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Sample records for exposure translating pharmacokinetics

  1. Pharmacogenetics of Statin-Induced Myopathy: A Focused Review of the Clinical Translation of Pharmacokinetic Genetic Variants

    PubMed Central

    Talameh, Jasmine A; Kitzmiller, Joseph P

    2014-01-01

    Statins are the most commonly prescribed drugs in the United States and are extremely effective in reducing major cardiovascular events in the millions of Americans with hyperlipidemia. However, many patients (up to 25%) cannot tolerate or discontinue statin therapy due to statin-induced myopathy (SIM). Patients will continue to experience SIM at unacceptably high rates or experience unnecessary cardiovascular events (as a result of discontinuing or decreasing their statin therapy) until strategies for predicting or mitigating SIM are identified. A promising strategy for predicting or mitigating SIM is pharmacogenetic testing, particularly of pharmacokinetic genetic variants as SIM is related to statin exposure. Data is emerging on the association between pharmacokinetic genetic variants and SIM. A current, critical evaluation of the literature on pharmacokinetic genetic variants and SIM for potential translation to clinical practice is lacking. This review focuses specifically on pharmacokinetic genetic variants and their association with SIM clinical outcomes. We also discuss future directions, specific to the research on pharmacokinetic genetic variants, which could speed the translation into clinical practice. For simvastatin, we did not find sufficient evidence to support the clinical translation of pharmacokinetic genetic variants other than SLCO1B1. However, SLCO1B1 may also be clinically relevant for pravastatin- and pitavastatin-induced myopathy, but additional studies assessing SIM clinical outcome are needed. CYP2D6*4 may be clinically relevant for atorvastatin-induced myopathy, but mechanistic studies are needed. Future research efforts need to incorporate statin-specific analyses, multi-variant analyses, and a standard definition of SIM. As the use of statins is extremely common and SIM continues to occur in a significant number of patients, future research investments in pharmacokinetic genetic variants have the potential to make a profound impact on

  2. Reconstructing Exposures from Biomarkers using Exposure-Pharmacokinetic Modeling - A Case Study with Carbaryl

    EPA Science Inventory

    Sources of uncertainty involved in exposure reconstruction for a short half-life chemical, carbaryl, were characterized using the Cumulative and Aggregate Risk Evaluation System (CARES), an exposure model, and a human physiologically based pharmacokinetic (PBPK) model. CARES was...

  3. TOLUENE EXPERIMENTAL EXPOSURES IN HUMANS: PHARMACOKINETICS AND BEHAVIOR

    EPA Science Inventory

    Toluene Experimental Exposures in Humans:
    Pharmacokinetics and Behavioral Effects
    (Ongoing Research)

    Vernon A. Benignus1, Philip J. Bushnell2 and William K. Boyes2

    Human subjects will be exposed to 250 and 500 ppm toluene for one hour in the Human St...

  4. Biodistribution and translational pharmacokinetic modeling of a human recombinant alkaline phosphatase.

    PubMed

    Peters, Esther; Stevens, Jasper; Arend, Jacques; Guan, Zheng; Raaben, Willem; Laverman, Peter; van Elsas, Andrea; Masereeuw, Rosalinde; Pickkers, Peter

    2015-11-10

    Clinical trials showed renal protective effects of bovine intestinal alkaline phosphatase (AP) in patients with sepsis-associated acute kidney injury (AKI). Subsequently, a human recombinant chimeric AP (recAP) was developed as a pharmaceutically acceptable alternative. Here, we investigated the biodistribution and pharmacokinetics (PK) of recAP and developed a translational population PK model. Biodistribution was studied during LPS-induced AKI in rats. Iodine-125-labeled recAP was primarily taken up by liver, spleen, adrenals, heart, lungs and kidneys followed by the gastro-intestinal tract and thyroid. Tissue distribution was not critically affected by endotoxemia. PK parameters were determined in rats and minipigs during IV bolus injections of recAP, administered once, or once daily during seven consecutive days. Plasma concentrations of recAP increased with increasing dose and disappeared in a biphasic manner. Exposure to recAP, estimated by AUC and Cmax, was similar on days 1 and 7. Subsequently, population approach nonlinear mixed effects modeling was performed with recAP rat and minipig and biAP phase I PK data. Concentration versus time data was accurately described in all species by a two-compartmental model with allometric scaling based on body weight. This model provides a solid foundation for determining the optimal dose and duration of first-in-man recAP studies. PMID:26325308

  5. A Translatable Predictor of Human Radiation Exposure

    PubMed Central

    Suchindran, Sunil; Nakamura, Mai; Chao, Nelson J.; Himburg, Heather; Minor, Kerry; Phillips, Gary; Ross, Joel; Abedi, Majid; Terbrueggen, Robert; Chute, John P.

    2014-01-01

    Terrorism using radiological dirty bombs or improvised nuclear devices is recognized as a major threat to both public health and national security. In the event of a radiological or nuclear disaster, rapid and accurate biodosimetry of thousands of potentially affected individuals will be essential for effective medical management to occur. Currently, health care providers lack an accurate, high-throughput biodosimetric assay which is suitable for the triage of large numbers of radiation injury victims. Here, we describe the development of a biodosimetric assay based on the analysis of irradiated mice, ex vivo-irradiated human peripheral blood (PB) and humans treated with total body irradiation (TBI). Interestingly, a gene expression profile developed via analysis of murine PB radiation response alone was inaccurate in predicting human radiation injury. In contrast, generation of a gene expression profile which incorporated data from ex vivo irradiated human PB and human TBI patients yielded an 18-gene radiation classifier which was highly accurate at predicting human radiation status and discriminating medically relevant radiation dose levels in human samples. Although the patient population was relatively small, the accuracy of this classifier in discriminating radiation dose levels in human TBI patients was not substantially confounded by gender, diagnosis or prior exposure to chemotherapy. We have further incorporated genes from this human radiation signature into a rapid and high-throughput chemical ligation-dependent probe amplification assay (CLPA) which was able to discriminate radiation dose levels in a pilot study of ex vivo irradiated human blood and samples from human TBI patients. Our results illustrate the potential for translation of a human genetic signature for the diagnosis of human radiation exposure and suggest the basis for further testing of CLPA as a candidate biodosimetric assay. PMID:25255453

  6. Eravacycline Pharmacokinetics and Challenges in Defining Humanized Exposure In Vivo.

    PubMed

    Thabit, Abrar K; Monogue, Marguerite L; Nicolau, David P

    2016-08-01

    We assessed the pharmacokinetic profile of eravacycline, a novel antibiotic of the tetracycline class, and determined the dose in an immunocompetent murine thigh infection model that would provide free-drug exposure similar to that observed in humans after the administration of 1 mg/kg intravenously (i.v.) every 12 h (q12h). Eravacycline demonstrated a nonlinear protein-binding profile. The 2.5-mg/kg i.v. q12h dose in mice resulted in an area under the concentration-time curve for the free, unbound fraction of the drug of 1.64 mg · h/liter, which closely resembles the human exposure level. PMID:27353264

  7. USE OF PHARMACOKINETIC MODELS TO ASSESS OCCUPATIONAL AND RESIDENTIAL PESTICIDE EXPOSURE

    EPA Science Inventory

    Urinary biomarker measurements were analyzed using a dynamic pharmacokinetic model. The dynamic model provided the structure to link spot urine samples with corresponding exposure and absorbed dose. Data from both occupational and residential studies were analyzed. In the Agri...

  8. Emerging Insights for Translational Pharmacokinetic and Pharmacokinetic-Pharmacodynamic Studies: Towards Prediction of Nose-to-Brain Transport in Humans.

    PubMed

    Ruigrok, Mitchel J R; de Lange, Elizabeth C M

    2015-05-01

    To investigate the potential added value of intranasal drug administration, preclinical studies to date have typically used the area under the curve (AUC) in brain tissue or cerebrospinal fluid (CSF) compared to plasma following intranasal and intravenous administration to calculate measures of extent like drug targeting efficiencies (%DTE) and nose-to-brain transport percentages (%DTP). However, CSF does not necessarily provide direct information on the target site concentrations, while total brain concentrations are not specific to that end either as non-specific binding is not explicitly considered. Moreover, to predict nose-to-brain transport in humans, the use of descriptive analysis of preclinical data does not suffice. Therefore, nose-to-brain research should be performed translationally and focus on preclinical studies to obtain specific information on absorption from the nose, and distinguish between the different transport routes to the brain (absorption directly from the nose to the brain, absorption from the nose into the systemic circulation, and distribution between the systemic circulation and the brain), in terms of extent as well as rate. This can be accomplished by the use of unbound concentrations obtained from plasma and brain, with subsequent advanced mathematical modeling. To that end, brain extracellular fluid (ECF) is a preferred sampling site as it represents most closely the site of action for many targets. Furthermore, differences in nose characteristics between preclinical species and humans should be considered. Finally, pharmacodynamic measurements that can be obtained in both animals and humans should be included to further improve the prediction of the pharmacokinetic-pharmacodynamic relationship of intranasally administered CNS drugs in humans. PMID:25693488

  9. Reconstructing exposures from biomarkers using exposure-pharmacokinetic modeling--A case study with carbaryl.

    PubMed

    Brown, Kathleen; Phillips, Martin; Grulke, Christopher; Yoon, Miyoung; Young, Bruce; McDougall, Robin; Leonard, Jeremy; Lu, Jingtao; Lefew, William; Tan, Yu-Mei

    2015-12-01

    Sources of uncertainty involved in exposure reconstruction for short half-life chemicals were characterized using computational models that link external exposures to biomarkers. Using carbaryl as an example, an exposure model, the Cumulative and Aggregate Risk Evaluation System (CARES), was used to generate time-concentration profiles for 500 virtual individuals exposed to carbaryl. These exposure profiles were used as inputs into a physiologically based pharmacokinetic (PBPK) model to predict urinary biomarker concentrations. These matching dietary intake levels and biomarker concentrations were used to (1) compare three reverse dosimetry approaches based on their ability to predict the central tendency of the intake dose distribution; and (2) identify parameters necessary for a more accurate exposure reconstruction. This study illustrates the trade-offs between using non-iterative reverse dosimetry methods that are fast, less precise and iterative methods that are slow, more precise. This study also intimates the necessity of including urine flow rate and elapsed time between last dose and urine sampling as part of the biomarker sampling collection for better interpretation of urinary biomarker data of short biological half-life chemicals. Resolution of these critical data gaps can allow exposure reconstruction methods to better predict population-level intake doses from large biomonitoring studies. PMID:26545325

  10. EFFECT OF ROUTE AND PATTERN OF EXPOSURE ON THE PHARMACOKINETICS AND ACUTE HEPATOTOXICITY OF CARBON TETRACHLORIDE

    EPA Science Inventory

    The objectives of this study were to evaluate the influence of both route and pattern of exposure on the pharmacokinetics and target organ toxicity of a common VOC, carbon tetrachloride (CCl4). ale Sprague-Dawley rats, 325-275 g, inhaled 100 or 1,000 ppm CCl4 for 2 hr through a o...

  11. Pharmacokinetics in Drug Discovery: An Exposure-Centred Approach to Optimising and Predicting Drug Efficacy and Safety.

    PubMed

    Reichel, Andreas; Lienau, Philip

    2016-01-01

    The role of pharmacokinetics (PK) in drug discovery is to support the optimisation of the absorption, distribution, metabolism and excretion (ADME) properties of lead compounds with the ultimate goal to attain a clinical candidate which achieves a concentration-time profile in the body that is adequate for the desired efficacy and safety profile. A thorough characterisation of the lead compounds aiming at the identification of the inherent PK liabilities also includes an early generation of PK/PD relationships linking in vitro potency and target exposure/engagement with expression of pharmacological activity (mode-of-action) and efficacy in animal studies. The chapter describes an exposure-centred approach to lead generation, lead optimisation and candidate selection and profiling that focuses on a stepwise generation of an understanding between PK/exposure and PD/efficacy relationships by capturing target exposure or surrogates thereof and cellular mode-of-action readouts in vivo. Once robust PK/PD relationship in animal PD models has been constructed, it is translated to anticipate the pharmacologically active plasma concentrations in patients and the human therapeutic dose and dosing schedule which is also based on the prediction of the PK behaviour in human as described herein. The chapter outlines how the level of confidence in the predictions increases with the level of understanding of both the PK and the PK/PD of the new chemical entities (NCE) in relation to the disease hypothesis and the ability to propose safe and efficacious doses and dosing schedules in responsive patient populations. A sound identification of potential drug metabolism and pharmacokinetics (DMPK)-related development risks allows proposing of an effective de-risking strategy for the progression of the project that is able to reduce uncertainties and to increase the probability of success during preclinical and clinical development. PMID:26330260

  12. Explicit Pharmacokinetic Modeling: Tools for Documentation, Verification, and Portability

    EPA Science Inventory

    Quantitative estimates of tissue dosimetry of environmental chemicals due to multiple exposure pathways require the use of complex mathematical models, such as physiologically-based pharmacokinetic (PBPK) models. The process of translating the abstract mathematics of a PBPK mode...

  13. Pharmacokinetics of nicotine in rats after multiple-cigarette smoke exposure

    SciTech Connect

    Rotenberg, K.S.; Adir, J.

    1983-06-15

    The pharmacokinetics of nicotine and its major metabolites was evaluated in male rats after multiple-cigarette smoke exposure. A smoke-exposure apparatus was used to deliver cigarette smoke to the exposure chamber. The rats were exposed to smoke from a single cigarette every 8 hr for 14 days and to the smoke of a cigarette spiked with radiolabeled nicotine on the 15th day. Blood and urine samples were collected at timed intervals during the 10-min smoke-exposure period of the last cigarette and up to 48 hr thereafter. Nicotine, cotinine, and other polar metabolites were separated by thin-layer chromatography and quantified by liquid scintillation counting. The data were analyzed by computer fitting, and the derived pharmacokinetic parameters were compared to those observed after a single iv injection of nicotine and after a single-cigarette smoke exposure. The results indicated that the amount of nicotine absorbed from multiple-cigarette smoke was approximately 10-fold greater than that absorbed from a single cigarette. Also, unlike the single-cigarette smoke exposure experiment, nicotine plasma levels did not decay monotonically but increased after the 5th hr, and high plasma concentrations persisted for 30 hr. The rate and extent of the formation of cotinine, the major metabolite of nicotine, were decreased as compared with their values following a single-cigarette smoke exposure. It was concluded that nicotine or a constituent of tobacco smoke inhibits the formation of cotinine and may affect the biotransformation of other metabolites. Urinary excretion tended to support the conclusions that the pharmacokinetic parameters of nicotine and its metabolites were altered upon multiple as compared to single dose exposure.

  14. Physiologically-based pharmacokinetic (PBPK) models in human exposure assessment

    SciTech Connect

    Krishnan, K.

    1995-12-31

    The potential dose received by an individual during defined exposure situations can be determined using personal dosimeters or estimated by combining information on exposure scenarios with the environmental concentration (C.) of chemicals. With the latter approach, not only the potential dose but also the internal dose (i.e., amount of chemical that has been absorbed and available for interaction with receptors) and biologically-effective dose (i.e., amount of chemical that actually reaches the cellular sites where interaction with macromolecules occur) can be estimated if C. is provided as an input to PBPK models. These models are mathematical representations of the interrelationships among the critical determinants of the absorption, distribution, metabolism and excretion of chemicals in biota. Since the compartments in this model correspond to biologically relevant tissues or tissue groups, the amount of chemical reaching specific target organ(s) can be estimated. Further, the PBPK models permit the use of biological monitoring data such as urinary levels of metabolites, hemoglobin adduct levels, and alveolar air concentrations, to reconstruct the exposure levels and scenarios for specific subgroups of populations. These models are also useful in providing estimates of target tissue dose in humans simultaneously exposed to chemicals in various media (air, water, soil, food) by different routes (oral, dermal, inhalation). Several examples of exposure assessment for volatile organic chemicals using PBPK models for mammals will be presented, and the strategies for development of these models for other classes of chemicals highlighted.

  15. PHARMACOKINETICALLY BASED RISK ASSESSMENT OF WORKPLACE EXPOSURE OF BENZENE

    EPA Science Inventory

    Cancer risk from exposure to benzene for a working lifetime was estimated from data obtained in studies with rodents. ancers of the Zymbal gland and the blood-forming system were selected as endpoints for the assessment because of their consistent occurrence. he combined metaboli...

  16. Effect of In Vivo Nicotine Exposure on Chlorpyrifos Pharmacokinetics and Pharmacodynamics in Rats

    SciTech Connect

    Lee, Sookwang; Poet, Torka S.; Smith, Jordan N.; Busby-Hjerpe, Andrea L.; Timchalk, Charles

    2010-03-30

    Routine use of tobacco products may modify physiological and metabolic functions, including drug metabolizing enzymes, which may impact the pharmacokinetics of environmental contaminants. Chlorpyrifos is an organophosphorus (OP) insecticide that is bioactivated to chlorpyrifos-oxon, and manifests its neurotoxicity by inhibiting acetylcholinesterase (AChE). The objective of this study was to evaluate the impact of repeated nicotine exposure on the pharmacokinetics of chlorpyrifos (CPF) and its major metabolite, 3,5,6-trichloro-2-pyridinol (TCPy) in blood and urine and also to determine the impact on cholinesterase (ChE) activity in plasma and brain. Animals were exposed to 7-daily doses of either 1 mg nicotine/kg or saline (sc), and to either a single oral dose of 35 mg CPF/kg or a repeated dose of 5 mg CPF/kg/day for 7 days. Groups of rats were then sacrificed at multiple time-points after receiving the last dose of CPF. Repeated nicotine and CPF exposures resulted in enhanced metabolism of CPF to TCPy, as evidenced by increases in the measured TCPy concentration and AUC in blood. However, there was no significant difference in the amount of TCPy (free or total) excreted in the urine. The extent of brain acetylcholinesterase (AChE) inhibition was reduced due to nicotine co-exposure consistent with an increase in CYP450-mediated dearylation (detoxification) versus desulfuration. It was of interest to note that the impact of nicotine co-exposure was experimentally observed only after repeated CPF doses. Physiologically based pharmacokinetic model simulations of CPF-oxon concentrations in blood and brain were predicted to be lower in nicotine treated groups, which were simulated by increasing the dearylation Vmax based upon previously conducted in vitro metabolism studies. These results were consistent with the experimental data. The current study demonstrated that repeated nicotine exposure could alter CPF metabolism in vivo, further modulating brain AChE inhibition.

  17. A physiologically based pharmacokinetic model for developmental exposure to BDE-47 in rats

    SciTech Connect

    Emond, Claude; Raymer, James H.; Studabaker, William B.; Garner, C. Edwin; Birnbaum, Linda S.

    2010-02-01

    Polybrominated diphenyl ethers (PBDEs) are used commercially as additive flame retardants and have been shown to transfer into environmental compartments, where they have the potential to bioaccumulate in wildlife and humans. Of the 209 possible PBDEs, 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) is usually the dominant congener found in human blood and milk samples. BDE-47 has been shown to have endocrine activity and produce developmental, reproductive, and neurotoxic effects. The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for BDE-47 in male and female (pregnant and non-pregnant) adult rats to facilitate investigations of developmental exposure. This model consists of eight compartments: liver, brain, adipose tissue, kidney, placenta, fetus, blood, and the rest of the body. Concentrations of BDE-47 from the literature and from maternal-fetal pharmacokinetic studies conducted at RTI International were used to parameterize and evaluate the model. The results showed that the model simulated BDE-47 tissue concentrations in adult male, maternal, and fetal compartments within the standard deviations of the experimental data. The model's ability to estimate BDE-47 concentrations in the fetus after maternal exposure will be useful to design in utero exposure/effect studies. This PBPK model is the first one designed for any PBDE pharmaco/toxicokinetic description. The next steps will be to expand this model to simulate BDE-47 pharmacokinetics and distributions across species (mice), and then extrapolate it to humans. After mouse and human model development, additional PBDE congeners will be incorporated into the model and simulated as a mixture.

  18. Development of a physiologically based pharmacokinetic model for assessment of human exposure to bisphenol A.

    PubMed

    Yang, Xiaoxia; Doerge, Daniel R; Teeguarden, Justin G; Fisher, Jeffrey W

    2015-12-15

    A previously developed physiologically based pharmacokinetic (PBPK) model for bisphenol A (BPA) in adult rhesus monkeys was modified to characterize the pharmacokinetics of BPA and its phase II conjugates in adult humans following oral ingestion. Coupled with in vitro studies on BPA metabolism in the liver and the small intestine, the PBPK model was parameterized using oral pharmacokinetic data with deuterated-BPA (d6-BPA) delivered in cookies to adult humans after overnight fasting. The availability of the serum concentration time course of unconjugated d6-BPA offered direct empirical evidence for the calibration of BPA model parameters. The recalibrated PBPK adult human model for BPA was then evaluated against published human pharmacokinetic studies with BPA. A hypothesis of decreased oral uptake was needed to account for the reduced peak levels observed in adult humans, where d6-BPA was delivered in soup and food was provided prior to BPA ingestion, suggesting the potential impact of dosing vehicles and/or fasting on BPA disposition. With the incorporation of Monte Carlo analysis, the recalibrated adult human model was used to address the inter-individual variability in the internal dose metrics of BPA for the U.S. general population. Model-predicted peak BPA serum levels were in the range of pM, with 95% of human variability falling within an order of magnitude. This recalibrated PBPK model for BPA in adult humans provides a scientific basis for assessing human exposure to BPA that can serve to minimize uncertainties incurred during extrapolations across doses and species. PMID:26522835

  19. Inhaled today, not gone tomorrow: pharmacokinetics and environmental exposure of volatiles in exhaled breath.

    PubMed

    Beauchamp, J

    2011-09-01

    The chemical analysis of exhaled breath gas to assess state of health or identify disease biomarkers has gained growing interest in recent years, with advances in new technologies providing scientists and physicians with a powerful analytical arsenal with which to tackle pertinent issues. The application of these methods for pharmacokinetic studies, however, has received less attention despite its enormous potential in this field. For instance, breath gas analysis may be employed to characterize uptake and distribution within the body of exogenous volatile compounds, either from a pharmaceutical point of view, or in relation to environmental inhalation exposure. Both of these topics can benefit greatly from utilizing breath gas complementarily or as a surrogate to blood as an analytical medium, since breath sampling is non-invasive, inexhaustible, and is achievable with a frequency far exceeding that which is feasible for blood. However, because of the efficiency with which certain exogenous compounds are reflected in breath, this can also often be a significant source of confounding variables that require consideration in routine breath gas analyses. This paper provides an overview of the possibilities of breath gas analysis for pharmacokinetics and environmental exposure investigations and discusses the presence of exogenous compounds in standard breath analyses and their repercussions in terms of erroneous data interpretation. PMID:21654021

  20. Clinical trial simulation to evaluate population pharmacokinetics and food effect: capturing abiraterone and nilotinib exposures.

    PubMed

    Li, Claire H; Sherer, Eric A; Lewis, Lionel D; Bies, Robert R

    2015-05-01

    The objectives of this study were to determine (1) the accuracy with which individual patient level exposure can be determined and (2) whether a known food effect can be identified in a trial simulation of a typical population pharmacokinetic trial. Clinical trial simulations were undertaken using NONMEM VII to assess a typical oncology pharmacokinetic trial design. Nine virtual trials for each compound were performed for combinations of different levels of between-occasion variability, number of patients in the trial, and magnitude of a food covariate on oral clearance. Less than 5% and 20% bias and precision were obtained in individual clearance estimated for both abiraterone and nilotinib using this design. This design resulted in biased and imprecise population clearance estimates for abiraterone. The between-occasion variability in most trials was captured with less than 30% of percent bias and precision. The food effect was detectable as a statistically significant covariate on oral clearance for abiraterone and nilotinib with percent bias and precision of the food covariate less than 20%. These results demonstrate that clinical trial simulation can be used to explore the ability of specific trial designs to evaluate the power to identify individual and population level exposures, covariate, and variability effects. PMID:25511575

  1. Clinical Trial Simulation to Evaluate Population Pharmacokinetics and Food Effect: Capturing Abiraterone and Nilotinib Exposures

    PubMed Central

    Sherer, Eric A.; Lewis, Lionel D.; Bies, Robert R.

    2015-01-01

    The objectives of this study were to determine (1) the accuracy with which individual patient level exposure can be determined and (2) whether a known food effect can be identified in a trial simulation of a typical population pharmacokinetic trial. Clinical trial simulations were undertaken using NONMEM VII to assess a typical oncology pharmacokinetic trial design. Nine virtual trials for each compound were performed for combinations of different level of between-occasion variability, number of patients in the trial and magnitude of a food covariate on oral clearance. Less than 5% and 20% bias and precision were obtained in individual clearance estimated for both abiraterone and nilotinib using this design. This design resulted biased and imprecise population clearance estimates for abiraterone. The between-occasion variability in most trials was captured with less than 30% of percent bias and precision. The food effect was detectable as a statistically significant covariate on oral clearance for abiraterone and nilotinib with percent bias and precision of the food covariate less than 20%. These results demonstrate that clinical trial simulation can be used to explore the ability of specific trial designs to evaluate the power to identify individual and population level exposures,covariate and variability effects. PMID:25511575

  2. Variability of Sorafenib Toxicity and Exposure over Time: A Pharmacokinetic/Pharmacodynamic Analysis

    PubMed Central

    Ropert, Stanislas; Mir, Olivier; Coriat, Romain; Billemont, Bertrand; Tod, Michel; Cabanes, Laure; Franck, Nathalie; Blanchet, Benoit; Goldwasser, François

    2012-01-01

    Background. Sorafenib displays major interpatient pharmacokinetic variability. It is unknown whether the pharmacokinetics of sorafenib influence its toxicity. Methods. We analyzed the severity and kinetics of sorafenib-induced toxicities in unselected consecutive patients with cancer, as well as their relationship with biological, clinical, and pharmacokinetic parameters. Toxicity was recorded bimonthly. Sorafenib plasma concentrations were assessed by liquid chromatography. Results. For 83 patients (median age, 62 years; range, 21–84 years), median sorafenib 12-hour area under the curve (AUC0–12) was 52.8 mg · h/L (range: 11.8–199.6). A total of 51 patients (61%) experienced grade 3–4 toxicities, including hand-foot skin reactions (23%), asthenia (18%), and diarrhea (11%). Sorafenib AUC0–12 preceding grade 3–4 toxicities was significantly higher than that observed in the remaining population (61.9 mg · h/L vs. 53 mg · h/L). In 25 patients treated with fixed doses of sorafenib for the first 4 months, median dose-normalized AUC0–12 on day 120 was significantly lower than on day 15 (63 vs. 102 mg · h/L). The incidence of hypertension and hand-foot skin reactions significantly decreased over time. Conclusion. Sorafenib AUC0–12 decreases over time, similarly to the incidence of hypertension and hand-foot skin reactions. Monitoring of sorafenib plasma concentrations may help to prevent acute severe toxicities and detect patients with suboptimal exposure at disease progression. PMID:22752067

  3. Effect of in vivo nicotine exposure on chlorpyrifos pharmacokinetics and pharmacodynamics in rats

    SciTech Connect

    Lee, Soo Kwang; Poet, Torka S.; Smith, Jordan N.; Busby-Hjerpe, Andrea L.; Timchalk, Charles

    2010-03-30

    Chlorpyrifos (CPF) is one of the most studied and widely used broad spectrum organophosphorus (OP) insecticides. The neurotoxicity of CPF results from inhibition of cholinesterase (ChE) by its metabolite, chlorpyrifos-oxon (CPF-oxon), which subsequently leads to cholinergic hyperstimulation. The routine consumption of alcoholic beverages and tobacco products will modify a number of metabolic and physiological processes which may impact the metabolism and pharmacokinetics of other xenobiotics including pesticides. The objective of this study was to evaluate the influence of repeated ethanol and nicotine co-exposure on in vivo CPF pharmacokinetics and pharmacodynamics. The major CPF metabolite, 3,5,6-trichloro-2-pyridinol (TCPy) in blood and urine along with changes in plasma and brain AChE activities were measured in male Sprague-Dawley (S-D) rats. Animals were repeatedly treated with either saline or ethanol (1 g/kg/day, po) and nicotine (1 mg/kg/day, sc) in addition to CPF (1 or 5 mg/kg/day, po) for 7 days. Rats were sacrificed at times from 1 to 24 hr post-last dosing of CPF. There were apparent differences in blood TCPy pharmacokinetics following ethanol and nicotine pretreatments in both CPF dose groups, which showed higher TCPy peak concentrations and increased blood TCPy AUC in ethanol and nicotine groups over CPF-only (~1.8- and 3.8-fold at 1 and 5 mg CPF doses, respectively). Brain acetylcholinesterase (AChE) activities from both ethanol and nicotine-treated groups showed substantially less inhibition following repeated 5 mg CPF/kg dosing compared to CPF-only controls (96 ± 13 and 66 ± 7% of naïve at 4 hr post-last CPF dosing, respectively). Inhibition of brain AChE activities was minimal in both 1 mg CPF/kg/day dosing groups, but a similar trend indicating less inhibition following ethanol/nicotine pretreatment was apparent. No differences were observed in plasma ChE activities due to the combined alcohol and nicotine treatments. In vitro, CPF

  4. Effect of temperature on the pharmacokinetics of benzocaine in rainbow trout (Oncorhynchus mykiss) after bath exposures

    USGS Publications Warehouse

    Stehly, G.R.; Meinertz, J.R.; Gingerich, W.H.

    1998-01-01

    The pharmacokinetics of benzocaine during bath exposures at 1 mg/L were determined in rainbow trout acclimated at 6 °C, 12 °C or 18 °C for at least 1 month. Individual fish were exposed to benzocaine in a recirculating system for 4 h and pharmacokinetic parameters were estimated in a unique manner from the concentration of benzocaine in the bath water vs. time curve. Elimination from plasma was also determined after the 4 h exposure. The uptake clearance and metabolic clearance increased with increased acclimatization temperatures (uptake clearance 581 ± 179 mL/min/kg at 6 °C and 1154 ± 447 mL/ min/kg at 18 °C; metabolic clearance 15.2 ± 4.1 mL/min/kg at 6 °C and 22.3 ± 4.2 mL/min/kg at 18 °C). The apparent volume of distribution had a trend for increasing with temperature that was not significant at the 5% level (2369 ± 678 mL/kg at 6 °C to 3260 ± 1182 mL/kg at 18 °C). The elimination half-life of benzocaine in plasma was variable and did not differ significantly with temperature (60.8 ± 30.3 min at 6 °C to 35.9 ± 13.0 min at 12 °C). Elimination of benzocaine from rainbow trout is relatively rapid and even more rapid at higher acclimatization temperatures based on calculated metabolic clearances and measured plasma concentrations, but was not evident by measurement of terminal plasma half-lifes.

  5. Estimating Margin of Exposure to Thyroid Peroxidase Inhibitors Using High-Throughput in vitro Data, High-Throughput Exposure Modeling, and Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling.

    PubMed

    Leonard, Jeremy A; Tan, Yu-Mei; Gilbert, Mary; Isaacs, Kristin; El-Masri, Hisham

    2016-05-01

    Some pharmaceuticals and environmental chemicals bind the thyroid peroxidase (TPO) enzyme and disrupt thyroid hormone production. The potential for TPO inhibition is a function of both the binding affinity and concentration of the chemical within the thyroid gland. The former can be determined through in vitro assays, and the latter is influenced by pharmacokinetic properties, along with environmental exposure levels. In this study, a physiologically based pharmacokinetic (PBPK) model was integrated with a pharmacodynamic (PD) model to establish internal doses capable of inhibiting TPO in relation to external exposure levels predicted through exposure modeling. The PBPK/PD model was evaluated using published serum or thyroid gland chemical concentrations or circulating thyroxine (T4) and triiodothyronine (T3) hormone levels measured in rats and humans. After evaluation, the model was used to estimate human equivalent intake doses resulting in reduction of T4 and T3 levels by 10% (ED10) for 6 chemicals of varying TPO-inhibiting potencies. These chemicals were methimazole, 6-propylthiouracil, resorcinol, benzophenone-2, 2-mercaptobenzothiazole, and triclosan. Margin of exposure values were estimated for these chemicals using the ED10 and predicted population exposure levels for females of child-bearing age. The modeling approach presented here revealed that examining hazard or exposure alone when prioritizing chemicals for risk assessment may be insufficient, and that consideration of pharmacokinetic properties is warranted. This approach also provides a mechanism for integrating in vitro data, pharmacokinetic properties, and exposure levels predicted through high-throughput means when interpreting adverse outcome pathways based on biological responses. PMID:26865668

  6. Enhancing exposure-based therapy from a translational research perspective

    PubMed Central

    Hofmann, Stefan G.

    2007-01-01

    Combining an effective psychological treatment with conventional anxiolytic medication is typically not more effective than unimodal therapy for treating anxiety disorders. However, recent advances in the neuroscience of fear reduction have led to novel approaches for combining psychological therapy and pharmacological agents. Exposure-based treatments in humans partly rely on extinction to reduce the fear response in anxiety disorders. Animal studies have shown that d-cycloserine (DCS), a partial agonist at the glycine recognition site of the glutamatergic N-methyl- d-aspartate receptor facilitates extinction learning. Similarly, recent human trials have shown that DCS enhances fear reduction during exposure therapy of some anxiety disorders. This article discusses the biological and psychological mechanisms of extinction learning and the therapeutic value of DCS as an augmentation strategy for exposure therapy. Areas of future research will be identified. PMID:17659253

  7. Linear pharmacokinetic models for evaluating unusual work schedules, exposure limits and body burdens of pollutants.

    PubMed

    Saltzman, B E

    1988-05-01

    The adverse effects of workplace exposures to pollutants relate more accurately to the concentrations of pollutants in the body than in the environment. In many cases pharmacokinetic models may represent the external to internal concentration relationships with useful accuracy. Simplified equations are presented for stepwise calculations on a series of time-averaged, external concentrations to give a corresponding series of internal concentrations. Accurate results were obtained for averaging times not exceeding one-fourth of the biological half-life of the pollutant. A convenient measure of internal concentration is the external concentration that would be at in vivo equilibrium with it (termed biologically effective concentration). Three measures of damage burden are proposed, each appropriate for different toxic mechanisms. The calculations readily may be carried out on a programmable calculator or microcomputer. Illustrative examples show how unusual work schedules may be compared with an 8 hr/day, 5 days/week schedule and how appropriate short- and long-term exposure limits may be determined. Other examples, illustrated for lead, relate absorbed mass rates to body concentrations and body burdens in a two-compartment kinetic model. These calculations should provide a more accurate evaluation of fluctuating concentrations, which can be handled easily. PMID:3400585

  8. Concomitant efavirenz reduces pharmacokinetic exposure to the antimalarial drug artemether-lumefantrine in healthy volunteers

    PubMed Central

    Huang, Liusheng; Parikh, Sunil; Rosenthal, Philip J.; Lizak, Patricia; Marzan, Florence; Dorsey, Grant; Havlir, Diane; Aweeka, Francesca T.

    2012-01-01

    Background The antiretroviral drug efavirenz (EFV) and the antimalarial artemisinin-based combination therapy (ACT) artemether-lumefantrine (AL) are commonly co-administered to treat HIV and malaria. EFV is a known inducer of cytochrome P450 3A4, which converts artemether to dihydroartemisinin (DHA) that is also active and metabolizes longer acting lumefantrine (LR). A study in healthy volunteers was completed to address the concern that EFV impacts AL pharmacokinetics (PK). Methods Adults received AL (80/480 mg BID) for 3-days prior to and during EFV co-administration (600 mg daily for 26-days) with intensive PK for artemether, DHA, and LR conducted after the last AL dose for each period. EFV PK was evaluated with and without AL. PK parameters were estimated using non-compartmental methods. Results Twelve subjects completed the two-period study. PK exposure for artemether, DHA, and LR [as estimated by the area under the concentration time curve (AUClast)] decreased or trended toward decrease with EFV, compared to when administered alone [−51% (p=0.084), −46% (p=0.005), and −21% (p=0.102), respectively]. Day 7 LR levels, previously deemed predictive of treatment success, were 46% lower (p=0.002) with EFV, but the LR half-life was unchanged. EFV PK exposure was minimally altered following AL co-administration [AUC0–24h decreased by 17% (p=0.034)]. Conclusions Exposure to DHA, but not LR, was significantly lower during EFV-AL co-administration compared to that during administration of AL alone. These findings may have implications for the treatment efficacy of AL, particularly in children. However, the observed modest changes probably do not warrant dosage adjustment during co-administration of AL with EFV. PMID:22918158

  9. Comparative pharmacokinetic study of the role of gender and developmental differences in occupational and environmental exposure to benzene. Master's thesis

    SciTech Connect

    Brown, E.A.

    1994-09-01

    The purpose of this study is two-fold. First, it shows that physiological differences between men and women result in gender-specific exposures with respect to benzene. Second, it assesses the potential for a lactating woman's occupational and personal benzene exposure to impact a nursing infant's exposure, highlighting the possibility of subjecting an infant to the effects of industrial chemicals via breast feeding. This study employs physiologically based pharmacokinetic (PBPK) modeling to investigate the influence of physiological parameters and to evaluate the ability of inhaled benzene to transfer from mother to infant through breastmilk. The models are run through scenarios that simulate occupational, smoking, and background exposures. The gender comparison is facilitated by a sensitivity analysis. The blood/air partition coefficient and maximum velocity of metabolism were found to substantially impact model output. These values were both higher in women and caused an increase in the percentage of benzene metabolized in all of the exposure scenarios. The study of lactating women and infants is essentially theoretical. There is evidence that over 65% of an infant's benzene exposure can be attributed to contaminated breastmilk. A large portion of the ingested exposure can be eliminated by adjusting the mother's working or nursing schedule. Benzene, Physiologically based pharmacokinetics, PBPK.

  10. Nevirapine exposure with WHO pediatric weight band dosing: enhanced therapeutic concentrations predicted based on extensive international pharmacokinetic experience.

    PubMed

    Nikanjam, Mina; Kabamba, Desiré; Cressey, Tim R; Burger, David; Aweeka, Francesca T; Acosta, Edward P; Spector, Stephen A; Capparelli, Edmund V

    2012-10-01

    Nevirapine (NVP) is a nonnucleoside reverse transcriptase inhibitor (NNRTI) used worldwide as part of combination antiretroviral therapy in infants and children to treat HIV infection. Dosing based on either weight or body surface area has been approved by the U.S. Food and Drug Administration (FDA) but can be difficult to implement in resource-limited settings. The World Health Organization (WHO) has developed simplified weight band dosing for NVP, but it has not been critically evaluated. NVP pharmacokinetic data were combined from eight pediatric clinical trials (Pediatric AIDS Clinical Trials Group [PACTG] studies 245, 356, 366, 377, 403, 1056, and 1069 and Children with HIV in Africa Pharmacokinetics and Adherence of Simple Antiretroviral Regimens [CHAPAS]) representing subjects from multiple continents and across the pediatric age continuum. A population pharmacokinetic model was developed to characterize developmental changes in NVP disposition, identify potential sources of NVP pharmacokinetic variability, and assess various pediatric dosing strategies and their impact on NVP exposure. Age, CYP2B6 genotype, and ritonavir were independent predictors of oral NVP clearance. The Triomune fixed-dose tablet was an independent predictor of bioavailability compared to the liquid and other tablet formulations. Monte Carlo simulations of the final model were used to assess WHO weight band dosing recommendations. The final pharmacokinetic model indicated that WHO weight band dosing is likely to result in a percentage of children with NVP exposure within the target range similar to that obtained with FDA dosing. Weight band dosing of NVP proposed by the WHO has the potential to provide a simple and effective dosing strategy for resource limited settings. PMID:22869579

  11. Mucosal tissue pharmacokinetics of the integrase inhibitor raltegravir in a humanized mouse model: Implications for HIV pre-exposure prophylaxis.

    PubMed

    Veselinovic, Milena; Yang, Kuo-Hsiung; Sykes, Craig; Remling-Mulder, Leila; Kashuba, Angela D M; Akkina, Ramesh

    2016-02-01

    Orally administered anti-retroviral drugs show considerable promise for HIV/AIDS pre-exposure prophylaxis (PrEP). For the success of these strategies, pharmacokinetic (PK) data defining the optimal concentration of the drug needed for protection in relevant mucosal exposure sites is essential. Here we employed a humanized mouse model to derive comprehensive PK data on the HIV integrase inhibitor raltegravir (RAL), a leading PrEP drug candidate. Under steady state conditions following oral dosing, plasma and multiple mucosal tissues were sampled simultaneously. RAL exhibited higher drug exposure in mucosal tissues relative to that in plasma with one log higher exposure in vaginal and rectal tissue and two logs higher exposure in intestinal mucosa reflecting the trends seen in the human studies. These data demonstrate the suitability of RAL for HIV PrEP and validate the utility of humanized mouse models for deriving important preclinical PK-PD data. PMID:26771889

  12. COMPARISON OF THE USE OF A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL AND A CLASSICAL PHARMACOKINETIC MODEL FOR DIOXIN EXPOSURE ASSESSMENTS

    EPA Science Inventory

    In epidemiological studies, exposure assessments to TCDD, known as a possible human carcinogen, assume mono or biphasic elimination rates. Recent data suggests a dose dependent elimination rate for TCDD. A PBPK model, which uses a body burden dependent elimination rate, was dev...

  13. A pragmatic & translational approach of human biomonitoring to methyl isocyanate exposure in Bhopal

    PubMed Central

    Mishra, Pradyumna Kumar

    2012-01-01

    Human biomonitoring has evolved beyond margins to ascertain exposure-response relationship in environmental associated human diseases. As occupational ailments continue to dominate global concerns, biomonitoring strategies have evolved better in terms of evaluating health risks associated with systemic uptake from chronic (long-term) environment exposures. Even though contributions of acute toxic exposures (short-term) towards initiation of disease processes have been gradually recognized, a comprehensive approach delineating mechanistic insights of such an implication remains elusive. Molecular biomonitoring in a strictly selected defined surviving cohort of the infamous Bhopal gas tragedy “as a model”, could provide an unparallel opportunity to discern the long standing implications of acute exposures. Besides comprehending clinical significance of isocyanate toxicity, the results might provide a framework for understanding the molecular repercussions pertaining to a host of other such acute environmental exposures. The investigative strategy might also be helpful in identification of biomarkers with potential for translational research. PMID:22664494

  14. THE DEVELOPMENT AND TESTING OF A DERMAL EXPOSURE SYSTEM FOR PHARMACOKINETIC STUDIES OF ADMINISTERED AND AMBIENT WATER CONTAMINANTS: METHODS AND RESULTS

    EPA Science Inventory


    INTRODUCTION: In order to investigate the pharmacokinetics of water-borne chemicals while eliminating exposures by other routes, a dermal exposure system was developed to expose the hand and forearm of human subjects. METHODS: The goal was, primarily, to study the dermal phar...

  15. Is infant exposure to antiretroviral drugs during breastfeeding quantitatively important? A systematic review and meta-analysis of pharmacokinetic studies

    PubMed Central

    Waitt, Catriona John; Garner, Paul; Bonnett, Laura Jayne; Khoo, Saye Hock; Else, Laura Jayne

    2015-01-01

    Objectives The objectives of this study were to summarize antiretroviral drug concentrations in breast milk (BM) and exposure of breast-fed infants. Methods This was a systematic review of pharmacokinetic studies of HIV-positive women taking antiretrovirals that measured drugs in BM. The quality of pharmacokinetic and laboratory methods was assessed using pre-defined criteria. Pooled ratios and 95% CIs were calculated using the generalized inverse variance method and heterogeneity was estimated by the I2 statistic. PubMed Central, SCOPUS and LactMed databases were searched. No date or language restrictions were applied. Searches were conducted up to 10 November 2014. Clinical relevance was estimated by comparing ingested dose with the recommended therapeutic dose for each drug. Results Twenty-four studies were included. There was substantial variability in the clinical and laboratory methods used and in reported results. Relative to maternal plasma (MP), NRTIs accumulate in BM, with BM : MP ratios (95% CI estimates) from 0.89 to 1.21 (14 studies, 1159 paired BM and MP samples). NNRTI estimates were from 0.71 to 0.94 (17 studies, 965 paired samples) and PI estimates were from 0.17 to 0.21 (8 studies, 477 paired samples). Relative to the recommended paediatric doses, a breast-fed infant may ingest 8.4% (95% CI 1.9–15.0), 12.5% (95% CI 2.6–22.3) and 1.1% (95% CI 0–3.6) of lamivudine, nevirapine and efavirenz, respectively, via BM. Conclusions Transfer to untreated infants appears quantitatively important for some NRTIs and NNRTIs. The pharmacokinetic methods varied widely and we propose standards for the design, analysis and reporting of future pharmacokinetic studies of drug transfer during breastfeeding. PMID:25858354

  16. Pharmacokinetic Evaluation of the Equivalency of Gavage, Dietary, and Drinking Water Exposure to Manganese in F344 Rats

    PubMed Central

    Foster, Melanie L.; Bartnikas, Thomas B.; Johnson, Laura C.; Herrera, Carolina; Pettiglio, Michael A.; Keene, Athena M.; Taylor, Michael D.; Dorman, David C.

    2015-01-01

    Concerns exist as to whether individuals may be at greater risk for neurotoxicity following increased manganese (Mn) oral intake. The goals of this study were to determine the equivalence of 3 methods of oral exposure and the rate (mg Mn/kg/day) of exposure. Adult male rats were allocated to control diet (10 ppm), high manganese diet (200 ppm), manganese-supplemented drinking water, and manganese gavage treatment groups. Animals in the drinking water and gavage groups were given the 10 ppm manganese diet and supplemented with manganese chloride (MnCl2) in drinking water or once-daily gavage to provide a daily manganese intake equivalent to that seen in the high-manganese diet group. No statistically significant difference in body weight gain or terminal body weights was seen. Rats were anesthetized following 7 and 61 exposure days, and samples of bile and blood were collected. Rats were then euthanized and striatum, olfactory bulb, frontal cortex, cerebellum, liver, spleen, and femur samples were collected for chemical analysis. Hematocrit was unaffected by manganese exposure. Liver and bile manganese concentrations were elevated in all treatment groups on day 61 (relative to controls). Increased cerebellum manganese concentrations were seen in animals from the high-manganese diet group (day 61, relative to controls). Increased (relative to all treatment groups) femur, striatum, cerebellum, frontal cortex, and olfactory bulb manganese concentrations were also seen following gavage suggesting that dose rate is an important factor in the pharmacokinetics of oral manganese. These data will be used to refine physiologically based pharmacokinetic models, extending their utility for manganese risk assessment by including multiple dietary exposures. PMID:25724921

  17. 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...

  18. PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL FOR HUMAN EXPOSURES TO METHYL TERTIARY-BUTYL ETHER

    EPA Science Inventory

    Humans can be exposed by inhalation, ingestion, or dermal absorption to methyl tertiary-butyl ether (MTBE), an oxygenated fuel additive, from contaminated water sources. The purpose of this research was to develop a physiologically based pharmacokinetic model describing in human...

  19. Use of a Simple Pharmacokinetic Model to Characterize Exposure to Perchlorate [ Journal Article

    EPA Science Inventory

    This article is about how a simple two-compartment first-order pharmacokinetic model that predicts concentrations of perchlorate in blood and urine was constructed and validated. The model was validated using data from a high-dose experiment in humans where doses and resulting co...

  20. A distributed parameter physiologically-based pharmacokinetic model for dermal and inhalation exposure to volatile organic compounds

    SciTech Connect

    Roy, A.; Weisel, C.P.; Lioy, P.J.; Georgopouelous, P.G.

    1996-04-01

    Estimates of dermal dose from exposures to toxic chemicals are typically derived using models that assume instantaneous establishment of steady-state dermal mass flux. However, dermal absorption theory indicates that this assumption is invalid for short-term exposures to volatile organic chemicals (VOCs). A generalized distributed parameter physiologically-based pharmacokinetic model (DP-PBPK), which describes unsteady state dermal mass flux via a partial differential equation (Fickian diffusion), has been developed for inhalation and dermal absorption of VOCs. In the present study, the DP-PBPK model has been parameterized for chloroform, and compared with two simpler PBPK models of chloroform. The latter are lumped parameter models, employing ordinary differential equations, that do not account for the dermal absorption time lag associated with the accumulation of permeant chemical in tissue represented by permeability coefficients. All three models were evaluated by comparing simulated post-exposure exhaled breath concentration profiles with measured concentrations following environmental chloroform exposures. The DP-PBPK model predicted a time-lag in the exhaled breath concentration profile, consistent with the experimental data. The DP-PBPK model also predicted significant volatilization of chloroform, for a simulated dermal exposure scenario. The end-exposure dermal dose predicted by the DP-PBPK model is similar to that predicted by the EPA recommended method for short-term exposures, and is significantly greater than the end-exposure dose predicted by the lumped parameter models. However, the net dermal dose predicted by the DP-PBPK model is substantially less than that predicted by the EPA method, due to the post-exposure volatilization predicted by the DP-PBPK model. The net dermal dose of chloroform predicted by all three models was nearly the same, even though the lumped parameter models did not predict substantial volatilization. 30 refs., 8 figs., 1 tab.

  1. Exposure reconstruction for reducing uncertainty in risk assessment: example using MTBE biomarkers and a simple pharmacokinetic model.

    PubMed

    Pleil, J D; Kim, D; Prah, J D; Rappaport, S M

    2007-01-01

    Adverse health risks from environmental agents are generally related to average (long-term) exposures. Because a given individual's contact with a pollutant is highly variable and dependent on activity patterns, local sources and exposure pathways, simple 'snapshot' measurements of surrounding environmental media may not accurately assign the exposure level. Furthermore, susceptibility to adverse effects from contaminants is considered highly variable in the population so that even similar environmental exposure levels may result in differential health outcomes in different individuals. The use of biomarker measurements coupled to knowledge of rates of uptake, metabolism and elimination has been suggested as a remedy for reducing this type of uncertainty. To demonstrate the utility of such an approach, we invoke results from a series of controlled human exposure tests and classical first-order rate kinetic calculations to estimate how well spot measurements of methyl tertiary butyl ether and the primary metabolite, tertiary butyl alcohol, can be expected to predict different hypothetical scenarios of previous exposures. We found that blood and breath biomarker measurements give similar results and that the biological damping effect of the metabolite production gives more stable estimates of previous exposure. We also explore the value of a potential urinary biomarker, 2-hydroxyisobutyrate suggested in the literature. We find that individual biomarker measurements are a valuable tool in reconstruction of previous exposures and that a simple pharmacokinetic model can identify the time frames over which an exogenous chemical and the related chemical biomarker are useful. These techniques could be applied to broader ranges of environmental contaminants to assess cumulative exposure risks if ADME (Absorption, Distribution, Metabolization and Excretion) is understood and systemic biomarkers can be measured. PMID:17564841

  2. CO2 exposure as translational cross-species experimental model for panic.

    PubMed

    Leibold, N K; van den Hove, D L A; Viechtbauer, W; Buchanan, G F; Goossens, L; Lange, I; Knuts, I; Lesch, K P; Steinbusch, H W M; Schruers, K R J

    2016-01-01

    The current diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders are being challenged by the heterogeneity and the symptom overlap of psychiatric disorders. Therefore, a framework toward a more etiology-based classification has been initiated by the US National Institute of Mental Health, the research domain criteria project. The basic neurobiology of human psychiatric disorders is often studied in rodent models. However, the differences in outcome measurements hamper the translation of knowledge. Here, we aimed to present a translational panic model by using the same stimulus and by quantitatively comparing the same outcome measurements in rodents, healthy human subjects and panic disorder patients within one large project. We measured the behavioral-emotional and bodily response to CO2 exposure in all three samples, allowing for a reliable cross-species comparison. We show that CO2 exposure causes a robust fear response in terms of behavior in mice and panic symptom ratings in healthy volunteers and panic disorder patients. To improve comparability, we next assessed the respiratory and cardiovascular response to CO2, demonstrating corresponding respiratory and cardiovascular effects across both species. This project bridges the gap between basic and human research to improve the translation of knowledge between these disciplines. This will allow significant progress in unraveling the etiological basis of panic disorder and will be highly beneficial for refining the diagnostic categories as well as treatment strategies. PMID:27598969

  3. Accumulation and translation of ferritin heavy chain transcripts following anoxia exposure in a marine invertebrate.

    PubMed

    Larade, Kevin; Storey, Kenneth B

    2004-03-01

    Differential screening of a Littorina littorea (the common periwinkle) cDNA library identified ferritin heavy chain as an anoxia-induced gene in hepatopancreas. Northern blots showed that ferritin heavy chain transcript levels were elevated twofold during anoxia exposure, although nuclear run-off assays demonstrated that ferritin heavy chain mRNAs were not transcriptionally upregulated during anoxia. Polysome analysis indicated that existing ferritin transcripts were actively translated during the anoxic period. This result was confirmed via western blotting, which demonstrated a twofold increase in ferritin heavy chain protein levels during anoxia, with a subsequent decrease to control levels during normoxic recovery. Organ culture experiments using hepatopancreas slices demonstrated a >50% increase in ferritin heavy chain transcript levels in vitro under conditions of anoxia and freezing, as well as after incubation with the second messenger cGMP. Taken together, these results suggest that ferritin heavy chain is actively regulated during anoxia exposure in the marine snail, L. littorea. PMID:15010486

  4. Phase 1 Study of Safety, Tolerability, and Pharmacokinetics of PTC299, an Inhibitor of Stress-Regulated Protein Translation.

    PubMed

    Weetall, Marla; Davis, Thomas; Elfring, Gary; Northcutt, Valerie; Cao, Liangxian; Moon, Young-Choon; Riebling, Peter; Dali, Mandar; Hirawat, Samit; Babiak, John; Colacino, Joseph; Almstead, Neil; Spiegel, Robert; Peltz, Stuart W

    2016-07-01

    PTC299 is a novel small molecule that specifically blocks the production of protein from selected mRNAs that under certain conditions use noncanonical ribosomal translational pathways. Hypoxia, oncogenic transformation, and viral infections limit normal translation and turn on these noncanonical translation pathways that are sensitive to PTC299. Vascular endothelial cell growth factor (VEGF) is an example of a transcript that is posttranscriptionally regulated. Single doses of PTC299 (0.03 to 3 mg/kg) were administered orally to healthy volunteers in a phase 1 single ascending-dose study. In a subsequent multiple ascending-dose study in healthy volunteers, multiple-dose regimens (0.3 to 1.2 mg/kg twice a day or 1.6 mg/kg 3 times a day for 7 days) were evaluated. PTC299 was well tolerated in these studies. As expected in healthy volunteers, mean plasma VEGF levels did not change. Increases in Cmax and AUC of PTC299 were dose-proportional. The target trough plasma concentration associated with preclinical efficacy was achieved within 7 days at doses of 0.6 mg/kg twice daily and above. These data demonstrate that PTC299 is orally bioavailable and well tolerated and support clinical evaluation of PTC299 in cancer, certain viral infections, or other diseases in which deregulation of translational control is a causal factor. PMID:27310330

  5. Human inhalation exposures to toluene, ethylbenzene, and m-xylene and physiologically based pharmacokinetic modeling of exposure biomarkers in exhaled air, blood, and urine.

    PubMed

    Marchand, Axelle; Aranda-Rodriguez, Rocio; Tardif, Robert; Nong, Andy; Haddad, Sami

    2015-04-01

    Urinary biomarkers of exposure are used widely in biomonitoring studies. The commonly used urinary biomarkers for the aromatic solvents toluene (T), ethylbenzene (E), and m-xylene (X) are o-cresol, mandelic acid, and m-methylhippuric acid. The toxicokinetics of these biomarkers following inhalation exposure have yet to be described by physiologically based pharmacokinetic (PBPK) modeling. Five male volunteers were exposed for 6 h in an inhalation chamber to 1/8 or 1/4 of the time-weighted average exposure value (TWAEV) for each solvent: toluene, ethylbenzene, and m-xylene were quantified in blood and exhaled air and their corresponding urine biomarkers were measured in urine. Published PBPK model for parent compounds was used and simulations were compared with experimental blood and exhaled air concentration data. If discrepancies existed, Vmax and Km were optimized. Urinary excretion was modeled using parameters found in literature assuming simply stoichiometric yields from parent compound metabolism and first-order urinary excretion rate. Alternative models were also tested for (1) the possibility that CYP1A2 is the only enzyme implicated in o-cresol and (2) a 2-step model for describing serial metabolic steps for mandelic acid. Models adapted in this study for urinary excretion will be further used to interpret urinary biomarker kinetic data from mixed exposures of these solvents. PMID:25601989

  6. Using physiologically based pharmacokinetic modeling and benchmark dose methods to derive an occupational exposure limit for N-methylpyrrolidone.

    PubMed

    Poet, T S; Schlosser, P M; Rodriguez, C E; Parod, R J; Rodwell, D E; Kirman, C R

    2016-04-01

    The developmental effects of NMP are well studied in Sprague-Dawley rats following oral, inhalation, and dermal routes of exposure. Short-term and chronic occupational exposure limit (OEL) values were derived using an updated physiologically based pharmacokinetic (PBPK) model for NMP, along with benchmark dose modeling. Two suitable developmental endpoints were evaluated for human health risk assessment: (1) for acute exposures, the increased incidence of skeletal malformations, an effect noted only at oral doses that were toxic to the dam and fetus; and (2) for repeated exposures to NMP, changes in fetal/pup body weight. Where possible, data from multiple studies were pooled to increase the predictive power of the dose-response data sets. For the purposes of internal dose estimation, the window of susceptibility was estimated for each endpoint, and was used in the dose-response modeling. A point of departure value of 390 mg/L (in terms of peak NMP in blood) was calculated for skeletal malformations based on pooled data from oral and inhalation studies. Acceptable dose-response model fits were not obtained using the pooled data for fetal/pup body weight changes. These data sets were also assessed individually, from which the geometric mean value obtained from the inhalation studies (470 mg*hr/L), was used to derive the chronic OEL. A PBPK model for NMP in humans was used to calculate human equivalent concentrations corresponding to the internal dose point of departure values. Application of a net uncertainty factor of 20-21, which incorporates data-derived extrapolation factors, to the point of departure values yields short-term and chronic occupational exposure limit values of 86 and 24 ppm, respectively. PMID:26776754

  7. A comparative pharmacokinetic estimate of mercury in U.S. Infants following yearly exposures to inactivated influenza vaccines containing thimerosal.

    PubMed

    Mitkus, Robert J; King, David B; Walderhaug, Mark O; Forshee, Richard A

    2014-04-01

    The use of thimerosal preservative in childhood vaccines has been largely eliminated over the past decade in the United States because vaccines have been reformulated in single-dose vials that do not require preservative. An exception is the inactivated influenza vaccines, which are formulated in both multidose vials requiring preservative and preservative-free single-dose vials. As part of an ongoing evaluation by USFDA of the safety of biologics throughout their lifecycle, the infant body burden of mercury following scheduled exposures to thimerosal preservative in inactivated influenza vaccines in the United States was estimated and compared to the infant body burden of mercury following daily exposures to dietary methylmercury at the reference dose established by the USEPA. Body burdens were estimated using kinetic parameters derived from experiments conducted in infant monkeys that were exposed episodically to thimerosal or MeHg at identical doses. We found that the body burden of mercury (AUC) in infants (including low birth weight) over the first 4.5 years of life following yearly exposures to thimerosal was two orders of magnitude lower than that estimated for exposures to the lowest regulatory threshold for MeHg over the same time period. In addition, peak body burdens of mercury following episodic exposures to thimerosal in this worst-case analysis did not exceed the corresponding safe body burden of mercury from methylmercury at any time, even for low-birth-weight infants. Our pharmacokinetic analysis supports the acknowledged safety of thimerosal when used as a preservative at current levels in certain multidose infant vaccines in the United States. PMID:24117921

  8. Heat exposure of Cannabis sativa extracts affects the pharmacokinetic and metabolic profile in healthy male subjects.

    PubMed

    Eichler, Martin; Spinedi, Luca; Unfer-Grauwiler, Sandra; Bodmer, Michael; Surber, Christian; Luedi, Markus; Drewe, Juergen

    2012-05-01

    The most important psychoactive constituent of CANNABIS SATIVA L. is Δ (9)-tetrahydrocannabinol (THC). Cannabidiol (CBD), another important constituent, is able to modulate the distinct unwanted psychotropic effect of THC. In natural plant extracts of C. SATIVA, large amounts of THC and CBD appear in the form of THCA-A (THC-acid-A) and CBDA (cannabidiolic acid), which can be transformed to THC and CBD by heating. Previous reports of medicinal use of cannabis or cannabis preparations with higher CBD/THC ratios and use in its natural, unheated form have demonstrated that pharmacological effects were often accompanied with a lower rate of adverse effects. Therefore, in the present study, the pharmacokinetics and metabolic profiles of two different C. SATIVA extracts (heated and unheated) with a CBD/THC ratio > 1 were compared to synthetic THC (dronabinol) in a double-blind, randomized, single center, three-period cross-over study involving 9 healthy male volunteers. The pharmacokinetics of the cannabinoids was highly variable. The metabolic pattern was significantly different after administration of the different forms: the heated extract showed a lower median THC plasma AUC (24 h) than the unheated extract of 2.84 vs. 6.59 pmol h/mL, respectively. The later was slightly higher than that of dronabinol (4.58 pmol h/mL). On the other hand, the median sum of the metabolites (THC, 11-OH-THC, THC-COOH, CBN) plasma AUC (24 h) was higher for the heated than for the unheated extract. The median CBD plasma AUC (24 h) was almost 2-fold higher for the unheated than for the heated extract. These results indicate that use of unheated extracts may lead to a beneficial change in metabolic pattern and possibly better tolerability. PMID:22411724

  9. Using a physiologically based pharmacokinetic model to link urinary biomarker concentrations to dietary exposure of perchlorate

    EPA Science Inventory

    Exposure to perchlorate is widespread in the United States and many studies have attempted to character the perchlorate exposure by estimating the average daily intakes of perchlorate. These approaches provided population-based estimates, but did not provide individual-level exp...

  10. DRINKING WATER DISINFECTION BYPRODUCT PHARMACOKINETICS: LINKING BROMINATED TRIHALOMETHANE EXPOSURE TO HEALTH EFFECTS

    EPA Science Inventory

    Human dermal and inhalation exposure routes are likely more significant than oral exposure for extrahepatic/GI effects of BDCM. GST T1-1 is the primary catalyst for BDCM-glutathione conjugation, leading to product(s) that covalently modify DNA and form deoxyguanosine adducts in v...

  11. Clinical pharmacokinetics and exposure-toxicity relationship of a folate-Vinca alkaloid conjugate EC145 in cancer patients.

    PubMed

    Li, Jing; Sausville, Edward A; Klein, Patrick J; Morgenstern, David; Leamon, Christopher P; Messmann, Richard A; LoRusso, Patricia

    2009-12-01

    The clinical pharmacokinetics and exposure-toxicity relationship were determined for EC145, a conjugate of folic acid and the Vinca alkaloid desacetylvinblastine hydrazide (DAVLBH), in cancer patients. EC145 plasma concentration and toxicity data were obtained from a first-in-man phase I study and analyzed by nonlinear mixed effect modeling with NONMEM. EC145 concentration-time profile after intravenous administration was well described by a 2-compartment model with a first-order elimination process from the central compartment. BSA was identified as a significant covariate on EC145 clearance, accounting for 14.6% of interindividual variation on EC145 clearance. Population estimates for the clearance, steady-state volume of distribution, distribution, and elimination half-lives were 56.1 L/h, 26.1 L, 6 minutes, and 26 minutes, respectively. Constipation and peripheral neuropathy were the most common and clinically relevant toxicities. The clearance and area under the concentration-time curve (AUC) were significant predictors for the incidence of EC145-induced constipation but not peripheral neuropathy. In conclusion, EC145 is rapidly distributed and eliminated in cancer patients. BSA is a statistically significant covariate on EC145 clearance, but its clinical relevance remains to be defined. EC145-induced constipation occurs at a higher frequency in the patients with lower EC145 clearance, where the drug exposure tends to be higher. PMID:19837906

  12. Clinical Pharmacokinetics and Exposure-Toxicity Relationship of a Folate-Vinca Alkaloid Conjugate EC145 in Cancer Patients

    PubMed Central

    Li, Jing; Sausville, Edward A.; Klein, Patrick J.; Morgenstern, David; Leamon, Christopher P.; Messmann, Richard A.; LoRusso, Patricia

    2013-01-01

    The clinical pharmacokinetics and exposure-toxicity relationship were determined for EC145, a conjugate of folic acid and the Vinca alkaloid desacetylvinblastine hydrazide (DAVLBH), in cancer patients. EC145 plasma concentration and toxicity data were obtained from a first-in-man phase I study and analyzed by nonlinear mixed effect modeling with NONMEM. EC145 concentration-time profile after intravenous administration was well described by a 2-compartment model with a first-order elimination process from the central compartment. BSA was identified as a significant covariate on EC145 clearance, accounting for 14.6% of interindividual variation on EC145 clearance. Population estimates for the clearance, steady-state volume of distribution, distribution, and elimination half-lives were 56.1 L/h, 26.1 L, 6 minutes, and 26 minutes, respectively. Constipation and peripheral neuropathy were the most common and clinically relevant toxicities. The clearance and area under the concentration-time curve (AUC) were significant predictors for the incidence of EC145-induced constipation but not peripheral neuropathy. In conclusion, EC145 is rapidly distributed and eliminated in cancer patients. BSA is a statistically significant covariate on EC145 clearance, but its clinical relevance remains to be defined. EC145-induced constipation occurs at a higher frequency in the patients with lower EC145 clearance, where the drug exposure tends to be higher. PMID:19837906

  13. Bioenergetic and pharmacokinetic model for exposure of common loon (Gavia immer) chicks to methylmercury

    USGS Publications Warehouse

    Karasov, W.H.; Kenow, K.P.; Meyer, M.W.; Fournier, F.

    2007-01-01

    A bioenergetics model was used to predict food intake of common loon (Gavia immer) chicks as a function of body mass during development, and a pharmacokinetics model, based on first-order kinetics in a single compartment, was used to predict blood Hg level as a function of food intake rate, food Hg content, body mass, and Hg absorption and elimination. Predictions were tested in captive growing chicks fed trout (Salmo gairdneri) with average MeHg concentrations of 0.02 (control), 0.4, and 1.2 ??g/g wet mass (delivered as CH3HgCl). Predicted food intake matched observed intake through 50 d of age but then exceeded observed intake by an amount that grew progressively larger with age, reaching a significant overestimate of 28% by the end of the trial. Respiration in older, nongrowing birds probably was overestimated by using rates measured in younger, growing birds. Close agreement was found between simulations and measured blood Hg, which varied significantly with dietary Hg and age. Although chicks may hatch with different blood Hg levels, their blood level is determined mainly by dietary Hg level beyond approximately two weeks of age. The model also may be useful for predicting Hg levels in adults and in the eggs that they lay, but its accuracy in both chicks and adults needs to be tested in free-living birds. ?? 2007 SETAC.

  14. Development of a multi-compartment pharmacokinetic model to characterize the exposure to Hexamoll® DINCH®.

    PubMed

    Schütze, Andre; Lorber, Matthew; Gawrych, Katarzyna; Kolossa-Gehring, Marike; Apel, Petra; Brüning, Thomas; Koch, Holger M

    2015-06-01

    We developed and calibrated a multi compartment pharmacokinetic (PK) model to predict urinary concentrations after oral exposure of four specific DINCH metabolites: MINCH, OH-MINCH, cx-MINCH, and oxo-MINCH. This descriptive model has 4 compartments: a "stomach" (SC) compartment, a "holding" (HC) compartment, a "blood" (BC) compartment and a "bladder" (BLC) compartment. DINCH is assumed to first deposit into the SC, with transfer split between the HC and the BC. Unmetabolized DINCH from the HC then transfers to the BC. The DINCH metabolism is assumed to occur in the BC before excretion via the BLC. At each urination event, all the metabolite mass in the BLC is excreted. The model was calibrated using published urine metabolite data from 3 different male volunteers, each orally dosed with 50mg DINCH. Full urine voids were taken for 48 h after dosage. The predicted values showed a good agreement with the observed urinary DINCH metabolite concentrations, with a Spearman correlation coefficient exceeding 0.7 for all oxidized metabolites. We showed the importance of a holding reservoir. Without it, a good agreement could not be found. We applied the model to a set of 24-h general population samples measured for DINCH metabolites. The model was unable to duplicate the ratio of metabolites seen in the 24-h samples. Two possibilities were offered to explain the difference: the exposure pattern in the general population did not match the oral exposure in the dosing experiments, or the long-term toxicokinetics of DINCH was not captured in the 48-h controlled dosing experiments. PMID:25710321

  15. Lopinavir/ritonavir significantly influences pharmacokinetic exposure of artemether/lumefantrine in HIV-infected Ugandan adults

    PubMed Central

    Byakika-Kibwika, Pauline; Lamorde, Mohammed; Okaba-Kayom, Violet; Mayanja-Kizza, Harriet; Katabira, Elly; Hanpithakpong, Warunee; Pakker, Nadine; Dorlo, Thomas P. C.; Tarning, Joel; Lindegardh, Niklas; de Vries, Peter J.; Back, David; Khoo, Saye; Merry, Concepta

    2012-01-01

    Background Treatment of HIV/malaria-coinfected patients with antiretroviral therapy (ART) and artemisinin-based combination therapy has potential for drug interactions. We investigated the pharmacokinetics of artemether, dihydroartemisinin and lumefantrine after administration of a single dose of 80/480 mg of artemether/lumefantrine to HIV-infected adults, taken with and without lopinavir/ritonavir. Methods A two-arm parallel study of 13 HIV-infected ART-naive adults and 16 HIV-infected adults stable on 400/100 mg of lopinavir/ritonavir plus two nucleoside reverse transcriptase inhibitors (ClinicalTrials.gov, NCT 00619944). Each participant received a single dose of 80/480 mg of artemether/lumefantrine under continuous cardiac function monitoring. Plasma concentrations of artemether, dihydroartemisinin and lumefantrine were measured. Results Co-administration of artemether/lumefantrine with lopinavir/ritonavir significantly reduced artemether maximum concentration (Cmax) and area under the concentration–time curve (AUC) [median (range): 112 (20–362) versus 56 (17–236) ng/mL, P = 0.03; and 264 (92–1129) versus 151 (38–606) ng · h/mL, P < 0.01]. Dihydroartemisinin Cmax and AUC were not affected [66 (10–111) versus 73 (31–224) ng/mL, P = 0.55; and 213 (68–343) versus 175 (118–262) ng · h/mL P = 0.27]. Lumefantrine Cmax and AUC increased during co-administration [2532 (1071–5957) versus 7097 (2396–9462) ng/mL, P < 0.01; and 41 119 (12 850–125 200) versus 199 678 (71 205–251 015) ng · h/mL, P < 0.01]. Conclusions Co-administration of artemether/lumefantrine with lopinavir/ritonavir significantly increases lumefantrine exposure, but decreases artemether exposure. Population pharmacokinetic and pharmacodynamic trials will be highly valuable in evaluating the clinical significance of this interaction and determining whether dosage modifications are indicated. PMID:22316571

  16. Improvement in intraperitoneal intraoperative cisplatin exposure based on pharmacokinetic analysis in patients with ovarian cancer.

    PubMed

    Royer, Bernard; Delroeux, Delphine; Guardiola, Emmanuel; Combe, Marielle; Hoizey, Guillaume; Montange, Damien; Kantelip, Jean-Pierre; Chauffert, Bruno; Heyd, Bruno; Pivot, Xavier

    2008-03-01

    Ovarian cancer is the leading cause of gynecological cancer-related death in Western countries. The present treatment standards for ovarian cancer are based on the association of debulking surgery with platinum-based chemotherapy. Another strategy that could be further investigated is intraperitoneal chemotherapy (IP). We previously described that the 2-h administration of intraoperative IP cisplatin did not reach satisfactory concentrations. In the present study, we present the results of a pharmacokinetic analysis performed after two consecutive 1-h IP 30 mg/l cisplatin administrations. Twenty-seven patients with advanced epithelial cancer classified FIGO stage IIIC were included in the study. Blood and IP samples were taken over a 24-h period, during and after IP treatment. Both total and ultrafiltered (Uf) platinum (Pt) concentration levels were analyzed. Biological and clinical toxicities were also recorded. With this strategy, IP Pt concentrations stayed above the target concentration (10 mg/l) for a satisfactory length of time. The serum Pt concentrations were higher than those observed with the "one-bath" protocol and they induced the occurrence of recoverable renal toxicities (3 grade 1, 7 grade 2 and 4 grade 3). The best predictive parameter for renal failure was the total Pt 24-h Area Under the Curve (AUC) with a threshold value of 25 mg h/l RR = 0.31 (95% CI 0.13 - 0.49, P < 0.01). Administration of an increased amount of cisplatin is feasible and a satisfactory level of IP Pt concentrations is obtained. However, this improvement is associated with an increase in serum Pt levels and resulting renal toxicities. An attractive solution would be to decrease Pt transfer from peritoneum to bloodstream. A phase 1 study using intraoperative IP epinephrine in order to decrease this transfer is presently being carried out. PMID:17503047

  17. PRELIMINARY ASSESSMENTS OF IN VITRO PHARMACOKINETIC DATA AND EXPOSURE INFORMATION FOR THE TOXCAST PHASE II CHEMICALS

    EPA Science Inventory

    Momentum has been growing in Toxicology to assess the utility of high-throughput screening (HTS) assays in the determination of chemical testing priorities. However, in vitro potencies determined in these assays do not consider in vivo bioavailability, clearance or exposure estim...

  18. The Pharmacokinetic Exposure to Fexofenadine is Volume-Dependently Reduced in Healthy Subjects Following Oral Administration With Apple Juice.

    PubMed

    Luo, J; Imai, H; Ohyama, T; Hashimoto, S; Hasunuma, T; Inoue, Y; Kotegawa, T; Ohashi, K; Uemura, N

    2016-08-01

    Pharmacokinetic exposures to fexofenadine (FEX) are reduced by apple juice (AJ); however, the relationship between the AJ volume and the degree of AJ-FEX interaction has not been understood. In this crossover study, 10 healthy subjects received single doses of FEX 60 mg with different volumes (150, 300, and 600 mL) of AJ or water (control). To identify an AJ volume lacking clinically meaningful interaction, we tested a hypothesis that the 90% confidence interval (CI) for geometric mean ratio (GMR) of FEX AUCAJ /AUCwater is contained within a biocomparability bound of 0.5-2.0, with at least one tested volume of AJ. GMR (90% CI) of AUCAJ 150mL /AUCwater , AUCAJ 300mL /AUCwater , and AUCAJ 600mL /AUCwater were 0.903 (0.752-1.085), 0.593 (0.494-0.712), and 0.385 (0.321-0.462), respectively. While a moderate to large AJ-FEX interaction is caused by a larger volumes of AJ (e.g., 300 to 600 mL), the effect of a small volume (e.g., 150 mL) appears to be not meaningful. PMID:27197662

  19. Physiologically Based Pharmacokinetic modeling of the temperature-dependent dermal absorption of chloroform by humans following bath water exposures

    SciTech Connect

    Corley, Rick A. ); Gordon, Syd M.; Wallace, Lance A.

    2000-01-14

    The kinetics of chloroform in the exhaled breath of human volunteers exposed skin-only via bath water (concentrations < 100 ppb) were analyzed using a physiologically based pharmacokinetic (PBPK) model. Significant increases in exhaled chloroform (and thus bioavailability) were observed as exposure temperatures were increased from 30 to 40?C. The blood flows to the skin and effective skin permeability coefficients (Kp) were both varied to reflect the temperature-dependent changes in physiology and exhalation kinetics. At 40?C, no differences were observed between males and females. Therefore, Kp?s were determined ({approx}0.06 cm/hr) at a skin blood flow rate of 18% of the cardiac output. At 30 and 35?C, males exhaled more chloroform than females resulting in lower effective Kp?s calculated for females. At these lower temperatures, the blood flow to the skin was also reduced. Total amounts of chloroform absorbed averaged 41.9 and 43.6 mg for males and 11.5 and 39.9 mg for females exposed at 35 and 40?C, respectively. At 30?C, only 2/5 males and 1/5 females had detectable concentrations of chloroform in their exhaled breath. For perspective, the total intake of chloroform would have ranged from 79 - 194 mg if the volunteers had consumed 2 L of water orally at the concentrations used in this study. Thus, the relative contribution of dermal uptake of chloroform to the total body burdens associated with bathing for 30 min and drinking 2 L of water (ignoring contributions from inhalation exposures) was predicted to range from 1-28% depending on the temperature of the bath.

  20. Population Pharmacokinetics of Obinutuzumab (GA101) in Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin's Lymphoma and Exposure-Response in CLL.

    PubMed

    Gibiansky, E; Gibiansky, L; Carlile, D J; Jamois, C; Buchheit, V; Frey, N

    2014-01-01

    Treatment regimens involving obinutuzumab (GA101) demonstrated increased efficacy to rituximab in clinical trials for non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). However, the pharmacokinetic (PK) properties and the exposure-response relationships of obinutuzumab still need to be fully described. Data from four clinical trials of obinutuzumab were analyzed to describe the PK properties in patients with NHL or CLL and the pharmacodynamic (PD) properties in patients with CLL. A population PK model with linear time-dependent clearance described the obinutuzumab concentration-time course. Diagnosis, baseline tumor size (BSIZ), body weight, and gender were the main covariates affecting obinutuzumab exposure. In patients with CLL, exposure was not associated with safety but showed positive trends of correlation with efficacy. Although efficacy correlated positively with exposure, since both efficacy and exposure correlated negatively with BSIZ, it was not possible to determine with certainty whether it would be beneficial to adjust the dose according to BSIZ. PMID:25353187

  1. Blood Translation Elongation Factor-1δ Is a Novel Marker for Cadmium Exposure

    PubMed Central

    Lu, Qian; Lei, Yi-Xiong; He, Chao-Cai; Lei, Zi-Ning

    2013-01-01

    Translation elongation factor-1δ (TEF-1δ) has been identified as a novel cadmium-responsive proto-oncogene. However, it is still unclear whether TEF-1δ could be a potential biomarker of cadmium exposure. Rats were treated with CdCl2 at different concentrations (high dose 1.225, mid-dose 0.612 and low dose 0.306 mg/kg body weight, respectively) for 14 weeks, and the cadmium levels, weight coefficients, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), serum creatinine (SCR), 24-h urine protein (24hPro), urinary creatinine (Cr) and pathological features were determined. The TEF-1δ expression in white blood cells and multiple organs were examined by reverse transcription polymerase chain reaction (PCR) and were also confirmed with fluorescence quantitative PCR. A cadmium dose-dependent increase (p < 0.05) of cadmium levels in blood, urine, liver, kidney, heart and lung, and the weight coefficients was observed. The liver and renal function indictors including AST, ALT, SCR, BUN and 24hPro, were elevated in a cadmium dose-dependent manner (p < 0.05). Significant pathological changes in liver, kidney, heart and lung were indicated. The TEF-1δ expression was up-regulated in both blood and organs (p < 0.05). Moreover, the expression level of blood TEF-1δ was positively correlated to TEF-1δ expression level, cadmium level and toxicity in the organs (p < 0.01). This study indicates that blood TEF-1δ is a novel valuable biomarker for cadmium exposure and its organ toxicity. PMID:23459232

  2. An integrated exposure/pharmacokinetic based approach to the assessment of complex exposures. Lead: a case study

    SciTech Connect

    DeRosa, C.T.; Choudhury, H.; Peirano, W.B. )

    1991-07-01

    A problem in evaluating the hazard represented by an environmental toxicant is that exposures can occur via multiple media such as water, land, and air. Lead is one of the toxicants of concern that has been associated with adverse effects on heme metabolism, serum vitamin D levels, and the mental and physical development of infants and children exposed at very low environmental levels. Effects of lead on development are particularly disturbing in that the consequences of early delays or deficits in physical or mental development may have long-term consequences over the lifetime of affected individuals. Experimental and epidemiologic studies have indicated that blood lead levels in the range of 10-15 micrograms/dl, or possibly lower, are likely to produce subclinical toxicity. Since a discernible threshold has not been demonstrated, it is prudent to preclude development of a Reference Dose (RfD) for lead. As an alternate, the U.S. Environmental Protection Agency (U.S. EPA) has developed the uptake/biokinetic lead model that provides a means for evaluating the relative contribution of various media to establishing blood lead levels in children. This approach will allow for the identification of site- and situation-specific abatement strategies based on projected blood lead levels in vulnerable human populations exposed to lead in air, diet, water, soil/dust, and paint; thus making it possible to evaluate regulatory decisions concerning each medium on blood levels and potential health effects.35 references.

  3. No Need for Lopinavir Dose Adjustment during Pregnancy: a Population Pharmacokinetic and Exposure-Response Analysis in Pregnant and Nonpregnant HIV-Infected Subjects.

    PubMed

    Salem, Ahmed Hamed; Jones, Aksana Kaefer; Santini-Oliveira, Marilia; Taylor, Graham P; Patterson, Kristine B; Nilius, Angela M; Klein, Cheri Enders

    2016-01-01

    Lopinavir-ritonavir is frequently prescribed to HIV-1-infected women during pregnancy. Decreased lopinavir exposure has been reported during pregnancy, but the clinical significance of this reduction is uncertain. This analysis aimed to evaluate the need for lopinavir dose adjustment during pregnancy. We conducted a population pharmacokinetic analysis of lopinavir and ritonavir concentrations collected from 84 pregnant and 595 nonpregnant treatment-naive and -experienced HIV-1-infected subjects enrolled in six clinical studies. Lopinavir-ritonavir doses in the studies ranged between 400/100 and 600/150 mg twice daily. In addition, linear mixed-effect analysis was used to compare the area under the concentration-time curve from 0 to 12 h (AUC0-12) and concentration prior to dosing (Cpredose) in pregnant women and nonpregnant subjects. The relationship between lopinavir exposure and virologic suppression in pregnant women and nonpregnant subjects was evaluated. Population pharmacokinetic analysis estimated 17% higher lopinavir clearance in pregnant women than in nonpregnant subjects. Lopinavir clearance values postpartum were 26.4% and 37.1% lower than in nonpregnant subjects and pregnant women, respectively. As the tablet formulation was estimated to be 20% more bioavailable than the capsule formulation, no statistically significant differences between lopinavir exposure in pregnant women receiving the tablet formulation and nonpregnant subjects receiving the capsule formulation were identified. In the range of lopinavir AUC0-12 or Cpredose values observed in the third trimester, there was no correlation between lopinavir exposure and viral load or proportion of subjects with virologic suppression. Similar efficacy was observed between pregnant women and nonpregnant subjects receiving lopinavir-ritonavir at 400/100 mg twice daily. The pharmacokinetic and pharmacodynamic results support the use of a lopinavir-ritonavir 400/100-mg twice-daily dose during pregnancy

  4. No Need for Lopinavir Dose Adjustment during Pregnancy: a Population Pharmacokinetic and Exposure-Response Analysis in Pregnant and Nonpregnant HIV-Infected Subjects

    PubMed Central

    Jones, Aksana Kaefer; Santini-Oliveira, Marilia; Taylor, Graham P.; Patterson, Kristine B.; Nilius, Angela M.; Klein, Cheri Enders

    2015-01-01

    Lopinavir-ritonavir is frequently prescribed to HIV-1-infected women during pregnancy. Decreased lopinavir exposure has been reported during pregnancy, but the clinical significance of this reduction is uncertain. This analysis aimed to evaluate the need for lopinavir dose adjustment during pregnancy. We conducted a population pharmacokinetic analysis of lopinavir and ritonavir concentrations collected from 84 pregnant and 595 nonpregnant treatment-naive and -experienced HIV-1-infected subjects enrolled in six clinical studies. Lopinavir-ritonavir doses in the studies ranged between 400/100 and 600/150 mg twice daily. In addition, linear mixed-effect analysis was used to compare the area under the concentration-time curve from 0 to 12 h (AUC0–12) and concentration prior to dosing (Cpredose) in pregnant women and nonpregnant subjects. The relationship between lopinavir exposure and virologic suppression in pregnant women and nonpregnant subjects was evaluated. Population pharmacokinetic analysis estimated 17% higher lopinavir clearance in pregnant women than in nonpregnant subjects. Lopinavir clearance values postpartum were 26.4% and 37.1% lower than in nonpregnant subjects and pregnant women, respectively. As the tablet formulation was estimated to be 20% more bioavailable than the capsule formulation, no statistically significant differences between lopinavir exposure in pregnant women receiving the tablet formulation and nonpregnant subjects receiving the capsule formulation were identified. In the range of lopinavir AUC0–12 or Cpredose values observed in the third trimester, there was no correlation between lopinavir exposure and viral load or proportion of subjects with virologic suppression. Similar efficacy was observed between pregnant women and nonpregnant subjects receiving lopinavir-ritonavir at 400/100 mg twice daily. The pharmacokinetic and pharmacodynamic results support the use of a lopinavir-ritonavir 400/100-mg twice-daily dose during pregnancy

  5. 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 and 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.

  6. Uso de los Datos de Biomonitoreo para Informar sobre la Evaluacion Infantil (American translation is: USING BIOMONITORING DATA TO INFORM EXPOSURE ASSESSMENT IN CHILDREN)

    EPA Science Inventory

    Discussing the challenges associated with estimating and interpreting toxicant exposures and health risks from biomonitoring data. This extended abstract was translated in Spanish and published in Acta Toxicologica Argentina.

  7. Identification of a granulin-like transcript expressed during anoxic exposure and translated during aerobic recovery in a marine gastropod.

    PubMed

    Larade, Kevin; Storey, Kenneth B

    2008-02-29

    A novel transcript encoding a cysteine-rich granulin-like peptide (l-grn) was identified in the hepatopancreas of the marine intertidal gastropod, Littorina littorea, an anoxia-tolerant species. Experimental exposure of snails to anoxia induced a gradual accumulation of l-grn transcripts over time, with expression regulated in vitro through elements responsive to second messengers of protein kinases A, C and G. Translation of this transcript was analyzed by examining l-grn association with ribosomes during normoxia, anoxia, and aerobic recovery. Transcripts of l-grn were associated with polysomes during normoxia, moved into the monosome fractions under anoxia, but shifted back to the polysomal fractions during aerobic recovery. Western blotting confirmed this with a granulin-like protein detected under normoxic conditions, but not during anoxia exposure. A significant increase in the precursor protein and peptide (L-GRN) was observed during the aerobic recovery period. The accumulation of l-grn transcripts during anoxic exposure and subsequent translation following the return to aerobic conditions may be a response to oxidant damage that occurs during re-oxygenation. Overall, the data show that the l-grn gene is anoxia-responsive in this species and may have pro-survival functions during the recovery period. PMID:18187271

  8. Preserved pharmacokinetic exposure and distinct glycemic effects of insulin degludec and liraglutide in IDegLira, a fixed-ratio combination therapy.

    PubMed

    Kapitza, Christoph; Bode, Bruce; Ingwersen, Steen Hvass; Jacobsen, Lisbeth Vestergård; Poulsen, Pernille

    2015-12-01

    Insulin degludec/liraglutide (IDegLira) is a novel fixed-ratio combination of the basal insulin insulin degludec (IDeg) and liraglutide, a glucagon-like peptide-1 analog. The pharmacokinetics (PK) and pharmacodynamics of IDegLira were assessed versus its components. A single-dose, randomized, 4-period crossover clinical pharmacology study in healthy subjects compared the bioavailability of IDegLira with its monocomponents. Dose proportionality, covariate effects on exposure, and exposure-response for change in glycated hemoglobin were analyzed based on data from a randomized treat-to-target phase 3 study in subjects with type 2 diabetes. Overall, the PK properties of IDeg and liraglutide were preserved for IDegLira. Liraglutide exposure was lower when dosed as IDegLira but met the criterion for equivalence. No relevant deviations from dose proportionality for the IDegLira components were observed. Covariate effects on exposure were consistent with previous results. Glycemic response to IDegLira was larger than with IDeg or liraglutide alone, reflecting their distinct glucose-lowering effects throughout the dose/exposure range. PMID:25998481

  9. Experimental strategy for translational studies of organophosphorus pesticide neurotoxicity based on real-world occupational exposures to chlorpyrifos

    PubMed Central

    Lein, Pamela J.; Bonner, Matthew R.; Farahat, Fayssal M.; Olson, James R.; Rohlman, Diane S.; Fenske, Richard A.; Lattal, K. Matthew; Lasarev, Michael R.; Galvin, Kit; Farahat, Taghreed M.; Anger, W. Kent

    2012-01-01

    Translational research is needed to understand and predict the neurotoxic consequences associated with repeated occupational exposures to organophosphorus pesticides (OPs). In this report, we describe a research strategy for identifying biomarkers of OP neurotoxicity, and we characterize pesticide application workers in Egypt’s Menoufia Governorate who serve as our anchor human population for developing a parallel animal model with similar exposures and behavioral deficits and for examining the influence of human polymorphisms in cytochrome P450 (CYP) and paraoxonase 1 (PON1) enzymes on OP metabolism and toxicity. This population has previously been shown to have high occupational exposures and to exhibit a broad range of neurobehavioral deficits. In addition to observational studies of work practices in the field, questionnaires on demographics, lifestyle and work practices were administered to 146 Egyptian pesticide application workers applying pesticides to the cotton crop. Survey results indicated that the application workforce uses standard operating procedures and standardized equipment provided by Egypt’s Ministry of Agriculture, which provides a workforce with a stable work history. We also found that few workers report using personal protective equipment (PPE), which likely contributes to the relatively high exposures reported in these application workers. In summary, this population provides a unique opportunity for identifying biomarkers of OP-induced neurotoxicity associated with occupational exposure. PMID:22240005

  10. Population pharmacokinetics and exposure-uric acid analyses after single and multiple doses of ABT-639, a calcium channel blocker, in healthy volunteers.

    PubMed

    An, Guohua; Liu, Wei; Duan, W Rachel; Nothaft, Wolfram; Awni, Walid; Dutta, Sandeep

    2015-03-01

    ABT-639 is a selective T-type calcium channel blocker with efficacy in a wide range of preclinical models of nociceptive and neuropathic pain. In the current first-in-human (FIH) study, the pharmacokinetics, tolerability, and safety of ABT-639 after single- (up to 170 mg) and multiple doses (up to 160 mg BID) were evaluated in healthy volunteers in a randomized, double-blinded, placebo-controlled manner. ABT-639 demonstrated acceptable safety and pharmacokinetic profiles in human. Results from assessment of the routine laboratory variables showed an unexpected statistically significant and clinically relevant decrease in blood uric acid with the increase in ABT-639 dose, which is possibly due to inhibition in URAT1 transporter. Pharmacokinetic/pharmacodynamic models were constructed to characterize the relationship between ABT-639 exposure and uric acid response. The final model was a mechanism-based indirect response pharmacodynamic model with the stimulation of uric acid elimination by ABT-639. The model estimated K in values in males and females were 10.2 and 7.13 μmol/h, respectively. The model estimated K out was 0.033 1/h. ABT-639 concentration that can produce 50% stimulation in uric acid elimination was estimated to be 8,070 ng/mL. Based on the final model, further simulations were conducted to predict the effect of ABT-639 on uric acid in gout patients. The simulation results indicated that, if the urate-lowering response to ABT-639 in gout patients is similar to that in healthy subjects, ABT-639 BID doses of 140 mg or higher would be expected to provide clinically meaningful lowering of blood uric acid levels below the 380 μmol/L solubility limit of monosodium urate. PMID:25567367

  11. Effects on Pharmacokinetics of Propranolol and Other Factors in Rats After Acute Exposure to High Altitude at 4,010 m.

    PubMed

    Wenbin, Li; Rong, Wang; Hua, Xie; Juanhong, Zhang; Xiaoyu, Wu; Zhengping, Jia

    2015-05-01

    A series of pathological, physiological, and biochemical changes, even anatomical histological changes happen while humans arrive at the high plateau region from plain area. There is a certain relationship between the body's compensatory or decompensated adjustments to the environment and the changes of absorption, distribution, metabolism, and excretion of drugs. The objective of the study is to observe the effects of acute exposure to high altitude at 4,010 m on pharmacokinetics of propranolol in rats, and to provide basis and new ideas to adjust drug dosage and administration, so as to promote rational drug use in high altitude. 28 healthy male wistar rats were randomly divided into four groups, group A and B which were in plain area; group C and D which were acutely exposed to high altitude by aviation; group A and C were used for pharmacokinetics determination of propranolol, while group B and D had no drug administration for physiological and pathological changes research at high altitude. The pharmacokinetics of propranolol significantly changed; area under curve, C max (the peak concentration), mean residence time, and t 1/2 (the biological half-life) increased significantly by 481.72, 398.94, 44.87, and 58.77 %, respectively; clearance and V (apparent volume of distribution) decreased by 81.50 and 70.56 %, respectively, after acute exposure to high altitude at 4,010 m; Analytic results show that pH, buffer base, base excess, ctCO2 (content of total carbon dioxide), sO2 (oxygen saturation of arterial blood), pO2 (oxygen tension of arterial blood), and cNa(+) severely decreased by 2.43, 630.00, 311.00, 11.48, 91.38, 76.22, and 2.82 %, respectively, while pCO2 (carbon dioxide tension of arterial blood) and cCl(-) significantly increased by 47.40 and 6.76 %. Lactate dehydrogenase and total protein significantly decreased by 58.44 and 26.82 %, while total bilirubin and alkaline phosphatase severely increased by 338 and 24.94 % after acute exposure to high

  12. Translational Epidemiologic Approaches to Understanding the Consequences of Early-Life Exposures.

    PubMed

    D'Onofrio, Brian M; Class, Quetzal A; Rickert, Martin E; Sujan, Ayesha C; Larsson, Henrik; Kuja-Halkola, Ralf; Sjölander, Arvid; Almqvist, Catarina; Lichtenstein, Paul; Oberg, A Sara

    2016-05-01

    Prominent developmental theories posit a causal link between early-life exposures and later functioning. Yet, observed associations with early exposures may not reflect causal effects because of genetic and environmental confounding. The current manuscript describes how a systematic series of epidemiologic analyses that combine several genetically-informative designs and statistical approaches can help distinguish between competing theories. In particular, the manuscript details how combining the use of measured covariates with sibling-comparisons, cousin-comparisons, and additional designs can help elucidate the sources of covariation between early-life exposures and later outcomes, including the roles of (a) factors that are not shared in families, including a potential causal effect of the exposure; (b) carryover effects from the exposure of one child to the next; and (c) familial confounding. We also describe key assumptions and how they can be critically evaluated. Furthermore, we outline how subsequent analyses, including effect decomposition with respect to measured, plausible mediators, and quantitative genetic models can help further specify the underlying processes that account for the associations between early-life exposures and offspring outcomes. PMID:26590988

  13. Understanding the translation of scientific knowledge about arsenic risk exposure among private well water users in Nova Scotia.

    PubMed

    Chappells, Heather; Campbell, Norma; Drage, John; Fernandez, Conrad V; Parker, Louise; Dummer, Trevor J B

    2015-02-01

    Arsenic is a class I human carcinogen that has been identified as the second most important global health concern in groundwater supplies after contamination by pathogenic organisms. Hydrogeological assessments have shown naturally occurring arsenic to be widespread in groundwater across the northeastern United States and eastern Canada. Knowledge of arsenic risk exposure among private well users in these arsenic endemic areas has not yet been fully explored but research on water quality perceptions indicates a consistent misalignment between public and scientific assessments of environmental risk. This paper evaluates knowledge of arsenic risk exposure among a demographic cross-section of well users residing in 5 areas of Nova Scotia assessed to be at variable risk (high-low) of arsenic occurrence in groundwater based on water sample analysis. An integrated knowledge-to-action (KTA) methodological approach is utilized to comprehensively assess the personal, social and local factors shaping perception of well water contaminant risks and the translation of knowledge into routine water testing behaviors. Analysis of well user survey data (n=420) reveals a high level of confidence in well water quality that is unrelated to the relative risk of arsenic exposure or homeowner adherence to government testing recommendations. Further analysis from the survey and in-depth well user interviews (n=32) finds that well users' assessments of risk are influenced by personal experience, local knowledge, social networks and convenience of infrastructure rather than by formal information channels, which are largely failing to reach their target audiences. Insights from interviews with stakeholders representing government health and environment agencies (n=15) are used to reflect on the institutional barriers that mediate the translation of scientific knowledge into public awareness and stewardship behaviors. The utilization of local knowledge brokers, community-based networks and

  14. INTEGRATED PROBABILISTIC AND DETERMINISTIC MODELING TECHNIQUES IN ESTIMATING EXPOSURE TO WATER-BORNE CONTAMINANTS: PART 2 PHARMACOKINETIC MODELING

    EPA Science Inventory

    The Total Exposure Model (TEM) uses deterministic and stochastic methods to estimate the exposure of a person performing daily activities of eating, drinking, showering, and bathing. There were 250 time histories generated, by subject with activities, for the three exposure ro...

  15. Exposure to early adversity: Points of cross-species translation that can lead to improved understanding of depression.

    PubMed

    Andersen, Susan L

    2015-05-01

    The relationship between developmental exposure to adversity and affective disorders is reviewed. Adversity discussed herein includes physical and sexual abuse, neglect, or loss of a caregiver in humans. While these stressors can occur at any point during development, the unique temporal relationship to specific depressive symptoms was the focus of discussion. Further influences of stress exposure during sensitive periods can vary by gender and duration of abuse as well. Data from animal studies are presented to provide greater translational and causal understanding of how sensitive periods, different types of psychosocial stressors, and sex interact to produce depressive-like behaviors. Findings from maternal separation, isolation rearing, chronic variable stress, and peer-peer rearing paradigms clarify interpretation about how various depressive behaviors are influenced by age of exposure. Depressive behaviors are broken down into the following categories: mood and affect, anhedonia, energy, working memory, sleep-wake, appetite changes, suicide, and general malaise. Cross-species evidence from humans, nonhuman primates, rats, and mice within each of these categories is discussed. In conclusion, sensitive periods for affective-related behaviors (anxiety, mood, and controllability) occur earlier in life, while other aspects of depression are associated with adversity later during adolescence. PMID:25997766

  16. A Workflow to Investigate Exposure and Pharmacokinetic Influences on High-Throughput in Vitro Chemical Screening Based on Adverse Outcome Pathways

    PubMed Central

    Phillips, Martin B.; Leonard, Jeremy A.; Grulke, Christopher M.; Chang, Daniel T.; Edwards, Stephen W.; Brooks, Raina; Goldsmith, Michael-Rock; El-Masri, Hisham; Tan, Yu-Mei

    2015-01-01

    Background Adverse outcome pathways (AOPs) link adverse effects in individuals or populations to a molecular initiating event (MIE) that can be quantified using in vitro methods. Practical application of AOPs in chemical-specific risk assessment requires incorporation of knowledge on exposure, along with absorption, distribution, metabolism, and excretion (ADME) properties of chemicals. Objectives We developed a conceptual workflow to examine exposure and ADME properties in relation to an MIE. The utility of this workflow was evaluated using a previously established AOP, acetylcholinesterase (AChE) inhibition. Methods Thirty chemicals found to inhibit human AChE in the ToxCast™ assay were examined with respect to their exposure, absorption potential, and ability to cross the blood–brain barrier (BBB). Structures of active chemicals were compared against structures of 1,029 inactive chemicals to detect possible parent compounds that might have active metabolites. Results Application of the workflow screened 10 “low-priority” chemicals of 30 active chemicals. Fifty-two of the 1,029 inactive chemicals exhibited a similarity threshold of ≥ 75% with their nearest active neighbors. Of these 52 compounds, 30 were excluded due to poor absorption or distribution. The remaining 22 compounds may inhibit AChE in vivo either directly or as a result of metabolic activation. Conclusions The incorporation of exposure and ADME properties into the conceptual workflow eliminated 10 “low-priority” chemicals that may otherwise have undergone additional, resource-consuming analyses. Our workflow also increased confidence in interpretation of in vitro results by identifying possible “false negatives.” Citation Phillips MB, Leonard JA, Grulke CM, Chang DT, Edwards SW, Brooks R, Goldsmith MR, El-Masri H, Tan YM. 2016. A workflow to investigate exposure and pharmacokinetic influences on high-throughput in vitro chemical screening based on adverse outcome pathways. Environ

  17. Influence of virtual height exposure on postural reactions to support surface translations.

    PubMed

    Cleworth, Taylor W; Chua, Romeo; Inglis, J Timothy; Carpenter, Mark G

    2016-06-01

    As fear of falling is related to the increased likelihood of falls, it is important to understand the effects of threat-related factors (fear, anxiety and confidence) on dynamic postural reactions. Previous studies designed to examine threat effects on dynamic postural reactions have methodological limitations and lack a comprehensive analysis of simultaneous kinetic, kinematic and electromyographical recordings. The current study addressed these limitations by examining postural reactions of 26 healthy young adults to unpredictable anterior-posterior support-surface translations (acceleration=0.6m/s(2), constant velocity=0.25m/s, total displacement=0.75m) while standing on a narrow virtual surface at Low (0.4cm) and High (3.2m) virtual heights. Standing at virtual height increased fear and anxiety, and decreased confidence. Prior to perturbations, threat led to increased tonic muscle activity in tibialis anterior, resulting in a higher co-contraction index between lower leg muscles. For backward perturbations, muscle activity in the lower leg and arm, and center of pressure peak displacements, were earlier and larger when standing at virtual height. In addition, arm flexion significantly increased while leg, trunk and center of mass displacements remained unchanged across heights. When controlling for leaning, threat-related factors can influence the neuro-mechanical responses to an unpredictable perturbation, causing specific characteristics of postural reactions to be facilitated in young adults when their balance is threatened. PMID:27264411

  18. Effect of Short-Term Drinking Water Exposure to Dichloroacetate on its Pharmacokinetics and Oral Bioavailability in Human Volunteers: A Stable Isotope Study

    SciTech Connect

    Schultz, Irv R.; Shangraw, Robert E.

    2006-06-21

    Dichloroacetic acid (DCAA) is a by-product of drinking water disinfection, a known rodent hepatocarcinogen and is also used therapeutically to treat a variety of metabolic disorders in humans. We measured DCAA bioavailability in 16 human volunteers (8 male, 8 female) after simultaneous administration of oral and iv DCAA doses. Volunteers consumed DCAA-free bottled water for 2 weeks to wash out background effects of DCAA. Subsequently, each subject drank 12C-DCAA (2 mg/kg) in 500 ml water over three minutes. Five minutes after the start of the 12C-DCAA consumption, 13C-labeled DCAA (0.3 mg/kg) was administered iv over 20 seconds, and plasma 12C/13C-DCAA concentrations measured at predetermined time points over 4 h. Volunteers subsequently consumed DCAA 0.02 mg/kg/day in 500 ml water for 14 consecutive days to simulate a low-level chronic DCAA intake. Afterwards, the 12C/13C-DCAA administrations was repeated. Study endpoints were calculation of AUC0??, apparent volume of distribution (Vss), total body clearance (Clb), plasma elimination half-life (t?,?), oral absorption rate (Ka), and oral bioavailability. Oral bioavailability was estimated from dose-adjusted AUC ratios, and by using a compartmental pharmacokinetic model after simultaneous fitting of oral and iv DCAA concentration-time profiles. DCAA bioavailability had large inter-individual variation, ranging from 28 ? 100 %. In the absence of prior DCAA intake, there were no significant differences (p>0.05) in any pharmacokinetic parameters between male and female volunteers, although there was a trend that women absorbed DCAA was more rapidly (increased Ka), and cleared DCAA more slowly (decreased Clb), than men. Only women were affected by previous 14 d DCAA exposure, which increased the AUC0?? for both oral and i.v. DCAA doses (P<0.04; 0.014 respectively) with a corresponding decrease in the Clb.

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

    PubMed Central

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

    2016-01-01

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

  20. Age-dependent pharmacokinetic and pharmacodynamic response in preweanling rats following oral exposure to the organophosphorus insecticide chlorpyrifos

    SciTech Connect

    Timchalk, Chuck; Poet, Torka S.; Kousba, Ahmed A.

    2006-03-01

    Juvenile rats are more susceptible than adults to the acute toxicity of organophosphorus insecticides like chlorpyrifos (CPF). Age- and dose-dependent differences in metabolism may be responsible. Of importance is CYP450 activation and detoxification of CPF to CPF-oxon and 3,5,6-trichloro-2-pyridinol (TCP), as well as B-esterase (cholinesterase; ChE) and A-esterase (PON-1) detoxification of CPF-oxon to TCP. The pharmacokinetics of CPF, TCP, and the extent of blood (plasma/RBC), and brain ChE inhibition in rats were determined on postnatal days (PND) -5, -12, and -17 following oral gavage administration of 1 and 10 mg CPF/kg of body weight. For all neonatal ages the blood TCP exceeded the CPF concentration, and within each age group there was no evidence of non-linear kinetics over the dose range evaluated. Younger animals demonstrated a greater sensitivity to ChE inhibition as evident by the dose- and age-dependent inhibition of plasma, RBC, and brain ChE. Of particular importance was the observation that even in rats as young as PND-5, the CYP450 metabolic capacity was adequate to metabolize CPF to both TCP and CPF-oxon based on the detection of TCP in blood and extensive ChE inhibition (biomarker of CPF-oxon) at all ages. In addition, the increase in the blood TCP concentration ({approx}3-fold) in PND-17 rats relative to the response in the younger animals, and the higher blood concentrations of CPF in neonatal rats (1.7 to 7.5-fold) relative to adults was consistent with an increase in CYP450 metabolic capacity with age. This is the first reported study that evaluated both the pharmacokinetics of the parent pesticide, the major metabolite and the extent of ChE inhibition dynamics in the same animals as a function of neonatal age. The results suggest that in the neonatal rat, CPF was rapidly absorbed and metabolized, and the extent of metabolism was age-dependent.

  1. EXPOSURE RELATED DOSE ESTIMATING MODEL ( ERDEM ) A PHYSIOLOGICALLY-BASED PHARMACOKINETIC AND PHARMACODYNAMIC ( PBPK/PD ) MODEL FOR ASSESSING HUMAN EXPOSURE AND RISK

    EPA Science Inventory

    The Exposure Related Dose Estimating Model (ERDEM) is a PBPK/PD modeling system that was developed by EPA's National Exposure Research Laboratory (NERL). The ERDEM framework provides the flexibility either to use existing models and to build new PBPK and PBPK/PD models to address...

  2. Metabolite pharmacokinetics of soman, sarin, and GF in rats and biological monitoring of exposure to toxic organophosphorus agents

    SciTech Connect

    Shih, M.L.; McMonagle, J.D.; Dolzine, T.W.; Gresham, V.C.

    1993-05-13

    This study reports on the pharmacokinetics of the elimination of the metabolites of three toxic organophosphorus compounds (Soman, sarin, and GF). Urine, blood, and lung tissue were collected from rats dosed via subcutaneous route at 75 ug/Kg. Urinary excretion of the metabolite was the major elimination route for these three compounds. The major differences among them were primarily the extent and rate of excretion. The hydrolyzed form, alkylmethylphosphonic acid, was the single major metabolite formed and excreted in urine by a nonsaturable mechanism. Nearly total recoveries of the given doses for sarin and GF in metabolite form were obtained from the urine. The terminal elimination half-lives in urine were 6 and 15 hours for sarin and GF, respectively. Soman metabolite showed a biphasic elimination curve with terminal half-lives of 24 and 14 hours approximately. Soman was excreted at a slower rate with a recovery of only about 60%. Lung was the major organ of accumulation for soman. In blood the toxic agents were concentrated more in red blood cells than in plasma.

  3. A Semiphysiologically Based Pharmacokinetic Modeling Approach to Predict the Dose-Exposure Relationship of an Antiparasitic Prodrug/Active Metabolite Pair

    PubMed Central

    Yan, Grace Zhixia; Generaux, Claudia N.; Yoon, Miyoung; Goldsmith, Rachel B.; Tidwell, Richard R.; Hall, James E.; Olson, Carol A.; Clewell, Harvey J.; Brouwer, Kim L. R.

    2012-01-01

    Dose selection during antiparasitic drug development in animal models and humans traditionally has relied on correlations between plasma concentrations obtained at or below maximally tolerated doses that are efficacious. The objective of this study was to improve the understanding of the relationship between dose and plasma/tissue exposure of the model antiparasitic agent, pafuramidine, using a semiphysiologically based pharmacokinetic (semi-PBPK) modeling approach. Preclinical and clinical data generated during the development of pafuramidine, a prodrug of the active metabolite, furamidine, were used. A whole-body semi-PBPK model for rats was developed based on a whole-liver PBPK model using rat isolated perfused liver data. A whole-body semi-PBPK model for humans was developed on the basis of the whole-body rat model. Scaling factors were calculated using metabolic and transport clearance data generated from rat and human sandwich-cultured hepatocytes. Both whole-body models described pafuramidine and furamidine disposition in plasma and predicted furamidine tissue (liver and kidney) exposure and excretion profiles (biliary and renal). The whole-body models predicted that the intestine contributes significantly (30–40%) to presystemic furamidine formation in both rats and humans. The predicted terminal elimination half-life of furamidine in plasma was 3- to 4-fold longer than that of pafuramidine in rats (170 versus 47 h) and humans (64 versus 19 h). The dose-plasma/tissue exposure relationship for the prodrug/active metabolite pair was determined using the whole-body models. The human model proposed a dose regimen of pafuramidine (40 mg once daily) based on a predefined efficacy-safety index. A similar approach could be used to guide dose-ranging studies in humans for next-in-class compounds. PMID:21953913

  4. A pharmacokinetic model of cis- and trans-permethrin disposition in rats and humans with aggregate exposure application

    EPA Science Inventory

    Permethrin is a broad-spectrum pyrethroid insecticide and among the most widely used insecticides in homes and crops. Managing the risks for pesticides such as permethrin depends on the ability to consider diverse exposure scenarios and their relative risks. Physiologically-base...

  5. A PHARMACOKINETIC MODEL FOR ESTIMATING EXPOSURE OF AMERICANS TO DIOXIN-LIKE COMPOUNDS IN THE PAST, PRESENT, AND FUTURE

    EPA Science Inventory

    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 199...

  6. THE UNIQUE VALUE OF BREATH BIOMARKERS FOR ESTIMATING PHARMACOKINETIC RATE CONSTANTS AND BODY BURDEN FROM ENVIRONMENTAL EXPOSURES

    EPA Science Inventory

    Although detection of breath odor is the oldest of the medical diagnostic techniques, blood and urine biomarker measurements are the current "gold standard" for modern exposure and health assessments. Of late, it has been recognized that collecting exhaled breath is an attractiv...

  7. THE DEVELOPMENT OF PHARMACOKINETIC PARAMETERS FOR PREDICTING THE EFFECTS OF PESTICIDES

    EPA Science Inventory

    This research involves the development and improvement of pharmacokinetic data for predicting the effects of exposure to pyrethroid pesticides. Pharmacokinetics address the exposure-dose relationship in an organism, and resulting data are useful for making extrapolations between...

  8. The application of global sensitivity analysis in the development of a physiologically based pharmacokinetic model for m-xylene and ethanol co-exposure in humans.

    PubMed

    Loizou, George D; McNally, Kevin; Jones, Kate; Cocker, John

    2015-01-01

    Global sensitivity analysis (SA) was used during the development phase of a binary chemical physiologically based pharmacokinetic (PBPK) model used for the analysis of m-xylene and ethanol co-exposure in humans. SA was used to identify those parameters which had the most significant impact on variability of venous blood and exhaled m-xylene and urinary excretion of the major metabolite of m-xylene metabolism, 3-methyl hippuric acid. This analysis informed the selection of parameters for estimation/calibration by fitting to measured biological monitoring (BM) data in a Bayesian framework using Markov chain Monte Carlo (MCMC) simulation. Data generated in controlled human studies were shown to be useful for investigating the structure and quantitative outputs of PBPK models as well as the biological plausibility and variability of parameters for which measured values were not available. This approach ensured that a priori knowledge in the form of prior distributions was ascribed only to those parameters that were identified as having the greatest impact on variability. This is an efficient approach which helps reduce computational cost. PMID:26175688

  9. The application of global sensitivity analysis in the development of a physiologically based pharmacokinetic model for m-xylene and ethanol co-exposure in humans

    PubMed Central

    Loizou, George D.; McNally, Kevin; Jones, Kate; Cocker, John

    2015-01-01

    Global sensitivity analysis (SA) was used during the development phase of a binary chemical physiologically based pharmacokinetic (PBPK) model used for the analysis of m-xylene and ethanol co-exposure in humans. SA was used to identify those parameters which had the most significant impact on variability of venous blood and exhaled m-xylene and urinary excretion of the major metabolite of m-xylene metabolism, 3-methyl hippuric acid. This analysis informed the selection of parameters for estimation/calibration by fitting to measured biological monitoring (BM) data in a Bayesian framework using Markov chain Monte Carlo (MCMC) simulation. Data generated in controlled human studies were shown to be useful for investigating the structure and quantitative outputs of PBPK models as well as the biological plausibility and variability of parameters for which measured values were not available. This approach ensured that a priori knowledge in the form of prior distributions was ascribed only to those parameters that were identified as having the greatest impact on variability. This is an efficient approach which helps reduce computational cost. PMID:26175688

  10. Pharmacokinetic and Genomic Effects of Arsenite in Drinking Water on Mouse Lung in a 30-Day Exposure

    PubMed Central

    Chilakapati, Jaya; Wallace, Kathleen; Hernandez-Zavala, Araceli; Moore, Tanya; Ren, Hongzu

    2015-01-01

    The 2 objectives of this subchronic study were to determine the arsenite drinking water exposure dependent increases in female C3H mouse liver and lung tissue arsenicals and to characterize the dose response (to 0, 0.05, 0.25, 1, 10, and 85 ppm arsenite in drinking water for 30 days and a purified AIN-93M diet) for genomic mouse lung expression patterns. Mouse lungs were analyzed for inorganic arsenic, monomethylated, and dimethylated arsenicals by hydride generation atomic absorption spectroscopy. The total lung mean arsenical levels were 1.4, 22.5, 30.1, 50.9, 105.3, and 316.4 ng/g lung tissue after 0, 0.05, 0.25, 1, 10, and 85 ppm, respectively. At 85 ppm, the total mean lung arsenical levels increased 14-fold and 131-fold when compared to either the lowest noncontrol dose (0.05 ppm) or the control dose, respectively. We found that arsenic exposure elicited minimal numbers of differentially expressed genes (DEGs; 77, 38, 90, 87, and 87 DEGs) after 0.05, 0.25, 1, 10, and 85 ppm, respectively, which were associated with cardiovascular disease, development, differentiation, apoptosis, proliferation, and stress response. After 30 days of arsenite exposure, this study showed monotonic increases in mouse lung arsenical (total arsenic and dimethylarsinic acid) concentrations but no clear dose-related increases in DEG numbers. PMID:26674514

  11. Short inhalation exposures of the isolated and perfused rat lung to respirable dry particle aerosols; the detailed pharmacokinetics of budesonide, formoterol, and terbutaline.

    PubMed

    Ewing, Per; Eirefelt, Stefan J; Andersson, Paul; Blomgren, Anders; Ryrfeldt, Ake; Gerde, Per

    2008-06-01

    There is an increasing interest in using the lung as a route of entry for both local and systemic administration of drugs. However, because adequate technologies have been missing in the preclinical setting, few investigators have addressed the detailed disposition of drugs in the lung following short inhalation exposures to highly concentrated dry powder aerosols. New methods are needed to explore the disposition of drugs after short inhalation exposures, thus mimicking a future clinical use. Our aim was to study the pulmonary disposition of budesonide, formoterol, and terbutaline, which are clinically used for the treatment of bronchial asthma. Using the recently developed DustGun aerosol technology, we exposed by inhalation for approximately 1 min the isolated and perfused rat lung (IPL) to respirable dry particle aerosols of the three drugs at high concentrations. The typical aerosol concentration was 1 mug/mL, and the particle size distribution of the tested substances varied with a MMAD ranging from 2.3 to 5.3 mum. The IPL was perfused in single pass mode and repeated samples of the perfusate were taken for up to 80 min postexposure. The concentration of drug in perfusate and in lung extracts was measured using LC-MS/MS. The deposited dose was determined by adding the amounts of drug collected in perfusate to the amount extracted from the tissues at 80 min. Deposited amounts of budesonide, formoterol fumarate, and terbutaline sulphate were 23 +/- 17, 36 +/- 8, and 60 +/- 3.2 mug (mean +/- SD, n = 3), respectively. Retention in lung tissues at the end of the perfusion period expressed as fraction of deposited dose was 0.19 +/- 0.05, 0.19 +/- 0.06, and 0.04 +/- 0.01 (mean +/- SD, n = 3) for budesonide, formoterol, and terbutaline, respectively. Each short inhalation exposure to the highly concentrated aerosols consumed 1-3 mg powder. Hence, this system can be particularly useful for obtaining a detailed pharmacokinetic characterization of inhaled compounds in

  12. 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…

  13. The Safety and Pharmacokinetics of Carprofen, Flunixin and Phenylbutazone in the Cape Vulture (Gyps coprotheres) following Oral Exposure.

    PubMed

    Fourie, Tamsyn; Cromarty, Duncan; Duncan, Neil; Wolter, Kerri; Naidoo, Vinny

    2015-01-01

    The following study evaluates the overt toxic potential of carprofen (CRP), flunixin (FXN) and phenylbutazone (PBZ) in Old world vultures in relation to historic toxicity data for diclofenac and ketoprofen, with the Cape vulture (Gyps coprotheres) being the indicator species. The toxic potential of a single oral dose of CRP (11.5 mg/kg), FXN (1 mg/kg),PBZ (1.7 mg/kg) or water was evaluated by means of a four-way parallel study (n = 2), as means of ascertaining if these drugs were as toxic as diclofenac in the vulture. No unscheduled deaths or pathological lesions were noted following exposure. Clinical signs of lethargy and depression were, however, noted in one CRP, two FXN and one PBZ treated birds. Mild reversible inhibition of UA excretion was evident in all three groups, although UA remained within the population reference interval in contrast to the effects previously described for diclofenac and ketoprofen. All treatment groups had a drug concentration responsive increase in alanine transferase activity. CRP, FXN and PBZ were characterised by a maximum plasma concentration (Cmax) of 1051.8 ± 620.7 ng/ml, 335.9 ± 36.3 ng/ml and 11150 ± 2474.9 ng/ml at 4 ± 4.3, 0.45 ± 0.02 and 5.3 ± 5.2 hours (Tmax) respectively and a half-life of elimination of 13.3 ±5, 1.8±1 and 18.7 ±11.4 hours respectively. While we could not demonstrate a lethal effect of the tested substances, the presence of toxic clinical signs, clinical pathological changes and/or long half-lives of elimination suggests that all three drugs have a potential for toxicity in a larger population or on repeat administration. In conclusion while the studied substances were not as overtly toxic as diclofenac, they are of safety concern. PMID:26512724

  14. The Safety and Pharmacokinetics of Carprofen, Flunixin and Phenylbutazone in the Cape Vulture (Gyps coprotheres) following Oral Exposure

    PubMed Central

    Fourie, Tamsyn; Cromarty, Duncan; Duncan, Neil; Wolter, Kerri; Naidoo, Vinny

    2015-01-01

    The following study evaluates the overt toxic potential of carprofen (CRP), flunixin (FXN) and phenylbutazone (PBZ) in Old world vultures in relation to historic toxicity data for diclofenac and ketoprofen, with the Cape vulture (Gyps coprotheres) being the indicator species. The toxic potential of a single oral dose of CRP (11.5 mg/kg), FXN (1 mg/kg),PBZ (1.7 mg/kg) or water was evaluated by means of a four-way parallel study (n = 2), as means of ascertaining if these drugs were as toxic as diclofenac in the vulture. No unscheduled deaths or pathological lesions were noted following exposure. Clinical signs of lethargy and depression were, however, noted in one CRP, two FXN and one PBZ treated birds. Mild reversible inhibition of UA excretion was evident in all three groups, although UA remained within the population reference interval in contrast to the effects previously described for diclofenac and ketoprofen. All treatment groups had a drug concentration responsive increase in alanine transferase activity. CRP, FXN and PBZ were characterised by a maximum plasma concentration (Cmax) of 1051.8 ± 620.7 ng/ml, 335.9 ± 36.3 ng/ml and 11150 ± 2474.9 ng/ml at 4 ± 4.3, 0.45 ± 0.02 and 5.3 ± 5.2 hours (Tmax) respectively and a half-life of elimination of 13.3 ±5, 1.8±1 and 18.7 ±11.4 hours respectively. While we could not demonstrate a lethal effect of the tested substances, the presence of toxic clinical signs, clinical pathological changes and/or long half-lives of elimination suggests that all three drugs have a potential for toxicity in a larger population or on repeat administration. In conclusion while the studied substances were not as overtly toxic as diclofenac, they are of safety concern. PMID:26512724

  15. [Cephalexin pharmacokinetics].

    PubMed

    Koroleva, V G; Vasil'ev, V K; Danilova, V I; Firsov, A A

    1981-03-01

    The pharmacokinetics of cephalexin monohydrate after its oral administration in a single dose was studied on rats and dogs. The analysis of the pharmacokinetic data obtained with the one-compartmental model showed that the rate of the antibiotic absorption in the rats was higher than that in the dogs. The periods of the cephalexin half-absorption and maximum concentration were 0.2 and 1.1 hour in the rats and 0.64 and 1.9 hours in the dogs respectively. The period of the antibiotic half-life was almost the same in both animal species. Selective localization of cephalexin in the kidney and liver tissues was noted. The antibiotic was mainly excreted by the kidneys (98.8 per cent for 24 hours). PMID:7235651

  16. Modeling Pharmacokinetics.

    PubMed

    Bois, Frederic Y; Brochot, Céline

    2016-01-01

    Pharmacokinetics is the study of the fate of xenobiotics in a living organism. Physiologically based pharmacokinetic (PBPK) models provide realistic descriptions of xenobiotics' absorption, distribution, metabolism, and excretion processes. They model the body as a set of homogeneous compartments representing organs, and their parameters refer to anatomical, physiological, biochemical, and physicochemical entities. They offer a quantitative mechanistic framework to understand and simulate the time-course of the concentration of a substance in various organs and body fluids. These models are well suited for performing extrapolations inherent to toxicology and pharmacology (e.g., between species or doses) and for integrating data obtained from various sources (e.g., in vitro or in vivo experiments, structure-activity models). In this chapter, we describe the practical development and basic use of a PBPK model from model building to model simulations, through implementation with an easily accessible free software. PMID:27311461

  17. Vorinostat with Sustained Exposure and High Solubility in Poly(ethylene glycol)-b-poly(DL-lactic acid) Micelle Nanocarriers: Characterization and Effects on Pharmacokinetics in Rat Serum and Urine

    PubMed Central

    Mohamed, Elham A.; Zhao, Yunqi; Meshali, Mahasen M.; Remsberg, Connie M.; Borg, Thanaa M.; Foda, Abdel Monem M.; Takemoto, Jody K.; Sayre, Casey; Martinez, Stephanie; Davies, Neal M.; Forrest, M. Laird

    2015-01-01

    The histone deacetylase inhibitor suberoylanilide hydroxamic acid, known as vorinostat, is a promising anti-cancer drug with a unique mode of action; however, it is plagued by low water solubility, low permeability, and suboptimal pharmacokinetics. In this study, poly(ethylene glycol)-b-poly(DL-lactic acid) (PEG-b-PLA) micelles of vorinostat were developed. Vorinostat’s pharmacokinetics in rats were investigated after intravenous (i.v.) (10 mg/kg) and oral (50 mg/kg) micellar administrations and compared to a conventional PEG400 solution and methylcellulose suspension. The micelles increased the aqueous solubility of vorinostat from 0.2 mg/ml to 8.15 ± 0.60 mg/ml and 10.24 ± 0.92 mg/ml at drug to nanocarrier ratios of 1:10 and 1:15, respectively. Micelles had nanoscopic mean diameters of 75.67 ± 7.57 nm and 87.33 ± 8.62 nm for 1:10 and 1:15 micelles, respectively, with drug loading capacities of 9.93 ± 0.21% and 6.91 ± 1.19 %, and encapsulation efficiencies of 42.74 ± 1.67% and 73.29 ± 4.78%, respectively. The micelles provided sustained exposure and improved pharmacokinetics characterized by a significant increase in serum half-life, area under curve, and mean residence time. The micelles reduced vorinostat clearance particularly after i.v. dosing. Thus, PEG-b-PLA micelles significantly improved the oral and intravenous pharmacokinetics and bioavailability of vorinostat, which warrants further investigation. PMID:22806441

  18. Vorinostat with sustained exposure and high solubility in poly(ethylene glycol)-b-poly(DL-lactic acid) micelle nanocarriers: characterization and effects on pharmacokinetics in rat serum and urine.

    PubMed

    Mohamed, Elham A; Zhao, Yunqi; Meshali, Mahasen M; Remsberg, Connie M; Borg, Thanaa M; Foda, Abdel Monem M; Takemoto, Jody K; Sayre, Casey L; Martinez, Stephanie E; Davies, Neal M; Forrest, M Laird

    2012-10-01

    The histone deacetylase inhibitor suberoylanilide hydroxamic acid, known as vorinostat, is a promising anticancer drug with a unique mode of action; however, it is plagued by low water solubility, low permeability, and suboptimal pharmacokinetics. In this study, poly(ethylene glycol)-b-poly(DL-lactic acid) (PEG-b-PLA) micelles of vorinostat were developed. Vorinostat's pharmacokinetics in rats was investigated after intravenous (i.v.) (10 mg/kg) and oral (p.o.) (50 mg/kg) micellar administrations and compared with a conventional polyethylene glycol 400 solution and methylcellulose suspension. The micelles increased the aqueous solubility of vorinostat from 0.2 to 8.15 ± 0.60 and 10.24 ± 0.92 mg/mL at drug to nanocarrier ratios of 1:10 and 1:15, respectively. Micelles had nanoscopic mean diameters of 75.67 ± 7.57 and 87.33 ± 8.62 nm for 1:10 and 1:15 micelles, respectively, with drug loading capacities of 9.93 ± 0.21% and 6.91 ± 1.19%, and encapsulation efficiencies of 42.74 ± 1.67% and 73.29 ± 4.78%, respectively. The micelles provided sustained exposure and improved pharmacokinetics characterized by a significant increase in serum half-life, area under curve, and mean residence time. The micelles reduced vorinostat clearance particularly after i.v. dosing. Thus, PEG-b-PLA micelles significantly improved the p.o. and i.v. pharmacokinetics and bioavailability of vorinostat, which warrants further investigation. PMID:22806441

  19. Circulating factors induce coronary endothelial cell activation following exposure to inhaled diesel exhaust and nitrogen dioxide in humans: evidence from a novel translational in vitro model.

    PubMed

    Channell, Meghan M; Paffett, Michael L; Devlin, Robert B; Madden, Michael C; Campen, Matthew J

    2012-05-01

    The vascular toxicity of inhaled agents may be caused by soluble factors that are released into the systemic circulation. To confirm this in a straightforward manner, we obtained plasma from healthy human volunteers before and after exposure to diesel exhaust (DE) and nitrogen dioxide (NO(2)). Plasma samples were obtained from human volunteers exposed to 100 μg/m(3) DE or filtered air for 2 h. A second cohort was exposed to 500 ppb NO(2) or filtered air in an identical protocol. Primary human coronary artery endothelial cells (hCAECs) were grown to confluence and treated for 24 h with a 10 or 30% (in media) mixture of plasma obtained before, immediately post or 24 h postexposure to pollutant exposures. Messenger RNA (mRNA) was isolated from hCAECs following the incubation and probed for intracellular cell adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1) expression. ICAM-1 mRNA expression was increased by plasma obtained at both timepoints following the NO(2) exposures. VCAM-1 was significantly elevated in cells treated with plasma obtained 24 h following diesel exposure and at both timepoints following NO(2) exposure. Interleukin-8 protein was elevated in the hCAEC supernatant when cells were incubated with plasma from NO(2) exposures. These data indicate that proinflammatory circulating factors are elevated acutely following exposure to both DE and a primary component thereof, NO(2). These functional translational assays offer novel approaches to assessing the cardiovascular risk associated with air pollution exposure. PMID:22331494

  20. A PHYSIOLOGICALLY BASED PHARMACOKINETIC/PHARMACODYNAMIC (PBPK/PD) MODEL FOR ESTIMATION OF CUMULATIVE RISK FROM EXPOSURE TO THREE N-METHYL CARBAMATES: CARBARYL, ALDICARB, AND CARBOFURAN

    EPA Science Inventory

    A physiologically-based pharmacokinetic (PBPK) model for a mixture of N-methyl carbamate pesticides was developed based on single chemical models. The model was used to compare urinary metabolite concentrations to levels from National Health and Nutrition Examination Survey (NHA...

  1. PHARMACOKINETIC AND MECHANISTIC RESEARCH TO IMPROVE RISK ASSESSMENT FOR PRIORITY DISINFECTION BYPRODUCTS

    EPA Science Inventory

    A primary goal of this project is the development of physiologically based pharmacokinetics (PBPK) models for bromodichloromethane (BDCM) including a refined human pharmacokinetic model of the uptake and metabolism of BDCM administered by different routes of exposure. These effo...

  2. Pharmacokinetics and pharmacodynamics utilizing unbound target tissue exposure as part of a disposition-based rationale for lead optimization of benzoxaboroles in the treatment of Stage 2 Human African Trypanosomiasis.

    PubMed

    Wring, Stephen; Gaukel, Eric; Nare, Bakela; Jacobs, Robert; Beaudet, Beth; Bowling, Tana; Mercer, Luke; Bacchi, Cyrus; Yarlett, Nigel; Randolph, Ryan; Parham, Robin; Rewerts, Cindy; Platner, Jacob; Don, Robert

    2014-01-01

    SUMMARY This review presents a progression strategy for the discovery of new anti-parasitic drugs that uses in vitro susceptibility, time-kill and reversibility measures to define the therapeutically relevant exposure required in target tissues of animal infection models. The strategy is exemplified by the discovery of SCYX-7158 as a potential oral treatment for stage 2 (CNS) Human African Trypanosomiasis (HAT). A critique of current treatments for stage 2 HAT is included to provide context for the challenges of achieving target tissue disposition and the need for establishing pharmacokinetic-pharmacodynamic (PK-PD) measures early in the discovery paradigm. The strategy comprises 3 stages. Initially, compounds demonstrating promising in vitro activity and selectivity for the target organism over mammalian cells are advanced to in vitro metabolic stability, barrier permeability and tissue binding assays to establish that they will likely achieve and maintain therapeutic concentrations during in-life efficacy studies. Secondly, in vitro time-kill and reversibility kinetics are employed to correlate exposure (based on unbound concentrations) with in vitro activity, and to identify pharmacodynamic measures that would best predict efficacy. Lastly, this information is used to design dosing regimens for pivotal pharmacokinetic-pharmacodyamic studies in animal infection models. PMID:24007596

  3. Physiologically-based pharmacokinetic modelling of immune, reproductive and carcinogenic effects from contaminant exposure in polar bears (Ursus maritimus) across the Arctic.

    PubMed

    Dietz, Rune; Gustavson, Kim; Sonne, Christian; Desforges, Jean-Pierre; Rigét, Frank F; Pavlova, Viola; McKinney, Melissa A; Letcher, Robert J

    2015-07-01

    Polar bears (Ursus maritimus) consume large quantities of seal blubber and other high trophic marine mammals and consequently have some of the highest tissue concentrations of organohalogen contaminants (OHCs) among Arctic biota. In the present paper we carried out a risk quotient (RQ) evaluation on OHC-exposed polar bears harvested from 1999 to 2008 and from 11 circumpolar subpopulations spanning from Alaska to Svalbard in order to evaluate the risk of OHC-mediated reproductive effects (embryotoxicity, teratogenicity), immunotoxicity and carcinogenicity (genotoxicity). This RQ evaluation was based on the Critical Body Residue (CBR) concept and a Physiologically-Based Pharmacokinetic Modelling (PBPK) approach using OHC concentrations measured in polar bear adipose or liver tissue. The range of OHC concentrations within polar bear populations were as follows for adipose, sum polychlorinated biphenyls ∑PCBs (1797-10,537 ng/g lw), sum methylsulphone-PCB ∑MeSO2-PCBs (110-672 ng/g lw), sum chlordanes ∑CHLs (765-3477 ng/g lw), α-hexachlorocyclohexane α-HCH (8.5-91.3 ng/g lw), β-hexachlorocyclohexane β-HCH (65.5-542 ng/g lw), sum chlorbenzenes ∑ClBzs (145-304 ng/g lw), dichlorodiphenyltrichloroethane ∑DDTs (31.5-206 ng/g lw), dieldrin (69-249 ng/g lw), polybrominated diphenyl ethers ∑PBDEs (4.6-78.4 ng/g lw). For liver, the perfluorooctanesulfonic acid (PFOS) concentrations ranged from 231-2792 ng/g ww. The total additive RQ from all OHCs ranged from 4.3 in Alaska to 28.6 in East Greenland bears for effects on reproduction, immune health and carcinogenicity, highlighting the important result that the toxic effect threshold (i.e. RQ>1) was exceeded for all polar bear populations assessed. PCBs were the main contributors for all three effect categories, contributing from 70.6% to 94.3% of the total risk and a RQ between 3.8-22.5. ∑MeSO2-PCBs were the second highest effect contributor for reproductive and immunological effects (0.17

  4. Application of Physiologically Based Pharmacokinetic Models in Chemical Risk Assessment

    PubMed Central

    Mumtaz, Moiz; Fisher, Jeffrey; Blount, Benjamin; Ruiz, Patricia

    2012-01-01

    Post-exposure risk assessment of chemical and environmental stressors is a public health challenge. Linking exposure to health outcomes is a 4-step process: exposure assessment, hazard identification, dose response assessment, and risk characterization. This process is increasingly adopting “in silico” tools such as physiologically based pharmacokinetic (PBPK) models to fine-tune exposure assessments and determine internal doses in target organs/tissues. Many excellent PBPK models have been developed. But most, because of their scientific sophistication, have found limited field application—health assessors rarely use them. Over the years, government agencies, stakeholders/partners, and the scientific community have attempted to use these models or their underlying principles in combination with other practical procedures. During the past two decades, through cooperative agreements and contracts at several research and higher education institutions, ATSDR funded translational research has encouraged the use of various types of models. Such collaborative efforts have led to the development and use of transparent and user-friendly models. The “human PBPK model toolkit” is one such project. While not necessarily state of the art, this toolkit is sufficiently accurate for screening purposes. Highlighted in this paper are some selected examples of environmental and occupational exposure assessments of chemicals and their mixtures. PMID:22523493

  5. Pharmacokinetics in risk assessment: drinking water and health. Volume 8

    SciTech Connect

    Not Available

    1987-01-01

    Contents include: risk assessment: historical perspectives; tissue dosimetry in risk assessment; modeling: an introduction; physiologically based pharmacokinetic modeling; allometry: body-size constraints in animal design; prediction of in vivo parameters of drug metabolism and distribution from in-vitro studies; dose, species, and route extrapolation; uncertainty in pharmacokinetic models using SIMUSOLV; interspecies and dose-route extrapolations; carcinogen DNA adducts as a measure of biological dose for risk analysis of carcinogenic data; resources available for simulation in toxicology; route-to-route extrapolation of dichloromethane exposure using a physiological pharmacokinetic model; sensitivity analysis in pharmacokinetic modeling; mutation accumulation: chronic cytotoxicant exposure; model for ethylene chloride and its application in risk assessment; mathematical modeling of ozone absorption in the lower respiratory tract; development of a physiologically based pharmacokinetic model for multiday inhalation of carbon tetrachloride; the delivered/administered dose relationship and its impact on formaldehyde risk estimates; pharmacokinetic simulation in risk assessment; hazard assessment: ozone; role of pharmacokinetic modeling in risk assessment; development of multispecies, multiroute pharmacokinetic models for methylene chloride and 1,1,1-trichloroethane (methyl chloroform); methotrexate: pharmacokinetics and assessment of toxicity; prospective predictions and validations in anticancer therapy; the application of pharmacokinetic data in carcinogenic risk assessment.

  6. Clinical pharmacokinetics of ibuprofen arginine.

    PubMed

    Cattaneo, Dario; Clementi, Emilio

    2010-11-01

    Currently, several ibuprofen compounds are available on the market, mainly differing in terms of pharmaceutical composition that influence the pharmacokinetic profile and eventually the onset of drug action. This review will mainly deal with the clinical pharmacokinetics of ibuprofen arginine, an alternative formulation specifically designed to improve the absorption of ibuprofen. Indeed, available data from studies in healthy volunteers have consistently shown that the formulation of ibuprofen arginine is characterized by prompt absorption of ibuprofen as compared to the conventional formulation at all tested doses with higher peak plasma concentration and lower Tmax values. This trend has been confirmed also in studies dealing with chiral ibuprofen pharmacokinetics. Most importantly, the shortening in the absorption time observed either with racemic mixture or with the S(+)-enantiomer of ibuprofen arginine did not imply a faster drug elimination eventually leading to inadequate daily drug exposure, as documented by T1/2 and AUC values being comparable to those measured with the free acid form. Taken together, the pharmacokinetic/dynamic characteristics of ibuprofen arginine can be considered particularly favorable for several clinical conditions, such as moderate/severe pain, in which a rapid pharmacologic effect is required. PMID:20925647

  7. 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 ...

  8. Translators and Translation: 1974 Survey

    ERIC Educational Resources Information Center

    Caille, Pierre-Francois

    1974-01-01

    An international survey of conditions and practices involving translators deals with the following points: (1) change in the legal status and material situation of translators since 1968; (2) translators' associations; (3) translators' training, and (4) encouraging translation of contemporary works. (CK)

  9. Effect of short term and chronic administration of Sutherlandia frutescens on pharmacokinetics of nevirapine in rats

    PubMed Central

    Minocha, Mukul; Mandava, Nanda. K.; Kwatra, Deep; Pal, Dhananjay; Folk, William. R.; Earla, Ravinder; Mitra, Ashim. K.

    2011-01-01

    Sutherlandia frutescens (sutherlandia), an African herbal supplement is currently recommended by the South African Ministry of Health for the treatment of AIDS patients. However, no reports yet exist delineating the effect of sutherlandia on pharmacokinetics of antiretroviral agents. Therefore, this investigation aimed at screening the effects of short term and chronic exposure of sutherlandia on oral bioavailability and pharmacokinetics of nevirapine (NVP), a non nucleoside reverse transcriptase inhibitor, in Sprague Dawley rats. NVP (6 mg/kg) was administered orally alone (control) and with co-administration of sutherlandia; short term (12 mg/kg single dose) and long term (12mg/kg, once a day for 5 days). No significant difference in the pharmacokinetic parameters of NVP was found upon short term co-administration of Sutherlandia. However, there was a 50% decrease (p < 0.05) in the AUC and Cmax values of NVP after 5 days of chronic exposure with Sutherlandia. In addition, quantitative RT-PCR studies demonstrated a 2–3 fold increase in the hepatic and intestinal mRNA expression of CYP3A2, relative to vehicle control. To further confirm, if this could translate into a clinically relevant pharmacokinetic interaction in patients, we tested this hypothesis employing LS-180 cells as an in vitro induction model for human CYP3A4. Ninety six hours post treatment, similar to positive control rifampicin (25µM), sutherlandia extract (300µg/mL) resulted in elevated m-RNA expression levels and functional activity of CYP3A4 (human homologue of rodent CYP3A2) in LS-180 cells. Taken together, these results suggest that a potential drug-herb interaction is possible when NVP is co-administered with sutherlandia frutescens, although this hypothesis still remains to be investigated in a clinical setting. PMID:21545833

  10. Alteration at translational but not transcriptional level of transferrin receptor expression following manganese exposure at the blood-CSF barrier in vitro

    SciTech Connect

    Li, G. Jane; Zhao Qiuqu; Zheng Wei . E-mail: wzheng@purdue.edu

    2005-06-01

    Manganese exposure alters iron homeostasis in blood and cerebrospinal fluid (CSF), possibly by acting on iron transport mechanisms localized at the blood-brain barrier and/or blood-CSF barrier. This study was designed to test the hypothesis that manganese exposure may change the binding affinity of iron regulatory proteins (IRPs) to mRNAs encoding transferrin receptor (TfR), thereby influencing iron transport at the blood-CSF barrier. A primary culture of choroidal epithelial cells was adapted to grow on a permeable membrane sandwiched between two culture chambers to mimic blood-CSF barrier. Trace {sup 59}Fe was used to determine the transepithelial transport of iron. Following manganese treatment (100 {mu}M for 24 h), the initial flux rate constant (K {sub i}) of iron was increased by 34%, whereas the storage of iron in cells was reduced by 58%, as compared to controls. A gel shift assay demonstrated that manganese exposure increased the binding of IRP1 and IRP2 to the stem loop-containing mRNAs. Consequently, the cellular concentrations of TfR proteins were increased by 84% in comparison to controls. Assays utilizing RT-PCR, quantitative real-time reverse transcriptase-PCR, and nuclear run off techniques showed that manganese treatment did not affect the level of heterogeneous nuclear RNA (hnRNA) encoding TfR, nor did it affect the level of nascent TfR mRNA. However, manganese exposure resulted in a significantly increased level of TfR mRNA and reduced levels of ferritin mRNA. Taken together, these results suggest that manganese exposure increases iron transport at the blood-CSF barrier; the effect is likely due to manganese action on translational events relevant to the production of TfR, but not due to its action on transcriptional, gene expression of TfR. The disrupted protein-TfR mRNA interaction in the choroidal epithelial cells may explain the toxicity of manganese at the blood-CSF barrier.

  11. MOVING FROM EXTERNAL EXPOSURE CONCENTRATION TO INTERNAL DOSE: DURATION EXTRAPOLATION BASED ON PHYSIOLOGICALLY-BASED PHARMACOKINETIC-MODEL DERIVED ESTIMATES OF INTERNAL DOSE

    EPA Science Inventory

    The potential human health risk(s) from exposure to chemicals under conditions for which adequate human or animal data are not available must frequently be assessed. Exposure scenario is particularly important for the acute neurotoxic effects of volatile organic compounds (VOCs)...

  12. The Effects of Stress Exposure on Prefrontal Cortex: Translating Basic Research into Successful Treatments for Post-Traumatic Stress Disorder.

    PubMed

    Arnsten, Amy F T; Raskind, Murray A; Taylor, Fletcher B; Connor, Daniel F

    2015-01-01

    Research on the neurobiology of the stress response in animals has led to successful new treatments for Post-Traumatic Stress Disorder (PTSD) in humans. Basic research has found that high levels of catecholamine release during stress rapidly impair the top-down cognitive functions of the prefrontal cortex (PFC), while strengthening the emotional and habitual responses of the amygdala and basal ganglia. Chronic stress exposure leads to dendritic atrophy in PFC, dendritic extension in the amygdala, and strengthening of the noradrenergic (NE) system. High levels of NE release during stress engage low affinity alpha-1 adrenoceptors, (and likely beta-1 adrenoceptors), which rapidly reduce the firing of PFC neurons, but strengthen amygdala function. In contrast, moderate levels of NE release during nonstress conditions engage higher affinity alpha-2A receptors, which strengthen PFC, weaken amygdala, and regulate NE cell firing. Thus, either alpha-1 receptor blockade or alpha-2A receptor stimulation can protect PFC function during stress. Patients with PTSD have signs of PFC dysfunction. Clinical studies have found that blocking alpha-1 receptors with prazosin, or stimulating alpha-2A receptors with guanfacine or clonidine can be useful in reducing the symptoms of PTSD. Placebo-controlled trials have shown that prazosin is helpful in veterans, active duty soldiers and civilians with PTSD, including improvement of PFC symptoms such as impaired concentration and impulse control. Open label studies suggest that guanfacine may be especially helpful in treating children and adolescents who have experienced trauma. Thus, understanding the neurobiology of the stress response has begun to help patients with stress disorders. PMID:25436222

  13. The effects of stress exposure on prefrontal cortex: Translating basic research into successful treatments for post-traumatic stress disorder

    PubMed Central

    Arnsten, Amy F.T.; Raskind, Murray A.; Taylor, Fletcher B.; Connor, Daniel F.

    2014-01-01

    Research on the neurobiology of the stress response in animals has led to successful new treatments for Post-Traumatic Stress Disorder (PTSD) in humans. Basic research has found that high levels of catecholamine release during stress rapidly impair the top-down cognitive functions of the prefrontal cortex (PFC), while strengthening the emotional and habitual responses of the amygdala and basal ganglia. Chronic stress exposure leads to dendritic atrophy in PFC, dendritic extension in the amygdala, and strengthening of the noradrenergic (NE) system. High levels of NE release during stress engage low affinity alpha-1 adrenoceptors, (and likely beta-1 adrenoceptors), which rapidly reduce the firing of PFC neurons, but strengthen amygdala function. In contrast, moderate levels of NE release during nonstress conditions engage higher affinity alpha-2A receptors, which strengthen PFC, weaken amygdala, and regulate NE cell firing. Thus, either alpha-1 receptor blockade or alpha-2A receptor stimulation can protect PFC function during stress. Patients with PTSD have signs of PFC dysfunction. Clinical studies have found that blocking alpha-1 receptors with prazosin, or stimulating alpha-2A receptors with guanfacine or clonidine can be useful in reducing the symptoms of PTSD. Placebo-controlled trials have shown that prazosin is helpful in veterans, active duty soldiers and civilians with PTSD, including improvement of PFC symptoms such as impaired concentration and impulse control. Open label studies suggest that guanfacine may be especially helpful in treating children and adolescents who have experienced trauma. Thus, understanding the neurobiology of the stress response has begun to help patients with stress disorders. PMID:25436222

  14. Development of a Human Physiologically Based Pharmacokinetic (PBPK) Toolkit for Environmental Pollutants

    PubMed Central

    Ruiz, Patricia; Ray, Meredith; Fisher, Jeffrey; Mumtaz, Moiz

    2011-01-01

    Physiologically Based Pharmacokinetic (PBPK) models can be used to determine the internal dose and strengthen exposure assessment. Many PBPK models are available, but they are not easily accessible for field use. The Agency for Toxic Substances and Disease Registry (ATSDR) has conducted translational research to develop a human PBPK model toolkit by recoding published PBPK models. This toolkit, when fully developed, will provide a platform that consists of a series of priority PBPK models of environmental pollutants. Presented here is work on recoded PBPK models for volatile organic compounds (VOCs) and metals. Good agreement was generally obtained between the original and the recoded models. This toolkit will be available for ATSDR scientists and public health assessors to perform simulations of exposures from contaminated environmental media at sites of concern and to help interpret biomonitoring data. It can be used as screening tools that can provide useful information for the protection of the public. PMID:22174611

  15. Predicting neonatal pharmacokinetics from prior data using population pharmacokinetic modeling.

    PubMed

    Wang, Jian; Edginton, Andrea N; Avant, Debbie; Burckart, Gilbert J

    2015-10-01

    Selection of the first dose for neonates in clinical trials is very challenging. The objective of this analysis was to assess if a population pharmacokinetic (PK) model developed with data from infants to adults is predictive of neonatal clearance and to evaluate what age range of prior PK data is needed for informative modeling to predict neonate exposure. Two sources of pharmacokinetic data from 8 drugs were used to develop population models: (1) data from all patients > 2 years of age, and (2) data from all nonneonatal patients aged > 28 days. The prediction error based on the models using data from subjects > 2 years of age showed bias toward overprediction, with median average fold error (AFE) for CL predicted/CLobserved greater than 1.5. The bias for predicting neonatal PK was improved when using all prior PK data including infants as opposed to an assessment without infant PK data, with the median AFE 0.91. As an increased number of pediatric trials are conducted in neonates under the Food and Drug Administration Safety and Innovation Act, dose selection should be based on the best estimates of neonatal pharmacokinetics and pharmacodynamics prior to conducting efficacy and safety studies in neonates. PMID:25907280

  16. Physiologically based pharmacokinetic (PBPK) models for lifetime exposure to PCB 153 in male and female harbor porpoises (Phocoena phocoena): model development and evaluation.

    PubMed

    Weijs, Liesbeth; Yang, Raymond S H; Covaci, Adrian; Das, Krishna; Blust, Ronny

    2010-09-15

    Physiologically based pharmacokinetic (PBPK) models were developed for the most persistent polychlorinated biphenyl (PCB 153) in male and female harbor porpoises (Phocoena phocoena) to elucidate processes such as uptake, distribution, and elimination. Due to its limited metabolic capacities, long life span, and top position in marine food chains, this species is highly sensitive to pollution. The models consist of 5 compartments, liver, blubber, kidney, brain, and a compartment which accounts for the rest of the body, all connected through blood. All physiological and biochemical parameters were extracted from the literature, except for the brain/blood partition coefficient and rate of excretion, which were both fitted to data sets used for validation of the models. These data sets were compiled from our own analyses performed with GC-MS on tissue samples of harbor porpoises. The intake of PCB 153 was from milk from birth to 4 months, and after weaning fish was the main food source. Overall, these models reveal that concentrations of PCB 153 in males increase with age but suggest that, as the animals grow older, metabolic transformation can be a possible pathway for elimination as well. In contrast, the model for females confirms that gestation and lactation are key processes for eliminating PCB 153 as body burdens decrease with age. These PBPK models are capable of simulating the bioaccumulation of PCB 153 during the entire life span of approximately 20 years of the harbor porpoises. PMID:20718467

  17. Using physiologically-based pharmacokinetic-guided "body-on-a-chip" systems to predict mammalian response to drug and chemical exposure.

    PubMed

    Sung, Jong Hwan; Srinivasan, Balaji; Esch, Mandy Brigitte; McLamb, William T; Bernabini, Catia; Shuler, Michael L; Hickman, James J

    2014-09-01

    The continued development of in vitro systems that accurately emulate human response to drugs or chemical agents will impact drug development, our understanding of chemical toxicity, and enhance our ability to respond to threats from chemical or biological agents. A promising technology is to build microscale replicas of humans that capture essential elements of physiology, pharmacology, and/or toxicology (microphysiological systems). Here, we review progress on systems for microscale models of mammalian systems that include two or more integrated cellular components. These systems are described as a "body-on-a-chip", and utilize the concept of physiologically-based pharmacokinetic (PBPK) modeling in the design. These microscale systems can also be used as model systems to predict whole-body responses to drugs as well as study the mechanism of action of drugs using PBPK analysis. In this review, we provide examples of various approaches to construct such systems with a focus on their physiological usefulness and various approaches to measure responses (e.g. chemical, electrical, or mechanical force and cellular viability and morphology). While the goal is to predict human response, other mammalian cell types can be utilized with the same principle to predict animal response. These systems will be evaluated on their potential to be physiologically accurate, to provide effective and efficient platform for analytics with accessibility to a wide range of users, for ease of incorporation of analytics, functional for weeks to months, and the ability to replicate previously observed human responses. PMID:24951471

  18. Human safety and pharmacokinetics of the CFC alternative propellants HFC 134a (1,1,1,2-tetrafluoroethane) and HFC 227 (1,1,1,2,3,3, 3-heptafluoropropane) following whole-body exposure.

    PubMed

    Emmen, H H; Hoogendijk, E M; Klöpping-Ketelaars, W A; Muijser, H; Duistermaat, E; Ravensberg, J C; Alexander, D J; Borkhataria, D; Rusch, G M; Schmit, B

    2000-08-01

    HFC 134a (1,1,1,2-tetrafluoroethane) and HFC 227 (1,1,1,2,3,3, 3-heptafluoropropane) are used to replace chlorofluorocarbons (CFCs) in refrigerant and aerosol applications, including medical use in metered-dose inhalers. Production and consumption of CFCs are being phased out under the Montreal Protocol on Substances that Deplete the Ozone Layer. The safety and pharmacokinetics of HFC 134a and HFC 227 were assessed in two separate double-blind studies. Each HFC (hydrofluorocarbon) was administered via whole-body exposure as a vapor to eight (four male and four female) healthy volunteers. Volunteers were exposed, once weekly for 1 h, first to air and then to ascending concentrations of HFC (1000, 2000, 4000, and 8000 parts per million (ppm)), interspersed with a second air exposure and two CFC 12 (dichlorodifluoromethane) exposures (1000 and 4000 ppm). Comparison of either HFC 134a or HFC 227 to CFC 12 or air gave no clinically significant results for any of the measured laboratory parameters. There were no notable adverse events, there was no evidence of effects on the central nervous system, and there were no symptoms of upper respiratory tract irritation. HFC 134a, HFC 227, and CFC 12 blood concentrations increased rapidly and in an exposure-concentration-dependent manner, although not strictly proportionally, and approached steady state. Maximum blood concentrations (C(max)) tended to be higher in males than females; in the HFC 227 study, these were statistically significantly (P < 0. 05) higher in males for each HFC 227 and CFC 12 exposure level. In the HFC 134a study, the gender difference in C(max) was only statistically significant (P < 0.05) for CFC 12 at 4000 ppm and HFC 134a at 8000 ppm. Following the end of exposure, blood concentrations declined rapidly, predominantly biphasically and independent of exposure concentration. For the HFC 134a study, the t(1/2)alpha (alpha elimination half-life) was short for both CFC 12 and HFC 134a (<11 min). The t(1

  19. Pharmacokinetics and Pulmonary Disposition of Tedizolid and Linezolid in a Murine Pneumonia Model under Variable Conditions

    PubMed Central

    Keel, Rebecca A.; Crandon, Jared L.

    2012-01-01

    In vivo pharmacokinetics are often evaluated in only one variation of an infection model, and the resulting exposures are assumed to be similar in each model. We evaluated and compared the effect of lung infection and immune status on the murine pharmacokinetics and pulmonary disposition of tedizolid and linezolid. Both factors resulted in differing blood and pulmonary exposure profiles, with similar trends for tedizolid and linezolid. These data highlight the importance of pharmacokinetic confirmation in each model. PMID:22430966

  20. A workflow to investigate exposure and pharmacokinetic influences on high-throughput in vitro chemical screening based on adverse outcome pathways, OpenTox USA 2015 Poster

    EPA Science Inventory

    Adverse outcome pathways (AOP) link known population outcomes to a molecular initiating event (MIE) that can be quantified using high-throughput in vitro methods. Practical application of AOPs in chemical-specific risk assessment requires consideration of exposure and absorption,...

  1. Assessment of cytochrome P450-mediated drug-drug interaction potential of orteronel and exposure changes in patients with renal impairment using physiologically based pharmacokinetic modeling and simulation.

    PubMed

    Lu, Chuang; Suri, Ajit; Shyu, Wen Chyi; Prakash, Shimoga

    2014-12-01

    Orteronel is a nonsteroidal, selective inhibitor of 17,20-lyase that was recently in phase 3 clinical development as a treatment for castration-resistant prostate cancer. In humans, the primary clearance route for orteronel is renal excretion. Human liver microsomal studies indicated that orteronel weakly inhibits CYP1A2, 2C8, 2C9 and 2C19, with IC50 values of 17.8, 27.7, 30.8 and 38.8 µm, respectively, whereas orteronel does not inhibit CYP2B6, 2D6 or 3A4/5 (IC50  > 100 µm). Orteronel also does not exhibit time-dependent inhibition of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A4/5. The results of a static model indicated an [I]/Ki ratio >0.1 for CYP1A2, 2C8, 2C9 and 2C19. Therefore, a physiologically based pharmacokinetic (PBPK) model was developed to assess the potential for drug-drug interactions (DDIs) between orteronel and theophylline, repaglinide, (S)-warfarin and omeprazole, which are sensitive substrates of CYP1A2, 2C8, 2C9 and 2C19, respectively. Simulation of the area under the plasma concentration-time curve (AUC) of these four CYP substrates in the presence and absence of orteronel revealed geometric mean AUC ratios <1.25. Therefore, in accordance with the 2012 US FDA Draft Guidance on DDIs, orteronel can be labeled a 'non-inhibitor' and further clinical DDI evaluation is not required. In PBPK models of moderate and severe renal impairment, the AUC of orteronel was predicted to increase by 52% and 83%, respectively. These results are in agreement with those of a clinical trial in which AUC increases of 38% and 87% were observed in patients with moderate and severe renal impairment, respectively. PMID:25264242

  2. [Research progress on current pharmacokinetic evaluation of Chinese herbal medicines].

    PubMed

    Li, Guofu; Zhao, Haoru; Yang, Jin

    2011-03-01

    In order to prove safety and efficacy, herbal medicines must undergo the rigorous scientific researches such as pharmacokinetic and bioavailability, before they are put on the market in the foreign countries. Botanical Drug Products promulgated by the US FDA could guide industry sponsors to develop herbal drugs, which was also an important reference for investigating Chinese herbal medicines. This paper reviews and discusses novel approaches for how to assess systemic exposure and pharmacokinetic of Chinese herbal medicines, which were in line with FDA guidance. This mainly focus on identifying pharmacokinetic markers of botanical products, integral pharmacokinetic study of multiple components, Biopharmaceutics drug disposition classification system, and population pharmacokinetic-pharmacodynamic study in herb-drug interaction. PMID:21657088

  3. Pharmacokinetic enhancers in HIV therapeutics.

    PubMed

    Larson, Kajal B; Wang, Kun; Delille, Cecile; Otofokun, Igho; Acosta, Edward P

    2014-10-01

    Maximal and durable viral load suppression is one of the most important goals of HIV therapy and is directly related to adequate drug exposure. Protease inhibitors (PIs), an important component of the antiretroviral armada, were historically associated with poor oral bioavailability and high pill burden. However, because the PIs are metabolized by cytochrome P450 (CYP) 3A enzymes, intentional inhibition of these enzymes leads to higher drug exposure, lower pill burden, and therefore simplified dosing schedules with this class of drug. This is the basis of pharmacokinetic enhancement. In HIV therapy, two pharmacokinetic enhancers or boosting agents are used: ritonavir and cobicistat. Both agents inhibit CYP3A4, with cobicistat being a more specific CYP inhibitor than ritonavir. Unlike ritonavir, cobicistat does not have antiretroviral activity. Cobicistat has been evaluated in clinical trials and was recently approved in the USA as a fixed-dose combination with the integrase inhibitor, elvitegravir and two nucleos(t)ide analogs. Additional studies are examining cobicistat in fixed-dose combinations with various PIs. In this review, we summarize current knowledge of these agents and clinically relevant drug regimens and ongoing trials. Studies with elvitegravir and the novel PI TMC319011 are also discussed. PMID:25164142

  4. 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. PMID:27125257

  5. Evaluation of two different metabolic hypotheses for dichloromethane toxicity using physiologically based pharmacokinetic modeling for in vivo inhalation gas uptake data exposure in female B6C3F1 mice

    SciTech Connect

    Evans, M.V.; Caldwell, J.C.

    2010-05-01

    Dichloromethane (DCM, methylene chloride) is a lipophilic volatile compound readily absorbed and then metabolized to several metabolites that may lead to chronic toxicity in different target organs. Physiologically based pharmacokinetic (PBPK) models are useful tools for calculation of internal and target organ doses of parent compound and metabolites. PBPK models, coupled with in vivo inhalation gas-uptake data, can be useful to estimate total metabolism. Previously, such an approach was used to make predictions regarding the metabolism and to make subsequent inferences of DCM's mode of action for toxicity. However, current evidence warrants re-examination of this approach. The goal of this work was to examine two different hypotheses for DCM metabolism in mice. One hypothesis describes two metabolic pathways: one involving cytochrome P450 2E1 (CYP2E1) and a second glutathione (GSH). The second metabolic hypothesis describes only one pathway mediated by CYP2E1 that includes multiple binding sites. The results of our analysis show that the in vivo gas-uptake data fit both hypotheses well and the traditional analysis of the chamber concentration data is not sufficient to distinguish between them. Gas-uptake data were re-analyzed by construction of a velocity plot as a function of increasing DCM initial concentration. The velocity (slope) analysis revealed that there are two substantially different phases in velocity, one rate for lower exposures and a different rate for higher exposures. The concept of a 'metabolic switch,' namely that due to conformational changes in the enzyme after one site is occupied - a different metabolic rate is seen - is also consistent with the experimental data. Our analyses raise questions concerning the importance of GSH metabolism for DCM. Recent research results also question the importance of this pathway in the toxicity of DCM. GSH-related DNA adducts were not formed after in vivo DCM exposure in mice and DCM-induced DNA damage has

  6. Optimizing nanomedicine pharmacokinetics using physiologically based pharmacokinetics modelling

    PubMed Central

    Moss, Darren Michael; Siccardi, Marco

    2014-01-01

    The delivery of therapeutic agents is characterized by numerous challenges including poor absorption, low penetration in target tissues and non-specific dissemination in organs, leading to toxicity or poor drug exposure. Several nanomedicine strategies have emerged as an advanced approach to enhance drug delivery and improve the treatment of several diseases. Numerous processes mediate the pharmacokinetics of nanoformulations, with the absorption, distribution, metabolism and elimination (ADME) being poorly understood and often differing substantially from traditional formulations. Understanding how nanoformulation composition and physicochemical properties influence drug distribution in the human body is of central importance when developing future treatment strategies. A helpful pharmacological tool to simulate the distribution of nanoformulations is represented by physiologically based pharmacokinetics (PBPK) modelling, which integrates system data describing a population of interest with drug/nanoparticle in vitro data through a mathematical description of ADME. The application of PBPK models for nanomedicine is in its infancy and characterized by several challenges. The integration of property–distribution relationships in PBPK models may benefit nanomedicine research, giving opportunities for innovative development of nanotechnologies. PBPK modelling has the potential to improve our understanding of the mechanisms underpinning nanoformulation disposition and allow for more rapid and accurate determination of their kinetics. This review provides an overview of the current knowledge of nanomedicine distribution and the use of PBPK modelling in the characterization of nanoformulations with optimal pharmacokinetics. Linked Articles This article is part of a themed section on Nanomedicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-17 PMID:24467481

  7. High Throughput Pharmacokinetics for Environmental Chemicals (FutureToxII)

    EPA Science Inventory

    Pharmacokinetic (PK) models are critical to determine whether chemical exposures produce potentially hazardous tissue concentrations. For bioactivity identified in vitro (e.g. ToxCast) – hazardous or not – PK models can forecast exposure thresholds, below which no significant bio...

  8. Evaluation of two different metabolic hypotheses for dichloromethane toxicity using physiologically based pharmacokinetic (PBPK) modeling for in vivo inhalation gas uptake data exposure in female B6C3F1 mice *

    EPA Science Inventory

    Dichloromethane (DCM, methylene chloride) is a lipophilic volatile compound readily absorbed and then metabolized to several metabolites that may lead to chronic toxicity in different target organs. Physiologically based pharmacokinetic (PBPK) models are useful tools used for cal...

  9. Systemic exposure to parabens: pharmacokinetics, tissue distribution, excretion balance and plasma metabolites of [14C]-methyl-, propyl- and butylparaben in rats after oral, topical or subcutaneous administration.

    PubMed

    Aubert, Nicolas; Ameller, Thibault; Legrand, Jean-Jacques

    2012-03-01

    Parabens (PB) are preservatives used in food, drugs and personal care products preventing microbial and fungal contamination. We investigated ADME profiles of [14C]-methyl-, propyl- or butylparaben (MP, PP, BP) following single oral, dermal or subcutaneous (BP) doses at 100 mg/kg to Sprague-Dawley rats. Plasma Cmax and AUC values after oral or subcutaneous doses were 4- to 10-fold higher relative to respective values after dermal administration. tmax ranged from 0.5, 2 or 8 h after oral, subcutaneous or dermal administration, respectively. MP produced higher blood Cmax and AUC levels relative to those after PP or BP. Following oral or subcutaneous administration, urinary excretion was predominant (>70%, mainly during the first 24 h), less than 4% were eliminated in the feces, 2% were retained in the tissues and carcasses. Following dermal application, >50% of the dose was unabsorbed, 14-27% or <2% were respectively excreted in the urine or feces, respectively. Overall, parabens were well absorbed after oral and subcutaneous, and partially absorbed after dermal administration. All administration routes produced a single peak in the plasma, corresponding to that of para-hydroxybenzoic acid (PHBA) suggesting that PB produce no significant systemic exposure of mammalian organisms after oral, topical or subcutaneous administration. PMID:22265941

  10. Binary translation using peephole translation rules

    DOEpatents

    Bansal, Sorav; Aiken, Alex

    2010-05-04

    An efficient binary translator uses peephole translation rules to directly translate executable code from one instruction set to another. In a preferred embodiment, the translation rules are generated using superoptimization techniques that enable the translator to automatically learn translation rules for translating code from the source to target instruction set architecture.

  11. Pharmacokinetics of melatonin in preterm infants

    PubMed Central

    Merchant, Nazakat M; Azzopardi, Denis V; Hawwa, Ahmed F; McElnay, James C; Middleton, Benita; Arendt, J; Arichi, Tomoki; Gressens, Pierre; Edwards, A David

    2013-01-01

    Aims Preterm infants are deprived of the normal intra-uterine exposure to maternal melatonin and may benefit from replacement therapy. We conducted a pharmacokinetic study to guide potential therapeutic trials. Methods Melatonin was administered to 18 preterm infants in doses ranging from 0.04–0.6 μg kg−1 over 0.5–6 h. Pharmacokinetic profiles were analyzed individually and by population methods. Results Baseline melatonin was largely undetectable. Infants receiving melatonin at 0.1 μg kg−1 h−1 for 2 h showed a median half-life of 15.82 h and median maximum plasma concentration of 203.3 pg ml−1. On population pharmacokinetics, clearance was 0.045 l h−1, volume of distribution 1.098 l and elimination half-life 16.91 h with gender (P = 0.047) and race (P < 0.0001) as significant covariates. Conclusions A 2 h infusion of 0.1 μg kg−1 h−1 increased blood melatonin from undetectable to approximately peak adult concentrations. Slow clearance makes replacement of a typical maternal circadian rhythm problematic. The pharmacokinetic profile of melatonin in preterm infants differs from that of adults so dosage of melatonin for preterm infants cannot be extrapolated from adult studies. Data from this study can be used to guide therapeutic clinical trials of melatonin in preterm infants. PMID:23432339

  12. 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)...

  13. Precision translator

    DOEpatents

    Reedy, Robert P.; Crawford, Daniel W.

    1984-01-01

    A precision translator for focusing a beam of light on the end of a glass fiber which includes two turning fork-like members rigidly connected to each other. These members have two prongs each with its separation adjusted by a screw, thereby adjusting the orthogonal positioning of a glass fiber attached to one of the members. This translator is made of simple parts with capability to keep adjustment even in condition of rough handling.

  14. Precision translator

    DOEpatents

    Reedy, R.P.; Crawford, D.W.

    1982-03-09

    A precision translator for focusing a beam of light on the end of a glass fiber which includes two turning fork-like members rigidly connected to each other. These members have two prongs each with its separation adjusted by a screw, thereby adjusting the orthogonal positioning of a glass fiber attached to one of the members. This translator is made of simple parts with capability to keep adjustment even in condition of rough handling.

  15. Chemical contaminants, pharmacokinetics, and the lactating mother.

    PubMed Central

    Rogan, W J; Ragan, N B

    1994-01-01

    We review the commonly occurring persistent pesticides and industrial chemicals in breast milk. These chemicals are dichlorodiphenyl trichloroethane as dichlorodiphenyl dichloroethene dieldrin, chlordane as oxychlordane, heptachlor, polychlorinated biphenyls, polychlorinated dibenzofurans, and polychlorinated dibenzodioxins. We present a worked example of the kinds of pharmacokinetic assumptions and calculations necessary for setting regulatory limits of contaminants in the food supply, calculating dose of chemical contaminants to the nursed infant, converting risks from lifetime exposure in laboratory animals to risks for short-term exposure in humans, and estimating the excess cancer risk to the nursed infant. PMID:7737048

  16. Understanding the pharmacokinetics of Coartem®

    PubMed Central

    Djimdé, Abdoulaye; Lefèvre, Gilbert

    2009-01-01

    Artemether and lumefantrine (AL), the active constituents of Coartem® exhibit complementary pharmacokinetic profiles. Artemether is absorbed quickly; peak concentrations of artemether and its main active metabolite, dihydroartemisinin (DHA) occur at approximately two hours post-dose, leading to a rapid reduction in asexual parasite mass and a prompt resolution of symptoms. Lumefantrine is absorbed and cleared more slowly (terminal elimination half-life 3-4 days in malaria patients), and accumulates with successive doses, acting to prevent recrudescence by destroying any residual parasites that remain after artemether and DHA have been cleared from the body. Food intake significantly enhances the bioavailability of both artemether and lumefantrine, an effect which is more apparent for the highly lipophilic lumefantrine. However, a meal with only a small amount of fat (1.6 g) is considered sufficient to achieve adequate exposure to lumefantrine. The pharmacokinetics of artemether or lumefantrine are similar in children, when dosed according to their body weight, compared with adults. No randomized study has compared the pharmacokinetics of either agent in pregnant versus non-pregnant women. Studies in healthy volunteers and in children with malaria have confirmed that the pharmacokinetic characteristics of crushed standard AL tablets and the newly-developed Coartem® Dispersible tablet formulation are similar. Studies to date in healthy volunteers have not identified any clinically relevant drug-drug interactions; data relating to concomitant administration of HIV therapies are limited. While dose-response analyses are difficult to undertake because of the low rate of treatment failures under AL, it appears that artemether and DHA exposure impact on parasite clearance time while lumefantrine exposure is associated with cure rate, consistent with their respective modes of action. In conclusion, knowledge of the pharmacokinetic profiles of artemether and lumefantrine

  17. Pharmacokinetic/Pharmacodynamic-Driven Drug Development

    PubMed Central

    Gallo, James M.

    2010-01-01

    The drug discovery and development enterprise, traditionally an industrial juggernaut, has spanned into the academic arena that is partially motivated by the National Institutes of Health Roadmap highlighting translational science and medicine. Since drug discovery and development represents a pipeline of basic to clinical investigations it meshes well with the prime “bench to the bedside” directive of translational medicine. The renewed interest in drug discovery and develpoment in academia provides an opportunity to rethink the hiearchary of studies with the hope to improve the staid approaches that have been critizied for lacking innovation. One area that has received limited attention concerns the use of pharmacokinetic [PK] and pharmacodynamic [PD] studies in the drug development process. Using anticancer drug development as a focus, this review will address past and current deficencies in how PK/PD studies are conducted and offer new strategies that might bridge the gap between preclinical and clinical trials. PMID:20687184

  18. Nanodrugs: pharmacokinetics and safety.

    PubMed

    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

  19. VERSATILE GAS UPTAKE INHALATION SYSTEM USED IN PHARMACOKINETIC AN METABOLIC STUDIES OF VOLATILE ORGANIC COMPOUNDS

    EPA Science Inventory

    This paper describes an automated gas uptake system for pharmacokinetic research with volatiles, designed to operate within the parameters maintained during conventional whole body inhalation exposures, according to the Good Laboratory Practices (GLP) guidelines. he benefit is to...

  20. Pharmacokinetics of Antiretrovirals in Mucosal Tissue

    PubMed Central

    Cottrell, M.L.; Srinivas, N.; Kashuba, A.D.M.

    2015-01-01

    Introduction In the absence of an HIV vaccine or cure, antiretroviral (ARV) based prevention strategies are being investigated to reduce HIV incidence. These prevention strategies depend on achieving effective drug concentrations at the site HIV exposure which is most commonly the mucosal tissues of the lower gastrointestinal tract and the female genital tract. Areas covered This article collates all known data regarding drug exposure in these vulnerable mucosal tissues, and reviews important mechanisms of ARV drug distribution. Research papers and abstracts describing antiretroviral pharmacokinetics in the female genital tract and lower gastrointestinal mucosal tissues available in MEDLINE® or presented at scientific conferences prior to December 2014 are reviewed in detail. Important influences on ARV mucosal tissue distribution, including protein binding, active drug transport, and endogenous hormones, are also reviewed. Expert opinion ARVs exhibit highly variable pharmacokinetics in mucosal tissues. In general, antiretroviral exposure is higher in the lower gastrointestinal tract compared to the female genital tract, but concentrations required for protective efficacy are largely unknown. The expected site of HIV exposure represents an important consideration when designing and optimizing antiretroviral based prevention strategies. PMID:25797064

  1. Pharmacokinetics of a pyrethroid insecticide mixture in the rat

    EPA Science Inventory

    Pyrethroid insecticides are used and co-occur in the environment, in residences and day care facilities. Pharmacokinetic models of pyrethroids and assessment of risk from their exposure would be better informed if data are derived from studies using chemical mixtures. The objecti...

  2. PHARMACOKINETIC EVALUATION OF PERFLUOROOCTANOIC ACID IN THE MOUSE

    EPA Science Inventory

    Pharmacokinetic evaluation of perfluorooctanoic acid in the mouse.

    1C. Lau, 2M.J. Strynar, 2A.B. Lindstrom, 1R.G. Hanson, 1J.R. Thibodeaux and 3H.A. Barton.

    1Reproductive Toxicology Division, 3Experimental Toxicology Division, NHEERL, 2Human Exposure and Atmospheric...

  3. 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.

  4. Effect of N-methyl deuteration on metabolism and pharmacokinetics of enzalutamide

    PubMed Central

    Jiang, Jinfang; Pang, Xuehai; Li, Liang; Dai, Xiaojian; Diao, Xingxing; Chen, Xiaoyan; Zhong, Dafang; Wang, Yingwei; Chen, Yuanwei

    2016-01-01

    Background The replacement of hydrogen with deuterium invokes a kinetic isotope effect. Thus, this method is an attractive way to slow down the metabolic rate and modulate pharmacokinetics. Purpose Enzalutamide (ENT) acts as a competitive inhibitor of the androgen receptor and has been approved for the treatment of metastatic castration-resistant prostate cancer by the US Food and Drug Administration in 2012. To attenuate the N-demethylation pathway, hydrogen atoms of the N–CH3 moiety were replaced by the relatively stable isotope deuterium, which showed similar pharmacological activities but exhibited favorable pharmacokinetic properties. Methods We estimated in vitro and in vivo pharmacokinetic parameters for ENT and its deuterated analog (d3-ENT). For in vitro studies, intrinsic primary isotope effects (KH/KD) were determined by the ratio of intrinsic clearance (CLint) obtained for ENT and d3-ENT. The CLint values were obtained by the substrate depletion method. For in vivo studies, ENT and d3-ENT were orally given to male Sprague Dawley rats separately and simultaneously to assess the disposition and metabolism of them. We also investigated the main metabolic pathway of ENT by comparing the rate of oxidation and hydrolysis in vitro. Results The in vitro CLint (maximum velocity/Michaelis constant [Vmax/Km]) of d3-ENT in rat and human liver microsomes were 49.7% and 72.9% lower than those of the non-deuterated compound, corresponding to the KH/KD value of ~2. The maximum observed plasma concentration, Cmax, and area under the plasma concentration -time curve from time zero to the last measurable sampling time point (AUC0–t) were 35% and 102% higher than those of ENT when orally administered to rats (10 mg/kg). The exposure of the N-demethyl metabolite M2 was eightfold lower, whereas that of the amide hydrolysis metabolite M1 and other minor metabolites was unchanged. The observed hydrolysis rate of M2 was at least ten times higher than that of ENT and d3-ENT

  5. Systematic Assessment of the Benefits and Caveats in Mining Microbial Post-Translational Modifications from Shotgun Proteomic Data; Response of Shewanella oneidensis to Chromate Exposure

    SciTech Connect

    Thompson, Melissa R; Thompson, Dorothea K; Hettich, Robert {Bob} L

    2008-01-01

    Microbes are known to regulate both gene expression and protein activity through the use of post-translational modifications (PTMs). Common PTMs involved in cellular signaling and gene control include methylations, acetylations, and phosphorylations; whereas oxidations have been implicated as an indicator for stress. Shewanella oneidensis MR-1 is a gram-negative bacterium that demonstrates both respiratory versatility and the ability to sense and adapt to diverse environmental conditions. The dataset used in this study consisted of tandem mass spectra derived from mid-log phase aerobic cultures of S. oneidensis shocked either with or without 1 mM chromate [Cr(VI)]. In this study, three algorithms (DBDigger, Sequest, and InsPecT) were evaluated for their ability to scrutinize shotgun proteomic data for evidence of PTMs. The use of conservative scoring filters for peptides or proteins versus creating a sub-database first from a non-modification search was evaluated with DBDigger. The use of higher scoring filters for peptide identifications was found to result in optimal identifications of PTM peptides with a 2% false discovery rate (FDR) for the total dataset using the DBDigger algorithm. However, the FDR climbs to about 50% when considering PTM peptides only. Sequest was evaluated as a method for confirming PTM peptides putatively identified using DBDigger; however, there was a low identification rate (~25%) for the searched spectra. InsPecT was found to have a lower FDR (~9%) than DBDigger for PTM peptides. Comparisons between InsPecT and DBDigger were made with respect to both the FDR and PTM peptide identifications. As a demonstration of this approach, a number of S. oneidensis chemotaxis proteins as well as low-abundance signal transduction proteins were identified as being post-translationally modified in response to chromate challenge.

  6. Duloxetine: clinical pharmacokinetics and drug interactions.

    PubMed

    Knadler, Mary Pat; Lobo, Evelyn; Chappell, Jill; Bergstrom, Richard

    2011-05-01

    Duloxetine, a potent reuptake inhibitor of serotonin (5-HT) and norepinephrine, is effective for the treatment of major depressive disorder, diabetic neuropathic pain, stress urinary incontinence, generalized anxiety disorder and fibromyalgia. Duloxetine achieves a maximum plasma concentration (C(max)) of approximately 47 ng/mL (40 mg twice-daily dosing) to 110 ng/mL (80 mg twice-daily dosing) approximately 6 hours after dosing. The elimination half-life of duloxetine is approximately 10-12 hours and the volume of distribution is approximately 1640 L. The goal of this paper is to provide a review of the literature on intrinsic and extrinsic factors that may impact the pharmacokinetics of duloxetine with a focus on concomitant medications and their clinical implications. Patient demographic characteristics found to influence the pharmacokinetics of duloxetine include sex, smoking status, age, ethnicity, cytochrome P450 (CYP) 2D6 genotype, hepatic function and renal function. Of these, only impaired hepatic function or severely impaired renal function warrant specific warnings or dose recommendations. Pharmacokinetic results from drug interaction studies show that activated charcoal decreases duloxetine exposure, and that CYP1A2 inhibition increases duloxetine exposure to a clinically significant degree. Specifically, following oral administration in the presence of fluvoxamine, the area under the plasma concentration-time curve and C(max) of duloxetine significantly increased by 460% (90% CI 359, 584) and 141% (90% CI 93, 200), respectively. In addition, smoking is associated with a 30% decrease in duloxetine concentration. The exposure of duloxetine with CYP2D6 inhibitors or in CYP2D6 poor metabolizers is increased to a lesser extent than that observed with CYP1A2 inhibition and does not require a dose adjustment. In addition, duloxetine increases the exposure of drugs that are metabolized by CYP2D6, but not CYP1A2. Pharmacodynamic study results indicate

  7. USE OF EXPOSURE-RELATED DOSE ESTIMATING MODEL (ERDEM) FOR ASSESSMENT OF AGGREGATE EXPOSURE OF INFANT AND CHILDREN TO N-METHYL CARBAMATE INSECTICIDES

    EPA Science Inventory

    A physiologically based pharmacokinetic (PBPK) model was developed within the Exposure Related Dose Estimating Model (ERDEM) framework to investigate selected exposure inputs related to recognized exposure scenarios of infants and children to N-methyl carbamate pesticides as spec...

  8. Pharmacokinetic and pharmacodynamic variability of fluindione in octogenarians

    PubMed Central

    Comets, Emmanuelle; Diquet, Bertrand; Legrain, Sylvie; Huisse, Marie-Geneviève; Godon, Alban; Bruhat, Corinne; Chauveheid, Marie-Paule; Delpierre, Sandrine; Duval, Xavier; Berrut, Gilles; Verstuyft, Céline; Aumont, Marie-Claude; Mentré, France

    2012-01-01

    In the PREPA observational study, we investigated the factors influencing pharmacokinetic and pharmacodynamic variability in the response to fluindione, an oral anticoagulant drug, in a general population of octogenarians inpatients. Measurements of fluindione concentrations and INR (International Normalised Ratio) were obtained from 131 inpatients initiating fluindione treatment. Treatment was adjusted according to routine clinical practice. The data was analysed using non-linear mixed effect models, and the parameters were estimated using MONOLIX 3.2. The pharmacokinetics of fluindione was monocompartmental, while the evolution of INR was modelled according to a turnover model (inhibition of vitamin K recycling). Interindividual variability was very large. Clearance decreased with age and with prior administration of cordarone. Patients who underwent surgery before the study had lower IC50, leading to an increased sensitivity to fluindione. Pharmacokinetic exposure is substantially increased in elderly patients, warranting a lower dose of fluindione. PMID:22472992

  9. PHARMACOKINETIC EXPOSURE AND VIROLOGIC RESPONSE IN HIV-1 INFECTED PREGNANT WOMEN TREATED WITH LOPINAVIR/RITONAVIR: AIDS CLINICAL TRIALS GROUP PROTOCOL A5153S: A SUBSTUDY TO A5150

    PubMed Central

    Sha, Beverly E.; Tierney, Camlin; Sun, Xin; Stek, Alice; Cohn, Susan E.; Coombs, Robert W.; Bastow, Barbara; Aweeka, Francesca T.

    2015-01-01

    Objective We studied the pharmacokinetics and pharmacodynamics of boosted soft-gel lopinavir/ritonavir to assess if the area under the plasma concentration versus time curve (AUC) is altered in pregnancy and whether changes in AUC impacted HIV-1 control. Methods We enrolled pregnant women ≥13 years of age between 22 to 30 weeks gestation who expected to be on stable lopinavir/ritonavir for ≥8 weeks pre-delivery and ≥24 weeks post-delivery. Pharmacokinetic evaluations for lopinavir and ritonavir occurred at 36 weeks gestation and 6 and 24 weeks postpartum. Results Ten women underwent intensive pharmacokinetic evaluations for lopinavir and ritonavir at 36 weeks gestation and at 6 and 24 weeks postpartum. Estimated geometric mean (GM) AUC 0–6h (95% CI) for lopinavir were not significantly different at 26.5 (17.0, 41.4) and 41.9 (26.1, 67.5) mcg*hr/mL at 36 weeks gestation and 6 weeks postpartum, respectively (within-subject GM ratio 0.60 (0.25, 1.43); p=0.19). At 36 weeks gestation, 5 of 10 women had viral load <50 copies/mL and at 6 weeks postpartum 5 of 9 had viral load <50 copies/mL. Nine of ten infants for whom data were available were HIV negative. Conclusion Despite below target lopinavir levels (< 52 mcg*hr/mL except at 2 postpartum measurements), women maintained virologic control postpartum. Higher doses of lopinavir/ritonavir during pregnancy may not be necessary in all women. PMID:26878071

  10. Clinical pharmacokinetics of molsidomine.

    PubMed

    Rosenkranz, B; Winkelmann, B R; Parnham, M J

    1996-05-01

    Molsidomine is a prodrug for the formation of nitric oxide (NO). Its pharmacokinetics are characterised by rapid absorption and hydrolysis, taking a short time to achieve maximal systemic concentrations of both the parent compound and its active metabolite, SIN-1. The time to peak plasma drug concentration (tmax) is 1 to 2 hours. The bioavailability of the parent compound after oral administration in tablet form is 44 to 59%, but further metabolism to release NO and form polar metabolites is rapid; the half-life (t-1/2) of SIN-1 is 1 to 2 hours. Urinary excretion accounts for more than 90% of the part of the administered dose of molsidomine which is not excreted unchanged. Protein binding of the parent compound is very low (3 to 11%) and its volume of distribution (Vd) corresponds to the range of bodyweight. Single-dose studies (1, 2 and 4 mg) have revealed linear pharmacokinetics, and multiple dose studies in healthy individuals (2 mg 3 times daily for 7 days) and coronary artery disease (CAD) patients (4 mg 4 times daily for 4 weeks) do not show any accumulation of the drug. A study in young and elderly individuals indicated that the first-pass effect is decreased and t-1/2 prolonged with age, resulting in an increased area under the concentration-time curve (AUC) of molsidomine and SIN-1. In patients with liver disease and congestive heart failure similar changes were observed, but much less so in patients with CAD. Clearance was also impaired in patients with liver disease, but the pharmacokinetics of molsidomine were not markedly altered by impaired renal function. In general, due to a large therapeutic dose range, dosage adjustments are not required on the basis of clinical experience. In certain patients a lower starting dose may be recommended, such as in those with impaired liver or kidney function, in congestive heart failure or in the presence of concomitant treatment with other vasoactive compounds. A linear dose-effect relationship is observed with

  11. Russian Translation.

    PubMed

    O'dette, R E

    1957-03-29

    This discussion has described the status of the large United States program for translation from the Russian. A partial description of what is being done or planned, and by whom, has been provided as a guide for those who wish to follow the subject further. The urge to pass on useful information has necessarily restricted the space which might also have been profitably devoted to the philosophic aspects of the problem. Although it is not said with any sense of pride in achievement-because much more remains to be done than has been done-it would seem fair to describe the current national translation activity, including all contributions to it, as a phenomenon. Phenomena in scientific communication are not common: a full appreciation of their significance requires more analysis than results from a simple listing of their outward characteristics. But a few observations might be made in conclusion. Most United States scientists probably feel that, as a nation, we are and should be world leaders in science, even though this feeling is neither nurtured nor expressed in a spirit of violent competition. If this assumption is allowed, the point which seems to remain is that the United States will not retain its position casually. Our scientists expect to maintain an awareness of the scientific achievements and failures of the other nations of the world. But we must especially become more aware of the advances of Soviet science, both qualitatively and quantitatively. The evidence points toward this last conclusion, regardless of whether one is concerned with the production of ideas or things, increase in man's knowledge of himself and his environment, conflict between idealisms, or simply the national security. PMID:17836422

  12. Population pharmacokinetic analysis of voriconazole from a pharmacokinetic study with immunocompromised Japanese pediatric subjects.

    PubMed

    Muto, Chieko; Shoji, Satoshi; Tomono, Yoshiro; Liu, Ping

    2015-01-01

    A population pharmacokinetic (PK) analysis was conducted to characterize the voriconazole pharmacokinetic profiles in immunocompromised Japanese pediatric subjects and to compare them to those in immunocompromised non-Japanese pediatric subjects. A previously developed two-compartment pharmacokinetic model with first-order absorption and mixed linear and nonlinear elimination adequately described the voriconazole intravenous and oral data from Japanese pediatric subjects with few modifications. Bayesian priors were applied to this analysis by using the NONMEM routine NWPRI, which allowed priors for the fixed-effect parameter vector and variance matrix of the random-effect parameters to be a normal distribution and an inverse Wishart distribution, respectively. Large intersubject variabilities in oral bioavailability and voriconazole exposure were observed in these pediatric subjects. The mean oral bioavailability estimated in Japanese pediatric subjects was 73% (range, 17% to 99%), which is consistent with the reported estimates of 64% in the previous model and less than what was originally estimated for healthy adults-96%. Voriconazole exposures in Japanese pediatric subjects were generally comparable to those in non-Japanese pediatric subjects receiving the same dosing regimens, given the large intersubject variability. Consistent with the previous findings, the CYP2C19 genotyping status did not have a clinically relevant effect on voriconazole exposure in Japanese pediatric subjects, although it was identified as a covariate in the model to help explain the intersubject variability in voriconazole exposure. The CYP2C19 genotyping status alone does not warrant dose adjustment of voriconazole. No other factors besides age and weight were identified to explain the PK variability of voriconazole. PMID:25801557

  13. Phenotype of TPBG Gene Replacement in the Mouse and Impact on the Pharmacokinetics of an Antibody-Drug Conjugate.

    PubMed

    Hu, George; Leal, Mauricio; Lin, Qingcong; Affolter, Timothy; Sapra, Puja; Bates, Brian; Damelin, Marc

    2015-06-01

    The use of predictive preclinical models in drug discovery is critical for compound selection, optimization, preclinical to clinical translation, and strategic decision-making. Trophoblast glycoprotein (TPBG), also known as 5T4, is the therapeutic target of several anticancer agents currently in clinical development, largely due to its high expression in tumors and low expression in normal adult tissues. In this study, mice were engineered to express human TPBG under endogenous regulatory sequences by replacement of the murine Tpbg coding sequence. The gene replacement was considered functional since the hTPBG knockin (hTPBG-KI) mice did not exhibit clinical observations or histopathological phenotypes that are associated with Tpbg gene deletion, except in rare instances. The expression of hTPBG in certain epithelial cell types and in different microregions of the brain and spinal cord was consistent with previously reported phenotypes and expression patterns. In pharmacokinetic studies, the exposure of a clinical-stage anti-TPBG antibody-drug conjugate (ADC), A1mcMMAF, was lower in hTPBG-KI versus wild-type animals, which was evidence of target-related increased clearance in hTPBG-KI mice. Thus, the hTPBG-KI mice constitute an improved system for pharmacology studies with current and future TPBG-targeted therapies and can generate more precise pharmacokinetic and pharmacodynamic data. In general the strategy of employing gene replacement to improve pharmacokinetic assessments should be broadly applicable to the discovery and development of ADCs and other biotherapeutics. PMID:25423493

  14. Sorafenib in advanced melanoma: a critical role for pharmacokinetics?

    PubMed Central

    Pécuchet, N; Lebbe, C; Mir, O; Billemont, B; Blanchet, B; Franck, N; Viguier, M; Coriat, R; Tod, M; Avril, M-F; Goldwasser, F

    2012-01-01

    Background: Inter-patient pharmacokinetic variability can lead to suboptimal drug exposure, and therefore might impact the efficacy of sorafenib. This study reports long-term pharmacokinetic monitoring of patients treated with sorafenib and a retrospective pharmacodynamic/pharmacokinetic analysis in melanoma patients. Patients and methods: Heavily pretreated patients with stage IV melanoma were started on sorafenib 400 mg twice daily (bid). In the absence of limiting toxicity, dose escalation of 200 mg bid levels was done every 2 weeks. Plasma sorafenib measurement was performed at each visit, allowing a retrospective pharmacodynamic/pharmacokinetic analysis for safety and efficacy. Results: In all, 19 of 30 patients underwent dose escalation over 400 mg bid, and 28 were evaluable for response. The overall disease control rate was 61% (95% confidence interval (CI): 42.6–78.8), including three confirmed responses (12%). Disease control rate and progression-free survival (PFS) were improved in patients with high vs low exposure (80% vs 32%, P=0.02, and 5.25 vs 2.5 months, P=0.005, hazard ratio (HR)=0.28 (95% CI: 0.11–0.73)). In contrast, drug dosing had no effect on PFS. In multivariate analysis, drug exposure was the only factor associated with PFS (HR=0.36 (95% CI: 0.13–0.99)). Diarrhoea and anorexia were correlated with drug dosing, while hypertension and hand–foot skin reaction were correlated with drug exposure. Conclusions: Although sorafenib had modest efficacy in melanoma, these results suggest a correlation between exposure and efficacy of sorafenib. Therefore, dose optimisation in patients with low exposure at standard doses should be evaluated in validated indications. PMID:22767146

  15. Pharmacokinetics of pivmecillinam.

    PubMed

    Parsons, R L; Hossack, G A; Paddock, G M

    1977-06-01

    1 The plasma concentration/time curves of ampicillin and mecillinam in normal subjects were measured after oral administration of ampicillin (500 mg) and pivmecillinam (400 and 600 mg). 2 Similar plasma concentration/time curves of ampicillin and mecillinam in the starved normal subjects followed oral administration of ampicillin (500 mg) and pivmecillinam (600 mg). 3 The plasma concentration/time curve of mecillinam was measured in the same normal subjects after oral administration of pivmecillinam (400 mg) with a reproducible standardized Lundh test meal. 4 There was no statistically significant difference in the plasma concentration/time curve of mecillinam after pivmecillinam/400 mg) and the meal compared with the plasma concentration/time curve after oral pivmecillinam (400 mg) was given to the same subjects when starved. After administration of pivmecillinam (400 mg) with meal, Tasc was significantly delayed beyond the value obtained when the subjects were starved. 5 The pharmacokinetics of pivmecillinam in coeliac disease are normal. This finding contrasts with previous studies on the pharmacokinetics of another pivaloyloxymethylpenicillin ester, pivampicillin, in this condition. PMID:197981

  16. Pharmacokinetics of pivmecillinam.

    PubMed Central

    Parsons, R L; Hossack, G A; Paddock, G M

    1977-01-01

    1 The plasma concentration/time curves of ampicillin and mecillinam in normal subjects were measured after oral administration of ampicillin (500 mg) and pivmecillinam (400 and 600 mg). 2 Similar plasma concentration/time curves of ampicillin and mecillinam in the starved normal subjects followed oral administration of ampicillin (500 mg) and pivmecillinam (600 mg). 3 The plasma concentration/time curve of mecillinam was measured in the same normal subjects after oral administration of pivmecillinam (400 mg) with a reproducible standardized Lundh test meal. 4 There was no statistically significant difference in the plasma concentration/time curve of mecillinam after pivmecillinam/400 mg) and the meal compared with the plasma concentration/time curve after oral pivmecillinam (400 mg) was given to the same subjects when starved. After administration of pivmecillinam (400 mg) with meal, Tasc was significantly delayed beyond the value obtained when the subjects were starved. 5 The pharmacokinetics of pivmecillinam in coeliac disease are normal. This finding contrasts with previous studies on the pharmacokinetics of another pivaloyloxymethylpenicillin ester, pivampicillin, in this condition. PMID:197981

  17. An interface model for dosage adjustment connects hematotoxicity to pharmacokinetics.

    PubMed

    Meille, C; Iliadis, A; Barbolosi, D; Frances, N; Freyer, G

    2008-12-01

    When modeling is required to describe pharmacokinetics and pharmacodynamics simultaneously, it is difficult to link time-concentration profiles and drug effects. When patients are under chemotherapy, despite the huge amount of blood monitoring numerations, there is a lack of exposure variables to describe hematotoxicity linked with the circulating drug blood levels. We developed an interface model that transforms circulating pharmacokinetic concentrations to adequate exposures, destined to be inputs of the pharmacodynamic process. The model is materialized by a nonlinear differential equation involving three parameters. The relevance of the interface model for dosage adjustment is illustrated by numerous simulations. In particular, the interface model is incorporated into a complex system including pharmacokinetics and neutropenia induced by docetaxel and by cisplatin. Emphasis is placed on the sensitivity of neutropenia with respect to the variations of the drug amount. This complex system including pharmacokinetic, interface, and pharmacodynamic hematotoxicity models is an interesting tool for analysis of hematotoxicity induced by anticancer agents. The model could be a new basis for further improvements aimed at incorporating new experimental features. PMID:19107581

  18. Physiological, pharmacokinetic and liver metabolism comparisons between 3-, 6-, 12- and 18-month-old male Sprague Dawley rats under ketamine-xylazine anesthesia

    PubMed Central

    Giroux, Marie-Chantal; Santamaria, Raphael; Hélie, Pierre; Burns, Patrick; Beaudry, Francis; Vachon, Pascal

    2015-01-01

    The main objective of this study was to compare the physiological changes (withdrawal and corneal reflexes, respiratory and cardiac frequency, blood oxygen saturation, and rectal temperature) following intraperitoneal administration of ketamine (80 mg/kg) and xylazine (10 mg/kg) to 3-, 6-, 12- and 18-month-old male Sprague Dawley rats (n=6/age group). Plasma pharmacokinetics, liver metabolism, and blood biochemistry were examined for a limited number of animals to better explain anesthetic drug effects. Selected organs were collected for histopathology. The results for the withdrawal and corneal reflexes suggest a shorter duration and decreased depth of anesthesia with aging. Significant cardiac and respiratory depression, as well as decreased blood oxygen saturation, occurred in all age groups however, cardiac frequency was the most affected parameter with aging, since the 6-, 12-, and 18-month-old animals did not recuperate to normal values during recovery from anesthesia. Pharmacokinetic parameters (T1/2 and AUC) increased and drug clearance decreased with aging, which strongly suggests that drug exposure is associated with the physiological results. The findings for liver S9 fractions of 18-month-old rats compared with the other age groups suggest that following a normal ketamine anesthetic dose (80 mg/kg), drug metabolism is impaired, leading to a significant increase of drug exposure. In conclusion, age and related factors have a substantial effect on ketamine and xylazine availability, which is reflected by significant changes in pharmacokinetics and liver metabolism of these drugs, and this translates into shorter and less effective anesthesia with increasing age. PMID:26489361

  19. Clinical Pharmacokinetic and Pharmacodynamic Profile of Idelalisib.

    PubMed

    Ramanathan, Srinivasan; Jin, Feng; Sharma, Shringi; Kearney, Brian P

    2016-01-01

    Idelalisib is a potent and selective phosphatidylinositol 3-kinase-δ inhibitor, which is a first-in-class agent to be approved for the treatment of relapsed chronic lymphocytic leukaemia, follicular B cell non-Hodgkin's lymphoma and small lymphocytic lymphoma. In dose-ranging studies, idelalisib exposure increased in a less than dose-proportional manner, likely because of solubility-limited absorption. The approved starting dose of 150 mg twice daily was supported by extensive exposure-response evaluations, with dose reduction to 100 mg twice daily being allowed for specific toxicities. Idelalisib may be administered without regard to food on the basis of the absence of clinically relevant food effects, and was accordingly dosed in primary efficacy/safety studies. Idelalisib is metabolized primarily via aldehyde oxidase (AO) and, to a lesser extent, via cytochrome P450 (CYP) 3A. Coadministration with the strong CYP3A inhibitor ketoconazole 400 mg once daily resulted in a ~79 % increase in the idelalisib area under the plasma concentration-time curve (AUC). Administration with the potent inducer rifampin resulted in a 75 % decrease in idelalisib exposure (AUC) and, as such, coadministration with strong inducers should be avoided. GS-563117 is an inactive primary circulating metabolite of idelalisib formed mainly via AO. Unlike idelalisib, GS-563117 is a mechanism-based inhibitor of CYP3A. Accordingly, idelalisib 150 mg twice-daily dosing increases the midazolam AUC 5.4-fold. Clinically, idelalisib is not an inhibitor of the transporters P-glycoprotein, breast cancer resistance protein, organic anion-transporting polypeptide (OATP) 1B1 or OAPT1B3. In a population pharmacokinetic model, no meaningful impact on idelalisib pharmacokinetics was noted for any of the covariates tested. Idelalisib exposure was ~60 % higher with moderate/severe hepatic impairment; no relevant changes were observed with severe renal impairment. This article reviews a comprehensive

  20. Pharmacokinetics of cefixime

    SciTech Connect

    Tonelli, A.P.

    1987-01-01

    The serum protein binding of cefixime, was concentration-dependent. Below 30 mcg/mL, free-fractions (fu) of cefixime in dog serum were approximately 8%. As cefixime concentrations increased, concomitant increases in free-fraction were observed. At 328 mcg/mL almost half of the cefixime in serum was not bound. To examine the effect of this concentration-dependent binding on cefixime's pharmacokinetics, four dogs were administered 50 mg/kg of the carbon 14-labeled drug by the oral and intravenous routes. The absolute bioavailability of cefixime was 48.0 +/- 17% (mean +/- SD). Absorption of radioactivity was 51.9 +/- 18%. Cefixime's elimination was a function of its free-fraction in serum and reabsorption of filtered drug by the kidney.

  1. Clinical pharmacokinetics of anticonvulsants.

    PubMed

    Hvidberg, E F; Dam, M

    1976-01-01

    Anticonvulsant therapy was among the first areas to benefit from clinical pharmacokinetic studies. The most important advantage is that the frequent interindividual variation in the plasma level/dose ratio for these drugs can be circumvented by plasma level monitoring. For several anticonvulsants the brain concentration is shown to parallel the plasma concentration. Phenytoin (diphenylhydantoin) is stil the most important anticonvulsant and the one for which kinetics have been thoroughly investigated in man. These investigations have revealed several reasons for the wellknown difficulties in using this drug clinically. The absorption rate and fraction are very much dependent on the pharmaceutical preparation, and changes of brand may alter the plasma level of phenytoin in spite of unaltered dose. The elimination capacity is saturable causing dose dependent kinetics, which again means disproportional changes in plasma level with changes in dose. Great individual variations exist in the rate of metabolism, and several pharmacokinetic drug interactions are known. As an optimum therapeutic plasma concentration range has been established monitoring plasma levels must be strongly advocated. Interpretation of plasma levels in uraemic patients must take into account decreased protein binding of the drug. Carbamazepine is probably as effective as phenytoin. The elimination is a first order process, but the rate of metabolism increases after a few weeks' treatment. An active metabolite (epoxide) may be the cause of some side-effects. Combined treatment with other anticonvulsant drugs decreases the half-life and more frequent dosing may be necessary. An optimum therapeutic concentration range has been suggested and plasma monitoring is advocated, along with that of the active metabolite, the epoxide. Phenobarbitone is still much used but its kinetics have been investigated to a lesser extent. The main problem is the variability in the rate of elimination. In children the half

  2. APPLICATION OF IN VITRO BIOTRANSFORMATION DATA AND PHARMACOKINETIC MODELING TO RISK ASSESSMENT

    EPA Science Inventory

    The adverse biological effects of toxic substances are dependent upon the exposure concentration and the duration of exposure. Pharmacokinetic models can quantitatively relate the external concentration of a toxicant in the environment to the internal dose of the toxicant in the ...

  3. The pharmacokinetics of meloxicam in vultures.

    PubMed

    Naidoo, V; Wolter, K; Cromarty, A D; Bartels, P; Bekker, L; McGaw, L; Taggart, M A; Cuthbert, R; Swan, G E

    2008-04-01

    Vulture populations across the Asian subcontinent have declined dramatically in the last 15 years and are now on the verge of extinction. Although the cause of the population decline was initially unknown, the decrease has recently been conclusively linked to the use of the nonsteroidal anti-inflammatory drug diclofenac in cattle that inadvertently ended up in the vulture food chain. With the vulture numbers continuing to decline by up to 48% a year, the Indian, Nepali and Pakistan governments have recently banned the manufacture and importation of veterinary diclofenac. They have also suggested meloxicam as an alternate anti-inflammatory for use in cattle. This recommendation was based on extensive acute safety studies in the African White-backed vulture (Gyps africanus), which evaluated worst case scenarios of maximum intake based on a once in three day feeding pattern. However, the possible cumulative pharmacokinetic and pharmacodynamic effects in vultures receiving multiple daily doses of meloxicam over time were not assessed. At present very little pharmacokinetic or pharmacodynamic information is available to add further support for the safety of meloxicam in this animal species. This article discusses the oral and intramuscular pharmacokinetics of meloxicam in Cape Griffon vultures (Gyps coprotheres). Therapeutic drug monitoring was also undertaken in White-backed, Egyptian (Neophron pernopterus) and one Lappet Faced vulture (Torgos tracheliotos). In all these species, meloxicam was characterized by a short half-life of elimination. The rapid metabolism of meloxicam in combination with a short duration of effect in the studied species Gyps vultures shown in this study makes it unlikely that the drug could accumulate. This confirms the safety of repeated exposure to meloxicam in vultures of this genus. PMID:18307504

  4. Pharmacokinetics of macrolides in foals.

    PubMed

    Villarino, N; Martín-Jiménez, T

    2013-02-01

    Macrolides are used for treatment of pneumonia and extrapulmonary conditions caused by Rhodococcus equi. In foals, macrolides have an extraordinary capacity to accumulate in different lung tissue compartments. These drugs show unique pharmacokinetic features such as rapid and extensive distribution and long persistence in pulmonary epithelial lining fluid (PELF) and bronchoalveolar lavage (BAL) cells from foals. This article reviews the pharmacokinetic characteristics of erythromycin, azithromycin, clarithromycin, tulathromycin, telithromycin, gamithromycin, and tilmicosin in foals, with emphasis on PELF and BAL cell concentrations. PMID:23082900

  5. Translation Theory and Translation Studies in China

    ERIC Educational Resources Information Center

    Guo, Qin

    2012-01-01

    This dissertation is a comparative study of "translation theory" and "translation studies" in China and the West. Its focus is to investigate whether there is translation theory in the Chinese tradition. My study begins with an examination of the debate in China over whether there has already existed a system of translation…

  6. Can Computer Translation Replace Human Translation?

    ERIC Educational Resources Information Center

    Schairer, Karen

    1996-01-01

    Evaluates three commercial computer-based language translation programs' translation of a university social sciences telephone survey from English to Spanish. The three programs, "Spanish Scholar,""Spanish Assistant," and "Spanish Amigo," were rated as unacceptable in their quality of translations by native and near-native Spanish speakers. (nine…

  7. Estimation of pharmacokinetic model parameters.

    PubMed

    Timcenko, A; Reich, D L; Trunfio, G

    1995-01-01

    This paper addresses the problem of estimating the depth of anesthesia in clinical practice where many drugs are used in combination. The aim of the project is to use pharmacokinetically-derived data to predict episodes of light anesthesia. The weighted linear combination of anesthetic drug concentrations was computed using a stochastic pharmacokinetic model. The clinical definition of light anesthesia was based on the hemodynamic consequences of autonomic nervous system responses to surgical stimuli. A rule-based expert system was used to review anesthesia records to determine instances of light anesthesia using hemodynamic criteria. It was assumed that light anesthesia was a direct consequence of the weighted linear combination of drug concentrations in the patient's body that decreased below a certain threshold. We augmented traditional two-compartment models with a stochastic component of anesthetics' concentrations to compensate for interpatient pharmacokinetic and pharmacodynamic variability. A cohort of 532 clinical anesthesia cases was examined and parameters of two compartment pharmacokinetic models for 6 intravenously administered anesthetic drugs (fentanyl, thiopenthal, morphine, propofol, midazolam, ketamine) were estimated, as well as the parameters for 2 inhalational anesthetics (N2O and isoflurane). These parameters were then prospectively applied to 22 cases that were not used for parameter estimation, and the predictive ability of the pharmacokinetic model was determined. The goal of the study is the development of a pharmacokinetic model that will be useful in predicting light anesthesia in the clinically relevant circumstance where many drugs are used concurrently. PMID:8563327

  8. Comparative Pharmacokinetics of Chlorpyrifos versus its Major Metabolites Following Oral Administration in the Rat

    SciTech Connect

    Busby-Hjerpe, Andrea L.; Campbell, James A.; Smith, Jordan N.; Lee, Sookwang; Poet, Torka S.; Barr, Dana; Timchalk, Charles

    2010-01-31

    Chlorpyrifos (CPF) is a commonly used diethylphosphorothionate organophosphorus (OP) insecticide. Diethylphosphate (DEP), diethylthiophosphate (DETP) and 3,5,6-trichloro-2-pyridinol (TCPy) are products of in vivo metabolism and environmental degradation of CPF and are routinely measured in urine as biomarkers of exposure. Hence, urinary biomonitoring of TCPy, DEP and DETP may be reflective of an individual’s contact with both the parent pesticide and exposure to these metabolites. In the current study, simultaneous dosing of 13C- or 2H- isotopically labeled CPF (13Clabeled CPF, 5 13C on the TCPy ring; or 2H-labeled CPF, diethyl-D10 (deuterium labeled) on the side chain) were exploited to directly compare the pharmacokinetics and metabolism of CPF with TCPy, and DETP. Individual metabolites were co-administered (oral gavage) with the parent compound at equal molar doses (14 μmol/kg; ~5mg/kg CPF). The key objective in the current study was to quantitatively evaluate the pharmacokinetics of the individual metabolites relative to their formation following a dose of CPF. Major differences in the pharmacokinetics between CPF and metabolites doses were observed within the first 3 h of exposure, due to the required metabolism of CPF to initially form TCPy and DETP. Nonetheless, once a substantial amount of CPF has been metabolized (≥ 3 h post-dosing) pharmacokinetics for both treatment groups and metabolites were very comparable. Urinary excretion rates for orally administered TCPy and DETP relative to 13C-CPF or 2H-CPF derived 13C-TCPy and 2H-DETP were consistent with blood pharmacokinetics, and the urinary clearance of metabolite dosed groups were comparable with the results for the 13C- and 2H-CPF groups. Since the pharmacokinetics of the individual metabolites were not modified by co-exposure to 3 CPF; it suggests that environmental exposure to low dose mixtures of pesticides and metabolites will not impact the pharmacokinetics of either.

  9. Phthalates: European regulation, chemistry, pharmacokinetic and related toxicity.

    PubMed

    Ventrice, Pasquale; Ventrice, Domenica; Russo, Emilio; De Sarro, Giovambattista

    2013-07-01

    Phthalates are chemicals widely used in industry and the consequences for human health caused by exposure to these agents are of significant current interest. Phthalate toxicity targets the reproductive and respiratory systems primarily, but they also may be involved in the processes of carcinogenesis and even in autism spectrum disorders. This article discusses the molecular and cellular mechanisms involved in organ toxicity of phthalates; furthermore, pharmacokinetic, chemistry and the European regulation are summarized. PMID:23603460

  10. 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

  11. Pharmacokinetics and PBPK Models

    SciTech Connect

    Corley, Richard A.

    2010-07-01

    Since the landmark report Pesticides in the Diets of Infants and Children (NRC 1993), children at all stages of development, from fertilization through postnatal maturation, have explicitly been identified as an area of emphasis in human health risk assessments. Exposure to drugs or chemicals at any point in development has the potential for causing irreversible changes that can be unique to each stage of development (Grabowski and Daston 1983; Rodier 1978; Wilson 1973). While exposures of a developing embryo or fetus are mediated by the mother, postnatal exposures consist of maternal influences via breastfeeding as well as environmental factors (Figure 1). As a result, risk assessments for developmental toxicity must consider the sources as well as timing of potential exposures to adequately protect children when they may be the most exposed or the most sensitive to adverse consequences (NRC 1993).

  12. Pharmacokinetic study of sulbactomax.

    PubMed

    Payasi, Anurag; Chaudhary, Manu; Gupta, Ankush; Dwivedi, Vivek Kumar; Bhatnagar, Anuj

    2010-08-01

    We have evaluated pharmacokinetics of a fixed dose combination (FDC) of ceftriaxone and sulbactam (2:1) or sulbactomax in eight healthy volunteers. A 1.5 g dose of sulbactomax, 1 g dose of ceftriaxone and 0.5 g sulbactam were given intravenously in a balanced two-ways cross-over study. Serially collected plasma sample was analyzed for ceftriaxone and sulbactam by high performance liquid chromatography (HPLC). The mean peaks of ceftriaxone and sulbactam concentrations in plasma were 152.06+/-6.65 microg/ml and 21.32+/-1.80 microg/ml, respectively and plasma half-lives for ceftriaxone and sulbactam were 5.2+/-0.35 hr and 0.94+/-0.038 hr, respectively. The AUC0-24 for ceftriaxone and sulbactam was 760.16+/-27.68 microg.hr/ml and 20.74+/-2.34 microg.hr/ml, respectively, with elimination rate constant of 0.133+/-0.009 hr(-1) and 0.732+/-0.029 hr(-1), respectively. The kinetics of ceftriaxone and sulbactum did not change in combination as compared to the alone treatment. Also, concentration of the ceftriaxone after 24 hr is higher than the minimum inhibitory concentration (MIC) of the most of the gram positive and gram negative bacteria indicating that one dose in a day is sufficient to treat the disease caused by these organisms. PMID:20686332

  13. Clinical Pharmacokinetics of Antiretroviral Drugs in Older Persons

    PubMed Central

    Schoen, John C.; Erlandson, Kristine Mace

    2013-01-01

    Introduction Combination antiretroviral therapy has enabled HIV infected persons to reach older ages in high numbers. Hepatic and renal changes that normally occur with advancing age occur earlier and with higher incidence in HIV-infected individuals. A limited number of prospective controlled studies have demonstrated small reductions (17% to 41%) in lopinavir, atazanavir, and lamivudine clearance in older versus younger adults. A much larger number of retrospective studies in adults (age range ~20 to 60 years), including all antiretroviral drugs, have evaluated age as a covariate for pharmacokinetics. Most studies did not detect substantial associations between drug exposures and age. Areas Covered This review summarizes antiretroviral drug pharmacokinetics in older persons. The authors review articles from PubMed (search terms: elderly, antiretroviral, pharmacokinetics) in addition to the bibliographies of those selected. Expert Opinion The evidence to date does not support major pharmacokinetic changes in adults between ~20 and 60 years of age. However, additional prospective, well-controlled studies are needed in more persons > 60 years, including those with frailty and comorbidities, with assessment of unbound drug clearance, and incorporation of adherence, pharmacogenetics, and concomitant medications. Until then, guidelines for drug-drug interactions and dosing in renal and hepatic impairment should be followed in older HIV infected individuals. PMID:23514375

  14. Methods to identify and characterize developmental neurotoxicity for human health risk assessment. III: pharmacokinetic and pharmacodynamic considerations.

    PubMed Central

    Dorman, D C; Allen, S L; Byczkowski, J Z; Claudio, L; Fisher, J E; Fisher, J W; Harry, G J; Li, A A; Makris, S L; Padilla, S; Sultatos, L G; Mileson, B E

    2001-01-01

    We review pharmacokinetic and pharmacodynamic factors that should be considered in the design and interpretation of developmental neurotoxicity studies. Toxicologic effects on the developing nervous system depend on the delivered dose, exposure duration, and developmental stage at which exposure occurred. Several pharmacokinetic processes (absorption, distribution, metabolism, and excretion) govern chemical disposition within the dam and the nervous system of the offspring. In addition, unique physical features such as the presence or absence of a placental barrier and the gradual development of the blood--brain barrier influence chemical disposition and thus modulate developmental neurotoxicity. Neonatal exposure may depend on maternal pharmacokinetic processes and transfer of the xenobiotic through the milk, although direct exposure may occur through other routes (e.g., inhalation). Measurement of the xenobiotic in milk and evaluation of biomarkers of exposure or effect following exposure can confirm or characterize neonatal exposure. Physiologically based pharmacokinetic and pharmacodynamic models that incorporate these and other determinants can estimate tissue dose and biologic response following in utero or neonatal exposure. These models can characterize dose--response relationships and improve extrapolation of results from animal studies to humans. In addition, pharmacologic data allow an experimenter to determine whether exposure to the test chemical is adequate, whether exposure occurs during critical periods of nervous system development, whether route and duration of exposure are appropriate, and whether developmental neurotoxicity can be differentiated from direct actions of the xenobiotic. PMID:11250810

  15. 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)

  16. Literature in Translation.

    ERIC Educational Resources Information Center

    Snodgrass, Mary Ellen

    An examination of literature in translation is vital to literary interpretation and, ultimately, essential to mutual understanding among peoples from different cultures. Teaching translations requires consideration of linguistic, social, and temporal areas. Translations require alterations in language since languages never translate precisely from…

  17. Reporting guidelines for population pharmacokinetic analyses.

    PubMed

    Dykstra, Kevin; Mehrotra, Nitin; Tornøe, Christoffer Wenzel; Kastrissios, Helen; Patel, Bela; Al-Huniti, Nidal; Jadhav, Pravin; Wang, Yaning; Byon, Wonkyung

    2015-08-01

    The purpose of this work was to develop a consolidated set of guiding principles for the reporting of population pharmacokinetic (PK) analyses based on input from a survey of practitioners as well as discussions between industry, consulting, and regulatory scientists. The survey found that identification of population covariate effects on drug exposure and support for dose selection (in which population PK frequently serves as preparatory analysis for exposure-response modeling) are the main areas of influence for population PK analysis. The proposed guidelines consider 2 main purposes of population PK reports: (1) to present key analysis findings and their impact on drug development decisions, and (2) as documentation of the analysis methods for the dual purpose of enabling review of the analysis and facilitating future use of the models. This work also identified 2 main audiences for the reports: (1) a technically competent group responsible for in-depth review of the data, methodology, and results; and (2) a scientifically literate but not technically adept group, whose main interest is in the implications of the analysis for the broader drug development program. We recommend a generalized question-based approach with 6 questions that need to be addressed throughout the report. We recommend 8 sections (Synopsis, Introduction, Data, Methods, Results, Discussion, Conclusions, Appendix) with suggestions for the target audience and level of detail for each section. A section providing general expectations regarding population PK reporting from a regulatory perspective is also included. We consider this an important step toward industrialization of the field of pharmacometrics such that a nontechnical audience also understands the role of pharmacometric analyses in decision making. Population PK reports were chosen as representative reports to derive these recommendations; however, the guiding principles presented here are applicable for all pharmacometric reports

  18. Pharmacokinetics of ibuprofen enantiomers in rats after intravenous and oral administration of ibuprofen arginate.

    PubMed

    Wang, Xiao-Lin; Han, Jing; Zhang, Dan; Liu, Hui-Chen

    2012-01-01

    The pharmacokinetics of ibuprofen enantiomers were studied in rats after intravenous and oral administration of ibuprofen arginate by means of a chiral HPLC method. The pharmacokinetics of ibuprofen was stereoselective after intravenous and oral administration of ibuprofen arginate. The pharmacokinetic stereoselectivity was higher after oral administration than that after intravenous administration. The systematic (R)-(-)-to-(S)-(+) inversion might be more important than the presystematic one in the stereoselective pharmacokinetics after oral administration. Oral administration of ibuprofen arginate resulted in a very rapid absorption of (S)-(+)-ibuprofen (eutomer), and the absolute bioavailabilities of (S)-(+)-ibuprofen and (R)-(-)-ibuprofen were about 100% and 80%, respectively. Based on the systemic exposure of (S)-(+)-ibuprofen, it could be concluded that the pharmacological actions might be similar when ibuprofen arginate was given orally and intravenously, except some differences in the onset of action. PMID:22493811

  19. Translation-coupling systems

    DOEpatents

    Pfleger, Brian; Mendez-Perez, Daniel

    2015-05-19

    Disclosed are systems and methods for coupling translation of a target gene to a detectable response gene. A version of the invention includes a translation-coupling cassette. The translation-coupling cassette includes a target gene, a response gene, a response-gene translation control element, and a secondary structure-forming sequence that reversibly forms a secondary structure masking the response-gene translation control element. Masking of the response-gene translation control element inhibits translation of the response gene. Full translation of the target gene results in unfolding of the secondary structure and consequent translation of the response gene. Translation of the target gene is determined by detecting presence of the response-gene protein product. The invention further includes RNA transcripts of the translation-coupling cassettes, vectors comprising the translation-coupling cassettes, hosts comprising the translation-coupling cassettes, methods of using the translation-coupling cassettes, and gene products produced with the translation-coupling cassettes.

  20. Translation-coupling systems

    DOEpatents

    Pfleger, Brian; Mendez-Perez, Daniel

    2013-11-05

    Disclosed are systems and methods for coupling translation of a target gene to a detectable response gene. A version of the invention includes a translation-coupling cassette. The translation-coupling cassette includes a target gene, a response gene, a response-gene translation control element, and a secondary structure-forming sequence that reversibly forms a secondary structure masking the response-gene translation control element. Masking of the response-gene translation control element inhibits translation of the response gene. Full translation of the target gene results in unfolding of the secondary structure and consequent translation of the response gene. Translation of the target gene is determined by detecting presence of the response-gene protein product. The invention further includes RNA transcripts of the translation-coupling cassettes, vectors comprising the translation-coupling cassettes, hosts comprising the translation-coupling cassettes, methods of using the translation-coupling cassettes, and gene products produced with the translation-coupling cassettes.

  1. Pirbenicillin: Pharmacokinetic Parameters in Mice

    PubMed Central

    English, Arthur R.; Girard, Dennis; Retsema, James A.

    1976-01-01

    The rapid intravenous administration to mice of pirbenicillin, carbenicillin, and ampicillin produced biexponential blood concentration-time curves when assessed by frequent blood samplings at short intervals. The pharmacokinetic behavior of pirbenicillin and the other penicillins was analyzed by the two-compartment open model. This is thought to be the first study giving detailed pharmacokinetic values of penicillins in mice. Some significant differences were noted between the pharmacokinetic values of pirbenicillin, ampicillin, and carbenicillin. These values suggest that the interchange of pirbenicillin between the central and peripheral body compartments of the mouse was slower than that of either carbenicillin or ampicillin and indicated that a greater fraction of the pirbenicillin than the ampicillin dose reached the peripheral compartment. PMID:984791

  2. Clinical pharmacokinetics of metformin.

    PubMed

    Graham, Garry G; Punt, Jeroen; Arora, Manit; Day, Richard O; Doogue, Matthew P; Duong, Janna K; Furlong, Timothy J; Greenfield, Jerry R; Greenup, Louise C; Kirkpatrick, Carl M; Ray, John E; Timmins, Peter; Williams, Kenneth M

    2011-02-01

    Metformin is widely used for the treatment of type 2 diabetes mellitus. It is a biguanide developed from galegine, a guanidine derivative found in Galega officinalis (French lilac). Chemically, it is a hydrophilic base which exists at physiological pH as the cationic species (>99.9%). Consequently, its passive diffusion through cell membranes should be very limited. The mean ± SD fractional oral bioavailability (F) of metformin is 55 ± 16%. It is absorbed predominately from the small intestine. Metformin is excreted unchanged in urine. The elimination half-life (t(½)) of metformin during multiple dosages in patients with good renal function is approximately 5 hours. From published data on the pharmacokinetics of metformin, the population mean of its clearances were calculated. The population mean renal clearance (CL(R)) and apparent total clearance after oral administration (CL/F) of metformin were estimated to be 510 ± 130 mL/min and 1140 ± 330 mL/min, respectively, in healthy subjects and diabetic patients with good renal function. Over a range of renal function, the population mean values of CL(R) and CL/F of metformin are 4.3 ± 1.5 and 10.7 ± 3.5 times as great, respectively, as the clearance of creatinine (CL(CR)). As the CL(R) and CL/F decrease approximately in proportion to CL(CR), the dosage of metformin should be reduced in patients with renal impairment in proportion to the reduced CL(CR). The oral absorption, hepatic uptake and renal excretion of metformin are mediated very largely by organic cation transporters (OCTs). An intron variant of OCT1 (single nucleotide polymorphism [SNP] rs622342) has been associated with a decreased effect on blood glucose in heterozygotes and a lack of effect of metformin on plasma glucose in homozygotes. An intron variant of multidrug and toxin extrusion transporter [MATE1] (G>A, SNP rs2289669) has also been associated with a small increase in antihyperglycaemic effect of metformin. Overall, the effect of structural

  3. Pharmacokinetic interaction of intravenous fentanyl with ketoconazole.

    PubMed

    Ziesenitz, Victoria C; König, Sonja K; Mahlke, Nina S; Skopp, Gisela; Haefeli, Walter E; Mikus, Gerd

    2015-06-01

    Fentanyl is primarily metabolized by CYP3A, but has also been suggested to act as a weak inhibitor of CYP3A. We investigated the influence of CYP3A inhibition by ketoconazole on the pharmacokinetics of intravenously administered fentanyl and the effect of fentanyl on CYP3A activity. A prospective, open-label, randomized, monocentre, crossover study was conducted in 16 healthy volunteers. They received fentanyl alone (5 microgram per kilogram) or fentanyl plus ketoconazole (200 milligram orally B.I.D. over 2 days). Naloxone (2 × 0.2 milligram i.v.) was given simultaneously with fentanyl to mitigate any opioid effect. Midazolam was administered as a CYP3A probe drug. Fentanyl and its metabolites were quantified by LC/MS/MS in blood and urine samples obtained over 24 hour. Exposure of fentanyl (AUC0- ∞ ) was significantly increased to 133% and systemic clearance was reduced to 78% by ketoconazole, norfentanyl formation was significantly delayed and partial metabolic clearance decreased to 18%. Fentanyl had no influence on midazolam exposure and CYP3A activity whereas ketoconazole decreased CYP3A activity to 13%. Although fentanyl N-dealkylation is substantially inhibited by ketoconazole, exposure of fentanyl itself increased by one third only. Clinically fentanyl dosage adjustments may become necessary when ketoconazole or other strong CYP3A inhibitors are given simultaneously. Fentanyl itself does not influence CYP3A activity. PMID:25651378

  4. Pharmacokinetics and drug interactions of eslicarbazepine acetate.

    PubMed

    Bialer, Meir; Soares-da-Silva, Patricio

    2012-06-01

    Eslicarbazepine acetate (ESL) is a novel once-daily antiepileptic drug (AED) approved in Europe since 2009 that was found to be efficacious and well tolerated in a phase III clinical program in adult patients with partial onset seizures previously not controlled with treatment with one to three AEDs, including carbamazepine (CBZ). ESL shares with CBZ and oxcarbazepine (OXC) the dibenzazepine nucleus bearing the 5-carboxamide substitute, but is structurally different at the 10,11 position. This molecular variation results in differences in metabolism, preventing the formation of toxic epoxide metabolites such as carbamazepine-10,11-epoxide. Unlike OXC, which is metabolized to both eslicarbazepine and (R)-licarbazepine, ESL is extensively converted to eslicarbazepine. The systemic exposure to eslicarbazepine after ESL oral administration is approximately 94% of the parent dose, with minimal exposure to (R)-licarbazepine and OXC. After ESL oral administration, the effective half-life (t(1/2,eff) ) of eslicarbazepine was 20-24 h, which is approximately two times longer than its terminal half-life (t(1/2)). At clinically relevant doses (400-1,600 mg/day) ESL has linear pharmacokinetics (PK) with no effects of gender or moderate liver impairment. However, because eslicarbazepine is eliminated primarily (66%) by renal excretion, dose adjustment is recommended for patients with renal impairment. Eslicarbazepine clearance is induced by phenobarbital, phenytoin, and CBZ and it dose-dependently decreases plasma exposure of oral contraceptive and simvastatin. PMID:22612290

  5. 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.

  6. Circadian variation in tamoxifen pharmacokinetics in mice and breast cancer patients.

    PubMed

    Binkhorst, Lisette; Kloth, Jacqueline S L; de Wit, Annelieke S; de Bruijn, Peter; Lam, Mei H; Chaves, Ines; Burger, Herman; van Alphen, Robbert J; Hamberg, Paul; van Schaik, Ron H N; Jager, Agnes; Koch, Birgit C P; Wiemer, Erik A C; van Gelder, Teun; van der Horst, Gijsbertus T J; Mathijssen, Ron H J

    2015-07-01

    The anti-estrogen tamoxifen is characterized by a large variability in response, partly due to pharmacokinetic differences. We examined circadian variation in tamoxifen pharmacokinetics in mice and breast cancer patients. Pharmacokinetic analysis was performed in mice, dosed at six different times (24-h period). Tissue samples were used for mRNA expression analysis of drug-metabolizing enzymes. In patients, a cross-over study was performed. During three 24-h periods, after tamoxifen dosing at 8 a.m., 1 p.m., and 8 p.m., for at least 4 weeks, blood samples were collected for pharmacokinetic measurements. Differences in tamoxifen pharmacokinetics between administration times were assessed. The mRNA expression of drug-metabolizing enzymes showed circadian variation in mouse tissues. Tamoxifen exposure seemed to be highest after administration at midnight. In humans, marginal differences were observed in pharmacokinetic parameters between morning and evening administration. Tamoxifen C(max )and area under the curve (AUC)0-8 h were 20 % higher (P < 0.001), and tamoxifen t(max) was shorter (2.1 vs. 8.1 h; P = 0.001), indicating variation in absorption. Systemic exposure (AUC0-24 h) to endoxifen was 15 % higher (P < 0.001) following morning administration. The results suggest that dosing time is of marginal influence on tamoxifen pharmacokinetics. Our study was not designed to detect potential changes in clinical outcome or toxicity, based on a difference in the time of administration. Circadian rhythm may be one of the many determinants of the interpatient and intrapatient pharmacokinetic variability of tamoxifen. PMID:26050156

  7. Pharmacokinetics of mitragynine in man

    PubMed Central

    Trakulsrichai, Satariya; Sathirakul, Korbtham; Auparakkitanon, Saranya; Krongvorakul, Jatupon; Sueajai, Jetjamnong; Noumjad, Nantida; Sukasem, Chonlaphat; Wananukul, Winai

    2015-01-01

    Background Kratom, known botanically as Mitragyna speciosa (Korth.), is an indigenous tree in Southeast Asia. Kratom is currently easily available worldwide via special shops and the Internet to use as a drug of abuse, opioid alternative, or pain killer. So far, the pharmacokinetics of this plant has been studied only in animals, and there is no such study in humans. The major abundant active alkaloid in Kratom, mitragynine, is one of the promising new chemical substances to be developed as a new drug. The aim of this study was to examine the pharmacokinetics of mitragynine and assess the linearity in pharmacokinetics in chronic users. Methods Since Kratom is illegal in Thailand, studies in healthy subjects would be unethical. We therefore conducted a prospective study by enrolling ten chronic, regular, healthy users. We adjusted the steady state in each subject by giving a known amount of Kratom tea for 7 days before commencement of the experiment. We admitted and gave different oral doses to subjects to confirm linearity in pharmacokinetics. The mitragynine blood concentrations at 17 times points and the urine concentrations during the 24-hour period were collected and measured by liquid chromatography-tandem mass spectrometry method. Results Ten male subjects completed the study without adverse reactions. The median duration of abuse was 1.75 years. We analyzed one subject separately due to the abnormal behavior of blood concentration. From data of nine subjects, the pharmacokinetic parameters established were time to reach the maximum plasma concentration (0.83±0.35 hour), terminal half-life (23.24±16.07 hours), and the apparent volume of distribution (38.04±24.32 L/kg). The urine excretion of unchanged form was 0.14%. The pharmacokinetics were observed to be oral two-compartment model. Conclusion This was the first pharmacokinetic study in humans, which demonstrated linearity and was consistent with the oral two-compartment model with a terminal half

  8. RECONSTRUCTING EXPOSURE SCENARIOS USING DOSE BIOMARKERS - AN APPLICATION OF BAYESIAN UNCERTAINTY ANALYSIS

    EPA Science Inventory

    We use Bayesian uncertainty analysis to explore how to estimate pollutant exposures from biomarker concentrations. The growing number of national databases with exposure data makes such an analysis possible. They contain datasets of pharmacokinetic biomarkers for many polluta...

  9. MODEL DEVELOPMENT AND APPLICATION FOR ASSESSING HUMAN EXPOSURE AND DOSE TO TOXIC CHEMICALS AND POLLUTANTS

    EPA Science Inventory

    This project aims to strengthen the general scientific foundation of EPA's exposure and risk assessment processes by developing state-of-the-art exposure to dose computational models. This research will produce physiologically-based pharmacokinetic (PBPK) and pharmacodynamic (PD)...

  10. RECONSTRUCTING POPULATION EXPOSURES FROM DOSE BIOMARKERS: INHALATION OF TRICHLOROETHYLENE (TCE) AS A CASE STUDY

    EPA Science Inventory

    Physiologically based pharmacokinetic (PBPK) modeling is a well-established toxicological tool designed to relate exposure to a target tissue dose. The emergence of federal and state programs for environmental health tracking and the availability of exposure monitoring through bi...

  11. Clinical pharmacokinetics of dapsone.

    PubMed

    Zuidema, J; Hilbers-Modderman, E S; Merkus, F W

    1986-01-01

    Dapsone (DDS) has for about 4 decades been the most important antileprosy drug. Concentrations of dapsone and its monoacetyl metabolite, MADDS, can be determined in biological media by high-performance liquid chromatography. After oral administration, the drug is slowly absorbed, the maximum concentration in plasma being reached at about 4 hours, with an absorption half-life of about 1.1 hours. However, the extent of absorption has not been adequately determined. The elimination half-life of dapsone is about 30 hours. The drug shows linear pharmacokinetics within the therapeutic range and the time-course after oral administration fits a 2-compartment model. The concentration-time profile of dapsone after parenteral administration is reviewed. Of clinical importance is the development of a new long acting injection, which permits monthly supervised administration as recommended by the World Health Organization. Following dapsone injection in gluteal subcutaneous adipose tissue, a sufficiently sustained absorption for this purpose has been reported. Dapsone is about 70 to 90% protein bound and its monoacetylated metabolite (MADDS) is almost completely protein bound. The volume of distribution of dapsone is estimated to be 1.5 L/kg. It is distributed in most tissues, but M. leprae living in the Schwann cells of the nerves might be unaffected. Dapsone crosses the placenta and is excreted in breast milk and saliva. Dapsone is extensively metabolised. Dapsone, some MADDS and their hydroxylated metabolites are found in urine, partly conjugated as N-glucuronides and N-sulphates. The acetylation ratio (MADDS:dapsone) shows a genetically determined bimodal distribution and allows the definition of 'slow' and 'rapid' acetylators. As enterohepatic circulation occurs, the elimination half-life of dapsone is markedly decreased after oral administration of activated charcoal. This permits successful treatment in cases of intoxication. The daily dose of dapsone in leprosy is 50 to

  12. Translation between representation languages

    NASA Technical Reports Server (NTRS)

    Vanbaalen, Jeffrey

    1994-01-01

    A capability for translating between representation languages is critical for effective knowledge base reuse. A translation technology for knowledge representation languages based on the use of an interlingua for communicating knowledge is described. The interlingua-based translation process consists of three major steps: translation from the source language into a subset of the interlingua, translation between subsets of the interlingua, and translation from a subset of the interlingua into the target language. The first translation step into the interlingua can typically be specified in the form of a grammar that describes how each top-level form in the source language translates into the interlingua. In cases where the source language does not have a declarative semantics, such a grammar is also a specification of a declarative semantics for the language. A methodology for building translators that is currently under development is described. A 'translator shell' based on this methodology is also under development. The shell has been used to build translators for multiple representation languages and those translators have successfully translated nontrivial knowledge bases.

  13. Pharmacokinetics in the elderly.

    PubMed Central

    Mayersohn, M

    1994-01-01

    Animals undergo substantial changes in many physiologic and biochemical functions as a natural consequence of aging. In the absence of disease or other pathologic conditions, these changes occur in a gradual manner with time (generally expressed as a fractional or percentage change in that function per year or decade). Furthermore, for any given function and at any given chronologic age, there is large variation in that function among individuals. Given the increase in life expectancy, the substantial increase in the number of elderly (and aged elderly) in the population, and the escalating costs of health care, there is great interest in learning more about the risks associated with aging as a result of toxic exposure. Are the elderly at greater risk than younger adults to the toxic effects of drugs and environmental exposure? Is the elderly population an inherently more sensitive one? PMID:7737036

  14. PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODELING

    EPA Science Inventory

    Physiologically-based pharmacokinetic (PB-PK) models attempt to provide both a realistic anatomic description of the animal to which a drug or toxic chemical has been administered and a biologically accurate representation of the physiological pathways for chemical storage, metab...

  15. Aztreonam pharmacokinetics in burn patients.

    PubMed Central

    Friedrich, L V; White, R L; Kays, M B; Brundage, D M; Yarbrough, D

    1991-01-01

    The pharmacokinetics of aztreonam in eight adult patients with severe burn injuries (total body surface area burn, 49% +/- 21% [mean +/- standard deviation]) were studied. The time of initiation of study following burn injury was 7.0 +/- 1.4 days. Four patients at first dose and at steady state were studied. Aztreonam concentrations were measured by high-performance liquid chromatography, and a two-compartment model was used to fit the data. No significant differences in any pharmacokinetic parameters between first dose and steady state were observed. Volume of distribution of the central compartment after first dose (0.14 liters/kg) and volume of distribution at steady state (0.31 liters/kg) were approximately 30% higher than those reported for other patient populations. Total drug clearance and renal drug clearance when normalized to creatinine clearance (CLCR) were similar to those previously reported for other critically ill patients. CLCR was strongly correlated with renal drug clearance (r = 0.94) and total drug clearance (r = 0.95). The extent and degree of burn (percent second or third degree burn) were poorly correlated with all pharmacokinetic parameters with the exception of the volume of distribution at steady state, which was correlated with both total body surface area burn (r = 0.95) and percent second degree burn (r = 0.83). Aztreonam pharmacokinetics are altered as a result of thermal injury; however, CLCR can be used to assess the clearance of aztreonam in burn patients. PMID:2014982

  16. Pharmacokinetics of ricobendazole in calves.

    PubMed

    Formentini, E A; Mestorino, O N; Mariño, E L; Errecalde, J O

    2001-06-01

    The pharmacokinetics of ricobendazole (RBZ) and its major metabolite albendazole sulphone (ABZSO2) were studied in six calves, after administration of RBZ (7.5 mg/kg), using a 10% experimental solution by the intravenous (i.v.) route, a 10% commercial solution by the subcutaneous (s.c.) route, and a 10% experimental suspension by the intraruminal (i.r.) route. Blood samples were drawn during a 60-h period. Plasma drug and metabolite concentrations were determined by HPLC. The pharmacokinetic evaluation in each case was prepared by weighted least-squares nonlinear regression analysis. Ricobendazole i.v. data were best fitted by a two-compartment model. The best pharmacokinetic exponents and coefficients were estimated, and the pharmacokinetic variables for RBZ and ABZSO2 were calculated from them. Similar patterns of plasma disposition were found for RBZ after i.r. and s.c. administration, suggesting delayed release from the s.c. site resembling the slow release of the drug from the rumen. PMID:11442798

  17. Update on a Pharmacokinetic-Centric Alternative Tier II Program for MMT-Part I: Program Implementation and Lessons Learned.

    PubMed

    Dorman, David C; Andersen, Melvin E; Roper, Jerry M; Taylor, Michael D

    2012-01-01

    Concerns have been raised regarding environmental manganese exposure since high exposures have been associated with neurological disorders. The USA Environmental Protection Agency most recent human health risk assessment of inhaled manganese conducted in 1993 identified specific areas of uncertainty regarding manganese pharmacokinetics. This led to the development of a test rule under the USA Clean Air Act that required the generation of pharmacokinetic information on the inorganic manganese combustion products of the organometallic fuel additive methylcyclopentadienyl manganese tricarbonyl (MMT). The Alternative Tier 2 testing program for MMT, described in this paper, has yielded substantial pharmacokinetic data and has enabled the generation of physiologically based pharmacokinetic (PBPK) models for manganese. These models are capable of predicting tissue manganese concentrations across a variety of dose routes, levels, and durations while accounting for factors such as age, gender, and reproductive status, enabling the consideration of tissue dosimetry in future risk assessments. PMID:22545047

  18. Update on a Pharmacokinetic-Centric Alternative Tier II Program for MMT—Part I: Program Implementation and Lessons Learned

    PubMed Central

    Dorman, David C.; Andersen, Melvin E.; Roper, Jerry M.; Taylor, Michael D.

    2012-01-01

    Concerns have been raised regarding environmental manganese exposure since high exposures have been associated with neurological disorders. The USA Environmental Protection Agency most recent human health risk assessment of inhaled manganese conducted in 1993 identified specific areas of uncertainty regarding manganese pharmacokinetics. This led to the development of a test rule under the USA Clean Air Act that required the generation of pharmacokinetic information on the inorganic manganese combustion products of the organometallic fuel additive methylcyclopentadienyl manganese tricarbonyl (MMT). The Alternative Tier 2 testing program for MMT, described in this paper, has yielded substantial pharmacokinetic data and has enabled the generation of physiologically based pharmacokinetic (PBPK) models for manganese. These models are capable of predicting tissue manganese concentrations across a variety of dose routes, levels, and durations while accounting for factors such as age, gender, and reproductive status, enabling the consideration of tissue dosimetry in future risk assessments. PMID:22545047

  19. A pharmacokinetic comparison of two voriconazole formulations and the effect of CYP2C19 polymorphism on their pharmacokinetic profiles

    PubMed Central

    Chung, Hyewon; Lee, Howard; Han, HyeKyung; An, Hyungmi; Lim, Kyoung Soo; Lee, Yong Jin; Cho, Joo-Youn; Yoon, Seo Hyun; Jang, In-Jin; Yu, Kyung-Sang

    2015-01-01

    Purpose SYP-1018 is a lyophilized polymeric nanoparticle formulation of voriconazole that is under development for intravenous dosing. This study compared the pharmacokinetic and tolerability profiles of SYP-1018 with those of Vfend®, the marketed formulation of voriconazole. The effect of CYP2C19 polymorphism on the voriconazole pharmacokinetics was also evaluated. Methods An open-label, two-treatment, two-period, two-sequence crossover study was conducted in 52 healthy male volunteers, who randomly received a single intravenous infusion of either of the two voriconazole formulations at 200 mg. Blood samples were collected up to 24 hours after drug administration for pharmacokinetic analysis. The plasma concentrations of voriconazole were determined using liquid chromatography with tandem mass spectrometry, and the pharmacokinetic parameters were estimated using a noncompartmental method. CYP2C19 genotype was identified in 51 subjects. Results The geometric mean ratio (90% confidence interval) of SYP-1018 to Vfend® was 0.99 (0.93–1.04) for the maximum plasma concentrations (Cmax) and 0.97 (0.92–1.01) for the area under the concentration–time curve (AUC) from dosing to the last quantifiable concentration (AUClast). Nineteen homozygous extensive metabolizers (EMs, *1/*1), 19 intermediate metabolizers (IMs, *1/*2 or *1/*3), and ten poor metabolizers (PMs, *2/*2, *2/*3, or *3/*3) were identified, and the pharmacokinetic comparability between SYP-1018 and Vfend® was also noted when analyzed separately by genotype. The systemic exposure to voriconazole was greatest in the PM group, followed by the IM, and then the EM groups. Furthermore, the intrasubject variability for Cmax and AUClast was greater in IMs and PMs than in EMs. No serious adverse event occurred, and both treatments were well tolerated. Conclusion SYP-1018 had comparable pharmacokinetic and tolerability profiles to Vfend® after a single intravenous infusion. CYP2C19 genotype affected not only the

  20. Effects of Pharmacogenetics on the Pharmacokinetics and Pharmacodynamics of Tamoxifen.

    PubMed

    de Vries Schultink, Aurelia H M; Zwart, Wilbert; Linn, Sabine C; Beijnen, Jos H; Huitema, Alwin D R

    2015-08-01

    The antiestrogenic drug tamoxifen is widely used in the treatment of estrogen receptor-α-positive breast cancer and substantially decreases recurrence and mortality rates. However, high interindividual variability in response is observed, calling for a personalized approach to tamoxifen treatment. Tamoxifen is bioactivated by cytochrome P450 (CYP) enzymes such as CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5, resulting in the formation of active metabolites, including 4-hydroxy-tamoxifen and endoxifen. Therefore, polymorphisms in the genes encoding these enzymes are proposed to influence tamoxifen and active tamoxifen metabolites in the serum and consequently affect patient response rates. To tailor tamoxifen treatment, multiple studies have been performed to clarify the influence of polymorphisms on its pharmacokinetics and pharmacodynamics. Nevertheless, personalized treatment of tamoxifen based on genotyping has not yet met consensus. This article critically reviews the published data on the effect of various genetic polymorphisms on the pharmacokinetics and pharmacodynamics of tamoxifen, and reviews the clinical implications of its findings. For each CYP enzyme, the influence of polymorphisms on pharmacokinetic and pharmacodynamic outcome measures is described throughout this review. No clear effects on pharmacokinetics and pharmacodynamics were seen for various polymorphisms in the CYP encoding genes CYP2B6, CYP2C9, CYP2C19 and CYP3A4/5. For CYP2D6, there was a clear gene-exposure effect that was able to partially explain the interindividual variability in plasma concentrations of the pharmacologically most active metabolite endoxifen; however, a clear exposure-response effect remained controversial. These controversial findings and the partial contribution of genotype in explaining interindividual variability in plasma concentrations of, in particular, endoxifen, imply that tailored tamoxifen treatment may not be fully realized through pharmacogenetics of

  1. RATE Exposure Assessment Modules - EXA 408, EXA 409

    EPA Science Inventory

    EXA 408 – Interpreting Biomonitoring Data and Using Pharmacokinetic Modeling in Exposure Assessment Widespread acceptance and use of the CDC's National Health and Nutritional Examination Survey (NHANES) database, which, among other things, reports measured concentrations of...

  2. Nanoparticle Drug Loading as a Design Parameter to Improve Docetaxel Pharmacokinetics and Efficacy

    PubMed Central

    Chu, Kevin S.; Schorzman, Allison N.; Finniss, Mathew C.; Bowerman, Charles J.; Peng, Lei; Luft, J. Christopher; Madden, Andrew; Wang, Andrew Z.; Zamboni, William C.; DeSimone, Joseph M.

    2013-01-01

    Nanoparticle (NP) drug loading is one of the key defining characteristics of a NP formulation. However, the effect of NP drug loading on therapeutic efficacy and pharmacokinetics has not been thoroughly evaluated. Herein, we characterized the efficacy, toxicity and pharmacokinetic properties of NP docetaxel formulations that have differential drug loading but are otherwise identical. Particle Replication in Non-wetting Templates (PRINT®), a soft-lithography fabrication technique, was used to formulate NPs with identical size, shape and surface chemistry, but with variable docetaxel loading. The lower weight loading (9%-NP) of docetaxel was found to have a superior pharmacokinetic profile and enhanced efficacy in a murine cancer model when compared to that of a higher docetaxel loading (20%-NP). The 9%-NP docetaxel increased plasma and tumor docetaxel exposure and reduced liver, spleen and lung exposure when compared to that of 20%-NP docetaxel. PMID:23899444

  3. [Pharmacokinetics and pharmacodynamics of ceftaroline].

    PubMed

    Grau, Santiago; Sorlí, Luisa; Luque, Sonia

    2014-03-01

    Ceftaroline is administered intravenously in the form of a prodrug, ceftaroline fosamil, which is rapidly hydrolyzed by plasma phosphatases to its active form, ceftaroline. In general, the pharmacokinetics of ceftaroline differ little from those of other cephalosporins. A proportional increase in both the peak plasma concentration (Cmax) and the area under the curve (AUC) have been observed when the drug is administered in increasing doses, which demonstrates its linear pharmacokinetics. Half the dose of ceftaroline is excreted actively through the kidneys. The pharmacokinetic parameters of ceftaroline administered through the intramuscular route in diverse animal species were similar to those observed when the drug was administered intravenously and consequently clinical research into ceftaroline administered through this alternative route would be appropriate. Patients with moderate-severe alterations of renal function and those undergoing hemodialysis require dose adjustments. There is limited experience of the pharmacokinetics of ceftaroline in children, which has given rise to several schedules stratified by age groups. The pharmacodynamics of the drug have been studied in models of animal infection and in in vitro infections caused mainly by Staphylococcus aureus (including methicillin-resistant S. aureus [MRSA], strains with intermediate vancomycin sensitivity [hVISA or hGISA]) and by Streptococcus pneumoniae strains with distinct sensitivities to penicillin. Because ceftaroline is a time-dependent antibiotic, the most widely studied pharmacokinetic/pharmacodynamic (PK/PD) indicator is the time interval during which drug concentrations are maintained above the minimum inhibitory concentration (MIC), calculated both as total drug (T > MIC) and as free fraction of the drug (fT > MIC). The PK/PD simulations carried out in these models, developed on the basis of the concentrations obtained with routine doses in humans, have shown that ceftaroline has a good PK

  4. Toward Balance in Translation.

    ERIC Educational Resources Information Center

    Costello, Nancy A.

    A study compared translations of biblical passages into different languages in Papua New Guinea. The study looked for evidence of balance between literal and free interpretation in translation style in the gospel of Mark, which is narrative and didactic material, in 12 languages, and the mainly hortatory genre in translations of 4 epistles:…

  5. For "Translation and Theories"

    ERIC Educational Resources Information Center

    Ni, Lili

    2009-01-01

    Translation studies stem from comparative literature and contrastive analysis. It involves the transfer of messages between two different language systems and cultures, and Munday (2001, p.1) notes that translation "by its nature" "is multilingual and also interdisciplinary". Translation subjects are the texts in various…

  6. Machine Translation Project

    NASA Technical Reports Server (NTRS)

    Bajis, Katie

    1993-01-01

    The characteristics and capabilities of existing machine translation systems were examined and procurement recommendations were developed. Four systems, SYSTRAN, GLOBALINK, PC TRANSLATOR, and STYLUS, were determined to meet the NASA requirements for a machine translation system. Initially, four language pairs were selected for implementation. These are Russian-English, French-English, German-English, and Japanese-English.

  7. Pharmacokinetics of zidovudine dosed twice daily according to World Health Organization weight bands in Ugandan HIV-infected children.

    PubMed

    Fillekes, Quirine; Kendall, Lindsay; Kitaka, Sabrina; Mugyenyi, Peter; Musoke, Philippa; Ndigendawani, Milly; Bwakura-Dangarembizi, Mutsa; Gibb, Diana M; Burger, David; Walker, Ann Sarah

    2014-05-01

    Data on zidovudine pharmacokinetics in children dosed using World Health Organization weight bands are limited. About 45 HIV-infected, Ugandan children, 3.4 (2.6-6.2) years, had intensive pharmacokinetic sampling. Geometric mean zidovudine AUC0-12h was 3.0 h.mg/L, which is higher than previously observed in adults, and was independently higher in those receiving higher doses, younger and underweight children. Higher exposure was also marginally associated with lower hemoglobin. PMID:24736440

  8. Pharmacokinetics of cysteamine bitartrate following gastrointestinal infusion

    PubMed Central

    Fidler, Meredith C; Barshop, Bruce A; Gangoiti, Jon A; Deutsch, Reena; Martin, Michael; Schneider, Jerry A; Dohil, Ranjan

    2007-01-01

    Aims Although cysteamine was first used in the treatment of cystinosis in 1976 and approved by the FDA as cysteamine bitartrate (Cystagon™) in 1994, surprisingly little pharmacological data are available for this compound. Cysteamine and its related drugs are currently being evaluated for the treatment of Huntington’s and Parkinson’s disease. The aim of te study was to understand the pharmacokinetics of cysteamine bitartrate following gastrointestinal infusion. Method Cysteamine bitartrate was delivered through a naso-enteric catheter into the stomach (n = 8), small intestine (n = 8) and caecum (n = 4) of normal subjects. Plasma cysteamine concentrations were determined using LC-MS/MS. Results The rate and extent of drug absorption were assessed by comparing AUC(0, ∞), Cmax and tmax, among the gastrointestinal infusion sites. Total cysteamine exposure, expressed as area under the curve (AUC(0, ∞)) was greatest when the drug was infused into the small intestine (4331.3 ± 1907.6 min × µm) followed by stomach (3901.9 ± 1591.9 min × µm) and caecum (3141.4 ± 1627.6 min × µm). Cysteamine infusion into the small intestine resulted in the most rapid rise to maximal plasma concentrations (tmax = 21 ± 0.56 min); tmax was delayed to 50 ± 26 min and 64 ± 26 min after gastric and caecal infusion, respectively. The maximum cysteamine plasma concentration (Cmax) was reached after infusion of the drug into the small intestine (51 ± 21 µm), which was higher than plasma Cmax concentrations after gastric (39 ± 16 µm) and caecal infusion (23 ± 15 µm). Conclusions The pharmacokinetic data generated help extend our understanding of cysteamine. PMID:17229040

  9. Pharmacokinetics of metoprolol during pregnancy and lactation.

    PubMed

    Ryu, Rachel J; Eyal, Sara; Easterling, Thomas R; Caritis, Steve N; Venkataraman, Raman; Hankins, Gary; Rytting, Erik; Thummel, Kenneth; Kelly, Edward J; Risler, Linda; Phillips, Brian; Honaker, Matthew T; Shen, Danny D; Hebert, Mary F

    2016-05-01

    The objective of this study was to evaluate the steady-state pharmacokinetics of metoprolol during pregnancy and lactation. Serial plasma, urine, and breast milk concentrations of metoprolol and its metabolite, α-hydroxymetoprolol, were measured over 1 dosing interval in women treated with metoprolol (25-750 mg/day) during early pregnancy (n = 4), mid-pregnancy (n = 14), and late pregnancy (n = 15), as well as postpartum (n = 9) with (n = 4) and without (n = 5) lactation. Subjects were genotyped for CYP2D6 loss-of-function allelic variants. Using paired analysis, mean metoprolol apparent oral clearance was significantly higher in mid-pregnancy (361 ± 223 L/h, n = 5, P < .05) and late pregnancy (568 ± 273 L/h, n = 8, P < .05) compared with ≥3 months postpartum (200 ± 131 and 192 ± 98 L/h, respectively). When the comparison was limited to extensive metabolizers (EMs), metoprolol apparent oral clearance was significantly higher during both mid- and late pregnancy (P < .05). Relative infant exposure to metoprolol through breast milk was <1.0% of maternal weight-adjusted dose (n = 3). Because of the large, pregnancy-induced changes in metoprolol pharmacokinetics, if inadequate clinical responses are encountered, clinicians who prescribe metoprolol during pregnancy should be prepared to make aggressive changes in dosage (dose and frequency) or consider using an alternate beta-blocker. PMID:26461463

  10. 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

  11. Pharmacokinetics and toxicology of continuously infused nitroimidazoles

    SciTech Connect

    Eifel, P.J.; Brown, J.M.

    1984-08-01

    The pharmacokinetics and toxicology of misonidazole (MISO) and SR-2508 given by continuous intraperitoneal infusion were studied in female C/sub 3/H mice. The survival (time to death) of animals receiving continuous infusions of SR-2508 and MISO was compared and related to plasma concentration, rate of infusion and total amount of drug delivered. Brain and plasma concentrations were determined by HPLC. For SR-2508, plasma concentration was directly proportional to the infusion rate. However, as the infusion rate of MISO was doubled, the plasma concentration of MISO increased approximately 6-fold, reflecting a substantial increase in the apparent half-life. The brain/plasma concentration ratio in animals infused for up to 6 days with SR-2508 remained constant, at approximately 0.09. At plasma concentrations of 0.08-1.5 mM, animals receiving SR-2508 survived approximately 3 times as long as animals exposed to a comparable plasma concentration of MISO. Even at the lowest infusion rates employed in this study, the survival of mice receiving SR-2508 was much shorter than would have been predicted if the toxicity of these two drugs were solely related to the integral brain exposure. The low brain/plasma concentration ratio of SR-2508 was maintained throughout long continuous exposures.

  12. A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL FOR TOLUENE IN THE LONG EVANS RAT: BODY COMPOSITION AND PHYSICAL ACTIVITY.

    EPA Science Inventory

    A physiologically-based pharmacokinetic (PBPK) model for inhaled toluene was developed for Long-Evans rats as a component of an exposure-dose-response (EDR) model for volatile organic compounds. The PBPK model was needed to link airborne toluene exposure to its concentration in b...

  13. Identifying the translational gap in the evaluation of drug-induced QTc interval prolongation

    PubMed Central

    Chain, Anne SY; Dubois, Vincent FS; Danhof, Meindert; Sturkenboom, Miriam CJM; Della Pasqua, Oscar

    2013-01-01

    Aims Given the similarities in QTc response between dogs and humans, dogs are used in pre-clinical cardiovascular safety studies. The objective of our investigation was to characterize the PKPD relationships and identify translational gaps across species following the administration of three compounds known to cause QTc interval prolongation, namely cisapride, d, l-sotalol and moxifloxacin. Methods Pharmacokinetic and pharmacodynamic data from experiments in conscious dogs and clinical trials were included in this analysis. First, pharmacokinetic modelling and deconvolution methods were applied to derive drug concentrations at the time of each QT measurement. A Bayesian PKPD model was then used to describe QT prolongation, allowing discrimination of drug-specific effects from other physiological factors known to alter QT interval duration. A threshold of ≥10 ms was used to explore the probability of prolongation after drug administration. Results A linear relationship was found to best describe the pro-arrhythmic effects of cisapride, d,l-sotalol and moxifloxacin both in dogs and in humans. The drug-specific parameter (slope) in dogs was statistically significantly different from humans. Despite such differences, our results show that the probability of QTc prolongation ≥10 ms in dogs nears 100% for all three compounds at the therapeutic exposure range in humans. Conclusions Our findings indicate that the slope of PKPD relationship in conscious dogs may be used as the basis for the prediction of drug-induced QTc prolongation in humans. Furthermore, the risk of QTc prolongation can be expressed in terms of the probability associated with an increase ≥10 ms, allowing direct inferences about the clinical relevance of the pro-arrhythmic potential of a molecule. PMID:23351036

  14. In vitro and in vivo experimental data for pyrethroid pharmacokinetic models: the case of bifenthrin

    EPA Science Inventory

    Pyrethroids are a class of neurotoxic synthetic pesticides. Exposure to pyrethroids has increased due to declining use of other classes of pesticides. Our studies are focused on generating in vitro and in vivo data for the development of pharmacokinetic models for pyrethroids. Us...

  15. Evaluating Pharmacokinetic and Pharmacodynamic Interactions with Computational Models in Cumulative Risk Assessment

    EPA Science Inventory

    Simultaneous or sequential exposure to multiple chemicals may cause interactions in the pharmacokinetics (PK) and/or pharmacodynamics (PD) of the individual chemicals. Such interactions can cause modification of the internal or target dose/response of one chemical in the mixture ...

  16. Physiologically based pharmacokinetic modeling of ethyl acetate and ethanol in rodents and humans.

    PubMed

    Crowell, S R; Smith, J N; Creim, J A; Faber, W; Teeguarden, J G

    2015-10-01

    A physiologically based pharmacokinetic (PBPK) model was developed and applied to a metabolic series approach for the ethyl series (i.e., ethyl acetate, ethanol, acetaldehyde, and acetate). This approach bases toxicity information on dosimetry analyses for metabolically linked compounds using pharmacokinetic data for each compound and toxicity data for parent or individual compounds. In vivo pharmacokinetic studies of ethyl acetate and ethanol were conducted in rats following IV and inhalation exposure. Regardless of route, ethyl acetate was rapidly converted to ethanol. Blood concentrations of ethyl acetate and ethanol following both IV bolus and infusion suggested linear kinetics across blood concentrations from 0.1 to 10 mM ethyl acetate and 0.01-0.8 mM ethanol. Metabolic parameters were optimized and evaluated based on available pharmacokinetic data. The respiratory bioavailability of ethyl acetate and ethanol were estimated from closed chamber inhalation studies and measured ventilation rates. The resulting ethyl series model successfully reproduces blood ethyl acetate and ethanol kinetics following IV administration and inhalation exposure in rats, and blood ethanol kinetics following inhalation exposure to ethanol in humans. The extrapolated human model was used to derive human equivalent concentrations for the occupational setting of 257-2120 ppm ethyl acetate and 72-517 ppm ethyl acetate for continuous exposure, corresponding to rat LOAELs of 350 and 1500 ppm. PMID:26297692

  17. Semi-mechanistic physiologically-based pharmacokinetic modeling of clinical glibenclamide pharmacokinetics and drug-drug-interactions.

    PubMed

    Greupink, Rick; Schreurs, Marieke; Benne, Marina S; Huisman, Maarten T; Russel, Frans G M

    2013-08-16

    We studied if the clinical pharmacokinetics and drug-drug interactions (DDIs) of the sulfonylurea-derivative glibenclamide can be simulated via a physiologically-based pharmacokinetic modeling approach. To this end, a glibenclamide PBPK-model was build in Simcyp using in vitro physicochemical and biotransformation data of the drug, and was subsequently optimized using plasma disappearance data observed after i.v. administration. The model was validated against data observed after glibenclamide oral dosing, including DDIs. We found that glibenclamide pharmacokinetics could be adequately modeled if next to CYP metabolism an active hepatic uptake process was assumed. This hepatic uptake process was subsequently included in the model in a non-mechanistic manner. After an oral dose of 0.875 mg predicted Cmax and AUC were 39.7 (95% CI:37.0-42.7)ng/mL and 108 (95% CI: 96.9-120)ng/mLh, respectively, which is in line with observed values of 43.6 (95% CI: 37.7-49.5)ng/mL and 133 (95% CI: 107-159)ng/mLh. For a 1.75 mg oral dose, the predicted and observed values were 82.5 (95% CI:76.6-88.9)ng/mL vs 91.1 (95% CI: 67.9-115.9) for Cmax and 224 (95% CI: 202-248) vs 324 (95% CI: 197-451)ng/mLh for AUC, respectively. The model correctly predicted a decrease in exposure after rifampicin pre-treatment. An increase in glibenclamide exposure after clarithromycin co-treatment was predicted, but the magnitude of the effect was underestimated because part of this DDI is the result of an interaction at the transporter level. Finally, the effects of glibenclamide and fluconazol co-administration were simulated. Our simulations indicated that co-administration of this potent CYP450 inhibitor will profoundly increase glibenclamide exposure, which is in line with clinical observations linking the glibenclamide-fluconazol combination to an increased risk of hypoglycemia. In conclusion, glibenclamide pharmacokinetics and its CYP-mediated DDIs can be simulated via PBPK-modeling. In addition, our

  18. Stochastic Control of Pharmacokinetic Systems

    PubMed Central

    Schumitzky, Alan; Milman, Mark; Katz, Darryl; D'Argenio, David Z.; Jelliffe, Roger W.

    1983-01-01

    The application of stochastic control theory to the clinical problem of designing a dosage regimen for a pharmacokinetic system is considered. This involves defining a patient-dependent pharmacokinetic model and a clinically appropriate therapeutic goal. Most investigators have attacked the dosage regimen problem by first estimating the values of the patient's unknown model parameters and then controlling the system as if those parameter estimates were in fact the true values. We have developed an alternative approach utilizing stochastic control theory in which the estimation and control phases of the problem are not separated. Mathematical results are given which show that this approach yields significant potential improvement in attaining, for example, therapeutic serum level goals over methods in which estimation and control are separated. Finally, a computer simulation is given for the optimal stochastic control of an aminoglycoside regimen which shows that this approach is feasible for practical applications.

  19. [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. PMID:15079908

  20. 40 CFR 158.1020 - Applicator exposure data requirements table.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...) PESTICIDE PROGRAMS DATA REQUIREMENTS FOR PESTICIDES Human Exposure § 158.1020 Applicator exposure data... inhalation exposure data, provided the human pharmacokinetics of the pesticide and/or metabolite/analog compounds (i.e., whichever method is selected as an indicator of body burden or internal dose) allow for...

  1. 40 CFR 158.1020 - Applicator exposure data requirements table.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ...) PESTICIDE PROGRAMS DATA REQUIREMENTS FOR PESTICIDES Human Exposure § 158.1020 Applicator exposure data... inhalation exposure data, provided the human pharmacokinetics of the pesticide and/or metabolite/analog compounds (i.e., whichever method is selected as an indicator of body burden or internal dose) allow for...

  2. 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.

  3. 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. PMID:27082931

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

    PubMed

    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

  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. Sulfur mustard toxicity: history, chemistry, pharmacokinetics, and pharmacodynamics.

    PubMed

    Ghabili, Kamyar; Agutter, Paul S; Ghanei, Mostafa; Ansarin, Khalil; Panahi, Yunes; Shoja, Mohammadali M

    2011-05-01

    Sulfur mustard (SM) and similar bifunctional agents have been used as chemical weapons for almost 100 years. Victims of high-dose exposure, both combatants and civilians, may die within hours or weeks, but low-dose exposure causes both acute injury to the eyes, skin, respiratory tract and other parts of the body, and chronic sequelae in these organs are often debilitating and have a serious impact on quality of life. Ever since they were first used in warfare in 1917, SM and other mustard agents have been the subjects of intensive research, and their chemistry, pharmacokinetics and mechanisms of toxic action are now fairly well understood. In the present article we review this knowledge and relate the molecular-biological basis of SM toxicity, as far as it has been elucidated, to the pathological effects on exposure victims. PMID:21329486

  7. Multiple-dose acetaminophen pharmacokinetics.

    PubMed

    Sahajwalla, C G; Ayres, J W

    1991-09-01

    Four different treatments of acetaminophen (Tylenol) were administered in multiple doses to eight healthy volunteers. Each treatment (325, 650, 825, and 1000 mg) was administered five times at 6-h intervals. Saliva acetaminophen concentration versus time profiles were determined. Noncompartmental pharmacokinetic parameters were calculated and compared to determine whether acetaminophen exhibited linear or dose-dependent pharmacokinetics. For doses less than or equal to 18 mg/kg, area under the curve (AUC), half-life (t1/2), mean residence time (MRT), and ratio of AUC to dose for the first dose were compared with the last dose. No statistically significant differences were observed in dose-corrected AUC for the first or last dose among subjects or treatments. Half-lives and MRT were not significantly different among treatments for the first or the last dose. Statistically significant differences in t1/2 and MRT were noted (p less than 0.05) among subjects for the last dose. A plot of AUC versus dose for the first and the last doses exhibited a linear relationship. Dose-corrected saliva concentration versus time curves for the treatments were superimposable. Thus, acetaminophen exhibits linear pharmacokinetics for doses of 18 mg/kg or less. Plots of AUC versus dose for one subject who received doses higher than 18 mg/kg were curved, suggesting nonlinear behavior of acetaminophen in this subject. PMID:1800709

  8. Pharmacokinetics of drugs in pregnancy

    PubMed Central

    Feghali, Maisa; Venkataramanan, Raman; Caritis, Steve

    2016-01-01

    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. PMID:26452316

  9. The cancerous translation apparatus.

    PubMed

    Stumpf, Craig R; Ruggero, Davide

    2011-08-01

    Deregulations in translational control are critical features of cancer initiation and progression. Activation of key oncogenic pathways promotes rapid and dramatic translational reprogramming, not simply by increasing overall protein synthesis, but also by modulating specific mRNA networks that promote cellular transformation. Additionally, ribosomopathies caused by mutations in ribosome components alter translational regulation leading to specific pathological features, including cancer susceptibility. Exciting advances in our understanding of translational control in cancer have illuminated a striking specificity innate to the translational apparatus. Characterizing this specificity will provide novel insights into how cells normally utilize translational control to modulate gene expression, how it is deregulated in cancer, and how these processes can be targeted to develop new cancer therapies. PMID:21543223

  10. Pharmacokinetic interactions of cimetidine 1987.

    PubMed

    Somogyi, A; Muirhead, M

    1987-05-01

    The number of studies on drug interactions with cimetidine has increased at a rapid rate over the past 5 years, with many of the interactions being solely pharmacokinetic in origin. Very few studies have investigated the clinical relevance of such pharmacokinetic interactions by measuring pharmacodynamic responses or clinical endpoints. Apart from pharmacokinetic studies, invariably conducted in young, healthy subjects, there have been a large number of in vitro and in vivo animal studies, case reports, clinical observations and general reviews on the subject, which is tending to develop an industry of its own accord. Nevertheless, where specific mechanisms have been considered, these have undoubtedly increased our knowledge on the way in which humans eliminate xenobiotics. There is now sufficient information to predict the likelihood of a pharmacokinetic drug-drug interaction with cimetidine and to make specific clinical recommendations. Pharmacokinetic drug interactions with cimetidine occur at the sites of gastrointestinal absorption and elimination including metabolism and excretion. Cimetidine has been found to reduce the plasma concentrations of ketoconazole, indomethacin and chlorpromazine by reducing their absorption. In the case of ketoconazole the interaction was clinically important. Cimetidine does not inhibit conjugation mechanisms including glucuronidation, sulphation and acetylation, or deacetylation or ethanol dehydrogenation. It binds to the haem portion of cytochrome P-450 and is thus an inhibitor of phase I drug metabolism (i.e. hydroxylation, dealkylation). Although generally recognised as a nonspecific inhibitor of this type of metabolism, cimetidine does demonstrate some degree of specificity. To date, theophylline 8-oxidation, tolbutamide hydroxylation, ibuprofen hydroxylation, misonidazole demethylation, carbamazepine epoxidation, mexiletine oxidation and steroid hydroxylation have not been shown to be inhibited by cimetidine in humans but

  11. [Tetrahydrocannabinol pharmacokinetics; new synthetic cannabinoids; road safety and cannabis].

    PubMed

    Goullé, Jean-Perre; Guerbet, Michel

    2014-03-01

    Delta-9-tetrahydrocannabinol (THC) is the main psychoactive ingredient of cannabis, a drug which is commonly smoked This paper focuses on the pharmacokinetics of THC. The average THC content in cannabis plant material has risen by a factor offour over the past 20 years, from 4% to 16%. This increase has important implications not only for the pharmacokinetics but also for the pharmacology of THC The mean bioavailability of THC in smoked cannabis is about 25%. In a cigarette containing 3.55% of THC, a peak plasma level of about 160 ng/mL occurs approximately 10 min after inhalation. THC is quickly cleared from plasma in a multiphasic manner and is widely distributed to tissues, leading to its pharmacologic effects. Body fat is a long-term storage site. This particular pharmacokinetic behavior explains the lack of correlation between the THC blood level and clinical effects, contrary to ethanol. The main THC metabolites are 11-OH-THC (the only active metabolite) and THC-COOH, which is eliminated in feces and urine over several weeks. Therefore, abstinence can be established by analyzing THC-COOH in urine, while blood THC analysis is used to confirm recent exposure. Cannabis is the main illicit drug found among vehicle drivers. Various traffic safety studies indicate that recent use of this drug at least doubles the risk of causing an accident, and that simultaneous alcohol consumption multiplies this risk by afactor of 14. Since 2009, synthetic cannabinoids have emerged on the illicit drug market. These substances act on the same CB1 receptors as THC, but with higher afinity. Their pharmacokinetics differs from that of THC, as they are metabolized into multiple derivatives, most of which are more active than THC itself. PMID:26427296

  12. Allopregnanolone preclinical acute pharmacokinetic and pharmacodynamic studies to predict tolerability and efficacy for Alzheimer's disease.

    PubMed

    Irwin, Ronald W; Solinsky, Christine M; Loya, Carlos M; Salituro, Francesco G; Rodgers, Kathleen E; Bauer, Gerhard; Rogawski, Michael A; Brinton, Roberta Diaz

    2015-01-01

    To develop allopregnanolone as a therapeutic for Alzheimer's disease, we investigated multiple formulations and routes of administration in translationally relevant animal models of both sexes. Subcutaneous, topical (transdermal and intranasal), intramuscular, and intravenous allopregnanolone were bolus-administered. Pharmacokinetic analyses of intravenous allopregnanolone in rabbit and mouse indicated that peak plasma and brain levels (3-fold brain/plasma ratios) at 5min were sufficient to activate neuroregenerative responses at sub-sedative doses. Slow-release subcutaneous suspension of allopregnanolone displayed 5-fold brain/plasma ratio at Cmax at 30min. At therapeutic doses by either subcutaneous or intravenous routes, allopregnanolone mouse plasma levels ranged between 34-51ng/ml by 30min, comparable to published endogenous human level in the third trimester of pregnancy. Exposure to subcutaneous, topical, intramuscular, and intravenous allopregnanolone, at safe and tolerable doses, increased hippocampal markers of neurogenesis including BrdU and PCNA in young 3xTgAD and aged wildtype mice. Intravenous allopregnanolone transiently and robustly phosphorylated CREB within 5min and increased levels of neuronal differentiation transcription factor NeuroD within 4h. Neurogenic efficacy was achieved with allopregnanolone brain exposure of 300-500hr*ng/g. Formulations were tested to determine the no observable adverse effect level (NOAEL) and maximally tolerated doses (MTD) in male and female rats by sedation behavior time course. Sex differences were apparent, males exhibited ≥40% more sedation time compared to females. Allopregnanolone formulated in sulfobutyl-ether-beta-cyclodextrin at optimized complexation ratio maximized allopregnanolone delivery and neurogenic efficacy. To establish the NOAEL and MTD for Allo-induced sedation using a once-per-week intravenous regenerative treatment regimen: In female rats the NOAEL was 0.5mg/kg and MTD 2mg/kg. The predicted

  13. Trusted Translation Services

    NASA Astrophysics Data System (ADS)

    Atif, Yacine; Serhani, Mohamed Adel; Campbell, Piers; Mathew, Sujith Samuel

    Administering multilingual Web sites and applications reliably, involves interconnected and multipart tasks, where trust in the involved parties and content translation sources is paramount. Published Web sites may reflect content from databases, content management systems and other repositories to manage related Web content. But a Web site mirrored wholly or selectively onto a target language version requires streamlined trusted processes. Traditionally, files are translated and transferred via FTP, e-mail, or other communication means. Similarly, translation instructions are communicated between involved parties through verbal instruction, e-mail, and instruction files lead to a variety of inconsistencies and lack of trust in the translation process. This paper proposes a Web service approach to streamline the translation processes and an integration of trust properties in the proposed translation Web services. Web Services have been instrumental in handling problems inherent to systems integration, allowing web-based systems to converse and communicate data automatically. The OASIS Translation Web Services Technical Committee has released a standard way for Web Services to serve the translation and localization business. This article proposes a framework to centralize translation services at a reputable source providing a workflow and a mechanism to quantify service trust. An implementation of the framework is also described in the context of a localization case study.

  14. An integrated pharmacokinetics ontology and corpus for text mining

    PubMed Central

    2013-01-01

    Background Drug pharmacokinetics parameters, drug interaction parameters, and pharmacogenetics data have been unevenly collected in different databases and published extensively in the literature. Without appropriate pharmacokinetics ontology and a well annotated pharmacokinetics corpus, it will be difficult to develop text mining tools for pharmacokinetics data collection from the literature and pharmacokinetics data integration from multiple databases. Description A comprehensive pharmacokinetics ontology was constructed. It can annotate all aspects of in vitro pharmacokinetics experiments and in vivo pharmacokinetics studies. It covers all drug metabolism and transportation enzymes. Using our pharmacokinetics ontology, a PK-corpus was constructed to present four classes of pharmacokinetics abstracts: in vivo pharmacokinetics studies, in vivo pharmacogenetic studies, in vivo drug interaction studies, and in vitro drug interaction studies. A novel hierarchical three level annotation scheme was proposed and implemented to tag key terms, drug interaction sentences, and drug interaction pairs. The utility of the pharmacokinetics ontology was demonstrated by annotating three pharmacokinetics studies; and the utility of the PK-corpus was demonstrated by a drug interaction extraction text mining analysis. Conclusions The pharmacokinetics ontology annotates both in vitro pharmacokinetics experiments and in vivo pharmacokinetics studies. The PK-corpus is a highly valuable resource for the text mining of pharmacokinetics parameters and drug interactions. PMID:23374886

  15. COMPUTATIONAL PHARMACOKINETICS DURING DEVELOPMENTAL WINDOWS OF SUSPECTIBILITY

    EPA Science Inventory

    ABSTRACT

    Computational modeling has an increasing role in analyses of biological effects including how the body handles chemicals (i.e. pharmacokinetics or toxicokinetics) and how the body responds to chemicals (i.e. pharmacodynamics or toxicodynamics). Pharmacokinetic mo...

  16. 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…

  17. Population Pharmacokinetics of Abacavir in Pregnant Women

    PubMed Central

    Treluyer, Jean-Marc; Préta, Laure-Helene; Valade, Elodie; Pannier, Emmanuelle; Urien, Saik; Hirt, Déborah

    2014-01-01

    For the first time, a population approach was used to describe abacavir (ABC) pharmacokinetics in HIV-infected pregnant and nonpregnant women. A total of 266 samples from 150 women were obtained. No covariate effect (from age, body weight, pregnancy, or gestational age) on ABC pharmacokinetics was found. Thus, it seems unnecessary to adapt the ABC dosing regimen during pregnancy. PMID:25070097

  18. Idioms and Back Translation

    ERIC Educational Resources Information Center

    Griffin, Frank

    2004-01-01

    The challenges of intercultural communication are an integral part of many undergraduate business communication courses. Marketing gaffes clearly illustrate the pitfalls of translation and underscore the importance of a knowledge of the culture with which one is attempting to communicate. A good way to approach the topic of translation pitfalls in…

  19. Creativity, Culture and Translation

    ERIC Educational Resources Information Center

    Babaee, Siamak; Wan Yahya, Wan Roselezam; Babaee, Ruzbeh

    2014-01-01

    Some scholars (Bassnett-McGuire, Catford, Brislin) suggest that a good piece of translation should be a strict reflection of the style of the original text while some others (Gui, Newmark, Wilss) consider the original text untranslatable unless it is reproduced. Opposing views by different critics suggest that translation is still a challenging…

  20. Universal Semantics in Translation

    ERIC Educational Resources Information Center

    Wang, Zhenying

    2009-01-01

    What and how we translate are questions often argued about. No matter what kind of answers one may give, priority in translation should be granted to meaning, especially those meanings that exist in all concerned languages. In this paper the author defines them as universal sememes, and the study of them as universal semantics, of which…

  1. Plurality in Translation.

    ERIC Educational Resources Information Center

    Farahzad, Farzaneh

    This paper discusses factors contributing to differing translations of the same source text, arguing that translation occurs on a continuum rather than having absolute criteria and procedures. Issues examined include the formal properties of the text, the text's "invariant core of meaning," stability in the semantic elements of the text, the text…

  2. Science Explorers Translation Project.

    ERIC Educational Resources Information Center

    Jacobs, Dolores

    This paper describes a pilot project of Los Alamos National Laboratory (New Mexico) to translate a science education curriculum for junior and senior high school students into Navajo. The project consisted of translating a video, a teacher's guide, and an interactive multimedia product on the 1993 hantavirus outbreak in the Four Corners area…

  3. Translation as Literary Criticism.

    ERIC Educational Resources Information Center

    di Stefano, B. Follkart

    1982-01-01

    It is proposed that literary translation is intrinsically an act of literary criticism. This theory is illustrated by discussion of specific problems in translating Sartre's "La Nausee" and Leonard Forest's "Le pays de la Sagouine," especially the use of verb tense. (MSE)

  4. Translation as (Global) Writing

    ERIC Educational Resources Information Center

    Horner, Bruce; Tetreault, Laura

    2016-01-01

    This article explores translation as a useful point of departure and framework for taking a translingual approach to writing engaging globalization. Globalization and the knowledge economy are putting renewed emphasis on translation as a key site of contest between a dominant language ideology of monolingualism aligned with fast capitalist…

  5. Text Coherence in Translation

    ERIC Educational Resources Information Center

    Zheng, Yanping

    2009-01-01

    In the thesis a coherent text is defined as a continuity of senses of the outcome of combining concepts and relations into a network composed of knowledge space centered around main topics. And the author maintains that in order to obtain the coherence of a target language text from a source text during the process of translation, a translator can…

  6. Examining English-German Translation Ambiguity Using Primed Translation Recognition

    ERIC Educational Resources Information Center

    Eddington, Chelsea M.; Tokowicz, Natasha

    2013-01-01

    Many words have more than one translation across languages. Such "translation-ambiguous" words are translated more slowly and less accurately than their unambiguous counterparts. We examine the extent to which word context and translation dominance influence the processing of translation-ambiguous words. We further examine how these factors…

  7. Translation Ambiguity but Not Word Class Predicts Translation Performance

    ERIC Educational Resources Information Center

    Prior, Anat; Kroll, Judith F.; Macwhinney, Brian

    2013-01-01

    We investigated the influence of word class and translation ambiguity on cross-linguistic representation and processing. Bilingual speakers of English and Spanish performed translation production and translation recognition tasks on nouns and verbs in both languages. Words either had a single translation or more than one translation. Translation…

  8. Applications of physiologic pharmacokinetic modeling in carcinogenic risk assessment.

    PubMed Central

    Krewski, D; Withey, J R; Ku, L F; Andersen, M E

    1994-01-01

    The use of physiologically based pharmacokinetic (PBPK) models has been proposed as a means of estimating the dose of the reactive metabolites of carcinogenic xenobiotics reaching target tissues, thereby affording an opportunity to base estimates of potential cancer risk on tissue dose rather than external levels of exposure. In this article, we demonstrate how a PBPK model can be constructed by specifying mass-balance equations for each physiological compartment included in the model. In general, this leads to a system of nonlinear partial differential equations with which to characterize the compartment system. These equations then can be solved numerically to determine the concentration of metabolites in each compartment as functions of time. In the special case of a linear pharmacokinetic system, we present simple closed-form expressions for the area under the concentration-time curves (AUC) in individual tissue compartments. A general relationship between the AUC in blood and other tissue compartments is also established. These results are of use in identifying those parameters in the models that characterize the integrated tissue dose, and which should therefore be the primary focus of sensitivity analyses. Applications of PBPK modeling for purposes of tissue dosimetry are reviewed, including models developed for methylene chloride, ethylene oxide, 1,4-dioxane, 1-nitropyrene, as well as polychlorinated biphenyls, dioxins, and furans. Special considerations in PBPK modeling related to aging, topical absorption, pregnancy, and mixed exposures are discussed. The linkage between pharmacokinetic models used for tissue dosimetry and pharmacodynamic models for neoplastic transformation of stem cells in the target tissue is explored. PMID:7737040

  9. Inhalation pharmacokinetics of isoprene in rats and mice.

    PubMed Central

    Peter, H; Wiegand, H J; Filser, J G; Bolt, H M; Laib, R J

    1990-01-01

    Studies on inhalation pharmacokinetics of isoprene were conducted in rats (Wistar) and mice (B6C3F1) to investigate possible species differences in metabolism of this compound. Pharmacokinetic analysis of isoprene inhaled by rats and mice revealed saturation kinetics of isoprene metabolism in both species. For rats and mice, linear pharmacokinetics apply at exposure concentrations below 300 ppm isoprene. Saturation of isoprene metabolism is practically complete at atmospheric concentrations of about 1000 ppm in rats and about 2000 ppm in mice. In the lower concentration range where first-order metabolism applies, metabolic clearance (related to the concentration in the atmosphere) of inhaled isoprene per kilogram body weight was 6200 mL/hr for rats and 12,000 mL/hr for mice. The estimated maximal metabolic elimination rates were 130 mumole/hr/kg for rats and 400 mumole/hr/kg for mice. This shows that the rate of isoprene metabolism in mice is about two or three times that in rats. When the untreated animals are kept in a closed all-glass exposure system, the exhalation of isoprene into the system can be measured. This shows that the isoprene endogenously produced by the animals is systemically available within the animal organism. From such experiments the endogenous production rate of isoprene was calculated to be 1.9 mumole/hr/kg for rats and 0.4 mumole/hr/kg for mice. Our data indicate that the endogenous production of isoprene should be accounted for when discussing a possible carcinogenic or mutagenic risk of this compound. PMID:2401276

  10. Developmental pharmacokinetics of propylene glycol in preterm and term neonates

    PubMed Central

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

    2013-01-01

    AIM Propylene glycol (PG) is often applied as an excipient in drug formulations. As these formulations may also be used in neonates, the aim of this study was to characterize the pharmacokinetics of propylene glycol, co-administered intravenously with paracetamol (800 mg PG/1000 mg paracetamol) or phenobarbital (700 mg PG/200 mg phenobarbital) in preterm and term neonates. METHODS A population pharmacokinetic analysis was performed based on 372 PG plasma concentrations from 62 (pre)term neonates (birth weight (bBW) 630–3980 g, postnatal age (PNA) 1–30 days) using NONMEM 6.2. The model was subsequently used to simulate PG exposure upon administration of paracetamol or phenobarbital in neonates (gestational age 24–40 weeks). RESULTS In a one compartment model, birth weight and PNA were both identified as covariates for PG clearance using an allometric function (CLi= 0.0849 × {(bBW/2720)1.69× (PNA/3)0.201}). Volume of distribution scaled allometrically with current bodyweight (Vi= 0.967 × {(BW/2720)1.45}) and was estimated 1.77 times higher when co-administered with phenobarbital compared with paracetamol. By introducing these covariates a large part of the interindividual variability on clearance (65%) as well as on volume of distribution (53%) was explained. The final model shows that for commonly used dosing regimens, the population mean PG peak and trough concentrations range between 33–144 and 28–218 mg l−1 (peak) and 19–109 and 6–112 mg l−1 (trough) for paracetamol and phenobarbital formulations, respectively, depending on birth weight and age of the neonates. CONCLUSION A pharmacokinetic model was developed for PG co-administered with paracetamol or phenobarbital in neonates. As such, large variability in PG exposure may be expected in neonates which is dependent on birth weight and PNA. PMID:22536830

  11. Reporting guidelines for population pharmacokinetic analyses.

    PubMed

    Dykstra, Kevin; Mehrotra, Nitin; Tornøe, Christoffer Wenzel; Kastrissios, Helen; Patel, Bela; Al-Huniti, Nidal; Jadhav, Pravin; Wang, Yaning; Byon, Wonkyung

    2015-06-01

    The purpose of this work was to develop a consolidated set of guiding principles for reporting of population pharmacokinetic (PK) analyses based on input from a survey of practitioners as well as discussions between industry, consulting and regulatory scientists. The survey found that identification of population covariate effects on drug exposure and support for dose selection (where population PK frequently serves as preparatory analysis to exposure-response modeling) are the main areas of influence for population PK analysis. The proposed guidelines consider two main purposes of population PK reports (1) to present key analysis findings and their impact on drug development decisions, and (2) as documentation of the analysis methods for the dual purpose of enabling review of the analysis and facilitating future use of the models. This work also identified two main audiences for the reports: (1) a technically competent group responsible for in-depth review of the data, methodology, and results, and (2) a scientifically literate, but not technically adept group, whose main interest is in the implications of the analysis for the broader drug development program. We recommend a generalized question-based approach with six questions that need to be addressed throughout the report. We recommend eight sections (Synopsis, Introduction, Data, Methods, Results, Discussion, Conclusions, Appendix) with suggestions for the target audience and level of detail for each section. A section providing general expectations regarding population PK reporting from a regulatory perspective is also included. We consider this an important step towards industrialization of the field of pharmacometrics such that non-technical audience also understands the role of pharmacometrics analyses in decision making. Population PK reports were chosen as representative reports to derive these recommendations; however, the guiding principles presented here are applicable for all pharmacometric reports

  12. Pharmacokinetics and toxicology of therapeutic proteins: Advances and challenges

    PubMed Central

    Vugmeyster, Yulia; Xu, Xin; Theil, Frank-Peter; Khawli, Leslie A; Leach, Michael W

    2012-01-01

    Significant progress has been made in understanding pharmacokinetics (PK), pharmacodynamics (PD), as well as toxicity profiles of therapeutic proteins in animals and humans, which have been in commercial development for more than three decades. However, in the PK arena, many fundamental questions remain to be resolved. Investigative and bioanalytical tools need to be established to improve the translation of PK data from animals to humans, and from in vitro assays to in vivo readouts, which would ultimately lead to a higher success rate in drug development. In toxicology, it is known, in general, what studies are needed to safely develop therapeutic proteins, and what studies do not provide relevant information. One of the major complicating factors in nonclinical and clinical programs for therapeutic proteins is the impact of immunogenicity. In this review, we will highlight the emerging science and technology, as well as the challenges around the pharmacokinetic- and safety-related issues in drug development of mAbs and other therapeutic proteins. PMID:22558487

  13. Population pharmacokinetics of tamsulosin hydrochloride in paediatric patients with neuropathic and non-neuropathic bladder

    PubMed Central

    Tsuda, Yasuhiro; Tatami, Shinji; Yamamura, Norio; Tadayasu, Yusuke; Sarashina, Akiko; Liesenfeld, Karl-Heinz; Staab, Alexander; Schäfer, Hans-Günter; Ieiri, Ichiro; Higuchi, Shun

    2010-01-01

    AIMS The main objective of this study was to characterize the population pharmacokinetics of tamsulosin hydrochloride (HCl) in paediatric patients with neuropathic and non-neuropathic bladder. A secondary objective was to compare the pharmacokinetics in paediatric patients and adults. METHODS Tamsulosin HCl plasma concentrations in 1082 plasma samples from 189 paediatric patients (age range 2–16 years) were analyzed with NONMEM, applying a one compartment model with first-order absorption. Based on the principles of allometry, body weight was incorporated in the base model, along with fixed allometric exponents. Covariate analysis was performed by means of a stepwise forward inclusion and backward elimination procedure. Simulations based on the final model were used to compare the pharmacokinetics with those in adults. RESULTS Beside the priori-implemented body weight, only α1-acid glycoprotein had an effect on both apparent clearance and apparent volume of distribution. No other investigated covariates, including gender, age, race, patient population and concomitant therapy with anti-cholinergics, significantly affected the pharmacokinetics of tamsulosin HCl (P < 0.001). The results of simulations indicated that the exposure in 12.5 kg paediatric patients was 3.5–4.3 fold higher than that in 70.0 kg adults. After a weight-based dose administration, the exposure in paediatric patients was comparable with that in healthy adults. CONCLUSIONS A population pharmacokinetic model of tamsulosin HCl in paediatric patients was established and it described the data well. There was no major difference in the pharmacokinetics of tamsulosin HCl between paediatric patients (age range 2–16 years) and adults when the effect of body weight was taken into consideration. PMID:20642551

  14. Assessing Predictive Performance of Published Population Pharmacokinetic Models of Intravenous Tobramycin in Pediatric Patients.

    PubMed

    Bloomfield, Celeste; Staatz, Christine E; Unwin, Sean; Hennig, Stefanie

    2016-06-01

    Several population pharmacokinetic models describe the dose-exposure relationship of tobramycin in pediatric patients. Before the implementation of these models in clinical practice for dosage adjustment, their predictive performance should be externally evaluated. This study tested the predictive performance of all published population pharmacokinetic models of tobramycin developed for pediatric patients with an independent patient cohort. A literature search was conducted to identify suitable models for testing. Demographic and pharmacokinetic data were collected retrospectively from the medical records of pediatric patients who had received intravenous tobramycin. Tobramycin exposure was predicted from each model. Predictive performance was assessed by visual comparison of predictions to observations, by calculation of bias and imprecision, and through the use of simulation-based diagnostics. Eight population pharmacokinetic models were identified. A total of 269 concentration-time points from 41 pediatric patients with cystic fibrosis were collected for external evaluation. Three models consistently performed best in all evaluations and had mean errors ranging from -0.4 to 1.8 mg/liter, relative mean errors ranging from 4.9 to 29.4%, and root mean square errors ranging from 47.8 to 66.9%. Simulation-based diagnostics supported these findings. Models that allowed a two-compartment disposition generally had better predictive performance than those that used a one-compartment disposition model. Several published models of the pharmacokinetics of tobramycin showed reasonable low levels of bias, although all models seemed to have some problems with imprecision. This suggests that knowledge of typical pharmacokinetic behavior and patient covariate values alone without feedback concentration measurements from individual patients is not sufficient to make precise predictions. PMID:27001806

  15. Development of a physiologically based pharmacokinetic model for bisphenol A in pregnant mice

    SciTech Connect

    Kawamoto, Yuko; Matsuyama, Wakoto; Wada, Masahiro; Hishikawa, Junko; Chan, Melissa Pui Ling; Nakayama, Aki; Morisawa, Shinsuke

    2007-10-15

    Bisphenol A (BPA) is a weakly estrogenic monomer used to produce polymers for food contact and other applications, so there is potential for oral exposure of humans to trace amounts via ingestion. To date, no physiologically based pharmacokinetic (PBPK) model has been located for BPA in pregnant mice with or without fetuses. An estimate by a mathematical model is essential since information on humans is difficult to obtain experimentally. The PBPK model was constructed based on the pharmacokinetic data of our experiment following single oral administration of BPA to pregnant mice. The risk assessment of bisphenol A (BPA) on the development of human offspring is an important issue. There have been limited data on the exposure level of human fetuses to BPA (e.g. BPA concentration in cord blood) and no information is available on the pharmacokinetics of BPA in humans with or without fetuses. In the present study, we developed a physiologically based pharmacokinetic (PBPK) model describing the pharmacokinetics of BPA in a pregnant mouse with the prospect of future extrapolation to humans. The PBPK model was constructed based on the pharmacokinetic data of an experiment we executed on pregnant mice following single oral administration of BPA. The model could describe the rapid transfer of BPA through the placenta to the fetus and the slow disappearance from fetuses. The simulated time courses after three-time repeated oral administrations of BPA by the constructed model fitted well with the experimental data, and the simulation for the 10 times lower dose was also consistent with the experiment. This suggested that the PBPK model for BPA in pregnant mice was successfully verified and is highly promising for extrapolation to humans who are expected to be exposed more chronically to lower doses.

  16. Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics of Immunosuppressants in Allogeneic Hematopoietic Cell Transplantation: Part II.

    PubMed

    McCune, Jeannine S; Bemer, Meagan J; Long-Boyle, Janel

    2016-05-01

    Part I of this article included a pertinent review of allogeneic hematopoietic cell transplantation (alloHCT), the role of postgraft immunosuppression in alloHCT, and the pharmacokinetics, pharmacodynamics, and pharmacogenomics of the calcineurin inhibitors and methotrexate. In this article (Part II), we review the pharmacokinetics, pharmacodynamics, and pharmacogenomics of mycophenolic acid (MPA), sirolimus, and the antithymocyte globulins (ATG). We then discuss target concentration intervention (TCI) of these postgraft immunosuppressants in alloHCT patients, with a focus on current evidence for TCI and on how TCI may improve clinical management in these patients. Currently, TCI using trough concentrations is conducted for sirolimus in alloHCT patients. Several studies demonstrate that MPA plasma exposure is associated with clinical outcomes, with an increasing number of alloHCT patients needing TCI of MPA. Compared with MPA, there are fewer pharmacokinetic/dynamic studies of rabbit ATG and horse ATG in alloHCT patients. Future pharmacokinetic/dynamic research of postgraft immunosuppressants should include '-omics'-based tools: pharmacogenomics may be used to gain an improved understanding of the covariates influencing pharmacokinetics as well as proteomics and metabolomics as novel methods to elucidate pharmacodynamic responses. PMID:26620047

  17. Theory of Test Translation Error

    ERIC Educational Resources Information Center

    Solano-Flores, Guillermo; Backhoff, Eduardo; Contreras-Nino, Luis Angel

    2009-01-01

    In this article, we present a theory of test translation whose intent is to provide the conceptual foundation for effective, systematic work in the process of test translation and test translation review. According to the theory, translation error is multidimensional; it is not simply the consequence of defective translation but an inevitable fact…

  18. Effects of tetrahydrouridine on pharmacokinetics and pharmacodynamics of oral decitabine.

    PubMed

    Lavelle, Donald; Vaitkus, Kestis; Ling, Yonghua; Ruiz, Maria A; Mahfouz, Reda; Ng, Kwok Peng; Negrotto, Soledad; Smith, Nicola; Terse, Pramod; Engelke, Kory J; Covey, Joseph; Chan, Kenneth K; Desimone, Joseph; Saunthararajah, Yogen

    2012-02-01

    The deoxycytidine analog decitabine (DAC) can deplete DNA methyl-transferase 1 (DNMT1) and thereby modify cellular epigenetics, gene expression, and differentiation. However, a barrier to efficacious and accessible DNMT1-targeted therapy is cytidine deaminase, an enzyme highly expressed in the intestine and liver that rapidly metabolizes DAC into inactive uridine counterparts, severely limiting exposure time and oral bioavailability. In the present study, the effects of tetrahydrouridine (THU), a competitive inhibitor of cytidine deaminase, on the pharmacokinetics and pharmacodynamics of oral DAC were evaluated in mice and nonhuman primates. Oral administration of THU before oral DAC extended DAC absorption time and widened the concentration-time profile, increasing the exposure time for S-phase-specific depletion of DNMT1 without the high peak DAC levels that can cause DNA damage and cytotoxicity. THU also decreased interindividual variability in pharmacokinetics seen with DAC alone. One potential clinical application of DNMT1-targeted therapy is to increase fetal hemoglobin and treat hemoglobinopathy. Oral THU-DAC at a dose that would produce peak DAC concentrations of less than 0.2μM administered 2×/wk for 8 weeks to nonhuman primates was not myelotoxic, hypomethylated DNA in the γ-globin gene promoter, and produced large cumulative increases in fetal hemoglobin. Combining oral THU with oral DAC changes DAC pharmacology in a manner that may facilitate accessible noncytotoxic DNMT1-targeted therapy. PMID:22160381

  19. Effects of tetrahydrouridine on pharmacokinetics and pharmacodynamics of oral decitabine

    PubMed Central

    Lavelle, Donald; Vaitkus, Kestis; Ling, Yonghua; Ruiz, Maria A.; Mahfouz, Reda; Ng, Kwok Peng; Negrotto, Soledad; Smith, Nicola; Terse, Pramod; Engelke, Kory J.; Covey, Joseph; Chan, Kenneth K.; DeSimone, Joseph

    2012-01-01

    The deoxycytidine analog decitabine (DAC) can deplete DNA methyl-transferase 1 (DNMT1) and thereby modify cellular epigenetics, gene expression, and differentiation. However, a barrier to efficacious and accessible DNMT1-targeted therapy is cytidine deaminase, an enzyme highly expressed in the intestine and liver that rapidly metabolizes DAC into inactive uridine counterparts, severely limiting exposure time and oral bioavailability. In the present study, the effects of tetrahydrouridine (THU), a competitive inhibitor of cytidine deaminase, on the pharmacokinetics and pharmacodynamics of oral DAC were evaluated in mice and nonhuman primates. Oral administration of THU before oral DAC extended DAC absorption time and widened the concentration-time profile, increasing the exposure time for S-phase–specific depletion of DNMT1 without the high peak DAC levels that can cause DNA damage and cytotoxicity. THU also decreased interindividual variability in pharmacokinetics seen with DAC alone. One potential clinical application of DNMT1-targeted therapy is to increase fetal hemoglobin and treat hemoglobinopathy. Oral THU-DAC at a dose that would produce peak DAC concentrations of less than 0.2μM administered 2×/wk for 8 weeks to nonhuman primates was not myelotoxic, hypomethylated DNA in the γ-globin gene promoter, and produced large cumulative increases in fetal hemoglobin. Combining oral THU with oral DAC changes DAC pharmacology in a manner that may facilitate accessible noncytotoxic DNMT1-targeted therapy. PMID:22160381

  20. Translational Epidemiology in Psychiatry

    PubMed Central

    Weissman, Myrna M.; Brown, Alan S.; Talati, Ardesheer

    2012-01-01

    Translational research generally refers to the application of knowledge generated by advances in basic sciences research translated into new approaches for diagnosis, prevention, and treatment of disease. This direction is called bench-to-bedside. Psychiatry has similarly emphasized the basic sciences as the starting point of translational research. This article introduces the term translational epidemiology for psychiatry research as a bidirectional concept in which the knowledge generated from the bedside or the population can also be translated to the benches of laboratory science. Epidemiologic studies are primarily observational but can generate representative samples, novel designs, and hypotheses that can be translated into more tractable experimental approaches in the clinical and basic sciences. This bedside-to-bench concept has not been explicated in psychiatry, although there are an increasing number of examples in the research literature. This article describes selected epidemiologic designs, providing examples and opportunities for translational research from community surveys and prospective, birth cohort, and family-based designs. Rapid developments in informatics, emphases on large sample collection for genetic and biomarker studies, and interest in personalized medicine—which requires information on relative and absolute risk factors—make this topic timely. The approach described has implications for providing fresh metaphors to communicate complex issues in interdisciplinary collaborations and for training in epidemiology and other sciences in psychiatry. PMID:21646577

  1. Pharmacokinetics of Indomethacin in Pregnancy

    PubMed Central

    Rytting, Erik; Nanovskaya, Tatiana N.; Wang, Xiaoming; Vernikovskaya, Daria I.; Clark, Shannon M.; Cochran, Marlo; Abdel-Rahman, Susan M.; Venkataramanan, Raman; Caritis, Steve N.; Hankins, Gary D. V.; Ahmed, Mahmoud S.

    2014-01-01

    Background and objectives Although indomethacin has been widely used for the treatment of preterm labor over the past 40 years, there are few reports regarding its pharmacokinetics in pregnant women. Methods This opportunistic study assessed the steady-state pharmacokinetics of indomethacin in pregnant subjects to whom an oral dose of 25 mg every 6 h was prescribed. Indomethacin concentrations in plasma and urine were analyzed by a validated high-performance liquid chromatography method with mass spectrometric detection. Results The mean area under the plasma concentration versus time curve at steady state (AUCss) was 1.91 ± 0.53 lg h/mL, mean peak plasma concentration (Cmax) was 1.02 ± 0.49 lg/mL, and mean time to reach Cmax (tmax) was 1.3 ± 0.7 h. The mean apparent clearance at steady state was 14.5 ± 5.5 L/h, which is higher than the apparent clearance reported in the literature for non-pregnant subjects. Indomethacin crosses the placenta; the mean fetal/maternal ratio from five sets of cord blood samples collected at delivery was 4.0 ± 1.1. Conclusions Further studies are needed to determine whether any dose adjustments are necessary as a result of the increased clearance of indomethacin during pregnancy. PMID:24493205

  2. Pharmacokinetics of ciprofloxacin in ponies.

    PubMed

    Dowling, P M; Wilson, R C; Tyler, J W; Duran, S H

    1995-02-01

    The pharmacokinetics of ciprofloxacin was investigated in healthy, mature ponies. Ciprofloxacin was administered intravenously to six ponies at a dose of 5 mg per kg body weight. Seven days later, ciprofloxacin was administered orally to each pony at the same dose. Intravenous ciprofloxacin concentration vs. time data best fit a two-compartment open model with first-order elimination from the central compartment. Mean plasma half-life, based on the terminal phase, was 157.89 min (harmonic mean). Total body clearance of ciprofloxacin was 18.12 +/- 3.99 mL/min/kg. Volume of distribution at steady-state was 3.45 +/- 0.72 L/kg. From the pharmacokinetic data and reported minimum inhibitory concentrations for equine gram-negative pathogens, the appropriate dosage of ciprofloxacin was determined to be 5.32 mg per kg body weight at 12 h intervals. Bioavailability of oral ciprofloxacin in ponies was 6.8 +/- 5.33%. Owing to the poor bioavailability, a dosage regimen could not be proposed for oral ciprofloxacin administration in horses. Ciprofloxacin concentrations were determined in tissues and body fluids at 1, 2 and 4 h after intravenous administration. At all times, tissue concentrations exceeded plasma concentrations of ciprofloxacin. Highest concentrations were achieved in kidneys and urine. Potentially therapeutic concentrations were obtained in cerebrospinal and joint fluid, but low concentrations were achieved in aqueous humour. PMID:7752310

  3. Pharmacokinetic evaluation of fosaprepitant dimeglumine

    PubMed Central

    Colon-Gonzalez, Francheska; Kraft, Walter K.

    2011-01-01

    Importance of the field Chemotherapy induced nausea and vomiting (CINV) is a common complication in the treatment of patients with cancer. The introduction of the first in class neurokinin-1 receptor antagonist aprepitant provided additive control on CINV in combination to existing antiemetics. Due to formulation issues, aprepitant is only available for oral administration. Fosaprepitant, a prodrug of aprepitant, was introduced to the market in 2008 as an intravenous bioequivalent to aprepitant. Areas covered in this review This review examines the chemical development of fosaprepitant, its pharmacokinetic properties, approved uses, and potential applications. What the reader will gain The reader will get up-to-date information on the pharmacology and clinical uses of fosaprepitant. Clinical studies have demonstrated pharmacokinetic bioequivalence of aprepitant 125-mg to fosaprepitant 115-mg, as well as comparable efficacy in prevention of acute and delayed emesis following the first day of chemotherapy regimens. Take home message Fosaprepitant is an IV pro-drug of aprepitant that offers a new alternative to patients with CINV. Currently, fosaprepitant can substitute oral aprepitant in the first day of a 3-day regimen. Current studies show that a single-day fosaprepitant regimen is also bioequivalent to the 3-day aprepitant regimen, this could significantly simplify the care for CINV patients in the future. PMID:20795794

  4. PHARMACOKINETIC AND PHARMACODYNAMIC INTERACTION FOR A BINARY MIXTURE OF CHLORPYRIFOS AND DIAZINON IN THE RAT

    SciTech Connect

    Timchalk, Chuck; Poet, Torka S.; Hinman, Melissa N.; Busby, Andrea L.; Kousba, Ahmed A.

    2005-05-15

    Chlorpyrifos (CPF) and diazinon (DZN) are two commonly used organophosphorus (OP) insecticides and potential exists for concurrent exposures. The primary neurotoxic effects from OP pesticide exposures result from the inhibition of acetylcholinesterase (AChE) by their oxon metabolites. The pharmacokinetic and pharmacodynamic impact of acute binary exposures to CPF and DZN in rats were evaluated in this study. Rats were orally administered CPF, DZN or a CPF/DZN mixture (0, 15, 30 or 60 mg/kg) and blood (plasma and RBC), and brain were collected at 0, 3, 6, 12 and 24 h post-dosing, urine was also collected at 24 h. Chlorpyrifos, DZN and their respective metabolites 3,5,6-trichloro-2-pyridinol (TCP) and 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMHP) were quantified in blood and/or urine and cholinesterase (ChE) inhibition was measured in brain, RBCs and plasma. Co-exposure to CPF/DZN at 15/15 mg/kg, did not appreciably alter the pharmacokinetics of CPF, DZN or their metabolites in blood; whereas, a 60/60 mg/kg dose resulted in a transient increase in Cmax, AUC, and decreased clearance of both compounds, likely due to competition between CPF and DZN for CYP450 metabolism. At lower doses, most likely to be encountered in occupational or environmental exposures, the pharmacokinetics were linear. A dose-dependent inhibition of ChE was noted in tissues for both the single and co-exposures. The overall potency for ChE inhibition was greater for CPF than DZN and the binary mixture response appeared to be strongly influenced by CPF. A comparison of the ChE binary response at the low dose (15 mg/kg), where there were no apparent pharmacokinetic interactions, suggested that the overall ChE response was additive. These are the first reported experiments we are aware of that characterize both the pharmacokinetic and pharmacodynamic interactions between CPF and DZN in the rat, and will be used to further develop a binary physiologically based pharmacokinetic and pharmacodynamic

  5. Subtitling: Diagonal Translation.

    ERIC Educational Resources Information Center

    Gottlieb, Henrik

    1994-01-01

    Discusses the effects of translating televised foreign language materials, including changes in mode and timing. Outlines the necessary skills by which successful subtitlers overcome these complexities. Suggests nine basic fields to consider when creating and evaluating interlingual subtitles. (HB)

  6. Life is translation

    PubMed Central

    Zagrovic, Bojan

    2014-01-01

    Evolutionary origin of translation represents one of the key questions that Carl Woese addressed in his work. Here we give a personal account of his results in this area and the effect they have had on the field. PMID:24572678

  7. Lost in Translation

    NASA Astrophysics Data System (ADS)

    Lass, Wiebke; Reusswig, Fritz

    2014-05-01

    Lost in Translation? Introducing Planetary Boundaries into Social Systems. Fritz Reusswig, Wiebke Lass Potsdam Institute for Climate Impact Research, Potsdam, Germany Identifying and quantifying planetary boundaries by interdisciplinary science efforts is a challenging task—and a risky one, as the 1972 Limits to Growth publication has shown. Even if we may be assured that scientific understanding of underlying processes of the Earth system has significantly improved since then, the challenge of translating these findings into the social systems of the planet remains crucial for any kind of action, and in many respects far more challenging. We would like to conceptualize what could also be termed a problem of coupling social and natural systems as a nested set of social translation processes, well aware of the limited applicability of the language-related translation metaphor. Societies must, first, perceive these boundaries, and they have to understand their relevance. This includes, among many other things, the organization of transdisciplinary scientific cooperation. They will then have to translate this understood perception into possible actions, i.e. strategies for different local bodies, actors, and institutional settings. This implies a lot of 'internal' translation processes, e.g. from the scientific subsystem to the mass media, the political and the economic subsystem. And it implies to develop subsystem-specific schemes of evaluation for these alternatives, e.g. convincing narratives, cost-benefit analyses, or ethical legitimacy considerations. And, finally, societies do have to translate chosen action alternatives into monitoring and evaluation schemes, e.g. for agricultural production or renewable energies. This process includes the continuation of observing and re-analyzing the planetary boundary concept itself, as a re-adjustment of these boundaries in the light of new scientific insights cannot be excluded. Taken all together, societies may well

  8. Pharmacokinetic modeling and dosage adaptation of biapenem in Japanese patients during continuous venovenous hemodiafiltration.

    PubMed

    Ikawa, Kazuro; Morikawa, Norifumi; Ikeda, Kayo; Suyama, Hidemichi

    2008-02-01

    The present study examined the pharmacokinetics of biapenem during continuous venovenous hemodiafiltration (CVVHDF) and assessed the pharmacodynamic exposure, based on a pharmacokinetic model, to consider biapenem dosage adaptation in CVVHDF. Biapenem (300 mg) was administered by 2-h infusion to seven critically ill patients receiving CVVHDF. The flow rates were 60 ml/min for blood, 800 ml/h for filtrate, and 600 ml/h for dialysate. The drug concentrations in plasma and filtrate-dialysate were determined by high-performance liquid chromatography and analyzed pharmacokinetically. The sieving coefficient was 0.92 +/- 0.06 (mean +/- SD). The simulation curves, using a multicompartment model, were well fitted to the measurements in plasma and filtrate-dialysate. The clearance by CVVHDF and the clearance by non-CVVHDF routes were 1.29 +/- 0.08 and 6.14 +/- 1.89 l/h, respectively. The multicompartment model was used to assess the pharmacodynamic exposure (time above the minimum inhibitory concentration of 4 microg/ml) in plasma. When the total daily dose was 600 mg, the duration of time was greater at 300 mg every 12 h than at 600 mg every 24 h. The minimum dosages needed to achieve more than 30% of the dosing interval at filtrate-dialysate flow rates of 1.4, 2.8, and 5.6 l/h were 300 mg every 12 h, 600 mg every 12 h, and 600 mg every 12 h, respectively. These results suggested that low doses or increased dosing intervals should be avoided in patients receiving this renal replacement technique. Information on pharmacodynamic exposure obtained from this model may help us to determine the appropriate biapenem dosage for CVVHDF. Moreover, our pharmacokinetic model may be useful for further pharmacokinetic studies of biapenem. PMID:18297447

  9. Machine Translation from Text

    NASA Astrophysics Data System (ADS)

    Habash, Nizar; Olive, Joseph; Christianson, Caitlin; McCary, John

    Machine translation (MT) from text, the topic of this chapter, is perhaps the heart of the GALE project. Beyond being a well defined application that stands on its own, MT from text is the link between the automatic speech recognition component and the distillation component. The focus of MT in GALE is on translating from Arabic or Chinese to English. The three languages represent a wide range of linguistic diversity and make the GALE MT task rather challenging and exciting.

  10. Translation readthrough mitigation.

    PubMed

    Arribere, Joshua A; Cenik, Elif S; Jain, Nimit; Hess, Gaelen T; Lee, Cameron H; Bassik, Michael C; Fire, Andrew Z

    2016-06-30

    A fraction of ribosomes engaged in translation will fail to terminate when reaching a stop codon, yielding nascent proteins inappropriately extended on their C termini. Although such extended proteins can interfere with normal cellular processes, known mechanisms of translational surveillance are insufficient to protect cells from potential dominant consequences. Here, through a combination of transgenics and CRISPR–Cas9 gene editing in Caenorhabditis elegans, we demonstrate a consistent ability of cells to block accumulation of C-terminal-extended proteins that result from failure to terminate at stop codons. Sequences encoded by the 3′ untranslated region (UTR) were sufficient to lower protein levels. Measurements of mRNA levels and translation suggested a co- or post-translational mechanism of action for these sequences in C. elegans. Similar mechanisms evidently operate in human cells, in which we observed a comparable tendency for translated human 3′ UTR sequences to reduce mature protein expression in tissue culture assays, including 3′ UTR sequences from the hypomorphic ‘Constant Spring’ haemoglobin stop codon variant. We suggest that 3′ UTRs may encode peptide sequences that destabilize the attached protein, providing mitigation of unwelcome and varied translation errors. PMID:27281202

  11. Translating Alcohol Research

    PubMed Central

    Batman, Angela M.; Miles, Michael F.

    2015-01-01

    Alcohol use disorder (AUD) and its sequelae impose a major burden on the public health of the United States, and adequate long-term control of this disorder has not been achieved. Molecular and behavioral basic science research findings are providing the groundwork for understanding the mechanisms underlying AUD and have identified multiple candidate targets for ongoing clinical trials. However, the translation of basic research or clinical findings into improved therapeutic approaches for AUD must become more efficient. Translational research is a multistage process of streamlining the movement of basic biomedical research findings into clinical research and then to the clinical target populations. This process demands efficient bidirectional communication across basic, applied, and clinical science as well as with clinical practitioners. Ongoing work suggests rapid progress is being made with an evolving translational framework within the alcohol research field. This is helped by multiple interdisciplinary collaborative research structures that have been developed to advance translational work on AUD. Moreover, the integration of systems biology approaches with collaborative clinical studies may yield novel insights for future translational success. Finally, appreciation of genetic variation in pharmacological or behavioral treatment responses and optimal communication from bench to bedside and back may strengthen the success of translational research applications to AUD. PMID:26259085

  12. LUNG, ARSENIC EXPOSURE, AND TISSUE REMODELING

    EPA Science Inventory

    In Specific Aim 1, we will develop a lung model of in utero arsenic exposure. We will assess the best graft conditions, including size, site and initial stage to ensure optimal graft survival and maturation. In addition, we will study the pharmacokinetic relationship between a...

  13. Development of a physiologically based pharmacokinetic model for inhalation of jet fuels in the rat.

    PubMed

    Martin, Sheppard A; Campbell, Jerry L; Tremblay, Raphael T; Fisher, Jeffrey W

    2012-01-01

    The pharmacokinetic behavior of the majority of jet fuel constituents has not been previously described in the framework of a physiologically based pharmacokinetic (PBPK) model for inhalation exposure. Toxic effects have been reported in multiple organ systems, though exposure methods varied across studies, utilizing either vaporized or aerosolized fuels. The purpose of this work was to assess the pharmacokinetics of aerosolized and vaporized fuels, and develop a PBPK model capable of describing both types of exposures. To support model development, n-tetradecane and n-octane exposures were conducted at 89 mg/m(3) aerosol+vapor and 1000-5000 ppm vapor, respectively. Exposures to JP-8 and S-8 were conducted at ~900-1000 mg/m(3), and ~200 mg/m(3) to a 50:50 blend of both fuels. Sub-models were developed to assess the behavior of representative constituents and grouped unquantified constituents, termed "lumps", accounting for the remaining fuel mass. The sub-models were combined into the first PBPK model for petroleum and synthetic jet fuels. Inhalation of hydrocarbon vapors was described with simple gas-exchange assumptions for uptake and exhalation. For aerosol droplets systemic uptake occurred in the thoracic region. Visceral tissues were described using perfusion and diffusion-limited equations. The model described kinetics at multiple fuel concentrations, utilizing a chemical "lumping" strategy to estimate parameters for fractions of speciated and unspeciated hydrocarbons and gauge metabolic interactions. The model more accurately simulated aromatic and lower molecular weight (MW) n-alkanes than some higher MW chemicals. Metabolic interactions were more pronounced at high (~2700-1000 mg/m(3)) concentrations. This research represents the most detailed assessment of fuel pharmacokinetics to date. PMID:22188408

  14. Pharmacokinetics in Animals and Humans of a First-in-Class Peptide Deformylase Inhibitor

    PubMed Central

    Ramanathan-Girish, Sandhya; McColm, Juliet; Clements, John M.; Taupin, Phil; Barrowcliffe, Sue; Hevizi, John; Safrin, Sharon; Moore, Clive; Patou, Gary; Moser, Heinz; Gadd, Alison; Hoch, Ute; Jiang, Vernon; Lofland, Denene; Johnson, Kirk W.

    2004-01-01

    BB-83698, a potent and selective inhibitor of peptide deformylase, was the first compound of this novel antibacterial class to progress to clinical trials. Single- and/or multiple-dose studies with doses ranging from 10 to 50 mg of BB-83698/kg of body weight were done with mice, rats, and dogs. Intravenous pharmacokinetics were characterized by low to moderate clearances and moderate volumes of distribution for all species. In dogs, but not in rodents, central nervous system (CNS) effects were dose limiting for intravenously administered BB-83698 and were suspected to be related to a high maximum concentration of the agent in plasma (Cmax) rather than to total systemic exposure. Controlled infusion studies with dogs demonstrated that CNS effects could be avoided without compromising systemic exposure by reducing the Cmax. A randomized, double-blind, placebo-controlled, five-way-crossover, single-dose-escalation, phase I study to explore the safety, tolerability, and pharmacokinetics of intravenous BB-83698 at doses ranging from 10 to 475 mg was performed with healthy male volunteers. Systemic exposures were generally in linear relationships with administered doses in animals and humans. Pharmacokinetics were consistent, predictable, and exhibited good allometric scaling among all species (r2 >0.98). Moreover, BB-83698 dosing in humans proceeded to a predicted efficacious exposure (the area under the concentration-time curve/MIC ratio, up to 184) without any clinically significant adverse effects. PMID:15561864

  15. Pharmacokinetics in animals and humans of a first-in-class peptide deformylase inhibitor.

    PubMed

    Ramanathan-Girish, Sandhya; McColm, Juliet; Clements, John M; Taupin, Phil; Barrowcliffe, Sue; Hevizi, John; Safrin, Sharon; Moore, Clive; Patou, Gary; Moser, Heinz; Gadd, Alison; Hoch, Ute; Jiang, Vernon; Lofland, Denene; Johnson, Kirk W

    2004-12-01

    BB-83698, a potent and selective inhibitor of peptide deformylase, was the first compound of this novel antibacterial class to progress to clinical trials. Single- and/or multiple-dose studies with doses ranging from 10 to 50 mg of BB-83698/kg of body weight were done with mice, rats, and dogs. Intravenous pharmacokinetics were characterized by low to moderate clearances and moderate volumes of distribution for all species. In dogs, but not in rodents, central nervous system (CNS) effects were dose limiting for intravenously administered BB-83698 and were suspected to be related to a high maximum concentration of the agent in plasma (Cmax) rather than to total systemic exposure. Controlled infusion studies with dogs demonstrated that CNS effects could be avoided without compromising systemic exposure by reducing the Cmax. A randomized, double-blind, placebo-controlled, five-way-crossover, single-dose-escalation, phase I study to explore the safety, tolerability, and pharmacokinetics of intravenous BB-83698 at doses ranging from 10 to 475 mg was performed with healthy male volunteers. Systemic exposures were generally in linear relationships with administered doses in animals and humans. Pharmacokinetics were consistent, predictable, and exhibited good allometric scaling among all species (r2 >0.98). Moreover, BB-83698 dosing in humans proceeded to a predicted efficacious exposure (the area under the concentration-time curve/MIC ratio, up to 184) without any clinically significant adverse effects. PMID:15561864

  16. Clinical pharmacokinetics and pharmacodynamics of mycophenolate in patients with autoimmune disease.

    PubMed

    Abd Rahman, Azrin N; Tett, Susan E; Staatz, Christine E

    2013-05-01

    Mycophenolic acid (MPA), the active drug moiety of mycophenolate, is a potent immunosuppressant agent, which is increasingly being used in the treatment of patients with various autoimmune diseases. An understanding of the pharmacokinetics and pharmacodynamics of mycophenolate in this population should assist the clinician with rational dosage decisions. This review aims to provide an overview of the published literature on the clinical pharmacokinetics of mycophenolate in autoimmune disease and a briefer summary of current pharmacodynamic knowledge, and to identify areas of potential future research in this field. A literature search was conducted using PubMed and EMBASE databases as well as bibliographies of relevant articles and 'on-line early' pages of key journals. Twenty-six pharmacokinetic/pharmacodynamic studies of mycophenolate in people with autoimmune disease were identified and appraised. Twenty-two of these studies used non-compartmental analysis techniques and four used population modelling methods to estimate mycophenolate pharmacokinetic parameters. Seven studies linked mycophenolate exposure to treatment outcomes. Only four studies measured free (unbound) as well as total mycophenolate exposure and only two studies characterised MPA disposition following enteric-coated mycophenolate sodium (EC-MPS) administration. Across all studies MPA displayed erratic and complex pharmacokinetics with substantial between-subject variability. Based on total drug measurement, the dose-normalised MPA area under the plasma concentration-time curve (AUC) from 0 to 12 h post-dose (AUC12) varied at least five- to ten-fold between subjects. Typical values for apparent oral clearance (CL/F) of MPA during nonlinear mixed-effects modelling ranged from 8.3 to 25.3 L/h. Patient renal function, serum albumin levels, sex, ethnicity, food intake, concurrent administration of interacting drugs such as antacids, metal-containing medications and proton pump inhibitors and

  17. USE OF EXPOSURE RELATED DOSE ESTIMATING MODEL ( ERDEM ) TO CONSTRUCT A PBPK /MODEL FOR CARBOFURAN WITH THE REPORTED EXPERIMENTAL DATA IN THE RAT

    EPA Science Inventory

    To better understand the relationships among carbofuran exposure, dose, and effects, a physiologically-based pharmacokinetic and pharmacodynamic (PBPK/PD) model was developed for the rat using the Exposure Related Dose Estimating Model (ERDEM) framework.

  18. PHARMACOKINETIC PROFILES OF PERFLUOROOCTANOIC ACID IN MICE AFTER CHRONIC EXPOSURE

    EPA Science Inventory

    Perfluorooctanoic acid (PFOA) is highly persistent in humans, with serum half-life estimates of 2.3 to 3.8 years. In the mouse, elimination of PFOA appears to be first-order after a single oral administration, with serum half-life estimates of 16 days for females and 22 days for ...

  19. The Effect of Translators' Emotional Intelligence on Their Translation Quality

    ERIC Educational Resources Information Center

    Varzande, Mohsen; Jadidi, Esmaeil

    2015-01-01

    Translators differ from each other in many ways in terms of their knowledge, professional and psychological conditions that may directly influence their translation. The present study aimed at investigating the impact of translators' Emotional Intelligence on their translation quality. Following a "causal-comparative study," a sample of…

  20. The Impact of Translators' Academic Experience on Their Translation Quality

    ERIC Educational Resources Information Center

    Varzande, Mohsen; Jadidi, Esmaeil

    2015-01-01

    Translators differ from each other in many ways in terms of their knowledge and professional conditions that may directly influence their translation. The present study aimed at investigating the impact of translators' academic experience on their translation quality. Following a "causal-comparative study", a sample of 100 male and…

  1. Pharmacokinetics of cannabidiol in dogs.

    PubMed

    Samara, E; Bialer, M; Mechoulam, R

    1988-01-01

    Cannabidiol (CBD) is one of the major nonpsychoactive cannabinoids produced by Cannabis sativa L. Recent studies have shown that CBD has a high protective index, comparable to that of phenobarbital and phenytoin. Because CBD has been reported to possess both anticonvulsant and antiepileptic activity, its pharmacokinetics were studied in dogs after the administration of two iv doses (45 and 90 mg) and one oral dose (180 mg) to dogs. After iv administration, CBD was rapidly distributed, followed by a prolonged elimination. It has a terminal half-life of 9 hr. CBD plasma levels declined in a triphasic fashion. The total body clearance of CBD was 17 liters/hr (after the 45-mg dose) and 16 liters/hr (after the 90-mg dose). This clearance value, after its normalization to blood clearance using mathematical equations, approaches the value of the hepatic blood flow; the extraction ratio in the liver is 0.74. CBD was observed to have a large volume of distribution, approximately 100 liters. In the dose range of 45 to 90 mg, the increase in the AUC was proportional to the dose, a fact that indicates that the pharmacokinetic profile of CBD in this dose range was not dose dependent. In three of the six dogs studied, CBD could not be detected in the plasma after oral administration. In the other three, the oral bioavailability ranged from 13 to 19%. The results of this study show that CBD is barely absorbed after oral administration to dogs. This low bioavailability may be due to a first pass effect. PMID:2900742

  2. Data sharing for pharmacokinetic studies.

    PubMed

    Anderson, Brian J; Merry, Alan F

    2009-10-01

    Pooling data from different pediatric studies can provide a single robust pharmacokinetic analysis that allows covariate analysis and hypothesis testing. Data sharing should be driven by the altruistic purpose of improving drug understanding to the clinical benefit of children. Electronic communications have rendered the sharing of data relatively easy, and data sharing within the wider scientific community has become commonplace. Data sharing allows verification of results, save costs and time, allows new interpretation of old data, and can fulfill teaching benefits. It may stimulate cooperative competition between researchers and allow individual researchers to concentrate on unique aspects of the scientific puzzle. However, there is occasionally a reluctance to share, in part because of fear of others stealing the hard work of a research group, which may not be recognized in subsequent publications that reuse data. Providing data may require additional effort for presentation in a suitable format. Data may be abused or used for purposes other than those for which they were collected. Propriety claims may limit access to industry-sponsored drug research. The question of who has ownership of data is contentious. Investigators often consider data they have collected to be their own property. Reputations and grants may be hinge on ownership of a data set. However, other team members, institutions, funding agencies, and the public also have a stake. The difficulties identified in the general scientific community also apply to data sharing for pediatric pharmacokinetic studies. There are few clearly established rules at present, and consideration of the issues hinges on ethical and philosophical arguments. The development of databases will depend on collaboration and cooperation and greater clarity and consensus over appropriate processes and procedures. PMID:19558615

  3. Use of novel inhalation kinetic studies to refine physiologically-based-pharmacokinetic models for ethanol in non-pregnant and pregnant rats

    EPA Science Inventory

    Ethanol (EtOH) exposure induces a variety of concentration-dependent neurological and developmental effects in the rat. Physiologically-based pharmacokinetic (PBPK) models have been used to predict the inhalation exposure concentrations necessary to produce blood EtOH concentrat...

  4. 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...

  5. 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.

  6. Molecular pharmacokinetics of catharanthus (vinca) alkaloids.

    PubMed

    Levêque, Dominique; Jehl, François

    2007-05-01

    This review focuses on the published data regarding the molecular determinants (enzymes, transporters, orphan nuclear receptors) of Catharanthus (vinca) alkaloids pharmacokinetics in humans. The clinical impact of these determinants (drug disposition, drug-drug interactions) is also discussed. PMID:17442684

  7. Development of quantitative structure-pharmacokinetic relationships.

    PubMed Central

    Mayer, J M; van de Waterbeemd, H

    1985-01-01

    Quantitative structure-activity relationships (QSAR) relating biological activity to physiochemical descriptors have been successfully used for a number of years. It is also long recognized that pharmacokinetic parameters may play an important and even determinant role in drug action. This prompted several researchers to focus attention to pharmacokinetic parameters as potential descriptors in quantitative drug design. A number of examples of quantitative structure-pharmacokinetic relationships (QSPR) have appeared in the literature. The present contribution reviews some developments in this field. In particular, a number of concepts and problems are critically discussed, rather than compilations of examples already published in recent reviews. Attention will be paid to the main processes of the pharmacokinetic or toxicokinetic phase in drug action, including absorption, distribution and elimination (biotransformation and excretion). It is clear that quantitative approaches are of considerable interest to toxicologists, since these methods may contribute to the development of real predictive toxicology. PMID:3905378

  8. Erythropoietin for Neuroprotection in Neonatal Encephalopathy: Safety and Pharmacokinetics

    PubMed Central

    Bauer, Larry A.; Ballard, Roberta A.; Ferriero, Donna M.; Glidden, David V.; Mayock, Dennis E.; Chang, Taeun; Durand, David J.; Song, Dongli; Bonifacio, Sonia L.; Gonzalez, Fernando F.; Glass, Hannah C.; Juul, Sandra E.

    2012-01-01

    OBJECTIVE: To determine the safety and pharmacokinetics of erythropoietin (Epo) given in conjunction with hypothermia for hypoxic-ischemic encephalopathy (HIE). We hypothesized that high dose Epo would produce plasma concentrations that are neuroprotective in animal studies (ie, maximum concentration = 6000–10 000 U/L; area under the curve = 117 000–140 000 U*h/L). METHODS: In this multicenter, open-label, dose-escalation, phase I study, we enrolled 24 newborns undergoing hypothermia for HIE. All patients had decreased consciousness and acidosis (pH < 7.00 or base deficit ≥ 12), 10-minute Apgar score ≤ 5, or ongoing resuscitation at 10 minutes. Patients received 1 of 4 Epo doses intravenously: 250 (N = 3), 500 (N = 6), 1000 (N = 7), or 2500 U/kg per dose (N = 8). We gave up to 6 doses every 48 hours starting at <24 hours of age and performed pharmacokinetic and safety analyses. RESULTS: Patients received mean 4.8 ± 1.2 Epo doses. Although Epo followed nonlinear pharmacokinetics, excessive accumulation did not occur during multiple dosing. At 500, 1000, and 2500 U/kg Epo, half-life was 7.2, 15.0, and 18.7 hours; maximum concentration was 7046, 13 780, and 33 316 U/L, and total Epo exposure (area under the curve) was 50 306, 131 054, and 328 002 U*h/L, respectively. Drug clearance at a given dose was slower than reported in uncooled preterm infants. No deaths or serious adverse effects were seen. CONCLUSIONS: Epo 1000 U/kg per dose intravenously given in conjunction with hypothermia is well tolerated and produces plasma concentrations that are neuroprotective in animals. A large efficacy trial is needed to determine whether Epo add-on therapy further improves outcome in infants undergoing hypothermia for HIE. PMID:23008465

  9. Pharmacokinetic interaction of riociguat with ketoconazole, clarithromycin, and midazolam

    PubMed Central

    Frey, Reiner; Unger, Sigrun; Thomas, Dirk; Reber, Michael; Weimann, Gerrit; Dietrich, Hartmut; Arens, Erich R.; Mück, Wolfgang

    2016-01-01

    Abstract Riociguat is a soluble guanylate cyclase stimulator for the treatment of pulmonary hypertension that is principally metabolized via the cytochrome P450 (CYP) pathway. Three studies in healthy males investigated potential pharmacokinetic interactions between riociguat and CYP inhibitors (ketoconazole, clarithromycin, and midazolam). In two studies, subjects were pretreated with either once-daily ketoconazole 400 mg or twice-daily clarithromycin 500 mg for 4 days before cotreatment with either riociguat 0.5 mg ± ketoconazole 400 mg or riociguat 1.0 mg ± clarithromycin 500 mg. In the third study, subjects received riociguat 2.5 mg 3 times daily (tid) for 3 days, followed by cotreatment with riociguat 2.5 mg tid ± midazolam 7.5 mg. Pharmacokinetic parameters, the effect of smoking on riociguat pharmacokinetics, safety, and tolerability were assessed. Pre- and cotreatment with ketoconazole and clarithromycin led to increased riociguat exposure. Pre- and cotreatment with riociguat had no significant effect on midazolam plasma concentrations. In all studies, the bioavailability of riociguat was reduced in smokers because its clearance to the metabolite M1 increased. Riociguat ± ketoconazole, clarithromycin, or midazolam was generally well tolerated. The most common treatment-emergent adverse events (TEAEs) across all studies were headache and dyspepsia. One serious TEAE was reported in the midazolam study. Owing to the potential for hypotension, concomitant use of riociguat with multipathway inhibitors, such as ketoconazole, should be approached with caution. Coadministration of riociguat with strong CYP3A4 inhibitors, for example, clarithromycin, does not require additional dose adjustment. No significant drug-drug interaction was revealed between riociguat and midazolam. PMID:27162627

  10. Oritavancin Pharmacokinetics and Bone Penetration in Rabbits

    PubMed Central

    Ostiguy, Valerie; Cadieux, Cordelia; Malouin, Mireille; Belanger, Odette; Far, Adel Rafai; Parr, Thomas R.

    2015-01-01

    The pharmacokinetics and bone concentrations of oritavancin were investigated after a single intravenous dose was administered to rabbits. The pharmacokinetic profile of oritavancin in rabbits showed that it is rapidly distributed to bone tissues, with concentrations remaining stable for up to 168 h, the last measured time point. Based on these findings, further evaluation of oritavancin for the treatment of infections in bone tissues is warranted. PMID:26239977

  11. Clinical Pharmacokinetics: A Simplified Approach, Part 2

    PubMed Central

    Perlin, Elliott; Taylor, Robert E.; Peck, Carl C.

    1986-01-01

    Part 1 of this two-part series in clinical pharmacokinetics (J Natl Med Assoc 1985; 77:475-482) introduced the clinician to the basic principles required for rational therapeutic drug management at the bedside. Practical problems were included that demonstrated how these principles could be put to clinical use. In Part 2 the clinical pharmacology of three commonly used drugs (theophylline, digoxin and gentamicin) are discussed, and practical problems are presented to illustrate the use of their pharmacokinetic profiles. PMID:3783759

  12. Life-Stage PBPK Models for Multiple Routes of Ethanol Exposure in the Rat

    EPA Science Inventory

    Ethanol is commonly blended with gasoline (10% ethanol) in the US, and higher ethanol concentrations are being considered. While the pharmacokinetics and toxicity of orally-ingested ethanol are widely reported, comparable work is limited for inhalation exposure (IE), particularly...

  13. PROcEED: Probabilistic reverse dosimetry approaches for estimating exposure distributions

    EPA Science Inventory

    As increasing amounts of biomonitoring survey data become available, a new discipline focused on converting such data into estimates of chemical exposures has developed. Reverse dosimetry uses a pharmacokinetic model along with measured biomarker concentrations to determine the p...

  14. POLIBROMINATED DIPHENYL ETHERS: A CASE STUDY FOR APPLICATION OF BIOMONITORING DATA TO CHARACTERIZE EXPOSURE

    EPA Science Inventory

    The presence and steady increase in environmental and human concentrations of PBDEs (polybrominated diphenyl ethers) has heightened interest in the potential toxicological consequences of these chemicals. Currently available data on exposure, pharmacokinetics, toxicity, and biom...

  15. UNCERTAINTY ANALYSIS OF TCE USING THE DOSE EXPOSURE ESTIMATING MODEL (DEEM) IN ACSL

    EPA Science Inventory

    The ACSL-based Dose Exposure Estimating Model(DEEM) under development by EPA is used to perform art uncertainty analysis of a physiologically based pharmacokinetic (PSPK) model of trichloroethylene (TCE). This model involves several circulating metabolites such as trichloroacet...

  16. Single-dose pharmacokinetics of bupropion hydrobromide and metabolites in healthy adolescent and adult subjects.

    PubMed

    Oh, D Alexander; Crean, Christopher S

    2015-09-01

    Data from 2 pediatric single-dose studies, conducted at the same center, were combined to evaluate exposure levels of bupropion and metabolites in adolescents 12-17 years old, compared with adults > 18 years. Pharmacokinetic analyses of bupropion and its metabolites were performed using normalization and pharmacological/convulsive weighting methods on exposure. When compared with adults (>18 years), subjects 12-14 years had an increase in weight-normalized exposure to bupropion (ie, Cmax , 78%; AUC0-t , 83%; and AUCinf , 85%). Variability in this younger age group was also higher, with observations of a 3- to 4-fold increase in exposure. When the changes in metabolites were accounted within pharmacological and convulsive-weighted exposures, the relative ratio of 12-14 years to adults in body weight-normalized Cmax was 127% and 110%, respectively. Subjects 15-17 years did not exhibit a difference in exposure compared with adults. The influence of age on bupropion pharmacokinetics demonstrates that, in general, healthy adolescent subjects cannot be considered smaller healthy adult subjects; the increase in exposure is inversely related to age and appears to be solely associated with bupropion, not with its metabolites. Because there are no clinical safety and efficacy data of bupropion in adolescents, this data may shift its risk-benefit profile. PMID:27137143

  17. PHYSIOLOGICALLY-BASED PHARMACOKINETIC AND PHARMACODYNAMIC (PBPK/PD) MODEL FOR PREDICTING THE DERMAL DOSE AND DISPOSITION OF ORGANOPHOSPHORUS INSECTICIDES

    EPA Science Inventory

    Physiologically-based pharmacokinetic/ pharmacodynamic (PBPK/PD) models are particularly suited for interpretation of cumulative risk via the dermal route for which aggregate exposure must be assessed for chemicals having a common mechanism of toxicity. To this end, a quantita...

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

    PubMed Central

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

    2016-01-01

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

  19. Atazanavir and Atazanavir/Ritonavir Pharmacokinetics in HIV-Infected Infants, Children, and Adolescents

    PubMed Central

    Kiser, Jennifer J.; Rutstein, Richard M.; Samson, Pearl; Graham, Bobbie; Aldrovandi, Grace; Mofenson, Lynne M.; Smith, Elizabeth; Schnittman, Steven; Fenton, Terry; Brundage, Richard C.; Fletcher, Courtney V.

    2011-01-01

    Objective To describe the pharmacokinetics of atazanavir (ATV) and ritonavir-boosted ATV/r in children ages 91 days to 21 years. Design Phase I/II, open label, multicenter study of once daily ATV and ATV/r as part of combination antiretroviral treatment in HIV-infected treatment experienced and naïve children. Setting Sites in the United States and South Africa. Subjects 195 children enrolled; 172 had evaluable ATV pharmacokinetics on day seven. Intervention Children were entered in age, dose and formulation (powder or capsule) cohorts. Intensive pharmacokinetic sampling occurred seven days after starting ATV. ATV doses were increased or decreased if the 24-hour area under the concentration time curves (AUC0–24hr) were <30 or >90 mcg*hr/mL, respectively. Main outcomes Cohorts satisfied protocol-defined pharmacokinetic criteria if the median ATV AUC0–24hr ≤60 mcg*hr/mL, and AUC0–24hr and ATV concentrations 24 hours post-dose (C24) were >30 mcg*hr/mL and ≥60 ng/mL, respectively, in ≥ 80% of children, with no individual AUC0–24hr <15 mcg*hr/mL. Results Unboosted ATV capsules satisfied pharmacokinetic criteria at a dose of 520 mg/m2 for those >2 to ≤ 13 years and 620 mg/m2 for those >13 to ≤ 21 years. ATV/r capsules satisfied criteria at a dose of 205 mg/m2 for those >2 to ≤ 21 years. ATV/r powder satisfied criteria at a dose of 310 mg/m2 for those >2 to ≤ 13 years, but pharmacokinetics in those ≤ 2 years were highly variable. Conclusions Body surface area-determined doses of ATV capsules and ATV/r powder and capsules provide ATV exposures in children >2 years that approximate values in adults receiving ATV/r. PMID:21610486

  20. Liraglutide in Type 2 Diabetes Mellitus: Clinical Pharmacokinetics and Pharmacodynamics.

    PubMed

    Jacobsen, Lisbeth V; Flint, Anne; Olsen, Anette K; Ingwersen, Steen H

    2016-06-01

    Liraglutide is an acylated glucagon-like peptide-1 analogue with 97 % amino acid homology with native glucagon-like peptide-1 and greatly protracted action. It is widely used for the treatment of type 2 diabetes mellitus, and administered by subcutaneous injection once daily. The pharmacokinetic properties of liraglutide enable 24-h exposure coverage, a requirement for 24-h glycaemic control with once-daily dosing. The mechanism of protraction relates to slowed release from the injection site, and a reduced elimination rate owing to metabolic stabilisation and reduced renal filtration. Drug exposure is largely independent of injection site, as well as age, race and ethnicity. Increasing body weight and male sex are associated with reduced concentrations, but there is substantial overlap between subgroups; therefore, dose escalation should be based on individual treatment outcome. Exposure is reduced with mild, moderate or severe renal or hepatic impairment. There are no clinically relevant changes in overall concentrations of various drugs (e.g. paracetamol, atorvastatin, griseofulvin, digoxin, lisinopril and oral combination contraceptives) when co-administered with liraglutide. Pharmacodynamic studies show multiple beneficial actions with liraglutide, including improved fasting and postprandial glycaemic control (mediated by increased insulin and reduced glucagon levels and minor delays in gastric emptying), reduced appetite and energy intake, and effects on postprandial lipid profiles. The counter-regulatory hormone response to hypoglycaemia is largely unaltered. The effects of liraglutide on insulin and glucagon secretion are glucose dependent, and hence the risk of hypoglycaemia is low. The pharmacokinetic and pharmacodynamic properties of liraglutide make it an important treatment option for many patients with type 2 diabetes. PMID:26597252

  1. Pharmacokinetics of bisphenol A in neonatal and adult rhesus monkeys

    SciTech Connect

    Doerge, Daniel R.; Twaddle, Nathan C.; Woodling, Kellie A.; Fisher, Jeffrey W.

    2010-10-01

    Bisphenol A (BPA) is a high-production volume industrial chemical used in the manufacture of polycarbonate plastic products and epoxy resin-based food can liners. The presence of BPA in urine of > 90% of Americans aged 6-60 is controversial because of the potential for endocrine disruption, particularly during perinatal development, as suggested by in vitro, experimental animal, and epidemiological studies. The current study used LC/MS/MS to measure serum pharmacokinetics of aglycone (active) and conjugated (inactive) BPA in adult and neonatal rhesus monkeys by oral (PND 5, 35, 70) and intravenous injection (PND 77) routes using d6-BPA to avoid sample contamination. The concentration-time profiles observed in adult monkeys following oral administration of 100 {mu}g/kg bw were remarkably similar to those previously reported in human volunteers given a similar dose; moreover, minimal pharmacokinetic differences were observed between neonatal and adult monkeys for the receptor-active aglycone form of BPA. Circulating concentrations of BPA aglycone were quite low following oral administration (< 1% of total), which reflects the redundancy of active UDP-glucuronosyl transferase isoforms in both gut and liver. No age-related changes were seen in internal exposure metrics for aglycone BPA in monkeys, a result clearly different from developing rats where significant inverse age-related changes, based on immaturity of Phase II metabolism and renal excretion, were recently reported. These observations imply that any toxicological effect observed in rats from early postnatal exposures to BPA could over-predict those possible in primates of the same age, based on significantly higher internal exposures and overall immaturity at birth.

  2. Evaluation of effect of impaired renal function on lamivudine pharmacokinetics

    PubMed Central

    Bouazza, Naïm; Tréluyer, Jean-Marc; Ghosn, Jade; Hirt, Déborah; Benaboud, Sihem; Foissac, Frantz; Viard, Jean-Paul; Urien, Saik

    2014-01-01

    Aims This study aimed to describe lamivudine pharmacokinetics in patients with impaired renal function and to evaluate the consistency of current dosing recommendations. Methods A total of 244 patients, ranging in age from 18 to 79 years (median 40 years) and in bodyweight from 38 to 117 kg (median 71 kg), with 344 lamivudine plasma concentrations, were analysed using a population pharmacokinetic analysis. Serum creatinine clearance (CLCR) was calculated using the Cockcroft–Gault formula; 177 patients had normal renal function (CLCR > 90 ml min−1), 50 patients had mild renal impairment (CLCR = 60–90 ml min−1), 20 patients had moderate renal impairment (CLCR = 30–60 ml min−1), and five patients had severe renal impairment (CLCR < 30 ml min−1). Results A two-compartment model adequately described the data. Typical population estimates (percentage interindividual variability) of the apparent clearance (CL/F), central (Vc/F) and peripheral volumes of distribution (Vp/F), intercompartmental clearance (Q/F) and absorption rate constant (Ka) were 29.7 l h−1 (32%), 68.2 l, 114 l, 10.1 l h−1 (85%) and 1 h−1, respectively. Clearance increased significantly and gradually with CLCR. Our simulations showed that a dose of 300 mg day−1 in patients with mild renal impairment could overexpose them. A dose of 200 mg day−1 maintained an exposure close to that of adults with normal renal function. However, the current US Food and Drug Administration recommendations for lamivudine in other categories of patients (from severe to moderate renal impairment) provided optimal exposures. Conclusions Lamivudine elimination clearance is related to renal function. To provide optimal exposure, patients with mild renal impairment should receive 200 mg day−1 instead of 300 mg day−1. PMID:24750102

  3. Implementing and maintaining a private pharmacokinetics practice.

    PubMed

    Murphy, J E; Ward, E S; Job, M L

    1990-03-01

    The development and maintenance of a private-practice pharmacokinetics service is described. A contracted pharmacokinetics service has been in place at Georgia Baptist Medical Center, a 525-bed hospital, for the past eight years. Physician support, inhouse study results, and literature documentation of the benefits of scheduling drug concentration determinations were used to convince hospital administrators of the value of a pharmacokinetics service. Services were reimbursed by increasing the fee charged for each drug concentration determination, with payment made to the pharmacokinetics service on a monthly basis. The service is associated with the pathology department for administrative purposes. Each member of the pharmacokinetics service is credentialed by the medical staff. The group trains part-time personnel to provide services when needed. Services provided by the group but not required by the contract include collecting quality assurance data, conducting research, serving on hospital committees, writing newsletter articles, conducting inservice-education programs, and providing clinical interventions for nonconsultation patients. This private-practice pharmacokinetics service provides high-quality services and is well accepted within the institution. PMID:2316544

  4. 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. PMID:25427541

  5. Integration of efficacy, pharmacokinetic and safety assessment of interleukin-1 receptor antagonist in a preclinical model of arthritis.

    PubMed

    Zuurmond, Anne-Marie; Koudijs, Angela; van El, Benno; Doornbos, Robert P; van Manen-Vernooij, Babs C T; Bastiaans, Jacqueline H M W; Penninks, André H; van Bilsen, Jolanda H M; Cnubben, Nicole H P; Degroot, Jeroen

    2011-04-01

    Pharmacokinetic properties and safety profile of a drug are likely influenced by the disease state of a patient. In this study, we investigated the influence of arthritic processes on pharmacokinetics and immunotoxicity of interleukin-1 receptor antagonist (Anakinra) in the rat adjuvant arthritis model. Anakinra dose-dependently suppressed joint inflammation and degradation as demonstrated by reduced clinical arthritis score, paw thickness, synovial infiltration and bone degradation. In addition, plasma levels of chemokines MCP-1 and GRO/KC were reduced. Pharmacokinetic behaviour of Anakinra was influenced by disease state of the rats as judged from a decrease in C(max) and an increase of the MRT as the disease progressed at a dose of 24 and 72 mg Anakinra/kg body weight. The pharmacokinetic parameters increased dose-dependently, but non-proportionally with increasing dose. Low level anti-Anakinra antibody formation was observed at prolonged exposure to the biologic. Safety parameters, including haematology, splenic lymphocyte subset analysis, ex vivo stimulation of spleen cells and histopathology of immune system organs were affected by the disease itself to such extent that no additional effects of Anakinra could be observed. In conclusion, we demonstrated that pharmacokinetic behaviour of Anakinra was influenced by the arthritis background of the rats resulting in decreased internal exposure. PMID:21300126

  6. Translation in a Borderless World.

    ERIC Educational Resources Information Center

    Weiss, Timothy

    1995-01-01

    Suggests that in a world of interlinked economies and communication networks, the translation of pragmatic documents is prevalent, important, and costly. Treats concepts and practices of pragmatic translation, summarizes interviews with translators and translation professors (conducted in Morocco), and makes recommendations regarding language…

  7. The Translation Profession. ERIC Digest.

    ERIC Educational Resources Information Center

    Hammond, Deanna Lindberg

    The demand for competent translators is at an all-time high. Translators work with written language, and generally work either in-house for a business, translation agency, or other institution, or as free-lancers. Leading employers of translators in the United States are the federal government, domestic and multinational corporations and…

  8. Translation: Elements of a Craft.

    ERIC Educational Resources Information Center

    Heiderson, Mazin A.

    An overview of the skills, techniques, tools, and compensation of language translators and interpreters is offered. It begins with a definition of translation and a brief history of translation in the western world. Basic principles of translation dating back to Roman writers are also outlined. A five-step process in producing a good translation…

  9. Translating and Transforming Care

    PubMed Central

    Gillespie, Alex; Moore, Helen

    2015-01-01

    This article examines how the Disability Living Allowance claim form, used in the United Kingdom to allocate £13 billion of disability benefits, translates and transforms disability and care. Twenty-two people with acquired brain injury and their main informal caregivers (n = 44) were video-recorded filling in the disability claim form. Participants disagreed on 26% of the questions, revealing two types of problems. Translation problems arose as participants struggled to provide categorical responses to ambiguous questions and were unable to report contextual variability in care needs or divergences of perception. Transformation problems arose as participants resisted the way in which the form positioned them, forcing them to conceptualize their relationship in terms of dependency and burden. The disability claim form co-opts claimants to translate care and disability into bureaucratically predefined categories, and it transforms the care relationship that it purports to document. PMID:25792487

  10. Translational research to develop a human PBPK models tool kit-volatile organic compounds (VOCs).

    PubMed

    Mumtaz, M Moiz; Ray, Meredith; Crowell, Susan R; Keys, Deborah; Fisher, Jeffrey; Ruiz, Patricia

    2012-01-01

    Toxicity and exposure evaluations remain the two of the key components of human health assessment. While improvement in exposure assessment relies on a better understanding of human behavior patterns, toxicity assessment still relies to a great extent on animal toxicity testing and human epidemiological studies. Recent advances in computer modeling of the dose-response relationship and distribution of xenobiotics in humans to important target tissues have advanced our abilities to assess toxicity. In particular, physiologically based pharmacokinetic (PBPK) models are among the tools than can enhance toxicity assessment accuracy. Many PBPK models are available to the health assessor, but most are so difficult to use that health assessors rarely use them. To encourage their use these models need to have transparent and user-friendly formats. To this end the Agency for Toxic Substances and Disease Registry (ATSDR) is using translational research to increase PBPK model accessibility, understandability, and use in the site-specific health assessment arena. The agency has initiated development of a human PBPK tool-kit for certain high priority pollutants. The tool kit comprises a series of suitable models. The models are recoded in a single computer simulation language and evaluated for use by health assessors. While not necessarily being state-of-the-art code for each chemical, the models will be sufficiently accurate to use for screening purposes. This article presents a generic, seven-compartment PBPK model for six priority volatile organic compounds (VOCs): benzene (BEN), carbon tetrachloride (CCl(4)), dichloromethane (DCM), perchloroethylene (PCE), trichloroethylene (TCE), and vinyl chloride (VC). Limited comparisons of the generic and original model predictions to published kinetic data were conducted. A goodness of fit was determined by calculating the means of the sum of the squared differences (MSSDs) for simulation vs. experimental kinetic data using the

  11. On translation of antibody drug conjugates efficacy from mouse experimental tumors to the clinic: a PK/PD approach.

    PubMed

    Haddish-Berhane, Nahor; Shah, Dhaval K; Ma, Dangshe; Leal, Mauricio; Gerber, Hans-Peter; Sapra, Puja; Barton, Hugh A; Betts, Alison M

    2013-10-01

    Objectives of the present investigation were: (1) to compare three literature reported tumor growth inhibition (TGI) pharmacodynamic (PD) models and propose an optimal new model that best describes the xenograft TGI data for antibody drug conjugates (ADC), (2) to translate efficacy of the ADC Trastuzumab-emtansine (T-DM1) from mice to patients using the optimized PD model, and (3) to apply the translational strategy to predict clinically efficacious concentrations of a novel in-house anti-5T4 ADC, A1mcMMAF. First, the performance of all four of the PD models (i.e. 3 literature reported + 1 proposed) was evaluated using TGI data of T-DM1 obtained from four different xenografts. Based on the estimates of the pharmacodynamic/pharmacokinetic (PK/PD) modeling, a secondary parameter representing the efficacy index of the drug was calculated, which is termed as the tumor static concentration (TSC). TSC values derived from all four of the models were compared with each other, and with literature reported values, to assess the performance of these models. Subsequently, using the optimized PK/PD model, PD parameters obtained from different cell lines, human PK, and the proposed translational strategy, clinically efficacious doses of T-DM1 were projected. The accuracy of projected efficacious dose range for T-DM1 was verified by comparison with the clinical doses. Aforementioned strategy was then applied to A1mcMMAF for projecting its efficacious concentrations in clinic. TSC values for A1mcMMAF, obtained by fitting TGI data from 4 different xenografts with the proposed PK/PD model, were estimated to range from 0.6 to 11.5 μg mL⁻¹. Accordingly, the clinically efficacious doses for A1mcMMAF were projected retrospectively. All in all, the improved PD model and proposed translational strategy presented here suggest that appropriate correction for the clinical exposure and employing the TSC criterion can help translate mouse TGI data to predict first in human doses of ADCs

  12. Pharmacokinetics, safety, and tolerability of voriconazole in immunocompromised children.

    PubMed

    Walsh, Thomas J; Driscoll, Timothy; Milligan, Peter A; Wood, Nolan D; Schlamm, Haran; Groll, Andreas H; Jafri, Hasan; Arrieta, Antonio C; Klein, Nigel J; Lutsar, Irja

    2010-10-01

    The pharmacokinetics of voriconazole in children receiving 4 mg/kg intravenously (i.v.) demonstrate substantially lower plasma exposures (as defined by area under the concentration-time curve [AUC]) than those in adults receiving the same therapeutic dosage. These differences in pharmacokinetics between children and adults limit accurate prediction of pediatric voriconazole exposure based on adult dosages. We therefore studied the pharmacokinetics and tolerability of higher dosages of an i.v.-to-oral regimen of voriconazole in immunocompromised children aged 2 to <12 years in two dosage cohorts for the prevention of invasive fungal infections. The first cohort received 4 mg/kg i.v. every 12 h (q12h), then 6 mg/kg i.v. q12h, and then 4 mg/kg orally (p.o.) q12h; the second received 6 mg/kg i.v. q12h, then 8 mg/kg i.v. q12h, and then 6 mg/kg p.o. q12h. The mean values for the AUC over the dosing interval (AUCτ) for 4 mg/kg and 6 mg/kg i.v. in cohort 1 were 11,827 and 22,914 ng.h/ml, respectively, whereas the mean AUCτ values for 6 mg/kg and 8 mg/kg i.v. in cohort 2 were 17,249 and 29,776 ng.h/ml, respectively. High interpatient variability was observed. The bioavailability of the oral formulation in children was approximately 65%. The safety profiles were similar in the two cohorts and age groups. The most common treatment-related adverse event was increased gamma glutamyl transpeptidase levels. There was no correlation between adverse events and voriconazole exposure. In summary, voriconazole was tolerated to a similar degree regardless of dosage and age; the mean plasma AUCτ for 8 mg/kg i.v. in children approached that for 4 mg/kg i.v. in adults, thus representing a rationally selected dosage for the pediatric population. PMID:20660687

  13. Data format translation routines

    SciTech Connect

    Burris, R.D.

    1981-02-01

    To enable the effective connection of several dissimilar computers into a network, modification of the data being passed from one computer to another may become necessary. This document describes a package of routines which permit the translation of data in PDP-8 formats to PDP-11 or DECsystem-10 formats or from PDP-11 format to DECsystem-10 format. Additional routines are described which permit the effective use of the translation routines in the environment of the Fusion Energy Division (FED) network and the Elmo Bumpy Torus (EBT) data base.

  14. Pharmacokinetic evaluation of single-dose intravenous daptomycin in patients with thermal burn injury.

    PubMed

    Mohr, John F; Ostrosky-Zeichner, Luis; Wainright, David J; Parks, Donald H; Hollenbeck, Timothy C; Ericsson, Charles D

    2008-05-01

    Daptomycin pharmacokinetics were evaluated for burn patients. Burn patients had decreases in the maximum concentration of the drug in serum (44%) and the area under the concentration-time curve (47%) and increases in the volume of distribution (64%) and total clearance (77%) compared to healthy volunteers. In burn patients, daptomycin at 10 to 12 mg/kg of body weight/day would be required to achieve drug exposures similar to those for healthy volunteers receiving 6 mg/kg. PMID:18299410

  15. Application of Physiologically Based Pharmacokinetic Modeling to Predict Acetaminophen Metabolism and Pharmacokinetics in Children

    PubMed Central

    Jiang, X-L; Zhao, P; Barrett, J S; Lesko, L J; Schmidt, S

    2013-01-01

    Acetaminophen (APAP) is a widely used analgesic and antipyretic drug that undergoes extensive phase I and II metabolism. To better understand the kinetics of this process and to characterize the dynamic changes in metabolism and pharmacokinetics (PK) between children and adults, we developed a physiologically based PK (PBPK) model for APAP integrating in silico, in vitro, and in vivo PK data into a single model. The model was developed and qualified for adults and subsequently expanded for application in children by accounting for maturational changes from birth. Once developed and qualified, it was able to predict clinical PK data in neonates (0–28 days), infants (29 days to <2 years), children (2 to <12 years), and adolescents (12–17 years) following intravenous and orally administered APAP. This approach represents a general strategy for projecting drug exposure in children, in the absence of pediatric PK information, using previous drug- and system-specific information of adults and children through PBPK modeling. PMID:24132164

  16. Automatic translation among spoken languages

    NASA Astrophysics Data System (ADS)

    Walter, Sharon M.; Costigan, Kelly

    1994-02-01

    The Machine Aided Voice Translation (MAVT) system was developed in response to the shortage of experienced military field interrogators with both foreign language proficiency and interrogation skills. Combining speech recognition, machine translation, and speech generation technologies, the MAVT accepts an interrogator's spoken English question and translates it into spoken Spanish. The spoken Spanish response of the potential informant can then be translated into spoken English. Potential military and civilian applications for automatic spoken language translation technology are discussed in this paper.

  17. Automatic translation among spoken languages

    NASA Technical Reports Server (NTRS)

    Walter, Sharon M.; Costigan, Kelly

    1994-01-01

    The Machine Aided Voice Translation (MAVT) system was developed in response to the shortage of experienced military field interrogators with both foreign language proficiency and interrogation skills. Combining speech recognition, machine translation, and speech generation technologies, the MAVT accepts an interrogator's spoken English question and translates it into spoken Spanish. The spoken Spanish response of the potential informant can then be translated into spoken English. Potential military and civilian applications for automatic spoken language translation technology are discussed in this paper.

  18. Drug Dosing in Obese Children: A Systematic Review of Current Pharmacokinetic Data

    PubMed Central

    Harskamp-van Ginkel, Margreet W.; Hill, Kevin D.; Becker, Kristian; Testoni, Daniela; Cohen-Wolkowiez, Michael; Gonzalez, Daniel; Barrett, Jeffrey S.; Benjamin, Daniel K.; Siegel, David A.; Banks, Patricia; Watt, Kevin M.

    2015-01-01

    IMPORTANCE Obesity affects nearly one sixth of U.S. children and results in alterations to body composition and physiology that can affect drug disposition, possibly leading to therapeutic failure or toxicity. The depth of available literature regarding obesity’s effect on drug safety, pharmacokinetics (PK) and dosing in obese children is unknown. OBJECTIVE To perform a systematic literature review describing the current evidence of the effect of obesity on drug disposition in children. EVIDENCE REVIEW We searched the Medline, Cochrane, and Embase databases (January 1970–December 2012) and included studies if they contained clearance, volume of distribution, or drug concentration data in obese children (age ≤18 years). We compared exposure and weight-normalized volume of distribution and clearance between obese and non-obese children. We explored the relationship between drug physicochemical properties and clearance and volume of distribution. FINDINGS Twenty studies met inclusion criteria and contained pharmacokinetic data for 21 drugs. The median number of obese children studied per drug was 10 (range 1–112), ages ranged from 0–29 years. Dosing schema varied and were based on a fixed dose (n=6, 29%), body weight (n=10, 48%), and body surface area (n=4, 19%). Clinically significant pharmacokinetic alterations were observed in obese children for 65% (11/17) of studied drugs. Pharmacokinetic alterations resulted in substantial differences in exposure between obese and non-obese children for 38% (5/13) of drugs. We found no association between drug lipophilicity or Biopharmaceutical Drug Disposition Classification System class and changes in volume of distribution or clearance due to obesity. CONCLUSIONS AND RELEVANCE Consensus is lacking on the most appropriate weight-based dosing strategy. Prospective pharmacokinetic trials in obese children are needed to ensure therapeutic efficacy and enhance drug safety. PMID:25961828

  19. Oral, subcutaneous, and intravenous pharmacokinetics of ondansetron in healthy cats

    PubMed Central

    Quimby, J. M.; Lake, R. C.; Hansen, R. J.; Lunghofer, P. J.; Gustafson, D. L.

    2014-01-01

    Ondansetron is a 5-HT3 receptor antagonist that is an effective anti-emetic in cats. The purpose of this study was to evaluate the pharmacokinetics of ondansetron in healthy cats. Six cats with normal complete blood count, serum biochemistry, and urinalysis received 2 mg oral (mean 0.43 mg/kg), subcutaneous (mean 0.4 mg/kg), and intravenous (mean 0.4 mg/kg) ondansetron in a cross-over manner with a 5-day wash out. Serum was collected prior to, and at 0.25, 0.5, 1, 2, 4, 8, 12, 18, and 24 h after administration of ondansetron. Ondansetron concentrations were measured using liquid chromatography coupled to tandem mass spectrometry. Noncompartmental pharmacokinetic modeling and dose interval modeling were performed. Repeated measures anova was used to compare parameters between administration routes. Bioavailability of ondansetron was 32% (oral) and 75% (subcutaneous). Calculated elimination half-life of ondansetron was 1.84 ± 0.58 h (intravenous), 1.18 ± 0.27 h (oral) and 3.17 ± 0.53 h (subcutaneous). The calculated elimination half-life of subcutaneous ondansetron was significantly longer (P < 0.05) than oral or intravenous administration. Subcutaneous administration of ondansetron to healthy cats is more bioavailable and results in a more prolonged exposure than oral administration. This information will aid management of emesis in feline patients. PMID:24330064

  20. Oral, subcutaneous, and intravenous pharmacokinetics of ondansetron in healthy cats.

    PubMed

    Quimby, J M; Lake, R C; Hansen, R J; Lunghofer, P J; Gustafson, D L

    2014-08-01

    Ondansetron is a 5-HT3 receptor antagonist that is an effective anti-emetic in cats. The purpose of this study was to evaluate the pharmacokinetics of ondansetron in healthy cats. Six cats with normal complete blood count, serum biochemistry, and urinalysis received 2 mg oral (mean 0.43 mg/kg), subcutaneous (mean 0.4 mg/kg), and intravenous (mean 0.4 mg/kg) ondansetron in a cross-over manner with a 5-day wash out. Serum was collected prior to, and at 0.25, 0.5, 1, 2, 4, 8, 12, 18, and 24 h after administration of ondansetron. Ondansetron concentrations were measured using liquid chromatography coupled to tandem mass spectrometry. Noncompartmental pharmacokinetic modeling and dose interval modeling were performed. Repeated measures anova was used to compare parameters between administration routes. Bioavailability of ondansetron was 32% (oral) and 75% (subcutaneous). Calculated elimination half-life of ondansetron was 1.84 ± 0.58 h (intravenous), 1.18 ± 0.27 h (oral) and 3.17 ± 0.53 h (subcutaneous). The calculated elimination half-life of subcutaneous ondansetron was significantly longer (P < 0.05) than oral or intravenous administration. Subcutaneous administration of ondansetron to healthy cats is more bioavailable and results in a more prolonged exposure than oral administration. This information will aid management of emesis in feline patients. PMID:24330064

  1. Preliminary animal pharmacokinetics of the parenteral antifungal agent MK-0991 (L-743,872).

    PubMed

    Hajdu, R; Thompson, R; Sundelof, J G; Pelak, B A; Bouffard, F A; Dropinski, J F; Kropp, H

    1997-11-01

    MK-0991 (L-743,872) is a potent antifungal agent featuring long half-life pharmacokinetics. The pharmacokinetics of MK-0991 administered intravenously to mice, rats, rhesus monkeys, and chimpanzees is presented. Unique to MK-0991 is its consistent cross-species performance. The range of values for the pharmacokinetic parameters were as follows: clearance, 0.26 to 0.51 ml/min/kg; half-life, 5.2 to 7.6 h; and distributive volume, 0.11 to 0.27 liters/kg. The level of protein binding of MK-0991 was determined to be 96% in mouse and human serum. The compound exhibited high affinities for human serum albumin and at least two lipid components. The rationale for the selection of MK-0991 as a drug development candidate was based on its two- to threefold superior pharmacokinetic performance in chimpanzees over the performance of an otherwise equivalent analog, L-733,560. Once-daily dosing for MK-0991 is indicated by a graphical comparison of levels in the circulations of chimpanzees and mice. In a study of the pharmacokinetics of MK-0991 in mouse tissue, the organs were assayed following intraperitoneal administration. The area under the concentration-versus-time curves (AUC) segregated the tissues into three exposure categories relative to plasma. The tissues with greater exposure than that for plasma were liver (16 times), kidney (3 times), and large intestine (2 times). The exposure for small intestine, lung, and spleen were equivalent to that for plasma. Organs with lower levels of exposure were the heart (0.3 times that for plasma), thigh (0.2 times), and brain (0.06 times). Kinetically, drug was cleared more slowly from all tissues than from plasma, indicating that terminal-phase equilibrium had not been achieved by 24 h. Thus, some measure of accumulation is predicted for all tissues. Single daily doses of MK-0991 should provide adequate systemic levels of fungicidal activity as a result of its long half-life pharmacokinetics, wide distribution, and slowly

  2. Pharmacokinetics of budesonide (Entocort EC) capsules for Crohn's disease.

    PubMed

    Edsbäcker, Staffan; Andersson, Tommy

    2004-01-01

    This overview summarises available pharmacokinetic data on budesonide capsules (Entocort EC), approved for the treatment of mild-to-moderate active Crohn's disease involving the ileum and/or ascending colon and for prolongation of symptom control. Budesonide is a locally-acting glucocorticosteroid with an extensive, primarily hepatic, metabolism after oral administration. It is rapidly absorbed and biotransformed by cytochrome P450 (CYP) 3A to metabolites with negligible glucocorticoid activity. Entocort EC, a pH- and time-dependent oral formulation of budesonide, was developed to optimise drug delivery to the ileum and throughout the colon. Pharmaco-scintigraphic studies have confirmed that the Entocort EC formulation delays budesonide absorption and prolongs the rate of elimination but maintains complete absorption. This improves the delivery of budesonide to the intestinal lumen relative to a plain formulation. A low systemic availability of 9-21% indicates extensive first-pass elimination. Food appears to have little impact on the absorption of budesonide from Entocort EC capsules and the pharmacokinetics are dose-proportional between 3 and 15 mg. On average, systemic availability was 2.5-fold higher in patients with cirrhosis compared with healthy controls; however, mild liver impairment had little effect on systemic exposure. Pharmacokinetics appear unaffected by gender and age, although this has not been tested in younger children. Renal impairment is not expected to have an impact on the kinetics of Entocort EC. Budesonide is unlikely to inhibit the metabolism of other drugs, including CYP3A4 substrates, mainly because of the very low plasma concentrations obtained with the compound even after high doses of Entocort trade mark EC capsules. Strong CYP3A4 inhibitors, such as ketoconazole, will inhibit the metabolism of budesonide, resulting in several-fold increases in the area under the concentration-time curve of budesonide. Also, grapefruit juice intake

  3. Population pharmacokinetics of intravenous artesunate: a pooled analysis of individual data from patients with severe malaria.

    PubMed

    Zaloumis, S G; Tarning, J; Krishna, S; Price, R N; White, N J; Davis, T M E; McCaw, J M; Olliaro, P; Maude, R J; Kremsner, P; Dondorp, A; Gomes, M; Barnes, K; Simpson, J A

    2014-01-01

    There are ~660,000 deaths from severe malaria each year. Intravenous artesunate (i.v. ARS) is the first-line treatment in adults and children. To optimize the dosing regimen of i.v. ARS, the largest pooled population pharmacokinetic study to date of the active metabolite dihydroartemisinin (DHA) was performed. The pooled dataset consisted of 71 adults and 195 children with severe malaria, with a mixture of sparse and rich sampling within the first 12 h after drug administration. A one-compartment model described the population pharmacokinetics of DHA adequately. Body weight had the greatest impact on DHA pharmacokinetics, resulting in lower DHA exposure for smaller children (6-10 kg) than adults. Post hoc estimates of DHA exposure were not significantly associated with parasitological outcomes. Comparable DHA exposure in smaller children and adults after i.v. ARS was achieved under a dose modification for intramuscular ARS proposed in a separate analysis of children. PMID:25372510

  4. Pharmacokinetic drug interactions of macrolides.

    PubMed

    Periti, P; Mazzei, T; Mini, E; Novelli, A

    1992-08-01

    The macrolide antibiotics include natural members, prodrugs and semisynthetic derivatives. These drugs are indicated in a variety of infections and are often combined with other drug therapies, thus creating the potential for pharmacokinetic interactions. Macrolides can both inhibit drug metabolism in the liver by complex formation and inactivation of microsomal drug oxidising enzymes and also interfere with microorganisms of the enteric flora through their antibiotic effects. Over the past 20 years, a number of reports have incriminated macrolides as a potential source of clinically severe drug interactions. However, differences have been found between the various macrolides in this regard and not all macrolides are responsible for drug interactions. With the recent advent of many semisynthetic macrolide antibiotics it is now evident that they may be classified into 3 different groups in causing drug interactions. The first group (e.g. troleandomycin, erythromycins) are those prone to forming nitrosoalkanes and the consequent formation of inactive cytochrome P450-metabolite complexes. The second group (e.g. josamycin, flurithromycin, roxithromycin, clarithromycin, miocamycin and midecamycin) form complexes to a lesser extent and rarely produce drug interactions. The last group (e.g. spiramycin, rokitamycin, dirithromycin and azithromycin) do not inactivate cytochrome P450 and are unable to modify the pharmacokinetics of other compounds. It appears that 2 structural factors are important for a macrolide antibiotic to lead to the induction of cytochrome P450 and the formation in vivo or in vitro of an inhibitory cytochrome P450-iron-nitrosoalkane metabolite complex: the presence in the macrolide molecules of a non-hindered readily accessible N-dimethylamino group and the hydrophobic character of the drug. Troleandomycin ranks first as a potent inhibitor of microsomal liver enzymes, causing a significant decrease of the metabolism of methylprednisolone, theophylline

  5. Pharmacokinetics of pantoprazole in man.

    PubMed

    Huber, R; Hartmann, M; Bliesath, H; Lühmann, R; Steinijans, V W; Zech, K

    1996-05-01

    The proton pump inhibitor pantoprazole is a substituted benzimidazole sulphoxide for the treatment of acid-related gastrointestinal diseases such as reflux esophagitis, duodenal and gastric ulcers. Pantoprazole, administered as a 40 mg enteric coated tablet, is quantitatively absorbed. Its absolute bioavailability is 77% and does not change upon multiple dosing. Following a single oral dose of 40 mg, Cmax is approximately 2.5 mg/l, with a tmax of 2-3 h. The AUC(0,inf.) is approximately 5 mgxh/l. Pantoprazole shows linear pharmacokinetics after both i.v. and oral administration. Pantoprazole is extensively metabolized in the liver, has a total serum clearance of 0.1 l/h/kg, a serum elimination half-life of about 1.1 h, and an apparent volume of distribution of 0.15 l/kg. 98% of pantoprazole is bound to serum proteins. Elimination half-life, clearance and volume of distribution are independent of the dose. The main serum metabolite is formed by demethylation at the 4-position of the pyridine ring, followed by conjugation with sulphate. Almost 80% of an oral or intravenous dose is excreted as metabolites in urine; the remainder is found in feces and originates from biliary secretion. The pharmacokinetics of pantoprazole are unaltered in patients with renal failure. In patients with severe liver cirrhosis, the decreased rate of metabolism results in a half-life of 7-9 h. The clearance of pantoprazole is only slightly affected by age, its half-life being approximately 1.25 h in the elderly. Concomitant intake of food had no influence on the bioavailability of pantoprazole. Pantoprazole showed lack of cytochrome P450 interaction with concomitantly administered drugs in any of the studies conducted to date. Lack of interaction was also demonstrated with a coadministered antacid. The absence of inductive effects on metabolism after chronic administration was first shown by using antipyrine as a probe for mixed functional oxidative cytochrome P450 enzymes. Absence of CYP1A2

  6. Pharmacokinetics of pantoprazole in man.

    PubMed

    Huber, R; Hartmann, M; Bliesath, H; Lühmann, R; Steinijans, V W; Zech, K

    1996-05-01

    The proton pump inhibitor pantoprazole is a substituted benzimidazole sulphoxide for the treatment of acid-related gastrointestinal diseases such as reflux esophagitis, duodenal and gastric ulcers. Pantoprazole, administered as a 40 mg enteric coated tablet, is quantitatively absorbed. Its absolute bioavailability is 77% and does not change upon multiple dosing. Following a single oral dose of 40 mg, Cmax is approximately 2.5 mg/l, with a tmax of 2-3 h. The AUC(O,inf.) is approximately 5 mgxh/l. Pantoprazole shows linear pharmacokinetics after both i.v. and oral administration. Pantoprazole is extensively metabolized in the liver, has a total serum clearance of 0.1 l/h/kg, a serum elimination halflife of about 1.1 h, and an apparent volume of distribution of 0.15 l/kg. 98% of pantoprazole is bound to serum proteins. Elimination half-life, clearance and volume of distribution are independent of the dose. The main serum metabolite is formed by demethylation at the 4-position of the pyridine ring, followed by conjugation with sulphate. Almost 80% of an oral or intravenous dose is excreted as metabolites in urine; the remainder is found in feces and originates from biliary secretion. The pharmacokinetics of pantoprazole are unaltered in patients with renal failure. In patients with severe liver cirrhosis, the decreased rate of metabolism results in a half-life of 7-9 h. The clearance of pantoprazole is only slightly affected by age, its half-life being approximately 1.25 h in the elderly. Concomitant intake of food had no influence on the bioavailability of pantoprazole. Pantoprazole showed lack of cytochrome P450 interaction with concomitantly administered drugs in any of the studies conducted to date. Lack of interaction was also demonstrated with a coadministered antacid. The absence of inductive effects on metabolism after chronic administration was first shown by using antipyrine as a probe for mixed functional oxidative cytochrome P450 enzymes. Absence of CYP1A2

  7. Clinical pharmacokinetics of the salicylates.

    PubMed

    Needs, C J; Brooks, P M

    1985-01-01

    -order kinetics. The serum half-life of salicylic acid is dose-dependent; thus, the larger the dose employed, the longer it will take to reach steady-state. There is also evidence that enzyme induction of salicyluric acid formation occurs. No significant differences exist between the pharmacokinetics of the salicylates in the elderly or in children when compared with young adults. Apart from differences in free versus albumin-bound salicylate in various disease states and physiological conditions associated with low serum albumin, pharmacokinetic parameters in patients with rheumatoid arthritis, osteoarthritis, chronic renal failure or liver disease are essentially the same.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:3888490

  8. UHV piezoelectric translator

    SciTech Connect

    Oversluizen, T.; Watson, G.

    1985-01-01

    A UHV compatible piezoelectric translator has been developed to correct for angular misalignments in the crysals of a UHV x-ray monochromator. The unit is small, bakeable to 150/sup 0/C, and uses only ceramic materials for insulation. We report on the construction details, vacuum compatibility, mechanical properties, and uses of the device.

  9. "Rose Blanche" in Translation

    ERIC Educational Resources Information Center

    Stan, Susan

    2004-01-01

    This comparative study focuses on three editions of "Rose Blanche," Roberto Innocenti's picturebook portrayal of a young girl who discovers a Nazi concentration camp on the outskirts of her German city. The original text, written in French by Christophe Gallaz to accompany Innocenti's illustrations, was translated into English and published in the…

  10. Innovation, Translation, and Cooperation.

    PubMed

    Fu, Xiaobing

    2016-03-01

    The 9th Wound Healing and Tissue Repair and Regeneration Annual Meeting of Chinese Tissue Repair Society was hold in Wuhan, China. This meeting was focused on the innovation, translation application, and cooperation in wound care both in China and other countries. More than 400 delegates took part in this meeting and communicated successfully. PMID:25515372

  11. Grammatical Gender in Translation

    ERIC Educational Resources Information Center

    Bordag, Denisa; Pechmann, Thomas

    2008-01-01

    In three experiments native speakers of Czech translated bare nouns and gender-marked adjective + noun phrases into German, their second language (L2). In Experiments 1-3 we explored the so-called gender interference effect from first language (L1) as observed in previous picture naming studies (naming latencies were longer when the L1 noun and…

  12. [Topics for translational research].

    PubMed

    Suzuki, Atsushi

    2016-01-01

    This report focused on translational research presented in ASBMR 2015 held in Seattle, WA in October 2015. Comorbidity with chronic diseases such as diabetes and chronic kidney disease and the relationship between skeletal and extraskeltal tissues give us more complexed pathophysiological issues to be clarified in superaged society. PMID:26728541

  13. Cultural Knowledge in Translation.

    ERIC Educational Resources Information Center

    Olk, Harald

    2003-01-01

    Describes a study exploring the influence of cultural knowledge on the translation performance of German students of English. Found that the students often lacked sufficient knowledge about British culture to deal with widely-used cultural concepts. Findings suggest that factual reference sources have an important role to play in translation…

  14. Allopregnanolone Preclinical Acute Pharmacokinetic and Pharmacodynamic Studies to Predict Tolerability and Efficacy for Alzheimer’s Disease

    PubMed Central

    Irwin, Ronald W.; Solinsky, Christine M.; Loya, Carlos M.; Salituro, Francesco G.; Rodgers, Kathleen E.; Bauer, Gerhard; Rogawski, Michael A.; Brinton, Roberta Diaz

    2015-01-01

    To develop allopregnanolone as a therapeutic for Alzheimer’s disease, we investigated multiple formulations and routes of administration in translationally relevant animal models of both sexes. Subcutaneous, topical (transdermal and intranasal), intramuscular, and intravenous allopregnanolone were bolus-administered. Pharmacokinetic analyses of intravenous allopregnanolone in rabbit and mouse indicated that peak plasma and brain levels (3-fold brain/plasma ratios) at 5min were sufficient to activate neuroregenerative responses at sub-sedative doses. Slow-release subcutaneous suspension of allopregnanolone displayed 5-fold brain/plasma ratio at Cmax at 30min. At therapeutic doses by either subcutaneous or intravenous routes, allopregnanolone mouse plasma levels ranged between 34-51ng/ml by 30min, comparable to published endogenous human level in the third trimester of pregnancy. Exposure to subcutaneous, topical, intramuscular, and intravenous allopregnanolone, at safe and tolerable doses, increased hippocampal markers of neurogenesis including BrdU and PCNA in young 3xTgAD and aged wildtype mice. Intravenous allopregnanolone transiently and robustly phosphorylated CREB within 5min and increased levels of neuronal differentiation transcription factor NeuroD within 4h. Neurogenic efficacy was achieved with allopregnanolone brain exposure of 300-500hr*ng/g. Formulations were tested to determine the no observable adverse effect level (NOAEL) and maximally tolerated doses (MTD) in male and female rats by sedation behavior time course. Sex differences were apparent, males exhibited ≥40% more sedation time compared to females. Allopregnanolone formulated in sulfobutyl-ether-beta-cyclodextrin at optimized complexation ratio maximized allopregnanolone delivery and neurogenic efficacy. To establish the NOAEL and MTD for Allo-induced sedation using a once-per-week intravenous regenerative treatment regimen: In female rats the NOAEL was 0.5mg/kg and MTD 2mg/kg. The

  15. Pharmacokinetics of Zidovudine Dosed Twice Daily According to World Health Organization Weight Bands in Ugandan HIV-infected Children

    PubMed Central

    2014-01-01

    Data on zidovudine pharmacokinetics in children dosed using World Health Organization weight bands are limited. About 45 HIV-infected, Ugandan children, 3.4 (2.6–6.2) years, had intensive pharmacokinetic sampling. Geometric mean zidovudine AUC0–12h was 3.0 h.mg/L, which is higher than previously observed in adults, and was independently higher in those receiving higher doses, younger and underweight children. Higher exposure was also marginally associated with lower hemoglobin. PMID:24736440

  16. Effect of SLCO1B1 Polymorphisms on Rifabutin Pharmacokinetics in African HIV-Infected Patients with Tuberculosis

    PubMed Central

    Naiker, Suhashni; Reddy, Tarylee; Egan, Deirdre; Kellerman, Tracy; Wiesner, Lubbe; Owen, Andrew; McIlleron, Helen; Pym, Alexander

    2015-01-01

    Rifabutin, used to treat HIV-infected tuberculosis, shows highly variable drug exposure, complicating dosing. Effects of SLCO1B1 polymorphisms on rifabutin pharmacokinetics were investigated in 35 African HIV-infected tuberculosis patients after multiple doses. Nonlinear mixed-effects modeling found that influential covariates for the pharmacokinetics were weight, sex, and a 30% increased bioavailability among heterozygous carriers of SLCO1B1 rs1104581 (previously associated with low rifampin concentrations). Larger studies are needed to understand the complex interactions of host genetics in HIV-infected tuberculosis patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00640887.) PMID:26482301

  17. Atomoxetine: A Review of Its Pharmacokinetics and Pharmacogenomics Relative to Drug Disposition.

    PubMed

    Yu, Guo; Li, Guo-Fu; Markowitz, John S

    2016-05-01

    Atomoxetine is a selective norepinephrine (NE) reuptake inhibitor approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children (≥6 years of age), adolescents, and adults. Its metabolism and disposition are fairly complex, and primarily governed by cytochrome P450 (CYP) 2D6 (CYP2D6), whose protein expression varies substantially from person to person, and by race and ethnicity because of genetic polymorphism. These differences can be substantial, resulting in 8-10-fold differences in atomoxetine exposure between CYP2D6 poor metabolizers and extensive metabolizers. In this review, we have attempted to revisit and analyze all published clinical pharmacokinetic data on atomoxetine inclusive of public access documents from the new drug application submitted to the United States Food and Drug Administration (FDA). The present review focuses on atomoxetine metabolism, disposition, and genetic polymorphisms of CYP2D6 as they specifically relate to atomoxetine, and provides an in-depth discussion of the fundamental pharmacokinetics of the drug including its absorption, distribution, metabolism, and excretion in pediatric and adult populations. Further, a summary of relationships between genetic variants of CYP2D6 and to some degree, CYP2C19, are provided with respect to atomoxetine plasma concentrations, central nervous system (CNS) pharmacokinetics, and associated clinical implications for pharmacotherapy. Lastly, dosage adjustments based on pharmacokinetic principles are discussed. PMID:26859445

  18. 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. PMID:25782034

  19. Tilt and Translation Motion Perception during Pitch Tilt with Visual Surround Translation

    NASA Technical Reports Server (NTRS)

    O'Sullivan, Brita M.; Harm, Deborah L.; Reschke, Millard F.; Wood, Scott J.

    2006-01-01

    The central nervous system must resolve the ambiguity of inertial motion sensory cues in order to derive an accurate representation of spatial orientation. Previous studies suggest that multisensory integration is critical for discriminating linear accelerations arising from tilt and translation head motion. Visual input is especially important at low frequencies where canal input is declining. The NASA Tilt Translation Device (TTD) was designed to recreate postflight orientation disturbances by exposing subjects to matching tilt self motion with conflicting visual surround translation. Previous studies have demonstrated that brief exposures to pitch tilt with foreaft visual surround translation produced changes in compensatory vertical eye movement responses, postural equilibrium, and motion sickness symptoms. Adaptation appeared greatest with visual scene motion leading (versus lagging) the tilt motion, and the adaptation time constant appeared to be approximately 30 min. The purpose of this study was to compare motion perception when the visual surround translation was inphase versus outofphase with pitch tilt. The inphase stimulus presented visual surround motion one would experience if the linear acceleration was due to foreaft self translation within a stationary surround, while the outofphase stimulus had the visual scene motion leading the tilt by 90 deg as previously used. The tilt stimuli in these conditions were asymmetrical, ranging from an upright orientation to 10 deg pitch back. Another objective of the study was to compare motion perception with the inphase stimulus when the tilts were asymmetrical relative to upright (0 to 10 deg back) versus symmetrical (10 deg forward to 10 deg back). Twelve subjects (6M, 6F, 22-55 yrs) were tested during 3 sessions separated by at least one week. During each of the three sessions (out-of-phase asymmetrical, in-phase asymmetrical, inphase symmetrical), subjects were exposed to visual surround translation

  20. Defining a therapeutic window for the novel TGF-β inhibitor LY2157299 monohydrate based on a pharmacokinetic/pharmacodynamic model

    PubMed Central

    Gueorguieva, Ivelina; Cleverly, Ann L; Stauber, Anja; Pillay, N Sada; Rodon, Jordi A; Miles, Colin P; Yingling, Jonathan M; Lahn, Michael M

    2014-01-01

    AIMS To identify prospectively a safe therapeutic window for administration of a novel oral transforming growth factor β (TGF-β) inhibitor, LY2157299 monohydrate, based on a pharmacokinetic/pharmacodynamic (PK/PD) model. Simulations of population plasma exposures and biomarker responses in tumour were performed for future trials of LY2157299 in glioblastoma and other cancer populations. METHODS The model was updated after completion of each cohort during the first-in-human dose (FHD) study. The flexible design allowed continuous assessment of PK variability by recruiting the required number of patients in each cohort. Based on 30% inhibition of TGF-β RI kinase phosphorylates (pSMAD), biologically effective exposures were anticipated to be reached from 160 mg onwards. The therapeutic window was predicted, based on animal data, to be between 160 and 360 mg. RESULTS No medically significant safety issues were observed and no dose limiting toxicities were established in this study. Observed plasma exposures (medians 2.43 to 3.7 mg l−1 h, respectively) with doses of 160 mg to 300 mg were within the predicted therapeutic window. Responses, based on the MacDonald criteria, were observed in these patients. CONCLUSIONS A therapeutic window for the clinical investigation of LY2157299 in cancer patients was defined using a targeted PK/PD approach, which integrated translational biomarkers and preclinical toxicity. The study supports using a therapeutic window based on a PK/PD model in early oncology development. PMID:24868575

  1. Pharmacokinetics of Fluoxetine in Pregnant Baboons (Papio spp.)

    PubMed Central

    Shoulson, Rivka L; Stark, Raymond L; Garland, Marianne

    2014-01-01

    Fluoxetine is used to treat a number of psychiatric conditions in humans and behavioral problems in animals. Its use in pregnancy must balance maternal benefit with potential risk to the fetus. Knowledge of adult and fetal drug disposition can assist clinicians in selecting therapy that minimizes adverse effects to the fetus. Nonhuman primate models are used frequently in drug dose-translation studies, and pregnancy in baboons has many similarities to human pregnancy. Accordingly, pharmacokinetic analysis of a series of fluoxetine and norfluoxetine administrations to pregnant baboons was performed. The mean maternal baboon steady-state clearance of fluoxetine (42 mL/min/kg) was considerably higher than that in humans. Norfluoxetine, the major active metabolite, had a higher metabolite-to-drug ratio (8.7) than that found in humans, particularly with oral dosing. These results are consistent with more extensive metabolism in baboons than in humans and leads to a higher clearance than would be expected from allometric scaling. Fetal-to-maternal fluoxetine and norfluoxetine ratios under steady-state conditions were similar to those in humans, with fetal concentrations of fluoxetine 42% and norfluoxetine 47% of maternal concentrations. The fetal clearance of fluoxetine (303 ± 176 mL/min) and norfluoxetine (450 mL/min) exceeded reported placental blood flow. Understanding these species-associated differences in metabolism is a prerequisite to extrapolating data between species. Nonetheless, nonhuman primates are likely to remain valuable models for pharmacokinetic studies during pregnancy, particularly those directed toward fetal neurodevelopmental effects. Our results also are applicable to determining appropriate dosing of nonhuman primates in clinical settings. PMID:25650979

  2. Impact of special patient populations on the pharmacokinetics of echinocandins.

    PubMed

    Muilwijk, Eline W; Lempers, Vincent J C; Burger, David M; Warris, Adilia; Pickkers, Peter; Aarnoutse, Rob E; Brüggemann, Roger J M

    2015-06-01

    Echinocandins belong to the class of antifungal agents. Currently, three echinocandin drugs are licensed for intravenous treatment of invasive fungal infections: anidulafungin, caspofungin and micafungin. While their antifungal activity overlaps, there are substantial differences in pharmacokinetics (PK). Numerous factors may account for variability in PK of echinocandins including age (pediatrics vs adults), body surface area and body composition (normal weight vs obesity), disease status (e.g., critically ill and burn patients) and organ dysfunction (kidney and liver impairment). Subsequent effects of altered exposure might impact efficacy and safety. Knowledge of PK behavior is crucial in optimal clinical utilization of echinocandin in a specific patient or patient population. This review provides up-to-date information on PK data of anidulafungin, caspofungin and micafungin in special patient populations. Patient populations addressed are neonates, children and adolescents, obese patients, patients with hepatic or renal impairment, critically ill patients (including burn patients) and patients with hematological diseases. PMID:25947367

  3. In Vitro Measurements of Metabolism for Application in Pharmacokinetic Modeling

    SciTech Connect

    Lipscomb, John C.; Poet, Torka S.

    2008-04-01

    Abstract Human risk and exposure assessments require dosimetry information. Species-specific tissue dose response will be driven by physiological and biochemical processes. While metabolism and pharmacokinetic data are often not available in humans, they are much more available in laboratory animals; metabolic rate constants can be readily derived in vitro. The physiological differences between laboratory animals and humans are known. Biochemical processes, especially metabolism, can be measured in vitro and extrapolated to account for in vivo metabolism through clearance models or when linked to a physiologically based biological (PBPK) model to describe the physiological processes, such as drug delivery to the metabolic organ. This review focuses on the different organ, cellular, and subcellular systems that can be used to measure in vitro metabolic rate constants and how that data is extrapolated to be used in biokinetic modeling.

  4. Development of a Rat Plasma and Brain Extracellular Fluid Pharmacokinetic Model for Bupropion and Hydroxybupropion Based on Microdialysis Sampling, and Application to Predict Human Brain Concentrations.

    PubMed

    Cremers, Thomas I F H; Flik, Gunnar; Folgering, Joost H A; Rollema, Hans; Stratford, Robert E

    2016-05-01

    Administration of bupropion [(±)-2-(tert-butylamino)-1-(3-chlorophenyl)propan-1-one] and its preformed active metabolite, hydroxybupropion [(±)-1-(3-chlorophenyl)-2-[(1-hydroxy-2-methyl-2-propanyl)amino]-1-propanone], to rats with measurement of unbound concentrations by quantitative microdialysis sampling of plasma and brain extracellular fluid was used to develop a compartmental pharmacokinetics model to describe the blood-brain barrier transport of both substances. The population model revealed rapid equilibration of both entities across the blood-brain barrier, with resultant steady-state brain extracellular fluid/plasma unbound concentration ratio estimates of 1.9 and 1.7 for bupropion and hydroxybupropion, respectively, which is thus indicative of a net uptake asymmetry. An overshoot of the brain extracellular fluid/plasma unbound concentration ratio at early time points was observed with bupropion; this was modeled as a time-dependent uptake clearance of the drug across the blood-brain barrier. Translation of the model was used to predict bupropion and hydroxybupropion exposure in human brain extracellular fluid after twice-daily administration of 150 mg bupropion. Predicted concentrations indicate that preferential inhibition of the dopamine and norepinephrine transporters by the metabolite, with little to no contribution by bupropion, would be expected at this therapeutic dose. Therefore, these results extend nuclear imaging studies on dopamine transporter occupancy and suggest that inhibition of both transporters contributes significantly to bupropion's therapeutic efficacy. PMID:26916207

  5. 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.

  6. Calcium carbonate does not affect imatinib pharmacokinetics in healthy volunteers

    PubMed Central

    Tawbi, Hussein; Christner, Susan M.; Lin, Yan; Johnson, Matthew; Mowrey, Emily T.; Cherrin, Craig; Chu, Edward; Lee, James J.; Puhalla, Shannon; Stoller, Ronald; Appleman, Leonard R.; Miller, Brian M.; Beumer, Jan H.

    2013-01-01

    Purpose Imatinib mesylate (Gleevec®/Glivec®), has revolutionized the treatment of chronic myeloid leukemias (CML) and gastrointestinal stromal tumors (GIST), and there is evidence for an exposure response relationship. Calcium carbonate is increasingly used as a calcium supplement and in the setting of gastric upset associated with imatinib therapy. Calcium carbonate could conceivably elevate gastric pH and complex imatinib, thereby influencing imatinib absorption and exposure. We aimed to evaluate whether use of calcium carbonate has a significant effect on imatinib pharmacokinetics. Methods Eleven healthy subjects were enrolled in a 2-period, open-label, single-institution, randomized cross-over, fixed-schedule study. In one period, each subject received 400 mg of imatinib p.o.. In the other period, 4000 mg calcium carbonate (Tums Ultra®) was administered p.o. 15 min before 400 mg of imatinib. Plasma concentrations of imatinib and its active N-desmethyl metabolite CGP74588 were assayed by LC-MS; data were analyzed non-compartmentally, and compared after log transformation. Results Calcium carbonate administration did not significantly affect the imatinib area under the plasma concentration versus time curve (AUC) (41.2 μg/mL•h alone versus 40.8 μg/mL•h with calcium carbonate, P=0.99), maximum plasma concentration (Cmax) (2.35 μg/mL alone versus 2.39 μg/mL with calcium carbonate, P=0.89). Conclusions Our results indicate that the use of calcium carbonate does not significantly affect imatinib pharmacokinetics. PMID:24170263

  7. Validation and application of pharmacokinetic models for interspecies extrapolations in toxicity risk assessments of volatile organics. Annual report No. 2, 1 July 1988-30 June 1989

    SciTech Connect

    Dallas, C.E.; Bruckner, J.V.; Gallo, J.; Ramanathan, R.; Muralidhara, S.

    1989-07-21

    In pursuit of the goal of establishing a scientific basis for the interspecies extrapolation of pharmacokinetic data in health-risk assessments, a series of studies were conducted involving pharmacokinetic determinations in rats to several aliphatic halocarbons (with parallel studies initiated in the dog). Direct measurements of the uptake and elimination of halocarbon in rats were completed during the following inhalation exposures and following oral administration of dichloroethylene (DCE) and perchloroethylene (PCE). An assay for the measurement of halocarbons in the tissues of exposed animals has been successfully developed, and tissue-concentration profiles in the liver, kidney, lung, fat, brain, muscle, and heart were completed for oral and intraarterial administrations of PCE. The utility of the physiologically-based pharmacokinetic model for the accurate computer simulations of the pharmacokinetics of three halocarbons with wide variation in physicochemical properties (TRI, TCE, and PCE) has been demonstrated.

  8. Pharmacokinetic profile that reduces nephrotoxicity of gentamicin in a perfused kidney-on-a-chip.

    PubMed

    Kim, Sejoong; LesherPerez, Sasha Cai; Kim, Byoung Choul C; Yamanishi, Cameron; Labuz, Joseph M; Leung, Brendan; Takayama, Shuichi

    2016-03-01

    Nephrotoxicity is often underestimated because renal clearance in animals is higher compared to in humans. This paper aims to illustrate the potential to fill in such pharmacokinetic gaps between animals and humans using a microfluidic kidney model. As an initial demonstration, we compare nephrotoxicity of a drug, administered at the same total dosage, but using different pharmacokinetic regimens. Kidney epithelial cell, cultured under physiological shear stress conditions, are exposed to gentamicin using regimens that mimic the pharmacokinetics of bolus injection or continuous infusion in humans. The perfusion culture utilized is important both for controlling drug exposure and for providing cells with physiological shear stress (1.0 dyn cm(-2)). Compared to static cultures, perfusion culture improves epithelial barrier function. We tested two drug treatment regimens that give the same gentamycin dose over a 24 h period. In one regimen, we mimicked drug clearance profiles for human bolus injection by starting cell exposure at 19.2 mM of gentamicin and reducing the dosage level by half every 2 h over a 24 h period. In the other regimen, we continuously infused gentamicin (3 mM for 24 h). Although junctional protein immunoreactivity was decreased with both regimens, ZO-1 and occludin fluorescence decreased less with the bolus injection mimicking regimen. The bolus injection mimicking regimen also led to less cytotoxicity and allowed the epithelium to maintain low permeability, while continuous infusion led to an increase in cytotoxicity and permeability. These data show that gentamicin disrupts cell-cell junctions, increases membrane permeability, and decreases cell viability particularly with prolonged low-level exposure. Importantly a bolus injection mimicking regimen alleviates much of the nephrotoxicity compared to the continuous infused regimen. In addition to potential relevance to clinical gentamicin administration regimens, the results are important in

  9. Progress in Documentation: Machine Translation and Machine-Aided Translation.

    ERIC Educational Resources Information Center

    Hutchins, W. J.

    1978-01-01

    Discusses the prospects for fully automatic machine translation of good quality. Sections include history and background, operational and experimental machine translation systems of recent years, descriptions of interactive systems and machine-assisted translation, and a general survey of present problems and future possibilities. (VT)

  10. Lost in Translation: Examining Translation Errors Associated with Mathematical Representations

    ERIC Educational Resources Information Center

    Adu-Gyamfi, Kwaku; Stiff, Lee V.; Bosse, Michael J.

    2012-01-01

    Translation errors and conceptual misunderstandings made by students translating among graphical, tabular, and symbolic representations of linear functions were examined. The study situated student errors in the context of the "Translation-Verification Model" developed specifically for the purpose of explaining student behavior during the process…

  11. Cross-Cultural Instrument Translation: Assessment, Translation, and Statistical Applications

    ERIC Educational Resources Information Center

    Mason, Teresa Crowe

    2005-01-01

    This article has four major sections: (a) general issues of assessment; (b) assessment of ethnic-group members, including those who are deaf; (c) translation of assessment tools, emphasizing translation into American Sign Language (ASL); and (d) statistical applications for translated instruments. The purpose of the article is to provide insight…

  12. Steady-state pharmacokinetics of lithium carbonate in healthy subjects.

    PubMed Central

    Hunter, R

    1988-01-01

    1. The pharmacokinetics of lithium in six healthy volunteers stabilised on lithium were investigated and appropriate pharmacokinetic parameters calculated. 2. The results illustrate important differences in single and multiple dose lithium pharmacokinetics; the implications for minimising lithium-induced renal damage are discussed. PMID:3129009

  13. 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.

  14. Clinical pharmacokinetics of camptothecin topoisomerase I inhibitors.

    PubMed

    Herben, V M; Ten Bokkel Huinink, W W; Schellens, J H; Beijnen, J H

    1998-08-01

    In this review the clinical pharmacokinetics of camptothecin topoisomerase I inhibitors, an important new class of anticancer drugs, is discussed. Two prototypes, topotecan and irinotecan, are currently marketed in many European countries and the USA for the treatment of patients with ovarian and colorectal cancer, respectively. Other camptothecin derivatives, including lurtotecan, 9-aminocamptothecin (9-AC) and 9-nitrocamptothecin (9-NC), are at different stages of clinical development. The common property of camptothecin analogues is their action against DNA topoisomerase I, but beyond this similarity the compounds differ widely in terms of antitumour efficacy, pharmacology, pharmacokinetics and metabolism. We review chemistry, mechanism of action, stability and bioanalysis of the camptothecins. Dosage and administration, status of clinical application, pharmacokinetics, pharmacodynamics and drug interactions are discussed. PMID:9762728

  15. Factors affecting the pharmacokinetics and pharmacodynamics of PEGylated liposomal irinotecan (IHL-305) in patients with advanced solid tumors

    PubMed Central

    Wu, Huali; Infante, Jeffrey R; Keedy, Vicki L; Jones, Suzanne F; Chan, Emily; Bendell, Johanna C; Lee, Wooin; Kirschbrown, Whitney P; Zamboni, Beth A; Ikeda, Satoshi; Kodaira, Hiroshi; Rothenberg, Mace L; Burris, Howard A; Zamboni, William C

    2015-01-01

    IHL-305 is a PEGylated liposomal formulation of irinotecan (CPT-11). The objective of this study was to evaluate the factors associated with interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 in patients with advanced solid tumors. IHL-305 was administered intravenously once every 4 weeks as part of a Phase I study. Pharmacokinetic studies of the liposomal sum total CPT-11, released CPT-11, SN-38, SN-38G, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin, and 7-ethyl-10-[4-amino-1-piperidino]-carbonyloxycamptothecin in plasma were performed. Noncompartmental and compartmental pharmacokinetic analyses were conducted using pharmacokinetic data for sum total CPT-11. The pharmacokinetic variability of IHL-305 is associated with linear and nonlinear clearance. Patients whose age and body composition (ratio of total body weight to ideal body weight [TBW/IBW]) were greater than the median age and TBW/IBW of the study had a 1.7-fold to 2.6-fold higher ratio of released CPT-11 area under the concentration versus time curve (AUC) to sum total CPT-11 AUC. Patients aged <60 years had a 1.3-fold higher ratio of percent decrease in monocytes at nadir to percent decrease in absolute neutrophil count at nadir as compared with patients aged ≥60 years. There was an inverse relationship between patient age and percent decrease in monocytes at nadir, ie, younger patients have a higher percent decrease in monocytes. Patients with a higher percent decrease in monocytes at nadir have a decreased plasma exposure of sum total CPT-11. The pharmacokinetics and pharmacodynamics of IHL-305 are consistent with those of other PEGylated liposomal carriers. Interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 was associated with age, body composition, and monocytes. PMID:25709442

  16. Factors affecting the pharmacokinetics and pharmacodynamics of PEGylated liposomal irinotecan (IHL-305) in patients with advanced solid tumors.

    PubMed

    Wu, Huali; Infante, Jeffrey R; Keedy, Vicki L; Jones, Suzanne F; Chan, Emily; Bendell, Johanna C; Lee, Wooin; Kirschbrown, Whitney P; Zamboni, Beth A; Ikeda, Satoshi; Kodaira, Hiroshi; Rothenberg, Mace L; Burris, Howard A; Zamboni, William C

    2015-01-01

    IHL-305 is a PEGylated liposomal formulation of irinotecan (CPT-11). The objective of this study was to evaluate the factors associated with interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 in patients with advanced solid tumors. IHL-305 was administered intravenously once every 4 weeks as part of a Phase I study. Pharmacokinetic studies of the liposomal sum total CPT-11, released CPT-11, SN-38, SN-38G, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin, and 7-ethyl-10-[4-amino-1-piperidino]-carbonyloxycamptothecin in plasma were performed. Noncompartmental and compartmental pharmacokinetic analyses were conducted using pharmacokinetic data for sum total CPT-11. The pharmacokinetic variability of IHL-305 is associated with linear and nonlinear clearance. Patients whose age and body composition (ratio of total body weight to ideal body weight [TBW/IBW]) were greater than the median age and TBW/IBW of the study had a 1.7-fold to 2.6-fold higher ratio of released CPT-11 area under the concentration versus time curve (AUC) to sum total CPT-11 AUC. Patients aged <60 years had a 1.3-fold higher ratio of percent decrease in monocytes at nadir to percent decrease in absolute neutrophil count at nadir as compared with patients aged ≥60 years. There was an inverse relationship between patient age and percent decrease in monocytes at nadir, ie, younger patients have a higher percent decrease in monocytes. Patients with a higher percent decrease in monocytes at nadir have a decreased plasma exposure of sum total CPT-11. The pharmacokinetics and pharmacodynamics of IHL-305 are consistent with those of other PEGylated liposomal carriers. Interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 was associated with age, body composition, and monocytes. PMID:25709442

  17. Translational Research in Space Exploration

    NASA Technical Reports Server (NTRS)

    Iyengar, M. Sriram; Johnson-Throop, Kathy A.; Bernstam, Elmer; Meric-Bernstam, Funda

    2007-01-01

    This viewgraph presentation reviews NASA's role in medical translational research, and the importance in research for space exploration. The application of medical research for space exploration translates to health care in space medicine, and on earth.

  18. On Literal Translation of English Idioms

    ERIC Educational Resources Information Center

    Chen, Linli

    2009-01-01

    There are six translation tactics in translating English idioms into Chinese: literal translation, compensatory translation, free translation, explanational translation, borrowing, integrated approach. Each tactic should be reasonably employed in the process of translating, so as to keep the flavor of the original English idioms as well as to…

  19. Interspecies pharmacokinetics as applied to the hard drug photosensitizing agent meta(tetrahydroxphenyl)chlorin

    NASA Astrophysics Data System (ADS)

    Ronn, Avigdor M.; Lofgren, Lennart A.; Westerborn, Anders

    1996-01-01

    Having successfully completed an extensive three year study of the pharmacokinetics and efficacy of m-THPC as a photosensitizer in three different animal models (rabbit, dog and nude rats) we began a phase one human trial in two centers. At the Orebro Medical Center Hospital, Sweden ten patients were selected for the treatment of bronchial, prostate, skin, laryngeal and nasopharyngeal tumors while at Long Island Jewish Medical Center Hospital four patients were treated for laryngeal cancers. These studies were designed to study the optimal parameters for human treatment and as such relied on data from the animal studies mentioned above. De-escalating drug doses of 0.3, 0.15, 0.075 and 0.0375 mg/kg were chosen and the pharmacokinetics of the patients plasma, tumor and adjacent healthy tissues were measured spectrofluorometrically following chemical extraction of the drug. The half life of the drug in our Cotton tail rabbit model was measured as 24.7 hours as opposed to the human half life of 44.5 hours within the studied dosing range. This illustrates the extreme care that must be exercised before translating animal pharmacokinetics data to human dosing decision.

  20. Maternal Pharmacokinetics and Fetal Disposition of (±)-Citalopram during Mouse Pregnancy.

    PubMed

    Velasquez, Juan C; Goeden, Nick; Herod, Skyla M; Bonnin, Alexandre

    2016-03-16

    While selective-serotonin reuptake inhibitor (SSRI) antidepressants are commonly prescribed in the treatment of depression, their use during pregnancy leads to fetal drug exposures. According to recent reports, such exposures could affect fetal development and long-term offspring health. A central question is how pregnancy-induced physical and physiological changes in mothers, fetuses, and the placenta influence fetal SSRI exposures during gestation. In this study, we examined the effects of gestational stage on the maternal pharmacokinetics and fetal disposition of the SSRI (±)-citalopram (CIT) in a mouse model. We determined the maternal and fetal CIT serum concentration-time profiles following acute maternal administration on gestational days (GD)14 and GD18, as well as the fetal brain drug disposition. The results show that pregnancy affects the pharmacokinetics of CIT and that maternal drug clearance increases as gestation progresses. The data further show that CIT and its primary metabolite desmethylcitalopram (DCIT) readily cross the placenta into the fetal compartment, and fetal exposure to CIT exceeds that of the mother during gestation 2 h after maternal administration. Enzymatic activity assays revealed that fetal drug metabolic capacity develops in late gestation, resulting in elevated circulating and brain concentrations of DCIT at embryonic day (E)18. Fetal exposure to the SSRI CIT in murine pregnancy is therefore influenced by both maternal gestational stage and embryonic development, suggesting potential time-dependent effects on fetal brain development. PMID:26765210

  1. Knowledge Translation: Implications for Evaluation

    ERIC Educational Resources Information Center

    Davison, Colleen M.

    2009-01-01

    Translation theory originates in the field of applied linguistics and communication. The term knowledge translation has been adopted in health and other fields to refer to the exchange, synthesis, and application of knowledge. The logic model is a circular or iterative loop among various knowledge translation actors (knowledge producers and users)…

  2. Lexical Discourse Analysis in Translation

    ERIC Educational Resources Information Center

    Al Khotaba, Eissa; Al Tarawneh, Khaled

    2015-01-01

    Lexical Discourse very often depend on lexis. Lexical Discourse analysis, however, has not yet been given enough consideration of the phenomenon of translation. This paper investigates lexical discourse analysis in translation from one language to another. This qualitative study comprises 15 text translated by M.A. students at the Department of…

  3. Discourse Analysis and the Translator.

    ERIC Educational Resources Information Center

    Lang, Margaret

    Discourse analysis, as an approach to text, provides the teacher, student, and professional translator with resources for achieving objectivity and for making and justifying translation decisions. It offers a strategy for relating the problems and processes and discourse and the specific concerns to the objectives of the translator. It can be…

  4. The Measurement of Translation Ability.

    ERIC Educational Resources Information Center

    Stansfield, Charles W.; And Others

    1992-01-01

    Variables that constitute translation ability are discussed, based on a two-year development and validation study of job-related tests of translation ability for the Federal Bureau of Investigation. The project involved the development of two parallel forms of the Spanish into English Verbatim Translation Exam (SEVTE). (five references) (LB)

  5. Machine Translation for Academic Purposes

    ERIC Educational Resources Information Center

    Lin, Grace Hui-chin; Chien, Paul Shih Chieh

    2009-01-01

    Due to the globalization trend and knowledge boost in the second millennium, multi-lingual translation has become a noteworthy issue. For the purposes of learning knowledge in academic fields, Machine Translation (MT) should be noticed not only academically but also practically. MT should be informed to the translating learners because it is a…

  6. Tools to evaluate pharmacokinetics data for establishing maximum residue limits for approved veterinary drugs: examples from JECFA's work.

    PubMed

    Sanders, P; Henri, J; Laurentie, M

    2016-05-01

    Maximum residue limits (MRLs) for residues of veterinary drugs are the maximum concentrations of residues permitted in or on a food by national or regional legislation. In the process of MRLs recommendations by the Joint FAO/WHO Expert Committee on Food Additives (JECFA), analysis of pharmacokinetic data describing the ADME process (absorption, distribution, metabolism and excretion) is a crucial step and requires the use of different pharmacokinetic tools. The results of animal metabolism studies are the prime determinants of the residue definition in food commodities. Substances labelled with radioactive isotopes are used so that the disposition of the residue can be followed as total residue and main metabolites concentrations. Residue depletion studies with radiolabelled parent drug will lead to the estimate of the time course of the total residue and to determine a marker residue. Depletion studies with an unlabelled drug provide more information on the time course of the marker residue in raw commodities after administration under approved practical conditions of use. By use of this information and after conversion with the total/residue marker ratio, MRLs are derived by comparison of the acceptable daily intake with the daily intakes calculated with different scenarios of dietary exposure. Progress in pharmacokinetic model such as physiologically based pharmacokinetics and population pharmacokinetics will drive the future research in this field to improved veterinary drug development. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27443212

  7. Physiologically based modeling of the pharmacokinetics of acetaminophen and its major metabolites in humans using a Bayesian population approach.

    PubMed

    Zurlinden, Todd J; Reisfeld, Brad

    2016-06-01

    The principal aim of this study was to develop, validate, and demonstrate a physiologically based pharmacokinetic (PBPK) model to predict and characterize the absorption, distribution, metabolism, and excretion of acetaminophen (APAP) in humans. A PBPK model was created that included pharmacologically and toxicologically relevant tissue compartments and incorporated mechanistic descriptions of the absorption and metabolism of APAP, such as gastric emptying time, cofactor kinetics, and transporter-mediated movement of conjugated metabolites in the liver. Through the use of a hierarchical Bayesian framework, unknown model parameters were estimated using a large training set of data from human pharmacokinetic studies, resulting in parameter distributions that account for data uncertainty and inter-study variability. Predictions from the model showed good agreement to a diverse test set of data across several measures, including plasma concentrations over time, renal clearance, APAP absorption, and pharmacokinetic and exposure metrics. The utility of the model was then demonstrated through predictions of cofactor depletion, dose response of several pharmacokinetic endpoints, and the relationship between APAP biomarker levels in the plasma and those in the liver. The model addressed several limitations in previous PBPK models for APAP, and it is anticipated that it will be useful in predicting the pharmacokinetics of APAP in a number of contexts, such as extrapolating across doses, estimating internal concentrations, quantifying population variability, assessing possible impacts of drug coadministration, and, when coupled with a suitable pharmacodynamic model, predicting toxicity. PMID:25636597

  8. Preclinical pharmacology and pharmacokinetics of AZD3783, a selective 5-hydroxytryptamine 1B receptor antagonist.

    PubMed

    Zhang, Minli; Zhou, Diansong; Wang, Yi; Maier, Donna L; Widzowski, Daniel V; Sobotka-Briner, Cynthia D; Brockel, Becky J; Potts, William M; Shenvi, Ashok B; Bernstein, Peter R; Pierson, M Edward

    2011-11-01

    The preclinical pharmacology and pharmacokinetic properties of (2R)-6-methoxy-8-(4-methylpiperazin-1-yl)-N-(4-morpholin-4-ylphenyl)chromane-2-carboxamide (AZD3783), a potent 5-hydroxytryptamine 1B (5-HT(1B)) receptor antagonist, were characterized as part of translational pharmacokinetic/pharmacodynamic hypothesis testing in human clinical trials. The affinity of AZD3783 to the 5-HT(1B) receptor was measured in vitro by using membrane preparations containing recombinant human or guinea pig 5-HT(1B) receptors and in native guinea pig brain tissue. In vivo antagonist potency of AZD3783 for the 5HT(1B) receptor was investigated by measuring the blockade of 5-HT(1B) agonist-induced guinea pig hypothermia. The anxiolytic-like potency was assessed using the suppression of separation-induced vocalization in guinea pig pups. The affinity of AZD3783 for human and guinea pig 5-HT(1B) receptor (K(i), 12.5 and 11.1 nM, respectively) was similar to unbound plasma EC(50) values for guinea pig receptor occupancy (11 nM) and reduction of agonist-induced hypothermia (18 nM) in guinea pig. Active doses of AZD3783 in the hypothermia assay were similar to doses that reduced separation-induced vocalization in guinea pig pups. AZD3783 demonstrated favorable pharmacokinetic properties. The predicted pharmacokinetic parameters (total plasma clearance, 6.5 ml/min/kg; steady-state volume of distribution, 6.4 l/kg) were within 2-fold of the values observed in healthy male volunteers after a single 20-mg oral dose. This investigation presents a direct link between AZD3783 in vitro affinity and in vivo receptor occupancy to preclinical disease model efficacy. Together with predicted human pharmacokinetic properties, we have provided a model for the quantitative translational pharmacology of AZD3783 that increases confidence in the optimal human receptor occupancy required for antidepressant and anxiolytic effects in patients. PMID:21825000

  9. Application of a Bayesian approach to physiological modelling of mavoglurant population pharmacokinetics.

    PubMed

    Wendling, Thierry; Dumitras, Swati; Ogungbenro, Kayode; Aarons, Leon

    2015-12-01

    Mavoglurant (MVG) is an antagonist at the metabotropic glutamate receptor-5 currently under clinical development at Novartis Pharma AG for the treatment of central nervous system diseases. The aim of this study was to develop and optimise a population whole-body physiologically-based pharmacokinetic (WBPBPK) model for MVG, to predict the impact of drug-drug interaction (DDI) and age on its pharmacokinetics. In a first step, the model was fitted to intravenous (IV) data from a clinical study in adults using a Bayesian approach. In a second step, the optimised model was used together with a mechanistic absorption model for exploratory Monte Carlo simulations. The ability of the model to predict MVG pharmacokinetics when orally co-administered with ketoconazole in adults or administered alone in 3-11 year-old children was evaluated using data from three other clinical studies. The population model provided a good description of both the median trend and variability in MVG plasma pharmacokinetics following IV administration in adults. The Bayesian approach offered a continuous flow of information from pre-clinical to clinical studies. Prediction of the DDI with ketoconazole was consistent with the results of a non-compartmental analysis of the clinical data (threefold increase in systemic exposure). Scaling of the WBPBPK model allowed reasonable extrapolation of MVG pharmacokinetics from adults to children. The model can be used to predict plasma and brain (target site) concentration-time profiles following oral administration of various immediate-release formulations of MVG alone or when co-administered with other drugs, in adults as well as in children. PMID:26231433

  10. Effects of amoxicillin/clavulanic acid on the pharmacokinetics of valproic acid

    PubMed Central

    Lee, Soo-Yun; Huh, Wooseong; Jung, Jin Ah; Yoo, Hye Min; Ko, Jae-Wook; Kim, Jung-Ryul

    2015-01-01

    Valproic acid (VPA) is mainly metabolized via glucuronide, which is hydrolyzed by β-glucuronidase and undergoes enterohepatic circulation. Amoxicillin/clavulanic acid (AMC) administration leads to decreased levels of β-glucuronidase-producing bacteria, suggesting that these antibiotics could interrupt enterohepatic circulation and thereby alter the pharmacokinetics of VPA. This study aimed to evaluate the effects of AMC on the pharmacokinetics of VPA. This was an open-label, two-treatment, one-sequence study in 16 healthy volunteers. Two treatments were evaluated; treatment VPA, in which a single dose of VPA 500 mg was administered, and treatment AMC + VPA, in which multiple doses of AMC 500/125 mg were administered three times daily for 7 days and then a single dose of VPA was administered. Blood samples were collected up to 48 hours. Pharmacokinetic parameters were calculated using noncompartmental methods. Fifteen subjects completed the study. Systemic exposures and peak concentrations of VPA were slightly lower with treatment AMC + VPA than with treatment VPA (AUClast, 851.0 h·mg/L vs 889.6 h·mg/L; Cmax, 52.1 mg/L vs 53.0 mg/L). There were no significant between-treatment effects on pharmacokinetics (95% confidence interval [CI]) of AUClast and Cmax (95.7 [85.9–106.5] and 98.3 [91.6–105.6], respectively). Multiple doses of AMC had no significant effects on the pharmacokinetics of VPA; thus, no dose adjustment is necessary. PMID:26309401

  11. Clinical Pharmacokinetics of IPX066: Evaluation of Dose Proportionality and Effect of Food in Healthy Volunteers

    PubMed Central

    Yao, Hsuan-Ming; Hsu, Ann; Gupta, Suneel; Modi, Nishit B.

    2016-01-01

    Objectives IPX066 is an oral, extended-release capsule formulation of carbidopa-levodopa (CD-LD) available in 4 strengths. The goals of this investigation were to assess the dose proportionality of IPX066 and to study the effects of a high-fat, high-calorie meal and of sprinkling the capsule contents on applesauce on the pharmacokinetics of IPX066 in healthy volunteers. Methods Three open-label studies were conducted. In the first study, subjects received 1 capsule of each IPX066 strength (23.75–95, 36.25–145, 48.75–195, and 61.25–245 mg of CD-LD). In the second study, subjects received 1 and 2 capsules of IPX066 245-mg LD under fasting conditions. In the third study, subjects received 2 capsules of IPX066 245-mg LD under 3 conditions: fasting; following a high-fat, high-calorie breakfast; and with the capsule contents sprinkled on applesauce under fasting conditions. Results Peak plasma concentrations (Cmax) and systemic exposure (AUCt, AUCinf) for LD and CD increased dose-proportionally over the range of the IPX066 capsule strengths. Comparison of 1 and 2 IPX066 245-mg LD capsules showed dose-proportional pharmacokinetics for Cmax and AUCt. Sprinkling the capsule contents on applesauce did not affect the pharmacokinetics. A high-fat, high-calorie meal delayed the initial increase in LD concentration by approximately 1 to 2 hours, reduced Cmax by 21%, and increased AUCinf by 13% compared with the fasted state. Conclusions IPX066 shows dose-proportional pharmacokinetics. Sprinkling the capsule contents on applesauce does not affect the pharmacokinetics; a high-fat, high-calorie meal delayed absorption by 1 to 2 hours, slightly reduced Cmax, and slightly increased extent of absorption. PMID:26626430

  12. Use of biological markers and pharmacokinetics in human health risk assessment.

    PubMed Central

    Hattis, D

    1991-01-01

    There are two reasons to connect discussions of biological markers and pharmacokinetics. First, both tend to open up the black box between exposure and effect. Doing this promises more complete scientific understanding than simple input-output analysis, the possibility of better mechanism-based projection of risk beyond the range of possible direct observations, and the possibility of greater sensitivity of analysis, in some cases going from the organism to the cell as the unit of analysis. Second, pharmacokinetic (or similar pharmacodynamic) analysis will often be essential for appropriate interpretation of biological marker information. One needs some sort of dynamic model of the generation and loss of the marker in relation to exposure in order to use a biological marker, either to form a better measure of dosage (either accumulated past dose, or biologically relevant dose), or to make an improved prediction of effect. (For example, the use of a blood cadmium level alone to predict kidney effects might be inferior to predictions based on aggregate past accumulation of cadmium in the kidney, based on the past history of cadmium blood levels x time). Several examples will be discussed of the use of biomarkers and pharmacokinetics in risk assessments for both carcinogenesis and other effects. PMID:2050066

  13. Physiologically based Pharmacokinetic Modeling of 1,4-Dioxane in Rats, Mice, and Humans

    SciTech Connect

    Sweeney, Lisa M.; Thrall, Karla D.; Poet, Torka S.; Corley, Rick; Weber, Thomas J.; Locey, B. J.; Clarkson, Jacquelyn; Sager, S.; Gargas, M. L.

    2008-01-01

    ABSTRACT 1,4-Dioxane (CAS No. 123-91-1) is used primarily as a solvent or as a solvent stabilizer. It can cause lung, liver and kidney damage at sufficiently high exposure levels. Two physiologically-based pharmacokinetic (PBPK) models of 1,4-dioxane and its major metabolite, hydroxyethoxyacetic acid (HEAA), were published in 1990. These models have uncertainties and deficiencies that could be addressed and the model strengthened for use in a contemporary cancer risk assessment for 1,4-dioxane. Studies were performed to fill data gaps and reduce uncertainties pertaining to the pharmacokinetics of 1,4-dioxane and HEAA in rats, mice, and humans. Three types of studies were performed:partition coefficient measurements, blood time course in mice, and in vitro pharmacokinetics using rat, mouse, and human hepatocytes. Updated PBPK models were developed based on these new data and previously available data. The optimized rate of metabolism for the mouse was significantly higher than the value previously estimated. The optimized rat kinetic parameters were similar to those in the 1990 models. Only two human studies were identified. Model predictions were consistent with one study, but did not fit the second as well. In addition, a rat nasal exposure was completed. The results confirmed water directly contacts rat nasal tissues during drinking water under bioassays. Consistent with previous PBPK models, nasal tissues were not specifically included in the model. Use of these models will reduce the uncertainty in future 1,4-dioxane risk assessments.

  14. Developing reimbursable clinical pharmacy programs: pharmacokinetic dosing service.

    PubMed

    Moore, T D; Schneider, P J; Nold, E G

    1979-11-01

    The development, operation and evaluation of a pharmacy-conducted pharmacokinetic dosing service is described. Pharmacists recommend individualized drug dosing regimens based on pharmacokinetic models and equations clinically tested for accuracy by the pharmacy department. Pharmacokinetic values are determined with the aid of online computer programs developed by the department. Drug assays are provided by the hospital's laboratory. All of the department's pharmacists were trained to provide the 24-hour service. The pharmacy department's $20 pharmacokinetic dosing service fee is reimbursed by Blue Cross. The pharmacokinetic dosing service is the first nonteaching, nonproduct-oriented pharmaceutical service whose cost-effectiveness has been recognized by a third-party payer. PMID:517538

  15. Air Pollution Exposure

    PubMed Central

    Balmes, John R.; Collard, Harold R.

    2015-01-01

    Air pollution exposure is a well-established risk factor for several adverse respiratory outcomes, including airways diseases and lung cancer. Few studies have investigated the relationship between air pollution and interstitial lung disease (ILD) despite many forms of ILD arising from environmental exposures. There are potential mechanisms by which air pollution could cause, exacerbate, or accelerate the progression of certain forms of ILD via pulmonary and systemic inflammation as well as oxidative stress. This article will review the current epidemiologic and translational data supporting the plausibility of this relationship and propose a new conceptual framework for characterizing novel environmental risk factors for these forms of lung disease. PMID:25846532

  16. Ethnic and genetic factors in methadone pharmacokinetics: A population pharmacokinetic study☆

    PubMed Central

    Bart, Gavin; Lenz, Scott; Straka, Robert J.; Brundage, Richard C.

    2014-01-01

    Background Treatment of opiate use disorders with methadone is complicated by wide interindividual variability in pharmacokinetics. To identify potentially contributing covariates in methadone pharmacokinetics, we used population pharmacokinetic modeling to estimate clearance (CL/F) and volume of distribution (V/F) for each methadone enantiomer in an ethnically diverse methadone maintained population. Methods Plasma levels of the opiate-active R-methadone and opiate-inactive S-methadone were measured in 206 methadone maintained subjects approximately two and twenty-three hours after a daily oral dose of racmethadone. A linear one-compartment population pharmacokinetic model with first-order conditional estimation with interaction (FOCE-I) was used to evaluate methadone CL/F and V/F. The influence of covariates on parameter estimates was evaluated using stepwise covariate modeling. Covariates included ethnicity, gender, weight, BMI, age, methadone dose, and 21 single nucleotide polymorphisms in genes implicated in methadone pharmacokinetics. Results In the final model, for each enantiomer, Hmong ethnicity reduced CL/F by approximately 30% and the rs2032582 (ABCB1 2677G > T/A) GG genotype was associated with a 20% reduction in CL/F. The presence of the rs3745274 minor allele (CYP2B6 515G > T) reduced CL/F by up to 20% for S-methadone only. A smaller effect of age was noted on CL/F for R-methadone. Conclusion This is the first report showing the influence of the rs2032582 and rs3745274 variants on methadone pharmacokinetics rather than simply dose requirements or plasma levels. Population pharmacokinetics is a valuable method for identifying the influences on methadone pharmacokinetic variability. PMID:25456329

  17. Pharmacokinetics, pharmacokinetic-pharmacodynamic relationship, and withdrawal period of amoxicillin sodium in olive flounder (Paralichthys olivaceus).

    PubMed

    Park, Ji-Yong; Awji, Elias Gebru; Suh, Joo-Won; Park, Seung-Chun

    2016-06-01

    1. The pharmacokinetics (PK) and withdrawal period of amoxicillin sodium in olive flounder and its activity against pathogenic bacteria of olive flounder were investigated. 2. Intramuscular administration (12.5 or 125 mg/kg, n = 160) and HPLC analysis of sera were used. 3. Rapid absorption (Tmax 2.6 and 2.2 h), prolonged action (terminal half-life, 15.52 and 10.42 h; MRT, 18.79 and 14.44 h), and dose-proportional exposure (AUC0-∞, 273.69 and 2755.37 h. μg/ml) were observed after 12.5 and 125 mg/kg doses. 4. The withdrawal period of amoxicillin sodium from muscle plus skin of olive flounder (n =40, water temperature, 23 °C) was 12 d (276 degree days). 5. Amoxicillin sodium had small MICs against Streptococcus iniae (0.008-0.06 μg/ml) and Streptococcus parauberis (0.03-1.0 μg/ml), whereas higher concentrations were required to inhibit Edwardsiella tarda isolates (0.06-16 μg/ml). 6. While large AUC0-24 h/MIC90 and Cmax/MIC90 ratios were obtained for S. iniae and S. parauberis, with drug concentrations in serum greater than MICs for the entire dosing interval (T > MIC90 of 100%), the lower dose (12.5 mg/kg) could not achieve target values of the PK-pharmacodynamic (PD) indices for E. tarda isolates, suggesting the need for higher doses to combat pathogenic bacteria with large MICs. PMID:26407038

  18. Pharmacokinetics and pharmacodynamics of antifungals in children and their clinical implications.

    PubMed

    Stockmann, Chris; Constance, Jonathan E; Roberts, Jessica K; Olson, Jared; Doby, Elizabeth H; Ampofo, Krow; Stiers, Justin; Spigarelli, Michael G; Sherwin, Catherine M T

    2014-05-01

    by the cytochrome P450 (CYP) 2C19 genotype and hepatic impairment. Therapeutic drug monitoring is recommended as voriconazole pharmacokinetics are highly variable and small dose increases can result in marked changes in plasma concentrations. For the echinocandins, the primary source of pharmacokinetic variability stems from an age-dependent decrease in clearance with increasing age. Consequently, young children require larger doses per kilogram of body weight than older children and adults. Routine therapeutic drug monitoring for the echinocandins is not recommended. The effectiveness of many systemic antifungal agents has been correlated with pharmacodynamic targets in in vitro and in murine models of invasive candidiasis and aspergillosis. Further study is needed to translate these findings into optimal dosing regimens for children and to understand how these agents interact when multiple antifungal agents are used in combination. PMID:24595533

  19. Pharmacokinetics and pharmacodynamics of cannabinoids.

    PubMed

    Grotenhermen, Franjo

    2003-01-01

    Delta(9)-Tetrahydrocannabinol (THC) is the main source of the pharmacological effects caused by the consumption of cannabis, both the marijuana-like action and the medicinal benefits of the plant. However, its acid metabolite THC-COOH, the non-psychotropic cannabidiol (CBD), several cannabinoid analogues and newly discovered modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoids exert many effects through activation of G-protein-coupled cannabinoid receptors in the brain and peripheral tissues. Additionally, there is evidence for non-receptor-dependent mechanisms. Natural cannabis products and single cannabinoids are usually inhaled or taken orally; the rectal route, sublingual administration, transdermal delivery, eye drops and aerosols have only been used in a few studies and are of little relevance in practice today. The pharmacokinetics of THC vary as a function of its route of administration. Pulmonary assimilation of inhaled THC causes a maximum plasma concentration within minutes, psychotropic effects start within seconds to a few minutes, reach a maximum after 15-30 minutes, and taper off within 2-3 hours. Following oral ingestion, psychotropic effects set in with a delay of 30-90 minutes, reach their maximum after 2-3 hours and last for about 4-12 hours, depending on dose and specific effect. At doses exceeding the psychotropic threshold, ingestion of cannabis usually causes enhanced well-being and relaxation with an intensification of ordinary sensory experiences. The most important acute adverse effects caused by overdosing are anxiety and panic attacks, and with regard to somatic effects increased heart rate and changes in blood pressure. Regular use of cannabis may lead to dependency and to a mild withdrawal syndrome. The existence and the intensity of possible long-term adverse effects on psyche and cognition, immune system, fertility and pregnancy remain controversial

  20. Ebola: translational science considerations.

    PubMed

    Chiappelli, Francesco; Bakhordarian, Andre; Thames, April D; Du, Angela M; Jan, Allison L; Nahcivan, Melissa; Nguyen, Mia T; Sama, Nateli; Manfrini, Ercolano; Piva, Francesco; Rocha, Rafael Malagoli; Maida, Carl A

    2015-01-01

    We are currently in the midst of the most aggressive and fulminating outbreak of Ebola-related disease, commonly referred to as "Ebola", ever recorded. In less than a year, the Ebola virus (EBOV, Zaire ebolavirus species) has infected over 10,000 people, indiscriminately of gender or age, with a fatality rate of about 50%. Whereas at its onset this Ebola outbreak was limited to three countries in West Africa (Guinea, where it was first reported in late March 2014, Liberia, where it has been most rampant in its capital city, Monrovia and other metropolitan cities, and Sierra Leone), cases were later reported in Nigeria, Mali and Senegal, as well as in Western Europe (i.e., Madrid, Spain) and the US (i.e., Dallas, Texas; New York City) by late October 2014. World and US health agencies declared that the current Ebola virus disease (EVD) outbreak has a strong likelihood of growing exponentially across the world before an effective vaccine, treatment or cure can be developed, tested, validated and distributed widely. In the meantime, the spread of the disease may rapidly evolve from an epidemics to a full-blown pandemic. The scientific and healthcare communities actively research and define an emerging kaleidoscope of knowledge about critical translational research parameters, including the virology of EBOV, the molecular biomarkers of the pathological manifestations of EVD, putative central nervous system involvement in EVD, and the cellular immune surveillance to EBOV, patient-centered anthropological and societal parameters of EVD, as well as translational effectiveness about novel putative patient-targeted vaccine and pharmaceutical interventions, which hold strong promise, if not hope, to curb this and future Ebola outbreaks. This work reviews and discusses the principal known facts about EBOV and EVD, and certain among the most interesting ongoing or future avenues of research in the field, including vaccination programs for the wild animal vectors of the virus

  1. Using dried blood spot sampling to improve data quality and reduce animal use in mouse pharmacokinetic studies.

    PubMed

    Wickremsinhe, Enaksha R; Perkins, Everett J

    2015-03-01

    Traditional pharmacokinetic analysis in nonclinical studies is based on the concentration of a test compound in plasma and requires approximately 100 to 200 μL blood collected per time point. However, the total blood volume of mice limits the number of samples that can be collected from an individual animal-often to a single collection per mouse-thus necessitating dosing multiple mice to generate a pharmacokinetic profile in a sparse-sampling design. Compared with traditional methods, dried blood spot (DBS) analysis requires smaller volumes of blood (15 to 20 μL), thus supporting serial blood sampling and the generation of a complete pharmacokinetic profile from a single mouse. Here we compare plasma-derived data with DBS-derived data, explain how to adopt DBS sampling to support discovery mouse studies, and describe how to generate pharmacokinetic and pharmacodynamic data from a single mouse. Executing novel study designs that use DBS enhances the ability to identify and streamline better drug candidates during drug discovery. Implementing DBS sampling can reduce the number of mice needed in a drug discovery program. In addition, the simplicity of DBS sampling and the smaller numbers of mice needed translate to decreased study costs. Overall, DBS sampling is consistent with 3Rs principles by achieving reductions in the number of animals used, decreased restraint-associated stress, improved data quality, direct comparison of interanimal variability, and the generation of multiple endpoints from a single study. PMID:25836959

  2. Using Dried Blood Spot Sampling to Improve Data Quality and Reduce Animal Use in Mouse Pharmacokinetic Studies

    PubMed Central

    Wickremsinhe, Enaksha R; Perkins, Everett J

    2015-01-01

    Traditional pharmacokinetic analysis in nonclinical studies is based on the concentration of a test compound in plasma and requires approximately 100 to 200 µL blood collected per time point. However, the total blood volume of mice limits the number of samples that can be collected from an individual animal—often to a single collection per mouse—thus necessitating dosing multiple mice to generate a pharmacokinetic profile in a sparse-sampling design. Compared with traditional methods, dried blood spot (DBS) analysis requires smaller volumes of blood (15 to 20 µL), thus supporting serial blood sampling and the generation of a complete pharmacokinetic profile from a single mouse. Here we compare plasma-derived data with DBS-derived data, explain how to adopt DBS sampling to support discovery mouse studies, and describe how to generate pharmacokinetic and pharmacodynamic data from a single mouse. Executing novel study designs that use DBS enhances the ability to identify and streamline better drug candidates during drug discovery. Implementing DBS sampling can reduce the number of mice needed in a drug discovery program. In addition, the simplicity of DBS sampling and the smaller numbers of mice needed translate to decreased study costs. Overall, DBS sampling is consistent with 3Rs principles by achieving reductions in the number of animals used, decreased restraint-associated stress, improved data quality, direct comparison of interanimal variability, and the generation of multiple endpoints from a single study. PMID:25836959

  3. 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…

  4. A Terminal Pharmaceutics Course in Clinical Pharmacokinetics.

    ERIC Educational Resources Information Center

    Reuning, Richard H.; Krautheim, Daniel

    1978-01-01

    At Ohio State University, an undergraduate course extends the course sequence in biopharmaceutics and pharmacokinetics to application to problems in optimizing drug therapy. Course content, structure, instructional methods, and student term projects are described, and a course outline, typical projects, and some behavioral objectives are appended.…

  5. Pharmacokinetics of Drug Entry into Cochlear Fluids

    ERIC Educational Resources Information Center

    Salt, Alec N.

    2005-01-01

    The inner ear is exposed to aminoglycosides or other drugs either intentionally or as a side effect of clinical treatments directed at other regions of the body. An understanding of the effects of drugs on the inner ear requires knowledge of the pharmacokinetics of the drug once it reaches the cochlear fluids, specifically how much of it reaches…

  6. Pharmacokinetics of Peptide-Fc fusion proteins.

    PubMed

    Wu, Benjamin; Sun, Yu-Nien

    2014-01-01

    Peptide-Fc fusion proteins (or peptibodies) are chimeric proteins generated by fusing a biologically active peptide with the Fc-domain of immunoglobulin G. In this review, we describe recent studies that have evaluated the absorption, distribution, metabolism, and excretion characteristics of peptibodies. Key features of the pharmacokinetics of peptibodies include their extended half-life due to recycling by the neonatal Fc receptor (FcRn), a substantial contribution by renal excretion to total clearance and, for certain peptibodies, target-mediated drug disposition. The prolonged half-life of peptibodies permits less-frequent dose administration compared with small therapeutic peptides, thereby supporting patient convenience and compliance. Hence, a considerable number of peptibodies are currently in preclinical and clinical development. Investigation of the metabolism (biotransformation) of biologics is an evolving area of research: ligand-binding mass spectrometry techniques have been employed for the characterization of the peptibody romiplostim, providing a new approach to evaluation of the degradation products of biologics. Pharmacokinetic/pharmacodynamic modeling and simulation techniques have been used to predict the pharmacokinetics of peptibodies which can inform clinical decision-making, particularly selection of dosing regimens. This integrated review highlights the distinct pharmacokinetic characteristics of peptibodies and their influence on the drug development process for this emerging family of therapeutics. PMID:24285510

  7. FIRST REPORTS OF CLINICAL PHARMACOKINETICS IN NIGERIA

    PubMed Central

    Michael, O.S.

    2015-01-01

    The German Friedrich Hartmut Dost (1910-1985) introduced the word Pharmacokinetics. Clinical pharmacokinetics is the direct application of knowledge regarding a drug's pharmacokinetics to a therapeutic situation in an individual or a population. It is the basis of therapeutic drug monitoring with the ultimate goal of keeping drugs safe. This branch of pharmacology has become the most relevant to the sub-specialty of clinical pharmacology. First reports of Clinical Pharmacokinetics in Nigeria can be credited to two gifted Nigerians, Prof Ayodele O. Iyun and Prof Lateef A. Salako, both of whom were affiliated to the great institutions- University of Ibadan (UI) and the Teaching Hospital, University College Hospital (UCH). Prof A.O Iyun was Nigeria's first home-trained Clinical Pharmacologist, while Prof L.A. Salako played a most significant role in the creation of the Department of Clinical Pharmacology, UCH. This edition of the Chronicles highlights a few of the first reports of this exciting branch of pharmacology in Nigeria. This historical review is based on publications listed on the United States National Library of Medicine database (PUBMED). PMID:26807087

  8. FIRST REPORTS OF CLINICAL PHARMACOKINETICS IN NIGERIA.

    PubMed

    Michael, O S

    2015-06-01

    The German Friedrich Hartmut Dost (1910-1985) introduced the word Pharmacokinetics. Clinical pharmacokinetics is the direct application of knowledge regarding a drug's pharmacokinetics to a therapeutic situation in an individual or a population. It is the basis of therapeutic drug monitoring with the ultimate goal of keeping drugs safe. This branch of pharmacology has become the most relevant to the sub-specialty of clinical pharmacology. First reports of Clinical Pharmacokinetics in Nigeria can be credited to two gifted Nigerians, Prof Ayodele O. Iyun and Prof Lateef A. Salako, both of whom were affiliated to the great institutions- University of Ibadan (UI) and the Teaching Hospital, University College Hospital (UCH). Prof A.O Iyun was Nigeria's first home-trained Clinical Pharmacologist, while Prof L.A. Salako played a most significant role in the creation of the Department of Clinical Pharmacology, UCH. This edition of the Chronicles highlights a few of the first reports of this exciting branch of pharmacology in Nigeria. This historical review is based on publications listed on the United States National Library of Medicine database (PUBMED). PMID:26807087

  9. Axitinib plasma pharmacokinetics and ethnic differences.

    PubMed

    Chen, Ying; Suzuki, Akiyuki; Tortorici, Michael A; Garrett, May; LaBadie, Robert R; Umeyama, Yoshiko; Pithavala, Yazdi K

    2015-04-01

    Axitinib, a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, showed improved progression-free survival over sorafenib in patients previously treated for advanced renal cell carcinoma in the AXIS trial. Although a few studies had established the efficacy and safety of axitinib in Asian patients, additional evaluation was necessary to obtain regulatory approval in several Asian countries, especially in light of ethnic differences that are known to exist in genetic polymorphisms for metabolizing enzymes such as cytochrome P450 (CYP) 3A5, CYP2C19 and uridine diphosphate glucuronosyltransferase (UGT) 1A1, which are involved in axitinib metabolism. Axitinib plasma pharmacokinetics following single or multiple administration of oral axitinib in Asian (Japanese or Chinese) healthy subjects as well as Asian patients with advanced solid tumors was compared with that obtained in Caucasians. Upon review, the data demonstrated that axitinib can be characterized as not sensitive to ethnic factors based on its pharmacokinetic and pharmacodynamic properties. Axitinib exhibited similar pharmacokinetics in Asian and non-Asian subjects. A pooled population pharmacokinetic analysis indicated lack of a clinically meaningful effect of ethnicity on axitinib disposition. Therefore, dose adjustment for axitinib on the basis of ethnicity is not currently warranted. PMID:25663295

  10. Pharmacokinetic Modeling of Perfluoroalkyl Acids in Rodents

    EPA Science Inventory

    Perfluorooctanoic acid (PFOA) has pharmacokinetic properties that appear consistent with a number of processes that are currently not well understood. Studies in mice exposed orally at lower doses (1 and 10 mg/kg) demonstrated blood, liver, and kidney concentration time courses ...

  11. Heritability of metoprolol and torsemide pharmacokinetics.

    PubMed

    Matthaei, J; Brockmöller, J; Tzvetkov, M V; Sehrt, D; Sachse-Seeboth, C; Hjelmborg, J B; Möller, S; Halekoh, U; Hofmann, U; Schwab, M; Kerb, R

    2015-12-01

    Genetic variation in the pharmacokinetics of metoprolol and torsemide due to polymorphisms in CYP2D6, CYP2C9, and OATP1B1 has been extensively studied. However, it is still unknown how much of the variation in pharmacokinetics of these two clinically important drugs in total is due to genetic factors. Metoprolol and torsemide were intravenously administered to 44 monozygotic and 14 dizygotic twin pairs. Metoprolol area under the curve (AUC) varied 4.7-fold and torsemide AUC 3.5-fold. A very high fraction of AUC variations, 91% of metoprolol and 86% of torsemide, were found to be due to additive genetic effects. However, known genetic variants of CYP2D6, -2C9, and OATP1B1 explained only 39%, 2%, and 39% of that variation, respectively. Comparable results for genetically explained variation in pharmacokinetics and pharmacodynamics have been found for other substrates of these enzymes earlier. These findings indicate that a substantial fraction of the heritable variability in the pharmacokinetics of metoprolol and torsemide remains to be elucidated. PMID:26344676

  12. The influence of paroxetine on the pharmacokinetics of atomoxetine and its main metabolite

    PubMed Central

    TODOR, IOANA; POPA, ADINA; NEAG, MARIA; MUNTEAN, DANA; BOCSAN, CORINA; BUZOIANU, ANCA; VLASE, LAURIAN; GHELDIU, ANA-MARIA; CHIRA, RUXANDRA; BRICIU, CORINA

    2015-01-01

    Background and aims To evaluate the effects of paroxetine on the pharmacokinetics of atomoxetine and its main metabolite, 4-hydroxyatomoxetine-O-glucuronide, after coadministration of atomoxetine and paroxetine in healthy volunteers. Methods 22 healthy volunteers, extensive metabolizers, took part in this open-label, non-randomized, clinical trial. The study consisted of two periods: Reference, when a single oral dose of 25 mg atomoxetine was administrated to each subject and Test, when 25 mg atomoxetine and 20 mg paroxetine were coadministered. Between the two periods, the volunteers received an oral daily dose of 20–40 mg paroxetine, for 6 days. Atomoxetine and 4-hydroxyatomoxetine-O-glucuronide plasma concentrations were determined within the first 48 hours following drug administration. The pharmacokinetic parameters of both compounds were assessed using a non-compartmental method and the analysis of variance aimed at identifying any statistical significant differences between the pharmacokinetic parameters of atomoxetine and its main metabolite, corresponding to each study period. Results Paroxetine modified the pharmacokinetic parameters of atomoxetine. Cmax increased from 221.26±94.93 to 372.53±128.28 ng/mL, while AUC0-t and AUC0-∞ also increased from 1151.19±686.52 to 6452.37±3388.76 ng*h/mL, and from 1229.15±751.04 to 7111.74±4195.17 ng*h/mL respectively. The main metabolite pharmacokinetics was also influenced by paroxetine intake, namely Cmax, AUC0-t and AUC0-∞ decreased from 688.76±270.27 to 131.01±100.43 ng*h/mL, and from 4810.93±845.06 to 2606.04±923.88 and from 4928.55±853.25 to 3029.82 ±941.84 respectively. Conclusions Multiple-dose paroxetine intake significantly influenced atomoxetine and its active metabolite pharmacokinetics, causing a 5.8-fold increased exposure to atomoxetine and 1.6-fold reduced exposure to 4-hydroxyatomoxetine-O-glucuronide. PMID:26733750

  13. Modulation of the pharmacokinetics of zinc oxide nanoparticles and their fates in vivo

    NASA Astrophysics Data System (ADS)

    Paek, Hee-Jeong; Lee, Youn-Joung; Chung, Hea-Eun; Yoo, Nan-Hui; Lee, Jeong-A.; Kim, Mi-Kyung; Lee, Jong Kwon; Jeong, Jayoung; Choi, Soo-Jin

    2013-11-01

    In the present study, the effects of particle size (20 nm or 70 nm) and surface charge (negative or positive) on the pharmacokinetics, tissue distributions, and excretion of ZnO nanoparticles were examined following the administration of a single oral dose to rats. Pharmacokinetic profiles and biodistributions were not affected by particle size or gender. However, ZnO (-) particles were markedly more absorbed by the systemic circulation than ZnO (+) particles. Furthermore, the kinetic behaviors of ZnO nanoparticles differed from those of zinc ions, as evidenced by the low dissolution (13-14%) of ZnO nanoparticles under gastric conditions. The kidneys, liver, and lungs were found to be target organs. However, the major biological fate of ZnO nanoparticles in tissues was the ionic form, not the particulate form, and this was independent of exposure routes (oral and intravenous). Particle size was only found to affect excretion kinetics, and 20 nm particles were more rapidly eliminated. Most nanoparticles were excreted via the biliary and fecal routes, but a small amount of the nanoparticles was excreted via urine. The study shows that surface charge, rather than particle size or gender, is the critical modulator of the pharmacokinetic behavior of ZnO nanoparticles.In the present study, the effects of particle size (20 nm or 70 nm) and surface charge (negative or positive) on the pharmacokinetics, tissue distributions, and excretion of ZnO nanoparticles were examined following the administration of a single oral dose to rats. Pharmacokinetic profiles and biodistributions were not affected by particle size or gender. However, ZnO (-) particles were markedly more absorbed by the systemic circulation than ZnO (+) particles. Furthermore, the kinetic behaviors of ZnO nanoparticles differed from those of zinc ions, as evidenced by the low dissolution (13-14%) of ZnO nanoparticles under gastric conditions. The kidneys, liver, and lungs were found to be target organs. However

  14. Lack of racial differences in the pharmacokinetics of subcutaneous golimumab in healthy Japanese and Caucasian male subjects.

    PubMed

    Ling, Jie; Lyn, Sally; Xu, Zhenhua; Achira, Meguru; Bouman-Thio, Esther; Shishido, Akira; Ford, Joyce; Shankar, Gopi; Wagner, Carrie; Kim, Kenneth T; Davis, Hugh M; Zhou, Honghui

    2010-07-01

    This phase 1 study evaluated the single-dose pharmacokinetics and safety of subcutaneous golimumab, a human anti-tumor necrosis factor-alpha monoclonal antibody, in healthy Japanese and Caucasian subjects. Eligible subjects were males, aged 20 to 45 years, weighing 50 to 90 kg with a body mass index of 19 to 30 kg/m(2). Japanese and Caucasian subjects were matched by body weight and dose group. Blood samples were collected through day 50 following a single subcutaneous injection of golimumab 50 or 100 mg. The pharmacokinetic parameters were determined using a noncompartmental method. All 51 subjects (24 Japanese, 27 Caucasian) were included in the safety analysis; 47 completed the study and were included in the pharmacokinetic analysis. The pharmacokinetics of golimumab were comparable in both race groups. Peak concentrations were observed approximately 4 to 6 days after administration. No significant differences in exposure or mean half-life (range, 11-13 days) were observed between Japanese and Caucasian subjects at the same dose level. Regardless of race, serum golimumab exposure increased with increasing dose. Mean apparent clearance ranged from 12 to 19 mL/kg/d. Mean apparent volume of distribution (224-262 mL/kg) remained constant with an increase in dose. No antibodies to golimumab were detected. Single subcutaneous injections of golimumab 50 mg or 100 mg were generally well tolerated in these healthy male Japanese and Caucasian subjects. PMID:20133508

  15. Magnetic translator bearings

    NASA Technical Reports Server (NTRS)

    Hockney, Richard L. (Inventor); Downer, James R. (Inventor); Eisenhaure, David B. (Inventor); Hawkey, Timothy J. (Inventor); Johnson, Bruce G. (Inventor)

    1990-01-01

    A magnetic bearing system for enabling translational motion includes a carriage and a shaft for movably supporting the carriage; a first magnetic bearing fixed to one of the carriage and shaft and slidably received in a first channel of the other of the carriage and shaft. The first channel is generally U shaped with two side walls and a back wall. The magnetic bearing includes a pair of spaced magnetic pole pieces, each pole piece having a pair of electromagnetic coils mounted on poles on opposite ends of the pole piece proximate the side walls, and a third electromagnetic coil mounted on a pole of the pole piece proximate the backwall; a motion sensor for sensing translational motion along two axes and rotationally about three axes of the carriage and shaft relative to each other; and a correction circuit responsive to the sensor for generating a correction signal to drive the coils to compensate for any misalignment sensed between the carriage and the shaft.

  16. Review: Translational GTPases.

    PubMed

    Maracci, Cristina; Rodnina, Marina V

    2016-08-01

    Translational GTPases (trGTPases) play key roles in facilitating protein synthesis on the ribosome. Despite the high degree of evolutionary conservation in the sequences of their GTP-binding domains, the rates of GTP hydrolysis and nucleotide exchange vary broadly between different trGTPases. EF-Tu, one of the best-characterized model G proteins, evolved an exceptionally rapid and tightly regulated GTPase activity, which ensures rapid and accurate incorporation of amino acids into the nascent chain. Other trGTPases instead use the energy of GTP hydrolysis to promote movement or to ensure the forward commitment of translation reactions. Recent data suggest the GTPase mechanism of EF-Tu and provide an insight in the catalysis of GTP hydrolysis by its unusual activator, the ribosome. Here we summarize these advances in understanding the functional cycle and the regulation of trGTPases, stimulated by the elucidation of their structures on the ribosome and the progress in dissecting the reaction mechanism of GTPases. © 2016 Wiley Periodicals, Inc. Biopolymers 105: 463-475, 2016. PMID:26971860

  17. Pharmacokinetics and Drug Dosing in Obese Children

    PubMed Central

    Kendrick, Jennifer G.; Carr, Roxane R.; Ensom, Mary H.H.

    2010-01-01

    OBJECTIVES To review pharmacokinetics in obese children and to provide medication dosing recommendations. METHODS EMBASE, MEDLINE, and International Pharmaceutical Abstracts databases were searched using the following terms: obesity, morbid obesity, overweight, pharmacokinetics, drug, dose, kidney function test, creatinine, pediatric, and child. RESULTS We identified 10 studies in which the authors examined drug dosing or pharmacokinetics for obese children. No information was found for drug absorption or metabolism. Obese children have a higher percent fat mass and a lower percent lean mass compared with normal-weight children. Therefore, in obese children, the volume of distribution of lipophilic drugs is most likely higher, and that of hydrophilic drugs is most likely lower, than in normal-weight children. Serum creatinine concentrations are higher in obese than normal-weight children. Total body weight is an appropriate size descriptor for calculating doses of antineoplastics, cefazolin, and succinylcholine in obese children. Initial tobramycin doses may be determined using an adjusted body weight, although using total body weight in the context of monitoring serum tobramycin concentrations would also be an appropriate strategy. We found no information for any of the opioids; antibiotics such as penicillins, carbapenems, vancomycin, and linezolid; antifungals; cardiac drugs such as digoxin and amiodarone; corticosteroids; benzodiazepines; and anticonvulsants. In particular, we found no information about medications that are widely distributed to adipose tissue or that can accumulate there. CONCLUSIONS The available data are limited because of the small numbers of participating children, study design, or both. The number and type of drugs that have been studied limit our understanding of the pharmacokinetics in obese children. In the absence of dosing information for obese children, it is important to consider the nature and severity of a child's illness

  18. Population Pharmacokinetics of Pyronaridine in Pediatric Malaria Patients

    PubMed Central

    Ayyoub, Amal; Methaneethorn, Janthima; Ramharter, Michael; Djimde, Abdoulaye A.; Tekete, Mamadou; Duparc, Stephan; Borghini-Fuhrer, Isabelle; Shin, Jang-Sik

    2015-01-01

    Pyramax is a pyronaridine (PYR)-artesunate (PA) combination for the treatment of uncomplicated malaria in adult and pediatric patients. A granule formulation of this combination is being developed for treatment of uncomplicated P. falciparum and P. vivax malaria in pediatric patients. The aims of this study were to describe the pharmacokinetics of PYR using a total of 1,085 blood PYR concentrations available from 349 malaria patients younger than 16 years of age with mild to moderate uncomplicated malaria and to confirm the dosing regimen for the pediatric granule formulation. Nonlinear mixed-effects modeling using NONMEM software was used to obtain the pharmacokinetic and inter- and intraindividual variability parameter estimates. The population pharmacokinetics of PYR were described by a two-compartment model with first-order absorption and elimination. Allometric scaling was implemented to address the effect of body weight on clearance and volume parameters. The final parameter estimates of PYR apparent clearance (CL/F), central volume of distribution (V2/F), peripheral volume of distribution (V3/F), intercompartmental clearance (Q/F), and absorption rate constant (Ka) were 377 liters/day, 2,230 liters, 3,230 liters, 804 liters/day and 17.9 day−1, respectively. Covariate model building conducted using forward addition (P < 0.05) followed by backward elimination (P < 0.001) yielded two significant covariate-parameter relationships, i.e., age on V2/F and formulation on Ka. Evaluation of bootstrapping, visual predictive check, and condition number indicated that the final model displayed satisfactory robustness, predictive power, and stability. Simulations of PYR concentration-time profiles generated from the final model show similar exposures across pediatric weight ranges, supporting the proposed labeling for weight-based dosing of Pyramax granules. (These studies have been registered at ClinicalTrials.gov under registration no. NCT00331136 [phase II study] and

  19. Population Pharmacokinetics of Pyronaridine in Pediatric Malaria Patients.

    PubMed

    Ayyoub, Amal; Methaneethorn, Janthima; Ramharter, Michael; Djimde, Abdoulaye A; Tekete, Mamadou; Duparc, Stephan; Borghini-Fuhrer, Isabelle; Shin, Jang-Sik; Fleckenstein, Lawrence

    2016-03-01

    Pyramax is a pyronaridine (PYR)-artesunate (PA) combination for the treatment of uncomplicated malaria in adult and pediatric patients. A granule formulation of this combination is being developed for treatment of uncomplicated P. falciparum and P. vivax malaria in pediatric patients. The aims of this study were to describe the pharmacokinetics of PYR using a total of 1,085 blood PYR concentrations available from 349 malaria patients younger than 16 years of age with mild to moderate uncomplicated malaria and to confirm the dosing regimen for the pediatric granule formulation. Nonlinear mixed-effects modeling using NONMEM software was used to obtain the pharmacokinetic and inter- and intraindividual variability parameter estimates. The population pharmacokinetics of PYR were described by a two-compartment model with first-order absorption and elimination. Allometric scaling was implemented to address the effect of body weight on clearance and volume parameters. The final parameter estimates of PYR apparent clearance (CL/F), central volume of distribution (V2/F), peripheral volume of distribution (V3/F), intercompartmental clearance (Q/F), and absorption rate constant (Ka) were 377 liters/day, 2,230 liters, 3,230 liters, 804 liters/day and 17.9 day(-1), respectively. Covariate model building conducted using forward addition (P < 0.05) followed by backward elimination (P < 0.001) yielded two significant covariate-parameter relationships, i.e., age on V2/F and formulation on Ka. Evaluation of bootstrapping, visual predictive check, and condition number indicated that the final model displayed satisfactory robustness, predictive power, and stability. Simulations of PYR concentration-time profiles generated from the final model show similar exposures across pediatric weight ranges, supporting the proposed labeling for weight-based dosing of Pyramax granules. (These studies have been registered at ClinicalTrials.gov under registration no. NCT00331136 [phase II study] and

  20. Pharmacokinetic Properties of Artemether, Dihydroartemisinin, Lumefantrine, and Quinine in Pregnant Women with Uncomplicated Plasmodium falciparum Malaria in Uganda

    PubMed Central

    Kloprogge, Frank; Dhorda, Mehul; Jullien, Vincent; Nosten, Francois; White, Nicholas J.; Guerin, Philippe J.; Piola, Patrice

    2013-01-01

    Pregnancy alters the pharmacokinetic properties of many drugs used in the treatment of malaria, usually resulting in lower drug exposures. This increases the risks of treatment failure, adverse outcomes for the fetus, and the development of resistance. The pharmacokinetic properties of artemether and its principal metabolite dihydroartemisinin (n = 21), quinine (n = 21), and lumefantrine (n = 26) in pregnant Ugandan women were studied. Lumefantrine pharmacokinetics in a nonpregnant control group (n = 17) were also studied. Frequently sampled patient data were evaluated with noncompartmental analysis. No significant correlation was observed between estimated gestational age and artemether, dihydroartemisinin, lumefantrine, or quinine exposures. Artemether/dihydroartemisinin and quinine exposures were generally low in these pregnant women compared to values reported previously for nonpregnant patients. Median day 7 lumefantrine concentrations were 488 (range, 30.7 to 3,550) ng/ml in pregnant women compared to 720 (339 to 2,150) ng/ml in nonpregnant women (P = 0.128). There was no statistical difference in total lumefantrine exposure or maximum concentration. More studies with appropriate control groups in larger series are needed to characterize the degree to which pregnant women are underdosed with current antimalarial dosing regimens. PMID:23917320

  1. Influence of tobacco smoke on the pharmacokinetics of citalopram and its enantiomers.

    PubMed

    Majcherczyk, J; Kulza, M; Senczuk-Przybylowska, M; Florek, E; Jawien, W; Piekoszewski, W

    2012-02-01

    The purpose of this study was to evaluate the influence of tobacco smoke on the pharmacokinetics of citalopram (CIT) and desmethylcitalopram (DCIT) and its enantiomers on an animal model. High performance liquid chromatography (HPLC) with a diode array detector (DAD) was used for the identification and quantification of the studied compounds. The HPLC quantification of racemic mixtures of CIT was performed on a C18 column. The limits of detection (LOD) and quantification (LOQ) were: 7 and 10 ng/ml respectively. HPLC separation of citalopram enantiomers (S- and R-CIT) was performed on a Chirobiotic V column. The limits of detection (LOD) and quantification (LOQ) were: 6 and 15 ng/ml for R- and S-CIT respectively. The experiment was carried out on male Wistar rats. The rats were exposed to tobacco smoke for five days (6 hours per day). After the exposure, citalopram was administered in a dose of 10 mg/kg intragastrically. In the control group (non-exposed animals), citalopram was administered in the same way and at an equal dose. The blood of the animals was collected at nine time points. It was found that tobacco smoke exposure inhibits the biotransformation of citalopram. The half-life of the racemic mixture of citalopram after intragastric administration was increased by about 287%. Changes in the pharmacokinetic parameters of S-citalopram (active isomer) show a similar tendency to those of the racemic mixture. The pharmacokinetics of R-citalopram showed no statistically important differences after tobacco smoke exposure. Alterations in the pharmacological parameters of desmethylcitalopram presented an opposite trend to the parent drug. After exposure to tobacco smoke, the induction of metabolism of this compound was observed. PMID:22460466

  2. Etravirine Pharmacokinetics in HIV-Infected Pregnant Women

    PubMed Central

    Mulligan, Nikki; Schalkwijk, Stein; Best, Brookie M.; Colbers, Angela; Wang, Jiajia; Capparelli, Edmund V.; Moltó, José; Stek, Alice M.; Taylor, Graham; Smith, Elizabeth; Hidalgo Tenorio, Carmen; Chakhtoura, Nahida; van Kasteren, Marjo; Fletcher, Courtney V.; Mirochnick, Mark; Burger, David

    2016-01-01

    Background: The study goal was to describe etravirine pharmacokinetics during pregnancy and postpartum in HIV-infected women. Methods: IMPAACT P1026s and PANNA are on-going, non-randomized, open-label, parallel-group, multi-center phase-IV prospective studies in HIV-infected pregnant women. Intensive steady-state 12-h pharmacokinetic profiles were performed from 2nd trimester through postpartum. Etravirine was measured at two labs using validated ultra performance liquid chromatography (detection limits: 0.020 and 0.026 mcg/mL). Results: Fifteen women took etravirine 200 mg twice-daily. Etravirine AUC0–12 was higher in the 3rd trimester compared to paired postpartum data by 34% (median 8.3 vs. 5.3 mcg*h/mL, p = 0.068). Etravirine apparent oral clearance was significantly lower in the 3rd trimester of pregnancy compared to paired postpartum data by 52% (median 24 vs. 38 L/h, p = 0.025). The median ratio of cord blood to maternal plasma concentration at delivery was 0.52 (range: 0.19–4.25) and no perinatal transmission occurred. Conclusion: Etravirine apparent oral clearance is reduced and exposure increased during the third trimester of pregnancy. Based on prior dose-ranging and safety data, no dose adjustment is necessary for maternal health but the effects of etravirine in utero are unknown. Maternal health and infant outcomes should be closely monitored until further infant safety data are available. Clinical Trial registration: The IMPAACT protocol P1026s and PANNA study are registered at ClinicalTrials.gov under NCT00042289 and NCT00825929. PMID:27540363

  3. Safety and Pharmacokinetics of Solithromycin in Subjects with Hepatic Impairment

    PubMed Central

    Ciric, Sabrina; Fernandes, Prabhavathi

    2015-01-01

    Solithromycin, a new macrolide and the first fluoroketolide, is in late-stage clinical development and, like older macrolides, is primarily metabolized and excreted through liver-dependent mechanisms. This study evaluated the safety and pharmacokinetics of solithromycin in patients with chronic liver disease. This open-label, multiple-dose study in subjects with hepatic impairment and in healthy control subjects (matched for age, weight, and sex) enrolled 8 Child-Pugh class A (mild), 8 class B (moderate), and 8 class C (severe) patients and 9 healthy controls. Subjects (n = 33) received one 800-mg dose on day 1 followed by once-daily doses of 400 mg on days 2 through 5. The most commonly reported adverse events were mild diarrhea and mild headache, and no significant differences were noted between hepatically impaired subjects and healthy controls. The pharmacokinetics of plasma solithromycin in subjects with mild and moderate impairment was similar to that in control subjects. In subjects with severe impairment, total exposure to solithromycin at steady state (area under the plasma concentration-time curve [AUC0–tau]) was decreased compared to that in control subjects, which may have been related to the higher body mass index of individuals in this group. No greater accumulation was noted in any hepatically impaired cohort on day 5 compared to that in control subjects. No decrease in dosage is therefore needed when administering solithromycin to patients with mild, moderate, or severe hepatic impairment. Solithromycin was well tolerated in this patient population, and no significant differences in safety, compared to healthy controls, were noted. PMID:25870056

  4. Physiologically based pharmacokinetic models for everolimus and sorafenib in mice

    PubMed Central

    Pawaskar, Dipti K.; Straubinger, Robert M.; Fetterly, Gerald J.; Hylander, Bonnie H.; Repasky, Elizabeth A.; Ma, Wen W.

    2013-01-01

    Purpose Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved as an immunosuppressant and for second-line therapy of hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). Sorafenib is a multikinase inhibitor used as first-line therapy in HCC and RCC. This study assessed the pharmacokinetics (PK) of everolimus and sorafenib alone and in combination in plasma and tissues, developed physiologically based pharmacokinetic (PBPK) models in mice, and assessed the possibility of PK drug interactions. Methods Single and multiple oral doses of everolimus and sorafenib were administered alone and in combination in immunocompetent male mice and to severe combined immune-deficient (SCID) mice bearing low-passage, patient-derived pancreatic adenocarcinoma in seven different studies. Plasma and tissue samples including tumor were collected over a 24-h period and analyzed by liquid chromatography-tandem mass spectrometry (LC–MS/MS). Distribution of everolimus and sorafenib to the brain, muscle, adipose, lungs, kidneys, pancreas, spleen, liver, GI, and tumor was modeled as perfusion rate-limited, and all data from the diverse studies were fitted simultaneously using a population approach. Results PBPK models were developed for everolimus and sorafenib. PBPK analysis showed that the two drugs in combination had the same PK as each drug given alone. A twofold increase in sorafenib dose increased tumor exposure tenfold, thus suggesting involvement of transporters in tumor deposition of sorafenib. Conclusions The developed PBPK models suggested the absence of PK interaction between the two drugs in mice. These studies provide the basis for pharmacodynamic evaluation of these drugs in patient-derived primary pancreatic adenocarcinomas explants. PMID:23455451

  5. Pharmacokinetics of micafungin in subjects with severe hepatic dysfunction.

    PubMed

    Undre, Nasrullah; Pretorius, Benjamin; Stevenson, Paul

    2015-09-01

    Micafungin is an echinocandin with potent activity against a broad range of fungal species, including Candida species. The pharmacokinetic and safety profiles of micafungin have been evaluated in individuals with mild-to-moderate hepatic dysfunction, but not in individuals with severe hepatic dysfunction. Therefore, the present study assessed the pharmacokinetics and safety of a single 100 mg dose of micafungin in healthy subjects (n = 8) and subjects with severe hepatic dysfunction (n = 8). Mean maximum plasma concentration of micafungin and mean area under the plasma micafungin concentration-time curve extrapolated to infinity were lower in subjects with severe hepatic dysfunction (7.3 ± 2.4 µg/mL and 100.1 ± 34.5 h·μg/mL, respectively) than in subjects with normal hepatic function (10.3 ± 2.5 µg/mL and 142.4 ± 28.9 h·μg/mL, respectively). Mean clearance was higher in subjects with severe hepatic dysfunction (1,098 ± 347 mL/h) than in subjects with normal hepatic function (728 ± 149 mL/h). Concentrations of albumin in subjects with severe hepatic dysfunction were lower. Assessments of micafungin plasma protein binding suggested that the higher clearance in subjects with severe hepatic dysfunction may be due to higher unbound concentrations. However, the magnitude of the differences was not considered clinically meaningful and is comparable with exposures reported elsewhere for a 100-mg dose in patients treated for invasive candidiasis. Thus, dose adjustment in subjects with severe hepatic dysfunction is not warranted. Micafungin was well tolerated in all subjects throughout the study. PMID:24888485

  6. Pharmacokinetics and Pharmacodynamics of Antifungals in Children: Clinical Implications

    PubMed Central

    Autmizguine, Julie; Guptill, Jeffrey T.; Cohen-Wolkowiez, Michael; Benjamin, Daniel K.; Capparelli, Edmund V.

    2014-01-01

    Invasive fungal disease (IFD) remains life-threatening in premature infants and immunocompromised children despite the recent development of new antifungal agents. Optimal dosing of antifungals is one of the few factors clinicians can control to improve outcomes of IFD. However, dosing in children cannot be extrapolated from adult data because IFD pathophysiology, immune response, and drug disposition differ from adults. We critically examined the literature on pharmacokinetics (PK) and pharmacodynamics (PD) of antifungal agents and highlight recent developments in treating pediatric IFD. To match adult exposure in pediatric patients, dosing adjustment is necessary for almost all antifungals. In young infants, the maturation of renal and metabolic functions occurs rapidly and can significantly influence drug exposure. Fluconazole clearance doubles from birth to 28 days of life and, beyond the neonatal period, agents like fluconazole, voriconazole, and micafungin require higher dosing than in adults due to faster clearance in children. As a result, dosing recommendations are specific to bracketed ranges of age. Pharmacodynamics principles of antifungals mostly rely on in vitro and in vivo models but very few pharmacodynamics studies specifically address IFD in children. Exposure-response relationship may differ in younger children compared with adults, especially in infants with invasive candidiasis who are at higher risk of disseminated disease and meningoencephalitis, and by extension severe neurodevelopmental impairment. Micafungin is the only antifungal agent for which a specific target of exposure was proposed based on a neonatal hematogenous Candida meningoencephalitis animal model. In this review, we found that pediatric data on drug disposition of newer triazoles and echinocandins are lacking, dosing of older antifungals such as fluconazole and amphotericin B products still need optimization in young infants, and that target PK/PD indices need to be

  7. Fore–aft translation aftereffects

    PubMed Central

    2012-01-01

    A general theme in sensory perception is that exposure to a stimulus makes it seem more neutral such that perception of subsequent stimuli is shifted in the opposite direction. The visual motion aftereffect (MAE) is an extensively studied example of this. Although similar effects have been described in other sensory systems, it has not previously been described in the vestibular system. Velocity storage has been extensively studied in the vestibular system and suggests a persistence of perception in the direction of the initial movement. The current study sought to determine how motion perception is influenced by prior movement in darkness. Thirteen human subjects (mean age 41, range 21–68) underwent whole-body fore–aft translation. The threshold of vestibular motion discrimination perception was measured using a single interval (1I) of motion lasting 0.5 s in which subjects identified their direction of motion as forward or backward using an adaptive staircase. The translation aftereffect (TAE) was measured in 2-interval (2I) experiments: The adapting stimulus moved 15 cm in 1.5 s (peak velocity 20 cm/s, peak acceleration 42 cm/s2). After a fixed inter-stimulus interval (ISI) of 0.5, 1.0, 1.5, or 3 s, a second stimulus lasting 0.5 s was delivered and the subject identified the perceived direction of the second test stimulus. The test stimulus was determined using an adaptive staircase. The ISI was constant within the block, but adapting stimuli directions were randomly interleaved. During the 1I condition, the response bias was near zero in all subjects. With a 2I stimulus, 8 of 13 subjects demonstrated a significant bias. At an ISI of 0.5 s, a minority of subjects demonstrated a bias in the same direction as the adapter. When the ISI was 1, 1.5, or 3 s, all subjects who demonstrated a significant TAE had one in the opposite direction of the adapter, similar to that seen for MAE. When averaged across subjects, the TAE was significant with ISIs of 1.0 s and

  8. Effect of faldaprevir on raltegravir pharmacokinetics in healthy volunteers.

    PubMed

    Joseph, David; Rose, Peter; Strelkowa, Natalja; Schultz, Armin; Garcia, Jeanette; Elgadi, Mabrouk; Huang, Fenglei

    2015-04-01

    Faldaprevir is a potent hepatitis C virus (HCV) NS3/4A protease inhibitor and an inhibitor of UDP-glucuronosyltransferase-1A1 (UGT1A1), which is involved in raltegravir clearance. Raltegravir, an HIV integrase inhibitor, may be used in combination with HCV treatment in HCV/HIV co-infected patients. In this open-label, 2-period, fixed-sequence study, 24 healthy volunteers (12 males) received faldaprevir 240 mg and raltegravir 400 mg in 2 treatment schedules (A and B) separated by a washout phase of ≥7 days: (A) twice-daily raltegravir (Days 1-3), once-daily raltegravir (Day 4); (B) twice-daily raltegravir and twice-daily faldaprevir (loading dose, Day 1), twice-daily raltegravir and once-daily faldaprevir (Days 2-5), once-daily raltegravir and once-daily faldaprevir (Day 6). Pharmacokinetics and safety were assessed over 132 hours post-dosing. Compared with raltegravir alone, co-administration with faldaprevir led to 2.7-fold and 2.5-fold increases in raltegravir geometric mean AUC(τ,ss) and C(max,ss), respectively, and a similar increase in raltegravir glucuronide metabolite exposure. No serious adverse events (AEs) were reported and no subject discontinued due to AEs. Faldaprevir and raltegravir co-administration was well tolerated and resulted in a moderate increase in raltegravir exposure. PMID:25352040

  9. Determination of a suitable voriconazole pharmacokinetic model for personalised dosing.

    PubMed

    McDougall, David A J; Martin, Jennifer; Playford, E Geoffrey; Green, Bruce

    2016-04-01

    Model based personalised dosing (MBPD) is a sophisticated form of individualised therapy, where a population pharmacokinetic (PK) or pharmacodynamic model is utilised to estimate the dose required to reach a target exposure or effect. The choice of which model to implement in MBPD is a subjective decision. By choosing one model, information from the remaining models is ignored, as well as the rest of the literature base. This manuscript describes a methodology to develop a 'hybrid' model for voriconazole that incorporated information from prior models in a biologically plausible manner. Voriconazole is a triazole antifungal with difficult to predict PK, although it does have a defined exposure-response relationship. Nine population PK models of voriconazole were identified from the literature. The models differed significantly in structural components. The hybrid model contained a two-compartment disposition model with mixed linear and nonlinear time-dependent clearance. The parameters for the hybrid model were determined using simulation techniques. Validation of the hybrid model was assessed via visual predictive checks, which indicated the majority of the variability in the literature models was captured by the hybrid model. The predictive performance was assessed using four different sampling strategies of limited concentrations from ten richly PK sampled subjects to predict future concentrations. Overall, the hybrid model predicted future concentrations with good precision. Further prospective and retrospective validation of the hybrid model is required before it could be used in clinical practice. PMID:26676909

  10. Pharmacokinetics of Prophylactic Cefazolin in Parturients Undergoing Cesarean Delivery

    PubMed Central

    Elkomy, Mohammed H.; Sultan, Pervez; Epshtein, Ekaterina; Galinkin, Jeffery L.; Carvalho, Brendan

    2014-01-01

    The objectives of this work were (i) to characterize the pharmacokinetics of cefazolin in pregnant women undergoing elective cesarean delivery and in their neonates; (ii) to assess cefazolin transplacental transmission; (iii) to evaluate the dosing and timing of preoperative, prophylactic administration of cefazolin to pregnant women; and (iv) to investigate the impact of maternal dosing on therapeutic duration and exposure in newborns. Twenty women received 1 g of cefazolin preoperatively. Plasma concentrations of total cefazolin were analyzed from maternal blood samples taken before, during, and after delivery; umbilical cord blood samples obtained at delivery; and neonatal blood samples collected 24 h after birth. The distribution volume of cefazolin was 9.44 liters/h. The values for pre- and postdelivery clearance were 7.18 and 4.12 liters/h, respectively. Computer simulations revealed that the probability of maintaining free cefazolin concentrations in plasma above 8 mg/liter during scheduled caesarean surgery was <50% in the cord blood when cefazolin was administered in doses of <2 g or when it was administered <1 h before delivery. Therapeutic concentrations of cefazolin persisted in neonates >5 h after birth. Cefazolin clearance increases during pregnancy, and larger doses are recommended for surgical prophylaxis in pregnant women to obtain the same antibacterial effect as in nonpregnant patients. Cefazolin has a longer half-life in neonates than in adults. Maternal administration of up to 2 g of cefazolin is effective and produces exposure within clinically approved limits in neonates. PMID:24733461

  11. Translational toxicology: a developmental focus for integrated research strategies

    PubMed Central

    2013-01-01

    Background Given that toxicology studies the potential adverse effects of environmental exposures on various forms of life and that clinical toxicology typically focuses on human health effects, what can and should the relatively new term of "translational toxicology" be taken to mean? Discussion Our assertion is that the core concept of translational toxicology must incorporate existing principles of toxicology and epidemiology, but be driven by the aim of developing safe and effective interventions beyond simple reduction or avoidance of exposure to prevent, mitigate or reverse adverse human health effects of exposures. The field of toxicology has now reached a point where advances in multiple areas of biomedical research and information technologies empower us to make fundamental transitions in directly impacting human health. Translational toxicology must encompass four action elements as follows: 1) Assessing human exposures in critical windows across the lifespan 2) Defining modes of action and relevance of data from animal models 3) Use of mathematical models to develop plausible predictions as the basis for 4) Protective and restorative human health interventions. The discussion focuses on the critical window of in-utero development. Summary Exposure assessment, basic toxicology and development of certain categories of mathematical models are not new areas of research; however overtly integrating these in order to conceive, assess and validate effective interventions to mitigate or reverse adverse effects of environmental exposures is our novel opportunity. This is what we should do in translational toxicology so that we have a portfolio of interventional options to improve human health that include both minimizing exposures and specific preventative/restorative/mitigative therapeutics. PMID:24079609

  12. DEVELOPMENT OF A HUMAN PHYSIOLOGICALLY-BASED PHARMACOKINETIC (PBPK) MODEL FOR INORGANIC ARSENIC AND ITS MONO- AND DI-METHYLATED METABOLITES

    EPA Science Inventory

    A physiologically-based pharmacokinetic (PBPK) model was developed to estimate levels of arsenic and its metabolites in human tissues and urine after oral exposure to either arsenate (AsV) or arsnite (AsIII). The model consists of interconnected individual ...

  13. Switching from body surface area-based to fixed dosing for the investigational proteasome inhibitor ixazomib: a population pharmacokinetic analysis

    PubMed Central

    Gupta, Neeraj; Zhao, Yuan; Hui, Ai-Min; Esseltine, Dixie-Lee; Venkatakrishnan, Karthik

    2015-01-01

    Aims This population pharmacokinetic analysis of the investigational oral proteasome inhibitor ixazomib assessed the feasibility of switching from body surface area (BSA)-based to fixed dosing, and the impact of baseline covariates on ixazomib pharmacokinetics. Methods Data were pooled from 226 adult patients with multiple myeloma, lymphoma or solid tumours in four phase 1 studies, in which ixazomib dosing (oral/intravenous, once/twice weekly) was based on BSA. Population pharmacokinetic modelling was undertaken using nonmem version 7.2. Results Ixazomib pharmacokinetics were well described by a three compartment model with first order absorption and linear elimination. Ixazomib was absorbed rapidly (Ka 0.5 h−1), with dose- and time-independent pharmacokinetics. Estimated absolute bioavailability and clearance were 60% and 2 l h−1, respectively. Although a small effect of BSA (range 1.3–2.6 m2) was observed on the peripheral volume of distribution (V4), reducing the corresponding inter-individual variability by 12.9%, there was no relationship between BSA and ixazomib clearance (the parameter that dictates total systemic exposure following fixed dosing). Consistently, based on simulations (n = 1000), median AUCs (including interquartile range) were similar after BSA-based (2.23 mg m−2) and fixed (4 mg) oral dosing with no trend in simulated AUC vs. BSA for fixed dosing (P = 0.42). No other covariates, including creatinine clearance (22–213.7 ml min−1) and age (23–86 years), influenced ixazomib pharmacokinetics. Conclusions This analysis supports a switch from BSA-based to fixed dosing, without dose modification for mild/moderate renal impairment or age, in future adult studies of ixazomib, simplifying dosing guidance and clinical development. PMID:25377318

  14. The Translation and the Translator of the Peshitta of Hosea

    ERIC Educational Resources Information Center

    Tully, Eric J.

    2012-01-01

    This comprehensive examination of the Syriac Peshitta of Hosea (P-Hosea) is the first study of the Peshitta conducted via insights and methods from the discipline of Translation Studies. It uses in particular Andrew Chesterman's Causal Model and Gideon Toury's descriptive approach. Every translator leaves residue of his or her…

  15. Global arrest of translation during invertebrate quiescence.

    PubMed

    Hofmann, G E; Hand, S C

    1994-08-30

    Comparing the translational capacities of cell-free systems from aerobically developing embryos of the brine shrimp Artemia franciscana vs. quiescent embryos has revealed a global arrest of protein synthesis. Incorporation rates of [3H]leucine by lysates from 4-h anoxic embryos were 8% of those from aerobic (control) embryos, when assayed at the respective pH values measured for each treatment in vivo. Exposure of embryos to 4 h of aerobic acidosis (elevated CO2 in the presence of oxygen) suppressed protein synthesis to 3% of control values. These latter two experimental treatments promote developmental arrest of Artemia embryos and, concomitantly, cause acute declines in intracellular pH. When lysates from each treatment were assayed over a range of physiologically relevant pH values (pH 6.4-8.0), amino acid incorporation rates in lysates from quiescent embryos were consistently lower than values for the aerobic controls. Acute reversal of pH to alkaline values during the 6-min assays was not sufficient to return the incorporation rates of quiescent lysates to control values. Thus, a stable alteration in translational capacity of quiescent lysates is indicated. Addition of exogenous mRNA did not rescue the suppressed protein synthesis in quiescent lysates, which suggests that the acute blockage of amino acid incorporation is apparently not due to limitation in message. Thus, the results support a role for intracellular pH as an initial signaling event in translational control during quiescence yet, at the same time, indicate that a direct proton effect on the translational machinery is not the sole proximal agent for biosynthetic arrest in this primitive crustacean. PMID:8078909

  16. Global arrest of translation during invertebrate quiescence.

    PubMed Central

    Hofmann, G E; Hand, S C

    1994-01-01

    Comparing the translational capacities of cell-free systems from aerobically developing embryos of the brine shrimp Artemia franciscana vs. quiescent embryos has revealed a global arrest of protein synthesis. Incorporation rates of [3H]leucine by lysates from 4-h anoxic embryos were 8% of those from aerobic (control) embryos, when assayed at the respective pH values measured for each treatment in vivo. Exposure of embryos to 4 h of aerobic acidosis (elevated CO2 in the presence of oxygen) suppressed protein synthesis to 3% of control values. These latter two experimental treatments promote developmental arrest of Artemia embryos and, concomitantly, cause acute declines in intracellular pH. When lysates from each treatment were assayed over a range of physiologically relevant pH values (pH 6.4-8.0), amino acid incorporation rates in lysates from quiescent embryos were consistently lower than values for the aerobic controls. Acute reversal of pH to alkaline values during the 6-min assays was not sufficient to return the incorporation rates of quiescent lysates to control values. Thus, a stable alteration in translational capacity of quiescent lysates is indicated. Addition of exogenous mRNA did not rescue the suppressed protein synthesis in quiescent lysates, which suggests that the acute blockage of amino acid incorporation is apparently not due to limitation in message. Thus, the results support a role for intracellular pH as an initial signaling event in translational control during quiescence yet, at the same time, indicate that a direct proton effect on the translational machinery is not the sole proximal agent for biosynthetic arrest in this primitive crustacean. PMID:8078909

  17. Pharmacokinetics of melatonin in human sexual maturation.

    PubMed

    Cavallo, A; Ritschel, W A

    1996-05-01

    To determine whether melatonin pharmacokinetics change during puberty, we infused melatonin iv in 9 prepubertal, 8 pubertal, and 16 adult subjects and measured melatonin in serum and saliva, and 6-hydroxymelatonin sulfate in urine. A pilot study of 3 adult males showed dose linearity, absence of saturation kinetics, and unaltered metabolism and urinary excretion for doses of 0.1, 0.5, and 5.0 micrograms/kg. All other subjects received 0.5 microgram/kg melatonin. The results of pharmacokinetic parameters calculated from serum melatonin showed no significant gender differences in adults. However, developmental differences were significant between prepubertal children and adults for terminal elimination rate constant (1.08 +/- 0.25 vs. 0.89 +/- 0.11 h-1), elimination half-life (0.67 +/- 0.12 vs. 0.79 +/- 0.10 h), and area under the concentration-time curve (250.9 +/- 91.8 vs. 376.9 +/- 154.3 (pg/mL).h, respectively). At all time points melatonin levels were higher in serum than in saliva, and the ratio between serum and salivary melatonin varied up to 55-fold within and between individuals. Results based on salivary melatonin showed significant differences between prepubertal children and adults for the terminal elimination rate constant (1.90 +/- 0.95 vs. 1.06 +/- 0.28 h-1). The described group differences in pharmacokinetic parameters suggest that prepubertal children metabolize melatonin faster than adults. The inconsistent ratio between serum and salivary melatonin calls for caution in the use of salivary melatonin for pharmacokinetic studies or to infer pineal function. The present findings, suggestive of faster melatonin metabolism in prepubertal children, combined with the known decline of serum melatonin with age and higher excretion rate of the metabolite in prepubertal children lead us to conclude that the prepubertal pineal gland has a higher melatonin secretion rate than the adult gland. PMID:8626852

  18. Pharmacokinetics of Tenofovir During Pregnancy and Postpartum

    PubMed Central

    Best, Brookie M.; Burchett, Sandra; Li, Hong; Stek, Alice; Hu, Chengcheng; Wang, Jiajia; Hawkins, Elizabeth; Byroads, Mark; Watts, D. Heather; Smith, Elizabeth; Fletcher, Courtney V.; Capparelli, Edmund V.; Mirochnick, Mark

    2016-01-01

    Objectives Tenofovir disoproxol fumarate (TDF) is increasingly used in HAART regimens of pregnant women, but limited data exist on pregnancy pharmacokinetics of chronically-dosed TDF. This study described tenofovir pharmacokinetics during pregnancy and postpartum. Methods IMPAACT P1026s is a prospective, non-blinded pharmacokinetic study of HIV-infected pregnant women that included a cohort receiving 300 mg TDF once daily. Steady-state 24-hour pharmacokinetic profiles were measured at 2nd and 3rd trimester and postpartum, with maternal and umbilical cord samples at delivery. Tenofovir was measured by LC-MS. The target AUC was ≥ 1.99 mcg•hr/mL (non-pregnant historical control 10th percentile). Results Median tenofovir AUC was decreased during the 2nd (1.9 mcg•hr/mL) and 3rd (2.4 mcg•hr/mL, p=0.005) trimesters versus postpartum (3.0 mcg•hr/mL). Tenofovir AUC exceeded the target for 2/4 (50%) 2nd trimester; 27/37 (73%; 95% CI: 56%, 86%) 3rd trimester; and 27/32 (84%; 95% CI: 67%, 95%) postpartum women (p>0.05). Median 2nd/3rd trimester troughs were lower (39/54 ng/mL) than postpartum (61 ng/mL). Median 3rd trimester weight was heavier for subjects below target AUC versus those above target (97.9 vs. 74.2 kg, p = 0.006). Median ratio of cord blood to maternal concentrations was 0.88. No infants were HIV infected. Conclusions This study found lower tenofovir AUC and troughs during pregnancy. Transplacental passage with chronic TDF use during pregnancy was high. Standard TDF doses appear appropriate for most HIV-infected pregnant women but therapeutic drug monitoring with dose adjustment should be considered in pregnant women with high weight (> 90kg) or inadequate HIV RNA response. PMID:25959631

  19. Pharmacokinetic Profile of Spectinomycin in Rats

    PubMed Central

    Madhura, Dora Babu; Lee, Richard; Meibohm, Bernd

    2014-01-01

    Short Summary Following intravenous (IV) administration, the pharmacokinetics of spectinomycin in rats was found to be on par with its profile in other mammalian species including humans with respect to its overall excretion and half-life at effective concentrations. This study, however, indicates that a small fraction of the spectinomycin dose is retained in peripheral tissues for a prolonged period of time at low concentrations. PMID:24020122

  20. High prevalence of potential drug interactions affecting mycophenolic acid pharmacokinetics in nonmyeloablative hematopoietic stem cell transplant recipients

    PubMed Central

    Jaklič, Alenka; Collins, Carol J.; Mrhar, Aleš; Sorror, Mohamed L.; Sandmaier, Brenda M.; Bemer, Meagan J.; Locatelli, Igor; McCune, Jeannine S.

    2013-01-01

    Objective: Mycophenolic acid (MPA) exposure is associated with clinical outcomes in hematopoietic cell transplant (HCT) recipients. Various drug interaction studies, predominantly in healthy volunteers or solid organ transplant recipients, have identified medications which impact MPA pharmacokinetics. Recipients of nonmyeloablative HCT, however, have an increased burden of comorbidities, potentially increasing the number of concomitant medications and potential drug interactions (PDI) affecting MPA exposure. Thus, we sought to be the first to characterize these PDI in nonmyeloablative HCT recipients. Materials and methods: We compiled PDI affecting MPA pharmacokinetics and characterized the prevalence of PDI in nonmyeloablative HCT recipients. A comprehensive literature evaluation of four databases and PubMed was conducted to identify medications with PDI affecting MPA pharmacokinetics. Subsequently, a retrospective medication review was conducted to characterize the cumulative PDI burden, defined as the number of PDI for an individual patient over the first 21 days after allogeneic graft infusion, in 84 nonmyeloablative HCT recipients. Results: Of the 187 concomitant medications, 11 (5.9%) had a PDI affecting MPA pharmacokinetics. 87% of 84 patients had one PDI, with a median cumulative PDI burden of 2 (range 0 – 4). The most common PDI, in descending order, were cyclosporine, omeprazole and pantoprazole. Conclusion: Only a minority of medications (5.9%) have a PDI affecting MPA pharmacokinetics. However, the majority of nonmyeloablative HCT recipients had a PDI, with cyclosporine and the proton pump inhibitors being the most common. A better understanding of PDI and their management should lead to safer medication regimens for nonmyeloablative HCT recipients. PMID:23782584

  1. A Population Pharmacokinetic and Pharmacodynamic Analysis of Peginesatide in Patients with Chronic Kidney Disease on Dialysis

    PubMed Central

    Naik, Himanshu; Tsai, Max C.; Fiedler-Kelly, Jill; Qiu, Ping; Vakilynejad, Majid

    2013-01-01

    Peginesatide (OMONTYS®) is an erythropoiesis-stimulating agent that was indicated in the United States for the treatment of anemia due to chronic kidney disease in adult patients on dialysis prior to its recent marketing withdrawal by the manufacturer. The objective of this analysis was to develop a population pharmacokinetic and pharmacodynamic model to characterize the time-course of peginesatide plasma and hemoglobin concentrations following intravenous and subcutaneous administration. Plasma samples (n = 2,665) from 672 patients with chronic kidney disease (on or not on dialysis) and hemoglobin samples (n = 18,857) from 517 hemodialysis patients (subset of the 672 patients), were used for pharmacokinetic-pharmacodynamic model development in NONMEM VI. The pharmacokinetic profile of peginesatide was best described by a two-compartment model with first-order absorption and saturable elimination. The relationship between peginesatide and hemoglobin plasma concentrations was best characterized by a modified precursor-dependent lifespan indirect response model. The estimate of maximal stimulatory effect of peginesatide on the endogenous production rate of progenitor cells (Emax) was 0.54. The estimate of peginesatide drug concentration required for 50% of maximal response (EC50) estimates was 0.4 µg/mL. Several significant (P<0.005) covariates affected simulated peginesatide exposure by ≤36%. Based upon ≤0.2 g/dL effects on simulated hemoglobin levels, none were considered clinically relevant. PMID:23840463

  2. Population Pharmacokinetics and Dose Optimization of Mycophenolic Acid in HCT Recipients Receiving Oral Mycophenolate Mofetil

    PubMed Central

    Li, H; Mager, D E; Sandmaier, B M; Maloney, D G; Bemer, M J; McCune, J S

    2012-01-01

    We sought to create a population pharmacokinetic model for total mycophenolic acid (MPA), to study the effects of different covariates on MPA pharmacokinetics, to create a limited sampling schedule (LSS) to characterize MPA exposure (i.e., area under the curve or AUC) with maximum a posteriori Bayesian estimation, and to simulate an optimized dosing scheme for allogeneic hematopoietic cell transplantation (HCT) recipients. 4,496 MPA concentration-time points from 408 HCT recipients were analyzed retrospectively using a nonlinear mixed effects modeling approach. MPA pharmacokinetics was characterized with a two-compartment model with first-order elimination and a time-lagged first-order absorption process. Concomitant cyclosporine and serum albumin were significant covariates. The median MPA clearance and volume of the central compartment were 24.2 L/hr and 36.4 L, respectively, for a 70 kg patient receiving tacrolimus with a serum albumin of 3.4 g/dL. Dosing simulations indicated that higher oral MMF doses are needed with concomitant cyclosporine, which increases MPA clearance by 33.8%. The optimal LSS was immediately before and at 0.25, 1.25, 2, and 4hr after oral MMF administration. MPA AUC in an individual HCT recipient can be accurately estimated using a five-sample LSS and maximum a posteriori Bayesian estimation. PMID:23382105

  3. Population pharmacokinetics and dose optimization of mycophenolic acid in HCT recipients receiving oral mycophenolate mofetil.

    PubMed

    Li, H; Mager, D E; Sandmaier, B M; Maloney, D G; Bemer, M J; McCune, J S

    2013-04-01

    We sought to create a population pharmacokinetic model for total mycophenolic acid (MPA), to study the effects of different covariates on MPA pharmacokinetics, to create a limited sampling schedule (LSS) to characterize MPA exposure (i.e., area under the curve or AUC) with maximum a posteriori Bayesian estimation, and to simulate an optimized dosing scheme for allogeneic hematopoietic cell transplantation (HCT) recipients. Four thousand four hundred ninety-six MPA concentration-time points from 408 HCT recipients were analyzed retrospectively using a nonlinear mixed effects modeling approach. MPA pharmacokinetics was characterized with a two-compartment model with first-order elimination and a time-lagged first-order absorption process. Concomitant cyclosporine and serum albumin were significant covariates. The median MPA clearance (CL) and volume of the central compartment were 24.2 L/hour and 36.4 L, respectively, for a 70 kg patient receiving tacrolimus with a serum albumin of 3.4 g/dL. Dosing simulations indicated that higher oral MMF doses are needed with concomitant cyclosporine, which increases MPA CL by 33.8%. The optimal LSS was immediately before and at 0.25 hours, 1.25 hours, 2 hours, and 4 hours after oral mycophenolate mofetil administration. MPA AUC in an individual HCT recipient can be accurately estimated using a five-sample LSS and maximum a posteriori Bayesian estimation. PMID:23382105

  4. Psychedelic 5-Methoxy-N,N-dimethyltryptamine: Metabolism, Pharmacokinetics, Drug Interactions, and Pharmacological Actions

    PubMed Central

    Shen, Hong-Wu; Jiang, Xi-Ling; Winter, Jerrold C.; Yu, Ai-Ming

    2011-01-01

    5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) belongs to a group of naturally-occurring psychoactive indolealkylamine drugs. It acts as a nonselective serotonin (5-HT) agonist and causes many physiological and behavioral changes. 5-MeO-DMT is O-demethylated by polymorphic cytochrome P450 2D6 (CYP2D6) to an active metabolite, bufotenine, while it is mainly inactivated through the deamination pathway mediated by monoamine oxidase A (MAO-A). 5-MeO-DMT is often used with MAO-A inhibitors such as harmaline. Concurrent use of harmaline reduces 5-MeO-DMT deamination metabolism and leads to a prolonged and increased exposure to the parent drug 5-MeO-DMT, as well as the active metabolite bufotenine. Harmaline, 5-MeO-DMT and bufotenine act agonistically on serotonergic systems and may result in hyperserotonergic effects or serotonin toxicity. Interestingly, CYP2D6 also has important contribution to harmaline metabolism, and CYP2D6 genetic polymorphism may cause considerable variability in the metabolism, pharmacokinetics and dynamics of harmaline and its interaction with 5-MeO-DMT. Therefore, this review summarizes recent findings on biotransformation, pharmacokinetics, and pharmacological actions of 5-MeO-DMT. In addition, the pharmacokinetic and pharmacodynamic drug-drug interactions between harmaline and 5-MeO-DMT, potential involvement of CYP2D6 pharmacogenetics, and risks of 5-MeO-DMT intoxication are discussed. PMID:20942780

  5. Psychedelic 5-methoxy-N,N-dimethyltryptamine: metabolism, pharmacokinetics, drug interactions, and pharmacological actions.

    PubMed

    Shen, Hong-Wu; Jiang, Xi-Ling; Winter, Jerrold C; Yu, Ai-Ming

    2010-10-01

    5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) belongs to a group of naturally-occurring psychoactive indolealkylamine drugs. It acts as a nonselective serotonin (5-HT) agonist and causes many physiological and behavioral changes. 5-MeO-DMT is O-demethylated by polymorphic cytochrome P450 2D6 (CYP2D6) to an active metabolite, bufotenine, while it is mainly inactivated through the deamination pathway mediated by monoamine oxidase A (MAO-A). 5-MeO-DMT is often used with MAO-A inhibitors such as harmaline. Concurrent use of harmaline reduces 5-MeO-DMT deamination metabolism and leads to a prolonged and increased exposure to the parent drug 5-MeO-DMT, as well as the active metabolite bufotenine. Harmaline, 5-MeO-DMT and bufotenine act agonistically on serotonergic systems and may result in hyperserotonergic effects or serotonin toxicity. Interestingly, CYP2D6 also has important contribution to harmaline metabolism, and CYP2D6 genetic polymorphism may cause considerable variability in the metabolism, pharmacokinetics and dynamics of harmaline and its interaction with 5-MeO-DMT. Therefore, this review summarizes recent findings on biotransformation, pharmacokinetics, and pharmacological actions of 5-MeO-DMT. In addition, the pharmacokinetic and pharmacodynamic drug-drug interactions between harmaline and 5-MeO-DMT, potential involvement of CYP2D6 pharmacogenetics, and risks of 5-MeO-DMT intoxication are discussed. PMID:20942780

  6. Sirolimus formulation with improved pharmacokinetic properties produced by a continuous flow method.

    PubMed

    Solymosi, Tamás; Angi, Réka; Basa-Dénes, Orsolya; Ránky, Soma; Ötvös, Zsolt; Glavinas, Hristos; Filipcsei, Genovéva; Heltovics, Gábor

    2015-08-01

    The oral bioavailability of Sirolimus is limited by poor dissolution of the compound in the gastrointestinal tract resulting in a low bioavailability and large inter-individual differences in blood levels. Several different formulation approaches were applied to overcome these disadvantageous pharmacokinetic properties including the marketed oral solution and a tablet form containing wet milled nanocrystals. These approaches deliver improved pharmacokinetics, yet, they share the characteristics of complex production method and composition. We have developed a nanostructured Sirolimus formulation prepared by the controlled continuous flow precipitation of the compound from its solution in the presence of stabilizers. We have shown that contrary to the batch production the process could be easily intensified and scaled up; apparently the uniformity of the precipitation is heavily dependent on the production parameters, most likely the mixing of the solvent and antisolvent. We compared the physicochemical and pharmacokinetic properties of the nanostructured formula with the marketed nanoformula. We found that our method produces particles in the size range of less than 100nm. The solid form redispersed instantaneously in water and in biorelevant media. Both the solid form and the redispersed colloid solution showed excellent stability even in accelerated test conditions. The oral administration of the nanostructured formula resulted in faster absorption, higher exposure and higher trough concentrations when compared to the marked form. These advantageous properties could allow the development of solid oral Sirolimus formulae with lower strength and gel based topical delivery systems. PMID:26003815

  7. An Oracle: Antituberculosis Pharmacokinetics-Pharmacodynamics, Clinical Correlation, and Clinical Trial Simulations To Predict the Future▿

    PubMed Central

    Pasipanodya, Jotam; Gumbo, Tawanda

    2011-01-01

    Antimicrobial pharmacokinetic-pharmacodynamic (PK/PD) science and clinical trial simulations have not been adequately applied to the design of doses and dose schedules of antituberculosis regimens because many researchers are skeptical about their clinical applicability. We compared findings of preclinical PK/PD studies of current first-line antituberculosis drugs to findings from several clinical publications that included microbiologic outcome and pharmacokinetic data or had a dose-scheduling design. Without exception, the antimicrobial PK/PD parameters linked to optimal effect were similar in preclinical models and in tuberculosis patients. Thus, exposure-effect relationships derived in the preclinical models can be used in the design of optimal antituberculosis doses, by incorporating population pharmacokinetics of the drugs and MIC distributions in Monte Carlo simulations. When this has been performed, doses and dose schedules of rifampin, isoniazid, pyrazinamide, and moxifloxacin with the potential to shorten antituberculosis therapy have been identified. In addition, different susceptibility breakpoints than those in current use have been identified. These steps outline a more rational approach than that of current methods for designing regimens and predicting outcome so that both new and older antituberculosis agents can shorten therapy duration. PMID:20937778

  8. Flucytosine Pharmacokinetics in a Critically Ill Patient Receiving Continuous Renal Replacement Therapy

    PubMed Central

    Kunka, Megan E.; Cady, Elizabeth A.; Woo, Heejung C.; Thompson Bastin, Melissa L.

    2015-01-01

    Purpose. A case report evaluating flucytosine dosing in a critically ill patient receiving continuous renal replacement therapy. Summary. This case report outlines an 81-year-old male who was receiving continuous venovenous hemofiltration (CVVH) for acute renal failure and was being treated with flucytosine for the treatment of disseminated Cryptococcus neoformans infection. Due to patient specific factors, flucytosine was empirically dose adjusted approximately 50% lower than intermittent hemodialysis (iHD) recommendations and approximately 33% lower than CRRT recommendations. Peak and trough levels were obtained, which were supratherapeutic, and pharmacokinetic parameters were calculated. The patient experienced thrombocytopenia, likely due to elevated flucytosine levels, and flucytosine was ultimately discontinued. Conclusion. Despite conservative flucytosine dosing for a patient receiving CVVH, peak and trough serum flucytosine levels were supratherapeutic (120 μg/mL at 2 hours and 81 μg/mL at 11.5 hours), which increased drug-related adverse effects. The results indicate that this conservative dosing regimen utilizing the patient's actual body weight was too aggressive. This case report provides insight into flucytosine dosing in CVVH, a topic that has not been investigated previously. Further pharmacokinetic studies of flucytosine dosing in critically ill patients receiving CVVH are needed in order to optimize pharmacokinetic and pharmacodynamic parameters while avoiding toxic flucytosine exposure. PMID:26246919

  9. Effects of age and sex on the pharmacokinetics of LCZ696, an angiotensin receptor neprilysin inhibitor.

    PubMed

    Gan, Lu; Langenickel, Thomas; Petruck, Jesika; Kode, Kiran; Rajman, Iris; Chandra, Priya; Zhou, Wei; Rebello, Sam; Sunkara, Gangadhar

    2016-01-01

    LCZ696, a novel angiotensin receptor neprilysin inhibitor, is in development for the treatment of heart failure. Administration of LCZ696 results in systemic exposure to sacubitril (inactive prodrug of LBQ657), LBQ657 (neprilysin inhibitor), and valsartan (angiotensin II receptor blocker). We investigated the potential effects of age and sex on the pharmacokinetics of LCZ696 analytes (LBQ657 and valsartan) in an open-label, single oral dose (400 mg), parallel-group study in healthy subjects. Among 36 enrolled subjects, there were 19 male and 17 female subjects; 18 subjects were 18-45 years old (young), and 18 subjects were 65 years of age or older (elderly). Compared with young subjects, the AUCinf and T1/2 for LBQ657 were 42% and 30% greater, respectively, in elderly subjects. The Cmax for LBQ657 was similar between age groups. The AUCinf, Cmax, and T1/2 for valsartan were 30%, 24% greater, and 3.35 hours longer, respectively, in the elderly when compared with young subjects. All pharmacokinetic parameters of LCZ696 analytes (LBQ657 and valsartan) were similar between male and female subjects, indicating no effect on the pharmacokinetics of LCZ696 analytes based on sex. Considering the magnitude of change and its clinical significance, dose adjustment based on age or sex is not considered necessary. PMID:26073563

  10. [Pharmacokinetics--pharmacodynamics of modafinil in mice].

    PubMed

    Ma, Zhang-Qing; Hong, Zong-Yuan; Wang, Wu-San; Tao, Fang

    2012-01-01

    To guide the reasonable clinical application of modafinil (MOD), pharmacokinetics and pharmacodynamics of MOD in mice and the correlation between them were investigated. Male mice (Kunming strain) were given a single oral dose of MOD (120 mg x kg(-1)). The plasma concentration of MOD was measured by HPLC and the pharmacokinetic parameters were calculated with DAS 3.0 software. For another batch of male Kunming strain mice, their locomotor activities were recorded by an infrared ray passive sensor after a same oral dose of MOD, and the synchronization and correlation between the changes of MOD plasma concentration and the locomotor activity induced by MOD were compared and analyzed. The results showed that the plasma concentration-time curve of MOD was fitted to two-compartment open model with a first order absorption. The main pharmacokinetic parameters t1/2alpha, t1/2beta, t(max), C(max) and AUC(0-inifinity) were 0.42 h, 3.10 h, 1.00 h, 41.34 mg x L(-1) and 142.22 mg x L(-1) x h, respectively. MOD significantly increased locomotor activity and the effect lasted for about 4 h. The changes of MOD plasma concentration and the locomotor activity induced by MOD were synchronous. In conclusion, there is a significant correlation between the effect of MOD and its plasma concentration after administration of 120 mg x kg(-1) in mice. PMID:22493813

  11. Pharmacokinetics of Hoasca alkaloids in healthy humans.

    PubMed

    Callaway, J C; McKenna, D J; Grob, C S; Brito, G S; Raymon, L P; Poland, R E; Andrade, E N; Andrade, E O; Mash, D C

    1999-06-01

    N,N-Dimethyltryptamine (DMT), harmine, harmaline and tetrahydroharmine (THH) are the characteristic alkaloids found in Amazonian sacraments known as hoasca, ayahuasca, and yajè. Such beverages are characterized by the presence of these three harmala alkaloids, where harmine and harmaline reversibly inhibit monoamine oxidase A (MAO-A) while tetrahydroharmine weakly inhibits the uptake of serotonin. Together, both actions increase central and peripheral serotonergic activity while facilitating the psychoactivity of DMT. Though the use of such 'teas' has be known to western science for over 100 years, little is known of their pharmacokinetics. In this study, hoasca was prepared and administered in a ceremonial context. All four alkaloids were measured in the tea and in the plasma of 15 volunteers, subsequent to the ingestion of 2 ml hoasca/kg body weight, using gas (GC) and high pressure liquid chromatographic (HPLC) methods. Pharmacokinetic parameters were calculated and peak times of psychoactivity coincided with high alkaloid concentrations, particularly DMT which had an average Tmax of 107.5 +/- 32.5 min. While DMT parameters correlated with those of harmine, THH showed a pharmacokinetic profile relatively independent of harmine's. PMID:10404423

  12. Pharmacokinetics of intravitreal antibiotics in endophthalmitis

    PubMed Central

    2014-01-01

    Intravitreal antibiotics are the mainstay of treatment in the management of infectious endophthalmitis. Basic knowledge of the commonly used intravitreal antibiotics, which includes their pharmacokinetics, half-life, duration of action and clearance, is essential for elimination of intraocular infection without any iatrogenic adverse effect to the ocular tissue. Various drugs have been studied over the past century to achieve this goal. We performed a comprehensive review of the antibiotics which have been used for intravitreal route and the pharmacokinetic factors influencing the drug delivery and safety profile of these antibiotics. Using online resources like PubMed and Google Scholar, articles were reviewed. The articles were confined to the English language only. We present a broad overview of pharmacokinetic concepts fundamental for use of intravitreal antibiotics in endophthalmitis along with a tabulated compendium of the intravitreal antibiotics using available literature. Recent advances for increasing bioavailability of antibiotics to the posterior segment with the development of controlled drug delivery devices are also described. PMID:25667683

  13. Pharmacokinetics of ketoprofen syrup in small children.

    PubMed

    Kokki, H; Le Liboux, A; Jekunen, A; Montay, G; Heikkinen, M

    2000-04-01

    Ketoprofen is a nonsteroidal anti-inflammatory drug with analgesic, anti-inflammatory, and antipyretic properties. Its pharmacokinetics has not been determined in small children. The objective here was to determine the pharmacokinetics of ketoprofen syrup, 0.5 mg/kg, in two groups of 10 children. Group 1 was from ages 6 months up to 2 years (7/10 younger than 1 year), and Group 2 was from ages 2 to 7 years. Venous blood samples were collected before drug administration and 0.5, 1, 2, 4, 6, 8, and 12 hours after. A validated HPLC method was used to determine plasma levels of ketoprofen. The lower limit of quantification was 0.02 microgram/ml of plasma. Ketoprofen syrup was absorbed rapidly, the plasma level reaching its maximum at 0.5 hours, with C0.5 hours = 3 micrograms/ml. The pharmacokinetics was similar between the two groups of children. The elimination half-life, 2.0 hours in Group 1 or 1.9 hours in Group 2, was similar to that reported in adults. PMID:10761162

  14. Clinical pharmacokinetics in infants and children.

    PubMed

    Rane, A; Wilson, J T

    1976-01-01

    Wide variations in drug dose recommendations for children of the same or different ages reflect the inadequacy of data on pharmacokinetics and pharmacodynamics in children. Selected aspects of available literature on pharmacokinetics of drugs used in older infants and children has been reviewed with special attention to calculation of an age-appropriate dose. During the neonatal period and early infancy the elimination of many drugs that are excreted in the urine in unchanged form is restricted by the immaturity of glomerular filtration and renal tubular secretion. On the other hand, in late infancy and/or in childhood, a similar or greater rate of elimination from plasma than in adults has been observed for many drugs, notably digoxin, phenobarbitone, phenytoin, carbamazepine, ethosuximide, diazoxide, clindamycin and propoxyphene. Consistent with this, it has been shown that some drugs exhibit a lower plasma level/dose ratio in infancy and early childhood as compared with the adult. This is true for phenobarbitone, phenytoin and ethosuximide. Some age groups of children remain uninvestigated with regard to pharmacokinetics, even for the drugs reviewed. Therefore, pediatric therapy remains empirically based for many drugs. PMID:1017153

  15. Physiologically based pharmacokinetic modeling to investigate regional brain distribution kinetics in rats.

    PubMed

    Westerhout, Joost; Ploeger, Bart; Smeets, Jean; Danhof, Meindert; de Lange, Elizabeth C M

    2012-09-01

    One of the major challenges in the development of central nervous system (CNS)-targeted drugs is predicting CNS exposure in human from preclinical data. In this study, we present a methodology to investigate brain disposition in rats using a physiologically based modeling approach aiming at improving the prediction of human brain exposure. We specifically focused on quantifying regional diffusion and fluid flow processes within the brain. Acetaminophen was used as a test compound as it is not subjected to active transport processes. Microdialysis probes were implanted in striatum, for sampling brain extracellular fluid (ECF) concentrations, and in lateral ventricle (LV) and cisterna magna (CM), for sampling cerebrospinal fluid (CSF) concentrations. Serial blood samples were taken in parallel. These data, in addition to physiological parameters from literature, were used to develop a physiologically based model to describe the regional brain pharmacokinetics of acetaminophen. The concentration-time profiles of brain ECF, CSF(LV), and CSF(CM) indicate a rapid equilibrium with plasma. However, brain ECF concentrations are on average fourfold higher than CSF concentrations, with average brain-to-plasma AUC(0-240) ratios of 121%, 28%, and 35% for brain ECF, CSF(LV), and CSF(CM), respectively. It is concluded that for acetaminophen, a model compound for passive transport into, within, and out of the brain, differences exist between the brain ECF and the CSF pharmacokinetics. The physiologically based pharmacokinetic modeling approach is important, as it allowed the prediction of human brain ECF exposure on the basis of human CSF concentrations. PMID:22588644

  16. The influence of dietary sodium content on the pharmacokinetics and pharmacodynamics of fimasartan.

    PubMed

    Gu, Namyi; Cho, Joo-Youn; Shin, Kwang-Hee; Jang, In-Jin; Rhee, Moo-Yong

    2016-01-01

    A low sodium diet enhances the hemodynamic effect of renin-angiotensin system blockers. It was suggested that the substrates of P-glycoprotein or cytochrome P450 3A4 were reduced on a high sodium diet. This study aimed to investigate the influence of high sodium diet on the pharmacokinetics and pharmacodynamics of fimasartan, which is a substrate of cytochrome P450 3A4 but not P-glycoprotein. The study design was a two-diet, two-period, two-sequence, randomized, open-label, and crossover with 1-week washout for diet. Eligible subjects were fed with either low sodium (50 mEq/day) diet or high sodium diet (300 mEq/day) for 7 days in the first hospitalization period and the other diet in the second period. On the seventh morning of each period, subjects received a single dose of fimasartan 60 mg in a fasted state. The serial plasma concentrations of fimasartan, serum aldosterone concentration (SAC), and plasma renin activity (PRA) were measured for pharmacokinetic-pharmacodynamic analysis. Sixteen subjects completed the study satisfying the compliance test for diets. Although the mean systemic exposure of fimasartan is slightly (≈10%) decreased on a high sodium diet, the difference was not statistically or clinically significant (P>0.05). The SAC and PRA after fimasartan administration were highly dependent on their baseline levels. The dietary sodium content influenced the baseline of SAC and PRA, but did not influence the ratio change of SAC and PRA after fimasartan treatment. The ratio change of SAC after fimasartan treatment was correlated to the systemic exposure of fimasartan (P<0.05), while the correlation between the ratio change of PRA after fimasartan treatment and the individual systemic exposure of fimasartan was not significant (P>0.05). In conclusion, the pharmacokinetics of fimasartan and ratio changes of SAC and PRA after fimasartan treatment were not significantly influenced by dietary sodium content. PMID:27143858

  17. Translation as a Teaching Device.

    ERIC Educational Resources Information Center

    Engelhardt, Klaus

    This paper describes and explains a classroom exercise in French translation, with a view to promoting translation as an integral part of language instruction, particularly at the third-year college level when the student can be expected to have acquired an advanced knowledge of the parts of speech, of the grammatical distribution and their…

  18. Translational control in cancer etiology.

    PubMed

    Ruggero, Davide

    2013-02-01

    The link between perturbations in translational control and cancer etiology is becoming a primary focus in cancer research. It has now been established that genetic alterations in several components of the translational apparatus underlie spontaneous cancers as well as an entire class of inherited syndromes known as "ribosomopathies" associated with increased cancer susceptibility. These discoveries have illuminated the importance of deregulations in translational control to very specific cellular processes that contribute to cancer etiology. In addition, a growing body of evidence supports the view that deregulation of translational control is a common mechanism by which diverse oncogenic pathways promote cellular transformation and tumor development. Indeed, activation of these key oncogenic pathways induces rapid and dramatic translational reprogramming both by increasing overall protein synthesis and by modulating specific mRNA networks. These translational changes promote cellular transformation, impacting almost every phase of tumor development. This paradigm represents a new frontier in the multihit model of cancer formation and offers significant promise for innovative cancer therapies. Current research, in conjunction with cutting edge technologies, will further enable us to explore novel mechanisms of translational control, functionally identify translationally controlled mRNA groups, and unravel their impact on cellular transformation and tumorigenesis. PMID:22767671

  19. Translation as a Psycholinguistic Phenomenon

    ERIC Educational Resources Information Center

    Zasyekin, Serhiy

    2010-01-01

    The article sketches the outlines of a theoretical framework for the analysis of translation of literary texts, viewed as psycho-semiotic phenomenon and based on evaluation of earlier attempts in this direction, and on the results of a psycholinguistic empirical study of translations. Central to this framework is the recent insight that the human…

  20. Rescuing the Lost in Translation.

    PubMed

    Gehr, Sinje; Garner, Craig C

    2016-05-01

    The translation of medically relevant academic inventions that could transform public health has been notoriously difficult, stemming largely from cultural differences been academia and industry. New initiatives to kindle academic entrepreneurship and establish stronger public/private partnerships are helping to align these differences and accelerating the translation of promising new therapies. PMID:27153487

  1. Translational Control in Cancer Etiology

    PubMed Central

    Ruggero, Davide

    2013-01-01

    The link between perturbations in translational control and cancer etiology is becoming a primary focus in cancer research. It has now been established that genetic alterations in several components of the translational apparatus underlie spontaneous cancers as well as an entire class of inherited syndromes known as “ribosomopathies” associated with increased cancer susceptibility. These discoveries have illuminated the importance of deregulations in translational control to very specific cellular processes that contribute to cancer etiology. In addition, a growing body of evidence supports the view that deregulation of translational control is a common mechanism by which diverse oncogenic pathways promote cellular transformation and tumor development. Indeed, activation of these key oncogenic pathways induces rapid and dramatic translational reprogramming both by increasing overall protein synthesis and by modulating specific mRNA networks. These translational changes promote cellular transformation, impacting almost every phase of tumor development. This paradigm represents a new frontier in the multihit model of cancer formation and offers significant promise for innovative cancer therapies. Current research, in conjunction with cutting edge technologies, will further enable us to explore novel mechanisms of translational control, functionally identify translationally controlled mRNA groups, and unravel their impact on cellular transformation and tumorigenesis. PMID:22767671

  2. Translation: in retrospect and prospect.

    PubMed Central

    Woese, C R

    2001-01-01

    This review is occasioned by the fact that the problem of translation, which has simmered on the biological sidelines for the last 40 years, is about to erupt center stage--thanks to the recent spectacular advances in ribosome structure. This most complex, beautiful, and fascinating of cellular mechanisms, the translation apparatus, is also the most important. Translation not only defines gene expression, but it is the sine qua non without which modern (protein-based) cells would not have come into existence. Yet from the start, the problem of translation has been misunderstood--a reflection of the molecular perspective that dominated Biology of the last century. In that the our conception of translation will play a significant role in creating the structure that is 21st century Biology, it is critical that our current (and fundamentally flawed) view of translation be understood for what it is and be reformulated to become an all-embracing perspective about which 21st century Biology can develop. Therefore, the present review is both a retrospective and a plea to biologists to establish a new evolutionary, RNA-World-centered concept of translation. What is needed is an evolutionarily oriented perspective that, first and foremost, focuses on the nature (and origin) of a primitive translation apparatus, the apparatus that transformed an ancient evolutionary era of nucleic acid life, the RNA World, into the world of modern cells. PMID:11497425

  3. A PC-based graphical simulator for physiological pharmacokinetic models.

    PubMed

    Wada, D R; Stanski, D R; Ebling, W F

    1995-04-01

    Since many intravenous anesthetic drugs alter blood flows, physiologically-based pharmacokinetic models describing drug disposition may be time-varying. Using the commercially available programming software MATLAB, a platform to simulate time-varying physiological pharmacokinetic models was developed. The platform is based upon a library of pharmacokinetic blocks which mimic physiological structure. The blocks can be linked together flexibly to form models for different drugs. Because of MATLAB's additional numerical capabilities (e.g. non-linear optimization), the platform provides a complete graphical microcomputer-based tool for physiologic pharmacokinetic modeling. PMID:7656558

  4. Knowledge Translation in Audiology

    PubMed Central

    Kothari, Anita; Bagatto, Marlene P.; Seewald, Richard; Miller, Linda T.; Scollie, Susan D.

    2011-01-01

    The impetus for evidence-based practice (EBP) has grown out of widespread concern with the quality, effectiveness (including cost-effectiveness), and efficiency of medical care received by the public. Although initially focused on medicine, EBP principles have been adopted by many of the health care professions and are often represented in practice through the development and use of clinical practice guidelines (CPGs). Audiology has been working on incorporating EBP principles into its mandate for professional practice since the mid-1990s. Despite widespread efforts to implement EBP and guidelines into audiology practice, gaps still exist between the best evidence based on research and what is being done in clinical practice. A collaborative dynamic and iterative integrated knowledge translation (KT) framework rather than a researcher-driven hierarchical approach to EBP and the development of CPGs has been shown to reduce the knowledge-to-clinical action gaps. This article provides a brief overview of EBP and CPGs, including a discussion of the barriers to implementing CPGs into clinical practice. It then offers a discussion of how an integrated KT process combined with a community of practice (CoP) might facilitate the development and dissemination of evidence for clinical audiology practice. Finally, a project that uses the knowledge-to-action (KTA) framework for the development of outcome measures in pediatric audiology is introduced. PMID:22194314

  5. Biomedical informatics and translational medicine

    PubMed Central

    2010-01-01

    Biomedical informatics involves a core set of methodologies that can provide a foundation for crossing the "translational barriers" associated with translational medicine. To this end, the fundamental aspects of biomedical informatics (e.g., bioinformatics, imaging informatics, clinical informatics, and public health informatics) may be essential in helping improve the ability to bring basic research findings to the bedside, evaluate the efficacy of interventions across communities, and enable the assessment of the eventual impact of translational medicine innovations on health policies. Here, a brief description is provided for a selection of key biomedical informatics topics (Decision Support, Natural Language Processing, Standards, Information Retrieval, and Electronic Health Records) and their relevance to translational medicine. Based on contributions and advancements in each of these topic areas, the article proposes that biomedical informatics practitioners ("biomedical informaticians") can be essential members of translational medicine teams. PMID:20187952

  6. Subminiature infrared detector translation stage

    NASA Technical Reports Server (NTRS)

    Bell, Alan D.

    1989-01-01

    This paper describes a precision subminiature three-axis translation stage used in the GOES Sounder to provide positional adjustment of 12 cooled infrared detectors. Four separate translation stages and detectors are packaged into a detector mechanism which has an overall size of 0.850 x 1.230 x 0.600 inches. Each translation stage is capable of + or - 0.015 inch motion in the X and Y axes and +0.050/-0.025 inch motion in the Z axis with a sensitivity of 0.0002 inches. The function of the detector translation stage allows real time detector signal peaking during Sounder alignment. The translation stage operates in a cryogenic environment under a 10 to the -6th torr vacuum.

  7. USE OF PBPK MODELS FOR ASSESSING ABSORBED DOSE AND CHE INHIBITION FROM AGGREGATE EXPOSURE OF INFANTS AND CHILDREN TO ORGANOPHOSPHORUS INSECTICIDES

    EPA Science Inventory

    A physiological pharmacokinetic (PBPK) modeling framework has been established to assess cumulative risk of dose and injury of infants and children to organophosphorus (OP) insecticides from aggregate sources and routes. Exposure inputs were drawn from all reasonable sources, pr...

  8. The effects of colesevelam HCl on the single-dose pharmacokinetics of glimepiride, extended-release glipizide, and olmesartan medoxomil.

    PubMed

    He, Ling; Wickremasingha, Prachi; Lee, James; Tao, Ben; Mendell-Harary, Jeanne; Walker, Joseph; Wight, Douglas

    2014-01-01

    Bile acid sequestrants can potentially bind to concomitant drugs. Single-dose studies evaluated the effects of colesevelam on the pharmacokinetics of glimepiride, glipizide extended-release (ER), and olmesartan medoxomil. Each study enrolled healthy subjects aged 18-45 years. The olmesartan medoxomil study used a randomized adaptive crossover design that initially compared olmesartan medoxomil alone versus simultaneously with colesevelam, then olmesartan medoxomil alone versus 4 hours before colesevelam. The other studies used a three-period crossover design (test drug alone, test drug simultaneously with colesevelam, and test drug 4 hours before colesevelam). For the colesevelam coadministration periods, 3,750 mg once daily was dosed throughout the pharmacokinetic sampling period. After each single dose of test drug, serial blood samples were collected for determination of plasma drug concentrations and calculation of pharmacokinetic parameters. Administering colesevelam simultaneously with glimepiride or glipizide ER resulted in minor reductions (18% and 13%, respectively) in total exposure that were negated by staggering colesevelam dosing by 4 hours. Administering colesevelam simultaneously with olmesartan medoxomil resulted in a major reduction (39%) in olmesartan exposure that was reduced by staggering colesevelam dosing by 4 hours. This reduction in olmesartan exposure is not predicted to have a clinically significant impact on blood pressure control. PMID:24019110

  9. Estimating exposure and dose to characterize health risks: the role of human tissue monitoring in exposure assessment.

    PubMed Central

    Sexton, K; Callahan, M A; Bryan, E F

    1995-01-01

    Exposure assessment is an integral part of health risk characterization. Exposure assessments typically address three critical aspects of exposure: the number of people exposed to the environmental toxicant, at specific concentrations, for the time period of interest; the resulting dose; and the relative contribution of important sources and pathways to exposure/dose. Because historically both "point-of-contact" measurements and information about dose and related pharmacokinetic processes have been lacking, exposure assessments have had to rely on construction of "scenarios" to estimate exposure and dose. This could change, however, as advances in development of biologic markers of exposure and dose make it possible to measure and interpret toxicant concentrations in accessible human tissues. The increasing availability of "biomarkers," coupled with improvements in pharmacokinetic understanding, present opportunities to estimate ("reconstruct") exposure from measurements of dose and knowledge of intake and uptake parameters. Human tissue monitoring, however, is not a substitute for more traditional methods of measuring exposure, but rather a complementary approach. A combination of exposure measurements and dose measurements provides the most credible scientific basis for exposure assessment. PMID:7635107

  10. Pharmacokinetics of bisphenol A in neonatal and adult Sprague-Dawley rats

    SciTech Connect

    Doerge, Daniel R.; Twaddle, Nathan C.; Vanlandingham, Michelle; Fisher, Jeffrey W.

    2010-09-01

    Bisphenol A (BPA) is an important industrial chemical used in the manufacture of polycarbonate plastic products and epoxy resin-based food can liners. The presence of BPA in urine of > 90% of Americans aged 6-60 suggests ubiquitous and frequent exposure. The current study used LC/MS/MS to measure serum pharmacokinetics of aglycone (active) and conjugated (inactive) BPA in adult and neonatal Sprague-Dawley rats by oral and injection routes. Deuterated BPA was used to avoid issues of background contamination. Linear pharmacokinetics were observed in adult rats treated orally in the range of 0-200 {mu}g/kg bw. Evidence for enterohepatic recirculation of conjugated, but not aglycone, BPA was observed in adult rats. Significant inverse relationships were observed between postnatal age and measures of internal exposures to aglycone BPA and its elimination. In neonatal rats treated orally, internal exposures to aglycone BPA were substantially lower than from subcutaneous injection. The results reinforce the critical role for first-pass Phase II metabolism of BPA in gut and liver after oral exposure that attenuates internal exposure to the aglycone form in rats of all ages. The internal exposures to aglycone BPA observed in adult and neonatal rats following a single oral dose of 100 {mu}g/kg bw are inconsistent with effects mediated by classical estrogen receptors based on binding affinities. However, an impact on alternative estrogen signaling pathways that have higher receptor affinity cannot be excluded in neonatal rats. These findings emphasize the importance of matching aglycone BPA internal dosimetry with receptor affinities in experimental animal studies reporting toxicity.

  11. Pharmacokinetic and Tumor Distribution Characteristics of Temsirolimus in Patients with Recurrent Malignant Glioma

    PubMed Central

    Kuhn, John G.; Chang, Susan M.; Wen, Patrick Y.; Cloughesy, Timothy F.; Greenberg, Harry; Schiff, David; Conrad, Charles; Fink, Karen L.; Robins, H. Ian; Mehta, Minesh; DeAngelis, Lisa; Raizer, Jeffrey; Hess, Kenneth; Lamborn, Kathleen R.; Dancey, Janet; Prados, Michael D.

    2016-01-01

    Purpose To characterize the pharmacokinetics of temsirolimus and its major metabolite, sirolimus, in patients receiving enzyme-inducing antiepileptic drugs (EIAED) compared with patients receiving non-EIAEDs. An additional objective was to determine whether concentrations of temsirolimus or sirolimus were achieved in brain tumor tissue. Experimental Design Patients with recurrent malignant gliomas not receiving EIAEDs initially received temsirolimus weekly at a dose of 250 mg i.v. The dose was subsequently reduced to 170 mg due to intolerable side effects. For patients taking EIAEDs, the starting dose of temsirolimus was 250 mg with standard dose escalation until the maximal tolerated dose was established. Ten whole blood samples were obtained over a period of 24 h after administration of temsirolimus for pharmacokinetic assessments. Patients eligible for cytoreductive surgery received temsirolimus before tumor resection. Whole blood and tumor tissue were obtained for analysis. Results Significant differences in the pharmacokinetic variables for temsirolimus and sirolimus were observed between the two patient groups at a comparable dose level of 250 mg. For patients receiving EIAEDs, the systemic exposure to temsirolimus was lower by 1.5-fold. Likewise, peak concentrations and exposure to sirolimus were lower by 2-fold. Measurable concentrations of temsirolimus and sirolimus were observed in brain tumor specimens. The average tissue to whole blood ratio for temsirolimus was 1.43 and 0.84 for sirolimus. Conclusions Drugs that induce cytochrome P450 3A4, such as EIAEDs, significantly affect the pharmacokinetics of temsirolimus and its active metabolite, sirolimus. Total exposure to temsirolimus and sirolimus was lower in the EIAED group at the maximum tolerated dose of 250 mg compared with the non-EIAED group at the maximum tolerated dose of 170 mg. However, brain tumor tissue concentrations of temsirolimus and sirolimus were relatively comparable in both groups of

  12. Pharmacokinetics and expert systems as aids for risk assessment in reproductive toxicology.

    PubMed Central

    Mattison, D R; Jelovsek, F R

    1987-01-01

    A minimal approach to risk assessment in reproductive toxicology involves four components: hazard identification, hazard characterization, exposure characterization, and risk characterization. In practice, risk assessment in reproductive toxicology has been reduced to arbitrary safety factors or mathematical models of the dose-response relationship. These approaches obscure biological differences across species rather than using this important and frequently accessible information. Two approaches that are formally capable of using biologically relevant information (pharmacokinetics and expert system shells) are explored as aids to risk assessment in reproductive toxicology. PMID:3447888

  13. Pharmacokinetics and expert systems as aids for risk assessment in reproductive toxicology

    SciTech Connect

    Mattison, D.R.; Jelovsek, F.R.

    1987-12-01

    A minimal approach to risk assessment in reproductive toxicology involves four components: hazard identification, hazard characterization, exposure characterization, and risk characterization. In practice, risk assessment in reproductive toxicology has been reduced to arbitrary safety factors or mathematical models of the dose-response relationship. These approaches obscure biological differences across species rather than using this important and frequently accessible information. Two approaches that are formally capable of using biologically relevant information (pharmacokinetics and expert system shells) are explored as aids to risk assessment in reproductive toxicology.

  14. Pharmacokinetics of tilidine and naloxone in patients with severe hepatic impairment.

    PubMed

    Brennscheidt, Ulrich; Brunnmüller, Ulrike; Proppe, Dietfried; Thomann, Peter; Seiler, Klaus-Ulrich

    2007-01-01

    The objective of the present study was to evaluate the pharmacokinetics of tilidine (CAS 20380-58-9), naloxone (CAS 465-65-6) and tilidine metabolites after administration of a single oral dose of a solution containing 100 mg tilidine hydrochloride and 8 mg naloxone hydrochloride (equivalent to 1.44 ml Valoron N solution) to patients with severe hepatic impairment. The investigation was carried out as an open single-dose study in 8 patients suffering from liver cirrhosis. Patients qualified for study enrollment if they had a Child-Pugh score of > or = 7 and a mono-ethyl-glycine-xylidide (MEGX) 15-min test value < 50 ng/ ml. Blood samples were taken over a period of 28 h and analyzed for the prodrug tilidine, its active metabolite nortilidine, bisnortilidine, and naloxone (total and non-glucuronidated fraction). Pharmacokinetic parameters were compared with data from a previous study performed in healthy volunteers. Tilidine, nortilidine and unconjugated naloxone pharmacokinetic parameters showed a high variability between patients. Compared to previous results obtained in healthy volunteers, maximum plasma concentration (Cmax) of nortilidine was reduced by 44%, whereas elimination half-life (t1/2) was prolonged by factor 2. The area under the curve (AUC) showed a slight reduction of approximately 20%. For total naloxone, no relevant change was observed. However, in contrast to the results obtained in healthy subjects, unconjugated naloxone could be measured in plasma from patients with cirrhosis, possibly due to a reduced glucuronidation capacity of the liver in these patients. In conclusion, severe hepatic impairment has a relatively minor influence on the exposure (AUC) to the active metabolite of tilidine (i.e., nortilidine). However, a straightforward interpretation of the results was confounded by pronounced variability in nortilidine pharmacokinetics. In individual patients with severely affected liver function, satisfactory analgesia with tilidine

  15. Gender based Dosing of Metoprolol in the Elderly using Population Pharmacokinetic Modeling and Simulations

    PubMed Central

    Eugene, Andy R.

    2016-01-01

    Introduction This article seeks to clarify if gender-based differences occur in the pharmacokinetics of metoprolol in the elderly patients. There are a series of physiologic changes that occur in the elderly ranging from decreased hepatic blood flow to increased adiposity causing higher plasma concentrations at therapeutic doses as compared to the healthy young population. Methods Population pharmacokinetic modeling were performed using MONOLIX and Monte-Carlo simulations were conducted using MATLAB. The data was based from a previously published dataset where elderly patients, having multiple comorbidities, were administered a 50mg dose of metoprolol. Results Metoprolol was modeled using a one-compartment model and resulted in the following population pharmacokinetic parameters: volume of distribution, V=38L (CV=155%), clearance rates, CL-Men=105L/hour and CL-Women=59.1L/hour (38%), time lag, Tlag=0.469 hour (CV=17%), and the absorption rate constant, Ka=0.235 hr-1 (CV=23%). Conclusion Gender stratified doses resulting in an equivalent systemic metoprolol exposure in geriatric patients have been identified. Metoprolol doses resulting a similar AUC in a healthy young male administered 50mg tablet were 15mg for geriatric women and 25mg for geriatric men. Further, Metoprolol doses of 25mg for geriatric women and 50mg for geriatric men resulted in an equivalent AUC to a healthy young males dosed with a 100mg tablet. A 15mg Metoprolol tablet may need to be compounded to account for the gender differences in Metoprolol pharmacokinetics.

  16. Knowledge translation of research findings

    PubMed Central

    2012-01-01

    Background One of the most consistent findings from clinical and health services research is the failure to translate research into practice and policy. As a result of these evidence-practice and policy gaps, patients fail to benefit optimally from advances in healthcare and are exposed to unnecessary risks of iatrogenic harms, and healthcare systems are exposed to unnecessary expenditure resulting in significant opportunity costs. Over the last decade, there has been increasing international policy and research attention on how to reduce the evidence-practice and policy gap. In this paper, we summarise the current concepts and evidence to guide knowledge translation activities, defined as T2 research (the translation of new clinical knowledge into improved health). We structure the article around five key questions: what should be transferred; to whom should research knowledge be transferred; by whom should research knowledge be transferred; how should research knowledge be transferred; and, with what effect should research knowledge be transferred? Discussion We suggest that the basic unit of knowledge translation should usually be up-to-date systematic reviews or other syntheses of research findings. Knowledge translators need to identify the key messages for different target audiences and to fashion these in language and knowledge translation products that are easily assimilated by different audiences. The relative importance of knowledge translation to different target audiences will vary by the type of research and appropriate endpoints of knowledge translation may vary across different stakeholder groups. There are a large number of planned knowledge translation models, derived from different disciplinary, contextual (i.e., setting), and target audience viewpoints. Most of these suggest that planned knowledge translation for healthcare professionals and consumers is more likely to be successful if the choice of knowledge translation strategy is informed by

  17. Hydrophobic interactions between polymeric carrier and palmitic acid-conjugated siRNA improve PEGylated polyplex stability and enhance in vivo pharmacokinetics and tumor gene silencing.

    PubMed

    Sarett, Samantha M; Werfel, Thomas A; Chandra, Irene; Jackson, Meredith A; Kavanaugh, Taylor E; Hattaway, Madison E; Giorgio, Todd D; Duvall, Craig L

    2016-08-01

    Formation of stable, long-circulating siRNA polyplexes is a significant challenge in translation of intravenously-delivered, polymeric RNAi cancer therapies. Here, we report that siRNA hydrophobization through conjugation to palmitic acid (siPA) improves stability, in vivo pharmacokinetics, and tumor gene silencing of PEGylated nanopolyplexes (siPA-NPs) with balanced cationic and hydrophobic content in the core relative to the analogous polyplexes formed with unmodified siRNA, si-NPs. Hydrophobized siPA loaded into the NPs at a lower charge ratio (N(+):P(-)) relative to unmodified siRNA, and siPA-NPs had superior resistance to siRNA cargo unpackaging in comparison to si-NPs upon exposure to the competing polyanion heparin and serum. In vitro, siPA-NPs increased uptake in MDA-MB-231 breast cancer cells (100% positive cells vs. 60% positive cells) but exhibited equivalent silencing of the model gene luciferase relative to si-NPs. In vivo in a murine model, the circulation half-life of intravenously-injected siPA-NPs was double that of si-NPs, resulting in a >2-fold increase in siRNA biodistribution to orthotopic MDA-MB-231 mammary tumors. The increased circulation half-life of siPA-NPs was dependent upon the hydrophobic interactions of the siRNA and the NP core component and not just siRNA hydrophobization, as siPA did not contribute to improved circulation time relative to unmodified siRNA when delivered using polyplexes with a fully cationic core. Intravenous delivery of siPA-NPs also achieved significant silencing of the model gene luciferase in vivo (∼40% at 24 h after one treatment and ∼60% at 48 h after two treatments) in the murine MDA-MB-231 tumor model, while si-NPs only produced a significant silencing effect after two treatments. These data suggest that stabilization of PEGylated siRNA polyplexes through a combination of hydrophobic and electrostatic interactions between siRNA cargo and the polymeric carrier improves in vivo pharmacokinetics and

  18. [Biomarkers: "Found in translation"].

    PubMed

    Lockhart, Brian P; Walther, Bernard

    2009-04-01

    Despite continued increase in global Pharma R & D expenditure, the number of innovative drugs obtaining market approval has declined since 1994. The pharmaceutical industry is now entering a crucial juncture where increasing rates of attrition in clinical drug development as well as increasing development timelines are impacted by external factors such as intense regulatory pricing and safety pressures, increasing sales erosion due to generics, as well as exponential increases in the costs of bringing a drug to market. Despite these difficulties, numerous opportunities exist such as multiple unmet medical needs, the increasing incidence of certain diseases such as Alzheimer's disease, cancer, diabetes and obesity due to demographic changes, as well as the emergence of evolving markets such as China, India, and Eastern Europe. Consequently, Pharma is now responding to this challenge by improving both the productivity and the innovation in its drug discovery and development pipelines. In this regard, the advent of new technologies and expertise such as genomics, proteomics, structural biology, and molecular informatics in an integrated systems biology approach also provides a powerful opportunity for Pharma to address some of these difficulties. The key features behind this new strategy imply a discovery process based on an improved understanding of the molecular mechanism of diseases and drugs, translational research that places the patient at the center of the research process, and the application of biomarkers throughout the discovery and development phases. Moreover, new paradigms are required to improve target validation and develop more predictive cellular and animal models of human pathologies, a greater capacity in informatics-based analysis, and, consequently, a greater access to the vast sources of accumulating biological data and its integrated analysis. In the present review, we will address some of these issues and in particular emphasize how the

  19. Development of a physiologically based pharmacokinetic model of trichloroethylene and its metabolites for use in risk assessment.

    PubMed Central

    Clewell, H J; Gentry, P R; Covington, T R; Gearhart, J M

    2000-01-01

    A physiologically based pharmacokinetic (PBPK) model was developed that provides a comprehensive description of the kinetics of trichloroethylene (TCE) and its metabolites, trichloroethanol (TCOH), trichloroacetic acid (TCA), and dichloroacetic acid (DCA), in the mouse, rat, and human for both oral and inhalation exposure. The model includes descriptions of the three principal target tissues for cancer identified in animal bioassays: liver, lung, and kidney. Cancer dose metrics provided in the model include the area under the concentration curve (AUC) for TCA and DCA in the plasma, the peak concentration and AUC for chloral in the tracheobronchial region of the lung, and the production of a thioacetylating intermediate from dichlorovinylcysteine in the kidney. Additional dose metrics provided for noncancer risk assessment include the peak concentrations and AUCs for TCE and TCOH in the blood, as well as the total metabolism of TCE divided by the body weight. Sensitivity and uncertainty analyses were performed on the model to evaluate its suitability for use in a pharmacokinetic risk assessment for TCE. Model predictions of TCE, TCA, DCA, and TCOH concentrations in rodents and humans are in good agreement with a variety of experimental data, suggesting that the model should provide a useful basis for evaluating cross-species differences in pharmacokinetics for these chemicals. In the case of the lung and kidney target tissues, however, only limited data are available for establishing cross-species pharmacokinetics. As a result, PBPK model calculations of target tissue dose for lung and kidney should be used with caution. PMID:10807559

  20. 22 CFR 92.78 - Translating documents.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... Service are not authorized to translate documents or to certify to the correctness of translations... of a translation; to take an acknowledgment of the preparation of a translation; and to authenticate the seal and signature of a local official affixed to a translation. Separate fees should be...

  1. 22 CFR 92.78 - Translating documents.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... Service are not authorized to translate documents or to certify to the correctness of translations... of a translation; to take an acknowledgment of the preparation of a translation; and to authenticate the seal and signature of a local official affixed to a translation. Separate fees should be...

  2. The "Pedagogue as Translator" in the Classroom

    ERIC Educational Resources Information Center

    Dobson, Stephen

    2012-01-01

    Translation theory has faced criticism from professional translators for adopting an ivory tower stance to the "real world" challenges of translation. This article argues that a case can be made for considering the challenges of translation as it takes place in the school classroom. In support of such an argument the pedagogue as translator is…

  3. Inhalation pharmacokinetics of ethylbenzene in B6C3F1 mice

    SciTech Connect

    Charest-Tardif, G.; Tardif, R.; Krishnan, K. . E-mail: Kannan.krishnan@umontreal.ca

    2006-01-15

    The objective of the present study was to characterize the inhalation pharmacokinetics of ethylbenzene (EB) in male and female B6C3F1 mice following single and repeated exposures. Initially, groups of 28 male and female mice were exposed for 4 h to 75, 200, 500, or 1000 ppm in order to determine potential non-linearity in the kinetics of EB. Then, groups of male and female mice were exposed for 6 h to 75 ppm and 750 ppm (corresponding to the NTP exposures) for 1 or 7 consecutive days, to evaluate whether EB kinetics was altered during repeated exposures, The maximal blood concentration (C {sub max}; mean {+-} SD, n = 4) observed in female mice at the end of a 4-h exposure to 75, 200, 500, and 1000 ppm was 0.53 {+-} 0.18, 2.26 {+-} 0.38, 19.17 {+-} 2.74, and 82.36 {+-} 16.66 mg/L, respectively. The areas under the concentration vs. time curve (AUCs) following 4-h exposure to 75, 200, 500, and 1000 ppm were 88.5, 414.0, 3612.2, and 19,104.1 mg/L/min, respectively, in female mice, and 116.7, 425.7, 3148.3, and 16,039.1 mg/L/min in male mice. The comparison of C {sub max} and the kinetic profile of EB in mice exposed to 75 ppm suggests that they are similar between 1-day and 7-day exposures. However, at 750 ppm, the rate of EB elimination would appear to be greater after repeated exposures than single exposure, the pattern being evident in both male and female mice. Overall, the single and repeated exposure pharmacokinetic data collected in the present study suggest that EB kinetics is saturable at exposure concentrations exceeding 500 ppm (and therefore at 750 ppm used in the NTP mouse cancer bioassay) but is in the linear range at the lower concentration used in the bioassay (75 ppm). These data suggest that consideration of the nature and magnitude of non-linear kinetics and induction of metabolism during repeated exposures is essential for the conduct of a scientifically sound analysis of EB cancer dose-response data collected in B6C3F1 mice.

  4. Translating the covenant: The behavior analyst as ambassador and translator

    PubMed Central

    Foxx, R. M.

    1996-01-01

    Behavior analysts should be sensitive to how others react to and interpret our language because it is inextricably related to our image. Our use of conceptual revision, with such terms as punishment, has created communicative confusion and hostility on the part of general and professional audiences we have attempted to influence. We must, therefore, adopt the role of ambassador and translator in the nonbehavioral world. A number of recommendations are offered for promoting, translating, and disseminating behavior analysis. PMID:22478256

  5. Automatically structuring and translating CLIPS

    NASA Technical Reports Server (NTRS)

    Geissman, James R.

    1990-01-01

    Expert systems become more valuable when they can be integrated into production environments. Code that is written for easy maintainability and that can be ported to different machines can be easily integrated. This paper discusses two ports of CLIPS, implemented using the Metapack translation system developed by Abacus Programming Corporation. One translation converts positional form CLIPS into 'structured' or 'template' CLIPS, a form that is more easily maintained. The other translation converts either form of CLIPS into OPS83, a semantically similar forward-chaining language that has somewhat higher performance resulting from its being compiled.

  6. Inhalation pharmacokinetics of 1,3-butadiene and 1,2-epoxybutene-3 in rats and mice.

    PubMed Central

    Laib, R J; Filser, J G; Kreiling, R; Vangala, R R; Bolt, H M

    1990-01-01

    Studies were conducted on inhalation pharmacokinetics of 1,3-butadiene and of its primary reactive metabolic intermediate 1,2-epoxybutene-3 in rats (Sprague-Dawley) and mice (B6C3F1). Investigations of inhalation pharmacokinetics of 1,3-butadiene revealed saturation kinetics of 1,3-butadiene metabolism in both species. For rats and mice linear pharmacokinetics apply at exposure concentrations below 1000 ppm 1,3-butadiene; saturation of 1,3-butadiene metabolism is observed at atmospheric concentrations of about 2000 ppm. The estimated maximal metabolic elimination rates were 400 mumole/hr/kg for mice and 200 mumole/hr/kg for rats. This shows that 1,3-butadiene is metabolized by mice at about twice the rate of rats. Investigations of inhalation pharmacokinetics of 1,2-epoxybutene-3 revealed major differences in metabolism of this compound between both species. No indication of saturation kinetics of 1,2-epoxybutene-3 metabolism could be observed in rats up to exposure concentrations of 5000 ppm, whereas in mice the saturation of epoxybutene metabolism became apparent at atmospheric concentrations of about 500 ppm. The estimated maximal metabolic rate for 1,2-epoxybutene-3 was 350 mumole/hr/kg in mice and greater than 2600 mumole/hr/kg in rats. When the animals are exposed to high concentrations of 1,3-butadiene, 1,2-epoxybutene-3 is exhaled by rats and mice. For rats 1,2-epoxybutene-3 concentration in the gas phase of the system reaches a plateau at about 4 ppm. For mice, 1,2-epoxybutene-3 concentration increases with exposure time until, at about 10 ppm, signs of acute toxicity are observed. Under these conditions hepatic nonprotein sulfhydryl compounds are virtually depleted in mice but not in rats.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2401272

  7. Effects of age and sex on the pharmacokinetics of the soluble guanylate cyclase stimulator riociguat (BAY 63-2521)

    PubMed Central

    2016-01-01

    Abstract Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). This randomized, double-blind, placebo-controlled study investigated the pharmacokinetics of riociguat and its metabolite M1 in young (18–45 years) and elderly (64.5–80 years) healthy volunteers of both sexes to assist planning of the dose regimens for clinical trials. The data were also used to draw comparisons with the effects of age and sex on riociguat pharmacokinetics in patients with PAH and CTEPH from the riociguat phase 3 trials, PATENT and CHEST. Volunteers received an oral dose of either riociguat 2.5 mg or placebo, and the concentrations of riociguat and M1 in blood and urine samples were determined using mass spectrometry. In elderly healthy volunteers, overall riociguat and M1 exposure tended to be higher than in young healthy volunteers (P > 0.05), partly because of reduced renal clearance (approximately 28% reduction) and differences in body weight. Although the mean maximum concentrations of riociguat and M1 were significantly higher in women than in men (35% and 50% higher, respectively), total exposure was similar. Despite differences in riociguat and M1 pharmacokinetics, riociguat was well tolerated with a comparable safety profile across all subgroups, suggesting that differences in drug exposure due to age or sex were not sufficient to warrant a dose adjustment in clinical trials. Furthermore, similar pharmacokinetics were observed in patients with PAH and CTEPH. However, particular care should be exercised during individual dose titration of riociguat in elderly patients. PMID:27162629

  8. Translational pathology of neoplasia

    PubMed Central

    Grizzle, William E.; Srivastava, Sudhir; Manne, Upender

    2012-01-01

    this manuscript is to introduce the reader to how biomarkers may be used and the limitations on the uses of biomarkers in translational research. PMID:22112467

  9. Translational pathology of neoplasia.

    PubMed

    Grizzle, William E; Srivastava, Sudhir; Manne, Upender

    2010-01-01

    this manuscript is to introduce the reader to how biomarkers may be used and the limitations on the uses of biomarkers in translational research. PMID:22112467

  10. Multiple-Dose Pharmacokinetics of Fluvoxamine in Children and Adolescents.

    ERIC Educational Resources Information Center

    Labellarte, Michael; Biederman, Joseph; Emslie, Graham; Ferguson, James; Khan, Arifulla; Ruckle, Jon; Sallee, Randy; Riddle, Mark

    2004-01-01

    Objective: To determine the pharmacokinetics of fluvoxamine in children and adolescents and to compare pharmacokinetic data from adolescents to adults from a previous study. Method: Fluvoxamine was titrated to a target dose of 100 mg b.i.d. in children (6-11 years) and 150 mg b.i.d. in adolescents (12-17 years) with obsessive-compulsive disorder…

  11. PHARMACOKINETIC MODELING FOR PERFLUORINATED CHEMICALS USED IN HOUSEHOLD CONSUMER PRODUCTS

    EPA Science Inventory

    PHARMACOKINETIC MODELING FOR PERFLUORONATED CHEMICALS USED IN HOUSEHOLD CONSUMER PRODUCTS
    Leona H. Clark and Hugh A. Barton
    US Environmental Protection Agency, ORD, NHEERL, ETD, Research Triangle Park, NC

    The physiologically-based pharmacokinetic model to be presente...

  12. 40 CFR 795.228 - Oral/dermal pharmacokinetics.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... addition to the reporting requirements as specified in 40 CFR part 792, the following specific information... pharmacokinetics and metabolism of a chemical substance or mixture (“test substance”) are similar after oral and... administration. (3) Examine the effects of repeated dosing on the pharmacokinetics and metabolism of the...

  13. 40 CFR 795.231 - Pharmacokinetics of isopropanal.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... requirements as specified in the EPA Good Laboratory Practice Standards (40 CFR 792.185), the following... whether the pharmacokinetics and metabolism of the “test substance” are similar after oral and inhalation...) Examine the effects of repeated dosing on the pharmacokinetics and metabolism of the test substance....

  14. 40 CFR 795.228 - Oral/dermal pharmacokinetics.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... addition to the reporting requirements as specified in 40 CFR part 792, the following specific information... pharmacokinetics and metabolism of a chemical substance or mixture (“test substance”) are similar after oral and... administration. (3) Examine the effects of repeated dosing on the pharmacokinetics and metabolism of the...

  15. 40 CFR 795.231 - Pharmacokinetics of isopropanal.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... requirements as specified in the EPA Good Laboratory Practice Standards (40 CFR 792.185), the following... whether the pharmacokinetics and metabolism of the “test substance” are similar after oral and inhalation...) Examine the effects of repeated dosing on the pharmacokinetics and metabolism of the test substance....

  16. 40 CFR 795.231 - Pharmacokinetics of isopropanal.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... requirements as specified in the EPA Good Laboratory Practice Standards (40 CFR 792.185), the following... whether the pharmacokinetics and metabolism of the “test substance” are similar after oral and inhalation...) Examine the effects of repeated dosing on the pharmacokinetics and metabolism of the test substance....

  17. 40 CFR 795.231 - Pharmacokinetics of isopropanal.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... requirements as specified in the EPA Good Laboratory Practice Standards (40 CFR 792.185), the following... whether the pharmacokinetics and metabolism of the “test substance” are similar after oral and inhalation...) Examine the effects of repeated dosing on the pharmacokinetics and metabolism of the test substance....

  18. 40 CFR 795.228 - Oral/dermal pharmacokinetics.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... addition to the reporting requirements as specified in 40 CFR part 792, the following specific information... pharmacokinetics and metabolism of a chemical substance or mixture (“test substance”) are similar after oral and... administration. (3) Examine the effects of repeated dosing on the pharmacokinetics and metabolism of the...

  19. 40 CFR 795.228 - Oral/dermal pharmacokinetics.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... addition to the reporting requirements as specified in 40 CFR part 792, the following specific information... pharmacokinetics and metabolism of a chemical substance or mixture (“test substance”) are similar after oral and... administration. (3) Examine the effects of repeated dosing on the pharmacokinetics and metabolism of the...

  20. PHARMACOKINETIC/PHARMACODYNAMIC MODELING OF PERMETHRIN IN THE RAT

    EPA Science Inventory

    A physiologically-based pharmacokinetic (PBPK) model was used to describe pharmacokinetics of permethrin and calibrated using experimental data on the concentration time-course of cis- and trans-permethrin in rat blood and brain tissues following oral administration...

  1. KINPLOT: An Interactive Pharmacokinetics Graphics Program for Digital Computers.

    ERIC Educational Resources Information Center

    Wilson, Robert C.; And Others

    1982-01-01

    Inability to see the relevance of mathematics to understanding the time course of drugs in the body may discourage interest in pharmacokinetics. A UNC-developed computer graphics simulation program helps visualize the nature of pharmacokinetic-patient interactions, generates classroom handouts, and is used in the pharmaceuticals industry to…

  2. Daptomycin Pharmacokinetics and Pharmacodynamics in Septic and Critically Ill Patients.

    PubMed

    D'Avolio, Antonio; Pensi, Debora; Baietto, Lorena; Pacini, Giovanni; Di Perri, Giovanni; De Rosa, Francesco Giuseppe

    2016-08-01

    Infections, including sepsis, are associated with high mortality rates in critically ill patients in the intensive care unit (ICU). Appropriate antibiotic selection and adequate dosing are important for improving patient outcomes. Daptomycin is bactericidal in bloodstream infections caused by Staphylococcus aureus and other Gram-positive pathogens cultured in ICU patients. The drug has concentration-dependent activity, and the area under the curve/minimum inhibitory concentration ratio is the pharmacokinetic/pharmacodynamic (PK/PD) index that best correlates with daptomycin activity, whereas toxicity correlates well with daptomycin plasma trough concentrations (or minimum concentration [C min]). Adequate daptomycin exposure can be difficult to achieve in ICU patients; multiple PK alterations can result in highly variable plasma concentrations, which are difficult to predict. For this reason, therapeutic drug monitoring could help clinicians optimize daptomycin dosing, thus improving efficacy while decreasing the likelihood of serious adverse events. This paper reviews the literature on daptomycin in ICU patients with sepsis, focusing on dosing and PK and PD parameters. PMID:27412121

  3. Population pharmacokinetic and pharmacodynamic analysis in allergic diseases.

    PubMed

    Lovern, Mark; Sargentini-Maier, Maria-Laura; Otoul, Christian; Watelet, Jean-Baptiste

    2009-01-01

    In this chapter, we introduce the concepts and methodologies of population analysis as applied to analyzing pharmacokinetic and pharmacodynamic data. One of the key determining characteristics of the population approach is that through it, one seeks not only to characterize deterministic trends in the data, but also to identify and estimate the magnitudes of the important sources of variability within the data. The first section of this chapter provides an introduction to the primary concepts of, and motivation for, population modeling by way of a hypothetical case study. Then, the various methodologies that have been employed throughout the history of population analysis are described in further detail. Of these, the most commonly employed today is nonlinear mixed-effects (NLME) modeling. Finally, notable examples of the application of population PK and PK/PD modeling to treatments for allergies and asthma are discussed. Population PK models have frequently been used to extrapolate exposures to special populations, such as pediatrics, as well as to optimize treatment regimens and trial designs for these populations. Population PK/PD models have most frequently been applied to analyzing and interpreting data from wheal and flare trials, but are also becoming increasingly important in the analysis of PD data from monoclonal antibodies. PMID:19601723

  4. Pharmacokinetics, Safety, and Tolerability of Metformin in Healthy Elderly Subjects.

    PubMed

    Jang, Kyungho; Chung, Hyewon; Yoon, Jang-Soo; Moon, Seol-Joo; Yoon, Seo Hyun; Yu, Kyung-Sang; Kim, Kwangil; Chung, Jae-Yong

    2016-09-01

    Age-related physiological changes are known to alter the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs. Metformin is commonly used as first-line medication for management of diabetes in elderly patients. However, the PK and PD of metformin have not been sufficiently studied in elderly subjects. Here, 12 elderly subjects, aged 65 to 85 years, and 20 younger healthy volunteers were orally administered 750 mg of metformin 2 hours after dinner, followed by administration of a second dose (500 mg) 12 hours later. An oral glucose tolerance test (OGTT) was performed 2 hours after the second dose, with 75 g of glucose administered. Blood samples were collected at specific time points after the second metformin dose for the assessment of PK and the glucose-lowering effect of metformin. Elderly subjects exhibited 1.7 and 2.0 times higher average Cmax and AUC∞ than the younger subjects, respectively (P = .007 and .001, respectively), and t1/2 was comparable between the elderly and younger subjects. However, relative glucose level changes from baseline after metformin administration tended to be lower in elderly subjects. Systemic exposure to metformin was elevated by 50% or more in elderly subjects, whereas the glucose-lowering effect was similar compared to younger subjects after 2 doses of metformin. PMID:26710683

  5. Lifetime pharmacokinetic model for hydrophobic contaminants in marine mammals

    SciTech Connect

    Hickie, B.E.; Mackay, D.; Koning, J. de

    1999-11-01

    A physiologically based pharmacokinetic model is developed that describes the uptake and release of a hydrophobic organic chemical by a marine mammal over its entire lifetime, i.e., from birth to death. This model is applied to polychlorinated biphenyls (PCBs) in the beluga whale (Delphinapterus leucas). The processes treated are growth; uptake from food, milk, and air; disposition of the chemical among arterial and venous blood, liver, muscle, blubber, and rapidly perfused tissues; and losses by metabolism, release in exhaled air; and by egestion. A separate model is developed for females, which includes pregnancy, birth, and lactation. Food consumption is deduced from size, growth, and from activity-dependent bioenergetic data. The results obtained by simulating continuous PCB exposure over a 30-year period are in accordance with reported concentrations and show the importance of milk transfer to both mother and progeny and the tendency for continued accumulation over the animal's lifetime. Implications of the results are discussed, especially the need for improved data on diets, gut absorption characteristics, and various physiological parameters used in the model.

  6. Population Pharmacokinetics of Inhaled Tobramycin Powder in Cystic Fibrosis Patients

    PubMed Central

    Ting, L; Aksenov, S; Bhansali, S G; Ramakrishna, R; Tang, P; Geller, D E

    2014-01-01

    Tobramycin powder for inhalation (TOBI Podhaler or TIP) is approved for the treatment of Pseudomonas aeruginosa airway infection in patients with cystic fibrosis (CF). A population pharmacokinetic model for tobramycin inhalation powder (TIP) in CF patients was developed to characterize the effect of covariates including body mass index (BMI) and lung function (forced expiratory volume in 1 s as percent of the predicted value (FEV1% predicted) at baseline) on the serum exposure parameters. A two-compartment model with first-order elimination and first-order absorption was developed. Across a range of baseline demographic values in the study population, the predicted mean values for the maximum (Cmax) and trough (Ctrough) plasma concentrations at steady state were at least 7.5 and 5-fold lower, respectively, than the recommended thresholds for tobramycin toxicity (12 µg/ml for Cmax and 2 µg/ml for Ctrough). This model adequately described the tobramycin serum concentration–time course in CF patients following inhalation of TIP. The results indicate that no BMI- or FEV1-based dose adjustment is needed for use of TIP in CF patients. PMID:24522146

  7. Safety and Pharmacokinetics of Lisinopril in Pediatric Kidney Transplant Recipients

    PubMed Central

    Trachtman, Howard; Frymoyer, Adam; Lewandowski, Andrew; Greenbaum, Larry A.; Feig, Daniel I.; Gipson, Debbie S.; Warady, Bradley A.; Goebel, Jens W.; Schwartz, George J.; Lewis, Kenneth; Anand, Ravinder; Patel, Uptal D.

    2015-01-01

    Hypertension in pediatric kidney transplant recipients contributes to long-term graft loss, yet treatment options—including angiotensin-converting enzyme inhibitors—are poorly characterized in this vulnerable population. We conducted a multicenter, open-label pharmacokinetic (PK) study of daily oral lisinopril in 22 children (ages 7–17 years) with stable kidney transplant function. Standard non-compartmental PK analyses were performed at steady state. Effects on blood pressure were examined in lisinopril-naïve patients (n=13). Oral clearance declined in proportion to underlying kidney function; however, in patients with low estimated glomerular filtration rate (30–59 ml/min per 1.73m2), exposure (standardized to 0.1 mg/kg/day dose) was within the range reported previously in children without a kidney transplant. In lisinopril-naïve patients, 85% and 77% had a ≥6 mmHg reduction in systolic and diastolic blood pressure, respectively. Lisinopril was well tolerated. Our study provides initial insight on lisinopril use in children with a kidney transplant, including starting dose considerations. PMID:25807932

  8. Murine pharmacokinetics of rifapentine delivered as an inhalable dry powder.

    PubMed

    Chan, John G Y; Tyne, Anneliese S; Pang, Angel; McLachlan, Andrew J; Perera, Vidya; Chan, Joseph C Y; Britton, Warwick J; Chan, Hak Kim; Duke, Colin C; Young, Paul M; Traini, Daniela

    2015-03-01

    A novel inhalable rifapentine dry powder formulation could improve pulmonary rifapentine concentrations resulting in a significantly shorter time to treat tuberculosis infection. The pharmacokinetics of rifapentine (20mg/kg) in healthy mice was compared following intratracheal (IT) and intraperitoneal (IP) administration. Plasma, bronchoalveolar lavage (BAL) and tissue samples were collected and drug levels were quantified at time points up to 24h. Concentration-time data were analysed using a mixed-effects modelling approach to provide model-based estimates of area under the concentration-time curve from time 0 to infinity (AUC0-∞). IT delivery had considerably higher peak rifapentine lung and BAL concentrations and associated AUC0-∞ compared with IP delivery. The plasma AUC0-∞ following IT dry powder delivery was ca. four-fold smaller than the value for IP delivery. Inhaled delivery of rifapentine has the potential to selectively enhance therapeutic efficacy at the pulmonary site of infection whilst minimising systemic exposure and related toxicity. PMID:25554469

  9. Dose Reconstruction of Di(2-ethylhexyl) Phthalate Using a Simple Pharmacokinetic Model

    PubMed Central

    Calafat, Antonia M.

    2012-01-01

    Background: Di(2-ethylhexyl) phthalate (DEHP), used primarily as a plasticizer for polyvinyl chloride, is found in a variety of products. Previous studies have quantified human exposure by back calculating intakes based on DEHP metabolite concentrations in urine and by determining concentrations of DEHP in exposure media (e.g., air, food, dust). Objectives: To better understand the timing and extent of DEHP exposure, we used a simple pharmacokinetic model to “reconstruct” the DEHP dose responsible for the presence of DEHP metabolites in urine. Methods: We analyzed urine samples from eight adults for four DEHP metabolites [mono(2-ethylhexyl) phthalate, mono(2-ethyl-5-hydroxyhexyl) phthalate, mono(2-ethyl-5-oxohexyl) phthalate, and mono(2-ethyl-5-carboxypentyl) phthalate]. Participants provided full volumes of all voids over 1 week and recorded the time of each void and information on diet, driving, and outdoor activities. Using a model previously calibrated on a single person self-dosed with DEHP in conjunction with the eight participants’ data, we used a simple trial-and-error method to determine times and doses of DEHP that resulted in a best fit of predicted and observed urinary concentrations of the metabolites. Results: The average daily mean and median reconstructed DEHP doses were 10.9 and 5.0 µg/kg-day, respectively. The highest single modeled dose of 60 µg/kg occurred when one study participant reported consuming coffee and a bagel with egg and sausage that was purchased at a gas station. About two-thirds of all modeled intake events occurred near the time of reported food or beverage consumption. Twenty percent of the modeled DEHP exposure occurred between 2200 hours and 0500 hours. Conclusions: Dose reconstruction using pharmacokinetic models—in conjunction with biomonitoring data, diary information, and other related data—can provide a powerful means to define timing, magnitude, and possible sources of exposure to a given contaminant. PMID

  10. Concurrent determination of bisphenol A pharmacokinetics in maternal and fetal rhesus monkeys

    SciTech Connect

    Patterson, Tucker A.; Twaddle, Nathan C.; Roegge, Cindy S.; Callicott, Ralph J.; Fisher, Jeffrey W.; Doerge, Daniel R.

    2013-02-15

    Bisphenol A (BPA) is an important industrial chemical used as the monomer for polycarbonate plastic and in epoxy resins for food can liners. Worldwide biomonitoring studies consistently find a high prevalence of BPA conjugates in urine (> 90%) in amounts consistent with aggregate exposure at levels below 1 μg/kg bw/d. The current study used LC/MS/MS to measure concurrently the pharmacokinetics of aglycone (active) and conjugated (inactive) deuterated BPA (d6) in maternal and fetal rhesus monkey serum, amniotic fluid, and placenta following intravenous injection in the dam (100 μg/kg bw). Internal exposures of the fetus to aglycone d6-BPA (serum AUC) were attenuated by maternal, placental, and fetal Phase II metabolism to less than half that in the dam. Levels of aglycone and conjugated d6-BPA measured in whole placenta were consistent with a role in metabolic detoxification. The monotonic elimination of aglycone d6-BPA from the fetal compartment accompanied by persistent conjugate levels provides further evidence arguing against the hypothesis that BPA conjugates are selectively deconjugated by either the placenta or fetus. These results also provide benchmarks to guide the interpretation of human cord blood, amniotic fluid, and placenta sampling and measurement strategies as a basis for estimating fetal exposures to BPA. This study in a non-human primate model provides additional pharmacokinetic data for use in PBPK modeling of perinatal exposures to BPA from food contact, medical devices, and other environmental sources. - Highlights: ► Maternal, placental, and fetal Phase II metabolism attenuate fetal exposure to BPA. ► Serum AUC for aglycone BPA in fetal monkeys is less than half of that in the dam. ► BPA profiles in monkey fetus rule out selective deconjugation and accumulation. ► BPA levels in monkey placenta are similar to other metabolically active tissues. ► Some published human cord blood data for BPA are inconsistent with these measurements.

  11. Technical Translation and Industrial Terminology

    ERIC Educational Resources Information Center

    Longyka, Tomaz

    1973-01-01

    Paper presented at the symposium on The Importance and Problems of Translation in Sciences, Technology, and Economic Life.'' in Ohrid, Yugoslavia. Argues for the adoption of artificial languages as an international terminological means in science and technology. (RS)

  12. Translational Control in Oocyte Development

    PubMed Central

    Richter, Joel D.; Lasko, Paul

    2011-01-01

    Translational control of specific mRNAs is a widespread mechanism of gene regulation, and it is especially important in pattern formation in the oocytes of organisms in which the embryonic axes are established maternally. Drosophila and Xenopus have been especially valuable in elucidating the relevant molecular mechanisms. Here, we comprehensively review what is known about translational control in these two systems, focusing on examples that illustrate key concepts that have emerged. We focus on protein-mediated translational control, rather than regulation mediated by small RNAs, as the former appears to be predominant in controlling these developmental events. Mechanisms that modulate the ability of the specific mRNAs to be recruited to the ribosome, that regulate polyadenylation of specific mRNAs, or that control the association of particular mRNAs into translationally inert ribonucleoprotein complexes will all be discussed. PMID:21690213

  13. Charting the dynamics of translation.

    PubMed

    Chu, Dominique; Thompson, James; von der Haar, Tobias

    2014-05-01

    Codon usage bias (CUB) is the well-known phenomenon that the frequency of synonymous codons is unequal. This is presumably the result of adaptive pressures favouring some codons over others. The underlying reason for this pressure is unknown, although a large number of possible driver mechanisms have been proposed. According to one hypothesis, the decoding time could be such a driver. A tacit assumption of this hypothesis is that faster codons lead to a higher translation rate which in turn is more resource efficient. While it is generally assumed that there is such a link, there are no rigorous studies to establish under which conditions the link between translation speed and rate actually exists. Using a computational simulation model and explicitly calculated codon decoding times, this contribution maps the entire range of dynamical regimes of translation. These simulations make it possible to understand precisely under which conditions translation speed and rate are linked. PMID:24631460

  14. Pharmacokinetic analysis and comparison of caffeine administered rapidly or slowly in coffee chilled or hot versus chilled energy drink in healthy young adults

    PubMed Central

    White, John R.; Padowski, Jeannie M.; Zhong, Yili; Chen, Gang; Luo, Shaman; Lazarus, Philip; Layton, Matthew E.; McPherson, Sterling

    2016-01-01

    Abstract Context: There is a paucity of data describing the impact of type of beverage (coffee versus energy drink), different rates of consumption and different temperature of beverages on the pharmacokinetic disposition of caffeine. Additionally, there is concern that inordinately high levels of caffeine may result from the rapid consumption of cold energy drinks. Objective: The objective of this study was to compare the pharmacokinetics of caffeine under various drink temperature, rate of consumption and vehicle (coffee versus energy drink) conditions. Materials: Five caffeine (dose = 160 mg) conditions were evaluated in an open-label, group-randomized, crossover fashion. After the administration of each caffeine dose, 10 serial plasma samples were harvested. Caffeine concentration was measured via liquid chromatography–mass spectrometry (LC–MS), and those concentrations were assessed by non-compartmental pharmacokinetic analysis. The calculated mean pharmacokinetic parameters were analyzed statistically by one-way repeated measures analysis of variance (RM ANOVA). If differences were found, each group was compared to the other by all pair-wise multiple comparison. Results: Twenty-four healthy subjects ranging in age from 18 to 30 completed the study. The mean caffeine concentration time profiles were similar with overlapping SDs at all measured time points. The ANOVA revealed significant differences in mean C max and V d ss/F, but no pair-wise comparisons reached statistical significance. No other differences in pharmacokinetic parameters were found. Discussion: The results of this study are consistent with previous caffeine pharmacokinetic studies and suggest that while rate of consumption, temperature of beverage and vehicle (coffee versus energy drink) may be associated with slightly different pharmacokinetic parameters, the overall impact of these variables is small. Conclusion: This study suggests that caffeine absorption and exposure from

  15. Population Pharmacokinetics Study of Recommended Zidovudine Doses in HIV-1-Infected Children

    PubMed Central

    Treluyer, Jean-Marc; Frange, Pierre; Urien, Saik; Foissac, Frantz; Bouazza, Naim; Benaboud, Sihem; Blanche, Stephane; Hirt, Déborah

    2013-01-01

    The aims of this study were to describe the pharmacokinetics of zidovudine (ZDV) and its biotransformation to its metabolite, 3*-azido-3*-deoxy-5*-glucuronylthymidine (G-ZDV), in HIV-infected children, to identify factors that influence the pharmacokinetics of ZDV, and to compare and evaluate the doses recommended by the World Health Organization (WHO) and the Food and Drug Administration (FDA). ZDV concentrations in 782 samples and G-ZDV concentrations in 554 samples from 247 children ranging in age from 0.5 to 18 years were retrospectively measured. A population pharmacokinetic model was developed with NONMEM software (version 6.2), and the pharmacokinetics of ZDV were best described by a one-compartment model with first-order absorption and elimination. The effect of body weight on the apparent elimination clearance and volume of distribution was significant. The mean population parameter estimates were as follows: absorption rate, 2.86 h−1; apparent elimination clearance, 89.7 liters · h−1 (between-subject variability, 0.701 liters · h−1); apparent volume of distribution, 229 liters (between-subject variability, 0.807 liters); metabolic formation rate constant, 12.6 h−1 (between-subject variability, 0.352 h−1); and elimination rate constant of G-ZDV, 2.27 h−1. On the basis of simulations with FDA and WHO dosing recommendations, the probabilities of observing efficient exposures (doses resulting in exposures of between 3 and 5 mg/liter · h) with less adverse events (doses resulting in exposures below 8.4 mg/liter · h) were higher when the FDA recommendations than when the WHO recommendations were followed. In order to improve the FDA recommendations, ZDV doses should be reconsidered for the weight band (WB) of 20 to 40 kg. The most appropriate doses should be decreased from 9 to 8 mg/kg of body weight twice a day (BID) for the WB from 20 to 29.9 kg and from 300 to 250 mg BID for the WB from 30 to 39.9 kg. The highest dose, 300 mg BID, should be

  16. Pharmacokinetic Interaction between Voriconazole and Methadone at Steady State in Patients on Methadone Therapy▿

    PubMed Central

    Liu, Ping; Foster, Grover; LaBadie, Robert; Somoza, Eugene; Sharma, Amarnath

    2007-01-01

    This trial was aimed to estimate the pharmacokinetic interaction between voriconazole and methadone at steady state in male patients on methadone therapy and to characterize the safety and tolerability profile during the coadministration. Twenty-three patients on individualized methadone therapy (30 to 100 mg once daily) were enrolled into this randomized, patient- and investigator-blind, placebo-controlled, parallel-group study. Methadone pharmacokinetic samples were collected from patients receiving methadone alone as the baseline before they were randomized to coadminister either 200 mg voriconazole twice daily (BID) (400-mg BID loading doses on the first day) (n = 16) or matching placebo (n = 7) for the next 5 days. Pharmacokinetic samples for methadone and voriconazole were collected on the last day of voriconazole dosing. The safety data were collected throughout the study. Voriconazole increased the steady-state exposure of pharmacologically active enantiomer (R)-methadone: the mean area under the concentration-time curve from 0 to 24 h (AUC0-24) was increased by 47.2% (90% confidence intervals [CI]: 37.7%, 57.4%), and the mean peak concentration (Cmax) was increased by 30.7% (90% CI: 22.2%, 39.8%). The magnitude of increase in (S)-methadone exposure was greater than that of (R)-methadone: the AUC0-24 was increased by 103.4% (90% CI: 85.0%, 123.6%), and the Cmax was increased by 65.4% (90% CI: 52.6%, 79.2%). Methadone appeared to have no effect on the steady-state voriconazole pharmacokinetics compared to the historical data for voriconazole alone. Methadone patients receiving voriconazole showed no signs or symptoms of significant opioid withdrawal or overdose. Coadministration of 200 mg voriconazole BID with methadone was generally safe and well tolerated. Nevertheless, caution should be exercised when voriconazole is coadministered with methadone due to the increase in (R)-methadone exposure, which in turn may require a dose reduction of methadone. PMID

  17. Ocular pharmacokinetics of cephalosporins using microdialysis.

    PubMed

    Macha, S; Mitra, A K

    2001-10-01

    The purpose of this study was to delineate the ocular pharmacokinetics of cephalosporins and investigate the presence of peptide transporters in the retina. New Zealand albino rabbits were kept under anesthesia. A concentric microdialysis probe was implanted in the vitreous chamber and linear probe across the cornea in the aqueous humor. Isotonic phosphate buffer saline was perfused through the probes, and samples were collected every 20 min over a period of 10 hr. A 500 microg dose of cephalexin, cephazolin, and cephalothin was administered intravitreally. Inhibition experiments were carried out in vivo, using gly-pro and gly-sar. The vitreal half-lives of cephalexin, cefazolin, and cephalothin were 185.38 +/- 27.25 min, 111.40 +/- 17.17 min, and 146.68 +/- 47.52 min, respectively. Cephalexin generated higher aqueous humor concentrations compared to cefazolin. The pharmacokinetic parameters of cephalexin in the presence of gly-pro, i.e., AUC (44452.06 +/- 3326.55 microg x min/ml), clearance (0.0013 +/- 0.0004 ml/min) and vitreal half-life (825.12 +/- 499.95 min) were different from that of the control (14612.83 +/- 4036.47 microg x min/ml, 0.0036 +/- 0.0011 ml/min, and 187.96 +/- 65.12 min, respectively). Gly-pro did not inhibit cefazolin, and gly-sar showed no effect on the pharmacokinetics of both drugs. These studies indicate the involvement of a peptide carrier in the transport of cephalosporins across the retina. Although gly-pro inhibited the elimination of cephalexin from the vitreous, the effect of an alpha-amino group on peptide carriers was not clearly evident. PMID:11765153

  18. Developing a Process-Oriented Translation Test for Assessing English-Arabic Basic Translation Skills

    ERIC Educational Resources Information Center

    Abdellah, Antar Solhy

    2007-01-01

    The study reviews translation validated tests and proposes a process-oriented translation test for assessing basic translation skills for freshmen English majors at the faculty of Education. The proposed test is developed based on the process approach to translating and translation teaching, and is confined to translation from English to Arabic.…

  19. Translational progress on tumor biomarkers

    PubMed Central

    Guo, Hongwei; Zhou, Xiaolin; Lu, Yi; Xie, Liye; Chen, Qian; Keller, Evan T; Liu, Qian; Zhou, Qinghua; Zhang, Jian

    2015-01-01

    There is an urgent need to apply basic research achievements to the clinic. In particular, mechanistic studies should be developed by bench researchers, depending upon clinical demands, in order to improve the survival and quality of life of cancer patients. To date, translational medicine has been addressed in cancer biology, particularly in the identification and characterization of novel tumor biomarkers. This review focuses on the recent achievements and clinical application prospects in tumor biomarkers based on translational medicine. PMID:26557902

  20. Population pharmacokinetic modelling to assess the impact of CYP2D6 and CYP3A metabolic phenotypes on the pharmacokinetics of tamoxifen and endoxifen

    PubMed Central

    ter Heine, Rob; Binkhorst, Lisette; de Graan, Anne Joy M; de Bruijn, Peter; Beijnen, Jos H; Mathijssen, Ron H J; Huitema, Alwin D R

    2014-01-01

    Aims Tamoxifen is considered a pro-drug of its active metabolite endoxifen. The major metabolic enzymes involved in endoxifen formation are CYP2D6 and CYP3A. There is considerable evidence that variability in activity of these enzymes influences endoxifen exposure and thereby may influence the clinical outcome of tamoxifen treatment. We aimed to quantify the impact of metabolic phenotype on the pharmacokinetics of tamoxifen and endoxifen. Methods We assessed the CYP2D6 and CYP3A metabolic phenotypes in 40 breast cancer patients on tamoxifen treatment with a single dose of dextromethorphan as a dual phenotypic probe for CYP2D6 and CYP3A. The pharmacokinetics of dextromethorphan, tamoxifen and their relevant metabolites were analyzed using non-linear mixed effects modelling. Results Population pharmacokinetic models were developed for dextromethorphan, tamoxifen and their metabolites. In the final model for tamoxifen, the dextromethorphan derived metabolic phenotypes for CYP2D6 as well as CYP3A significantly (P < 0.0001) explained 54% of the observed variability in endoxifen formation (inter-individual variability reduced from 55% to 25%). Conclusions We have shown that not only CYP2D6, but also CYP3A enzyme activity influences the tamoxifen to endoxifen conversion in breast cancer patients. Our developed model may be used to assess separately the impact of CYP2D6 and CYP3A mediated drug–drug interactions with tamoxifen without the necessity of administering this anti-oestrogenic drug and to support Bayesian guided therapeutic drug monitoring of tamoxifen in routine clinical practice. PMID:24697814