INTRODUÇÃO: As doenças cardiovasculares (DCV) aparecem em primeiro lugar entre as principais causas de mortalidade no mundo, representando 46,2% do total de mortes, número muito próximo aos encontrados no Brasil, impactando os gastos com saúde. A prevenção baseia-se em estilo de vida saudável, contudo, uma vez instaladas, é consenso o tratamento medicamentoso com estatinas. Alguns tratamentos alternativos vêm sendo estudados como o ômega-3 (w-3) na prevenção das DCV. Apesar das evidências clínicas favoráveis, não existem muitos estudos acerca da viabilidade econômica de tais tratamentos. OBJETIVO: Avaliar o custo-efetividade das intervenções com w-3 isolado ou associado às estatinas na redução dos fatores de risco cardiovascular sob a perspectiva do Sistema Único de Saúde (SUS). MATERIAL E MÉTODOS: Para avaliar a efetividade do w-3 isolado e combinado com estatina foram utilizados os dados secundários do ensaio clínico CARDIONUTRI no momento basal e após 8 semanas. A amostra foi composta por 186 indivíduos com idade entre 30 e 74 anos divididos entre aqueles que não tomavam medicação e os que tomavam estatinas. Aleatoriamente, uma parcela deles recebeu cápsulas de 1 g de w-3 (37% de ácido eicosapentaenoico e 23% de docosaexaenoico) ou cápsulas de placebo. A recomendação era de que todos deveriam tomar 3 cápsulas ao dia, totalizando 3g/dia (de w-3 ou placebo) durante 8 semanas. Ao final, obteve-se quatro grupos: a) w-3; b) placebo; c) w-3 + estatina; e d) estatina. Para a avaliação do impacto foi usado o método Diferenças em Diferenças com a adição de variáveis de controle: densidade calórica do consumo alimentar, Índice de Massa Corporal (IMC), prática de atividade física, idade, sexo, raça, hábito tabagista, escolaridade e grau de adesão. Os custos dos tratamentos foram estimados com base no custo médio ponderado pelas probabilidades das eventuais intercorrências relacionadas a efeitos adversos e de sucesso e fracasso por meio do método da árvore de decisão. Foi considerado para fins do cômputo dos custos o período de 2 meses de tratamento. RESULTADOS: Nos quatro grupos, a maioria eram mulheres, obesas e com escore de risco muito alto para DCV. Os grupos w-3 e placebo possuíam maior escolaridade e renda comparadas a aqueles que tomavam estatinas. Todas as variáveis de controle foram estatisticamente significantes em pelo menos um dos modelos, exceto raça. A suplementação com w-3 associada às estatinas mostrou efetividade sobre HDLPEQUENA, com diminuição de 2,211 mg/dL e custo-efetividade de R$ 109,31 por redução em mg/dl da lipoproteína em 2 meses de tratamento. CONCLUSÃO: O tratamento com 1,8g de óleo de peixe isolado ou associado às estatinas em intervenção primária não evidenciou efeitos significativos nas mudanças dos parâmetros lipídicos, exceto no caso da HDLPEQUENA com o tratamento associado, mostrando não ser custo-efetivo na redução dos fatores de risco cardiovascular em geral. Em virtude da existência de controvérsias acerca de seus potenciais efeitos, sugere-se que os ensaios clínicos utilizem métodos estatísticos mais robustos para avaliar o impacto líquido da suplementação. / INTRODUCTION: Cardiovascular diseases (CVD) are among the leading causes of death worldwide, accounting for 46.2% of all cases, very close to those found in Brazil, impacting health expenses. Current prevention is based on a healthy lifestyle, and once a CVD diagnosis is made, the current consensus is drug treatments with statins. Some alternative treatments such as omega-3 (w-3) have been studied in the prevention of these diseases. However, despite favorable clinical evidence, there are not many studies of economic viability of this treatment. OBJECTIVE: To evaluate the cost-effectiveness of interventions with w-3 alone or associated with statins in reducing cardiovascular risk factors from the perspective of the Unified Health System (SUS). METHODS: To assess the effectiveness of w-3 alone and its combination with statin, the secondary data of the classic lipid profile and lipoprotein size of the CARDIONUTRI clinical trial were used at baseline and after 8 weeks. The sample consisted of 186 subjects aged 30 to 74 years randomly received capsules containing 3g of w-3 per day (37% of eicosapentaenoic acid and 23% of docosahexaenoic acid) or 3g of mineral oil (placebo). Capsules were randomly assigned to individuals who were not taking medication or were already taking statins, separated into four groups: a) w-3; b) placebo; c) w-3 associated with statins; d) statins. Data analysis was conducted using the Difference in Differences statistical method with the addition of control variables: caloric density of food consumption, Body Mass Index (BMI), physical activity practice, age, sex, race, smoking, educational level and adherence to the treatment. The treatment costs were estimated based on the weighted average cost by the probabilities of the eventual intercurrences related to adverse effects and of success and failure by means of the decision tree method elapsed in 2 months of treatment. RESULTS: In all four groups, the majority were women, obese and with a very high-risk score for CVD. W-3 and placebo groups had higher educational level and income compared to those who were already taking statins. All control variables were statistically significant in at least one of the models except race. W-3 supplementation showed efficacy on HDLSMALL among those who consumed w-3 + statins with a reduction of 2,211 mg /dL and cost-effectiveness R$ 109.31 per mg/dL for 2 months of treatment. CONCLUSION: The treatment with 1.8g of fish oil isolated or associated with statins in primary intervention did not show significant effects on changes in lipid parameters except HDLSMALL of interventions associated with statins. Therefore it was not cost-effective in reducing cardiovascular risk factors. Due to the existence of controversies about its potential effects, it is suggested that clinical trials use more robust statistical methods to assess the net impact of supplementation.

INTRODUÇÃO: A urticária crônica igmaidiopática (UCI) é uma doença desencadeada pela desgranulação de basófilos e mastócitos com consequente liberação de histamina, sendo que o perfil imunológico nesta doença não é bem estabelecido. As estatinas, inibidores da 3-hidroxi-3-metilglutaril coenzima A redutase, apresentam efeitos antiinflamatórios e imunomodulatórios. O efeito desta droga tem sido estudado em muitas doenças inflamatórias crônicas, incluindo doenças autoimunes, mas não existem evidências na UCI. OBJETIVOS: O objetivo deste estudo foi analisar o efeito das estatinas na resposta imune e sua a influência na expressão de genes regulatórios e relacionados com a resposta inflamatória. MÉTODOS: A resposta limfoproliferativa a mitógenos e antígeno-específica de 22 pacientes com UCI e 41 controles na presença de estatinas (0,25-25 µM) foi analisada pela incorporação de timidina após 3 ou 6 dias de cultura. A progressão do ciclo celular e apoptose foi realizada pela incorporação de bromodeoxiuridina (Brdu) ao DNA após estímulo por PHA ou PWM e analisada por citometria de fluxo. A secreção de citocinas foi quantificada por ELISA e a expressão de mRNA de fatores regulatórios e pró-inflamatórios quantificados por real-time PCR. RESULTADOS: Os resultados evidenciaram que as estatinas em elevadas concentrações são capazes de inibir a capacidade mitogênica das células T e B seja dos indivíduos saudáveis ou de pacientes com UCI. A inibição da proliferação celular mediada pelas estatinas foi decorrente ao bloqueio na etapa inicial do ciclo celular (Fase G0/1), o que impediu o prosseguimento para outras fases do ciclo (S e G2/M). A diminuição da resposta proliferativa em resposta a um mitógeno como a PHA resultou na inibição da ativação celular pela estatina e a significante redução na produção de citocinas como IFN-?, IL-10, IL-17A e IL-5. Em contraste, o efeito modulatório das estatinas ao estímulo com LPS inibiu a produção de TNF-? e MIP-1? pelas células dos controles, mas não influenciou na produção de citocinas pró-inflamatórias pelas CMN dos pacientes com UCI. Somente a incubação prévia das células com as drogas, em alta concentração (25µM), foi possível verificar a modulação negativa na produção de IL-6 e MIP1-? para ambos os grupos, mas não para o TNF-? para os pacientes. A sinvastatina foi capaz exercer efeito modulatório mais pronunciado que a lovastatina na produção de citocinas induzidas por LPS. Os resultados evidenciaram que os pacientes com UCI possuem uma diminuição da expressão da enzima IDO e aumento de SOCS3 nas CMN. A sinvastina não altera esse perfil e previne a expressão de fatores inflamatórios como RORC?t e NALP3 inflamassomas. CONCLUSÕES: Em conjunto, os resultados sugerem um desequilíbrio dos mecanismos regulatórios que poderiam contribuir com a cronicidade e o perfil inflamatório na UCI. As estatinas apresentam maior efeito antiinflamatório que pró-inflamatório, sugerindo ter potencial clínico para o tratamento de doenças crônicas como a UCI. / INTRODUCTION: Chronic Idiopathic Urticaria (CIU) is a disease triggered by degranulation of basophils and mast cells with consequent histamine release and the CIU immunological profile is not well established. Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, also display a broad immunomodulatory property. Statins have been studied in several chronic inflammatory diseases, including autoimmune disorders, but there are no evidences in CIU disease. OBJECTIVES: The aim of this study was to verify the effect of statins the immune response, and the expression of genes related to regulatory and inflammatory response focusing in CIU patients and healthy controls (HC). METHODS: Lymphoproliferative response to mitogens or recall antigens of 22 patients with CIU and 41 HC with statins (0,25-25µM) was analyzed by timidine incorporation after 3 or 6 days of cell cultures. Cell cycle progression and apoptosis were assessed by bromodeoxyiridine (BrDU) incorporation to DNA upon PHA or PWM stimulus by flow cytometry. Cytokines secretion was measured by ELISA and mRNA of regulatory and proinflammatory genes were analyzed by quantitative real-time PCR. RESULTS: The results showed that high concentrations of statins can inhibit the mitogenic capacity of T and B cells of HC or CIU patients. The inhibition of cell proliferation mediated by statins was due to blockage in the initial phase of the cell cycle (G0/1), which prevented progress to cycle phases (S and G2/M). The decreased proliferative response in response to PHA mediated by statin resulted in a significant inhibition of IFN-?, IL-10, IL-17A and IL-5 secretion levels. Statin effect in response to LPS showed inhibition of TNF-? and MIP-1? secretion by cells from HC, but did not influence the production by PBMC of CIU. It was necessary the pre-incubation of cells with drugs at high concentration (25µM) to verify the negative modulation of IL-6 and MIP1-? secretion in both groups, except for TNF-? in CIU. Simvastatin was able to exert more pronounced modulatory effect than lovastatin in cytokine production induced by LPS. Furthermore, CIU patients have a decreased expression of the enzyme IDO and increased of SOCS3 in PBMC, which were not modified by simvastatin, whereas prevented the upregulation of proinflammatory factor as RORC?t and NALP3 inflammasomes. CONCLUSIONS: Altogether, the results evidenced an imbalance of regulatory mechanisms that could contribute to chronic evolution and inflammatory profile in CIU. Statins exhibited more anti-inflammatory effects than proinflammatory, suggesting a potential clinical role for treatment in chronic diseases as CIU.

Cheng Wai Ring Caroline. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references (leaves 74-84). / Abstracts in English and Chinese. / Acknowledgement --- p.i / Abstract --- p.ii / 摘要 --- p.iv / Table of contents --- p.vi / Publications --- p.x / List of figures --- p.xi / List of tables --- p.xii / Abbreviations --- p.xiii / Chapter Chapter 1 --- Introduction / Chapter 1.1 --- Coronary Heart Disease --- p.2 / Chapter 1.1.1 --- Epidemiology --- p.2 / Chapter 1.2 --- Hypercholesterolemia and CHD --- p.3 / Chapter 1.2.1 --- Atherosclerotic plaque and lipoprotein --- p.4 / Chapter 1.2.2 --- NCEP ATP III guidelines --- p.5 / Chapter 1.2.2.1 --- CHD risk assessment --- p.5 / Chapter 1.2.2.2 --- Target lipid control --- p.8 / Chapter 1.2.2.3 --- Therapeutic lifestyle changes --- p.9 / Chapter 1.2.2.4 --- Pharmacological interventions --- p.10 / Chapter 1.2.2.5 --- Adherence to lipid-lowering therapy --- p.13 / Chapter 1.3 --- Adherence to drug therapy --- p.14 / Chapter 1.3.1 --- Definition of adherence --- p.14 / Chapter 1.3.2 --- Methods to assess adherence --- p.16 / Chapter 1.3.2.1 --- Expressions of adherence measurements --- p.20 / Chapter 1.3.3 --- Time effect on adherence --- p.21 / Chapter 1.3.4 --- Predictors of adherence --- p.22 / Chapter 1.3.5 --- Impact of poor adherence to statins --- p.23 / Chapter 1.4 --- Objectives and hypotheses --- p.25 / Chapter Chapter 2 --- Materials and Methods / Chapter 2.1 --- Study site --- p.27 / Chapter 2.2 --- Patient selection criteria --- p.28 / Chapter 2.2.1 --- Inclusion criteria --- p.28 / Chapter 2.2.2 --- Exclusion criteria --- p.29 / Chapter 2.3 --- Patient recruitment --- p.30 / Chapter 2.4 --- Assessments --- p.32 / Chapter 2.4.1 --- Adherence assessment --- p.32 / Chapter 2.4.1.1 --- Electronic monitoring --- p.32 / Chapter 2.4.1.2 --- Patient report --- p.33 / Chapter 2.4.1.3 --- Pill count --- p.34 / Chapter 2.4.1.4 --- Predictors of adherence --- p.34 / Chapter 2.4.2 --- Clinical outcome assessment --- p.35 / Chapter 2.4.2.1 --- Lipid control --- p.35 / Chapter 2.4.3 --- Economic outcome assessment --- p.35 / Chapter 2.4.3.1 --- Total direct medical cost --- p.35 / Chapter 2.4.3.2 --- Healthcare cost per member per month --- p.36 / Chapter 2.5 --- Sample size --- p.36 / Chapter 2.6 --- Statistical analysis --- p.37 / Chapter Chapter 3 --- Results / Chapter 3.1 --- Study sample --- p.40 / Chapter 3.1.1 --- Demographic characteristics --- p.41 / Chapter 3.1.2 --- Co-morbidity factors --- p.42 / Chapter 3.2 --- Adherence measurement --- p.44 / Chapter 3.2.1 --- Electronic monitoring --- p.44 / Chapter 3.2.2 --- Patient report --- p.45 / Chapter 3.2.3 --- Pill Count --- p.46 / Chapter 3.2.4 --- Correlation among methods for measuring adherence --- p.47 / Chapter 3.2.5 --- Trend of adherence and persistence over time --- p.48 / Chapter 3.2.6 --- Independent predictors of adherence --- p.49 / Chapter 3.3 --- Outcome assessment --- p.52 / Chapter 3.3.1 --- Clinical outcomes --- p.52 / Chapter 3.3.2 --- Economic outcomes --- p.52 / Chapter 3.4 --- Association between adherence and clinical outcomes --- p.53 / Chapter 3.4.1 --- Adherence and LDL-C reduction --- p.53 / Chapter 3.4.2 --- Adherence and NCEP ATP III target --- p.55 / Chapter 3.5 --- Association between adherence and economic outcomes --- p.55 / Chapter 3.5.1 --- Adherence and healthcare utilization --- p.55 / Chapter Chapter 4 --- Discussion and Conclusion / Chapter 4.1 --- Discussion --- p.59 / Chapter 4.1.1 --- Accuracy of patient report and pill count --- p.59 / Chapter 4.1.2 --- Persistence to statin therapy over time --- p.62 / Chapter 4.1.3 --- Predictors for patient adherence --- p.63 / Chapter 4.1.4 --- Clinical impacts of patient adherence --- p.66 / Chapter 4.1.5 --- Economic impacts of patient adherence --- p.68 / Chapter 4.1.6 --- Limitations --- p.70 / Chapter 4.2 --- Conclusion --- p.71 / References --- p.74 / Appendices / Appendix A-1. Framingham risk scoring system for male --- p.86 / Appendix A-2. Framingham risk scoring system for female --- p.87 / Appendix B-1. Information sheet provided to nurses of the Cardiology clinic --- p.88 / Appendix B-2. Information sheet provided to nurses of the Diabetes clinic --- p.89 / Appendix B-3. Information sheet provided to nurses of the Lipid clinic --- p.90 / Appendix C. Data collection form --- p.91 / Appendix D. Instruction sheet provided to the study patient --- p.94 / Appendix E. Unit cost of items from electronic dispensing record and Hong Kong Gazette 2003 for estimating total direct medical cost --- p.95

A total of 146 Chinese patients with various degrees of hyperlipidaemia and high cardiovascular risk, suitable for treatment with rosuvastatin 10 mg daily and in whom it was possible to obtain baseline lipid profiles measured on no lipid lowering drug, were enrolled in to the study. The drug compliance was assessed by personal interview and 9 patients were excluded from the efficacy analysis because they stated their compliance was less than 80%. From the remaining 137 subjects, 62 had a clinical diagnosis of familial hypercholesterolaemia. Data for dietary intake were available in 121 of the 137 subjects. The average reduction in LDL-cholesterol in these subjects was 48.8 +/- 12.8% and as anticipated there was a wide range between individuals. The percentage reductions in LDL-cholesterol were significantly greater in the female than in the male subjects (-51.35 +/-10.89% vs. -46.38 +/-13.96%; p = 0.025), but this was no longer significant after adjustment for body weight. In patients with familial hypercholesterolaemia the absolute reductions in total cholesterol and LDL-cholesterol were significantly greater (p<0.001) than in those without familial hypercholesterolaemia, but the percentage reductions were not significantly different in the two groups. The increases in HDL-cholesterol and the decreases in triglycerides were significantly greater in the subjects with familial hypercholesterolaemia than in those without familial hypercholesterolaemia, both for the absolute changes and for the percentage changes. There were no significant effects on the percentage changes in lipids with rosuvastatin treatment due to age, measurements of body fatness, smoking or alcohol drinking status, or having hypertension or diabetes. / Polymorphisms in the CYP2D6 gene were analyzed and the subjects were divided into 4 groups as wild-type or extensive metabolisers, heterozygotes for CYP2D6*10 and wild-type, homozygotes for CYP2D6*10, and subjects with one allele for poor metaboliser status. The groups in this order would be expected to have decreasing activity of the CYP2D6 enzyme. There was a tendency for greater reduction in LDL-cholesterol in groups with lower CYP2D6 activity, most obvious in male subjects and this was significant in the patients with familial hypercholesterolaemia comparing the first 3 groups. The fourth group had a low number of subjects, which may have biased that result. In the subjects without familial hypercholesterolaemia, the % change in LDL-cholesterol was similar in all genotype groups, but the % reduction in triglycerides was numerically higher in the wild-type group than in groups with CYP2D6*10 alleles and the group with poor metaboliser status showed a lower % reduction. These differences were not significant and may be influenced by the baseline levels of triglycerides, which were not corrected for in this analysis. / The daily calorie intake and percentage of different macronutrient intake was obtained by using seven days food recall records. Dietary intake of most nutrients with higher in male than in female patients and was higher in the patients compared to gender-matched population data. Higher intake of most nutrients was associated with higher baseline triglyceride levels, but not LDL-cholesterol levels in all patients, and in lower HDL-cholesterol levels in the patients without familial hypercholesterolaemia. Higher intake of total calories was associated with less percentage reduction in LDL-cholesterol with rosuvastatin in the patients without familial hypercholesterolaemia and a similar non-significant tendency was seen with higher intake of total fat, saturated fat and cholesterol. / The study described in this thesis examined the role of the CYP2D6*10 polymorphism on the lipid response to rosuvastatin in addition to a number of phenotypic factors such as diet, gender, measures of obesity and other medical conditions. / These findings suggest that the CYP2D6 genotype may have some influence on the lipid response to rosuvastatin, but it appears to interact with other factors including, gender, diet and the presence of familial hypercholesterolaemia. (Abstract shortened by UMI.) / Lui, Siu Hung. / "February 2007." / Adviser: Brian Tomlinson. / Source: Dissertation Abstracts International, Volume: 69-01, Section: B, page: 0248. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (p. 165-190). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Although the clinical efficacy of statins has been well established, there is a wide inter-individual variation in the lipid responses to statins. Pharmacogenetic studies have identified some genetic differences that contribute to the variation, but overall the results have been disappointing. The studies described in this thesis were performed to examine whether certain genetic variants predicted the lipid responses to rosuvastatin in Chinese patients. Over 400 Chinese patients with increased risk of cardiovascular disease (CVD) who were treated with rosuvastatin 10 mg daily for at least 4 weeks (more than 97% of patients had at least 6 weeks treatment) were studied, including 166 having familial hypercholesterolaemia (FH) and 36 having rheumatoid arthritis (RA). They were genotyped for 135 polymorphisms in 62 candidate genes/loci potentially related to pharmacokinetics or pharmacodynamics of statins and lipid metabolism. Associations between genetic polymorphisms and the lipid responses to rosuvastatin were analyzed in 386 patients with good compliance. The associations between genetic polymorphisms and some risk factors for CVD including baseline lipid levels, high-sensitivity C-reactive protein (hsCRP), uric acid and bilirubin levels were also analyzed. / Some novel genetic determinants of the LDL-C response to rosuvastatin treatment have been identified in this study. The responses in HDL-C and triglycerides were related more closely to the baseline levels of these lipids than to any of the polymorphisms examined. Genetic associations with baseline lipid parameters, hsCRP, uric acid and bilirubin were identified and generally correspond with some of the previous reports of studies in Chinese and other ethnic groups. / The key findings of the study are as follows: 1. The polymorphisms most highly associated with the low-density lipoprotein cholesterol (LDL-C) response were 421C>A in the ATP-binding cassette G2 (ABCG2) gene (P=9.2x10 -7), followed by 18281G>A (V257M) in the flavin-containing monooxygenase 3 (FMO3) gene (P=0.0002), 1421C>G in the lipoprotein lipase (LPL) gene (P=0.002), and rs4420638 in the apolipoprotein E/C-I/C-IV/C-II (APOE/C1/C4/C2) gene cluster (P=0.004). These genetic polymorphisms and having FH totally explained 13.6% of the variance in percentage change in LDL-C in response to rosuvastatin. The greater percentage reduction in LDL-C in patients with the ABCG2 421AA genotype compared to those with the ABCG2 421CC genotype was equivalent to at least doubling the dose of rosuvastatin. 2. Three SNPs (glucokinase regulator [ GCKR] rs1260326, apolipoprotein AS [APOA5] -1131T>C and the solute carrier organic anion transporter 1B1 [SLCO1B1] 521T>C) tended to be associated with percentage changes in high-density lipoprotein cholesterol (HDL-C) (P<0.05), but none of these reached the overall significance level. In multivariate stepwise regression analysis, baseline HDL-C (P=1.6x10 -6), having diabetes (P=0.0004) or RA (P=0.002) and the SLCO1B1 521T>C polymorphism (P=0.03) were determinants of HDL-C responses, contributing 9.9% of the variance in percentage change in HDL-C, but the genetic factors only contributed to 0.8% of the variance. 3. The triglyceride response to rosuvastatin was highly variable and was strongly related to baseline levels. The diacylglycerol acyltransferase-2 (DGAT2) rs10899113 C>T polymorphism tended to be associated with reduced triglyceride response in a gene-dose dependent manner. However, in multivariate stepwise regression analysis, baseline triglyceride level was the only factor that strongly related to the triglyceride response, explaining 14.4% of the variance. 4. This study has also analyzed relationships between on-treatment plasma hsCRP concentrations and cardiovascular risk factors and 14 single nucleotide polymorphisms in CRP and other candidate genes, which showed that central obesity, low HDL-C and CRP polymorphisms are major determinants of higher hsCRP levels in Chinese patients on treatment with rosuvastatin. 5. The association between genetic polymorphisms and lipid traits were analyzed in FH and non-FH patients separately due to their different lipid profiles. The analysis has shown that there were different genetic predictors of lipid levels in patients with and without FH and that more genetic factors appeared to affect the baseline lipid levels in patients with FH compared to non-FH patients, suggesting complex interactions between genetic and environmental factors and plasma cholesterol levels in patients with and without FH. 6. The SLC2A9 (solute carrier family 2, member 9) rs1014290 T>C was significantly associated with plasma uric acid levels in a gene-dose dependent manner (P=1.0x10-5) and the relationship was more pronounced in women or in patients without hypertension than in men or patients with hypertension. The ABCG2 421 C>A did not show a significant effect on uric acid levels. 7. The UGT1A1 (uridine diphosphate glucuronosyltransferases family, polypeptide A1) variants *28 (P=1.5x10 -9) and *6 (P=2.2x10-7) were independently associated with increased baseline bilirubin levels. Polymorphisms in SLCO1B1 did not appear to affect bilirubin levels in this study. / Hu, Miao. / Adviser: Brian Tomlinson. / Source: Dissertation Abstracts International, Volume: 72-04, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 230-264). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

O Brasil, que conta hoje com 7% de idosos, será a sexta maior população de idosos do Planeta em 2020. A doença cardiovascular aumenta significativamente com a idade e evidências indicam a importância do endotélio e da hipercolesterolemia na aterosclerose. Contudo, não está bem estabelecido, que o tratamento da dislipidemia em idosos melhora a função vasomotora. Objetivos: Analisar a resposta vasomotora e parâmetros metabólicos em idosos com hipercolesterolemia ao tratamento com estatina. Delineamento: Ensaio Clínico Randomizado Duplo Cego. Casuística e Métodos: 72 idosos com idade 65 anos [75 ± 7,7 (65 a 92)], 64% mulheres, excluídos diabéticos, hipertensos graves, obesos, corticoterapia, reposição hormonal, doença em estágio terminal; todos realizaram avaliação clínica, laboratorial (glicose, lípides, TGO, TGP, CPK, Proteina C reativa ultra-sensível (PCR)) e função vasomotora por ultra-sonografia de alta resolução da artéria braquial, com equipamento ATL HDI 5000 e transdutor multifreqüencial de 7 a 10 MHz, segundo Diretrizes. Utilizou-se hiperemia reativa para resposta vasomotora dependente do endotélio (DMF) e nitrato sub-lingual para a independente do endotélio (DNT). Destes, 47 pacientes apresentaram LDL 130 mg/dL e foram randomicamente designados para grupo placebo (GP) e grupo tratamento (GT); todos realizaram avaliação antes e depois da intervenção (placebo ou atorvastatina 20mg oral por 30 dias). Para a análise estatística, utilizaram-se testes paramétricos e não-paramétricos, valores de p 0,05 foram considerados estatisticamente significantes. Resultados: Os grupos foram semelhantes em suas características basais; a DMF não apresentou diferença estatisticamente significante entre o GP e GT após intervenção [6,2 ± 6,2 (-4,8 23,7) e mediana = 6,4 vs. 5,0±5,6 (-5,1 18,9) e mediana= 3,5 p = 0,551], o mesmo ocorrendo para a DNT [7,1 ± 4,7 (-1,3 21,2) e mediana = 6,8 vs. 8,6±5,0 (1,4 21,6) e mediana = 6,8 p = 0,373). A análise estratificada sugere potencial modificador de efeito das co-variáveis estratificadas sexos, estratos etários (<80 e 80 anos) e níveis de LDL (< 160mg/dL e 160mg/dL) em relação à associação atorvastatina e função vasomotora. A PCR diminuiu 64% no grupo estatina (mediana no GP = 0,3 mg/dL vs. GT = 0,1 mg/dL p = 0,014). A redução do colesterol total foi de 27%, LDL = 41%, VLDL = 20% e triglicérides = 34%; o HDL elevou 12% no GT. A maior elevação enzimática não ultrapassou 3 vezes o limite e não ocorreram mialgias. Conclusões: Apesar da diminuição dos lípides, não houve modificações significativas da função vasomotora, o que sugere alterações intrínsecas do vaso associado ao envelhecimento. Os níveis de PCR reduziram significativamente, sugerindo um provável efeito antiinflamatório / The Brazil, where old people make up 7% of the population, will have the sixth greatest population of elderly people in the world. Cardiovascular disease increases significantly as a person grows older and evidences show the importance of the endothelium and hypercholesterolemia in arteriosclerosis. However, it has not been established yet if treating dyslipidemia in the elderly will improve this function. Objectives: To evaluate vasomotor response in elders suffering from hypercholesterolemia to the treatment with statin and to evaluate their lipids, c-Reactive Protein (CRP). Design: Double-blind randomized clinical trial. Methods: Seventy-two elderly people aged >65 years old [75 ± 7.7 (65 to 92)], 65% of women, excluding those suffering from diabetes, serious hypertension, obesity, steroid use, hormone replacement, end-stage disease; all of them underwent clinical evaluation, laboratorial evaluation (glucose, lipids, liver enzymes, CPK, high sensitivity CRP (CRP). Vasomotor response was evaluated by means of ATL HDI 5000 high resolution ultrasound scan of the brachial artery and multifrequency transduction of 7 to 10 MHz. Reactive hyperemia was used for endothelium-dependent flow response (DMF) and sublingual nitrate for the endothelium-independent dilation (DNT). Out of those patients, 47 presented LDL 130 mg/dl and were ramdonly divided into placebo (n = 23) and treatment group (n = 24); all of them had underwent evaluation before and after intervention (placebo or atorvastatin 20 mg, orally, during 30 days); for statistic analysis parametric and non-parametric tests were used and p 0.05 values were considered statistically significant. Results: The groups were similar in their basal characteristics; DMF did not present any statistically significant difference between placebo and treatment group after intervention [6.2 ± 6.2 (-4,8 - 23.7) and median = 6.4 vs. 5.0 ± 5.6 (-5.1 - 18.9) and median = 3.5 p = 0.551], the same occurred to DNT [7.1 ± 4,7 (-1.3 - 21.2) and median = 6.8 vs. 8.6 ± 5.0 (1.4 - 21.6) and median = 6.8 p = 0.373). Stratified analysis suggests effect modifying factor of the gender, age strata (< 80 and 80 years of age) and LDL (< 160 mg/dL e 160 mg/dL). CRP diminished 64% in the treatment group (median in the placebo group = 0.3 mg/dL vs. treatment group = 0.1 mg/dL p = 0.014). The reduction of total cholesterol was 27%, LDL = 41%, VLDL = 20% and triglycerides = 34%; HDL raised 12% in the treatmente group in relation to the placebo group. The highest enzymatic elevation did not surpass 3 times the limit and there were no myalgia. Conclusions: In spite of a significant decrease in lipids, there were no significant changes in vasomotion response with statin therapy, suggesting intrinsic alterations of the vessel associated with ageing. However, CRP reduction suggested an anti-inflammatory effect

Clopidogrel is an antiplatelet drug prescribed to prevent stent thrombosis after a percutaneous coronary intervention (PCI). Previous evidence suggests that some widely prescribed statins may inhibit the antiplatelet effects of clopidogrel via competitive metabolism of its activating enzyme cytochrome P450 3A4 (CYP3A4). / The objective was to investigate the possibility of an interaction post-PCI between statins and clopidogrel. / We carried out a population-based cohort study identifying 10,491 patients using clopidogrel post-PCI (2001-2004). The outcome was a composite of death of any cause, myocardial infarction, unstable angina, repeat revascularization, and cerebrovascular events. We found that co-prescription of CYP3A4-metabolized statins (hazard ratio (HR) 0.95, 95% confidence interval (CI) 0.79-1.15), or non-CYP3A4-metabolized statins (HR 0.82, 95% CI 0.63-1.07) with clopidogrel was not associated with increase in adverse outcomes. / We observed no evidence of interaction between clopidogrel and statins in a large population cohort of PCI patients, suggesting unlikelihood of an important interaction.

Aukšto laipsnio prostatos intraepitelinė neoplazija (ALPIN, angl. – HGPIN – high grade prostatic intraepithelial neoplasia ) priskiriama prie priešvėžinių būklių ( arba prostatos vėžio prekursorių) ir susijusi su padidėjusia kartu esamo vėžio diagnozavimo rizika arba vėlesne jos progresija iki vėžio. Manoma, kad pacientai, kuriems nustatyta ALPIN prostatos biopsinėje medžiagoje, yra tinkami kandidatai chemoprevencijai. Šio darbo tikslas buvo nustatyti 5-alfa reduktazės inhibitoriaus dutasterido reikšmę prostatos vėžio prevencijai esant didelei šios ligos rizikai. Darbo uždaviniai : 1. Nustatyti prostatos vėžio dažnį esant didelei šios ligos rizikai (biopsinėje medžiagoje nustatyta aukšto laipsnio prostatos intraepitelinė neoplazija). 2. Įvertinti pakartotinių biopsijų reikšmę prostatos vėžio diagnozavimo dažniui. 3. Įvertinti tiriamojo vaisto reikšmę prostatos vėžio prevencijai (ar sumažina prostatos vėžio diagozavimo dažnį) esant didelei šios ligos rizikai. 4. Palyginti diagnozuoto prostatos vėžio diferenciacijos skirtumus tiriamosiose grupėse. / A high grade prostatic intraepithelial neoplasia (HPIN) is traditionally ascribed to pre-cancerous conditions or prostate cancer (PC) precursors, and associated with an increased risk of concomitant cancer or its later progression to malignant disease. After evaluation of the data indicating HPIN as a pre–cancerous condition, it is thought that the patients having HPIN in the prostate biopsy material are suitable candidates for chemoprevention.The aim of the study was to find out the significance of dutasteride, a 5–alpha reductase inhibitor, for the prevention of development of prostate cancer in case of a high risk for the disease. Objectives of the study: 1. To determine the rate of prostate cancer in case of a high risk for the disease (when a high grade prostatic intraepithelial neoplasia is found in biopsy material). 2. To find out the significance of repeat biopsies for the detection rate of prostate cancer. 3. To find out the significance of the investigatory medication for the prevention of development of prostate cancer in case of a high risk for the disease. 4. To compare the differences in the differentiation of diagnosed prostate cancer between the study groups.

Thesis (Ph. D.)--University of Alabama at Birmingham, 2008. / Title from first page of PDF file (viewed June 6, 2008). Includes bibliographical references.

Thesis (Ph.D.)--University of Alabama at Birmingham, 2008. / Title from PDF title page (viewed on July 16, 2010). Includes bibliographical references.