2C9), on four occasions: an oral (1) and intravenous (2) administration after an overnight fast (control) and an oral (3) and intravenous (4) administration after 36 h of fasting. Pharmacokinetic parameters of the probe drugs were analyzed using the nonlinear mixed-effects modeling software NONMEM. Short-term fasting increased systemic caffeine clearance by 17% (p = 0.04) and metoprolol clearance by 13% (p < 0.01), whereas S-warfarin clearance decreased by 19% (p < 0.01). Fasting did not affect bioavailability. The study demonstrates that short-term fasting alters CYP-mediated drug metabolism in a non-uniform pattern without affecting oral bioavailability.

Progress on Shape Memory Alloy Actuator Development for Active Clearance Control

NASA Technical Reports Server (NTRS)

DeCastro, Jonathan; Melcher, Kevin; Noebe, Ronald

2006-01-01

Results of a numerical analysis evaluating the feasibility of high-temperature shape memory alloys (HTSMA) for active clearance control actuation in the high-pressure turbine section of a modern turbofan engine has been conducted. The prototype actuator concept considered here consists of parallel HTSMA wires attached to the shroud that is located on the exterior of the turbine case. A transient model of an HTSMA actuator was used to evaluate active clearance control at various operating points in a test bed aircraft engine simulation. For the engine under consideration, each actuator must be designed to counteract loads from 380 to 2000 lbf and displace at least 0.033 in. Design results show that an actuator comprised of 10 wires 2 in. in length is adequate for control at critical engine operating points and still exhibit acceptable failsafe operability and cycle life. A proportional-integral-derivative (PID) controller with integrator windup protection was implemented to control clearance amidst engine transients during a normal mission. Simulation results show that the control system exhibits minimal variability in clearance control performance across the operating envelope. The final actuator design is sufficiently small to fit within the limited space outside the high-pressure turbine case and is shown to consume only small amounts of bleed air to adequately regulate temperature.

Self-clearance from BVDV infections--a frequent finding in dairy herds in an endemically infected region in Peru.

PubMed

Ståhl, K; Lindberg, A; Rivera, H; Ortiz, C; Moreno-López, J

2008-03-17

In this cross-sectional study, a stratified two-stage random sampling procedure was employed to select 221 dairy herds for bulk tank milk (BTM) sampling, and a subset of 55 dairy herds for individual blood sampling of a number of young animals (spot test), to predict presence or absence of current BVDV infection, and for data collection. The prediction was based on the high probability of seropositivity in groups of animals where PI animals are present because of the efficient spread of virus from PI animals to the surrounding group. BTM samples were collected in August 2003 (n=192) and February 2004 (n=195), and the 55 herds selected for spot testing and data collection were visited in December 2003. All samples were tested for presence of BVDV specific antibodies using a commercial indirect ELISA (SVANOVA Biotech AB, Uppsala, Sweden). The results demonstrated a very high level of exposure to BVDV in the region, and the proportion of herds with high antibody levels in the BTM was above 95% on both occasions. Despite this, almost two thirds of the herds had spot test results indicating absence of current infection, suggesting a high probability of self-clearance. A logistic regression model with the results from the spot tests as dependent variable was used to investigate possible herd and management factors associated with self-clearance, and suggested that this may occur regardless of herd size. Even though it is well established that the process of identification and elimination of PI animals is required within a systematic BVDV eradication programme, the present study strongly suggests that many herds may be cleared without intervention even in regions with high cattle density and high BVDV prevalence. Consequently, in any BVDV infected population (regardless of the herd-level BVDV seroprevalence), and at any given point of time, a large proportion of the herds will be free from infection due to self-clearance. Self-clearance is therefore a process that works in favour of any effort to control BVDV, which should be taken into account when planning and assessing the cost-effectiveness of a systematic control programme.

Mutations in Plasmodium falciparum K13 propeller gene from Bangladesh (2009-2013).

PubMed

Mohon, Abu Naser; Alam, Mohammad Shafiul; Bayih, Abebe Genetu; Folefoc, Asongna; Shahinas, Dea; Haque, Rashidul; Pillai, Dylan R

2014-11-18

Bangladesh is a malaria hypo-endemic country sharing borders with India and Myanmar. Artemisinin combination therapy (ACT) remains successful in Bangladesh. An increase of artemisinin-resistant malaria parasites on the Thai-Cambodia and Thai-Myanmar borders is worrisome. K13 propeller gene (PF3D7_1343700 or PF13_0238) mutations have been linked to both in vitro artemisinin resistance and in vivo slow parasite clearance rates. This group undertook to evaluate if mutations seen in Cambodia have emerged in Bangladesh where ACT use is now standard for a decade. Samples were obtained from Plasmodium falciparum-infected malaria patients from Upazila health complexes (UHC) between 2009 and 2013 in seven endemic districts of Bangladesh. These districts included Khagrachari (Matiranga UHC), Rangamati (Rajasthali UHC), Cox's Bazar (Ramu and Ukhia UHC), Bandarban (Lama UHC), Mymensingh (Haluaghat UHC), Netrokona (Durgapur and Kalmakanda UHC), and Moulvibazar (Sreemangal and Kamalganj UHC). Out of 296 microscopically positive P. falciparum samples, 271 (91.6%) were confirmed as mono-infections by both real-time PCR and nested PCR. The K13 propeller gene from 253 (93.4%) samples was sequenced bi-directionally. One non-synonymous mutation (A578S) was found in Bangladeshi clinical isolates. The A578S mutation was confirmed and lies adjacent to the C580Y mutation, the major mutation causing delayed parasite clearance in Cambodia. Based on computational modeling A578S should have a significant effect on tertiary structure of the protein. The data suggest that P. falciparum in Bangladesh remains free of the C580Y mutation linked to delayed parasite clearance. However, the mutation A578S is present and based on structural analysis could affect K13 gene function. Further in vivo clinical studies are required to validate the effect of this mutation.

Follow-on to a report on the Applicability of the “Gallet equation” to the vegetation clearances of NERC Reliability Standard FAC-003-2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kirkham, Harold

2012-08-31

In earlier work, a study done at the Pacific Northwest National Laboratory examined a NERC proposed standard specifying clearances between vegetation and power lines. The method proposed for calculating the clearances was based on the results of testing for high-voltage line designs. An equation developed to relate the results of testing with rod-plane gaps to proposed tower window sizes was incorporated into the calculations. The equation in question, sometimes called the “Gallet equation,” describes the insulation performance of the atmosphere for air gaps of a few meters. The equation was described in the PNNL study as a good and simple-to-usemore » way to solve a problem made difficult by the nonlinear interactions of the variables. For calculations based on this equation, a certain set of assumptions must be made. In particular, a value for a quantity called the “gap factor” is needed. This is the amount by which the gap to be modeled by the equation is stronger than the reference gap that was used in developing the Gallet equation. That reference gap is the gap between a rod and a plane. This follow-on report examines the effect on flashover probabilities of assuming an incorrect value for the gap factor. In particular, the flashover probability is found that would result from using a value of 1.3 when a gap factor of 1.0 should be applied. It is shown that with these assumptions the probability of a flashover changes from being extremely unlikely (about 1 in 1000 chance) to a virtual certainty (about 97% chance).« less

Evaluation of Eu(II) -based positive contrast enhancement after intravenous, intraperitoneal, and subcutaneous injections.

PubMed

Ekanger, Levi A; Polin, Lisa A; Shen, Yimin; Haacke, E Mark; Allen, Matthew J

2016-07-01

Eu(II) -based contrast agents offer physiologically relevant, metal-based redox sensing that is unachievable with Gd(III) -based contrast agents. To evaluate the in vivo contrast enhancement of Eu(II) as a function of injection type, we performed intravenous, intraperitoneal, and subcutaneous injections in mice. Our data reveal a correlation between reported oxygen content and expected rates of diffusion with the persistence of Eu(II) -based contrast enhancement. Biodistribution studies revealed europium clearance through the liver and kidneys for intravenous and intraperitoneal injections, but no contrast enhancement was observed in organs associated with clearance. These data represent a step toward understanding the behavior of Eu(II) -based complexes in vivo. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

[Quantitative evaluation of fabricating complete denture by computer numerical control in manufacturing dentition and baseplate separately plus adhesive molding].

PubMed

Wang, H; Lv, P J; Wang, Y; Sun, Y C

2016-10-18

To quantitatively evaluate the assembly precision of fabricating complete denture by computer numerical control (CNC) in manufacturing dentition and baseplate separately plus adhesive molding. The 3D surface data of a standard edentulous maxilla plaster cast model and the temporary base-plate were obtained using an Activity 880 3D scanner. The data (data1) of a complete denture were designed using a set of computer aided design (CAD) software developed by the research group of this study. The pins without undercut were designed as 3D shape of the joining area of the dentition and the baseplate by using the software of Imageware 13.2 and Geomagic Studio 2013. Zero in the top and 0.05 mm in the rest surfaces of the retention pins were set for adhesive clearance. Zenotec T1 (5-axis milling machine) was employed to manufacture polymethyl methacrylate (PMMA) dentition and baseplate. Double sides posterior and one anterior "union teeth" were got. The teeth were inserted into the retention pins in the baseplate and cemented with self-curing resin (Huge Dental Material Co., Ltd). The denture was scanned with the 3D scanner to obtain dataset Data4. Data2 and Data3 registration was set in Data4, Data2 and Data3 were united to gain Data 5. The adhesive clearance on the top of the retentional pins was measured, which was originally designed into 0 mm, and the assembly precision of dentition and baseplate obtained. The average clearance measurements between the dentition and the baseplate: left molar teeth (0.44±0.04) mm, max 0.52 mm, min 0.29 mm; right molar teeth (0.52±0.07) mm, max 0.64 mm, min 0.28 mm; anterior teeth (0.60±0.10) mm, max 0.81 mm, min 0.40 mm; total average clearance (0.52±0.10) mm. The adhesive clearance can be controlled to the level of 0.5 mm when the joining part of the artificial teeth and the base was designed into the shape of retentional pins and the artificial dentition divided into 3 parts. We succeeded in using the CAD/ computer aided manufacturing (CAM) technology to fabricate the complete denture. Although the assembly precision of the dentition and the baseplate is not perfect, the results have proved that the technical routes are workable.

Renal hemodynamic effects of the HMG-CoA reductase inhibitors in autosomal dominant polycystic kidney disease

PubMed Central

Zand, Ladan; Torres, Vicente E.; Larson, Timothy S.; King, Bernard F.; Sethi, Sanjeev; Bergstralh, Eric J.; Angioi, Andrea; Fervenza, Fernando C.

2016-01-01

Background To determine the effect of statins on renal hemodynamics in normal volunteers and those with autosomal dominant polycystic kidney disease either with mild or moderate renal dysfunction. Methods Thirty-two study subjects were enrolled in this study: 11 normal volunteers, 11 study subjects with autosomal dominant polycystic kidney disease (ADPKD) and mild kidney disease and 10 study subjects with ADPKD and moderate kidney disease. Subjects in each group received simvastatin 40 mg once daily for a period of 4 weeks. Renal blood flow was measured based on para-amino-hippurate (PAH) clearance and with the use of a magnetic resonance (MR) scanner at the beginning and following 4 weeks of therapy with statins. Results At the end of the study, except for the lipid profile, which was significantly lower in all groups, other laboratory results showed no change. Four weeks of therapy with simvastatin resulted in no change in serum creatinine, 24-h urinary protein, sodium, iothalamate clearance, PAH clearance or renal blood flow as measured by MRI or based on PAH clearance. Conclusions Four weeks of therapy with simvastatin did not change renal blood flow in the study subjects with ADPKD with mild-to-moderate renal dysfunction or in healthy volunteers. Clinical Trial Registration Number NCT02511418. PMID:26614268

Renal ultrafiltration changes induced by focused US.

PubMed

Fischer, Krisztina; McDannold, Nathan J; Zhang, Yongzhi; Kardos, Magdolna; Szabo, Andras; Szabo, Antal; Reusz, Gyorgy S; Jolesz, Ferenc A

2009-12-01

To determine if focused ultrasonography (US) combined with a diagnostic microbubble-based US contrast agent can be used to modulate glomerular ultrafiltration and size selectivity. The experiments were approved by the animal care committee. The left kidney of 17 healthy rabbits was sonicated by using a 260-kHz focused US transducer in the presence of a microbubble-based US contrast agent. The right kidney served as the control. Three acoustic power levels were applied: 0.4 W (six rabbits), 0.9 W (six rabbits), and 1.7 W (five rabbits). Three rabbits were not treated with focused US and served as control animals. The authors evaluated changes in glomerular size selectivity by measuring the clearance rates of 3000- and 70,000-Da fluorescence-neutral dextrans. The creatinine clearance was calculated for estimation of the glomerular filtration rate. The urinary protein-creatinine ratio was monitored during the experiments. The authors assessed tubular function by evaluating the fractional sodium excretion, tubular reabsorption of phosphate, and gamma-glutamyltransferase-creatinine ratio. Whole-kidney histologic analysis was performed. For each measurement, the values obtained before and after sonication were compared by using the paired t test. Significant (P < .05) increases in the relative (ratio of treated kidney value/nontreated kidney value) clearance of small- and large-molecule agents and the urine flow rates that resulted from the focused US treatments were observed. Overall, 1.23-, 1.23-, 1.61-, and 1.47-fold enhancement of creatinine clearance, 3000-Da dextran clearance, 70 000-Da dextran clearance, and urine flow rate, respectively, were observed. Focal tubular hemorrhage and transient functional tubular alterations were observed at only the highest (1.7-W) acoustic power level tested. Glomerular ultrafiltration and size selectivity can be temporarily modified with simultaneous application of US and microbubbles. This method could offer new opportunities for treatment of renal disease.

Research turbine for high-temperature core engine application. 2: Effect of rotor tip clearance on overall performance

NASA Technical Reports Server (NTRS)

Szanca, E. M.; Behning, F. P.; Schum, H. J.

1974-01-01

A 25.4-cm (10-in) tip diameter turbine was tested to determine the effect of rotor radial tip clearance on turbine overall performance. The test turbine was a half-scale model of a 50.8-cm-(20-in.-) diameter research turbine designed for high-temperature core engine application. The test turbine was fabricated with solid vanes and blades with no provision for cooling air and tested at much reduced inlet conditions. The tests were run at design speed over a range of pressure ratios for three different rotor clearances ranging from 2.3 to 6.7 percent of the annular blade passage height. The results obtained are compared to the results obtained with three other turbines of varying amounts of reaction.

Innate immunity and chronic rhinosinusitis: What we have learned from animal models.

PubMed

London, Nyall R; Lane, Andrew P

2016-06-01

Chronic rhinosinusitis (CRS) is a heterogeneous and multifactorial disease characterized by dysregulated inflammation. Abnormalities in innate immune function including sinonasal epithelial cell barrier function, mucociliary clearance, response to pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs), and the contribution of innate immune cells will be highlighted in this review. PubMed literature review. A review of the literature was conducted to determine what we have learned from animal models in relation to innate immunity and chronic rhinosinusitis. Dysregulation of innate immune mechanisms including sinonasal barrier function, mucociliary clearance, PAMPs, and innate immune cells such as eosinophils, mast cells, and innate lymphoid cells may contribute to CRS pathogenesis. Sinonasal inflammation has been studied using mouse, rat, rabbit, pig, and sheep explant or in vivo models. Study using these models has allowed for analysis of experimental therapeutics and furthered our understanding of the aforementioned aspects of the innate immune mechanism as it relates to sinonasal inflammation. These include augmenting mucociliary clearance through activation of the cystic fibrosis transmembrane conductance regulator (CFTR) and study of drug toxicity on ciliary beat frequency. Knockout models of Toll-like receptors (TLR) have demonstrated the critical role these PRRs play in allergic inflammation as loss of TLR2 and TLR4 leads to decreased lower airway inflammation. Mast cell deficient mice are less susceptible to ovalbumin-induced sinonasal inflammation. Animal models have shed light as to the potential contribution of dysregulated innate immunity in chronic sinonasal inflammation.

A polymorphism near IL28B is associated with spontaneous clearance of acute hepatitis C virus and jaundice.

PubMed

Tillmann, Hans L; Thompson, Alex J; Patel, Keyur; Wiese, Manfred; Tenckhoff, Hannelore; Nischalke, Hans D; Lokhnygina, Yuliya; Kullig, Ulrike; Göbel, Uwe; Capka, Emanuela; Wiegand, Johannes; Schiefke, Ingolf; Güthoff, Wolfgang; Grüngreiff, Kurt; König, Ingrid; Spengler, Ulrich; McCarthy, Jeanette; Shianna, Kevin V; Goldstein, David B; McHutchison, John G; Timm, Jörg; Nattermann, Jacob

2010-11-01

A single nucleotide polymorphism (SNP) upstream of the IL28B gene has been associated with response of patients with chronic hepatitis C to therapy with pegylated interferon and ribavirin and also with spontaneous clearance of acute hepatitis C in a heterogeneous population. We analyzed the association between IL28B and the clinical presentation of acute hepatitis C virus (HCV) infection in a homogeneous population. We analyzed the SNP rs12979860 in 190 women from the German anti-D cohort (infected with HCV genotype 1b via contaminated rhesus prophylaxis) and its association with spontaneous clearance. Clinical data were available in 136 women with acute infection who were also evaluated for IL28B genotype. Based on results of a TaqMan polymerase chain reaction assay, the rs12979860 SNP genotypes studied were C/C, C/T, or T/T. Spontaneous clearance was more common in patients with the C/C genotype (43/67; 64%) compared with C/T (22/90; 24%) or T/T (2/33; 6%) (P < .001). Jaundice during acute infection was more common among patients with C/C genotype (32.7%) than non-C/C patients (with C/T or T/T) (16.1%; P = .032). In C/C patients, jaundice during acute infection was not associated with an increased chance of spontaneous clearance (56.3%) compared with those without jaundice (60.6%). In contrast, in non-C/C patients, jaundice was associated with a higher likelihood of spontaneous clearance (42.9%) compared with those without jaundice (13.7%). The SNP rs12979860 upstream of IL28B is associated with spontaneous clearance of HCV. Women with the C/T or T/T genotype who did not develop jaundice had a lower chance of spontaneous clearance of HCV infection. Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

Zolpidem metabolism in vitro: responsible cytochromes, chemical inhibitors, and in vivo correlations.

PubMed

Von Moltke, L L; Greenblatt, D J; Granda, B W; Duan, S X; Grassi, J M; Venkatakrishnan, K; Harmatz, J S; Shader, R I

1999-07-01

To determine the human cytochromes mediating biotransformation of the imidazopyridine hypnotic, zolpidem, and the clinical correlates of the findings. Kinetic properties of zolpidem biotransformation to its three hydroxylated metabolites were studied in vitro using human liver microsomes and heterologously expressed individual human cytochromes. The metabolic product termed M-3 accounted for more than 80% of net intrinsic clearance by liver microsomes in vitro. Microsomes containing human cytochromes CYP1A2, 2C9, 2C19, 2D6, and 3 A4 expressed by cDNA-transfected human lymphoblastoid cells mediated zolpidem metabolism in vitro. The kinetic profile for zolpidem metabolite formation by each individual cytochrome was combined with estimated relative abundances based on immunological quantification, yielding projected contributions to net intrinsic clearance of: 61% for 3 A4, 22% for 2C9, 14% for 1A2, and less than 3% for 2D6 and 2C19. These values were consistent with inhibitory effects of ketoconazole and sulfaphenazole on zolpidem biotransformation by liver microsomes. Ketoconazole had a 50% inhibitory concentration (IC50 ) of 0.61 microm vs formation of the M-3 metabolite of zolpidem in vitro; in a clinical study, ketoconazole coadministration reduced zolpidem oral clearance by approximately 40%, somewhat less than anticipated based on the IC50 value and total plasma ketoconazole levels, but much more than predicted based on unbound plasma ketoconazole levels. The incomplete dependence of zolpidem clearance on CYP3A activity has clinical implications for susceptibility to metabolic inhibition.

Timing of dornase alfa inhalation for cystic fibrosis.

PubMed

Dentice, Ruth; Elkins, Mark

2016-07-26

Inhalation of the enzyme dornase alfa reduces sputum viscosity and improves clinical outcomes of people with cystic fibrosis. This is an update of a previously published Cochrane review. To determine the effect of timing of dornase alfa inhalation on measures of clinical efficacy in people with cystic fibrosis (in relation to airway clearance techniques or time of day). Relevant randomised and quasi-randomised controlled trials were identified from the Cochrane Cystic Fibrosis Trials Register, Physiotherapy Evidence Database (PEDro), and international cystic fibrosis conference proceedings.Date of the most recent search: 25 April 2016. Any trial of dornase alfa in people with cystic fibrosis where timing of inhalation was the randomised element in the study with either: inhalation before compared to after airway clearance techniques; or morning compared to evening inhalation. Both authors independently selected trials, assessed risk of bias and extracted data with disagreements resolved by discussion. Relevant data were extracted and, where possible, meta-analysed. We identified 115 trial reports representing 55 studies, of which five studies (providing data on 122 participants) met our inclusion criteria. All five studies used a cross-over design. Intervention periods ranged from two to eight weeks. Four trials compared dornase alfa inhalation before versus after airway clearance techniques. Inhalation after instead of before airway clearance did not significantly change forced expiratory volume at one second. Similarly, forced vital capacity and quality of life were not significantly affected; forced expiratory flow at 25% was significantly worse with dornase alfa inhalation after airway clearance, mean difference -0.17 litres (95% confidence interval -0.28 to -0.05), based on the pooled data from two small studies in children (seven to 19 years) with well-preserved lung function. All other secondary outcomes were statistically non-significant.In one trial, morning versus evening inhalation had no impact on lung function or symptoms. The current evidence derived from a small number of participants does not indicate that inhalation of dornase alfa after airway clearance techniques is more or less effective than the traditional recommendation to inhale nebulised dornase alfa 30 minutes prior to airway clearance techniques, for most outcomes. For children with well-preserved lung function, inhalation before airway clearance may be more beneficial for small airway function than inhalation after. However, this result relied on a measure with high variability and studies with variable follow up. In the absence of strong evidence to indicate that one timing regimen is better than another, the timing of dornase alpha inhalation can be largely based on pragmatic reasons or individual preference with respect to the time of airway clearance and time of day. Further research is warranted.

Computational strategy for quantifying human pesticide exposure based upon a saliva measurement

DOE Office of Scientific and Technical Information (OSTI.GOV)

Timchalk, Charles; Weber, Thomas J.; Smith, Jordan N.

The National Research Council of the National Academies report, Toxicity Testing in the 21st Century: A Vision and Strategy, highlighted the importance of quantitative exposure data for evaluating human toxicity risk and noted that biomonitoring is a critical tool for quantitatively evaluating exposure from both environmental and occupational settings. Direct measurement of chemical exposures using personal monitoring provides the most accurate estimation of a subject’s true exposure, and non-invasive methods have also been advocated for quantifying the pharmacokinetics and bioavailability of drugs and xenobiotics. In this regard, there is a need to identify chemicals that are readily cleared in salivamore » at concentrations that can be quantified to support the implementation of this approach.. The current manuscript describes the use of computational modeling approaches that are closely coupled to in vivo and in vitro experiments to predict salivary uptake and clearance of xenobiotics. The primary mechanism by which xenobiotics leave the blood and enter saliva is thought to involve paracellular transport, passive transcellular diffusion, or trancellular active transport with the majority of drugs and xenobiotics cleared from plasma into saliva by passive diffusion. The transcellular or paracellular diffusion of unbound chemicals in plasma to saliva has been computational modeled using a combination of compartmental and physiologically based approaches. Of key importance for determining the plasma:saliva partitioning was the utilization of a modified Schmitt algorithm that calculates partitioning based upon the tissue composition, pH, chemical pKa and plasma protein-binding. Sensitivity analysis of key model parameters specifically identified that both protein-binding and pKa (for weak acids and bases) had the most significant impact on the determination of partitioning and that there were clear species dependent differences based upon physiological variance between rats and humans. Ongoing efforts are focused on extending this modeling strategy to an in vitro salivary acinar cell based system that will be utilized to experimentally determine and computationally predict salivary gland uptake and clearance for a broad range of xenobiotics. Hence, it is envisioned that a combination of salivary biomonitoring and computational modeling will enable the non-invasive measurement of both environmental and occupational exposure in human populations using saliva.« less

Computational 3-D Model of the Human Respiratory System

EPA Science Inventory

We are developing a comprehensive, morphologically-realistic computational model of the human respiratory system that can be used to study the inhalation, deposition, and clearance of contaminants, while being adaptable for age, race, gender, and health/disease status. The model ...

Pharmacokinetics and C-Reactive Protein Modelling of Anti-IL-6 Antibody (PF-04236921) in Healthy Volunteers and Patients with Autoimmune Disease.

PubMed

Li, Cheryl; Shoji, Satoshi; Beebe, Jean

2018-05-18

The purpose of this study was to characterize pharmacokinetics (PK) of PF-04236921, a novel anti-IL-6 monoclonal antibody, and its pharmacokinetics/pharmacodynamics (PK/PD) relationship on serum C-Reactive Protein (CRP) in healthy volunteers and patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Crohn's disease (CD) METHODS: Population modelling analyses were conducted using nonlinear mixed effects modelling. Data from 2 phase 1 healthy volunteer studies, a phase 1 RA study, a Phase 2 CD study, and a Phase 2 SLE study were included. A 2-compartment model with first order absorption and linear elimination and a mechanism-based indirect response model adequately described the PK and PK/PD relationships, respectively. Central compartment volume of distribution (Vc) positively correlated with body weight. Clearance (CL) negatively correlated with baseline albumin concentration and positively correlated with baseline CRP and creatinine clearance, and was slightly lower in females. After correcting for covariates, CL in CD subjects was approximately 60% higher than other populations. Maximum inhibition of PF-04236921 on CRP production (I max ) negatively correlated with baseline albumin. I max positively correlated with baseline CRP and the relationship was captured as a covariance structure in the PK/PD model. Integrated population PK and PK/PD models of PF-04236921 have been developed using pooled data from healthy subjects and autoimmune patients. The current model enables simulation of PF-04236921 PK and PD profiles under various dosing regimens and patient populations and should facilitate future clinical study of PF-04236921 and other anti-IL6 monoclonal antibodies. This article is protected by copyright. All rights reserved.

A computational study of astrocytic glutamate influence on post-synaptic neuronal excitability.

PubMed

Flanagan, Bronac; McDaid, Liam; Wade, John; Wong-Lin, KongFatt; Harkin, Jim

2018-04-01

The ability of astrocytes to rapidly clear synaptic glutamate and purposefully release the excitatory transmitter is critical in the functioning of synapses and neuronal circuits. Dysfunctions of these homeostatic functions have been implicated in the pathology of brain disorders such as mesial temporal lobe epilepsy. However, the reasons for these dysfunctions are not clear from experimental data and computational models have been developed to provide further understanding of the implications of glutamate clearance from the extracellular space, as a result of EAAT2 downregulation: although they only partially account for the glutamate clearance process. In this work, we develop an explicit model of the astrocytic glutamate transporters, providing a more complete description of the glutamate chemical potential across the astrocytic membrane and its contribution to glutamate transporter driving force based on thermodynamic principles and experimental data. Analysis of our model demonstrates that increased astrocytic glutamate content due to glutamine synthetase downregulation also results in increased postsynaptic quantal size due to gliotransmission. Moreover, the proposed model demonstrates that increased astrocytic glutamate could prolong the time course of glutamate in the synaptic cleft and enhances astrocyte-induced slow inward currents, causing a disruption to the clarity of synaptic signalling and the occurrence of intervals of higher frequency postsynaptic firing. Overall, our work distilled the necessity of a low astrocytic glutamate concentration for reliable synaptic transmission of information and the possible implications of enhanced glutamate levels as in epilepsy.

Hover and Wind-Tunnel Testing of Shrouded Rotors for Improved Micro Air Vehicle Design

DTIC Science & Technology

2008-01-01

and the shroud surface pressure distributions. The uniformity of the wake was improved by the presence of the shrouds and by decreasing the blade tip...213 3.35 Effect of blade tip clearance on shrouded-rotor exit-plane wake profiles215 3.36 Effects of changing blade tip clearance on induced...Wright [139] developed a vortex wake model for heavily loaded ducted fans, in which the “inner vortex sheets [shed from the blades ] move at a different

Application of time-frequency analysis to the evaluation of the condition of car suspension

NASA Astrophysics Data System (ADS)

Szymański, G. M.; Josko, M.; Tomaszewski, F.; Filipiak, R.

2015-06-01

The article presents possibilities of use of vibration signal parameters for the evaluation of elements' clearance in the car suspension system. The time-spectrum analysis has been proposed to determine the frequency band connected with car body free vibration generated by impacts of suspension elements in case of clearance in suspension elements fixing to the car body. Diagnostic models allowing evaluation of shock absorber fastening to the car body are described in this work.

LRP1 in brain vascular smooth muscle cells mediates local clearance of Alzheimer's amyloid-β.

PubMed

Kanekiyo, Takahisa; Liu, Chia-Chen; Shinohara, Mitsuru; Li, Jie; Bu, Guojun

2012-11-14

Impaired clearance of amyloid-β (Aβ) is a major pathogenic event for Alzheimer's disease (AD). Aβ depositions in brain parenchyma as senile plaques and along cerebrovasculature as cerebral amyloid angiopathy (CAA) are hallmarks of AD. A major pathway that mediates brain Aβ clearance is the cerebrovascular system where Aβ is eliminated through the blood-brain barrier (BBB) and/or degraded by cerebrovascular cells along the interstitial fluid drainage pathway. An Aβ clearance receptor, the low-density lipoprotein receptor-related protein 1 (LRP1), is abundantly expressed in cerebrovasculature, in particular in vascular smooth muscle cells. Previous studies have indicated a role of LRP1 in endothelial cells in transcytosing Aβ out of the brain across the BBB; however, whether this represents a significant pathway for brain Aβ clearance remains controversial. Here, we demonstrate that Aβ can be cleared locally in the cerebrovasculature by an LRP1-dependent endocytic pathway in smooth muscle cells. The uptake and degradation of both endogenous and exogenous Aβ were significantly reduced in LRP1-suppressed human brain vascular smooth muscle cells. Conditional deletion of Lrp1 in vascular smooth muscle cell in amyloid model APP/PS1 mice accelerated brain Aβ accumulation and exacerbated Aβ deposition as amyloid plaques and CAA without affecting Aβ production. Our results demonstrate that LRP1 is a major Aβ clearance receptor in cerebral vascular smooth muscle cell and a disturbance of this pathway contributes to Aβ accumulation. These studies establish critical functions of the cerebrovasculature system in Aβ metabolism and identify a new pathway involved in the pathogenesis of both AD and CAA.

Deposition and clearance of 2 μ particles in the tracheobronchial tree of normal subjects—smokers and nonsmokers

PubMed Central

Lourenço, Ruy V.; Klimek, Mary F.; Borowski, Claudia J.

1971-01-01

Deposition and clearance of inhaled particles of iron oxide labeled with 198Au were studied in 19 normal subjects (10 nonsmokers and 9 smokers). For this purpose, monodisperse aerosols of particles with a 2 μ diameter were produced in a spinning disc atomizer. Thoracic counts and images with a scintillation camera were begun immediately after inhalation of the aerosol and continued for 6 hr. In all subjects, smokers and nonsmokers, the deposition of the particles was uniform throughout both lung fields, with approximately half of the particles deposited in the ciliated airways (tracheobronchial deposition) and half in the nonciliated airways (alveolar deposition). Tracheobronchial clearance in nonsmokers occurred immediately after inhalation, first at a fast rate for particles deposited in the largest and most central airways, and then at a slower rate for particles from the smaller and more peripheral airways. Photoscintigrams showed that the particles cleared steadily with no retention in any area. The general pattern of clearance may be likened to a model of multiple conveyor belts with speed increasing from the peripheral to the central airways in such a way as to prevent “particle jams” at airway confluence points. In smokers, tracheobronchial clearance was delayed for periods of 1-4 hr after inhalation. Furthermore, in contrast with the findings in nonsmokers, significant clearance was still occurring in many of the smokers in the 5th and 6th hr after inhalation. Also, photoscintigrams showed an abnormal accumulation of particles in the large airways several hours after inhalation of the aerosol. Images PMID:5090057

Hepatic Scavenger Receptor BI Protects Against Polymicrobial-induced Sepsis through Promoting LPS Clearance in Mice*

PubMed Central

Guo, Ling; Zheng, Zhong; Ai, Junting; Huang, Bin; Li, Xiang-An

2014-01-01

Recent studies revealed that scavenger receptor BI (SR-BI or Scarb1) plays a critical protective role in sepsis. However, the mechanisms underlying this protection remain largely unknown. In this study, using Scarb1I179N mice, a mouse model specifically deficient in hepatic SR-BI, we report that hepatic SR-BI protects against cecal ligation and puncture (CLP)-induced sepsis as shown by 75% fatality in Scarb1I179N mice, but only 21% fatality in C57BL/6J control mice. The increase in fatality in Scarb1I179N mice was associated with an exacerbated inflammatory cytokine production. Further study demonstrated that hepatic SR-BI exerts its protection against sepsis through its role in promoting LPS clearance without affecting the inflammatory response in macrophages, the glucocorticoid production in adrenal glands, the leukocyte recruitment to peritoneum or the bacterial clearance in liver. Our findings reveal hepatic SR-BI as a critical protective factor in sepsis and point out that promoting hepatic SR-BI-mediated LPS clearance may provide a therapeutic approach for sepsis. PMID:24719333

An on-line calibration technique for improved blade by blade tip clearance measurement

NASA Astrophysics Data System (ADS)

Sheard, A. G.; Westerman, G. C.; Killeen, B.

A description of a capacitance-based tip clearance measurement system which integrates a novel technique for calibrating the capacitance probe in situ is presented. The on-line calibration system allows the capacitance probe to be calibrated immediately prior to use, providing substantial operational advantages and maximizing measurement accuracy. The possible error sources when it is used in service are considered, and laboratory studies of performance to ascertain their magnitude are discussed. The 1.2-mm diameter FM capacitance probe is demonstrated to be insensitive to variations in blade tip thickness from 1.25 to 1.45 mm. Over typical compressor blading the probe's range was four times the variation in blade to blade clearance encountered in engine run components.

Adapting viral safety assurance strategies to continuous processing of biological products.

PubMed

Johnson, Sarah A; Brown, Matthew R; Lute, Scott C; Brorson, Kurt A

2017-01-01

There has been a recent drive in commercial large-scale production of biotechnology products to convert current batch mode processing to continuous processing manufacturing. There have been reports of model systems capable of adapting and linking upstream and downstream technologies into a continuous manufacturing pipeline. However, in many of these proposed continuous processing model systems, viral safety has not been comprehensively addressed. Viral safety and detection is a highly important and often expensive regulatory requirement for any new biological product. To ensure success in the adaption of continuous processing to large-scale production, there is a need to consider the development of approaches that allow for seamless incorporation of viral testing and clearance/inactivation methods. In this review, we outline potential strategies to apply current viral testing and clearance/inactivation technologies to continuous processing, as well as modifications of existing unit operations to ensure the successful integration of viral clearance into the continuous processing of biological products. Biotechnol. Bioeng. 2017;114: 21-32. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Correlates of diuretic renography in experimental hydronephrosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kekomaeki, M.R.; Rikalainen, H.; Ruotsalainen, P.

1989-02-01

We studied the correlations between diuretic renographs and kidney function in experimental hydronephrosis in rabbits. Features of furosemide-stimulated /sup 99m/Tc-diethylenetriamine-pentaacetic acid renographs were compared to the growth rate, thirst test and endogenous creatinine clearance rate in a chronic solitary-kidney animal model. Intravenous pyelograms, done four weeks after laparotomy, left nephrectomy, bladder resection and constriction of the right pyeloureteric junction, showed signs of obstruction in all the 12 animals of the experimental group. An absent tracer washout after intravenous furosemide, found in five animals, was associated with retarded growth, isosthenuria and an abnormal creatinine clearance. In all of the other sevenmore » animals, a distinct tracer washout after intravenous furosemide was accompanied with a normal growth rate and creatinine clearance. However, no one of these seven animals had a normal ability to retain water and concentrate urine in the thirst test. We conclude that, in this experimental model, a furosemide-induced tracer washout from the kidney pelvis cannot be taken as a proof of the absence of any upper urinary tract obstruction.« less

Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB.

PubMed

Polito, Vinicia A; Li, Hongmei; Martini-Stoica, Heidi; Wang, Baiping; Yang, Li; Xu, Yin; Swartzlander, Daniel B; Palmieri, Michela; di Ronza, Alberto; Lee, Virginia M-Y; Sardiello, Marco; Ballabio, Andrea; Zheng, Hui

2014-09-01

Accumulating evidence implicates impairment of the autophagy-lysosome pathway in Alzheimer's disease (AD). Recently discovered, transcription factor EB (TFEB) is a molecule shown to play central roles in cellular degradative processes. Here we investigate the role of TFEB in AD mouse models. In this study, we demonstrate that TFEB effectively reduces neurofibrillary tangle pathology and rescues behavioral and synaptic deficits and neurodegeneration in the rTg4510 mouse model of tauopathy with no detectable adverse effects when expressed in wild-type mice. TFEB specifically targets hyperphosphorylated and misfolded Tau species present in both soluble and aggregated fractions while leaving normal Tau intact. We provide in vitro evidence that this effect requires lysosomal activity and we identify phosphatase and tensin homolog (PTEN) as a direct target of TFEB that is required for TFEB-dependent aberrant Tau clearance. The specificity and efficacy of TFEB in mediating the clearance of toxic Tau species makes it an attractive therapeutic target for treating diseases of tauopathy including AD. © 2014 The Authors. Published under the terms of the CC BY 4.0 license.

A Knowledge-based System for Estimating Incident Clearance Duration for Maryland : I-95 a Case Study for the Project of MD-17-SHA/UM/4-19 : “Development of a Traffic Management Decision Support Tool for Freeway Incident Traffic Management (FITM) Plan Deployment”

DOT National Transportation Integrated Search

2017-12-01

For the incident response operations to be appreciated by the general public, it is essential that responsible highway agencies be capable of providing the estimated clearance duration of a detected incident at the level sufficiently reliable for mot...

Population Pharmacokinetic Modeling of Olmesartan, the Active Metabolite of Olmesartan Medoxomil, in Patients with Hypertension.

PubMed

Kodati, Devender; Kotakonda, Harish Kaushik; Yellu, Narsimhareddy

2017-08-01

Olmesartan medoxomil is an orally given angiotensin II receptor antagonist indicated for the treatment of hypertension. The aim of the study was to establish a population pharmacokinetic model for olmesartan, the active metabolite of olmesartan medoxomil, in Indian hypertensive patients, and to evaluate effects of covariates on the volume of distribution (V/F) and oral clearance (CL/F) of olmesartan. The population pharmacokinetic model for olmesartan was developed using Phoenix NLME 1.3 with a non-linear mixed-effect model. Bootstrap and visual predictive check were used simultaneously to validate the final population pharmacokinetic models. The covariates included age, sex, body surface area (BSA), bodyweight, height, creatinine clearance (CL CR ) as an index of renal function and liver parameters as indices of hepatic function. A total of 205 olmesartan plasma sample concentrations from 69 patients with hypertension were collected in this study. The pharmacokinetic data of olmesartan was well described by a two-compartment linear pharmacokinetic model with first-order absorption and an absorption lag-time. The mean values of CL/F and V/F of olmesartan in the patients were 0.31565 L/h and 44.5162 L, respectively. Analysis of covariates showed that age and CL CR were factors influencing the clearance of olmesartan and the volume of distribution of olmesartan was dependent on age and BSA. The final population pharmacokinetic model was demonstrated to be appropriate and effective and it can be used to assess the pharmacokinetic parameters of olmesartan in Indian patients with hypertension.

Pharmacokinetic modeling: Prediction and evaluation of route dependent dosimetry of bisphenol A in monkeys with extrapolation to humans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fisher, Jeffrey W., E-mail: jeffrey.fisher@fda.hhs.gov; Twaddle, Nathan C.; Vanlandingham, Michelle

A physiologically based pharmacokinetic (PBPK) model was developed for bisphenol A (BPA) in adult rhesus monkeys using intravenous (iv) and oral bolus doses of 100 {mu}g d6-BPA/kg (). This calibrated PBPK adult monkey model for BPA was then evaluated against published monkey kinetic studies with BPA. Using two versions of the adult monkey model based on monkey BPA kinetic data from and , the aglycone BPA pharmacokinetics were simulated for human oral ingestion of 5 mg d16-BPA per person (Voelkel et al., 2002). Voelkel et al. were unable to detect the aglycone BPA in plasma, but were able to detectmore » BPA metabolites. These human model predictions of the aglycone BPA in plasma were then compared to previously published PBPK model predictions obtained by simulating the Voelkel et al. kinetic study. Our BPA human model, using two parameter sets reflecting two adult monkey studies, both predicted lower aglycone levels in human serum than the previous human BPA PBPK model predictions. BPA was metabolized at all ages of monkey (PND 5 to adult) by the gut wall and liver. However, the hepatic metabolism of BPA and systemic clearance of its phase II metabolites appear to be slower in younger monkeys than adults. The use of the current non-human primate BPA model parameters provides more confidence in predicting the aglycone BPA in serum levels in humans after oral ingestion of BPA. -- Highlights: Black-Right-Pointing-Pointer A bisphenol A (BPA) PBPK model for the infant and adult monkey was constructed. Black-Right-Pointing-Pointer The hepatic metabolic rate of BPA increased with age of the monkey. Black-Right-Pointing-Pointer The systemic clearance rate of metabolites increased with age of the monkey. Black-Right-Pointing-Pointer Gut wall metabolism of orally administered BPA was substantial across all ages of monkeys. Black-Right-Pointing-Pointer Aglycone BPA plasma concentrations were predicted in humans orally given oral doses of deuterated BPA.« less

Determination of glomerular function in advanced renal failure.

PubMed Central

Manz, F; Alatas, H; Kochen, W; Lutz, P; Rebien, W; Schärer, K

1977-01-01

In 15 children with advanced chronic renal failure, glomerular filtration rate was determined by different methods. Inulin clearance correlated well with the mean of creatinine and urea clearance, and also with 51-chromium edetic acid (EDTA) clearance measured over 24 hours. The absolute values of creatinine clearance and of 51Cr-EDTA clearance measured up to 8 hours were higher than inulin clearance. In advanced renal failure both the 51Cr-EDTA clearance measured over 24 hours, and the mean of creatinine and urea clearance, provide acceptable estimates of true glomerular filtration rate. PMID:411426

Plasmodium falciparum clearance in clinical studies of artesunate-amodiaquine and comparator treatments in sub-Saharan Africa, 1999–2009

PubMed Central

2014-01-01

Background Artemisinin-based combination therapy (ACT) is the recommended first-line therapy for uncomplicated Plasmodium falciparum malaria worldwide but decreased artemisinin susceptibility, phenotypically characterized as slow parasite clearance time (PCT), has now been reported in Southeast Asia. This makes it all too important to measure the dynamics of parasite clearance in African patients treated with ACT over time, to understand trends and detect changes early enough to intervene Methods Individual patient data from 27 clinical trials of artesunate-amodiaquine (ASAQ) vs comparators conducted between 1999 and 2009 were analysed for parasite clearance on modified intent-to-treat (ITT) basis. Results Overall 15,017 patients treated for uncomplicated P. falciparum malaria at 44 sites in 20 sub-Saharan African countries were included in the analysis; 51% (n=7,660) vs 49% (n=7,357) were treated with ASAQ and comparator treatments, respectively. Seventy-seven per cent (77%) were children under six years of age. The proportion of the patients treated with ASAQ with persistent parasitaemia on Day 2 was 8.6%, and 1.5% on Day 3. Risk factor for not clearing parasites on Day 2 and Day 3 calculated by multivariate logistic regression with random effect on site and controlling for treatment were: high parasitaemia before treatment was (adjusted risk ratios (AOR) 2.12, 95% CI 1.91-2.35, AOR 2.43, 95% CI 1.98-3.00, respectively); non-ACT treatment (p=0.001, for all comparisons). Anaemia (p=0.001) was an additional factor for Day 2 and young age (p=0.005) for Day 3. In patients treated with ASAQ in studies who had complete parasitaemia data every 24 hours up to Day 3 and additionally Day 7, the parasite reduction ratio was 93.9% by Day 1 and 99.9% by Day 2. Using the median parasitaemia before treatment (p0=27,125 μL) and a fitted model, the predicted PCT (pPCT = 3.614*ln (p0) – 6.135, r² = 0.94) in ASAQ recipients was 31 hours. Conclusion Within the period covered by these studies, rapid Plasmodium falciparum clearance continues to be achieved in Sub-Saharan African patients treated with ACT, and in particular with ASAQ. The prediction formula for parasite clearance time could be a pragmatic tool for studies with binary outcomes and once-daily sampling, both for research and monitoring purposes. PMID:24666562

Application of Quantitative Pharmacology Approaches in Bridging Pharmacokinetics and Pharmacodynamics of Domagrozumab From Adult Healthy Subjects to Pediatric Patients With Duchenne Muscular Disease.

PubMed

Bhattacharya, Indranil; Manukyan, Zorayr; Chan, Phylinda; Heatherington, Anne; Harnisch, Lutz

2017-10-12

Domagrozumab, a monoclonal antibody that binds to myostatin, is being developed for Duchenne muscular dystrophy (DMD) boys following a first-in-human study in healthy adults. Literature reporting pharmacokinetic parameters of monoclonal antibodies suggested that body-weight- and body-surface-area-adjusted clearance and volume of distribution estimates between adults and children are similar for subjects older than 6 years. Population modeling identified a Michaelis-Menten binding kinetics model to optimally characterize the target mediated drug disposition profile of domagrozumab and identified body mass index on the volume of distribution as the only significant covariate. Model parameters were predicted with high-precision pharmacokinetics (clearance 1.01 × 10 -4 L/[h·kg]; central volume of distribution 457 × 10 -4 L/kg; maximum elimination rate 17.5 × 10 -4 nmol/[h·kg], Km 10.6 nmol/L) and pharmacodynamics (myostatin turnover rate 457 × 10 -4 h -1 ; complex removal rate 90 × 10 -4 h -1 ; half-saturation constant 4.32 nmol/L) and were used to predict target coverage for dosage selection in the DMD population. Additionally, allometric approaches (estimated scaling exponents (standard error) for clearance and volume were 0.81 [0.01] and 0.98 [0.02], respectively) in conjunction with a separate analysis to obtain the population mean weight and standard deviation suggested that if dosed per body weight, an only 11% difference in clearance is expected between the heaviest and lightest patient, thus preventing the need for dose adjustment. In summary, quantitative approaches were instrumental in bridging and derisking the fast-track development of domagrozumab in DMD. © 2017, The American College of Clinical Pharmacology.

Effects of copper nanoparticle exposure on host defense in a murine pulmonary infection model

PubMed Central

2011-01-01

Background Human exposure to nanoparticles (NPs) and environmental bacteria can occur simultaneously. NPs induce inflammatory responses and oxidative stress but may also have immune-suppressive effects, impairing macrophage function and altering epithelial barrier functions. The purpose of this study was to assess the potential pulmonary effects of inhalation and instillation exposure to copper (Cu) NPs using a model of lung inflammation and host defense. Methods We used Klebsiella pneumoniae (K.p.) in a murine lung infection model to determine if pulmonary bacterial clearance is enhanced or impaired by Cu NP exposure. Two different exposure modes were tested: sub-acute inhalation (4 hr/day, 5 d/week for 2 weeks, 3.5 mg/m3) and intratracheal instillation (24 hr post-exposure, 3, 35, and 100 μg/mouse). Pulmonary responses were evaluated by lung histopathology plus measurement of differential cell counts, total protein, lactate dehydrogenase (LDH) activity, and inflammatory cytokines in bronchoalveolar lavage (BAL) fluid. Results Cu NP exposure induced inflammatory responses with increased recruitment of total cells and neutrophils to the lungs as well as increased total protein and LDH activity in BAL fluid. Both inhalation and instillation exposure to Cu NPs significantly decreased the pulmonary clearance of K.p.-exposed mice measured 24 hr after bacterial infection following Cu NP exposure versus sham-exposed mice also challenged with K.p (1.4 × 105 bacteria/mouse). Conclusions Cu NP exposure impaired host defense against bacterial lung infections and induced a dose-dependent decrease in bacterial clearance in which even our lowest dose demonstrated significantly lower clearance than observed in sham-exposed mice. Thus, exposure to Cu NPs may increase the risk of pulmonary infection. PMID:21943386

Effect of clenbuterol on tracheal mucociliary transport in horses undergoing simulated long-distance transportation.

PubMed

Norton, J L; Jackson, K; Chen, J W; Boston, R; Nolen-Walston, R D

2013-01-01

Pneumonia is observed in horses after long-distance transportation in association with confinement of head position leading to reduction in tracheal mucociliary clearance rate (TMCR). Clenbuterol, a beta-2 agonist shown to increase TMCR in the horse, will ameliorate the effects of a fixed elevated head position on large airway contamination and inflammation in a model of long-distance transportation model. Six adult horses. A cross-over designed prospective study. Horses were maintained with a fixed elevated head position for 48 hours to simulate long-distance transport, and treated with clenbuterol (0.8 μg/kg PO q12h) or a placebo starting 12 hours before simulated transportation. TMCR was measured using a charcoal clearance technique. Data were collected at baseline and 48 hours, and included TMCR, tracheal wash cytology and quantitative culture, rectal temperature, CBC, fibrinogen, and serum TNFα, IL-10, and IL-2 levels. There was a 18-21 day washout between study arms, and data were analyzed using regression analysis and Wilcoxon rank-sum tests. Tracheal mucociliary clearance rate was significantly decreased after transportation in both treatment (P = .002) and placebo (P = .03) groups. There was a significant effect of treatment on TMCR, with the treatment group showing half the reduction in TMCR compared with the placebo group (P = .002). Other significant differences between before- and after-transportation samples occurred for serum fibrinogen, peripheral eosinophil count, quantitative culture, tracheal bacteria, and degenerate neutrophils, though no treatment effect was found. Treatment with clenbuterol modestly attenuates the deleterious effects of this long-distance transportation model on tracheal mucociliary clearance. Copyright © 2013 by the American College of Veterinary Internal Medicine.

Differential T cell response against BK virus regulatory and structural antigens: A viral dynamics modelling approach.

PubMed

Blazquez-Navarro, Arturo; Schachtner, Thomas; Stervbo, Ulrik; Sefrin, Anett; Stein, Maik; Westhoff, Timm H; Reinke, Petra; Klipp, Edda; Babel, Nina; Neumann, Avidan U; Or-Guil, Michal

2018-05-01

BK virus (BKV) associated nephropathy affects 1-10% of kidney transplant recipients, leading to graft failure in about 50% of cases. Immune responses against different BKV antigens have been shown to have a prognostic value for disease development. Data currently suggest that the structural antigens and regulatory antigens of BKV might each trigger a different mode of action of the immune response. To study the influence of different modes of action of the cellular immune response on BKV clearance dynamics, we have analysed the kinetics of BKV plasma load and anti-BKV T cell response (Elispot) in six patients with BKV associated nephropathy using ODE modelling. The results show that only a small number of hypotheses on the mode of action are compatible with the empirical data. The hypothesis with the highest empirical support is that structural antigens trigger blocking of virus production from infected cells, whereas regulatory antigens trigger an acceleration of death of infected cells. These differential modes of action could be important for our understanding of BKV resolution, as according to the hypothesis, only regulatory antigens would trigger a fast and continuous clearance of the viral load. Other hypotheses showed a lower degree of empirical support, but could potentially explain the clearing mechanisms of individual patients. Our results highlight the heterogeneity of the dynamics, including the delay between immune response against structural versus regulatory antigens, and its relevance for BKV clearance. Our modelling approach is the first that studies the process of BKV clearance by bringing together viral and immune kinetics and can provide a framework for personalised hypotheses generation on the interrelations between cellular immunity and viral dynamics.

Dexmedetomidine Pharmacology in Neonates and Infants After Open Heart Surgery.

PubMed

Su, Felice; Gastonguay, Marc R; Nicolson, Susan C; DiLiberto, MaryAnn; Ocampo-Pelland, Alanna; Zuppa, Athena F

2016-05-01

Dexmedetomidine is a highly selective α2-agonist with hypnotic, analgesic, and anxiolytic properties. Despite off-label administration, dexmedetomidine has found a niche in critically ill neonates and infants with congenital heart disease because of its minimal effects on respiratory function at sedative doses, facilitating early extubation and fast-track postoperative care. There are little pharmacokinetic data regarding newborns who have immature drug metabolizing capacity and who are at risk for reduced dexmedetomidine clearance and drug toxicity. The aim of this study was to determine the pharmacokinetics of dexmedetomidine in neonates and infants after open heart surgery. This study included 23 evaluable neonates (age, 1 day-1 month) and 36 evaluable infants (age, 1 month-24 months) after open heart surgery. Full-term neonates and infants requiring mechanical ventilation after open heart surgery received dexmedetomidine in a dose-escalation study. Dexmedetomidine was administered as a loading dose over 10 minutes followed by a continuous IV infusion up to 24 hours. Cohorts of 12 infants were enrolled sequentially to receive 0.35, 0.7, or 1 μg/kg dexmedetomidine followed by 0.25, 0.5, or 0.75 μg/kg/h dexmedetomidine, respectively. Cohorts of 9 neonates received 0.25, 0.35, or 0.5 μg/kg dexmedetomidine followed by 0.2, 0.3, or 0.4 μg/kg/h dexmedetomidine, respectively. Plasma dexmedetomidine concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry assay. A population nonlinear mixed effects modeling approach was used to characterize dexmedetomidine pharmacokinetics. Pharmacokinetic parameters of dexmedetomidine were estimated using a 2-compartment disposition model with weight allometrically scaled as a covariate on drug clearance, intercompartmental clearance, central and peripheral volume of distributions and age, total bypass time, and intracardiac shunting on clearance. Dexmedetomidine demonstrated a plasma drug clearance of 657 × (weight/70) mL/min, intercompartmental clearance of 6780 × (weight/70) mL/min, central volume of distribution of 88 × (weight/70) L and peripheral volume of distribution of 112 × (weight/70) L for a typical subject with age >1 month with a cardiopulmonary bypass time of 60 minutes and without right-to-left intracardiac shunt. Dexmedetomidine pharmacokinetics may be influenced by age during the neonatal period, weight, total bypass time, and presence of intracardiac shunt. Dexmedetomidine clearance is significantly diminished in full-term newborns and increases rapidly in the first few weeks of life. The dependence of clearance on age during the first few weeks of life reflects the relative immaturity of metabolic processes during the newborn period. Continuous infusions of up to 0.3 μg/kg/h in neonates and 0.75 μg/kg/h in infants were well tolerated after open heart surgery.

Modeling the Role of the Glymphatic Pathway and Cerebral Blood Vessel Properties in Alzheimer’s Disease Pathogenesis

PubMed Central

Kyrtsos, Christina Rose; Baras, John S.

2015-01-01

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly, affecting over 10% population over the age of 65 years. Clinically, AD is described by the symptom set of short term memory loss and cognitive decline, changes in mentation and behavior, and eventually long-term memory deficit as the disease progresses. On imaging studies, significant atrophy with subsequent increase in ventricular volume have been observed. Pathology on post-mortem brain specimens demonstrates the classic findings of increased beta amyloid (Aβ) deposition and the presence of neurofibrillary tangles (NFTs) within affected neurons. Neuroinflammation, dysregulation of blood-brain barrier transport and clearance, deposition of Aβ in cerebral blood vessels, vascular risk factors such as atherosclerosis and diabetes, and the presence of the apolipoprotein E4 allele have all been identified as playing possible roles in AD pathogenesis. Recent research has demonstrated the importance of the glymphatic system in the clearance of Aβ from the brain via the perivascular space surrounding cerebral blood vessels. Given the variety of hypotheses that have been proposed for AD pathogenesis, an interconnected, multilayer model offers a unique opportunity to combine these ideas into a single unifying model. Results of this model demonstrate the importance of vessel stiffness and heart rate in maintaining adequate clearance of Aβ from the brain. PMID:26448331

Creatinine Clearance Is Not Equal to Glomerular Filtration Rate and Cockcroft-Gault Equation Is Not Equal to CKD-EPI Collaboration Equation.

PubMed

Fernandez-Prado, Raul; Castillo-Rodriguez, Esmeralda; Velez-Arribas, Fernando Javier; Gracia-Iguacel, Carolina; Ortiz, Alberto

2016-12-01

Direct oral anticoagulants (DOACs) may require dose reduction or avoidance when glomerular filtration rate is low. However, glomerular filtration rate is not usually measured in routine clinical practice. Rather, equations that incorporate different variables use serum creatinine to estimate either creatinine clearance in mL/min or glomerular filtration rate in mL/min/1.73 m 2 . The Cockcroft-Gault equation estimates creatinine clearance and incorporates weight into the equation. By contrast, the Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations estimate glomerular filtration rate and incorporate ethnicity but not weight. As a result, an individual patient may have very different renal function estimates, depending on the equation used. We now highlight these differences and discuss the impact on routine clinical care for anticoagulation to prevent embolization in atrial fibrillation. Pivotal DOAC clinical trials used creatinine clearance as a criterion for patient enrollment, and dose adjustment and Federal Drug Administration recommendations are based on creatinine clearance. However, clinical biochemistry laboratories provide CKD-EPI glomerular filtration rate estimations, resulting in discrepancies between clinical trial and routine use of the drugs. Copyright © 2016 Elsevier Inc. All rights reserved.

A prototype wireless inertial-sensing device for measuring toe clearance.

PubMed

Lai, Daniel T H; Charry, E; Begg, R; Palaniswami, M

2008-01-01

Tripping and slipping are serious health concerns for the elderly because they result in life threatening injuries i.e., fractures and high medical costs. Our recent work in detection of tripping gait patterns has demonstrated that minimum toe clearance (MTC) is a sensitive falls risk predictor. MTC measurement has previously been done in gait laboratories and on treadmills which potentially imposes controlled walking conditions. In this paper, we describe a prototype design of a wireless device for monitoring vertical toe clearance. The sensors consists of a tri-axis accelerometer and dual-axis gyroscope connected to Crossbow sensor motes for wireless data transmission. Sensor data are transmitted to a laptop and displayed on a Matlab graphic user interface (GUI). We have performed zero base and treadmill experiments to investigate sensor performance to environmental variations and compared the calculated toe clearance against measurements made by an Optotrak motion system. It was found that device outputs were approximately independent of small ambient temperature variations, had a reliable range of 20m indoors and 50m outdoors and a maximum transmission rate of 20 packets/s. Toe clearance measurements were found to follow the Optotrak measurement trend but could be improved further by dealing with double integration errors and improving data transmission rates.

Enhanced model of gear transmission dynamics for condition monitoring applications: Effects of torque, friction and bearing clearance

NASA Astrophysics Data System (ADS)

Fernandez-del-Rincon, A.; Garcia, P.; Diez-Ibarbia, A.; de-Juan, A.; Iglesias, M.; Viadero, F.

2017-02-01

Gear transmissions remain as one of the most complex mechanical systems from the point of view of noise and vibration behavior. Research on gear modeling leading to the obtaining of models capable of accurately reproduce the dynamic behavior of real gear transmissions has spread out the last decades. Most of these models, although useful for design stages, often include simplifications that impede their application for condition monitoring purposes. Trying to filling this gap, the model presented in this paper allows us to simulate gear transmission dynamics including most of these features usually neglected by the state of the art models. This work presents a model capable of considering simultaneously the internal excitations due to the variable meshing stiffness (including the coupling among successive tooth pairs in contact, the non-linearity linked with the contacts between surfaces and the dissipative effects), and those excitations consequence of the bearing variable compliance (including clearances or pre-loads). The model can also simulate gear dynamics in a realistic torque dependent scenario. The proposed model combines a hybrid formulation for calculation of meshing forces with a non-linear variable compliance approach for bearings. Meshing forces are obtained by means of a double approach which combines numerical and analytical aspects. The methodology used provides a detailed description of the meshing forces, allowing their calculation even when gear center distance is modified due to shaft and bearing flexibilities, which are unavoidable in real transmissions. On the other hand, forces at bearing level were obtained considering a variable number of supporting rolling elements, depending on the applied load and clearances. Both formulations have been developed and applied to the simulation of the vibration of a sample transmission, focusing the attention on the transmitted load, friction meshing forces and bearing preloads.