Made available in DSpace on 2014-12-17T14:13:35Z (GMT). No. of bitstreams: 1 BolivarPGLD_DISSERT.pdf: 1624811 bytes, checksum: 4e49d5598ae806bbd9ddd7c33b6e903c (MD5) Previous issue date: 2010-06-19 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico / Several pharmaceutical products have been developed in recent years aiming to enhance the treatment of diseases by increasing the effectiveness of drugs. Many of these new products are based on new drug delivery systems. Among these, microemulsions, which were first studied in 1943 by Hoar and Schulman, is of great interest. Microemulsion can be defined as a thermodynamically stable, isotropic, translucent and transparent system of two immiscible liquids stabilized by a surfactant film located in the oil / water interface. The aim os this work was the incorporation of Amphotericin B and Simvasatin to a microemulsion system and analyzes its physicochemical properties and their therapeutical activity when incorporated into this system. Some very promising results were achieved as the reduction of the toxicity and maintenance of the efficacy of the Amphotericin B incorpored into a microemulsion, which was demonstrated in the in vitro pharmacotoxicological study. As for the incorporation of Simvastatin in microemulsion, it was observed a significant improvement in the potential antiinflammatory and anti-infective properties when the system was use to treat infected wounds (simvastatin pleiotropic effects). Therefore, it can be concluded that the incorporation of these drugs into microemulsion system reveal the potential of microemulsions as a promising and novel dosage form, qualifying them for future trials in order to make them available in the pharmaceutical market / In?meros produtos farmac?uticos v?m sendo desenvolvidos nos ?ltimos anos com a finalidade de incrementar o tratamento de doen?as pelo aumento da efic?cia de f?rmacos. Grande parte destes novos produtos est? baseada nos novos sistemas transportadores de f?rmacos. Entre eles destacamse as microemuls?es, que foram primeiramente estudadas em 1943 por Hoar e Schulman. Microemuls?o pode ser definida como um sistema termodinamicamente est?vel, isotr?pico, transl?cido e transparente de dois l?quidos imisc?veis estabilizados por um filme de tensoativos localizados na interface ?leo/?gua. O objetivo deste trabalho foi incorporar anfotericina B e sinvastatina em um sistema microemulsionado e analisar suas propriedades f?sico-qu?micas e suas a??es terap?uticas ap?s a incorpora??o destes f?rmacos ao sistema. Alguns resultados muito promissores foram alcan?ados como a redu??o da toxicidade e a perman?ncia da efic?cia da anfotericina B incorporada em uma microemuls?o durante o estudo farmacotoxicol?gico in vitro. Quanto ? incorpora??o da sinvastatina na microemuls?o, foi constatada uma melhora significativa no potencial antiinflamat?rio e antiinfeccioso (efeitos pleiotr?picos da sinvastatina) em feridas tratadas com esse sistema. Portanto, podemos concluir que a incorpora??o desses f?rmacos em sistemas microemulsionados faz das microemuls?es uma nova e promissora apresenta??o farmac?utica, habilitando-a a futuros ensaios com a finalidade de torn?-los dispon?veis no mercado farmac?utico

Made available in DSpace on 2014-12-17T14:25:23Z (GMT). No. of bitstreams: 1 MaraRWV_TESE.pdf: 3541177 bytes, checksum: 2415c9163a59f9b397912f22608eefbc (MD5) Previous issue date: 2014-05-29 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / This thesis aimed to assess the increase in solubility of simvastatin (SINV) with solid dispersions using techniques such as kneading (MA), co-solvent evaporation (ES), melting carrier (FC) and spray dryer (SD). Soluplus (SOL), PEG 6000 (PEG), PVP K-30 (PVP) e sodium lauryl sulphate (LSS) were used as carriers. The solid dispersions containing PEG [PEG-2(SD)], Soluplus [SOL-2(MA)] and sodium lauryl sulphate [LSS-2(ES)] were presented with a greater increase in solubility (5.02, 5.60 and 5.43 times respectively); analyses by ANOVA between the three groups did not present significant difference (p<0.05). In the phase solubility study, the calculation of the Gibbs free energy (&#916;G) revealed that the spontaneity of solubilisation of SINV occurred in the order SOL>PEG >PVP 75%>LSS, always 80%. The phase diagrams of PEG and LSS presented solubilization stoichiometry of type 1:1 (type AL). The diagrams with PVP and SOL tend to 1:2 stoichiometry (type AL + AP). The stability coefficients (Ks) of the phase diagrams revealed that the most stable reactions occurred with LSS and PVP. The solid dispersions were characterized by Fourier transform infrared (FTIR), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), particle size distribution (PSD), near-infrared spectroscopy imaging (NIR-CI) and X-ray diffraction of the powder using the Topas software (PDRX-TOPAS). The solid dispersion PEG-2(SD) presented the greatest homogeneity and the lowest degree of crystallinity (18.2%). The accelerated stability study revealed that the solid dispersions are less stable than SINV, with PEG-2(SD) being the least stable, confirmed by FTIR and DSC. The analyses by PDRX-TOPAS revealed the amorphous character of the dispersions and the mechanism of increasing solubility / Esta tese teve como objetivo avaliar o aumento de solubilidade da sinvastatina (SINV) atrav?s de dispers?es s?lidas utilizando as t?cnicas de malaxagem (MA), evapora??o com co- solvente (ES), fus?o com carreador (FC) e secagem por spray dryer (SD). Foram utilizados os carreadores Soluplus (SOL), PEG 6000 (PEG), PVP K-30 (PVP) e lauril sulfato de s?dio (LSS). As dispers?es s?lidas contendo PEG [PEG-2(SD)], Soluplus [SOL-2(MA)] e lauril sulfato de s?dio [LSS-2(ES)] apresentaram maior aumento de solubilidade (5,02; 5,60 e 5,43 vezes, respectivamente); a an?lise por ANOVA entre os tr?s grupos n?o demonstrou diferen?a significativa (p<0,05). No estudo de solubilidade de fases, o c?lculo da energia livre de Gibbs (&#916;G) revelou que a espontaneidade de solubiliza??o da SINV ocorreu na ordem SOL>PEG >PVP 75%>LSS, sempre a 80%. Os diagramas de fases de PEG e LSS apresentaram estequiometria de solubiliza??o 1:1 (tipo AL). Os diagramas de PVP e SOL possuem uma tend?ncia a estequiometria 1:2 (tipo AL + AP). Os valores de coeficiente de estabilidade (Ks) dos diagramas de fases revelaram que as rea??es mais est?veis ocorreram com LSS e PVP. As dispers?es s?lidas foram caracterizadas atrav?s de infravermelho com transformada de Fourier (FTIR), calorimetria explorat?ria diferencial (DSC), microscopia eletr?nica de varredura (MEV), distribui??o de tamanho de part?cula (DTP), espectroscopia de imagem no infravermelho pr?ximo (NIR-CI) e difratometria de raios X do P? utilizando o software Topas (PDRX-TOPAS). A dispers?o s?lida PEG-2(SD) apresentou a maior homogeneidade e o menor grau de cristalinidade (18,2%). O estudo de estabilidade revelou que as dispers?es s?lidas s?o menos est?veis que SINV, sendo PEG-2(SD) a de menor estabilidade, confirmada por FTIR e DSC. As an?lises por PDRX-TOPAS revelaram a cristalinidade das dispers?es e o mecanismo de aumento de solubilidade

Multiple sclerosis (MS), degenerative disease characterized by defects in the myelin membrane of neural cells, takes place probably by oxidative, inflammatory and autoimmune mechanisms in genetically vulnerable individuals, under the influence of environmental factors associated with feeding. [Hypothesis] As the structural composition of biological membranes is largely affected by diet, physical activity and use of medicines, the interference of environmental factors in the homeostasis of structural membranes of neural cells in carriers of MS must also be shared by other post-mitotic cells of the body, such as erythrocytes. [Objective] This study aimed to investigate the influence of statin use on the stability of erythrocytes membranes against hypotonic shock and chaotropic action of ethanol in patients with MS. [Methods] The population was composed of 16 women suffering from MS (26-58 years) who were being monitored at the Clinical Hospital of the Federal University of Uberlândia. They were divided into two groups, one group treated with 20 mg/day of simvastatin for 2.66 ± 1.03 years (n = 6) and another group without the use of statin (n = 10). A control group consisted of 6 healthy women with BMI and age (28-56 years) similar to problem group, all without the use of medications and without chronic consumption of alcohol. We evaluated the scores of patients in the Expanded Disability Status Scale (EDSS), hematological and biochemical variables, in addition to the stability of erythrocytes against hypotonic shock and ethanol. The stability of erythrocytes was evaluated by the half-transition points, H50 and D50, obtained from the curves of hemolysis induced by hypotonic shock and chaotropic action of ethanol, respectively. Statistical comparisons of results between groups were made by ANOVA and Tukey post-hoc test. [Results] There were no statistically significant differences in EDSS scores or the hematological variables between groups, but the MS patients under use of statin showed levels of total cholesterol and LDL-cholesterol significantly lower than those without use of that drug. The values of H50 of the MS patients without use of statins (0.472 ± 0.013 g.dL-1 NaCl) were significantly higher than those of volunteers in the control group (0.427 ± 0.015 g.dL-1 NaCl). The H50 values of the carriers of MS with use of statins (0.457 ± 0.013 g.dL-1 NaCl) declined (although not in a statistically significant basis) compared to carriers of MS without the use of statins, but they were not equal to the values of H50 of volunteers in the control group. Moreover, the values of D50 of MS patients without use of statin (13.87 ± 0.74% v/v ethanol) were significantly lower than those of volunteers in the control group (15.38 ± 0.24 g.dL-1 NaCl), but the values of D50 in the MS patients under statin therapy (15.20 ± 0.15 g.dL-1 NaCl) were not significantly different from those of volunteers in the control group, although they had been significantly higher than those of MS patients without use of statins. [Conclusions] The carriers of MS without use of statin showed erythrocytes less stable against hypotonic chock and action of ethanol than the control group. The use of statins increased the stability of erythrocytes against ethanol in the MS patients, making it similar to the RBC stability of the volunteers without the disease. But the use of statins did not increase osmotic stability of the erythrocyte membrane against hypotonicity in such a way to make it similar to the membrane stability of the volunteers without the disease. These findings are important and reflect the homeostatic conditions in the erythrocytes membranes by the moment of their evaluation. This could be merely a consequence of changes in lifestyle associated with the development of the disease, but could also be associated with a lifestyle that may have implications in the development of MS. The reasons for believing in the validity of the last hypothesis are discussed. / A esclerose múltipla (EM), doença degenerativa caracterizada por defeitos na membrana de mielina das células neurais, desenvolve-se provavelmente por mecanismos oxidativos, inflamatórios e auto-imunes em indivíduos geneticamente vulneráveis, sob a influência de fatores ambientais associados à alimentação. [Hipótese] Como a composição estrutural das membranas biológicas é largamente afetada pela alimentação, padrão de atividade física e uso de medicamentos, se houver interferência de fatores ambientais na homeostase estrutural das membranas das células neurais em portadores de EM, ela deve ser também compartilhada por outras células pós-mitóticas do organismo, como os eritrócitos. [Objetivo] Este trabalho teve como objetivo estudar a influência do uso de estatina sobre estabilidade de membrana de eritrócitos contra choque hipotônico e ação caotrópica do etanol em portadores de esclerose múltipla. [Métodos] A população foi constituída por 16 mulheres portadoras de EM (26-58 anos), que estavam em acompanhamento no Hospital de Clínicas da Universidade Federal de Uberlândia. Elas foram divididas em dois grupos, um grupo tratado com 20 mg/dia de sinvastatina durante 2,66 ± 1,03 anos (n = 6) e outro grupo sem uso de estatina (n = 10). Um grupo controle foi constituído por 6 mulheres saudáveis, com IMC e idades (28-56 anos) equiparáveis ao grupo problema, todas sem uso de medicações e sem consumo crônico de bebida alcoólica. Foram avaliados escores da escala expandida do estado de incapacidade (EDSS), variáveis hematológicas e bioquímicas, além da estabilidade de membrana de eritrócitos contra choque hipotônico e etanol. A estabilidade de eritrócitos foi avaliada pelas constantes de meia-transição de lise, H50 e D50, obtidas a partir das curvas de hemólise por choque hipotônico e ação caotrópica do etanol, respectivamente. Comparações estatísticas dos resultados entre os grupos foram feitas por ANOVA, utilizando pós-teste de Tukey. [Resultados] Não houve diferenças estatisticamente significantes nos escores de EDSS nem nas variáveis hematológicas entre os grupos, mas as portadoras de EM sob uso de estatina apresentaram níveis de colesterol total e LDL-colesterol significantemente menores do que aquelas sem uso daquela droga. Os valores de H50 das portadoras de EM sem uso de estatina (0,472 ± 0,013 g.dL-1 NaCl) foram significantemente maiores do que aqueles das voluntárias do grupo controle (0,427 ± 0,015 g.dL-1 NaCl). Os valores de H50 das portadoras de EM com uso de estatina (0,457 ± 0,013 g.dL-1 NaCl) declinaram (ainda que sem significância estatística) em relação à portadoras de EM sem uso de estatina, sem se igualar aos valores de H50 das voluntárias do grupo controle. Por outro lado, os valores de D50 das portadoras de EM sem uso de estatina (13,87 ± 0,74% v/v etanol) foram significantemente menores do que os das voluntárias do grupo controle (15,38 ± 0,24% v/v etanol), mas os valores de D50 das portadoras de EM sob uso de estatina (15,20 ± 0,15% v/v etanol) não foram significantemente diferentes daqueles das voluntárias do grupo controle, embora eles tenham sido significantemente maiores do que aqueles das portadoras de EM sem uso de estatina. [Conclusões] As portadoras de EM sem uso de estatina apresentaram eritrócitos menos estáveis contra hipotonicidade e contra a ação do etanol que as voluntárias do grupo controle. O uso de estatina aumentou a estabilidade de eritrócitos contra etanol nas portadoras de EM, tornando esta estabilidade semelhante àquela das voluntárias sem a doença. Porém o uso de estatina não aumentou a estabilidade de membrana dos eritrócitos contra hipotonicidade a ponto de torná-la semelhante à estabilidade de membrana das voluntárias sem a doença. Esses achados são importantes e refletem as condições da homeostase de membrana dos eritrócitos, no período de sua determinação. Eles poderiam ser mera conseqüência de mudanças no estilo de vida associadas ao desenvolvimento da doença, mas poderiam também estar associadas a um estilo de vida que possa ter tido implicações no desenvolvimento da EM. As razões para acreditar na validade desta última hipótese são discutidas. / Mestre em Genética e Bioquímica

Orientador: André Almeida Schenka / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-26T23:14:31Z (GMT). No. of bitstreams: 1 Costa_MonalisaNogueira_M.pdf: 3298749 bytes, checksum: ed49b381d19bdf264ab8c172dee5e277 (MD5) Previous issue date: 2015 / Resumo: A sinvastatina pertence à classe das estatinas, drogas capazes de inibir a enzima 3-hidroxi-3-metil-glutaril-coenzima A redutase (HMG-CoA redutase), interferindo desse modo com a síntese intracelular e os níveis plasmáticos de colesterol no organismo. Embora tradicionalmente utilizadas na prevenção primária e secundária de doenças cardiovasculares, as estatinas vêm sendo testadas nas últimas décadas como possíveis drogas antineoplásicas em estudos experimentais pré-clínicos. Parte da ação antineoplásica demonstrada até o momento parecer estar relacionada a um efeito inibitório sobre as chamadas células-tronco neoplásicas (CTNs), que representam uma pequena subpopulação celular emleucemias e tumores sólidossendo consistentemente associadasa(1) potencial metastático, (2) à resistência a quimio- e radioterapias, e (3) a pior prognóstico. Estudos realizados por este grupo de pesquisa confirmam os efeitos antitumorais e anti-CTN da sinvastatina quando esta é administrada cronicamente, em dosesrelativamente baixas (i.e., comparáveis às doses antidislipidêmicas, em humanos). Contudo, até o presente momento, não há registros na literatura sobre a existência de efeitos antineoplásicos ou anti-CTN agudos, utilizando-se o referido fármaco em doses altas. Em outras palavras, não existem evidências de que a sinvastatina poderia ser utilizada com sucesso em um esquema posológico intermitente de alta dosagem (quimioterapia clássica em ciclos). Assim sendo, o objetivo principal do presente trabalho foi confirmar e caracterizar a ocorrência de efeitos antineoplásicos e anti-CTN com o uso de sinvastatina em regime agudo e de alta dosagem. Para tanto, ratas Sprague-Dawley portadoras de carcinomas mamários invasivos induzidos por 7,12-dimetil-benz-(a)- antraceno (DMBA) foram tratadas com uma dose única intragástrica de sinvastatina (250mg/kg; n=6) ou de seu diluente (óleo de soja; n=6), sendo os efeitos sobre a morte celular, atividade proliferativa e expressão imunoistoquímica de marcadores CTN clássicos avaliados 24h depois. Observou-se que o tratamento com sinvastatina promoveu agudamente uma redução do índice de proliferação celular (de cerca de 54%; p=0.037), associada a uma diminuição nas expressões de alguns marcadores CTN, tais como ALDH1 (74%, p=0.004) e OCT3/4 (72%; p=0.036). Em contrapartida, não observamos alterações na frequência de células CD44+, CD133+, EPCAM+, CD24-/CD44+ ou CD133+/EPCAM+ (p>0.05), tão pouco no número de células em apoptose (células positivas para caspase 3). Paradoxalmente, encontramos um aumento na frequência relativa de células CD24+ de cerca de 17X (p=0.010). Em conclusão, pode-se afirmar que a sinvastatina em dose alta apresenta precocemente (agudamente): (1) ação antineoplásica do tipo citostática (já que reduz a proliferação celular, sem causar morte) e (2) anti-CTN limitada (isto é, restrita a células que expressam ALDH1 e OCT3/4) / Abstract: Simvastatin belongs to a group of pharmacological agents called statins ¿ drugs that inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase), thus interfering with the intracellular synthesis and serum levels of cholesterol in the organism. Although traditionally used in primary and secondary prevention of cardiovascular diseases, statins have been tested in the last decades as putative antineoplastic drugs, in pre-clinical (experimental) studies. Part of the antineoplastic action so far demonstrated seems to be related to an inhibitory effect on the so-called cancer stem cells (CSCs), a small cell subpopulation of leukemias and solid tumors, which are consistently associated to (1) metastatic potential, (2) chemo- and radiotherapy resistance, and (3) worse prognosis. Accumulated evidence provided by this group confirm the anti-tumoral and anti-CSC effects of simvastatin, when it is given chronicallyand in relatively low doses (i.e., similar to antidyslipidemic doses, in humans). However, up to the present moment, there are no records in the literature describing the existence of acute antineoplastic or anti-CSC effects using the mentioned drug in high doses. In other words, there is no evidence that simvastatin could be used successfully in an intermittent high-dosage schedule (classic cyclic chemotherapy). Therefore, the main goal of the present study was to confirm and characterize the antineoplastic and anti-CSC effects of an intermittent single high-dosage schedule of simvastatin.In order to do so, female Sprague-Dawley rats bearing invasive carcinomas previously induced by 7,12-dimethyl-benz-(a)- anthracene (DMBA) were treated with a single intragastric doseof simvastatin (250mg/kg; n=6) orofits diluent (soy oil; n=6), and the effects oncell death, proliferation activity and immunoexpression of classic CSC markers were assessed 24h later. Treatment with simvastatin resulted, acutely, in a reduction of proliferation index (of approximately approximately 54%, p=0.037), associated to a decrease in the expression of some of the CSC markers, such as ALDH1 (74%, p=0.004) and OCT3/4 (72%; p=0.036). On the other hand, there were no significant alterations in the frequency of CD44+, CD133+, EPCAM+, CD24-/CD44+ or CD133+/EPCAM+ cells (p>0.05), nor in the number of apoptotic cells (caspase 3+ cells). Paradoxically, we found an 17-fold increase in the frequency of CD24+ cells (p=0.010). In conclusion, high-dose simvastatin presents acutely (early) with: (1) a cytostatic antineoplastic action (since it reduces cell proliferation but not cell death) and (2) a limited anti-CSCeffect (i.e., restricted to ALDH1+and OCT3/4+ cells) / Mestrado / Fisiopatologia Médica / Mestra em Ciências

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O objetivo deste estudo foi avaliar o efeito da sinvastatina, isolada e associada ao &#945;-tocoferol e à L-arginina, sobre os inibidores endógenos da óxido nítrico sintase, os metabólitos do óxido nítrico e tióis, em pacientes hipercolesterolêmicos. Analisou-se um grupo de 16 pacientes hipercolesterolêmicos que seguiram o seguinte protocolo: período de washout (sem medicação), 1 mês; sinvastatina (20mg/dia), 2 meses; sinvastatina (20mg/dia) + &#945;-tocoferol (400U/dia), 2 meses; sinvastatina (20mg/dia, washout), 1 mês; sinvastatina (20mg/dia) + L-arginina (7g/dia), 2 meses. A sinvastatina reduziu significativamente as concentrações do colesterol total e LDL-colesterol e a razão LDL-colesterol/HDL-colesterol. O tratamento com sinvastatina, isolada e associada ao &#945;-tocoferol, promoveu diminuição nas concentrações de S-nitrosotióis. A L-arginina associada à sinvastatina, aumentou os níveis de colesterol total quando comparada com a sinvastatina isoladamente. As concentrações plasmáticas de &#945;-tocoferol e L-arginina não aumentaram em decorrência da suplementação, devido à grande dispersão dos dados obtidos, embora as medianas das concentrações plasmáticas de Larginina e &#945;-tocoferol tenham sido mais elevadas após as suplementações. O tratamento com sinvastatina, isolada ou associada à L-arginina e ao &#945;-tocoferol, não alterou as concentrações dos inibidores endógenos da óxido nítrico sintase (ADMA e SDMA), dos metabólitos do óxido nítrico, da nitrotirosina total e dos tióis analisados. / The aim of this study was to evaluate the effect of sinvastatin, isolated and associated to &#945;-tocopherol and to L-arginine, on the endogenous inhibitors of nitric oxide synthase, on nitric oxide metabolytes and thiols, in hypercholesterolemic patients. A group of 16 hypercholesterolemic patients were analysed, acconting to the protocol: a washout period (without medication) of 1 month, sinvastatin (20 mg/day) for 2 months; sinvastatin (20 mg/day) + &#945;-tocopherol (400U/day) for 2 months; sinvastatin (20 mg/day) for 1 months (washout period), sinvastatin (20 mg/day) + L-arginine (7g/day) for 2 months. Sinvastatin significantly reduced the concentrations of total cholesterol and LDL-cholesterol, as well as the LDL-cholesterol/HDLcholesterol ratio. The treatment with sinvastatina, alone and associate to &#945;-tocoferol, resulted in a reduction of RSNO concentration. The L-arginine associated with sinvastatin, increase the level of total cholesterol as compared with simvastatin alone. The plasma concentrations of a-tocopherol and Larginine did not increase following supplementation due to the large dispersion of the data obtained, even though the median plasma concentrations of L-arginine and a-tocopherol were elevated after supplementation. Treatment with simvastatin, alone or associated to L-arginine and a-tocopherol did not alter the concentrations of the endogenous inhibitors of nitric oxide synthase (ADMA and SDMA), or that of nitric oxide metabolytes, total nitrotyrosine or the thiols analysed.

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.

A Doença Pulmonar Obstrutiva Crônica (DPOC) é caracterizada pela limitação persistente de trocas gasosas, usualmente progressiva e associada a uma resposta inflamatória crônica exacerbada das vias aéreas a partículas e gases nocivos. Apesar de prevenível e tratável, não se logrou até o presente uma terapêutica eficaz, que resulte na cura da doença. Neste cenário, a terapia celular apresenta-se como uma alternativa terapêutica potencialmente promissora em DPOC, bem como em outras doenças pulmonares degenerativas e de caráter inflamatório. Porém, vários aspectos da terapia celular carecem de um melhor entendimento. Um dos principais desafios ao sucesso da terapia celular são as baixas taxas de sobrevivência das células transplantadas. O Inibidor do Ativador de Plasminogênio 1 (Plasminogen Activator Inhibitor 1 - PAI-1) pode representar um potencial mediador da sobrevivência de células estromais mesenquimais (CTM) pós-transplante, pois tem sido proposto que anticorpos neutralizadores do PAI-1 auxiliam no aumento da sobrevivência de CTM no tecido-alvo da terapia celular. Desta forma, a diminuição dos níveis de PAI-1 possui um potencial terapêutico interessante, ao modular os principais processos envolvidos na criação de um ambiente pouco propício ao \"homing\" celular durante o processo de injúria. A diminuição dos níveis de PAI-1 é promovida, pela sinvastatina, fármaco da família das estatinas. Desta forma, objetivou-se com este trabalho analisar os efeitos da sinvastatina sobre a expressão do PAI-1, bem como sua influência na sobrevivência das células infundidas para terapia celular de enfisema pulmonar em modelo murino. Camundongos da linhagem FVB foram submetidos à instilação intranasal de elastase para indução de enfisema pulmonar e, posteriormente, tratados com CTM do tecido adiposo e sinvastatina. Os resultados mostraram que, quanto aos aspectos morfológicos e funcionais, considerando-se a análise conjunta de ambos os pulmões, não houve diferença estatisticamente significativa entre os grupos submetidos à instilação intranasal de elastase e submetidos à terapia celular com CTM tratados ou não com sinvastatina. Quando porém os pulmões foram analisados individualmente constatou-se que não houve diferença estatisticamente significativa entre os grupos controle e os resultados referentes ao lado direito do pulmão dos animais tratados com elastase e que receberam sinvastatina e infusão de CTM. Diferenças anatômicas entre os lados direito e esquerdo do pulmão, levaram a uma maior deposição de células no lado direito, como evidenciado pelos resultados obtidos nos ensaios de bioluminescência. Pode-se, portanto, inferir que a recuperação morfológica no lado direito do pulmão de animais com DPOC/enfisema poderia ser decorrente de um efeito regenerativo parácrino das CTM associadas à sinvastatina. / Chronic Obstructive Pulmonary Disease - COPD is characterized by the persistent limitation of gas exchange, is usually progressive, and associated to a chronic augmented inflammatory response of the airways to particles and noxious gases. Despite preventable e treatable, an effective, curative therapeutic approach is yet to be achieved. In this context, cell therapy presents itself as a promising therapeutic approach for COPD and other pulmonary inflammatory and degenerative diseases. However, many aspects of cell therapy with stem cells remain unclear. One of the major challenges to the success of cell therapy are the low survival rates of transplanted cells. The Plasminogen Activator Inhibitor 1 (PAI-1) is a potential mediator of the survival of mesenchymal stromal cells (MSC) after transplantation, since PAI-1 neutralizing antibodies have been shown to increase the survival rate of MSC in the target tissue of cell therapy. Thus, the decreased levels of PAI-1 has an interesting therapeutic potential to modulate key processes involved in creating an inhospitable environment, during the process of injury, to the homing of transplanted cells. Decreased levels of PAI-1 are promoted by simvastatin, a drug of the statins family. Thus, the goal of this work was to evaluate the effect of simvastatin in vivo on the expression of PAI-1, as well as its influence on the survival rate of infused cells in mice model of cell therapy for pulmonary COPD/emphysema. FVB mice were submitted pulmonary emphysema induction by means of intranasal instillation of elastase and than treated with adipose-derived mesenchymal stem cells and simvastatin. The results regarding morphological and functional aspects, when considering the analisys of both lungs, presented no statistically significant difference among the groups submitted to intranasal instillation of elastase and cell therapy with MSC, treated or not with simvastatin. However, when the lungs where analyzed individually, it was found that there was no statistically significant difference between the control group and the results regarding the right lung of animals treated with elastase and that received simvastatin and MSC infusion. Anatomical differences between the right and left sides of the lung lead to a higher deposition of cells in the right side, as observed in the bioluminescence assays. Thus, it is possible to infer that the morphological recovery in the right side of the lung of animals with DPOC/emphysema could be due to a regenerative paracrine effect of mesenchymal stem cells associated with simvastatin.