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Le contexte international de la pharmacoépidémiologie, marqué par la mise en œuvre d’un nombre croissant d’études multi-sources, a fait émerger un certain nombre de questionnements autour de la gestion de données conflictuelles ou de l’impact des choix méthodologiques sur les résultats.Accroître la confiance dans ces études observationnelles et renforcer leur crédibilité face aux données issues des essais cliniques représente un enjeu majeur, qui dépend étroitement de la robustesse des conclusions produites. Dans ce domaine, la mesure de l’exposition médicamenteuse revêt donc une importance toute particulière, tant pour des études portant sur l’estimation d’un risque ou d’un critère d’efficacité, que lors de la description des modalités d’utilisation en vie réelle. L’exposition médicamenteuse reste un phénomène complexe qui se caractérise la plupart du temps par des cycles discontinus, marqués par des évolutions de doses et la présence de médicaments concomitants. Compte tenu des caractéristiques pharmacodynamiques et pharmacocinétiques / The multinational context of pharmacoepidemiology, and the resulting increased number ofmulti-sources studies have generated concerns in relation with conflicting results and the question of the impact of methodological choices on study results. Increasing the confidence in the conclusions derived from these observational studies is a crucial issue, which is closely related to the robustness of the evidence produced. In this area, impact of drug exposure measurement and risk window might be crucial.Drug exposure is mostly characterized by discontinuous episodes, marked by changes in doses and presence of concomitant medications. Considering the pharmacokinetic and pharmacodynamics characteristics specific to each individual drug, the way in which the drug exposure is presented is of great importance. However, methods used for handling drug exposure episodes in electronic healthcare databases are varying widely according studies. However, the impact of these methods

abstract: Children removed from methamphetamine laboratories are a severely understudied population despite the widespread deprivation parental methamphetamine abuse has on children, particularly in homes where methamphetamine is produced. Arizona's children are uniquely affected by the use and manufacturing of methamphetamine due to the geographic location and landscape of the state. A sample of 144 children removed from their homes during the seizure of methamphetamine laboratories, as part of the Arizona Drug Endangered Children program between 1999 and 2003, was investigated. Results indicate that younger children were more likely to be reported by Child Protective Services as high or moderate risk of further abuse, test positive for methamphetamine, and have maternal alleged perpetrators of abuse. Older children were more likely to be reported as low risk for further abuse, test negative for methamphetamine, and have paternal alleged perpetrators of abuse. Results also show that children initially placed in foster care were more likely to remain in foster care at the final assessment than to be living with a parent or kin. These findings have implications for individuals working with children removed from methamphetamine laboratories, including Child Protective Services case workers, medical personnel, temporary and permanent child caregivers (i.e., foster care, kin care, adoptive parents, and shelters), and community members (i.e., teachers). Recommendations based on study findings are offered to child and family advocates and interventionists. / Dissertation/Thesis / M.S. Family and Human Development 2011

Combating drug resistant malaria has been historically challenging, and remains so today. Recent reports from Southeast Asia show that Plasmodium falciparum is developing resistance to even our best defenses; artemisinin-based therapies. This development threatens to become a significant challenge in controlling malaria infections worldwide, making research into developing and characterizing new antimalarial drugs increasingly important. The purpose of this study was to characterize the resistance potential of novel antimalarial compound JPC-3210 in vitro using P. falciparum clones. JPC-3210 is a new long acting drug with potential to be used in combination with fast-acting drugs like artemisinins to cure drug resistant malaria. In this study several methods were used to characterize the efficacy and resistance potential of JPC-3210. To determine the frequency of resistance generation in P. falciparum clones, parasites were kept under continuous drug pressure for thirty days, at which point drug pressure was removed and cultures were observed for signs of recrudescence. P. falciparum clones also were exposed to increasing levels of intermittent drug pressure that involved 3-4 days of drug exposure followed by a recovery period. The step-wise experiment was conducted over three months with drug pressure being increased step-wise until a maximal concentration of 700 ng/ml of JPC-3210; resistance was measured phenotypically in drug susceptibility assays at multiple time points. Additionally, the ability of JPC-3210 to induce dormant stage parasites, and its effect on dihydroartemisinin (DHA)-induced dormant stages was assessed in both a chloroquine resistant parasite (W2) and in an artemisinin resistant clone (4G). Results showed that the frequency of resistance against JPC-3210 in W2 clones was less when compared to that of atovaquone. The step-wise pulse exposure of JPC-3210 induced resistance in W2 clones, however, resistance proved unstable. Dormant stage parasites were not induced by JPC-3210, even at high concentrations in W2 or 4G clones, furthermore, the effect of JPC-3210 on dormant-induced parasites was found to be dose dependent, yet the drug did not kill DHA-induced dormant rings. JPC-3210 appears to be a good drug to use in combination with other antimalarial compounds for treatment of P. falciparum, but further research is needed. Future studies to assess the field performance of new antimalarial compounds by investigating resistance and dormancy profiles in vitro, and thereby maximizing out understanding of such drugs and their optimal implementation, are of the utmost importance.

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.

No description available.

Passive exposure of children to drugs is common, but difficult to ascertain as direct studies are in many cases not possible, and currently available indirect measures of drug exposure, such as maternal reports, are likely to be inaccurate. Novel, indirect methods to evaluate drug exposure in the uterus and early life are needed, and may provide risk estimates that can be later correlated with clinical outcomes. In the studies presented here, I have applied novel methods such as measurement of hair drug concentrations and population pharmacokinetics modeling and simulation to evaluate fetal and infant exposure to drugs and potential associated risks. Testing for methamphetamine allowed demonstration, for the first time, that it freely crosses the human placenta. In contrast, analysis of paired maternal–infant hair showed limited cocaine placental transfer, in agreement with animal models. Results of hair tests from children found in marihuana grow houses and other drug operations showed that passive exposure tends to be higher in infants, likely due to higher dependence on, and proximity to care givers. We also demonstrated the importance of measuring drug metabolites to distinguish between systemic exposure to MDMA and simple external hair contamination secondary to drug present in the home environment. Finally, we developed a population pharmacokinetics and simulation approach to accurately estimate drug excretion into breast milk. This novel technique was applied to fluoxetine and to nifurtimox. Use of our approach allowed us to define, for the first time, the limited extent to which fluoxetine and nifurtimox would be expected to cross into breast milk and estimate potential degree of exposure of breastfed infants. In summary, results presented here support the value of these novel methods for the evaluation of fetal and infant drug exposure and suggest a promising value in estimating risks to children passively exposed to drugs.

Passive exposure of children to drugs is common, but difficult to ascertain as direct studies are in many cases not possible, and currently available indirect measures of drug exposure, such as maternal reports, are likely to be inaccurate. Novel, indirect methods to evaluate drug exposure in the uterus and early life are needed, and may provide risk estimates that can be later correlated with clinical outcomes. In the studies presented here, I have applied novel methods such as measurement of hair drug concentrations and population pharmacokinetics modeling and simulation to evaluate fetal and infant exposure to drugs and potential associated risks. Testing for methamphetamine allowed demonstration, for the first time, that it freely crosses the human placenta. In contrast, analysis of paired maternal–infant hair showed limited cocaine placental transfer, in agreement with animal models. Results of hair tests from children found in marihuana grow houses and other drug operations showed that passive exposure tends to be higher in infants, likely due to higher dependence on, and proximity to care givers. We also demonstrated the importance of measuring drug metabolites to distinguish between systemic exposure to MDMA and simple external hair contamination secondary to drug present in the home environment. Finally, we developed a population pharmacokinetics and simulation approach to accurately estimate drug excretion into breast milk. This novel technique was applied to fluoxetine and to nifurtimox. Use of our approach allowed us to define, for the first time, the limited extent to which fluoxetine and nifurtimox would be expected to cross into breast milk and estimate potential degree of exposure of breastfed infants. In summary, results presented here support the value of these novel methods for the evaluation of fetal and infant drug exposure and suggest a promising value in estimating risks to children passively exposed to drugs.

With the incidence of prenatal drug exposure increasing, it is important that preschool teachers are prepared and confident in serving the needs of children affected by this exposure. Teachers need more training and education to prepare them for working with children with prenatal drug exposure. The purpose of this sequential mixed-methods study was to explore the perceptions, training, and shared experiences of preschool teachers when working with 4- and 5-year-old preschool children who have experienced prenatal drug exposure. The researcher invited 77 preschool teachers in northeast Tennessee working in either Head Start or Tennessee Voluntary Pre-K Initiative programs to complete an initial quantitative survey – of which 53 participated. Of the survey participants, 34 reported they might have worked with a child with prenatal drug exposure. Six of those teachers who said they had experience with children with prenatal drug exposure participated in a follow up semi-structured interview with the researcher. The findings revealed that preschool teachers were favorable toward children with prenatal drug exposure regarding the children’s ability to learn. Preschool teachers were already using many effective interventions (e.g., working one-on-one with the child, offering flexible seating options, repetition of information) that they may have used with other children with special needs, but they were eager for more information about the best way to work with these children. School leaders and those in teacher preparation programs would be excellent advocates in spreading knowledge and translating medical knowledge into resources more applicable to the teaching and childcare profession. It is important that the information become more accessible to all teachers and stakeholders in education.

[pt] O consumo de álcool durante gravidez pode alterar o desenvolvimento neural do feto, causando defeitos ao longo da vida. As consequências são diversas e compõe o termo coletivo: Transtorno do Espectro Alcoólico Fetal (TEAF). Esse transtorno é considerado a causa mais comum de deficiência cognitiva evitável no mundo. Estimativas apontam que no Brasil entre 1 e 1,5% das crianças nascem com alterações no sistema nervoso devido à exposição ao álcool in útero. O consumo do álcool é frequente entre mulheres grávidas muitas vezes por desconhecimento dos seus efeitos adversos no desenvolvimento do feto. Outra droga comumente utilizada por mulheres grávidas é a maconha com intuito de amenizar o enjoo durante a gestação. A presente dissertação explora os efeitos da exposição pré-natal ao álcool no feto (em conjunto ou não do uso da maconha) em estudos pré-clínicos e clínicos. Dois artigos foram gerados para a realização deste trabalho. O primeiro artigo relata os mecanismos e as consequências do consumo simultâneo de álcool e maconha durante gravidez, cujo efeito é ainda mais nocivo ao desenvolvimento do feto do que apenas a exposição ao álcool. Dados recentes demonstram a interação do etanol e da maconha com o sistema Endocanabinoide, que tem um papel importante no neurodesenvolvimento. Depois do fechamento do tubo neural, que acontece durante a terceira semana da gestação humana, os olhos e o cérebro se desenvolvem do neuroepitélio. Ambos, o álcool e maconha interferem sinergicamente nesse processo via receptores canabinóides, alterando assim a sinalização “sonichedgehog”, que por sua vez, resulta em alterações morfológicas e comportamentais em modelos animais. Além disso, o artigo relata os mais recentes achados de estudos clínicos sobre a combinação da dose e tipo de constituintes químicos da machonha, bem como os desfechos morfológicos e neurocomportamentais da exposição conjunta do álcool e da maconha. O segundo artigo é uma revisão sistemática que investiga as pesquisas realizadas no Brasil sobre o TEAF, com ênfase nos instrumentos usados para a avaliação neuropsicológica de indivíduos com TEAF. Enquanto países desenvolvidos têm décadas de pesquisa sobre o TEAF, no Brasil, inúmeros fatores comprometem o progresso nesta e outras áreas de pesquisa. Entre esses fatores podemos citar, divergências socioeconômicas, culturais e geopolíticas, que dificultam o desenvolvimento, adaptação e validação de instrumentos utilizados no diagnóstico e na avaliação neuropsicológica do TEAF. Além disso, vale ressaltar que a vulnerabilidade socioeconômica da população brasileira é um fator importante no aumento da ocorrência de formas mais graves de TEAF. A revisão sistemática aponta para a necessidade da validação das ferramentas neuropsicológicas de diagnóstico e avaliação cognitiva de pessoas com TEAF e da participação de uma equipe multidisciplinar no diagnóstico do TEAF. / [en] Alcohol consumption during pregnancy may damage the development of the fetus, resulting in the most common preventable cause of neurodevelopmental disability in the world: Fetal Alcohol Spectrum Disorders (FASD). The present dissertation aims to discuss the effects of alcohol on the developing CNS through two articles. The first article elucidates the mechanisms and outcomes of the combined alcohol and cannabis exposure in the offspring through preclinical studies. Alcohol teratogenesis is more potent when administered with cannabis and has more negative effects on the fetus than alcohol alone. Recent data demonstrate the interaction of ethanol and cannabis with the Endocannabinoid system, which plays an important role in neurodevelopment and explains the morphological and behavioral changes seen in preclinical studies. The second article is a systematic review that investigates Brazilian research on FASD, focusing on the instruments used for the neuropsychological assessment of individuals with FASD. While developed countries have decades of research on FASD, in Brazil numerous factors slow down the progress of in this and other areas of research. Socioeconomic status, cultural, and geopolitical divergences are some of these factors, which hinder the development, adaptation, and validation of instruments used in the diagnosis and neuropsychological assessment of FASD. In addition, it is worth noting that the socioeconomic vulnerability of the Brazilian population is an important factor in the increase in the occurrence of more severe forms of FASD. The systematic review points to the need to validate neuropsychological tools for the diagnosis and cognitive assessment of individuals with FASD in Brazil, and the participation of a multidisciplinary team in the diagnosis of FASD.