Contexte : Les neuroleptiques sont souvent prescrits chez les sujets âgés et les patients souffrant de schizophrénie qui sont des personnes vulnérables. Notre objectif était d'étudier l'impact des NLP en situation réelle de prescription, dans ces deux populations. Etude 1. Consommation de neuroleptiques et décès en période de canicule chez les sujets âgés. A partir de données de l'Assurance Maladie, nous avons comparé les prescriptions de NLP chez des sujets âgés décédés pendant la canicule d'août 2003 (n=11624) aux prescriptions de témoins non décédés. Nous avons mis en évidence une association entre risque de décès et consommation de neuroleptiques, que ce soit juste avant ou pendant le pic de canicule et indépendamment d'autres médicaments, d'une démence ou d'une pathologie cardiaque. Etude 2. Efficacité réelle des NLP chez les patients souffrant de schizophrénie. A partir de données d'une cohorte observationnelle ayant inclus en France entière des schizophrènes adultes, nous avons montré que chez les patients déjà traités par NLP (n=5500), il y avait une association entre traitement par antipsychotique atypique (vs. NLP classique) et une meilleure satisfaction avec les soins et ce, pour tous les AA pris en compte et indépendamment du niveau de symptomatologie. Par ailleurs, chez les patients naïfs vis-à-vis de tout NLP et pour qui un traitement était introduit pour la première fois (n=467), un tiers des patients ne s'améliorait pas. Les facteurs prédictifs d'une meilleure réponse clinique étaient une moindre sévérité initiale globale des symptômes et des symptômes négatifs de schizophrénie. Au total, il existait cinq types de trajectoires d'évolution clinique.

The global anti-dyslipidemic market grew by 19% from 2000 to 2001, achieving sales of over $21 billion (Smith, 2004: 2). This market is currently well sewed by a number of effective and well-tolerated treatments. Lipid-lowering drugs are considered as the first choice drugs in control of dyslipidemias and they are well tolerated by most patients. As with many drug therapies, there should be a balance between the benefits of cholesterol lowering agents, increased medication cost and the overall risk of adverse drug reactions. According to Ballesteros (2001: 514), hypolipidemic drugs are consumed on a large scale and most consumers are elderly. This warrants a study of expenditure incurred because of inadequate prescribing of these agents. The general objective of this study was to determine the utilisation and cost of hypolipidemic drugs in the private health care environment in South Africa. A quantitative retrospective drug utilisation review was performed using a medicine claims database. Data for twenty-four consecutive months (May 1, 2001 to April 30, 2003) were used to determine and compare the utilisation patterns and cost of drugs associated with the management of dyslipidemia a year before (1st May 2001 to 30 April 2002) and a year after (1st May 2002 to 30 April 2003) the implementation of a medicine reference price system (MPL). Data analysis was done by calculating the average value, the standard deviation, effect size, and cost-prevalence indices. The results of this study revealed that hypolipidemic drugs constituted 2.70% (n = 21820911) and 2.78% (n =27277825) of the total number of all medicine items for the first and the second study years respectively. On the other hand, the total cost of all hypolipidemic drugs accounted for 6.33% (n= R3 097 604 602) and 6.23 % (n= R 4 053 280 295) of the total cost of all medicine items claimed during the first and the second study years respectively. The prevalence of generic hypolipidemic drugs accounted for 0.89% (n=589036) and 4.88% (n=759675) of the total number of hypolipidemic drugs claimed during the first and second study year respectively. Innovator drugs, on the other hand, constituted 99.1 1% (n=589036) and 95.11% (n=759675) of the total number of hypolipidemic drugs claimed during the first and second study years respectively. It was found that R23 694.5 and R603 277.36 could have been saved for generic bezafibrate and generic simvastatin respectively if they had been sold at ME'L prices. The total cost of generic hypolipidemic drugs accounted for 0.60% and 2.94%. The total cost of innovator hypolipidemic drugs accounted for 99.40% and 97.06% of the total cost of hypolipidemic drugs claimed during the first (n=R 196 076 050) and second (n=R 252 919 285) study year respectively. With respect to the prescribed daily dose, it was found that most prescriptions for individual hypolipidemic drugs did not conform to the defined daily dose. It was, however, found that most prescriptions whose prescribed daily dose was for one tablet once daily and whose strength was similar to the defined daily dose conformed to the defined daily dose. The conclusion is that there was an insignificant difference in both the prevalence and cost of hypolipidemic drugs a year before and after the implementation of MPL. It was further concluded that increased utilisation of generic hypolipidemic medicine items a year after the implementation of the MPL, could have been brought about by the introduction of generic simvastatin into the market as opposed to the implementation of the MPL. Recommendations for further studies will be formulated. / Thesis (M.Pharm. (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2005.

"Diabetes mellitus" refers to a spectrum of conditions, which all present with hyperglycaemia as a common medical finding. Diabetes was once thought of as a single disease, but according to Setter et a/. (2000:378), it includes a heterogeneous group of disorders that are secondary to various genetic predispositions and precipitating factors. Type 1 diabetes mellitus (DM) accounts for 10 to 15% of all cases of diabetes mellitus and is clinically characterised by hyperglycaemia and a propensity to diabetic keto-acidosis. Its control requires chronic insulin treatment. Although it may occur at any age, it most commonly develops in childhood or adolescence and is the predominant type of diabetes mellitus diagnosed before age 30 (Beers & Berkow, 2004). Type 2 DM is usually the type diagnosed in patients older than 30 years of age. It is also commonly associated with obesity (Berkow, 1992:1108). The objective of this study was to review the usage and cost of antidiabetic drugs and to determine the influence of the pricing regulations on the cost of these drugs. This research can be classified as retrospective and quantitative. Data were obtained from a prescription claims database, and the study population consisted of all the antidiabetic prescriptions for the year 1 January 2004 to 31 December 2004. The one-year period was divided into three study periods, namely January to April, May to August and September to December. Firstly diabetes mellitus was investigated in order to understand the disease and to determine the prevalence and treatment thereof. It was found that diabetes mellitus is a heterogeneous disorder acquired from both genetic and environmental factors and that education for the general population, and in particular for the patients, is the key to preventing and controlling diabetes and reducing the complications arising from it. Secondly managed health care, pharmaco-economics and a drug utilisation review were investigated in order to understand these concepts. The influence of the South African Government on health care was discussed, including the new pricing regulations of medicine in South Africa. Thirdly, the utilisation patterns of antidiabetic drugs were reviewed, analysed and interpreted. It was determined that the oral antidiabetic agents are relatively less expensive than the insulins and that they are prescribed more frequently, and secondly that the biguanides presented almost half (49.4%, n = 116 138) of all the oral antidiabetic agents. It was also determined that the average cost of the oral antidiabetic drugs was between 21 .O% and 28.0% lower in 2004 than in 1996 - an indication that, despite inflation, the antidiabetic drugs were less expensive in 2004 than eight years ago in 1996. It was also calculated that the total cost savings in antidiabetic medication could have been R1 448 682.26 if the lower price of antidiabetic agents had been implemented during the period January to April. And finally it was also determined that further substantial "cost savings" could have been possible if all the innovator antidiabetic products had been substituted for less expensive generic antidiabetic products. Abstract / Thesis (M.Pharm. (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2006.

Background: Calcium channel blockers are mainly divided into antihypertensive and antianginal treatment agents. In 2000 it was estimated that 972 million adults worldwide were living with hypertension and it is expected to affect 1.56 billion patients by 2025. The incremental expenditure for the antihypertensive therapeutic group in the United States of America was estimated at $US 55 billion per annum in 2006. It was stated that around seven million people in the United States of America suffered from angina, with around 400 000 new reports every year. Objective: To determine the prescribing patterns of calcium channel blocker medicine items during 2005 to 2008 in a section of the private health care sector of South Africa. Methods: A retrospective quantitative drug utilisation review was done using a medicine claims database ranging over four years from 1 January 2005 to 31 December 2008. The total medicine claims database was divided into cardiovascular medicine items and then into calcium channel blockers. These were analysed according to age as well as gender. Further analysis included adherence of calcium channel blockers as well as an analysis of prescribers of these items during the study period. Results: The total number of patients on the medicine claims database consisted of 1 509 621 patients in 2005. This number decreased to 974 497 patients in 2008. The most medicine items were dispensed in 2006 (n = 21 113 422) with an average cost of R 92.82 (SD = 196.42) per medicine item. It was noted that 16.05% (n = 242 264) of patients used at least one cardiovascular item in 2005. The percentage of cardiovascular medicine item users increased by 4.36% during the study period to 20.41% (n = 198 847) in 2008. In 2008 the cardiovascular medicine items dispensed were responsible for 19.18% (R 342 565 308.41) of the total cost of all medicine items claimed. In 2005 the results revealed that 1.63% (n = 318 258) of all medicine items dispensed were calcium channel blocker medicine items. The percentage of calcium channel blockers increased to 2.24% (n = 367 437) of the total number of medicine items in 2008. The cost prevalence index was calculated for the calcium channel blockers and the value declined from 1.5 in 2005 to 1.22 in 2008, which indicated that the items dispensed were relatively expensive, but less than in 2005. An increase of 16.17% in the usage of generic medicine items were noted from 2005 to 2008. More female patients than male patients claimed medicine items during the study period. A higher percentage of male patients used a cardiovascular medicine item as well as calcium channel blockers during the study period compared to females and a larger percentage of their medicine expenditure was used on cardiovascular medicine items as well as calcium channel blockers compared to females. The usage of cardiovascular medicine items as well as calcium channel blocker medicine items increased with patient age. In 2008, 17.98% of patients older than 65 years of age used a calcium channel blocker compared to 0.97% of patients aged > 25 <= 35 years. Only 60.34% of calcium channel blockers items were used with acceptable refill adherence rates during the study. More than a third of the calcium channel blockers medicine items used had unacceptable low adherence rates from 2005 to 2008. In each of the study years the highest potential saving with generic substitution was seen with amlodipine containing items. It was also observed that some generic substitutions could be relatively more expensive than the innovator products and an increased cost instead of a saving through generic substitution may have occurred. Conclusion: This study highlighted the prescribing patterns and cost implications of calcium channel blockers in the private health care sector of South Africa. It is recommended that a more in–depth study of the adherence of calcium channel blockers be done. This study should also include the cost strategies of generic substitution of calcium channel blockers in South Africa. / Thesis (M.Pharm (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2011.

Background: Calcium channel blockers are mainly divided into antihypertensive and antianginal treatment agents. In 2000 it was estimated that 972 million adults worldwide were living with hypertension and it is expected to affect 1.56 billion patients by 2025. The incremental expenditure for the antihypertensive therapeutic group in the United States of America was estimated at $US 55 billion per annum in 2006. It was stated that around seven million people in the United States of America suffered from angina, with around 400 000 new reports every year. Objective: To determine the prescribing patterns of calcium channel blocker medicine items during 2005 to 2008 in a section of the private health care sector of South Africa. Methods: A retrospective quantitative drug utilisation review was done using a medicine claims database ranging over four years from 1 January 2005 to 31 December 2008. The total medicine claims database was divided into cardiovascular medicine items and then into calcium channel blockers. These were analysed according to age as well as gender. Further analysis included adherence of calcium channel blockers as well as an analysis of prescribers of these items during the study period. Results: The total number of patients on the medicine claims database consisted of 1 509 621 patients in 2005. This number decreased to 974 497 patients in 2008. The most medicine items were dispensed in 2006 (n = 21 113 422) with an average cost of R 92.82 (SD = 196.42) per medicine item. It was noted that 16.05% (n = 242 264) of patients used at least one cardiovascular item in 2005. The percentage of cardiovascular medicine item users increased by 4.36% during the study period to 20.41% (n = 198 847) in 2008. In 2008 the cardiovascular medicine items dispensed were responsible for 19.18% (R 342 565 308.41) of the total cost of all medicine items claimed. In 2005 the results revealed that 1.63% (n = 318 258) of all medicine items dispensed were calcium channel blocker medicine items. The percentage of calcium channel blockers increased to 2.24% (n = 367 437) of the total number of medicine items in 2008. The cost prevalence index was calculated for the calcium channel blockers and the value declined from 1.5 in 2005 to 1.22 in 2008, which indicated that the items dispensed were relatively expensive, but less than in 2005. An increase of 16.17% in the usage of generic medicine items were noted from 2005 to 2008. More female patients than male patients claimed medicine items during the study period. A higher percentage of male patients used a cardiovascular medicine item as well as calcium channel blockers during the study period compared to females and a larger percentage of their medicine expenditure was used on cardiovascular medicine items as well as calcium channel blockers compared to females. The usage of cardiovascular medicine items as well as calcium channel blocker medicine items increased with patient age. In 2008, 17.98% of patients older than 65 years of age used a calcium channel blocker compared to 0.97% of patients aged > 25 <= 35 years. Only 60.34% of calcium channel blockers items were used with acceptable refill adherence rates during the study. More than a third of the calcium channel blockers medicine items used had unacceptable low adherence rates from 2005 to 2008. In each of the study years the highest potential saving with generic substitution was seen with amlodipine containing items. It was also observed that some generic substitutions could be relatively more expensive than the innovator products and an increased cost instead of a saving through generic substitution may have occurred. Conclusion: This study highlighted the prescribing patterns and cost implications of calcium channel blockers in the private health care sector of South Africa. It is recommended that a more in–depth study of the adherence of calcium channel blockers be done. This study should also include the cost strategies of generic substitution of calcium channel blockers in South Africa. / Thesis (M.Pharm (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2011.

Magister Scientiae Dentium - MSc(Dent) / AIM:The aim of this study was to review the data available from the Department of Health(DOH), on pre-school paediatric patients treated under Dental General Anaesthesia(DGA), at public health facilities in the Western Cape (WC) in order to ascertain the type and nature of treatment provided.METHODOLOGY:This retrospective descriptive study reviewed the records on the Department of Health(DoH) Database of 16 732 pre-school patients treated under dental general anaesthesia in the period 1 January 2005 until 31 December 2007. A questionnaire was also completed telephonically with 22 dentists from the district dental health clinics.Summary descriptive statistics were calculated from data collected and comparisons were drawn between services available at the health districts and academic hospitals.RESULTS:Of the 58 255 procedures recorded for pre-school patients in the district health clinics in the Western Cape, 99.94% were for extractions provided and 0.5% for restorations.The average number of teeth extracted was 10.4 (SD ±3.9).The average rate of DGA per 1000 of the population was 1.06. Only 9% (2) of dentists at district clinics reported that pre-DGA prevention was provided and 5% (1) reported including post-DGA prevention. The Academic Hospital at Tygerberg Oral Health Centre was the only facility in the Western Cape that provided comprehensive dental treatment for pre-school patients which included restorations, extractions, pre and post DGA prevention. Red Cross Children’s Hospital provided treatment for pre-school patients under DGA that included extractions, pre- and post DGA, but no restorative treatment. CONCLUSION:The demand for DGA in pre-school patients in the WC was high. The lack of prevention associated with DGA in the public health service is the most likely reason the retreatment rate under DGA was reported by dentists as being 77%. There was an absence of protocol regarding DGA for pre-school patients in the public health service.RECOMMENDATIONS:Guidelines formulated were recommended for use in the public service for pre-school patients being treated under DGA and includes the provision of preventive interventions such as regular topical fluoride applications, oral hygiene instruction and dietary advice.

Les antidépresseurs figurent parmi les médicaments les plus prescrits dans les pays industrialisés, incluant la France. L’utilisation croissante de ces médicaments dans la population générale suscite de multiples préoccupations quant à leurs effets indésirables sur la santé des populations. Plusieurs travaux de recherche se sont récemment intéressés à l’impact de l’utilisation prolongée de ces médicaments sur le risque cardiométabolique. Toutefois, les résultats produits sont contradictoires, limitées et ne concernaient pas la population Française. L’objectif général de ce travail de thèse consiste donc à étudier, à partir des données de deux grandes cohortes françaises (E3N et D.E.S.I.R.), l’association entre l’utilisation de médicaments antidépresseurs et le risque cardiométabolique, en essayant d’en comprendre les mécanismes sous-jacents. La première étude a montré que l’utilisation d’antidépresseurs était associée à un risque accru de diabète de type II. Cependant, l’association était évidente uniquement chez les femmes qui avaient plus de consultations médicales au cours des douze derniers mois. Les résultats de la seconde étude n’ont montré aucune association entre l’utilisation d’antidépresseurs et les marqueurs physio-biologiques qui caractérisent le diabète tels que : la glycémie à jeun, l’hémoglobine glyquée, la fonction des cellules β et la sensibilité à l’insuline. Enfin la troisième étude de ce travail de thèse a mis en évidence un risque accru de syndrome métabolique chez les utilisateurs d’antidépresseurs même si l’effet semblait se potentialiser chez les hommes uniquement. Les résultats de ces études apportent des éléments en faveur de l’hypothèse d’un biais de détection pour expliquer l’association observée entre utilisation d’antidépresseurs et diabète. Ce travail de thèse a permis de clarifier l’association entre l’utilisation d’antidépresseurs chez l’adulte et le risque cardiométabolique. Les implications scientifiques, cliniques et de santé publique sont discutées. / Antidepressants are among the most frequently prescribed medications in industrialized countries, including France. The increasing use of antidepressants in the general population has led to concerns about their adverse effects on health. Recently, important research work has focused on the impact of the prolonged use of antidepressants on cardiometabolic risk. However, the results produced were conflicting, limited and were not based on French population. The general objective of this thesis is therefore to study, based on data from two large French cohorts (E3N and D.E.S.I.R.), the association between the use of antidepressant drugs and cardiometabolic risk, with the ambition to understand the underlying mechanisms. The first study showed antidepressant medication use to be associated with an increased risk of type II diabetes. However, this association was evident only in women with more medical visits in the last twelve months. The results of the second study shows no association between antidepressant medication use and physio-biological markers that characterize diabetes such as fasting plasma glucose, glycated haemoglobin, β-cell function and insulin sensitivity. Finally, the third study showed an increased risk of metabolic syndrome among users of antidepressants, although the effect was apparent in men only. The results of these studies provide evidence supporting the hypothesis of a detection bias to explain the observed association between antidepressants use and diabetes. This work has helped to clarify the association between the use of antidepressants in adults and cardiometabolic risk. The scientific, clinical and public health implications are discussed.

La cardiopathie ischémique incluant l’insuffisance cardiaque est la deuxième cause de mortalité annuelle au Canada. Bien que de nombreuses stratégies préventives et des thérapies pharmacologiques retardent la progression de la maladie, il n’existe aucune solution qui module directement aux les remaniements pathologiques et la perte de cardiomyocytes. Au cours des 25 dernières années, de multiples progrès dans les domaines de la médecine régénérative et de la thérapie cellulaire ont annoncé des résultats prometteurs, mais les résultats d’études cliniques contemporaines demeurent plutôt mitigés. COMPARE-AMI, une étude randomisée-contrôlée de phase II, a évalué l’effet d’injections intracoronariennes de cellules souches hématopoïétiques CD133+ chez des patients souffrant d’infarctus aigu. IMPACT-CABG, une ÉRC de phase II a également évalué l’effet d’injections intramyocardiques de cellules CD133+ chez les patients souffrant de cardiomyopathie ischémique chronique nécessitant une revascularisation chirurgicale. Nous avons émis l’hypothèse que les cellules CD133+ utilisées dans des études cliniques de cardiomyopathies ischémiques aiguës et chroniques des patients répondant à la thérapie cellulaire exhibent des signatures transcriptomiques communes responsables de leur effet thérapeutique. En classant les patients en tant que répondants et non-répondants selon leur fonction cardiaque, nous avons évalué, a posteriori, ces patrons d’expression. Les cellules CD133+ autologues de patients jugés répondants expriment des signatures qui sont hautement conservées entre elles (incluant l’angiogénèse, la régulation de la réponse au stress et la survie cellulaire) et uniques d’un modèle à l’autre et qui pourraient, en partie, exprimer les issus cliniques des patients. Afin de maximiser les effets de la thérapie cellulaire aux cellules souches, nous avons par la suite tenté de reproduire ces phénotypes par stimulation pharmacologique avec des inhibiteurs d’HSP90 pour leurs effets qui semblent reproduire ces signatures. Ainsi, nous avons démontré qu’une stimulation de cellules souches mésenchymateuses humaines (CSMh) au Célastrol (inhibiteur HSP90) pouvait répliquer certains de ces phénotypes. Notamment, des CSMh conditionnées activent des voies de signalisation de type ‘RISK’ et augmentent leur sécrétion de protéines en lien avec la réponse au stress ainsi que d’exosomes contenant des molécules impliquées dans la communication intercellulaire sans être liées à un changement de type cellulaire. De plus, les CSMh traitées semblent améliorer la guérison de plaie par activité paracrine et sont plus résistante à la sénescence oxydative. Ces résultats encourageants nous permettent d’envisager des stratégies plus poussées de pré-conditionnement cellulaire ex vivo de cellules CD133+ avant leur implantation. À terme, cela pourrait mener à une optimisation de la thérapie cellulaire afin d’en maximiser les bénéfices cliniques et d’en exploiter leur plein potentiel. / Ischemic cardiomyopathy and heart failure are the second annual cause of mortality in Canada. Despite rigorous prevention strategies and drug regimens preventing progression, no therapeutic modality can currently reverse the pathologic modifications of the disease. In the last quarter century, numerous advances in the field of regenerative medicine and cell therapy have demonstrated promising effects. COMPARE-AMI, a phase II randomized controlled trial (RCT), evaluated the effect of intracoronary injection of CD133+ cells in acute myocardial infarction following percutaneous intervention. IMPACTCABG, also a phase II RCT, evaluated the effect of intramyocardial injection of CD133+ hematopoietic stem cells in chronic ischemic cardiomyopathy at the time of surgical revascularization. That being said, we believe that the CD133+ cells used in therapy have shared transcriptomic signatures that are responsible for their clinical effects. By classifying patients into responders and non-responders according to an improvement in ejection fraction, we evaluated, a posteriori, those expression patterns. Autologous CD133+ cells of patients classified as responders expressed highly conserved transcriptomic signatures that could be responsible for the clinical outcomes of patients. Notably, these signatures were related to cardioprotective mechanisms including angiogenesis, stress response regulation and cell survival. In order to harness the full potential of stem cell therapy, we attempted to reproduce the identified phenotypes by pharmacological intervention with HSP90 inhibitors which are known to mimic some of these effets. Conditioned human mesenchymal stem cells (hMSC) activated ‘RISK’-type signaling pathways and augmented exosome and protein secretion relating to the response to cellular stress; this activation was unrelated to a switch of cell type. Furthermore, treated hMSC seemed to favour improved wound healing by paracrine activity and were more resistant to oxidative senescence. These encouraging results allow us to develop novel, more advance, strategies of ex vivo cell preconditioning before implantation, including of CD133+ cells. Ultimately, we hope that optimisation of cells through this mechanism and others will allow us to unleash the full potential of stem cell therapy.

L'obtention des données a été subventionnée par CIORA (Canadian Initiative for Outcomes in Rheumatology Care). CIORA a aussi financé l'analyse des données effectuées par Justine Zehr. L'Initiative Canadienne Pour Des Resultats En Soins Rhumatologiques (ICORA) a financé l'obtention des données et une partie de l'analyse statistique présentée dans ce mémoire. / La plupart des femmes ayant été atteintes d’arthrite juvénile idiopathique (AJI) continuent de souffrir d’arthrite à l’âge adulte. Certains des médicaments utilisés dans le traitement de l’arthrite tels que les corticostéroïdes et les antiinflammatoires non stéroïdiens (AINS) ne sont pas recommandés durant la grossesse. Le but de ce mémoire est d’estimer l’impact de la prise de ces médicaments sur les événements néfastes à l’accouchement chez ces femmes et leur bébé. Des données administratives sur les prescriptions de médicaments et les hospitalisations d’une cohorte de 1756 femmes ayant souffert d’AJI sont utilisées. Elles ont permis de reconstruire l’historique de consommation de médicaments contre l’arthrite chez les femmes durant la grossesse et l’année précédente. Pour ce faire, deux sous-cohortes de femmes ayant souffert d’AJI ont été formées : une pour la période grossesse et une autre pour la grossesse et l’année précédant celle-ci. Les événements d’intérêt étaient : malformations congénitales, complications néonatales, complications maternelles et petit poids pour l’âge gestationnel. Les proportions de cas présentant l’un de ces événements variaient entre 11,52% et 37,08%. Les médicaments ont été modélisés en terme d’utilisation ou de durée totale de consommation durant la période d’étude. Pour chaque événement, des modèles logistiques ont été estimés pour mesurer l’association entre la prise de médicaments et l’événement, en ajustant pour des variables de confusion potentielles : hypertension avant la grossesse, âge à l’accouchement et obtention du diplôme de secondaire. La consommation de corticostéroïdes semble augmenter statistiquement significativement le risque de présenter des malformations congénitales mais n’avoir aucun impact sur les autres événements. Aucun lien statistiquement significatif n’a été observé entre la consommation de AINS et les événements d’intérêt. / Most women diagnosed with juvenile idiopathic arthritis (JIA) continue to suffer from arthritis in adulthood. Some of the drugs used to treat arthritis such as corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) are not recommended during pregnancy. The objective of this thesis is to estimate the impact of these drugs on adverse birth outcomes in women previously diagnosed with JIA and their baby. Administrative data on drug prescriptions and hospitalizations in a cohort of 1756 women with a history of JIA were used to determine individual histories of drug use for the treatment of arthritis during pregnancy and during the year leading to the pregnancy. Two sub-cohorts of women who suffered from JIA were created : one corresponding to the pregnancy and the other to the pregnancy and the year leading to the pregnancy. The events of interest were : congenital anomalies, neonatal adverse outcomes, maternal adverse outcomes and small for gestational age babies. Proportions of the events ranged between 11,52% and 37,08%. Drugs were modelled in terms of use or duration of use during each of the study periods. Logistic regression models were fitted to measure the association between drugs and each of the events, adjusting for the following potential confounding variables : hypertension before pregnancy, maternal age and graduating from high school. The consumption of corticosteroids was associated with a statistically significant increased risk of congenital anomalies but had no impact on the other adverse events. No statistically significant associations were observed between consumption of NSAIDs and the adverse events of interest.

Introdução: A administração de morfina através de bomba de infusão controlada pelo paciente (ACP) no tratamento da dor pós-cirurgica e traumática tem-se mostrado promissora e faz parte da rotina terapêutica de muitos hospitais. No entanto, doses altas ou repetidas deste opióide estão associadas a efeitos adversos dose dependentes, dentre eles, a depressão respiratória. No caso de pacientes submetidos a cirurgias de tórax, além da analgesia pós-operatória, devem também ser considerados como parâmetros relevantes a anestesia regional (intratecal) no intra-operatório, a qual pode contribuir para melhora da função pulmonar pós-operatória e extubação precoce no pós-operatório e a circulação extracorpórea (CEC), potencial fator de alteração na cinética de fármacos. Objetivos: Investigar a influência da morfina intratecal e da circulação extracorpórea (CEC) sobre o consumo de morfina ACP, área sob a curva e escores de dor no período pós-operatório, bem como propor modelo farmacocinético-farmacodinâmico (PK-PD) para correlação dessas variáveis. Adicionalmente, foi desenvolvido método analítico para quantificação da morfina plasmática. Métodos: 59 pacientes submetidos à cirurgia eletiva de revascularização com CEC e sem CEC, na presença ou não de morfina intratecal intra-operatória foram distribuídos em grupos com base na combinação das intervenções acima mencionadas. No período pós-operatório, todos os pacientes receberam bolus IV de 1mg de morfina, e então o dispositivo ACP foi instalado na unidade de terapia intensiva, através de cateter venoso após a extubação orotraqueal. A morfina ACP foi liberada através de livre demanda solicitada pelo paciente (bolus de 1 mg), lock-out de 5 min até 36 horas do pós-operatório. Coletaram-se amostras seriadas de sangue de cateter venoso no período (3,6,12,18,24,36 horas) e a morfina plasmática foi determinada através da cromatografia líquida - espectrometria de massas (LC-MS/MS ESI+) após a purificação das amostras de plasma. A intensidade da dor foi monitorada no mesmo período pela escala análoga visual (EAV). A modelagem PK-PD foi investigada pelo GraphPad Prism 5.0. Resultados: O consumo de morfina e a intensidade da dor diferiram entre os grupos. O modelo do EMAX e a curva de histerese foram propostos pela modelagem PK-PD. Conclusões: O método analítico mostrou-se adequado na determinação da morfina plasmática. O consumo de morfina os escores de dor EAV no pós-operatório diferiram pela comparação dos grupos de pacientes investigados. Menores doses de morfina ACP foram requeridas pelos pacientes que receberam morfina intratecal intra-operatória. Demonstrou-se através do modelo do EMAX correlação não linear entre os parâmetros consumo de morfina e AUC0-36, e curva de histerese foi obtida quando se plotou consumo de morfina versus escore de dor. / Introduction: Morphine administration using patient controlled analgesia (PCA) for treatment of post surgical and traumatic pain has been a current practice in many hospitals. However, large or repeated doses of this opioid are associated to dose dependent adverse events, including, respiratory depression. Considering patients submitted to thoracic surgery, in addition to the postoperatory analgesia, two other relevant parameters must be considered: regional anesthesia (intrathecal) in the intra-operatory period, which should contribute to the respiratory function improvement and decrease in the extubation time; and the cardiopulmonary bypass (OPCAB), that potentially alters the drugs\' kinetics. Objectives: To investigate the influence of intrathecal morphine administration and cardiopulmonary bypass (OPCAB) in the morphine PCA drug requirements, area under the curve of morphine plasma concentration versus time and pain scores in the postoperative period, and to choose a pharmacokinetic-pharmacodynamic model to correlate these variables. In addition, an analytical method was developed to quantify morphine in plasma. Methods: 59 patients submitted to elective coronary artery bypass grafting (CABG) with (CPB) and without cardiopulmonary bypass (OPCAB), with and without intrathecal morphine in the intra-operative period were distributed by the combination of the above mentioned interventions. In the postoperative period, all the patients were given an IV bolus of 1mg of morphine, and then PCA device was installed in the intensive care unit by a venous catheter after the orotracheal extubation. Morphine PCA was delivered on demand (boluses of 1 mg), lock-out of 5 min until 36 hours of the postoperative period. A serial of blood samples were collected from venous catheter of patients at the postoperative period (3,6,12,18,24,36 hrs) and morphine plasma concentrations were determined by Liquid Chromatography-Mass Spectrometry ((LC-MS/MS ESI+)) after the purification of plasma samples. Pain scores were monitored during the same period by a visual analogue scale, VAS or 1-2-3 pain scale. PK-PD modeling was investigated by applying the GraphPad Prism 5.0. Results: Drug dose requirements and analgesia were significant different in patients of groups investigated. EMAX model and the hysteresis curve were proposed by PK-PD modeling to correlate drug requirements and AUC 0-36 or VAS. Conclusions: LC-MS/MS (ESI+) method was adequate for drug measurements in plasma. Morphine dose requirements and analgesia were different by comparison of groups. Lower doses of morphine by PCA were required for the groups that have received intrathecal morphine intraoperatively. It was demonstrated a non linear correlation between parameters by EMAX model when drug requirements and AUC0-36 were plotted, and the hysteresis curve was obtained when analgesia dose requirements was plotted against pain score.