The aim of this study is to determine how Volume of Distribution (VD) – one of the main characters of pharmacokinetic data is obtained, what methods are used, how reliable values they give, and a new computational QSAR algorithm for prediction of VD is built and discussed. The development of a new drug estimated total time of more than 14 years with investment exceeding U$900 million in 1990-ies up to €1 billion in 2000. Studies show that elimination of new developed drugs from the last stage screening process or even withdrawal from market usually is a result of poorly predicted pharmacokinetic data. The main goal of our study was to build a new computational algorithm for prediction of VD that would result in lessened cost and time consumption. The prediction of VD using quantity-structure activity relationship (QSAR) method the algorithm shows VD values statistically better than obtained in other methods of. We based experimental algorithm on 760 values of VD compiled from literature, original articles, and Internet databases and proved data quality as 'Good', 'Moderate', 'Bad' or 'Very bad'. We investigated literature sources to have data mostly after intravenous bolus administration of the drug, VSS, and tested the algorithm on 96 more newly obtained drug VD values that were not included in building the computational algorithm. Mean fold error for Training Set was 1,87, and 2,08 for Testing Set. We built and concluded the module to be good for prediction of VD for acid... [to full text]

Many methods exist in the literature for the prediction of pharmacokinetic parameters which describe drug distribution in rat and human, such as tissue-to-plasma partition coefficients (Kps) and volume of distribution (Vss). However, none of these methods make use of the in vivo information obtained at the early stages of the drug development process in the form of plasma concentration vs. time profiles. The overall aim of the presented study was to improve upon an existing Kp prediction method by making use of the distribution information contained within this experimental data. Chapter 2 shows that Kp values can be successfully obtained experimentally, but that this process is expensive and time-consuming. Chapter 3 compares six Kp prediction methods taken from the literature for their ability to predict the Kp values of 80 drugs. The Rodgers et al. model was found to be the most accurate, with over 77% of predictions within 3-fold of experimental values. This Chapter also discusses the Vss prediction ability of some of these methods, with the Poulin & Theil and Rodgers et al. models shown to be the most accurate predictors for rat Vss and human Vss respectively. Chapter 4 investigates the relationship between muscle Kp and the Kps of all other tissues, to show that experimental muscle Kp can be used as a surrogate from which all other non-adipose Kp values can be predicted. However, the predictions made using this method were shown to be less accurate than predictions made by the Rodgers et al. model for the same dataset of drugs. A relationship was identified between muscle Kp and tumour Kp in rat, suggesting a potential way to predict tumour Kp in the future. In Chapter 5, a novel method is developed whereby Kp predictions made by the Rodgers et al. model are updated using prior information obtained from the in vivo concentration-time profile. These updated values are then used within a physiologically-based pharmacokinetic (PBPK) model and are shown in Chapter 6 to generate improved predictions for other pharmacokinetic parameters such as Vss and clearance in both rat and human. 100% of human Vss predictions made by the most accurate of the novel methods presented here were within 3-fold of experimental values, compared to 68.8% of predictions made by the Rodgers et al. model. The work presented here has highlighted the need for a more accurate method for the prediction of Kp values, and has addressed this need by generating a model which improves upon the most accurate Kp prediction method currently found in the literature. This will lead to an increase in confidence in the use of predicted pharmacokinetic parameters within PBPK modelling.

A novel technique to study the two-phase flow field around an asymmetric diaphragm in a vertical pipe is presented, that enables producing data for CFD code validation in complex geometries. Main feature is a translocation of the diaphragm to scan the 3D void field with a stationary wire-mesh sensor. Besides the measurement of time-averaged void fraction fields, a novel data evaluation method was developed to extract estimated liquid velocity profiles from the wire-mesh sensor data. The flow around an obstacle of the chosen geometry has many topological similarities with complex flow situations in bends, T-junctions, valves, safety valves and other components of power plant equipment and flow phenomena like curved stream lines, which form significant angles with the gravity vector, flow separation at sharp edges and recirculation zones in their wake are present. In order to assess the quality of the CFD code and their underlying multiphase flow and turbulence models pre-test calculations by ANSYS CFX 10.0 were carried out. A comparison between the calculation results and the experimental data shows a good agreement in term of all significant qualitative details of the void fraction and liquid velocity distributions. Furthermore, the report contains a method to assess the lateral components of bubble velocities in the form of a basic theoretical description and visualisation examples. The plots show the deviation of the flow around the obstacle in term of vectors represented the average velocities of the instantaneous cross-sections of all bubbles in the time interval when they pass the measuring plane. A detailed uncertainty analyse of the velocity assessments concludes the presented report. It includes remarks about the comparison with a second method for calculating bubble velocity profiles - the cross-correlation. In addition, this chapter gives an overview about the influence of acceleration and deceleration effects on the velocity estimation.

Two-phase flow experiments at vertical pipes are much suitable for studying the action of different constitutive relations characterizing the momentum exchange at the gas/liquid interface as well as the dynamic behaviour of the gas/liquid interface itself. The flow can be observed in its movement along the pipe and, in particular, within the shear field close to the pipe wall over a considerable vertical distance and, consequently, over a comparatively long time without the immediate separation of gas and liquid characteristic for horizontal flows. Wire-mesh sensors, which were the working horse in the described experiments, supplied sequences of instantaneous two-dimensional gas fraction distributions with a high-resolution in space and time. This allows to derive from the data not only void fraction and bubble velocity profiles, but also bubble size distributions, bubble-size resolved radial gas fraction profiles as well as the axial evolution of these distributions. An interfacial surface reconstruction algorithm was developed in order to extract the extension of interfacial area from the wire-mesh sensor data. The sensors were upgraded to withstand parameters that are close to nuclear reactor conditions. Most of the experiments were performed for both air/water flow at ambient pressure and steam/water flow of up to 6.5 MPa at identical combinations of the gas and liquid superficial velocities. This offers excellent conditions for studying the influence of the fluid properties.

A novel technique to study the two-phase flow field around an asymmetric diaphragm in a vertical pipe is presented, that enables producing data for CFD code validation in complex geometries. Main feature is a translocation of the diaphragm to scan the 3D void field with a stationary wire-mesh sensor. Besides the measurement of time-averaged void fraction fields, a novel data evaluation method was developed to extract estimated liquid velocity profiles from the wire-mesh sensor data. The flow around an obstacle of the chosen geometry has many topological similarities with complex flow situations in bends, T-junctions, valves, safety valves and other components of power plant equipment and flow phenomena like curved stream lines, which form significant angles with the gravity vector, flow separation at sharp edges and recirculation zones in their wake are present. In order to assess the quality of the CFD code and their underlying multiphase flow and turbulence models pre-test calculations by ANSYS CFX 10.0 were carried out. A comparison between the calculation results and the experimental data shows a good agreement in term of all significant qualitative details of the void fraction and liquid velocity distributions. Furthermore, the report contains a method to assess the lateral components of bubble velocities in the form of a basic theoretical description and visualisation examples. The plots show the deviation of the flow around the obstacle in term of vectors represented the average velocities of the instantaneous cross-sections of all bubbles in the time interval when they pass the measuring plane. A detailed uncertainty analyse of the velocity assessments concludes the presented report. It includes remarks about the comparison with a second method for calculating bubble velocity profiles - the cross-correlation. In addition, this chapter gives an overview about the influence of acceleration and deceleration effects on the velocity estimation.

Two-phase flow experiments at vertical pipes are much suitable for studying the action of different constitutive relations characterizing the momentum exchange at the gas/liquid interface as well as the dynamic behaviour of the gas/liquid interface itself. The flow can be observed in its movement along the pipe and, in particular, within the shear field close to the pipe wall over a considerable vertical distance and, consequently, over a comparatively long time without the immediate separation of gas and liquid characteristic for horizontal flows. Wire-mesh sensors, which were the working horse in the described experiments, supplied sequences of instantaneous two-dimensional gas fraction distributions with a high-resolution in space and time. This allows to derive from the data not only void fraction and bubble velocity profiles, but also bubble size distributions, bubble-size resolved radial gas fraction profiles as well as the axial evolution of these distributions. An interfacial surface reconstruction algorithm was developed in order to extract the extension of interfacial area from the wire-mesh sensor data. The sensors were upgraded to withstand parameters that are close to nuclear reactor conditions. Most of the experiments were performed for both air/water flow at ambient pressure and steam/water flow of up to 6.5 MPa at identical combinations of the gas and liquid superficial velocities. This offers excellent conditions for studying the influence of the fluid properties.

The extensive experimental results presented in this report provide a high-quality database for air-/water flows in a vertical pipe with a nominal diameter of 200 mm. This database can be used for the development and validation of CFD-like models for two-phase flows, e.g. for bubble coalescence and fragmentation. In particular, the investigations aim on the evolution of the two-phase flow along the pipe height. Therefore, up to 18 single measurements with varying distances between the gas injection and measurement plane were realised for each of the 92 combinations of gas and water flow rates. The pressure at the position of the activated gas injection was kept constant at 0.25 MPa(a). This boundary condition has the advantage that the measured data represent exactly the evolution of the flow along the pipe, i.e. they reflect a configuration at which the gas injection is at a fixed height position, while the measurement plane varies. Important results of this test series are time averaged radial profiles of the gas fraction, and the gas velocity, as well as the time and cross-section averaged bubble size distributions. Furthermore, gas fraction data resolved regarding the bubble size and spatial distribution are presented. As in previous test series, flow patterns were analysed, whereby the classification results from the bubble size. A substantial part of these new air/water experiments were quality and plausibility checks of the measured data. In the result, a clear and consistent trend regarding their evolution with increasing distance from the position of the gas injection was found. Comparisons of the trend of time and cross section averaged gas volume fraction along the pipe height with the theoretically expected values were carried out. The influence of the orifice diameter of the gas injection on flow patterns is also discussed in the report.

Die im Rahmen dieser Versuchsserie erzielten umfangreichen experimentellen Ergebnisse bilden eine hochwertige Datenbasis für Luft-Wasser-Strömungen in einem vertikalen DN200-Rohr, die für die Entwicklung und Validierung von CFD-Modellen, beispielweise bzgl. Blasenkoaleszenz und -fragmentierung, genutzt werden können. Besonderes interessant ist die Untersuchung der Entwicklung der Zweiphasenströmung über der Rohrhöhe. Aus diesem Grund wurden für jede der 92 betrachteten Kombinationen aus Gas- und Wasser-Volumenstromdichten bis zu 18 Messungen mit variablen Abständen zwischen Gaseinspeisung und Messebene durchgeführt. Dabei wurde der Druck an der Gaseinspeisestelle konstant auf 0,25 MPa(a) gehalten. Diese Randbedingung bietet den Vorteil, dass die so gemessenen Daten die Entwicklung der Strömung über der Rohrhöhe widerspiegeln, d.h. eine Konfiguration beschreiben, bei der das Gas an einer festen Höhenposition eingespeist wird und die Messungen in verschiedenen darüberliegenden Ebenen erfolgen. Wesentliche Ergebnisse dieser Messserie sind radiale zeitgemittelte Profile für den Gasgehalt und die Gasgeschwindigkeit sowie zeit- und querschnittsgemittelte Blasengrößenverteilungen. Außerdem liegen blasengrößen- und ortsaufgelöste Gasgehaltsdaten vor. Wie bereits bei früheren Versuchsserien wurden auch in diesem Fall die Strömungsformen analysiert, wobei die Klassifizierung anhand der Blasengröße erfolgte. Ein wesentlicher Bestandteil dieser neuen Luft/Wasser-Versuche war die Qualitäts- und Plausibilitätsprüfung der Messdaten. Es konnte festgestellt werden, dass die Daten einen eindeutigen, widerspruchsfreien Trend bzgl. ihrer Entwicklung mit zunehmendem Abstand von der Gaseinspeisung aufweisen. Zur Plausibilitätsprüfung wurden Vergleiche des Gasgehaltsverlaufes über der Rohrhöhe mit theoretisch zu erwartenden Kurven durchgeführt. Zusätzlich zu diesen Ergebnissen enthält der Bericht eine Einschätzung des Einflusses des Bohrungsdurchmessers an der Gaseinspeisung auf die sich einstellende Strömung.

>Magister Scientiae - MSc / The aim of this study was to compare the trough plasma levels of Aspen-Vancomycin® (AV); and Sandoz-Vancocin CP® (SV) in premature infants with suspected Methicillin Resistant Staphylococcus aureus (MRSA) infection. The study was designed as a prospective, double blind, randomised trial involving male and female premature infants admitted in the Neonatal Intensive care Unit (NICU) at Netcare Blaauwberg and N1-city Hospitals for treatment of suspected MRSA-infection between April 2012 and June 2013. The inclusion criteria were: 29-35 weeks postmenstrual age (PMA), informed and written consent from parents of each premature infant enrolled in the study. Blood samples (0.3-0.4ml) were collected for renal function test and vancomycin trough levels determination. Blood samples for vancomycin trough level assay were collected thirty minutes prior to the administration of the third dose of vancomycin. Statistical analysis was performed and estimation was made giving an indication of how many infants will be needed to make the study statistically significant. Wilcoxon Two-Sample test was performed to determine the p-values and Spearman correlation coefficients were used to determine the correlation between trough levels and variables. P-values < 0.05 were considered significant. A total of 19 premature infants met with study criteria, 10 (5 females and 5 males) received AV and 9 (6 females and 3 males) receive d SV. There was no statistical significant difference between the demographic (GA, BW, PMA, PNA, weight at trial entry, height at trial entry) and biological (albumin, serum creatinine concentration and glomerular filtration rate) parameters of the premature infants in the AV and SV group. There were no statistical significant difference between trough level 1 of AV and SV, although trough level 1 had a lower trend in the SV group (p=0.118). No AV trough level 1 was below the minimum effective concentration (<5μg/ml). It was found that 30% of AV trough level 1 was within the therapeutic range (5-10μg/ml) and 70% of AV trough level 1, were above minimum toxic concentration (>10mg/l). It was found that 22.2% of SV trough level 1 was below minimum effective concentration, 44.4% of SV trough level 1 was within therapeutic range and 33.3% of trough level 1 was above minimum toxic concentration. No correlation was found between trough level 1 and the demographic and biological parameters of the premature infants in the AV group. SV had a positive correlation with GA, BBW, PMA and a negative correlation with PNA

The extensive experimental results presented in this report provide a high-quality database for air-/water flows in a vertical pipe with a nominal diameter of 200 mm. This database can be used for the development and validation of CFD-like models for two-phase flows, e.g. for bubble coalescence and fragmentation. In particular, the investigations aim on the evolution of the two-phase flow along the pipe height. Therefore, up to 18 single measurements with varying distances between the gas injection and measurement plane were realised for each of the 92 combinations of gas and water flow rates. The pressure at the position of the activated gas injection was kept constant at 0.25 MPa(a). This boundary condition has the advantage that the measured data represent exactly the evolution of the flow along the pipe, i.e. they reflect a configuration at which the gas injection is at a fixed height position, while the measurement plane varies. Important results of this test series are time averaged radial profiles of the gas fraction, and the gas velocity, as well as the time and cross-section averaged bubble size distributions. Furthermore, gas fraction data resolved regarding the bubble size and spatial distribution are presented. As in previous test series, flow patterns were analysed, whereby the classification results from the bubble size. A substantial part of these new air/water experiments were quality and plausibility checks of the measured data. In the result, a clear and consistent trend regarding their evolution with increasing distance from the position of the gas injection was found. Comparisons of the trend of time and cross section averaged gas volume fraction along the pipe height with the theoretically expected values were carried out. The influence of the orifice diameter of the gas injection on flow patterns is also discussed in the report.