Les maladies cardiovasculaires représentent la principale cause de décès dans le monde et elles sont souvent causées par l’athérosclérose coronarienne caractérisée par l’accumulation de plaques dans la paroi des artères menant à leur rétrécissement et à la réduction ou l’abolition de l’apport sanguin régional au muscle cardiaque. Les anomalies du métabolisme des lipides, incluant l’élévation du cholestérol dans les lipoprotéines de basse densité (LDL-cholestérol) contribuent au processus d’athérosclérose. Plusieurs traitements existent pour réduire les taux de lipides plasmatiques chez les sujets à risque, dont le principal est les statines. Cependant, les statines ne permettent pas toujours d’atteindre les cibles thérapeutiques, ce qui justifie la recherche de nouveaux traitements pouvant modifier les lipides plasmatiques. Une avenue potentielle de traitement à explorer est le beta-glucane, une fibre soluble contenue dans l’avoine pour laquelle certaines données suggèrent un effet hypolipidémiant. L’objectif de ce mémoire était d’évaluer l’efficacité d’un supplément de beta-glucane dans la réduction des taux plasmatiques de LDL-C chez les patients atteints de dyslipidémie à travers le Canada. Pour ce faire, nous avons effectué un essai clinique randomisé en double aveugle contrôlé par placebo dans une population de 264 sujets atteints d’hyperlipidémie qui ont reçus aléatoirement des traitements de beta-glucane à doses de 1.5 g, 3 g et 6 g ou un placebo durant 12 semaines. Tout au long du traitement, des mesures du taux plasmatique de LDL-C ont été effectuées et des analyses statistiques de covariance (ANCOVA) ont été faites pour comparer ces taux entre les groupes actifs et placebos afin d’observer s’il y avait des changements significatifs. La mesure d’efficacité établie était une réduction du taux de LDL-C d’au moins 0.30 mmol/L. Nos résultats suggèrent que le supplément de beta-glucane à doses de 1.5 g, 3 g et 6 g n’est pas efficace pour réduire les taux de lipides sériques. Il n’y a pas eu de variation significative dans les taux de LDL-C lorsque les groupes actifs ont été comparé au groupe placebo. / Cardiovascular diseases are the principal cause of death in the world, and they are often caused by coronary atherosclerosis characterized by the accumulation of plaques in the wall of arteries leading to their narrowing and reduction or disappearance of regional blood supply to the cardiac muscle. Abnormalities of lipid metabolism, including elevated cholesterol in low-density lipoproteins (LDL-C), contribute to the atherosclerotic process. Several treatments exist to reduce levels of plasma lipids in patients at risk, the main one being statins. However, a substantial number of patients do not reach recommended therapeutic targets while treated with statins which creates the impetus for the search of new lipid-modifying treatments. One potential avenue of treatment worthy of investigation is beta-glucan, a soluble fiber found in oats, for which some data have suggested a lipid-lowering effect. The objective of this thesis was to evaluate the efficacy of a beta-glucan supplement in reducing plasma LDL-C levels in patients with dyslipidemia across Canada. To do this, we conducted a randomized, double-blind, placebo-controlled clinical trial in a population of 264 subjects with hyperlipidemia who randomly received beta-glucan treatments at doses of 1.5 g, 3 g and 6 g or a placebo for 12 weeks. Throughout the treatment, LDL-C plasma measurements were taken and statistical analyzes of covariance (ANCOVA) were done to compare these levels between the active and placebo groups to observe if there were any significant changes. The established measure of efficacy was a reduction in LDL-C of at least 0.30 mmol/L. Briefly, our results have shown that beta-glucan in doses of 1.5 g, 3 g and 6 g is not efficacious in reducing plasma lipid levels. There was no significant change in LDL-C levels when the active groups were compared to the placebo group.

Résumé : Contexte: Les maladies cardiovasculaires (MCV) sont un enjeu contemporain de santé publique. Or, des recherches cliniques démontrent que certaines interventions sont efficaces dans leur traitement et prévention. Il s’agit d’interventions nutritionnelles éducatives priorisant des aliments végétaux minimalement transformés (VMT). Ces interventions promeuvent l’adoption de postures alimentaires se caractérisant par la consommation à volonté d’une grande variété d’aliments d’origine végétale (e.g. légumineuses, céréales entières, fruits, légumes) et par une diminution de la consommation d’aliments d’origine animale (e.g. viandes, œufs et produits laitiers) et ultra-transformés (e.g. riches en sucres, sel ou gras, et faibles en fibres). Objectifs: À l’aide d’un devis mixte concomitant imbriqué, nous avons évalué les effets d’un programme d’interventions éducatives visant à augmenter la consommation de VMT chez des adultes à risque de MCV et exploré les déterminants des modifications comportementales observées. Méthodologie : Divers paramètres physiologiques et anthropométriques ont été mesurés pré-post programme (n = 72) puis analysés avec un test t pour échantillons appariés ou un test signé des rangs de Wilcoxon. D’autre part, 10 entretiens semi-dirigés ont été réalisés post-programme et soutenus par un guide d’entretien basé sur le Food Choice Process Model. Les verbatims intégraux ont été codés selon la méthode d’analyse thématique. Résultats : Après 12 semaines, le poids (-10,5 lb, IC 95 %: 9,0-12,0), le tour de taille (-7,4 cm, IC 95 %:6,5-8,4), la tension artérielle diastolique (-3,2 mmHg, IC 95 %: 0,1-6,3), le cholestérol total (-0,87 mmol/ L, IC 95 %:0,57-1,17), le cholestérol LDL (-0,84 mmol/ L, IC 95 %: 0,55-1,13) et l’hémoglobine glyquée (-1,32 %, IC 95 %:-0,17-2,80) se sont significativement améliorés. L’analyse thématique des données qualitatives révèle que le programme, par la stimulation de valeurs de santé, d’éthique et d’intégrité, favorise la transformation des choix alimentaires vers une posture davantage axée sur les VMT durant une période clé du parcours de vie (i.e. pré-retraite). D’autres déterminants pouvant favoriser l’adoption d’une alimentation VMT ont été identifiés, dont les bénéfices importants observables à court terme, l’absence de restriction à l’égard de la quantité d’aliments VMT et le développement de compétences de planification dans l’acquisition et la préparation des aliments. Conclusion : Une intervention priorisant les VMT permet d’améliorer le profil cardiométabolique d’individus pré-retraités en raison de ses caractéristiques intrinsèques, mais aussi parce qu’elle modifie les valeurs impliquées dans les choix alimentaires. / Abstract : Background: Cardiovascular disease (CVD) is a contemporary public health issue. However, clinical research shows that some interventions are effective in its treatment and prevention: nutrition education programs prioritizing whole plant foods (WPF). These interventions promote the adoption of diets characterized by the unlimited consumption of a wide variety of plant foods (e.g. legumes, whole grains, fruits, vegetables) and a decrease in consumption of animal (e.g. meat, eggs and dairy products) and highly processed foods (e.g. high in sugar, salt or fat and low in fiber). Objectives: Using a nested concomitant mixed design, we evaluated the effects of a nutrition education program to increase the consumption of WPF in adults at risk of CVD and explored the determinants of the observed behavioral changes. Methodology: Various physiological and anthropometric parameters were measured pre-post program (n = 72) and analyzed with t test for paired samples or signed rank test Wilcoxon. Also, 10 semi-structured interviews were conducted post-program, supported by an interview guide based on the Food Choice Process Model. The full transcripts were coded according to thematic analysis method. Results: After 12 weeks, weight (-10.5 lbs, 95 % CI: 9.0-12.0), waist circumference (-7.4 cm, 95 % CI: 6.5-8.4), diastolic blood pressure (-3.2 mmHg, 95 % CI: 0.1-6.3), total cholesterol (-0.87 mmol/ L, 95 % CI: 0.57-1.17), LDL cholesterol (-0.84 mmol/ L, 95 % CI: 0.55-1.13) and HbA1c (-1.32 %, 95 % CI - 0.17-2.80) improved significantly. Thematic analysis of qualitative data reveals that the program, by stimulating values such as health, ethics and integrity, promote the transformation of food choices towards a more whole-foods plant-based dietary pattern during a key period of participants’ life course (i.e. early retirement). Other determinants that can help orient food trajectory towards more WPF have been identified, including the significant short term benefits, the lack of restriction on the amount of WPF and development of planning skills in acquiring and preparing food. Conclusion: A nutrition education program prioritizing WPF improves the cardio-metabolic profile individuals in their pre-retirement because of its intrinsic characteristics, but also because it changes their food choice values. / Resumen : Contexto: Las enfermedades cardiovasculares (ECV) son un asunto contemporáneo de salud pública. Sin embargo, la investigación clínica demuestra que algunas intervenciones son eficaces en su tratamiento y prevención. Se trata de intervenciones nutricionales educativas que priorizan los alimentos vegetales mínimamente procesados (AVMP). Estas intervenciones promueven la adopción de posturas alimenticias que se caracterizan por el consumo ilimitado de una amplia variedad de alimentos de origen vegetal (e.g. legumbres, granos enteros, frutas, verduras) y una disminución en el consumo de alimentos de origen animal (e.g. carne, huevos y productos lácteos) y altamente procesados (e.g. es decir, alto contenido de azúcar, sal o grasa y bajo en fibras). Objetivo: Con el uso de un diseño mixto concurrente se evaluaron los efectos de un programa compuesto de diversas intervenciones educativas enfocadas en el incremento del consumo de AVMP en adultos en situación de riesgo de ECV. Así mismo, se exploraron los determinantes de los cambios de comportamientos observados. Material y métodos: Se midieron varios parámetros fisiológicos y antropométricos antes y después del programa (n = 72) los cuales se analizaron con la prueba t para muestras pareadas o prueba de los rangos con signo de Wilcoxon. Ademas, se llevaron a cabo 10 entrevistas semi-estructuradas post-programa apoyados por una guía de entrevista basada en el Food Choice Process Model. Las transcripciones completas fueron codificadas de acuerdo al método de análisis temático. Resultados: Después de 12 semanas, el peso (-10.5 lbs, IC 95 %: 9.0 a 12.0), la circunferencia de la cintura (-7.4 cm, IC 95 %: 6.5 a 8.4), la presión arterial diastólica (-3.2 mmHg, IC 95 %: 0.1 a 6.3), el colesterol total (-0.87 mmol/ L; IC 95 %: 0.57 a 1.17), el colesterol LDL (-0.84mmol/ L, IC 95 %: 0.55 a 1.13) y la HbA1c (-1.32 %, IC 95 % - 0.17 a 2.80) mejoraron significativamente. El análisis temático de los datos cualitativos revela que el programa, mediante la estimulación de valores de la salud, la ética y la integridad, favorece la transformación de la elección de alimentos hacia una postura más centrada en los AVMP durante un período clave del ciclo de vida (e.g. la jubilación temprana). Otros determinantes que pueden promover la adopción de una postura alimenticia más centrada en los AVMP han sido identificados, incluyendo los beneficios significativos observados a corto plazo, la falta de restricción en la cantidad de AVMP y el desarrollo de habilidades de planificación en la adquisición y preparación de alimentos. Conclusiones: Un programa de intervenciones educativas que favorece el consumo de AVMP mejora el perfil cardio-metabólico de las personas pre-jubiladas no sólo gracias a sus características intrínsecas, sino también al cambio de valores que intervienen en la elección de los alimentos.

Atherosclerosis, one major cause of morbidity and mortality worldwide, is a complex and multifactorial disease that involves three mainly conditions: chronic inflammation, dyslipidemia and oxidative stress. Although statins are the first-line therapy for LDL cholesterol (LDL-C) lowering, the efficacy of cardiovascular events prevention is limited to 30-40%. This residual risk brought attention to the need of new therapies and clinical targets beyond LDL-C, such as inflammation and oxidative stress. Importantly, suboptimal treatment and/or statin discontinuation due to adverse effects have also been a very challenging clinical problem. Complementary diet therapy can be an effective and safe approach to support pharmacological treatment, especially when drugs alone are insufficient to attenuate risk factors and/or the recommended dose is not well tolerated. The aim of this study was to evaluate the effects of three bioactive components, namely omega-3 fatty acids, plant sterols and polyphenols, on markers of dyslipidemia, inflammation and oxidative stress in patients treated with statins. A randomized, crossover clinical study was carried out, with the participation of 53 subjects. At each intervention period, study participants received a packaged for the functional or control treatment. Functional treatment consisted of fish oil (1.7 g of EPA+DHA/day), chocolate containing plant sterols (2.2 g/day) and green tea (two tea sachets/day). Control treatment consisted of soy oil softgels, regular chocolate and anise tea. After 6 weeks of intervention, functional treatment reduced plasma LDL-C (-13.7% ± 3.7, p=0.002) and C-reactive protein (-35.5% ± 5.9, p=0.027). Plasma triacylglycerol (-15.68% ± 5.94, p=0.02) and MDA (-40.98% ± 6.74, p=0.04) were reduced in subgroups of patients (n=23) with baseline values above the median (93 mg/dL and 2.23 umol/L, respectively). Analysis of lathosterol and campesterol in plasma suggested that intensity of LDL-C reduction was influenced by cholesterol absorption rate rather than its endogenous synthesis. After multivariate analysis, patients identified as \"good responders\" to supplementation (n=10) were recruited for a pilot protocol of statin dose reduction with complementary diet therapy. Responders received the functional treatment for 12 weeks: standard statin therapy was kept during the first 6 weeks and reduced by 50% from weeks 6 to 12. No difference was observed for plasma lipids and inflammation biomarkers, cholesterol efflux capacity or HDL particle number after statin dose reduction when compared to standard therapy. Although limited by the small sample size, our study demonstrates the potential for a new therapeutic approach combining lower statin dose and specific dietary compounds. This may be particularly helpful for the many patients with, and at risk for, CVD who cannot tolerate high-dose statin therapy. / A aterosclerose, uma importante causa mundial de morbidade e mortalidade, é uma doença complexa e multifatorial que envolve três principais condições: inflamação crônica, dislipidemia e estresse oxidativo. Embora as estatinas sejam fármacos de primeira linha para redução de LDL colesterol (LDL-C), sua eficácia na prevenção de eventos cardiovasculares é limitadada a 30-40%. Este risco cardiovascular residual evidencia a necessidade de novas terapias e marcadores clínicos que vão além do LDL-C, como inflamação e estresse oxidativo. Não obstante, tratamento subótimo e/ou interrupção do uso de estatinas devido à ocorrencia de efeitos adversos também é um grave obstáculo na clínica médica. Neste contexto, a terapia dietética complementar representa uma abordagem efetiva e segura para o suporte do tratamento farmacológico, especialmente quando as drogas são insuficientes para atenuar fatores de risco e/ou quando a dose recomendada não é bem tolerada. O objetivo do presente estudo foi avaliar o efeito de três compostos bioativos - ácidos graxos ômega 3, fitosteróis e polifenóis - sobre marcadores de inflamação, lipemia e estresse oxidativo em indivíduos tradados com estatinas. Foi realizado um estudo clínico randomizado, de delineamento crossover, com a participação de 53 voluntários. A cada período de intervenção, os participantes receberam um tratamento funcional ou controle. O tratamento funcional foi composto por cápsulas de óleo de peixe (1.7 g/dia de EPA+DHA), chocolate contendo fitosteróis (2.2 g/dia) e chá verde (dois sachês/dia). O tratamento controle foi composto por cápsulas de óleo de soja, chocolate sem adição de fitosteróis e chá de anis. Após 6 semanas de intervenção, o tratamento funcional reduziu a concentração plasmática de LDL-C (-13.7% ± 3.7, p=0.002) e proteína C-reativa (-35.5% ± 5.9, p=0.027). Triglicerídeos (- 15.68% ± 5.94, p=0.02) e malondialdeído (-40.98% ± 6.74, p=0.04) foram reduzidas apenas em subgrupos de indivíduos que apresentavam valores basais acima da mediana (93 mg/dL e 2.23 umol/L, respectivamente). A análise de latosterol e campesterol no plasma sugeriu que a intensidade da redução de LDL-C não foi influenciada pela síntese endógena de colesterol, mas sim pela taxa de absorção. Após análise multivariada dos resultados, pacientes identificados como \"good responders\" à suplementação (n=10) foram recrutados para um estudo piloto de redução da dosagem da estatina, aliado à terapia dietética complementar. Estes pacientes receberam o tratamento funcional por 12 semanas: durante as 6 primeiras semanas mantevese a dosagem de estatina, que em seguida foi reduzida em 50% das semanas 6 a 12. Não foram observadas diferenças para os marcadores plasmáticos de lipídeos, inflamação, capacidade de efluxo de colesterol ou número de partículas de HDL após a redução da dose de estatina, quando comparada à terapia convencional. Embora limitado pelo reduzido número de pacientes, o estudo demonstra o potencial para uma nova abordagem terapêutica, combinando reduzida dose de estatina com específicos compostos bioativos. Esta pode ser uma importante alternativa para muitos pacientes em risco cardiovascular e que são intolerantes à terapia com altas doses de estatina.

L’hypertriglycéridémie (HTG) correspond à une accumulation des lipoprotéines riches en triglycérides (LRTG) dans la circulation plasmatique, conséquence d’une augmentation de leur synthèse ou plus classiquement décrit, d’une diminution de leur catabolisme. Dans près de 50% des cas, aucune cause génétique n’est identifiée chez les patients présentant une présentant une HTG sévère, aussi bien dans le cadre du syndrome de chylomicronémie familiale (FCS) que dans celui du syndrome de chylomicronémie multifactorielle (MCS). Pour améliorer nos connaissances et la caractérisation de ces patients, la conduction de corrélations phénotypes-génotypes précises grâce à une collaboration clinico-biologique étroite, ainsi que le développement d’outils de diagnostic moléculaire performants, demeurent un enjeu majeur. Premièrement, l’évaluation de la concentration pré-héparinique en LPL et l’activité post-héparinique 60 minutes après l’injection d’héparine chez 62 patients MCS caractérises génétiquement a permis la mise en évidence deux sous-groupes chez ces patients. Deuxièmement, le développement d’une stratégie séquençage de nouvelle génération permettant d’explorer simultanément les 9 gènes les plus prévalents dans les hypercholestérolémies, les hypocholestérolémies et les hypertriglycéridémies, a permis de détecter les variants nucléotidiques avec une sensibilité équivalente au séquençage Sanger mais aussi de détecter des grands réarrangements. L’ensemble des résultats souligne la complexité des mécanismes de régulation du métabolisme des LRTG et l’intérêt de l’étude des interactions gène-gène. Ainsi, ces travaux ont permis de mettre en évidence de nouvelles hypothèses à explorer pour la compréhension des mécanismes physiopathologiques des HTG sévères et d’améliorer les outils disponibles pour les études de corrélation génotype-phénotype / Hypertriglyceridemia (HTG) correspond to an increase of triglyceride-rich lipoproteins (TGRL) circulating concentration, as a consequence of an increase in the synthesis of or a decrease in their catabolism, most classically described. In nearly 50% of patients with severe hypertriglyceridemia (HTG), no genetic cause is identified, either in familial chylomicronemia syndrome (FCS) or in multifactorial chylomicronemia syndrome (MCS). To gain new insights and to improve patient’s characterization, it remains important to conduct accurate phenotype-genotype association studies through close collaboration with referent lipidologists, and to develop high-performance tools for molecular diagnosis. Firstly, the assessment of pre-heparin LPL concentration as well as LPL activity 60 minutes after heparin injection, enabled the identification of two subgroups within 62 genotyped MCS patients Secondly, the development of a new sequencing generation workflow exploring simultaneously the 9 most prevalent genes in dyslipidemia, allowed the detection of single nucleotide variations with sensitivity equivalent to Sanger sequencing, but also allowed the detection of copy number variations. Collective consideration of the results underlines the complexity of the regulation mechanisms of TGRL metabolism and the interest of gene-gene interactions study. Thus, the studies presented herein bring new hypothesis to explore for understanding the pathophysiological mechanisms of severe HTG and to improve molecular diagnosis tools available for phenotype-genotype association studies

Objectives and methods: DETECT is a cross-sectional study of 55,518 unselected consecutive patients in 3188 representative primary care offices in Germany. In a random subset of 7519 patients, an extensive standardized laboratory program was undertaken. The study investigated the prevalence of cardiovascular disease, known risk factors (such as diabetes, hypertension and dyslipidemia and their co-morbid manifestation), as well as treatment patterns. The present analysis of the DETECT laboratory dataset focused on the prevalence and treatment of dyslipidemia in primary medical care in Germany. Coronary artery disease (CAD), risk categories and LDL-C target achievement rates were determined in the subset of 6815 patients according to the National Cholesterol Education Program (NCEP) ATP III Guidelines. Results: Of all patients, 54.3% had dyslipidemia. Only 54.4% of the NCEP-classified dyslipidemic patients were diagnosed as ‘dyslipidemic’ by their physicians. Only 27% of all dyslipidemic patients (and 40.7% of the recognized dyslipidemic patients) were treated with lipid-lowering medications, and 11.1% of all dyslipidemic patients (41.4% of the patients treated with lipid-lowering drugs) achieved their LDL-C treatment goals. In conclusion, 80.3% of patients in the sample with dyslipidemia went undiagnosed, un-treated or under-treated.

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.

Metabolic syndrome is a cluster of disorders including central obesity, hypertension, dyslipidemia, and hyperglycemia. Today's metabolic syndrome definitions identify central obesity by waist circumference (WC) measurements. A recent pilot study suggests that cut-points derived from a waist-to-height ratio (WHtR), or Index of Central Obesity (ICO), is a more accurate measurement of central obesity. This study compared the association between the metabolic syndrome components and central obese parameters (ICO and WC) among the white, black, and Hispanic adults in the United States. The subjects' data was obtained from the 2005-2006 National Health and Nutrition Examination Survey. ICO was highly correlated with metabolic syndrome components among white subjects and the least correlated in Hispanic subjects. Multivariate logistic regression analysis did not indicate that ICO was a better parameter for metabolic syndrome than WC. Other WHtR cut-points may be more sensitive in predicting metabolic syndrome components than the values used in this study.

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.

Dyslipidemia can be a comorbidity of both insulin-resistance and atherosclerosis. Hypertriglyceridemia is common in hyperglycemia and is associated with hypoalphalipoproteinemia (low HDL) and with altered nucleotide or purinergic signaling. We therefore hypothesized that extracellular nucleotides may affect hepatic lipoprotein metabolism. Our studies confirm this view and show that nucleotides regulate cellular proteolytic pathways in liver cells and thereby control lipoprotein secretion and their metabolism by hepatic lipase (HL). Treatment of liver cells with the nucleotide, adenosine diphosphate (ADP), stimulates VLDL-apoB100 and apoE secretion, but blocks HDL-apoA-I and HL secretion. ADP functions like a proteasomal inhibitor to block proteasomal degradation and stimulate apoB100 secretion. Blocking the proteosome is known to activate autophagic pathways. The nucleotide consequently stimulates autophagic degradation in liver cells and increases cellular levels of the autophagic proteins, LC3 and p62. Confocal studies show that ADP increases cellular LC3 levels and promotes co-localization of LC3 and apoA-I in an autophagosomal degradation compartment. ADP acts through the G-protein coupled receptor, P2Y13, to stimulate autophagy and block both HDL and HL secretion. Overexpression of P2Y13 increases cellular LC3 levels and blocks the induction of both HDL and HL secretion, while P2Y13 siRNA reduce LC3 protein levels and cause up to a ten-fold stimulation in HDL and HL secretion. P2Y13 gene expression regulates autophagy through the insulin receptor (IR-β). A reduction in P2Y13 expression increases the phosphorylation of IR-β and protein kinase B (Akt) >3-fold, while increasing P2Y13 expression inhibits the activation of IR-β and Akt. Experiments with epitope-labeled apoA-I and HL show that activation of purinergic pathways has no effect on the internalization and degradation of extracellular apoA-I and HL, which confirms the view that nucleotides primarily impact intracellular protein transport and degradation. In conclusion, elevated blood glucose levels may promote dyslipidemia by stimulating purinergic signaling through P2Y13 and IR-β and perturbing the intracellular degradation and secretion of both HDL and VLDL.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The physiological state of menopause is characterized by an irreversible loss of ovarian function, with a resulting decrease in estrogen production, leading to the appearance of metabolic, cognitive, and behavioral alterations. For this reason, understanding how the decrease in the estrogen production contributes to the progress of menopausal symptoms can be very useful for the development of alternative therapies than hormone replacement therapy. In this context, the data show that ovariectomized Wistar rats treated with (PhSe)2 at a dose of 5 mg/kg once a day for 30 days presented lower plasma triglyceride levels and increased HDL levels when compared to control ones. Moreover, (PhSe)2 administration reduced the weight gain and fat abdominal accumulation induced by ovariectomy. It was also observed that (PhSe)2 treatment improved hepatic oxidative stress parameters in ovariectomized rats (ascorbic acid and reduced glutathione levels, and glutathione S-transferase and catalase activities). Additionally, (PhSe)2 treatment at a dose of 5 mg/kg once a day for 30 days improved the performance of ovariectomized Wistar rats in the Morris Water Maze test, possibly by inhibiting the increase in brain acetylcholinesterase activity induced by ovariectomy. The present results suggest a promising role of (PhSe)2 against the cognitive decline related to menopause. The transition to menopause is associated with an increased risk of depressed mood. On this bases, the obtained results demonstrate that the prolongation of immobility time in the tail suspension test and forced swimming test in ovariectomized mice submitted to subchronic stress protocol was prevented by (PhSe)2 treatment at a dose of 10 mg/kg. It was also found a possible involvement of the serotonin system in this effect, demonstrated by the modulation of 5-HT2A/2C and 5-HT3 receptor subtypes. Although (PhSe)2 had inhibited in vitro monoamine oxidase A and B activities, treatment of ovariectomized mice with (PhSe)2 did not alter neither MAO-A nor MAO-B ex vivo activity. These findings suggest that (PhSe)2 treatment could influence mood and behavior in postmenopausal women. In order to investigate a possible mechanism of action for the hypocholesterolemic effect of (PhSe)2 it was observed that (PhSe)2 treatment increases the LDL receptor levels and augment the adenosine monophosphate (AMP)-activated kinase (AMPK) activation state without inhibiting directly 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) enzyme activity in HepG2 cell cultures. These findings are in accordance with those from in vivo studies previously published. In addition, L6 skeletal muscle cells treated with (PhSe)2 presented an augment in glucose transporter 4 (GLUT4) translocation from the cytosol to the cell membrane via an increase in AMPK phosphorylation state, which could be linked to the hypoglycemic properties presented by (PhSe)2 in other studies. In conclusion, the body of evidence presented in this thesis points to the use of (PhSe)2 as a promising alternative therapy for the management of postmenopausal symptoms. However, it is important to mention that the global net effects of (PhSe)2 still need to be better described in order to identify possible negative side effects. / A menopausa caracteriza-se pela suspensão irreversível da função ovariana, com declínio da produção de hormônios estrogênicos. A falta desses hormônios culmina no aparecimento de alterações metabólicas, cognitivas e comportamentais. Por essa razão, entender de que maneira a depleção de hormônios ovarianos contribui para o surgimento dos sintomas característicos da menopausa pode ser extremamente útil para o desenvolvimento de tratamentos alternativos à terapia de reposição hormonal. Nesse contexto, os dados aqui apresentados demonstram que ratas Wistar ovariectomizadas que foram tratadas com disseleneto de difenila [(PhSe)2] na dose de 5 mg/kg uma vez ao dia durante um período de 30 dias possuíam reduzidos níveis plasmáticos de triglicerídeos e aumentados níveis de HDL quando comparadas as ratas controle não ovariectomizadas. Além disso, a administração de (PhSe)2 foi capaz de reduzir o ganho de peso e o acúmulo de gordura abdominal nas ratas ovariectomizadas. Também foi observado que o tratamento com (PhSe)2 melhorou parâmetros hepáticos relacionados a estresse oxidativo nas ratas ovariectomizadas (níveis de ácido ascórbico e glutationa reduzida (GSH) e atividade das enzimas glutationa S-transferase e catalase). O tratamento com (PhSe)2 na dose de 5 mg/kg uma vez ao dia durante um período de 30 dias também melhorou o desempenho das ratas Wistar ovariectomizadas no teste do Labirinto Aquático de Morris, possivelmente por impedir o aumento da atividade da enzima acetilcolinesterase cerebral observado nas ratas ovariectomizadas. Dessa forma, os resultados sugerem um possível efeito benéfico do (PhSe)2 para o tratamento do declínio cognitivo associado a menopausa. Ainda com relação aos sintomas apresentados pelas mulheres durante a menopausa, dados da literatura mostram que a transição para a menopausa associa-se a um risco aumentado para o aparecimento de sintomas do tipo depressivos. Com base nisso, foi evidenciado que fêmeas ovariectomizadas de camundongos Swiss submetidas a um protocolo de estresse sub-crônico apresentavam aumento no tempo de imobilidade nos testes de Suspensão da Cauda e do Nado Forçado, ambos preditivos de comportamento do tipo depressivo.Também foi observado que esse prolongamento no tempo de imobilidade apresentado pelas fêmeas ovariectomizadas foi prevenido pelo tratamento com (PhSe)2 na dose de 10 mg/kg administrado 30 minutos antes de cada exposição ao protocolo de estresse. Além disso, evidenciou-se o envolvimento dos receptores de serotonina do tipo 5-HT2A/2C e 5-HT3 no efeito do tipo antidepressivo apresentado pelo (PhSe)2. Embora o (PhSe)2 tenha inibido a atividade de ambas isoformas da enzima monoamino oxidase (MAO-A e MAO-B) in vitro, não foi observada inibição da atividade de tais enzimas quando sua atividade foi determinada ex vivo. Com base nesses resultados sugere-se que o tratamento com (PhSe)2 pode influenciar aspectos relacionados ao humor e ao comportamento em mulheres no período pós-menopausa. No intuito de elucidar os mecanismos envolvidos no efeito hipocolesterolêmico do (PhSe)2 em culturas de células HepG2 observou-se que este composto orgânico de selênio leva a um aumento nos níveis de receptores de LDL e a um aumento no estado de ativação da enzima adenosina monofosfato (AMP) quinase (AMPK), sem inibir diretamente a atividade da HMG-CoA redutase. Esses resultados corroboram com os achados de outros trabalhos, os quais demonstram um efeito hipocolesterolêmico do (PhSe)2 in vivo. Além disso, também foi buscado um possível mecanismo para o efeito hipoglicemiante apresentado pelo (PhSe)2 em trabalhos anteriores: resultados obtidos a partir de culturas de células L6 (células de músculo esquelético de ratos), sugerem que o (PhSe)2 aumenta a translocação do transportador de glicose 4 (GLUT4) do citosol para a membrana celular devido a um aumento no estado de ativação da enzima AMPK. Em conclusão, o conjunto de resultados apresentado nesta tese aponta o uso do (PhSe)2 como uma terapia alternativa bastante promissora para o tratamento de algumas das principais conseqüências da menopausa, a saber aumento no ganho de peso, dislipidemia, prejuízos cognitivos e ocorrência de episódios depressivos. Entretanto, faz-se importante mencionar que os efeitos globais do (PhSe)2 ainda precisam ser melhor caracterizados no intuito de verificar a existência de possíveis efeitos adversos.