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

Dissertation (Ph.D.)--University of South Florida, 2009. / Includes vita. Includes bibliographical references. Also available online.

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

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.

Orientador: André Almeida Schenka / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-25T22:24:18Z (GMT). No. of bitstreams: 1 Renno_AndreLisboa_D.pdf: 23208237 bytes, checksum: c782ca447d3fee7cb5573e4b122b7f94 (MD5) Previous issue date: 2014 / Resumo: O câncer mamário é a neoplasia maligna mais incidente e a principal causa de óbito por malignidade no sexo feminino no Brasil e no mundo. Estipula-se que há mais de 1.2 milhões de novos casos anuais de câncer de mama, e que a heterogeneidade e a complexidade molecular do câncer de mama dificultam estratégias terapêuticas de prevenção e tratamento desta doença. Atualmente, acredita-se que, em diversas neoplasias, incluindo o câncer de mama, a célula alvo de mutações cumulativas responsáveis pelo desenvolvimento do fenótipo canceroso é uma célula-tronco adulta. Independentemente da origem da neoplasia (se em célula madura/diferenciada ou em CT), é possível constatar in vitro e in vivo, na grande maioria dos tumores malignos, uma subpopulação de células indiferenciadas, com características fenotípicas de célula-tronco. Tais células são designadas como "células tronco cancerosas ou neoplásicas (CTNs)". Com frequência, especula-se se as CTNs seriam responsáveis pela heterogeneidade morfológica e molecular de algumas neoplasias mamárias. Em conjunto, essas peculiaridades das CTNs as tornam importantes alvos no desenvolvimento de novas abordagens farmacoterapêuticas antineoplásicas. Recentemente, Gauthaman et al (2009) demonstraram de forma inédita em estudos in vitro que estatinas apresentam efeito inibitório específico sobre células tronco embrionárias com alterações cariotípicas e células de linhagens neoplásicas mamárias com fenótipo CTN, não afetando o crescimento de células tronco normais. As estatinas são inibidores competitivos da 3-hidroxi-3-metilglutaril coenzima A (HMG-CoA) e são amplamente utilizada para o tratamento de doenças cardiovascular primário e secundário. Além de amplamente utilizadas na prevenção e tratamento de doenças cardiovasculares secundárias a dislipidemias, evidências cumulativas apontam para um possível papel destas drogas na prevenção ou regressão de processos neoplásicos. Entre os efeitos antineoplásicos comprovados das estatinas, destacam-se: a inibição da proliferação celular, a promoção de apoptose, a inibição da angiogênese e a prevenção de metástases. Assim, buscou-se neste trabalho elucidar o efeito da sinvastatina e pravastatina sobre células progenitoras e CTNs e em algumas vias de sinalização intracelular em modelo de carcinogênese mamária (baseado na indução com 7,12 dimetilbenz(a)antraceno[DMBA]) em ratas Sprague-Dawley. Após um tratamento de 14 dias com as estatinas, as mamas das ratas foram analisadas para verificar a imunoexpressão de células progenitoras e CTNs (CD133, CD24, CD44 e EpCAM), variáveis biológicas (volume tumoral, mitose, índice proliferativo) além da análise proteica de Akt e Src. A maior dose da sinvastatina testada (40 mg/Kg) diminui o número de tumores desenvolvidos, volume e incremento tumoral e os índices de proliferação celular. Não houve alteração da percentagem de necrose com o tratamento com as estatinas. Ainda, sinvastatina diminuiu os níveis da fosforilação da Akt e aumento da PTEN, não havendo diferenças significantes nos níveis da Src. Sinvastatina também foi capaz de reduzir o número de células positivas CD133, CD24 e CD44. Pelas doses testadas, não houve diferença dos parâmetros biológicos analisados com o tratamento com a pravastatina. Em conclusão, neste modelo, o tratamento crônico com a sinvastatina apresentou efeitos citostáticos, ações reguladoras na via da Akt além do controle de células progenitoras e CTNs em modelo in vivo de carcinoma mamário / Abstract: Breast cancer is the malignant neoplasm with the highest incidence and the main cause of death by cancer within females in Brazil and in the world. It is estimated that there are over 1.2 million new annual cases of breast cancer. The heterogeneity and the molecular complexity of this type of cancer complicate the therapeutic strategies for its prevention and treatment. Nowadays, it is believed that in many different neoplasms, including breast cancer, the cell which is the target of cumulative mutations responsible for the development of the cancerous phenotype is an adult stem cell. Regardless the origin of the neoplasm (whether in mature/differentiated cell or in SC), a subpopulation of undifferentiated cells with phenotypic characteristics of stem cells can be seen in vitro and in vivo in most malignant tumours. These cells are designated as "neoplastics or cancer stem cells (CSCs)". It is often especulated whether CSCs would be responsible for the molecular and morphological heterogeneity in some breast neoplasms. The peculiarities of the CSCs make them a relevant/an important/a serious object for the development of new antineoplastic pharmacotherapeutic approaches. Recently, Gauthaman et al (2009) demonstrated in unprecedented in vitro studies that statins exhibit specific inhibitory effect on embryonic stem cells with karyotypic alterations and neoplastic mammary cell lines with phenotype CSC, not affecting the growth of normal stem cells. Statins are competitive inhibitors of coenzyme 3-hydroxy-3-methylglutaryl A (HMG-CoA) reductase and are widely used for the primary and secondary treatment of cardiovascular diseases. Moreover, cumulative evidence points to a possible role of these drugs in the prevention or regression of neoplastic processes. Amongst the proven anticancer effects of statins, some of them stand out such as: inhibition of cell proliferation, promotion of apoptosis, inhibition of angiogenesis and metastasis prevention. Thus, this study sough to elucidate simvastatin and pravastatin effects on progenitor cells and NSCs, and on some signaling pathways in breast carcinogenesis model (based on induction 7,12 dimethylbenz (a) anthracene [DMBA]) in female Sprague-Dawley rats. After a 14 days treatment with the statins, the rats' breasts were examined to verify immunostaining of progenitor cells and CSCs (CD133, CD24, CD44 and EpCAM), biological variables (tumor volume, mitosis, proliferation index) in addition to protein analysis of Akt and Src. The highest dose of the tested simvastatin (40mg/kg) decreased the number of tumors developed, volume and tumor growth as well as the cell proliferation index. There was no change in the percentage of necrosis to treatment with statins. Furthermore, simvastatin decreased the levels of Akt phosphorylation and increased PTEN levels, without significant differences in Src levels. Simvastatin was also able to reduce the number of CD133, CD24 and CD44 positive cells. For the doses tested, there was no difference on the analyzed parameters in the treatment with pravastatin. As a conclusion, in this model, chronic treatment with simvastatin showed cytostatic effects, regulatory actions towards Akt, as well as the control of CSCs and progenitor cells in the in vivo model of mammary carcinoma / Doutorado / Farmacologia / Doutor em Farmacologia

No description available.

Introdução: A associação de uma estatina com ezetimiba é tão eficaz quanto altas doses da mesma estatina na redução do LDL-colesterol. Os efeitos que não dependem dessa redução são chamados de pleiotrópicos, entre os quais podemos citar: melhora da função endotelial, efeitos anti-oxidantes, efeitos anti- inflamatórios, entre outros. Objetivo: comparar a ação de dois esquemas de tratamento que obtêm reduções equivalentes de LDL-colesterol (sinvastatina 80 mg ao dia e associação sinvastatina 10mg/ezetimiba 10 mg ao dia), sobre os efeitos pleiotrópicos: inflamação, função endotelial e oxidação da LDL. Métodos: estudamos 23 pacientes randomizados e na forma de cross-over 2x2. A inflamação foi mensurada através da PCR-us, a função endotelial por meio de ultra-sonografia e a oxidação de LDL pelas dosagens de LDL eletronegativa (LDL-) e do anticorpo anti-LDL-. Resultados: A redução do LDL-colesterol foi similar nos dois grupos (45,27% no grupo sinvastatina/ezetimiba (p<0,001) e 49,05% no grupo sinvastatina (p<0,001), sem diferença entre os tratamentos (p=0,968)). Os dois grupos apresentaram melhora da função endotelial (3,61% no grupo sinvastatina/ezetimiba (p=0,003) e 5,08% no grupo sinvastatina (p<0,001), não houve diferença entre os tratamentos (p=0,291)). Houve melhora nos níveis da PCR-us (redução de -22,8% no grupo sinvastatina/ezetimiba (p=0,004) e de 29,69% no grupo sinvastatina (p=0,01), sem diferenças entre os tratamentos (p=0,380)). Não houve redução significativa da LDL-. Ocorreu aumento na concentração do anticorpo anti-LDL eletronegativa apenas no grupo sinvastatina (p=0,045). Conclusões: as duas formas de tratamento são eficazes na melhora da função endotelial e dos níveis de PCR-us. Somente com o uso da sinvastatina em alta dose houve aumento nos níveis de anticorpos anti-LDL-. / Introduction: The co-administration of a statin with ezetimibe is as effective as high doses of the same statin in the reduction of the LDL-cholesterol. The effects which don´t depend of this reduction are called pleiotropic effects, some among them can be cited: endothelial function improvement, antioxidative and anti-inflammatory effects. Objective: compare the effectiveness of these two different treatments that obtain equivalent reductions of LDLcholesterol (simvastatin 80 mg once a day and co-administration of simvastatin 10 mg once a day and ezetimibe 10 mg once a day), about pleiotropic effects: inflammation, endothelial function and LDL oxidation. Methods: we have studied 23 randomized patients in a 2x2 cross-over study. Inflammation was measured by high-sensitive C reactive protein, endothelial function by echocardiography and LDL oxidation by electronegative LDL and electronegative anti-LDL antibodies levels. Results: the LDL-cholesterol was similar between the two groups (45,27% reduction in the simvastatin/ezetimibe group (p<0,001) and 49,05% reduction in the simvastatin group (p<0,001); no difference between treatments was found (p=0,968). The two groups had improvement in endothelial function (3,61% in the simvastatin/ezetimibe group (p=0,003) and 5,08% in the simvastatin group (p<0,001)), no differences was found between the two groups (p=0,291). High-sensitive C reactive protein had a 22,8% reduction in the simvastatin/ezetimiba group (p=0,004) and 29,69% reduction in the simvastatin group (p=0,01), with no significative difference in any of the two treatments (p=0,380). There was no significative difference in LDL- levels. The anti-LDL- antibodies concentration was increased only in the simvastatin group (p=0,045). Conclusion: the two forms of treatments presented some similar pleiotropic effects - improvement in endothelial function and decreased hs-CRP levels. Only with a high simvastatim dose the anti-LDL- antibodies concentration was increased.

Introdução: As avaliações econômicas completas do tipo custo-utilidade, suportadas por dados de efetividade do mundo real, permitem uma perspectiva diferenciada da avaliação de tecnologia em saúde. Objetivo: Realizar uma análise de custo-utilidade do uso de estatinas para a prevenção secundária de eventos cardiovasculares em portadores de doença cardiovascular isquêmica, e avaliar a variabilidade da efetividade e da razão de custo-efetividade incremental com diferentes classificações de usuários de estatina (incidentes e prevalentes). Método: Um modelo de microssimulação de Markov com 5 estados, ciclos anuais e horizonte temporal de 20 anos, com taxas de desconto de 5% foi desenvolvido. As probabilidades de transição para mortalidade por todas as causas foram extraídas após pareamento por escore de propensão dos dados e tratamento de dados ausentes de uma base secundária de registro assistencial com linkage determinístico com a base de mortalidade do Ministério da Saúde. As probabilidades dos desfechos não-fatais foram obtidas na literatura. As medidas de efetividade (QALY) foram calculadas com dados publicados dos domínios do SF-36 de um estudo realizado com a população do mesmo hospital, no mesmo período e com as mesmas condições clínicas e transformados em medidas de utilidade por modelo validado. Somente custos diretos na perspectiva do reembolso do SUS foram considerados. Resultados: 3.150 pacientes foram pareados após o escore de propensão, 1.050 não usuários de estatina, 1.050 usuários de estatinas classificados como prevalentes e 1.050 usuários de estatinas classificados como incidentes, com diagnóstico de doença cardiovascular isquêmica prévia, com seguimento médio de 5,1 anos. A efetividade das estatinas quando considerados todos os usuários em relação aos não usuários resultou em um HR para mortalidade de 0,992 (IC 95% 0,85; 0,96) e de 0,90 (IC 95% 0,85; 0,96) para os usuários incidentes. A RCEI comparando todos os usuários de estatinas versus não usuários foi de R$5.846,10/QALY e de R$7.275,61/QALY para os usuários incidentes. Conclusão: As estatinas diminuíram a mortalidade por todas as causas, e a análise incluindo usuários prevalentes diminui o tamanho do efeito. O tratamento possui custo-efetividade favorável dentro do limiar de disponibilidade a pagar definido, sendo modificado pela forma de extração do dado de efetividade / Background: The complete economic evaluations, such as cost-utility analysis, supported by real world data of effectiveness lead to a more realistic perspective of a health technology assessment. Objective: Perform a cost-utility analysis of statins for secondary prevention in ischemic cardiovascular disease patients based on effectiveness from real world data and evaluate the variability of effectiveness and incremental cost-effectiveness ratio (ICER) considering prevalent and incident users. Methods: A Markov microssimulation model with five states, annual cycle and time horizon (TH) of 20 years, with discount rate of 5% was developed. Transition probabilities for all cause mortality was derived from a secondary database of a teaching hospital after record linkage with national registry of mortality database and an analysis of propensity score matching and multiple imputation analysis for missing data. Non-fatal endpoints were derived from a published meta-analysis. Utility measures was calculated with a validated model to derive values from published domains of SF-36 QoL questionnaire, domains was measured for a published RCT in the same teaching hospital, over the same period, with similar age and diagnostic characteristics. Only direct costs were analyzed from the Brazilian public health reimbursement perspective. Results: 3150 patients were matched, 1050 non-statins users (CG), 1050 prevalent statins users (PSU) and 1050 incident statins users (ISU) with previous cardiovascular disease, with mean follow-up of 5,1 years. Treatment effects on the treatment group considering all statins users for all cause mortality had a hazard ratio of HR:0,992 (IC 95% 0,85 - 0,96) and HR: 0,90 (IC 95% 0,85 - 0,96) only for ISU. The ICER comparing all users with non-users was R$5.846,10 per QALY and for ISU was R$7.275,61 per QALY. Conclusion: Real world evidence demonstrated that statins are an effective treatment to reduce all cause mortality in secondary prevention and are a cost-effective strategy considering the willingness to pay established, but the prevalent users resulted in less effectiveness of the drug when included in the analysis and influenced the ICER

Clinical evidence suggested patients with lower plasma C-reactive protein (CRP) levels after statin therapy could have better clinical outcome. The last part of the study was to measure on-treatment high sensitivity CRP (hsCRP) levels among 229 Chinese patients with hyperlipidaemia undergoing treatment with simvastatin 40 mg daily. The patients were genotyped for 15 SNPs or haplotypes in 11 candidate genes that would have significant allele frequency among Chinese patients and may be linked to statin efficacy or hsCRP levels. The analysis suggested BMI is the largest single contributing factor of 15.0% of the variation in hsCRP levels, followed by plasma triglycerides levels contributing 4.7% and male gender 1.6% (all P&lt;0.05). However comparisons of hsCRP levels among genotype groups did not reveal any significant findings, with or without adjustment with covariate genotypic or phenotypic factors. To further categorize individuals as high or medium risk, we set a threshold hsCRP level of 1 mg/L as the benchmark for evaluation. The CRPc.3872G>A SNP was related to lower risk compared to the homozygous wild-type genotype (adjusted odds ratio AOR = 0.289; P = 0.014) after adjusting for phenotypic factors of age, gender, smoking status, BMI, waist circumference, hip circumference, plasma lipid profiles, co-existing disease and co-medications. Another marginal finding included the HNF1A c.79A>C SNP (AOR = 0.575; P = 0.118). / Polymorphisms in the drug transporters are likely to be more important with hydrophilic statins such as pitavastatin, which undergoes transporter mediated distribution. The SLCO1B1 c.388A>G polymorphism in the gene encoding the uptake transporter organic anion transporting polypeptide (OATP1B1) is common in Chinese and the variant was associated with increases of 63--68% in maximum plasma concentration and 44--47% in systemic exposure of both the lactone and acid compared to wild-type subjects (P&lt;0.05). Co-administration of pitavastatin with grapefruit juice (GFJ) resulted in a small increase of the area under the plasma concentration time curve (AVC) by 15--16% for both the acid and lactone (P&lt;0.05). However, there was no significant effect on the drug-food interaction in relation to relevant SNPs in the enzymes and transporters examined. / The SNPs examined included those in the genes for the enzymes and transporters involved in the metabolic pathway or the distribution of simvastatin. Cytochrome P450 (CYP) enzymes are involved in hepatic and intestinal metabolism of several statins and simvastatin is known to undergo extensive metabolism via the CYP3A4/3A5 pathway. The common candidate SNPs in the CYP3A4/3A5 enzymes found in Chinese populations include CYP3A4*1G, CYP3AP1*3 and CYP3A5*3 , which are associated with altered enzyme expression and activity. However, no statistically significant relationship was found between these SNPs and a potential phenotypic marker of enzyme activity, the urinary ratio of 6beta-hydroxy-cortisol/cortisol (6beta-OHC/C) concentrations. The analysis of lipid lowering responses in relation to individual SNPs or combinations from gene-gene interactions also revealed no statistically significant findings. In the subgroup of patients with familial hypercholesterolaemia, the CYP3A4*1G, CYP3AP1*3 and CYP3A5*3 polymorphisms appeared to have a small effect on the changes in LDL-C and total cholesterol with the subjects with the CYP3A5*3 and CYP3AP1*3 variants showing less reduction and those with the CYP3A4*1G variant showing more reduction than subjects with the wild-type genotype with a tendency for a gene-dose effect. It is difficult to interpret these findings and the significance may be related to multiple testing. / The statins, or 3-hydroxymethyl-3-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, act on the rate limiting step in endogenous cholesterol synthesis. Their primary action results in reduction of plasma low-density lipoprotein cholesterol (LDL-C) levels and this is thought to be the major mechanism by which they reduce cardiovascular events. There are considerable differences between subjects in both the plasma levels of the statins and in their effects on LDL-C and other lipid parameters and some of this variation appears to be related to genetic differences in the pathways of drug metabolism and distribution and in the pathways involved in lipid metabolism. / The variation in response may be related to variations in systemic or hepatic exposure to the drug, which in turn will be related to the pharmacokinetics. This is also likely to play a role in the adverse effects of myopathy and therapeutic tolerance. In a pharmacokinetic study in healthy male Chinese subjects, the common polymorphism of CYP2D6*10 was analyzed in relation to the pharmacokinetics of lovastatin and simvastatin. There was a tendency for reduced clearance of simvastatin lactone by 30% (P>0.05) in subjects with the CYP2D6*10/*10 genotype. With lovastatin, there were similar findings with 38.5--84.9% decrease in clearance which appeared to be related to enzyme activity according to genotype, with *5 carriers showing a greater decline in clearance than *10 carriers (P&lt;0.05). / These results provide some insights into the pharmacokinetics and pharmacodynamics of statins and the pharamacogenetic relationships to candidate SNPs. Future research in this field should help to facilitate safer and more effective treatment with these commonly used medications, resulting in personalized therapy and optimal clinical benefits for patients with cardiovascular disease. / This thesis describes a study of 270 patients recruited from the outpatient clinics at the Prince of Wales Hospital who were treated with simvastatin 40 mg daily for at least 4 weeks. Their mean (+/-SD) LDL-C baseline level was 5.38+/-1.68 mmol/L and the reduction in LDL-C after simvastatin treatment was 2.81+/-0.99 mmol/L or -47.1+/-12.5%. / Mak, Wah Lun Valiant. / Adviser: Brian Tomlinson. / Source: Dissertation Abstracts International, Volume: 73-06, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 253-289). / 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, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Les données épidémiologiques montrent une association inverse entre les taux de HDL-cholestérol (HDL-C) et le risque d'évènements cardiovasculaires. Des traitements ayant montré une augmentation significative du HDL-C, comme les inhibiteurs de la protéine de transfert des esters de cholestérol, devraient donc permettre de réduire le risque cardio-vasculaire. En utilisant différentes techniques de modélisation, nous avons tenté de quantifier l'efficacité attendue sur les événements cardiovasculaires de l'un d'entre eux, le dalcétrapib, ne disposant que de données pharmacocinétiques et pharmacodynamiques. Tout d’abord, afin d'établir la relation pharmacocinétique / pharmacodynamique entre les concentrations et la modification de HDL-C, nous avons analysé les données individuelles des patients dyslipidémiques par une approche de population. Une hausse moyenne de HDL-C de 26.4 % par rapport au placebo était alors anticipée. Nous avons ensuite tenté de corréler l'effet observé sur l'HDL-C et l'effet clinique à partir de données d'autres études par méta-régression des essais évaluant l'effet des principaux hypolipémiants en prévention secondaire. Cette modélisation n'a pas permis de montrer de corrélation entre le changement de l’HDL-C (P5 P95 :-3.0 et 36 %) et la réduction du risque cardiovasculaire. Une analyse de sensibilité par type de traitement suggère qu'une même hausse de HDL-C entre deux classes thérapeutiques pourrait se traduire par un effet clinique dissemblable, indiquant que HDL-C ne peut pas être utilisé comme critère intermédiaire puisqu'il ne serait pas un prédicteur indépendant du risque cardiovasculaire / Epidemiological data demonstrate an inverse correlation between HDL-cholesterol (HDL-C) levels and cardiovascular risk. Therefore, drugs as cholesteryl ester transfer protein (CETP) inhibitors that lead to a significant HDL-C increase are believed to reduce the occurrence of coronary events. We aimed to evaluate the clinical efficacy of one CETP inhibitor, dalcetrapib, by using various modeling techniques while only pharmacokinetic (PK) and pharmacodynamlc (PD) data were available. First, we analyzed individual data from dyslipidemic patients using a population approach in order to establish the PK/PD relationship between dalcetrapib concentrations and HDL-C change. The results show that an average raise of 26.4 % is expected in comparison to placebo with the 5th (P5) and 95th (P95) percentile of the mean average at 20.7 % and 31.9 % respectively. The increase in HDL-C is explained by a delayed catabolism following the transfer inhibition of cholesterol ester from HDL to Apo-B rich lipoproteins. We endeavored then to correlate HDL-C increase to coronary events by using a meta-regression analysis on randomized trials that evaluated the clinical efficacy of main dyslipidemic drugs on coronary events in secondary prevention. The modeling did not show a statistical association between HDL-C change (P5-P95:-3.0 and 36 %) and coronary risk reduction. A sensitivity analysis by drug class suggests that the same HDL-C increase resulting from different mechanisms of action may not impact the cardiovascular risk in the same way. This would indicate that HDL-C could not be used as a risk marker since it might not be an independent predictor of cardiovascular risk