The United States is in the midst of an opioid epidemic. In addition to other system level interventions, almost all states have responded to the crisis by implementing prescription drug monitoring programs (PDMPs). PDMPs are state-level interventions that track the dispensing of Controlled Substances. Data generated at the time of medication dispensing is uploaded to a central data server that may be used to assist in identifying drug diversion, medication misuse, or potentially aberrant prescribing practices. Prior studies assessing the impact of PDMPs on trends in opioid-related morbidity have often failed to take into account the wide heterogeneity of program features and how the effectiveness of these features may be mitigated by insurance status. Previous research has also failed to differentiate the effects of these programs on prescription vs. illicit opioid-related morbidity. The studies in this dissertation attempt to address these gaps using epidemiological techniques to examine the associations between specific PDMP features and trends in prescription and illicit opioid-related poisonings in populations of different insurance beneficiaries. Results of these studies demonstrate that implementation of specific PDMP features is significantly associated with differential trends in prescription and illicit-opioid related poisonings and that the effectiveness of these features vary depending on the insurance status of the population studied. These results suggest that PDMPs offer a valuable tool in addressing the United States’ opioid epidemic, and may be used as empirical evidence to support PDMP best practices in the future.

Increased opioid analgesic (OA) prescribing has been associated with increased risk of prescription opioid diversion, misuse, and abuse. States established prescription drug monitoring programs (PDMPs) to collect and analyze electronic records for dispensed controlled substances to reduce prescription drug abuse and diversion. PDMP data can be used by prescribers for tracking patient’s history of controlled substance prescribing to inform clinical decisions. The studies in this dissertation are focused on the less utilized potential of the PDMP data to enhance public health surveillance to monitor OA prescribing and co-prescribing and association with opioid overdose mortality and morbidity. Longitudinal analysis of OA prescribing and evaluation of the effect of recent policies and opioid prescribing guidelines require consensus measures for OA utilization and computational tools for uniform operationalization by researchers and agencies. Statistical macros and computational tools for OA utilization measures were developed and tested with Kentucky PDMP data. A set of covariate measures using mortality and morbidity surveillance data were also developed as proxy measures for prevalence of painful conditions justifying OA utilization, and availability of heroin and medication treatment for opioid use disorder. A series of epidemiological studies used the developed OA measures as outcomes, and adjusted for time-varying socio-demographic and health care utilization covariates in population-averaged statistical models to assess longitudinal trend and pattern changes in OA utilization in Kentucky in recent years. The first study, “Trends and Patterns of OA Prescribing: Regional and Rural-Urban Variations in Kentucky from 2012 to 2015,” shows significant downward trends in rates of residents with OA prescriptions. Despite the significant decline over time, and after accounting for prevalence of injuries and cancer, the rate of dispensed OA prescriptions among residents in Kentucky Appalachian counties remained significantly higher than the rest of the state. The second study, “Population-Level Measures for High-Risk OA Prescribing: Longitudinal Trends and Relationships with Pain-Associated Conditions,” shows significant reduction in high-risk OA prescribing (e.g., high daily dosage, long-term use, concurrent prescriptions for OA and benzodiazepines) from 2012 to 2016, significantly positive associations between high-risk OA prescribing and cancer mortality rates with no substantial change in the association magnitude over time, and declining strengths of positive associations between high-risk OA prescribing and acute traumatic injuries or chronic non-cancer pain over the study period. The third study, “A Reciprocal Association between Longitudinal Trends of Buprenorphine/Naloxone Prescribing and High-Dose OA Prescribing,” indicates a significant reciprocal relationship between high-dose OA prescribing and buprenorphine/ naloxone prescribing, and a clinically meaningful effect of buprenorphine/naloxone prescribing on reducing OA utilization. The results from the studies advanced the understanding of the epidemiology of opioid use and misuse in Kentucky, and identified actionable risk and protective factors that can inform policy, education, and drug overdose prevention interventions. The developed operational definition inventory and computational tools could stimulate further research in Kentucky and comparative studies in other states.

Dans la pratique courante, la posologie des anticancéreux est le plus souvent normalisée parrapport à la surface corporelle du patient (parfois son poids). Cependant, cette adaptation de dose neprend pas en compte la variabilité interindividuelle pharmacologique du médicament. Les facteursmodulant cette dernière sont nombreux, dont notamment les capacités individuelles de métabolisme etd’élimination. A dose égale, l’exposition systémique du patient peut donc varier, et entraîner un risquede surdosage pour certains patients, avec la survenue de toxicités, ou de sous-dosage pour d’autres,associée à une limitation de l’efficacité thérapeutique. Des alternatives à l’utilisation de la surfacecorporelle ont donc été proposées afin de prendre en compte de façon plus importante la variabilitéinterindividuelle des patients, tel que le suivi thérapeutique pharmacologique ou lapharmacogénétique. Les polymorphismes des gènes codants pour des enzymes impliquées dans lemétabolisme ou le transport des cytotoxiques peuvent modifier leur activité et donc influer sur lapharmacocinétique d’un médicament donné. Le développement des connaissances dans ces domainespourrait permettre la mise en place, de façon progressive, de nouvelles méthodes d’ajustement de laposologie.Ce projet de thèse porte sur l’individualisation de la posologie des anticancéreux ens’intéressant aussi bien aux chimiothérapies cytotoxiques, avec pour modèle l’irinotecan, qu’auxthérapies ciblées, en distinguant dans cette même classe les inhibiteurs de tyrosine kinase et lesanticorps monoclonaux (modèle du bévacizumab). Afin d’optimiser l’index thérapeutique de cestraitements, l’adaptation de la posologie a été abordée selon le profil pharmacogénétique maiségalement selon le profil pharmacocinétique.Une étude clinique a été mise en place afin d’évaluer, en terme de toxicité et d’efficacité,l’intérêt d’une adaptation de posologie de l’irinotécan dans le cadre d’une polychimiothérapie dans letraitement du cancer colorectal (FOLFIRI +/- bévacizumab ou cétuximab), en se basant sur unpolymorphisme génétique de l’UGT1A1, enzyme impliquée dans son métabolisme. Les résultats del’étude intermédiaire de cet essai de phase II, mené chez 16 patients, sont en faveur de la poursuite del’étude avec 12,5% de toxicités hématologiques de grade 4 et un taux de réponse objective de 58,3 %.L’objectif secondaire a été l’étude de la pharmacocinétique de l’irinotécan et de ses métabolites lorsd’une des cures de chimiothérapie. Ces dosages ont été réalisés par chromatographie liquide couplée àla spectrométrie de masse. Cette technique, largement utilisée pour la quantification plasmatique desmédicaments, a été développée et validée selon les normes en vigueur. Le dosage du bévacizumab, unanticorps monoclonal associé au FOLFIRI dans le traitement du cancer colorectal, a lui aussi étédéveloppé par cette technique et a fait l’objet d’un travail de mise au point avec l’identification despeptides spécifiques, ainsi que l’optimisation des étapes de prétraitement de l’échantillon et de latechnique analytique.En parallèle, la mise en place du dosage des inhibiteurs de tyrosine kinase par spectrométrie demasse, ainsi que sa validation, ont fait partie de ce travail de thèse, et autorisent son utilisation enroutine hospitalière dans le cadre du suivi thérapeutique pharmacologique.Mots-clés : suivi thérapeutique pharmacologique, pharmacogénétique, irinotécan, chromatographie / Usually, the dosage of anticancer is normalized with used to the patient's body surface area(sometimes its weight). However, this adaptation does not take into account the interindividualpharmacological variability in the pharmacokinetics of the drug. Factors modulating thispharmacokinetics are numerous, including interindividual capacities of metabolism and elimination.At the same dosage, the systemic exposure of the patient can thus be changed, and cause a risk ofoverdosing for some patients, with the development of toxicities, or under dosing for others, withlimiting the therapeutic efficacy. Alternatives to the use of the body surface area have been proposedin order to more take account of inter-individual variability of patients, such as therapeutic drugmonitoring or pharmacogenetics. Genetic polymorphisms of enzymes involved in the metabolism ortransport of a cytotoxic, can change and modify their activity, and impact on drug’s metabolism. Thedevelopment of knowledge in these areas could allow the establishment of new methods to dosage’sadjustment.This PhD project focuses on individualizing dosage of anticancer focusing in both cytotoxicchemotherapies with the model of irinotecan, as targeted therapies, distinguishing in this same classtyrosine kinase inhibitors and monoclonal antibodies (bevacizumab model). To optimize thetherapeutic index of these therapies, the dose adjustment was according to pharmacogenetics profile,but also according to the pharmacokinetics profile.A clinical study was developed to studying, in terms of toxicity and efficacy, the interest ofadapting dosage of irinotecan in combination of chemotherapy to traitement of metastatic colorectalcancer (FOLFIRI +/- bevacizumab or cetuximab), based on a genetic polymorphism of UGT1A1, anenzyme involved in its metabolism. Results of the interim study of this phase II trial, conducted in 16patients, are in favor of study continuation with 12.5% grade 4 hematological toxicities, and objectiveresponse rate of 58.3%. The secondary objective was to study the pharmacokinetics of irinotecan andits metabolites during one cycle. These assays were performed by liquid chromatography-massspectrometry. This technique, widely used for quantification of drug in plasma was developed andvalidated according to standards. The dosage of bevacizumab, a monoclonal antibody used tocolorectal cancer treatment (associated to FOLFIRI) was also developed by this technique, withspecific peptide identification, and optimization of sample preparation and analytical technique.In parallel, the implementation of the determination of tyrosine kinase inhibitors by massspectrometry and its validation were part of this PhD project, and allow its use in hospital routine intherapeutic drug monitoring.

<p>Non-adherence to medication is a major obstacle in the treatment of depression. The objectives of the present study were to explore the effect of two interventions aiming to increase antidepressant treatment adherence, and to examine long-term consequences and costs of depression in adherent and non-adherent primary care patients. </p><p>A randomised controlled design was used to assess the respective effects of a written educational adherence enhancing programme and therapeutic drug monitoring in patients with major depression treated with sertraline for 24 weeks. All patients were prospectively followed during two years. </p><p>Treatment adherence was found in 41% of the 1031 included patients. None of the interventions resulted in a significant increase in adherence rate. However, significantly more patients in the group receiving the written educational material had responded at week 24 as compared to patients in the control group. </p><p>The overall remission rate after two years was 68%. In total, 34% of the responders experienced at least one relapse. Response and remission rates at week 24, year 1 and year 2 were significantly higher in adherent as compared to non-adherent patients. No relationship between adherence and relapse rate was seen. </p><p>The mean total cost per patient during two years was KSEK 363 whereof indirect costs represented 87%. No significant differences in costs between intervention groups or between adherent and non-adherent patients could be demonstrated. However, the mean cost per patient was 39% lower for treatment responders as compared to non-responders. </p><p>Non-adherence was predicted by age below 35 or above 64 years, no concomitant medications, personality disorder, sensation seeking personality traits and substance abuse. </p><p>The results indicate a strong positive relationship between treatment adherence and clinical outcome. In addition, the study shows that depression is a costly disease and that certain patient characteristics predict non-adherence.</p>

Non-adherence to medication is a major obstacle in the treatment of depression. The objectives of the present study were to explore the effect of two interventions aiming to increase antidepressant treatment adherence, and to examine long-term consequences and costs of depression in adherent and non-adherent primary care patients. A randomised controlled design was used to assess the respective effects of a written educational adherence enhancing programme and therapeutic drug monitoring in patients with major depression treated with sertraline for 24 weeks. All patients were prospectively followed during two years. Treatment adherence was found in 41% of the 1031 included patients. None of the interventions resulted in a significant increase in adherence rate. However, significantly more patients in the group receiving the written educational material had responded at week 24 as compared to patients in the control group. The overall remission rate after two years was 68%. In total, 34% of the responders experienced at least one relapse. Response and remission rates at week 24, year 1 and year 2 were significantly higher in adherent as compared to non-adherent patients. No relationship between adherence and relapse rate was seen. The mean total cost per patient during two years was KSEK 363 whereof indirect costs represented 87%. No significant differences in costs between intervention groups or between adherent and non-adherent patients could be demonstrated. However, the mean cost per patient was 39% lower for treatment responders as compared to non-responders. Non-adherence was predicted by age below 35 or above 64 years, no concomitant medications, personality disorder, sensation seeking personality traits and substance abuse. The results indicate a strong positive relationship between treatment adherence and clinical outcome. In addition, the study shows that depression is a costly disease and that certain patient characteristics predict non-adherence.

The aim of this study was to investigate the possible toxicity of the flavonoid-containing plant, Artemisia afra and especially establish the safety of the aqueous extract of this plant after acute and chronic administration to mice and rats respectively.

The aim of this study was to investigate the possible toxicity of the flavonoid-containing plant, Artemisia afra and especially establish the safety of the aqueous extract of this plant after acute and chronic administration to mice and rats respectively.

Diss. Linköping : Univ., 2003.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2007. / Härtill 4 uppsatser.

Durant la dernière décennie, les inhibiteurs de tyrosine kinases (ITK) ont radicalement changé l’évolution de certains cancers comme la leucémie myéloïde chronique (LMC) ou les tumeurs stromales gastro-intestinales (GIST). Ils sont aujourd’hui largement utilisés dans le traitement de diverses pathologies malignes, permettant un allongement de la survie globale. Cependant, certains patients ne montrent pas d’amélioration au cours du traitement par ITK. Les mécanismes évoqués sont multifactoriels et possèdent une origine pharmacocinétique, pharmacodynamique ou pharmacogénétique. En effet, l’une des causes majeures de variabilité commune à tous ces ITK réside dans un métabolisme impliquant le cytochrome 3A4, dont l’expression est soumise à de nombreux facteurs. L’objectif de cette thèse a été d’approfondir ces mécanismes et d’évaluer certaines stratégies afin d’augmenter l’efficacité de ces médicaments. Ce travail a consisté en premier lieu à développer une méthode chromatographique sensible et rapide permettant le dosage de neufs ITK commercialisés ou en phase avancée de développement. Cet outil, à la base du suivi thérapeutique pharmacologique, a été utilisé dans le cadre de la LMC pour mesurer les concentrations plasmatiques d’imatinib de plus de 3000 patients. Les informations cliniques de ces patients ont été saisies dans une base de données servant de support à l’évaluation de la réponse en fonction de la concentration. Nous avons ainsi confirmé que les patients présentant des concentrations supérieures au seuil d’efficacité de 1000 ng/mL avaient une plus grande probabilité de réponse. Dans la continuité de ce projet, nous avons évalué la relation concentration-efficacité de l’imatinib dans les GIST et trouvé un seuil d’efficacité voisin de 800 ng/mL. Tous les facteurs de variabilités ne sont cependant pas maitrisables avec un dosage plasmatique. La littérature rapporte en effet que certains ITK sont des substrats de transporteurs cellulaires potentiellement impliqués dans la résistance au traitement. Nous avons donc entrepris de doser ces ITK à l’intérieur même des cellules, d’abord in vitro afin d’évaluer ces mécanismes de transport, puis in vivo dans les cellules de patients traités par ces ITK. Un lien a ainsi été montré entre la capacité d’incorporation des molécules et la réponse au traitement. Enfin, le versant pharmacogénétique de l’un de ces transporteurs (MDR1) a été étudié, indiquant une relation entre certains haplotypes ou polymorphismes et la concentration plasmatique d’une part et la réponse à l’imatinib d’autre part. En conclusion, ces différentes stratégies basées sur le dosage plasmatique ou intracellulaire et sur la pharmacogénétique semblent apporter des éléments permettant l’amélioration de la réponse au ITK ou la détection précoce de mauvaise réponse. / During the last decade, tyrosine kinases inhibitors (TKI) have dramatically changed the prognosis of several cancers such as chronic myeloid leukaemia (CML) or gastro-intestinal stromal tumours (GIST). They are widely used in the treatment of various malignant pathologies, leading to a prolonged overall survival. However, some patients do not show improvement when treated with TKI. The supposed mechanisms are multifactorial and could have an origin in pharmacokinetics, pharmacodynamics or pharmacogenomics. Indeed, one of the major reasons of common variability of these TKI involves their metabolism by cytochrome 3A4, whose expression is subjected to many factors. The aim of this thesis was to deepen these mechanisms and to assess some strategies to increase the efficacy of these drugs. This work consisted first in developing a rapid and sensitive chromatographic method allowing determination of nine commercialised (or in advanced clinical development) TKI. Serving as a basis for therapeutic drug monitoring, this was used as part of CML management to measure imatinib plasmatic concentration of more than 3000 patients. The clinical information of these patients was recorded in a database and used as support for the evaluation of the response according to concentration. Thus, we confirmed that patients having concentration higher than the effectiveness threshold of 1000 ng/mL got higher probability of response. In the same way, we assessed relationship between imatinib concentration and efficacy in GIST and found an effectiveness threshold closed to 800 ng/mL. However, several factors of variability remain unmanageable with only plasmatic determination. Indeed, literature reported that some TKI were substrates of cellular transporters, potentially involved in the resistance to treatment. We therefore decided to determine concentration of these TKI into the cells, first in vitro to assess these mechanisms of transport, and then in vivo into the cells of patients treated by these TKI. A link was shown between the incorporation ability of molecules and the response to the treatment. Finally, a pharmacogenetic approach showed a relationship between some haplotypes or polymorphisms of a transporter (MDR1) and plasmatic concentration on one hand, and response to the imatinib on the other hand. In conclusion, these different strategies based on plasmatic or intracellular determination of TKI and on pharmacogenomics contribute to improvement of the response to TKI or early detection of non-response.