Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2014-08-15T11:02:06Z No. of bitstreams: 2 license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Tese Marilia M Guimaraes-1.pdf: 1332028 bytes, checksum: f4ace0b858817c6979b387f231975b09 (MD5) / Made available in DSpace on 2014-08-15T11:02:06Z (GMT). No. of bitstreams: 2 license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Tese Marilia M Guimaraes-1.pdf: 1332028 bytes, checksum: f4ace0b858817c6979b387f231975b09 (MD5) Previous issue date: 2012-02-02 / Chromium dietary interventions have been used to investigate the improvement in insulin sensitivity due to the role of chromium as a central component of the glucose tolerance factor. This study aims investigate the effect of chromium nicotinate supplementation on insulin sensitivity and anthropometry in type 2 diabetic subjects. In double-blind trial, fifty-six type 2 diabetic subjects with Body Mass Index 25 kg/m2 and increased waist circumference were randomized into three groups: placebo (NC0), 50μg (NC50) and 200μg (NC200) of chromium nicotinate. Status of chromium, insulin resistance, cell function, glycemic control, lipid profile, anthropometry, intensity and energy expenditure in physical activity were assessed at the beginning, 45 and 90 days of intervention. Energy consumption was assessed at the beginning, between the beginning and 45 days and between 45 and 90 days of study. Most subjects had low serum levels of chromium (71.88%), normal levels of urinary chromium (80.65%) and insulin resistance (73.80%). Chromium serum concentrations did not differ between groups over time (p = 0.2549). Changes in concentrations of serum and urinary chromium were not related to changes in fasting glucose (p> 0.05). At 90 days, there was no significant intra-group difference in fasting plasma glucose, glycosylated hemoglobin, HOMA-IR, total cholesterol, LDL cholesterol, waist circumference, % body fat and % lean mass. There was an increase in HOMA- (p = 0.0349) and HDL cholesterol (p = 0.0425) in the group NC0, reduction in triglycerides in NC0 group (p = 0.0177) and NC50 (p = 0.0336) and reduced of 1.08 kg in the NC50 group (p = 0.0048). No difference was found at intra-group physical activity intensity and between supplemented groups (NC50 and NC200) and placebo (NC0) at 90 days (p>0.05). There was an increase in physical activity energy expenditure in NC50 group at 90 days (p = 0.0371). As for total energy intake, there was no difference within and between groups during the study (p> 0.05). Supplementation with 50 μg and 200 μg chromium nicotinate for 90 days did not promote improvements in glucose homeostasis, lipid profile and anthropometry in individuals with type 2 diabetes mellitus. / Intervenções dietéticas com cromo têm sido utilizadas para investigar a melhora na sensibilidade à insulina, devido à função do cromo como componente central do fator de tolerância à glicose. O objetivo deste estudo foi investigar o efeito da suplementação com nicotinato de cromo na sensibilidade à insulina e na antropometria de indivíduos diabéticos tipo 2. Em ensaio clínico duplo-cego, cinqüenta e seis indivíduos diabéticos tipo 2, com Índice de Massa Corporal 25 kg/m2 e circunferência da cintura aumentada foram randomizados em três grupos: placebo (NC0), 50μg (NC50) e 200μg (NC200) de nicotinato de cromo. O status de cromo, resistência à insulina, função das células , controle glicêmico, perfil lipídico, antropometria, intensidade e gasto energético em atividade física foram avaliados ao início, aos 45 e 90 dias de intervenção. A ingestão energética foi avaliada ao início, entre o início e 45 dias e entre 45 e 90 dias de estudo. A maioria dos indivíduos apresentou, ao início, baixas concentrações de cromo sérico (71,88%), concentrações normais de cromo urinário (80,65%) e resistência à insulina (73,80%). As concentrações de cromo sérico não diferiram entre os grupos ao longo do tempo (p = 0,2549). As mudanças nas concentrações de cromo sérico e urinário não se relacionaram às mudanças na glicemia de jejum (p>0,05). Aos 90 dias, não houve diferença significativa intragrupo na glicemia de jejum, hemoglobina glicada, HOMA-IR, colesterol total, LDL, circunferência da cintura, % gordura corporal e % massa magra. Houve aumento no HOMA- (p=0,0349) e HDL (p=0,0425) no grupo NC0, redução no triglicérides no grupo NC0 (p = 0,0177) e NC50 (p = 0,0336) e redução de 1,08 kg no grupo NC50 (p = 0,0048). Não se observou diferença na intensidade de atividade física intra-grupo e na comparação entre os grupos suplementados (NC50 e NC200) e placebo (NC0) aos 90 dias (p>0,05). Houve aumento no gasto energético em atividade física aos 90 dias de intervenção nos indivíduos do grupo NC50 (p = 0,0371). Quanto à ingestão energética total, não houve diferença intra e entre grupos no decorrer do estudo (p>0,05). A suplementação com 50 μg e 200 μg de nicotinato de cromo durante 90 dias não promoveu melhorias na homeostase glicêmica, perfil lipídico e antropometria em indivíduos com diabetes mellitus tipo 2.

O objetivo foi avaliar, por meio de uma abordagem meta-analítica, quais os principais fatores que influenciam no desempenho produtivo e reprodutivo de novilhas e vacas primíparas de corte. Para tanto, foram utilizados, de forma agregada, dados de 3.933 novilhas e vacas primíparas de corte, provenientes de 29 estudos (dissertações e teses) e 43 experimentos. As informações relacionadas à metodologia e aos resultados de cada trabalho foram tabuladas em planilha, constituindo a sistematização dos dados. Por meio dos dados disponibilizados, três artigos foram realizados. No primeiro deles, as variáveis independentes analisadas foram: idade das novilhas (14 ou 24 meses de idade) e vacas primíparas (24 ou 36 meses de idade) no momento em que foram expostas à reprodução, tipo de pastagem (pastagens de ciclo hiberno-primaveril ou natural) e tipo racial (taurinas ou mestiças). As variáveis respostas foram os pesos e escores de condição corporal ao início e final do período reprodutivo e a taxa de prenhez. Maiores pesos corporais ao início do acasalamento e taxa de prenhez foram observados nas novilhas expostas à reprodução aos 24 meses (325,25±1,55 kg e 73,84±1,41%), nas mestiças (321,41±2,15 kg e 70,88±1,63%) e nas que pastejaram pastagens de ciclo hiberno-primaveril no pré-acasalamento (318,34±2,01 kg e 82,43±1,60%). Maiores pesos corporais foram observados nas vacas primíparas expostas à reprodução aos 36 meses de idade (376,09±1,55 kg), nas mestiças (373,56±1,54 kg) e nas que pastejaram pastagens de ciclo hiberno-primaveril (377,80±2,29 kg). A maior prenhez foi observada nas primíparas aos 24 meses de idade (83,44±3,03%, nas taurinas (88,53±2,61%) e nas que pastejaram pastagens de ciclo hiberno-primaveril (77,68±1,93%). No segundo trabalho, a taxa de prenhez foi considerada a variável resposta. Foram realizadas análises de sub-grupos entre categoria animal (novilhas e vacas primíparas), idade das fêmeas no momento em que foram expostas à reprodução (14, 24 ou 36 meses de idade), tipo de pastagem (pastagens de ciclo hiberno-primaveril ou natural) e tipo racial (taurinas ou mestiças). Novilhas e vacas primíparas, expostas à reprodução apresentaram maior taxa de prenhez (80,24%). No terceiro trabalho, a variável resposta foi a taxa de prenhez.Fatores explanatórios foram categoria animal (novilhas ou vacas primíparas), peso corporal ao início do período reprodutivo, ganho médio diário durante a reprodução, tipo racial (taurinas e mestiças) e taxa de lotação. O peso ao início da reprodução influenciou 93,1% da taxa de prenhez. Por meio da presente meta-análise, a idade à qual as fêmeas foram expostas à reprodução, a raça, o tipo de pastagem utilizada no pré-acasalamento, o peso corporal ao início da reprodução e a taxa de lotação são fatores que influenciam o desempenho produtivo e reprodutivo de novilhas e vacas primíparas de corte no sul do Brasil. / The aim was to evaluate, through a meta-analytical approach, the main factors that influence the productive and reproductive performance of heifers and primiparous cows. We used, in aggregate, data from 3,933 heifers and primiparous cows from 29 studies (dissertations and theses) and 43 experiments. The information related to the methodology and the results of each work were tabulated in a spreadsheet, constituting the systematization of the data. Through the available data, three articles were made. In the first one, the independent variables analyzed were: age of heifers (14 or 24 months of age) and primiparous cows (24 or 36 months of age) at the time they were exposed to reproduction, type of pasture (winter-spring cycle or natural pasture) and breed (Taurine or crossbred). The variables responses were the weight and body condition scores at the beginning and end of the reproductive period and the pregnancy rate. Larger body weights at the beginning of the breeding season and pregnancy rate were observed in heifers exposed to reproduction at 24 months (325.25±1.55 kg and 73.84±1.41%), in crossbreed (321.41±2,15 kg and 70.88±1.63%) and in those that grazed winter-spring cycle pastures in pre-mating (318.34±2.01 kg and 82.43±1.60%). Higher body weights were observed in the primiparous cows exposed to the breeding season at 36 months of age (376.09±1.55 kg), in the crossbreed (373.56±1.54 kg) and in those that grazed hiberno-spring cycle (377.80±2.29 kg). The highest pregnancy was observed in the primiparous cows at the 24 months of age (83.44±3.03%), in the taurine (88.53±2.61%) and in those that grazed winter-spring cycle pastures (77.68±1.93%). In the second study, the pregnancy rate was considered the response variable. Was evaluated analysis of subgroups between animal categories (heifers and primiparous cows), age of females at the time of the breeding season (14, 24 or 36 months of age), type of pasture (winter-spring cycle or natural pasture) and breed (Taurine or crossbreed). Heifers and primiparous cows, exposed to reproduction, had a higher pregnancy rate (80.24%). In the third study, the response variable was the pregnancy rate. Explanatory factors were animal category (heifers or primiparous cows), body weight at the beginning of the breeding season, average daily gain during the breeding season, breed (Taurine and crossbreed) and stocking rate. Through the present meta-analysis, the age at the which females were exposed to the breeding season, breed, type of pasture used in pre-mating, body weight at the beginning of the breeding season and stocking rate are factors that influence productive performance and reproductive performance of heifers and primiparous beef cattle in southern Brazil.

Thesis (M.A. (Clinical Psychology)) --University of Limpopo, 2006 / The purpose of the research study is to investigate the relationship between body mass and self-concept among adolescent female university students. First year female students from three different Schools and Faculties at the University of Limpopo, Turfloop Campus participated in the study. They were 75 in number. The study has both a quantitative and qualitative aspects. The qualitative was used to complement the quantitative aspect. The Rosenberg Self-esteem Measure was used to measure self-esteem. For the qualitative aspect, a topic guide was used for the focus group discussion prepared and used for the focus group discussion. Analysis of Variance (ANOVA) and the Pearson’s Product Moment Correlation were used to analyse the quantitative data. Results show that there is a relationship between body mass and self-concept and that overweight participants tend to have a low self-esteem. This low self-esteem was perceived to be aggravated by a number of factors like the attitude of the media and the society. Participants who are overweight also indicated that they are limited in certain areas of their lives (e.g., sports) as a result of their body mass. They expressed mixed feelings and frustration when it comes to such areas of like. Support groups, life-skills programmes and psychotherapy should be made available and attainable for overweight female adolescents.

Obesity is a major public health problem and is a risk factor for hypertension, diabetes, heart disease and cancer. In addition, the prevalence of obesity appears to be increasing worldwide, making it important to determine the nature and extent of obesity in populations at risk. The aim of this study was to determine the predictors of body mass index (BMI) in Taiwanese adults 19 through 44 years old. Independent variables from the Nutrition and Health Survey in Taiwan (NAHSIT) included biological factors (age and sex), dietary factors (energy intake and fat intake), environmental factors (educational level, residence area, and nutrition knowledge), and lifestyle factors (leisure time physical activity, smoking habits, and alcohol consumption). Results indicated that nearly 40% of the 1,182 adult survey participants were obese or overweight, by Taiwanese standards. Regression analysis found that significant predictors of BMI were residence area, educational level, and age. Taiwanese adults more likely to have higher BMIs were from the mountainous area, had less education. An increase in ten years of age was related to an average increase in BMI of 1.13 kg/m�� (p<0.0001), controlling for other variables. These three factors accounted for 21% of the variance in all adults (15% of the variance in men, and 28% of the variance in women). In addition, smoking was a predictor of higher BMI in males, and alcohol intake was a predictor for higher BMI in females. Energy intake, fat intake, leisure time physical activity, and nutrition knowledge were not significant predictors for either males or females. The findings from this study will help public health professionals identify target areas and program needs to reduce obesity in Taiwan, particularly in the mountainous areas where the prevalence of obesity/overweight was seventy percent. / Graduation date: 2004

The purpose of this research was to examine psychosocial and body weight correlates of dietary behavior in low-income tri-ethnic women. In Study 1, a semi-quantitative food frequency questionnaire (FFQ) was developed and validated against diet records in 95 college women and 50 low-income postpartum women. Pearson's correlations were 0.42 among college women and 0.45 among low-income women. Cross-classification of participants into quartiles resulted in 76% of college women and 79% of low-income women being classified correctly. These results suggested that the FFQ was valid for dietary assessment among young women in the southwestern United States. In Study 2, approximately 160 mothers were recruited in the hospital 0-1 days following childbirth, and prepregnancy weight and demographic information were obtained. Weight was measured at 6 months and 1 year postpartum; psychosocial factors were assessed at 1 year. Diet during pregnancy and postpartum was assessed via food frequency questionnaires administered at 1.5 months, and at 6 and 12 months postpartum, respectively. From pregnancy to postpartum, % calories from fat (delta = +1.1%, p<0.05) and added sugar (delta = +2.0%, p<0.05) increased. A greater percentage of lactating than non-lactating women (64% vs. 38%, p<0.05) met recommendations for fruits during pregnancy. Mean intakes of calcium, vitamin A and dairy foods were higher in women who had retained <10% of their prepregnancy weight at 1 year postpartum than in those who had gained [greater-than or equal to] 10%. During late postpartum, women in the highest tertile of compliance with dietary recommendations had a more positive body image (p<0.041) than those in the lowest tertile, and less neglect of self-care (p<0.001), weight-related distress (p<0.006), stress (p<0.009), depressive symptoms (p<0.020), and perceived barriers to weight loss (p<0.039). These findings suggest that the transition from pregnancy to postpartum is associated with a negative impact on dietary behavior in low-income women. Intakes of calcium, vitamin A and dairy foods may be associated with lower weight retention in postpartum. Furthermore, psychosocial variables may influence adherence to dietary guidelines during this time. / text

Außerhalb ihrer ursprünglichen Heimat in Südamerika steigt die Anzahl der Alpakas stetig an. Die Tiere erfreuen sich auch in Deutschland einer großen Beliebtheit. Aktuellen Schätzungen zufolge leben in Deutschland circa 10.000 Alpakas. Siewerden zur Wollgewinnung, sowie als Begleit- und Therapietiere in kleinen Hobbyhaltungen oder in Beständen mit einer Herdengröße von bis zu 150 Tieren gehalten. Damit verbunden werden auch zunehmende Ansprüche an die Qualität der tierärztlichen Betreuung dieser Neuweltkameliden gestellt. Die Beurteilung des Wachstums und der Entwicklung junger Alpakas bildet dabei, genauso wie im Rahmen der Zucht, eine wichtige Grundlage. Derzeit existieren nur unzureichende Informationen über den Wachstumsverlauf beim Alpaka. Bisher dienten proportional angepasste Daten vom Lama zur Orientierung. Das Ziel dieser Arbeit ist die auf morphometrischen Daten basierende Beschreibung der physiologischen Entwicklung des Skelettes und des Körpergewichtes beim Alpaka in den ersten 36 Lebensmonaten. Weiterhin soll untersucht werden, welche Faktoren Einfluss auf das Wachstum junger Alpakas haben. Die Bestimmung einer Gleichung zur Berechnung des Körpergewichtes stellt einen weiteren Schwerpunkt der Arbeit dar. Über einen Zeitraum von 12 Monaten wurden 162 Alpakas im Alter von wenigen Tagen bis zu 36 Monaten vermessen. In einem zweiwöchentlichen Rhythmus wurden 9 verschiedene Parameter bei jedem Tier erfasst: Gewicht, Widerristhöhe, Hüfthöhe, Rückenlänge, Rumpflänge, Tuberculum majus-Olecranon-Distanz (TOD), Basis patellae-Tuber ischiadicum-Distanz (BTD), Thoraxumfang und Body Condition Score. Mit Hilfe von speziell angefertigten Messschiebern, einer digitalen Waage und einem flexiblen Maßband erfolgte die Datenerhebung am stehenden Tier. Das Wachstum beeinflussende Faktoren wurden mittels Allgemeiner Untersuchung der Tiere, stichprobenartigen Kotprobenuntersuchungen, Futtermittelanalysen und vom Halter ausgefüllten Fragebögen erfasst. Die erhobenen Messwerte wurden unter Verwendung der nichtparametrischen Regression LOESS (locally weighted scatterplot smoothing) zur Erstellung von Wachstumskurven genutzt, die den durchschnittlichen Wachstumsverlauf des Körpergewichtes, sowie verschiedener Körpermaße von bis zu 36 Monate alten Alpakas darstellen. Sie ermöglichen die Beurteilung der körperlichen Entwicklung eines Alpakas. Unter Anwendung der LMS-Methode (Schiefe der Verteilung der Messwerte λ [L], Mittelwert M, Standardabweichung S) wurden Perzentilkurven von vier Parametern erstellt, die als Referenzkurven und Richtlinien zur Beurteilung der tierartspezifischen Größe und des Gewichtes genutzt werden können. Wachstumsprognosen und Rückschlüsse auf das Alter eines Alpakas sind mit Hilfe der Perzentilkurven möglich. Sowohl die Wachstumskurven als auch die Perzentilkurven lassen erkennen, dass Alpakas mit 36 Monaten noch nicht ausgewachsen sind. Die Kurven wurden anhand von Messwerten von Alpakas erarbeitet, die unter Bedingungen gehalten wurden, die keinen beziehungsweise einen minimalen Einfluss auf das Wachstum haben. Dies ist anhand der Ergebnisse der parasitologischen Untersuchungen und der Futtermittelanalysen erkennbar. Weitere Auswertungen der Messdaten zeigen, dass keine signifikanten Entwicklungsunterschiede zwischen Hengsten und Stuten beziehungsweise zwischen der Rasse Huacaya und der Rasse Suri bestehen. Ähnlich wie bei anderen Tierarten auch, eignet sich der Thoraxumfang zur zuverlässigen Berechnung des Körpergewichtes besonders gut. Eine große Korrelation besteht auch zwischen der Rumpf- beziehungsweise der Rückenlänge und dem Körpergewicht. Praktische Bedeutung haben die Erkenntnisse dieser Arbeit vor allem für Alpakazüchter und –halter, sowie für Veterinärmediziner. Die Ergebnisse bilden eine wichtige Grundlage für das Fütterungs- und Reproduktionsmanagement beim Alpaka. / The number of alpacas bred outside their natural habitat in South America increases continuously. Alpacas become more and more popular in Germany. According to recent estimates about 10.000 alpacas live in Germany. They are used for wool production, as companion animal and for therapeutic treatments. The alpacas are kept as pets in smaller groups or as livestock in herds of up to 150 animals. Due to the rising number of these camelids in Germany and more intense use, higher demands on the quality of veterinary care of alpacas occur. Knowledge and data on growth and development in young alpacas are essential for an objective health evaluation as well as for breeding management. Currently very limited information is available on growth of alpacas and the data published have been adapted by calculation using measurements performed on llamas. The primary objective of this study was to determine the physiological development of the skeleton and the body weight of alpacas from birth until 36 months of age based on morphometric data. An additional aim was to analyze factors that influence the growth of young alpacas. A third focus of this study was to generate a mathematical formula to calculate the body weight. The measurements were performed on 162 alpacas with an age ranging from the first day of life up to 36 months. For each alpaca nine different parameters were determined every two weeks: body weight, height at withers, height in the hip, thoracic circumference, length of the back, length of the trunk, Greater tubercle-Olecranon-distance (TOD), Base of the patella-Ischial tuber-distance (BTD) and body condition score. All measurements were carried out on standing animals. Three custom designed caliper gauges, a digital balance and a flexible measuring tape were used to obtain the nine parameters. Factors that influence growth were captured by clinical examination, randomized fecal samples, analysis of forage and a questionnaire completed by the breeder. Based on the data collected growth curves were developed using the nonparametric regression LOESS (locally weighted scatterplot smoothing). These curves represent the average growth pattern of body weight and various body measurements of up to 36 months old alpacas. Using theses curves the physical development of this species can be assessed. By applying the LMS-Method (skewness of the measurement distribution λ [L], mean M, coefficient of variation S) percentile curves of four different parameters have been generated. They can serve as reference curves and as guidelines for objective evaluation of species specific size and weight. Using the percentile curves a reliable prediction of growth or conclusions regarding the age of an alpaca are possible. The growth curves as well as the percentile curves show that alpacas are not mature at the age of 36 months. The curves are based upon data from alpacas who were raised under environmental conditions which have no or minimized influence on growth. This is evident in the results of the parasitological examinations and the feed analysis. Further analyses indicate that no significant differences in growth exist between males and females respectively between the two breeds Huacaya and Suri. Like in other species the thoracic circumference is particularly suitable for estimating the body weight. A strong correlation exists between body weight and the length of the trunk as well as the length of the back. The results of this study are of practical significance for alpaca owners, breeders and veterinarians. They provide a sound basis for recommendations in feeding and management of reproduction.

Abstract The global aims of this thesis were: to evaluate if an individualised dose strategy for enoxaparin, based on lean body weight and renal function, resulted in a reduction in the prevalence of bleeding and bruising events when compared to conventional dosing; to further understand the dose-exposure-response relationship for enoxaparin using population pharmacokinetic-pharmacodynamic (PKPD) modelling. This thesis comprises seven chapters: an introduction to the current knowledge and literature pertaining to low-molecular-weight heparins (LMWHs), in particular enoxaparin; five research chapters; and a discussion. Each of the five research chapters consists of a manuscript that has been published in, accepted or submitted for peer review in a scientific journal. Preceding each chapter is a synopsis of the important features of the publication. Supplementary information that supports the findings of the publication, but could not be included in the publication, is provided at the end of the chapter. Appendices relevant to each chapter are located at the end of the thesis. Chapter one is the introduction to this thesis. It commences with an overview of the LMWHs, their mechanism of action, customary uses, licensed doses and adverse effects. There is a brief introduction to renal function and body composition; physiological factors that influence the disposition of LMWHs. As much of this thesis is centred on defining the dose-exposure-response relationship for enoxaparin, there is a critique of the existing literature relevant to each segment of this relationship, namely: dose-exposure, exposure-response and dose-response. To conclude this chapter there is a review of pharmacostatistical models and population modelling, followed by an appraisal of population PK and PKPD models that have previously been developed for enoxaparin, including the two key publications that are critical to this thesis. These two papers were the first to fully describe the dose-exposure relationship for enoxaparin in subjects with renal impairment and obesity. It is from these studies that the individualised dosing strategy, explored throughout this thesis, was developed. The specific aims of the five research chapters are then stated. Chapter two describes a confirmatory, randomised controlled trial (RCT) to compare an individualised dose of enoxaparin to conventional, label based dosing. The RCT was conducted at a major tertiary teaching hospital over an 18 month period. The primary endpoint was the prevalence of overt bleeding events and the secondary endpoint a combination of bleeding or major bruising events. A time-to-bleeding event analysis (Kaplan-Meier) was used and markers of effectiveness such as mortality and readmission were assessed out to 30 days post recruitment. Bleeding and bruising data, along with anti-Xa (aXa)-concentrations were collected for use in additional research described in chapters four and five. Chapter three details the evolution, progression and contemporary knowledge of drug dosing based on body composition and focuses on dosing in obese subjects with cardiovascular disease. The concept of dose-individualisation is explored in this chapter with reference to the methods used to normalise drug exposure across the spectrum of body compositions. Subsequently, there is a review of body size descriptors, such as lean body weight, that are used to scale dosing in the obese. Enoxaparin is used as a motivating example, with reference to data presented in Chapter two of this thesis. There is also a discussion about the type of research designs that are required to maximise information about PK parameters. This chapter was published within a book chapter which was intended for clinical practitioners in the discipline of cardiology. Chapter four is focused on the development and evaluation of population PK and PKPD models to describe the time-course of effects for enoxaparin. A population PK model linked to a proportional-odds model was used to describe the severity of an adverse event as a function of exposure and demographic variables. The final model was used to explore the likely occurrence of bleeding and bruising events in patients with obesity and / or renal impairment dosed using either the individualised or conventional dose strategies from Chapter two. Chapter five describes a study that was undertaken to evaluate the ability of the individualised dosing strategy to achieve and maintain aXa-concentrations within the therapeutic range (500 to 1000 IU L-1), by comparison to conventional dosing. As the confirmatory study focused on the prevalence of adverse events there was no assessment of the therapeutic capability of the dose strategies however, as aXa-concentrations were collected using a sparse design during the confirmatory study, the two dose strategies could not be compared using observed data. Therefore, the population PK model developed in Chapter four was used to predict individual subject concentration-time profiles to 120 hours of enoxaparin therapy. The time spent in the therapeutic, supra-therapeutic and sub-therapeutic ranges was computed for each subject and the dosing strategies statistically compared. This study also allowed the evaluation of the results from Chapter two from a dose-exposure perspective. Chapter six of this thesis describes a survey. The aim of this survey was to gain an understanding of how dosing strategies of enoxaparin vary in four countries, investigate if clinicians are prescribing according to the Product label, and determine the methods used to dose-individualise enoxaparin. In doing so, individual hospitals in the international community will be able to compare, critique or benchmark their own strategies to peer hospitals, as well as the current literature. The publication arising from this survey would assist in the dissemination of knowledge gained from the earlier chapters of this thesis. Chapter seven is the final discussion and conclusions of the thesis along with prospects for future research.

Optimal pharmacotherapy requires an understanding of the dose-exposure (pharmacokinetics or PK) to response (pharmacodynamic or PD) relationship. Little is known about the influence of obesity on this dynamic system as PK studies in obesity have been largely descriptive rather than explanatory. This has led to a paucity of dosing guidelines for the obese, and arbitrary dose selection in the clinic. There is a need to quantify the impact of obesity on drug clearance (CL) to ensure that exposure is matched across patients of different body compositions, thereby improving therapeutic outcomes and minimising adverse events. The global aim of this thesis was to use prior published data and new clinical trial data to understand how body composition impacts upon drug CL and renal function, and to determine how clinical study design influences the identification of these relationships. Chapter 2 of this thesis determined if conventional body size descriptors that have been used to scale drug doses to body size were appropriate. In the clinical setting, a body size descriptor commonly used for determining dose requirements is total body weight (WT), based on the assumption that physiological function and PK parameters vary according to body size. However, dosing algorithms based on WT might be unsuitable for the obese due to their altered body composition which, if inaccurate, could ultimately lead to overdoses. Alternative body size descriptors such as body surface area and ideal body weight have been used, but are limited when extrapolated to obese patients as they do not take into account the covariates required to describe differences in body composition between individuals. In contrast, it was demonstrated that lean body weight (LBW), as derived by Janmahasatian et al, had the potential to scale CL across a wide range of body compositions. This literature review and systematic analysis of previously published obesity data led to the proposal of a hypothesis that body composition is sufficient to explain the influence of obesity on drug CL and that dosing for obese patients should be based on LBW. When conducting clinical studies, the selection of an appropriate body size descriptor for scaling doses across individuals of different body compositions can be aided by a study design that allows for the identification of parameter-covariate relationships which are transportable to the obese. Chapter 3 of this thesis quantified the probability of identifying these parameter-covariate relationships as a function of differing study designs. Demographics were generated using a multivariate lognormal covariate distribution with truncation at different WT limits under both a non-stratified and stratified design. PK data were simulated from a 1-compartment, first order input, first order elimination model with LBW as the covariate on CL, termed the ‘True Model’. The ‘False Model’ had WT as the covariate on CL. Both models were fitted to the simulated data and the preferred model was selected based on the difference in objective function values. Each design was evaluated under differing magnitudes of random effects, as well as under a D-optimal sparse sampling scheme. It was shown under a simulation platform that the use of stratification and a wide covariate range enhanced the probability of selecting the true covariate from two competing covariate models. The aforementioned findings regarding LBW and stratification were used to design a new clinical study investigating the influence of obesity on renal drug elimination pathways. This work forms Chapters 4 and 5 of this thesis. Non-obese and obese healthy volunteers were recruited using a study design stratified for LBW. These subjects were administered a combination of four renal markers for the simultaneous assessment of various renal processes. One of the renal markers was para-aminohippuric acid (PAH), which provides an estimation of renal plasma flow (RPF). A population PK model was developed for PAH, which revealed that body size alone was insufficient to explain variability in RPF across healthy individuals of a large range of body compositions, although LBW emerged as the preferred covariate (p=0.053) among the body size descriptors tested. This weak covariate effect was in contrast with prior research supporting the use of LBW in normalising the effect of obesity on glomerular filtration rate (GFR), implying that body composition could play a greater role in influencing GFR than RPF. This thesis has applied new methods to the design of drug CL studies in obesity, and offered results and future directions to maximise the information gained from such clinical studies. A better understanding of alterations in PK and physiological function arising from changes in body composition should aid in optimising dose adjustments for obese patients, which is of great importance given the increasing prevalence of obesity in today’s society.

Thesis (Ph.D. in Nursing) -- University of Colorado Denver, 2008. / Typescript. Includes bibliographical references (leaves 127-142). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;

Thesis (Ph.D.)--University of Alabama at Birmingham, 2009. / Title from PDF title page (viewed on Sept. 10, 2009). Includes bibliographical references (p. 160-172).