The frequency of fungal infections has risen drastically during the last decades due to the increasing human lifespan, even in cases of grave sickness, because of the advance in the capacity of science and medical technology. This survival rate has brought about a manifestation of fungal infections at new proportions, which has raised the interest in studying anti-fungal drugs. Ciclopirox olamina is a synthetic anti-fungal agent with a wide spectrum of action, with inherent anti-inflammatory and anti-bacterial activities. This drug does not have an official monograph in the Brazilian Pharmacopeia. In this study, methods for the quantification of ciclopirox olamina as a raw material and in a topical solution were developed and validated, using High Performance Liquid Chromatography (HPLC) with detection in the ultraviolet region, and a microbiological assay by agar diffusion. In the determination by HPLC-UV, the analyses were conducted in a reverse phase column C18, at a temperature of 30º. In the microbiological assay by agar diffusion, 3x3 planning was used, employing Candida albicans ATCC 10231 as a microorganism test. Both methods presented adequate linearity, precision and accuracy. / A freqüência de infecções fúngicas tem aumentado, drasticamente, nas duas últimas décadas em decorrência do prolongamento da vida, inclusive de pacientes gravemente enfermos, em razão do avanço da capacidade da ciência e da tecnologia médica. Esta sobrevida ocasionou a manifestação de infecções fúngicas em novas proporções, o que aumentou o interesse pelo estudo dos fármacos antifúngicos. O ciclopirox olamina é um agente antifúngico sintético com amplo espectro de ação, com atividades antinflamatória e antibacteriana inerentes. Este fármaco não possui monografia oficial na Farmacopéia Brasileira. Neste trabalho foram desenvolvidos e validados métodos para quantificação de ciclopirox olamina matéria-prima e solução tópica, utilizando-se Cromatografia Líquida de Alta Eficiência (CLAE) com detecção espectrofotométrica na região do ultravioleta (UV) e Ensaio Microbiológico por difusão em ágar. Na determinação por CLAE-UV, as análises foram conduzidas em coluna de fase reversa C18, na temperatura de 30 °C. No Ensaio microbiológico por difusão em ágar utilizou-se planejamento 3x3, empregando Candida albicans ATCC 10231 como microrganismo teste. Ambos os métodos apresentaram linearidade, precisão e exatidão adequados.

This essay considers the interplay between character narrators, the implied author, and the authorial audience in Octavia Butler’s Parable of the Talents. The aim of the study was to investigate how narrators, the implied author, and readers position themselves in relation to each other and in relation to the novel’s ethical dimensions. The theoretical framework is based on James Phelan’s theories on the rhetorical and ethical aspects of fiction. The essay argues that the implied author’s communication to the authorial audience is one of the reasons that the novel, like its prequel Parable of the Sower, often succeeds to function as warnings to the audience of dangers ahead. This is especially true regarding one of the implied author’s most consistent messages to the audience throughout the Parable novels: every choice has consequences, and those consequences need to be considered when we decide how to act and react in different circumstances, both as individuals and as a society.

Octavia E. Butler (1947-2006), the first major African-American woman science fiction writer and the only science-fiction author to win the MacArthur "genius" grant, died from an accidental fall in February 2006. She is remembered for her work, which clearly fits into the science-fiction tradition, with imagined near- and far-future technologies, telepathy, aliens, space travel, and time travel. Yet Butler's stories are not clichéd space operas featuring white men in spaceship battles. Whatever the near- or far-future setting, the challenging themes that form the substance of Butler's writing are always power, dominance, slavery, and the complexity of human relationships. Butler's best-known works include the Parable novels (Parable of the Sower and Parable of the Talents), in which the main character Lauren Olamina writes a series of verses that become a new religion in an imagined near-future dystopian version of the United States. This dissertation is a composition for SATB chorus, orchestra, and speaker based on these verses and on quotations from Butler herself describing how she became a writer and the genesis of the Parable series. The musical setting of these quotations highlights parallels between Butler's novels and her own life. In the accompanying paper I analyze my process of extrapolating selected themes from Butler's life and work. My intent is to demonstrate how these themes are interwoven into the musical setting at many levels, and to show how the particular quotations and themes I chose to set musically reveal Butler's insights about present-day human experience on a larger scale. / text

Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2017-02-13T13:18:57Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) TESE colação de grau.pdf: 1971286 bytes, checksum: 680d0e24d2f0efbe0313ab8752f1cc93 (MD5) / Made available in DSpace on 2017-02-13T13:18:57Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) TESE colação de grau.pdf: 1971286 bytes, checksum: 680d0e24d2f0efbe0313ab8752f1cc93 (MD5) Previous issue date: 2013-02-22 / CNPq / A criptococose é uma infecção fúngica predominantemente oportunista cujos principais agentes etiológicos são Cryptococcus neoformans e C. gattii. O tratamento de escolha para a micose é a anfotericina B associada ou não a 5-fluorocitosina seguido de terapia de manutenção com fluconazol. Contudo, falhas no tratamento associadas à toxicidade e ao aparecimento de resistência aos fármacos têm sido relatadas, o que torna essencial a descoberta de novas alternativas terapêuticas, como a ciclopirox olamina (CPO). Neste contexto, o objetivo deste estudo foi caracterizar e avaliar a ação in vitro e in vivo da CPO livre e encapsulada em lipossomas frente a amostras de Cryptococcus neoformans para futura aplicação no tratamento da criptococose sistêmica. Foram obtidas 30 amostras de Cryptococcus neoformans provenientes de pacientes imunocomprometidos. A preparação dos lipossomas convencionais e furtivos de CPO foi realizada pelo método da hidratação do filme lipídico e a caracterização foi realizada avaliando os seguintes parâmetros: tamanho de partícula, Índice de Polidispersão (PDI) e taxa de encapsulação (EE%). Para otimização dos constituintes lipídicos, foi realizado um planejamento fatorial fracionado a 24-1 a partir da melhor formulação obtida nos estudos de pré-formulação. A cinética de liberação in vitro foi conduzida para avaliar e comparar estatisticamente o perfil de liberação dos sistemas convencional e furtivo. Adicionalmente, testes de susceptibilidade antifúngica foram realizados de acordo com Clinical and Laboratotry Standards Institute (CLSI). Para caracterização molecular dos isolados, PCR fingerprinting foi conduzida utilizando os primers M13 e URA5. O estudo in vivo foi conduzido com camundongos imunossuprimidos, infectados com Cryptococcus neoformans (106 cels/mL) e tratados com CPO lipossomal (Lipo-CPO) (0.5 mg/Kg). As concentrações de CPO utilizadas na forma livre e encapsuladas em lipossomas convencionais e furtivos variaram de 0,30 a 625 µg/mL. Os resultados do planejamento fatorial mostraram que o ponto central apresentou características proeminentes com redução do tamanho de partícula em 17,1%; melhora do PDI em 15,34% e da quantidade de fármaco encapsulado (25%). A cinética do lipossoma furtivo apresentou uma velocidade de liberação mais controlada quando comparada ao lipossoma convencional. Com relação ao teste de susceptibilidade, todos os inóculos foram susceptíveis a CPO livre, com atividade fungistática entre 0,30 e 0,61 g/mL e fungicida entre 1,22 e 4,88 g/mL. Não houve diferença relacionada à atividade antifúngica entre as formulações lipossomais convencionais e furtivas. A atividade fungistática dos lipossomas foi observada em concentrações variando de 1,22 e 2,44 g/mL. A faixa das concentrações fungicidas foi de 1,22 a 9,76 g/mL. O padrão de bandas do URA5 revelou que todos os isolados apresentam genótipo VNI, característico de C. neoformans. Lipo-CPO apresentou eficácia antifúngica comparada à anfotericina B após 14 dias de infecção, reduzindo a carga fúngica em aproximadamente 8% no baço, 41% no fígado, 63% no pulmão e 89% no cérebro. O exame histológico evidenciou infiltrado celular no fígado dos grupos tratados com Lipo-CPO e anfotericina B, porém com menor intensidade quando comparado ao grupo controle. O estudo sugere que a CPO encapsulada em lipossomas apresenta significativa ação antimicótica frente às amostras sistêmicas de C. neoformans, reforçando seu potencial na terapêutica da criptococose. / Cryptococcosis is an opportunistic fungal infection whose the main ethiological agents are Cryptococcus neoformans and C. gattii. The treatment of choice for this mycosis is amphotericin B combined or not with 5-fluorocytosine, followed by maintenance therapy with fluconazole. However treatment failures associated with toxicity and drug resistance has been reported, which makes it essential to the discovery of new therapies, such as ciclopirox olamine (CPO). The purpose of this study was to characterize and evaluate the in vitro and in vivo antifungal activity of ciclopirox olamine in its free form and encapsulated in liposomes against thirty Cryptococcus neoformans isolates obtained from immunocompromised patients for future application in systemic cryptococcosis treatment. Preparation of conventional and stealth liposomes was performed to define particle size, polydispersity index (PDI), CPO amount of encapsulated and efficiency of encapsulation (EE%). For optimization of liposomal lipid constituents, a 24-1 fractional factorial design was carried out from the prominent formulation obtained in pre-characterization studies. In vitro release kinetics was conducted to evaluate and compare statistically the release profile of conventional and stealth liposomes. Antifungal susceptibility testing was conducted in accordance with the reference method. Regarding molecular characterization, PCR fingerprinting was carried out by using MT3 and URA5 primers. Concentrations of CPO used in free form and encapsulated into stealth and conventional liposomes ranged from 625 to 0.3 g.mL-1. Despite of the central point of the factorial design have increased the total lipids amount in 35.52%, it showed prominent characteristics when compared with the L4 formulation with improvement of the mean size in 17.1%, PDI in 15.34% and CPO amount in 25%. The minimum concentrations of stearylamine to obtain the stable formulation for one month was 5.88 mM. . Kinetics of stealth liposomes showed a release profile more controlled as compared to conventional liposomes. All inoculations were susceptible to CPO in its free form, presenting fungistatic activity between 0.3 and 0.61 g.mL-1 and fungicidal activity between 1.22 and 4.88 g.mL-1. There was no difference with respect to antimycotic activity between conventional and stealth liposomal formulations. Fungistatic activity of liposomes was observed at concentrations ranging from 1.22 and 2.44 g.mL-1. Fungicidal concentration range was 1.22-9.76 g.mL-1. The URA5 profile analized demonstrated all isolates are VNI genotype (C. neoformans). The treatment with Lipo-CPO showed a reduction of 8% of the C. neoformans population in spleen, 40.8% in liver, 63% in lungs and 89% in brain after 14 days of infection. Histological examination revealed cell infiltrate either Lipo-CPO or Amphotericin B treated groups, but less intense when compared to control group. The results suggest that Ciclopirox olamine loaded-liposomes have significant antimycotic activity against Cryptoccocus spp, reinforcing its potential for in vivo studies and its application in cryptococcosis treatment.