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Sample records for key pharmacokinetic parameters

  1. A Bayesian approach to tracking patients having changing pharmacokinetic parameters

    NASA Technical Reports Server (NTRS)

    Bayard, David S.; Jelliffe, Roger W.

    2004-01-01

    This paper considers the updating of Bayesian posterior densities for pharmacokinetic models associated with patients having changing parameter values. For estimation purposes it is proposed to use the Interacting Multiple Model (IMM) estimation algorithm, which is currently a popular algorithm in the aerospace community for tracking maneuvering targets. The IMM algorithm is described, and compared to the multiple model (MM) and Maximum A-Posteriori (MAP) Bayesian estimation methods, which are presently used for posterior updating when pharmacokinetic parameters do not change. Both the MM and MAP Bayesian estimation methods are used in their sequential forms, to facilitate tracking of changing parameters. Results indicate that the IMM algorithm is well suited for tracking time-varying pharmacokinetic parameters in acutely ill and unstable patients, incurring only about half of the integrated error compared to the sequential MM and MAP methods on the same example.

  2. Experimental design and efficient parameter estimation in preclinical pharmacokinetic studies.

    PubMed

    Ette, E I; Howie, C A; Kelman, A W; Whiting, B

    1995-05-01

    Monte Carlo simulation technique used to evaluate the effect of the arrangement of concentrations on the efficiency of estimation of population pharmacokinetic parameters in the preclinical setting is described. Although the simulations were restricted to the one compartment model with intravenous bolus input, they provide the basis of discussing some structural aspects involved in designing a destructive ("quantic") preclinical population pharmacokinetic study with a fixed sample size as is usually the case in such studies. The efficiency of parameter estimation obtained with sampling strategies based on the three and four time point designs were evaluated in terms of the percent prediction error, design number, individual and joint confidence intervals coverage for parameter estimates approaches, and correlation analysis. The data sets contained random terms for both inter- and residual intra-animal variability. The results showed that the typical population parameter estimates for clearance and volume were efficiently (accurately and precisely) estimated for both designs, while interanimal variability (the only random effect parameter that could be estimated) was inefficiently (inaccurately and imprecisely) estimated with most sampling schedules of the two designs. The exact location of the third and fourth time point for the three and four time point designs, respectively, was not critical to the efficiency of overall estimation of all population parameters of the model. However, some individual population pharmacokinetic parameters were sensitive to the location of these times.

  3. [Diagnostic value of quantitative pharmacokinetic parameters and relative quantitative pharmacokinetic parameters in breast lesions with dynamic contrast-enhanced MRI].

    PubMed

    Sun, T T; Liu, W H; Zhang, Y Q; Li, L H; Wang, R; Ye, Y Y

    2017-08-01

    Objective: To explore the differential between the value of dynamic contrast-enhanced MRI quantitative pharmacokinetic parameters and relative pharmacokinetic quantitative parameters in breast lesions. Methods: Retrospective analysis of 255 patients(262 breast lesions) who was obtained by clinical palpation , ultrasound or full-field digital mammography , and then all lessions were pathologically confirmed in Zhongda Hospital, Southeast University from May 2012 to May 2016. A 3.0 T MRI scanner was used to obtain the quantitative MR pharmacokinetic parameters: volume transfer constant (K(trans)), exchange rate constant (k(ep))and extravascular extracellular volume fraction (V(e)). And measured the quantitative pharmacokinetic parameters of normal glands tissues which on the same side of the same level of the lesions; and then calculated the value of relative pharmacokinetic parameters: rK(rans)、rk(ep) and rV(e).To explore the diagnostic value of two pharmacokinetic parameters in differential diagnosis of benign and malignant breast lesions using receiver operating curves and model of logistic regression. Results: (1)There were significant differences between benign lesions and malignant lesions in K(trans) and k(ep) ( t =15.489, 15.022, respectively, P <0.05), there were no significant differences between benign lesions and malignant lesions in V(e)( t =-2.346, P >0.05). The areas under the ROC curve(AUC)of K(trans), k(ep) and V(e) between malignant and benign lesions were 0.933, 0.948 and 0.387, the sensitivity of K(trans), k(ep) and V(e) were 77.1%, 85.0%, 51.0% , and the specificity of K(trans), k(ep) and V(e) were 96.3%, 93.6%, 60.8% for the differential diagnosis of breast lesions if taken the maximum Youden's index as cut-off. (2)There were significant differences between benign lesions and malignant lesions in rK(trans), rk(ep) and rV(e) ( t =14.177, 11.726, 2.477, respectively, P <0.05). The AUC of rK(trans), rk(ep) and rV(e) between malignant and benign

  4. Influence of Differing Analgesic Formulations of Aspirin on Pharmacokinetic Parameters.

    PubMed

    Kanani, Kunal; Gatoulis, Sergio C; Voelker, Michael

    2015-08-03

    Aspirin has been used therapeutically for over 100 years. As the originator and an important marketer of aspirin-containing products, Bayer's clinical trial database contains numerous reports of the pharmacokinetics of various aspirin formulations. These include evaluations of plain tablets, effervescent tablets, granules, chewable tablets, and fast-release tablets. This publication seeks to expand upon the available pharmacokinetic information concerning aspirin formulations. In the pre-systemic circulation, acetylsalicylic acid (ASA) is rapidly converted into its main active metabolite, salicylic acid (SA). Therefore, both substances are measured in plasma and reported in the results. The 500 mg strength of each formulation was chosen for analysis as this is the most commonly used for analgesia. A total of 22 studies were included in the analysis. All formulations of 500 mg aspirin result in comparable plasma exposure to ASA and SA as evidenced by AUC. Tablets and dry granules provide a consistently lower Cmax compared to effervescent, granules in suspension and fast release tablets. Effervescent tablets, fast release tablets, and granules in suspension provide a consistently lower median Tmax compared to dry granules and tablets for both ASA and SA. This report reinforces the importance of formulation differences and their impact on pharmacokinetic parameters.

  5. Influence of Differing Analgesic Formulations of Aspirin on Pharmacokinetic Parameters

    PubMed Central

    Kanani, Kunal; Gatoulis, Sergio C.; Voelker, Michael

    2015-01-01

    Aspirin has been used therapeutically for over 100 years. As the originator and an important marketer of aspirin-containing products, Bayer’s clinical trial database contains numerous reports of the pharmacokinetics of various aspirin formulations. These include evaluations of plain tablets, effervescent tablets, granules, chewable tablets, and fast-release tablets. This publication seeks to expand upon the available pharmacokinetic information concerning aspirin formulations. In the pre-systemic circulation, acetylsalicylic acid (ASA) is rapidly converted into its main active metabolite, salicylic acid (SA). Therefore, both substances are measured in plasma and reported in the results. The 500 mg strength of each formulation was chosen for analysis as this is the most commonly used for analgesia. A total of 22 studies were included in the analysis. All formulations of 500 mg aspirin result in comparable plasma exposure to ASA and SA as evidenced by AUC. Tablets and dry granules provide a consistently lower Cmax compared to effervescent, granules in suspension and fast release tablets. Effervescent tablets, fast release tablets, and granules in suspension provide a consistently lower median Tmax compared to dry granules and tablets for both ASA and SA. This report reinforces the importance of formulation differences and their impact on pharmacokinetic parameters. PMID:26247959

  6. Partially Turboelectric Aircraft Drive Key Performance Parameters

    NASA Technical Reports Server (NTRS)

    Jansen, Ralph H.; Duffy, Kirsten P.; Brown, Gerald V.

    2017-01-01

    The purpose of this paper is to propose electric drive specific power, electric drive efficiency, and electrical propulsion fraction as the key performance parameters for a partially turboelectric aircraft power system and to investigate their impact on the overall aircraft performance. Breguet range equations for a base conventional turbofan aircraft and a partially turboelectric aircraft are found. The benefits and costs that may result from the partially turboelectric system are enumerated. A break even analysis is conducted to find the minimum allowable electric drive specific power and efficiency, for a given electrical propulsion fraction, that can preserve the range, fuel weight, operating empty weight, and payload weight of the conventional aircraft. Current and future power system performance is compared to the required performance to determine the potential benefit.

  7. The pharmacokinetics of letrozole: association with key body mass metrics.

    PubMed

    Jin, Seok-Joon; Jung, Jin Ah; Cho, Sang-Heon; Kim, Un-Jib; Choe, Sangmin; Ghim, Jong-Lyul; Noh, Yook-Hwan; Park, Hyun-Jung; Kim, Jung-Chul; Jung, Jin-A; Lim, Hyeong-Seok; Bae, Kyun-Seop

    2012-08-01

    To characterize the pharmacokinetics (PK) of letrozole by noncompartmental and mixed effect modeling analysis with the exploration of effect of body compositions on the PK. The PK data of 52 normal healthy male subjects with intensive PK sampling from two separate studies were included in this analysis. Subjects were given a single oral administration of 2.5 mg letrozole (Femara®), an antiestrogenic aromatase inhibitor used to treat breast cancer. Letrozole concentrations were measured using validated high-performance liquid chromatography with tandem mass spectrometry. PK analysis was performed using NONMEM® 7.2 with first-order conditional estimation with interaction method. The association of body composition (body mass index, soft lean mass, fat free mass, body fat mass), CYP2A6 genotype (*1/*1, *1/*4), and CYP3A5 genotype (*1/*1, *1/*3, *3/*3) with the PK of letrozole were tested. A two-compartment model with mixed first and zero order absorption and first order elimination best described the letrozole concentration-time profile. Body weight and body fat mass were significant covariates for central volume of distribution and peripheral volume of distribution (Vp), respectively. In another model built using more readily available body composition measures, body mass index was also a significant covariate of Vp. However, no significant association was shown between CYP2A6 and CYP3A5 genetic polymorphism and the PK of letrozole in this study. Our results indicate that body weight, body fat mass, body mass index are associated with the volume of distribution of letrozole. This study provides an initial step toward the development of individualized letrozole therapy based on body composition.

  8. High Throughput pharmacokinetic modeling using computationally predicted parameter values: dissociation constants (TDS)

    EPA Science Inventory

    Estimates of the ionization association and dissociation constant (pKa) are vital to modeling the pharmacokinetic behavior of chemicals in vivo. Methodologies for the prediction of compound sequestration in specific tissues using partition coefficients require a parameter that ch...

  9. Estimation of pharmacokinetic parameters from non-compartmental variables using Microsoft Excel.

    PubMed

    Dansirikul, Chantaratsamon; Choi, Malcolm; Duffull, Stephen B

    2005-06-01

    This study was conducted to develop a method, termed 'back analysis (BA)', for converting non-compartmental variables to compartment model dependent pharmacokinetic parameters for both one- and two-compartment models. A Microsoft Excel spreadsheet was implemented with the use of Solver and visual basic functions. The performance of the BA method in estimating pharmacokinetic parameter values was evaluated by comparing the parameter values obtained to a standard modelling software program, NONMEM, using simulated data. The results show that the BA method was reasonably precise and provided low bias in estimating fixed and random effect parameters for both one- and two-compartment models. The pharmacokinetic parameters estimated from the BA method were similar to those of NONMEM estimation.

  10. SUITABILITY OF USING IN VITRO AND COMPUTATIONALLY ESTIMATED PARAMETERS IN SIMPLIFIED PHARMACOKINETIC MODELS

    EPA Science Inventory

    A challenge in PBPK model development is estimating the parameters for absorption, distribution, metabolism, and excretion of the parent compound and metabolites of interest. One approach to reduce the number of parameters has been to simplify pharmacokinetic models by lumping p...

  11. Pharmacokinetic parameters explain the therapeutic activity of antimicrobial agents in a silkworm infection model.

    PubMed

    Paudel, Atmika; Panthee, Suresh; Urai, Makoto; Hamamoto, Hiroshi; Ohwada, Tomohiko; Sekimizu, Kazuhisa

    2018-01-25

    Poor pharmacokinetic parameters are a major reason for the lack of therapeutic activity of some drug candidates. Determining the pharmacokinetic parameters of drug candidates at an early stage of development requires an inexpensive animal model with few associated ethical issues. In this study, we used the silkworm infection model to perform structure-activity relationship studies of an antimicrobial agent, GPI0039, a novel nitrofuran dichloro-benzyl ester, and successfully identified compound 5, a nitrothiophene dichloro-benzyl ester, as a potent antimicrobial agent with superior therapeutic activity in the silkworm infection model. Further, we compared the pharmacokinetic parameters of compound 5 with a nitrothiophene benzyl ester lacking chlorine, compound 7, that exerted similar antimicrobial activity but had less therapeutic activity in silkworms, and examined the metabolism of these antimicrobial agents in human liver fractions in vitro. Compound 5 had appropriate pharmacokinetic parameters, such as an adequate half-life, slow clearance, large area under the curve, low volume of distribution, and long mean residence time, compared with compound 7, and was slowly metabolized by human liver fractions. These findings suggest that the therapeutic effectiveness of an antimicrobial agent in the silkworms reflects appropriate pharmacokinetic properties.

  12. Advantage of population pharmacokinetic method for evaluating the bioequivalence and accuracy of parameter estimation of pidotimod.

    PubMed

    Huang, Jihan; Li, Mengying; Lv, Yinghua; Yang, Juan; Xu, Ling; Wang, Jingjing; Chen, Junchao; Wang, Kun; He, Yingchun; Zheng, Qingshan

    2016-09-01

    This study was aimed at exploring the accuracy of population pharmacokinetic method in evaluating the bioequivalence of pidotimod with sparse data profiles and whether this method is suitable for bioequivalence evaluation in special populations such as children with fewer samplings. Methods In this single-dose, two-period crossover study, 20 healthy male Chinese volunteers were randomized 1 : 1 to receive either the test or reference formulation, with a 1-week washout before receiving the alternative formulation. Noncompartmental and population compartmental pharmacokinetic analyses were conducted. Simulated data were analyzed to graphically evaluate the model and the pharmacokinetic characteristics of the two pidotimod formulations. Various sparse sampling scenarios were generated from the real bioequivalence clinical trial data and evaluated by population pharmacokinetic method. The 90% confidence intervals (CIs) for AUC0-12h, AUC0-∞, and Cmax were 97.3 - 118.7%, 96.9 - 118.7%, and 95.1 - 109.8%, respectively, within the 80 - 125% range for bioequivalence using noncompartmental analysis. The population compartmental pharmacokinetics of pidotimod were described using a one-compartment model with first-order absorption and lag time. In the comparison of estimations in different dataset, the estimation of random three- and< fixed four-point sampling strategies can provide results similar to those obtained through rich sampling. The nonlinear mixed-effects model requires fewer data points. Moreover, compared with the noncompartmental analysis method, the pharmacokinetic parameters can be more accurately estimated using nonlinear mixed-effects model. The population pharmacokinetic modeling method was used to assess the bioequivalence of two pidotimod formulations with relatively few sampling points and further validated the bioequivalence of the two formulations. This method may provide useful information for regulating bioequivalence evaluation in special

  13. TC > 0.05 as a Pharmacokinetic Parameter of Paclitaxel for Therapeutic Efficacy and Toxicity in Cancer Patients.

    PubMed

    Xin, D S; Zhou, L; Li, C Z; Zhang, S Q; Huang, H Q; Qiu, G D; Lin, L F; She, Y Q; Zheng, J T; Chen, C; Fang, L; Chen, Zhe-Sheng; Zhang, S Y

    2018-03-05

    Paclitaxel (PTX) has remarkable anti-tumor activity, but it causes severe toxicities. There is an urgent need to seek an appropriate pharmacokinetic parameter of PTX to improve treatment efficacy and reduce adverse effects. To evaluate the association of pharmacokinetic parameter TC>0.05 of paclitaxel (PTX) and its therapeutic efficacy and toxicity in patients with solid tumors. A total of 295 patients with ovarian cancer, esophageal cancer, breast cancer, and non-small cell lung cancer (NSCLC), who were admitted to the Tumor Hospital of Shantou University Medical College, China, were recruited for this study. Patients received 3 weeks of PTX chemotherapy. The plasma concentrations of PTX were examined using the MyPaclitaxelTM kit. The patients' PTX TC>0.05 (the time during which PTX plasma concentration exceed 0.05 μmol/L) were calculated based on pharmacokinetic analysis. The results showed that: (1) the concentrations of PTX in these 295 patients ranged from 0.0358-0.127 μmol/L; (2) the PTX TC> 0.05 ranged from 14 to 38 h with a median time of 27 h; (3) among all treatment cycles, there was a statistically significant difference in the PTX TC>0.05 between CR+PR and SD+PD; (4) with the increasing value of TC>0.05, level of leukopenia and leukopenic fever increased; (5) high PTX TC>0.05 led to the occurrence of neutropenia, neutropenic fever, severe anemia, and severe peripheral neurotoxicity. Taken together, our results indicated that the pharmacokinetic parameter PTX TC>0.05 was an effective measure of treatment efficacy and toxicity in patients with solid tumors. Maintaining PTX TC>0.05 at 26 to 30 h could improve its efficacy and reduce the incidence of leukopenia, neutropenia, anemia, and peripheral neurotoxicity in these patients. PTX TC>0.05 is a key pharmacokinetic parameter of PTX which should be monitored to optimize individual treatment in patients with solid tumors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  14. Effect of co-medication on the pharmacokinetic parameters of phenobarbital in asphyxiated newborns.

    PubMed

    Šíma, M; Pokorná, P; Hronová, K; Slanař, O

    2015-01-01

    Phenobarbital is an anticonvulsive drug widely used in newborns with hypoxic-ischemic encephalopathy. The objective of our study was to describe possible effect of frequently co-administered medications (dopamine, dobutamine, norepinephrine, furosemide, phenytoin, and analgesics) on the phenobarbital pharmacokinetics in full term newborns with hypoxic-ischemic encephalopathy. Phenobarbital pharmacokinetic parameters (standardized intravenous loading dose was 10-20 mg/kg, maintenance dose 2-6 mg/kg/day) were computed using non-compartmental analysis. Co-medication was evaluated throughout the whole treatment period up to 5 days. Volume of distribution, clearance, and half-life median values (95 % CI) for phenobarbital in the whole study population (n=37) were 0.48 (0.41-0.56) l/kg, 0.0034 (0.0028-0.0040) l/h/kg, and 93.7 (88.1-99.2) h, respectively. Phenobarbital pharmacokinetic parameters were not significantly affected by vasoactive drugs (dopamine, dobutamine, and norepinephrine), furosemide, phenytoin, or analgesics. Furthermore, no dose-dependent alteration of phenobarbital pharmacokinetic parameters was noted for vasoactive medication at doses equivalent to cumulative vasoactive-inotropic score (area under the curve in a plot of vasoactive-inotropic score against time) 143.2-8473.6, furosemide at cumulative doses of 0.2-42.9 mg/kg, or phenytoin at cumulative doses of 10.3-46.2 mg/kg. Phenobarbital pharmacokinetics was not affected by investigated co-administered drugs used in newborns with hypoxic-ischemic encephalopathy in real clinical settings.

  15. Uncertainty and Variability in Physiologically-Based Pharmacokinetic (PBPK) Models: Key Issues and Case Studies (Final Report)

    EPA Science Inventory

    EPA announced the availability of the final report, Uncertainty and Variability in Physiologically-Based Pharmacokinetic (PBPK) Models: Key Issues and Case Studies. This report summarizes some of the recent progress in characterizing uncertainty and variability in physi...

  16. An annotated corpus with nanomedicine and pharmacokinetic parameters

    PubMed Central

    Lewinski, Nastassja A; Jimenez, Ivan; McInnes, Bridget T

    2017-01-01

    A vast amount of data on nanomedicines is being generated and published, and natural language processing (NLP) approaches can automate the extraction of unstructured text-based data. Annotated corpora are a key resource for NLP and information extraction methods which employ machine learning. Although corpora are available for pharmaceuticals, resources for nanomedicines and nanotechnology are still limited. To foster nanotechnology text mining (NanoNLP) efforts, we have constructed a corpus of annotated drug product inserts taken from the US Food and Drug Administration’s Drugs@FDA online database. In this work, we present the development of the Engineered Nanomedicine Database corpus to support the evaluation of nanomedicine entity extraction. The data were manually annotated for 21 entity mentions consisting of nanomedicine physicochemical characterization, exposure, and biologic response information of 41 Food and Drug Administration-approved nanomedicines. We evaluate the reliability of the manual annotations and demonstrate the use of the corpus by evaluating two state-of-the-art named entity extraction systems, OpenNLP and Stanford NER. The annotated corpus is available open source and, based on these results, guidelines and suggestions for future development of additional nanomedicine corpora are provided. PMID:29066897

  17. Population Pharmacokinetics of Intravenous Methotrexate in Patients with Hematological Malignancies: Utilization of Routine Clinical Monitoring Parameters.

    PubMed

    Nader, Ahmed; Zahran, Noran; Alshammaa, Aya; Altaweel, Heba; Kassem, Nancy; Wilby, Kyle John

    2017-04-01

    Clinical response to methotrexate in cancer is variable and depends on several factors including serum drug exposure. This study aimed to develop a population pharmacokinetic model describing methotrexate disposition in cancer patients using retrospective chart review data available from routine clinical practice. A retrospective review of medical records was conducted for cancer patients in Qatar. Relevant data (methotrexate dosing/concentrations from multiple occasions, patient history, and laboratory values) were extracted and analyzed using NONMEM VII ® . A population pharmacokinetic model was developed and used to estimate inter-individual and inter-occasion variability terms on methotrexate pharmacokinetic parameters, as well as patient factors affecting methotrexate pharmacokinetics. Methotrexate disposition was described by a two-compartment model with clearance (CL) of 15.7 L/h and central volume of distribution (V c ) of 79.2 L. Patient weight and hematocrit levels were significant covariates on methotrexate V c and CL, respectively. Methotrexate CL changed by 50 % with changes in hematocrit levels from 23 to 50 %. Inter-occasion variability in methotrexate CL was estimated for patients administered the drug on multiple occasions (48 and 31 % for 2nd and 3rd visits, respectively). Therapeutic drug monitoring data collected during routine clinical practice can provide a useful tool for understanding factors affecting methotrexate pharmacokinetics. Patient weight and hematocrit levels may play a clinically important role in determining methotrexate serum exposure and dosing requirements. Future prospective studies are needed to validate results of the developed model and evaluate its usefulness to predict methotrexate exposure and optimize dosing regimens.

  18. Gestation-Specific Changes in the Anatomy and Physiology of Healthy Pregnant Women: An Extended Repository of Model Parameters for Physiologically Based Pharmacokinetic Modeling in Pregnancy.

    PubMed

    Dallmann, André; Ince, Ibrahim; Meyer, Michaela; Willmann, Stefan; Eissing, Thomas; Hempel, Georg

    2017-11-01

    In the past years, several repositories for anatomical and physiological parameters required for physiologically based pharmacokinetic modeling in pregnant women have been published. While providing a good basis, some important aspects can be further detailed. For example, they did not account for the variability associated with parameters or were lacking key parameters necessary for developing more detailed mechanistic pregnancy physiologically based pharmacokinetic models, such as the composition of pregnancy-specific tissues. The aim of this meta-analysis was to provide an updated and extended database of anatomical and physiological parameters in healthy pregnant women that also accounts for changes in the variability of a parameter throughout gestation and for the composition of pregnancy-specific tissues. A systematic literature search was carried out to collect study data on pregnancy-related changes of anatomical and physiological parameters. For each parameter, a set of mathematical functions was fitted to the data and to the standard deviation observed among the data. The best performing functions were selected based on numerical and visual diagnostics as well as based on physiological plausibility. The literature search yielded 473 studies, 302 of which met the criteria to be further analyzed and compiled in a database. In total, the database encompassed 7729 data. Although the availability of quantitative data for some parameters remained limited, mathematical functions could be generated for many important parameters. Gaps were filled based on qualitative knowledge and based on physiologically plausible assumptions. The presented results facilitate the integration of pregnancy-dependent changes in anatomy and physiology into mechanistic population physiologically based pharmacokinetic models. Such models can ultimately provide a valuable tool to investigate the pharmacokinetics during pregnancy in silico and support informed decision making regarding

  19. Direct reconstruction of pharmacokinetic parameters in dynamic fluorescence molecular tomography by the augmented Lagrangian method

    NASA Astrophysics Data System (ADS)

    Zhu, Dianwen; Zhang, Wei; Zhao, Yue; Li, Changqing

    2016-03-01

    Dynamic fluorescence molecular tomography (FMT) has the potential to quantify physiological or biochemical information, known as pharmacokinetic parameters, which are important for cancer detection, drug development and delivery etc. To image those parameters, there are indirect methods, which are easier to implement but tend to provide images with low signal-to-noise ratio, and direct methods, which model all the measurement noises together and are statistically more efficient. The direct reconstruction methods in dynamic FMT have attracted a lot of attention recently. However, the coupling of tomographic image reconstruction and nonlinearity of kinetic parameter estimation due to the compartment modeling has imposed a huge computational burden to the direct reconstruction of the kinetic parameters. In this paper, we propose to take advantage of both the direct and indirect reconstruction ideas through a variable splitting strategy under the augmented Lagrangian framework. Each iteration of the direct reconstruction is split into two steps: the dynamic FMT image reconstruction and the node-wise nonlinear least squares fitting of the pharmacokinetic parameter images. Through numerical simulation studies, we have found that the proposed algorithm can achieve good reconstruction results within a small amount of time. This will be the first step for a combined dynamic PET and FMT imaging in the future.

  20. Turboelectric Aircraft Drive Key Performance Parameters and Functional Requirements

    NASA Technical Reports Server (NTRS)

    Jansen, Ralph H.; Brown, Gerald V.; Felder, James L.; Duffy, Kirsten P.

    2016-01-01

    The purpose of this paper is to propose specific power and efficiency as the key performance parameters for a turboelectric aircraft power system and investigate their impact on the overall aircraft. Key functional requirements are identified that impact the power system design. Breguet range equations for a base aircraft and a turboelectric aircraft are found. The benefits and costs that may result from the turboelectric system are enumerated. A break-even analysis is conducted to find the minimum allowable electric drive specific power and efficiency that can preserve the range, initial weight, operating empty weight, and payload weight of the base aircraft.

  1. Turboelectric Aircraft Drive Key Performance Parameters and Functional Requirements

    NASA Technical Reports Server (NTRS)

    Jansen, Ralph; Brown, Gerald V.; Felder, James L.; Duffy, Kirsten P.

    2015-01-01

    The purpose of this presentation is to propose specific power and efficiency as the key performance parameters for a turboelectric aircraft power system and investigate their impact on the overall aircraft. Key functional requirements are identified that impact the power system design. Breguet range equations for a base aircraft and a turboelectric aircraft are found. The benefits and costs that may result from the turboelectric system are enumerated. A break-even analysis is conducted to find the minimum allowable electric drive specific power and efficiency that can preserve the range, initial weight, operating empty weight, and payload weight of the base aircraft.

  2. Turboelectric Aircraft Drive Key Performance Parameters and Functional Requirements

    NASA Technical Reports Server (NTRS)

    Jansen, Ralph H.; Brown, Gerald V.; Felder, James L.; Duffy, Kirsten P.

    2015-01-01

    The purpose of this paper is to propose specific power and efficiency as the key performance parameters for a turboelectric aircraft power system and investigate their impact on the overall aircraft. Key functional requirements are identified that impact the power system design. Breguet range equations for a base aircraft and a turboelectric aircraft are found. The benefits and costs that may result from the turboelectric system are enumerated. A break-even analysis is conducted to find the minimum allowable electric drive specific power and efficiency that can preserve the range, initial weight, operating empty weight, and payload weight of the base aircraft.

  3. Gaussian process inference for estimating pharmacokinetic parameters of dynamic contrast-enhanced MR images.

    PubMed

    Wang, Shijun; Liu, Peter; Turkbey, Baris; Choyke, Peter; Pinto, Peter; Summers, Ronald M

    2012-01-01

    In this paper, we propose a new pharmacokinetic model for parameter estimation of dynamic contrast-enhanced (DCE) MRI by using Gaussian process inference. Our model is based on the Tofts dual-compartment model for the description of tracer kinetics and the observed time series from DCE-MRI is treated as a Gaussian stochastic process. The parameter estimation is done through a maximum likelihood approach and we propose a variant of the coordinate descent method to solve this likelihood maximization problem. The new model was shown to outperform a baseline method on simulated data. Parametric maps generated on prostate DCE data with the new model also provided better enhancement of tumors, lower intensity on false positives, and better boundary delineation when compared with the baseline method. New statistical parameter maps from the process model were also found to be informative, particularly when paired with the PK parameter maps.

  4. Dynamic Contrast-enhanced MR Imaging in Renal Cell Carcinoma: Reproducibility of Histogram Analysis on Pharmacokinetic Parameters

    PubMed Central

    Wang, Hai-yi; Su, Zi-hua; Xu, Xiao; Sun, Zhi-peng; Duan, Fei-xue; Song, Yuan-yuan; Li, Lu; Wang, Ying-wei; Ma, Xin; Guo, Ai-tao; Ma, Lin; Ye, Hui-yi

    2016-01-01

    Pharmacokinetic parameters derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) have been increasingly used to evaluate the permeability of tumor vessel. Histogram metrics are a recognized promising method of quantitative MR imaging that has been recently introduced in analysis of DCE-MRI pharmacokinetic parameters in oncology due to tumor heterogeneity. In this study, 21 patients with renal cell carcinoma (RCC) underwent paired DCE-MRI studies on a 3.0 T MR system. Extended Tofts model and population-based arterial input function were used to calculate kinetic parameters of RCC tumors. Mean value and histogram metrics (Mode, Skewness and Kurtosis) of each pharmacokinetic parameter were generated automatically using ImageJ software. Intra- and inter-observer reproducibility and scan–rescan reproducibility were evaluated using intra-class correlation coefficients (ICCs) and coefficient of variation (CoV). Our results demonstrated that the histogram method (Mode, Skewness and Kurtosis) was not superior to the conventional Mean value method in reproducibility evaluation on DCE-MRI pharmacokinetic parameters (K trans & Ve) in renal cell carcinoma, especially for Skewness and Kurtosis which showed lower intra-, inter-observer and scan-rescan reproducibility than Mean value. Our findings suggest that additional studies are necessary before wide incorporation of histogram metrics in quantitative analysis of DCE-MRI pharmacokinetic parameters. PMID:27380733

  5. Diagnosis of Spinal Lesions Using Heuristic and Pharmacokinetic Parameters Measured by Dynamic Contrast-Enhanced MRI.

    PubMed

    Lang, Ning; Yuan, Huishu; Yu, Hon J; Su, Min-Ying

    2017-07-01

    This study aimed to evaluate the diagnostic performance of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in differentiation of four spinal lesions by using heuristic and pharmacokinetic parameters analyzed from DCE signal intensity time course. DCE-MRI of 62 subjects with confirmed myeloma (n = 9), metastatic cancer (n = 22), lymphoma (n = 7), and inflammatory tuberculosis (TB) (n = 24) in the spine were analyzed retrospectively. The region of interest was placed on strongly enhanced tissues. The DCE time course was categorized as the "wash-out," "plateau," or "persistent enhancement" pattern. The maximum enhancement, steepest wash-in enhancement, and wash-out slope using the signal intensity at 67 seconds after contrast injection as reference were measured. The Tofts 2-compartmental pharmacokinetic model was applied to obtain K trans and k ep . Pearson correlation between heuristic and pharmacokinetic parameters was evaluated, and receiver operating characteristic curve analysis was performed for pairwise group differentiation. The mean wash-out slope was -22% ± 10% for myeloma, 1% ± 0.4% for metastatic cancer, 3% ± 3% for lymphoma, and 7% ± 10% for TB, and it could significantly distinguish myeloma from metastasis (area under the curve [AUC] = 0.884), lymphoma (AUC = 1.0), and TB (AUC = 1.0) with P = .001, and distinguish metastasis from TB (AUC = 0.741) with P = .005. The k ep and wash-out slope were highly correlated (r = 0.92), and they showed a similar diagnostic performance. The K trans was significantly correlated with the maximum enhancement (r = 0.71) and the steepest wash-in enhancement (r = 0.85), but they had inferior diagnostic performance compared to the wash-out slope. DCE-MRI may provide additional diagnostic information, and a simple wash-out slope had the best diagnostic performance. The heuristic and pharmacokinetic parameters were highly correlated

  6. Relative sensitivities of DCE-MRI pharmacokinetic parameters to arterial input function (AIF) scaling

    NASA Astrophysics Data System (ADS)

    Li, Xin; Cai, Yu; Moloney, Brendan; Chen, Yiyi; Huang, Wei; Woods, Mark; Coakley, Fergus V.; Rooney, William D.; Garzotto, Mark G.; Springer, Charles S.

    2016-08-01

    Dynamic-Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) has been used widely for clinical applications. Pharmacokinetic modeling of DCE-MRI data that extracts quantitative contrast reagent/tissue-specific model parameters is the most investigated method. One of the primary challenges in pharmacokinetic analysis of DCE-MRI data is accurate and reliable measurement of the arterial input function (AIF), which is the driving force behind all pharmacokinetics. Because of effects such as inflow and partial volume averaging, AIF measured from individual arteries sometimes require amplitude scaling for better representation of the blood contrast reagent (CR) concentration time-courses. Empirical approaches like blinded AIF estimation or reference tissue AIF derivation can be useful and practical, especially when there is no clearly visible blood vessel within the imaging field-of-view (FOV). Similarly, these approaches generally also require magnitude scaling of the derived AIF time-courses. Since the AIF varies among individuals even with the same CR injection protocol and the perfect scaling factor for reconstructing the ground truth AIF often remains unknown, variations in estimated pharmacokinetic parameters due to varying AIF scaling factors are of special interest. In this work, using simulated and real prostate cancer DCE-MRI data, we examined parameter variations associated with AIF scaling. Our results show that, for both the fast-exchange-limit (FXL) Tofts model and the water exchange sensitized fast-exchange-regime (FXR) model, the commonly fitted CR transfer constant (Ktrans) and the extravascular, extracellular volume fraction (ve) scale nearly proportionally with the AIF, whereas the FXR-specific unidirectional cellular water efflux rate constant, kio, and the CR intravasation rate constant, kep, are both AIF scaling insensitive. This indicates that, for DCE-MRI of prostate cancer and possibly other cancers, kio and kep may be more suitable imaging

  7. Relative sensitivities of DCE-MRI pharmacokinetic parameters to arterial input function (AIF) scaling.

    PubMed

    Li, Xin; Cai, Yu; Moloney, Brendan; Chen, Yiyi; Huang, Wei; Woods, Mark; Coakley, Fergus V; Rooney, William D; Garzotto, Mark G; Springer, Charles S

    2016-08-01

    Dynamic-Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) has been used widely for clinical applications. Pharmacokinetic modeling of DCE-MRI data that extracts quantitative contrast reagent/tissue-specific model parameters is the most investigated method. One of the primary challenges in pharmacokinetic analysis of DCE-MRI data is accurate and reliable measurement of the arterial input function (AIF), which is the driving force behind all pharmacokinetics. Because of effects such as inflow and partial volume averaging, AIF measured from individual arteries sometimes require amplitude scaling for better representation of the blood contrast reagent (CR) concentration time-courses. Empirical approaches like blinded AIF estimation or reference tissue AIF derivation can be useful and practical, especially when there is no clearly visible blood vessel within the imaging field-of-view (FOV). Similarly, these approaches generally also require magnitude scaling of the derived AIF time-courses. Since the AIF varies among individuals even with the same CR injection protocol and the perfect scaling factor for reconstructing the ground truth AIF often remains unknown, variations in estimated pharmacokinetic parameters due to varying AIF scaling factors are of special interest. In this work, using simulated and real prostate cancer DCE-MRI data, we examined parameter variations associated with AIF scaling. Our results show that, for both the fast-exchange-limit (FXL) Tofts model and the water exchange sensitized fast-exchange-regime (FXR) model, the commonly fitted CR transfer constant (K(trans)) and the extravascular, extracellular volume fraction (ve) scale nearly proportionally with the AIF, whereas the FXR-specific unidirectional cellular water efflux rate constant, kio, and the CR intravasation rate constant, kep, are both AIF scaling insensitive. This indicates that, for DCE-MRI of prostate cancer and possibly other cancers, kio and kep may be more suitable imaging

  8. Evaluation of pharmacokinetic and pharmacodynamic parameters following single dose of sitagliptin in healthy Indian males.

    PubMed

    Sangle, Ganesh V; Patil, Mohan; Deshmukh, Nitin J; Shengule, Sushant A; Kamble, Shantibhushan; Vuppalavanchu, Kiran Kumar; Kale, Sushil; Baig, Mirza Layeeq Ahmed; Singh, Geetchandra; Shaikh, Javed; Tripathi, Jitendra; Aravindababu, P

    2018-05-01

    Sitagliptin, a dipeptidyl peptidase (DPP)-IV inhibitor approved for the treatment of type 2 diabetes, is reported to be more efficacious in Indian patients than non-Indian patient population. The objective of the study was to evaluate pharmacokinetic and pharmacodynamic (PK/PD) parameters of single-dose sitagliptin 100 mg (Januvia) in healthy Indian male participants. In a randomised, single-dose, open-label, three-treatment, three-period, three-sequence, crossover bioavailability study, 18 healthy male participants received single-dose of sitagliptin under fasted and fed conditions. PK parameters (C max , T max , AUC 0-∞ and t 1/2 ) were determined using Phoenix WinNonlin software. PD parameters [DPP-IV inhibition, active glucagon-like peptide-1 (GLP-1) and insulin] were determined using established methods. PK parameters expressed in mean (SD) were C max 491.7 (135.9) ng/mL; AUC 0-∞ 4256.1 (509.9) ng· hr/mL, T max 2.9 (1.0) hr and t 1/2 10.4 (3.0) hr. The weighted average (WA) plasma DPP-4 inhibition over 24 h was 89.6% and WA of plasma active GLP-1 over 2 h after standardised meal (geometric mean ratio) was 11.1 (9.9) pM/L which is two- to- four fold higher compared to that reported in other populations. The mean average (SD) AUC of plasma insulin over 2 h of standardised meal was 47.9 (24.9) μIU/mL. Although, there are differences in pharmacokinetic parameters, no clinically meaningful differences were observed with respect to DPP-IV inhibition between Indian and non-Indian population.

  9. Key parameters controlling the performance of catalytic motors

    SciTech Connect

    Esplandiu, Maria J.; Afshar Farniya, Ali; Reguera, David, E-mail: dreguera@ub.edu

    2016-03-28

    The development of autonomous micro/nanomotors driven by self-generated chemical gradients is a topic of high interest given their potential impact in medicine and environmental remediation. Although impressive functionalities of these devices have been demonstrated, a detailed understanding of the propulsion mechanism is still lacking. In this work, we perform a comprehensive numerical analysis of the key parameters governing the actuation of bimetallic catalytic micropumps. We show that the fluid motion is driven by self-generated electro-osmosis where the electric field originates by a proton current rather than by a lateral charge asymmetry inside the double layer. Hence, the surface potential andmore » the electric field are the key parameters for setting the pumping strength and directionality. The proton flux that generates the electric field stems from the proton gradient induced by the electrochemical reactions taken place at the pump. Surprisingly the electric field and consequently the fluid flow are mainly controlled by the ionic strength and not by the conductivity of the solution, as one could have expected. We have also analyzed the influence of the chemical fuel concentration, electrochemical reaction rates, and size of the metallic structures for an optimized pump performance. Our findings cast light on the complex chemomechanical actuation of catalytic motors and provide important clues for the search, design, and optimization of novel catalytic actuators.« less

  10. Key parameters controlling the performance of catalytic motors.

    PubMed

    Esplandiu, Maria J; Afshar Farniya, Ali; Reguera, David

    2016-03-28

    The development of autonomous micro/nanomotors driven by self-generated chemical gradients is a topic of high interest given their potential impact in medicine and environmental remediation. Although impressive functionalities of these devices have been demonstrated, a detailed understanding of the propulsion mechanism is still lacking. In this work, we perform a comprehensive numerical analysis of the key parameters governing the actuation of bimetallic catalytic micropumps. We show that the fluid motion is driven by self-generated electro-osmosis where the electric field originates by a proton current rather than by a lateral charge asymmetry inside the double layer. Hence, the surface potential and the electric field are the key parameters for setting the pumping strength and directionality. The proton flux that generates the electric field stems from the proton gradient induced by the electrochemical reactions taken place at the pump. Surprisingly the electric field and consequently the fluid flow are mainly controlled by the ionic strength and not by the conductivity of the solution, as one could have expected. We have also analyzed the influence of the chemical fuel concentration, electrochemical reaction rates, and size of the metallic structures for an optimized pump performance. Our findings cast light on the complex chemomechanical actuation of catalytic motors and provide important clues for the search, design, and optimization of novel catalytic actuators.

  11. Obesity and drug pharmacology: a review of the influence of obesity on pharmacokinetic and pharmacodynamic parameters.

    PubMed

    Smit, Cornelis; De Hoogd, Sjoerd; Brüggemann, Roger J M; Knibbe, Catherijne A J

    2018-03-01

    The rising prevalence of obesity confronts clinicians with dosing problems in the (extreme) overweight population. Obesity has a great impact on key organs that play a role in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs, however the ultimate impact of these changes on how to adapt the dose may not always be known. Areas covered: In this review, physiological changes associated with obesity are discussed. An overview is provided on the alterations in absorption, distribution, drug metabolism and clearance in (morbid) obesity focusing on general principles that can be extracted from pharmacokinetic studies. Also, relevant pharmacodynamic considerations in obesity are discussed. Expert opinion: Over the last two decades, increased knowledge is generated on PK and PD in obesity. Future research should focus on filling in the knowledge gaps that remain, especially in connecting obesity-related physiological changes with changes in PK and/or PD and vice versa. Ultimately, this knowledge can be used to develop physiologically based PK and PD models on the basis of quantitative systems pharmacology principles. Moreover, efforts should focus on thorough prospective evaluation of developed model-based doses with subsequent implementation of these dosing recommendations in clinical practice.

  12. Determination of key parameters of vector multifractal vector fields

    NASA Astrophysics Data System (ADS)

    Schertzer, D. J. M.; Tchiguirinskaia, I.

    2017-12-01

    For too long time, multifractal analyses and simulations have been restricted to scalar-valued fields (Schertzer and Tchiguirinskaia, 2017a,b). For instance, the wind velocity multifractality has been mostly analysed in terms of scalar structure functions and with the scalar energy flux. This restriction has had the unfortunate consequences that multifractals were applicable to their full extent in geophysics, whereas it has inspired them. Indeed a key question in geophysics is the complexity of the interactions between various fields or they components. Nevertheless, sophisticated methods have been developed to determine the key parameters of scalar valued fields. In this communication, we first present the vector extensions of the universal multifractal analysis techniques to multifractals whose generator belong to a Levy-Clifford algebra (Schertzer and Tchiguirinskaia, 2015). We point out further extensions noting the increased complexity. For instance, the (scalar) index of multifractality becomes a matrice. Schertzer, D. and Tchiguirinskaia, I. (2015) `Multifractal vector fields and stochastic Clifford algebra', Chaos: An Interdisciplinary Journal of Nonlinear Science, 25(12), p. 123127. doi: 10.1063/1.4937364. Schertzer, D. and Tchiguirinskaia, I. (2017) `An Introduction to Multifractals and Scale Symmetry Groups', in Ghanbarian, B. and Hunt, A. (eds) Fractals: Concepts and Applications in Geosciences. CRC Press, p. (in press). Schertzer, D. and Tchiguirinskaia, I. (2017b) `Pandora Box of Multifractals: Barely Open ?', in Tsonis, A. A. (ed.) 30 Years of Nonlinear Dynamics in Geophysics. Berlin: Springer, p. (in press).

  13. Full-direct method for imaging pharmacokinetic parameters in dynamic fluorescence molecular tomography

    SciTech Connect

    Zhang, Guanglei, E-mail: guangleizhang@bjtu.edu.cn; Department of Biomedical Engineering, School of Computer and Information Technology, Beijing Jiaotong University, Beijing 100044; Pu, Huangsheng

    2015-02-23

    Images of pharmacokinetic parameters (also known as parametric images) in dynamic fluorescence molecular tomography (FMT) can provide three-dimensional metabolic information for biological studies and drug development. However, the ill-posed nature of FMT and the high temporal variation of fluorophore concentration together make it difficult to obtain accurate parametric images in small animals in vivo. In this letter, we present a method to directly reconstruct the parametric images from the boundary measurements based on hybrid FMT/X-ray computed tomography (XCT) system. This method can not only utilize structural priors obtained from the XCT system to mitigate the ill-posedness of FMT but alsomore » make full use of the temporal correlations of boundary measurements to model the high temporal variation of fluorophore concentration. The results of numerical simulation and mouse experiment demonstrate that the proposed method leads to significant improvements in the reconstruction quality of parametric images.« less

  14. Effect of sampling schedule on pharmacokinetic parameter estimates of promethazine in astronauts

    NASA Astrophysics Data System (ADS)

    Boyd, Jason L.; Wang, Zuwei; Putcha, Lakshmi

    2005-08-01

    Six astronauts on the Shuttle Transport System (STS) participated in an investigation on the pharmacokinetics of promethazine (PMZ), a medication used for the treatment of space motion sickness (SMS) during flight. Each crewmember completed the protocol once during flight and repeated thirty days after returned to Earth. Saliva samples were collected at scheduled times for 72 h after PMZ administration; more frequent samples were collected on the ground than during flight owing to schedule constraints in flight. PMZ concentrations in saliva were determined by a liquid chromatographic/mass spectrometric (LC-MS) assay and pharmacokinetic parameters (PKPs) were calculated using actual flight and ground-based data sets and using time-matched sampling schedule on ground to that during flight. Volume of distribution (Vc) and clearance (Cls) decreased during flight compared to that from time-matched ground data set; however, ClS and Vc estimates were higher for all subjects when partial ground data sets were used for analysis. Area under the curve (AUC) normalized with administered dose was similar in flight and partial ground data; however AUC was significantly lower using time-matched sampling compared with the full data set on ground. Half life (t1/2) was longest during flight, shorter with matched-sampling schedule on ground and shortest when complete data set from ground was used. Maximum concentration (Cmax), time for Cmax (tmax), parameters of drug absorption, depicted a similar trend with lowest and longest respectively, during flight, lower with time- matched ground data and highest and shortest with full ground data.

  15. Effect of Sampling Schedule on Pharmacokinetic Parameter Estimates of Promethazine in Astronauts

    NASA Technical Reports Server (NTRS)

    Boyd, Jason L.; Wang, Zuwei; Putcha, Lakshmi

    2005-01-01

    Six astronauts on the Shuttle Transport System (STS) participated in an investigation on the pharmacokinetics of promethazine (PMZ), a medication used for the treatment of space motion sickness (SMS) during flight. Each crewmember completed the protocol once during flight and repeated thirty days after returned to Earth. Saliva samples were collected at scheduled times for 72 h after PMZ administration; more frequent samples were collected on the ground than during flight owing to schedule constraints in flight. PMZ concentrations in saliva were determined by a liquid chromatographic/mass spectrometric (LC-MS) assay and pharmacokinetic parameters (PKPs) were calculated using actual flight and ground-based data sets and using time-matched sampling schedule on ground to that during flight. Volume of distribution (V(sub c)) and clearance (Cl(sub s),) decreased during flight compared to that from time-matched ground data set; however, Cl(sub s) and V(sub c) estimates were higher for all subjects when partial ground data sets were used for analysis. Area under the curve (AUC) normalized with administered dose was similar in flight and partial ground data; however AUC was significantly lower using time-matched sampling compared with the full data set on ground. Half life (t(sub 1/2)) was longest during flight, shorter with matched-sampling schedule on ground and shortest when complete data set from ground was used. Maximum concentration (C(sub max)), time for C(sub max), (t(sub max)), parameters of drug absorption, depicted a similar trend with lowest and longest respectively, during flight, lower with time-matched ground data and highest and shortest with full ground data.

  16. Dark energy and key physical parameters of clusters of galaxies

    NASA Astrophysics Data System (ADS)

    Bisnovatyi-Kogan, G. S.; Chernin, A. D.

    2012-04-01

    We study physics of clusters of galaxies embedded in the cosmic dark energy background. Under the assumption that dark energy is described by the cosmological constant, we show that the dynamical effects of dark energy are strong in clusters like the Virgo cluster. Specifically, the key physical parameters of the dark mater halos in clusters are determined by dark energy: (1) the halo cut-off radius is practically, if not exactly, equal to the zero-gravity radius at which the dark matter gravity is balanced by the dark energy antigravity; (2) the halo averaged density is equal to two densities of dark energy; (3) the halo edge (cut-off) density is the dark energy density with a numerical factor of the unity order slightly depending on the halo profile. The cluster gravitational potential well in which the particles of the dark halo (as well as galaxies and intracluster plasma) move is strongly affected by dark energy: the maximum of the potential is located at the zero-gravity radius of the cluster.

  17. Investigating the Martian Ionospheric Conductivity Using MAVEN Key Parameter Data

    NASA Astrophysics Data System (ADS)

    Aleryani, O.; Raftery, C. L.; Fillingim, M. O.; Fogle, A. L.; Dunn, P.; McFadden, J. P.; Connerney, J. E. P.; Mahaffy, P. R.; Ergun, R. E.; Andersson, L.

    2015-12-01

    Since the Viking orbiters and landers in 1976, the Martian atmospheric composition has scarcely been investigated. New data from the Mars Atmosphere and Volatile EvolutioN (MAVEN) mission, launched in 2013, allows for a thorough study of the electrically conductive nature of the Martian ionosphere. Determinations of the electrical conductivity will be made using in-situ atmospheric and ionospheric measurements, rather than scientific models for the first time. The objective of this project is to calculate the conductivity of the Martian atmosphere, whenever possible, throughout the trajectory of the MAVEN spacecraft. MAVEN instrumentation used includes the Neutral Gas and Ion Mass Spectrometer (NGIMS) for neutral species density, the Suprathermal and Thermal Ion Compositions (STATIC) for ion composition, temperature and density, the Magnetometer (MAG) for the magnetic field strength and the Langmuir Probe and Waves (LPW) for electron temperature and density. MAVEN key parameter data are used for these calculations. We compare our results with previous, model-based estimates of the conductivity. These results will allow us to quantify the flow of atmospheric electric currents which can be analyzed further for a deeper understanding of the Martian ionospheric electrodynamics, bringing us closer to understanding the mystery of the loss of the Martian atmosphere.

  18. Pharmacokinetic design optimization in children and estimation of maturation parameters: example of cytochrome P450 3A4.

    PubMed

    Bouillon-Pichault, Marion; Jullien, Vincent; Bazzoli, Caroline; Pons, Gérard; Tod, Michel

    2011-02-01

    The aim of this work was to determine whether optimizing the study design in terms of ages and sampling times for a drug eliminated solely via cytochrome P450 3A4 (CYP3A4) would allow us to accurately estimate the pharmacokinetic parameters throughout the entire childhood timespan, while taking into account age- and weight-related changes. A linear monocompartmental model with first-order absorption was used successively with three different residual error models and previously published pharmacokinetic parameters ("true values"). The optimal ages were established by D-optimization using the CYP3A4 maturation function to create "optimized demographic databases." The post-dose times for each previously selected age were determined by D-optimization using the pharmacokinetic model to create "optimized sparse sampling databases." We simulated concentrations by applying the population pharmacokinetic model to the optimized sparse sampling databases to create optimized concentration databases. The latter were modeled to estimate population pharmacokinetic parameters. We then compared true and estimated parameter values. The established optimal design comprised four age ranges: 0.008 years old (i.e., around 3 days), 0.192 years old (i.e., around 2 months), 1.325 years old, and adults, with the same number of subjects per group and three or four samples per subject, in accordance with the error model. The population pharmacokinetic parameters that we estimated with this design were precise and unbiased (root mean square error [RMSE] and mean prediction error [MPE] less than 11% for clearance and distribution volume and less than 18% for k(a)), whereas the maturation parameters were unbiased but less precise (MPE < 6% and RMSE < 37%). Based on our results, taking growth and maturation into account a priori in a pediatric pharmacokinetic study is theoretically feasible. However, it requires that very early ages be included in studies, which may present an obstacle to the

  19. Key Parameters Evaluation for Hip Prosthesis with Finite Element Analysis

    NASA Astrophysics Data System (ADS)

    Guo, Hongqiang; Li, Dichen; Lian, Qin; Li, Xiang; Jin, Zhongmin

    2007-09-01

    Stem length and cross section are two key parameters that influence the stability and longevity of metallic hip prosthesis in the total hip arthroplasty (THA). In order to assess their influence to the stress and fatigue behavior of hip prosthesis, a series model of hip prosthesis with round-shaped or drum-shaped cross section, and with different stem lengths were created. These models were analyzed under both static and dynamic loading conditions with finite element analysis, and dynamic loading represents normal walking was used in the dynamic analysis. The stress on the metallic stem, cement, and adjacent bone were got, micromotion on the cement-metal interface were got too. Safety factors for fatigue life of the hip prothesis were calculated based on data obtained from dynamic analysis. Static analysis shows that drum-shaped cross section can decrease the displacement of the stem, that stress on drum-shaped stem focus on the corner of the femoral neck and the distal part of hip prosthesis, whereas the stress on the round-shaped stem distributes evenly over most part of the stem, and maximum stress on stem prosthesis fluctuates with stem length bottoming out at stem length range from 80 mm to 110 mm, that drum-shaped stems with drum height 8 mm generate more stress at the distal part of stem than drum-shaped stems with drum height 10 mm and round stems do. Dynamic and fatigue analysis shows that drum-shaped stem with drum height 10 mm and stem length 90 mm has the greatest safety factor therefore long fatigue life.

  20. Excitation-resolved multispectral method for imaging pharmacokinetic parameters in dynamic fluorescent molecular tomography

    NASA Astrophysics Data System (ADS)

    Chen, Maomao; Zhou, Yuan; Su, Han; Zhang, Dong; Luo, Jianwen

    2017-04-01

    Imaging of the pharmacokinetic parameters in dynamic fluorescence molecular tomography (DFMT) can provide three-dimensional metabolic information for biological studies and drug development. However, owing to the ill-posed nature of the FMT inverse problem, the relatively low quality of the parametric images makes it difficult to investigate the different metabolic processes of the fluorescent targets with small distances. An excitation-resolved multispectral DFMT method is proposed; it is based on the fact that the fluorescent targets with different concentrations show different variations in the excitation spectral domain and can be considered independent signal sources. With an independent component analysis method, the spatial locations of different fluorescent targets can be decomposed, and the fluorescent yields of the targets at different time points can be recovered. Therefore, the metabolic process of each component can be independently investigated. Simulations and phantom experiments are carried out to evaluate the performance of the proposed method. The results demonstrated that the proposed excitation-resolved multispectral method can effectively improve the reconstruction accuracy of the parametric images in DFMT.

  1. Comparison of predictability for human pharmacokinetics parameters among monkeys, rats, and chimeric mice with humanised liver.

    PubMed

    Miyamoto, Maki; Iwasaki, Shinji; Chisaki, Ikumi; Nakagawa, Sayaka; Amano, Nobuyuki; Hirabayashi, Hideki

    2017-12-01

    1. The aim of the present study was to evaluate the usefulness of chimeric mice with humanised liver (PXB mice) for the prediction of clearance (CL t ) and volume of distribution at steady state (Vd ss ), in comparison with monkeys, which have been reported as a reliable model for human pharmacokinetics (PK) prediction, and with rats, as a conventional PK model. 2. CL t and Vd ss values in PXB mice, monkeys and rats were determined following intravenous administration of 30 compounds known to be mainly eliminated in humans via the hepatic metabolism by various drug-metabolising enzymes. Using single-species allometric scaling, human CL t and Vd ss values were predicted from the three animal models. 3. Predicted CL t values from PXB mice exhibited the highest predictability: 25 for PXB mice, 21 for monkeys and 14 for rats were predicted within a three-fold range of actual values among 30 compounds. For predicted human Vd ss values, the number of compounds falling within a three-fold range was 23 for PXB mice, 24 for monkeys, and 16 for rats among 29 compounds. PXB mice indicated a higher predictability for CL t and Vd ss values than the other animal models. 4. These results demonstrate the utility of PXB mice in predicting human PK parameters.

  2. Development and optimization of carvedilol orodispersible tablets: enhancement of pharmacokinetic parameters in rabbits

    PubMed Central

    Aljimaee, Yazeed HM; El-Helw, Abdel-Rahim M; Ahmed, Osama AA; El-Say, Khalid M

    2015-01-01

    Background Carvedilol (CVD) is used for the treatment of essential hypertension, heart failure, and systolic dysfunction after myocardial infarction. Due to its lower aqueous solubility and extensive first-pass metabolism, the absolute bioavailability of CVD does not exceed 30%. To overcome these drawbacks, the objective of this work was to improve the solubility and onset of action of CVD through complexation with hydroxypropyl-β-cyclodextrin and formulation of the prepared complex as orodispersible tablets (ODTs). Methods Compatibility among CVD and all tablet excipients using differential scanning calorimetry and Fourier transform infrared spectroscopy, complexation of CVD with different polymers, and determination of the solubility of CVD in the prepared complexes were first determined. A Box-Behnken design (BBD) was used to study the effect of tablet formulation variables on the characteristics of the prepared tablets and to optimize preparation conditions. According to BBD design, 15 formulations of CVD-ODTs were prepared by direct compression and then evaluated for their quality attributes. The relative pharmacokinetic parameters of the optimized CVD-ODTs were compared with those of the marketed CVD tablet. A single dose, equivalent to 2.5 mg/kg CVD, was administered orally to New Zealand white rabbits using a double-blind, randomized, crossover design. Results The solubility of CVD was improved from 7.32 to 22.92 mg/mL after complexation with hydroxypropyl-β-cyclodextrin at a molar ratio of 1:2 (CVD to cyclodextrin). The formulated CVD-ODTs showed satisfactory results concerning tablet hardness (5.35 kg/cm2), disintegration time (18 seconds), and maximum amount of CVD released (99.72%). The pharmacokinetic data for the optimized CVD-ODT showed a significant (P<0.05) increase in maximum plasma concentration from 363.667 to 496.4 ng/mL, and a shortening of the time taken to reach maximum plasma concentration to 2 hours in comparison with the marketed tablet

  3. The effects of febuxostat on the pharmacokinetic parameters of rosiglitazone, a CYP2C8 substrate

    PubMed Central

    Naik, Himanshu; Wu, Jing-tao; Palmer, Robert; McLean, Lachy

    2012-01-01

    AIMS To determine the effect of febuxostat on cytochrome P450 2C8 (CYP2C8) activity using rosiglitazone as a CYP2C8 substrate. METHODS Healthy subjects received febuxostat 120 mg daily (regimen A) or matching placebo (regimen B) for 9 days along with a single oral dose of rosiglitazone 4 mg on day 5 in a double-blind, randomized, cross-over fashion (≥7 day washout between periods). Plasma samples for analysis of the impact of febuxostat on the pharmacokinetics (PK) of rosiglitazone and its metabolite, N-desmethylrosiglitazone, were collected for 120 h after co-administration. RESULTS Of the 39 subjects enrolled, 36 completed the study and were included in the PK analyses. Rosiglitazone PK parameters were comparable between regimens A and B. Median time to maximal plasma concentration, mean maximal plasma concentration (Cmax), area under the concentration-time curve (AUC) from time zero to the last quantifiable concentration (AUC0–tlqc), AUC from time zero to infinity (AUC0–∞), and terminal elimination half-life for regimen A were 0.50 h, 308.6 ng ml−1, 1594.9 ng h ml−1, 1616.0 ng h ml−1 and 4.1 h, respectively, and for regimen B they were 0.50 h, 327.6 ng ml−1, 1564.5 ng h ml−1, 1584.2 ng h ml−1 and 4.0 h, respectively. Point estimates for the ratio of regimen A to regimen B (90% confidence intervals) for rosiglitazone Cmax, AUC0–tlqc and AUC0–∞ central values were 0.94 (0.89–1.00), 1.02 (1.00–1.04) and 1.02 (1.00–1.04), respectively. CONCLUSIONS Co-administration of febuxostat had no effect on rosiglitazone or N-desmethylrosiglitazone PK parameters, suggesting that febuxostat can be given safely with drugs metabolized through CYP2C8. PMID:22242967

  4. [Effects of sanguisorba tannins and saponins compatibility on pharmacokinetic parameters of catechin, epicatechin and ziyuglycoside Ⅰ in rats].

    PubMed

    Xiong, Yong-Ai; Yang, Ming

    2016-10-01

    To study the effects of sanguisorba tannins and saponins compatibility at different proportions [tannins-saponins (1∶1) and tannins-saponins(8∶1)] after intragastric administration (50 mg•kg⁻¹) on pharmacokinetic parameters of catechin, epicatechin and ziyuglycoside Ⅰ in rats by using pharmacokinetic techniques and methods. Kinetica 5.0 software was used to calculate the pharmacokinetic parameters. The results showed that the specificity, linearity, recovery rate, precision and stability of the established detection method were in line with the test requirements. When the sanguisorba tannins and eaponins were combined at the rate of 1∶1, Vd and CL of catechin and epicatechin were increased significantly(P<0.05); MRT was significantly shortened(P<0.05); Cmax and AUC were significantly reduced(P<0.05). When the sanguisorba tannins and saponins were combined at the rate of 8∶1, Vd and CL of catechin and epicatechin were significantly reduced(P<0.05); MRT was significantly prolonged(P<0.05); Cmax and AUC were increased significantly(P<0.05). In addition, with the increase in proportion of sanguisorba tannins in the compatibility, Cmax and AUC of ziyuglycoside Ⅰ were increased significantly(P<0.05); Vd and CL were significantly reduced(P<0.05), Tmax was obviously lagging behind, and MRT was also significantly prolonged(P<0.05). In our present study, catechin, epicatechin and ziyuglycoside Ⅰ showed good pharmacokinetic behavior in rats when sanguisorba tannins and saponins were combined at the rate of 8∶1 in compatibility, which could be used as a reference for the proportion in sanguisorba tannins and saponins compatibility. Copyright© by the Chinese Pharmaceutical Association.

  5. Nanoparticles for Radiation Therapy Enhancement: the Key Parameters

    PubMed Central

    Retif, Paul; Pinel, Sophie; Toussaint, Magali; Frochot, Céline; Chouikrat, Rima; Bastogne, Thierry; Barberi-Heyob, Muriel

    2015-01-01

    This review focuses on the radiosensitization strategies that use high-Z nanoparticles. It does not establish an exhaustive list of the works in this field but rather propose constructive criticisms pointing out critical factors that could improve the nano-radiation therapy. Whereas most reviews show the chemists and/or biologists points of view, the present analysis is also seen through the prism of the medical physicist. In particular, we described and evaluated the influence of X-rays energy spectra using a numerical analysis. We observed a lack of standardization in preclinical studies that could partially explain the low number of translation to clinical applications for this innovative therapeutic strategy. Pointing out the critical parameters of high-Z nanoparticles radiosensitization, this review is expected to contribute to a larger preclinical and clinical development. PMID:26155318

  6. Nanoparticles for Radiation Therapy Enhancement: the Key Parameters.

    PubMed

    Retif, Paul; Pinel, Sophie; Toussaint, Magali; Frochot, Céline; Chouikrat, Rima; Bastogne, Thierry; Barberi-Heyob, Muriel

    2015-01-01

    This review focuses on the radiosensitization strategies that use high-Z nanoparticles. It does not establish an exhaustive list of the works in this field but rather propose constructive criticisms pointing out critical factors that could improve the nano-radiation therapy. Whereas most reviews show the chemists and/or biologists points of view, the present analysis is also seen through the prism of the medical physicist. In particular, we described and evaluated the influence of X-rays energy spectra using a numerical analysis. We observed a lack of standardization in preclinical studies that could partially explain the low number of translation to clinical applications for this innovative therapeutic strategy. Pointing out the critical parameters of high-Z nanoparticles radiosensitization, this review is expected to contribute to a larger preclinical and clinical development.

  7. Feasibility of Metabolic Parameter Estimation in Pharmacokinetic Models of Carbon Tetrachloride Exposure in Rats

    EPA Science Inventory

    Carbon tetrachloride (CCl4) is a toxic chemical that was once used in degreasers and detergents, and some remnants of the chemical may be present in the water supply. Physiologically based pharmacokinetic (PBPK) modeling can assist in understanding resulting internal d...

  8. Determination of the key parameters affecting historic communications satellite trends

    NASA Technical Reports Server (NTRS)

    Namkoong, D.

    1984-01-01

    Data representing 13 series of commercial communications satellites procured between 1968 and 1982 were analyzed to determine the factors that have contributed to the general reduction over time of the per circuit cost of communications satellites. The model by which the data were analyzed was derived from a general telecommunications application and modified to be more directly applicable for communications satellites. In this model satellite mass, bandwidth-years, and technological change were the variable parameters. A linear, least squares, multiple regression routine was used to obtain the measure of significance of the model. Correlation was measured by coefficient of determination (R super 2) and t-statistic. The results showed that no correlation could be established with satellite mass. Bandwidth-year however, did show a significant correlation. Technological change in the bandwidth-year case was a significant factor in the model. This analysis and the conclusions derived are based on mature technologies, i.e., satellite designs that are evolutions of earlier designs rather than the first of a new generation. The findings, therefore, are appropriate to future satellites only if they are a continuation of design evolution.

  9. Is midsole thickness a key parameter for the running pattern?

    PubMed

    Chambon, Nicolas; Delattre, Nicolas; Guéguen, Nils; Berton, Eric; Rao, Guillaume

    2014-01-01

    Many studies have highlighted differences in foot strike pattern comparing habitually shod runners who ran barefoot and with running shoes. Barefoot running results in a flatter foot landing and in a decreased vertical ground reaction force compared to shod running. The aim of this study was to investigate one possible parameter influencing running pattern: the midsole thickness. Fifteen participants ran overground at 3.3 ms(-1) barefoot and with five shoes of different midsole thickness (0 mm, 2 mm, 4 mm, 8 mm, 16 mm) with no difference of height between rearfoot and forefoot. Impact magnitude was evaluated using transient peak of vertical ground reaction force, loading rate, tibial acceleration peak and rate. Hip, knee and ankle flexion angles were computed at touch-down and during stance phase (range of motion and maximum values). External net joint moments and stiffness for hip, knee and ankle joints were also observed as well as global leg stiffness. No significant effect of midsole thickness was observed on ground reaction force and tibial acceleration. However, the contact time increased with midsole thickness. Barefoot running compared to shod running induced ankle in plantar flexion at touch-down, higher ankle dorsiflexion and lower knee flexion during stance phase. These adjustments are suspected to explain the absence of difference on ground reaction force and tibial acceleration. This study showed that the presence of very thin footwear upper and sole was sufficient to significantly influence the running pattern. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. Correction for photobleaching in dynamic fluorescence microscopy: application in the assessment of pharmacokinetic parameters in ultrasound-mediated drug delivery

    NASA Astrophysics Data System (ADS)

    Derieppe, M.; Bos, C.; de Greef, M.; Moonen, C.; de Senneville, B. Denis

    2016-01-01

    We have previously demonstrated the feasibility of monitoring ultrasound-mediated uptake of a hydrophilic model drug in real time with dynamic confocal fluorescence microscopy. In this study, we evaluate and correct the impact of photobleaching to improve the accuracy of pharmacokinetic parameter estimates. To model photobleaching of the fluorescent model drug SYTOX Green, a photobleaching process was added to the current two-compartment model describing cell uptake. After collection of the uptake profile, a second acquisition was performed when SYTOX Green was equilibrated, to evaluate the photobleaching rate experimentally. Photobleaching rates up to 5.0 10-3 s-1 were measured when applying power densities up to 0.2 W.cm-2. By applying the three-compartment model, the model drug uptake rate of 6.0 10-3 s-1 was measured independent of the applied laser power. The impact of photobleaching on uptake rate estimates measured by dynamic fluorescence microscopy was evaluated. Subsequent compensation improved the accuracy of pharmacokinetic parameter estimates in the cell population subjected to sonopermeabilization.

  11. Prediction of chemotherapeutic response in bladder cancer using k-means clustering of DCE-MRI pharmacokinetic parameters

    PubMed Central

    Nguyen, Huyen T.; Jia, Guang; Shah, Zarine K.; Pohar, Kamal; Mortazavi, Amir; Zynger, Debra L.; Wei, Lai; Yang, Xiangyu; Clark, Daniel; Knopp, Michael V.

    2015-01-01

    Purpose To apply k-means clustering of two pharmacokinetic parameters derived from 3T DCE-MRI to predict chemotherapeutic response in bladder cancer at the mid-cycle time-point. Materials and Methods With the pre-determined number of 3 clusters, k-means clustering was performed on non-dimensionalized Amp and kep estimates of each bladder tumor. Three cluster volume fractions (VFs) were calculated for each tumor at baseline and mid-cycle. The changes of three cluster VFs from baseline to mid-cycle were correlated with the tumor’s chemotherapeutic response. Receiver-operating-characteristics curve analysis was used to evaluate the performance of each cluster VF change as a biomarker of chemotherapeutic response in bladder cancer. Results k-means clustering partitioned each bladder tumor into cluster 1 (low kep and low Amp), cluster 2 (low kep and high Amp), cluster 3 (high kep and low Amp). The changes of all three cluster VFs were found to be associated with bladder tumor response to chemotherapy. The VF change of cluster 2 presented with the highest area-under-the-curve value (0.96) and the highest sensitivity/specificity/accuracy (96%/100%/97%) with a selected cutoff value. Conclusion k-means clustering of the two DCE-MRI pharmacokinetic parameters can characterize the complex microcirculatory changes within a bladder tumor to enable early prediction of the tumor’s chemotherapeutic response. PMID:24943272

  12. Oxaliplatin in patients with metastatic colorectal cancer: efficacy and pharmacokinetics parameters.

    PubMed

    Burz, C; Berindan-Neagoe, I; Balacescu, O; Todor, N; Pelau, D; Floares, C; Kacso, G; Tanaselia, C; Ursu, M; Vlase, L; Leucuta, S E; Cristea, V; Irimie, A

    2010-01-01

    The aim of this study was to investigate the efficiency of the FOLFOX-4 regimen and to evaluate the pharmacokinetics of oxaliplatin in untreated patients with metastatic colorectal cancer. 43 patients were enrolled in the study. Patients received oxaliplatin 85 mg/m(2) as 2-h i.v. infusion, on day 1, and bolus 5-fluorouracil (5FU) 400 mg/m(2) plus leucovorin (LV) 200 mg/m(2) followed by 5FU 600 mg/m(2) as 22-h infusion on day 1 and 2, every 2 weeks. The pharmacokinetics of oxaliplatin evaluated in 4 patients was performed in blood, plasma and ultrafiltered plasma (UFT) by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). The overall response rate and the median time to progression (TTP) were 53.49% and 7.1 months, respectively. Grade 3-4 toxic effects were observed in 11 (25.5%) patients. Grade 3 neuropathy was observed in 13.95% of the cases. In univariate analysis only Eastern Cooperative Oncology Group (ECOG) performance status (PS) was correlated with response. No correlation was found between grade 3-4 adverse events and the patient characteristics. The area under the time-concentration curve (AUC) in UFT was 4.8 + or - 0.72 standard deviation (SD) microg h/ml and the total clearance 30.17 + or - 7.75 l/min. The values for volume of distribution and the maximum concentration were 567 + or - 20 liters and 0.38 + or - 0.17 ug/ml, respectively. FOLFOX-4 was an effective regimen with good tolerability in previously untreated metastatic colorectal cancer patients. The pharmacokinetics of oxaliplatin was triphasic with a short initial distribution phase and a long terminal elimination phase.

  13. Prediction of pharmacokinetic and toxicological parameters of a 4-phenylcoumarin isolated from geopropolis: In silico and in vitro approaches.

    PubMed

    da Cunha, Marcos Guilherme; Franco, Gilson César Nobre; Franchin, Marcelo; Beutler, John A; de Alencar, Severino Matias; Ikegaki, Masaharu; Rosalen, Pedro Luiz

    2016-11-30

    In silico and in vitro methodologies have been used as important tools in the drug discovery process, including from natural sources. The aim of this study was to predict pharmacokinetic and toxicity (ADME/Tox) properties of a coumarin isolated from geopropolis using in silico and in vitro approaches. Cinnamoyloxy-mammeisin (CNM) isolated from Brazilian M. scutellaris geopropolis was evaluated for its pharmacokinetic parameters by in silico models (ACD/Percepta™ and MetaDrug™ software). Genotoxicity was assessed by in vitro DNA damage signaling PCR array. CNM did not pass all parameters of Lipinski's rule of five, with a predicted low oral bioavailability and high plasma protein binding, but with good predicted blood brain barrier penetration. CNM was predicted to show low affinity to cytochrome P450 family members. Furthermore, the predicted Ames test indicated potential mutagenicity of CNM. Also, the probability of toxicity for organs and tissues was classified as moderate and high for liver and kidney, and moderate and low for skin and eye irritation, respectively. The PCR array analysis showed that CNM significantly upregulated about 7% of all DNA damage-related genes. By exploring the biological function of these genes, it was found that the predicted CNM genotoxicity is likely to be mediated by apoptosis. The predicted ADME/Tox profile suggests that external use of CNM may be preferable to systemic exposure, while its genotoxicity was characterized by the upregulation of apoptosis-related genes after treatment. The combined use of in silico and in vitro approaches to evaluate these parameters generated useful hypotheses to guide further preclinical studies. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  14. Association of pharmacokinetic and metabolic parameters derived using simultaneous PET/MRI: Initial findings and impact on response evaluation in breast cancer.

    PubMed

    Jena, Amarnath; Taneja, Sangeeta; Singh, Aru; Negi, Pradeep; Mehta, Shashi Bhushan; Ahuja, Aashim; Singhal, Manish; Sarin, Ramesh

    2017-07-01

    To study relationships among pharmacokinetic and 18 F-fluorodeoxyglucose ( 18 F-FDG) PET parameters obtained through simultaneous PET/MRI in breast cancer patients and evaluate their combined potential for response evaluation. The study included 41 breast cancer patients for correlation study and 9 patients (pre and post therapy) for response evaluation. All patients underwent simultaneous PET/MRI with dedicated breast imaging. Pharmacokinetic parameters and PET parameters for tumor were derived using an in- house developed and vendor provided softwares respectively. Relationships between SUV and pharmacokinetic parameters and clinical as well as histopathologic parameters were evaluated using Spearman correlation analysis. Response to chemotherapy was derived as percentage reduction in size and in parameters post therapy. Significant correlations were observed between SUVmean, max, peak, TLG with K trans (ρ=0.446, 0.417, 0.491, 0.430; p≤0.01); with Kep(ρ=0.303, ρ=0.315, ρ=0.319; p≤0.05); and with iAUC(ρ=0.401, ρ=0.410, ρ=0.379; p≤0.05, p≤0.01). The ratio of ve/iAUC showed significant negative correlation to SUVmean, max, peak and TLG (ρ=0.420, 0.446, 0.443, 0.426; p≤0.01). Ability of SUV as well as pharmacokinetic parameters to predict response to therapy matched the RECIST criteria in 9 out of 11 lesions in 9 patients. Maximum post therapy quantitative reduction was observed in SUVpeak, TLG and K trans . Simultaneous PET/MRI enables illustration of close interactions between glucose metabolism and pharmacokinetic parameters in breast cancer patients and potential of their simultaneity in response assessment to therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Cost-constrained optimal sampling for system identification in pharmacokinetics applications with population priors and nuisance parameters.

    PubMed

    Sorzano, Carlos Oscars S; Pérez-De-La-Cruz Moreno, Maria Angeles; Burguet-Castell, Jordi; Montejo, Consuelo; Ros, Antonio Aguilar

    2015-06-01

    Pharmacokinetics (PK) applications can be seen as a special case of nonlinear, causal systems with memory. There are cases in which prior knowledge exists about the distribution of the system parameters in a population. However, for a specific patient in a clinical setting, we need to determine her system parameters so that the therapy can be personalized. This system identification is performed many times by measuring drug concentrations in plasma. The objective of this work is to provide an irregular sampling strategy that minimizes the uncertainty about the system parameters with a fixed amount of samples (cost constrained). We use Monte Carlo simulations to estimate the average Fisher's information matrix associated to the PK problem, and then estimate the sampling points that minimize the maximum uncertainty associated to system parameters (a minimax criterion). The minimization is performed employing a genetic algorithm. We show that such a sampling scheme can be designed in a way that is adapted to a particular patient and that it can accommodate any dosing regimen as well as it allows flexible therapeutic strategies. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  16. Association of the clinical efficacy of vancomycin with the novel pharmacokinetic parameter area under the trough level (AUTL) in elderly patients with hospital-acquired pneumonia.

    PubMed

    Fukumori, S; Tsuji, Y; Mizoguchi, A; Kasai, H; Ishibashi, T; Iwamura, N; To, H

    2016-08-01

    The pharmacokinetic-pharmacodynamic parameter that best predicts the efficacy of vancomycin is the ratio of the area under the concentration versus time curve (AUC) to the minimum inhibitory concentration (MIC). A 24-h AUC (AUC24 )/MIC ratio ≥ 400 was recommended in an American consensus review, but vancomycin treatment occasionally fails despite maintenance of AUC24 /MIC ≥ 400. We evaluated the association between clinical efficacy of vancomycin and two novel pharmacokinetic parameters, the 'area under the trough level' (AUTL) and the 'area above the trough level' (AATL), in hospitalized elderly patients with methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. The subjects were hospitalized elderly patients who were administered vancomycin for treatment of MRSA pneumonia between 2006 and 2012 at Sasebo Chuo Hospital (Nagasaki, Japan). Pharmacokinetic parameters of vancomycin were estimated for each patient by Bayesian analysis using population pharmacokinetic parameters for Japanese patients. Based on the patient-specific parameters thus obtained, AUC24 values were calculated as the vancomycin dosage divided by vancomycin clearance. AUTL was calculated as the trough serum concentration multiplied by 24 h, whereas AATL was calculated by subtracting AUTL from AUC24 . Logistic regression analysis demonstrated that efficacy of vancomycin was more strongly associated with AUTL than AUC24 . The optimal cut-off value of AUTL was 331 μg∙h/mL, which means that the optimal cut-off value of the trough serum concentration was 13·8 μg/mL. Efficacy of vancomycin was associated with AUTL, a novel pharmacokinetic parameter. Determining the target AUTL or trough concentration may enhance the efficacy of vancomycin therapy in elderly patients with MRSA pneumonia. Given that nephrotoxicity may increase with a Ctrough in excess of 15 μg/mL, this level should ideally not be exceeded. © 2016 John Wiley & Sons Ltd.

  17. Patient-specific pharmacokinetic parameter estimation on dynamic contrast-enhanced MRI of prostate: Preliminary evaluation of a novel AIF-free estimation method.

    PubMed

    Ginsburg, Shoshana B; Taimen, Pekka; Merisaari, Harri; Vainio, Paula; Boström, Peter J; Aronen, Hannu J; Jambor, Ivan; Madabhushi, Anant

    2016-12-01

    To develop and evaluate a prostate-based method (PBM) for estimating pharmacokinetic parameters on dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) by leveraging inherent differences in pharmacokinetic characteristics between the peripheral zone (PZ) and transition zone (TZ). This retrospective study, approved by the Institutional Review Board, included 40 patients who underwent a multiparametric 3T MRI examination and subsequent radical prostatectomy. A two-step PBM for estimating pharmacokinetic parameters exploited the inherent differences in pharmacokinetic characteristics associated with the TZ and PZ. First, the reference region model was implemented to estimate ratios of K trans between normal TZ and PZ. Subsequently, the reference region model was leveraged again to estimate values for K trans and v e for every prostate voxel. The parameters of PBM were compared with those estimated using an arterial input function (AIF) derived from the femoral arteries. The ability of the parameters to differentiate prostate cancer (PCa) from benign tissue was evaluated on a voxel and lesion level. Additionally, the effect of temporal downsampling of the DCE MRI data was assessed. Significant differences (P < 0.05) in PBM K trans between PCa lesions and benign tissue were found in 26/27 patients with TZ lesions and in 33/38 patients with PZ lesions; significant differences in AIF-based K trans occurred in 26/27 and 30/38 patients, respectively. The 75 th and 100 th percentiles of K trans and v e estimated using PBM positively correlated with lesion size (P < 0.05). Pharmacokinetic parameters estimated via PBM outperformed AIF-based parameters in PCa detection. J. Magn. Reson. Imaging 2016;44:1405-1414. © 2016 International Society for Magnetic Resonance in Medicine.

  18. Patient-Specific Pharmacokinetic Parameter Estimation on Dynamic Contrast-Enhanced MRI of Prostate: Preliminary Evaluation of a Novel AIF-Free Estimation Method

    PubMed Central

    Ginsburg, Shoshana B.; Taimen, Pekka; Merisaari, Harri; Vainio, Paula; Boström, Peter J.; Aronen, Hannu J.; Jambor, Ivan; Madabhushi, Anant

    2017-01-01

    Purpose To develop and evaluate a prostate-based method (PBM) for estimating pharmacokinetic parameters on dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) by leveraging inherent differences in pharmacokinetic characteristics between the peripheral zone (PZ) and transition zone (TZ). Materials and Methods This retrospective study, approved by the Institutional Review Board, included 40 patients who underwent a multiparametric 3T MRI examination and subsequent radical prostatectomy. A two-step PBM for estimating pharmacokinetic parameters exploited the inherent differences in pharmacokinetic characteristics associated with the TZ and PZ. First, the reference region model was implemented to estimate ratios of Ktrans between normal TZ and PZ. Subsequently, the reference region model was leveraged again to estimate values for Ktrans and ve for every prostate voxel. The parameters of PBM were compared with those estimated using an arterial input function (AIF) derived from the femoral arteries. The ability of the parameters to differentiate prostate cancer (PCa) from benign tissue was evaluated on a voxel and lesion level. Additionally, the effect of temporal downsampling of the DCE MRI data was assessed. Results Significant differences (P < 0.05) in PBM Ktrans between PCa lesions and benign tissue were found in 26/27 patients with TZ lesions and in 33/38 patients with PZ lesions; significant differences in AIF-based Ktrans occurred in 26/27 and 30/38 patients, respectively. The 75th and 100th percentiles of Ktrans and ve estimated using PBM positively correlated with lesion size (P < 0.05). Conclusion Pharmacokinetic parameters estimated via PBM outperformed AIF-based parameters in PCa detection. PMID:27285161

  19. Pharmacokinetics and metabolism of benzene in Zymbal gland and other key target tissues after oral administration in rats.

    PubMed Central

    Low, L K; Meeks, J R; Norris, K J; Mehlman, M A; Mackerer, C R

    1989-01-01

    Solid tumors have been reported in the Zymbal gland, oral and nasal cavities, and mammary gland of Sprague-Dawley rats following chronic oral administration of benzene. The cause for the specificity of such lesions remains unclear, but it is possible that tissue-specific metabolism or pharmacokinetics of benzene is responsible. Metabolism and pharmacokinetic studies were carried out in our laboratory with 14C-benzene at oral doses of 0.15 to 500 mg/kg to ascertain tissue retention, metabolite profile, and elimination kinetics in target and nontarget organs and in blood. Findings from those studies indicate the following: a) the Zymbal gland is not a sink or a site of accumulation for benzene or its metabolites even after a single high dose (500 mg/kg) or after repeated oral administration; b) the metabolite profile is quantitatively different in target tissues (e.g., Zymbal gland, nasal cavity), nontarget tissues and blood; and (c) pharmacokinetic studies show that the elimination of radioactivity from the Zymbal gland is biphasic. PMID:2792043

  20. Relationships of Changes in Pharmacokinetic Parameters of Substrate Drugs in Drug-Drug Interactions on Metabolizing Enzymes and Transporters.

    PubMed

    Yamazaki, Shinji

    2018-05-03

    A general objective of drug-drug interaction (DDI) studies is to determine whether potential interactions of new molecular entities with concomitantly administered other drugs exist and, if DDIs occur, whether dosage adjustments are required. A typical end point for DDI evaluations is the ratio of area under the plasma concentration-time curve (AUC) of substrate drugs (AUCR), whereas the ratios of maximal plasma concentration (C max ) and terminal half-life (t 1/2 ) are also important to understand DDI mechanisms (C max R and t 1/2 R, respectively). Because changes in substrate AUC by precipitant drugs ultimately result from alterations of C max and t 1/2 , AUCR can be considered a hybrid parameter of C max R and t 1/2 R, for example, AUCR ≈ C max R  ×  t 1/2 R. The primary objective of this study was to investigate the relationships between AUCR, C max R, and t 1/2 R in physiologically based pharmacokinetic model-predicted and clinically observed DDI results. First, the model-predicted results showed the excellent proportional relationship between AUCR and (C max R × t 1/2 R) in DDI results of virtual substrates having a wide range of oral bioavailability with coadministration of ketoconazole, ritonavir, and rifampin. Second, the reasonable proportional relationships were also observed in the clinically observed DDI results of midazolam and statins (atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin) with various inhibitors and inducers. Finally, these results suggest that utilization of the proportional relationship between AUCR and (C max R × t 1/2 R) can provide an additional framework to further interpret DDI results reasonably and clearly. Furthermore, the proportional relationship can be purposely used to assess study design and pharmacokinetic analyses in DDI studies. © 2018, The American College of Clinical Pharmacology.

  1. The effects of yohimbine on the pharmacokinetic parameters of detomidine in the horse.

    PubMed

    Knych, Heather K; Steffey, Eugene P; Stanley, Scott D

    2012-05-01

    To describe the pharmacokinetics of detomidine and yohimbine when administered in combination. Randomized crossover design. Nine healthy adult horses aged 9 ± 4 years and weighing of 561 ± 56 kg. Three dose regimens were employed in the current study. 1) 0.03 mg kg(-1) detomidine IV (D), 2) 0.2 mg kg(-1) yohimbine IV (Y) and 3) 0.03 mg kg(-1) detomidine IV followed 15 minutes later by 0.2 mg kg(-1) yohimbine IV (DY). Each horse received all three dose regimens with a minimum of 1 week in between subsequent regimens. Blood samples were obtained and plasma analyzed for detomidine and yohimbine concentrations by liquid chromatography-mass spectrometry. Data were analyzed using both non-compartmental and compartmental analysis. The maximum measured detomidine concentrations were 76.0 and 129.9 ng mL(-1) for the D and DY treatments, respectively. Systemic clearance and volume of distribution of detomidine were not significantly different for either treatment. There was a significant increase in the maximum measured yohimbine plasma concentrations from Y (173.9 ng mL(-1)) to DY (289.8 ng mL(-1)). Both the Cl and V(d) for yohimbine were significantly less (6.8 mL minute(-1) kg(-1) (Cl) and 1.7 L kg(-1) (V(d) )) for the DY as compared to the Y treatments (13.9 mL minute(-1) kg(-1) (Cl) and 2.7 L kg(-1) (V(d))). Plasma concentrations were below the limit of quantitation (0.05 and 0.5 ng mL(-1)) by 18 hours for both detomidine and yohimbine. The Cl and V(d) of yohimbine were affected by prior administration of detomidine. The elimination half life of yohimbine remained unaffected when administered subsequent to detomidine. However, the increased plasma concentrations in the presence of detomidine has the potential to cause untoward effects and therefore further studies to assess the physiologic effects of this combination of drugs are warranted. © 2012 The Authors. Veterinary Anaesthesia and Analgesia. © 2012 Association of Veterinary Anaesthetists and the American

  2. Using Chemical Structure Information to Predict In Vitro Pharmacokinetic Parameters (SOT)

    EPA Science Inventory

    Toxicokinetic data are key for relating exposure and internal dose when building in vitro-based risk assessment models. However, conducting in vivo toxicokinetic studies has time and cost limitations, and in vitro toxicokinetic data is available only for a limited set of chemical...

  3. [Value influence of different compatibilities of main active parts in yangyintongnao granule on pharmacokinetics parameters in rats with cerebral ischemia reperfusion injury by total amount statistic moment method].

    PubMed

    Guo, Ying; Yang, Jiehong; Znang, Hengyi; Fu, Xuchun; Zhnag, Yuyan; Wan, Haitong

    2010-02-01

    To study the influence of the different combinations of the main active parts in Yangyintongnao granule on the pharmacokinetics parameters of the two active components--ligustrazine and puerarin using the method of total amount statistic moment for pharmacokinetics. Combinations were formed according to the dosages of the four active parts (alkaloid, flavone, saponin, naphtha) by orthogonal experiment L9 (3(4)). Blood concentrations of ligustrazine and puerarin were determinated by HPLC at different time. Zero rank moment (AUC) and one rank moment (MRT, mean residence time) of ligustrazine and puerarin have been worked out to calculate the total amount statistic moment parameters was analyzed of Yangyintongnao granule by the method of the total amount statistic moment. The influence of different compatibilities on the pharmacokinetics parameters was analyzed by orthogonal test. Flavone has the strongest effect than saponin on the total AUC. Ligustrazine has the strongest effect on the total MRT. Saponin has little effect on the two parameters, but naphtha has more effect on both of them. It indicates that naphtha may promote metabolism of ligustrazine and puerarin in rat. Total amount statistic moment parameters can be used to guide for compatibilities of TCM.

  4. Parameter Estimation with Almost No Public Communication for Continuous-Variable Quantum Key Distribution

    NASA Astrophysics Data System (ADS)

    Lupo, Cosmo; Ottaviani, Carlo; Papanastasiou, Panagiotis; Pirandola, Stefano

    2018-06-01

    One crucial step in any quantum key distribution (QKD) scheme is parameter estimation. In a typical QKD protocol the users have to sacrifice part of their raw data to estimate the parameters of the communication channel as, for example, the error rate. This introduces a trade-off between the secret key rate and the accuracy of parameter estimation in the finite-size regime. Here we show that continuous-variable QKD is not subject to this constraint as the whole raw keys can be used for both parameter estimation and secret key generation, without compromising the security. First, we show that this property holds for measurement-device-independent (MDI) protocols, as a consequence of the fact that in a MDI protocol the correlations between Alice and Bob are postselected by the measurement performed by an untrusted relay. This result is then extended beyond the MDI framework by exploiting the fact that MDI protocols can simulate device-dependent one-way QKD with arbitrarily high precision.

  5. Quantifying Key Climate Parameter Uncertainties Using an Earth System Model with a Dynamic 3D Ocean

    NASA Astrophysics Data System (ADS)

    Olson, R.; Sriver, R. L.; Goes, M. P.; Urban, N.; Matthews, D.; Haran, M.; Keller, K.

    2011-12-01

    Climate projections hinge critically on uncertain climate model parameters such as climate sensitivity, vertical ocean diffusivity and anthropogenic sulfate aerosol forcings. Climate sensitivity is defined as the equilibrium global mean temperature response to a doubling of atmospheric CO2 concentrations. Vertical ocean diffusivity parameterizes sub-grid scale ocean vertical mixing processes. These parameters are typically estimated using Intermediate Complexity Earth System Models (EMICs) that lack a full 3D representation of the oceans, thereby neglecting the effects of mixing on ocean dynamics and meridional overturning. We improve on these studies by employing an EMIC with a dynamic 3D ocean model to estimate these parameters. We carry out historical climate simulations with the University of Victoria Earth System Climate Model (UVic ESCM) varying parameters that affect climate sensitivity, vertical ocean mixing, and effects of anthropogenic sulfate aerosols. We use a Bayesian approach whereby the likelihood of each parameter combination depends on how well the model simulates surface air temperature and upper ocean heat content. We use a Gaussian process emulator to interpolate the model output to an arbitrary parameter setting. We use Markov Chain Monte Carlo method to estimate the posterior probability distribution function (pdf) of these parameters. We explore the sensitivity of the results to prior assumptions about the parameters. In addition, we estimate the relative skill of different observations to constrain the parameters. We quantify the uncertainty in parameter estimates stemming from climate variability, model and observational errors. We explore the sensitivity of key decision-relevant climate projections to these parameters. We find that climate sensitivity and vertical ocean diffusivity estimates are consistent with previously published results. The climate sensitivity pdf is strongly affected by the prior assumptions, and by the scaling

  6. The effect of breed and sex on sulfamethazine, enrofloxacin, fenbendazole and flunixin meglumine pharmacokinetic parameters in swine.

    PubMed

    Howard, J T; Baynes, R E; Brooks, J D; Yeatts, J L; Bellis, B; Ashwell, M S; Routh, P; O'Nan, A T; Maltecca, C

    2014-12-01

    Drug use in livestock has received increased attention due to welfare concerns and food safety. Characterizing heterogeneity in the way swine populations respond to drugs could allow for group-specific dose or drug recommendations. Our objective was to determine whether drug clearance differs across genetic backgrounds and sex for sulfamethazine, enrofloxacin, fenbendazole and flunixin meglumine. Two sires from each of four breeds were mated to a common sow population. The nursery pigs generated (n = 114) were utilized in a random crossover design. Drugs were administered intravenously and blood collected a minimum of 10 times over 48 h. A non-compartmental analysis of drug and metabolite plasma concentration vs. time profiles was performed. Within-drug and metabolite analysis of pharmacokinetic parameters included fixed effects of drug administration date, sex and breed of sire. Breed differences existed for flunixin meglumine (P-value<0.05; Cl, Vdss ) and oxfendazole (P-value<0.05, AUC0→∞ ). Sex differences existed for oxfendazole (P-value < 0.05; Tmax ) and sulfamethazine (P-value < 0.05, Cl). Differences in drug clearance were seen, and future work will determine the degree of additive genetic variation utilizing a larger population. © 2014 John Wiley & Sons Ltd.

  7. Predictive performance of the 'Minto' remifentanil pharmacokinetic parameter set in morbidly obese patients ensuing from a new method for calculating lean body mass.

    PubMed

    La Colla, Luca; Albertin, Andrea; La Colla, Giorgio; Porta, Andrea; Aldegheri, Giorgio; Di Candia, Domenico; Gigli, Fausto

    2010-01-01

    In a previous article, we showed that the pharmacokinetic set of remifentanil used for target-controlled infusion (TCI) might be biased in obese patients because it incorporates flawed equations for the calculation of lean body mass (LBM), which is a covariate of several pharmacokinetic parameters in this set. The objectives of this study were to determine the predictive performance of the original pharmacokinetic set, which incorporates the James equation for LBM calculation, and to determine the predictive performance of the pharmacokinetic set when a new method to calculate LBM was used (the Janmahasatian equations). This was an observational study with intraoperative observations and no follow-up. Fifteen morbidly obese inpatients scheduled for bariatric surgery were included in the study. The intervention included manually controlled continuous infusion of remifentanil during the surgery and analysis of arterial blood samples to determine the arterial remifentanil concentration, to be compared with concentrations predicted by either the unadjusted or the adjusted pharmacokinetic set. The statistical analysis included parametric and non-parametric tests on continuous variables and determination of the median performance error (MDPE), median absolute performance error (MDAPE), divergence and wobble. The median values (interquartile ranges) of the MDPE, MDAPE, divergence and wobble for the James equations during maintenance were -53.4% (-58.7% to -49.2%), 53.4% (49.0-58.7%), 3.3% (2.9-4.7%) and 1.4% h(-1) (1.1-2.5% h(-1)), respectively. The respective values for the Janmahasatian equations were -18.9% (-24.2% to -10.4%), 20.5% (13.3-24.8%), 2.6% (-0.7% to 4.5%) and 1.9% h(-1) (1.4-3.0% h(-1)). The performance (in terms of the MDPE and MDAPE) of the corrected pharmacokinetic set was better than that of the uncorrected one. The predictive performance of the original pharmacokinetic set is not clinically acceptable. Use of a corrected LBM value in morbidly obese

  8. Sequential weighted Wiener estimation for extraction of key tissue parameters in color imaging: a phantom study

    NASA Astrophysics Data System (ADS)

    Chen, Shuo; Lin, Xiaoqian; Zhu, Caigang; Liu, Quan

    2014-12-01

    Key tissue parameters, e.g., total hemoglobin concentration and tissue oxygenation, are important biomarkers in clinical diagnosis for various diseases. Although point measurement techniques based on diffuse reflectance spectroscopy can accurately recover these tissue parameters, they are not suitable for the examination of a large tissue region due to slow data acquisition. The previous imaging studies have shown that hemoglobin concentration and oxygenation can be estimated from color measurements with the assumption of known scattering properties, which is impractical in clinical applications. To overcome this limitation and speed-up image processing, we propose a method of sequential weighted Wiener estimation (WE) to quickly extract key tissue parameters, including total hemoglobin concentration (CtHb), hemoglobin oxygenation (StO2), scatterer density (α), and scattering power (β), from wide-band color measurements. This method takes advantage of the fact that each parameter is sensitive to the color measurements in a different way and attempts to maximize the contribution of those color measurements likely to generate correct results in WE. The method was evaluated on skin phantoms with varying CtHb, StO2, and scattering properties. The results demonstrate excellent agreement between the estimated tissue parameters and the corresponding reference values. Compared with traditional WE, the sequential weighted WE shows significant improvement in the estimation accuracy. This method could be used to monitor tissue parameters in an imaging setup in real time.

  9. Calculations of key magnetospheric parameters using the isotropic and anisotropic SPSU global MHD code

    NASA Astrophysics Data System (ADS)

    Samsonov, Andrey; Gordeev, Evgeny; Sergeev, Victor

    2017-04-01

    As it was recently suggested (e.g., Gordeev et al., 2015), the global magnetospheric configuration can be characterized by a set of key parameters, such as the magnetopause distance at the subsolar point and on the terminator plane, the magnetic field in the magnetotail lobe and the plasma sheet thermal pressure, the cross polar cap electric potential drop and the total field-aligned current. For given solar wind conditions, the values of these parameters can be obtained from both empirical models and global MHD simulations. We validate the recently developed global MHD code SPSU-16 using the key magnetospheric parameters mentioned above. The code SPSU-16 can calculate both the isotropic and anisotropic MHD equations. In the anisotropic version, we use the modified double-adiabatic equations in which the T⊥/T∥ (the ratio of perpendicular to parallel thermal pressures) has been bounded from above by the mirror and ion-cyclotron thresholds and from below by the firehose threshold. The results of validation for the SPSU-16 code well agree with the previously published results of other global codes. Some key parameters coincide in the isotropic and anisotropic MHD simulations, but some are different.

  10. Channel-parameter estimation for satellite-to-submarine continuous-variable quantum key distribution

    NASA Astrophysics Data System (ADS)

    Guo, Ying; Xie, Cailang; Huang, Peng; Li, Jiawei; Zhang, Ling; Huang, Duan; Zeng, Guihua

    2018-05-01

    This paper deals with a channel-parameter estimation for continuous-variable quantum key distribution (CV-QKD) over a satellite-to-submarine link. In particular, we focus on the channel transmittances and the excess noise which are affected by atmospheric turbulence, surface roughness, zenith angle of the satellite, wind speed, submarine depth, etc. The estimation method is based on proposed algorithms and is applied to low-Earth orbits using the Monte Carlo approach. For light at 550 nm with a repetition frequency of 1 MHz, the effects of the estimated parameters on the performance of the CV-QKD system are assessed by a simulation by comparing the secret key bit rate in the daytime and at night. Our results show the feasibility of satellite-to-submarine CV-QKD, providing an unconditionally secure approach to achieve global networks for underwater communications.

  11. Development and Validation of Limited-Sampling Strategies for Predicting Amoxicillin Pharmacokinetic and Pharmacodynamic Parameters

    PubMed Central

    Suarez-Kurtz, Guilherme; Ribeiro, Frederico Mota; Vicente, Flávio L.; Struchiner, Claudio J.

    2001-01-01

    Amoxicillin plasma concentrations (n = 1,152) obtained from 48 healthy subjects in two bioequivalence studies were used to develop limited-sampling strategy (LSS) models for estimating the area under the concentration-time curve (AUC), the maximum concentration of drug in plasma (Cmax), and the time interval of concentration above MIC susceptibility breakpoints in plasma (T>MIC). Each subject received 500-mg amoxicillin, as reference and test capsules or suspensions, and plasma concentrations were measured by a validated microbiological assay. Linear regression analysis and a “jack-knife” procedure revealed that three-point LSS models accurately estimated (R2, 0.92; precision, <5.8%) the AUC from 0 h to infinity (AUC0-∞) of amoxicillin for the four formulations tested. Validation tests indicated that a three-point LSS model (1, 2, and 5 h) developed for the reference capsule formulation predicts the following accurately (R2, 0.94 to 0.99): (i) the individual AUC0-∞ for the test capsule formulation in the same subjects, (ii) the individual AUC0-∞ for both reference and test suspensions in 24 other subjects, and (iii) the average AUC0-∞ following single oral doses (250 to 1,000 mg) of various amoxicillin formulations in 11 previously published studies. A linear regression equation was derived, using the same sampling time points of the LSS model for the AUC0-∞, but using different coefficients and intercept, for estimating Cmax. Bioequivalence assessments based on LSS-derived AUC0-∞'s and Cmax's provided results similar to those obtained using the original values for these parameters. Finally, two-point LSS models (R2 = 0.86 to 0.95) were developed for T>MICs of 0.25 or 2.0 μg/ml, which are representative of microorganisms susceptible and resistant to amoxicillin. PMID:11600352

  12. Key parameters design of an aerial target detection system on a space-based platform

    NASA Astrophysics Data System (ADS)

    Zhu, Hanlu; Li, Yejin; Hu, Tingliang; Rao, Peng

    2018-02-01

    To ensure flight safety of an aerial aircraft and avoid recurrence of aircraft collisions, a method of multi-information fusion is proposed to design the key parameter to realize aircraft target detection on a space-based platform. The key parameters of a detection wave band and spatial resolution using the target-background absolute contrast, target-background relative contrast, and signal-to-clutter ratio were determined. This study also presented the signal-to-interference ratio for analyzing system performance. Key parameters are obtained through the simulation of a specific aircraft. And the simulation results show that the boundary ground sampling distance is 30 and 35 m in the mid- wavelength infrared (MWIR) and long-wavelength infrared (LWIR) bands for most aircraft detection, and the most reasonable detection wavebands is 3.4 to 4.2 μm and 4.35 to 4.5 μm in the MWIR bands, and 9.2 to 9.8 μm in the LWIR bands. We also found that the direction of detection has a great impact on the detection efficiency, especially in MWIR bands.

  13. A system of equations to approximate the pharmacokinetic parameters of lacosamide at steady state from one plasma sample.

    PubMed

    Cawello, Willi; Schäfer, Carina

    2014-08-01

    Frequent plasma sampling to monitor pharmacokinetic (PK) profile of antiepileptic drugs (AEDs), is invasive, costly and time consuming. For drugs with a well-defined PK profile, such as AED lacosamide, equations can accurately approximate PK parameters from one steady-state plasma sample. Equations were derived to approximate steady-state peak and trough lacosamide plasma concentrations (Cpeak,ss and Ctrough,ss, respectively) and area under concentration-time curve during dosing interval (AUCτ,ss) from one plasma sample. Lacosamide (ka: ∼2 h(-1); ke: ∼0.05 h(-1), corresponding to half-life of 13 h) was calculated to reach Cpeak,ss after ∼1 h (tmax,ss). Equations were validated by comparing approximations to reference PK parameters obtained from single plasma samples drawn 3-12h following lacosamide administration, using data from double-blind, placebo-controlled, parallel-group PK study. Values of relative bias (accuracy) between -15% and +15%, and root mean square error (RMSE) values≤15% (precision) were considered acceptable for validation. Thirty-five healthy subjects (12 young males; 11 elderly males, 12 elderly females) received lacosamide 100mg/day for 4.5 days. Equation-derived PK values were compared to reference mean Cpeak,ss, Ctrough,ss and AUCτ,ss values. Equation-derived PK data had a precision of 6.2% and accuracy of -8.0%, 2.9%, and -0.11%, respectively. Equation-derived versus reference PK values for individual samples obtained 3-12h after lacosamide administration showed correlation (R2) range of 0.88-0.97 for AUCτ,ss. Correlation range for Cpeak,ss and Ctrough,ss was 0.65-0.87. Error analyses for individual sample comparisons were independent of time. Derived equations approximated lacosamide Cpeak,ss, Ctrough,ss and AUCτ,ss using one steady-state plasma sample within validation range. Approximated PK parameters were within accepted validation criteria when compared to reference PK values. Copyright © 2014 Elsevier B.V. All rights

  14. Variability and epistemic uncertainty in water ingestion rates and pharmacokinetic parameters, and impact on the association between perfluorooctanoate and preeclampsia in the C8 Health Project population.

    PubMed

    Avanasi, Raghavendhran; Shin, Hyeong-Moo; Vieira, Veronica M; Bartell, Scott M

    2016-04-01

    We recently utilized a suite of environmental fate and transport models and an integrated exposure and pharmacokinetic model to estimate individual perfluorooctanoate (PFOA) serum concentrations, and also assessed the association of those concentrations with preeclampsia for participants in the C8 Health Project (a cross-sectional study of over 69,000 people who were environmentally exposed to PFOA near a major U.S. fluoropolymer production facility located in West Virginia). However, the exposure estimates from this integrated model relied on default values for key independent exposure parameters including water ingestion rates, the serum PFOA half-life, and the volume of distribution for PFOA. The aim of the present study is to assess the impact of inter-individual variability and epistemic uncertainty in these parameters on the exposure estimates and subsequently, the epidemiological association between PFOA exposure and preeclampsia. We used Monte Carlo simulation to propagate inter-individual variability/epistemic uncertainty in the exposure assessment and reanalyzed the epidemiological association. Inter-individual variability in these parameters mildly impacted the serum PFOA concentration predictions (the lowest mean rank correlation between the estimated serum concentrations in our study and the original predicted serum concentrations was 0.95) and there was a negligible impact on the epidemiological association with preeclampsia (no change in the mean adjusted odds ratio (AOR) and the contribution of exposure uncertainty to the total uncertainty including sampling variability was 7%). However, when epistemic uncertainty was added along with the inter-individual variability, serum PFOA concentration predictions and their association with preeclampsia were moderately impacted (the mean AOR of preeclampsia occurrence was reduced from 1.12 to 1.09, and the contribution of exposure uncertainty to the total uncertainty was increased up to 33%). In conclusion

  15. Resilience of Key Biological Parameters of the Senegalese Flat Sardinella to Overfishing and Climate Change.

    PubMed

    Ba, Kamarel; Thiaw, Modou; Lazar, Najih; Sarr, Alassane; Brochier, Timothée; Ndiaye, Ismaïla; Faye, Alioune; Sadio, Oumar; Panfili, Jacques; Thiaw, Omar Thiom; Brehmer, Patrice

    2016-01-01

    The stock of the Senegalese flat sardinella, Sardinella maderensis, is highly exploited in Senegal, West Africa. Its growth and reproduction parameters are key biological indicators for improving fisheries management. This study reviewed these parameters using landing data from small-scale fisheries in Senegal and literature information dated back more than 25 years. Age was estimated using length-frequency data to calculate growth parameters and assess the growth performance index. With global climate change there has been an increase in the average sea surface temperature along the Senegalese coast but the length-weight parameters, sex ratio, size at first sexual maturity, period of reproduction and condition factor of S. maderensis have not changed significantly. The above parameters of S. maderensis have hardly changed, despite high exploitation and fluctuations in environmental conditions that affect the early development phases of small pelagic fish in West Africa. This lack of plasticity of the species regarding of the biological parameters studied should be considered when planning relevant fishery management plans.

  16. The Research and Implementation of Vehicle Bluetooth Hands-free Devices Key Parameters Downloading Algorithm

    NASA Astrophysics Data System (ADS)

    Zhang, Xiao-bo; Wang, Zhi-xue; Li, Jian-xin; Ma, Jian-hui; Li, Yang; Li, Yan-qiang

    In order to facilitate Bluetooth function realization and information can be effectively tracked in the process of production, the vehicle Bluetooth hands-free devices need to download such key parameters as Bluetooth address, CVC license and base plate numbers, etc. Therefore, it is the aim to search simple and effective methods to download parameters for each vehicle Bluetooth hands-free device, and to control and record the use of parameters. In this paper, by means of Bluetooth Serial Peripheral Interface programmer device, the parallel port is switched to SPI. The first step is to download parameters is simulating SPI with the parallel port. To perform SPI function, operating the parallel port in accordance with the SPI timing. The next step is to achieve SPI data transceiver functions according to the programming parameters of options. Utilizing the new method, downloading parameters is fast and accurate. It fully meets vehicle Bluetooth hands-free devices production requirements. In the production line, it has played a large role.

  17. Measuring Two Key Parameters of H3 Color Centers in Diamond

    NASA Technical Reports Server (NTRS)

    Roberts, W. Thomas

    2005-01-01

    A method of measuring two key parameters of H3 color centers in diamond has been created as part of a continuing effort to develop tunable, continuous-wave, visible lasers that would utilize diamond as the lasing medium. (An H3 color center in a diamond crystal lattice comprises two nitrogen atoms substituted for two carbon atoms bonded to a third carbon atom. H3 color centers can be induced artificially; they also occur naturally. If present in sufficient density, they impart a yellow hue.) The method may also be applicable to the corresponding parameters of other candidate lasing media. One of the parameters is the number density of color centers, which is needed for designing an efficient laser. The other parameter is an optical-absorption cross section, which, as explained below, is needed for determining the number density. The present method represents an improvement over prior methods in which optical-absorption measurements have been used to determine absorption cross sections or number densities. Heretofore, in order to determine a number density from such measurements, it has been necessary to know the applicable absorption cross section; alternatively, to determine the absorption cross section from such measurements, it has been necessary to know the number density. If, as in this case, both the number density and the absorption cross section are initially unknown, then it is impossible to determine either parameter in the absence of additional information.

  18. Crop Damage by Primates: Quantifying the Key Parameters of Crop-Raiding Events

    PubMed Central

    Wallace, Graham E.; Hill, Catherine M.

    2012-01-01

    Human-wildlife conflict often arises from crop-raiding, and insights regarding which aspects of raiding events determine crop loss are essential when developing and evaluating deterrents. However, because accounts of crop-raiding behaviour are frequently indirect, these parameters are rarely quantified or explicitly linked to crop damage. Using systematic observations of the behaviour of non-human primates on farms in western Uganda, this research identifies number of individuals raiding and duration of raid as the primary parameters determining crop loss. Secondary factors include distance travelled onto farm, age composition of the raiding group, and whether raids are in series. Regression models accounted for greater proportions of variation in crop loss when increasingly crop and species specific. Parameter values varied across primate species, probably reflecting differences in raiding tactics or perceptions of risk, and thereby providing indices of how comfortable primates are on-farm. Median raiding-group sizes were markedly smaller than the typical sizes of social groups. The research suggests that key parameters of raiding events can be used to measure the behavioural impacts of deterrents to raiding. Furthermore, farmers will benefit most from methods that discourage raiding by multiple individuals, reduce the size of raiding groups, or decrease the amount of time primates are on-farm. This study demonstrates the importance of directly relating crop loss to the parameters of raiding events, using systematic observations of the behaviour of multiple primate species. PMID:23056378

  19. Prediction of Geomagnetic Activity and Key Parameters in High-Latitude Ionosphere-Basic Elements

    NASA Technical Reports Server (NTRS)

    Lyatsky, W.; Khazanov, G. V.

    2007-01-01

    Prediction of geomagnetic activity and related events in the Earth's magnetosphere and ionosphere is an important task of the Space Weather program. Prediction reliability is dependent on the prediction method and elements included in the prediction scheme. Two main elements are a suitable geomagnetic activity index and coupling function -- the combination of solar wind parameters providing the best correlation between upstream solar wind data and geomagnetic activity. The appropriate choice of these two elements is imperative for any reliable prediction model. The purpose of this work was to elaborate on these two elements -- the appropriate geomagnetic activity index and the coupling function -- and investigate the opportunity to improve the reliability of the prediction of geomagnetic activity and other events in the Earth's magnetosphere. The new polar magnetic index of geomagnetic activity and the new version of the coupling function lead to a significant increase in the reliability of predicting the geomagnetic activity and some key parameters, such as cross-polar cap voltage and total Joule heating in high-latitude ionosphere, which play a very important role in the development of geomagnetic and other activity in the Earth s magnetosphere, and are widely used as key input parameters in modeling magnetospheric, ionospheric, and thermospheric processes.

  20. A microdose study of ¹⁴C-AR-709 in healthy men: pharmacokinetics, absolute bioavailability and concentrations in key compartments of the lung.

    PubMed

    Lappin, G; Boyce, M J; Matzow, T; Lociuro, S; Seymour, M; Warrington, S J

    2013-09-01

    To explore, in a microdose (phase-0) study, the pharmacokinetics, bioavailability and concentrations in key compartments of the lung, of AR-709, a novel diaminopyrimidine antibiotic for the treatment of respiratory infection. Four healthy men each received two single, 100 μg microdoses of ¹⁴C-AR-709, 7 days apart: the first was administered intravenously (IV), the second orally. Plasma pharmacokinetics of ¹⁴C and unchanged AR-709 were obtained by high-performance liquid chromatography and accelerator mass spectrometry (AMS). Next, 15 healthy men received a single, 100 μg microdose of ¹⁴C-AR-709 IV. Plasma, bronchoalveolar lavage fluid, alveolar macrophages and bronchial mucosal biopsy samples were analysed by AMS. After IV administration, clearance of AR-709 was 496 mL/min, volume of distribution was 1,700 L and the absolute oral bioavailability was 2.5 %. Excretion in urine was negligible. At 8-12 h after IV dosing, ¹⁴C concentrations in lung samples were 15- (bronchial mucosa) to 200- (alveolar macrophages) fold higher than in plasma. In alveolar macrophages, ¹⁴C was still mostly associated with AR-709 at 12 h after dosing. The results of this microdose study indicate that AR-709 attains concentrations appreciably higher within the lung than in plasma. Its low oral bioavailability however, precludes oral administration. Although IV administration would appear to be an effective route of administration, this would limit the use of AR-709 to a clinical setting and would therefore be economically unsustainable. If further clinical development were to be undertaken, therefore, an alternative route of administration would be necessary.

  1. Effect of the Key Mixture Parameters on Shrinkage of Reactive Powder Concrete

    PubMed Central

    Zubair, Ahmed

    2014-01-01

    Reactive powder concrete (RPC) mixtures are reported to have excellent mechanical and durability characteristics. However, such concrete mixtures having high amount of cementitious materials may have high early shrinkage causing cracking of concrete. In the present work, an attempt has been made to study the simultaneous effects of three key mixture parameters on shrinkage of the RPC mixtures. Considering three different levels of the three key mixture factors, a total of 27 mixtures of RPC were prepared according to 33 factorial experiment design. The specimens belonging to all 27 mixtures were monitored for shrinkage at different ages over a total period of 90 days. The test results were plotted to observe the variation of shrinkage with time and to see the effects of the key mixture factors. The experimental data pertaining to 90-day shrinkage were used to conduct analysis of variance to identify significance of each factor and to obtain an empirical equation correlating the shrinkage of RPC with the three key mixture factors. The rate of development of shrinkage at early ages was higher. The water to binder ratio was found to be the most prominent factor followed by cement content with the least effect of silica fume content. PMID:25050395

  2. Effect of the key mixture parameters on shrinkage of reactive powder concrete.

    PubMed

    Ahmad, Shamsad; Zubair, Ahmed; Maslehuddin, Mohammed

    2014-01-01

    Reactive powder concrete (RPC) mixtures are reported to have excellent mechanical and durability characteristics. However, such concrete mixtures having high amount of cementitious materials may have high early shrinkage causing cracking of concrete. In the present work, an attempt has been made to study the simultaneous effects of three key mixture parameters on shrinkage of the RPC mixtures. Considering three different levels of the three key mixture factors, a total of 27 mixtures of RPC were prepared according to 3(3) factorial experiment design. The specimens belonging to all 27 mixtures were monitored for shrinkage at different ages over a total period of 90 days. The test results were plotted to observe the variation of shrinkage with time and to see the effects of the key mixture factors. The experimental data pertaining to 90-day shrinkage were used to conduct analysis of variance to identify significance of each factor and to obtain an empirical equation correlating the shrinkage of RPC with the three key mixture factors. The rate of development of shrinkage at early ages was higher. The water to binder ratio was found to be the most prominent factor followed by cement content with the least effect of silica fume content.

  3. Turbulence study in the vicinity of piano key weir: relevance, instrumentation, parameters and methods

    NASA Astrophysics Data System (ADS)

    Tiwari, Harinarayan; Sharma, Nayan

    2017-05-01

    This research paper focuses on the need of turbulence, instruments reliable to capture turbulence, different turbulence parameters and some advance methodology which can decompose various turbulence structures at different levels near hydraulic structures. Small-scale turbulence research has valid prospects in open channel flow. The relevance of the study is amplified as we introduce any hydraulic structure in the channel which disturbs the natural flow and creates discontinuity. To recover this discontinuity, the piano key weir (PKW) might be used with sloped keys. Constraints of empirical results in the vicinity of PKW necessitate extensive laboratory experiments with fair and reliable instrumentation techniques. Acoustic Doppler velocimeter was established to be best suited within range of some limitations using principal component analysis. Wavelet analysis is proposed to decompose the underlying turbulence structure in a better way.

  4. Key Parameters for Operator Diagnosis of BWR Plant Condition during a Severe Accident

    SciTech Connect

    Clayton, Dwight A.; Poore, III, Willis P.

    2015-01-01

    The objective of this research is to examine the key information needed from nuclear power plant instrumentation to guide severe accident management and mitigation for boiling water reactor (BWR) designs (specifically, a BWR/4-Mark I), estimate environmental conditions that the instrumentation will experience during a severe accident, and identify potential gaps in existing instrumentation that may require further research and development. This report notes the key parameters that instrumentation needs to measure to help operators respond to severe accidents. A follow-up report will assess severe accident environmental conditions as estimated by severe accident simulation model analysis for a specific US BWR/4-Markmore » I plant for those instrumentation systems considered most important for accident management purposes.« less

  5. Key Performance Parameter Driven Technology Goals for Electric Machines and Power Systems

    NASA Technical Reports Server (NTRS)

    Bowman, Cheryl; Jansen, Ralph; Brown, Gerald; Duffy, Kirsten; Trudell, Jeffrey

    2015-01-01

    Transitioning aviation to low carbon propulsion is one of the crucial strategic research thrust and is a driver in the search for alternative propulsion system for advanced aircraft configurations. This work requires multidisciplinary skills coming from multiple entities. The feasibility of scaling up various electric drive system technologies to meet the requirements of a large commercial transport is discussed in terms of key parameters. Functional requirements are identified that impact the power system design. A breakeven analysis is presented to find the minimum allowable electric drive specific power and efficiency that can preserve the range, initial weight, operating empty weight, and payload weight of the base aircraft.

  6. A key factor to the spin parameter of uniformly rotating compact stars: crust structure

    NASA Astrophysics Data System (ADS)

    Qi, Bin; Zhang, Nai-Bo; Sun, Bao-Yuan; Wang, Shou-Yu; Gao, Jian-Hua

    2016-04-01

    We study the dimensionless spin parameter j ≡ cJ/(GM2) of different kinds of uniformly rotating compact stars, including traditional neutron stars, hyperonic neutron stars and hybrid stars, based on relativistic mean field theory and the MIT bag model. It is found that jmax ˜ 0.7, which had been suggested in traditional neutron stars, is sustained for hyperonic neutron stars and hybrid stars with M > 0.5 M⊙. Not the interior but rather the crust structure of the stars is a key factor to determine jmax for three kinds of selected compact stars. Furthermore, a universal formula j = 0.63(f/fK) - 0.42(f/fK)2 + 0.48(f/fK)3 is suggested to determine the spin parameter at any rotational frequency f smaller than the Keplerian frequency fK.

  7. A systemic study on key parameters affecting nanocomposite coatings on magnesium substrates.

    PubMed

    Johnson, Ian; Wang, Sebo Michelle; Silken, Christine; Liu, Huinan

    2016-05-01

    Nanocomposite coatings offer multiple functions simultaneously to improve the interfacial properties of magnesium (Mg) alloys for skeletal implant applications, e.g., controlling the degradation rate of Mg substrates, improving bone cell functions, and providing drug delivery capability. However, the effective service time of nanocomposite coatings may be limited due to their early delamination from the Mg-based substrates. Therefore, the objective of this study was to address the delamination issue of nanocomposite coatings, improve the coating properties for reducing the degradation of Mg-based substrates, and thus improve their cytocompatibility with bone marrow derived mesenchymal stem cells (BMSCs). The surface conditions of the substrates, polymer component type of the nanocomposite coatings, and post-deposition processing are the key parameters that contribute to the efficacy of the nanocomposite coatings in regulating substrate degradation and bone cell responses. Specifically, the effects of metallic surface versus alkaline heat-treated hydroxide surface of the substrates on coating quality were investigated. For the nanocomposite coatings, nanophase hydroxyapatite (nHA) was dispersed in three types of biodegradable polymers, i.e., poly(lactic-co-glycolic acid) (PLGA), poly(l-lactic acid) (PLLA), or poly(caprolactone) (PCL) to determine which polymer component could provide integrated properties for slowest Mg degradation. The nanocomposite coatings with or without post-deposition processing, i.e., melting, annealing, were compared to determine which processing route improved the properties of the nanocomposite coatings most significantly. The results showed that optimizing the coating processes addressed the delamination issue. The melted then annealed nHA/PCL coating on the metallic Mg substrates showed the slowest degradation and the best coating adhesion, among all the combinations of conditions studied; and, it improved the adhesion density of BMSCs

  8. [Analysis of parameters of serum concentration and pharmacokinetic of liposome and aqueous solution of toatal ginsenoside of ginseng stems and leaves in rats].

    PubMed

    Zha, Lin; Zhao, Yan; Zhu, Hong-Yan; Cai, En-Bo; Liu, Shuang-Li; Yang, He; Zhao, Ying; Gao, Yu-Gang; Zhang, Lian-Xue

    2017-05-01

    The experiment was aimed to investigate the difference of plasma concentration and pharmacokinetic parameters between liposome and aqueous solution of toatal ginsenoside of ginseng stems and leaves in rats, such as ginsenosides Rg₁, Re, Rf, Rb₁, Rg₂, Rc, Rb₂, Rb₃, Rd. After intravenous injection of liposome and aqueous solution in rats, the blood was taken from the femoral vein to detect the plasma concentration of the above 9 ginsenoside monomers in different time points by using HPLC. The concentration-time curve was obtained and 3p97 pharmacokinetic software was used to get the pharmacokinetic parameters. After the intravenous injection of ginsenosides to rats, nine ginsenosides were detected in plasma. In general, among these ginsenosides, the peak time of the aqueous solution was between 0.05 to 0.083 3 h, and the serum concentration peak of liposome usually appeared after 0.5 h. After software fitting, the aqueous solution of ginsenoside monomers Rg₁, Re, Rf, Rg₂, Rc, Rd, Rb₃ was two-compartment model, and the liposomes were one-compartment model; aqueous solution and liposome of ginsenoside monomers Rb₁ were three-compartment model; aqueous solution of ginsenoside monomers Rb₂ was three-compartment model, and its liposome was one-compartment model. Area under the drug time curve (AUC) of these 9 kinds of saponin liposomes was larger than that of aqueous solution, and the retention time of the liposomes was longer than that of the aqueous solution; the removal rate was slower than that of the aqueous solution, and the half-life was longer than that of the water solution. The results from the experiment showed that by intravenous administration, the pharmacokinetic parameters of two formulations were significantly different from each other; the liposomes could not only remain the drug for a longer time in vivo, but also reduce the elimination rate and increase the treatment efficacy. As compared with the traditional dosage forms, the total

  9. Estimation of Key Parameters of the Coupled Energy and Water Model by Assimilating Land Surface Data

    NASA Astrophysics Data System (ADS)

    Abdolghafoorian, A.; Farhadi, L.

    2017-12-01

    Accurate estimation of land surface heat and moisture fluxes, as well as root zone soil moisture, is crucial in various hydrological, meteorological, and agricultural applications. Field measurements of these fluxes are costly and cannot be readily scaled to large areas relevant to weather and climate studies. Therefore, there is a need for techniques to make quantitative estimates of heat and moisture fluxes using land surface state observations that are widely available from remote sensing across a range of scale. In this work, we applies the variational data assimilation approach to estimate land surface fluxes and soil moisture profile from the implicit information contained Land Surface Temperature (LST) and Soil Moisture (SM) (hereafter the VDA model). The VDA model is focused on the estimation of three key parameters: 1- neutral bulk heat transfer coefficient (CHN), 2- evaporative fraction from soil and canopy (EF), and 3- saturated hydraulic conductivity (Ksat). CHN and EF regulate the partitioning of available energy between sensible and latent heat fluxes. Ksat is one of the main parameters used in determining infiltration, runoff, groundwater recharge, and in simulating hydrological processes. In this study, a system of coupled parsimonious energy and water model will constrain the estimation of three unknown parameters in the VDA model. The profile of SM (LST) at multiple depths is estimated using moisture diffusion (heat diffusion) equation. In this study, the uncertainties of retrieved unknown parameters and fluxes are estimated from the inverse of Hesian matrix of cost function which is computed using the Lagrangian methodology. Analysis of uncertainty provides valuable information about the accuracy of estimated parameters and their correlation and guide the formulation of a well-posed estimation problem. The results of proposed algorithm are validated with a series of experiments using a synthetic data set generated by the simultaneous heat and

  10. Effect of varying two key parameters in simulating evacuation for a dormitory in China

    NASA Astrophysics Data System (ADS)

    Lei, Wenjun; Li, Angui; Gao, Ran

    2013-01-01

    Student dormitories are both living and resting areas for students in their spare time. There are many small rooms in the dormitories. And the students are distributed densely in the dormitories. High occupant density is the main characteristic of student dormitories. Once there is an accident, such as fire or earthquake, the losses will be cruel. Computer evacuation models developed overseas are commonly applied in working out safety management schemes. The average minimum widths of corridor and exit are the two key parameters affecting the evacuation for the dormitory. The effect of varying these two parameters will be studied in this paper by taking a dormitory in our university as an example. Evacuation performance is predicted with the software FDS + Evac. The default values in the software are used and adjusted through a field survey. The effect of varying either of the two parameters is discussed. It is found that the simulated results agree well with the experimental results. From our study it seems that the evacuation time is not in proportion to the evacuation distance. And we also named a phenomenon of “the closer is not the faster”. For the building researched in this article, a corridor width of 3 m is the most appropriate. And the suitable exit width of the dormitory for evacuation is about 2.5 to 3 m. The number of people has great influence on the walking speed of people. The purpose of this study is to optimize the building, and to make the building in favor of personnel evacuation. Then the damage could be minimized.

  11. 3-D simulations of M9 earthquakes on the Cascadia Megathrust: Key parameters and uncertainty

    USGS Publications Warehouse

    Wirth, Erin; Frankel, Arthur; Vidale, John; Marafi, Nasser A.; Stephenson, William J.

    2017-01-01

    Geologic and historical records indicate that the Cascadia subduction zone is capable of generating large, megathrust earthquakes up to magnitude 9. The last great Cascadia earthquake occurred in 1700, and thus there is no direct measure on the intensity of ground shaking or specific rupture parameters from seismic recordings. We use 3-D numerical simulations to generate broadband (0-10 Hz) synthetic seismograms for 50 M9 rupture scenarios on the Cascadia megathrust. Slip consists of multiple high-stress drop subevents (~M8) with short rise times on the deeper portion of the fault, superimposed on a background slip distribution with longer rise times. We find a >4x variation in the intensity of ground shaking depending upon several key parameters, including the down-dip limit of rupture, the slip distribution and location of strong-motion-generating subevents, and the hypocenter location. We find that extending the down-dip limit of rupture to the top of the non-volcanic tremor zone results in a ~2-3x increase in peak ground acceleration for the inland city of Seattle, Washington, compared to a completely offshore rupture. However, our simulations show that allowing the rupture to extend to the up-dip limit of tremor (i.e., the deepest rupture extent in the National Seismic Hazard Maps), even when tapering the slip to zero at the down-dip edge, results in multiple areas of coseismic coastal uplift. This is inconsistent with coastal geologic evidence (e.g., buried soils, submerged forests), which suggests predominantly coastal subsidence for the 1700 earthquake and previous events. Defining the down-dip limit of rupture as the 1 cm/yr locking contour (i.e., mostly offshore) results in primarily coseismic subsidence at coastal sites. We also find that the presence of deep subevents can produce along-strike variations in subsidence and ground shaking along the coast. Our results demonstrate the wide range of possible ground motions from an M9 megathrust earthquake in

  12. Prediction of chemotherapeutic response in bladder cancer using K-means clustering of dynamic contrast-enhanced (DCE)-MRI pharmacokinetic parameters.

    PubMed

    Nguyen, Huyen T; Jia, Guang; Shah, Zarine K; Pohar, Kamal; Mortazavi, Amir; Zynger, Debra L; Wei, Lai; Yang, Xiangyu; Clark, Daniel; Knopp, Michael V

    2015-05-01

    To apply k-means clustering of two pharmacokinetic parameters derived from 3T dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to predict the chemotherapeutic response in bladder cancer at the mid-cycle timepoint. With the predetermined number of three clusters, k-means clustering was performed on nondimensionalized Amp and kep estimates of each bladder tumor. Three cluster volume fractions (VFs) were calculated for each tumor at baseline and mid-cycle. The changes of three cluster VFs from baseline to mid-cycle were correlated with the tumor's chemotherapeutic response. Receiver-operating-characteristics curve analysis was used to evaluate the performance of each cluster VF change as a biomarker of chemotherapeutic response in bladder cancer. The k-means clustering partitioned each bladder tumor into cluster 1 (low kep and low Amp), cluster 2 (low kep and high Amp), cluster 3 (high kep and low Amp). The changes of all three cluster VFs were found to be associated with bladder tumor response to chemotherapy. The VF change of cluster 2 presented with the highest area-under-the-curve value (0.96) and the highest sensitivity/specificity/accuracy (96%/100%/97%) with a selected cutoff value. The k-means clustering of the two DCE-MRI pharmacokinetic parameters can characterize the complex microcirculatory changes within a bladder tumor to enable early prediction of the tumor's chemotherapeutic response. © 2014 Wiley Periodicals, Inc.

  13. Prediction of the Pharmacokinetic Parameters of Triptolide in Rats Based on Endogenous Molecules in Pre-Dose Baseline Serum

    PubMed Central

    Aa, Jiye; Zheng, Tian; Shi, Jian; Li, Mengjie; Wang, Xinwen; Zhao, Chunyan; Xiao, Wenjing; Yu, Xiaoyi; Sun, Runbin; Gu, Rongrong; Zhou, Jun; Wu, Liang; Hao, Gang; Zhu, Xuanxuan; Wang, Guangji

    2012-01-01

    Background Individual variances usually affect drug metabolism and disposition, and hence result in either ineffectiveness or toxicity of a drug. In addition to genetic polymorphism, the multiple confounding factors of lifestyles, such as dietary preferences, contribute partially to individual variances. However, the difficulty of quantifying individual diversity greatly challenges the realization of individualized drug therapy. This study aims at quantitative evaluating the association between individual variances and the pharmacokinetics. Methodology/Principal Findings Molecules in pre-dose baseline serum were profiled using gas chromatography mass spectrometry to represent the individual variances of the model rats provided with high fat diets (HFD), routine chows and calorie restricted (CR) chows. Triptolide and its metabolites were determined using high performance liquid chromatography mass spectrometry. Metabonomic and pharmacokinetic data revealed that rats treated with the varied diets had distinctly different metabolic patterns and showed differential Cmax values, AUC and drug metabolism after oral administration of triptolide. Rats with fatty chows had the lowest Cmax and AUC values and the highest percentage of triptolide metabolic transformation, while rats with CR chows had the highest Cmax and AUC values and the least percentage of triptolide transformation. Multivariate linear regression revealed that in baseline serum, the concentrations of creatinine and glutamic acid, which is the precursor of GSH, were linearly negatively correlated to Cmax and AUC values. The glutamic acid and creatinine in baseline serum were suggested as the potential markers to represent individual diversity and as predictors of the disposal and pharmacokinetics of triptolide. Conclusions/Significance These results highlight the robust potential of metabonomics in characterizing individual variances and identifying relevant markers that have the potential to facilitate

  14. Key parameters of the sediment surface morphodynamics in an estuary - An assessment of model solutions

    NASA Astrophysics Data System (ADS)

    Sampath, D. M. R.; Boski, T.

    2018-05-01

    Large-scale geomorphological evolution of an estuarine system was simulated by means of a hybrid estuarine sedimentation model (HESM) applied to the Guadiana Estuary, in Southwest Iberia. The model simulates the decadal-scale morphodynamics of the system under environmental forcing, using a set of analytical solutions to simplified equations of tidal wave propagation in shallow waters, constrained by empirical knowledge of estuarine sedimentary dynamics and topography. The key controlling parameters of the model are bed friction (f), current velocity power of the erosion rate function (N), and sea-level rise rate. An assessment of sensitivity of the simulated sediment surface elevation (SSE) change to these controlling parameters was performed. The model predicted the spatial differentiation of accretion and erosion, the latter especially marked in the mudflats within mean sea level and low tide level and accretion was mainly in a subtidal channel. The average SSE change mutually depended on both the friction coefficient and power of the current velocity. Analysis of the average annual SSE change suggests that the state of intertidal and subtidal compartments of the estuarine system vary differently according to the dominant processes (erosion and accretion). As the Guadiana estuarine system shows dominant erosional behaviour in the context of sea-level rise and sediment supply reduction after the closure of the Alqueva Dam, the most plausible sets of parameter values for the Guadiana Estuary are N = 1.8 and f = 0.8f0, or N = 2 and f = f0, where f0 is the empirically estimated value. For these sets of parameter values, the relative errors in SSE change did not exceed ±20% in 73% of simulation cells in the studied area. Such a limit of accuracy can be acceptable for an idealized modelling of coastal evolution in response to uncertain sea-level rise scenarios in the context of reduced sediment supply due to flow regulation. Therefore, the idealized but cost

  15. Using a Functional Simulation of Crisis Management to Test the C2 Agility Model Parameters on Key Performance Variables

    DTIC Science & Technology

    2013-06-01

    1 18th ICCRTS Using a Functional Simulation of Crisis Management to Test the C2 Agility Model Parameters on Key Performance Variables...AND SUBTITLE Using a Functional Simulation of Crisis Management to Test the C2 Agility Model Parameters on Key Performance Variables 5a. CONTRACT...command in crisis management. C2 Agility Model Agility can be conceptualized at a number of different levels; for instance at the team

  16. Influence of key processing parameters and seeding density effects of microencapsulated chondrocytes fabricated using electrohydrodynamic spraying.

    PubMed

    Gansau, Jennifer; Kelly, Lara; Buckley, Conor

    2018-06-11

    Cell delivery and leakage during injection remains a challenge for cell-based intervertebral disc regeneration strategies. Cellular microencapsulation may offer a promising approach to overcome these limitations by providing a protective niche during intradiscal injection. Electrohydrodynamic spraying (EHDS) is a versatile one-step approach for microencapsulation of cells using a high voltage electric field. The primary objective of this work was to characterise key processing parameters such as applied voltage (0, 5, 10 or 15kV), emitter needle gauge (21, 26 or 30G), alginate concentration (1, 2 or 3%) and flow rate (50, 100, 250 or 500 µl/min) to regulate the morphology of alginate microcapsules and subsequent cell viability when altering these parameters. The effect of initial cell seeding density (5, 10 and 20x10<sup>6</sup> cells/ml) on subsequent matrix accumulation of microencapsulated articular chondrocytes was also evaluated. Results showed that increasing alginate concentration and thus viscosity increased overall microcapsule size but also affected the geometry towards ellipsoidal-shaped gels. Altering the electric field strength and needle diameter regulated microcapsule size towards a smaller diameter with increasing voltage and smaller needle diameter. Needle size did not appear to affect cell viability when operating with lower alginate concentrations (1% and 2%), although higher concentrations (3%) and thus higher viscosity hydrogels resulted in diminished viability with decreasing needle diameter. Increasing cell density resulted in decreased cell viability and a concomitant decrease in DNA content, perhaps due to competing nutrient demands as a result of more closely packed cells. However, higher cell densities resulted in increased levels of extracellular matrix accumulated. Overall, this work highlights the potential of EHDS as a controllable and versatile approach to fabricate microcapsules for injectable delivery which can be

  17. Dynamic contrast-enhanced MR imaging pharmacokinetic parameters as predictors of treatment response of brain metastases in patients with lung cancer.

    PubMed

    Kuchcinski, Grégory; Le Rhun, Emilie; Cortot, Alexis B; Drumez, Elodie; Duhal, Romain; Lalisse, Maxime; Dumont, Julien; Lopes, Renaud; Pruvo, Jean-Pierre; Leclerc, Xavier; Delmaire, Christine

    2017-09-01

    To determine the diagnostic accuracy of pharmacokinetic parameters measured by dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) in predicting the response of brain metastases to antineoplastic therapy in patients with lung cancer. Forty-four consecutive patients with lung cancer, harbouring 123 newly diagnosed brain metastases prospectively underwent conventional 3-T MRI at baseline (within 1 month before treatment), during the early (7-10 weeks) and midterm (5-7 months) post-treatment period. An additional DCE MRI sequence was performed during baseline and early post-treatment MRI to evaluate baseline pharmacokinetic parameters (K trans , k ep , v e , v p ) and their early variation (∆K trans , ∆k ep , ∆v e , ∆v p ). The objective response was judged by the volume variation of each metastasis from baseline to midterm MRI. ROC curve analysis determined the best DCE MRI parameter to predict the objective response. Baseline DCE MRI parameters were not associated with the objective response. Early ∆K trans , ∆v e and ∆v p were significantly associated with the objective response (p = 0.02, p = 0.001 and p = 0.02, respectively). The best predictor of objective response was ∆v e with an area under the curve of 0.93 [95% CI = 0.87, 0.99]. DCE MRI and early ∆v e may be a useful tool to predict the objective response of brain metastases in patients with lung cancer. • DCE MRI could predict the response of brain metastases from lung cancer • ∆v e was the best predictor of response • DCE MRI could be used to individualize patients' follow-up.

  18. Integrated pharmacokinetics/pharmacodynamics parameters-based dosing guidelines of enrofloxacin in grass carp Ctenopharyngodon idella to minimize selection of drug resistance

    PubMed Central

    2013-01-01

    Background Antibiotic resistance has become a serious global problem and is steadily increasing worldwide in almost every bacterial species treated with antibiotics. In aquaculture, the therapeutic options for the treatment of A. hydrophila infection were only limited to several antibiotics, which contributed for the fast-speed emergence of drug tolerance. Accordingly, the aim of this study was to establish a medication regimen to prevent drug resistant bacteria. To determine a rational therapeutic guideline, integrated pharmacodynamics and pharmacokinetics parameters were based to predict dose and dosage interval of enrofloxacin in grass carp Ctenopharyngodon idella infected by a field-isolated A. hydrophila strain. Results The pathogenic A. hydrophila strain (AH10) in grass carp was identified and found to be sensitive to enrofloxacin. The mutant selection window (MSW) of enrofloxacin on isolate AH10 was determined to be 0.5 - 3 μg/mL based on the mutant prevention concentration (MPC) and minimum inhibitory concentration (MIC) value. By using high-performance liquid chromatography (HPLC) system, the Pharmacokinetic (PK) parameters of enrofloxacin and its metabolite ciprofloxacin in grass carp were monitored after a single oral gavage of 10, 20, 30 μg enrofloxacin per g body weight. Dosing of 30 μg/g resulted in serum maximum concentration (Cmax) of 7.151 μg/mL, and concentration in serum was above MPC till 24 h post the single dose. Once-daily dosing of 30 μg/g was determined to be the rational choice for controlling AH10 infection and preventing mutant selection in grass carp. Data of mean residue time (MRT) and body clearance (CLz) indicated that both enrofloxacin and its metabolite ciprofloxacin present similar eliminating rate and pattern in serum, muscle and liver. A withdraw time of more than 32 d was suggested based on the drug eliminating rate and pharmacokinetic model described by a polyexponential equation. Conclusions Based on integrated PK

  19. Integrated pharmacokinetics/pharmacodynamics parameters-based dosing guidelines of enrofloxacin in grass carp Ctenopharyngodon idella to minimize selection of drug resistance.

    PubMed

    Xu, Lijuan; Wang, Hao; Yang, Xianle; Lu, Liqun

    2013-06-25

    Antibiotic resistance has become a serious global problem and is steadily increasing worldwide in almost every bacterial species treated with antibiotics. In aquaculture, the therapeutic options for the treatment of A. hydrophila infection were only limited to several antibiotics, which contributed for the fast-speed emergence of drug tolerance. Accordingly, the aim of this study was to establish a medication regimen to prevent drug resistant bacteria. To determine a rational therapeutic guideline, integrated pharmacodynamics and pharmacokinetics parameters were based to predict dose and dosage interval of enrofloxacin in grass carp Ctenopharyngodon idella infected by a field-isolated A. hydrophila strain. The pathogenic A. hydrophila strain (AH10) in grass carp was identified and found to be sensitive to enrofloxacin. The mutant selection window (MSW) of enrofloxacin on isolate AH10 was determined to be 0.5-3 μg/mL based on the mutant prevention concentration (MPC) and minimum inhibitory concentration (MIC) value. By using high-performance liquid chromatography (HPLC) system, the Pharmacokinetic (PK) parameters of enrofloxacin and its metabolite ciprofloxacin in grass carp were monitored after a single oral gavage of 10, 20, 30 μg enrofloxacin per g body weight. Dosing of 30 μg/g resulted in serum maximum concentration (Cmax) of 7.151 μg/mL, and concentration in serum was above MPC till 24 h post the single dose. Once-daily dosing of 30 μg/g was determined to be the rational choice for controlling AH10 infection and preventing mutant selection in grass carp. Data of mean residue time (MRT) and body clearance (CLz) indicated that both enrofloxacin and its metabolite ciprofloxacin present similar eliminating rate and pattern in serum, muscle and liver. A withdraw time of more than 32 d was suggested based on the drug eliminating rate and pharmacokinetic model described by a polyexponential equation. Based on integrated PK/PD parameters (AUC/MIC, Cmax/MIC, and T

  20. Soil biochar amendment as a climate change mitigation tool: Key parameters and mechanisms involved.

    PubMed

    Brassard, Patrick; Godbout, Stéphane; Raghavan, Vijaya

    2016-10-01

    Biochar, a solid porous material obtained from the carbonization of biomass under low or no oxygen conditions, has been proposed as a climate change mitigation tool because it is expected to sequester carbon (C) for centuries and to reduce greenhouse gas (GHG) emissions from soils. This review aimed to identify key biochar properties and production parameters that have an effect on these specific applications of the biochar. Moreover, mechanisms involved in interactions between biochar and soils were highlighted. Following a compilation and comparison of the characteristics of 76 biochars from 40 research studies, biochars with a lower N content, and consequently a higher C/N ratio (>30), were found to be more suitable for mitigation of N2O emissions from soils. Moreover, biochars produced at a higher pyrolysis temperature, and with O/C ratio <0.2, H/Corg ratio <0.4 and volatile matter below 80% may have high C sequestration potential. Based on these observations, biochar production and application to the field can be used as a tool to mitigate climate change. However, it is important to determine the pyrolysis conditions and feedstock needed to produce a biochar with the desired properties for a specific application. More research studies are needed to identify the exact mechanisms involved following biochar amendment to soil. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Key Physiological Parameters Dictate Triggering of Activity-Dependent Bulk Endocytosis in Hippocampal Synapses

    PubMed Central

    Wenzel, Eva M.; Morton, Andrew; Ebert, Katrin; Welzel, Oliver; Kornhuber, Johannes; Cousin, Michael A.; Groemer, Teja W.

    2012-01-01

    To maintain neurotransmission in central neurons, several mechanisms are employed to retrieve synaptically exocytosed membrane. The two major modes of synaptic vesicle (SV) retrieval are clathrin-mediated endocytosis and activity-dependent bulk endocytosis (ADBE). ADBE is the dominant SV retrieval mode during intense stimulation, however the precise physiological conditions that trigger this mode are not resolved. To determine these parameters we manipulated rat hippocampal neurons using a wide spectrum of stimuli by varying both the pattern and duration of stimulation. Using live-cell fluorescence imaging and electron microscopy approaches, we established that stimulation frequency, rather than the stimulation load, was critical in the triggering of ADBE. Thus two hundred action potentials, when delivered at high frequency, were sufficient to induce near maximal bulk formation. Furthermore we observed a strong correlation between SV pool size and ability to perform ADBE. We also identified that inhibitory nerve terminals were more likely to utilize ADBE and had a larger SV recycling pool. Thus ADBE in hippocampal synaptic terminals is tightly coupled to stimulation frequency and is more likely to occur in terminals with large SV pools. These results implicate ADBE as a key modulator of both hippocampal neurotransmission and plasticity. PMID:22675521

  2. Key parameters and practices controlling pesticide degradation efficiency of biobed substrates.

    PubMed

    Karanasios, Evangelos; Karpouzas, Dimitrios G; Tsiropoulos, Nikolaos G

    2012-01-01

    We studied the contribution of each of the components of a compost-based biomixture (BX), commonly used in Europe, on pesticide degradation. The impact of other key parameters including pesticide dose, temperature and repeated applications on the degradation of eight pesticides, applied as a mixture, in a BX and a peat-based biomixture (OBX) was compared and contrasted to their degradation in soil. Incubation studies showed that straw was essential in maintaining a high pesticide degradation capacity of the biomixture, whereas compost, when mixed with soil, retarded pesticide degradation. The highest rates of degradation were shown in the biomixture composed of soil/compost/straw suggesting that all three components are essential for maximum biobed performance. Increasing doses prolonged the persistence of most pesticides with biomixtures showing a higher tolerance to high pesticide dose levels compared to soil. Increasing the incubation temperature from 15 °C to 25 °C resulted in lower t(1/2) values, with biomixtures performing better than soil at the lower temperature. Repeated applications led to a decrease in the degradation rates of most pesticides in all the substrates, with the exception of iprodione and metalaxyl. Overall, our results stress the ability of biomixtures to perform better than soil under unfavorable conditions and extreme pesticide dose levels. Copyright © Taylor & Francis Group, LLC

  3. Effects of intravenous temazepam. II. A study of the long-term reproducibility of pharmacokinetics, pharmacodynamics, and concentration-effect parameters.

    PubMed

    van Steveninck, A L; Schoemaker, H C; den Hartigh, J; Pieters, M S; Breimer, D D; Cohen, A F

    1994-05-01

    To evaluate the long-term reproducibility of pharmacokinetic, pharmacodynamic, and concentration-effect parameters after intravenous administration of temazepam. Nine healthy volunteers were studied. Temazepam, 0.4 mg/kg, was infused intravenously for 30 minutes on two occasions 6 months apart. Venous plasma concentrations of temazepam were measured by HPLC in samples obtained between 0 and 24 hours. Pharmacodynamic effects were evaluated up to 8 hours for saccadic peak velocity and electroencephalogram (EEG) beta amplitudes. Subjects' state and trait anxiety were assessed by use of the Spielberger anxiety inventory. Significant correlations between occasions were found for area under the plasma concentration-time curve (AUC) values (r = 0.91; p < 0.01) but not for maximum concentration and half-life. Significant correlations were also found for area under the effect-time curve (AUEC) values of peak velocity (r = 0.88; p < 0.01) but not for peak velocity (r = 0.48; p > 0.05). Significant differences between the slopes of concentration effect plots on different occasions were observed in two subjects for EEG beta and in three subjects for peak velocity, with one subject showing a similar change for both parameters. Trait anxiety scores were higher on the first occasion (33 +/- 7) than on the second occasion (29 +/- 7; p < 0.01). A negative correlation was found between trait anxiety scores and the slopes of concentration-effect plots for peak velocity (r = -0.63; p < 0.01). For AUC and AUEC values the results indicate a reasonable long-term reproducibility of differences between subjects in the pharmacokinetics and pharmacodynamics of temazepam. However, there were limitations to the predictive value of derived concentration-effect parameters.

  4. Application of whole-lesion histogram analysis of pharmacokinetic parameters in dynamic contrast-enhanced MRI of breast lesions with the CAIPIRINHA-Dixon-TWIST-VIBE technique.

    PubMed

    Li, Zhiwei; Ai, Tao; Hu, Yiqi; Yan, Xu; Nickel, Marcel Dominik; Xu, Xiao; Xia, Liming

    2018-01-01

    To investigate the application of whole-lesion histogram analysis of pharmacokinetic parameters for differentiating malignant from benign breast lesions on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). In all, 92 women with 97 breast lesions (26 benign and 71 malignant lesions) were enrolled in this study. Patients underwent dynamic breast MRI at 3T using a prototypical CAIPIRINHA-Dixon-TWIST-VIBE (CDT-VIBE) sequence and a subsequent surgery or biopsy. Inflow rate of the agent between plasma and interstitium (K trans ), outflow rate of agent between interstitium and plasma (K ep ), extravascular space volume per unit volume of tissue (v e ) including mean value, 25th/50th/75th/90th percentiles, skewness, and kurtosis were then calculated based on the whole lesion. A single-sample Kolmogorov-Smirnov test, paired t-test, and receiver operating characteristic curve (ROC) analysis were used for statistical analysis. Malignant breast lesions had significantly higher K trans , K ep , and lower v e in mean values, 25th/50th/75th/90th percentiles, and significantly higher skewness of v e than benign breast lesions (all P < 0.05). There was no significant difference in kurtosis values between malignant and benign breast lesions (all P > 0.05). The 90th percentile of K trans , the 90th percentile of K ep , and the 50th percentile of v e showed the greatest areas under the ROC curve (AUC) for each pharmacokinetic parameter derived from DCE-MRI. The 90th percentile of K ep achieved the highest AUC value (0.927) among all histogram-derived values. The whole-lesion histogram analysis of pharmacokinetic parameters can improve the diagnostic accuracy of breast DCE-MRI with the CDT-VIBE technique. The 90th percentile of K ep may be the best indicator in differentiation between malignant and benign breast lesions. 4 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2018;47:91-96. © 2017 International Society for Magnetic Resonance in Medicine.

  5. Key Parameters for the Use of AbobotulinumtoxinA in Aesthetics: Onset and Duration

    PubMed Central

    Ablon, Glynis; Pickett, Andy

    2017-01-01

    Abstract Time to onset of response and duration of response are key measures of botulinum toxin efficacy that have a considerable influence on patient satisfaction with aesthetic treatment. However, there is no overall accepted definition of efficacy for aesthetic uses of botulinumtoxinA (BoNT-A). Mechanical methods of assessment do not lend themselves to clinical practice and clinicians rely instead on assessment scales such as the Frontalis Activity Measurement Standard, Frontalis Rating Scale, Wrinkle Severity Scale, and Subject Global Assessment Scale, but not all of these have been fully validated. Onset of activity is typically seen within 5 days of injection, but has also been recorded within 12 hours with abobotulinumtoxinA. Duration of effect is more variable, and is influenced by parameters such as muscle mass (including the effects of age and sex) and type of product used. Even when larger muscles are treated with higher doses of BoNT-A, the duration of effect is still shorter than that for smaller muscles. Muscle injection technique, including dilution of the toxin, the volume of solution injected, and the positioning of the injections, can also have an important influence on onset and duration of activity. Comparison of the efficacy of different forms of BoNT-A must be made with the full understanding that the dosing units are not equivalent. Range of equivalence studies for abobotulinumtoxinA (Azzalure; Ipsen Limited, Slough UK/Galderma, Lausanne CH/Dysport, Ipsen Biopharm Limited, Wrexham UK/Galderma LP, Fort Worth, TX) and onabotulinumtoxinA (Botox; Allergan, Parsippany, NJ) have been conducted, and results indicate that the number of units of abobotulinumtoxinA needs to be approximately twice as high as that of onabotulinumtoxinA to achieve the same effect. An appreciation of the potential influence of all of the parameters that influence onset and duration of activity of BoNT-A, along with a thorough understanding of the anatomy of the face and

  6. Lead-acid batteries in micro-hybrid applications. Part I. Selected key parameters

    NASA Astrophysics Data System (ADS)

    Schaeck, S.; Stoermer, A. O.; Kaiser, F.; Koehler, L.; Albers, J.; Kabza, H.

    Micro-hybrid electric vehicles were launched by BMW in March 2007. These are equipped with brake energy regeneration (BER) and the automatic start and stop function (ASSF) of the internal combustion engine. These functions are based on common 14 V series components and lead-acid (LA) batteries. The novelty is given by the intelligent onboard energy management, which upgrades the conventional electric system to the micro-hybrid power system (MHPS). In part I of this publication the key factors for the operation of LA batteries in the MHPS are discussed. Especially for BER one is high dynamic charge acceptance (DCA) for effective boost charging. Vehicle rest time is identified as a particular negative parameter for DCA. It can be refreshed by regular fully charging at elevated charge voltage. Thus, the batteries have to be outstandingly robust against overcharge and water loss. This can be accomplished for valve-regulated lead-acid (VRLA) batteries at least if they are mounted in the trunk. ASSF goes along with frequent high-rate loads for warm cranking. The internal resistance determines the drop of the power net voltage during cranking and is preferably low for reasons of power net stability even after years of operation. Investigations have to be done with aged 90 Ah VRLA-absorbent glass mat (AGM) batteries. Battery operation at partial state-of-charge gives a higher risk of deep discharging (overdischarging). Subsequent re-charging then is likely to lead to the formation of micro-short circuits in the absorbent glass mat separator.

  7. Impact of imipenem and amikacin pharmacokinetic/pharmacodynamic parameters on microbiological outcome of Gram-negative bacilli ventilator-associated pneumonia.

    PubMed

    Pajot, O; Burdet, C; Couffignal, C; Massias, L; Armand-Lefevre, L; Foucrier, A; Da Silva, D; Lasocki, S; Laouénan, C; Mentec, H; Mentré, F; Wolff, M

    2015-05-01

    Despite recent advances, antibiotic therapy of ventilator-associated pneumonia (VAP) in ICU patients is still challenging. We assessed the impact of imipenem and amikacin pharmacokinetic and pharmacodynamic parameters on microbiological outcome in these patients. Patients with Gram-negative bacilli (GNB) VAP were prospectively included. Blood samples for pharmacokinetic analysis were collected after empirical administration of a combination of imipenem three times daily and one single dose of amikacin. MICs were estimated for each GNB obtained from respiratory samples. Microbiological success was defined as a ≥10(3) cfu/mL decrease in bacterial count in quantitative cultures between baseline and the third day of treatment. Thirty-nine patients [median (min-max) age = 60 years (28-84) and median SAPS2 at inclusion = 40 (19-73)] were included. Median MICs of imipenem and amikacin were 0.25 mg/L (0.094-16) and 2 mg/L (1-32), respectively. Median times over MIC and over 5× MIC for imipenem were 100% (8-100) and 74% (3-100), respectively. The median C1/MIC ratio for amikacin was 23 (1-76); 34 patients (87%) achieved a C1/MIC ≥10. Microbiological success occurred in 29 patients (74%). No imipenem pharmacodynamic parameter was significantly associated with the microbiological success. For amikacin, C1/MIC was significantly higher in the microbiological success group: 26 (1-76) versus 11 (3-26) (P = 0.004). In ICU patients with VAP, classic imipenem pharmacodynamic targets are easily reached with usual dosing regimens. In this context, for amikacin, a higher C1/MIC ratio than previously described might be necessary. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  8. Organophosphorus Insecticide Pharmacokinetics

    SciTech Connect

    Timchalk, Charles

    2010-01-01

    This chapter highlights a number of current and future applications of pharmacokinetics to assess organophosphate (OP) insecticide dosimetry, biological response and risk in humans exposed to these agents. Organophosphates represent a large family of pesticides where insecticidal as well as toxicological mode of action is associated with their ability to target and inhibit acetylcholinesterase (AChE). Pharmacokinetics entails the quantitative integration of physiological and metabolic processes associated with the absorption, distribution, metabolism and excretion (ADME) of drugs and xenobiotics. Pharmacokinetic studies provide important data on the amount of toxicant delivered to a target site as well as species-, age-, gender-specific andmore » dose-dependent differences in biological response. These studies have been conducted with organophosphorus insecticides in multiple species, at various dose levels, and across different routes of exposure to understand their in vivo pharmacokinetics and how they contribute to the observed toxicological response. To access human exposure to organophosphorus insecticides, human pharmacokinetic studies have been conducted and used to develop biological monitoring strategies based on the quantitation of key metabolites in biological fluids. Pharmacokinetic studies with these insecticides are also useful to facilitate extrapolation of dosimetry and biological response from animals to humans and for the assessment of human health risk. In this regard, physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models are being utilized to assess risk and understand the toxicological implications of known or suspected exposures to various insecticides. In this chapter a number of examples are presented that illustrate the utility and limitation of pharmacokinetic studies to address human health concerns associated with organophosphorus insecticides.« less

  9. Plasma and cerebrospinal fluid pharmacokinetic parameters after single-dose administration of intravenous, oral, or rectal acetaminophen.

    PubMed

    Singla, Neil K; Parulan, Cherri; Samson, Roselle; Hutchinson, Joel; Bushnell, Rick; Beja, Evelyn G; Ang, Robert; Royal, Mike A

    2012-09-01

    This is the first study to compare plasma and cerebrospinal fluid (CSF) pharmacokinetics of intravenous (IV), oral (PO), or rectal (PR) formulations of acetaminophen. Healthy male subjects (N = 6) were randomized to receive a single dose of IV (OFIRMEV(®) ; Cadence) 1,000 mg (15 minute infusion), PO (2 Tylenol(®) 500 mg caplets; McNeil Consumer Healthcare), or PR acetaminophen (2 Feverall(®) 650 mg suppositories; Actavis) with a 1-day washout period between doses. The 1,300 mg PR concentrations were standardized to 1,000 mg. Acetaminophen plasma and CSF levels were obtained at T0, 0.25, 0.5, 0.75, 1, 2, 3, 4, and 6 hours. IV acetaminophen showed earlier and higher plasma and CSF levels compared with PO or PR administration. CSF bioavailability over 6 hours (AUC(0-6)) for IV, PO, and PR 1 g was 24.9, 14.2, and 10.3 μg·h/mL, respectively. No treatment-related adverse events were reported. One subject was replaced because of premature failure of his lumbar spinal catheter. The mean CSF level in the IV group was similar to plasma from 3 to 4 hours and higher from 4 hours on. Absorption phase, variability in plasma, and CSF were greater in PO and PR groups than variability with IV administration. These results demonstrate that earlier and greater CSF penetration occurs as a result of the earlier and higher plasma peak with IV administration compared with PO or PR. © 2012 Lotus Clinical Research, LLC. Pain Practice © 2012 World Institute of Pain.

  10. In vitro enantioselective human liver microsomal metabolism and prediction of in vivo pharmacokinetic parameters of tetrabenazine by DLLME-CE.

    PubMed

    Bocato, Mariana Zuccherato; de Lima Moreira, Fernanda; de Albuquerque, Nayara Cristina Perez; de Gaitani, Cristiane Masetto; de Oliveira, Anderson Rodrigo Moraes

    2016-09-05

    A new capillary electrophoresis method for the enantioselective analysis of cis- and trans- dihydrotetrabenazine (diHTBZ) after in vitro metabolism by human liver microsomes (HLMs) was developed. The chiral electrophoretic separations were performed by using tris-phosphate buffer (pH 2.5) containing 1% (w/v) carboxymethyl-β-CD as background electrolyte with an applied voltage of +15kV and capillary temperature kept at 15°C. Dispersive liquid-liquid microextraction was employed to extract the analytes from HLMs. Dichloromethane was used as extraction solvent (75μL) and acetone as disperser solvent (150μL). The method was validated according to official guidelines and showed to be linear over the concentration range of 0.29-19.57μmolL(-1) (r=0.9955) for each metabolite enantiomer. Within- and between-day precision and accuracy evaluated by relative standard deviation and relative error were lower than 15% for all enantiomers. The stability assay showed that the analytes kept stable under handling, storage and in metabolism conditions. After method validation, an enantioselective in vitro metabolism and in vivo pharmacokinetic prediction was carried out. This study showed a stereoselective metabolism and the observed kinetic profile indicated a substrate inhibition behavior. DiHTBZ enantiomers were catalyzed mainly by CYP2C19 and the predicted clearance suggests that liver metabolism is the main route for TBZ elimination which supports the literature data. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Determination of quantitative retention-activity relationships between pharmacokinetic parameters and biological effectiveness fingerprints of Salvia miltiorrhiza constituents using biopartitioning and microemulsion high-performance liquid chromatography.

    PubMed

    Gao, Haoshi; Huang, Hongzhang; Zheng, Aini; Yu, Nuojun; Li, Ning

    2017-11-01

    In this study, we analyzed danshen (Salvia miltiorrhiza) constituents using biopartitioning and microemulsion high-performance liquid chromatography (MELC). The quantitative retention-activity relationships (QRARs) of the constituents were established to model their pharmacokinetic (PK) parameters and chromatographic retention data, and generate their biological effectiveness fingerprints. A high-performance liquid chromatography (HPLC) method was established to determine the abundance of the extracted danshen constituents, such as sodium danshensu, rosmarinic acid, salvianolic acid B, protocatechuic aldehyde, cryptotanshinone, and tanshinone IIA. And another HPLC protocol was established to determine the abundance of those constituents in rat plasma samples. An experimental model was built in Sprague Dawley (SD) rats, and calculated the corresponding PK parameterst with 3P97 software package. Thirty-five model drugs were selected to test the PK parameter prediction capacities of the various MELC systems and to optimize the chromatographic protocols. QRARs and generated PK fingerprints were established. The test included water/oil-soluble danshen constituents and the prediction capacity of the regression model was validated. The results showed that the model had good predictability. Copyright © 2017. Published by Elsevier B.V.

  12. Simulation-based Extraction of Key Material Parameters from Atomic Force Microscopy

    NASA Astrophysics Data System (ADS)

    Alsafi, Huseen; Peninngton, Gray

    Models for the atomic force microscopy (AFM) tip and sample interaction contain numerous material parameters that are often poorly known. This is especially true when dealing with novel material systems or when imaging samples that are exposed to complicated interactions with the local environment. In this work we use Monte Carlo methods to extract sample material parameters from the experimental AFM analysis of a test sample. The parameterized theoretical model that we use is based on the Virtual Environment for Dynamic AFM (VEDA) [1]. The extracted material parameters are then compared with the accepted values for our test sample. Using this procedure, we suggest a method that can be used to successfully determine unknown material properties in novel and complicated material systems. We acknowledge Fisher Endowment Grant support from the Jess and Mildred Fisher College of Science and Mathematics,Towson University.

  13. An investigation of the key parameters for predicting PV soiling losses

    DOE PAGES

    Micheli, Leonardo; Muller, Matthew

    2017-01-25

    One hundred and two environmental and meteorological parameters have been investigated and compared with the performance of 20 soiling stations installed in the USA, in order to determine their ability to predict the soiling losses occurring on PV systems. The results of this investigation showed that the annual average of the daily mean particulate matter values recorded by monitoring stations deployed near the PV systems are the best soiling predictors, with coefficients of determination ( R 2) as high as 0.82. The precipitation pattern was also found to be relevant: among the different meteorological parameters, the average length of drymore » periods had the best correlation with the soiling ratio. Lastly, a preliminary investigation of two-variable regressions was attempted and resulted in an adjusted R 2 of 0.90 when a combination of PM 2.5 and a binary classification for the average length of the dry period was introduced.« less

  14. Assessment of chronic kidney disease using skin texture as a key parameter: for South Indian population.

    PubMed

    Udhayarasu, Madhanlal; Ramakrishnan, Kalpana; Periasamy, Soundararajan

    2017-12-01

    Periodical monitoring of renal function, specifically for subjects with history of diabetic or hypertension would prevent them from entering into chronic kidney disease (CKD) condition. The recent increase in numbers may be due to food habits or lack of physical exercise, necessitates a rapid kidney function monitoring system. Presently, it is determined by evaluating glomerular filtration rate (GFR) that is mainly dependent on serum creatinine value and demographic parameters and ethnic value. Attempted here is to develop ethnic parameter based on skin texture for every individual. This value when used in GFR computation, the results are much agreeable with GFR obtained through standard modification of diet in renal disease and CKD epidemiology collaboration equations. Once correlation between CKD and skin texture is established, classification tool using artificial neural network is built to categorise CKD level based on demographic values and parameter obtained through skin texture (without using creatinine). This network when tested gives almost at par results with the network that is trained with demographic and creatinine values. The results of this Letter demonstrate the possibility of non-invasively determining kidney function and hence for making a device that would readily assess the kidney function even at home.

  15. Prediction of Geomagnetic Activity and Key Parameters in High-latitude Ionosphere

    NASA Technical Reports Server (NTRS)

    Khazanov, George V.; Lyatsky, Wladislaw; Tan, Arjun; Ridley, Aaron

    2007-01-01

    Prediction of geomagnetic activity and related events in the Earth's magnetosphere and ionosphere are important tasks of US Space Weather Program. Prediction reliability is dependent on the prediction method, and elements included in the prediction scheme. Two of the main elements of such prediction scheme are: an appropriate geomagnetic activity index, and an appropriate coupling function (the combination of solar wind parameters providing the best correlation between upstream solar wind data and geomagnetic activity). We have developed a new index of geomagnetic activity, the Polar Magnetic (PM) index and an improved version of solar wind coupling function. PM index is similar to the existing polar cap PC index but it shows much better correlation with upstream solar wind/IMF data and other events in the magnetosphere and ionosphere. We investigate the correlation of PM index with upstream solar wind/IMF data for 10 years (1995-2004) that include both low and high solar activity. We also have introduced a new prediction function for the predicting of cross-polar-cap voltage and Joule heating based on using both PM index and upstream solar wind/IMF data. As we show such prediction function significantly increase the reliability of prediction of these important parameters. The correlation coefficients between the actual and predicted values of these parameters are approx. 0.9 and higher.

  16. Solar oxidation and removal of arsenic--Key parameters for continuous flow applications.

    PubMed

    Gill, L W; O'Farrell, C

    2015-12-01

    Solar oxidation to remove arsenic from water has previously been investigated as a batch process. This research has investigated the kinetic parameters for the design of a continuous flow solar reactor to remove arsenic from contaminated groundwater supplies. Continuous flow recirculated batch experiments were carried out under artificial UV light to investigate the effect of different parameters on arsenic removal efficiency. Inlet water arsenic concentrations of up to 1000 μg/L were reduced to below 10 μg/L requiring 12 mg/L iron after receiving 12 kJUV/L radiation. Citrate however was somewhat surprisingly found to promote a detrimental effect on the removal process in the continuous flow reactor studies which is contrary to results found in batch scale tests. The impact of other typical water groundwater quality parameters (phosphate and silica) on the process due to their competition with arsenic for photooxidation products revealed a much higher sensitivity to phosphate ions compared to silicate. Other results showed no benefit from the addition of TiO2 photocatalyst but enhanced arsenic removal at higher temperatures up to 40 °C. Overall, these results have indicated the kinetic envelope from which a continuous flow SORAS single pass system could be more confidently designed for a full-scale community groundwater application at a village level. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Robust and efficient pharmacokinetic parameter non-linear least squares estimation for dynamic contrast enhanced MRI of the prostate.

    PubMed

    Kargar, Soudabeh; Borisch, Eric A; Froemming, Adam T; Kawashima, Akira; Mynderse, Lance A; Stinson, Eric G; Trzasko, Joshua D; Riederer, Stephen J

    2018-05-01

    To describe an efficient numerical optimization technique using non-linear least squares to estimate perfusion parameters for the Tofts and extended Tofts models from dynamic contrast enhanced (DCE) MRI data and apply the technique to prostate cancer. Parameters were estimated by fitting the two Tofts-based perfusion models to the acquired data via non-linear least squares. We apply Variable Projection (VP) to convert the fitting problem from a multi-dimensional to a one-dimensional line search to improve computational efficiency and robustness. Using simulation and DCE-MRI studies in twenty patients with suspected prostate cancer, the VP-based solver was compared against the traditional Levenberg-Marquardt (LM) strategy for accuracy, noise amplification, robustness to converge, and computation time. The simulation demonstrated that VP and LM were both accurate in that the medians closely matched assumed values across typical signal to noise ratio (SNR) levels for both Tofts models. VP and LM showed similar noise sensitivity. Studies using the patient data showed that the VP method reliably converged and matched results from LM with approximate 3× and 2× reductions in computation time for the standard (two-parameter) and extended (three-parameter) Tofts models. While LM failed to converge in 14% of the patient data, VP converged in the ideal 100%. The VP-based method for non-linear least squares estimation of perfusion parameters for prostate MRI is equivalent in accuracy and robustness to noise, while being more reliably (100%) convergent and computationally about 3× (TM) and 2× (ETM) faster than the LM-based method. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. [Key physical parameters of hawthorn leaf granules by stepwise regression analysis method].

    PubMed

    Jiang, Qie-Ying; Zeng, Rong-Gui; Li, Zhe; Luo, Juan; Zhao, Guo-Wei; Lv, Dan; Liao, Zheng-Gen

    2017-05-01

    The purpose of this study was to investigate the effect of key physical properties of hawthorn leaf granule on its dissolution behavior. Hawthorn leaves extract was utilized as a model drug. The extract was mixed with microcrystalline cellulose or starch with the same ratio by using different methods. Appropriate amount of lubricant and disintegrating agent was added into part of the mixed powder, and then the granules were prepared by using extrusion granulation and high shear granulation. The granules dissolution behavior was evaluated by using equilibrium dissolution quantity and dissolution rate constant of the hypericin as the indicators. Then the effect of physical properties on dissolution behavior was analyzed through the stepwise regression analysis method. The equilibrium dissolution quantity of hypericin and adsorption heat constant in hawthorn leaves were positively correlated with the monolayer adsorption capacity and negatively correlated with the moisture absorption rate constant. The dissolution rate constants were decreased with the increase of Hausner rate, monolayer adsorption capacity and adsorption heat constant, and were increased with the increase of Carr index and specific surface area. Adsorption heat constant, monolayer adsorption capacity, moisture absorption rate constant, Carr index and specific surface area were the key physical properties of hawthorn leaf granule to affect its dissolution behavior. Copyright© by the Chinese Pharmaceutical Association.

  19. Measurement of Key Pool BOiling Parameters in nanofluids for Nuclerar Applications

    SciTech Connect

    Bang, In C; Buongiorno, Jdacopo; Hu, Lin-wen

    Nanofluids, colloidal dispersions of nanoparticles in a base fluid such as water, can afford very significant Critical Heat Flux (CHF) enhancement. Such engineered fluids potentially could be employed in reactors as advanced coolants in safety systems with significant safety and economic advantages. However, a satisfactory explanation of the CHF enhancement mechanism in nanofluids is lacking. To close this gap, we have identified the important boiling parameters to be measured. These are the properties (e.g., density, viscosity, thermal conductivity, specific heat, vaporization enthalpy, surface tension), hydrodynamic parameters (i.e., bubble size, bubble velocity, departure frequency, hot/dry spot dynamics) and surface conditions (i.e.,more » contact angle, nucleation site density). We have also deployed a pool boiling facility in which many such parameters can be measured. The facility is equipped with a thin indium-tin-oxide heater deposited over a sapphire substrate. An infra-red high-speed camera and an optical probe are used to measure the temperature distribution on the heater and the hydrodynamics above the heater, respectively. The first data generated with this facility already provide some clue on the CHF enhancement mechanism in nanofluids. Specifically, the progression to burnout in a pure fluid (ethanol in this case) is characterized by a smoothly-shaped and steadily-expanding hot spot. By contrast, in the ethanol-based nanofluid the hot spot pulsates and the progression to burnout lasts longer, although the nanofluid CHF is higher than the pure fluid CHF. The presence of a nanoparticle deposition layer on the heater surface seems to enhance wettability and aid hot spot dissipation, thus delaying burnout.« less

  20. Seasonal microbial and environmental parameters at Crocker Reef, Florida Keys, 2014–2015

    USGS Publications Warehouse

    Kellogg, Christina A.; Yates, Kimberly K.; Lawler, Stephanie N.; Moore, Christopher S.; Smiley, Nathan A.

    2015-11-04

    Microbial measurements included enumeration of total bacteria, enumeration of virus-like particles, and plate counts of Vibrio spp. colony-forming units (CFU). These measurements were intended to give a sense of any seasonal changes in the total microbial load and to provide an indication of water quality. Additional environmental parameters measured included water temperature, salinity, dissolved oxygen, and pH. Four sites (table 1) were intensively sampled for periods of approximately 48 hours during summer (July 2014) and winter (January–February 2015), during which water samples were collected every 4 hours for analysis, except when prevented by weather conditions.

  1. Parameter optimization in biased decoy-state quantum key distribution with both source errors and statistical fluctuations

    NASA Astrophysics Data System (ADS)

    Zhu, Jian-Rong; Li, Jian; Zhang, Chun-Mei; Wang, Qin

    2017-10-01

    The decoy-state method has been widely used in commercial quantum key distribution (QKD) systems. In view of the practical decoy-state QKD with both source errors and statistical fluctuations, we propose a universal model of full parameter optimization in biased decoy-state QKD with phase-randomized sources. Besides, we adopt this model to carry out simulations of two widely used sources: weak coherent source (WCS) and heralded single-photon source (HSPS). Results show that full parameter optimization can significantly improve not only the secure transmission distance but also the final key generation rate. And when taking source errors and statistical fluctuations into account, the performance of decoy-state QKD using HSPS suffered less than that of decoy-state QKD using WCS.

  2. The Thermal Conductivity of Earth's Core: A Key Geophysical Parameter's Constraints and Uncertainties

    NASA Astrophysics Data System (ADS)

    Williams, Q.

    2018-05-01

    The thermal conductivity of iron alloys at high pressures and temperatures is a critical parameter in governing ( a) the present-day heat flow out of Earth's core, ( b) the inferred age of Earth's inner core, and ( c) the thermal evolution of Earth's core and lowermost mantle. It is, however, one of the least well-constrained important geophysical parameters, with current estimates for end-member iron under core-mantle boundary conditions varying by about a factor of 6. Here, the current state of calculations, measurements, and inferences that constrain thermal conductivity at core conditions are reviewed. The applicability of the Wiedemann-Franz law, commonly used to convert electrical resistivity data to thermal conductivity data, is probed: Here, whether the constant of proportionality, the Lorenz number, is constant at extreme conditions is of vital importance. Electron-electron inelastic scattering and increases in Fermi-liquid-like behavior may cause uncertainties in thermal conductivities derived from both first-principles-associated calculations and electrical conductivity measurements. Additional uncertainties include the role of alloying constituents and local magnetic moments of iron in modulating the thermal conductivity. Thus, uncertainties in thermal conductivity remain pervasive, and hence a broad range of core heat flows and inner core ages appear to remain plausible.

  3. A Bayesian Framework for Coupled Estimation of Key Unknown Parameters of Land Water and Energy Balance Equations

    NASA Astrophysics Data System (ADS)

    Farhadi, L.; Abdolghafoorian, A.

    2015-12-01

    The land surface is a key component of climate system. It controls the partitioning of available energy at the surface between sensible and latent heat, and partitioning of available water between evaporation and runoff. Water and energy cycle are intrinsically coupled through evaporation, which represents a heat exchange as latent heat flux. Accurate estimation of fluxes of heat and moisture are of significant importance in many fields such as hydrology, climatology and meteorology. In this study we develop and apply a Bayesian framework for estimating the key unknown parameters of terrestrial water and energy balance equations (i.e. moisture and heat diffusion) and their uncertainty in land surface models. These equations are coupled through flux of evaporation. The estimation system is based on the adjoint method for solving a least-squares optimization problem. The cost function consists of aggregated errors on state (i.e. moisture and temperature) with respect to observation and parameters estimation with respect to prior values over the entire assimilation period. This cost function is minimized with respect to parameters to identify models of sensible heat, latent heat/evaporation and drainage and runoff. Inverse of Hessian of the cost function is an approximation of the posterior uncertainty of parameter estimates. Uncertainty of estimated fluxes is estimated by propagating the uncertainty for linear and nonlinear function of key parameters through the method of First Order Second Moment (FOSM). Uncertainty analysis is used in this method to guide the formulation of a well-posed estimation problem. Accuracy of the method is assessed at point scale using surface energy and water fluxes generated by the Simultaneous Heat and Water (SHAW) model at the selected AmeriFlux stations. This method can be applied to diverse climates and land surface conditions with different spatial scales, using remotely sensed measurements of surface moisture and temperature states

  4. Key performance indicators for stroke from the Ministry of Health of Brazil: benchmarking and indicator parameters.

    PubMed

    Lange, Marcos C; Braga, Gabriel Pereira; Nóvak, Edison M; Harger, Rodrigo; Felippe, Maria Justina Dalla Bernardina; Canever, Mariana; Dall'Asta, Isabella; Rauen, Jordana; Bazan, Rodrigo; Zetola, Viviane

    2017-06-01

    All 16 KPIs were analyzed, including the percentage of patients admitted to the stroke unit, venous thromboembolism prophylaxis in the first 48 hours after admission, pneumonia and hospital mortality due to stroke, and hospital discharge on antithrombotic therapy in patients without cardioembolic mechanism. Both centers admitted over 80% of the patients in their stroke unit. The incidence of venous thromboembolism prophylaxis was > 85%, that of in-hospital pneumonia was < 13%, the hospital mortality for stroke was < 15%, and the hospital discharge on antithrombotic therapy was > 70%. Our results suggest using the parameters of all of the 16 KPIs required by the Ministry of Health of Brazil, and the present results for the two stroke units for future benchmarking.

  5. Laser contrast and other key parameters enhancing the laser conversion efficiency in ion acceleration regime

    NASA Astrophysics Data System (ADS)

    Torrisi, Lorenzo

    2018-01-01

    Measurements of ion acceleration in plasma produced by fs lasers at intensity of the order of 1018 W/cm2 have been performed in different European laboratories. The forward emission in target-normal-sheath-acceleration (TNSA) regime indicated that the maximum energy is a function of the laser parameters, of the irradiation conditions and of the target properties.In particular the laser intensity and contrast play an important role to maximize the ion acceleration enhancing the conversion efficiency. Also the use of suitable prepulses, focal distances and polarized laser light has important roles. Finally the target composition, surface, geometry and multilayered structure, permit to enhance the electric field driving the forward ion acceleration.Experimental measurements will be reported and discussed.

  6. Study of the Influence of Key Process Parameters on Furfural Production.

    PubMed

    Fele Žilnik, Ljudmila; Grilc, Viktor; Mirt, Ivan; Cerovečki, Željko

    2016-01-01

    The present work reports the influence of key process variables on the furfural formation from leached chestnut-wood chips in a pressurized reactor. Effect of temperature, pressure, type and concentration of the catalyst solution, the steam flow rate or stripping module, the moisture content of the wood particles and geometric characteristics such as size and type of the reactor, particle size and bed height were considered systematically. One stage process was only taken into consideration. Lab-scale and pilot-scale studies were performed. The results of the non-catalysed laboratory experiments were compared with an actual non-catalysed (auto-catalysed) industrial process and with experiments on the pilot scale, the latter with 28% higher furfural yield compared to the others. Application of sulphuric acid as catalyst, in an amount of 0.03-0.05 g (H2SO4 100%)/g d.m. (dry material), enables a higher production of furfural at lower temperature and pressure of steam in a shorter reaction time. Pilot scale catalysed experiments have revealed very good performance for furfural formation under less severe operating conditions, with a maximum furfural yield as much as 88% of the theoretical value.

  7. Total solids content: a key parameter of metabolic pathways in dry anaerobic digestion

    PubMed Central

    2013-01-01

    Background In solid-state anaerobic digestion (AD) bioprocesses, hydrolytic and acidogenic microbial metabolisms have not yet been clarified. Since these stages are particularly important for the establishment of the biological reaction, better knowledge could optimize the process performances by process parameters adjustment. Results This study demonstrated the effect of total solids (TS) content on microbial fermentation of wheat straw with six different TS contents ranging from wet to dry conditions (10 to 33% TS). Three groups of metabolic behaviors were distinguished based on wheat straw conversion rates with 2,200, 1,600, and 1,400 mmol.kgVS-1 of fermentative products under wet (10 and 14% TS), dry (19 to 28% TS), and highly dry (28 to 33% TS) conditions, respectively. Furthermore, both wet and dry fermentations showed acetic and butyric acid metabolisms, whereas a mainly butyric acid metabolism occurred in highly dry fermentation. Conclusion Substrate conversion was reduced with no changes of the metabolic pathways until a clear limit at 28% TS content, which corresponded to the threshold value of free water content of wheat straw. This study suggested that metabolic pathways present a limit of TS content for high-solid AD. PMID:24261971

  8. Investigation of Key Parameters of Rock Cracking Using the Expansion of Vermiculite Materia.

    PubMed

    Ahn, Chi-Hyung; Hu, Jong Wan

    2015-10-12

    The demand for the development of underground spaces has been sharply increased in lieu of saturated ground spaces because the residents of cities have steadily increased since the 1980s. The traditional widely used excavation methods ( i.e ., explosion and shield) have caused many problems, such as noise, vibration, extended schedule, and increased costs. The vibration-free (and explosion-free) excavation method has currently attracted attention in the construction site because of the advantage of definitively solving these issues. For such reason, a new excavation method that utilizes the expansion of vermiculite with relatively fewer defects is proposed in this study. In general, vermiculite materials are rapidly expanded in volume when they receive thermal energy. Expansion pressure can be produced by thermal expansion of vermiculite in a steel tube, and measured by laboratory tests. The experimental tests are performed with various influencing parameters in an effort to seek the optimal condition to effectively increase expansion pressure at the same temperature. Then, calibrated expansion pressure is estimated, and compared to each model. After analyzing test results for expansion pressure, it is verified that vermiculite expanded by heat can provide enough internal pressure to break hard rock during tunneling work.

  9. Structure-activity modelling of essential oils, their components, and key molecular parameters and descriptors.

    PubMed

    Owen, Lucy; Laird, Katie; Wilson, Philippe B

    2018-04-01

    Many essential oil components are known to possess broad spectrum antimicrobial activity, including against antibiotic resistant bacteria. These compounds may be a useful source of new and novel antimicrobials. However, there is limited research on the structure-activity relationship (SAR) of essential oil compounds, which is important for target identification and lead optimization. This study aimed to elucidate SARs of essential oil components from experimental and literature sources. Minimum Inhibitory Concentrations (MICs) of essential oil components were determined against Escherichia coli and Staphylococcus aureus using a microdilution method and then compared to those in published in literature. Of 12 essential oil components tested, carvacrol and cuminaldehyde were most potent with MICs of 1.98 and 2.10 mM, respectively. The activity of 21 compounds obtained from the literature, MICs ranged from 0.004 mM for limonene to 36.18 mM for α-terpineol. A 3D qualitative SAR model was generated from MICs using FORGE software by consideration of electrostatic and steric parameters. An r 2 value of 0.807 for training and cross-validation sets was achieved with the model developed. Ligand efficiency was found to correlate well to the observed activity (r 2  = 0.792), while strongly negative electrostatic regions were present in potent molecules. These descriptors may be useful for target identification of essential oils or their major components in antimicrobial/drug development. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Investigation of Key Parameters of Rock Cracking Using the Expansion of Vermiculite Materials

    PubMed Central

    Ahn, Chi-Hyung; Hu, Jong Wan

    2015-01-01

    The demand for the development of underground spaces has been sharply increased in lieu of saturated ground spaces because the residents of cities have steadily increased since the 1980s. The traditional widely used excavation methods (i.e., explosion and shield) have caused many problems, such as noise, vibration, extended schedule, and increased costs. The vibration-free (and explosion-free) excavation method has currently attracted attention in the construction site because of the advantage of definitively solving these issues. For such reason, a new excavation method that utilizes the expansion of vermiculite with relatively fewer defects is proposed in this study. In general, vermiculite materials are rapidly expanded in volume when they receive thermal energy. Expansion pressure can be produced by thermal expansion of vermiculite in a steel tube, and measured by laboratory tests. The experimental tests are performed with various influencing parameters in an effort to seek the optimal condition to effectively increase expansion pressure at the same temperature. Then, calibrated expansion pressure is estimated, and compared to each model. After analyzing test results for expansion pressure, it is verified that vermiculite expanded by heat can provide enough internal pressure to break hard rock during tunneling work. PMID:28793610

  11. Key process parameters involved in the treatment of olive mill wastewater by membrane bioreactor.

    PubMed

    Jaouad, Y; Villain-Gambier, M; Mandi, L; Marrot, B; Ouazzani, N

    2018-04-18

    The Olive Mill Wastewater (OMWW) biodegradation in an external ceramic membrane bioreactor (MBR) was investigated with a starting acclimation step with a Ultrafiltration (UF) membrane (150 kDa) and no sludge discharge in order to develop a specific biomass adapted to OMWW biodegradation. After acclimation step, UF was replaced by an Microfiltration (MF) membrane (0.1 µm). Sludge Retention Time (SRT) was set around 25 days and Food to Microorganisms ratio (F/M) was fixed at 0.2 kg COD  kg MLVSS -1  d -1 . At stable state, removal of the main phenolic compounds (hydroxytyrosol and tyrosol) and Chemical Oxygen Demand (COD) were successfully reached (95% both). Considered as a predominant fouling factor, but never quantified in MBR treated OMWW, Soluble Microbial Products (SMP) proteins, polysaccharides and humic substances concentrations were determined (80, 110 and 360 mg L -1 respectively). At the same time, fouling was easily managed due to favourable hydraulic conditions of external ceramic MBR. Therefore, OMWW could be efficiently and durably treated by an MF MBR process under adapted operating parameters.

  12. [The key parameters of design research and analysis of the Chinese reading visual acuity chart].

    PubMed

    Wang, Chen-xiao; Liu, Zhi-hui; Gao, Ji-tuo; Guo, Ying-xuan; He, Ji-cang; Qu, Jia; Lü, Fan

    2013-06-01

    Reading is a visual function human being used to understand environmental events based on writing materials. This study investigated the feasibility of reading visual acuity chart in assessment of reading ability by analysis of the key factors involved in the design of the visual acuity chart. The reading level was determined as grade 3 primary school with Song as the font and 30 characters included in the sentences. Each of the sentences consisted of 27 commonly-used Chinese characters (9 characters between any two punctuations) and 3 punctuations. There were no contextual clues between the 80 sentences selected. The characters had 13 different sizes with an increment of 0.1 log unit (e.g.1.2589) and 2.5 pt was determined as the critical threshold. Readable test for visual target was followed as (1) 29 candidates with a raw or corrected visual acuity (VA)of at least 1.0 were selected to read 80 selected sentences with the size of characters of 2.5 pt at a distance of 40 cm, (2) the time used for reading with the number of characters wrongly read was recorded, (3) 39 sentences were selected as visual targets based on reading speed, effective reading position and total number of character strokes, (4) The 39 selected sentences were then randomly divided into 3 groups with no significant difference among the groups in the 3 factors listed at (3) with paired t-test. This reading visual chart was at level of Grade 3 primary school with a total stroke number of 165-210(Mean 185 ± 10), 13 font sizes a 0.1 log unit increment, a song pattern and 2.5 pt as the critical threshold. All candidates achieved 100% correct in reading test under 2.5 pt with an effective reading speed as 120.65-162 wpm (Mean 142.93 ± 11.80) and effective reading position as 36.03-61.48(Mean 48.85 ± 6.81). The reading test for the 3 groups of sentences showed effective reading speed as (142.49 ± 12.14) wpm,(142.86 ± 12.55) wpm and (143.44 ± 11.63) wpm respectively(t1-2 = -0.899, t2-3 = -1

  13. Estimation of key parameters in adaptive neuron model according to firing patterns based on improved particle swarm optimization algorithm

    NASA Astrophysics Data System (ADS)

    Yuan, Chunhua; Wang, Jiang; Yi, Guosheng

    2017-03-01

    Estimation of ion channel parameters is crucial to spike initiation of neurons. The biophysical neuron models have numerous ion channel parameters, but only a few of them play key roles in the firing patterns of the models. So we choose three parameters featuring the adaptation in the Ermentrout neuron model to be estimated. However, the traditional particle swarm optimization (PSO) algorithm is still easy to fall into local optimum and has the premature convergence phenomenon in the study of some problems. In this paper, we propose an improved method that uses a concave function and dynamic logistic chaotic mapping mixed to adjust the inertia weights of the fitness value, effectively improve the global convergence ability of the algorithm. The perfect predicting firing trajectories of the rebuilt model using the estimated parameters prove that only estimating a few important ion channel parameters can establish the model well and the proposed algorithm is effective. Estimations using two classic PSO algorithms are also compared to the improved PSO to verify that the algorithm proposed in this paper can avoid local optimum and quickly converge to the optimal value. The results provide important theoretical foundations for building biologically realistic neuron models.

  14. Putting the Biology Back in Astrobiology: Defining Key Habitat Parameters with EJSM

    NASA Astrophysics Data System (ADS)

    Bowman, J. S.; Schmidt, B. E.

    2010-12-01

    habitat parameters that can be directly assessed via IPR, and discuss biological questions that EJSM may answer in the context of terrestrial analogues with an emphasis on multiyear sea ice (MYI). Although subglacial lakes may be analogues for a biosphere deep in the Europan ocean, MYI may share more structural similarities with the Europan ice shell than grounded glacial ice. Calculations suggest that organic and inorganic materials within the interstial spaces of MYI are concentrated as much as 500 fold, possibly aiding microbial metabolism through periods of very low temperature. In a similar manner organic carbon from endogenic or exogenic sources on Europa would concentrate in these spaces, serving as a valuable electron donor or acceptor for organisms in the ice. An environment’s physical structure helps structure the community which inhabits it, thus the MYI microbial community should inform a developing model of a hypothetical Europan ecosystem. Recent applications of 454 sequencing technology to the MYI community indicates a surprising degree of diversity within this environment, similar to that of underlying seawater. These findings suggest the potential for a diverse Europan microbial ecosystem despite energy limitations imposed by a permanent ice cover.

  15. Unbounded and revocable hierarchical identity-based encryption with adaptive security, decryption key exposure resistant, and short public parameters

    PubMed Central

    Wang, Baosheng; Tao, Jing

    2018-01-01

    Revocation functionality and hierarchy key delegation are two necessary and crucial requirements to identity-based cryptosystems. Revocable hierarchical identity-based encryption (RHIBE) has attracted a lot of attention in recent years, many RHIBE schemes have been proposed but shown to be either insecure or bounded where they have to fix the maximum hierarchical depth of RHIBE at setup. In this paper, we propose a new unbounded RHIBE scheme with decryption key exposure resilience and with short public system parameters, and prove our RHIBE scheme to be adaptively secure. Our system model is scalable inherently to accommodate more levels of user adaptively with no adding workload or restarting the system. By carefully designing the hybrid games, we overcome the subtle obstacle in applying the dual system encryption methodology for the unbounded and revocable HIBE. To the best of our knowledge, this is the first construction of adaptively secure unbounded RHIBE scheme. PMID:29649326

  16. The logic of comparative life history studies for estimating key parameters, with a focus on natural mortality rate

    USGS Publications Warehouse

    Hoenig, John M; Then, Amy Y.-H.; Babcock, Elizabeth A.; Hall, Norman G.; Hewitt, David A.; Hesp, Sybrand A.

    2016-01-01

    There are a number of key parameters in population dynamics that are difficult to estimate, such as natural mortality rate, intrinsic rate of population growth, and stock-recruitment relationships. Often, these parameters of a stock are, or can be, estimated indirectly on the basis of comparative life history studies. That is, the relationship between a difficult to estimate parameter and life history correlates is examined over a wide variety of species in order to develop predictive equations. The form of these equations may be derived from life history theory or simply be suggested by exploratory data analysis. Similarly, population characteristics such as potential yield can be estimated by making use of a relationship between the population parameter and bio-chemico–physical characteristics of the ecosystem. Surprisingly, little work has been done to evaluate how well these indirect estimators work and, in fact, there is little guidance on how to conduct comparative life history studies and how to evaluate them. We consider five issues arising in such studies: (i) the parameters of interest may be ill-defined idealizations of the real world, (ii) true values of the parameters are not known for any species, (iii) selecting data based on the quality of the estimates can introduce a host of problems, (iv) the estimates that are available for comparison constitute a non-random sample of species from an ill-defined population of species of interest, and (v) the hierarchical nature of the data (e.g. stocks within species within genera within families, etc., with multiple observations at each level) warrants consideration. We discuss how these issues can be handled and how they shape the kinds of questions that can be asked of a database of life history studies.

  17. Integrating machine learning to achieve an automatic parameter prediction for practical continuous-variable quantum key distribution

    NASA Astrophysics Data System (ADS)

    Liu, Weiqi; Huang, Peng; Peng, Jinye; Fan, Jianping; Zeng, Guihua

    2018-02-01

    For supporting practical quantum key distribution (QKD), it is critical to stabilize the physical parameters of signals, e.g., the intensity, phase, and polarization of the laser signals, so that such QKD systems can achieve better performance and practical security. In this paper, an approach is developed by integrating a support vector regression (SVR) model to optimize the performance and practical security of the QKD system. First, a SVR model is learned to precisely predict the time-along evolutions of the physical parameters of signals. Second, such predicted time-along evolutions are employed as feedback to control the QKD system for achieving the optimal performance and practical security. Finally, our proposed approach is exemplified by using the intensity evolution of laser light and a local oscillator pulse in the Gaussian modulated coherent state QKD system. Our experimental results have demonstrated three significant benefits of our SVR-based approach: (1) it can allow the QKD system to achieve optimal performance and practical security, (2) it does not require any additional resources and any real-time monitoring module to support automatic prediction of the time-along evolutions of the physical parameters of signals, and (3) it is applicable to any measurable physical parameter of signals in the practical QKD system.

  18. International Solar-Terrestrial Program Key Parameter Visualization Tool Data: USA_NASA_DDF_ISTP_KP_0139

    NASA Technical Reports Server (NTRS)

    Ocuna, M. H.; Ogilvie, K. W.; Baker, D. N.; Curtis, S. A.; Fairfield, D. H.; Mish, W. H.

    1999-01-01

    The Global Geospace Science Program (GGS) is designed to improve greatly the understanding of the flow of energy, mass and momentum in the solar-terrestrial environment with particular emphasis on "Geospace". The Global Geospace Science Program is the US contribution to the International Solar-Terrestrial Physics (ISTP) Science Initiative. This CD-ROM issue describes the WIND and POLAR spacecraft, the scientific experiments carried onboard, the Theoretical and Ground Based investigations which constitute the US Global Geospace Science Program and the ISTP Data Systems which support the data acquisition and analysis effort. The International Solar-Terrestrial Physics Program (ISTP) Key Parameter Visualization Tool (KPVT), provided on the CD-ROM, was developed at the ISTP Science Planning and Operations Facility (SPOF). The KPVT is a generic software package for visualizing the key parameter data produced from all ISTP missions, interactively and simultaneously. The tool is designed to facilitate correlative displays of ISTP data from multiple spacecraft and instruments, and thus the selection of candidate events and data quality control. The software, written in IDL, includes a graphical/widget user interface, and runs on many platforms, including various UNIX workstations, Alpha/Open VMS, Macintosh (680x0 and PowerPC), and PC/Windows NT, Windows 3.1, and Windows 95.

  19. International Solar-Terrestrial Program Key Parameter Visualization Tool Data: USA_NASA_DDF_ISTP_IM_KP_0185

    NASA Technical Reports Server (NTRS)

    Ocuna, M. H.; Ogilvie, K. W.; Baker, D. N.; Curtis, S. A.; Fairfield, D. H.; Mish, W. H.

    2000-01-01

    The Global Geospace Science Program (GGS) is designed to improve greatly the understanding of the flow of energy, mass and momentum in the solar-terrestrial environment with particular emphasis on "Geospace". The Global Geospace Science Program is the US contribution to the International Solar-Terrestrial Physics (ISTP) Science Initiative. This CD-ROM issue describes the WIND and POLAR spacecraft, the scientific experiments carried onboard, the Theoretical and Ground Based investigations which constitute the US Global Geospace Science Program and the ISTP Data Systems which support the data acquisition and analysis effort. The International Solar-Terrestrial Physics Program (ISTP) Key Parameter Visualization Tool (KPVT), provided on the CD-ROM, was developed at the ISTP Science Planning and Operations Facility (SPOF). The KPVT is a generic software package for visualizing the key parameter data produced from all ISTP missions, interactively and simultaneously. The tool is designed to facilitate correlative displays of ISTP data from multiple spacecraft and instruments, and thus the selection of candidate events and data quality control. The software, written in IDL, includes a graphical/widget user interface, and runs on many platforms, including various UNIX workstations, Alpha/Open VMS, Macintosh (680x0 and PowerPC), and PC/Windows NT, Windows 3.1, and Windows 95.

  20. At-line monitoring of key parameters of nisin fermentation by near infrared spectroscopy, chemometric modeling and model improvement.

    PubMed

    Guo, Wei-Liang; Du, Yi-Ping; Zhou, Yong-Can; Yang, Shuang; Lu, Jia-Hui; Zhao, Hong-Yu; Wang, Yao; Teng, Li-Rong

    2012-03-01

    An analytical procedure has been developed for at-line (fast off-line) monitoring of 4 key parameters including nisin titer (NT), the concentration of reducing sugars, cell concentration and pH during a nisin fermentation process. This procedure is based on near infrared (NIR) spectroscopy and Partial Least Squares (PLS). Samples without any preprocessing were collected at intervals of 1 h during fifteen batch of fermentations. These fermentation processes were implemented in 3 different 5 l fermentors at various conditions. NIR spectra of the samples were collected in 10 min. And then, PLS was used for modeling the relationship between NIR spectra and the key parameters which were determined by reference methods. Monte Carlo Partial Least Squares (MCPLS) was applied to identify the outliers and select the most efficacious methods for preprocessing spectra, wavelengths and the suitable number of latent variables (n (LV)). Then, the optimum models for determining NT, concentration of reducing sugars, cell concentration and pH were established. The correlation coefficients of calibration set (R (c)) were 0.8255, 0.9000, 0.9883 and 0.9581, respectively. These results demonstrated that this method can be successfully applied to at-line monitor of NT, concentration of reducing sugars, cell concentration and pH during nisin fermentation processes.

  1. International Solar-Terrestrial Program Key Parameter Visualization Tool Data: USA_NASA_DDF_ISTP_KP_0192

    NASA Technical Reports Server (NTRS)

    Ocuna, M. H.; Ogilvie, K. W.; Baker, D. N.; Curtis, S. A.; Fairfield, D. H.; Mish, W. H.

    2001-01-01

    The Global Geospace Science Program (GGS) is designed to improve greatly the understanding of the flow of energy, mass and momentum in the solar-terrestrial environment with particular emphasis on "Geospace". The Global Geospace Science Program is the US contribution to the International Solar-Terrestrial Physics (ISTP) Science Initiative. This CD-ROM issue describes the WIND and POLAR spacecraft, the scientific experiments carried onboard, the Theoretical and Ground Based investigations which constitute the US Global Geospace Science Program and the ISTP Data Systems which support the data acquisition and analysis effort. The International Solar-Terrestrial Physics Program (ISTP) Key Parameter Visualization Tool (KPVT), provided on the CD-ROM, was developed at the ISTP Science Planning and Operations Facility (SPOF). The KPVT is a generic software package for visualizing the key parameter data produced from all ISTP missions, interactively and simultaneously. The tool is designed to facilitate correlative displays of ISTP data from multiple spacecraft and instruments, and thus the selection of candidate events and data quality control. The software, written in IDL, includes a graphical/widget user interface, and runs on many platforms, including various UNIX workstations, Alpha/Open VMS, Macintosh (680x0 and PowerPC), and PC/Windows NT, Windows 3.1, and Windows 95.

  2. International Solar-Terrestrial Program Key Parameter Visualization Tool Data: USA_NASA_DDF_ISTP_IM_KP_0161

    NASA Technical Reports Server (NTRS)

    Ocuna, M. H.; Ogilvie, K. W.; Baker, D. N.; Curtis, S. A.; Fairfield, D. H.; Mish, W. H.

    2000-01-01

    The Global Geospace Science Program (GGS) is designed to improve greatly the understanding of the flow of energy, mass and momentum in the solar-terrestrial environment with particular emphasis on "Geospace". The Global Geospace Science Program is the US contribution to the International Solar-Terrestrial Physics (ISTP) Science Initiative. This CD-ROM issue describes the WIND and POLAR spacecraft, the scientific experiments carried onboard, the Theoretical and Ground Based investigations which constitute the US Global Geospace Science Program and the ISTP Data Systems which support the data acquisition and analysis effort. The International Solar-Terrestrial Physics Program (ISTP) Key Parameter Visualization Tool (KPVT), provided on the CD-ROM, was developed at the ISTP Science Planning and Operations Facility (SPOF). The KPVT is a generic software package for visualizing the key parameter data produced from all ISTP missions, interactively and simultaneously. The tool is designed to facilitate correlative displays of ISTP data from multiple spacecraft and instruments, and thus the selection of candidate events and data quality control. The software, written in IDL, includes a graphical/widget user interface, and runs on many platforms, including various UNIX workstations, Alpha/Open VMS, Macintosh (680x0 and PowerPC), and PC/Windows NT, Windows 3.1, and Windows 95.

  3. Assessing the performance of community-available global MHD models using key system parameters and empirical relationships

    NASA Astrophysics Data System (ADS)

    Gordeev, E.; Sergeev, V.; Honkonen, I.; Kuznetsova, M.; Rastätter, L.; Palmroth, M.; Janhunen, P.; Tóth, G.; Lyon, J.; Wiltberger, M.

    2015-12-01

    Global magnetohydrodynamic (MHD) modeling is a powerful tool in space weather research and predictions. There are several advanced and still developing global MHD (GMHD) models that are publicly available via Community Coordinated Modeling Center's (CCMC) Run on Request system, which allows the users to simulate the magnetospheric response to different solar wind conditions including extraordinary events, like geomagnetic storms. Systematic validation of GMHD models against observations still continues to be a challenge, as well as comparative benchmarking of different models against each other. In this paper we describe and test a new approach in which (i) a set of critical large-scale system parameters is explored/tested, which are produced by (ii) specially designed set of computer runs to simulate realistic statistical distributions of critical solar wind parameters and are compared to (iii) observation-based empirical relationships for these parameters. Being tested in approximately similar conditions (similar inputs, comparable grid resolution, etc.), the four models publicly available at the CCMC predict rather well the absolute values and variations of those key parameters (magnetospheric size, magnetic field, and pressure) which are directly related to the large-scale magnetospheric equilibrium in the outer magnetosphere, for which the MHD is supposed to be a valid approach. At the same time, the models have systematic differences in other parameters, being especially different in predicting the global convection rate, total field-aligned current, and magnetic flux loading into the magnetotail after the north-south interplanetary magnetic field turning. According to validation results, none of the models emerges as an absolute leader. The new approach suggested for the evaluation of the models performance against reality may be used by model users while planning their investigations, as well as by model developers and those interesting to quantitatively

  4. Investigating pulmonary and systemic pharmacokinetics of inhaled olodaterol in healthy volunteers using a population pharmacokinetic approach.

    PubMed

    Borghardt, Jens Markus; Weber, Benjamin; Staab, Alexander; Kunz, Christina; Formella, Stephan; Kloft, Charlotte

    2016-03-01

    Olodaterol, a novel β2-adrenergic receptor agonist, is a long-acting, once-daily inhaled bronchodilator approved for the treatment of chronic obstructive pulmonary disease. The aim of the present study was to describe the plasma and urine pharmacokinetics of olodaterol after intravenous administration and oral inhalation in healthy volunteers by population pharmacokinetic modelling and thereby to infer its pulmonary fate. Plasma and urine data after intravenous administration (0.5-25 μg) and oral inhalation (2.5-70 μg via the Respimat® inhaler) were available from a total of 148 healthy volunteers (single and multiple dosing). A stepwise model building approach was applied, using population pharmacokinetic modelling. Systemic disposition parameters were fixed to estimates obtained from intravenous data when modelling data after inhalation. A pharmacokinetic model, including three depot compartments with associated parallel first-order absorption processes (pulmonary model) on top of a four-compartment body model (systemic disposition model), was found to describe the data the best. The dose reaching the lung (pulmonary bioavailable fraction) was estimated to be 49.4% [95% confidence interval (CI) 46.1, 52.7%] of the dose released from the device. A large proportion of the pulmonary bioavailable fraction [70.1% (95% CI 66.8, 73.3%)] was absorbed with a half-life of 21.8 h (95% CI 19.7, 24.4 h). The plasma and urine pharmacokinetics of olodaterol after intravenous administration and oral inhalation in healthy volunteers were adequately described. The key finding was that a high proportion of the pulmonary bioavailable fraction had an extended pulmonary residence time. This finding was not expected based on the physicochemical properties of olodaterol. © 2015 The British Pharmacological Society.

  5. Pharmacokinetics & Neurophysiology

    ERIC Educational Resources Information Center

    Davis, Andrew S.; Salpekar, Jay A.

    2009-01-01

    Medications administered in clinical practice obtain their therapeutic effect only to the extent that the drug is present in the appropriate concentration at the desired site. To achieve this goal, the prescribing clinician must be aware of how a drug may interact with the physiology of the patient. Pharmacokinetics is the study of this process…

  6. On the accuracy of estimation of basic pharmacokinetic parameters by the traditional noncompartmental equations and the prediction of the steady-state volume of distribution in obese patients based upon data derived from normal subjects.

    PubMed

    Berezhkovskiy, Leonid M

    2011-06-01

    The steady-state and terminal volumes of distribution, as well as the mean residence time of drug in the body (V(ss), V(β), and MRT) are the common pharmacokinetic parameters calculated using the drug plasma concentration-time profile C(p) (t) following intravenous (i.v. bolus or constant rate infusion) drug administration. These calculations are valid for the linear pharmacokinetic system with central elimination (i.e., elimination rate being proportional to drug concentration in plasma). Formally, the assumption of central elimination is not normally met because the rate of drug elimination is proportional to the unbound drug concentration at elimination site, although equilibration between systemic circulation and the site of clearance for majority of small molecule drugs is fast. Thus, the assumption of central elimination is practically quite adequate. It appears reasonable to estimate the extent of possible errors in determination of these pharmacokinetic parameters due to the absence of central elimination. The comparison of V(ss), V(β), and MRT calculated by exact equations and the commonly used ones was made considering a simplified physiologically based pharmacokinetic model. It was found that if the drug plasma concentration profile is detected accurately, determination of drug distribution volumes and MRT using the traditional noncompartmental calculations of these parameters from C(p) (t) yields the values very close to that obtained from exact equations. Though in practice, the accurate measurement of C(p) (t), especially its terminal phase, may not always be possible. This is particularly applicable for obtaining the distribution volumes of lipophilic compounds in obese subjects, when the possibility of late terminal phase at low drug concentration is quite likely, specifically for compounds with high clearance. An accurate determination of V(ss) is much needed in clinical practice because it is critical for the proper selection of drug treatment

  7. 3-D Simulation of Earthquakes on the Cascadia Megathrust: Key Parameters and Constraints from Offshore Structure and Seismicity

    NASA Astrophysics Data System (ADS)

    Wirth, E. A.; Frankel, A. D.; Vidale, J. E.; Stone, I.; Nasser, M.; Stephenson, W. J.

    2017-12-01

    The Cascadia subduction zone has a long history of M8 to M9 earthquakes, inferred from coastal subsidence, tsunami records, and submarine landslides. These megathrust earthquakes occur mostly offshore, and an improved characterization of the megathrust is critical for accurate seismic hazard assessment in the Pacific Northwest. We run numerical simulations of 50 magnitude 9 earthquake rupture scenarios on the Cascadia megathrust, using a 3-D velocity model based on geologic constraints and regional seismicity, as well as active and passive source seismic studies. We identify key parameters that control the intensity of ground shaking and resulting seismic hazard. Variations in the down-dip limit of rupture (e.g., extending rupture to the top of the non-volcanic tremor zone, compared to a completely offshore rupture) result in a 2-3x difference in peak ground acceleration (PGA) for the inland city of Seattle, Washington. Comparisons of our simulations to paleoseismic data suggest that rupture extending to the 1 cm/yr locking contour (i.e., mostly offshore) provides the best fit to estimates of coastal subsidence during previous Cascadia earthquakes, but further constraints on the down-dip limit from microseismicity, offshore geodetics, and paleoseismic evidence are needed. Similarly, our simulations demonstrate that coastal communities experience a four-fold increase in PGA depending upon their proximity to strong-motion-generating areas (i.e., high strength asperities) on the deeper portions of the megathrust. An improved understanding of the structure and rheology of the plate interface and accretionary wedge, and better detection of offshore seismicity, may allow us to forecast locations of these asperities during a future Cascadia earthquake. In addition to these parameters, the seismic velocity and attenuation structure offshore also strongly affects the resulting ground shaking. This work outlines the range of plausible ground motions from an M9 Cascadia

  8. Response of key soil parameters during compost-assisted phytostabilization in extremely acidic tailings: effect of plant species.

    PubMed

    Solís-Dominguez, Fernando A; White, Scott A; Hutter, Travis Borrillo; Amistadi, Mary Kay; Root, Robert A; Chorover, Jon; Maier, Raina M

    2012-01-17

    Phytostabilization of mine tailings acts to mitigate both eolian dispersion and water erosion events which can disseminate barren tailings over large distances. This technology uses plants to establish a vegetative cover to permanently immobilize contaminants in the rooting zone, often requiring addition of an amendment to assist plant growth. Here we report the results of a greenhouse study that evaluated the ability of six native plant species to grow in extremely acidic (pH ∼ 2.5) metalliferous (As, Pb, Zn: 2000-3000 mg kg(-1)) mine tailings from Iron King Mine Humboldt Smelter Superfund site when amended with a range of compost concentrations. Results revealed that three of the six plant species tested (buffalo grass, mesquite, and catclaw acacia) are good candidates for phytostabilization at an optimum level of 15% compost (w/w) amendment showing good growth and minimal shoot accumulation of metal(loid)s. A fourth candidate, quailbush, also met all criteria except for exceeding the domestic animal toxicity limit for shoot accumulation of zinc. A key finding of this study was that the plant species that grew most successfully on these tailings significantly influenced key tailings parameters; direct correlations between plant biomass and both increased tailings pH and neutrophilic heterotrophic bacterial counts were observed. We also observed decreased iron oxidizer counts and decreased bioavailability of metal(loid)s mainly as a result of compost amendment. Taken together, these results suggest that the phytostabilization process reduced tailings toxicity as well as the potential for metal(loid) mobilization. This study provides practical information on plant and tailings characteristics that is critically needed for successful implementation of assisted phytostabilization on acidic, metalliferous mine tailings sites.

  9. Response of Key Soil Parameters During Compost-Assisted Phytostabilization in Extremely Acidic Tailings: Effect of Plant Species

    PubMed Central

    Solís-Dominguez, Fernando A.; White, Scott A.; Hutter, Travis Borrillo; Amistadi, Mary Kay; Root, Robert A.; Chorover, Jon; Maier, Raina M.

    2012-01-01

    Phytostabilization of mine tailings acts to mitigate both eolian dispersion and water erosion events which can disseminate barren tailings over large distances. This technology uses plants to establish a vegetative cover to permanently immobilize contaminants in the rooting zone, often requiring addition of an amendment to assist plant growth. Here we report the results of a greenhouse study that evaluated the ability of six native plant species to grow in extremely acidic (pH ~ 2.5) metalliferous (As, Pb, Zn: 2000–3000 mg kg−1) mine tailings from Iron King Mine Humboldt Smelter Superfund site when amended with a range of compost concentrations. Results revealed that three of the six plant species tested (buffalo grass, mesquite, and catclaw acacia) are good candidates for phytostabilization at an optimum level of 15% compost (w/w) amendment showing good growth and minimal shoot accumulation of metal(loid)s. A fourth candidate, quailbush, also met all criteria except for exceeding the domestic animal toxicity limit for shoot accumulation of zinc. A key finding of this study was that the plant species that grew most successfully on these tailings significantly influenced key tailings parameters; direct correlations between plant biomass and both increased tailings pH and neutrophilic heterotrophic bacterial counts were observed. We also observed decreased iron oxidizer counts and decreased bioavailability of metal(loid)s mainly as a result of compost amendment. Taken together, these results suggest that the phytostabilization process reduced tailings toxicity as well as the potential for metal(loid) mobilization. This study provides practical information on plant and tailings characteristics that is critically needed for successful implementation of assisted phytostabilization on acidic, metalliferous mine tailings sites. PMID:22191663

  10. Effect of Simultaneous Inoculation with Yeast and Bacteria on Fermentation Kinetics and Key Wine Parameters of Cool-Climate Chardonnay

    PubMed Central

    Jussier, Delphine; Dubé Morneau, Amélie; Mira de Orduña, Ramón

    2006-01-01

    Inoculating grape musts with wine yeast and lactic acid bacteria (LAB) concurrently in order to induce simultaneous alcoholic fermentation (AF) and malolactic fermentation (MLF) can be an efficient alternative to overcome potential inhibition of LAB in wines because of high ethanol concentrations and reduced nutrient content. In this study, the simultaneous inoculation of yeast and LAB into must was compared with a traditional vinification protocol, where MLF was induced after completion of AF. For this, two suitable commercial yeast-bacterium combinations were tested in cool-climate Chardonnay must. The time courses of glucose and fructose, acetaldehyde, several organic acids, and nitrogenous compounds were measured along with the final values of other key wine parameters. Sensory evaluation was done after 12 months of storage. The current study could not confirm a negative impact of simultaneous AF/MLF on fermentation success and kinetics or on final wine parameters. While acetic acid concentrations were slightly increased in wines after simultaneous AF/MLF, the differences were of neither practical nor legal significance. No statistically significant differences were found with regard to the final values of pH or total acidity and the concentrations of ethanol, acetaldehyde, glycerol, citric and lactic acids, and the nitrogen compounds arginine, ammonia, urea, citrulline, and ornithine. Sensory evaluation by a semiexpert panel confirmed the similarity of the wines. However, simultaneous inoculation led to considerable reductions in overall fermentation durations. Furthermore, differences of physiological and microbiological relevance were found. Specifically, we report the vinification of “super-dry” wines devoid of glucose and fructose after simultaneous inoculation of yeast and bacteria. PMID:16391046

  11. Impact of dissolved oxygen concentration on some key parameters and production of rhG-CSF in batch fermentation.

    PubMed

    Krishna Rao, Dasari V; Ramu, Chatadi T; Rao, Joginapally V; Narasu, Mangamoori L; Bhujanga Rao, Adibhatla Kali S

    2008-09-01

    The impact of different levels of agitation speed, carbondioxide and dissolved oxygen concentration on the key parameters and production of rhG-CSF in Escherichia coli BL21(DE3)PLysS were studied. Lower carbondioxide concentrations as well as higher agitation speeds and dissolved oxygen concentrations led to reduction in the acetate concentrations, and enhanced the cell growth, but inhibited plasmid stability and rhG-CSF expression. Similarly, higher carbondioxide concentrations and lower agitation speeds as well as dissolved oxygen concentrations led to enhanced acetate concentrations, but inhibited the cell growth and protein expression. To address the bottlenecks, a two-stage agitation control strategy (strategy-1) and two-stage dissolved oxygen control strategy (strategy-2) were employed to establish the physiological and metabolic conditions, so as to improve the expression of rhG-CSF. By adopting strategy-1 the yields were improved 1.4-fold over constant speed of 550 rpm, 1.1-fold over constant dissolved oxygen of 45%, respectively. Similarly, using strategy-2 the yields were improved 1.6-fold over constant speed of 550 rpm, 1.3-fold over constant dissolved oxygen of 45%, respectively.

  12. A Discussion of Oxygen Recovery Definitions and Key Performance Parameters for Closed-Loop Atmosphere Revitalization Life Support Technology Development

    NASA Technical Reports Server (NTRS)

    Abney, Morgan B.; Perry, Jay L.

    2016-01-01

    Over the last 55 years, NASA has evolved life support for crewed space exploration vehicles from simple resupply during Project Mercury to the complex and highly integrated system of systems aboard the International Space Station. As NASA targets exploration destinations farther from low Earth orbit and mission durations of 500 to 1000 days, life support systems must evolve to meet new requirements. In addition to having more robust, reliable, and maintainable hardware, limiting resupply becomes critical for managing mission logistics and cost. Supplying a crew with the basics of food, water, and oxygen become more challenging as the destination ventures further from Earth. Aboard ISS the Atmosphere Revitalization Subsystem (ARS) supplies the crew's oxygen demand by electrolyzing water. This approach makes water a primary logistics commodity that must be managed carefully. Chemical reduction of metabolic carbon dioxide (CO2) provides a method of recycling oxygen thereby reducing the net ARS water demand and therefore minimizing logistics needs. Multiple methods have been proposed to achieve this recovery and have been reported in the literature. However, depending on the architecture and the technology approach, "oxygen recovery" can be defined in various ways. This discontinuity makes it difficult to compare technologies directly. In an effort to clarify community discussions of Oxygen Recovery, we propose specific definitions and describe the methodology used to arrive at those definitions. Additionally, we discuss key performance parameters for Oxygen Recovery technology development including challenges with comparisons to state-of-the-art.

  13. Key parameters for behaviour related to source separation of household organic waste: A case study in Hanoi, Vietnam.

    PubMed

    Kawai, Kosuke; Huong, Luong Thi Mai

    2017-03-01

    Proper management of food waste, a major component of municipal solid waste (MSW), is needed, especially in developing Asian countries where most MSW is disposed of in landfill sites without any pretreatment. Source separation can contribute to solving problems derived from the disposal of food waste. An organic waste source separation and collection programme has been operated in model areas in Hanoi, Vietnam, since 2007. This study proposed three key parameters (participation rate, proper separation rate and proper discharge rate) for behaviour related to source separation of household organic waste, and monitored the progress of the programme based on the physical composition of household waste sampled from 558 households in model programme areas of Hanoi. The results showed that 13.8% of 558 households separated organic waste, and 33.0% discharged mixed (unseparated) waste improperly. About 41.5% (by weight) of the waste collected as organic waste was contaminated by inorganic waste, and one-third of the waste disposed of as organic waste by separators was inorganic waste. We proposed six hypothetical future household behaviour scenarios to help local officials identify a final or midterm goal for the programme. We also suggested that the city government take further actions to increase the number of people participating in separating organic waste, improve the accuracy of separation and prevent non-separators from discharging mixed waste improperly.

  14. Clinical Pharmacokinetics of Vemurafenib.

    PubMed

    Zhang, Weijiang; Heinzmann, Dominik; Grippo, Joseph F

    2017-09-01

    Vemurafenib is an orally administered small-molecule inhibitor of the oncogenic BRAF kinase that is indicated for the treatment of patients with unresectable or metastatic melanoma harbouring BRAF V600 mutations. Vemurafenib is absorbed rapidly after a single oral dose of 960 mg, reaching maximum drug concentration approximately 4 h after administration. Extensive accumulation occurs after multiple dosing at 960 mg twice daily. Steady state is achieved after approximately 15-21 days and exposure at steady state is relatively constant. Population pharmacokinetic analysis identified a vemurafenib half-life of ≈57 h and elimination appears to be predominantly via the hepatic route. Pharmacokinetic parameters are generally consistent regardless of age, sex or race. No dose adjustments are necessary for patients with mild or moderate hepatic or renal impairment, but the effects of severe hepatic or renal impairment on vemurafenib pharmacokinetics are uncertain. Vemurafenib appears to be a substrate and inducer of cytochrome P450 (CYP) 3A4, a moderate inhibitor of CYP1A2 and both a substrate and inhibitor of the drug efflux transporters P-glycoprotein and breast cancer resistance protein. The relationship between plasma vemurafenib concentrations and response remains to be clarified.

  15. In Vitro CYP2D Inhibitory Effect and Influence on Pharmacokinetics and Pharmacodynamic Parameters of Metoprolol Succinate by Terminalia arjuna in Rats.

    PubMed

    Varghese, Alice; Savai, Jay; Mistry, Shruti; Khandare, Preeti; Barve, Kalyani; Pandita, Nancy; Gaud, Ram

    2016-01-01

    Terminalia arjuna Wight & Arn. (Combretaceae) is a tree having an extensive medicinal potential in cardiovascular disorders. T. arjuna bark extract has been reported to play a significant role as a cardiac stimulant for its beneficial effects in angina. Herb - drug interactions (HDI) are one of the most important clinical concerns in the concomitant consumption of herbs and prescription drugs. Our study was to investigate the in vitro CYP2D inhibition potential of Terminalia arjuna (T. arjuna) extracts in rat liver microsomes and to study the influence of aqueous bark extract of T. arjuna on the oral pharmacokinetics and pharmacodynamics of metoprolol succinate in rats. The CYP2D inhibition potential of herbal extracts of T. arjuna was investigated in rat liver microsomes. Pharmacokinetic-pharmacodynamic interaction of aqueous extract of T. arjuna with metoprolol succinate was investigated in rats. The ethyl acetate, alcoholic & aqueous bark extracts of T. arjuna showed potent reversible non-competitive inhibition CYP2D enzyme in rat liver microsomes with IC50 values less than 40 μg/mL. Arjunic acid, arjunetin and arjungenin did not show significant inhibition of CYP2D enzyme in rat liver microsomes. Pharmacokinetic studies showed that aqueous bark extract of T. arjuna led to a significant reduction (P < 0.05) in AUC0-24h and Cmax of metoprolol succinate in rats, when co-administered. Pharmacodynamic studies reveal a significant reduction in therapeutic activity of metoprolol succinate on co-administration with aqueous bark extract of T. arjuna. Based on our in vitro and in vivo findings and until further clinical drug interaction experiments are conducted, the co-administration of drugs, especially those primarily cleared via CYP2D catalyzed metabolism, with T. arjuna extracts should be done with caution.

  16. Key parameters governing the densification of cubic-Li7La3Zr2O12 Li+ conductors

    NASA Astrophysics Data System (ADS)

    Yi, Eongyu; Wang, Weimin; Kieffer, John; Laine, Richard M.

    2017-06-01

    Cubic-Li7La3Zr2O12 (LLZO) is regarded as one of the most promising solid electrolytes for the construction of inherently safe, next generation all-solid-state Li batteries. Unfortunately, sintering these materials to full density with controlled grain sizes, mechanical and electrochemical properties relies on energy and equipment intensive processes. In this work, we elucidate key parameters dictating LLZO densification by tracing the compositional and structural changes during processing calcined and ball-milled Al3+ doped LLZO powders. We find that the powders undergo ion (Li+/H+) exchange during room temperature processing, such that on heating, the protonated LLZO lattice collapses and crystallizes to its constituent oxides, leading to reaction driven densification at < 1000 °C, prior to sintering of LLZO grains at higher temperatures. It is shown that small particle sizes and protonation cannot be decoupled, and actually aid densification. We conclude that using fully decomposed nanoparticle mixtures, as obtained by liquid-feed flame spray pyrolysis, provides an ideal approach to use high surface and reaction energy to drive densification, resulting in pressureless sintering of Ga3+ doped LLZO thin films (25 μm) at 1130 °C/0.3 h to ideal microstructures (95 ± 1% density, 1.2 ± 0.2 μm average grain size) normally accessible only by pressure-assisted sintering. Such films offer both high ionic conductivity (1.3 ± 0.1 mS cm-1) and record low ionic area specific resistance (2 Ω cm2).

  17. A no-key-exchange secure image sharing scheme based on Shamir's three-pass cryptography protocol and the multiple-parameter fractional Fourier transform.

    PubMed

    Lang, Jun

    2012-01-30

    In this paper, we propose a novel secure image sharing scheme based on Shamir's three-pass protocol and the multiple-parameter fractional Fourier transform (MPFRFT), which can safely exchange information with no advance distribution of either secret keys or public keys between users. The image is encrypted directly by the MPFRFT spectrum without the use of phase keys, and information can be shared by transmitting the encrypted image (or message) three times between users. Numerical simulation results are given to verify the performance of the proposed algorithm.

  18. GGOS and the EOP - the key role of SLR for a stable estimation of highly accurate Earth orientation parameters

    NASA Astrophysics Data System (ADS)

    Bloßfeld, Mathis; Panzetta, Francesca; Müller, Horst; Gerstl, Michael

    2016-04-01

    The GGOS vision is to integrate geometric and gravimetric observation techniques to estimate consistent geodetic-geophysical parameters. In order to reach this goal, the common estimation of station coordinates, Stokes coefficients and Earth Orientation Parameters (EOP) is necessary. Satellite Laser Ranging (SLR) provides the ability to study correlations between the different parameter groups since the observed satellite orbit dynamics are sensitive to the above mentioned geodetic parameters. To decrease the correlations, SLR observations to multiple satellites have to be combined. In this paper, we compare the estimated EOP of (i) single satellite SLR solutions and (ii) multi-satellite SLR solutions. Therefore, we jointly estimate station coordinates, EOP, Stokes coefficients and orbit parameters using different satellite constellations. A special focus in this investigation is put on the de-correlation of different geodetic parameter groups due to the combination of SLR observations. Besides SLR observations to spherical satellites (commonly used), we discuss the impact of SLR observations to non-spherical satellites such as, e.g., the JASON-2 satellite. The goal of this study is to discuss the existing parameter interactions and to present a strategy how to obtain reliable estimates of station coordinates, EOP, orbit parameter and Stokes coefficients in one common adjustment. Thereby, the benefits of a multi-satellite SLR solution are evaluated.

  19. A COMPREHENSIVE INSIGHT ON OCULAR PHARMACOKINETICS

    PubMed Central

    Agrahari, Vibhuti; Mandal, Abhirup; Agrahari, Vivek; Trinh, Hoang My; Joseph, Mary; Ray, Animikh; Hadji, Hicheme; Mitra, Ranjana; Pal, Dhananjay; Mitra, Ashim K.

    2017-01-01

    Eye is a distinctive organ with protective anatomy and physiology. Several pharmacokinetics compartment model of ocular drug delivery has been developed for describing the absorption, distribution and elimination of ocular drugs in the eye. Determining pharmacokinetics parameters in ocular tissues is a major challenge because of the complex anatomy and dynamic physiological barrier of the eye. In this review, pharmacokinetics of these compartments exploring different drugs, delivery systems and routes of administration are discussed including factors affecting intraocular bioavailability. Factors such as pre-corneal fluid drainage, drug binding to tear proteins, systemic drug absorption, corneal factors, melanin binding, drug metabolism renders ocular delivery challenging and elaborated in this manuscript. Several compartment models are discussed those are developed in ocular drug delivery to study the pharmacokinetics parameters. There are several transporters present in both anterior and posterior segments of the eye which play a significant role in ocular pharmacokinetics and summarized briefly. Moreover, several ocular pharmacokinetics animal models and relevant studies are reviewed and discussed in addition to the pharmacokinetics of various ocular formulations. PMID:27798766

  20. Fractal pharmacokinetics.

    PubMed

    Pereira, Luis M

    2010-06-01

    Pharmacokinetics (PK) has been traditionally dealt with under the homogeneity assumption. However, biological systems are nowadays comprehensively understood as being inherently fractal. Specifically, the microenvironments where drug molecules interact with membrane interfaces, metabolic enzymes or pharmacological receptors, are unanimously recognized as unstirred, space-restricted, heterogeneous and geometrically fractal. Therefore, classical Fickean diffusion and the notion of the compartment as a homogeneous kinetic space must be revisited. Diffusion in fractal spaces has been studied for a long time making use of fractional calculus and expanding on the notion of dimension. Combining this new paradigm with the need to describe and explain experimental data results in defining time-dependent rate constants with a characteristic fractal exponent. Under the one-compartment simplification this strategy is straightforward. However, precisely due to the heterogeneity of the underlying biology, often at least a two-compartment model is required to address macroscopic data such as drug concentrations. This simple modelling step-up implies significant analytical and numerical complications. However, a few methods are available that make possible the original desideratum. In fact, exploring the full range of parametric possibilities and looking at different drugs and respective biological concentrations, it may be concluded that all PK modelling approaches are indeed particular cases of the fractal PK theory.

  1. Developing a Physiologically-Based Pharmacokinetic Model Knowledgebase in Support of Provisional Model Construction

    EPA Science Inventory

    Developing physiologically-based pharmacokinetic (PBPK) models for chemicals can be resource-intensive, as neither chemical-specific parameters nor in vivo pharmacokinetic data are easily available for model construction. Previously developed, well-parameterized, and thoroughly-v...

  2. [Features of bemithyl pharmacokinetics upon inhalation administration].

    PubMed

    Kurpiakova, A F; Geĭbo, D S; Bykov, V N; Nikiforov, A S

    2014-01-01

    A comparative study of bemithyl pharmacokinetics was carried out upon its inhalation, intragastric and intravenous administration. The main drug metabolites were identified and the pharmacokinetic parameters were calculated. The obtained results suggest that the inhalation administration of bemithyl is a promising replacement for oral administration, which is related to high bioavailability of the drug and the absence of the effect of "first pass" through the liver.

  3. Pharmacokinetics of escin Ia in rats after intravenous administration.

    PubMed

    Wu, Xiu-Jun; Cui, Xiang-Yong; Tian, Lian-tian; Gao, Feng; Guan, Xin; Gu, Jing-Kai

    2014-10-28

    Escin, a natural mixture of triterpene saponins, is commonly utilized for the treatment of chronic venous insufficiency, hemorrhoids, inflammation and edema. Escin Ia is the chief active ingredient in escin and plays key role in mediating its pharmacological effects. Adequate pharmacokinetic data are essential for proper application of escin agent in clinical practice. However, pharmacokinetic properties of escin Ia are still poorly understood and this conflicts with the growing use of escin agent over the years. The goal of this study is to investigate the pharmacokinetic behavior of escin Ia in rats after low, medium and high-dose intravenous administration. Wistar rats were divided into 3 groups (n=6 per group) and escin Ia was administered via the caudal vein at doses of 0.5, 1.0 and 2.0 mg/kg, respectively. Subsequently, the concentrations of escin Ia and its metabolite isoescin Ia, a positional isomer of escin Ia, in rats׳ plasma were measured by an established liquid chromatography tandem mass spectrometry (LC-MS/MS) method at various time points following the administration of the drug. Main pharmacokinetic parameters were calculated by non-compartmental analysis using the TopFit 2.0 software package (Thomae GmbH, Germany). After intravenous administration, the Cmax and AUC of escin Ia increased in a dose-proportional manner at the dose of 0.5 mg/kg and 1.0 mg/kg, while increased in a more than dose-proportional manner at the doses of 1.0 mg/kg and 2.0 mg/kg. The t₁/₂ was significantly longer with increased intravenous doses, while other parameters such as CL and Vd also exhibit disagreement among three doses. Taken together, our data showed dose-dependent pharmacokinetic profile of escin Ia in rats after intravenous administration at the doses of 0.5-2.0 mg/kg. After intravenous administration, escin Ia was rapidly and extensively converted to isoescin Ia. The results suggested dose-dependent pharmacokinetics of escin Ia at the doses of 0.5-2.0 mg

  4. Pharmacokinetics and pharmacokinetic-pharmacodynamic relationships of monoclonal antibodies in children.

    PubMed

    Edlund, Helena; Melin, Johanna; Parra-Guillen, Zinnia P; Kloft, Charlotte

    2015-01-01

    Monoclonal antibodies (mAbs) constitute a therapeutically and economically important drug class with increasing use in both adult and paediatric patients. The rather complex pharmacokinetic and pharmacodynamic properties of mAbs have been extensively reviewed in adults. In children, however, limited information is currently available. This paper aims to comprehensively review published pharmacokinetic and pharmacokinetic-pharmacodynamic studies of mAbs in children. The current status of mAbs in the USA and in Europe is outlined, including a critical discussion of the dosing strategies of approved mAbs. The pharmacokinetic properties of mAbs in children are exhaustively summarised along with comparisons to reports in adults: for each pharmacokinetic process, we discuss the general principles and mechanisms of the pharmacokinetic/pharmacodynamic characteristics of mAbs, as well as key growth and maturational processes in children that might impact these characteristics. Throughout this review, considerable knowledge gaps are identified, especially regarding children-specific properties that influence pharmacokinetics, pharmacodynamics and immunogenicity. Furthermore, the large heterogeneity in the presentation of pharmacokinetic/pharmacodynamic data limited clinical inferences in many aspects of paediatric mAb therapy. Overall, further studies are needed to fully understand the impact of body size and maturational changes on drug exposure and response. To maximise future knowledge gain, we propose a 'Guideline for Best Practice' on how to report pharmacokinetic and pharmacokinetic-pharmacodynamic results from mAb studies in children which also facilitates comparisons. Finally, we advocate the use of more sophisticated modelling strategies (population analysis, physiology-based approaches) to appropriately characterise pharmacokinetic-pharmacodynamic relationships of mAbs and, thus, allow for a more rational use of mAb in the paediatric population.

  5. Key Parameters for Urban Heat Island Assessment in A Mediterranean Context: A Sensitivity Analysis Using the Urban Weather Generator Model

    NASA Astrophysics Data System (ADS)

    Salvati, Agnese; Palme, Massimo; Inostroza, Luis

    2017-10-01

    Although Urban Heat Island (UHI) is a fundamental effect modifying the urban climate, being widely studied, the relative weight of the parameters involved in its generation is still not clear. This paper investigates the hierarchy of importance of eight parameters responsible for UHI intensity in the Mediterranean context. Sensitivity analyses have been carried out using the Urban Weather Generator model, considering the range of variability of: 1) city radius, 2) urban morphology, 3) tree coverage, 4) anthropogenic heat from vehicles, 5) building’s cooling set point, 6) heat released to canyon from HVAC systems, 7) wall construction properties and 8) albedo of vertical and horizontal surfaces. Results show a clear hierarchy of significance among the considered parameters; the urban morphology is the most important variable, causing a relative change up to 120% of the annual average UHI intensity in the Mediterranean context. The impact of anthropogenic sources of heat such as cooling systems and vehicles is also significant. These results suggest that urban morphology parameters can be used as descriptors of the climatic performance of different urban areas, easing the work of urban planners and designers in understanding a complex physical phenomenon, such as the UHI.

  6. Population Pharmacokinetics of Bevacizumab in Children with Osteosarcoma: Implications for Dosing

    PubMed Central

    Turner, David C.; Navid, Fariba; Daw, Najat C.; Mao, Shenghua; Wu, Jianrong; Santana, Victor M.; Neel, Michael; Rao, Bhaskar; Willert, Jennifer Reikes; Loeb, David M.; Harstead, K. Elaine; Throm, Stacy L.; Freeman, Burgess B.; Stewart, Clinton F.

    2014-01-01

    Purpose To describe sources of interindividual variability in bevacizumab disposition in pediatric patients and explore associations among bevacizumab pharmacokinetics and clinical wound healing outcomes. Experimental Design Prior to tumor resection, three doses of bevacizumab (15 mg/kg) were administered to patients (median age 12.2 years) enrolled on a multi-institutional osteosarcoma trial. Serial sampling for bevacizumab pharmacokinetics was obtained from 27 patients. A population pharmacokinetic model was fit to the data, and patient demographics and clinical chemistry values were systematically tested as predictive covariates on model parameters. Associations between bevacizumab exposure and wound healing status were evaluated by logistic regression. Results Bevacizumab concentration-time data were adequately described by a two-compartment model. Pharmacokinetic parameter estimates were similar to those previously reported in adults with a long median (range) terminal half-life of 12.2 days (8.6 to 32.4 days) and a volume of distribution indicating confinement primarily to the vascular space,49.1 mL/kg (27.1 to 68.3 mL/kg). Body composition was a key determinant of bevacizumab exposure as body mass index percentile was significantly (p<0.05) correlated to body-weight normalized clearance and volume of distribution. Furthermore, bevacizumab exposure prior to primary tumor resection was associated with increased risk of major wound healing complications after surgery (p<0.05). Conclusion A population pharmacokinetic model for bevacizumab was developed which demonstrated that variability in bevacizumab exposure using weight-based dosing is related to body composition. Bevacizumab dosage scaling using ideal body weight would provide an improved dosing approach in children by minimizing pharmacokinetic variability and reducing likelihood of major wound healing complications. PMID:24637635

  7. LC-MS/MS method for the simultaneous quantification of luteolin, wedelolactone and apigenin in mice plasma using hansen solubility parameters for liquid-liquid extraction: Application to pharmacokinetics of Eclipta alba chloroform fraction.

    PubMed

    Cheruvu, Hanumanth Srikanth; Yadav, Navneet K; Valicherla, Guru R; Arya, Rakesh K; Hussain, Zakir; Sharma, Chetan; Arya, Kamal R; Singh, Rama K; Datta, Dipak; Gayen, Jiaur R

    2018-04-01

    Eclipta alba (Bhringraj) in ayurveda has been widely used as a traditional medicine for its multi-therapeutic properties for ages. Luteolin (LTL), wedelolactone (WDL) and apigenin (APG) are the three main bioactive phytochemicals present in Eclipta alba extract. However there was a lack of sensitive bioanalytical method for the pharmacokinetics of these free compounds in plasma which majorly contributes for their activities after oral administration of Eclipta alba. The present study aims to develop a sensitive, rapid and reliable liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the simultaneous estimation of mice plasma concentrations of LTL, WDL and APG using quercetin as an internal standard for the pharmacokinetic analysis. Analytes were separated on Phenomenex Luna C18 (150 × 4.6 mm, 3.0 μm) column with mobile phase containing methanol: acetonitrile (90: 10, v/v) and 0.1% formic acid in 10 mM ammonium formate buffer in the ratio of 70: 30 (v/v) in isocratic mode. Liquid-liquid extraction was optimized using Hansen solubility parameters and diethyl ether finalized as an extraction solvent for the recovery ranging from 61 to 76% for all analytes in mice plasma. The validated method has an accuracy and precision over the linearity range of 0.1-200 ng/mL with a correlation coefficient (r 2 ) of ≥0.997. The intra and inter-day assay accuracy was between 98.17 and 107% and 95.83-107.89% respectively and the intra and inter day assay precision ranged from 0.37-6.05% and 1.85-10.76%, respectively for all the analytes. This validated method can be used for future clinical investigation studies of Eclipta alba extracts. Copyright © 2018 Elsevier B.V. All rights reserved.

  8. Number of Nanoparticles per Cell through a Spectrophotometric Method - A key parameter to Assess Nanoparticle-based Cellular Assays.

    PubMed

    Unciti-Broceta, Juan D; Cano-Cortés, Victoria; Altea-Manzano, Patricia; Pernagallo, Salvatore; Díaz-Mochón, Juan J; Sánchez-Martín, Rosario M

    2015-05-15

    Engineered nanoparticles (eNPs) for biological and biomedical applications are produced from functionalised nanoparticles (NPs) after undergoing multiple handling steps, giving rise to an inevitable loss of NPs. Herein we present a practical method to quantify nanoparticles (NPs) number per volume in an aqueous suspension using standard spectrophotometers and minute amounts of the suspensions (up to 1 μL). This method allows, for the first time, to analyse cellular uptake by reporting NPs number added per cell, as opposed to current methods which are related to solid content (w/V) of NPs. In analogy to the parameter used in viral infective assays (multiplicity of infection), we propose to name this novel parameter as multiplicity of nanofection.

  9. Quantitative assessment of key parameters in qualitative vulnerability methods applied in karst systems based on an integrated numerical modelling approach

    NASA Astrophysics Data System (ADS)

    Doummar, Joanna; Kassem, Assaad

    2017-04-01

    In the framework of a three-year PEER (USAID/NSF) funded project, flow in a Karst system in Lebanon (Assal) dominated by snow and semi arid conditions was simulated and successfully calibrated using an integrated numerical model (MIKE-She 2016) based on high resolution input data and detailed catchment characterization. Point source infiltration and fast flow pathways were simulated by a bypass function and a high conductive lens respectively. The approach consisted of identifying all the factors used in qualitative vulnerability methods (COP, EPIK, PI, DRASTIC, GOD) applied in karst systems and to assess their influence on recharge signals in the different hydrological karst compartments (Atmosphere, Unsaturated zone and Saturated zone) based on the integrated numerical model. These parameters are usually attributed different weights according to their estimated impact on Groundwater vulnerability. The aim of this work is to quantify the importance of each of these parameters and outline parameters that are not accounted for in standard methods, but that might play a role in the vulnerability of a system. The spatial distribution of the detailed evapotranspiration, infiltration, and recharge signals from atmosphere to unsaturated zone to saturated zone was compared and contrasted among different surface settings and under varying flow conditions (e.g., in varying slopes, land cover, precipitation intensity, and soil properties as well point source infiltration). Furthermore a sensitivity analysis of individual or coupled major parameters allows quantifying their impact on recharge and indirectly on vulnerability. The preliminary analysis yields a new methodology that accounts for most of the factors influencing vulnerability while refining the weights attributed to each one of them, based on a quantitative approach.

  10. Pharmacokinetics and RC Circuit Concepts

    NASA Astrophysics Data System (ADS)

    Cock, Mieke De; Janssen, Paul

    2013-11-01

    Most introductory physics courses include a chapter on RC circuits in which the differential equations for the charging and discharging of a capacitor are derived. A number of papers in this journal describe lab experiments dealing with the measurement of different parameters in such RC circuits. In this contribution, we report on a lab experiment we developed for students majoring in pharmacy, using RC circuits to simulate a pharmacokinetic process.

  11. A review of the Z2-FET 1T-DRAM memory: Operation mechanisms and key parameters

    NASA Astrophysics Data System (ADS)

    Cristoloveanu, S.; Lee, K. H.; Parihar, M. S.; El Dirani, H.; Lacord, J.; Martinie, S.; Le Royer, C.; Barbe, J.-Ch.; Mescot, X.; Fonteneau, P.; Galy, Ph.; Gamiz, F.; Navarro, C.; Cheng, B.; Duan, M.; Adamu-Lema, F.; Asenov, A.; Taur, Y.; Xu, Y.; Kim, Y.-T.; Wan, J.; Bawedin, M.

    2018-05-01

    The band-modulation and sharp-switching mechanisms in Z2-FET device operated as a capacitorless 1T-DRAM memory are reviewed. The main parameters that govern the memory performance are discussed based on detailed experiments and simulations. This 1T-DRAM memory does not suffer from super-coupling effect and can be integrated in sub-10 nm thick SOI films. It offers low leakage current, high current margin, long retention, low operating voltage especially for programming, and high speed. The Z2-FET is suitable for embedded memory applications.

  12. [Study on differences between pharmacokinetics and chromatopharmacodynamics for Chinese materia medica formulae].

    PubMed

    He, Fuyuan; Deng, Kaiwen; Zou, Huan; Qiu, Yun; Chen, Feng; Zhou, Honghao

    2011-01-01

    To study on the differences between chromatopharmacokinetics (pharmacokinetics with fingerprint chromatography) and chromatopharmacodynamics (pharmacodynamics with fingerprint chromatography) of Chinese materia medica formulae to answer the question whether the pharmacokinetic parameters of multiple composites can be utilized to guide the medication of multiple composites. On the base of established four chromatopharmacology (pharmacology with chromatographic fingerprint), the pharmacokinetics, and pharmacodynamics were analyzed comparably on their mathematical model and parameter definition. On the basis of quantitative pharmacology, the function expressions and total statistical parameters, such as total zero moment, total first moment, total second moment of the pharmacokinetics, and pharmacodynamics were analyzed to the common expressions and elucidated results for single and multiple components in Chinese materia medica formulae. Total quantitative pharmacokinetic, i.e., chromatopharmacokinetic parameter were decided by each component pharmacokinetic parameters, whereas the total quantitative pharmacodynamic, i.e., chromatopharmacodynamic parameter were decided by both of pharmacokinetic and pharmacodynamic parameters of each components. The pharmacokinetic parameters were corresponded to pharmacodynamic parameters with an existing stable effective coefficient when the constitutive ratio of each composite was a constant. The effects of Chinese materia medica were all controlled by pharmacokinetic and pharmacodynamic coefficient. It is a special case that the pharmacokinetic parameter could independently guide the clinical medication for single component whereas the chromatopharmacokinetic parameters are not applied to the multiple drug combination system, and not be used to solve problems of chromatopharmacokinetic of Chinese materia medica formulae.

  13. Model selection for clustering of pharmacokinetic responses.

    PubMed

    Guerra, Rui P; Carvalho, Alexandra M; Mateus, Paulo

    2018-08-01

    Pharmacokinetics comprises the study of drug absorption, distribution, metabolism and excretion over time. Clinical pharmacokinetics, focusing on therapeutic management, offers important insights towards personalised medicine through the study of efficacy and toxicity of drug therapies. This study is hampered by subject's high variability in drug blood concentration, when starting a therapy with the same drug dosage. Clustering of pharmacokinetics responses has been addressed recently as a way to stratify subjects and provide different drug doses for each stratum. This clustering method, however, is not able to automatically determine the correct number of clusters, using an user-defined parameter for collapsing clusters that are closer than a given heuristic threshold. We aim to use information-theoretical approaches to address parameter-free model selection. We propose two model selection criteria for clustering pharmacokinetics responses, founded on the Minimum Description Length and on the Normalised Maximum Likelihood. Experimental results show the ability of model selection schemes to unveil the correct number of clusters underlying the mixture of pharmacokinetics responses. In this work we were able to devise two model selection criteria to determine the number of clusters in a mixture of pharmacokinetics curves, advancing over previous works. A cost-efficient parallel implementation in Java of the proposed method is publicly available for the community. Copyright © 2018 Elsevier B.V. All rights reserved.

  14. Dose- and time-dependent pharmacokinetics of apigenin trimethyl ether.

    PubMed

    Elhennawy, Mai Gamal; Lin, Hai-Shu

    2018-06-15

    Apigenin trimethyl ether (5,7,4'-trimethoxyflavone, ATE), one of the key polymethoxyflavones present in black ginger (rhizome of Kaempferia parviflora) possesses various health-promoting activities. To optimize its medicinal application, the pharmacokinetics of ATE was assessed in Sprague-Dawley rats with emphases to identify the impacts from dose and repeated dosing on its major pharmacokinetic parameters. Plasma ATE levels were monitored by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Upon single intravenous administration (2 mg/kg), plasma levels of ATE declined through an apparent first-order process while dose-escalation to 4 and 8 mg/kg led to its non-linear disposition, which could be described by the Michaelis-Menten model. Similarly, dose-dependent oral pharmacokinetics was confirmed and when the dose was escalated from 5 to 15 and 45 mg/kg, much longer mean residence time (MRT 0→last ), higher dose-normalized maximal plasma concentration (C max /Dose) and exposure (AUC/Dose) were observed at 15 and/or 45 mg/kg. One-week daily oral administration of ATE at 15 mg/kg caused its accelerated elimination and the plasma exposure (AUC) after intravenous (2 mg/kg) and oral administration (15 mg/kg) dropped ~40 and 60%, respectively. As ATE displayed both dose- and time-dependent pharmacokinetics, caution is needed in the medicinal applications of ATE and/or black ginger. Copyright © 2018 Elsevier B.V. All rights reserved.

  15. An Excel tool for deriving key photosynthetic parameters from combined gas exchange and chlorophyll fluorescence: theory and practice.

    PubMed

    Bellasio, Chandra; Beerling, David J; Griffiths, Howard

    2016-06-01

    Combined photosynthetic gas exchange and modulated fluorometres are widely used to evaluate physiological characteristics associated with phenotypic and genotypic variation, whether in response to genetic manipulation or resource limitation in natural vegetation or crops. After describing relatively simple experimental procedures, we present the theoretical background to the derivation of photosynthetic parameters, and provide a freely available Excel-based fitting tool (EFT) that will be of use to specialists and non-specialists alike. We use data acquired in concurrent variable fluorescence-gas exchange experiments, where A/Ci and light-response curves have been measured under ambient and low oxygen. From these data, the EFT derives light respiration, initial PSII (photosystem II) photochemical yield, initial quantum yield for CO2 fixation, fraction of incident light harvested by PSII, initial quantum yield for electron transport, electron transport rate, rate of photorespiration, stomatal limitation, Rubisco (ribulose 1·5-bisphosphate carboxylase/oxygenase) rate of carboxylation and oxygenation, Rubisco specificity factor, mesophyll conductance to CO2 diffusion, light and CO2 compensation point, Rubisco apparent Michaelis-Menten constant, and Rubisco CO2 -saturated carboxylation rate. As an example, a complete analysis of gas exchange data on tobacco plants is provided. We also discuss potential measurement problems and pitfalls, and suggest how such empirical data could subsequently be used to parameterize predictive photosynthetic models. © 2015 John Wiley & Sons Ltd.

  16. Species-Specific Standard Redox Potential of Thiol-Disulfide Systems: A Key Parameter to Develop Agents against Oxidative Stress

    NASA Astrophysics Data System (ADS)

    Mirzahosseini, Arash; Noszál, Béla

    2016-11-01

    Microscopic standard redox potential, a new physico-chemical parameter was introduced and determined to quantify thiol-disulfide equilibria of biological significance. The highly composite, codependent acid-base and redox equilibria of thiols could so far be converted into pH-dependent, apparent redox potentials (E’°) only. Since the formation of stable metal-thiolate complexes precludes the direct thiol-disulfide redox potential measurements by usual electrochemical techniques, an indirect method had to be elaborated. In this work, the species-specific, pH-independent standard redox potentials of glutathione were determined primarily by comparing it to 1-methylnicotinamide, the simplest NAD+ analogue. Secondarily, the species-specific standard redox potentials of the two-electron redox transitions of cysteamine, cysteine, homocysteine, penicillamine, and ovothiol were determined using their microscopic redox equilibrium constants with glutathione. The 30 different, microscopic standard redox potential values show close correlation with the respective thiolate basicities and provide sound means for the development of potent agents against oxidative stress.

  17. Identifying key demographic parameters of a small island–associated population of Indo-Pacific bottlenose dolphins (Reunion, Indian Ocean)

    PubMed Central

    Estrade, Vanessa; Fayan, Jacques

    2017-01-01

    Photo-identification surveys of Indo-Pacific bottlenose dolphins were conducted from 2009 to 2014 off Reunion Island (55°E33’/21°S07’), in the Indian Ocean. Robust Design models were applied to produce the most reliable estimate of population abundance and survival rate, while accounting for temporary emigration from the survey area (west coast). The sampling scheme consisted of a five-month (June–October) sampling period in each year of the study. The overall population size at Reunion was estimated to be 72 individuals (SE = 6.17, 95%CI = 61–85), based on a random temporary emigration (γ”) of 0.096 and a proportion of 0.70 (SE = 0.03) distinct individuals. The annual survival rate was 0.93 (±0.018 SE, 95%CI = 0.886–0.958) and was constant over time and between sexes. Models considering gender groups indicated different movement patterns between males and females. Males showed null or quasi-null temporary emigration (γ” = γ’ < 0.01), while females showed a random temporary emigration (γ”) of 0.10, suggesting that a small proportion of females was outside the survey area during each primary sampling period. Sex-specific temporary migration patterns were consistent with movement and residency patterns observed in other areas. The Robust Design approach provided an appropriate sampling scheme for deriving island-associated population parameters, while allowing to restrict survey effort both spatially (i.e. west coast only) and temporally (five months per year). Although abundance and survival were stable over the six years, the small population size of fewer than 100 individuals suggested that this population is highly vulnerable. Priority should be given to reducing any potential impact of human activity on the population and its habitat. PMID:28640918

  18. Identifying key demographic parameters of a small island-associated population of Indo-Pacific bottlenose dolphins (Reunion, Indian Ocean).

    PubMed

    Dulau, Violaine; Estrade, Vanessa; Fayan, Jacques

    2017-01-01

    Photo-identification surveys of Indo-Pacific bottlenose dolphins were conducted from 2009 to 2014 off Reunion Island (55°E33'/21°S07'), in the Indian Ocean. Robust Design models were applied to produce the most reliable estimate of population abundance and survival rate, while accounting for temporary emigration from the survey area (west coast). The sampling scheme consisted of a five-month (June-October) sampling period in each year of the study. The overall population size at Reunion was estimated to be 72 individuals (SE = 6.17, 95%CI = 61-85), based on a random temporary emigration (γ") of 0.096 and a proportion of 0.70 (SE = 0.03) distinct individuals. The annual survival rate was 0.93 (±0.018 SE, 95%CI = 0.886-0.958) and was constant over time and between sexes. Models considering gender groups indicated different movement patterns between males and females. Males showed null or quasi-null temporary emigration (γ" = γ' < 0.01), while females showed a random temporary emigration (γ") of 0.10, suggesting that a small proportion of females was outside the survey area during each primary sampling period. Sex-specific temporary migration patterns were consistent with movement and residency patterns observed in other areas. The Robust Design approach provided an appropriate sampling scheme for deriving island-associated population parameters, while allowing to restrict survey effort both spatially (i.e. west coast only) and temporally (five months per year). Although abundance and survival were stable over the six years, the small population size of fewer than 100 individuals suggested that this population is highly vulnerable. Priority should be given to reducing any potential impact of human activity on the population and its habitat.

  19. [The role of bemitil pharmacokinetics in realizing its therapeutic efficacy].

    PubMed

    Boĭko, S S; Zherdev, V P; Neznamov, G G

    1991-01-01

    The pharmacokinetics of a new psychotropic drug bemithil was studied after single and long-term administrations under monotherapy and in combination with phenazepam in patients with asthenoneurotic disturbances. A high degree of correlation for some pharmacokinetic parameters of bemithil following the administration of the drug test dose and its global therapeutic effect was established.

  20. Establishing the Capability of a 1D SVAT Modelling Scheme in Predicting Key Biophysical Vegetation Characterisation Parameters

    NASA Astrophysics Data System (ADS)

    Ireland, Gareth; Petropoulos, George P.; Carlson, Toby N.; Purdy, Sarah

    2015-04-01

    Sensitivity analysis (SA) consists of an integral and important validatory check of a computer simulation model before it is used to perform any kind of analysis. In the present work, we present the results from a SA performed on the SimSphere Soil Vegetation Atmosphere Transfer (SVAT) model utilising a cutting edge and robust Global Sensitivity Analysis (GSA) approach, based on the use of the Gaussian Emulation Machine for Sensitivity Analysis (GEM-SA) tool. The sensitivity of the following model outputs was evaluated: the ambient CO2 concentration and the rate of CO2 uptake by the plant, the ambient O3 concentration, the flux of O3 from the air to the plant/soil boundary, and the flux of O3 taken up by the plant alone. The most sensitive model inputs for the majority of model outputs were related to the structural properties of vegetation, namely, the Leaf Area Index, Fractional Vegetation Cover, Cuticle Resistance and Vegetation Height. External CO2 in the leaf and the O3 concentration in the air input parameters also exhibited significant influence on model outputs. This work presents a very important step towards an all-inclusive evaluation of SimSphere. Indeed, results from this study contribute decisively towards establishing its capability as a useful teaching and research tool in modelling Earth's land surface interactions. This is of considerable importance in the light of the rapidly expanding use of this model worldwide, which also includes research conducted by various Space Agencies examining its synergistic use with Earth Observation data towards the development of operational products at a global scale. This research was supported by the European Commission Marie Curie Re-Integration Grant "TRANSFORM-EO". SimSphere is currently maintained and freely distributed by the Department of Geography and Earth Sciences at Aberystwyth University (http://www.aber.ac.uk/simsphere). Keywords: CO2 flux, ambient CO2, O3 flux, SimSphere, Gaussian process emulators

  1. Population Pharmacokinetics of Intranasal Scopolamine

    NASA Technical Reports Server (NTRS)

    Wu, L.; Chow, D. S. L.; Putcha, L.

    2013-01-01

    Introduction: An intranasal gel dosage formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness (SMS).The bioavailability and pharmacokinetics (PK) was evaluated using data collected in Phase II IND protocols. We reported earlier statistically significant gender differences in PK parameters of INSCOP at a dose level of 0.4 mg. To identify covariates that influence PK parameters of INSCOP, we examined population covariates of INSCOP PK model for 0.4 mg dose. Methods: Plasma scopolamine concentrations versus time data were collected from 20 normal healthy human subjects (11 male/9 female) after a 0.4 mg dose. Phoenix NLME was employed for PK analysis of these data using gender, body weight and age as covariates for model selection. Model selection was based on a likelihood ratio test on the difference of criteria (-2LL). Statistical significance for base model building and individual covariate analysis was set at P less than 0.05{delta(-2LL)=3.84}. Results: A one-compartment pharmacokinetic model with first-order elimination best described INSCOP concentration ]time profiles. Inclusion of gender, body weight and age as covariates individually significantly reduced -2LL by the cut-off value of 3.84(P less than 0.05) when tested against the base model. After the forward stepwise selection and backward elimination steps, gender was selected to add to the final model which had significant influence on absorption rate constant (ka) and the volume of distribution (V) of INSCOP. Conclusion: A population pharmacokinetic model for INSCOP has been identified and gender was a significant contributing covariate for the final model. The volume of distribution and Ka were significantly higher in males than in females which confirm gender-dependent pharmacokinetics of scopolamine after administration of a 0.4 mg dose.

  2. The observed correlation between in vivo clinical pharmacokinetic parameters and in vitro potency of VEGFR-2 inhibitors. Can this be used as a prospective guide for the development of novel compounds?

    PubMed

    Benjamin, B; Sahu, M; Bhatnagar, U; Abhyankar, D; Srinivas, N R

    2012-04-01

    Literature data on the clinical pharmacokinetics of various VEGFR-2 inhibitors along with in vitro potency data were correlated and a linear relationship was established in spite of limited data set. In this work, a model set comprised of axitinib, recentin, sunitinib, pazopanib, and sorafenib were used. The in vitro potencies of the model set compounds were correlated with the published unbound plasma concentrations (Cmax, Cavg, Ctrough). The established linear regression (r2>0.90) equation was used to predict Cmax, Cavg, Ctrough of the 'prediction set' (motesanib, telatinib, CP547632, vatalanib, vandetanib) using in vitro potency and unbound protein free fraction. Cavg and Ctrough of prediction set were closely matched (0.2-1.8 fold of reported), demonstrating the usefulness of such predictions for tracking the target related modulation and/or efficacy signals within the clinically optimized population average. In case of Cmax where correlation was least anticipated, the predicted values were within 0.1-1.1 fold of those reported. Such predictions of appropriate parameters would provide rough estimates of whether or not therapeutically relevant dose(s) have been administered when clinical investigations of novel agents of this class are being performed. Therefore, it may aid in increasing clinical doses to a desired level if safety of the compound does not compromise such dose increases. In conclusion, the proposed model may prospectively guide the dosing strategies and would greatly aid the development of novel compounds in this class. © Georg Thieme Verlag KG Stuttgart · New York.

  3. Towards Improving our Understanding on the Retrievals of Key Parameters Characterising Land Surface Interactions from Space: Introduction & First Results from the PREMIER-EO Project

    NASA Astrophysics Data System (ADS)

    Ireland, Gareth; North, Matthew R.; Petropoulos, George P.; Srivastava, Prashant K.; Hodges, Crona

    2015-04-01

    Acquiring accurate information on the spatio-temporal variability of soil moisture content (SM) and evapotranspiration (ET) is of key importance to extend our understanding of the Earth system's physical processes, and is also required in a wide range of multi-disciplinary research studies and applications. The utility and applicability of Earth Observation (EO) technology provides an economically feasible solution to derive continuous spatio-temporal estimates of key parameters characterising land surface interactions, including ET as well as SM. Such information is of key value to practitioners, decision makers and scientists alike. The PREMIER-EO project recently funded by High Performance Computing Wales (HPCW) is a research initiative directed towards the development of a better understanding of EO technology's present ability to derive operational estimations of surface fluxes and SM. Moreover, the project aims at addressing knowledge gaps related to the operational estimation of such parameters, and thus contribute towards current ongoing global efforts towards enhancing the accuracy of those products. In this presentation we introduce the PREMIER-EO project, providing a detailed overview of the research aims and objectives for the 1 year duration of the project's implementation. Subsequently, we make available the initial results of the work carried out herein, in particular, related to an all-inclusive and robust evaluation of the accuracy of existing operational products of ET and SM from different ecosystems globally. The research outcomes of this project, once completed, will provide an important contribution towards addressing the knowledge gaps related to the operational estimation of ET and SM. This project results will also support efforts ongoing globally towards the operational development of related products using technologically advanced EO instruments which were launched recently or planned be launched in the next 1-2 years. Key Words: PREMIER

  4. Dynamic Contrast-Enhanced MRI in Head-and-Neck Cancer: The Impact of Region of Interest Selection on the Intra- and Interpatient Variability of Pharmacokinetic Parameters

    SciTech Connect

    Craciunescu, Oana I., E-mail: oana.craciunescu@duke.edu; Yoo, David S.; Cleland, Esi

    2012-03-01

    Purpose: Dynamic contrast-enhanced (DCE) MRI-extracted parameters measure tumor microvascular physiology and are usually calculated from an intratumor region of interest (ROI). Optimal ROI delineation is not established. The valid clinical use of DCE-MRI requires that the variation for any given parameter measured within a tumor be less than that observed between tumors in different patients. This work evaluates the impact of tumor ROI selection on the assessment of intra- and interpatient variability. Method and Materials: Head and neck cancer patients received initial targeted therapy (TT) treatment with erlotinib and/or bevacizumab, followed by radiotherapy and concurrent cisplatin with synchronous TT. DCE-MRImore » data from Baseline and the end of the TT regimen (Lead-In) were analyzed to generate the vascular transfer function (K{sup trans}), the extracellular volume fraction (v{sub e}), and the initial area under the concentration time curve (iAUC{sub 1min}). Four ROI sampling strategies were used: whole tumor or lymph node (Whole), the slice containing the most enhancing voxels (SliceMax), three slices centered in SliceMax (Partial), and the 5% most enhancing contiguous voxels within SliceMax (95Max). The average coefficient of variation (aCV) was calculated to establish intrapatient variability among ROI sets and interpatient variability for each ROI type. The average ratio between each intrapatient CV and the interpatient CV was calculated (aRCV). Results: Baseline primary/nodes aRCVs for different ROIs not including 95Max were, for all three MR parameters, in the range of 0.14-0.24, with Lead-In values between 0.09 and 0.2, meaning a low intrapatient vs. interpatient variation. For 95Max, intrapatient CVs approximated interpatient CVs, meaning similar data dispersion and higher aRCVs (0.6-1.27 for baseline) and 0.54-0.95 for Lead-In. Conclusion: Distinction between different patient's primary tumors and/or nodes cannot be made using 95Max ROIs. The

  5. Assessment of key transport parameters in a karst system under different dynamic conditions based on tracer experiments: the Jeita karst system, Lebanon

    NASA Astrophysics Data System (ADS)

    Doummar, Joanna; Margane, Armin; Geyer, Tobias; Sauter, Martin

    2018-03-01

    Artificial tracer experiments were conducted in the mature karst system of Jeita (Lebanon) under various flow conditions using surface and subsurface tracer injection points, to determine the variation of transport parameters (attenuation of peak concentration, velocity, transit times, dispersivity, and proportion of immobile and mobile regions) along fast and slow flow pathways. Tracer breakthrough curves (TBCs) observed at the karst spring were interpreted using a two-region nonequilibrium approach (2RNEM) to account for the skewness in the TBCs' long tailings. The conduit test results revealed a discharge threshold in the system dynamics, beyond which the transport parameters vary significantly. The polynomial relationship between transport velocity and discharge can be related to the variation of the conduit's cross-sectional area. Longitudinal dispersivity in the conduit system is not a constant value (α = 7-10 m) and decreases linearly with increasing flow rate because of dilution effects. Additionally, the proportion of immobile regions (arising from conduit irregularities) increases with decreasing water level in the conduit system. From tracer tests with injection at the surface, longitudinal dispersivity values are found to be large (8-27 m). The tailing observed in some TBCs is generated in the unsaturated zone before the tracer actually arrives at the major subsurface conduit draining the system. This work allows the estimation and prediction of the key transport parameters in karst aquifers. It shows that these parameters vary with time and flow dynamics, and they reflect the geometry of the flow pathway and the origin of infiltrating (potentially contaminated) recharge.

  6. USE OF A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL TO ESTIMATE ABSORBED CARBARYL DOSE IN CHILDREN AFTER TURF APPLICATION

    EPA Science Inventory

    A physiologically based pharmacokinetic (PBPK) model was developed to investigate exposure scenarios of children to carbaryl following turf application. Physiological, pharmacokinetic and pharmacodynamic parameters describing the fate and effects of carbaryl in rats were scaled ...

  7. Modelling the effect of heterogeneity of shedding on the within herd Coxiella burnetii spread and identification of key parameters by sensitivity analysis.

    PubMed

    Courcoul, Aurélie; Monod, Hervé; Nielen, Mirjam; Klinkenberg, Don; Hogerwerf, Lenny; Beaudeau, François; Vergu, Elisabeta

    2011-09-07

    Coxiella burnetii is the bacterium responsible for Q fever, a worldwide zoonosis. Ruminants, especially cattle, are recognized as the most important source of human infections. Although a great heterogeneity between shedder cows has been described, no previous studies have determined which features such as shedding route and duration or the quantity of bacteria shed have the strongest impact on the environmental contamination and thus on the zoonotic risk. Our objective was to identify key parameters whose variation highly influences C. burnetii spread within a dairy cattle herd, especially those related to the heterogeneity of shedding. To compare the impact of epidemiological parameters on different dynamical aspects of C. burnetii infection, we performed a sensitivity analysis on an original stochastic model describing the bacterium spread and representing the individual variability of the shedding duration, routes and intensity as well as herd demography. This sensitivity analysis consisted of a principal component analysis followed by an ANOVA. Our findings show that the most influential parameters are the probability distribution governing the levels of shedding, especially in vaginal mucus and faeces, the characteristics of the bacterium in the environment (i.e. its survival and the fraction of bacteria shed reaching the environment), and some physiological parameters related to the intermittency of shedding (transition probability from a non-shedding infected state to a shedding state) or to the transition from one type of shedder to another one (transition probability from a seronegative shedding state to a seropositive shedding state). Our study is crucial for the understanding of the dynamics of C. burnetii infection and optimization of control measures. Indeed, as control measures should impact the parameters influencing the bacterium spread most, our model can now be used to assess the effectiveness of different control strategies of Q fever within

  8. SaMpling Antibiotics in Renal Replacement Therapy (SMARRT): an observational pharmacokinetic study in critically ill patients.

    PubMed

    Roberts, Jason A; Choi, Gordon Y S; Joynt, Gavin M; Paul, Sanjoy K; Deans, Renae; Peake, Sandra; Cole, Louise; Stephens, Dianne; Bellomo, Rinaldo; Turnidge, John; Wallis, Steven C; Roberts, Michael S; Roberts, Darren M; Lassig-Smith, Melissa; Starr, Therese; Lipman, Jeffrey

    2016-03-01

    Optimal antibiotic dosing is key to maximising patient survival, and minimising the emergence of bacterial resistance. Evidence-based antibiotic dosing guidelines for critically ill patients receiving RRT are currently not available, as RRT techniques and settings vary greatly between ICUs and even individual patients. We aim to develop a robust, evidence-based antibiotic dosing guideline for critically ill patients receiving various forms of RRT. We further aim to observe whether therapeutic antibiotic concentrations are associated with reduced 28-day mortality. We designed a multi-national, observational pharmacokinetic study in critically ill patients requiring RRT. The study antibiotics will be vancomycin, linezolid, piperacillin/tazobactam and meropenem. Pharmacokinetic sampling of each patient's blood, RRT effluent and urine will take place during two separate dosing intervals. In addition, a comprehensive data set, which includes the patients' demographic and clinical parameters, as well as modality, technique and settings of RRT, will be collected. Pharmacokinetic data will be analysed using a population pharmacokinetic approach to identify covariates associated with changes in pharmacokinetic parameters in critically ill patients with AKI who are undergoing RRT for the five commonly prescribed antibiotics. Using the comprehensive data set collected, the pharmacokinetic profile of the five antibiotics will be constructed, including identification of RRT and other factors indicative of the need for altered antibiotic dosing requirements. This will enable us to develop a dosing guideline for each individual antibiotic that is likely to be relevant to any critically ill patient with acute kidney injury receiving any of the included forms of RRT. Australian New Zealand Clinical Trial Registry ( ACTRN12613000241730 ) registered 28 February 2013.

  9. Fine-tuning key parameters of an integrated reactor system for the simultaneous removal of COD, sulfate and ammonium and elemental sulfur reclamation.

    PubMed

    Yuan, Ye; Chen, Chuan; Liang, Bin; Huang, Cong; Zhao, Youkang; Xu, Xijun; Tan, Wenbo; Zhou, Xu; Gao, Shuang; Sun, Dezhi; Lee, Duujong; Zhou, Jizhong; Wang, Aijie

    2014-03-30

    In this paper, we proposed an integrated reactor system for simultaneous removal of COD, sulfate and ammonium (integrated C-S-N removal system) and investigated the key parameters of the system for a high level of elemental sulfur (S(0)) production. The system consisted of 4 main units: sulfate reduction and organic carbon removal (SR-CR), autotrophic and heterotrophic denitrifying sulfide removal (A&H-DSR), sulfur reclamation (SR), and aerated filter for aerobic nitrification (AN). In the system, the effects of key operational parameters on production of elemental sulfur were investigated, including hydraulic retention time (HRT) of each unit, sulfide/nitrate (S(2-)-S/NO3(-)-N) ratios, reflux ratios between the A&H-DSR and AN units, and loading rates of chemical oxygen demand (COD), sulfate and ammonium. Physico-chemical characteristics of biosulfur were studied for acquiring efficient S(0) recovery. The experiments successfully explored the optimum parameters for each unit and demonstrated 98% COD, 98% sulfate and 78% nitrogen removal efficiency. The optimum HRTs for SR-CR, A&H-DSR and AN were 12h, 3h and 3h, respectively. The reflux ratio of 3 could provide adequate S(2-)-S/NO3(-)-N ratio (approximately 1:1) to the A&H-DSR unit for obtaining maximum sulfur production. In this system, the maximum production of S(0) reached 90%, but only 60% S(0) was reclaimed from effluent. The S(0) that adhered to the outer layer of granules was deposited in the bottom of the A&H-DSR unit. Finally, the microbial community structure of the corresponding unit at different operational stage were analyzed by 16S rRNA gene based high throughput Illumina MiSeq sequencing and the potential function of dominant species were discussed. Copyright © 2013 Elsevier B.V. All rights reserved.

  10. PET Pharmacokinetic Modelling

    NASA Astrophysics Data System (ADS)

    Müller-Schauenburg, Wolfgang; Reimold, Matthias

    Positron Emission Tomography is a well-established technique that allows imaging and quantification of tissue properties in-vivo. The goal of pharmacokinetic modelling is to estimate physiological parameters, e.g. perfusion or receptor density from the measured time course of a radiotracer. After a brief overview of clinical application of PET, we summarize the fundamentals of modelling: distribution volume, Fick's principle of local balancing, extraction and perfusion, and how to calculate equilibrium data from measurements after bolus injection. Three fundamental models are considered: (i) the 1-tissue compartment model, e.g. for regional cerebral blood flow (rCBF) with the short-lived tracer [15O]water, (ii) the 2-tissue compartment model accounting for trapping (one exponential + constant), e.g. for glucose metabolism with [18F]FDG, (iii) the reversible 2-tissue compartment model (two exponentials), e.g. for receptor binding. Arterial blood sampling is required for classical PET modelling, but can often be avoided by comparing regions with specific binding with so called reference regions with negligible specific uptake, e.g. in receptor imaging. To estimate the model parameters, non-linear least square fits are the standard. Various linearizations have been proposed for rapid parameter estimation, e.g. on a pixel-by-pixel basis, for the prize of a bias. Such linear approaches exist for all three models; e.g. the PATLAK-plot for trapping substances like FDG, and the LOGAN-plot to obtain distribution volumes for reversibly binding tracers. The description of receptor modelling is dedicated to the approaches of the subsequent lecture (chapter) of Millet, who works in the tradition of Delforge with multiple-injection investigations.

  11. Microcomputer-Based Programs for Pharmacokinetic Simulations.

    ERIC Educational Resources Information Center

    Li, Ronald C.; And Others

    1995-01-01

    Microcomputer software that simulates drug-concentration time profiles based on user-assigned pharmacokinetic parameters such as central volume of distribution, elimination rate constant, absorption rate constant, dosing regimens, and compartmental transfer rate constants is described. The software is recommended for use in undergraduate…

  12. Lisdexamfetamine: A pharmacokinetic review.

    PubMed

    Comiran, Eloisa; Kessler, Félix Henrique; Fröehlich, Pedro Eduardo; Limberger, Renata Pereira

    2016-06-30

    Lisdexamfetamine (LDX) is a d-amphetamine (d-AMPH) pro-drug used to treat Attention Deficit and Hyperactivity Disorder (ADHD) and Binge Eating Disorder (BED) symptoms. The in vivo pharmacodynamics of LDX is the same as that of its active product d-AMPH, although there are a few qualitative and quantitative differences due to pharmacokinetics. Due to the specific pharmacokinetics of the long-acting stimulants, this article revises the pharmacokinetic studies on LDX, the newest amphetamine pro-drug. The Medline/Pubmed, Science Direct and Biblioteca Virtual em Saúde (Lilacs and Ibecs) (2007-2016) databases were searched for articles and their list of references. As for basic pharmacokinetics studies, since LDX is a newly developed medication, there are few results concerning biotransformation, distribution and the use of different biological matrices for analysis. This is the first robust review on this topic, gathering data from all clinical pharmacokinetics studies available in the literature. The particular pharmacokinetics of LDX plays a major role in studying this pro-drug, since this knowledge was essential to understand some reports on clinical effects in literature, e.g. the small likelihood of reducing the effect by interactions, the effect of long duration use and the still questionable reduction of the potential for abuse. In general the already well-known pharmacokinetic properties of amphetamine make LDX relatively predictable, simplifying the use of LDX in clinical practice. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Predicting Age-appropriate Pharmacokinetics of Six Volatile Organic Compounds in the Rat Utilizing Physiologically-based Pharmacokinetic Modeling (T)

    EPA Science Inventory

    The capability of physiologically-based pharmacokinetic (PBPK) models to incorporate ageappropriate physiological and chemical-specific parameters was utilized in this study to predict changes in internal dosimetry for six volatile organic compounds (VOCs) across different ages o...

  14. Predicting Age-Appropriate Pharmacokinetics of Six Volatile Organic Compounds in the Rat Utilizing Physiologically Based Pharmacokinetic Modeling

    EPA Science Inventory

    The capability of physiologically based pharmacokinetic models to incorporate age-appropriate physiological and chemical-specific parameters was utilized to predict changes in internal dosimetry for six volatile organic compounds (VOCs) across different ages of rats.

  15. Pharmacokinetic considerations for use of artemisinin-based combination therapies against falciparum malaria in different ethnic populations.

    PubMed

    Sugiarto, Sri Riyati; Davis, Timothy M E; Salman, Sam

    2017-11-01

    Artemisinin-based combination therapy (ACT) is used extensively as first-line treatment for uncomplicated falciparum malaria. There has been no rigorous assessment of the potential for racial/ethnic differences in the pharmacokinetic properties of ACTs that might influence their efficacy. Areas covered: A comprehensive literature search was performed that identified 72 publications in which the geographical origin of the patients could be ascertained and the key pharmacokinetic parameters maximum drug concentration (C max ), area under the plasma concentration-time curve (AUC) and elimination half-life (t ½β ) were available for one or more of the five WHO-recommended ACTs (artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, dihydroartemisinin-piperaquine and artesunate-sulfadoxine-pyrimethamine). Comparisons of each of the three pharmacokinetic parameters of interest were made by drug (artemisinin derivative and long half-life partner), race/ethnicity (African, Asian, Caucasian, Melanesian, South American) and patient categories based on age and pregnancy status. Expert opinion: The review identified no evidence of a clinically significant influence of race/ethnicity on the pharmacokinetic properties of the nine component drugs in the five ACTs currently recommended by WHO for first-line treatment of uncomplicated falciparum malaria. This provides reassurance for health workers in malaria-endemic regions that ACTs can be given in recommended doses with the expectation of adequate blood concentrations regardless of race/ethnicity.

  16. Middle Term Achievements of Project 5322: Retrieval Of Key Eco-Hydrological Parameters From Remote Sensing In The Watershed Allied Telemetry Experimental Research (Water)

    NASA Astrophysics Data System (ADS)

    Li, Xin; Menenti, Massimo

    2010-10-01

    The general objective of project 5322 in the Dragon 2 programme is to quantitatively retrieve some key eco- hydrological parameters by using remote sensed data, especially from ESA, Chinese, and the Third Party Mission (TPM). To achieve this goal, a comprehensive observation experiment, Watershed Allied Telemetry Experimental Research (WATER) was carried out. WARER is a simultaneously airborne, satellite-borne, and ground-based remote sensing experiment took place in the Heihe River Basin, a typical inland river basin in the northwest of China. This paper introduces the background and implementation of WATER. Data have been obtained so far are described in details. After a period of data analysis for two years, numerous results have also been achieved. This paper presents some early results of WATER as well.

  17. Concept design theory and model for multi-use space facilities: Analysis of key system design parameters through variance of mission requirements

    NASA Astrophysics Data System (ADS)

    Reynerson, Charles Martin

    This research has been performed to create concept design and economic feasibility data for space business parks. A space business park is a commercially run multi-use space station facility designed for use by a wide variety of customers. Both space hardware and crew are considered as revenue producing payloads. Examples of commercial markets may include biological and materials research, processing, and production, space tourism habitats, and satellite maintenance and resupply depots. This research develops a design methodology and an analytical tool to create feasible preliminary design information for space business parks. The design tool is validated against a number of real facility designs. Appropriate model variables are adjusted to ensure that statistical approximations are valid for subsequent analyses. The tool is used to analyze the effect of various payload requirements on the size, weight and power of the facility. The approach for the analytical tool was to input potential payloads as simple requirements, such as volume, weight, power, crew size, and endurance. In creating the theory, basic principles are used and combined with parametric estimation of data when necessary. Key system parameters are identified for overall system design. Typical ranges for these key parameters are identified based on real human spaceflight systems. To connect the economics to design, a life-cycle cost model is created based upon facility mass. This rough cost model estimates potential return on investments, initial investment requirements and number of years to return on the initial investment. Example cases are analyzed for both performance and cost driven requirements for space hotels, microgravity processing facilities, and multi-use facilities. In combining both engineering and economic models, a design-to-cost methodology is created for more accurately estimating the commercial viability for multiple space business park markets.

  18. Project 5322 Mid-Term Report: Key Eco-Hydrological Parameters Retrieval And Land Data Assimilation System Development In A Typical Inland River Basin Of Chinas Arid Region

    NASA Astrophysics Data System (ADS)

    Faivre, R.; Colin, J.; Menenti, M.; Lindenbergh, R.; Van Den Bergh, L.; Yu, H.; Jia, L.; Xin, L.

    2010-10-01

    Improving the understanding and the monitoring of high elevation regions hydrology is of major relevance from both societal and environmental points of view for many Asian countries, in particular in terms of flood and drought, but also in terms of food security in a chang- ing environment. Satellite and airborne remote sensing technologies are of utmost for such a challenge. Exist- ing imaging spectro-radiometers, radars, microwave ra- diometers and backscatter LIDAR provide a very com- prehensive suite of measurements over a wide rage of wavelengths, time frequencies and spatial resolu- tions. It is however needed to devise new algorithms to convert these radiometric measurements into useful eco-hydrological quantitative parameters for hydrologi- cal modeling and water management. The DRAGON II project entitled Key Eco-Hydrological Parameters Re- trieval and Land Data Assimilation System Development in a Typical Inland River Basin of Chinas Arid Region (ID 5322) aims at improving the monitoring, understand- ing, and predictability of hydrological and ecological pro- cesses at catchment scale, and promote the applicability of quantitative remote sensing in watershed science. Ex- isting Earth Observation platforms provided by the Euro- pean Space Agency as well as prototype airborne systems developed in China - ENVISAT/AATSR, ALOS/PRISM and PALSAR, Airborne LIDAR - are used and combined to retrieve advanced land surface physical properties over high elevation arid regions of China. The existing syn- ergies between this project, the CEOP-AEGIS project (FP7) and the WATER project (CAS) provide incentives for innovative studies. The investigations presented in the following report focus on the development of advanced and innovative methodologies and algorithms to monitor both the state and the trend of key eco-hydrological vari- ables: 3D vegetation properties, land surface evaporation, glacier mass balance and drought indicators.

  19. Clarification of contraceptive drug pharmacokinetics in obesity☆

    PubMed Central

    Jusko, William J.

    2017-01-01

    Related to concerns about the role of obesity in the efficacy of contraceptive drugs, a review of the literature was carried out in regard to the pharmacokinetics of ethinyl estradiol and various progestins given by various routes of administration. Most studies show that obese women exhibit modestly lower plasma concentrations of these drugs (circa 30%) when given the same doses as normal-weight women. While the mechanism is uncertain, precedence in the literature suggests that this is due to body weight-related differences in metabolism rates. Confusing in some of the literature is that a few studies have reported erroneously calculated pharmacokinetic parameters after multiple dosing of oral contraceptives. A demonstration of appropriate pharmacokinetic methodology is provided. PMID:27542520

  20. An interactive program for pharmacokinetic modeling.

    PubMed

    Lu, D R; Mao, F

    1993-05-01

    A computer program, PharmK, was developed for pharmacokinetic modeling of experimental data. The program was written in C computer language based on the high-level user-interface Macintosh operating system. The intention was to provide a user-friendly tool for users of Macintosh computers. An interactive algorithm based on the exponential stripping method is used for the initial parameter estimation. Nonlinear pharmacokinetic model fitting is based on the maximum likelihood estimation method and is performed by the Levenberg-Marquardt method based on chi 2 criterion. Several methods are available to aid the evaluation of the fitting results. Pharmacokinetic data sets have been examined with the PharmK program, and the results are comparable with those obtained with other programs that are currently available for IBM PC-compatible and other types of computers.

  1. A Review on Pharmacokinetic Modeling and the Effects of Environmental Stressors on Pharmacokinetics for Operational Medicine: Operational Pharmacokinetics

    DTIC Science & Technology

    2009-09-01

    hypercholesterolemia Two-compartment model Ezzet, Krishna et al. 2001 Antilipemics Statins: simvastatin, rosuvastatin, atorvastatin Treatment of...Pharmacokinetic model* & rosuvastatin Scopus 14 3 PubMed 9 3 Pharmacokinetic model* & atorvastatin Scopus 49 4 Pharmacokinetic model* & zaleplon...Fentanyl & pharmacokinetic & heat 9 2 Fentanyl & pharmacokinetic & cold 4 0 Fentanyl & pharmacokinetic & blood loss 19 5 Atorvastatin

  2. Parameter Estimations of Dynamic Energy Budget (DEB) Model over the Life History of a Key Antarctic Species: The Antarctic Sea Star Odontaster validus Koehler, 1906.

    PubMed

    Agüera, Antonio; Collard, Marie; Jossart, Quentin; Moreau, Camille; Danis, Bruno

    2015-01-01

    Marine organisms in Antarctica are adapted to an extreme ecosystem including extremely stable temperatures and strong seasonality due to changes in day length. It is now largely accepted that Southern Ocean organisms are particularly vulnerable to global warming with some regions already being challenged by a rapid increase of temperature. Climate change affects both the physical and biotic components of marine ecosystems and will have an impact on the distribution and population dynamics of Antarctic marine organisms. To predict and assess the effect of climate change on marine ecosystems a more comprehensive knowledge of the life history and physiology of key species is urgently needed. In this study we estimate the Dynamic Energy Budget (DEB) model parameters for key benthic Antarctic species the sea star Odontaster validus using available information from literature and experiments. The DEB theory is unique in capturing the metabolic processes of an organism through its entire life cycle as a function of temperature and food availability. The DEB model allows for the inclusion of the different life history stages, and thus, becomes a tool that can be used to model lifetime feeding, growth, reproduction, and their responses to changes in biotic and abiotic conditions. The DEB model presented here includes the estimation of reproduction handling rules for the development of simultaneous oocyte cohorts within the gonad. Additionally it links the DEB model reserves to the pyloric caeca an organ whose function has long been ascribed to energy storage. Model parameters described a slowed down metabolism of long living animals that mature slowly. O. validus has a large reserve that-matching low maintenance costs- allow withstanding long periods of starvation. Gonad development is continuous and individual cohorts developed within the gonads grow in biomass following a power function of the age of the cohort. The DEB model developed here for O. validus allowed us to

  3. 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

  4. UNCERTAINTIES IN TRICHLOROETHYLENE PHARMACOKINETIC MODELS

    EPA Science Inventory

    Understanding the pharmacokinetics of a chemical¯its absorption, distribution, metabolism, and excretion in humans and laboratory animals ¯ is critical to the assessment of its human health risks. For trichloroethylene (TCE), numerous physiologically-based pharmacokinetic (PBPK)...

  5. Magnetic hyperthermia properties of nanoparticles inside lysosomes using kinetic Monte Carlo simulations: Influence of key parameters and dipolar interactions, and evidence for strong spatial variation of heating power

    NASA Astrophysics Data System (ADS)

    Tan, R. P.; Carrey, J.; Respaud, M.

    2014-12-01

    Understanding the influence of dipolar interactions in magnetic hyperthermia experiments is of crucial importance for fine optimization of nanoparticle (NP) heating power. In this study we use a kinetic Monte Carlo algorithm to calculate hysteresis loops that correctly account for both time and temperature. This algorithm is shown to correctly reproduce the high-frequency hysteresis loop of both superparamagnetic and ferromagnetic NPs without any ad hoc or artificial parameters. The algorithm is easily parallelizable with a good speed-up behavior, which considerably decreases the calculation time on several processors and enables the study of assemblies of several thousands of NPs. The specific absorption rate (SAR) of magnetic NPs dispersed inside spherical lysosomes is studied as a function of several key parameters: volume concentration, applied magnetic field, lysosome size, NP diameter, and anisotropy. The influence of these parameters is illustrated and comprehensively explained. In summary, magnetic interactions increase the coercive field, saturation field, and hysteresis area of major loops. However, for small amplitude magnetic fields such as those used in magnetic hyperthermia, the heating power as a function of concentration can increase, decrease, or display a bell shape, depending on the relationship between the applied magnetic field and the coercive/saturation fields of the NPs. The hysteresis area is found to be well correlated with the parallel or antiparallel nature of the dipolar field acting on each particle. The heating power of a given NP is strongly influenced by a local concentration involving approximately 20 neighbors. Because this local concentration strongly decreases upon approaching the surface, the heating power increases or decreases in the vicinity of the lysosome membrane. The amplitude of variation reaches more than one order of magnitude in certain conditions. This transition occurs on a thickness corresponding to approximately

  6. Is the Frequency in Somatosensory Electrical Stimulation the Key Parameter in Modulating the Corticospinal Excitability of Healthy Volunteers and Stroke Patients with Spasticity?

    PubMed

    Garcia, Marco Antonio Cavalcanti; Catunda, João Marcos Yamasaki; de Souza, Marcio Nogueira; Fontana, Ana Paula; Sperandei, Sandro; Vargas, Claudia D

    2016-01-01

    Somatosensory electrical stimulation (SES) has been proposed as an approach to treat patients with sensory-motor impairment such as spasticity. However, there is still no consensus regarding which would be the adequate SES parameters to treat those deficits. Therefore, the aim of this study was to evaluate the effects of applying SES over the forearm muscles at four different frequencies of stimulation (3, 30, 150, and 300 Hz) and in two intervals of time (5' and 30') by means of transcranial magnetic stimulation and Hoffmann's reflex (H-reflex) in healthy volunteers (Experiments  I and II). A group of stroke patients (Experiment  III) was also preliminary evaluated to ascertain SES effects at a low frequency (3 Hz) applied for 30' over the forearm spastic flexors muscles by measuring the wrist joint passive torque. Motor evoked potentials and the H-reflex were collected from different forearm and hand muscles immediately before and after SES and up to 5' (Experiment  I) and 10' (Experiments  I and II) later. None of the investigated frequencies of SES was able to operate as a key in switching modulatory effects in the central nervous system of healthy volunteers and stroke patients with spasticity.

  7. State-of-the-Art Review on Physiologically Based Pharmacokinetic Modeling in Pediatric Drug Development.

    PubMed

    Yellepeddi, Venkata; Rower, Joseph; Liu, Xiaoxi; Kumar, Shaun; Rashid, Jahidur; Sherwin, Catherine M T

    2018-05-18

    Physiologically based pharmacokinetic modeling and simulation is an important tool for predicting the pharmacokinetics, pharmacodynamics, and safety of drugs in pediatrics. Physiologically based pharmacokinetic modeling is applied in pediatric drug development for first-time-in-pediatric dose selection, simulation-based trial design, correlation with target organ toxicities, risk assessment by investigating possible drug-drug interactions, real-time assessment of pharmacokinetic-safety relationships, and assessment of non-systemic biodistribution targets. This review summarizes the details of a physiologically based pharmacokinetic modeling approach in pediatric drug research, emphasizing reports on pediatric physiologically based pharmacokinetic models of individual drugs. We also compare and contrast the strategies employed by various researchers in pediatric physiologically based pharmacokinetic modeling and provide a comprehensive overview of physiologically based pharmacokinetic modeling strategies and approaches in pediatrics. We discuss the impact of physiologically based pharmacokinetic models on regulatory reviews and product labels in the field of pediatric pharmacotherapy. Additionally, we examine in detail the current limitations and future directions of physiologically based pharmacokinetic modeling in pediatrics with regard to the ability to predict plasma concentrations and pharmacokinetic parameters. Despite the skepticism and concern in the pediatric community about the reliability of physiologically based pharmacokinetic models, there is substantial evidence that pediatric physiologically based pharmacokinetic models have been used successfully to predict differences in pharmacokinetics between adults and children for several drugs. It is obvious that the use of physiologically based pharmacokinetic modeling to support various stages of pediatric drug development is highly attractive and will rapidly increase, provided the robustness and

  8. A comprehensive physiologically based pharmacokinetic ...

    EPA Pesticide Factsheets

    Published physiologically based pharmacokinetic (PBPK) models from peer-reviewed articles are often well-parameterized, thoroughly-vetted, and can be utilized as excellent resources for the construction of models pertaining to related chemicals. Specifically, chemical-specific parameters and in vivo pharmacokinetic data used to calibrate these published models can act as valuable starting points for model development of new chemicals with similar molecular structures. A knowledgebase for published PBPK-related articles was compiled to support PBPK model construction for new chemicals based on their close analogues within the knowledgebase, and a web-based interface was developed to allow users to query those close analogues. A list of 689 unique chemicals and their corresponding 1751 articles was created after analysis of 2,245 PBPK-related articles. For each model, the PMID, chemical name, major metabolites, species, gender, life stages and tissue compartments were extracted from the published articles. PaDEL-Descriptor, a Chemistry Development Kit based software, was used to calculate molecular fingerprints. Tanimoto index was implemented in the user interface as measurement of structural similarity. The utility of the PBPK knowledgebase and web-based user interface was demonstrated using two case studies with ethylbenzene and gefitinib. Our PBPK knowledgebase is a novel tool for ranking chemicals based on similarities to other chemicals associated with existi

  9. Technical Approach for Determining Key Parameters Needed for Modeling the Performance of Cast Stone for the Integrated Disposal Facility Performance Assessment

    SciTech Connect

    Yabusaki, Steven B.; Serne, R. Jeffrey; Rockhold, Mark L.

    2015-03-30

    provides the critical link between the short-term understanding from laboratory and field tests, and the prediction of repository performance over repository time frames and scales. One common recommendation is that experiments be designed to permit the appropriate scaling in the models. There is a large contrast in the physical and chemical properties between the Cast Stone waste package and the IDF backfill and surrounding sediments. Cast Stone exhibits low permeability, high tortuosity, low carbonate, high pH, and low Eh whereas the backfill and native sediments have high permeability, low tortuosity, high carbonate, circumneutral pH, and high Eh. These contrasts have important implications for flow, transport, and reactions across the Cast Stone – backfill interface. Over time with transport across the interface and subsequent reactions, the sharp geochemical contrast will blur and there will be a range of spatially-distributed conditions. In general, COC mobility and transport will be sensitive to these geochemical variations, which also include physical changes in porosity and permeability from mineral reactions. Therefore, PA modeling must address processes, properties, and conditions that alter the physical and chemical controls on COC transport in the cementitious waste forms over time. Section 2 of this document reviews past Hanford PAs and SRS Saltstone PAs, which to date have mostly relied on the lumped parameter COC release conceptual models for TSPA predictions, and provides some details on the chosen values for the lumped parameters. Section 3 provides more details on the hierarchical modeling strategy and processes and mechanisms that control COC release. Section 4 summarizes and lists the key parameters for which numerical values are needed to perform PAs. Section 5 provides brief summaries of the methods used to measure the needed parameters and references to get more details.« less

  10. Does Critical Illness Change Levofloxacin Pharmacokinetics?

    PubMed

    Roberts, Jason A; Cotta, Menino Osbert; Cojutti, Piergiorgio; Lugano, Manuela; Della Rocca, Giorgio; Pea, Federico

    2015-12-14

    Levofloxacin is commonly used in critically ill patients for which existing data suggest nonstandard dosing regimens should be used. The objective of this study was to compare the population pharmacokinetics of levofloxacin in critically ill and in non-critically ill patients. Adult patients with a clinical indication for levofloxacin were eligible for participation in this prospective pharmacokinetic study. Patients were given 500 mg or 750 mg daily by intravenous administration with up to 11 blood samples taken on day 1 or 2 of therapy. Plasma samples were analyzed and population pharmacokinetic analysis was undertaken using Pmetrics. Thirty-five patients (18 critically ill) were included. The mean (standard deviation [SD]) age, weight, and Cockcroft-Gault creatinine clearance for the critically ill and for the non-critically ill patients were 60.3 (16.4) and 72.0 (11.6) years, 78.5 (14.8) and 70.9 (15.8) kg, and 71.9 (65.8) and 68.2 (30.1) ml/min, respectively. A two-compartment linear model best described the data. Increasing creatinine clearance was the only covariate associated with increasing drug clearance. The presence of critical illness did not significantly affect any pharmacokinetic parameter. The mean (SD) parameter estimates were as follows: clearance, 8.66 (3.85) liters/h; volume of the central compartment (Vc), 41.5 (24.5) liters; intercompartmental clearance constants from central to peripheral, 2.58 (3.51) liters/h; and peripheral to central compartments, 0.90 (0.58) liters/h. Monte Carlo dosing simulations demonstrated that achievement of therapeutic exposures was dependent on renal function, pathogen, and MIC. Critical illness appears to have no independent effect on levofloxacin pharmacokinetics that cannot be explained by altered renal function. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  11. Does Critical Illness Change Levofloxacin Pharmacokinetics?

    PubMed Central

    Cotta, Menino Osbert; Cojutti, Piergiorgio; Lugano, Manuela; Rocca, Giorgio Della; Pea, Federico

    2015-01-01

    Levofloxacin is commonly used in critically ill patients for which existing data suggest nonstandard dosing regimens should be used. The objective of this study was to compare the population pharmacokinetics of levofloxacin in critically ill and in non-critically ill patients. Adult patients with a clinical indication for levofloxacin were eligible for participation in this prospective pharmacokinetic study. Patients were given 500 mg or 750 mg daily by intravenous administration with up to 11 blood samples taken on day 1 or 2 of therapy. Plasma samples were analyzed and population pharmacokinetic analysis was undertaken using Pmetrics. Thirty-five patients (18 critically ill) were included. The mean (standard deviation [SD]) age, weight, and Cockcroft-Gault creatinine clearance for the critically ill and for the non-critically ill patients were 60.3 (16.4) and 72.0 (11.6) years, 78.5 (14.8) and 70.9 (15.8) kg, and 71.9 (65.8) and 68.2 (30.1) ml/min, respectively. A two-compartment linear model best described the data. Increasing creatinine clearance was the only covariate associated with increasing drug clearance. The presence of critical illness did not significantly affect any pharmacokinetic parameter. The mean (SD) parameter estimates were as follows: clearance, 8.66 (3.85) liters/h; volume of the central compartment (Vc), 41.5 (24.5) liters; intercompartmental clearance constants from central to peripheral, 2.58 (3.51) liters/h; and peripheral to central compartments, 0.90 (0.58) liters/h. Monte Carlo dosing simulations demonstrated that achievement of therapeutic exposures was dependent on renal function, pathogen, and MIC. Critical illness appears to have no independent effect on levofloxacin pharmacokinetics that cannot be explained by altered renal function. PMID:26666946

  12. Propofol pharmacokinetics in a dwarfism patient.

    PubMed

    Tsubokawa, T; Yamamoto, K; Komuro, A; Ishizuka, S; Kobayashi, T

    2003-04-01

    Pharmacokinetic information is important to control anesthetic depth. However, there are few available pharmacokinetic data of propofol in dwarfism patients. We anesthetized a dwarfism patient who underwent spinal decompression, and investigated the pharmacokinetics of propofol. The patient was a 40-year-old man suffering from muscle weakness and numbness in the arms. The operation consisted of two stages; anterior approach in the supine position and posterior approach in the prone position. We also obtained arterial blood for pharmacokinetic analysis. Distribution volume at steady-state and clearance in the supine position was 180 and 0.92 l min- 1, respectively, and in the prone position 127 and 0.74 l min- 1, respectively, in spite of a continuous infusion of dopamine. The data in the supine position were well predicted by Gepts' parameters (used in Diprifusor Zeneca Ltd, Cheshire, UK), which means the target-controlled infusion (TCI) technique can be available in the supine position, while attention is necessary to avoid overdosing when a patient is placed in the prone position.

  13. [Impact of ECMO on drugs pharmacokinetics].

    PubMed

    Hasni, Nesrine; Lemaitre, Florian; Fernandez, Christine; Combes, Alain; Farinotti, Robert

    2011-01-01

    Extracorporeal membrane oxygenation (ECMO) is a life support system used in the treatment of patients of all ages with severe respiratory or cardiorespiratory failure. Despite the intensive use of drugs in the treatment of patients on ECMO, few studies have been conducted to determine the impact of this device on the pharmacokinetics of drugs. Publications in this field have shown pharmacokinetics changes resulting in an increase in volume of distribution of drugs and/or decreased clearance with consequent increase of their half-life. Reduced plasma concentrations of some drugs due to their adsorption on the different components of the circuit further complicates the determination of pharmacokinetic parameters of patients treated by ECMO. The literature published up to now on the pharmacokinetic changes associated with ECMO provide preliminary support for dosage adjustment. However, more research is needed to identify dosage strategies for this patient population. © 2011 Société Française de Pharmacologie et de Thérapeutique.

  14. Nanodrugs: pharmacokinetics and safety

    PubMed Central

    Onoue, Satomi; Yamada, Shizuo; Chan, Hak-Kim

    2014-01-01

    To date, various nanodrug systems have been developed for different routes of administration, which include dendrimers, nanocrystals, emulsions, liposomes, solid lipid nanoparticles, micelles, and polymeric nanoparticles. Nanodrug systems have been employed to improve the efficacy, safety, physicochemical properties, and pharmacokinetic/pharmacodynamic profile of pharmaceutical substances. In particular, functionalized nanodrug systems can offer enhanced bioavailability of orally taken drugs, prolonged half-life of injected drugs (by reducing immunogenicity), and targeted delivery to specific tissues. Thus, nanodrug systems might lower the frequency of administration while providing maximized pharmacological effects and minimized systemic side effects, possibly leading to better therapeutic compliance and clinical outcomes. In spite of these attractive pharmacokinetic advantages, recent attention has been drawn to the toxic potential of nanodrugs since they often exhibit in vitro and in vivo cytotoxicity, oxidative stress, inflammation, and genotoxicity. A better understanding of the pharmacokinetic and safety characteristics of nanodrugs and the limitations of each delivery option is necessary for the further development of efficacious nanodrugs with high therapeutic potential and a wide safety margin. This review highlights the recent progress in nanodrug system development, with a focus on the pharmacokinetic advantages and safety challenges. PMID:24591825

  15. Population pharmacokinetics of aripiprazole in healthy Korean subjects.

    PubMed

    Jeon, Ji-Young; Chae, Soo-Wan; Kim, Min-Gul

    2016-04-01

    Aripiprazole is widely used to treat schizophrenia and bipolar disorder. This study aimed to develop a combined population pharmacokinetic model for aripiprazole in healthy Korean subjects and to identify the significant covariates in the pharmacokinetic variability of aripiprazole. Aripiprazole plasma concentrations and demographic data were collected retrospectively from previous bioequivalence studies that were conducted in Chonbuk National University Hospital. Informed consent was obtained from subjects for cytochrome P450 (CYP) genotyping. The population pharmacokinetic parameters of aripiprazole were estimated using nonlinear mixed-effect modeling with first-order conditional estimation with interaction method. The effects of age, sex, weight, height, and CYP genotype were assessed as covariates. A total of 1,508 samples from 88 subjects in three bioequivalence studies were collected. The two-compartment model was adopted, and the final population model showed that the CYP2D6 genotype polymorphism, height and weight significantly affect aripiprazole disposition. The bootstrap and visual predictive check results were evaluated, showing that the accuracy of the pharmacokinetic model was acceptable. A population pharmacokinetic model of aripiprazole was developed for Korean subjects. CYP2D6 genotype polymorphism, weight, and height were included as significant factors affecting aripiprazole disposition. The population pharmacokinetic parameters of aripiprazole estimated in the present study may be useful for individualizing clinical dosages and for studying the concentration-effect relationship of the drug.

  16. [Population pharmacokinetics applied to optimising cisplatin doses in cancer patients].

    PubMed

    Ramón-López, A; Escudero-Ortiz, V; Carbonell, V; Pérez-Ruixo, J J; Valenzuela, B

    2012-01-01

    To develop and internally validate a population pharmacokinetics model for cisplatin and assess its prediction capacity for personalising doses in cancer patients. Cisplatin plasma concentrations in forty-six cancer patients were used to determine the pharmacokinetic parameters of a two-compartment pharmacokinetic model implemented in NONMEN VI software. Pharmacokinetic parameter identification capacity was assessed using the parametric bootstrap method and the model was validated using the nonparametric bootstrap method and standardised visual and numerical predictive checks. The final model's prediction capacity was evaluated in terms of accuracy and precision during the first (a priori) and second (a posteriori) chemotherapy cycles. Mean population cisplatin clearance is 1.03 L/h with an interpatient variability of 78.0%. Estimated distribution volume at steady state was 48.3 L, with inter- and intrapatient variabilities of 31,3% and 11,7%, respectively. Internal validation confirmed that the population pharmacokinetics model is appropriate to describe changes over time in cisplatin plasma concentrations, as well as its variability in the study population. The accuracy and precision of a posteriori prediction of cisplatin concentrations improved by 21% and 54% compared to a priori prediction. The population pharmacokinetic model developed adequately described the changes in cisplatin plasma concentrations in cancer patients and can be used to optimise cisplatin dosing regimes accurately and precisely. Copyright © 2011 SEFH. Published by Elsevier Espana. All rights reserved.

  17. Key performance indicators score (KPIs-score) based on clinical and laboratorial parameters can establish benchmarks for internal quality control in an ART program.

    PubMed

    Franco, José G; Petersen, Claudia G; Mauri, Ana L; Vagnini, Laura D; Renzi, Adriana; Petersen, Bruna; Mattila, M C; Comar, Vanessa A; Ricci, Juliana; Dieamant, Felipe; Oliveira, João Batista A; Baruffi, Ricardo L R

    2017-06-01

    KPIs have been employed for internal quality control (IQC) in ART. However, clinical KPIs (C-KPIs) such as age, AMH and number of oocytes collected are never added to laboratory KPIs (L-KPIs), such as fertilization rate and morphological quality of the embryos for analysis, even though the final endpoint is the evaluation of clinical pregnancy rates. This paper analyzed if a KPIs-score strategy with clinical and laboratorial parameters could be used to establish benchmarks for IQC in ART cycles. In this prospective cohort study, 280 patients (36.4±4.3years) underwent ART. The total KPIs-score was obtained by the analysis of age, AMH (AMH Gen II ELISA/pre-mixing modified, Beckman Coulter Inc.), number of metaphase-II oocytes, fertilization rates and morphological quality of the embryonic lot. The total KPIs-score (C-KPIs+L-KPIs) was correlated with the presence or absence of clinical pregnancy. The relationship between the C-KPIs and L-KPIs scores was analyzed to establish quality standards, to increase the performance of clinical and laboratorial processes in ART. The logistic regression model (LRM), with respect to pregnancy and total KPIs-score (280 patients/102 clinical pregnancies), yielded an odds ratio of 1.24 (95%CI = 1.16-1.32). There was also a significant difference (p<0.0001) with respect to the total KPIs-score mean value between the group of patients with clinical pregnancies (total KPIs-score=20.4±3.7) and the group without clinical pregnancies (total KPIs-score=15.9±5). Clinical pregnancy probabilities (CPP) can be obtained using the LRM (prediction key) with the total KPIs-score as a predictor variable. The mean C-KPIs and L-KPIs scores obtained in the pregnancy group were 11.9±2.9 and 8.5±1.7, respectively. Routinely, in all cases where the C-KPIs score was ≥9, after the procedure, the L-KPIs score obtained was ≤6, a revision of the laboratory procedure was performed to assess quality standards. This total KPIs-score could set up

  18. Identification and determination of trapping parameters as key site parameters for CO2 storage for the active CO2 storage site in Ketzin (Germany) - Comparison of different experimental approaches and analysis of field data

    NASA Astrophysics Data System (ADS)

    Zemke, Kornelia; Liebscher, Axel

    2015-04-01

    Petrophysical properties like porosity and permeability are key parameters for a safe long-term storage of CO2 but also for the injection operation itself. The accurate quantification of residual trapping is difficult, but very important for both storage containment security and storage capacity; it is also an important parameter for dynamic simulation. The German CO2 pilot storage in Ketzin is a Triassic saline aquifer with initial conditions of the target sandstone horizon of 33.5 ° C/6.1 MPa at 630 m. One injection and two observation wells were drilled in 2007 and nearly 200 m of core material was recovered for site characterization. From June 2008 to September 2013, slightly more than 67 kt food-grade CO2 has been injected and continuously monitored. A fourth observation well has been drilled after 61 kt injected CO2 in summer 2012 at only 25 m distance to the injection well and new core material was recovered that allow study CO2 induced changes in petrophysical properties. The observed only minor differences between pre-injection and post-injection petrophysical parameters of the heterogeneous formation have no severe consequences on reservoir and cap rock integrity or on the injection behavior. Residual brine saturation for the Ketzin reservoir core material was estimated by different methods. Brine-CO2 flooding experiments for two reservoir samples resulted in 36% and 55% residual brine saturation (Kiessling, 2011). Centrifuge capillary pressure measurements (pc = 0.22 MPa) yielded the smallest residual brine saturation values with ~20% for the lower part of the reservoir sandstone and ~28% for the upper part (Fleury, 2010). The method by Cerepi (2002), which calculates the residual mercury saturation after pressure release on the imbibition path as trapped porosity and the retracted mercury volume as free porosity, yielded unrealistic low free porosity values of only a few percent, because over 80% of the penetrated mercury remained in the samples after

  19. Population Pharmacokinetic Modeling of Diltiazem in Chinese Renal Transplant Recipients.

    PubMed

    Guan, Xiao-Feng; Li, Dai-Yang; Yin, Wen-Jun; Ding, Jun-Jie; Zhou, Ling-Yun; Wang, Jiang-Lin; Ma, Rong-Rong; Zuo, Xiao-Cong

    2018-02-01

    Diltiazem is a benzothiazepine calcium blocker and widely used in renal transplant patients since it improves the level of tacrolimus or cyclosporine A concentration. Several population pharmacokinetic (PopPK) models had been established for cyclosporine A and tacrolimus but no specific PopPK model was established for diltiazem. The aim of the study is to develop a PopPK model for diltiazem in renal transplant recipients and provide relevant pharmacokinetic parameters of diltiazem for further pharmacokinetic interaction study. Patients received tacrolimus as primary immunosuppressant agent after renal transplant and started administration of diltiazem 90 mg twice daily on 5th day. The concentration of diltiazem at 0, 0.5, 1, 2, 8, and 12 h was measured by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Genotyping for CYP3A4*1G, CYP3A5*3, and MDR1 3435 was conducted by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). 25 covariates were considered in the stepwise covariate model (SCM) building procedure. One-compartment structural pharmacokinetic model with first-order absorption and elimination was used to describe the pharmacokinetic characteristics of diltiazem. Total bilirubin (TBIL) influenced apparent volume of distribution (V/F) of diltiazem in the forward selection. The absorption rate constant (K a ), V/F, and apparent oral clearance (CL/F) of the final population pharmacokinetic (PopPK) model of diltiazem were 1.96/h, 3550 L, and 92.4 L/h, respectively. A PopPK model of diltiazem is established in Chinese renal transplant recipients and it will provide relevant pharmacokinetic parameters of diltiazem for further pharmacokinetic interaction study.

  20. A Multi-Route Model of Nicotine-Cotinine Pharmacokinetics, Pharmacodynamics and Brain Nicotinic Acetylcholine Receptor Binding in Humans

    SciTech Connect

    Teeguarden, Justin G.; Housand, Conrad; Smith, Jordan N.

    The pharmacokinetics of nicotine, the pharmacologically active alkaloid in tobacco responsible for addiction, are well characterized in humans. We developed a physiologically based pharmacokinetic/pharmacodynamic model of nicotine pharmacokinetics, brain dosimetry and brain nicotinic acetylcholine receptor (nAChRs) occupancy. A Bayesian framework was applied to optimize model parameters against multiple human data sets. The resulting model was consistent with both calibration and test data sets, but in general underestimated variability. A pharmacodynamic model relating nicotine levels to increases in heart rate as a proxy for the pharmacological effects of nicotine accurately described the nicotine related changes in heart rate and the developmentmore » and decay of tolerance to nicotine. The PBPK model was utilized to quantitatively capture the combined impact of variation in physiological and metabolic parameters, nicotine availability and smoking compensation on the change in number of cigarettes smoked and toxicant exposure in a population of 10,000 people presented with a reduced toxicant (50%), reduced nicotine (50%) cigarette Across the population, toxicant exposure is reduced in some but not all smokers. Reductions are not in proportion to reductions in toxicant yields, largely due to partial compensation in response to reduced nicotine yields. This framework can be used as a key element of a dosimetry-driven risk assessment strategy for cigarette smoke constituents.« less

  1. Pharmacokinetic consequences of spaceflight

    NASA Technical Reports Server (NTRS)

    Putcha, L.; Cintron, N. M.

    1991-01-01

    Spaceflight induces a wide range of physiological and biochemical changes, including disruption of gastrointestinal (GI) function, fluid and electrolyte balance, circulatory dynamics, and organ blood flow, as well as hormonal and metabolic perturbations. Any of these changes can influence the pharmacokinetics and pharmacodynamics of in-flight medication. That spaceflight may alter bioavailability was proposed when drugs prescribed to alleviate space motion sickness (SMS) had little therapeutic effect. Characterization of the pharmacokinetic and/or pharmacodynamic behavior of operationally critical medications is crucial for their effective use in flight; as a first step, we sought to determine whether drugs administered in space actually reach the site of action at concentrations sufficient to elicit the therapeutic response.

  2. Developing a Physiologically-Based Pharmacokinetic Model Knowledgebase in Support of Provisional Model Construction - poster

    EPA Science Inventory

    Building new physiologically based pharmacokinetic (PBPK) models requires a lot data, such as the chemical-specific parameters and in vivo pharmacokinetic data. Previously-developed, well-parameterized, and thoroughly-vetted models can be great resource for supporting the constr...

  3. Tubocurarine and pancuronium: a pharmacokinetic view.

    PubMed

    Shanks, C A; Somogyi, A A; Ramzan, M I; Triggs, E J

    1980-02-01

    This review is an attempt to bring together the pharmacokinetic data on d-tubocurarine and pancuronium with clinical observations on relaxant dosage and effect. The modelling techniques used here represent an oversimplification of the relationships between relaxant plasma concentration and response as they do not predict either the time of onset of paralysis or its peak intensity. However, they do enable calculation of a bolus dose of relaxant required to achieve a particular intensity of paralysis for the average patient once pseudo-distribution equilibrium has been achieved. This has been further extended to predict the cumulation of the relaxants with subsequent dosage in average patients. Suggested regimens incorporating bolus and infusion doses of the relaxants to achieve continuous neuromuscular blockade have been calculated also. Averaged pharmacokinetic parameters derived from patients with renal or hepatic dysfunction have been used to predict the likely duration and intensities of paralysis for the relaxants.

  4. [Pharmacokinetics of crocetin in rats].

    PubMed

    Liu, Tong-zheng; Qian, Zhi-yu

    2002-05-01

    To develop an HPLC method for the determination of crocetin in rat plasma and study the pharmacokinetics in rats. Hypersil C18 column (5 microns, 4.6 mm x 200 mm) was used at column temperature 30 degrees C. The mobile phase consisted of methanol-water-acetic acid (75:24.5:0.5) at the flow rate of 1.0 mL.min-1. The UV detection wave length was 423 nm. The calibration curve was linear (gamma = 0.9996) in the range from 0.49 microgram.mL-1 to 7.87 micrograms.mL-1 for crocetin. The mean recovery was 105.2%. The lowest detectable concentration of crocetin was 0.14 microgram.mL-1 (S/N = 3). The RSDs of within-day and between-day were all less than 5%. The plasma crocetin was steady. The HPLC method of determination of crocetin in the plasma was established. After single dose of 50 mg.kg-1 ig in 10 rats, the main pharmacokinetic parameters were estimated as follows: T1/2 alpha (30 +/- 6) min, Tmax(65 +/- 16) min, Cmax(5.0 +/- 1.0) microgram.mL-1, AUC0-T(845 +/- 109) microgram.min.mL-1, Vd(5.0 +/- 0.8) L.kg-1. Crocetin was shown to be absorbed into the blood through the gastrointestinal tract. This method is quick, precise and reliable. Crocetin was shown to be quickly absorbed in rats.

  5. Clinical Pharmacokinetics and Pharmacodynamics of Febuxostat.

    PubMed

    Kamel, Bishoy; Graham, Garry G; Williams, Kenneth M; Pile, Kevin D; Day, Richard O

    2017-05-01

    Febuxostat is a xanthine oxidoreductase inhibitor that has been developed to treat chronic gout. In healthy subjects, the pharmacokinetic parameters of febuxostat after multiple oral dose administration include an oral availability of about 85 %, an apparent oral clearance (CL/F) of 10.5 ± 3.4 L/h and an apparent volume of distribution at steady state (V ss /F) of 48 ± 23 L. The time course of plasma concentrations follows a two-compartment model. The initial half-life (t ½ ) is approximately 2 h and the terminal t ½ determined at daily doses of 40 mg or more is 9.4 ± 4.9 h. Febuxostat is administered once daily. The maximum (peak) plasma concentrations are approximately 100-fold greater than the trough concentrations. Consequently, there is no significant accumulation of the drug during multiple dose administration. There are few data on the pharmacokinetics of febuxostat in patients with gout. While the pharmacokinetic parameters are not affected by mild to moderate hepatic impairment, there is no consensus on whether renal impairment has any effect on the pharmacokinetics of febuxostat. Febuxostat is extensively metabolised by oxidation (approximately 35 %) and acyl glucuronidation (up to 40 %); febuxostat acyl glucuronides are cleared by the kidney. In healthy subjects treated with multiple doses of febuxostat 10-240 mg, the concentrations of serum urate are reduced by a maximum of about 80 %. The percentage reduction in the concentrations of serum urate is slightly less in gouty patients than in healthy subjects.

  6. Development of an Agent-Based Model (ABM) to Simulate the Immune System and Integration of a Regression Method to Estimate the Key ABM Parameters by Fitting the Experimental Data

    PubMed Central

    Tong, Xuming; Chen, Jinghang; Miao, Hongyu; Li, Tingting; Zhang, Le

    2015-01-01

    Agent-based models (ABM) and differential equations (DE) are two commonly used methods for immune system simulation. However, it is difficult for ABM to estimate key parameters of the model by incorporating experimental data, whereas the differential equation model is incapable of describing the complicated immune system in detail. To overcome these problems, we developed an integrated ABM regression model (IABMR). It can combine the advantages of ABM and DE by employing ABM to mimic the multi-scale immune system with various phenotypes and types of cells as well as using the input and output of ABM to build up the Loess regression for key parameter estimation. Next, we employed the greedy algorithm to estimate the key parameters of the ABM with respect to the same experimental data set and used ABM to describe a 3D immune system similar to previous studies that employed the DE model. These results indicate that IABMR not only has the potential to simulate the immune system at various scales, phenotypes and cell types, but can also accurately infer the key parameters like DE model. Therefore, this study innovatively developed a complex system development mechanism that could simulate the complicated immune system in detail like ABM and validate the reliability and efficiency of model like DE by fitting the experimental data. PMID:26535589

  7. Rabbit as an animal model for intravitreal pharmacokinetics: Clinical predictability and quality of the published data.

    PubMed

    Del Amo, Eva M; Urtti, Arto

    2015-08-01

    Intravitreal administration is the method of choice in drug delivery to the retina and/or choroid. Rabbit is the most commonly used animal species in intravitreal pharmacokinetics, but it has been criticized as being a poor model of human eye. The critique is based on some anatomical differences, properties of the vitreous humor, and observed differences in drug concentrations in the anterior chamber after intravitreal injections. We have systematically analyzed all published information on intravitreal pharmacokinetics in the rabbit and human eye. The analysis revealed major problems in the design of the pharmacokinetic studies. In this review we provide advice for study design. Overall, the pharmacokinetic parameters (clearance, volume of distribution, half-life) in the human and rabbit eye have good correlation and comparable absolute values. Therefore, reliable rabbit-to-man translation of intravitreal pharmacokinetics should be feasible. The relevant anatomical and physiological parameters in rabbit and man show only small differences. Furthermore, the claimed discrepancy between drug concentrations in the human and rabbit aqueous humor is not supported by the data analysis. Based on the available and properly conducted pharmacokinetic studies, the differences in the vitreous structure in rabbits and human patients do not lead to significant pharmacokinetic differences. This review is the first step towards inter-species translation of intravitreal pharmacokinetics. More information is still needed to dissect the roles of drug delivery systems, disease states, age and ocular manipulation on the intravitreal pharmacokinetics in rabbit and man. Anyway, the published data and the derived pharmacokinetic parameters indicate that the rabbit is a useful animal model in intravitreal pharmacokinetics. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  8. Ethanol Pharmacokinetics in Neonates and Infants

    PubMed Central

    Marek, Elizabeth; Kraft, Walter K.

    2014-01-01

    Introduction Ethanol has been used for years in neonatal and infant liquid medications, yet the pharmacokinetics, pharmacodynamics, and safety of ethanol in this vulnerable population have not been well characterized. The purpose of this review is to raise awareness of ethanol use as an excipient in neonatal and infant medications and to provide insight, based on the available evidence, into clearance rates of ethanol in babies. We also discuss ethanol pharmacokinetics in adults, theoretical pharmacokinetic changes in neonates and infants as it may apply to ethanol disposition, and case reports involving ethanol exposure in neonates and infants. Materials and methods This study was a narrative review in which relevant papers were selected using databases and scientific search engines such as PubMed with the key words ethanol, infant, and newborninfant. Results It remains unclear what ethanol exposure is safe for neonates and infants. The Food and Drug Administration and American Academy of Pediatrics have both taken action, by either setting limits of ethanol content in over-the-counter medications or by recommending restricted exposure to ethanol-containing pediatric formulations. Conclusions Until the short- and long-term health effects of chronic ethanol administration can be further characterized, ethanol-containing medications should be used with caution. PMID:25379066

  9. [Pharmacokinetics of domestic actoprotector drug Metaprot in healthy volunteers].

    PubMed

    Kibal'chich, D A; Belolipetskaia, V G; Blagodatskikh, S V; Martsevich, S Iu; Rudenko, L I; Iatsuk, V R

    2011-01-01

    Pharmacokinetics of the actoprotector Metaprot, an original Russian drug, has been studied in a group of healthy adult volunteers. Metaprot in capsules was administrated orally as a single dose of 250 mg. The concentration of the active substance (ethylthiobenzimidazole) in the blood serum was determined by high-performance liquid chromatography (HPLC) with UV detection. The pharmacokinetic parameters were calculated by the model-independent method. The peak concentration of ethylthiobenzimidazole in plasma was Cmax = 0.91 +/- 1.05 microg/ml and the average time to peak concentration was t(max) = 1.06 +/- 0.16 h. A polymodal character of the distribution of pharmacokinetic parameters in the test group was revealed.

  10. Methods of mesophyll conductance estimation: its impact on key biochemical parameters and photosynthetic limitations in phosphorus-stressed soybean across CO2

    USDA-ARS?s Scientific Manuscript database

    Photosynthetic potential in C3 plants is largely limited by CO2 diffusion through stomata (Ls) and mesophyll (Lm) and photo-biochemical (Lb) processes. Accurate estimation of mesophyll conductance (gm) using gas exchange (GE) and chlorophyll fluorescence (CF) parameters of the photosynthetic proces...

  11. An Algorithm and R Program for Fitting and Simulation of Pharmacokinetic and Pharmacodynamic Data.

    PubMed

    Li, Jijie; Yan, Kewei; Hou, Lisha; Du, Xudong; Zhu, Ping; Zheng, Li; Zhu, Cairong

    2017-06-01

    Pharmacokinetic/pharmacodynamic link models are widely used in dose-finding studies. By applying such models, the results of initial pharmacokinetic/pharmacodynamic studies can be used to predict the potential therapeutic dose range. This knowledge can improve the design of later comparative large-scale clinical trials by reducing the number of participants and saving time and resources. However, the modeling process can be challenging, time consuming, and costly, even when using cutting-edge, powerful pharmacological software. Here, we provide a freely available R program for expediently analyzing pharmacokinetic/pharmacodynamic data, including data importation, parameter estimation, simulation, and model diagnostics. First, we explain the theory related to the establishment of the pharmacokinetic/pharmacodynamic link model. Subsequently, we present the algorithms used for parameter estimation and potential therapeutic dose computation. The implementation of the R program is illustrated by a clinical example. The software package is then validated by comparing the model parameters and the goodness-of-fit statistics generated by our R package with those generated by the widely used pharmacological software WinNonlin. The pharmacokinetic and pharmacodynamic parameters as well as the potential recommended therapeutic dose can be acquired with the R package. The validation process shows that the parameters estimated using our package are satisfactory. The R program developed and presented here provides pharmacokinetic researchers with a simple and easy-to-access tool for pharmacokinetic/pharmacodynamic analysis on personal computers.

  12. Pharmacokinetics in pregnancy; clinical significance.

    PubMed

    Koren, Gideon

    2011-01-01

    In pharmacokinetics drug absorption, distribution, clearance, and bioequivalence are usually considered, but during pregnancy the most important variable is adherence or compliance. Pharmacokinetic changes during pregnancy that may lead to changes in maternal drug use are described through presentation of cases highlighting the relevance of these changes. Non-invasive methods of pharmacokinetic analysis, such as determining concentrations of drug in hair, are now being tested and used.Pharmacokinetics are important, but one needs to consider the entire pregnant state and its circumstances when treating women. One treats people, not a "volume of distribution" or a drug level. Therapy should be individualized as much as possible, addressing kinetic changes in the context of dynamic alterations and the effects of underlying medical conditions. To ensure that women are not orphaned from advances in drug therapy, much more research is needed into the determinants of pharmacokinetic and pharmacodynamic changes in pregnancy.

  13. Pharmacokinetics of Snake Venom

    PubMed Central

    Sanhajariya, Suchaya; Duffull, Stephen B.

    2018-01-01

    Understanding snake venom pharmacokinetics is essential for developing risk assessment strategies and determining the optimal dose and timing of antivenom required to bind all venom in snakebite patients. This review aims to explore the current knowledge of snake venom pharmacokinetics in animals and humans. Literature searches were conducted using EMBASE (1974–present) and Medline (1946–present). For animals, 12 out of 520 initially identified studies met the inclusion criteria. In general, the disposition of snake venom was described by a two-compartment model consisting of a rapid distribution phase and a slow elimination phase, with half-lives of 5 to 48 min and 0.8 to 28 h, respectively, following rapid intravenous injection of the venoms or toxins. When the venoms or toxins were administered intramuscularly or subcutaneously, an initial absorption phase and slow elimination phase were observed. The bioavailability of venoms or toxins ranged from 4 to 81.5% following intramuscular administration and 60% following subcutaneous administration. The volume of distribution and the clearance varied between snake species. For humans, 24 out of 666 initially identified publications contained sufficient information and timed venom concentrations in the absence of antivenom therapy for data extraction. The data were extracted and modelled in NONMEM. A one-compartment model provided the best fit, with an elimination half-life of 9.71 ± 1.29 h. It is intended that the quantitative information provided in this review will provide a useful basis for future studies that address the pharmacokinetics of snakebite in humans. PMID:29414889

  14. Determination of key diffusion and partition parameters and their use in migration modelling of benzophenone from low-density polyethylene (LDPE) into different foodstuffs.

    PubMed

    Maia, Joaquim; Rodríguez-Bernaldo de Quirós, Ana; Sendón, Raquel; Cruz, José Manuel; Seiler, Annika; Franz, Roland; Simoneau, Catherine; Castle, Laurence; Driffield, Malcolm; Mercea, Peter; Oldring, Peter; Tosa, Valer; Paseiro, Perfecto

    2016-01-01

    The mass transport process (migration) of a model substance, benzophenone (BZP), from LDPE into selected foodstuffs at three temperatures was studied. A mathematical model based on Fick's Second Law of Diffusion was used to simulate the migration process and a good correlation between experimental and predicted values was found. The acquired results contribute to a better understanding of this phenomenon and the parameters so-derived were incorporated into the migration module of the recently launched FACET tool (Flavourings, Additives and Food Contact Materials Exposure Tool). The migration tests were carried out at different time-temperature conditions, and BZP was extracted from LDPE and analysed by HPLC-DAD. With all data, the parameters for migration modelling (diffusion and partition coefficients) were calculated. Results showed that the diffusion coefficients (within both the polymer and the foodstuff) are greatly affected by the temperature and food's physical state, whereas the partition coefficient was affected significantly only by food characteristics, particularly fat content.

  15. Pharmacokinetics and absolute bioavailability of phenobarbital in neonates and young infants, a population pharmacokinetic modelling approach.

    PubMed

    Marsot, Amélie; Brevaut-Malaty, Véronique; Vialet, Renaud; Boulamery, Audrey; Bruguerolle, Bernard; Simon, Nicolas

    2014-08-01

    Phenobarbital is widely used for treatment of neonatal seizures. Its optimal use in neonates and young infants requires information regarding pharmacokinetics. The objective of this study is to characterize the absolute bioavailability of phenobarbital in neonates and young infants, a pharmacokinetic parameter which has not yet been investigated. Routine clinical pharmacokinetic data were retrospectively collected from 48 neonates and infants (weight: 0.7-10 kg; patient's postnatal age: 0-206 days; GA: 27-42 weeks) treated with phenobarbital, who were administered as intravenous or suspension by oral routes and hospitalized in a paediatric intensive care unit. Total mean dose of 4.6 mg/kg (3.1-10.6 mg/kg) per day was administered by 30-min infusion or by oral route. Pharmacokinetic analysis was performed using a nonlinear mixed-effect population model software). Data were modelled with an allometric pharmacokinetic model, using three-fourths scaling exponent for clearance (CL). The population typical mean [per cent relative standard error (%RSE)] values for CL, apparent volume of distribution (Vd ) and bioavailability (F) were 0.0054 L/H/kg (7%), 0.64 L/kg (15%) and 48.9% (22%), respectively. The interindividual variability of CL, Vd , F (%RSE) and residual variability (%RSE) was 17% (31%), 50% (27%), 39% (27%) and 7.2 mg/L (29%), respectively. The absolute bioavailability of phenobarbital in neonates and infants was estimated. The dose should be increased when switching from intravenous to oral administration. © 2013 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.

  16. The Importance of Parameter Variances, Correlations Lengths, and Cross-Correlations in Reactive Transport Models: Key Considerations for Assessing the Need for Microscale Information (Invited)

    NASA Astrophysics Data System (ADS)

    Reimus, P. W.

    2010-12-01

    A process-oriented modeling approach is implemented to examine the importance of parameter variances, correlation lengths, and especially cross-correlations in contaminant transport predictions over large scales. It is shown that the most important consideration is the correlation between flow rates and retardation processes (e.g., sorption, matrix diffusion) in the system. If flow rates are negatively correlated with retardation factors in systems containing multiple flow pathways, then characterizing these negative correlation(s) may have more impact on reactive transport modeling than microscale information. Such negative correlations are expected in porous-media systems where permeability is negatively correlated with clay content and rock alteration (which are usually associated with increased sorption). Likewise, negative correlations are expected in fractured rocks where permeability is positively correlated with fracture apertures, which in turn are negatively correlated with sorption and matrix diffusion. Parameter variances and correlation lengths are also shown to have important effects on reactive transport predictions, but they are less important than parameter cross-correlations. Microscale information pertaining to contaminant transport has become more readily available as characterization methods and spectroscopic instrumentation have achieved lower detection limits, greater resolution, and better precision. Obtaining detailed mechanistic insights into contaminant-rock-water interactions is becoming a routine practice in characterizing reactive transport processes in groundwater systems (almost necessary for high-profile publications). Unfortunately, a quantitative link between microscale information and flow and transport parameter distributions or cross-correlations has not yet been established. One reason for this is that quantitative microscale information is difficult to obtain in complex, heterogeneous systems, so simple systems that lack the

  17. Pharmacokinetic and pharmacodynamic study of dexmedetomidine in elderly patients during spinal anesthesia.

    PubMed

    Kuang, Yun; Zhang, Ran-Ran; Pei, Qi; Tan, Hong-Yi; Guo, Cheng-Xian; Huang, Jie; Xiang, Yu-Xia; Ouyang, Wen; Duan, Kai-Ming; Wang, Sai-Ying; Yang, Guo-Ping

    2015-12-01

    administration); while SBP was significantly different between the groups, this differential declined in a time-dependent manner, and there were no significant attendant differences in the D-value. The observed values and D-values of DBP and HR were similar in the groups, but the observed value and D-value of SpO₂did differ. There were 14 drug-related adverse events in the young group, and 26 drug-related adverse events in the elderly group, a 46% differential. The percentage of patients who requiring intervention during surgery was 68.75% (11/16) in the elderly group and 36.84% (7/19) in the young group, with no significant difference between the two groups once age was factored in (p = 0.06). None of the pharmacodynamic indices, however, correlated with the key pharmacokinetic parameters (Cmax, AUC(0→t), AUC(0→∞)) of dexmedetomidine. The clearance of dexmedetomidine in elderly patients showed a declining trend compared to young patients. Interventions in the elderly group were more frequent than in the young group, and the elderly group showed significant adverse effects. It is suggested that elderly patients who use dexmedetomidine may benefit from a different dose. However, further research with a larger population size is required to confirm these findings.

  18. Two-Compartment Pharmacokinetic Models for Chemical Engineers

    ERIC Educational Resources Information Center

    Kanneganti, Kumud; Simon, Laurent

    2011-01-01

    The transport of potassium permanganate between two continuous-stirred vessels was investigated to help chemical and biomedical engineering students understand two-compartment pharmacokinetic models. Concepts of modeling, mass balance, parameter estimation and Laplace transform were applied to the two-unit process. A good agreement was achieved…

  19. Tranexamic Acid Mechanisms and Pharmacokinetics in Traumatic Injury

    DTIC Science & Technology

    2015-10-01

    study. Finally, we have established a DSMB and DSMB charter. 15. SUBJECT TERMS Trauma, hemorrhage, transfusion , fibrinolysis, immune suppression...injury parameters. 2. KEYWORDS: Trauma, hemorrhage, transfusion , fibrinolysis, immune suppression, pharmacokinetics, outcomes, adverse events. 3...impact on expenditures Nothing to Report Significant changes in use or care of human subjects, vertebrate animals , biohazards, and/or select agents

  20. Two Key Parameters Controlling Particle Clumping Caused by Streaming Instability in the Dead-zone Dust Layer of a Protoplanetary Disk

    NASA Astrophysics Data System (ADS)

    Sekiya, Minoru; Onishi, Isamu K.

    2018-06-01

    The streaming instability and Kelvin–Helmholtz instability are considered the two major sources causing clumping of dust particles and turbulence in the dust layer of a protoplanetary disk as long as we consider the dead zone where the magnetorotational instability does not grow. Extensive numerical simulations have been carried out in order to elucidate the condition for the development of particle clumping caused by the streaming instability. In this paper, a set of two parameters suitable for classifying the numerical results is proposed. One is the Stokes number that has been employed in previous works and the other is the dust particle column density that is nondimensionalized using the gas density in the midplane, Keplerian angular velocity, and difference between the Keplerian and gaseous orbital velocities. The magnitude of dust clumping is a measure of the behavior of the dust layer. Using three-dimensional numerical simulations of dust particles and gas based on Athena code v. 4.2, it is confirmed that the magnitude of dust clumping for two disk models are similar if the corresponding sets of values of the two parameters are identical to each other, even if the values of the metallicity (i.e., the ratio of the columns density of the dust particles to that of the gas) are different.

  1. Translating Pharmacokinetic and Pharmacodynamic Data into Practice.

    PubMed

    Visser, Marike

    2018-05-01

    Pharmacokinetic (PK) and pharmacodynamic (PD) publications provide scientific evidence for incorporation in evidence-based veterinary medicine, aiding the clinician in selecting doses and dosing intervals. PK and PD studies have reported wide variations within exotic species, due to physiologic differences in absorption, distribution, metabolism, and excretion. PK studies offer species-specific data to help tailor doses and dosing routes to individual patients, minimize toxicity, and provide a cornerstone for PD studies to determine drug efficacy. This article reviews the application of PK parameters and the challenges in determining the PD activity of drugs, with a particular emphasis on exotic species. Copyright © 2018 Elsevier Inc. All rights reserved.

  2. Raltegravir Pharmacokinetics in Patients on Asunaprevir-Daclatasvir

    PubMed Central

    Vincent, Corine; Furlan, Valérie; Rosa, Isabelle; Rosenthal, Eric; Cheret, Antoine; Molina, Jean-Michel; Taburet, Anne-Marie; Piroth, Lionel

    2015-01-01

    Raltegravir pharmacokinetics was studied in 20 patients included in the ANRS HC30 QUADRIH Study before and after addition of anti-hepatitis C virus (anti-HCV) quadritherapy, including pegylated-interferon–ribavirin and asunaprevir plus daclatasvir. Raltegravir pharmacokinetic parameters remained unchanged whether administered on or off anti-HCV therapy. In addition, concentrations of raltegravir, asunaprevir, and daclatasvir were not affected by liver cirrhosis. These data suggest that in human immunodeficiency virus (HIV)-HCV-coinfected patients, whether cirrhotic or not, asunaprevir and daclatasvir could be administered safely with raltegravir. PMID:26438504

  3. Characterization of the pH and Temperature in the Rabbit, Pig, and Monkey Eye: Key Parameters for the Development of Long-Acting Delivery Ocular Strategies.

    PubMed

    Lorget, Florence; Parenteau, Audrey; Carrier, Michel; Lambert, Daniel; Gueorguieva, Ana; Schuetz, Chris; Bantseev, Vlad; Thackaberry, Evan

    2016-09-06

    Many long-acting delivery strategies for ocular indications rely on pH- and/or temperature-driven release of the therapeutic agent and degradation of the drug carrier. Yet, these physiological parameters are poorly characterized in ocular animal models. These strategies aim at reducing the frequency of dosing, which is of particular interest for the treatment of chronic disorders affecting the posterior segment of the eye, such as macular degeneration that warrants monthly or every other month intravitreal injections. We used anesthetized white New Zealand rabbits, Yucatan mini pigs, and cynomolgus monkeys to characterize pH and temperature in several vitreous locations and the central aqueous location. We also established post mortem pH changes in the vitreous. Our data showed regional and species differences, which need to be factored into strategies for developing biodegradable long-acting delivery systems.

  4. Albendazole nanocrystals with improved pharmacokinetic performance in mice.

    PubMed

    Paredes, Alejandro J; Bruni, Sergio Sánchez; Allemandi, Daniel; Lanusse, Carlos; Palma, Santiago D

    2018-02-01

    Albendazole (ABZ) is a broad-spectrum antiparasitic agent with poor aqueous solubility, which leads to poor/erratic bioavailability and therapeutic failures. Here, we aimed to produce a novel formulation of ABZ nanocrystals (ABZNC) and assess its pharmacokinetic performance in mice. Results/methodology: ABZNC were prepared by high-pressure homogenization and spray-drying processes. Redispersion capacity and solid yield were measured in order to obtain an optimized product. The final particle size was 415.69±7.40 nm and the solid yield was 72.32%. The pharmacokinetic parameters obtained in a mice model for ABZNC were enhanced (p < 0.05) with respect to the control formulation. ABZNC with improved pharmacokinetic behavior were produced by a simple, inexpensive and potentially scalable methodology.

  5. Atomoxetine pharmacogenetics: associations with pharmacokinetics, treatment response and tolerability.

    PubMed

    Brown, Jacob T; Bishop, Jeffrey R

    2015-01-01

    Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder and is predominantly metabolized by the CYP2D6 enzyme. Differences in pharmacokinetic parameters as well as clinical treatment outcomes across CYP2D6 genotype groups have resulted in dosing recommendations within the product label, but clinical studies supporting the use of genotype guided dosing are currently lacking. Furthermore, pharmacokinetic and clinical studies have primarily focused on extensive as compared with poor metabolizers, with little information known about other metabolizer categories as well as genes involved in the pharmacodynamics of atomoxetine. This review describes the pharmacogenetic associations with atomoxetine pharmacokinetics, treatment response and tolerability with considerations for the clinical utility of this information.

  6. The Pressure Dependence of Thermal Expansion of Core-Forming Alloys: A Key Parameter in Determining the Convective Style of Planetary Cores

    NASA Astrophysics Data System (ADS)

    Williams, Q. C.; Manghnani, M. H.

    2017-12-01

    The convective style of planetary cores is critically dependent on the thermal properties of iron alloys. In particular, the relation between the adiabatic gradient and the melting curve governs whether planetary cores solidify from their top down (when the adiabat is steeper than the melting curve) or the bottom up (the converse). Molten iron alloys, in general, have large, ambient pressure thermal expansions: values in excess of 1.2 x 10^-4/K are dictated by data derived from levitated and sessile drop techniques. These high values of the thermal expansion imply that the adiabatic gradients within early planetesimals and present day moons that have comparatively low-pressure, iron-rich cores are steep (typically greater than 35 K/GPa at low pressures): values, at low pressures, that are greater than the slope of the melting curve, and hence show that the cores of small solar system objects probably crystallize from the top-down. Here, we deploy a different manifestation of these large values of thermal expansion to determine the pressure dependence of thermal expansion in iron-rich liquids: a difficult parameter to experimentally measure, and critical for determining the size range of cores in which top-down core solidification predominates. In particular, the difference between the adiabatic and isothermal bulk moduli of iron liquids is in the 20-30% range at the melting temperature, and scales as the product of the thermal expansion, the Grüneisen parameter, and the temperature. Hence, ultrasonic (and adiabatic) moduli of iron alloy liquids, when coupled with isothermal sink-float measurements, can yield quantitative constraints on the pressure dependence of thermal expansion. For liquid iron alloys containing 17 wt% Si, we find that the thermal expansion is reduced by 50% over the first 8 GPa of compression. This "squeezing out" of the anomalously high low-pressure thermal expansion of iron-rich alloys at relatively modest conditions likely limits the size

  7. Pharmacokinetics of ginkgolide B injection in beagle dogs.

    PubMed

    Song, H; Bu, F; Wei, C; Yuan, G; Liu, X; Wang, B; Guo, R

    2012-12-01

    A liquid chromatography-mass spectrometry method was developed, validated, and applied to the pharmacokinetic study with doses of 0.68, 2.73 and 10.92 mg/kg of ginkgolide B in beagle dogs after intravenous infusion.An aliquot of blood samples were -collected, separated and quantitatively analyzed by liquid chromatography-mass spectrometry method with mobile phase of acetonitrile-0.02% ammonia solution (33:67, v/v) at a flow rate of 0.8 mL/min on the UltimateTM XB-C18 column (5 μm, 4.6×150 mm).The method was sensitive, accurate and convenient, and can be used for the determination of ginkgolide B in beagle dogs. The Cmax and AUC0-∞ of GB increased with dose escalation, but ANOVA analyses showed that no significant difference was observed in other pharmacokinetic parameters between different doses.An LC/MS method was developed with good sensitivity, reproducibility and specificity. In the pharmacokinetic study of GB in beagle dogs, linear pharmacokinetics was found at doses from 0.62 to 10.92 mg/kg after a single-dose intravenous infusion. Gender differences were not observed in the pharmacokinetics of GB. © Georg Thieme Verlag KG Stuttgart · New York.

  8. Florida Keys

    NASA Image and Video Library

    2002-12-13

    The Florida Keys are a chain of islands, islets and reefs extending from Virginia Key to the Dry Tortugas for about 309 kilometers (192 miles). The keys are chiefly limestone and coral formations. The larger islands of the group are Key West (with its airport), Key Largo, Sugarloaf Key, and Boca Chica Key. A causeway extends from the mainland to Key West. This image was acquired on October 28, 2001, by the Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) on NASA's Terra satellite. With its 14 spectral bands from the visible to the thermal infrared wavelength region, and its high spatial resolution of 15 to 90 meters (about 50 to 300 feet), ASTER images Earth to map and monitor the changing surface of our planet. http://photojournal.jpl.nasa.gov/catalog/PIA03890

  9. Rapid effects of essential fatty acid deficiency on growth and development parameters and transcription of key fatty acid metabolism genes in juvenile barramundi (Lates calcarifer).

    PubMed

    Salini, Michael J; Turchini, Giovanni M; Wade, Nicholas M; Glencross, Brett D

    2015-12-14

    Barramundi (Lates calcarifer), a catadromous teleost of significant and growing commercial importance, are reported to have limited fatty acid bioconversion capability and therefore require preformed long-chain PUFA (LC-PUFA) as dietary essential fatty acid (EFA). In this study, the response of juvenile barramundi (47·0 g/fish initial weight) fed isolipidic and isoenergetic diets with 8·2% added oil was tested. The experimental test diets were either devoid of fish oil (FO), and thus with no n-3 LC-PUFA (FO FREE diet), or with a low inclusion of FO (FO LOW diet). These were compared against a control diet containing only FO (FO CTRL diet) as the added lipid source, over an 8-week period. Interim samples and measurements were taken fortnightly during the trial in order to define the aetiology of the onset and progression of EFA deficiency. After 2 weeks, the fish fed the FO FREE and FO LOW diets had significantly lower live-weights, and after 8 weeks significant differences were detected for all performance parameters. The fish fed the FO FREE diet also had a significantly higher incidence of external abnormalities. The transcription of several genes involved in fatty acid metabolism was affected after 2 weeks of feeding, showing a rapid nutritional regulation. This experiment documents the aetiology of the onset and the progression of EFA deficiency in juvenile barramundi and demonstrates that such deficiencies can be detected within 2 weeks in juvenile fish.

  10. Environment and Colonisation Sequence Are Key Parameters Driving Cooperation and Competition between Pseudomonas aeruginosa Cystic Fibrosis Strains and Oral Commensal Streptococci

    PubMed Central

    Whiley, Robert A.; Fleming, Emily V.; Makhija, Ridhima; Waite, Richard D.

    2015-01-01

    Cystic fibrosis (CF) patient airways harbour diverse microbial consortia that, in addition to the recognized principal pathogen Pseudomonas aeruginosa, include other bacteria commonly regarded as commensals. The latter include the oral (viridans) streptococci, which recent evidence indicates play an active role during infection of this environmentally diverse niche. As the interactions between inhabitants of the CF airway can potentially alter disease progression, it is important to identify key cooperators/competitors and environmental influences if therapeutic intervention is to be improved and pulmonary decline arrested. Importantly, we recently showed that virulence of the P. aeruginosa Liverpool Epidemic Strain (LES) could be potentiated by the Anginosus-group of streptococci (AGS). In the present study we explored the relationships between other viridans streptococci (Streptococcus oralis, Streptococcus mitis, Streptococcus gordonii and Streptococcus sanguinis) and the LES and observed that co-culture outcome was dependent upon inoculation sequence and environment. All four streptococcal species were shown to potentiate LES virulence factor production in co-culture biofilms. However, in the case of S. oralis interactions were environmentally determined; in air cooperation within a high cell density co-culture biofilm occurred together with stimulation of LES virulence factor production, while in an atmosphere containing added CO2 this species became a competitor antagonising LES growth through hydrogen peroxide (H2O2) production, significantly altering biofilm population dynamics and appearance. Streptococcus mitis, S. gordonii and S. sanguinis were also capable of H2O2 mediated inhibition of P. aeruginosa growth, but this was only visible when inoculated as a primary coloniser prior to introduction of the LES. Therefore, these observations, which are made in conditions relevant to the biology of CF disease pathogenesis, show that the pathogenic and

  11. Development of a novel biochar/PSF mixed matrix membrane and study of key parameters in treatment of copper and lead contaminated water.

    PubMed

    He, Jinsong; Song, Yihua; Chen, J Paul

    2017-11-01

    Mixed matrix membrane (MMM) has attracted increasing attentions in various applications, such as water treatment. In this study, an innovative biochar/polysulfone (PSF) mixed matrix hollow fiber membrane was fabricated by incorporating micro-sized biochar particles in the PSF matrix. It was demonstrated that the membrane was more hydrophilic than the pure PSF membrane. Higher water flux was obtained. The adsorption of copper and lead on the MMM increased as the pH was increased with the maximum adsorption capacity observed at pH > 4.5. The adsorption equilibrium was established in 7 and 12 h for lead and copper, respectively. The adsorption kinetics and isotherm followed the intraparticle surface diffusion model and Freundlich isotherm, respectively. The presence of humic acid (HA) had a little effect on the adsorption, while the ionic strength showed an adverse effect on the removal. In addition, the feed concentration and cross flow rate significantly affected the removal efficiency in a continuous filtration mode. The increase in feed concentration and cross flow rate resulted in a reduction in the volume of treated permeate that had the copper/lead concentrations below the regulated levels for drinking water. The MMM exhibited an excellent regeneration-reuse performance in the removal of both copper and lead. Finally, our mechanism studies indicated that the uptake of heavy metals was controlled by a combination of key reactions of complexation, ion-exchange and precipitation. This study indicated that the MMM can be applied as an effective and eco-friendly material for the treatment of heavy metals contaminated water. Copyright © 2017. Published by Elsevier Ltd.

  12. Pharmacokinetic interaction between scutellarin and valsartan in rats.

    PubMed

    Cui, Ming-Yu; Tian, Chong-Chong; Ju, Ai-Xia; Zhang, Chun-Ting; Li, Qiu-Hong

    2013-04-01

    Scutellarin is the main effective constituent of breviscapine, a flavonoid mixture isolated from the dried whole plant of Erigeron breviscapus (Vant.) Hand-Mazz, and valsartan is used as an antihypertensive drug. These two drugs have already been clinically used together to treat diabetic nephropathy (DN) in China, and the combined medications showed some enhanced protection against DN. The aim of this study is to investigate the potential pharmacokinetic interaction between scutellarin and valsartan in rats. Breviscapine injection (20 mg x kg(-1), i.v.) and valsartan (15 mg x kg-, i.g.), either alone or together were given to 18 male Sprague-Dawley rats. Concentrations of scutellarin and valsartan were quantified by HPLC, and pharmacokinetic parameters were calculated by non-compartmental methods. We found that the pharmacokinetic parameters of scutellarin altered significantly after co-administration of oral valsartan. The plasma clearance (CL(p)) and the bile clearance (CL(b)) of scutellarin were reduced significantly in the presence of valsartan. After oral administration of valsartan with or without intravenous scutellarin, however, the pharmacokinetic parameters of valsartan were comparable. In conclusion, our data suggests that the concurrent use of valsartan reduces the biliary excretion of scutellarin, and this may be due to the inhibitory effect of valsartan on the biliary excretion of scutellarin mediated by Mrp2 (Multidrug resistance-associated protein 2).

  13. Phosphorus saturation and superficial fertilizer application as key parameters to assess the risk of diffuse phosphorus losses from agricultural soils in Brazil.

    PubMed

    Fischer, P; Pöthig, R; Gücker, B; Venohr, M

    2018-07-15

    In Brazil, a steady increase in phosphorus (P) fertilizer application and agricultural intensification has been reported for recent decades. The concomitant P accumulation in soils potentially threatens surface water bodies with eutrophication through diffuse P losses. Here, we demonstrated the applicability of a soil type-independent approach for estimating the degree of P saturation (DPS; a risk parameter of P loss) by a standard method of water-soluble phosphorus (WSP) for two major soil types (Oxisols, Entisols) of the São Francisco catchment in Brazil. Subsequently, soil Mehlich-1P (M1P) levels recommended by Brazilian agricultural institutions were transformed into DPS values. Recommended M1P values for optimal agronomic production corresponded to DPS values below critical thresholds of high risks of P losses (DPS=80%) for major crops of the catchment. Higher risks of reaching critical DPS values due to P accumulation were found for Entisols due to their total sorption capacities being only half those of Oxisols. For complementary information on soil mineralogy and its influence on P sorption and P binding forms, Fourier transformation infrared (FTIR) spectroscopic analyses were executed. FTIR analyses suggested the occurrence of the clay minerals palygorskite and sepiolite in some of the analyzed Entisols and the formation of crandallite as the soil specific P binding form in the investigated Oxisols. Palygorskite and sepiolite can enhance P solubility and hence the risk of P losses. In contrast, the reshaping of superphosphate grains into crandallite may explain the chemical processes leading to previously observed low dissolved P concentrations in surface runoff from Oxisols. To prevent high risk of P losses, we recommend avoiding superficial fertilizer application and establishing environmental thresholds for soil M1P based on DPS. These measures could help to prevent eutrophication of naturally oligotrophic surface waters, and subsequent adverse effects

  14. Pharmacokinetic Studies in Neonates: The Utility of an Opportunistic Sampling Design.

    PubMed

    Leroux, Stéphanie; Turner, Mark A; Guellec, Chantal Barin-Le; Hill, Helen; van den Anker, Johannes N; Kearns, Gregory L; Jacqz-Aigrain, Evelyne; Zhao, Wei

    2015-12-01

    The use of an opportunistic (also called scavenged) sampling strategy in a prospective pharmacokinetic study combined with population pharmacokinetic modelling has been proposed as an alternative strategy to conventional methods for accomplishing pharmacokinetic studies in neonates. However, the reliability of this approach in this particular paediatric population has not been evaluated. The objective of the present study was to evaluate the performance of an opportunistic sampling strategy for a population pharmacokinetic estimation, as well as dose prediction, and compare this strategy with a predetermined pharmacokinetic sampling approach. Three population pharmacokinetic models were derived for ciprofloxacin from opportunistic blood samples (SC model), predetermined (i.e. scheduled) samples (TR model) and all samples (full model used to previously characterize ciprofloxacin pharmacokinetics), using NONMEM software. The predictive performance of developed models was evaluated in an independent group of patients. Pharmacokinetic data from 60 newborns were obtained with a total of 430 samples available for analysis; 265 collected at predetermined times and 165 that were scavenged from those obtained as part of clinical care. All datasets were fit using a two-compartment model with first-order elimination. The SC model could identify the most significant covariates and provided reasonable estimates of population pharmacokinetic parameters (clearance and steady-state volume of distribution) compared with the TR and full models. Their predictive performances were further confirmed in an external validation by Bayesian estimation, and showed similar results. Monte Carlo simulation based on area under the concentration-time curve from zero to 24 h (AUC24)/minimum inhibitory concentration (MIC) using either the SC or the TR model gave similar dose prediction for ciprofloxacin. Blood samples scavenged in the course of caring for neonates can be used to estimate

  15. Population Pharmacokinetics and Therapeutic Efficacy of Febuxostat in Patients with Severe Renal Impairment.

    PubMed

    Hira, Daiki; Chisaki, Yugo; Noda, Satoshi; Araki, Hisazumi; Uzu, Takashi; Maegawa, Hiroshi; Yano, Yoshitaka; Morita, Shin-Ya; Terada, Tomohiro

    2015-01-01

    The aim of the present study was to determine the influence of severe renal dysfunction (estimated glomerular filtration rate <30 ml/min/1.73 m(2), including hemodialysis) on the pharmacokinetics and therapeutic effects of febuxostat using a population pharmacokinetic analysis. This study recruited patients with hyperuricemia who were initially treated with allopurinol, but were switched to febuxostat, and it consists of 2 sub-studies: a pharmacokinetic study (26 patients) and retrospective efficacy evaluation study (51 patients). The demographic and clinical data of patients were collected from electronic medical records. Plasma febuxostat concentrations were obtained at each hospital visit. Population pharmacokinetic modeling was performed with NONMEM version 7.2. A total of 128 plasma febuxostat concentrations from 26 patients were used in the population pharmacokinetic analysis. The data were best described by a 1-compartment model with first order absorption. Covariate analysis revealed that renal function did not influence the pharmacokinetics of febuxostat, whereas actual body weight significantly influenced apparent clearance and apparent volume of distribution. The retrospective efficacy analysis showed the favorable therapeutic response of febuxostat switched from allopurinol in patients with moderate to severe renal impairment. No serious adverse event associated with febuxostat was observed irrespective of renal function. The population pharmacokinetic analysis and therapeutic analysis of febuxostat revealed that severe renal dysfunction had no influence on the pharmacokinetic parameters of febuxostat. These results suggest that febuxostat is tolerated well by patients with severe renal impairment. © 2015 S. Karger AG, Basel.

  16. GLP-1 agonists for type 2 diabetes: pharmacokinetic and toxicological considerations.

    PubMed

    Jespersen, Maria J; Knop, Filip K; Christensen, Mikkel

    2013-01-01

    Within recent years, glucagon-like peptide 1 receptor agonists (GLP-1-RA) have emerged as a new treatment option for type 2 diabetes. The GLP-1-RA are administered subcutaneously and differ substantially in pharmacokinetic profiles. This review describes the pharmacokinetics and safety aspects of the currently available GLP-1 receptor agonists, liraglutide (based on the structure of native GLP-1), exenatide twice daily and exenatide once weekly (based on exendin-4) in relation to the kinetics and toxicology of native GLP-1. The review is based on electronic literature searches and legal documents in the form of assessment reports from the European Medicines Agency and the United States Food and Drug Administration. GLP-1-based therapy combines several unique mechanisms of action and have the potential to gain widespread use in the fight against diabetes and obesity. The difference in chemical structure have strong implications for key pharmacokinetic parameters such as absorption and clearance, and eventually the safety and efficacy of the individual GLP-1-RA. The main safety concerns are pancreatitis and neoplasms, for which there are no identifiable differences in risk between the available agents. Antibody formation and injection site reactions are more frequent with the exendin-4-based compounds. The efficacy with regard to Hb(A1c) reduction is superior with the longer-acting agonists, whereas the shorter-acting GLP-1-RA seems to provide greater postprandial glucose control and lower tolerability as a possible consequence of less induction of tachyphylaxis. The future place of these agents will depend on the added safety and efficacy data in the several ongoing cardiovascular outcome trials.

  17. Pharmacokinetics of a slow-release formulation of soybean isoflavones in healthy postmenopausal women.

    PubMed

    Setchell, Kenneth D R; Brzezinski, Amnon; Brown, Nadine M; Desai, Pankaj B; Melhem, Murad; Meredith, Trevor; Zimmer-Nechimias, Linda; Wolfe, Brian; Cohen, Yoram; Blatt, Yoav

    2005-03-23

    Pharmacokinetic studies of soybean isoflavones have shown that following oral ingestion, the two major isoflavones, daidzin and genistin, are hydrolyzed in the intestine, rapidly absorbed into the peripheral circulation, and eliminated from the body with a terminal half-life of 7-8 h. These characteristics make maintenance of steady-state plasma isoflavone concentrations difficult to attain unless there is repeated daily ingestion of foods or supplements containing isoflavones. In an attempt to sustain more constant plasma isoflavone concentrations, a new slow-release formulation of a soybean isoflavone extract was prepared by microencapsulation with a mixture of hydroxypropylcellulose and ethylcellulose to alter its dissolution characteristics. In vitro experiments confirmed slow aqueous dissolution of isoflavones from this formulation when compared with the conventional isoflavone extract. The pharmacokinetics of this slow-release isoflavone extract was studied in 10 healthy postmenopausal women after oral administration of a single capsule containing the equivalent of 22.3 mg of genistein and 7.47 mg of daidzein expressed as aglycons. A comparison of the key pharmacokinetic parameters obtained in this study with those established in extensive studies performed previously in this laboratory indicated that the mean residence time of genistein and daidzein increased 2-fold with microencapsulation. These findings are indicative of a decreased rate of absorption, consistent with the observed slow in vitro dissolution rate. These findings show that it is feasible to employ polymer matrices that slow the aqueous dissolution for preparing sustained-release formulations of soy isoflavones. Further studies to optimize such formulations are warranted.

  18. Pharmacokinetics of cefpirome during the posttraumatic systemic inflammatory response syndrome.

    PubMed

    Jacolot, A; Incagnoli, P; Edouard, A R; Tod, M; Petitjean, O; Samii, K; Mimoz, O

    1999-05-01

    To determine the pharmacokinetic parameters of cefpirome, a new so-called fourth-generation cephalosporin, in previously healthy trauma patients with posttraumatic systemic inflammatory response syndrome (SIRS) and to compare them to parameters obtained in matched, healthy volunteers. A prospective study. 12-bed surgical intensive care unit in a university hospital. 9 severe [Injury Severity Score, median (range) 29 (16-50)] trauma patients on mechanical ventilation with proven or suspected cefpirome-susceptible nosocomial infection, with no renal or hepatic failure, and healthy volunteers matched for age (+/- 5 years), sex, and body surface area (+/- 10%) were enrolled. All were men. Cefpirome (2 g twice daily) was continuously infused over a 0.5 h period alone or concomitantly with ciprofloxacin (400 mg over 1 h, twice daily). Antibiotic concentrations in plasma were measured by high-performance liquid chromatography; their pharmacokinetic parameters were evaluated at 12 time points after the first drug administration using a noncompartmental model. Cefpirome pharmacokinetic parameters for the two groups were similar despite a wider variation for trauma patients. Specifically, the median (range) time during which the cefpirome concentration in plasma remained over 4 mg/l (corresponding to the French lower cutoff determining cefpirome susceptibility) was 9.5 (7- > 12) and 9 (8-12) h for trauma patients and healthy volunteers, respectively. In the group of five patients receiving combined antibiotic therapy, the interindividual variability of pharmacokinetics was wider for ciprofloxacin than for cefpirome. No major pharmacokinetic modification was noted when cefpirome was given to trauma patients with posttraumatic SIRS without significant organ failure, indicating that no dosage adjustment seems required in this population. However, larger studies including determination of antibiotic levels in tissues are warranted to confirm these results.

  19. Pharmacokinetics of Doxorubicin in Pregnant Women

    PubMed Central

    Ryu, Rachel J.; Eyal, Sara; Kaplan, Henry G.; Akbarzadeh, Arezoo; Hays, Karen; Puhl, Kristin; Easterling, Thomas R.; Berg, Stacey L.; Scorsone, Kathleen A.; Feldman, Eric M.; Umans, Jason G.; Miodovnik, Menachem; Hebert, Mary F.

    2014-01-01

    Purpose Our objective was to evaluate the pharmacokinetics (PK) of doxorubicin during pregnancy compared to previously published data from non-pregnant subjects. Methods During mid- to late-pregnancy, serial blood and urine samples were collected over 72 hours from 7 women treated with doxorubicin for malignancies. PK parameters were estimated using noncompartmental techniques. Pregnancy parameters were compared to those previously reported non-pregnant subjects. Results During pregnancy, mean (± SD) doxorubicin PK parameters utilizing 72 hour sampling were: clearance (CL), 412 ± 80 mL/min/m2; steady-state volume of distribution (Vss), 1132 ± 476 L/m2; and terminal half-life (T1/2), 40.3 ± 8.9 hr. The BSA-adjusted CL was significantly decreased (p < 0.01) and T1/2 was not different compared to non-pregnant women. Truncating our data to 48 hours, PK parameters were: CL, 499 ± 116 ml/min/m2; Vss, 843 ± 391 L/m2; and T1/2, 24.8 ± 5.9 hr. The BSA-adjusted CL in pregnancy compared to non-pregnant data was significantly decreased in 2 of 3 non-pregnant studies (p < 0.05, < 0.05, NS). Vss and T1/2 were not significantly different. Conclusions In pregnant subjects, we observed significantly lower doxorubicin CL in our 72 hour and most of our 48 hour sampling comparisons with previously reported non-pregnant subjects. However, the parameters were within the range previously reported in smaller studies. At this time, we cannot recommend alternate dosage strategies for pregnant women. Further research is needed to understand the mechanism of doxorubicin pharmacokinetic changes during pregnancy and optimize care for pregnant women. PMID:24531558

  20. Lymphatic route of transport and pharmacokinetics of Micrurus fulvius (coral snake) venom in sheep.

    PubMed

    Paniagua, D; Jiménez, L; Romero, C; Vergara, I; Calderón, A; Benard, M; Bernas, M J; Rilo, H; de Roodt, A; D' Suze, G; Witte, M H; Boyer, L; Alagón, A

    2012-12-01

    The contribution of the lymphatic system to the absorption and systemic bioavailability of Micrurus fulvius venom after subcutaneous (SC) administration was assessed using a central lymph-cannulated sheep model. Micrurus fulvius venom was administered either by intravenous bolus (IV) or subcutaneous injection (SC) in 12 sheep with and without thoracic duct cannulation and drainage. Venom concentration in serum and lymph was determined by a sandwich enzyme-linked immunosorbent assay (ELISA) in samples collected over a 6-hour period and in tissues harvested at the end of the experiment. Pharmacokinetic parameters were determined by a non-compartmental analysis. In the lymphatic cannulated group, over the 6 hours after the venom was administered, 69% of administered dose was accounted for in blood (45%) and lymph (25%). Negligible levels of venom were detected in organs and urine implying that the steady state observed after SC administration is maintained by a slow absorption process. Comparison of kinetics of the thoracic duct cannulated and non-cannulated groups showed that lymphatic absorption contributed in an important way to maintenance of this steady state. These results show that the limiting process in the pharmacokinetics of Micrurus fulvius venom following SC administration is absorption, and that the lymphatic system plays a key role in this process.

  1. The Use of Wireless Laptop Computers for Computer-Assisted Learning in Pharmacokinetics

    PubMed Central

    Munar, Myrna Y.; Singh, Harleen; Belle, Donna; Brackett, Carolyn C.; Earle, Sandra B.

    2006-01-01

    Objective To implement computer-assisted learning workshops into pharmacokinetics courses in a doctor of pharmacy (PharmD) program. Design Workshops were designed for students to utilize computer software programs on laptop computers to build pharmacokinetic models to predict drug concentrations resulting from various dosage regimens. In addition, students were able to visualize through graphing programs how altering different parameters changed drug concentration-time curves. Surveys were conducted to measure students’ attitudes toward computer technology before and after implementation. Finally, traditional examinations were used to evaluate student learning. Assessment Doctor of pharmacy students responded favorably to the use of wireless laptop computers in problem-based pharmacokinetic workshops. Eighty-eight percent (n = 61/69) and 82% (n = 55/67) of PharmD students completed surveys before and after computer implementation, respectively. Prior to implementation, 95% of students agreed that computers would enhance learning in pharmacokinetics. After implementation, 98% of students strongly agreed (p < 0.05) that computers enhanced learning. Examination results were significantly higher after computer implementation (89% with computers vs. 84% without computers; p = 0.01). Conclusion Implementation of wireless laptop computers in a pharmacokinetic course enabled students to construct their own pharmacokinetic models that could respond to changing parameters. Students had greater comprehension and were better able to interpret results and provide appropriate recommendations. Computer-assisted pharmacokinetic techniques can be powerful tools when making decisions about drug therapy. PMID:17136147

  2. The use of wireless laptop computers for computer-assisted learning in pharmacokinetics.

    PubMed

    Munar, Myrna Y; Singh, Harleen; Belle, Donna; Brackett, Carolyn C; Earle, Sandra B

    2006-02-15

    To implement computer-assisted learning workshops into pharmacokinetics courses in a doctor of pharmacy (PharmD) program. Workshops were designed for students to utilize computer software programs on laptop computers to build pharmacokinetic models to predict drug concentrations resulting from various dosage regimens. In addition, students were able to visualize through graphing programs how altering different parameters changed drug concentration-time curves. Surveys were conducted to measure students' attitudes toward computer technology before and after implementation. Finally, traditional examinations were used to evaluate student learning. Doctor of pharmacy students responded favorably to the use of wireless laptop computers in problem-based pharmacokinetic workshops. Eighty-eight percent (n = 61/69) and 82% (n = 55/67) of PharmD students completed surveys before and after computer implementation, respectively. Prior to implementation, 95% of students agreed that computers would enhance learning in pharmacokinetics. After implementation, 98% of students strongly agreed (p < 0.05) that computers enhanced learning. Examination results were significantly higher after computer implementation (89% with computers vs. 84% without computers; p = 0.01). Implementation of wireless laptop computers in a pharmacokinetic course enabled students to construct their own pharmacokinetic models that could respond to changing parameters. Students had greater comprehension and were better able to interpret results and provide appropriate recommendations. Computer-assisted pharmacokinetic techniques can be powerful tools when making decisions about drug therapy.

  3. Pharmacokinetics and Pharmacodynamics in Space

    NASA Technical Reports Server (NTRS)

    Putcha, Lakshmi; Cintron, Nitza M.

    1990-01-01

    The Pharmacokinetics and Pharmacodynamics Panel met on 29-30 Aug. 1988 at the Lunar and Planetary Institute in Houston, Texas to discuss pharmacokinetic and pharmacodynamic implications of space flight and make recommendations for operational and research strategies. Based on the knowledge available on the physiological changes that occur during space flight, the dependence of pharmacokinetics on physiological factors, and the therapeutic requirements for future space missions, the panel made several recommendations for research. It was suggested that using medications available with a large (wide) therapeutic window will avoid unforeseen therapeutic consequences during flight. The sequence for conducting research was outlined as follows: (1) identify ground-based simulation models (e.g., antiorthostatic bed rest) for conducting pharmacokinetic and pharmacodynamic research; (2) estimate parametric changes in these models using pharmacologic agents that have different pharmacokinetic characteristics and a narrow therapeutic index; (3) verify these findings during flight; and (4) develop and identify appropriate and effective drug delivery systems, dosage forms, and regimens. The panel recommended gaining a thorough understanding of the pharmacokinetic deviations of medications that have a narrow therapeutic index (e.g. cardiovascular drugs and sedative hypnotics) in order to ensure safe and effective treatment during flight with these agents. It was also suggested that basic information on physiological factors such as organ blood flow, protein composition and binding, tissue distribution, and metabolism by hepatic enzymes must be accumulated by conducting ground-based animal and human studies using models of weightlessness. This information will be useful to construct and identify physiologically based pharmacokinetic models that can provide valuable information on the pharmacodynamic consequences of space flight and aid in identifying appropriate therapeutic

  4. Pharmacokinetics of metronomic chemotherapy: a neglected but crucial aspect.

    PubMed

    Bocci, Guido; Kerbel, Robert S

    2016-11-01

    Metronomic chemotherapy describes the close, regular administration of chemotherapy drugs at less-toxic doses over prolonged periods of time. In 2015, the results of randomized phase III clinical trials demonstrated encouraging, albeit limited, efficacy benefits of metronomic chemotherapy regimens administered as adjuvant maintenance therapy for the treatment of breast cancer, or as maintenance therapy in combination with an antiangiogenic agent for metastatic colorectal cancer. Owing to the investigational nature of this approach, metronomic chemotherapy regimens are highly empirical in terms of the optimal dose and schedule for the drugs administered; therefore, greater knowledge of the pharmacokinetics of metronomic chemotherapy is critical to the future success of this treatment strategy. Unfortunately, such preclinical and clinical pharmacokinetic studies are rare. Herein, we present situations in which active drug concentrations have been achieved with metronomic schedules, and discuss their associated pharmacokinetic parameters. We summarize examples from the limited number of clinical studies in order to illustrate the importance of assessing such pharmacokinetic parameters, and discuss the influence this information can have on improving efficacy and reducing toxicity.

  5. Pharmacokinetic disposition and arthropathic potential of oral ofloxacin in dogs.

    PubMed

    Yoshida, K; Yabe, K; Nishida, S; Yamamoto, N; Ohshima, C; Sekiguchi, M; Yamada, K; Furuhama, K

    1998-04-01

    We examined the relation between the pharmacokinetic disposition and arthropathic potential of ofloxacin, a new quinolone antibacterial agent, using both male immature (3-month-old) and mature (18-month-old) beagles. Ofloxacin was orally administered to these dogs at 20 mg/kg once daily for 8 consecutive days, and the animals were killed 2 h after the last treatment. Serum ofloxacin concentrations were repeatedly measured on days 1 and 7 by use of high-performance liquid chromatography (HPLC), and pharmacokinetic parameters were calculated. In addition, on day 8, the drug concentrations in the joint synovial fluid and humeral and femoral condyles were measured. Clinico-pathological tests of blood and serum or histopathological examination of bone specimens were also performed. Arthropathy was macroscopically observed in the cartilage surface of all immature dogs, but not in mature dogs. There were, however, no noticeable differences in pharmacokinetic parameters between the two age groups of dogs or between single and 7-day treatments. In contrast to the occurrence of arthropathic lesions, the synovial fluid and condylar drug concentrations in immature dogs was equal to or lower than those in mature dogs, suggesting that the pharmacokinetic disposition of ofloxacin may not be essential for cartilage lesions.

  6. Clinical pharmacokinetic and pharmacodynamic profile of lacosamide.

    PubMed

    Cawello, Willi

    2015-09-01

    Lacosamide-a third-generation antiepileptic drug available in multiple formulations-was first approved in 2008 as adjunctive therapy for partial-onset seizures (POS) in adults. In 2014, lacosamide was approved as monotherapy for POS by the US Food and Drug Administration (FDA). A loading dose administration was approved in 2013 by the European Medicines Agency and in 2014 by the FDA. Unlike traditional sodium channel blockers affecting fast inactivation, lacosamide selectively enhances sodium channel slow inactivation. This mechanism of action results in stabilization of hyperexcitable neuronal membranes, inhibition of neuronal firing and reduction in long-term channel availability without affecting physiological function. Lacosamide is rapidly absorbed, with maximum plasma concentrations reached 0.5-4 h after intake. Oral bioavailability is high (100 %) for a dose up to 800 mg. Bioavailability is irrespective of food intake. Variability in pharmacokinetic parameters is low (coefficients of variation almost all <20 %). The pharmacokinetic profile of lacosamide is consistent in healthy subjects and across different patient populations studied. Lacosamide elimination from plasma occurs with a terminal half-life of approximately 13 h in young subjects and 14-16 h in elderly subjects; this difference does not impact the dose regimen. Lacosamide produces a pharmacodynamic effect that is closely correlated with its plasma concentration. The pharmacokinetic and pharmacodynamic relationship for reduction of seizure frequency can be described by a maximum effect (E max) model. Lacosamide does not induce or inhibit cytochrome P450 enzymes or known drug transporter systems, has low protein binding of less than 15 % and, because it has multiple elimination pathways, it has no clinically relevant interactions with commonly prescribed medications.

  7. Pharmacokinetic Studies of Oxathio-Heterocycle Fused Chalcones.

    PubMed

    Okoniewska, Krystyna; Konieczny, Marek T; Lemke, Krzysztof; Grabowski, Tomasz

    2017-02-01

    Chalcone constitutes one of the most used molecular frameworks in medicinal chemistry and its derivatives exhibit a broad spectrum of biological activities. Low absolute bioavailability, poor distribution, intensive metabolism and elimination of chalcones are the main problems in designing new drugs based on their structure. One of the fundamental steps in evaluation of drug candidates is a comparative analysis of pharmacokinetic parameters. The aim of the studies was the pharmacokinetic characterization of the selected oxathio-heterocycle fused chalcones. The pharmacokinetic parameters of 19 compounds were reported. The analyzed chalcones were examined after a single intravenous administration to forty 7-week-old mature male rats of Wistar stock. Pharmacokinetic analysis was performed independently using SHAM (slopes, highest, amounts, and moments) and the two-compartment model. Basic physiochemical parameters were calculated. The bioanalytical methods were validated in terms of repeatability, linearity, accuracy, precision, and selectivity. The pharmacokinetics of the examined group of chalcones are compatible with the two-compartment model. The physicochemical characteristics of this group are quite homogeneous. The kinetics of the examined chalcones are indicative of a distribution to the tissue compartment with the predominance of a rate constant from central to peripheral compartments (k 12 ) over the rate constant from peripheral to central compartments (k 21 ). The elimination from the central compartment (k 10 ) is higher than the transfer from the central compartment to the tissues (k 10  > k 12 ) in almost all examined cases. The presented group of compounds may form a starting point for studies into drugs treating autoimmune diseases of the gastro-intestinal tract.

  8. Pharmacokinetic evaluation of losartan.

    PubMed

    Burnier, Michel; Wuerzner, Grégoire

    2011-05-01

    Blockade of the renin-angiotensin system is one of the major therapeutic strategies in the management of patients with essential hypertension, congestive heart failure and diabetic as well as non-diabetic renal diseases. As the first angiotensin II receptor blocker (ARB) on the market, losartan belongs to the most frequently prescribed ARB. The present review examines the pharmacokinetics of losartan with a special discussion on the dose of losartan that should be used in clinical practice to obtain the maximal benefits of the drug. Readers are provided with arguments suggesting that the dose of 50 mg losartan is probably too low and that losartan should preferably be prescribed at the dose of 100 mg/day or higher. Losartan is an effective antagonist of angiotensin II AT(1) receptors which has been shown to provide important clinical benefits in patients with hypertension, congestive heart failure and renal diseases. Losartan should be prescribed at the dose of 100 mg/day and the use of higher doses should be reconsidered in future studies to improve its clinical efficacy.

  9. 4-Hydroxyanisole: human pharmacokinetics.

    PubMed

    Belcher, H J; Barsted, C G; Dawson, C M

    1990-12-01

    The pharmacokinetic behaviour of 4-hydroxyanisole (4HA) has been studied in ten female patients with recurrent malignant melanoma confined to the lower limb. Ten grams of 4HA was infused twice each day via a catheter placed in the common femoral artery for a maximum of 4 days. Blood samples were collected after the first and fourth infusions in all patients and the serum 4HA concentration assayed. Following infusion, the serum 4HA concentration declined in two phases, the half-lives (t1/2) of the distribution and elimination phases being 6.3 and 70.9 min, respectively. The serum 4HA concentrations and area under the curve (AUC) declined significantly between the first and fourth infusions. There was a significant rise in the apparent volume of distribution (VD) of 4HA between these times but no change in the t1/2 of the elimination phase or the clearance rate. It is concluded that there is no evidence that enzyme induction influences the clearance of 4-hydroxyanisole from the bloodstream in the short-term. However, it may be appropriate to adjust dosage regimens to take account of the change in VD that occurs with time.

  10. Colistin Pharmacokinetics in Burn Patients during Continuous Venovenous Hemofiltration

    PubMed Central

    Rowan, Matthew P.; Niece, Krista L.; Stewart, Ian J.; Mende, Katrin; Cota, Jason M.; Murray, Clinton K.; Chung, Kevin K.

    2014-01-01

    While colistin is considered a last resort for the treatment of multidrug-resistant Gram-negative bacterial infections, there has been an increase in its use due to the increasing prevalence of drug-resistant infections worldwide. The pharmacology of colistin is complex, and pharmacokinetic data are limited, especially in patients requiring renal replacement therapy. As a result, dosing for patients who require renal replacement remains a challenge. Here, we present pharmacokinetic data for colistin from two burn patients (37 and 68 years old) infected with colistin-susceptible isoclonal Acinetobacter baumannii and receiving continuous venovenous hemofiltration (CVVH). To our knowledge, we are the first to examine data from before and during CVVH (for one patient), allowing analysis of the effect of CVVH on colistin pharmacokinetics. Pharmacokinetic/pharmacodynamic analysis indicated that a dose increase from 1.5 to 2.2 mg/kg of body weight colistin base activity on CVVH was insufficient to satisfy the target parameter of an AUC24/MIC (area under the concentration-time curve over 24 h in the steady state divided by the MIC) of ≥60 at an MIC of ≥1 μg/ml in one patient with residual endogenous renal function. Plasma concentrations of colistin ranged from 0 to 15 μg/ml, with free colistin levels ranging from 0.4 to 2.2 μg/ml. While both patients resolved their clinical infections and survived to discharge, colistin-resistant colonizing isolates resulted from therapy in one patient. The variabilities observed in colistin concentrations and pharmacokinetic characteristics highlight the importance of pharmacokinetic monitoring of antibiotics in patients undergoing renal replacement therapy. PMID:25313211

  11. Applied Pharmacokinetics: Course Description and Retrospective Evaluation.

    ERIC Educational Resources Information Center

    Beck, Diane E.

    1984-01-01

    An applied course designed to allow students to formulate pharmacokinetic recommendations individually for actual patient data and compare their recommendations to those of a pharmacokinetic consulting service is described and evaluated, and an objective student evaluation method is outlined. (MSE)

  12. Nitrate pharmacokinetics: Taking note of the difference.

    PubMed

    James, Philip E; Willis, Gareth R; Allen, Jason D; Winyard, Paul G; Jones, Andrew M

    2015-08-01

    It is now recognised that administration of oral nitrate (NO3(-)), in its various forms, increases the level of nitric oxide (NO) metabolites in the circulation of humans. Its application to modulate physiology and alleviate cardiovascular dysfunction in some patients is now recorded and shows particular promise in hypertension, in modifying platelet activation/aggregation, and in conditions where tissue ischaemia prevails. The potential of oral NO3(-) to modify exercise/performance via elevation of plasma nitrite concentration ([NO2(-)]) has been applied across a range of human test systems. Herein we discuss how the choice of NO3(-) source, route of administration and resulting pharmacokinetics might influence the outcome of physiological measures and potentially contribute to discrepancies in performance trials. There are but a few examples of detailed pharmacokinetic data on which the majority of researchers base their test protocols in different cohorts/settings. We compare and contrast the results of key publications with the aim of highlighting a consensus of our current understanding and critical considerations for those entering the field. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Comparative pharmacokinetic study of the main components of cortex fraxini after oral administration in normal and hyperuricemic rats.

    PubMed

    Wang, Yinan; Zhao, Min; Ye, Hao; Shao, Yizhen; Yu, Yongbo; Wang, Miao; Zhao, Chunjie

    2017-08-01

    Cortex Fraxini is an important traditional Chinese herbal medicine used for the treatment of gout and hyperuricemia. An efficient and rapid ultra-performance liquid chromatography mass spectrometry method was developed and validated for simultaneous quantitation of six coumarins (aesculin, fraxin, aesculetin, fraxetin, sopoletin and 7-hydroxycoumarin) in normal and hyperuricemic rats plasma after oral administration of Cortex Fraxini. The method could successfully be applied for pharmacokinetics studies. The pharmacokinetic behavior of six coumarins in normal and hyperuricemia rats plasma was determined. Results showed that, for some of analytes, the pharmacokinetic parameters (AUC 0-t , AUC 0-∞ , C max , T max and CL) were significantly different between normal and hyperuricemic rats. The different pharmacokinetic parameters might result from renal impairment or a change of metabolic enzymes in the pathological state. The pharmacokinetic study in pathological state could provide more useful information to guide the clinical use of traditional Chinese herbal medicine. Copyright © 2017 John Wiley & Sons, Ltd.

  14. Pharmacokinetics of oral gabapentin in Greyhound dogs

    PubMed Central

    KuKanich, Butch; Cohen, Rachael L

    2009-01-01

    The purpose of this study was to assess the pharmacokinetics of gabapentin in healthy Greyhound dogs after single oral doses targeted at 10 and 20 mg/kg PO. Six healthy Greyhounds were enrolled (3 males, 3 females). Blood was obtained at predetermined times for the measurement of gabapentin plasma concentrations by liquid chromatography/mass spectrometry. Pharmacokinetic parameters were determined with computer software. The actual mean (and range) doses administered were 10.2 (9.1–12.0) mg/kg and 20.5 (18.2 – 24) mg/kg for the 10 mg/kg and 20 mg/kg targeted dose groups. The mean CMAX for the 10 and 20 mg/kg groups were 8.54 and 13.22 μg/mL at 1.3 and 1.5 h, and the terminal half-lives were 3.3 and 3.4 h, respectively. The relative bioavailability of the 10 mg/kg group was 1.13 compared to the 20 mg/kg group. Gabapentin was rapidly absorbed and eliminated in dogs indicating frequent dosing is needed to maintain minimum targeted plasma concentrations. PMID:19854080

  15. Pharmacokinetics of oral gabapentin in greyhound dogs.

    PubMed

    Kukanich, Butch; Cohen, Rachael L

    2011-01-01

    The purpose of this study was to assess the pharmacokinetics of gabapentin in healthy greyhound dogs after single oral doses targeted at 10 and 20mg/kg PO. Six healthy greyhounds were enrolled (3 males, 3 females). Blood was obtained at predetermined times for the measurement of gabapentin plasma concentrations by liquid chromatography/mass spectrometry. Pharmacokinetic parameters were determined with computer software. The actual mean (and range) doses administered were 10.2 (9.1-12.0) mg/kg and 20.5 (18.2-24) mg/kg for the 10mg/kg and 20mg/kg targeted dose groups. The mean C(MAX) for the 10 and 20mg/kg groups were 8.54 and 13.22 microg/mL at 1.3 and 1.5h, and the terminal half-lives were 3.3 and 3.4h, respectively. The relative bioavailability of the 10mg/kg group was 1.13 compared to the 20mg/kg group. Gabapentin was rapidly absorbed and eliminated in dogs, indicating that frequent dosing is needed to maintain minimum targeted plasma concentrations. 2009 Elsevier Ltd. All rights reserved.

  16. 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

  17. Issues in the Pharmacokinetics of Trichloroethylene and Its Metabolites

    PubMed Central

    Chiu, Weihsueh A.; Okino, Miles S.; Lipscomb, John C.; Evans, Marina V.

    2006-01-01

    Much progress has been made in understanding the complex pharmacokinetics of trichloroethylene (TCE). Qualitatively, it is clear that TCE is metabolized to multiple metabolites either locally or into systemic circulation. Many of these metabolites are thought to have toxicologic importance. In addition, efforts to develop physiologically based pharmacokinetic (PBPK) models have led to a better quantitative assessment of the dosimetry of TCE and several of its metabolites. As part of a mini-monograph on key issues in the health risk assessment of TCE, this article is a review of a number of the current scientific issues in TCE pharmacokinetics and recent PBPK modeling efforts with a focus on literature published since 2000. Particular attention is paid to factors affecting PBPK modeling for application to risk assessment. Recent TCE PBPK modeling efforts, coupled with methodologic advances in characterizing uncertainty and variability, suggest that rigorous application of PBPK modeling to TCE risk assessment appears feasible at least for TCE and its major oxidative metabolites trichloroacetic acid and trichloroethanol. However, a number of basic structural hypotheses such as enterohepatic recirculation, plasma binding, and flow- or diffusion-limited treatment of tissue distribution require additional evaluation and analysis. Moreover, there are a number of metabolites of potential toxicologic interest, such as chloral, dichloroacetic acid, and those derived from glutathione conjugation, for which reliable pharmacokinetic data is sparse because of analytical difficulties or low concentrations in systemic circulation. It will be a challenge to develop reliable dosimetry for such cases. PMID:16966104

  18. Physiologically-based pharmacokinetic models: approaches for enabling personalized medicine.

    PubMed

    Hartmanshenn, Clara; Scherholz, Megerle; Androulakis, Ioannis P

    2016-10-01

    Personalized medicine strives to deliver the 'right drug at the right dose' by considering inter-person variability, one of the causes for therapeutic failure in specialized populations of patients. Physiologically-based pharmacokinetic (PBPK) modeling is a key tool in the advancement of personalized medicine to evaluate complex clinical scenarios, making use of physiological information as well as physicochemical data to simulate various physiological states to predict the distribution of pharmacokinetic responses. The increased dependency on PBPK models to address regulatory questions is aligned with the ability of PBPK models to minimize ethical and technical difficulties associated with pharmacokinetic and toxicology experiments for special patient populations. Subpopulation modeling can be achieved through an iterative and integrative approach using an adopt, adapt, develop, assess, amend, and deliver methodology. PBPK modeling has two valuable applications in personalized medicine: (1) determining the importance of certain subpopulations within a distribution of pharmacokinetic responses for a given drug formulation and (2) establishing the formulation design space needed to attain a targeted drug plasma concentration profile. This review article focuses on model development for physiological differences associated with sex (male vs. female), age (pediatric vs. young adults vs. elderly), disease state (healthy vs. unhealthy), and temporal variation (influence of biological rhythms), connecting them to drug product formulation development within the quality by design framework. Although PBPK modeling has come a long way, there is still a lengthy road before it can be fully accepted by pharmacologists, clinicians, and the broader industry.

  19. PHARMACOLOGY PART 2: INTRODUCTION TO PHARMACOKINETICS.

    PubMed

    Currie, Geoffrey M

    2018-05-03

    Pharmacology principles provide key understanding that underpins the clinical and research roles of nuclear medicine practitioners. This article is the second in a series of articles that aims to enhance the understanding of pharmacological principles relevant to nuclear medicine. This article will build on the introductory concepts, terminology and principles of pharmacodynamics explored in the first article in the series. Specifically, this article will focus on the basic principles associated with pharmacokinetics. Article 3 will outline pharmacology relevant to pharmaceutical interventions and adjunctive medications employed in general nuclear medicine, the fourth pharmacology relevant to pharmaceutical interventions and adjunctive medications employed in nuclear cardiology, the fifth the pharmacology related to contrast media associated with computed tomography (CT) and magnetic resonance imaging (MRI), and the final article will address drugs in the emergency trolley. Copyright © 2018 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  20. Population Pharmacokinetic Model for Cancer Chemoprevention With Sulindac in Healthy Subjects

    PubMed Central

    Berg, Alexander K.; Mandrekar, Sumithra J.; Ziegler, Katie L. Allen; Carlson, Elsa C.; Szabo, Eva; Ames, Mathew M.; Boring, Daniel; Limburg, Paul J.; Reid, Joel M.

    2014-01-01

    Sulindac is a prescription-based non-steroidal anti-inflammatory drug (NSAID) that continues to be actively investigated as a candidate cancer chemoprevention agent. To further current understanding of sulindac bioavailability, metabolism, and disposition, we developed a population pharmacokinetic model for the parent compound and its active metabolites, sulindac sulfide, and exisulind. This analysis was based on data from 24 healthy subjects who participated in a bioequivalence study comparing two formulations of sulindac. The complex disposition of sulindac and its metabolites was described by a seven-compartment model featuring enterohepatic recirculation and is the first reported population pharmacokinetic model for sulindac. The derived model was used to explore effects of clinical variables on sulindac pharmacokinetics and revealed that body weight, creatinine clearance, and gender were significantly correlated with pharmacokinetic parameters. Moreover, the model quantifies the relative bioavailability of the sulindac formulations and illustrates the utility of population pharmacokinetics in bioequivalence assessment. This novel population pharmacokinetic model provides new insights regarding the factors that may affect the pharmacokinetics of sulindac and the exisulind and sulindac sulfide metabolites in generally healthy subjects, which have implications for future chemoprevention trial design for this widely available agent. PMID:23436338

  1. A physiologically based model for tramadol pharmacokinetics in horses.

    PubMed

    Abbiati, Roberto Andrea; Cagnardi, Petra; Ravasio, Giuliano; Villa, Roberto; Manca, Davide

    2017-09-21

    This work proposes an application of a minimal complexity physiologically based pharmacokinetic model to predict tramadol concentration vs time profiles in horses. Tramadol is an opioid analgesic also used for veterinary treatments. Researchers and medical doctors can profit from the application of mathematical models as supporting tools to optimize the pharmacological treatment of animal species. The proposed model is based on physiology but adopts the minimal compartmental architecture necessary to describe the experimental data. The model features a system of ordinary differential equations, where most of the model parameters are either assigned or individualized for a given horse, using literature data and correlations. Conversely, residual parameters, whose value is unknown, are regressed exploiting experimental data. The model proved capable of simulating pharmacokinetic profiles with accuracy. In addition, it provides further insights on un-observable tramadol data, as for instance tramadol concentration in the liver or hepatic metabolism and renal excretion extent. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Population pharmacokinetics of phenytoin in critically ill children.

    PubMed

    Hennig, Stefanie; Norris, Ross; Tu, Quyen; van Breda, Karin; Riney, Kate; Foster, Kelly; Lister, Bruce; Charles, Bruce

    2015-03-01

    The objective was to study the population pharmacokinetics of bound and unbound phenytoin in critically ill children, including influences on the protein binding profile. A population pharmacokinetic approach was used to analyze paired protein-unbound and total phenytoin plasma concentrations (n = 146 each) from 32 critically ill children (0.08-17 years of age) who were admitted to a pediatric hospital, primarily intensive care unit. The pharmacokinetics of unbound and bound phenytoin and the influence of possible influential covariates were modeled and evaluated using visual predictive checks and bootstrapping. The pharmacokinetics of protein-unbound phenytoin was described satisfactorily by a 1-compartment model with first-order absorption in conjunction with a linear partition coefficient parameter to describe the binding of phenytoin to albumin. The partitioning coefficient describing protein binding and distribution to bound phenytoin was estimated to be 8.22. Nonlinear elimination of unbound phenytoin was not supported in this patient group. Weight, allometrically scaled for clearance and volume of distribution for the unbound and bound compartments, and albumin concentration significantly influenced the partition coefficient for protein binding of phenytoin. The population model can be applied to estimate the fraction of unbound phenytoin in critically ill children given an individual's albumin concentration. © 2014, The American College of Clinical Pharmacology.

  3. Pharmacokinetics of fentanyl in patients undergoing abdominal aortic surgery.

    PubMed

    Hudson, R J; Thomson, I R; Cannon, J E; Friesen, R M; Meatherall, R C

    1986-03-01

    The authors determined the pharmacokinetics of fentanyl 100 micrograms X kg-1 iv in patients undergoing elective abdominal aortic surgery. The mean (+/- SD) age of the ten patients was 67.2 +/- 8.7 yr; their mean weight was 78.5 +/- 13.7 kg. Seven patients had aortic aneurysm repair, and the other three patients had aortobifemoral grafts. Serum fentanyl concentrations were determined from samples drawn at increasing intervals over a 24-h period. A three-compartment pharmacokinetic model was fit to the concentration versus time data. Total drug clearance was 9.8 +/- 1.8 ml X min-1 X kg-1. The volume of distribution at steady-state (Vdss) was 5.4 +/- 1.9 X 1 kg-1. Elimination half-time was 8.7 +/- 2.5 h. There were no significant correlations between these pharmacokinetic parameters and patient's age, duration of aortic cross-clamping, duration of surgery, intraoperative blood loss, or volume of iv fluids given intraoperatively. In healthy volunteers or patients undergoing general surgery, other investigators report mean elimination half-times for fentanyl ranging from 1.7 to 4.4 h. The prolonged elimination half-time in patients having abdominal aortic surgery has important clinical implications. In particular, recovery from large doses will take much longer than would have been anticipated from previously published fentanyl pharmacokinetic data.

  4. Pharmacokinetics of drospirenone and ethinylestradiol in Caucasian and Japanese women.

    PubMed

    Blode, Hartmut; Kowal, Kristin; Roth, Katrin; Reif, Stefanie

    2012-08-01

    To investigate the pharmacokinetics of drospirenone (DRSP) and ethinylestradiol (EE) in Caucasian and Japanese women. Three open-label, non-randomised studies were performed to assess the pharmacokinetics following single doses of EE 0.02 mg/DRSP 3 mg or DRSP monotherapy (1, 3 or 6 mg) in Caucasian (Study 1) and Japanese (Study 2) women, and daily doses with EE 0.02 mg/DRSP 3 mg over 21 consecutive days in Caucasian and Japanese women (Study 3). In Studies 1 and 2, there was a linear dose-dependent increase in DRSP C(max) and systemic exposure across the range of doses used in both ethnic groups. The co- administration of EE had no relevant effect on the pharmacokinetic parameters of 3 mg DRSP. In Study 3, steady-state DRSP concentrations were achieved after about eight days of treatment in both ethnic groups with approximately a threefold accumulation. There was about a twofold EE accumulation over 21 days in both ethnic groups. There were no differences in DRSP or EE exposure at day 21 between ethnic groups; the ratio of the geometric means (Japanese/Caucasian) of the AUC(0-24h) were 1.05 (90% CI: 0.95-1.17) and 1.02 (90% CI: 0.76-1.38), respectively. Ethnic origin had no clinically relevant influence on the pharmacokinetics of DRSP and EE.

  5. Pharmacokinetics of drospirenone and ethinylestradiol in Caucasian and Japanese women

    PubMed Central

    Blode, Hartmut; Kowal, Kristin; Roth, Katrin; Reif, Stefanie

    2012-01-01

    Objective To investigate the pharmacokinetics of drospirenone (DRSP) and ethinylestradiol (EE) in Caucasian and Japanese women. Method Three open-label, non-randomised studies were performed to assess the pharmacokinetics following single doses of EE 0.02 mg/DRSP 3 mg or DRSP monotherapy (1, 3 or 6 mg) in Caucasian (Study 1) and Japanese (Study 2) women, and daily doses with EE 0.02 mg/DRSP 3 mg over 21 consecutive days in Caucasian and Japanese women (Study 3). Results In Studies 1 and 2, there was a linear dose-dependent increase in DRSP Cmax and systemic exposure across the range of doses used in both ethnic groups. The coadministration of EE had no relevant effect on the pharmacokinetic parameters of 3 mg DRSP. In Study 3, steady-state DRSP concentrations were achieved after about eight days of treatment in both ethnic groups with approximately a threefold accumulation.There was about a twofold EE accumulation over 21 days in both ethnic groups. There were no differences in DRSP or EE exposure at day 21 between ethnic groups; the ratio of the geometric means (Japanese/Caucasian) of the AUC0−24h were 1.05 (90% CI: 0.95–1.17) and 1.02 (90% CI: 0.76–1.38), respectively. Conclusion Ethnic origin had no clinically relevant influence on the pharmacokinetics of DRSP and EE. PMID:22680989

  6. Key Nutrients.

    ERIC Educational Resources Information Center

    Federal Extension Service (USDA), Washington, DC.

    Lessons written to help trainer agents prepare aides for work with families in the Food and Nutrition Program are presented in this booklet. The key nutrients discussed in the 10 lessons are protein, carbohydrates, fat, calcium, iron, iodine, and Vitamins A, B, C, and D. the format of each lesson is as follows: Purpose, Presentation, Application…

  7. Gender differences in pharmacokinetics and pharmacodynamics of methadone substitution therapy.

    PubMed

    Graziani, Manuela; Nisticò, Robert

    2015-01-01

    Gender-related differences in the pharmacological effects of drug are an emerging topic. This review examines gender differences in both pharmacokinetic and pharmacodynamic aspects of methadone, a long-acting opioid agonist that is prescribed as a treatment for opioid dependence and the management of chronic pain. We performed a search in the Medline database from 1990 to 2014 in order to find published literature related to gender differences in pharmacokinetics (PK) and pharmacodynamics (PD) of methadone. None of the studies were carried out with the primary or secondary aim to identify any gender differences in the pharmacokinetic profile of methadone. Importantly; high inter-subjects variability in PK parameters was found also intra female population. The reported differences in volume of distribution could be ascribed to the physiological differences between men and women in body weight and composition, taking into account that the dose of methadone was established irrespective of body weight of patients (Peles and Adelson, 2006). On the other hand, the few studies present in literature found no gender difference in some direct pharmacodynamic parameters. Some reports have suggested that female gender is associated with an increased risk for long-QT-related cardiac arrhythmias in methadone maintenance subjects. Even though it may be too simplistic to expect variability only in one parameter to explain inter-individual variation in methadone response, we believe that a better knowledge of gender-related differences might have significant implications for better outcomes in opioid dependence substitution therapy in women.

  8. Investigation of an alternative generic model for predicting pharmacokinetic changes during physiological stress.

    PubMed

    Peng, Henry T; Edginton, Andrea N; Cheung, Bob

    2013-10-01

    Physiologically based pharmacokinetic models were developed using MATLAB Simulink® and PK-Sim®. We compared the capability and usefulness of these two models by simulating pharmacokinetic changes of midazolam under exercise and heat stress to verify the usefulness of MATLAB Simulink® as a generic PBPK modeling software. Although both models show good agreement with experimental data obtained under resting condition, their predictions of pharmacokinetics changes are less accurate in the stressful conditions. However, MATLAB Simulink® may be more flexible to include physiologically based processes such as oral absorption and simulate various stress parameters such as stress intensity, duration and timing of drug administration to improve model performance. Further work will be conducted to modify algorithms in our generic model developed using MATLAB Simulink® and to investigate pharmacokinetics under other physiological stress such as trauma. © The Author(s) 2013.

  9. A Mechanistic Pharmacokinetic Model for Liver Transporter Substrates Under Liver Cirrhosis Conditions

    PubMed Central

    Li, R; Barton, HA; Maurer, TS

    2015-01-01

    Liver cirrhosis is a disease characterized by the loss of functional liver mass. Physiologically based pharmacokinetic (PBPK) modeling was applied to interpret and predict how the interplay among physiological changes in cirrhosis affects pharmacokinetics. However, previous PBPK models under cirrhotic conditions were developed for permeable cytochrome P450 substrates and do not directly apply to substrates of liver transporters. This study characterizes a PBPK model for liver transporter substrates in relation to the severity of liver cirrhosis. A published PBPK model structure for liver transporter substrates under healthy conditions and the physiological changes for cirrhosis are combined to simulate pharmacokinetics of liver transporter substrates in patients with mild and moderate cirrhosis. The simulated pharmacokinetics under liver cirrhosis reasonably approximate observations. This analysis includes meta-analysis to obtain system-dependent parameters in cirrhosis patients and a top-down approach to improve understanding of the effect of cirrhosis on transporter-mediated drug disposition under cirrhotic conditions. PMID:26225262

  10. Checking distributional assumptions for pharmacokinetic summary statistics based on simulations with compartmental models.

    PubMed

    Shen, Meiyu; Russek-Cohen, Estelle; Slud, Eric V

    2016-08-12

    Bioequivalence (BE) studies are an essential part of the evaluation of generic drugs. The most common in vivo BE study design is the two-period two-treatment crossover design. AUC (area under the concentration-time curve) and Cmax (maximum concentration) are obtained from the observed concentration-time profiles for each subject from each treatment under each sequence. In the BE evaluation of pharmacokinetic crossover studies, the normality of the univariate response variable, e.g. log(AUC) 1 or log(Cmax), is often assumed in the literature without much evidence. Therefore, we investigate the distributional assumption of the normality of response variables, log(AUC) and log(Cmax), by simulating concentration-time profiles from two-stage pharmacokinetic models (commonly used in pharmacokinetic research) for a wide range of pharmacokinetic parameters and measurement error structures. Our simulations show that, under reasonable distributional assumptions on the pharmacokinetic parameters, log(AUC) has heavy tails and log(Cmax) is skewed. Sensitivity analyses are conducted to investigate how the distribution of the standardized log(AUC) (or the standardized log(Cmax)) for a large number of simulated subjects deviates from normality if distributions of errors in the pharmacokinetic model for plasma concentrations deviate from normality and if the plasma concentration can be described by different compartmental models.

  11. Pharmacokinetic Interpretation of Cephradine Levels in Serum After Intravenous and Extravascular Administration in Humans

    PubMed Central

    Rattie, Elisabeth S.; Bernardo, Peter D.; Ravin, Louis J.

    1976-01-01

    Pharmacokinetic parameters were calculated from intravenous data based upon a two-compartment open model. These parameters were subsequently used to determine the absorption rates and bioavailability of cephradine administered intramuscularly and orally. The results indicate that cephradine obeys dose-independent kinetics and that biological availability is complete from all dosage forms. PMID:984770

  12. Population pharmacokinetics of tafenoquine during malaria prophylaxis in healthy subjects.

    PubMed

    Charles, Bruce G; Miller, Ann K; Nasveld, Peter E; Reid, Mark G; Harris, Ivor E; Edstein, Michael D

    2007-08-01

    The population pharmacokinetics of tafenoquine were studied in Australian soldiers taking tafenoquine for malarial prophylaxis. The subjects (476 males and 14 females) received a loading dose of 200 mg tafenoquine base daily for 3 days, followed by a weekly dose of 200 mg tafenoquine for 6 months. Blood samples were collected from each subject after the last loading dose and then at weeks 4, 8, and 16. Plasma tafenoquine concentrations were determined by liquid chromatography-tandem mass spectrometry. Population modeling was performed with NONMEM, using a one-compartment model. Typical values of the first-order absorption rate constant (K(a)), clearance (CL/F), and volume of distribution (V/F) were 0.243 h(-1), 0.056 liters/h/kg, and 23.7 liters/kg, respectively. The intersubject variability (coefficient of variation) in CL/F and V/F was 18% and 22%, respectively. The interoccasion variability in CL/F was 18%, and the mean elimination half-life was 12.7 days. A positive linear association between weight and both CL/F and V/F was found, but this had insufficient impact to warrant dosage adjustments. Model robustness was assessed by a nonparametric bootstrap (200 samples). A degenerate visual predictive check indicated that the raw data mirrored the postdose concentration-time profiles simulated (n = 1,000) from the final model. Individual pharmacokinetic estimates for tafenoquine did not predict the prophylactic outcome with the drug for four subjects who relapsed with Plasmodium vivax malaria, as they had similar pharmacokinetics to those who were free of malaria infection. No obvious pattern existed between the plasma tafenoquine concentration and the pharmacokinetic parameter values for subjects with and without drug-associated moderate or severe adverse events. This validated population pharmacokinetic model satisfactorily describes the disposition and variability of tafenoquine used for long-term malaria prophylaxis in a large cohort of soldiers on military

  13. Population Pharmacokinetics of Tafenoquine during Malaria Prophylaxis in Healthy Subjects▿

    PubMed Central

    Charles, Bruce G.; Miller, Ann K.; Nasveld, Peter E.; Reid, Mark G.; Harris, Ivor E.; Edstein, Michael D.

    2007-01-01

    The population pharmacokinetics of tafenoquine were studied in Australian soldiers taking tafenoquine for malarial prophylaxis. The subjects (476 males and 14 females) received a loading dose of 200 mg tafenoquine base daily for 3 days, followed by a weekly dose of 200 mg tafenoquine for 6 months. Blood samples were collected from each subject after the last loading dose and then at weeks 4, 8, and 16. Plasma tafenoquine concentrations were determined by liquid chromatography-tandem mass spectrometry. Population modeling was performed with NONMEM, using a one-compartment model. Typical values of the first-order absorption rate constant (Ka), clearance (CL/F), and volume of distribution (V/F) were 0.243 h−1, 0.056 liters/h/kg, and 23.7 liters/kg, respectively. The intersubject variability (coefficient of variation) in CL/F and V/F was 18% and 22%, respectively. The interoccasion variability in CL/F was 18%, and the mean elimination half-life was 12.7 days. A positive linear association between weight and both CL/F and V/F was found, but this had insufficient impact to warrant dosage adjustments. Model robustness was assessed by a nonparametric bootstrap (200 samples). A degenerate visual predictive check indicated that the raw data mirrored the postdose concentration-time profiles simulated (n = 1,000) from the final model. Individual pharmacokinetic estimates for tafenoquine did not predict the prophylactic outcome with the drug for four subjects who relapsed with Plasmodium vivax malaria, as they had similar pharmacokinetics to those who were free of malaria infection. No obvious pattern existed between the plasma tafenoquine concentration and the pharmacokinetic parameter values for subjects with and without drug-associated moderate or severe adverse events. This validated population pharmacokinetic model satisfactorily describes the disposition and variability of tafenoquine used for long-term malaria prophylaxis in a large cohort of soldiers on military

  14. Pharmacokinetics and Pharmacodynamics of Lysergic Acid Diethylamide in Healthy Subjects.

    PubMed

    Dolder, Patrick C; Schmid, Yasmin; Steuer, Andrea E; Kraemer, Thomas; Rentsch, Katharina M; Hammann, Felix; Liechti, Matthias E

    2017-10-01

    Lysergic acid diethylamide (LSD) is used recreationally and in clinical research. The aim of the present study was to characterize the pharmacokinetics and exposure-response relationship of oral LSD. We analyzed pharmacokinetic data from two published placebo-controlled, double-blind, cross-over studies using oral administration of LSD 100 and 200 µg in 24 and 16 subjects, respectively. The pharmacokinetics of the 100-µg dose is shown for the first time and data for the 200-µg dose were reanalyzed and included. Plasma concentrations of LSD, subjective effects, and vital signs were repeatedly assessed. Pharmacokinetic parameters were determined using compartmental modeling. Concentration-effect relationships were described using pharmacokinetic-pharmacodynamic modeling. Geometric mean (95% confidence interval) maximum plasma concentration values of 1.3 (1.2-1.9) and 3.1 (2.6-4.0) ng/mL were reached 1.4 and 1.5 h after administration of 100 and 200 µg LSD, respectively. The plasma half-life was 2.6 h (2.2-3.4 h). The subjective effects lasted (mean ± standard deviation) 8.2 ± 2.1 and 11.6 ± 1.7 h for the 100- and 200-µg LSD doses, respectively. Subjective peak effects were reached 2.8 and 2.5 h after administration of LSD 100 and 200 µg, respectively. A close relationship was observed between the LSD concentration and subjective response within subjects, with moderate counterclockwise hysteresis. Half-maximal effective concentration values were in the range of 1 ng/mL. No correlations were found between plasma LSD concentrations and the effects of LSD across subjects at or near maximum plasma concentration and within dose groups. The present pharmacokinetic data are important for the evaluation of clinical study findings (e.g., functional magnetic resonance imaging studies) and the interpretation of LSD intoxication. Oral LSD presented dose-proportional pharmacokinetics and first-order elimination up to 12 h. The effects of LSD were related

  15. A phase 1 study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-063, a selective PDE10A inhibitor.

    PubMed

    Tsai, Max; Chrones, Lambros; Xie, Jinhui; Gevorkyan, Hakop; Macek, Thomas A

    2016-10-01

    Schizophrenia is a complex neuropsychiatric disorder characterized, in part, by impaired dopamine signaling. TAK-063 is a selective inhibitor of phosphodiesterase 10A, a key regulator of intracellular signaling pathways that is highly expressed in the striatum. Safety, tolerability, and pharmacokinetics of TAK-063 were evaluated in a phase 1 study. Healthy Japanese and non-Japanese volunteers were randomized into dose cohorts of 3, 10, 30, 100, 300, and 1000 mg. Each fasting volunteer randomly received a single dose of TAK-063 or placebo. Individuals from the 100-mg cohort also received a post-washout, 100-mg dose under fed conditions. A total of 84 volunteers enrolled (14 per cohort). The most common drug-related adverse events (AEs) were somnolence (33.3 %), orthostatic tachycardia (19.7 %), and orthostatic hypotension (9.1 %). The three severe AEs recorded occurred at the highest doses: orthostatic hypotension (n = 1; 300 mg) and somnolence (n = 2; 1000 mg). There were no deaths, serious AEs, or discontinuations due to AEs. TAK-063 exposure increased in a dose-dependent manner. Median T max was reached 3 to 4 h postdose. Fed conditions slowed absorption (T max =  6 h) and increased oral bioavailability. Renal elimination was negligible. Safety and pharmacokinetic parameters were similar between Japanese and non-Japanese subjects. Impairments in cognitive function consistent with the effects of other sedative or hypnotic agents were detected using a validated, computerized cognition battery, CNS Vital Signs. TAK-063 was safe and well tolerated at doses up to 1000 mg and demonstrated a pharmacokinetic profile supporting once-daily dosing. Further evaluation of the clinical safety and efficacy of TAK-063 is warranted.

  16. Representative Sinusoids for Hepatic Four-Scale Pharmacokinetics Simulations

    PubMed Central

    Schwen, Lars Ole; Schenk, Arne; Kreutz, Clemens; Timmer, Jens; Bartolomé Rodríguez, María Matilde; Kuepfer, Lars; Preusser, Tobias

    2015-01-01

    The mammalian liver plays a key role for metabolism and detoxification of xenobiotics in the body. The corresponding biochemical processes are typically subject to spatial variations at different length scales. Zonal enzyme expression along sinusoids leads to zonated metabolization already in the healthy state. Pathological states of the liver may involve liver cells affected in a zonated manner or heterogeneously across the whole organ. This spatial heterogeneity, however, cannot be described by most computational models which usually consider the liver as a homogeneous, well-stirred organ. The goal of this article is to present a methodology to extend whole-body pharmacokinetics models by a detailed liver model, combining different modeling approaches from the literature. This approach results in an integrated four-scale model, from single cells via sinusoids and the organ to the whole organism, capable of mechanistically representing metabolization inhomogeneity in livers at different spatial scales. Moreover, the model shows circulatory mixing effects due to a delayed recirculation through the surrounding organism. To show that this approach is generally applicable for different physiological processes, we show three applications as proofs of concept, covering a range of species, compounds, and diseased states: clearance of midazolam in steatotic human livers, clearance of caffeine in mouse livers regenerating from necrosis, and a parameter study on the impact of different cell entities on insulin uptake in mouse livers. The examples illustrate how variations only discernible at the local scale influence substance distribution in the plasma at the whole-body level. In particular, our results show that simultaneously considering variations at all relevant spatial scales may be necessary to understand their impact on observations at the organism scale. PMID:26222615

  17. 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

  18. Prednisone Pharmacokinetics During Pregnancy and Lactation.

    PubMed

    Ryu, Rachel J; Easterling, Thomas R; Caritis, Steve N; Venkataramanan, Raman; Umans, Jason G; Ahmed, Mahmoud S; Clark, Shannon; Kantrowitz-Gordon, Ira; Hays, Karen; Bennett, Brooke; Honaker, Matthew T; Thummel, Kenneth E; Shen, Danny D; Hebert, Mary F

    2018-05-07

    To evaluate the steady-state pharmacokinetics of prednisone and its metabolite prednisolone in pregnant and lactating female subjects, 19 subjects received prednisone (4-40 mg/day orally) in early (n = 3), mid (n = 9), and late (n = 13) pregnancy as well as postpartum with (n = 2) and without (n = 5) lactation. Serial blood and urine samples were collected over 1 dosing interval. Prednisone and its metabolite, prednisolone, steady-state noncompartmental pharmacokinetic parameters were estimated. During pregnancy, prednisone apparent oral clearance increased with dose (35.1 ± 11.4 L/h with 5 mg, 52.6 ± 5.2 L/h with 10 mg, and 64.3 ± 6.9 L/h with 20 mg, P = .001). Similarly, unbound prednisone apparent oral clearance increased with dose. In addition, prednisolone renal clearance increased with dose (0.3 ± 0.3 L/h with 5 mg, 0.5 ± 0.4 L/h with 10 mg, and 1.3 ± 1.1 L/h with 20 mg, P = .002). Higher prednisone (r = 0.57, P ≤ .05) and prednisolone (r = 0.75, P ≤ .05) concentrations led to a higher percentage of unbound drug. Breast-milk/plasma area under the concentration-time curve ratios were 0.5-0.6 for prednisone and 0.02-0.03 for prednisolone. Relative infant doses were 0.35% to 0.53% and 0.09% to 0.18%, for prednisone and prednisolone, respectively. Prednisone and prednisolone exhibit dose- and concentration-dependent pharmacokinetics during pregnancy, and infant exposure to these agents via breast milk is minimal. © 2018, The American College of Clinical Pharmacology.

  19. Pharmacokinetics of Intravenous Finafloxacin in Healthy Volunteers

    PubMed Central

    Chiesa, Joseph; Lückermann, Mark; Fischer, Carsten; Dalhoff, Axel; Fuhr, Uwe

    2017-01-01

    ABSTRACT Finafloxacin is a novel fluoroquinolone exhibiting enhanced activity under acidic conditions and a broad-spectrum antibacterial profile. The present study assessed the pharmacokinetic properties and the safety and tolerability of finafloxacin following intravenous infusions. In this mixed-parallel-group, crossover study, healthy male and female volunteers received single ascending doses (18 volunteers, 200 to 1,000 mg) or multiple ascending doses (40 volunteers, 600 to 1,000 mg) of finafloxacin or placebo. Plasma and urine samples were collected by a dense sampling scheme to determine the pharmacokinetics of finafloxacin using a noncompartmental approach. Standard safety and tolerability data were documented. Finafloxacin had a volume of distribution of 90 to 127 liters (range) at steady state and 446 to 550 liters at pseudoequilibrium, indicating the elimination of a large fraction before pseudoequilibrium was reached. Areas under the concentration-time curves and maximum plasma concentrations (geometric means) increased slightly more than proportionally (6.73 to 45.9 μg · h/ml and 2.56 to 20.2 μg/ml, respectively), the terminal elimination half-life increased (10.6 to 17.1 h), and the urinary recovery decreased (44.2% to 31.7%) with increasing finafloxacin doses (single doses of 200 to 1,000 mg). The pharmacokinetic profiles suggested multiphasic elimination by both glomerular filtration and saturable tubular secretion. The values of the parameters were similar for single and multiple administrations. The coefficient of variation for the between-subject variability of exposure ranged from 10% (≤600 mg) to 38% (>600 mg). Adverse events were mild and nonspecific, with no dependence of adverse events on dose or treatment (including placebo) being detected. Despite a relatively high interindividual variability at higher doses, the level of exposure following intravenous administration of finafloxacin appears to be predictable. Individual elimination

  20. The pharmacokinetics of intraosseous atropine in hypovolemic swine.

    PubMed

    Yost, Jonathan; Baldwin, Phillip; Bellenger, Sarah; Bradshaw, Freida; Causapin, Edna; Demotica, Richelle; Livingston, Michael; Lee, Cynthia; Gegel, Brian; Burgert, James; Claessens, Adam; Johnson, Don; Loughren, Michael

    2015-01-01

    Compare the pharmacokinetics of atropine administered via the intravenous (IV), intramuscular (IM), and intraosseous (IO) routes in a normovolemic and hypovolemic swine model. Prospective, between subjects, experimental study. Vivarium. Yorkshire-cross swine (N = 36). Atropine was administered via IV, IM, or IO routes to normovolemic and hypovolemic swine. Blood samples were drawn at regular intervals after atropine administration and analyzed for plasma atropine concentration. Pharmacokinetic parameters were obtained from modeling the plasma concentrations. Pharmacokinetic parameters, maximum concentration (Cmax) and time to maximum concentration (Tmax). The IV and IO groups in both the normovolemic and hypovolemic models reached peak plasma concentration immediately and had a very rapid distribution phase with no apparent absorption phase for the IO groups. Peak plasma concentration and time to reach peak concentration were both significantly lower for the IM groups. There was a significant increase in absorption time with IM administration in the hypovolemic model compared to the normovolemic model. The IO route is an effective method of administering atropine and is comparable to the IV route even under conditions of significant hemorrhage. Therapeutic levels of atropine may be delayed and possibly difficult to obtain via IM injection in the presence of hypovolemic shock.

  1. Pharmacokinetics of Peptide Mediated Delivery of Anticancer Drug Ellipticine

    PubMed Central

    Pan, Pei; Sadatmousavi, Parisa; Yuan, Yongfang; Chen, P.

    2012-01-01

    The amino acid pairing peptide EAK16-II (EAK) has shown the ability to stabilize the hydrophobic anticancer agent ellipticine (EPT) in aqueous solution. In this study, we investigate pharmacokinetics of the formulation of EAK-EPT complexes in vivo. The developed formulation can achieve a sufficiently high drug concentration required in vivo animal models. The nanostructure and surface properties of EAK-EPT complexes or nanoparticle were characterized by transmission electron microscopy (TEM) and zeta potential measurements, respectively. 12 healthy male SD rats were divided into EPT group and EAK-EPT group randomly. Rats in EPT group were tail intravenously injected with the EPT (20 mg/kg); rats in EAK-EPT group were injected with EAK-EPT complexes (EPT's concentration is 20 mg/kg). EPT was extracted from rat plasma with dexamethasone sodium phosphate as internal standards (IS). The pharmacokinetic parameters were obtained using high pressure liquid chromatography (HPLC). Significant differences in main pharmacokinetic parameters between EPT and EAK-EPT complexes were observed, demonstrating that the complexation with EAK prolongs the residence time of the drug and enlarges the area under the concentration-time curve (AUC). This means that EAK can serve as a suitable carrier to increase the bioavailability of EPT. PMID:22952737

  2. Pharmacokinetics of pyropheophorbide-a-hexyl ether in the dog.

    PubMed

    Payne, J T; McCaw, D L; Casteel, S W; Frazier, D; Rogers, K; Tompson, R V

    1996-01-01

    Pyropheophorbide-a-hexyl ether (HPPH) is a new compound being investigated for use as a photosensitizer for photodynamic therapy; however, the pharmacokinetics are not known for any of the target species likely to be treated with this drug. The objective of this study was to determine the pharmacokinetic parameters of this drug prior to institution of a clinical trial in canine patients with various cancers. HPPH (0.3mg/kg i.v.) was administered to 12 dogs and blood samples were drawn at intervals for 24 hours and plasma HPPH concentrations were determined. Pharmacokinetic parameters were calculated for each dog. No evidence of toxicity was noted in any dog. The mean half-life was calculated to be 26.98 +/- 2.35 hrs. The mean clearance was 5.061 +/- 0.214 ml/hr/kg. The mean volume of distribution of the central compartment was 0.069 +/- 0.003 L/kg, and the mean steady state volume of distribution was 4.47 +/- 0.25 L/kg. The conclusion is that 0.3 mg/kg HPPH injected intravenously resulted in measurable plasma levels for 24 hrs, and resulted in no detectable adverse reactions.

  3. [Interspecies differences of noopept pharmacokinetics].

    PubMed

    Boĭko, S S; Korotkov, S A; Zherdev, V P; Gudasheva, T A; Ostrovskaia, R U; Voronina, T A

    2004-01-01

    Significant interspecific differences in the pharmacokinetics of noopept are manifested by a decrease in the drug elimination rate on the passage from rats to rabbits and humans. Very intensive metabolism of noopept was observed upon intravenous administration in rats. In these animals, presystemic elimination mechanisms lead to the formation of a specific metabolite representing a product of drug biotransformation hydroxylated at the phenyl ring. In rabbits, unchanged noopept circulates in the blood for a longer time upon both intravenous and peroral introduction, biotransformation proceeds at a much slower rate, and no metabolites analogous to that found in rats are detected. The noopept pharmacokinetics in humans differs from that in animals by still slower elimination and considerable individual variability. No drug metabolites are found in the human blood plasma, probably because of a relatively small dose and low concentration.

  4. Pregnancy-related pharmacokinetic changes.

    PubMed

    Tasnif, Y; Morado, J; Hebert, M F

    2016-07-01

    The pharmacokinetics of many drugs are altered by pregnancy. Drug distribution and protein binding are changed by pregnancy. While some drug metabolizing enzymes have an apparent increase in activity, others have an apparent decrease in activity. Not only is drug metabolism affected by pregnancy, but renal filtration is also increased. In addition, pregnancy alters the apparent activities of multiple drug transporters resulting in changes in the net renal secretion of drugs. © 2016 American Society for Clinical Pharmacology and Therapeutics.

  5. Comparative pharmacokinetics of chlorogenic acid after oral administration in rats

    PubMed Central

    Qi, Wei; Zhao, Ting; Yang, Wen-Wen; Wang, Guang-Hou; Yu, Hua; Zhao, Hai-Xiao; Yang, Chen; Sun, Li-Xin

    2011-01-01

    The present study was aimed at the comparison of the pharmacokinetics of pure chlorogenic acid and extract of Solanum lyratum Thunb. The animals were allocated to two groups, and were administered chlorogenic acid or extract of S. lyratum Thunb. at a dose of 50.0 mg/kg orally. Blood samples were collected up to 8 h post-dosing. Plasma chlorogenic acid analyses were performed using an HPLC method with UV detector. The pharmacokinetic parameters were evaluated using non-compartmental assessment. Significant differences existed in the two groups for AUC0−t, AUC0−∞ and CLz/F. The reliable HPLC method was successfully applied to the determination of chlorogenic acid in rat plasma at dosage of 50.0 mg/kg. PMID:29403709

  6. Dose Schedule Optimization and the Pharmacokinetic Driver of Neutropenia

    PubMed Central

    Patel, Mayankbhai; Palani, Santhosh; Chakravarty, Arijit; Yang, Johnny; Shyu, Wen Chyi; Mettetal, Jerome T.

    2014-01-01

    Toxicity often limits the utility of oncology drugs, and optimization of dose schedule represents one option for mitigation of this toxicity. Here we explore the schedule-dependency of neutropenia, a common dose-limiting toxicity. To this end, we analyze previously published mathematical models of neutropenia to identify a pharmacokinetic (PK) predictor of the neutrophil nadir, and confirm this PK predictor in an in vivo experimental system. Specifically, we find total AUC and Cmax are poor predictors of the neutrophil nadir, while a PK measure based on the moving average of the drug concentration correlates highly with neutropenia. Further, we confirm this PK parameter for its ability to predict neutropenia in vivo following treatment with different doses and schedules. This work represents an attempt at mechanistically deriving a fundamental understanding of the underlying pharmacokinetic drivers of neutropenia, and provides insights that can be leveraged in a translational setting during schedule selection. PMID:25360756

  7. Compartmental analysis and its manifold applications to pharmacokinetics.

    PubMed

    Rescigno, Aldo

    2010-03-01

    In this paper, I show how the concept of compartment evolved from the simple dilution of a substance in a physiological volume to its distribution in a network of interconnected spaces. The differential equations describing the fate of a substance in a living being can be solved, qualitatively and quantitatively, with the help of a number of mathematical techniques. A number of parameters of pharmacokinetic interest can be computed from the experimental data; often, the data available are not sufficient to determine some parameters, but it is possible to determine their range.

  8. Pharmacokinetics of drugs in pregnancy.

    PubMed

    Feghali, Maisa; Venkataramanan, Raman; Caritis, Steve

    2015-11-01

    Pregnancy is a complex state where changes in maternal physiology have evolved to favor the development and growth of the placenta and the fetus. These adaptations may affect preexisting disease or result in pregnancy-specific disorders. Similarly, variations in physiology may alter the pharmacokinetics or pharmacodynamics that determines drug dosing and effect. It follows that detailed pharmacologic information is required to adjust therapeutic treatment strategies during pregnancy. Understanding both pregnancy physiology and the gestation-specific pharmacology of different agents is necessary to achieve effective treatment and limit maternal and fetal risk. Unfortunately, most drug studies have excluded pregnant women based on often-mistaken concerns regarding fetal risk. Furthermore, over two-thirds of women receive prescription drugs while pregnant, with treatment and dosing strategies based on data from healthy male volunteers and non-pregnant women, and with little adjustment for the complex physiology of pregnancy and its unique disease states. This review will describe basic concepts in pharmacokinetics and their clinical relevance and highlight the variations in pregnancy that may impact the pharmacokinetic properties of medications. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Cefazolin pharmacokinetics in cats under surgical conditions.

    PubMed

    Albarellos, Gabriela A; Montoya, Laura; Passini, Sabrina M; Lupi, Martín P; Lorenzini, Paula M; Landoni, María F

    2017-10-01

    Objectives The aim of this study was to determine the plasma pharmacokinetic profile, tissue concentrations and urine elimination of cefazolin in cats under surgical conditions after a single intravenous dose of 20 mg/kg. Methods Intravenous cefazolin (20 mg/kg) was administered to nine young mixed-breed cats 30 mins before they underwent surgical procedures (ovariectomy or orchiectomy). After antibiotic administration, samples from blood, some tissues and urine were taken. Cefazolin concentrations were determined in all biological matrices and pharmacokinetic parameters were estimated. Results Initial plasma concentrations were high (C p(0) , 134.80 ± 40.54 µg/ml), with fast and moderately wide distribution (distribution half-life [t ½(d) ] 0.16 ± 0.15 h; volume of distribution at steady state [V (d[ss]) ] 0.29 ± 0.10 l/kg) and rapid elimination (body clearance [Cl B ], 0.21 ± 0.06 l/h/kg; elimination half-life [t ½ ], 1.18 ± 0.27 h; mean residence time 1.42 ± 0.36 h). Thirty to 60 mins after intravenous administration, cefazolin tissue concentrations ranged from 9.24 µg/ml (subcutaneous tissue) to 26.44 µg/ml (ovary). The tissue/plasma concentration ratio ranged from 0.18 (muscle) to 0.58 (ovary). Cefazolin urine concentrations were high with 84.2% of the administered dose being eliminated in the first 6 h postadministration. Conclusions and relevance Cefazolin plasma concentrations remained above a minimum inhibitory concentration of ⩽2 µg/ml up to 4 h in all the studied cats. This suggests that a single intravenous dose of 20 mg/kg cefazolin would be adequate for perioperative prophylactic use in cats.

  10. A new amoxicillin/clavulanate therapeutic system: preparation, in vitro and pharmacokinetic evaluation.

    PubMed

    Kerc, Janez; Opara, Jerneja

    2007-04-20

    A new peroral amoxicillin/clavulanate therapeutic system composed of immediate release tablet and controlled release floating capsule was developed and evaluated by in vivo bioavailability study. Pharmacokinetic (PK) parameters for amoxicillin and clavulanic acid of the new therapeutic systems: AUCt, AUCi, (AUCt/AUCi), Cmax, Tmax, kel, T(1/2) and additionally for amoxicillin T(4) and T(2) were calculated from the plasma levels. The study confirmed enhanced pharmacokinetic parameters of a newly developed therapeutic system containing 1500 mg of amoxicillin and 125 mg of clavulanic acid. Prolonged time over MIC of amoxicillin in relation to a regular immediate release amoxicillin/clavulanate formulation was confirmed.

  11. [Effect of phenformin hydrochloride on pharmacokinetics of puerarin in rats].

    PubMed

    Deng, Ying; Li, Ning; Cui, Mei; Xiong, Zhi-li; Li, Fa-mei

    2012-10-01

    To study the effect of phenformin hydrochloride that may be illegally added in traditional Chinese medicine preparations on the pharmacokinetics of puerarin in rats. Rats were randomly divided into the single pueraria group and the phenformin hydrochloride combined with pueraria group. After oral administration in the two groups, their bloods were sampled at different time points to determine the drug concentration of puerarin in rat blood and calculate pharmacokinetic parameters. After oral administration with pueraria extracts and phenformin hydrochloride combined with pueraria extracts, the two groups showed main pharmacokinetic parameters as follows: Cmax were (2.39 +/- 1.01), (1.03 +/- 0.35) mg x L(-1), respectively; Tmax were (0.50 +/- 0.09), (1.5 +/- 0.5) h, respectively; Ke were (0.153 +/- 0.028), (0.172 +/- 0.042) h(-1), respectively; t(1/2) were (4.65 +/- 0.86), (4.20 +/- 0.81) h, respectively; AUC(0-t), were (5.73 +/- 2.60), (5.45 +/- 1.81) mg x h x L(-1), respectively; AUC(0-infinity) were (6.72 +/- 2.89), (6.26 +/- 1.88) mg x h x L(-1), respectively. Compared with the single puerarin group, the Cmax was significantly decreased (P < 0.05) and the Tmax was markedly longer (P < 0.01) than the hydrochloride combined with pueraria group. Phenformin hydrochloride can slow down the absorption process of puerarin and change the pharmacokinetic process of puerarin to some extent.

  12. Preliminary experiments on pharmacokinetic diffuse fluorescence tomography of CT-scanning mode

    NASA Astrophysics Data System (ADS)

    Zhang, Yanqi; Wang, Xin; Yin, Guoyan; Li, Jiao; Zhou, Zhongxing; Zhao, Huijuan; Gao, Feng; Zhang, Limin

    2016-10-01

    In vivo tomographic imaging of the fluorescence pharmacokinetic parameters in tissues can provide additional specific and quantitative physiological and pathological information to that of fluorescence concentration. This modality normally requires a highly-sensitive diffuse fluorescence tomography (DFT) working in dynamic way to finally extract the pharmacokinetic parameters from the measured pharmacokinetics-associated temporally-varying boundary intensity. This paper is devoted to preliminary experimental validation of our proposed direct reconstruction scheme of instantaneous sampling based pharmacokinetic-DFT: A highly-sensitive DFT system of CT-scanning mode working with parallel four photomultiplier-tube photon-counting channels is developed to generate an instantaneous sampling dataset; A direct reconstruction scheme then extracts images of the pharmacokinetic parameters using the adaptive-EKF strategy. We design a dynamic phantom that can simulate the agent metabolism in living tissue. The results of the dynamic phantom experiments verify the validity of the experiment system and reconstruction algorithms, and demonstrate that system provides good resolution, high sensitivity and quantitativeness at different pump speed.

  13. Pharmacokinetic study of gallocatechin-7-gallate from Pithecellobium clypearia Benth. in rats.

    PubMed

    Li, Chao; Song, Xiaowei; Song, Junke; Pang, Xiaocong; Wang, Zhe; Zhao, Ying; Lian, Wenwen; Liu, Ailin; Du, Guanhua

    2016-01-01

    The pharmacokinetic profile of gallocatechin-7-gallate (J10688) was studied in rats after intravenous administration. Male and female Sprague-Dawley (SD) rats received 1, 3, and 10 mg/kg (i.v.) of J10688 and plasma drug concentrations were determined by a high performance liquid chromatography-mass spectrometry (LC-MS) method. The pharmacokinetic software Data Analysis System (Version 3.0) was used to calculate the pharmacokinetic parameters. For different i.v. doses of J10688, the mean peak plasma concentration (C 0) values ranged from 11.26 to 50.82 mg/L, and mean area under the concentration-time curve (AUC0-t ) values ranged from 1.75 to 11.80 (mg·h/L). J10688 lacked dose-dependent pharmacokinetic properties within doses between 1 and 10 mg/kg, based on the power model. The method developed in this study was sensitive, precise, and stable. The pharmacokinetic properties of J10688 in SD rats were shown to have rapid distribution and clearance values. These pharmacokinetic results may contribute to an improved understanding of the pharmacological actions of J10688.

  14. Vascular input function correction of inflow enhancement for improved pharmacokinetic modeling of liver DCE-MRI.

    PubMed

    Ning, Jia; Schubert, Tilman; Johnson, Kevin M; Roldán-Alzate, Alejandro; Chen, Huijun; Yuan, Chun; Reeder, Scott B

    2018-06-01

    To propose a simple method to correct vascular input function (VIF) due to inflow effects and to test whether the proposed method can provide more accurate VIFs for improved pharmacokinetic modeling. A spoiled gradient echo sequence-based inflow quantification and contrast agent concentration correction method was proposed. Simulations were conducted to illustrate improvement in the accuracy of VIF estimation and pharmacokinetic fitting. Animal studies with dynamic contrast-enhanced MR scans were conducted before, 1 week after, and 2 weeks after portal vein embolization (PVE) was performed in the left portal circulation of pigs. The proposed method was applied to correct the VIFs for model fitting. Pharmacokinetic parameters fitted using corrected and uncorrected VIFs were compared between different lobes and visits. Simulation results demonstrated that the proposed method can improve accuracy of VIF estimation and pharmacokinetic fitting. In animal study results, pharmacokinetic fitting using corrected VIFs demonstrated changes in perfusion consistent with changes expected after PVE, whereas the perfusion estimates derived by uncorrected VIFs showed no significant changes. The proposed correction method improves accuracy of VIFs and therefore provides more precise pharmacokinetic fitting. This method may be promising in improving the reliability of perfusion quantification. Magn Reson Med 79:3093-3102, 2018. © 2017 International Society for Magnetic Resonance in Medicine. © 2017 International Society for Magnetic Resonance in Medicine.

  15. 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.

  16. Definition of variables required for comprehensive description of drug dosage and clinical pharmacokinetics.

    PubMed

    Medem, Anna V; Seidling, Hanna M; Eichler, Hans-Georg; Kaltschmidt, Jens; Metzner, Michael; Hubert, Carina M; Czock, David; Haefeli, Walter E

    2017-05-01

    Electronic clinical decision support systems (CDSS) require drug information that can be processed by computers. The goal of this project was to determine and evaluate a compilation of variables that comprehensively capture the information contained in the summary of product characteristic (SmPC) and unequivocally describe the drug, its dosage options, and clinical pharmacokinetics. An expert panel defined and structured a set of variables and drafted a guideline to extract and enter information on dosage and clinical pharmacokinetics from textual SmPCs as published by the European Medicines Agency (EMA). The set of variables was iteratively revised and evaluated by data extraction and variable allocation of roughly 7% of all centrally approved drugs. The information contained in the SmPC was allocated to three information clusters consisting of 260 variables. The cluster "drug characterization" specifies the nature of the drug. The cluster "dosage" provides information on approved drug dosages and defines corresponding specific conditions. The cluster "clinical pharmacokinetics" includes pharmacokinetic parameters of relevance for dosing in clinical practice. A first evaluation demonstrated that, despite the complexity of the current free text SmPCs, dosage and pharmacokinetic information can be reliably extracted from the SmPCs and comprehensively described by a limited set of variables. By proposing a compilation of variables well describing drug dosage and clinical pharmacokinetics, the project represents a step forward towards the development of a comprehensive database system serving as information source for sophisticated CDSS.

  17. Population Pharmacokinetics of Elagolix in Healthy Women and Women with Endometriosis.

    PubMed

    Winzenborg, Insa; Nader, Ahmed; Polepally, Akshanth R; Liu, Mohan; Degner, Jacob; Klein, Cheri E; Mostafa, Nael M; Noertersheuser, Peter; Ng, Juki

    2018-02-23

    Elagolix is a novel, orally active, non-peptide, competitive gonadotropin-releasing hormone (GnRH) receptor antagonist in development for the management of endometriosis with associated pain and heavy menstrual bleeding due to uterine fibroids. The pharmacokinetics of elagolix have been well-characterized in phase I studies; however, elagolix population pharmacokinetics have not been previously reported. Therefore, a robust model was developed to describe elagolix population pharmacokinetics and to evaluate factors affecting elagolix pharmacokinetic parameters. The data from nine clinical studies (a total of 1624 women) were included in the analysis: five phase I studies in healthy, premenopausal women and four phase III studies in premenopausal women with endometriosis. Elagolix population pharmacokinetics were best described by a two-compartment model with a lag time in absorption. Of the 15 covariates tested for effect on elagolix apparent clearance (CL/F) and/or volume of distribution only one covariate, organic anion transporting polypeptide (OATP) 1B1 genotype status, had a statistically significant, but not clinically meaningful, effect on elagolix CL/F. Elagolix pharmacokinetics were not affected by patient demographics and were similar between healthy women and women with endometriosis. Clinical Trial Registration Numbers NCT01403038, NCT01620528, NCT01760954, NCT01931670, NCT02143713.

  18. 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.

  19. 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.

  20. Psychomotor effect differences between l-methamphetamine and d-methamphetamine are independent of murine plasma and brain pharmacokinetics profiles.

    PubMed

    Nishimura, Tetsuya; Takahata, Kazue; Kosugi, Yuri; Tanabe, Takaaki; Muraoka, Shizuko

    2017-05-01

    l-Methamphetamine has been occasionally referred to as a stimulant similar to d-methamphetamine, probably owing to insufficient comparative studies. Here, we directly compared psychomotor efficacies and pharmacokinetics of methamphetamine enantiomers in mice. Only d-methamphetamine, but not l-methamphetamine, induced stereotypy and sensitization at 1-10 mg/kg. However, plasma pharmacokinetic parameters of 10 mg/kg l-methamphetamine were ≥tenfold those of 1 mg/kg d-methamphetamine. These results clearly indicate that differential psychomotor efficacies of methamphetamine enantiomers are independent of their pharmacokinetic profiles.

  1. A Combined Pharmacokinetic and Radiologic Assessment of Dynamic Contrast-Enhanced Magnetic Resonance Imaging Predicts Response to Chemoradiation in Locally Advanced Cervical Cancer

    SciTech Connect

    Semple, Scott; Harry, Vanessa N. MRCOG.; Parkin, David E.

    2009-10-01

    Purpose: To investigate the combination of pharmacokinetic and radiologic assessment of dynamic contrast-enhanced magnetic resonance imaging (MRI) as an early response indicator in women receiving chemoradiation for advanced cervical cancer. Methods and Materials: Twenty women with locally advanced cervical cancer were included in a prospective cohort study. Dynamic contrast-enhanced MRI was carried out before chemoradiation, after 2 weeks of therapy, and at the conclusion of therapy using a 1.5-T MRI scanner. Radiologic assessment of uptake parameters was obtained from resultant intensity curves. Pharmacokinetic analysis using a multicompartment model was also performed. General linear modeling was used to combine radiologic andmore » pharmacokinetic parameters and correlated with eventual response as determined by change in MRI tumor size and conventional clinical response. A subgroup of 11 women underwent repeat pretherapy MRI to test pharmacokinetic reproducibility. Results: Pretherapy radiologic parameters and pharmacokinetic K{sup trans} correlated with response (p < 0.01). General linear modeling demonstrated that a combination of radiologic and pharmacokinetic assessments before therapy was able to predict more than 88% of variance of response. Reproducibility of pharmacokinetic modeling was confirmed. Conclusions: A combination of radiologic assessment with pharmacokinetic modeling applied to dynamic MRI before the start of chemoradiation improves the predictive power of either by more than 20%. The potential improvements in therapy response prediction using this type of combined analysis of dynamic contrast-enhanced MRI may aid in the development of more individualized, effective therapy regimens for this patient group.« less

  2. Effects of etravirine on the pharmacokinetics and pharmacodynamics of warfarin in rats

    PubMed Central

    John, J; John, M; Wu, L; Hsiao, C; Abobo, CV; Liang, D

    2013-01-01

    Background and Purpose Warfarin is often used with etravirine (ETV) to prevent HIV-related thromboembolic events. As both warfarin and ETV bind to plasma proteins and are metabolized by hepatic cytochrome P450s, they are likely to interact. Hence, we evaluated the effect of ETV on the pharmacokinetics and blood clotting time of racemic warfarin in rats. Experimental Approach Two groups of male Sprague-Dawley rats, in which the jugular vein had been cannulated, were studied. The control group (n = 10) received 1 mg·kg−1 racemic warfarin i.v., and the test group (n = 13) 1 mg·kg−1 of racemic warfarin followed by 25 mg·kg−1 ETV i.v. Serial blood samples were collected for up to 144 h and the blood clotting time (calculated as international normalized ratio [INR]) measured in blood plasma at each sample point. Plasma concentrations of R-warfarin, S-warfarin, R-7-hydroxywarfarin and S-7-hydroxywarfarin were measured by a LC/MS/MS method using a chiral lux cellulose-1 column. Pharmacokinetic parameters were analysed using non-compartmental methods. Key Results ETV significantly increased, by threefold, the systemic clearance and volume of distribution of S-warfarin, but not those of R-warfarin. ETV decreased the total AUC of warfarin, but had no effect on its elimination half-life. ETV also increased the systemic clearance of both R-7-hydroxywarfarin and S-7-hydroxywarfarin but only increased the volume of distribution of R-7-hydroxywarfarin. Interestingly, the effect of warfarin on blood clotting time (INR) was significantly increased in the presence of etravirine. Conclusion and Implications Our data suggest that etravirine may potentiate the anticoagulant effect of warfarin and this could have clinical significance. PMID:23215758

  3. Population pharmacokinetics of levofloxacin in Korean patients.

    PubMed

    Kiem, Sungmin; Ryu, Sung-Mun; Lee, Yun-Mi; Schentag, Jerome J; Kim, Yang-Wook; Kim, Hyeon-Kuk; Jang, Hang-Jae; Joo, Yong-Don; Jin, Kyubok; Shin, Jae-Gook; Ghim, Jong-Lyul

    2016-08-01

    Levofloxacin (LVFX) has different effects depending on the area under the concentration-time curve (AUC)/minimum inhibitory concentration (MIC) ratio. While AUC can be expressed as dose/clearance (CL), we measured serial concentrations of LVFX in Koreans and tried to set a Korean-specific equation, estimating the CL of the antibiotic. In total, 38 patients, aged 18-87 years, received once daily intravenous LVFX doses of 500 mg or 250 mg, depending on their renal function. Four plasma samples were obtained according to a D optimal sampling design. The population pharmacokinetic (PK) parameters of LVFX were estimated using non-linear mixed-effect modeling (NONMEM, ver. 7.2). The CL of LVFX was dependent on creatinine clearance (CLCR) as a covariate. The mean population PK parameters of LVFX in Koreans were as follows: CL (l/hour) = 6.19 ×  (CLCR/75)(1.32). The CL of LVFX in Koreans is expected to be lower than that in Western people.

  4. Population pharmacokinetic modeling of epoetin delta in pediatric patients with chronic kidney disease.

    PubMed

    Knebel, William; Palmen, Mary; Dowell, James A; Gastonguay, Marc

    2008-07-01

    This analysis quantifies the population pharmacokinetics of subcutaneous and intravenous epoetin delta, an epoetin produced in a human cell line, in pediatric patients with chronic kidney disease and estimates the effects of covariate factors on epoetin delta and epoetin alfa pharmacokinetic parameters. Erythropoietin serum concentration data, taken from a phase III study conducted in 60 patients aged 1 to 17 years, were best described by a 1-compartment model with first-order absorption and elimination. The typical point estimates were clearance (0.268 L/h), central volume of distribution (1.03 L), absorption rate constant (0.0554 h(-1)), and bioavailability (0.708) for a 35-kg male < or = 10 years who was predialysis and on subcutaneous epoetin delta treatment. Erythropoietin pharmacokinetic parameters were similar in pediatric patients as compared with adults when scaled by weight. The subcutaneous administration of epoetin alfa exhibited lower systemic bioavailability than subcutaneous administration of epoetin delta.

  5. Pharmacokinetic Comparative Study of Gastrodin and Rhynchophylline after Oral Administration of Different Prescriptions of Yizhi Tablets in Rats by an HPLC-ESI/MS Method

    PubMed Central

    Ge, Zhaohui; Liang, Qionglin; Wang, Yiming; Luo, Guoan

    2014-01-01

    Pharmacokinetic characters of rhynchophylline (RIN), gastrodin (GAS), and gastrodigenin (p-hydroxybenzyl alcohol, HBA) were investigated after oral administration of different prescriptions of Yizhi: Yizhi tablets or effective parts of tianma (total saponins from Gastrodiae, EPT) and gouteng (rhynchophylla alkaloids, EPG). At different predetermined time points after administration, the concentrations of GAS, HBA, and RIN in rat plasma were determined by an HPLC-ESI/MS method, and the main pharmacokinetic parameters were investigated. The results showed that the pharmacokinetic parameters C max and AUC0–∞ (P < 0.05) were dramatically different after oral administration of different prescriptions of Yizhi. The data indicated that the pharmacokinetic processes of GAS, HBA, and RIN in rats would interact with each other or be affected by other components in Yizhi. The rationality of the compatibility of Uncaria and Gastrodia elata as a classic “herb pair” has been verified from the pharmacokinetic viewpoint. PMID:25610474

  6. Drug Transport and Pharmacokinetics for Chemical Engineers

    ERIC Educational Resources Information Center

    Simon, Laurent; Kanneganti, Kumud; Kim, Kwang Seok

    2010-01-01

    Experiments in continuous-stirred vessels were proposed to introduce methods in pharmacokinetics and drug transport to chemical engineering students. The activities can be incorporated into the curriculum to illustrate fundamentals learned in the classroom. An appreciation for the role of pharmacokinetics in drug discovery will also be gained…

  7. 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.

  8. Effect of feeding on the pharmacokinetics of oral minocycline in healthy research dogs.

    PubMed

    Hnot, Melanie L; Cole, Lynette K; Lorch, Gwendolen; Rajala-Schultz, Paivi J; Papich, Mark G

    2015-12-01

    The effect of food on minocycline oral absorption in dogs is unknown. The objective was to determine the pharmacokinetics of minocycline after administration of a single oral dose in fed and fasted dogs. Ten research hounds were administered oral minocycline (approximately 5 mg/kg) with and without food, in a crossover study, with a one-week wash-out between treatments. Blood samples were collected immediately prior to minocycline administration and over 24 h. Minocycline plasma drug concentrations were measured using high-performance liquid chromatography using ultraviolet detection and were analysed with compartmental modelling to determine primary pharmacokinetic parameters. Each dog was analysed independently, followed by calculation of means and variation of the dogs. The Wilcoxon signed-rank test [analysing secondary pharmacokinetic parameters - peak concentration (CMAX ), area under the concentration versus time curve (AUC)] was used to compare the two groups. A population pharmacokinetic modelling approach was performed using nonlinear mixed effects modelling of primary parameters for the population as fixed effects and the difference between subjects as a random effect. Covariate analysis was used to identify the source of variability in the population. No significant difference was found between treatments for AUC (P = 0.0645), although AUC was higher in fasted dogs. A significant difference was found for CMAX (P = 0.0059), with fasted dogs attaining a higher CMAX . The covariate of fed versus fasted accounted for a significant variation in the pharmacokinetics. Because feeding was a significant source of variation for the population's primary pharmacokinetic parameters and fasted dogs had higher minocycline concentrations, we recommend administering minocycline without food. © 2015 ESVD and ACVD.

  9. Physiologically based pharmacokinetic modeling of tea catechin mixture in rats and humans.

    PubMed

    Law, Francis C P; Yao, Meicun; Bi, Hui-Chang; Lam, Stephen

    2017-06-01

    Although green tea ( Camellia sinensis) (GT) contains a large number of polyphenolic compounds with anti-oxidative and anti-proliferative activities, little is known of the pharmacokinetics and tissue dose of tea catechins (TCs) as a chemical mixture in humans. The objectives of this study were to develop and validate a physiologically based pharmacokinetic (PBPK) model of tea catechin mixture (TCM) in rats and humans, and to predict an integrated or total concentration of TCM in the plasma of humans after consuming GT or Polyphenon E (PE). To this end, a PBPK model of epigallocatechin gallate (EGCg) consisting of 13 first-order, blood flow-limited tissue compartments was first developed in rats. The rat model was scaled up to humans by replacing its physiological parameters, pharmacokinetic parameters and tissue/blood partition coefficients (PCs) with human-specific values. Both rat and human EGCg models were then extrapolated to other TCs by substituting its physicochemical parameters, pharmacokinetic parameters, and PCs with catechin-specific values. Finally, a PBPK model of TCM was constructed by linking three rat (or human) tea catechin models together without including a description for pharmacokinetic interaction between the TCs. The mixture PBPK model accurately predicted the pharmacokinetic behaviors of three individual TCs in the plasma of rats and humans after GT or PE consumption. Model-predicted total TCM concentration in the plasma was linearly related to the dose consumed by humans. The mixture PBPK model is able to translate an external dose of TCM into internal target tissue doses for future safety assessment and dose-response analysis studies in humans. The modeling framework as described in this paper is also applicable to the bioactive chemical in other plant-based health products.

  10. Predicting Pharmacokinetic Stability by Multiple Oral Administration of Atypical Antipsychotics

    PubMed Central

    Aoki, Kazuo; Sakiyama, Yojiro; Ohnishi, Takashi; Sugita, Makoto

    2013-01-01

    Lower fluctuation, i.e., lower peak-to-trough plasma-concentration variation at steady-state pharmacokinetics, has several advantages for the treatment of schizophrenia with antipsychotics. The reduction of peak concentration can decrease the risk of dose-dependent side effects, such as extrapyramidal symptom and somnolence, and by contrast the increase in trough concentration can decrease the incidence of lack of efficacy due to subtherapeutic drug concentration. Using a one-compartment simulation technique with pharmacokinetic parameters of each atypical antipsychotic collected from package inserts, the fluctuation index was calculated. Among the antipsychotics, the indices varied from 0.018 to 1.9, depending on dosing regimens, formulations and several pharmacokinetic properties. The order of simulated fluctuation index is active-moiety aripiprazole (b.i.d.)

  11. Pharmacokinetics of lysine clonixinate in children in postoperative care.

    PubMed

    González-Martin, G; Cattan, C; Zuñiga, S

    1996-09-01

    The pharmacokinetics of 2 doses of intravenous lysine clonixinate (4 and 6 mg x kg-1) were studied in 10 children (age 4-10 years) under postoperative care. A single dose of the drug was injected in a forearm vein. Blood samples were collected at regular intervals for 3 hours. Serum clonixin concentrations (expressed as clonixin) were analyzed using a high pressure liquid chromatography method. Pharmacokinetic values were estimated by a nonlinear computer program. The distribution volume was similar in both groups of children (1.288 +/- 0.829 1 and 1. 139 +/- 0.667 1, respectively). There were no differences between the values of total plasma clearance and the administered doses (0.026 +/- 0.017 ml x min-1 and 0.017 +/- 0.008 ml x min-1, t = 1.07, p = 0.76). The elimination half-life was longer in children who received 6 mg x kg-1 (44.26 +/- 6.34 min vs 38.63 +/- 10.93 min) but this difference was not statistically significant (t = 0.99, p < 0.34). The pharmacokinetic parameters calculated in these children were different from those found by other authors in adults and experimental animals.

  12. Pharmacokinetic interaction between zolpidem and carbamazepine in healthy volunteers.

    PubMed

    Vlase, Laurian; Popa, Adina; Neag, Maria; Muntean, Dana; Bâldea, Ioan; Leucuţa, Sorin E

    2011-08-01

    The objective of this study was to evaluate the pharmacokinetic interaction between zolpidem and carbamazepine in healthy volunteers. The study consisted of 2 periods: period 1 (reference), when each volunteer received a single dose of 5 mg zolpidem, and period 2 (test), when each volunteer received a single dose of 5 mg zolpidem and 400 mg carbamazepine. Between the 2 periods, the participants were treated for 15 days with a single daily dose of 400 mg carbamazepine. Pharmacokinetic parameters of zolpidem administered in each treatment period were calculated using noncompartmental analysis. In the 2 periods of treatments, the mean peak plasma concentrations (C(max)) were 59 ng/mL (zolpidem alone) and 35 ng/mL (zolpidem after pretreatment with carbamazepine). The t(max), times taken to reach C(max), were 0.9 hours and 1.0 hour, respectively, and the total areas under the curve (AUC(0-∞)) were 234.9 ng·h/mL and 101.5 ng·h/mL, respectively. The half-life of zolpidem was 2.3 and 1.6 hours, respectively. Carbamazepine interacts with zolpidem in healthy volunteers and lowers its bioavailability by about 57%. The experimental data demonstrate the pharmacokinetic interaction between zolpidem and carbamazepine and suggest that the observed interaction may be clinically significant, but its relevance has to be confirmed.

  13. Effect of gemfibrozil on the pharmacokinetics of mitiglinide in rats.

    PubMed

    Jin, L; Cao, Q

    2012-01-01

    A sensitive and specific method was developed and validated for the determination of mitiglinide in plasma using LC-MS/MS. The effect of gemfibrozil on the pharmacokinetics of orally administered mitiglinide in rats was investigated. The validated method in positive electrospray ionization mode using MRM and fully validated according to commonly accepted criteria. The desired sensitivity of mitiglinide was achieved with an LOQ of 0.5 ng/mL and the short run time was suitable for analysis of the large batches of samples. The method was successfully used to analyze rats plasma samples for application in pharmacokinetic studies. Pharmacokinetic parameters of mitiglinide were determined in rats following oral (0.25, 0.5, 1 mg/kg) administration to rats in the presence and absence of gemfibrozil (1 mg/kg). Compared to those animals in an oral control group (given mitiglinide alone), the area under the plasma concentration-time curve (AUC) of mitiglinide were increased significantly by 2.8, 3.5, 4.1-fold (0.25, 0.5, 1 mg/kg) by gemfibrozil, respectively. Consequently, the bioavailability of mitiglinide in the presence of gemfibrozil was significantly enhanced compared to that in oral control group (only mitiglinide). Gemfibrozil significantly enhanced the oral bioavailability of mitiglinide, suggesting that concurrent use of gemfibrozil and mitiglinide should be monitored closely for potential drug interactions. © Georg Thieme Verlag KG Stuttgart · New York.

  14. [Pharmacokinetics of controlled-release oxycodone in patients with cancer pain].

    PubMed

    Nakamura, Kazuyo; Kokubun, Hideya; Komatsu, Toshiaki; Matoba, Motohiro; Hoka, Sumio; Yago, Kazuo

    2007-09-01

    Oxycodone is a useful analgesic for cancer patients in pain. However, its pharmacokinetics have not been sufficiently examined and there is a lack of information, with very few reports on pharmacokinetics concerning the absorption process in particular. With this in mind, we studied the pharmacokinetics of controlled-release oxycodone (Oxy contin). We measured its serum concentration in patients with cancer pain, and calculated parameters derived using the nonlinear least-squared method program (MULTI). In the result, pharmacokinetic parameters calculated at CL/F were: 45.6+/-22.0 L/hr (Mean+/-SD), Vd/F: 473.0+/-19 6.7 L, t(1/2): 7.2+/- 6.2 hr, kel: 0.103+/-0.034, kal: 1.082+/-0.604, Lag time: 0.9 9+/-0.40 hr. In addition, the serum oxycodone concentration hardly rose until 1 hour after and just before medication, whereupon a rapid increase was evident after 1 hour. The pharmacokinetics of controlled-release oxycodone in patients with cancer pain were clarified in this study. Especially during the absorption process, the lag time was calculated specifically at about 1 hour, making it approximately equal to MS contin.

  15. Fractal pharmacokinetics of the drug mibefradil in the liver

    NASA Astrophysics Data System (ADS)

    Fuite, J.; Marsh, R.; Tuszyński, J.

    2002-08-01

    We explore the ramifications of the fractal geometry of the key organ for drug elimination, the liver, on pharmacokinetic data analysis. A formalism is developed for the use of a combination of well-stirred Euclidean and fractal compartments in the body. Perturbation analysis is carried out to obtain analytical solutions for the drug concentration time evolution. These results are then fitted to experimental data collected from clinically instrumented dogs [see, A. Skerjanec et al., J. Pharm. Sci. 85, 189 (1995)] using the drug mibefradil. The thus obtained spectral fractal dimension has a range of values that is consistent with the value found in independently performed ultrasound experiments on the liver.

  16. Pharmacokinetics and Pharmacodynamics of Atazanavir in HIV-1-Infected Children Treated With Atazanavir Powder and Ritonavir: Combined Analysis of the PRINCE-1 and -2 Studies.

    PubMed

    Sevinsky, Heather; Zaru, Luna; Wang, Reena; Xu, Xiaohui; Pikora, Cheryl; Correll, Todd A; Eley, Timothy

    2018-06-01

    Two clinical studies (PRINCE-1 and -2) in HIV-1-infected children assessed the safety, efficacy and pharmacokinetics of dual nucleos(t)ide reverse transcriptase inhibitor background therapy plus once-daily atazanavir (ATV) powder formulation boosted with ritonavir (ATV + RTV). Here, we present a combined analysis of ATV pharmacokinetics and pharmacodynamics across these studies. Intensive 24-hour pharmacokinetic profiles at steady state compared ATV exposures (area under the concentration-time curve in one dosing interval) in 5 ATV + RTV baseline weight-band dosing categories, with historic data in adults receiving ATV + RTV 300/100 mg capsules. Repeated ATV Ctrough measurements over 48 weeks explored relationships between ATV composite Ctrough quartiles (CCQs) with virologic efficacy and key safety parameters. Of 146 children included in this combined analysis, 49.3% were male, 56.8% were Black/African American and 62.3% were antiretroviral experienced. Proportions with HIV-1 RNA <50 copies/mL at week 48 were 13/32, 24/32, 19/32 and 13/28 in the lowest through highest ATV CCQs, respectively. Mean changes from baseline in total bilirubin at week 48 were +0.3, +0.5, +0.6 and +1.0 mg/dL in the lowest through highest ATV CCQs, respectively. Corresponding proportions with adverse events of hyperbilirubinemia by week 48 were 1/36, 4/36, 5/36 and 13/35, respectively. Changes from baseline in total amylase or electrocardiogram parameters and adverse events of diarrhea did not vary by ATV CCQs. Weight-band dosing of ATV + RTV plus optimized dual nucleos(t)ide reverse transcriptase inhibitors in young HIV-1-infected children achieved similar ATV exposure to that in adults; no unexpected safety findings occurred, and with the exception of lower virologic suppression in the lowest ATV CCQ, there was no apparent trend in virologic suppression across ATV CCQs.

  17. Innovations and Improvements in Pharmacokinetic Models Based on Physiology.

    PubMed

    Abbiati, Roberto Andrea; Manca, Davide

    2017-01-01

    Accompanied by significant improvements of modeling techniques and computational methods in medical sciences, the last thirty years saw the flourishing of pharmacokinetic models for applications in the pharmacometric field. In particular, physiologically based pharmacokinetic (PBPK) models, grounded on a mechanistic foundation, have been applied to explore a multiplicity of aspects with possible applications in patient care and new drugs development, as in the case of siRNA therapies. This article summarizes the features we recently introduced in PBPK modeling within a threeyear research project funded by Italian Research Ministry. Four major points are detailed: (i) the mathematical formulation of the model, which allows modulating its complexity as a function of the administration route and active principle; (ii) a dedicated parameter of the PBPK model quantifies the drugprotein binding, which affects the active principle distribution; (iii) the gall bladder compartment and the bile enterohepatic circulation process; (iv) the coupling of the pharmacokinetic and pharmacodynamic models to produce an overall understanding of the drug effects on mammalian body. The proposed model is applied to two separate endovenous (remifentanil) and oral (sorafenib) drug administrations. The resulting PBPK simulations are consistent with the literature experimental data. Blood concentration predictability is confirmed in multiple reference subjects. Furthermore, in case of sorafenib administration in mice, it is possible to evaluate the drug concentration in the liver and reproduce the effects of the enterohepatic circulation. Finally, a preliminary application of the coupling of the pharmacokinetic/pharmacodynamic models is presented and discussed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  18. Effect of silibinin on the pharmacokinetics of nitrendipine in rabbits.

    PubMed

    Voruganti, Swathi; Yamsani, Shravan Kumar; Yamsani, Madhusudan Rao

    2014-12-01

    Silibinin, a major constituent of silymarin, is widely used for its hepatoprotective effects. This study investigated the effect of silibinin on the pharmacokinetics of oral nitrendipine in rabbits. In first set of experiment, male New Zealand rabbits were pretreated with silibinin (50 mg/kg, PO) for 7 days and on last day nitrendipine (10 mg/kg, PO) was administered. In second set, both silibinin and nitrendipine were coadministered to examine acute effect of silibinin on nitrendipine pharmacokinetics. The plasma concentration of nitrendipine was estimated by high performance liquid chromatography and different pharmacokinetic parameters were calculated using WinNonlin(®) software. Coadministration of silibinin had no significant effect on pharmacokinetics of nitrendipine when compared to control group. However, a 1.89-1.57-fold increase in area under the concentration-time curve and peak plasma concentration (C max), respectively, of nitrendipine was observed in silibinin pretreated group. The mean C max was 0.034 ± 0.005 μg/mL (nitrendipine alone) and 0.054 ± 0.006 μg/mL (nitrendipine after pretreatment with silibinin). The time to reach C max, elimination rate constant and elimination half-life of nitrendipine were not significantly different among control and silibinin treated groups. This study demonstrates that silibinin increase plasma concentration of nitrendipine. Henceforth, the pharmacodynamic influence of this interaction should be taken into consideration while prescribing nitrendipine to the patients already taking silymarin.

  19. Pharmacokinetic differences of mifepristone between sexes in animals.

    PubMed

    Chen, Wenge; Cheng, Yunlong; Chen, Jianzhong; Chen, Jiahang; Jiang, Kai; Zhou, Yuyang; Jia, Lee

    2018-05-30

    Mifepristone (RU486) is developed originally as a contraceptive used by hundreds of millions of women world-wide, and also reported as a safe and long-term psychotic depressant, or as a cancer chemotherapeutic agent used by both sexes. In our preliminary study aimed at developing mifepristone as a cancer metastatic chemopreventive, we coincidentally observed that blood mifepristone concentrations in female rats seem to be higher than those in male ones post administration. To substantiate if the pharmacokinetic differences between sexes exist, we established a fast UPLC-MS/MS method to determine mifepristone concentrations in plasma, and analyzed blood concentrations of mifepristone over time in rats and dogs of both sexes. Mifepristone in plasma or incubation liquid was recovered by liquid-liquid extraction using 1 mL of ethyl acetate. Chromatographic separation was performed on a C 18 column at 35 °C, with a gradient elution consisting of methanol and water containing 0.1% (v/v) formic acid at a flow rate of 0.3 mL/min. And pharmacokinetic parameters such as elimination half-life, and mean residence time were calculated by using the non-compartmental pharmacokinetics data analysis software. In this work, administrations of mifepristone to rats and beagle dogs revealed that the plasma concentrations of mifepristone (AUC, C max ) were significantly higher (P < 0.05) in females than that in males. In vitro liver microsomal incubation experiments showed that the metabolic rate of mifepristone in males was higher than that in females, which was consistent with the results of in vivo experiments. In general, we first found the sex-related differences about pharmacokinetic properties of mifepristone and revealed the metabolism difference of hepatic microsomal enzyme is the main reason. Copyright © 2018 Elsevier B.V. All rights reserved.

  20. Comprehensive pharmacogenetic analysis of irinotecan neutropenia and pharmacokinetics.

    PubMed

    Innocenti, Federico; Kroetz, Deanna L; Schuetz, Erin; Dolan, M Eileen; Ramírez, Jacqueline; Relling, Mary; Chen, Peixian; Das, Soma; Rosner, Gary L; Ratain, Mark J

    2009-06-01

    We aim to identify genetic variation, in addition to the UGT1A1*28 polymorphism, that can explain the variability in irinotecan (CPT-11) pharmacokinetics and neutropenia in cancer patients. Pharmacokinetic, genetic, and clinical data were obtained from 85 advanced cancer patients treated with single-agent CPT-11 every 3 weeks at doses of 300 mg/m(2) (n = 20) and 350 mg/m(2) (n = 65). Forty-two common variants were genotyped in 12 candidate genes of the CPT-11 pathway using several methodologies. Univariate and multivariate models of absolute neutrophil count (ANC) nadir and pharmacokinetic parameters were evaluated. Almost 50% of the variation in ANC nadir is explained by UGT1A1*93, ABCC1 IVS11 -48C>T, SLCO1B1*1b, ANC baseline levels, sex, and race (P < .0001). More than 40% of the variation in CPT-11 area under the curve (AUC) is explained by ABCC2 -24C>T, SLCO1B1*5, HNF1A 79A>C, age, and CPT-11 dose (P < .0001). Almost 30% of the variability in SN-38 (the active metabolite of CPT-11) AUC is explained by ABCC1 1684T>C, ABCB1 IVS9 -44A>G, and UGT1A1*93 (P = .004). Other models explained 17%, 23%, and 27% of the variation in APC (a metabolite of CPT-11), SN-38 glucuronide (SN-38G), and SN-38G/SN-38 AUCs, respectively. When tested in univariate models, pretreatment total bilirubin was able to modify the existing associations between genotypes and phenotypes. On the basis of this exploratory analysis, common polymorphisms in genes encoding for ABC and SLC transporters may have a significant impact on the pharmacokinetics and pharmacodynamics of CPT-11. Confirmatory studies are required.

  1. Bioavailability and Pharmacokinetics of Oral Cocaine in Humans.

    PubMed

    Coe, Marion A; Jufer Phipps, Rebecca A; Cone, Edward J; Walsh, Sharon L

    2018-06-01

    The pharmacokinetic profile of oral cocaine has not been fully characterized and prospective data on oral bioavailability are limited. A within-subject study was performed to characterize the bioavailability and pharmacokinetics of oral cocaine. Fourteen healthy inpatient participants (six males) with current histories of cocaine use were administered two oral doses (100 and 200 mg) and one intravenous (IV) dose (40 mg) of cocaine during three separate dosing sessions. Plasma samples were collected for up to 24 h after dosing and analyzed for cocaine and metabolites by gas chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by non-compartmental analysis, and a two-factor model was used to assess for dose and sex differences. The mean ± SEM oral cocaine bioavailability was 0.32 ± 0.04 after 100 and 0.45 ± 0.06 after 200 mg oral cocaine. Volume of distribution (Vd) and clearance (CL) were both greatest after 100 mg oral (Vd = 4.2 L/kg; CL = 116.2 mL/[min kg]) compared to 200 mg oral (Vd = 2.9 L/kg; CL = 87.5 mL/[min kg]) and 40 mg IV (Vd = 1.3 L/kg; CL = 32.7 mL/[min kg]). Oral cocaine area-under-thecurve (AUC) and peak concentration increased in a dose-related manner. AUC metabolite-to-parent ratios of benzoylecgonine and ecgonine methyl ester were significantly higher after oral compared to IV administration and highest after the lower oral dose. In addition, minor metabolites were detected in higher concentrations after oral compared to IV cocaine. Oral cocaine produced a pharmacokinetic profile different from IV cocaine, which appears as a rightward and downward shift in the concentration-time profile. Cocaine bioavailability values were similar to previous estimates. Oral cocaine also produced a unique metabolic profile, with greater concentrations of major and minor metabolites.

  2. A stochastic whole-body physiologically based pharmacokinetic model to assess the impact of inter-individual variability on tissue dosimetry over the human lifespan.

    PubMed

    Beaudouin, Rémy; Micallef, Sandrine; Brochot, Céline

    2010-06-01

    Physiologically based pharmacokinetic (PBPK) models have proven to be successful in integrating and evaluating the influence of age- or gender-dependent changes with respect to the pharmacokinetics of xenobiotics throughout entire lifetimes. Nevertheless, for an effective application of toxicokinetic modelling to chemical risk assessment, a PBPK model has to be detailed enough to include all the multiple tissues that could be targeted by the various xenobiotics present in the environment. For this reason, we developed a PBPK model based on a detailed compartmentalization of the human body and parameterized with new relationships describing the time evolution of physiological and anatomical parameters. To take into account the impact of human variability on the predicted toxicokinetics, we defined probability distributions for key parameters related to the xenobiotics absorption, distribution, metabolism and excretion. The model predictability was evaluated by a direct comparison between computational predictions and experimental data for the internal concentrations of two chemicals (1,3-butadiene and 2,3,7,8-tetrachlorodibenzo-p-dioxin). A good agreement between predictions and observed data was achieved for different scenarios of exposure (e.g., acute or chronic exposure and different populations). Our results support that the general stochastic PBPK model can be a valuable computational support in the area of chemical risk analysis. (c)2010 Elsevier Inc. All rights reserved.

  3. Optimal designs for population pharmacokinetic studies of the partner drugs co-administered with artemisinin derivatives in patients with uncomplicated falciparum malaria.

    PubMed

    Jamsen, Kris M; Duffull, Stephen B; Tarning, Joel; Lindegardh, Niklas; White, Nicholas J; Simpson, Julie A

    2012-07-11

    Artemisinin-based combination therapy (ACT) is currently recommended as first-line treatment for uncomplicated malaria, but of concern, it has been observed that the effectiveness of the main artemisinin derivative, artesunate, has been diminished due to parasite resistance. This reduction in effect highlights the importance of the partner drugs in ACT and provides motivation to gain more knowledge of their pharmacokinetic (PK) properties via population PK studies. Optimal design methodology has been developed for population PK studies, which analytically determines a sampling schedule that is clinically feasible and yields precise estimation of model parameters. In this work, optimal design methodology was used to determine sampling designs for typical future population PK studies of the partner drugs (mefloquine, lumefantrine, piperaquine and amodiaquine) co-administered with artemisinin derivatives. The optimal designs were determined using freely available software and were based on structural PK models from the literature and the key specifications of 100 patients with five samples per patient, with one sample taken on the seventh day of treatment. The derived optimal designs were then evaluated via a simulation-estimation procedure. For all partner drugs, designs consisting of two sampling schedules (50 patients per schedule) with five samples per patient resulted in acceptable precision of the model parameter estimates. The sampling schedules proposed in this paper should be considered in future population pharmacokinetic studies where intensive sampling over many days or weeks of follow-up is not possible due to either ethical, logistic or economical reasons.

  4. Pharmacokinetic Study of Piracetam in Focal Cerebral Ischemic Rats.

    PubMed

    Paliwal, Pankaj; Dash, Debabrata; Krishnamurthy, Sairam

    2018-04-01

    Cerebral ischemia affects hepatic enzymes and brain permeability extensively. Piracetam was investigated up to phase III of clinical trials and there is lack of data on brain penetration in cerebral ischemic condition. Thus, knowledge of the pharmacokinetics and brain penetration of piracetam during ischemic condition would aid to improve pharmacotherapeutics in ischemic stroke. Focal cerebral ischemia was induced by middle cerebral artery occlusion for 2 h in male Wistar rats followed by reperfusion. After 24 h of middle cerebral artery occlusion or 22 h of reperfusion, piracetam was administered for pharmacokinetic, brain penetration, and pharmacological experiments. In pharmacokinetic study, blood samples were collected at different time points after 200-mg/kg (oral) and 75-mg/kg (intravenous) administration of piracetam through right external jugular vein cannulation. In brain penetration study, the cerebrospinal fluid, systemic blood, portal blood, and brain samples were collected at pre-designated time points after 200-mg/kg oral administration of piracetam. In a separate experiment, the pharmacological effect of the single oral dose of piracetam in middle cerebral artery occlusion was assessed at a dose of 200 mg/kg. All the pharmacokinetic parameters of piracetam including area under curve (AUC 0-24 ), maximum plasma concentration (C max ), time to reach the maximum plasma concentration (t max ), elimination half-life (t 1/2 ), volume of distribution (V z ), total body clearance, mean residence time, and bioavailability were found to be similar in ischemic stroke condition except for brain penetration. Piracetam exposure (AUC 0-2 ) in brain and CSF were found to be 2.4- and 3.1-fold higher, respectively, in ischemic stroke compared to control rats. Piracetam significantly reduced infarct volume by 35.77% caused by middle cerebral artery occlusion. There was no change in the pharmacokinetic parameters of piracetam in the ischemic stroke model except for

  5. [Pharmacokinetic interactions of telaprevir with other drugs].

    PubMed

    Berenguer Berenguer, Juan; González-García, Juan

    2013-07-01

    Telaprevir is a new direct-acting antiviral drug for the treatment of hepatitis C virus (HCV) infection and is both a substrate and an inhibitor of cytochrome P450 (CYP450) isoenzymes. With the introduction of this new drug, assessment of drug-drug interactions has become a key factor in the evaluation of patients under treatment for HCV infection. During the treatment of this infection, many patients require other drugs to mitigate the adverse effects of anti-HCV drugs and to control other comorbidities. Moreover, most patients coinfected with HIV and HCV require antiretroviral therapy during treatment for HCV. Physicians should therefore be familiar with the pharmacokinetic properties of direct-acting antivirals for HCV treatment and their potential drug-drug interactions. The present article reviews the available information to date on the interactions of telaprevir with other drugs and provides recommendations for daily clinical practice. Copyright © 2013 Elsevier España, S.L. All rights reserved.

  6. Physiologically Based Pharmacokinetic Modeling of Therapeutic Proteins.

    PubMed

    Wong, Harvey; Chow, Timothy W

    2017-09-01

    Biologics or therapeutic proteins are becoming increasingly important as treatments for disease. The most common class of biologics are monoclonal antibodies (mAbs). Recently, there has been an increase in the use of physiologically based pharmacokinetic (PBPK) modeling in the pharmaceutical industry in drug development. We review PBPK models for therapeutic proteins with an emphasis on mAbs. Due to their size and similarity to endogenous antibodies, there are distinct differences between PBPK models for small molecules and mAbs. The high-level organization of a typical mAb PBPK model consists of a whole-body PBPK model with organ compartments interconnected by both blood and lymph flows. The whole-body PBPK model is coupled with tissue-level submodels used to describe key mechanisms governing mAb disposition including tissue efflux via the lymphatic system, elimination by catabolism, protection from catabolism binding to the neonatal Fc (FcRn) receptor, and nonlinear binding to specific pharmacological targets of interest. The use of PBPK modeling in the development of therapeutic proteins is still in its infancy. Further application of PBPK modeling for therapeutic proteins will help to define its developing role in drug discovery and development. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  7. Physiologically-based pharmacokinetic (PBPK) modeling to explore potential metabolic pathways of bromochloromethane in rats.

    EPA Science Inventory

    Bromochloromethane (BCM) is a volatile organic compound and a by-product of disinfection of water by chlorination. Physiologically based pharmacokinetic (PBPK) models are used in risk assessment applications and a PBPK model for BCM, Updated with F-344 specific input parameters,...

  8. Triprotic acid-base microequilibria and pharmacokinetic sequelae of cetirizine.

    PubMed

    Marosi, Attila; Kovács, Zsuzsanna; Béni, Szabolcs; Kökösi, József; Noszál, Béla

    2009-06-28

    (1)H NMR-pH titrations of cetirizine, the widely used antihistamine and four related compounds were carried out and the related 11 macroscopic protonation constants were determined. The interactivity parameter between the two piperazine amine groups was obtained from two symmetric piperazine derivatives. Combining these two types of datasets, all the 12 microconstants and derived tautomeric constants of cetirizine were calculated. Upon this basis, the conflicting literature data of cetirizine microspeciation were clarified, and the pharmacokinetic absorption-distribution properties could be interpreted. The pH-dependent distribution of the microspecies is provided.

  9. Pharmacokinetics of butafosfan after intravenous and intramuscular administration in piglets.

    PubMed

    Sun, F; Wang, J; Yang, S; Zhang, S; Shen, J; Xingyuan, C

    2017-04-01

    The pharmacokinetics and bioavailability of butafosfan in piglets were investigated following intravenous and intramuscular administration at a single dose of 10 mg/kg body weight. Plasma concentration-time data and relevant parameters were best described by noncompartmental analysis after intravenous and intramuscular injection. The data were analyzed through WinNolin 6.3 software. After intravenous administration, the mean pharmacokinetic parameters were determined as T 1/2λz of 3.30 h, Cl of 0.16 L kg/h, AUC of 64.49 ± 15.07 μg h/mL, V ss of 0.81 ± 0.44/kg, and MRT of 1.51 ± 0.27 h. Following intramuscular administration, the C max (28.11 μg/mL) was achieved at T max (0.31 h) with an absolute availability of 74.69%. Other major parameters including AUC and MRT were 48.29 ± 21.67 μg h/mL and 1.74 ± 0.29 h, respectively. © 2016 John Wiley & Sons Ltd.

  10. A Population Pharmacokinetic Model for a Solid Oral Tablet Formulation of Posaconazole.

    PubMed

    van Iersel, Marlou L P S; Rossenu, Stefaan; de Greef, Rik; Waskin, Hetty

    2018-04-30

    A delayed-release solid tablet formulation that releases posaconazole in the small intestine was developed to maximize systemic absorption. This study aimed to characterize the pharmacokinetics of the posaconazole solid tablet formulation in adult subjects and to investigate the potential impact of demographic and clinical factors on posaconazole exposure through a population pharmacokinetic approach. Nonlinear mixed-effects modeling was performed using data from several studies conducted in healthy volunteers and patients. The influence of demographic and clinical factors on pharmacokinetic parameters was evaluated using a stepwise forward inclusion/backward exclusion procedure. The final pharmacokinetic model was used to simulate posaconazole exposure in patients at high risk for invasive fungal diseases treated with the proposed posaconazole dose of 300 mg twice daily on day 1, followed by 300 mg daily for 27 days. A one-compartment pharmacokinetic model with sequential zero-order and first-order absorption and a first-order disposition from the central compartment adequately described the pharmacokinetic profile of the posaconazole solid tablet formulation. Significant covariates included disease state (acute myeloid leukemia/myelodysplasia vs allogeneic hematopoietic stem cell transplantation), body weight, and formulation on bioavailability; food status on first-order absorption rate; and dosing regimen (single dose vs multiple doses) on clearance. Except for body weight, the impact of these covariates on posaconazole exposure was considered clinically irrelevant. This population pharmacokinetic analysis confirmed that the proposed dose of the posaconazole solid tablet formulation provides adequate target therapeutic exposure (>0.5 mg/l) to a broad range of patients at high risk for invasive fungal disease. Copyright © 2018 American Society for Microbiology.

  11. Population pharmacokinetic modeling and simulation of huperzine A in elderly Chinese subjects

    PubMed Central

    Sheng, Lei; Qu, Yi; Yan, Jing; Liu, Gang-yi; Wang, Wei-liang; Wang, Yi-jun; Wang, Hong-yi; Zhang, Meng-qi; Lu, Chuan; Liu, Yun; Jia, Jing-yin; Hu, Chao-ying; Li, Xue-ning; Yu, Chen; Xu, Hong-rong

    2016-01-01

    Aim: Our preliminary results show that huperzine A, an acetylcholinesterase inhibitor used to treat Alzheimer's disease (AD) patients in China, exhibits different pharmacokinetic features in elderly and young healthy subjects. However, its pharmacokinetic data in elderly subjects remains unavailable to date. Thus, we developed a population pharmacokinetic (PPK) model of huperzine A in elderly Chinese people, and identified the covariate affecting its pharmacokinetics for optimal individual administration. Methods: A total of 341 serum huperzine A concentration records was obtained from 2 completed clinical trials (14 elderly healthy subjects in a phase I pharmacokinetic study; 35 elderly AD patients in a phase II study). Population pharmacokinetic analysis was performed using the non-linear mixed-effect modeling software Phoenix NLME1.1.1. The effects of age, gender, body weight, height, creatinine, endogenous creatinine clearance rate as well as drugs administered concomitantly were analyzed. Bootstrap and visual predictive checks were used simultaneously to validate the final population pharmacokinetics models. Results: The plasma concentration-time profile of huperzine A was best described by a one-compartment model with first-order absorption and elimination. Age was identified as the covariate having significant influence on huperzine A clearance. The final PPK model of huperzine A was: CL (L/h)=2.4649*(age/86)(−3.3856), Ka=0.6750 h−1, V (L)=104.216. The final PPK model was demonstrated to be suitable and effective by the bootstrap and visual predictive checks. Conclusion: A PPK model of huperzine A in elderly Chinese subjects is established, which can be used to predict PPK parameters of huperzine A in the treatment of elderly AD patients. PMID:27180987

  12. Pharmacokinetics and food interaction of a novel prodrug of tenofovir, tenofovir dipivoxil fumarate, in healthy volunteers.

    PubMed

    Lu, C; Jia, Y; Chen, L; Ding, Y; Yang, J; Chen, M; Song, Y; Sun, X; Wen, A

    2013-04-01

    Tenofovir dipivoxil fumarate is a novel ester prodrug of tenofovir, a specific anti-hepatitis B virus (HBV) drug candidate. The pharmacokinetic properties and the effects of food intake on tenofovir dipivoxil have not yet been reported in healthy adults. The aim of this study was to evaluate the pharmacokinetic properties and food interaction of tenofovir dipivoxil in healthy Chinese volunteers. Pharmacokinetic studies included an ascending single dose of 150, 300, 600 mg and multiple doses of 300 mg. Food interaction was evaluated following a single oral dose of tenofovir dipivoxil fumarate 300 mg administered with a high-fat and high-energy standard breakfast or after a 12-h fast. Pharmacokinetic parameters of tenofovir given in each treatment period were calculated using non-compartmental analysis. After a single dose of 150, 300 and 600 mg, the main pharmacokinetic parameters for tenofovir were as follows: Cmax 209·6, 456·7, 989·8 ng/mL; AUClast 1744·9, 2663·5, 6010·2 ng h/mL, respectively. After multiple doses of 300 mg, the main pharmacokinetic parameters for tenofovir were Cmax 523·4 ng/mL, AUClast 4152·4 ng h/mL. After a single dose of 300 mg with a high-fat and high-energy standard breakfast, the main pharmacokinetic parameters for tenofovir were Cmax 448·5 ng/mL, AUClast 3286·8 ng h/mL. The plasma Cmax and AUC of tenofovir showed significance difference between a single dose of 300 mg and the accordingly multiple doses (P < 0·05). A standard high-fat meal enhanced mean AUClast values of tenofovir (relative AUClast  = 125·8%; 90% CI 114·5, 136·2); however, food did not show any significant on Cmax (relative Cmax  = 103·4%; 90% CI 94·6, 112·6). Oral tenofovir dipivoxil fumarate produced predictable and dose-proportional plasma tenofovir pharmacokinetics. The accumulation ratio was 1·51, suggesting tenofovir dipivoxil fumarate displayed accumulation after repeated administration. The bioavailability of tenofovir

  13. Pharmacokinetic Evaluation of Empagliflozin in Healthy Egyptian Volunteers Using LC-MS/MS and Comparison with Other Ethnic Populations.

    PubMed

    Ayoub, Bassam M; Mowaka, Shereen; Elzanfaly, Eman S; Ashoush, Nermeen; Elmazar, Mohamed M; Mousa, Shaker A

    2017-05-31

    The present study considered the pharmacokinetic evaluation of empagliflozin after administration to Egyptian volunteers, and the results were compared with other ethnic populations. The FDA recognizes that standard methods of defining racial subgroups are necessary to compare results across pharmacokinetic studies and to assess potential subgroup differences. The design of the study was as an open labeled, randomized, one treatment, one period, single dose pharmacokinetic study. The main pharmacokinetic parameters estimated were C max , T max , t 1/2 , elimination rate constant, AUC 0-t and AUC 0-inf . The insignificant difference in pharmacokinetic parameters between Egyptians and white German subjects suggests that no dose adjustment should be considered with administration of 25 mg empagliflozin to Egyptian population. A new LC-MS/MS method was developed and validated, allowing sensitive estimation of empagliflozin (25-600 ng mL -1 ) in human plasma using dapagliflozin as an internal standard (IS). The method was applied successfully on the underlying pharmacokinetic study with enhanced sample preparation that involved liquid-liquid extraction. Multiple Reaction Monitoring (MRM) of the transition pairs of m/z 449.01 to 371.21 for empagliflozin and m/z 407.00 to 328.81 for dapagliflozin (IS) was employed utilizing negative mode Electro Spray Ionization (ESI). The validated LC-MS/MS method is suitable for further toxicodynamic and bioequivalence studies.

  14. Pharmacokinetics and Pharmacodynamics of Piperacillin-Tazobactam in 42 Patients Treated with Concomitant CRRT

    PubMed Central

    Bauer, Seth R.; Salem, Charbel; Connor, Michael J.; Groszek, Joseph; Taylor, Maria E.; Wei, Peilin; Tolwani, Ashita J.

    2012-01-01

    Summary Background and objectives Current recommendations for piperacillin-tazobactam dosing in patients receiving continuous renal replacement therapy originate from studies with relatively few patients and lower continuous renal replacement therapy doses than commonly used today. This study measured the pharmacokinetic and pharmacodynamic characteristics of piperacillin-tazobactam in patients treated with continuous renal replacement therapy using contemporary equipment and prescriptions. Design, setting, participants, & measurements A multicenter prospective observational study in the intensive care units of two academic medical centers was performed, enrolling patients with AKI or ESRD receiving piperacillin-tazobactam while being treated with continuous renal replacement therapy. Pregnant women, children, and patients with end stage liver disease were excluded from enrollment. Plasma and continuous renal replacement therapy effluent samples were analyzed for piperacillin and tazobactam levels using HPLC. Pharmacokinetic and pharmacodynamic parameters were calculated using standard equations. Multivariate analyses were used to examine the association of patient and continuous renal replacement therapy characteristics with piperacillin pharmacokinetic parameters. Results Forty-two of fifty-five subjects enrolled had complete sampling. Volume of distribution (median=0.38 L/kg, intraquartile range=0.20 L/kg) and elimination rate constants (median=0.104 h−1, intraquartile range=0.052 h−1) were highly variable, and clinical parameters could explain only a small fraction of the large variability in pharmacokinetic parameters. Probability of target attainment for piperacillin was 83% for total drug but only 77% when the unbound fraction was considered. Conclusions There is significant patient to patient variability in pharmacokinetic/pharmacodynamic parameters in patients receiving continuous renal replacement therapy. Many patients did not achieve pharmacodynamic

  15. Patient acceptability and practical implications of pharmacokinetic studies in patients with advanced cancer.

    PubMed

    Dobbs, N A; Twelves, C J; Ramirez, A J; Towlson, K E; Gregory, W M; Richards, M A

    1993-01-01

    We have studied the practical implications and acceptability to patients of pharmacokinetic studies in 34 women receiving anthracyclines for advanced breast cancer. The following parameters were recorded: age, ECOG performance status, psychological state (Rotterdam Symptom Checklist), cytotoxic drug and dose, number of venepunctures for treatment and sampling, and time when the sampling cannula was removed. Immediately after finishing pharmacokinetic sampling, patients completed a questionnaire which revealed that (i) all patients understood sampling was for research, (ii) 35% of patients experienced problems with sampling, (iii) benefits from participation were perceived by 56% of patients. Of 20 patients later questioned after completion of their treatment course, 40% recalled difficulties with blood sampling. Factors identifying in advance those patients who tolerate pharmacokinetic studies poorly were not identified but the number of venepunctures should be minimised. Patients may also perceive benefits from 'non-therapeutic' research.

  16. Dapoxetine has no pharmacokinetic or cognitive interactions with ethanol in healthy male volunteers.

    PubMed

    Modi, Nishit B; Dresser, Mark; Desai, Dhaval; Edgar, Christopher; Wesnes, Keith

    2007-03-01

    Dapoxetine is being investigated for the treatment of premature ejaculation. This study evaluated the potential pharmacokinetic and cognitive interactions of dapoxetine 60 mg with ethanol 0.5 g/kg in a single-center, double-blind, randomized, placebo-controlled crossover study in healthy adult male participants (n = 24). Dapoxetine was rapidly absorbed and eliminated; peak concentrations were noted 1.47 hours after administration and decreased with an alpha half-life of 1.33 hours and a terminal half-life of 15.6 hours. Pharmacokinetic parameters (C(max), AUC(infinity), t((1/2)), and t(max)) of dapoxetine were not altered with concurrent ethanol consumption. Furthermore, coadministration of dapoxetine did not affect the pharmacokinetics of ethanol or potentiate the cognitive and subjective effects of ethanol.

  17. Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults.

    PubMed

    Brown, Randall T; Nicholas, Christopher R; Cozzi, Nicholas V; Gassman, Michele C; Cooper, Karen M; Muller, Daniel; Thomas, Chantelle D; Hetzel, Scott J; Henriquez, Kelsey M; Ribaudo, Alexandra S; Hutson, Paul R

    2017-12-01

    Psilocybin is a psychedelic tryptamine that has shown promise in recent clinical trials for the treatment of depression and substance use disorders. This open-label study of the pharmacokinetics of psilocybin was performed to describe the pharmacokinetics and safety profile of psilocybin in sequential, escalating oral doses of 0.3, 0.45, and 0.6 mg/kg in 12 healthy adults. Eligible healthy adults received 6-8 h of preparatory counseling in anticipation of the first dose of psilocybin. The escalating oral psilocybin doses were administered at approximately monthly intervals in a controlled setting and subjects were monitored for 24 h. Blood and urine samples were collected over 24 h and assayed by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for psilocybin and psilocin, the active metabolite. The pharmacokinetics of psilocin were determined using both compartmental (NONMEM) and noncompartmental (WinNonlin) methods. No psilocybin was found in plasma or urine, and renal clearance of intact psilocin accounted for less than 2% of the total clearance. The pharmacokinetics of psilocin were linear within the twofold range of doses, and the elimination half-life of psilocin was 3 h (standard deviation 1.1). An extended elimination phase in some subjects suggests hydrolysis of the psilocin glucuronide metabolite. Variation in psilocin clearance was not predicted by body weight, and no serious adverse events occurred in the subjects studied. The small amount of psilocin renally excreted suggests that no dose reduction is needed for subjects with mild-moderate renal impairment. Simulation of fixed doses using the pharmacokinetic parameters suggest that an oral dose of 25 mg should approximate the drug exposure of a 0.3 mg/kg oral dose of psilocybin. Although doses of 0.6 mg/kg are in excess of likely therapeutic doses, no serious physical or psychological events occurred during or within 30 days of any dose. NCT02163707.

  18. Pharmacokinetics of Rilpivirine in HIV-Infected Pregnant Women.

    PubMed

    Tran, Anna H; Best, Brookie M; Stek, Alice; Wang, Jiajia; Capparelli, Edmund V; Burchett, Sandra K; Kreitchmann, Regis; Rungruengthanakit, Kittipong; George, Kathleen; Cressey, Tim R; Chakhtoura, Nahida; Smith, Elizabeth; Shapiro, David E; Mirochnick, Mark

    2016-07-01

    Rilpivirine pharmacokinetics is defined by its absorption, distribution, metabolism, and excretion. Pregnancy can affect these factors by changes in cardiac output, protein binding, volume of distribution, and cytochrome P450 (CYP) 3A4 activity. Rilpivirine is metabolized by CYP3A4. The impact of pregnancy on rilpivirine pharmacokinetics is largely unknown. International Maternal Pediatric Adolescent AIDS Clinical Trials P1026s is a multicenter, nonblinded, prospective study evaluating antiretroviral pharmacokinetics in HIV-infected pregnant women that included a cohort receiving rilpivirine 25 mg once daily as part of their combination antiretrovirals for clinical care. Thirty-two women were enrolled in this study. Intensive pharmacokinetic sampling was performed at steady state during the second trimester, the third trimester, and postpartum. Maternal and umbilical cord blood samples were obtained at delivery. Plasma rilpivirine concentration was measured using liquid chromatography-mass spectrometry; lower limit of quantitation was 10 ng/mL. Median (range) AUC0-24 were 1969 (867-4987, n = 15), 1669 (556-4312, n = 28), and 2387 (188-6736, n = 28) ng·h/mL in the second trimester, the third trimester, and postpartum, respectively (P < 0.05 for either trimester vs postpartum). Median (range) C24 were 63 (37-225, n = 17), 56 (<10-181, n = 30), and 81 (<10-299, n = 28) ng/mL (P < 0.05 for either trimester vs postpartum). High variability in pharmacokinetic parameters was observed between subjects. Median (range) cord blood/maternal concentration ratio was 0.55 (0.3-0.8, n = 21). Delivery HIV-1 RNA was ≤50 copies per milliliter in 70% and ≤400 copies per milliliter in 90% of women. Cmin were significantly lower at 15 visits with detectable HIV-1 RNA compared with 61 visits with undetectable HIV-1 RNA, 29 (<10-93) vs 63 (15-200) ng/mL (P = 0.0001). Cmin was below the protein binding-adjusted EC90 concentration (12.2 ng/mL) at 4 visits in 3 of 31 women (10

  19. Pharmacokinetics of Intravenous Posaconazole in Critically Ill Patients.

    PubMed

    Sime, Fekade B; Stuart, Janine; Butler, Jenie; Starr, Therese; Wallis, Steven C; Pandey, Saurabh; Lipman, Jeffrey; Roberts, Jason A

    2018-06-01

    To date, there is no information on the intravenous (i.v.) posaconazole pharmacokinetics for intensive care unit (ICU) patients. This prospective observational study aimed to describe the pharmacokinetics of a single dose of i.v. posaconazole in critically ill patients. Patients with no history of allergy to triazole antifungals and requiring systemic antifungal therapy were enrolled if they were aged ≥18 years, central venous access was available, they were not pregnant, and they had not received prior posaconazole or drugs interacting with posaconazole. A single dose of 300 mg posaconazole was administered over 90 min. Total plasma concentrations were measured from serial plasma samples collected over 48 h, using a validated chromatographic method. The pharmacokinetic data set was analyzed by noncompartmental methods. Eight patients (7 male) were enrolled with the following characteristics: median age, 46 years (interquartile range [IQR], 40 to 51 years); median weight, 68 kg (IQR, 65 to 82 kg); and median albumin concentration, 20 g/liter (IQR, 18 to 24 g/liter). Median (IQR) pharmacokinetic parameter estimates were as follows: observed maximum concentration during sampling period ( C max ), 1,702 ng/ml (1,352 to 2,141 ng/ml); area under the concentration-time curve from zero to infinity (AUC 0-∞ ), 17,932 ng · h/ml (13,823 to 27,905 ng · h/ml); clearance (CL), 16.8 liters/h (11.1 to 21.7 liters/h); and volume of distribution ( V ), 529.1 liters (352.2 to 720.6 liters). The V and CL were greater than 2-fold and the AUC 0-∞ was 39% of the values reported for heathy volunteers. The AUC 0-∞ was only 52% of the steady-state AUC 0-24 reported for hematology patients. The median of estimated average steady-state concentrations was 747 ng/ml (IQR, 576 to 1,163 ng/ml), which is within but close to the lower end of the previously recommended therapeutic range of 500 to 2,500 ng/ml. In conclusion, we observed different pharmacokinetics of i.v. posaconazole in

  20. Controversies with self-emulsifying drug delivery system from pharmacokinetic point of view.

    PubMed

    Chatterjee, Bappaditya; Hamed Almurisi, Samah; Ahmed Mahdi Dukhan, Ather; Mandal, Uttam Kumar; Sengupta, Pinaki

    2016-11-01

    Self-emulsifying drug delivery system (SEDDS) is an isotropic mixture of lipid, surfactant and co-surfactant, which forms a fine emulsion when comes in contact of an aqueous medium with mild agitation. SEDDS is considered as a potential platform for oral delivery of hydrophobic drug in order to overcome their poor and irregular bioavailability challenges. In spite of fewer advantages like improved solubility of drug, bypassing lymphatic transport etc., SEDDS faces different controversial issues such as the use of appropriate terminology (self-microemulsifying drug delivery system; SMEDDS or self-nanoemulsifying drug delivery system; SNEDDS), presence of high amount of surfactant, correlation of in vitro model to in vivo studies, lack of human volunteer study and effect of conversion of SEDDS to final administrable dosage form on pharmacokinetic behavior of the drug. In this review, potential issues or questions on SEDDS are identified and summarized from the pharmacokinetic point of view. Primarily this review includes the conflict between the influences of droplet size, variation in correlation between in vitro lipolysis or ex-vivo intestinal permeation and pharmacokinetic parameters, variation in in vivo results of solid and liquid SEDDS, and potential challenges or limitation of pharmacokinetic studies on human volunteers with orally administered SEDDS. In the past decades, hundreds of in vivo studies on SEDDS have been published. In the present study, only the relevant article on in vivo pharmacokinetic studies with orally administered SEDDS published in past 5-6 years are analyzed for an up to date compilation.

  1. Flip-flop pharmacokinetics – delivering a reversal of disposition: challenges and opportunities during drug development

    PubMed Central

    Yáñez, Jaime A; Remsberg, Connie M; Sayre, Casey L; Forrest, M Laird; Davies, Neal M

    2011-01-01

    Flip-flop pharmacokinetics is a phenomenon often encountered with extravascularly administered drugs. Occurrence of flip-flop spans preclinical to human studies. The purpose of this article is to analyze both the pharmacokinetic interpretation errors and opportunities underlying the presence of flip-flop pharmacokinetics during drug development. Flip-flop occurs when the rate of absorption is slower than the rate of elimination. If it is not recognized, it can create difficulties in the acquisition and interpretation of pharmacokinetic parameters. When flip-flop is expected or discovered, a longer duration of sampling may be necessary in order to avoid overestimation of fraction of dose absorbed. Common culprits of flip-flop disposition are modified dosage formulations; however, formulation characteristics such as the drug chemical entities themselves or the incorporated excipients can also cause the phenomenon. Yet another contributing factor is the physiological makeup of the extravascular site of administration. In this article, these causes of flip-flop pharmacokinetics are discussed with incorporation of relevant examples and the implications for drug development outlined. PMID:21837267

  2. [Pharmacokinetic study of six aconitine alkaloids in aconiti lateralis radix praeparata in beagle dogs].

    PubMed

    Xiao, Ri-Ping; Lai, Xiao-Ping; Zhao, Yai; Yu, Liang-Wen; Zhu, Yue-Lan; Li, Geng

    2014-02-01

    To study the pharmacokinetics characteristics of six Aconitum alkaloids aconitine (AC), mesaconitine (MA), hypaconitine (HA), benzoylaconine (BAC), benzoylmesaconine (BMA) and benzoylhypaconine (BHA) in beagle dogs. An ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed for simultaneous quantitation of six Aconitum alkaloids in beagle dog plasma after oral administration of Aconiti Lateralis Radix Praeparata decoction. UPLC/MS/MS system coupled with an electrospray ionization (ESI) source was performed in multiple-reaction monitoring (MRM) mode. Sample preparation was performed with solid-phase extraction(SPE) on a 3 mL HLB cartridge before the analysis. The separation was applied on a Waters C8 column (100 mm x 2.1 mm, 1.7 microm) and a gradient elution of methanol and 0.2% formic acid-water was used as mobile phase. The pharmacokinetic parameters were calculated by the results of the analysis through the DAS 2. 1 software (Drug and Statistics for Windows). The results showed that the fitting model for the six Aconitum alkaloids was the one-compartment model pharmacokinetics. The method is successfully used for the pharmacokinetic evaluation of the six Aconitum alkaloids in beagle dog plasma, it can help monitor the ADME/Tox process when taking Aconiti Lateralis Radix Praeparata by observing the pharmacokinetic process. The results provide a good reference for clinical treatment and safe application of Aconiti Lateralis Radix Praeparata.

  3. Population Pharmacokinetics of Phenobarbital in Infants with Neonatal Encephalopathy treated with Therapeutic Hypothermia

    PubMed Central

    Shellhaas, Renée A.; Ng, Chee M; Dillon, Christina H.; Barks, John D.E.; Bhatt-Mehta, Varsha

    2013-01-01

    Objective Phenobarbital is the first-line treatment for neonatal seizures. Many neonates with hypoxic ischemic encephalopathy (HIE) are treated with therapeutic hypothermia (TH) and about 40% have clinical seizures. Little is known about pharmacokinetics of phenobarbital in infants with HIE who undergo TH. The objective of this study was to determine the effect of TH on phenobarbital pharmacokinetics, taking into account maturational changes. Setting Level 3 neonatal intensive care unit. Patients Infants with HIE and suspected seizures, all treated with phenobarbital. Some of these infant also received treatment with TH. Interventions None. Design A retrospective cohort study of 39 infants with HIE treated with phenobarbital (20 were treated with TH and 19 were not). Measurements and main results Data were collected on phenobarbital plasma concentrations on 39 subjects with HIE with or without TH. Using nonlinear mixed-effects modeling, population pharmacokinetics of phenobarbital were developed with a total of 164 plasma concentrations. A one-compartment model best described the pharmacokinetics. The clearance (CL) of phenobarbital was linearly related to body weight and matured with increasing age with a maturation half-life of 22.1 days. TH did not influence the pharmacokinetic parameters of phenobarbital. Conclusions TH does not influence the CL of phenobarbital after accounting for weight and age. Standard phenobarbital dosing is appropriate for initial treatment of seizures in neonates with HIE treated with TH. PMID:23254984

  4. Population pharmacokinetics of phenobarbital in infants with neonatal encephalopathy treated with therapeutic hypothermia.

    PubMed

    Shellhaas, Renée A; Ng, Chee M; Dillon, Christina H; Barks, John D E; Bhatt-Mehta, Varsha

    2013-02-01

    Phenobarbital is the first-line treatment for neonatal seizures. Many neonates with hypoxic ischemic encephalopathy are treated with therapeutic hypothermia, and about 40% have clinical seizures. Little is known about the pharmacokinetics of phenobarbital in infants with hypoxic ischemic encephalopathy who undergo therapeutic hypothermia. The objective of this study was to determine the effect of therapeutic hypothermia on phenobarbital pharmacokinetics, taking into account maturational changes. Level 3 neonatal ICU. Infants with hypoxic ischemic encephalopathy and suspected seizures, all treated with phenobarbital. Some of these infants also received treatment with therapeutic hypothermia. None. A retrospective cohort study of 39 infants with hypoxic ischemic encephalopathy treated with phenobarbital (20 were treated with therapeutic hypothermia and 19 were not). Data on phenobarbital plasma concentrations were collected in 39 subjects with hypoxic ischemic encephalopathy with or without therapeutic hypothermia. Using nonlinear mixed-effects modeling, population pharmacokinetics of phenobarbital were developed with a total of 164 plasma concentrations. A one-compartment model best described the pharmacokinetics. The clearance of phenobarbital was linearly related to body weight and matured with increasing age with a maturation half-life of 22.1 days. Therapeutic hypothermia did not influence the pharmacokinetic parameters of phenobarbital. Therapeutic hypothermia does not influence the clearance of phenobarbital after accounting for weight and age. Standard phenobarbital dosing is appropriate for the initial treatment of seizures in neonates with hypoxic ischemic encephalopathy treated with therapeutic hypothermia.

  5. Population pharmacokinetics of oxycodone in patients with cancer-related pain.

    PubMed

    Komatsu, Toshiaki; Kokubun, Hideya; Suzuki, Ai; Takayanagi, Risa; Yamada, Yasuhiko; Matoba, Motohiro; Yago, Kazuo

    2012-09-01

    Oxycodone is an opioid widely prescribed to cancer patients for pain relief. However, the pharmacokinetics of oxycodone has not been sufficiently examined. Therefore the aim of this work was to study population pharmacokinetics of oxycodone in patients with cancer pain. The authors analyzed 108 serum oxycodone samples of 33 individuals with nonlinear mixed-effects model (NONMEM). Population pharmacokinetics was calculated using the one-compartment model of clearance, volume of distribution, bioavailability, absorption constant rate, and lag time. An exponential error model was used to determine interindividual variability and a relative error model was applied to assess residual variability. Population pharmacokinetics of oxycodone at the end point were as follows: CL(L/h) = 10.7 × [1 + (2 - Child-Pugh Classification)] (Class: A = 0, B = 1, C = 2); V(d) (L) = 193; k(a) (h(-1)) = 0.336; T(lag) (h) = 0.859; F (%) = 63.9. Interindividual variability was CL: 30.5%, V(d): 44.6%, and F: 37.0%, and residual variability was 16.2%. As the total clearance in patients with liver dysfunction (Child-Pugh class B) was reduced to 33.3%, serum concentration of oxycodone increased by 1.5. Therefore, it became clear that dose adjustments are essential when treating patients with liver dysfunction. These findings suggest that population parameters are useful for evaluating pharmacokinetics of oxycodone in patients with cancer pain.

  6. Effects of mesocaval shunt on the pharmacokinetics of metronidazole in young rats.

    PubMed

    Guillé, Beatriz E Perez; Alvarez, Fernando Villegas; Toledo López, Alejandra R; Bravo-Luna, Miguel A Jiménez; Soriano-Rosales, Rosa E; Lares-Asseff, Ismael; Arrellin, Gerardo; Guillé, Maria G Pérez

    2005-01-01

    Prophylactic and therapeutic management of portosystemic encephalopathies is based on protein restriction in the diet, and the use of lactulose and antibiotics such as metronidazole. These actions intend to reduce the main source of intestinal ammonia production and release into the systemic circulation. The aim of this study was to evaluate the medium-term effects of mesocaval shunt on the pharmacokinetics of metronidazole in rats with healthy livers. Male Lewis rats were divided into two groups. The first group was subjected to mesocaval shunt (MCS) and the other employed as a control. The following tests were carried out in both groups: metronidazole pharmacokinetics, determination of ALT, AST, albumin, urea and ammonium, liver weight and histomorphology. A loss in body and liver weight was registered in rats subjected to MCS. AST levels also increased compared to controls. Significant differences in almost all pharmacokinetic parameters were detected between MCS and control rats, especially in Kel, AUC and Cmax. Modifications in metronidazole pharmacokinetics and liver weight changes without microstructural modification secondary to MCS were found. We suggest that individual drug-monitoring and pharmacokinetic analysis must be carried out in metronidazole medicated patients with modifications in portal circulation with or with out macro or micro liver structural alterations.

  7. The Influence of Normalization Weight in Population Pharmacokinetic Covariate Models.

    PubMed

    Goulooze, Sebastiaan C; Völler, Swantje; Välitalo, Pyry A J; Calvier, Elisa A M; Aarons, Leon; Krekels, Elke H J; Knibbe, Catherijne A J

    2018-03-23

    In covariate (sub)models of population pharmacokinetic models, most covariates are normalized to the median value; however, for body weight, normalization to 70 kg or 1 kg is often applied. In this article, we illustrate the impact of normalization weight on the precision of population clearance (CL pop ) parameter estimates. The influence of normalization weight (70, 1 kg or median weight) on the precision of the CL pop estimate, expressed as relative standard error (RSE), was illustrated using data from a pharmacokinetic study in neonates with a median weight of 2.7 kg. In addition, a simulation study was performed to show the impact of normalization to 70 kg in pharmacokinetic studies with paediatric or obese patients. The RSE of the CL pop parameter estimate in the neonatal dataset was lowest with normalization to median weight (8.1%), compared with normalization to 1 kg (10.5%) or 70 kg (48.8%). Typical clearance (CL) predictions were independent of the normalization weight used. Simulations showed that the increase in RSE of the CL pop estimate with 70 kg normalization was highest in studies with a narrow weight range and a geometric mean weight away from 70 kg. When, instead of normalizing with median weight, a weight outside the observed range is used, the RSE of the CL pop estimate will be inflated, and should therefore not be used for model selection. Instead, established mathematical principles can be used to calculate the RSE of the typical CL (CL TV ) at a relevant weight to evaluate the precision of CL predictions.

  8. Citrate Pharmacokinetics in Critically Ill Patients with Acute Kidney Injury

    PubMed Central

    Zhu, Qiuyu; Liu, Junfeng; Qian, Jing; You, Huaizhou; Gu, Yong; Hao, Chuanming; Jiao, Zheng; Ding, Feng

    2013-01-01

    Introduction Regional citrate anticoagulation (RCA) is gaining popularity in continous renal replacement therapy (CRRT) for critically ill patients. The risk of citrate toxicity is a primary concern during the prolonged process. The aim of this study was to assess the pharmacokinetics of citrate in critically ill patients with AKI, and used the kinetic parameters to predict the risk of citrate accumulation in this population group undergoing continuous veno-venous hemofiltration (CVVH) with RCA. Methods Critically ill patients with AKI (n = 12) and healthy volunteers (n = 12) were investigated during infusing comparative dosage of citrate. Serial blood samples were taken before, during 120 min and up to 120 min after infusion. Citrate pharmacokinetics were calculated and compared between groups. Then the estimated kinetic parameters were applied to the citrate kinetic equation for validation in other ten patients’ CVVH sessions with citrate anticoagulation. Results Total body clearance of citrate was similar in critically ill patients with AKI and healthy volunteers (648.04±347.00 L/min versus 686.64±353.60 L/min; P = 0.624). Basal and peak citrate concentrations were similar in both groups (p = 0.423 and 0.247, respectively). The predicted citrate curve showed excellent fit to the measurements. Conclusions Citrate clearance is not impaired in critically ill patients with AKI in the absence of severe liver dysfunction. Citrate pharmacokinetic data can provide a basis for the clinical use of predicting the risk of citrate accumulation. Trial Registration ClinicalTrials.gov Identifier NCT00948558 PMID:23824037

  9. 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.

  10. Population pharmacokinetics of valnemulin in swine.

    PubMed

    Zhao, D H; Zhang, Z; Zhang, C Y; Liu, Z C; Deng, H; Yu, J J; Guo, J P; Liu, Y H

    2014-02-01

    This study was carried out in 121 pigs to develop a population pharmacokinetic (PPK) model by oral (p.o.) administration of valnemulin at a single dose of 10 mg/kg. Serum biochemistry parameters of each pig were determined prior to drug administration. Three to five blood samples were collected at random time points, but uniformly distributed in the absorption, distribution, and elimination phases of drug disposition. Plasma concentrations of valnemulin were determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The concentration-time data were fitted to PPK models using nonlinear mixed effect modeling (NONMEM) with G77 FORTRAN compiler. NONMEM runs were executed using Wings for NONMEM. Fixed effects of weight, age, sex as well as biochemistry parameters, which may influence the PK of valnemulin, were investigated. The drug concentration-time data were adequately described by a one-compartmental model with first-order absorption. A random effect model of valnemulin revealed a pattern of log-normal distribution, and it satisfactorily characterized the observed interindividual variability. The distribution of random residual errors, however, suggested an additive model for the initial phase (<12 h) followed by a combined model that consists of both proportional and additive features (≥ 12 h), so that the intra-individual variability could be sufficiently characterized. Covariate analysis indicated that body weight had a conspicuous effect on valnemulin clearance (CL/F). The featured population PK values of Ka , V/F and CL/F were 0.292/h, 63.0 L and 41.3 L/h, respectively. © 2013 John Wiley & Sons Ltd.

  11. Chiral Pesticide Pharmacokinetics: A Range of Values

    EPA Science Inventory

    Approximately 30% of pesticides are chiral and used as mixtures of two or more stereoisomers. In biological systems, these stereoisomers can exhibit significantly different pharmacokinetics (absorption, distribution, metabolism, and elimination). In spite of these differences, th...

  12. A PHARMACOKINETIC PROGRAM (PKFIT) FOR R

    EPA Science Inventory

    The purpose of this study was to create a nonlinear regression (including a genetic algorithm) program (R script) to deal with data fitting for pharmacokinetics (PK) in R environment using its available packages. We call this tool as PKfit.

  13. [Effects of ranitidine on pharmacokinetics of rhein from Dachengqi Decoction in rats after oral administration].

    PubMed

    Ren, Yan-yi; Gong, Han-lin; Tang, Wen-fu; Wan, Mei-fua; Huang, Xi

    2009-09-01

    To explore the effects of ranitidine on pharmacokinetics of rhein in rats after oral administration of Dachengqi Decoction (DCQD), a compound traditional Chinese herbal medicine. Twelve male Sprague-Dawley rats were divided into DCQD group and DCQD plus ranitidine group, and were orally administered with DCQD at a dose of 10 g/kg or DCQD (10 g/kg) combined with ranitidine (150 mg/kg), respectively. Blood samples were gathered after a series of time intervals. Metabolism of rhein was determined with a reversed-phase high-performance liquid chromatography with internal standard of 1, 8-dihydroxyanthraquinone and the data were analyzed with DAS 2.1 program. The pharmacokinetic parameters were compared between the two groups. The pharmacokinetic parameters of rhein in the DCQD group, including peak concentration (C(max)), area under the plasma concentration-time curve (AUC), distribution phase half-life (t(1/2alpha)), elimination rate constant (K(10)) and central to peripheral transfer rate constant (K(12)), were significantly different to those in the DCQD plus ranitidine group (P<0.05, P<0.01). There were no significant differences in the other parameters between the two groups. Ranitidine can influence the pharmacokinetics of rhein in rats after oral administration of DCQD.

  14. Pharmacokinetics and pharmacodynamics of the injectable formulation of methadone hydrochloride and methadone in lipid nanocarriers administered orally to horses.

    PubMed

    Crosignani, N; Luna, S P; Dalla Costa, T; Pimenta, E L; Detoni, C B; Guterres, S S; Puoli Filho, J N; Pantoja, J C; Pigatto, M C

    2017-08-01

    We investigated the thermal, electrical and mechanical antinociceptive and physiological effects (heart rate, respiratory rate, arterial blood pressure, head height and abdominal auscultation score), and pharmacokinetics, of 0.5 mg/kg of the injectable formulation (ORAL) or nanoparticulated methadone (NANO) given orally, in six adult mares, using a crossover, blind and prospective design. Repeated-measure models were used to compare parametric data between and within treatments, followed by Tukey's test. Nonparametric data were analysed with Wilcoxon signed-rank, adjusted by Bonferroni tests. Blood samples were also collected up to 6 h after dosing for plasma drug quantification by LC-MS/MS. Methadone pharmacokinetic parameters were determined by noncompartmental and compartmental approaches. There were no differences in pharmacodynamic parameters. No statistical differences were observed in the pharmacokinetic parameters from noncompartmental analysis for both groups, except a significant decrease in peak plasma concentration, increase in apparent volume of distribution per fraction absorbed (Vd ss /F) and increased mean residence time (MRT) for NANO. One-compartment open model with first order elimination best described the pharmacokinetic profiles for both groups. Neither ORAL nor NANO administered orally to horses produced antinociception. The nanoencapsulated formulation of methadone given orally to horses did not improve methadone pharmacokinetic parameters or increased systemic body exposure to methadone. © 2017 John Wiley & Sons Ltd.

  15. 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

  16. Lack of Effect of Vortioxetine on the Pharmacokinetics and Pharmacodynamics of Ethanol, Diazepam, and Lithium.

    PubMed

    Chen, Grace; Nomikos, George G; Affinito, John; Zhao, Zhen

    2016-09-01

    Because the multimodal antidepressant vortioxetine is likely to be coadministered with other central nervous system (CNS)-active drugs, potential drug-drug interactions warrant examination. These studies evaluated whether there are pharmacokinetic and/or pharmacodynamic interactions between vortioxetine and ethanol, diazepam, or lithium. This series of phase I studies included healthy men and women (only men in the lithium study) aged 18-45 years. The ethanol study was a randomized, double-blind, two-parallel group, four-period crossover study in which subjects received a single dose of vortioxetine (20 or 40 mg) or placebo with or without ethanol, and the diazepam study was a randomized, double-blind, placebo-controlled, two-sequence, two-period crossover study in which subjects received a single dose of diazepam following multiple doses of vortioxetine 10 mg/day or placebo. These two studies evaluated the effect of coadministration on standardized psychomotor parameters and on selected pharmacokinetic parameters of each drug. The lithium study was a single-blind, single-sequence study evaluating the effect of multiple doses of vortioxetine 10 mg/day on the steady-state pharmacokinetics of lithium. Concomitant administration of vortioxetine and single doses of either ethanol or diazepam had no significant effect on the psychomotor performance of subjects compared with administration of ethanol or diazepam alone. Vortioxetine had no significant effect on the pharmacokinetics of ethanol, diazepam, or lithium, and ethanol had no significant effect on the pharmacokinetics of vortioxetine. Concomitant administration of these agents with vortioxetine was generally well tolerated, with no clinically relevant drug-drug pharmacokinetic or pharmacodynamic interactions identified.

  17. 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

  18. Lack of sex-related differences in saquinavir pharmacokinetics in an HIV-seronegative cohort

    PubMed Central

    Robertson, Sarah M; Formentini, Elizabeth; Alfaro, Raul M; Natarajan, Ven; Falloon, Judith; Penzak, Scott R

    2006-01-01

    Aims To examine the influence of sex on steady-state saquinavir pharmacokinetics in HIV-seronegative volunteers administered saquinavir without a concomitant protease inhibitor. Methods Thirty-eight healthy volunteers (14 female) received saquinavir soft-gel capsules 1200 mg three times daily for 3 days to achieve steady-state conditions. Following administration of the 10th dose, blood was collected serially over 8 h for measurement of saquinavir plasma concentrations. Saquinavir pharmacokinetic parameter values were determined using noncompartmental methods and compared between males and females. CYP3A phenotype (using oral midazolam) and MDR-1 genotypes at positions 3435 and 2677 were determined for all subjects in order to characterize possible mechanisms for any observed sex-related differences. Results There was no significant difference in saquinavir AUC0−8 or any other pharmacokinetic parameter value between the sexes. These findings persisted after mathematically correcting for total body weight. The mean weight-normalized AUC0−8 was 29.9 (95% confidence interval 15.5, 44.3) and 29.8 (18.6, 40.9) ng h−1 ml−1 kg−1 for males and females, respectively. No significant difference in CYP3A phenotype was observed between the groups; likewise, the distribution of MDR-1 genotypes was similar for males and females. Conclusion In contrast to previous study findings, results from this investigation showed no difference in saquinavir pharmacokinetics between males and females. The discrepancy between our findings and those previously reported may be explained by the fact that we evaluated HIV-seronegative volunteers and administered saquinavir in the absence of concomitant protease inhibitors such as ritonavir. Caution must be exercised when extrapolating pharmacokinetic data from healthy volunteer studies (including sex-based pharmacokinetic differences) to HIV-infected populations or to patients receiving additional concurrent medications. PMID

  19. Correcting oral contraceptive pharmacokinetic alterations due to obesity. A randomized controlled trial

    PubMed Central

    Edelman, Alison B; Cherala, Ganesh; Munar, Myrna Y.; McInnis, Martha; Stanczyk, Frank Z.; Jensen, Jeffrey T

    2014-01-01

    Objective To determine if increasing the hormone dose or eliminating the hormone-free interval improves key pharmacokinetic (PK) alterations caused by obesity during oral contraceptive (OC) use. Study design Obese (BMI ≥ 30 kg/m2), ovulatory, otherwise healthy, women received an OC containing 20 mcg ethinyl estradiol (EE)/100 mcg levonorgestrel (LNG) dosed cyclically (21 days active pills with 7-day placebo week) for two cycles and then were randomized for two additional cycles to: Continuous Cycling [CC, a dose neutral arm using the same OC with no hormone-free interval] or Increased Dose [ID, a dose escalation arm using an OC containing 30 mcg EE/150 mcg LNG cyclically]. During Cycle 2, 3, and 4, outpatient visits were performed to assess maximum serum concentration (Cmax), area under the curve (AUC0-∞), and time to steady state as well as pharmacodynamics. These key PK parameters were calculated and compared within groups between baseline and treatment cycles. Results A total of 31 women enrolled and completed the study (CC group n = 16; ID group n = 15). Demographics were similar between groups [mean BMI: CC 38kg/m2 (SD 5.1), ID 41kg/m2 (SD 7.6)]. At baseline, the key LNG PK parameters were no different between groups; average time to reach steady-state was 12 days in both groups; Cmax were CC: 3.82 ± 1.28 ng/mL and ID: 3.13 ± 0.87 ng/mL; and AUC0-∞ were CC: 267 ± 115 hr*ng/mL and ID: 199±75 hr*ng/mL. Following randomization, the CC group maintained steady-state serum levels whereas the ID group had a significantly higher Cmax (p< 0.001) but again required 12 days to achieve steady-state. However, AUC was not significantly different between CC (412 ± 255 hr*ng/mL) and ID (283 ± 130 hr*ng/mL). Forty-five percent (14/31) of the study population had evidence of an active follicle-like structure prior to randomization and afterwards this decreased to 9% (3/31). Conclusion Both increasing the OC dose and continuous dosing appear to counteract the impact

  20. Pharmacokinetics of oral amantadine in greyhound dogs.

    PubMed

    Norkus, C; Rankin, D; Warner, M; KuKanich, B

    2015-06-01

    This study reports the pharmacokinetics of amantadine in greyhound dogs after oral administration. Five healthy greyhound dogs were used. A single oral dose of 100 mg amantadine hydrochloride (mean dose 2.8 mg/kg as amantadine hydrochloride) was administered to nonfasted subjects. Blood samples were collected at predetermined time points from 0 to 24 h after administration, and plasma concentrations of amantadine were measured by liquid chromatography with triple quadrupole mass spectrometry. Noncompartmental pharmacokinetic analyses were performed. Amantadine was well tolerated in all dogs with no adverse effects observed. The mean (range) amantadine CMAX was 275 ng/mL (225-351 ng/mL) at 2.6 h (1-4 h) with a terminal half-life of 4.96 h (4.11-6.59 h). The results of this study can be used to design dosages to assess multidose pharmacokinetics and dosages designed to achieve targeted concentrations in order to assess the clinical effects of amantadine in a variety of conditions including chronic pain. Further studies should also assess the pharmacokinetics of amantadine in other dog breeds or using population pharmacokinetics studies including multiple dog breeds to assess potential breed-specific differences in the pharmacokinetics of amantadine in dogs. © 2014 John Wiley & Sons Ltd.

  1. Effects of hypothermia on pharmacokinetics and pharmacodynamics: a systematic review of preclinical and clinical studies.

    PubMed

    van den Broek, Marcel P H; Groenendaal, Floris; Egberts, Antoine C G; Rademaker, Carin M A

    2010-05-01

    Examples of clinical applications of therapeutic hypothermia in modern clinical medicine include traumatic cardiac arrest, ischaemic stroke and, more recently, acute perinatal asphyxia in neonates. The exact mechanism of (neuro)protection by hypothermia is unknown. Since most enzymatic processes exhibit temperature dependency, it can be expected that therapeutic hypothermia may cause alterations in both pharmacokinetic and pharmacodynamic parameters, which could result in an increased risk of drug toxicity or therapy failure. Generalizable knowledge about the effect of therapeutic hypothermia on pharmacokinetics and pharmacodynamics could lead to more appropriate dosing and thereby prediction of clinical effects. This article reviews the evidence on the influence of therapeutic hypothermia on individual pharmacokinetic and pharmacodynamic parameters. A literature search was conducted within the PubMed, Embase and Cochrane databases from January 1965 to September 2008, comparing pharmacokinetic and/or pharmacodynamic parameters in hypothermia and normothermia regarding preclinical (animal) and clinical (human) studies. During hypothermia, pharmacokinetic parameters alter, resulting in drug and metabolite accumulation in the plasma for the majority of drugs. Impaired clearance is the most striking effect. Based on impaired clearance, dosages should be decreased considerably, especially for drugs with a low therapeutic index. Hypothetically, high-clearance compounds are affected more than low-clearance compounds because of the additional effect of impaired hepatic blood flow. The volume of distribution also changes, which may lead to therapy failure when it increases and could lead to toxicity when it decreases. The pH-partitioning hypothesis could contribute to the changes in the volumes of distribution for weak bases and acids, depending on their acid dissociation constants and acid-base status. Pharmacodynamic parameters may also alter, depending on the hypothermic

  2. Pharmacokinetics of orally administered DL-α-lipoic acid in dogs.

    PubMed

    Zicker, Steven C; Avila, Albert; Joshi, Dinesh K; Gross, Kathy L

    2010-11-01

    To determine the pharmacokinetics of DL-α-lipoic acid in dogs when administered at 3 dosages via 3 methods of delivery. 27 clinically normal Beagles. In a 3 × 3 factorial Latin square design, 3 dosages (2.5, 12.5, and 25 mg/kg) of DL-α-lipoic acid were administered orally in a capsule form and provided without a meal, in a capsule form and provided with a meal, and as an ingredient included in an extruded dog food. Food was withheld for 12 hours prior to DL-α-lipoic acid administration. Blood samples were collected before (0 minutes) and at 15, 30, 45, 60, and 120 minutes after administration. Plasma concentrations of DL-α-lipoic acid were determined via high-performance liquid chromatography. A generalized linear models procedure was used to evaluate the effects of method of delivery and dosage. Noncompartmental analysis was used to determine pharmacokinetic parameters of DL-α-lipoic acid. Nonparametric tests were used to detect significant differences between pharmacokinetic parameters among treatment groups. A significant effect of dosage was observed regardless of delivery method. Method of delivery also significantly affected plasma concentrations of DL-α-lipoic acid, with extruded foods resulting in lowest concentration for each dosage administered. Maximum plasma concentration was significantly affected by method of delivery at each dosage administered. Other significant changes in pharmacokinetic parameters were variable and dependent on dosage and method of delivery. Values for pharmacokinetic parameters of orally administered DL-α-lipoic acid may differ significantly when there are changes in dosage, method of administration, and fed status.

  3. General Pharmacokinetic Model for Topically Administered Ocular Drug Dosage Forms.

    PubMed

    Deng, Feng; Ranta, Veli-Pekka; Kidron, Heidi; Urtti, Arto

    2016-11-01

    In ocular drug development, an early estimate of drug behavior before any in vivo experiments is important. The pharmacokinetics (PK) and bioavailability depend not only on active compound and excipients but also on physicochemical properties of the ocular drug formulation. We propose to utilize PK modelling to predict how drug and formulational properties affect drug bioavailability and pharmacokinetics. A physiologically relevant PK model based on the rabbit eye was built to simulate the effect of formulation and physicochemical properties on PK of pilocarpine solutions and fluorometholone suspensions. The model consists of four compartments: solid and dissolved drug in tear fluid, drug in corneal epithelium and aqueous humor. Parameter values and in vivo PK data in rabbits were taken from published literature. The model predicted the pilocarpine and fluorometholone concentrations in the corneal epithelium and aqueous humor with a reasonable accuracy for many different formulations. The model includes a graphical user interface that enables the user to modify parameters easily and thus simulate various formulations. The model is suitable for the development of ophthalmic formulations and the planning of bioequivalence studies.

  4. Paracetamol plasma and cerebrospinal fluid pharmacokinetics in children

    PubMed Central

    Anderson, B J; Holford, N H G; Woollard, G A; Chan, P L S

    1998-01-01

    Aims Paracetamol has a central action for both antipyresis and analgesia. Maximum temperature decrease and peak analgesia are reported at 1–2 h after peak plasma paracetamol concentration. We wished to determine the relationship between plasma and cerebrospinal fluid (CSF) pharmacokinetics in children. Methods Concentration-time profiles in plasma and CSF after nasogastric paracetamol 40 mg kg−1 were measured in nine children who had indwelling ventricular drains. Estimation of population pharmacokinetic parameters was made using both a standard two-stage population approach (MKMODEL) and a nonlinear mixed effect model (NONMEM). Results were standardized to a 70 kg person using an allometric power model. Results Both approaches gave similar estimates. NONMEM parameter estimates were clearance 10.2 l h−1 (CV 47%), volume of distribution 67.1 l (CV 58%) and absorption rate constant 0.77 h−1 (CV 49%). Cerebrospinal fluid concentrations lagged behind those of plasma. The equilibration half time was 0.72 h (CV 117%). The CSF/plasma partition coefficient was 1.18 (CV 8%). Conclusions Higher concentrations in the CSF probably reflect the lower free water volume of plasma. The CSF equilibration half time suggests that CSF kinetics approximate more closely to the effect compartment than plasma, but further time is required for paracetamol to exert its effects. Effect site concentrations equilibrate slowly with plasma. Paracetamol should be given 1–2 h before anticipated pain or fever in children. PMID:9764964

  5. Pharmacokinetics and safety of eszopiclone in healthy Chinese volunteers.

    PubMed

    Wu, F; Zhao, X L; Wei, M J; Wang, S M; Zhou, H; Guo, S J; Zhang, P

    2012-12-01

    The main objective of this study was to investigate the pharmacokinetic characters of eszopiclone (CAS: 138729-47-2) after single and multiple-dose oral administration in healthy adult Chinese volunteers.In single-dose study, 12 subjects were given oral administrations of 1.5, 3 and 6 mg eszopiclone in an open-label, randomized, crossover fashion. In multiple-dose study, 8 subjects were given 3 mg eszopiclone once daily consecutively for 7 days. Blood samples were collected over 24 h and plasma eszopiclone were determined using a validated liquid chromatography/mass spectrometry (LC/MS/MS) assay. The safety and tolerability of eszopiclone was evaluated by adverse events recording, physical examination, laboratory testing, vital signs, and 12-lead ECG findings.The main pharmacokinetic parameters of eszopiclone after single-dose administration were as follows: doses of 1.5, 3 and 6 mg; Cmax of 18.08±4.65, 38.29±15.41 and 76.38±23.34 ng/ml; Tmax of 0.94±0.39, 1.04±0.63 and 1.08±0.51 h; AUC0-24 of 110.90±23.06, 227.36±62.41 and 504.10±140.13 ng*h/ml; elimination half-lives of 5.84±1.03, 5.53±1.91 and 6.17±1.23 h. After multiple-dose administration, the steady-state levels of eszopiclone were achieved by the 4th day, and the main pharmacokinetic parameters were Css_max at 33.43±5.63 ng/ml and AUCss (0-24) at 263.30±51.21 ng*h/ml. The most common adverse event was bitter or abnormal taste. All the adverse events were judged as mild to moderate and resolved without any medication.The pharmacokinetic character of eszopiclone is linear and dose-proportional over the range of 1.5-6 mg. The systemic exposure does not accumulate with once-daily administrations. Eszopiclone appears to have good safety and is well tolerated. © Georg Thieme Verlag KG Stuttgart · New York.

  6. Pharmacokinetics, Dose Proportionality, and Bioavailability of Bazedoxifene in Healthy Postmenopausal Women.

    PubMed

    McKeand, William

    2017-09-01

    Bazedoxifene is a selective estrogen receptor modulator that has estrogen agonist effects on bone and lipid metabolism while having neutral or estrogen antagonist effects on the breast and endometrium. The present report describes findings from 3 Phase I clinical studies that evaluated the single-dose pharmacokinetics (study 1; n = 84), multiple-dose pharmacokinetics (study 2; n = 23), and absolute bioavailability (study 3; n = 18) of bazedoxifene. All 3 studies enrolled healthy postmenopausal women who were either naturally postmenopausal or had undergone bilateral oophorectomy at least 6 months before the start of the study. Study 1 showed that unconjugated and total (unconjugated and conjugated) bazedoxifene levels increased proportionally with ascending oral doses of bazedoxifene (through the dose range of 5-120 mg). Evaluation with or without food intake was conducted at the 10-mg dose, with no clinically relevant effect on pharmacokinetic parameters. Study 2 showed that bazedoxifene achieved steady state in 1 week and exhibited linear pharmacokinetics in doses of 5 to 40 mg with no unexpected accumulation over the dose range. In accordance with a linear pharmacokinetic profile, mean maximum plasma concentration values increased with increasing dose, with values of 1.6, 6.2, and 12.5 ng/mL for the 5-, 20-, and 40-mg doses, respectively. In study 3, tablet and capsule formulations of bazedoxifene formulations had an estimated oral bioavailability of ~6%. The clearance of bazedoxifene was 0.4 (0.1) L/h/kg based on intravenous administration. The oral formulations had comparable exposure profiles with respect to AUC and AUC0-t, and the 90% CIs for these values were within the bioequivalence limits of 80% to 125%. Bazedoxifene was safe and well tolerated in all 3 studies. These pharmacokinetic evaluations in healthy postmenopausal women found that bazedoxifene displayed linear pharmacokinetics with doses ranging from 5 to 40 mg, with no unexpected accumulation

  7. One should avoid retro-orbital pharmacokinetic sample collections for intranasal dosing in rats: Illustration of spurious pharmacokinetics generated for anti-migraine drugs zolmitriptan and eletriptan.

    PubMed

    Patel, Harilal; Patel, Prakash; Modi, Nirav; Shah, Shaival; Ghoghari, Ashok; Variya, Bhavesh; Laddha, Ritu; Baradia, Dipesh; Dobaria, Nitin; Mehta, Pavak; Srinivas, Nuggehally R

    2017-08-30

    Because of the avoidance of first pass metabolic effects due to direct and rapid absorption with improved permeability, intranasal route represents a good alternative for extravascular drug administration. The aim of the study was to investigate the intranasal pharmacokinetics of two anti-migraine drugs (zolmitriptan and eletriptan), using retro-orbital sinus and jugular vein sites sampling. In a parallel study design, healthy male Sprague-Dawley (SD) rats aged between 8 and 12weeks were divided into groups (n=4 or 5/group). The animals of individual groups were dosed intranasal (~1.0mg/kg) and oral doses of 2.1mg/kg of either zolmitriptan or eletriptan. Serial blood sampling was performed from jugular vein or retro-orbital site and plasma samples were analyzed for drug concentrations using LC-MS/MS assay. Standard pharmacokinetics parameters such as T max , C max , AUC last , AUC 0-inf and T 1/2 were calculated and statistics of derived parameters was performed using unpaired t-test. After intranasal dosing, the mean pharmacokinetic parameters C max and AUC inf of zolmitriptan/eletriptan showed about 17-fold and 3-5-fold higher values for retro-orbital sampling as compared to the jugular vein sampling site. Whereas after oral administration such parameters derived for both drugs were largely comparable between the two sampling sites and statistically non-significant. In conclusion, the assessment of plasma levels after intranasal administration with retro-orbital sampling would result in spurious and misleading pharmacokinetics. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Effects of FMO3 Polymorphisms on Pharmacokinetics of Sulindac in Chinese Healthy Male Volunteers

    PubMed Central

    Tang, Yong-Jun; Hu, Kai; Liu, Zhi; Chen, Yao; Ouyang, Dong-Sheng; Zhou, Hong-Hao

    2017-01-01

    Sulindac is a nonsteroidal anti-inflammatory drug, which is clinically used for the ailments of various inflammations. This study investigated the allele frequencies of FMO3 E158K and E308G and evaluated the influences of these two genetic polymorphisms on the pharmacokinetics of sulindac and its metabolites in Chinese healthy male volunteers. Eight FMO3 wild-type (FMO3 HHDD) subjects and seven FMO3 homozygotes E158K and E308G mutant (FMO3 hhdd) subjects were recruited from 247 healthy male volunteers genotyped by PCR-RFLP method. The plasma concentrations of sulindac, sulindac sulfide, and sulindac sulfone were determined by UPLC, while the pharmacokinetic parameters of the two different FMO3 genotypes were compared with each other. The frequencies of FMO3 E158K and E308G were 20.3% and 20.1%, respectively, which were in line with Hardy-Weinberg equilibrium (D′ = 0.977, r2 = 0.944). The mean values of Cmax, AUC0–24, and AUC0–∞ of sulindac were significantly higher in FMO3 hhdd group than those of FMO3 HHDD group (P < 0.05), while the pharmacokinetic parameters except Tmax of sulindac sulfide and sulindac sulfone showed no statistical difference between the two groups. The two FMO3 mutants were in close linkage disequilibrium and might play an important role in the pharmacokinetics of sulindac in Chinese healthy male volunteers. PMID:28331852

  9. Pharmacokinetic evaluation of avicularin using a model-based development approach.

    PubMed

    Buqui, Gabriela Amaral; Gouvea, Dayana Rubio; Sy, Sherwin K B; Voelkner, Alexander; Singh, Ravi S P; da Silva, Denise Brentan; Kimura, Elza; Derendorf, Hartmut; Lopes, Norberto Peporine; Diniz, Andrea

    2015-03-01

    The aim of this study was to use the pharmacokinetic information of avicularin in rats to project a dose for humans using allometric scaling. A highly sensitive and specific bioanalytical assay to determine avicularin concentrations in the plasma was developed and validated for UPLC-MS/MS. The plasma protein binding of avicularin in rat plasma determined by the ultrafiltration method was 64%. The pharmacokinetics of avicularin in nine rats was studied following an intravenous bolus administration of 1 mg/kg and was found to be best described by a two-compartment model using a nonlinear mixed effects modeling approach. The pharmacokinetic parameters were allometrically scaled by body weight and centered to the median rat weight of 0.23 kg, with the power coefficient fixed at 0.75 for clearance and 1 for volume parameters. Avicularin was rapidly eliminated from the systemic circulation within 1 h post-dose, and the avicularin pharmacokinetic was linear up to 5 mg/kg based on exposure comparison to literature data for a 5-mg/kg single dose in rats. Using allometric scaling and Monte Carlo simulation approaches, the rat doses of 1 and 5 mg/kg correspond to the human equivalent doses of 30 and 150 mg, respectively, to achieve comparable plasma avicularin concentrations in humans. Georg Thieme Verlag KG Stuttgart · New York.

  10. Pharmacokinetics of paracetamol in patients with chronic pancreatitis.

    PubMed

    Siepsiak, Magdalena; Szałek, Edyta; Karbownik, Agnieszka; Grabowski, Tomasz; Mziray, Marzanna; Adrych, Krystian; Grześkowiak, Edmund

    2016-08-01

    Chronic pancreatitis (CP) is a progressive, irreversible disease causing damage of the gland. Abdominal pains are a typical symptom of pancreatitis both in the chronic and acute form. Paracetamol is one of analgesics used for treating mild or moderate pain. Functional and anatomical changes in the gastrointestinal tract caused by pancreatitis may influence on the pharmacokinetics of administered drugs. In the present study we analysed the pharmacokinetics of paracetamol after oral and intravenous administration to patients with CP. The patients were allocated to one of the two groups of the drug under study: I iv, intravenous administration of paracetamol 1000mg (n=17; mean [SD] age, 46.18 [13.78] years; and BMI, 22.03 [2.62]kg/m(2)) and II po, oral administration of paracetamol 1000mg (n=17; mean [SD] age, 48.29 [10.08] years; and BMI, 22.50 [2.92]kg/m(2). The plasma concentrations of paracetamol and its metabolite (glucuronide) were measured with the validated high-pressure liquid chromatography (HPLC) method with ultraviolet (UV) detection. The main pharmacokinetic parameters for paracetamol after iv and po administration to patients with CP were as follows: Cmax, 19.00 [4.50] and Cmax, 9.26 [3.35]μg/ml; AUC0-t, 42.37 [13.92] and 36.68 [11.7]μg×h/mL, respectively. After iv and po administration the AUC ratio between the metabolite (glucuronide) and paracetamol was enhanced. The research findings revealed that patients with chronic pancreatitis had lower concentrations of paracetamol. Therefore, it may be necessary to apply additional analgesic therapy. Moreover, we observed enhanced glucuronidation in our patients. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  11. Pharmacokinetics and brain penetration of carbapenems in mice.

    PubMed

    Matsumoto, Kazuaki; Kurihara, Yuji; Kuroda, Yuko; Hori, Seiji; Kizu, Junko

    2016-05-01

    An adverse effect associated with the administration of carbapenems is central nervous system (CNS) toxicity, with higher brain concentrations of carbapenems being linked to an increased risk of seizures. However, the pharmacokinetics and brain penetration of carbapenems have not yet been examined. Thus, the aim of this in vivo investigation was to determine the pharmacokinetics and brain penetration of carbapenems in mice. Blood samples and brain tissue samples were obtained 10, 20, 30, 60, and 120 min after the subcutaneous administration of carbapenems (91 mg/kg). We obtained the following values for the pharmacokinetic parameters of carbapenems in mice: 1.20-1.71 L/h/kg for CLtotal/F, 1.41-2.03 h(-1) for Ke, 0.34-0.51 h for T1/2, 0.66-0.95 L/kg for Vss/F, 0.49-0.73 h for MRT, 83.46-110.58 μg/mL for Cmax, plasma, and 0.28-0.83 μg/g for Cmax, brain tissue. The AUC0-∞ of the carbapenems tested in plasma were in the following order: doripenem > meropenem > biapenem > imipenem, and in brain tissue were: imipenem > doripenem > meropenem > biapenem. The degrees of brain tissue penetration, defined as the AUC0-∞, brain tissue/fAUC0-∞, plasma ratio, were 0.016 for imipenem, 0.004 for meropenem, 0.002 for biapenem, and 0.008 for doripenem. The results of the present study demonstrated that, of the carbapenems examined, imipenem penetrated brain tissue to the greatest extent. Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  12. Levofloxacin Pharmacokinetics and Pharmacodynamics in Patients with Severe Burn Injury

    PubMed Central

    Kiser, Tyree H.; Hoody, Dorie W.; Obritsch, Marilee D.; Wegzyn, Colleen O.; Bauling, Paulus C.; Fish, Douglas N.

    2006-01-01

    Levofloxacin pharmacokinetics were studied in 11 patients with severe burn injuries. Patients (values are means ± standard deviations; age, 41 ± 17 years; weight, 81 ± 12 kg; creatinine clearance, 114 ± 40 ml/min) received intravenous levofloxacin at 750 mg (n = 10 patients) or 500 mg (n = one patient) once daily. Blood samples were collected on day 1 of levofloxacin therapy; eight patients were studied again on days 4 to 6. The pharmacodynamic probability of target attainment (PTA) was evaluated by Monte Carlo simulation. Mean systemic clearance, half-life, and area under the concentration-time curve over 24 h after levofloxacin at 750 mg were 9.0 ± 3.2 liters/h, 7.8 ± 1.6 h, and 93 ± 31 mg · h/liter, respectively. There were no differences in pharmacokinetic parameters between day 1 and day 4; however, large intrapatient and interpatient variability was observed. Levofloxacin pharmacokinetics in burned patients were similar to those reported in other critically ill populations. Levofloxacin at 750 mg achieved >90% PTA for gram-negative and gram-positive pathogens with MICs of ≤0.5 μg/ml and MICs of ≤1 μg/ml, respectively. However, satisfactory PTA was not obtained with less-susceptible gram-negative organisms with MICs of 1 μg/ml or any organism with a MIC of ≥2 μg/ml. The results of this study indicate that levofloxacin should be administered at 750 mg/day for treatment of systemic infections in severely burned patients. However, even 750 mg/day may be inadequate for gram-negative organisms with MICs of 1 to 2 μg/ml even though they are defined as susceptible. Alternative antibiotics or treatment strategies should be considered for infections due to these pathogens. PMID:16723549

  13. Levofloxacin pharmacokinetics and pharmacodynamics in patients with severe burn injury.

    PubMed

    Kiser, Tyree H; Hoody, Dorie W; Obritsch, Marilee D; Wegzyn, Colleen O; Bauling, Paulus C; Fish, Douglas N

    2006-06-01

    Levofloxacin pharmacokinetics were studied in 11 patients with severe burn injuries. Patients (values are means +/- standard deviations; age, 41 +/- 17 years; weight, 81 +/- 12 kg; creatinine clearance, 114 +/- 40 ml/min) received intravenous levofloxacin at 750 mg (n = 10 patients) or 500 mg (n = one patient) once daily. Blood samples were collected on day 1 of levofloxacin therapy; eight patients were studied again on days 4 to 6. The pharmacodynamic probability of target attainment (PTA) was evaluated by Monte Carlo simulation. Mean systemic clearance, half-life, and area under the concentration-time curve over 24 h after levofloxacin at 750 mg were 9.0 +/- 3.2 liters/h, 7.8 +/- 1.6 h, and 93 +/- 31 mg . h/liter, respectively. There were no differences in pharmacokinetic parameters between day 1 and day 4; however, large intrapatient and interpatient variability was observed. Levofloxacin pharmacokinetics in burned patients were similar to those reported in other critically ill populations. Levofloxacin at 750 mg achieved >90% PTA for gram-negative and gram-positive pathogens with MICs of < or =0.5 microg/ml and MICs of < or =1 microg/ml, respectively. However, satisfactory PTA was not obtained with less-susceptible gram-negative organisms with MICs of 1 microg/ml or any organism with a MIC of > or =2 microg/ml. The results of this study indicate that levofloxacin should be administered at 750 mg/day for treatment of systemic infections in severely burned patients. However, even 750 mg/day may be inadequate for gram-negative organisms with MICs of 1 to 2 microg/ml even though they are defined as susceptible. Alternative antibiotics or treatment strategies should be considered for infections due to these pathogens.

  14. Formulation and Pharmacokinetic Evaluation of Polymeric Dispersions Containing Valsartan.

    PubMed

    Chella, Naveen; Daravath, Bhaskar; Kumar, Dinesh; Tadikonda, Rama Rao

    2016-10-01

    Valsartan exhibits poor aqueous solubility and dissolution rate limited absorption. The lower solubility in the upper part of gastrointestinal tract (pH-dependant solubility) where its absorption window exists further contributes to the low oral bioavailability of valsartan. The present work was aimed to improve the in vivo pharmacokinetics of valsartan by preparing amorphous polymeric dispersions using Eudragit E 100 as carrier. Eudragit E 100 is a cationic polymer soluble in gastric fluid up to pH 5.0 and exhibits pH-dependent release. Hence, the dispersions prepared using Eudragit E 100 rapidly dissolves at lower pH presenting drug in molecularly dispersed and soluble form at its absorption site. Polymeric solid dispersions were prepared in different drug-to-carrier ratios. The prepared dispersions were evaluated for drug-carrier interactions, solid-state transitions and drug-release properties with the help of Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and in vitro dissolution studies. The optimized formulation containing valsartan was tested in rats for bioavailability and pharmacokinetic parameters and compared with that of valsartan pure drug. The results from FTIR studies indicated no interactions between drug and excipients. DSC studies confirmed reduction in crystallinity of drug. The dissolution studies performed in 0.1 N HCl showed significant improvement (p < 0.05) in the dissolution of valsartan. In vivo pharmacokinetic studies showed 199 % relative bioavailability with significant improvement (p < 0.05) in area under the curve compared to valsartan pure drug. Eudragit E 100 can be used to improve the dissolution of drugs that show low solubility at lower pH and thereby enhancing the bioavailability.

  15. Pharmacokinetics of Epsilon-Aminocaproic Acid in Neonates

    PubMed Central

    Eaton, Michael P.; Alfieris, George M; Sweeney, Dawn M; Angona, Ronald E; Cholette, Jill M; Venuto, Charles; Anderson, Brian

    2016-01-01

    Background Antifibrinolytic medications such as epsilon-aminocaproic acid (EACA) are used in pediatric heart surgery to decrease surgical bleeding and transfusion. Dosing schemes for neonates are often based on adult regimens, or are simply empiric, in part due to the lack of neonatal pharmacokinetic information. We sought to determine the pharmacokinetics of EACA in neonates undergoing cardiac surgery and to devise a dosing regimen for this population. Methods Ten neonates undergoing cardiac surgery with cardiopulmonary bypass were given EACA according to standard practice, and blood was drawn at 10 time points to determine drug concentrations. Time-concentration profiles were analyzed using nonlinear mixed effects models. Parameter estimates (standardized to a 70 kg person) were used to develop a dosing regimen intended to maintain a target concentration shown to inhibit fibrinolysis in neonatal plasma (50 mg/L). Results Pharmacokinetics were described using a two compartment model plus an additional compartment for the cardiopulmonary bypass pump. First order elimination was described with a clearance of 5.07 L/h*(WT/70) 0.75. Simulation showed a dosing regimen with a loading dose of 40 mg/kg, and an infusion of 30 mg/kg/h, with a pump prime concentration of 100 mg/L maintained plasma concentrations above 50 mg/L in 90% of neonates during cardiopulmonary bypass surgery. Conclusions EACA clearance, expressed using allometry, is reduced in neonates compared to older children and adults. Loading dose and infusion dose are approximately half those required in children and adults. PMID:25723765

  16. Pharmacokinetics interaction between imatinib and genistein in rats.

    PubMed

    Wang, Zhe; Wang, Li; Xia, Meng-Ming; Sun, Wei; Huang, Cheng-Ke; Cui, Xiao; Hu, Guo-Xin; Lian, Qing-Quan; Wang, Zeng-Shou

    2015-01-01

    The objective of this work was to investigate the effect of orally administered genistein on the pharmacokinetics of imatinib and N-desmethyl imatinib in rats. Twenty-five healthy male SD (Sprague-Dawley) rats were randomly divided into five groups: A group (control group), B group (multiple dose of 100 mg/kg genistein for consecutive 15 days), C group (multiple dose of 50 mg/kg genistein for consecutive 15 days), D group (a single dose of 100 mg/kg genistein), and E group (a single dose of 50 mg/kg genistein). A single dose of imatinib is administered orally 30 min after administration of genistein (100 mg/kg or 50 mg/kg). The pharmacokinetic parameters of imatinib and N-desmethyl imatinib were calculated by DAS 3.0 software. The multiple dose of 100 mg/kg or 50 mg/kg genistein significantly (P < 0.05) decreased the AUC0-t and C max of imatinib. AUC0-t and the C max of N-desmethyl imatinib were also increased, but without any significant difference. However, the single dose of 100 mg/kg or 50 mg/kg genistein has no effect on the pharmacokinetics of imatinib and N-desmethyl imatinib. Those results indicated that multiple dose of genistein (100 mg/kg or 50 mg/kg) induces the metabolism of imatinib, while single dose of genistein has no effect.

  17. Individualized Hydrocodone Therapy Based on Phenotype, Pharmacogenetics, and Pharmacokinetic Dosing.

    PubMed

    Linares, Oscar A; Fudin, Jeffrey; Daly, Annemarie L; Boston, Raymond C

    2015-12-01

    (1) To quantify hydrocodone (HC) and hydromorphone (HM) metabolite pharmacokinetics with pharmacogenetics in CYP2D6 ultra-rapid metabolizer (UM), extensive metabolizer (EM), and poor metabolizer (PM) metabolizer phenotypes. (2) To develop an HC phenotype-specific dosing strategy for HC that accounts for HM production using clinical pharmacokinetics integrated with pharmacogenetics for patient safety. In silico clinical trial simulation. Healthy white men and women without comorbidities or history of opioid, or any other drug or nutraceutical use, age 26.3±5.7 years (mean±SD; range, 19 to 36 y) and weight 71.9±16.8 kg (range, 50 to 108 kg). CYP2D6 phenotype-specific HC clinical pharmacokinetic parameter estimates and phenotype-specific percentages of HM formed from HC. PMs had lower indices of HC disposition compared with UMs and EMs. Clearance was reduced by nearly 60% and the t1/2 was increased by about 68% compared with EMs. The canonical order for HC clearance was UM>EM>PM. HC elimination mainly by the liver, represented by ke, was reduced about 70% in PM. However, HC's apparent Vd was not significantly different among UMs, EMs, and PM. The canonical order of predicted plasma HM concentrations was UM>EM>PM. For each of the CYP2D6 phenotypes, the mean predicted HM levels were within HM's therapeutic range, which indicates HC has significant phenotype-dependent pro-drug effects. Our results demonstrate that pharmacogenetics afford clinicians an opportunity to individualize HC dosing, while adding enhanced opportunity to account for its conversion to HM in the body.

  18. Development of a simple chromatographic method for the determination of piracetam in human plasma and its pharmacokinetic evaluation.

    PubMed

    Barkat, K; Ahmad, M; Minhas, M U; Malik, M Z; Sohail, M

    2014-07-01

    The objective of study was to develop an accurate and reproducible HPLC method for determination of piracetam in human plasma and to evaluate pharmacokinetic parameters of 800 mg piracetam. A simple, rapid, accurate, precise and sensitive high pressure liquid chromatography method has been developed and subsequently validated for determination of piracetam. This study represents the results of a randomized, single-dose and single-period in 18 healthy male volunteers to assess pharmacokinetic parameters of 800 mg piracetam tablets. Various pharmacokinetic parameters were determined from plasma for piracetam and found to be in good agreement with previous reported values. The data was analyzed by using Kinetica® version 4.4 according to non-compartment model of pharmacokinetic analysis and after comparison with previous studies, no significant differences were found in present study of tested product. The major pharmacokinetic parameters for piracetam were as follows: t1/2 was (4.40 ± 0.179) h; Tmax value was (2.33 ± 0.105) h; Cmax was (14.53 ± 0.282) µg/mL; the AUC(0-∞) was (59.19 ± 4.402) µg · h/mL. AUMC(0-∞) was (367.23 ± 38.96) µg. (h)(2)/mL; Ke was (0.16 ± 0.006) h; MRT was (5.80 ± 0.227) h; Vd was (96.36 ± 8.917 L). A rapid, accurate and precise high pressure liquid chromatography method was developed and validated before the study. It is concluded that this method is very useful for the analysis of pharmacokinetic parameters, in human plasma and assured the safety and efficacy of piracetam, can be effectively used in medical practice. © Georg Thieme Verlag KG Stuttgart · New York.

  19. Influence of domperidone on pharmacokinetics, safety and tolerability of the dopamine agonist rotigotine

    PubMed Central

    Braun, Marina; Cawello, Willi; Boekens, Hilmar; Horstmann, Rolf

    2009-01-01

    AIMS To evaluate the influence of the antiemetic agent domperidone on steady-state pharmacokinetics, safety and tolerability of multiple-dose treatment of the transdermally applied non-ergolinic dopamine agonist rotigotine. METHODS Sixteen healthy male subjects (mean age 30.3 years) participated in a randomized, two-way crossover clinical trial. Treatment A consisted of transdermal rotigotine patch (2 mg (24 h)−1, 10 cm2, total drug content 4.5 mg) applied daily for 4 days, and concomitant oral domperidone (10 mg t.i.d.) for 5 days. For treatment B, subjects received only transdermal rotigotine treatment (daily for 4 days). Pharmacokinetic variables describing systemic exposure and renal elimination of rotigotine and metabolites, and safety and tolerability of the treatment were assessed. RESULTS The primary steady-state pharmacokinetic parameters (Cmax,ss and AUC(0–24),ss) were similar with or without co-administration of domperidone. Geometric mean ratios were close to 1 and respective 90% confidence intervals were within the acceptance range of bioequivalence (0.8, 1.25): Cmax,ss 0.96 (0.86, 1.08) and AUC(0–24),ss 0.97 (0.87, 1.08). tmax,ss, t1/2, secondary parameters calculated on days 4/5 after repeated patch application (Cmin,ss, Cave,ss, AUC(0–tz)) and renal elimination for unconjugated rotigotine and its metabolites were also similar with and without comedication of domperidone. A reduction in the dopaminergic side-effect nausea was seen with domperidone comedication. CONCLUSIONS No changes of pharmacokinetic parameters describing systemic exposure and renal elimination of rotigotine were observed when domperidone was administered concomitantly with rotigotine. The lack of pharmacokinetic interactions indicates that a dose adjustment of rotigotine transdermal patch is not necessary with concomitant use of domperidone. PMID:19094160

  20. Pharmacokinetics Application in Biophysics Experiments

    NASA Astrophysics Data System (ADS)

    Millet, Philippe; Lemoigne, Yves

    Among the available computerised tomography devices, the Positron Emission Tomography (PET) has the advantage to be sensitive to pico-molar concentrations of radiotracers inside living matter. Devices adapted to small animal imaging are now commercially available and allow us to study the function rather than the structure of living tissues by in vivo analysis. PET methodology, from the physics of electron-positron annihilation to the biophysics involved in tracers, is treated by other authors in this book. The basics of coincidence detection, image reconstruction, spatial resolution and sensitivity are discussed in the paper by R. Ott. The use of compartment analysis combined with pharmacokinetics is described here to illustrate an application to neuroimaging and to show how parametric imaging can bring insight on the in vivo bio-distribution of a radioactive tracer with small animal PET scanners. After reporting on the use of an intracerebral β+ radiosensitive probe (βP), we describe a small animal PET experiment used to measure the density of 5HT 1 a receptors in rat brain.

  1. Pharmacokinetics of Scopolamine Intranasal Gel Formulation (INSCOP) During Antiorthostatic Bedrest

    NASA Technical Reports Server (NTRS)

    Putcha, L.; Du, B.; Daniels, V.

    2010-01-01

    Space Motion Sickness (SMS) is experienced during early flight days of space missions and on reduced gravity simulation flights which require treatment with medications. Oral administration of scopolamine tablets is still a common practice to prevent SMS symptoms. Bioavailability of medications taken by mouth for SMS is often low and variable. Intranasal (IN) administration of medications has been reported to achieve higher and more reliable bioavailability than from an equivalent oral dose. In this FDA reviewed phase II clinical trial, we evaluated pharmacokinetics of an investigative new drug formulation, INSCOP during ambulatory (AMB) and antiorthostatic bedrest (HBR), a ground-based microgravity analog. Twelve subjects including 6 males and 6 females received 0.2 and 0.4 mg doses of INSCOP on separate days during AMB and ABR in a randomized, double blind cross over experimental design. Blood samples were collected at regular time intervals for 24 h post dose and analyzed for free scopolamine concentrations by an LC-MS-MS method. Pharmacokinetic parameters were calculated using concentration versus time data and compared between AMB and ABR conditions. Results indicated that maximum concentration and relative bioavailability increased marginally during ABR compared to AMB; differences in PK parameters between AMB and ABR were greater with 0.2 mg than with 0.4 mg dose. Gender specific differences in PK parameters was observed both during AMB and ABR with differences higher in females between the two conditions than in males. A significant observation is that while gender differences in PK appear to exist, the differences in primary PK parameters between AMB and ABR after IN administration, unlike oral administration, are minimal and may not be clinically significant for both genders.

  2. Population Pharmacokinetic-Pharmacodynamic Modeling of 5-Fluorouracil for Toxicities in Rats.

    PubMed

    Kobuchi, Shinji; Ito, Yukako; Sakaeda, Toshiyuki

    2017-08-01

    Myelosuppression is a dose-limiting toxicity of 5-fluorouracil (5-FU). Predicting the inter- and intra-patient variability in pharmacokinetics and toxicities of 5-FU may contribute to the individualized medicine. This study aimed to establish a population pharmacokinetic-pharmacodynamic model that could evaluate the inter- and intra-individual variability in the plasma 5-FU concentration, 5-FU-induced body weight loss and myelosuppression in rats. Plasma 5-FU concentrations, body weight loss, and blood cell counts in rats following the intravenous administration of various doses of 5-FU for 4 days were used to develop the population pharmacokinetic-pharmacodynamic model. The population pharmacokinetic model consisting of a two-compartment model with Michaelis-Menten elimination kinetics successfully characterized the individual and population predictions of the plasma concentration of 5-FU and provided credible parameter estimates. The estimates of inter-individual variability in maximal rate of saturable metabolism and residual variability were 8.1 and 22.0%, respectively. The population pharmacokinetic-pharmacodynamic model adequately described the individual complete time-course of alterations in body weight loss, erythrocyte, leukocyte, and lymphocyte counts in rats treated with various doses of 5-FU. The inter-individual variability of the drug effects in the pharmacodynamic model for body weight loss was 82.6%, which was relatively high. The results of the present study suggest that not only individual fluctuations in the 5-FU concentration but also the cell sensitivity would affect the onset and degree of 5-FU-induced toxicity. This population pharmacokinetic-pharmacodynamic model could evaluate the inter- and intra-individual variability in drug-induced toxicity and guide the assessments of novel anticancer agents in drug development.

  3. Pharmacokinetic properties of tandem d-peptides designed for treatment of Alzheimer's disease.

    PubMed

    Leithold, Leonie H E; Jiang, Nan; Post, Julia; Niemietz, Nicole; Schartmann, Elena; Ziehm, Tamar; Kutzsche, Janine; Shah, N Jon; Breitkreutz, Jörg; Langen, Karl-Josef; Willuweit, Antje; Willbold, Dieter

    2016-06-30

    Peptides are more and more considered for the development of drug candidates. However, they frequently exhibit severe disadvantages such as instability and unfavourable pharmacokinetic properties. Many peptides are rapidly cleared from the organism and oral bioavailabilities as well as in vivo half-lives often remain low. In contrast, some peptides consisting solely of d-enantiomeric amino acid residues were shown to combine promising therapeutic properties with high proteolytic stability and enhanced pharmacokinetic parameters. Recently, we have shown that D3 and RD2 have highly advantageous pharmacokinetic properties. Especially D3 has already proven promising properties suitable for treatment of Alzheimer's disease. Here, we analyse the pharmacokinetic profiles of D3D3 and RD2D3, which are head-to-tail tandem d-peptides built of D3 and its derivative RD2. Both D3D3 and RD2D3 show proteolytic stability in mouse plasma and organ homogenates for at least 24h and in murine and human liver microsomes for 4h. Notwithstanding their high affinity to plasma proteins, both peptides are taken up into the brain following i.v. as well as i.p. administration. Although both peptides contain identical d-amino acid residues, they are arranged in a different sequence order and the peptides show differences in pharmacokinetic properties. After i.p. administration RD2D3 exhibits lower plasma clearance and higher bioavailability than D3D3. We therefore concluded that the amino acid sequence of RD2 leads to more favourable pharmacokinetic properties within the tandem peptide, which underlines the importance of particular sequence motifs, even in short peptides, for the design of further therapeutic d-peptides. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Steady-state pharmacokinetics of (R)- and (S)-methadone in methadone maintenance patients

    PubMed Central

    Foster, David J R; Somogyi, Andrew A; Dyer, Kyle R; White, Jason M; Bochner, Felix

    2000-01-01

    Aims To investigate the steady-state pharmacokinetics of (R)- and (S)-methadone in a methadone maintenance population. Methods Eighteen patients recruited from a public methadone maintenance program underwent an interdosing interval pharmacokinetic study. Plasma and urine samples were collected and analysed for methadone and its major metabolite (EDDP) using stereoselective h.p.l.c. Methadone plasma protein binding was examined using ultrafiltration, and plasma α1-acid glycoprotein concentrations were quantified by radial immunoassay. Results (R)-methadone had a significantly (P < 0.05) greater unbound fraction (mean 173%) and total renal clearance (182%) compared with (S)-methadone, while maximum measured plasma concentrations (83%) and apparent partial clearance of methadone to EDDP (76%) were significantly (P < 0.001) lower. When protein binding was considered (R)-methadone plasma clearance of the unbound fraction (59%) and apparent partial intrinsic clearance to EDDP (44%) were significantly (P < 0.01) lower than for (S)-methadone, while AUCτSS, (167%) was significantly (P < 0.001) greater. There were no significant (P > 0.2) differences between the methadone enantiomers for AUCτSS, steady-state plasma clearance, trough plasma concentrations and unbound renal clearance. Patients excreted significantly (P < 0.0001) more (R)-methadone and (S)-EDDP than the corresponding enantiomers. Considerable interindividual variability was observed for the pharmacokinetic parameters, with coefficients of variation of up to 70%. Conclusions Steady-state pharmacokinetics of unbound methadone are stereoselective, and there is large interindividual variability consistent with CYP3A4 mediated metabolism to the major metabolite EDDP; the variability did not obscure a significant dose-plasma concentration relationship. Stereoselective differences in the pharmacokinetics of methadone may have important implications for pharmacokinetic-pharmacodynamic modelling but is unlikely to

  5. Effect of hepatic impairment on the pharmacokinetics of a single dose of cilostazol.

    PubMed

    Bramer, S L; Forbes, W P

    1999-01-01

    The pharmacokinetic profiles of cilostazol and its metabolites following a single oral dose of cilostazol 100 mg were compared between individuals with impaired and normal liver function. The study was conducted as a single-centre, open-label, single dose pharmacokinetic and tolerability trial. 12 patients with impaired and compensated liver function were compared with 12 volunteers with normal liver function. Participants in each group were matched for gender, age and weight. Of the 12 patients with hepatic impairment examined in this study, 10 had mild impairment (Child-Pugh class A) and 2 had moderate impairment (Child-Pugh class B). Blood and urine were collected up to 144 hours after drug administration. Pharmacokinetics were determined by noncompartmental methods. Protein binding did not differ between the groups (95.2% healthy volunteers, 94.6% hepatically impaired patients). Mean +/- SD unbound oral clearance of cilostazol decreased by 8.6% because of hepatic impairment (3380 +/- 1400 ml/min in healthy volunteers, 3260 +/- 2030 ml/min in hepatically impaired patients). Total urinary excretion of metabolites was significantly higher in healthy volunteers (26 vs 17% of dose). Overall, the pharmacokinetics of cilostazol and its metabolites, OPC-13213 and OPC-13015, were not substantially different in those with mild and moderate hepatic disease compared with values in healthy volunteers. Except for terminal-phase disposition half-life and apparent terminal-phase volume of distribution for cilostazol, the ratios of geometric means of pharmacokinetic parameters for plasma cilostazol, OPC-13213 and OPC-13015 in those with hepatic impairment versus healthy volunteers were close to 100%. Based on the results of the pharmacokinetic analysis, dose adjustment in patients with mild hepatic impairment is not necessary. However, caution should be exercised when cilostazol is administered to patients with moderate or severe hepatic impairment.

  6. Population Pharmacokinetics and Exploratory Pharmacodynamics of Lorazepam in Pediatric Status Epilepticus.

    PubMed

    Gonzalez, Daniel; Chamberlain, James M; Guptill, Jeffrey T; Cohen-Wolkowiez, Michael; Harper, Barrie; Zhao, Jian; Capparelli, Edmund V

    2017-08-01

    Lorazepam is one of the preferred agents used for intravenous treatment of status epilepticus (SE). We combined data from two pediatric clinical trials to characterize the population pharmacokinetics of intravenous lorazepam in infants and children aged 3 months to 17 years with active SE or a history of SE. We developed a population pharmacokinetic model for lorazepam using the NONMEM software. We then assessed exploratory exposure-response relationships using the overall efficacy and safety study endpoints, and performed dosing simulations. A total of 145 patients contributed 439 pharmacokinetic samples. The median (range) age and dose were 5.4 years (0.3-17.8) and 0.10 mg/kg (0.02-0.18), respectively. A two-compartment pharmacokinetic model with allometric scaling described the data well. In addition to total body weight (WT), younger age was associated with slightly higher weight-normalized clearance (CL). The following relationships characterized the typical values for the central compartment volume (V1), CL, peripheral compartment volume (V2), and intercompartmental CL (Q), using individual subject WT (kg) and age (years): V1 (L) = 0.879*WT; CL (L/h) = 0.115*(Age/4.7) 0.133 *WT 0.75 ; V2 (L) = 0.542*V1; Q (L/h) = 1.45*WT 0.75 . No pharmacokinetic parameters were associated with clinical outcomes. Simulations suggest uniform pediatric dosing (0.1 mg/kg, to a maximum of 4 mg) can be used to achieve concentrations of 50-100 ng/mL in children with SE, which have been previously associated with effective seizure control. The population pharmacokinetics of lorazepam were successfully described using a sparse sampling approach and a two-compartment model in pediatric patients with active SE.

  7. Compartmental Pharmacokinetics of the Antifungal Echinocandin Caspofungin (MK-0991) in Rabbits

    PubMed Central

    Groll, Andreas H.; Gullick, Bryan M.; Petraitiene, Ruta; Petraitis, Vidmantas; Candelario, Myrna; Piscitelli, Stephen C.; Walsh, Thomas J.

    2001-01-01

    The pharmacokinetics of the antifungal echinocandin-lipopeptide caspofungin (MK-0991) in plasma were studied in groups of three healthy rabbits after single and multiple daily intravenous administration of doses of 1, 3, and 6 mg/kg of body weight. Concentrations were measured by a validated high-performance liquid chromatography method and fitted into a three-compartment open pharmacokinetic model. Across the investigated dosage range, caspofungin displayed dose-independent pharmacokinetics. Following administration over 7 days, the mean peak concentration in plasma (Cmax) ± standard error of the mean increased from 16.01 ± 0.61 μg/ml at the 1-mg/kg dose to 105.52 ± 8.92 μg/ml at the 6-mg/kg dose; the mean area under the curve from 0 h to infinity rose from 13.15 ± 2.37 to 158.43 ± 15.58 μg · h/ml, respectively. The mean apparent volume of distribution at steady state (Vdss) was 0.299 ± 0.011 liter/kg at the 1-mg/kg dose and 0.351 ± 0.016 liter/kg at the 6-mg/kg dose (not significant [NS]). Clearance (CL) ranged from 0.086 ± 0.017 liter/kg/h at the 1-mg/kg dose to 0.043 ± 0.004 liter/kg/h at the 6-mg/kg dose (NS), and the mean terminal half-life was between 30 and 34 h (NS). Except for a trend towards an increased Vdss, there were no significant differences in pharmacokinetic parameters in comparison to those after single-dose administration. Caspofungin was well tolerated, displayed linear pharmacokinetics that fit into a three-compartment pharmacokinetic model, and achieved sustained concentrations in plasma that were multiple times in excess of reported MICs for susceptible opportunistic fungi. PMID:11158761

  8. Clinical Pharmacokinetics in Kidney Disease: Fundamental Principles.

    PubMed

    Lea-Henry, Tom N; Carland, Jane E; Stocker, Sophie L; Sevastos, Jacob; Roberts, Darren M

    2018-06-22

    Kidney disease is an increasingly common comorbidity that alters the pharmacokinetics of many drugs. Prescribing to patients with kidney disease requires knowledge about the drug, the extent of the patient's altered physiology, and pharmacokinetic principles that influence the design of dosing regimens. There are multiple physiologic effects of impaired kidney function, and the extent to which they occur in an individual at any given time can be difficult to define. Although some guidelines are available for dosing in kidney disease, they may be on the basis of limited data or not widely applicable, and therefore, an understanding of pharmacokinetic principles and how to apply them is important to the practicing clinician. Whether kidney disease is acute or chronic, drug clearance decreases, and the volume of distribution may remain the same or increase. Although in CKD, these changes progress relatively slowly, they are dynamic in AKI, and recovery is possible depending on the etiology and treatments. This, and the use of kidney replacement therapies further complicate attempts to quantify drug clearance at the time of prescribing and dosing in AKI. The required change in the dosing regimen can be estimated or even quantitated in certain instances through the application of pharmacokinetic principles to guide rational drug dosing. This offers an opportunity to provide personalized medical care and minimizes adverse drug events from either under- or overdosing. We discuss the principles of pharmacokinetics that are fundamental for the design of an appropriate dosing regimen in this review. Copyright © 2018 by the American Society of Nephrology.

  9. 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.

  10. Pharmacokinetics of dexmedetomidine administered to patients with end-stage renal failure and secondary hyperparathyroidism undergoing general anaesthesia.

    PubMed

    Zhong, W; Zhang, Y; Zhang, M-Z; Huang, X-H; Li, Y; Li, R; Liu, Q-W

    2018-06-01

    The primary objective of this study was to compare the pharmacokinetics of dexmedetomidine in patients with end-stage renal failure and secondary hyperparathyroidism with those in normal individuals. Fifteen patients with end-stage renal failure and secondary hyperparathyroidism (Renal-failure Group) and 8 patients with normal renal and parathyroid gland function (Control Group) received intravenous 0.6 μg/kg dexmedetomidine for 10 minutes before anaesthesia induction. Arterial blood samples for plasma dexmedetomidine concentration analysis were drawn at regular intervals after the infusion was stopped. The pharmacokinetics were analysed using a nonlinear mixed-effect model with NONMEM software. The statistical significance of covariates was examined using the objective function (-2 log likelihood). In the forward inclusion and backward deletion, covariates (age, weight, sex, height, lean body mass [LBM], body surface area [BSA], body mass index [BMI], plasma albumin and grouping factor [renal failure or not]) were tested for significant effects on pharmacokinetic parameters. The validity of our population model was also evaluated using bootstrap simulations. The dexmedetomidine concentration-time curves fitted best with the principles of a two-compartmental pharmacokinetic model. No covariate of systemic clearance further improved the model. The final pharmacokinetic parameter values were as follows: V 1  = 60.6 L, V 2  = 222 L, Cl 1  = 0.825 L/min and Cl 2  = 4.48 L/min. There was no influence of age, weight, sex, height, LBM, BSA, BMI, plasma albumin and grouping factor (renal failure or not) on pharmacokinetic parameters. Although the plasma albumin concentrations (35.46 ± 4.13 vs 44.10 ± 1.12 mmol/L, respectively, P < .05) and dosage of propofol were significantly lower in the Renal-failure Group than in the Control Group (81.68 ± 18.08 vs 63.07 ± 13.45 μg/kg/min, respectively, P < .05), there were no differences in the

  11. Rational Design of Glucose-Responsive Insulin Using Pharmacokinetic Modeling.

    PubMed

    Bakh, Naveed A; Bisker, Gili; Lee, Michael A; Gong, Xun; Strano, Michael S

    2017-11-01

    A glucose responsive insulin (GRI) is a therapeutic that modulates its potency, concentration, or dosing of insulin in relation to a patient's dynamic glucose concentration, thereby approximating aspects of a normally functioning pancreas. Current GRI design lacks a theoretical basis on which to base fundamental design parameters such as glucose reactivity, dissociation constant or potency, and in vivo efficacy. In this work, an approach to mathematically model the relevant parameter space for effective GRIs is induced, and design rules for linking GRI performance to therapeutic benefit are developed. Well-developed pharmacokinetic models of human glucose and insulin metabolism coupled to a kinetic model representation of a freely circulating GRI are used to determine the desired kinetic parameters and dosing for optimal glycemic control. The model examines a subcutaneous dose of GRI with kinetic parameters in an optimal range that results in successful glycemic control within prescribed constraints over a 24 h period. Additionally, it is demonstrated that the modeling approach can find GRI parameters that enable stable glucose levels that persist through a skipped meal. The results provide a framework for exploring the parameter space of GRIs, potentially without extensive, iterative in vivo animal testing. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Elucidation of arctigenin pharmacokinetics after intravenous and oral administrations in rats: integration of in vitro and in vivo findings via semi-mechanistic pharmacokinetic modeling.

    PubMed

    Gao, Qiong; Zhang, Yufeng; Wo, Siukwan; Zuo, Zhong

    2014-11-01

    Although arctigenin (AR) has attracted substantial research interests due to its promising and diverse therapeutic effects, studies regarding its biotransformation were limited. The current study aims to provide information regarding the pharmacokinetic properties of AR via various in vitro and in vivo experiments as well as semi-mechanistic pharmacokinetic modeling. Our in vitro rat microsome incubation studies revealed that glucuronidation was the main intestinal and liver metabolic pathway of AR, which occurred with V max, K m, and Clint of 47.5 ± 3.4 nmol/min/mg, 204 ± 22 μM, and 233 ± 9 μl/min/mg with intestinal microsomes and 2.92 ± 0.07 nmol/min/mg, 22.7 ± 1.2 μM, and 129 ± 4 μl/min/mg with liver microsomes, respectively. In addition, demethylation and hydrolysis of AR occurred with liver microsomes but not with intestinal microsomes. In vitro incubation of AR and its metabolites in intestinal content demonstrated that glucuronides of AR excreted in bile could be further hydrolyzed back to the parent compound, suggesting its potential enterohepatic circulation. Furthermore, rapid formation followed by fast elimination of arctigenic acid (AA) and arctigenin-4'-O-glucuronide (AG) was observed after both intravenous (IV) and oral administrations of AR in rats. Linear pharmacokinetics was observed at three different doses for AR, AA, and AG after IV administration of AR (0.48-2.4 mg/kg, r (2) > 0.99). Finally, an integrated semi-mechanistic pharmacokinetic model using in vitro enzyme kinetic and in vivo pharmacokinetic parameters was successfully developed to describe plasma concentrations of AR, AA, and AG after both IV and oral administration of AR at all tested doses.

  13. Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Modeling of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, in Support of Phase IIB Dose Selection.

    PubMed

    Namour, Florence; Diderichsen, Paul Matthias; Cox, Eugène; Vayssière, Béatrice; Van der Aa, Annegret; Tasset, Chantal; Van't Klooster, Gerben

    2015-08-01

    Filgotinib (GLPG0634) is a selective inhibitor of Janus kinase 1 (JAK1) currently in development for the treatment of rheumatoid arthritis and Crohn's disease. While less selective JAK inhibitors have shown long-term efficacy in treating inflammatory conditions, this was accompanied by dose-limiting side effects. Here, we describe the pharmacokinetics of filgotinib and its active metabolite in healthy volunteers and the use of pharmacokinetic-pharmacodynamic modeling and simulation to support dose selection for phase IIB in patients with rheumatoid arthritis. Two trials were conducted in healthy male volunteers. In the first trial, filgotinib was administered as single doses from 10 mg up to multiple daily doses of 200 mg. In the second trial, daily doses of 300 and 450 mg for 10 days were evaluated. Non-compartmental analysis was used to determine individual pharmacokinetic parameters for filgotinib and its metabolite. The overall pharmacodynamic activity for the two moieties was assessed in whole blood using interleukin-6-induced phosphorylation of signal-transducer and activator of transcription 1 as a biomarker for JAK1 activity. These data were used to conduct non-linear mixed-effects modeling to investigate a pharmacokinetic/pharmacodynamic relationship. Modeling and simulation on the basis of early clinical data suggest that the pharmacokinetics of filgotinib are dose proportional up to 200 mg, in agreement with observed data, and support that both filgotinib and its metabolite contribute to its pharmacodynamic effects. Simulation of biomarker response supports that the maximum pharmacodynamic effect is reached at a daily dose of 200 mg filgotinib. Based on these results, a daily dose range up to 200 mg has been selected for phase IIB dose-finding studies in patients with rheumatoid arthritis.

  14. Parameters for Pyrethroid Insecticide QSAR and PBPK/PD Models for Human Risk Assessment

    EPA Science Inventory

    This pyrethroid insecticide parameter review is an extension of our interest in developing quantitative structure–activity relationship–physiologically based pharmacokinetic/pharmacodynamic (QSAR-PBPK/PD) models for assessing health risks, which interest started with the organoph...

  15. Sleep and Alertness Management I: Pharmacokinetics of Hypnotics and Alertness Enhancers in Marmoset Monkeys (slaap- en alertheidsmanagement I: farmacokinetiek van slaap- en alertheidsverhogendemiddelen in marmosetapen)

    DTIC Science & Technology

    2006-10-01

    drugs. However, if these drugs are to be used in a novel animal model setting ( the marmoset), pharmacokinetics will be different and need to be re... pharmacokinetics are usually well- known for approved drugs. However, if these drugs are to be used in a novel animal model setting ( the marmoset...an adsorption phase and elimination phase. In Figure 7 the combined data of 30 mg/kg and repeated caffeine dosing was shown. Toxicokinetic parameters

  16. Calcium carbonate does not affect nilotinib pharmacokinetics in healthy volunteers.

    PubMed

    Tawbi, Hussein A; Tran, An L; Christner, Susan M; Lin, Yan; Johnson, Matthew; Mowrey, Emily; Appleman, Leonard R; Stoller, Ronald; Miller, Brian M; Egorin, Merrill J; Beumer, Jan H

    2013-11-01

    Gastric upset is a common side effect of nilotinib therapy, and calcium carbonate is frequently used concomitantly, either as antacid or as calcium supplementation. With the increasing number of oral agents in cancer therapy, oral drug-drug interactions are becoming more relevant. Nilotinib has already been shown to be absorbed to a much lesser extent when co-administered with proton pump inhibitors. Because exposure to sub-therapeutic concentrations of anticancer drugs such as nilotinib may result in selection of resistant clones and ultimately relapse, we studied the effect of a calcium carbonate supplement (Tums Ultra 1000®) on nilotinib pharmacokinetics. Calcium carbonate may be co-administered with nilotinib without significantly affecting the pharmacokinetics of nilotinib and potentially impacting efficacy. Nilotinib is a second-generation oral tyrosine kinase inhibitor with superior efficacy compared with imatinib mesylate in the treatment for chronic phase chronic myelogenous leukemia. Calcium carbonate is commonly used as a source of calcium supplementation or as antacid to ameliorate the gastrointestinal side effects associated with nilotinib, which could have unknown effects on nilotinib absorption. The purpose of this study was to provide information on the effect of calcium carbonate on the PK of nilotinib in healthy volunteers. Healthy subjects were enrolled in a two-period, open-label, single-institution, randomized, cross-over, fixed-schedule study. In one period, each subject received 400 mg of nilotinib p.o. In the other period, 4,000 mg of calcium carbonate (4 X Tums Ultra 1000®) was administered p.o. 15 min prior to the nilotinib dose. Plasma samples were collected at specified timepoints, concentrations of nilotinib were quantitated by LC-MS, and data were analyzed non-compartmentally. Eleven subjects were evaluable. Calcium supplementation did not significantly affect nilotinib pharmacokinetic parameters including area under the plasma

  17. Ocular pharmacokinetics and tolerability of bimatoprost ophthalmic solutions administered once or twice daily in rabbits, and clinical dosing implications

    PubMed Central

    Shen, Jie; Goodkin, Margot L; Tong, Warren; Attar, Mayssa

    2017-01-01

    Purpose Fixed-combination medications can benefit patients requiring multiple agents to lower their intraocular pressure (IOP), but combining agents with complementary mechanisms of action is challenging if their dosing frequency differs. This study compares in vivo pharmacokinetic and ocular tolerability of bimatoprost 0.01% ophthalmic solutions dosed once or twice daily. Reports of twice-daily dosing in glaucoma patients are also reviewed. Methods New Zealand White rabbits were administered bimatoprost 0.01% monotherapy or fixed-combination bimatoprost 0.01%/brimonidine 0.1%, once or twice daily in both eyes for 4 days. Ocular tissues were harvested and analyzed by liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters calculated included maximum observed concentration, time to maximum concentration, and area under the concentration-time curve. Results Due to extensive metabolism, bimatoprost concentration was below the quantitation limit by 1 hour post-dose in all samples. Bimatoprost acid exposure, however, could be measured up to 6–8 hours post-dose and was similar in the aqueous humor and iris-ciliary body (pharmacological site of action) of animals treated once or twice daily with either bimatoprost 0.01% or fixed-combination bimatoprost 0.01%/brimonidine 0.1%. Increasing dosage frequency in rabbits did not raise the incidence of drug-related conjunctival hyperemia (most common adverse event associated with bimatoprost use in humans), suggesting comparable ocular tolerability of the once- and twice-daily regimens for each formulation. Conclusion Bimatoprost 0.01% administered once or twice daily as monotherapy and in fixed-combination with brimonidine 0.1% in rabbits show similar pharmacokinetic profiles of bimatoprost acid, especially in the iris-ciliary body. Key findings from previous clinical studies suggest that by varying the concentration of benzalkonium chloride (a preservative with corneal penetration-enhancing properties

  18. Pharmacokinetics, pharmacodynamics and toxicology of theranostic nanoparticles

    NASA Astrophysics Data System (ADS)

    Kang, Homan; Mintri, Shrutika; Menon, Archita Venugopal; Lee, Hea Yeon; Choi, Hak Soo; Kim, Jonghan

    2015-11-01

    Nanoparticles (NPs) are considered a promising tool in both diagnosis and therapeutics. Theranostic NPs possess the combined properties of targeted imaging and drug delivery within a single entity. While the categorization of theranostic NPs is based on their structure and composition, the pharmacokinetics of NPs are significantly influenced by the physicochemical properties of theranostic NPs as well as the routes of administration. Consequently, altered pharmacokinetics modify the pharmacodynamic efficacy and toxicity of NPs. Although theranostic NPs hold great promise in nanomedicine and biomedical applications, a lack of understanding persists on the mechanisms of the biodistribution and adverse effects of NPs. To better understand the diagnostic and therapeutic functions of NPs, this review discusses the factors that influence the pharmacokinetics, pharmacodynamics and toxicology of theranostic NPs, along with several strategies for developing novel diagnostic and therapeutic modalities.

  19. Dose selection based on physiologically based pharmacokinetic (PBPK) approaches.

    PubMed

    Jones, Hannah M; Mayawala, Kapil; Poulin, Patrick

    2013-04-01

    Physiologically based pharmacokinetic (PBPK) models are built using differential equations to describe the physiology/anatomy of different biological systems. Readily available in vitro and in vivo preclinical data can be incorporated into these models to not only estimate pharmacokinetic (PK) parameters and plasma concentration-time profiles, but also to gain mechanistic insight into compound properties. They provide a mechanistic framework to understand and extrapolate PK and dose across in vitro and in vivo systems and across different species, populations and disease states. Using small molecule and large molecule examples from the literature and our own company, we have shown how PBPK techniques can be utilised for human PK and dose prediction. Such approaches have the potential to increase efficiency, reduce the need for animal studies, replace clinical trials and increase PK understanding. Given the mechanistic nature of these models, the future use of PBPK modelling in drug discovery and development is promising, however some limitations need to be addressed to realise its application and utility more broadly.

  20. Deferasirox pharmacokinetic evaluation in β-thalassaemia paediatric patients.

    PubMed

    Allegra, Sarah; Cusato, Jessica; De Francia, Silvia; Pirro, Elisa; Massano, Davide; Piga, Antonio; D'Avolio, Antonio

    2017-05-01

    Iron chelation in the transfusion-dependent anaemias management is essential to prevent end-organ damage and to improve survival. Deferasirox is a once-daily orally active tridentate selective iron chelator which pharmacokinetic disposition could influence treatment efficacy and toxicity. Therapeutic drug monitoring is an important tool for optimizing drug utilization and doses. A fully validated chromatographic method was used to quantify deferasirox concentration in plasma collected from paediatric patients with β-thalassaemia. Samples obtained after 5 days of washout or in naïve patients before and after 2, 4, 6 and 24 h drug administration were evaluated. Associations between variables were tested using the Pearson test. Twenty paediatric patients were enrolled; they were mainly men (13.65%), with median age of 6.35 years and body mass index of 15.45 kg/m 2 . Concerning pharmacokinetic parameters, a higher interindividual variability was shown. A positive, but not significant, correlation (r = 0.363; P = 0.115) was found between deferasirox area under the concentration curve over 24 h (AUC) and drug dose. Monitoring plasma deferasirox concentrations appears beneficial for guiding appropriate patient treatment, enhancing effectiveness and minimizing toxicity. © 2016 Royal Pharmaceutical Society.

  1. Pharmacokinetic model analysis of interaction between phenytoin and capecitabine.

    PubMed

    Miyazaki, Shohei; Satoh, Hiroki; Ikenishi, Masayuki; Sakurai, Miyuki; Ueda, Mutsuaki; Kawahara, Kaori; Ueda, Rie; Ohtori, Tohru; Matsuyama, Kenji; Miki, Akiko; Hori, Satoko; Fukui, Eiji; Nakatsuka, Eitaro; Sawada, Yasufumi

    2016-09-01

    Recent reports have shbown an increase in serum phenytoin levels resulting in phenytoin toxicity after initiation of luoropyrimidine chemotherapy. To prevent phenytoin intoxication, phenytoin dosage must be adjusted. We sought to develop a pharmacokinetic model of the interaction between phenytoin and capecitabine. We developed the phenytoin-capecitabine interaction model on the assumption that fluorouracil (5-FU) inhibits cytochrome P450 (CYP) 2C9 synthesis in a concentration- dependent manner. The plasma 5-FU concentration after oral administration of capecitabine was estimated using a conventional compartment model. Nonlinear pharmacokinetics of phenytoin was modeled by incorporating the Michaelis-Menten equation to represent the saturation of phenytoin metabolism. The resulting model was fitted to data from our previously-reported cases. The developed phenytoincapecitabine interaction model successfully described the profiles of serum phenytoin concentration in patients who received phenytoin and capecitabine concomitantly. The 50% inhibitory 5-FU concentration for CYP2C9 synthesis and the degradation rate constant of CYP2C9 were estimated to be 0.00310 ng/mL and 0.0768 day-1, respectively. This model and these parameters allow us to predict the appropriate phenytoin dosage schedule when capecitabine is administered concomitantly. This newly-developed model accurately describes changes in phenytoin concentration during concomitant capecitabine chemotherapy, and it may be clinically useful for predicting appropriate phenytoin dosage adjustments for maintaining serum phenytoin levels within the therapeutic range.

  2. Abnormal olanzapine toxicokinetic profiles--population pharmacokinetic analysis.

    PubMed

    Tylutki, Zofia; Jawień, Wojciech; Ciszowski, Krzysztof; Wilimowska, Jolanta; Anand, Jacek Sein

    2015-01-01

    Olanzapine is widely used in the treatment of schizophrenia and it is becoming more frequently responsible for overdoses. Standard pharmacokinetic models do not fit to the toxic concentration data. The aim of present study is to investigate the reasons for an abnormal olanzapine plasma concentration time curve in the range of toxic concentrations. Two hypotheses were verified: entering the enterohepatic cycle, and drug deposition and its desorption from activated charcoal used for gastrointestinal decontamination. One-hundred thirty-five plasma concentration data from 21 patients hospitalized for acute olanzapine poisoning were analyzed with the use of the population pharmacokinetic approach. A non-linear mixed-effects modeling approach with Monolix 4.3.1 was employed. A model assuming gallbladder emptying at irregular intervals was developed. Also, a model that describes desorption of olanzapine from the charcoal surface, in which the dose is divided into two absorbed fractions, was constructed. The analysis has found gastrointestinal decontamination and previous olanzapine treatment, as the significant covariates for toxicokinetic parameters of olanzapine. Our study provides interesting models for investigation of toxic concentration of olanzapine, which may also be used as the basis for further model development for other drugs as well. The investigated population was not large enough to reliably confirm any of the proposed models. It would be well worth continuing this study with more substantial data. Also, any additional information about olanzapine metabolite concentration could be vital.

  3. Pharmacokinetics of intravenous ketorolac in cats undergoing gonadectomy.

    PubMed

    Villa, R; Ravasio, G; Ferraresi, C; Zonca, A; Carli, S; Borghi, L; Cagnardi, P

    2015-05-01

    To determine the pharmacokinetics of ketorolac tromethamine (0.5 mg/kg) when administered I/V to cats undergoing gonadectomy. Ketorolac was administered to nine female and three male shorthair domestic cats as an I/V bolus of 0.5 mg/kg after intubation, and 20 minutes prior to ovariectomy or orchiectomy. Intra-operative cardiorespiratory variables were monitored and blood samples were collected over 24 hours. Concentrations of ketorolac in serum were determined by high-performance liquid chromatography to establish pharmacokinetic parameters. During surgery, mean end tidal isoflurane concentration was 1.63 (SD 0.24)% and normocapnia and spontaneous ventilation were maintained in all animals. The kinetics of ketorolac was described by a two-compartment model. The distribution and elimination half-lives were 0.09 (SD 0.06) and 4.14 (SD 1.18) hours, respectively. The body clearance was 56.8 (SD 33.1) mL/h/kg. The volume of distribution at steady-state and the mean residence time were 323.9 (SD 115.7) mL/kg and 6.47 (SD 2.86) hours, respectively. On the basis of the results, concentrations of ketorolac in serum in cats were above the human effective concentrations for 5-6 hours postoperatively. However, other studies including a control group are advocated to further investigate the ketorolac kinetics and the analgesic efficacy in this species.

  4. [Pharmacokinetic and clinical studies of flomoxef in the perinatal period].

    PubMed

    Matsuda, S; Hirayama, H; Oh, K; Tamate, K; Sengoku, K; Ishikawa, M; Shimizu, T; Haga, H; Hasegawa, T; Takada, H

    1993-07-01

    Pharmacokinetic and clinical studies on flomoxef (FMOX) in the perinatal period were carried out and following results were obtained 1. The pharmacokinetic parameter T1/2's of FMOX in maternal serum, umbilical cord serum and amniotic fluid in mothers after single intravenous injection of 1 g (n = 46) and 2 g (n = 34) were 1.11, 9.24, 9.24 hours and 2.54, 12.49, 12.49 hours, respectively. Cmax's and Tmax's of umbilical cord serum and amniotic fluid were 12.71, 11.77 micrograms/ml and 0.57, 3.35 hours upon single dose of 1 g i.v., and 35.17, 12.37 micrograms/ml and 0.32, 3.42 hours upon single dose of 2 g i.v., respectively. 2. Clinical usefulness were evaluated in 93 cases including were various infections in pregnancy and puerperal period. In pregnancy cases, clinical efficacy rate was 95.5% (21/22), and 100% in puerperal period. Bacteriological response rate was 84.6% (eradicated: 29, decreased: 4, unchanged: 2, replaced: 4 and unknown: 8 cases). No severe side effects nor clinical laboratory test results were observed in any cases. From above basic and clinical results, we conclude that FMOX is a useful and safe agent for various infections in pregnancy and puerperal period.

  5. Pharmacokinetics of theophylline: a dose-range study.

    PubMed Central

    Rovei, V; Chanoine, F; Strolin Benedetti, M

    1982-01-01

    1 Pharmacokinetics of theophylline were investigated in a group of healthy adult volunteers (non smokers and on xanthine-free diet) following single oral administration of 125, 250, 375 and 500 mg doses as tablets (Theodel). 2 Absorption of theophylline was rapid and followed first-order kinetics. Plasma curves were fitted according to a one compartment open model. 3 There was a linear relationship (P less than 0.001) between plasma Cmax or AUCx values and the administered dose. The analysis of variance showed that the pharmacokinetic parameters of theophylline (t1/2 abs, tmax, t1/2 beta, CL, CLR, Vd and F) were not modified at any dose. 4 Absorption of the drug was complete since the recovery in urine of theophylline (13.7 to 16.8% of the dose) and its major metabolites, 1,3-dimethyluric acid (35 to 42%), 1-methyluric acid (21.3 to 26.7%) and 3-methylxanthine (11.5 to 13.7%), accounted for the administered dose. Some impairment of demethylation to 3-methylxanthine was observed in two subjects, however the percentage of theophylline and its major metabolites excreted in urine was constant for all the four doses. 5 On the basis of these results, after single oral administration, elimination of theophylline followed first-order kinetics in the range of doses investigated (1.62 to 10.42 mg/kg). PMID:7150456

  6. Human pharmacokinetics of iohexol. A new nonionic contrast medium

    SciTech Connect

    Olsson, B.; Aulie, A.; Sveen, K.

    1983-03-01

    The pharmacokinetics of iohexol, a new nonionic, water-soluble contrast medium, have been determined after intravenous injection in 20 healthy volunteers, at four different dose levels (125-500 mg I/kg). The apparent volume of distribution was 0.27 1/kg, indicating distribution in the extracellular water. The biologic half-life was 121 minutes, comparable with that of other intravascular contrast media. Iohexol was excreted completely unmetabolized in the urine, with a 100% recovery 24 hours after injection. A comparison of iohexol and chromium-51 (/sup 51/Cr)-EDTA clearances indicates that iohexol is mainly excreted by glomerular filtration. The /sup 51/Cr-EDTA clearance was the same when injected separatelymore » and concomitantly with iohexol, indicating that glomerular filtration rate is not affected by iohexol. No dose dependency was observed in the investigated parameters t1/2 alpha, t1/2 beta, Vd, ClT or ClR. Iohexol pharmacokinetics are in correspondence with previously reported data on intravascular contrast media.« less

  7. A pharmacokinetic model of filgrastim and pegfilgrastim application in normal mice and those with cyclophosphamide-induced granulocytopaenia.

    PubMed

    Scholz, M; Ackermann, M; Engel, C; Emmrich, F; Loeffler, M; Kamprad, M

    2009-12-01

    Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is widely used as treatment for granulocytopaenia during cytotoxic chemotherapy; however, optimal scheduling of this pharmaceutical is unknown. Biomathematical models can help to pre-select optimal application schedules but precise pharmacokinetic properties of the pharmaceuticals are required at first. In this study, we have aimed to construct a pharmacokinetic model of G-CSF derivatives filgrastim and pegfilgrastim in mice. Healthy CD-1 mice and those with cyclophosphamide-induced granulocytopaenia were studied after administration of filgrastim and pegfilgrastim in different dosing and timing schedules. Close meshed time series of granulocytes and G-CSF plasma concentrations were determined. An ordinary differential equations model of pharmacokinetics was constructed on the basis of known mechanisms of drug distribution and degradation. Predictions of the model fit well with all experimental data for both filgrastim and pegfilgrastim. We obtained a unique parameter setting for all experimental scenarios. Differences in pharmacokinetics between filgrastim and pegfilgrastim can be explained by different estimates of model parameters rather than by different model mechanisms. Parameter estimates with respect to distribution and clearance of the drug derivatives are in agreement with qualitative experimental results. Dynamics of filgrastim and pegfilgrastim plasma levels can be explained by the same pharmacokinetic model but different model parameters. Beause of a strong clearance mechanism mediated by granulocytes, granulocytotic and granulocytopaenic conditions must be studied simultaneously to construct a reliable model. The pharmacokinetic model will be extended to a murine model of granulopoiesis under chemotherapy and G-CSF application.

  8. A PHARMACOKINETIC MODEL FOR ESTIMATING ...

    EPA Pesticide Factsheets

    Empirical evidence suggests that exposure of Americans to dioxin-like compounds was low during the early decades of the 20th century, then increased during the 1940s and 1950s reaching a peak in the 1960s and 1970s, and progressively decreased to lower levels in the 1980s and 1990s. Such evidence includes dioxin analysis of carbon-dated sediment cores of lakes and rivers, preserved meat samples from different decades of the 20th century, and limited body burden measurements of dioxin-like compounds. Pinsky and Lorber (1998) summarized studies measuring 2,3,7,8-TCDD in blood and adipose tissue finding a range of 10-20 pg/g (ppt) lipid during the 1970s, and 2-10 ppt lipid during the 1980s. This study reviews body burdens of dioxin toxic equivalents, TEQs, to find a range from about 50-80 ppt lipid during the 1970s, 30-50 ppt lipid during the 1980s, and 10-20 ppt lipid during the 1990s (TEQs comprised of the 17 dioxin and furan congeners only). Pinsky and Lorber (1998) investigated historical exposure trends for 2,3,7,8-TCDD by using a single-compartment, first-order pharmacokinetic model. The current study extends this prior effort by modeling dioxin TEQs instead of the single compound, 2,3,7,8-TCDD. TEQs are modeled as though they are a single compound, in contrast to an approach where the individual dioxin and furan congeners are modeled separately. It was found that body burdens of TEQs during the 1970s, 80s, and 90s could be modeled by assuming a histor

  9. Pharmacokinetic and pharmacogenetic markers of irinotecan toxicity.

    PubMed

    Hahn, Roberta Zilles; Antunes, Marina Venzon; Verza, Simone Gasparin; Perassolo, Magda Susana; Suyenaga, Edna Sayuri; Schwartsmann, Gilberto; Linden, Rafael

    2018-06-22

    Irinotecan (IRI) is a widely used chemotherapeutic drug, mostly used for first-line treatment of colorectal and pancreatic cancer. IRI doses are usually established based on patient's body surface area, an approach associated with large inter-individual variability in drug exposure and high incidence of severe toxicity. Toxic and therapeutic effects of IRI are also due to its active metabolite SN-38, reported to be up to 100 times more cytotoxic than IRI. SN-38 is detoxified by the formation of SN-38 glucuronide, through UGT1A1. Genetic polymorphisms in the UGT1A1 gene are associated to higher exposures to SN-38 and severe toxicity. Pharmacokinetic models to describe IRI and SN-38 kinetic profiles are available, with few studies exploring pharmacokinetic and pharmacogenetic-based dose individualization. The aim of this manuscript is to review the available evidence supporting pharmacogenetic and pharmacokinetic dose individualization of IRI in order to reduce the occurrence of severe toxicity during cancer treatment. The PubMed database was searched, considering papers published in the period from 1995-2017, using the keywords irinotecan, pharmacogenetics, metabolic genotyping, dose individualization, therapeutic drug monitoring, pharmacokinetics and pharmacodynamics, either alone or in combination, with original papers being selected based on the presence of relevant data. The findings of this review confirm the importance of considering individual patient characteristics to select IRI doses. Currently, the most straightforward approach for IRI dose individualization is UGT1A1 genotyping. However, this strategy is sub-optimal due to several other genetic and environmental contributions to the variable pharmacokinetics of IRI and its active metabolite. The use of dried blood spot sampling could allow the clinical application of complex sampling for the clinical use of limited sampling and population pharmacokinetic models for IRI doses individualization. Copyright

  10. Parameters of Technological Growth

    ERIC Educational Resources Information Center

    Starr, Chauncey; Rudman, Richard

    1973-01-01

    Examines the factors involved in technological growth and identifies the key parameters as societal resources and societal expectations. Concludes that quality of life can only be maintained by reducing population growth, since this parameter is the product of material levels, overcrowding, food, and pollution. (JR)

  11. A population pharmacokinetic analysis of the influence of nutritional status of digoxin in hospitalized Korean patients.

    PubMed

    Choi, Soo An; Yun, Hwi-yeol; Lee, Eun Sook; Shin, Wan Gyoon

    2014-03-01

    variability in digoxin pharmacokinetics and highlighted the relationship between pharmacokinetic parameters and nutritional status in hospitalized Korean patients. Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.

  12. Interactions of pharmacokinetic profile of different parts from Ginkgo biloba extract in rats.

    PubMed

    Guan, HanLiang; Qian, Dawei; Ren, Hao; Zhang, Wei; Nie, Hui; Shang, Erxing; Duan, Jinao

    2014-08-08

    Extracts from Ginkgo biloba L. leaves confer their therapeutic effects through the synergistic actions of flavonoid and terpenoid components, but some non-flavonoid and non-terpenoid components also exist in this extract. In the study of this paper, an investigation was carried out to compare the pharmacokinetic parameters of fourteen compounds to clarify the influences of non-flavonoid and non-terpenoid fraction (WEF) on the pharmacokinetics profile of the flavonoid fraction (FF) and the terpene lactone fraction (TLF) from Ginkgo biloba extracts. A selective and sensitive UPLC-MS/MS method was established to determine the plasma concentrations of the fourteen compounds to compare the pharmacokinetic parameters after orally administration of FF, TLF, FF-WEF, FF-TLF, TLF-WEF and FF-TLF-WEF with approximately the same dose. At different time points, the concentration of rutin (1), isoquercitrin (2), quercetin 3-O-[4-O-(-β-D-glucosyl)-α-L-rhamnoside] (3), ginkgolide C (4), bilobalide (5), quercitrin (6), ginkgolide B (7), ginkgolide A (8), luteolin (9), quercetin (10), apigenin (11), kaempferol (12), isorhamnetin (13), genkwanin (14) in rat plasma were determined and main pharmacokinetic parameters including T1/2, Tmax, Cmax and AUC were calculated using the DAS 3.2 software package. The statistical analysis was performed using the Student׳s t-test with P<0.05 as the level of significance. FF and WEF had no effect on the pharmacokinetic behaviors and parameters of the four terpene lactones, but the pharmacokinetic profiles and parameters of flavonoids changed while co-administered with non-flavonoid components. It was found that Cmax and AUC of six flavonoid aglycones in group FF-WEF, FF-TLF and FF-TLF-WEF had varying degrees of reduction in comparison with group FF, especially in group FF-TLF-WEF. On the contrary, the values of Cmax, Tmax and AUC of four flavonoid glycosides in group FF-TLF-WEF were significantly increased compared with those in group FF. These

  13. Population Pharmacokinetics of Atazanavir in Patients with Human Immunodeficiency Virus Infection▿

    PubMed Central

    Colombo, Sara ; Buclin, Thierry; Cavassini, Matthias; Décosterd, Laurent A.; Telenti, Amalio; Biollaz, Jérôme; Csajka, Chantal

    2006-01-01

    Atazanavir (ATV) is a new azapeptide protease inhibitor recently approved and currently used at a fixed dose of either 300 mg once per day (q.d.) in combination with 100 mg ritonavir (RTV) or 400 mg q.d. without boosting. ATV is highly bound to plasma proteins and extensively metabolized by CYP3A4. Since ATV plasma levels are highly variable and seem to be correlated with both viral response and toxicity, dosage individualization based on plasma concentration monitoring might be indicated. This study aimed to assess the ATV pharmacokinetic profile in a target population of HIV patients, to characterize interpatient and intrapatient variability, and to identify covariates that might influence ATV disposition. A population analysis was performed with NONMEM with 574 plasma samples from a cohort of 214 randomly selected patients receiving ATV. A total of 346 randomly collected ATV plasma levels and 19 full concentration-time profiles at steady state were available. The pharmacokinetic parameter estimates were an oral clearance (CL) of 12.9 liters/h (coefficient of variation [CV], 26%), a volume of distribution of 88.3 liters (CV, 29%), an absorption rate constant of 0.405 h−1 (CV, 122%), and a lag time of 0.88 h. A relative bioavailability value was introduced to account for undercompliance due to infrequent follow-ups (0.81; CV, 45%). Among the covariates tested, only RTV significantly reduced CL by 46%, thereby increasing the ATV elimination half-life from 4.6 h to 8.8 h. The pharmacokinetic parameters of ATV were adequately described by a one-compartment population model. The concomitant use of RTV improved the pharmacokinetic profile. However, the remaining high interpatient variability suggests the possibility of an impact of unmeasured covariates, such as genetic traits or environmental influences. This population pharmacokinetic model, together with therapeutic drug monitoring and Bayesian dosage adaptation, can be helpful in the selection and adaptation of

  14. Lack of a Pharmacokinetic Interaction Between Saxagliptin and Dapagliflozin in Healthy Subjects: A Randomized Crossover Study.

    PubMed

    Vakkalagadda, Blisse; Lubin, Susan; Reynolds, Laurie; Liang, Dan; Marion, Alan S; LaCreta, Frank; Boulton, David W

    2016-08-01

    This single-dose, open-label, randomized, 3-period, 3-treatment crossover drug-drug interaction study was conducted to evaluate differences in the pharmacokinetic properties of saxagliptin and dapagliflozin when coadministered. Healthy subjects (N = 42) were randomized to receive saxagliptin 5 mg alone, dapagliflozin 10 mg alone, or saxagliptin 5 mg plus dapagliflozin 10 mg coadministered; there was a washout period of ≥6 days between treatments. Serial blood samples for determining saxagliptin, 5-hydroxy saxagliptin (5-OH saxagliptin; major active metabolite) and dapagliflozin plasma concentrations and pharmacokinetic parameters were collected before and up to 60 hours after the dose. No interaction was to be concluded if the 90% CIs for the geometric mean ratios of the combination compared with each drug given alone for Cmax and AUCinf were within 0.80 to 1.25. The results indicated that dapagliflozin had no effect on the pharmacokinetic properties of saxagliptin, 5-OH saxagliptin, or saxagliptin total active moiety and vice versa. The 90% CIs for Cmax and AUCinf for all comparisons were contained entirely within the 0.80 to 1.25 equivalence intervals. Other pharmacokinetic parameters (apparent oral clearance or half-life) of saxagliptin or dapagliflozin were similar when each medicine was administered alone or when coadministered. No safety profile or tolerability findings of concern were observed during the study. All adverse events were mild, and no serious adverse events were reported. These data indicate that coadministration of saxagliptin and dapagliflozin exhibits no pharmacokinetic interaction and is well tolerated. ClinicalTrials.gov identifier: NCT01662999. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

  15. Towards a generic procedure for the detection of relevant contaminants from waste electric and electronic equipment (WEEE) in plastic food-contact materials: a review and selection of key parameters.

    PubMed

    Puype, Franky; Samsonek, Jiří; Vilímková, Věra; Kopečková, Šárka; Ratiborská, Andrea; Knoop, Jan; Egelkraut-Holtus, Marion; Ortlieb, Markus; Oppermann, Uwe

    2017-10-01

    Recently, traces of brominated flame retardants (BFRs) have been detected in black plastic food-contact materials (FCMs), indicating the presence of recycled plastics, mainly coming from waste electric and electronic equipment (WEEE) as BFRs are one of the main additives in electric applications. In order to evaluate efficiently and preliminary in situ the presence of WEEE in plastic FCMs, a generic procedure for the evaluation of WEEE presence in plastic FCMs by using defined parameters having each an associated importance level has been proposed. This can be achieved by combining parameters like overall bromine (Br) and antimony (Sb) content; additive and reactive BFR, rare earth element (REE) and WEEE-relevant elemental content and additionally polymer purity. In most of the cases, the WEEE contamination could be confirmed by combining X-ray fluorescence (XRF) spectrometry and thermal desorption/pyrolysis gas chromatography-mass spectrometry (GC-MS) at first. The Sb and REE content did not give a full confirmation as to the source of contamination, however for Sb the opposite counts: Sb was joined with elevated Br signals. Therefore, Br at first followed by Sb were used as WEEE precursors as both elements are used as synergetic flame-retardant systems. WEEE-specific REEs could be used for small WEEE (sWEEE) confirmation; however, this parameter should be interpreted with care. The polymer purity by Fourier-transform infrared spectrometer (FTIR) and pyrolysis GC-MS in many cases could not confirm WEEE-specific contamination; however, it can be used for purity measurements and for the suspicion of the usage of recycled fractions (WEEE and non-WEEE) as a third-line confirmation. To the best of our knowledge, the addition of WEEE waste to plastic FCMs is illegal; however, due to lack on screening mechanisms, there is still the breakthrough of such articles onto the market, and, therefore, our generic procedure enables the quick and effective screening of suspicious

  16. Pharmacokinetic study of single- and multiple-dosing with metolazone tablets in healthy Chinese population.

    PubMed

    Li, Xueqing; Wang, Rutao; Liu, Yang; Liu, Yun; Zheng, Heng; Feng, Yabo; Zhao, Na; Geng, Hongbin; Zhang, Wanzhi; Wen, Aidong

    2017-11-16

    Metolazone is a diuretic, saluretic and antihypertensive chemical compound from the quinazoline category that possesses medicinal features similar to those of other thiazide diuretic drugs. However, the pharmacokinetics of metolazone in the Chinese population has rarely been studied. This study aimed to examine the pharmacokinetic characteristics, safety characteristic, and tolerability of metolazone in healthy Chinese subjects after single and multiple doses taken orally as well as the effects that food and gender have on oral metolazone pharmacokinetic parameters. An open-label, randomized, and single- and multiple-dosing investigation was performed in healthy Chinese subjects. The investigation included 3 study groups: the 0.5 mg, 1 mg and 2 mg dose groups were the single-dose study groups in the first stage. Eligible volunteers were randomly and orally administered a single 0.5 mg, 1 mg, or 2 mg metolazone tablet. The 0.5 mg dose group was also part of the multiple-dose study group, and the 1 mg dose group was the food-effect study group in the second stage. Human plasma samples were gathered pre-dosing and up to 48 h after dosing. The human plasma sample concentration of metolazone was quantified using a validated liquid chromatography tandem mass spectrometry method. Pharmacokinetic data were calculated by a noncompartmental analysis method using WinNonlin version 6.4. Tolerability was evaluated based on adverse events, medical examination, 12-lead ECG, and other clinical laboratory exams. Thirty eligible subjects (15 men and 15 women) were registered in our investigation and completed all of the study stages. The AUC and C max showed dose proportionality after a single dose based on the linear-regression analysis. A comparison of the pharmacokinetic data revealed that the differences between the male and female groups were not statistically significant. The t max of metolazone was increased by approximately 100% in the fed condition. Metolazone was

  17. Clinical efficacy and pharmacokinetics of carprofen in the treatment of dogs with osteoarthritis.

    PubMed

    Lipscomb, V J; AliAbadi, F S; Lees, P; Pead, M J; Muir, P

    2002-06-01

    Six medium to large breed dogs with osteoarthritis were treated with 2 mg/kg of racemic carprofen, mixed with their morning feed, daily for 28 days. The treatment significantly (P < 0.01) reduced their mean lameness score, measured on a visual analogue scale, and there was a trend (P = 0.11) for the peak vertical forces exerted on a forceplate to be increased in the most severely affected limb. The plasma concentration-time relationships of the S(+) and R(-) enantiomers were studied for 24 hours after the first dose and after seven days and 28 days. There were no significant differences between the mean pharmacokinetic parameters measured on the three occasions, suggesting that carprofen was not accumulated and that tolerance to the drug did not develop. Although the pharmacokinetic parameters of the S(+) and R(-) enantiomers were generally very similar, there were wide variations both between and within dogs.

  18. Accelerated pharmacokinetic map determination for dynamic contrast enhanced MRI using frequency-domain based Tofts model.

    PubMed

    Vajuvalli, Nithin N; Nayak, Krupa N; Geethanath, Sairam

    2014-01-01

    Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) is widely used in the diagnosis of cancer and is also a promising tool for monitoring tumor response to treatment. The Tofts model has become a standard for the analysis of DCE-MRI. The process of curve fitting employed in the Tofts equation to obtain the pharmacokinetic (PK) parameters is time-consuming for high resolution scans. Current work demonstrates a frequency-domain approach applied to the standard Tofts equation to speed-up the process of curve-fitting in order to obtain the pharmacokinetic parameters. The results obtained show that using the frequency domain approach, the process of curve fitting is computationally more efficient compared to the time-domain approach.

  19. Pharmacokinetics in Morbid Obesity: Influence of Two Bariatric Surgery Techniques on Paracetamol and Caffeine Metabolism.

    PubMed

    Goday Arno, Albert; Farré, Magí; Rodríguez-Morató, Jose; Ramon, Jose M; Pérez-Mañá, Clara; Papaseit, Esther; Civit, Ester; Langohr, Klaus; Lí Carbó, Marcel; Boix, David Benaiges; Nino, Olga Castañer; Le Roux, Juana Antonia Flores; Pera, Manuel; Grande, Luis; de la Torre, Rafael

    2017-12-01

    The purpose of the study was to study the impact of the two