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.

Dissertation (Ph.D.)--University of South Florida, 2009. / Title from PDF of title page. Document formatted into pages; contains 86 pages. Includes vita. Includes bibliographical references.

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.

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.