O processo de configuração curricular: uma análise da compreensão de professores de educação física das séries iniciais do ensino fundamental

Pós-graduação em Educação - IBRC

Modeling of transfer kinetics at the serum-cerebrospinal fluid barrier in rabbits with experimental meningitis: application to grepafloxacin

The goals of the present study were to model the population kinetics of in vivo influx and efflux processes of grepafloxacin at the serum-cerebrospinal fluid (CSF) barrier and to propose a simulation-based approach to optimize the design of dose-finding trials in the meningitis rabbit model. Twenty-nine rabbits with pneumococcal meningitis receiving grepafloxacin at 15 mg/kg of body weight (intravenous administration at 0 h), 30 mg/kg (at 0 h), or 50 mg/kg twice (at 0 and 4 h) were studied. A three-compartment population pharmacokinetic model was fit to the data with the program NONMEM (Nonlinear Mixed Effects Modeling). Passive diffusion clearance (CL(diff)) and active efflux clearance (CL(active)) are transfer kinetic modeling parameters. Influx clearance is assumed to be equal to CL(diff), and efflux clearance is the sum of CL(diff), CL(active), and bulk flow clearance (CL(bulk)). The average influx clearance for the population was 0.0055 ml/min (interindividual variability, 17%). Passive diffusion clearance was greater in rabbits receiving grepafloxacin at 15 mg/kg than in those treated with higher doses (0.0088 versus 0.0034 ml/min). Assuming a CL(bulk) of 0.01 ml/min, CL(active) was estimated to be 0.017 ml/min (11%), and clearance by total efflux was estimated to be 0.032 ml/min. The population kinetic model allows not only to quantify in vivo efflux and influx mechanisms at the serum-CSF barrier but also to analyze the effects of different dose regimens on transfer kinetic parameters in the rabbit meningitis model. The modeling-based approach also provides a tool for the simulation and prediction of various outcomes in which researchers might be interested, which is of great potential in designing dose-finding trials.

Population pharmacokinetics of sevoflurane in conjunction with the AnaConDa: toward target-controlled infusion of volatiles into the breathing system

BACKGROUND: The Anesthetic Conserving Device (AnaConDa) uncouples delivery of a volatile anesthetic (VA) from fresh gas flow (FGF) using a continuous infusion of liquid volatile into a modified heat-moisture exchanger capable of adsorbing VA during expiration and releasing adsorbed VA during inspiration. It combines the simplicity and responsiveness of high FGF with low agent expenditures. We performed in vitro characterization of the device before developing a population pharmacokinetic model for sevoflurane administration with the AnaConDa, and retrospectively testing its performance (internal validation). MATERIALS AND METHODS: Eighteen females and 20 males, aged 31-87, BMI 20-38, were included. The end-tidal concentrations were varied and recorded together with the VA infusion rates into the device, ventilation and demographic data. The concentration-time course of sevoflurane was described using linear differential equations, and the most suitable structural model and typical parameter values were identified. The individual pharmacokinetic parameters were obtained and tested for covariate relationships. Prediction errors were calculated. RESULTS: In vitro studies assessed the contribution of the device to the pharmacokinetic model. In vivo, the sevoflurane concentration-time courses on the patient side of the AnaConDa were adequately described with a two-compartment model. The population median absolute prediction error was 27% (interquartile range 13-45%). CONCLUSION: The predictive performance of the two-compartment model was similar to that of models accepted for TCI administration of intravenous anesthetics, supporting open-loop administration of sevoflurane with the AnaConDa. Further studies will focus on prospective testing and external validation of the model implemented in a target-controlled infusion device.

Effect of VEGF treatment on the blood-spinal cord barrier permeability in experimental spinal cord injury: dynamic contrast-enhanced magnetic resonance imaging.

Compromised blood-spinal cord barrier (BSCB) is a factor in the outcome following traumatic spinal cord injury (SCI). Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis and vascular permeability. The role of VEGF in SCI is controversial. Relatively little is known about the spatial and temporal changes in the BSCB permeability following administration of VEGF in experimental SCI. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) studies were performed to noninvasively follow spatial and temporal changes in the BSCB permeability following acute administration of VEGF in experimental SCI over a post-injury period of 56 days. The DCE-MRI data was analyzed using a two-compartment pharmacokinetic model. Animals were assessed for open field locomotion using the Basso-Beattie-Bresnahan score. These studies demonstrate that the BSCB permeability was greater at all time points in the VEGF-treated animals compared to saline controls, most significantly in the epicenter region of injury. Although a significant temporal reduction in the BSCB permeability was observed in the VEGF-treated animals, BSCB permeability remained elevated even during the chronic phase. VEGF treatment resulted in earlier improvement in locomotor ability during the chronic phase of SCI. This study suggests a beneficial role of acutely administered VEGF in hastening neurobehavioral recovery after SCI.

Predicting Physical Activity in Adolescents: The Role of Compensatory Health Beliefs within the Health Action Process Approach

Objective: Compensatory health beliefs (CHBs), defined as beliefs that healthy behaviours can compensate for unhealthy behaviours, may be one possible factor hindering people in adopting a healthier lifestyle. This study examined the contribution of CHBs to the prediction of adolescents’ physical activity within the theoretical framework of the Health Action Process Approach (HAPA). Design: The study followed a prospective survey design with assessments at baseline (T1) and two weeks later (T2). Method: Questionnaire data on physical activity, HAPA variables and CHBs were obtained twice from 430 adolescents of four different Swiss schools. Multilevel modelling was applied. Results: CHBs added significantly to the prediction of intentions and change in intentions, in that higher CHBs were associated with lower intentions to be physically active at T2 and a reduction in intentions from T1 to T2. No effect of CHBs emerged for the prediction of self-reported levels of physical activity at T2 and change in physical activity from T1 to T2. Conclusion: Findings emphasise the relevance of examining CHBs in the context of an established health behaviour change model and suggest that CHBs are of particular importance in the process of intention formation.

Electrical decoupling effect on intermediate band Ti-implanted silicon layers

We investigated the electrical transport properties of ultraheavily Ti-implanted silicon layers subsequently pulsed laser melted (PLM). After PLM, the samples exhibit anomalous electrical behaviour in sheet resistance and Hall mobility measurements, which is associated with the formation of an intermediate band (IB) in the implanted layer. An analytical model that assumes IB formation and a current limitation effect between the implanted layer and the substrate was developed to analyse this anomalous behaviour. This model also describes the behaviour of the function V/Delta V and the electrical function F that can be extracted from the electrical measurements in the bilayer. After chemical etching of the implanted layer, the anomalous electrical behaviour observed in sheet resistance and Hall mobility measurements vanishes, recovering the unimplanted Si behaviour, in agreement with the analytical model. The behaviour of V/Delta V and the electrical function F can also be successfully described in terms of the analytical model in the bilayer structure with the implanted layer entirely stripped.

Desarrollo de un modelo de predimensionado de costes de construcción en el proyecto arquitectónico

El objetivo de la presente investigación es el desarrollo de un modelo de cálculo rápido, eficiente y preciso, para la estimación de los costes finales de construcción, en las fases preliminares del proyecto arquitectónico. Se trata de una herramienta a utilizar durante el proceso de elaboración de estudios previos, anteproyecto y proyecto básico, no siendo por tanto preciso para calcular el “predimensionado de costes” disponer de la total definición grafica y literal del proyecto. Se parte de la hipótesis de que en la aplicación práctica del modelo no se producirán desviaciones superiores al 10 % sobre el coste final de la obra proyectada. Para ello se formulan en el modelo de predimensionado cinco niveles de estimación de costes, de menor a mayor definición conceptual y gráfica del proyecto arquitectónico. Los cinco niveles de cálculo son: dos que toman como referencia los valores “exógenos” de venta de las viviendas (promoción inicial y promoción básica) y tres basados en cálculos de costes “endógenos” de la obra proyectada (estudios previos, anteproyecto y proyecto básico). El primer nivel de estimación de carácter “exógeno” (nivel .1), se calcula en base a la valoración de mercado de la promoción inmobiliaria y a su porcentaje de repercusión de suelo sobre el valor de venta de las viviendas. El quinto nivel de valoración, también de carácter “exógeno” (nivel .5), se calcula a partir del contraste entre el valor externo básico de mercado, los costes de construcción y los gastos de promoción estimados de la obra proyectada. Este contraste entre la “repercusión del coste de construcción” y el valor de mercado, supone una innovación respecto a los modelos de predimensionado de costes existentes, como proceso metodológico de verificación y validación extrínseca, de la precisión y validez de las estimaciones resultantes de la aplicación práctica del modelo, que se denomina Pcr.5n (Predimensionado costes de referencia con .5niveles de cálculo según fase de definición proyectual / ideación arquitectónica). Los otros tres niveles de predimensionado de costes de construcción “endógenos”, se estiman mediante cálculos analíticos internos por unidades de obra y cálculos sintéticos por sistemas constructivos y espacios funcionales, lo que se lleva a cabo en las etapas iniciales del proyecto correspondientes a estudios previos (nivel .2), anteproyecto (nivel .3) y proyecto básico (nivel .4). Estos cálculos teóricos internos son finalmente evaluados y validados mediante la aplicación práctica del modelo en obras de edificación residencial, de las que se conocen sus costes reales de liquidación final de obra. Según va evolucionando y se incrementa el nivel de definición y desarrollo del proyecto, desde los estudios previos hasta el proyecto básico, el cálculo se va perfeccionando en su nivel de eficiencia y precisión de la estimación, según la metodología aplicada: [aproximaciones sucesivas en intervalos finitos], siendo la hipótesis básica como anteriormente se ha avanzado, lograr una desviación máxima de una décima parte en el cálculo estimativo del predimensionado del coste real de obra. El cálculo del coste de ejecución material de la obra, se desarrolla en base a parámetros cúbicos funcionales “tridimensionales” del espacio proyectado y parámetros métricos constructivos “bidimensionales” de la envolvente exterior de cubierta/fachada y de la huella del edificio sobre el terreno. Los costes funcionales y constructivos se ponderan en cada fase del proceso de cálculo con sus parámetros “temáticos/específicos” de gestión (Pg), proyecto (Pp) y ejecución (Pe) de la concreta obra presupuestada, para finalmente estimar el coste de construcción por contrata, como resultado de incrementar al coste de ejecución material el porcentaje correspondiente al parámetro temático/especifico de la obra proyectada. El modelo de predimensionado de costes de construcción Pcr.5n, será una herramienta de gran interés y utilidad en el ámbito profesional, para la estimación del coste correspondiente al Proyecto Básico previsto en el marco técnico y legal de aplicación. Según el Anejo I del Código Técnico de la Edificación (CTE), es de obligado cumplimiento que el proyecto básico contenga una “Valoración aproximada de la ejecución material de la obra proyectada por capítulos”, es decir , que el Proyecto Básico ha de contener al menos un “presupuesto aproximado”, por capítulos, oficios ó tecnologías. El referido cálculo aproximado del presupuesto en el Proyecto Básico, necesariamente se ha de realizar mediante la técnica del predimensionado de costes, dado que en esta fase del proyecto arquitectónico aún no se dispone de cálculos de estructura, planos de acondicionamiento e instalaciones, ni de la resolución constructiva de la envolvente, por cuanto no se han desarrollado las especificaciones propias del posterior proyecto de ejecución. Esta estimación aproximada del coste de la obra, es sencilla de calcular mediante la aplicación práctica del modelo desarrollado, y ello tanto para estudiantes como para profesionales del sector de la construcción. Como se contiene y justifica en el presente trabajo, la aplicación práctica del modelo para el cálculo de costes en las fases preliminares del proyecto, es rápida y certera, siendo de sencilla aplicación tanto en vivienda unifamiliar (aisladas y pareadas), como en viviendas colectivas (bloques y manzanas). También, el modelo es de aplicación en el ámbito de la valoración inmobiliaria, tasaciones, análisis de viabilidad económica de promociones inmobiliarias, estimación de costes de obras terminadas y en general, cuando no se dispone del proyecto de ejecución y sea preciso calcular los costes de construcción de las obras proyectadas. Además, el modelo puede ser de aplicación para el chequeo de presupuestos calculados por el método analítico tradicional (estado de mediciones pormenorizadas por sus precios unitarios y costes descompuestos), tanto en obras de iniciativa privada como en obras promovidas por las Administraciones Públicas. Por último, como líneas abiertas a futuras investigaciones, el modelo de “predimensionado costes de referencia 5 niveles de cálculo”, se podría adaptar y aplicar para otros usos y tipologías diferentes a la residencial, como edificios de equipamientos y dotaciones públicas, valoración de edificios históricos, obras de urbanización interior y exterior de parcela, proyectos de parques y jardines, etc….. Estas lineas de investigación suponen trabajos paralelos al aquí desarrollado, y que a modo de avance parcial se recogen en las comunicaciones presentadas en los Congresos internacionales Scieconf/Junio 2013, Rics‐Cobra/Septiembre 2013 y en el IV Congreso nacional de patología en la edificación‐Ucam/Abril 2014. ABSTRACT The aim of this research is to develop a fast, efficient and accurate calculation model to estimate the final costs of construction, during the preliminary stages of the architectural project. It is a tool to be used during the preliminary study process, drafting and basic project. It is not therefore necessary to have the exact, graphic definition of the project in order to be able to calculate the cost‐scaling. It is assumed that no deviation 10% higher than the final cost of the projected work will occur during the implementation. To that purpose five levels of cost estimation are formulated in the scaling model, from a lower to a higher conceptual and graphic definition of the architectural project. The five calculation levels are: two that take as point of reference the ”exogenous” values of house sales (initial development and basic development), and three based on calculation of endogenous costs (preliminary study, drafting and basic project). The first ”exogenous” estimation level (level.1) is calculated over the market valuation of real estate development and the proportion the cost of land has over the value of the houses. The fifth level of valuation, also an ”exogenous” one (level.5) is calculated from the contrast between the basic external market value, the construction costs, and the estimated development costs of the projected work. This contrast between the ”repercussions of construction costs” and the market value is an innovation regarding the existing cost‐scaling models, as a methodological process of extrinsic verification and validation, of the accuracy and validity of the estimations obtained from the implementation of the model, which is called Pcr.5n (reference cost‐scaling with .5calculation levels according to the stage of project definition/ architectural conceptualization) The other three levels of “endogenous” construction cost‐scaling are estimated from internal analytical calculations by project units and synthetic calculations by construction systems and functional spaces. This is performed during the initial stages of the project corresponding to preliminary study process (level.2), drafting (level.3) and basic project (level.4). These theoretical internal calculations are finally evaluated and validated via implementation of the model in residential buildings, whose real costs on final payment of the works are known. As the level of definition and development of the project evolves, from preliminary study to basic project, the calculation improves in its level of efficiency and estimation accuracy, following the applied methodology: [successive approximations at finite intervals]. The basic hypothesis as above has been made, achieving a maximum deviation of one tenth, in the estimated calculation of the true cost of predimensioning work. The cost calculation for material execution of the works is developed from functional “three‐dimensional” cubic parameters for the planned space and constructive “two dimensional” metric parameters for the surface that envelopes around the facade and the building’s footprint on the plot. The functional and building costs are analyzed at every stage of the process of calculation with “thematic/specific” parameters of management (Pg), project (Pp) and execution (Pe) of the estimated work in question, and finally the cost of contractual construction is estimated, as a consequence of increasing the cost of material execution with the percentage pertaining to the thematic/specific parameter of the projected work. The construction cost‐scaling Pcr.5n model will be a useful tool of great interest in the professional field to estimate the cost of the Basic Project as prescribed in the technical and legal framework of application. According to the appendix of the Technical Building Code (CTE), it is compulsory that the basic project contains an “approximate valuation of the material execution of the work, projected by chapters”, that is, that the basic project must contain at least an “approximate estimate” by chapter, trade or technology. This approximate estimate in the Basic Project is to be performed through the cost‐scaling technique, given that structural calculations, reconditioning plans and definitive contruction details of the envelope are still not available at this stage of the architectural project, insofar as specifications pertaining to the later project have not yet been developed. This approximate estimate of the cost of the works is easy to calculate through the implementation of the given model, both for students and professionals of the building sector. As explained and justified in this work, the implementation of the model for cost‐scaling during the preliminary stage is fast and accurate, as well as easy to apply both in single‐family houses (detached and semi‐detached) and collective housing (blocks). The model can also be applied in the field of the real‐estate valuation, official appraisal, analysis of the economic viability of real estate developments, estimate of the cost of finished projects and, generally, when an implementation project is not available and it is necessary to calculate the building costs of the projected works. The model can also be applied to check estimates calculated by the traditional analytical method (state of measurements broken down into price per unit cost details), both in private works and those promoted by Public Authorities. Finally, as potential lines for future research, the “five levels of calculation cost‐scaling model”, could be adapted and applied to purposes and typologies other than the residential one, such as service buildings and public facilities, valuation of historical buildings, interior and exterior development works, park and garden planning, etc… These lines of investigation are parallel to this one and, by way of a preview, can be found in the dissertations given in the International Congresses Scieconf/June 2013, Rics‐Cobra/September 2013 and in the IV Congress on building pathology ‐Ucam/April 2014.

Justice and emotions in service recovery: a complaint in B2C e-commerce

This study proposes a marketing approach to service recovery (SR) models to explain what factors affect cumulative satisfaction, loyalty and word-of-mouth (WOM) following complaint behaviour. The model has its base on the definition of perceived justice and its influence on satisfaction with service recovery (SSR) and on emotions (positive and negative). Trust acts as a central construct in the model, receiving influence from the affective and cognitive aspect. The sample for this study consists of 303 Spanish business-to-consumer e-commerce (B2C-EC) users who made a complaint after an electronic transaction. Results from the analysis show the influence of perceived justice ? mainly interactional justice and procedural justice ? on SSR and the relevance of positive emotions as a key factor in SSR processes, in contrast to the major role that negative emotions have traditionally played in these models.

Toward better outcomes with tacrolimus therapy: Population pharmacokinetics and individualized dosage prediction in adult liver transplantation

Patient outcomes in transplantation would improve if dosing of immunosuppressive agents was individualized. The aim of this study is to develop a population pharmacokinetic model of tacrolimus in adult liver transplant recipients and test this model in individualizing therapy. Population analysis was performed on data from 68 patients. Estimates were sought for apparent clearance (CL/F) and apparent volume of distribution (V/F) using the nonlinear mixed effects model program (NONMEM). Factors screened for influence on these parameters were weight, age, sex, transplant type, biliary reconstructive procedure, postoperative day, days of therapy, liver function test results, creatinine clearance, hematocrit, corticosteroid dose, and interacting drugs. The predictive performance of the developed model was evaluated through Bayesian forecasting in an independent cohort of 36 patients. No linear correlation existed between tacrolimus dosage and trough concentration (r(2) = 0.005). Mean individual Bayesian estimates for CL/F and V/F were 26.5 8.2 (SD) L/hr and 399 +/- 185 L, respectively. CL/F was greater in patients with normal liver function. V/F increased with patient weight. CL/F decreased with increasing hematocrit. Based on the derived model, a 70-kg patient with an aspartate aminotransferase (AST) level less than 70 U/L would require a tacrolimus dose of 4.7 mg twice daily to achieve a steady-state trough concentration of 10 ng/mL. A 50-kg patient with an AST level greater than 70 U/L would require a dose of 2.6 mg. Marked interindividual variability (43% to 93%) and residual random error (3.3 ng/mL) were observed. Predictions made using the final model were reasonably nonbiased (0.56 ng/mL), but imprecise (4.8 ng/mL). Pharmacokinetic information obtained will assist in tacrolimus dosing; however, further investigation into reasons for the pharmacokinetic variability of tacrolimus is required.

Ion-trapping, microsomal binding, and unbound drug distribution in the hepatic retention of basic drugs

This study investigated the relative contribution of ion-trapping, microsomal binding, and distribution of unbound drug as determinants in the hepatic retention of basic drugs in the isolated perfused rat liver. The ionophore monensin was used to abolish the vesicular proton gradient and thus allow an estimation of ion-trapping by acidic hepatic vesicles of cationic drugs. In vitro microsomal studies were used to independently estimate microsomal binding and metabolism. Hepatic vesicular ion-trapping, intrinsic elimination clearance, permeability-surface area product, and intracellular binding were derived using a physiologically based pharmacokinetic model. Modeling showed that the ion-trapping was significantly lower after monensin treatment for atenolol and propranolol, but not for antipyrine. However, no changes induced by monensin treatment were observed in intrinsic clearance, permeability, or binding for the three model drugs. Monensin did not affect binding or metabolic activity in vitro for the drugs. The observed ion-trapping was similar to theoretical values estimated using the pHs and fractional volumes of the acidic vesicles and the pK(a) values of drugs. Lipophilicity and pK(a) determined hepatic drug retention: a drug with low pK(a) and low lipophilicity (e.g., antipyrine) distributes as unbound drug, a drug with high pK(a) and low lipophilicity (e.g., atenolol) by ion-trapping, and a drug with a high pK(a) and high lipophilicity (e.g., propranolol) is retained by ion-trapping and intracellular binding. In conclusion, monensin inhibits the ion-trapping of high pK(a) basic drugs, leading to a reduction in hepatic retention but with no effect on hepatic drug extraction.

Disposition kinetics of propranolol isomers in the perfused rat liver

The aim of this study was to define the determinants of the linear hepatic disposition kinetics of propranolol optical isomers using a perfused rat liver. Monensin was used to abolish the lysosomal proton gradient to allow an estimation of propranolol ion trapping by hepatic acidic vesicles. In vitro studies were used for independent estimates of microsomal binding and intrinsic clearance. Hepatic extraction and mean transit time were determined from outflow-concentration profiles using a nonparametric method. Kinetic parameters were derived from a physiologically based pharmacokinetic model. Modeling showed an approximate 34-fold decrease in ion trapping following monensin treatment. The observed model-derived ion trapping was similar to estimated theoretical values. No differences in ion-trapping values was found between R(+)- and S(-)- propranolol. Hepatic propranolol extraction was sensitive to changes in liver perfusate flow, permeability-surface area product, and intrinsic clearance. Ion trapping, microsomal and nonspecific binding, and distribution of unbound propranolol accounted for 47.4, 47.1, and 5.5% of the sequestration of propranolol in the liver, respectively. It is concluded that the physiologically more active S(-)- propranolol differs from the R(+)- isomer in higher permeability-surface area product, intrinsic clearance, and intracellular binding site values.

Reduced hepatic extraction of palmitate in steatosis correlated to lower level of liver fatty acid binding protein

Nonalcoholic fatty liver disease is the most common of all liver diseases. The hepatic disposition [H-3]palmitate and its low-molecular-weight metabolites in perfused normal and steatotic rat liver were studied using the multiple indicator dilution technique and a physiologically based slow diffusion/bound pharmacokinetic model. The steatotic rat model was established by administration of 17alpha-ethynylestradiol to female Wistar rats. Serum biochemistry markers and histology of treated and normal animals were assessed and indicated the presence of steatosis in the treatment group. The steatotic group showed a significantly higher alanine aminotransferase-to-aspartate aminotransferase ratio, lower levels of liver fatty acid binding protein and cytochrome P-450, as well as microvesicular steatosis with an enlargement of sinusoidal space. Hepatic extraction for unchanged [H-3]palmitate and production of low-molecular-weight metabolites were found to be significantly decreased in steatotic animals. Pharmacokinetic analysis suggested that the reduced extraction and sequestration for palmitate and its metabolites was mainly attributed to a reduction in liver fatty acid binding protein in steatosis.

The population pharmacokinetics of citalopram after deliberate self-poisoning: A Bayesian approach

Defining the pharmacokinetics of drugs in overdose is complicated. Deliberate self-poisoning is generally impulsive and associated with poor accuracy in dose history. In addition, early blood samples are rarely collected to characterize the whole plasma-concentration time profile and the effect of decontamination on the pharmacokinetics is uncertain. The aim of this study was to explore a fully Bayesian methodology for population pharmacokinetic analysis of data that arose from deliberate self-poisoning with citalopram. Prior information on the pharmacokinetic parameters was elicited from 14 published studies on citalopram when taken in therapeutic doses. The data set included concentration-time data from 53 patients studied after 63 citalopram overdose events (dose range: 20-1700 mg). Activated charcoal was administered between 0.5 and 4 h after 17 overdose events. The clinical investigator graded the veracity of the patients' dosing history on a 5-point ordinal scale. Inclusion of informative priors stabilised the pharmacokinetic model and the population mean values could be estimated well. There were no indications of non-linear clearance after excessive doses. The final model included an estimated uncertainty of the dose amount which in a simulation study was shown to not affect the model's ability to characterise the effects of activated charcoal. The effect of activated charcoal on clearance and bioavailability was pronounced and resulted in a 72% increase and 22% decrease, respectively. These findings suggest charcoal administration is potentially beneficial after citalopram overdose. The methodology explored seems promising for exploring the dose-exposure relationship in the toxicological settings.

Population pharmacokinetics of itraconazole and its active metabolite hydroxy-itraconazole in paediatric cystic fibrosis and bone marrow transplant patients

Objective: The objective of the study was to characterise the population pharmacokinetic properties of itraconazole and its active metabolite hydroxyitraconazole in a representative paediatric population of cystic fibrosis and bone marrow transplant (BMT) patients and to identify patient characteristics influencing the pharmacokinetics of itraconazole. The ultimate goals were to determine the relative bioavailability between the two oral formulations (capsules vs oral solution) and to optimise dosing regimens in these patients. Methods: All paediatric patients with cystic fibrosis or patients undergoing BMT at The Royal Children's Hospital, Brisbane, QLD, Australia, who were prescribed oral itraconazole for the treatment of allergic bronchopulmonary aspergillosis (cystic fibrosis patients) or for prophylaxis of any fungal infection (BMT patients) were eligible for the study. Blood samples were taken from the recruited patients as per an empirical sampling design either during hospitalisation or during outpatient clinic visits. ltraconazole and hydroxy-itraconazole plasma concentrations were determined by a validated high-performance liquid chromatography assay with fluorometric detection. A nonlinear mixed-effect modelling approach using the NONMEM software to simultaneously describe the pharmacokinetics of itraconazole and its metabolite. Results: A one-compartment model with first-order absorption described the itraconazole data, and the metabolism of the parent drug to hydroxy-itraconazole was described by a first-order rate constant. The metabolite data also showed one-compartment characteristics with linear elimination. For itraconazole the apparent clearance (CLitraconazole) was 35.5 L/hour, the apparent volume of distribution (V-d(itraconazole)) was 672L, the absorption rate constant for the capsule formulation was 0.0901 h(-1) and for the oral solution formulation was 0.96 h-1. The lag time was estimated to be 19.1 minutes and the relative bioavailability between capsules and oral solution (F-rel) was 0.55. For the metabolite, volume of distribution, V-m/(F (.) f(m)), and clearance, CL/(F (.) fm), were 10.6L and 5.28 L/h, respectively. The influence of total bodyweight was significant, added as a covariate on CLitraconazoie/F and V-d(itraconazole)/F (standardised to a 70kg person) using allometric three-quarter power scaling on CLitraconazole/F, which therefore reflected adult values. The unexplained between-subject variability (coefficient of variation %) was 68.7%, 75.8%, 73.4% and 61.1% for CLitraconazoie/F, Vd(itraconazole)/F, CLm/(F (.) fm) and F-rel, respectively. The correlation between random effects of CLitraconazole and Vd((itraconazole)) was 0.69. Conclusion: The developed population pharmacokinetic model adequately described the pharmacokinetics of itraconazole and its active metabolite, hydroxy-itraconazole, in paediatric patients with either cystic fibrosis or undergoing BMT. More appropriate dosing schedules have been developed for the oral solution and the capsules to secure a minimum therapeutic trough plasma concentration of 0.5 mg/L for these patients.

Hepatic pharmacokinetics of propranolol in rats with adjuvant-induced systemic inflammation

Systemic inflammation is known to affect drug disposition in the liver. This study sought to relate and quantitate changes in hepatic pharmacokinetics of propranolol with changes in hepatic architecture and physiology in adjuvant-treated rats. Transmission electron microscopy was used to assess morphological changes in mitochondria and lysosomes of adjuvant-treated rat livers. The disposition of propranolol was assessed in the perfused rat liver using the multiple indicator dilution technique. Hepatic extraction and mean transit time were determined from outflow-concentration profiles using a nonparametric method. Kinetic parameters were derived from a two-phase physiologically based organ pharmacokinetic model. Possible relationships were then explored between the changes in hepatic drug disposition and cytochrome P-450 activity and iron concentration. Adjuvant treatment induced the appearance of mitochondrial inclusions/tubularization and irregularly shaped lysosomes in rat livers. Livers from adjuvant-treated rats had (relative to normal) significantly higher alpha(1)-acid glycoprotein (orosomucoid) and iron tissue concentrations but lower cytochrome P-450 content. The hepatic extraction, metabolism, and ion trapping of propranolol were significantly impaired in adjuvant-treated rats and could be correlated with altered iron store and cytochrome P-450 activity. It is concluded that adjuvant-induced systemic inflammation alters hepatocellular morphology and biochemistry and consequently influences hepatic disposition of propranolol.