No description available.

Thesis (M.Sc. (Med.) (Epidemiology and Biostatistics))--University of the Witwatersrand, Faculty of Health Sciences, 2012. / Introduction Cryptococcal disease (CD) is the most common cause of morbidity and mortality among patients living with HIV I AIDS in many parts of sub-Saharan Africa. Globally the highest number of HIV -associated CD cases occur in sub-Saharan Africa (720 000/957 900) and mortality rates among patients on antifungal treatment remain unacceptably high. This study aimed to estimate and compare in-hospital mortality of HIV-associated CD among patients who were treated with amphotericin B versus fluconazole versus mixed treatment with amphotericin B and fluconazole. Materials and Methods We performed an analytical, cross-sectional analysis of data from a national laboratory-based surveillance programme through a network of public sector laboratories in South Africa. The study period was 1 January 2005 to 31 December 2006. The analysis used a subset of data from laboratory confirmed cases with completed case report forms and available data on outcome. The exposure was measured in 3 levels defined as treatment during the induction phase of therapy for at least 7 days with either amphotericin B or fluconazole or mixed treatment (initiation of treatment with one regimen and switching on to the other within 7 days of treatment). Outcome was defined as: patients who died between 7 and 30 days in hospital. Chi-squared test was used to compare characteristics among the treatment groups and multiple logistic regression models were constructed to identify risk factors for in-hospital death. Results Sixty two percent of the patients (1,363/2,211) were treated for ?:.7 days and 38% (848/2,211) for <7 days. In the group treated for ?:.7 days, mortality was 359/1,363 (26%) and the median time to death was 12 days (IQR 9-18). There was no significant difference in case fatality among patients treated with: amphotericin B (29%), fluconazole (27%) or mixed treatment (24%), (p-value = 0.28). On multivariate analysis, factors significantly associated with in-hospital mortality were: patients between the age group of 40-59 years, province in which the patients resided and altered mental status. In the group treated for <7 days patients treated with fluconazole were 82% less likely to die than patients treated with amphotericin B. Discusslon and Conclusion In-hospital mortality was high and similar among all treatment regimens in the ?:.7 days group. However a significant reduction in mortality was noted in the <7 days group treated with fluconazole. The reason for the later findings is unclear. It may be that amphotericin B alone is not superior but equivalent to fluconazole in the first 7 days of treatment and 5-flucytocine may be the intervention required to improve outcome in the first 7 days. Or it may be that patients are reaching care too late for a significant impact in disease outcome to be observed and prevention of CD is required in the form of ART and primary prophylaxis. Selection bias in that patients in the fluconazole group are less sick than in the amphotericin B-group is the most likely reason for lower mortality. The study findings call for more standardization of optimum treatment as well as advocacy for the availability of 5-flucytocine. Factors associated with high mortality require further investigations for interventions to improve patient outcomes.

Thesis (M. Sc.)(Biochemistry)--University of Pretoria, 2006. / Includes bibliographical references. Available on the Internet via the World Wide Web.

Made available in DSpace on 2014-06-11T19:32:09Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-08-18Bitstream added on 2014-06-13T18:43:05Z : No. of bitstreams: 1 franzini_cm_dr_arafcf.pdf: 2677878 bytes, checksum: 26759573900040571415a3fa5cbf34b2 (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Universidade Estadual Paulista (UNESP) / O tratamento das infecções fúngicas sistêmicas impõe grandes dificuldades devido ao fato da terapia endovenosa requerer administração do fármaco solubilizado ou disperso em partículas de diminutas dimensões, além da necessidade de hospitalização. A anfotericina B (AmB) continua sendo um dos antibióticos mais efetivos para tais tratamentos, apesar de sua baixa solubilidade e graves efeitos colaterais. Considerando que microemulsões permitem contornar esses problemas e proporcionar administração oral do fármaco, essas formulações lipídicas contendo AmB estão sendo cada vez mais estudadas. Adicionalmente, a formação de complexos de inclusão com ciclodextrinas (CDs) também tem sido promissora no desenvolvimento de novas formas farmacêuticas. Neste trabalho os parâmetros de formação de microemulsões (MEs) contendo fosfatidilcolina de soja (FS), Tween-20 (Tw) e oleato de sódio (OS) como tensoativos e colesterol (CHO) como fase oleosa e a formação de complexos de inclusão com diferentes derivados de CD e sua incorporação nas MEs foi estudado. Um diagrama de fases pseudoternário foi elaborado objetivando caracterizar MEs. O comportamento reológico e a estruturação interna foram empregadas para avaliação e ainda caracterização por espalhamento dinâmico de luz. Foi avaliado o efeito da proporção de tensoativo e óleo na determinação do diâmetro da fase interna nos sistemas com ou sem AmB, além da avaliação da contribuição da fase oleosa e do tensoativo na incorporação do fármaco nas MEs. Um diagrama de solubilidade de AmB em CDs foi desenvolvido e suas constantes de estabilidade determinadas. O preparo de ME contendo CDs em sua fase aquosa, parâmetros de incorporação de AmB e estudos de liberação foram realizados seguidos de análise termogravimétrica, difração de raios x (DRX) e ressonância magnética nuclear (RMN)... / The fungal infections treatment imposes many difficulties mainly because the intravenous therapy requires administration of solubilized or dispersed drug in particles of smaller dimension beyond the need for hospitalization. Despite its low solubility and serious adverse effects the amphotericin B (AmB) remains one of the most effective antibiotics to the treatment. Microemulsions allow circumvent these problems and provide oral administration. Therefore these lipid formulations containing AmB have been increasingly studied. Additionally, the formation of inclusion complexes with cyclodextrins (CDs) has also been promising in developing new dosage forms. In this work the formation parameters of microemulsions (MEs) containing soybean phosphatidylcholine (FS), Tween-20 (Tw) and sodium oleate (SO) as surfactant and cholesterol (CHO) as oil phase and the formation of inclusion complexes with different CDs derivatives and their incorporation into MEs were studied. The pseudo ternary phase diagram was built in order to characterize MEs. The rheological behavior and internal structure were evaluated and characterized by dynamic light scattering. The effect of the proportion of surfactant and oil phase in the diameter of the internal phase in systems with or without AmB was evaluated. Therefore the contribution of the oil phase and surfactant in the drug loading eficience was studied. The Solubility diagram of AmB in CDs was developed and its stability constants determined. The preparation of ME containing CDs in its aqueous phase, the incorporation AmB parameters and the release studies were performed followed by thermal analysis, x-ray (XRD) diffraction and nuclear magnetic resonance (NMR). The results reveal the MEs formation in regions containing up to 30% surfactant and about 11% of the oil phase. Under polarized light, the interest systems showed a dark background and lamellar structure... (Complete abstract click electronic access below)

Orientador: Liliana Scorzoni / Banca: Luciane Dias de Oliveira / Banca: Haroldo Cesar de Oliveira / Resumo: Cryptococcus neoformans são leveduras que acometem principalmente indivíduos imunocomprometidos, podendo causar a meningoencefalite dependendo do estado imunológico do hospedeiro. Os tratamentos convencionais têm enfrentado grandes desafios. Dessa forma, o objetivo desse estudo foi avaliar os efeitos antifúngicos dos fármacos cloridrato de verapamil (CV), cloridrato de fluoxetina (CF) e cloridrato de paroxetina (CP) isolados e combinados com anfotericina B (AmB) contra C. neoformans. Foram determinados os valores de Concentração Inibitória Mínima (CIM) e Concentração Fungicida Mínima (CFM) de acordo com a técnica de microdiluição em caldo proposta pelo Comitê Europeu de Teste de Susceptibilidade Antimicrobiana (EUCAST). Posteriormente, foi avaliada a atividade sinérgica dos fármacos combinados com AmB (EUCAST). Os efeitos das CIMs e das concentrações sinérgicas selecionadas foram avaliados em biofilmes, quantificando a biomassa por cristal violeta e sua viabilidade por contagem de colônias (UFC/mL). Além disso, foram analisados os efeitos dos mesmos na cápsula induzida desta levedura. Os ensaios in vivo foram realizados em Galleria mellonella avaliando a toxicidade dos compostos e a eficácia por análise de curva de sobrevivência e também o efeito em concentração de hemócitos. Os fármacos CV, CF e CP apresentaram valores de CIM de 113, 9,6 e 41µg/mL, respectivamente, e quando combinados com AmB resultaram em vinte concentrações sinérgicas, e uma concentração de cada combinação... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Cryptococcus neoformans are yeasts that mainly affect immunocompromised individuals, and may cause meningoencephalitis depending on the immunological state of the host. Conventional treatments have faced major challenges. Verapamil hydrochloride (CV), fluoxetine hydrochloride (CF) and paroxetine hydrochloride (CP) were isolated and combined with amphotericin B (AmB) against C. neoformans. Minimum Inhibitory Concentration (MIC) and minimum Fungicidal Concentration (CFM) values were determined according to the broth microdilution technique proposed by the European Committee for Antimicrobial Susceptibility Testing (EUCAST). Subsequently, the synergistic activity of drugs combined with AmB (EUCAST) was evaluated. The effects of MICs and selected synergistic concentrations were evaluated in biofilms, quantifying the biomass by violet crystal and its viability by colony-forming unit analysis (CFU / mL). In addition, the effects of the same in the induced capsule of this yeast were evaluated. In vivo assays were performed in Galleria mellonella evaluating the toxicity of the compounds and the efficacy by analysis of survival curve and also the effect on hemocyte concentration. The CV, CF and CP drugs had MIC values of 113, 9.6 and 41 μg / mL, respectively, and when combined with AmB resulted in twenty synergistic concentrations, and a concentration of each combination was chosen for the following trials. CV reduced biofilm biomass to 38%, while CF and CP reduced biomass to 22-30% w... (Complete abstract click electronic access below) / Mestre

Because of the increasing number of serious risk factors which predispose a normally immune competent host to infection, the incidence of systemic fungal infections is steadily increasing. This epidemiological rise has especially become apparent since the onset of the AIDS epidemic. Amphotericin B is the drug of choice for these life-threatening mycotic infections. Complications due to drug toxicity, however, severely limit amphotericin B's clinical usefulness. The major complication associated with the administration of amphotericin B is renal toxicity. Research has indicated, however, that besides its antifungal activities, amphotericin B may act as an immune stimulant of both humoral and cellular responses. A new formulation, liposomal amphotericin B, has been developed which has proven to be significantly less toxic to the kidneys. Research has suggested that liposomal amphotericin B may also act as an immune stimulant. Recent reports have also suggested that its stimulatory capabilities may possibly exceed those of the non-liposomal preparations. The purpose of this study was to quantify the specific effects of amphotericin B and liposomal amphotericin B on the in vitro indices: cellular viability, B- and T-lymphocyte proliferation and macrophage activation as indicators of immune system functions. Spleen cells from immune normal, and immune compromised BALB/c female mice were harvested following euthanasia and incubated in the presence of the two drugs. Drug doses were chosen to correlate with those surrounding clinically relevant plasma concentrations. Cyclosporine and cyclophosphamide were used as immune suppressants to simulate organ transplant patients and patients receiving cancer chemotherapy, respectively. Results indicated that amphotericin B consistently reduces the ability of B-cells and T-cells to proliferate and the ability of macrophages to produce interleukin-1. Though direct cytotoxicity may play a part in these assays, it is probably minor because viability studies show no more than a ten percent reduction due to amphotericin B compared with its liposomal analogue. Liposomal amphotericin B was shown to be non-toxic in each of the immune parameters. It appeared that liposomes may be an important means of delivering more drug to a host infected with a fungal organism without further compromising the patient's already suppressed immune system.

Thesis (Ph. D.)--University of Wisconsin--Madison, 2006. / Includes bibliographical references. Also available on the Internet.

Orientador: Anselmo Gomes de Oliveira / Banca: Eryvaldo Sócrates Tabosa do Egito / Banca: Maria Vitória Lopes Badra Bentley / Banca: Marcos Antonio Corrêa / Banca: Marlus Chorilli / Resumo: O tratamento das infecções fúngicas sistêmicas impõe grandes dificuldades devido ao fato da terapia endovenosa requerer administração do fármaco solubilizado ou disperso em partículas de diminutas dimensões, além da necessidade de hospitalização. A anfotericina B (AmB) continua sendo um dos antibióticos mais efetivos para tais tratamentos, apesar de sua baixa solubilidade e graves efeitos colaterais. Considerando que microemulsões permitem contornar esses problemas e proporcionar administração oral do fármaco, essas formulações lipídicas contendo AmB estão sendo cada vez mais estudadas. Adicionalmente, a formação de complexos de inclusão com ciclodextrinas (CDs) também tem sido promissora no desenvolvimento de novas formas farmacêuticas. Neste trabalho os parâmetros de formação de microemulsões (MEs) contendo fosfatidilcolina de soja (FS), Tween-20 (Tw) e oleato de sódio (OS) como tensoativos e colesterol (CHO) como fase oleosa e a formação de complexos de inclusão com diferentes derivados de CD e sua incorporação nas MEs foi estudado. Um diagrama de fases pseudoternário foi elaborado objetivando caracterizar MEs. O comportamento reológico e a estruturação interna foram empregadas para avaliação e ainda caracterização por espalhamento dinâmico de luz. Foi avaliado o efeito da proporção de tensoativo e óleo na determinação do diâmetro da fase interna nos sistemas com ou sem AmB, além da avaliação da contribuição da fase oleosa e do tensoativo na incorporação do fármaco nas MEs. Um diagrama de solubilidade de AmB em CDs foi desenvolvido e suas constantes de estabilidade determinadas. O preparo de ME contendo CDs em sua fase aquosa, parâmetros de incorporação de AmB e estudos de liberação foram realizados seguidos de análise termogravimétrica, difração de raios x (DRX) e ressonância magnética nuclear (RMN)... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The fungal infections treatment imposes many difficulties mainly because the intravenous therapy requires administration of solubilized or dispersed drug in particles of smaller dimension beyond the need for hospitalization. Despite its low solubility and serious adverse effects the amphotericin B (AmB) remains one of the most effective antibiotics to the treatment. Microemulsions allow circumvent these problems and provide oral administration. Therefore these lipid formulations containing AmB have been increasingly studied. Additionally, the formation of inclusion complexes with cyclodextrins (CDs) has also been promising in developing new dosage forms. In this work the formation parameters of microemulsions (MEs) containing soybean phosphatidylcholine (FS), Tween-20 (Tw) and sodium oleate (SO) as surfactant and cholesterol (CHO) as oil phase and the formation of inclusion complexes with different CDs derivatives and their incorporation into MEs were studied. The pseudo ternary phase diagram was built in order to characterize MEs. The rheological behavior and internal structure were evaluated and characterized by dynamic light scattering. The effect of the proportion of surfactant and oil phase in the diameter of the internal phase in systems with or without AmB was evaluated. Therefore the contribution of the oil phase and surfactant in the drug loading eficience was studied. The Solubility diagram of AmB in CDs was developed and its stability constants determined. The preparation of ME containing CDs in its aqueous phase, the incorporation AmB parameters and the release studies were performed followed by thermal analysis, x-ray (XRD) diffraction and nuclear magnetic resonance (NMR). The results reveal the MEs formation in regions containing up to 30% surfactant and about 11% of the oil phase. Under polarized light, the interest systems showed a dark background and lamellar structure... (Complete abstract click electronic access below) / Doutor

Made available in DSpace on 2014-06-11T19:24:11Z (GMT). No. of bitstreams: 0 Previous issue date: 2006-08-03Bitstream added on 2014-06-13T20:48:29Z : No. of bitstreams: 1 franzini_cm_me_arafcf.pdf: 1232208 bytes, checksum: d972d0938f33ec34d5b67691a2669a0a (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O objetivo esse trabalho foi o desenvolvimento de sistemas microemulsionados ou subemulsionados estabilizados por fosfatidilcolina de soja (FS) associada à tensoativos hidrofílicos para veiculação de AmB. Foi avaliada a utilização de pluronic (PLU) como co-tensoativo e observou-se o predomínio de sistemas mais viscosos. O estudo do comportamento reológico das MEs, mostrou que todas as amostras apresentaram comportamento Newtoniano, mantendo a viscosidade constante independente da velocidade de deformação. Os estados de agregação da AmB foram avaliados através de seus espectros de absorção relativos às diferentes concentrações, inclusão em ciclodextrinas e incorporação no sistema microemulsionado selecionado. Foi verificada uma modificação relativa na proporção de monômeros do fármaco. A técnica de nefelometria foi realizada e indicou aumento no tamanho das gotículas da ME com o aumento da concentração da AmB. Verificou-se que a incorporação de AmB nos sistemas desenvolvidos é dependente da proporção relativa da fase interna oleosa. A liberação de AmB, in vitro, é mais prolongada à medida que aumenta a proporção de fase interna oleosa. Os sistemas microemulsionados e subemulsionados mostraram-se eficazes na veiculação de AmB apresentando-se como sistema reservatório facilitando a liberação prolongada. / The objective of this work was the development of subemulsified and microemulsified systems stabilized by soya phosphatidylcholine (FS) and/or FS associated to hydrophylic surfactants to AmB veiculation. It was evaluated the use of pluronic (PLU) as co-surfactant and it was observed the predominancy of the more viscose systems. The study of the rheological behavior of MEs verified that all the samples have presented Newtonian behavior, maintaining the viscosity constant independent of the deformation speed. The states of aggregation of the AmB have been evaluated through its relative absorption specters to the different concentrations, inclusion in cyclodextrins and incorporation in the selected microemulsion system. A relative modification in the proportion of monomers of the drug was verified. The Nefelometry technique was performed and showed increase in the droplets size of the ME with increase to the AmB concentration. It was verified that the AmB incorporation in the developed systems is dependent on the oil phase. The in vitro release of AmB is more prolonged as long as the internal oil phase increases. The microemulsified and subemulsified systems appear as more effective in the AmB veiculation presenting themselves as reservatory system, facilitating the prolonged release.

Aspergillus fumigatus is a filamentous saprophytic mold that is found abundantly in the biosphere. A. fumigatus is also an airborne human pathogen and is considered the major cause of aspergillosis, infections caused by inhalation of conidia. In immunocompetent individuals, the spores rarely cause any harm as they are cleared by innate pulmonary defences; however, in immunocompromised patients, the host immune system can fail to clear the inhaled conidia and aspergillosis may develop. Indeed, aspergillosis represents a major cause of morbidity and mortality in these populations. Aspergillosis is commonly treated using triazole and amphotericin B (AMB) antifungal agents. However, the increasing prevalence of triazole resistant strains and emergence of AMB resistance has become a challenge in treatment. To further expand our knowledge on the mechanisms of antifungal resistance in the species, we tested previously known or associated genes for antifungal resistance as well as investigated novel mechanisms via multiple genome-wide association studies (GWAS), which used a total of 211 genomes from A. fumigatus strains in 12 countries. Our results identified many novel mutations related to triazole and AMB resistance. Specifically, using stepwise GWAS analyses, we identified 6 and 18 missense variants to be significantly associated with itraconazole and voriconazole resistance, respectively. A linkage disequilibrium analysis identified six additional missense variants associated with triazole resistance, with two of these six being consistently associated with pan-azole resistance across subsets of samples. Furthermore, examination of known mutation sites and genes overexpressed with triazole exposure found a total of 65 SNPs implicated in triazole resistance. For the AMB study, we identified a total of 34 mutations associated with AMB tolerance using a GWAS. Subsequent analysis with 143 progeny strains, generated from a laboratory cross and genotyped with PCR-RFLP, identified epistatic interactions between five of these SNP sites that impacted growth in different concentrations of AMB. With the expanding immunocompromised population and increasing frequency of antifungal resistance, our results will help in investigating novel resistance mechanisms in A. fumigatus and in expanding the molecular diagnostic toolset in resistance screening, to enable rapid and accurate diagnosis and treatment decision-making. / Thesis / Master of Science (MSc)