Made available in DSpace on 2014-12-17T14:13:53Z (GMT). No. of bitstreams: 1 MiguelASF_DISSERT.pdf: 792186 bytes, checksum: d323fa6e666b8282771fcc51f7c2abcc (MD5) Previous issue date: 2011-07-11 / The aim of this work was to evaluate how an aqueous micellar system containing Amphotericin B (AmB) and sodium deoxycholate (DOC) can be rebuilt after heating treatment. Also a review of the literature about the new physicochemical and biological properties of this new system was carried out. Afterwards, heated (AmB-DOC-H) and unheated (AmB-DOC) micelles were subsequently diluted at four different concentrations (50mg.L-1, 5mg.L-1, 0.5mg.L-1 and 0.05mg.L-1) to perform the physicochemical study and, then, the pharmacotoxicity assay, in which two cell models were used for the in vitro experiments, Red Blood Cells (RBC) from human donors and Candida parapisilosis (Cp). While potassium (K+) and hemoglobin leakage from RBC were the used parameters to evaluate the acute and chronic toxicity, respectively, the efficacy of AmB-DOC and AmB-DOC-H were assessed by K+ leakage and cell survival rate from Cp. The spectral study revealed a slight change on the aggregate peak from 327nm to 323nm for AmB-DOC-H compared to AmB-DOC. Concerning the toxicity, although AmB-DOC and AmB-DOC-H presented different behavior for hemoglobin leakage, AmB-DOC produced higher leakage than AmB-DOC-H at high concentrations (from 5mg.L-1) with values tending to zero. However, concerning K+ leakage, both AmB-DOC and AmB-DOC-H, showed similar profile for both cell models, RBC and Cp (p<0,05). AmB-DOC-H and AmB-DOC also revealed similar profile of activity against Cp with equivalent survival rate. In short, the AmB-DOC-H showed much less toxicity than AmB-DOC, but remained as active as the late one against fungal cell. Therefore, the results highlight the importance of this new procedure as a simple, inexpensive and safe alternative to produce a new kind of micelle system for treatment of systemic fungal infections / A anfotericina B micelar (AmB) ? um importante agente antimicrobiano utilizado contra infec??es f?ngicas sist?micas. No entanto, seu uso ? limitado devido a sua alta toxicidade. Formula??es de anfotericina B em estruturas lip?dicas s?o menos t?xicas, por?m apresentam elevado custo. A AmB em solu??o aquosa possui formas monom?ricas e agregadas, estes ?ltimos s?o os respons?veis pelas rea??es adversas. Este trabalho avaliou a AmB desoxicolato de s?dio (AmB-DOC) e AmB aquecida (AmBDOC- H) em rela??o a sua toxicidade e atividade, bem como perfil de seu espectro em quatro concentra??es diferentes (50mg.L-1, 5mg.L-1, 0,5mg.L-1 e 0.05mg.L-1). O aquecimento controlado das solu??es AmB levou a altera??es no espectro de 327nm AmB (agregados) para 323nm (superagregados). Al?m disso, quando as amostras foram submetidas ao processo de dilui??o, apresentam o mesmo comportamento espectrofotom?trico: ambas as amostras diminuem o pico das formas auto-associadas at? apresentarem apenas mon?meros com pico em 409nm, o que sugere um processo de libera??o de mon?meros por concentra??o-dependente. No que diz respeito ? toxicidade, AmB-DOC e AmB-DOC-H apresentaram comportamentos distintos: a taxa de libera??o de hemoglobina de hem?cias para AmB-DOC, em altas concentra??es, foi muito superior a AmB-DOC-H, cujos valores tendem a zero (p <0,05). J? em rela??o ? libera??o de K+ ambas as amostras apresentaram perfil semelhante. Sobre a atividade, AmB-H mant?m o mesmo perfil da AmB-DOC. Em suma, a AmB-DOC-H ? muito menos t?xica do que AmB-DOC e mantendo a atividade. Sendo este procedimento uma alternativa simples, de baixo custo e segura para, em um o futuro pr?ximo, ser utilizada no tratamento de infec??es f?ngicas sist?micas

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