The freshwater snail Biomphalaria glabrata is an intermediate host for Schistosoma mansoni parasites, causing one of the most prevalent parasitic infections in mammals, known as schistosomiasis (Bilharzia). Due to its importance in the spread of the disease B. glabrata has been selected for whole genome sequencing and is now a molluscan model organism. In order to aid the sequencing project and to understand the structure and organisation of B. glabrata’s genome at the chromosomal level, a G-banded karyotype has been established. Unlike in any other previous reports, two heteromorphic chromosomes have been identified in the genome of B. glabrata and for the first time snail ideograms have been produced. In addition to characterising the snail chromosomes, a methodology for mapping single copy B. glabrata genes onto these chromosomes has also been established, and 4 genes have successfully been mapped using fluorescence in situ hybridisation. In the relationship between a parasite and a host organism, it is of fundamental importance to understand the basic biology and interfere with the life cycle to reveal how the parasite controls and elicits host gene expression for its own benefit. This study is also directly addressing this aspect of host – parasite interactions by investigating the effects of schistosome infection on the genome and cell nuclei of the host snail B. glabrata. Upon infection with S. mansoni miracidia, genes known to be involved in the host response to the parasite are dramatically relocated within the interphase snail nuclei. These events are in conjunction with the up-regulation of gene expression, indicating a parasite induced nuclear event. Moreover, a differential response between the schistosome-resistant and schistosome-susceptible snails is also reported. This is the first time this has been described in a host – pathogen relationship. The precise organisation of the genome is critical for its correct functioning. The genome is non-randomly organised and this level of organisation is very much influenced by the nuclear architecture. Being a molluscan model organism with the availability of a unique cell line, B. glabrata is a remarkable organism for the studies of nuclear and genome biology. For this reason, in this thesis the snail nuclear architecture was also investigated. For the first time PML bodies, transcription factories, and nuclear myosin 1 beta have been visualised in the snail nuclei. A heat shock system was also developed to study the role of these structures in the snail. Upon heat stimuli gene loci were found to reposition and co-localise with transcription factories, which was in parallel with the up-regulation of gene expression. The mechanism of this genome reorganisation was explored by investigating nuclear motor structures in the snail. By using a motor inhibitor on snail cells, gene repositioning and subsequent expression after heat shock was blocked. This is the first time this has been shown in any organism. Thus, due to the ease of use of the snails with respect to maintenance, handling, and treatments, B. glabrata is making a very useful new model organism to study spatial genomic events.

Schistosomiasis is an important public health issue for rural communities located near,or around slow moving water bodies in the tropical and subtropical areas. Successful control of the disease involves multifaceted approaches, which include snail control, environmental sanitation, health education and chemotherapy. Although snail control might be an effective method of controlling schistosomiasis, there has been a general lack of control initiatives, largely due to the cost of available molluscicides. Plants offer a wide array of compounds which, on extraction, may show molluscicidal activity. If molluscicidal compounds that occur in indigenous plants can be extracted using local labour and simple technology, then there should be culturally acceptable and inexpensive molluscicides. The aim of this study was, therefore, to screen some Zulu medicinal plants for molluscicidal activity. We have also attempted to isolate the active chemical compounds from such plants. Aqueous and methanolic crude extracts of ten (10) Zulu medicinal plants, used for different medicinal and domestic purposes, were screened for molluscicidal activity on Biomphalaria pfeifferi and Bulinus africanas snails reared in the laboratory during the time of bioassay. Bayluscide® (niclosamide) was used as a positive control for comparison, while de-chlorinated tap water was used as the negative control. Six of the plants were not active against the snails. Extracts from four of the plants demonstrated weak to moderate molluscicidal activities. These plants are: (i) Sclerocarya birrea stembark, (ii) Psidium guajava (hybrid) leaves, (iii) Leonotis leonurus aerial parts and (iv) Ekerbegia capensis stem-bark. The LC50 values of the plant extracts were 78 ppm, 100 ppm, 398 ppm and 600 ppm respectively. Of the 4 plants that showed molluscicidal activity, S. birrea aqueous and methanol extracts were the most active against the snails, with LC50 values of 82 ppm and 78 ppm respectively. For the other plant extracts, only the methanolic extracts showed activity. Brine shrimp toxicity assay was performed with all the active extracts. Psidium guajava showed 10% survival of the shrimps at 1000 ppm, whereas no survival was observed for the other plant extracts at this concentration (1000 ppm). The results obtained in this study indicate that further studies have to be conducted, especially with S. birrea extracts, whose both aqueous and methanolic extracts showed significant activity against the snails. / Thesis (M.Med.Sc.)-University of Durban-Westville, 2002.

Schistosoma mansoni and Fasciola hepatica are parasitic trematodes which contain cytochrome c peroxidase (CcP) in their mitochondria, an enzyme that is absent in mammalian tissues. CcP reduces hydrogen peroxide to H2O using cytochrome c as the electron donor. Both parasites are catalase deficient; thus, cytochrome c peroxidase and glutathione peroxidase are the enzymes involved in the detoxification of H2O 2 in these organisms. The enzymatic activity of these two peroxidases may enable S. mansoni and F. hepatica to survive oxidative stress. The main objective of this study was to characterize cytochrome c peroxidase from S. mansoni and F. hepatica . Kinetic studies of this enzyme in crude homogenate and isolated mitochondria of S. mansoni were initially performed, followed by purification studies from S. mansoni and F. hepatica . The parasite enzyme has affinity for horse heart and yeast cytochrome c and it is inhibited by sodium azide and potassium cyanide. CcP was purified close to homogeneity and identified as a protein containing heme. The antioxidant capability of F. hepatica CcP was tested in vitro , demonstrating that CcP protected the sugar deoxyribose from oxidative degradation. Exposure of adult worms to H2O2 caused a decrease in S. mansoni CcP activity in vivo. An attempt was made to clone the S. mansoni CcP gene. The experiments did not result in the cloning of the CcP gene, but led to the identification and cloning of another protein, a component of a cytosolic chaperonin, t-complex polypeptide one (TCP-1). TCP-1 from S. mansoni is highly homologous to TCP-1 proteins from different organisms including, Chinese hamster, human, Drosophila and yeast and carries ATP binding amino acid motifs indicating that it has ATPase activity.

This study shows that resistance to killing by reactive oxygen intermediates (ROI) increases during migration and development in Schistosoma mansoni. Resistance is associated with the protective role of antioxidants as shown by the increased levels of superoxide dismutase and of the glutathione system enzymes. Hydroperoxide-dependent glutathione peroxidase activity was not detectable in newly transformed schistosomula, however the activity was present in the liver stages. The antischistosomal drug oltipraz (OPZ) decreased in an irreversible manner the activity of S. mansoni glutathione S-transferase (GST), an important protective enzyme, both in vivo and in vitro. The inhibition of GST activity was not isoenzyme restricted and was non-competitive with respect to the two substrates essential for GST activity. On the other hand, OPZ treatment increased the levels of mouse (S. mansoni host) liver GST activity in an isoenzyme specific manner, with the $ mu$ class subunit induction accounting for most of the increase. However, mammalian GST activity was inhibited by OPZ in vitro. However, the inhibition of mammalian GST activity was reversible upon addition of dithiol reducing compounds. OPZ inhibited the binding of ($ sp{14}$C) N-ethylmaleimide (specifically alkylates SH groups), suggesting that OPZ interacts with SH-groups of GST to inhibit its enzymatic activity. Another SH-dependent enzyme, hexokinase, from yeast and S. mansoni was reversibly inhibited by OPZ. The oxy-analogue of OPZ, in which the thione sulphur is replaced with oxygen, did not inhibit the enzymatic activity of GST and hexokinase. Many of the biochemical effects of OPZ on S. mansoni and its mammalian hosts may be related to its ability to bind to SH groups and inactivation of the functions of many essential proteins.

It has been postulated that the absence of human and cattle schistosomiasis in parts of southern Africa where lechwe antelope (Kobus leche) occur is a consequence of an immunologically-mediated protection induced by repeated exposure to the cercariae of Schistosoma margrebowiei and S. Leiperi, which are common parasites of these animals. The aim of the studies described was the development of animal models in which to investigate this hypothesis. The infection characteristics of the antelope schistosomes in BALB/c mice and Mastomys Coucha were assessed. Both schistosome species reached full patency in these hosts, although S. Margrebowiei infections deteriorated rapidly in M.Coucha. While they differed markedly in terms of egg production rates and preferred sites of tissue egg deposition, both species caused severe hepatosplenomegaly and portal hypertension in the mouse model. Modulation of the granulomatous responses to ova in the tissues was demonstrated. Mice harbouring mature antelope schistosome infections displayed strong partial resistance to challenge infections with both homologous parasites and the human schistosome, S. Mansoni. However, the failure of challenge parasites to become established was considered to be due largely to changes in the portal-hepatic vasculature resulting from egg-induced immunopathology. Resistance to S. Mansoni challenge did not develop in mice infected with radiation-attenuated cercariae of the antelope schistosomes. The suitability of rats and guinea pigs as alternative models was assessed. Worm recoveries from rats were low and there was no evidence of egg-deposition. Worm yields from the guinea pig were relatively high, but sexual development was poor and short-lived. Since excretion of S. Margrebowiei eggs has occasionally been reported from humans, and since the guinea pig supports full sexual maturation of S. Mansoni, this animal appeared to provide a particularly appropriate model for the present investigation. However, repeated exposure of guinea pigs to cercariae of the antelope schistosomes, over a period of 24 weeks, failed to induce significant resistance to S. Mansoni challenge infection. The need for further experimental and field studies is discussed. An area in the Okavango Delta (Ngamiland, Botswana) has been identified as a possible site for field work. / Thesis (M.Sc.)-University of Natal, Durban, 1992.

Schistosomiasis continues to be an important cause of parasitic morbidity and mortality world-wide. Determining the molecular mechanisms regulating the development of schistosome-induced pathology, including granuloma formation, fibrosis and splenomegaly, is essential for understanding how schistosomes influence the immune system of the mammalian host. I report on the first whole genome microarray analysis of the murine liver and spleen during the progression of Schistosoma japonicum infection and of S. japonicum-Soluble Egg Antigen (SEA)-stimulated macrophages. My analyses of the infected liver revealed a distinct temporal relationship between the expression of chemokines and the recruitment of cells to the liver. T-cell and B-cell chemoattractants were up-regulated earlier reflecting the recruitment of these cells to the liver as illustrated by flow cytometry. The later phases of the response corresponded with peak accumulation of eosinophils, neutrophils, macrophages and myofibroblasts/hepatic stellate cells (HSCs) and the expression of chemokines with activity for these cells including CCL11, members of the Monocyte-chemoattractant protein family (CCL7, CCL8, CCL12) and the hepatic stellate cell/myofibroblast chemoattractant CXCL1. Peak expression of macrophage chemoattractants (CCL6, CXCL14) and markers of alternatively-activated macrophages (e.g. Retnla) during this later phase provided further evidence for a role for these cells in schistosome-induced pathology. Additionally, I demonstrated that CCL7 immunolocalises to the fibrotic zone of granulomas. Furthermore, striking up-regulation of neutrophil markers and the localisation of neutrophils and the neutrophil chemokine S100A8 to fibrotic areas suggested the involvement of neutrophils in S. japonicum¬-induced hepatic fibrosis. The transcriptional profile of the spleen was closely related to changes in cellular composition illustrated by flow cytometry and immunohistochemistry. Significant up-regulation of genes associated with progression through the cell cycle, proliferation makers and genes involved in lymphocyte proliferation, paralleled the initial expansion of T-cells and B-cells and the increased cellularity of the spleen overtime. Accumulation of eosinophils, neutrophils and macrophages was paralleled by enhanced expression of markers for these cells and the declining proportion of B- and T-cells in the spleen over time was reflected in the decreased expression of B- and T-cell markers. Significant up-regulation of Chi3l3 and F4/80+ macrophages suggested the presence of alternatively activated macrophages in the spleen, where these cells could play an immunoregulatory role. Comparison of the liver and spleen profiles revealed divergent expression of chemokines and cell adhesion molecules. Expression of lymphocyte chemokines including the homeostatic chemokines, CXCL13, CCL19 and CCL21, were significantly up-regulated in the liver while down regulated in the spleen. Expression of chemokines with activity for eosinophils (CCL11, CCL24), neutrophils (CXCL1) and monocytes (CXCL14, CCL12) and the cell adhesion molecules VCAM1, NCAM1, PECAM1 were up-regulated in the liver while unchanged in the spleen. Chemokines up-regulated in both organs were expressed at significantly higher levels in the liver. Divergent expression of chemokines and cell adhesion molecules likely contributes to the development of a chemotactic signalling gradient that promotes recruitment of effector cells to the liver. The results of liver and spleen microarrays suggested an important role for alternatively activated macrophages in the development of schistosome-induced pathology. This led me to investigate the in vivo transcriptional profile of S. japonicum SEA-stimulated peritoneal macrophages. The transcriptional profile of these cells was characterised by up-regulation of alternatively activated macrophage makers (Chi3l3, Chi3l4, Arg1). Retnla was not significantly induced in these macrophages suggesting that the specific function of these cells may differ to those induced by S. mansoni and other parasites. Other features of the transcriptional profile of these cells included modulated expression of T-cell co-stimulatory molecules and chemokines which may confer immunomodulatory activity. S. japonicum-stimulated alternative activation of macrophages was additionally associated with deactivation of classical activation pathways and altered expression of cell surface receptors and complement components that may alter phagocytic activity. Together these data significantly enhance our understanding of the mechanisms associated with alternative activation of macrophages and provide significant insight into the role of these cells in schistosomiasis japonica. The findings presented in this thesis represent the most comprehensive description to date of the molecular mechanisms, and especially chemotactic signalling pathways, regulating the development of schistosome-induced granulomas, fibrosis, splenomegaly and alternative macrophage activation in the murine host. In summary, my data have revealed that co-ordinated gene expression of chemokines in the liver and spleen regulates the recruitment of cells to the liver during schistosome infection. My results provide additional evidence for a role for neutrophils and alternatively activated macrophages in the development of schistosome-induced pathology and provide further insight to the molecular basis of alternative macrophage activation during infection. Furthermore, my data serve to highlight clear differences in the pathogenesis of schistosomiasis mansoni and schistosomiasis japonica. Together these findings further our understanding of the systemic, local, cellular, and especially, chemokine signalling pathways that regulate the development of S. japonicum-induced pathology and offer correlative insight into the pathogenesis of other chronic inflammatory diseases where fibrosis, splenomegaly and alternative activation of macrophages are common features.

Resumo: A esquistossomose é um sério problema de saúde pública nos países tropicais. No Brasil, é causado pelo Schistossoma mansoni. O tratamento é feito com praziquantel, o qual é eficaz contra todas as espécies importantes de esquistossomos, que afetam os seres humanos, apesar de sua alta permeabilidade no Trato Gastrointestinal (TGI). Este fármaco tem solubilidade muito baixa em água, que pode limitar a sua absorção. Devido a essa limitação, a biodisponibilidade do PZQ é muito baixa e seu aumento é um aspecto importante e desafiador no desenvolvimento de formulações. O desenvolvimento de sistemas de liberação de fármacos tem sido muito utilizada no intuito de solucionar a necessidade de melhora de biodisponibilidade de fármacos. Os sistemas de liberação de fármacos permitem uma maior eficácia dos fármacos com a redução das doses e de sua freqüência de administração e redução dos efeitos adversos; aumentando a adesão aos tratamentos por parte dos pacientes. Muitas dessas estratégias estão sendo focadas nos sistemas matriciais poliméricos como, por exemplo, os hidrogéis, os quais são amplamente estudados por prolongarem a liberação dos fármacos. O dextrano é um polissacarídeo, que é altamente hidrofílico, atóxico, seguro, estável, biocompatível e biodegradável. O objetivo deste trabalho é o desenvolvimento de hidrogéis, utilizando dextrano com massas moleculares de 70kDa e 148kDa, e o praziquantel como fármaco-modelo. Os hidrogéis foram preparados e obtidos misturando dextrano e praziquantel em proporções fármaco:polímero de 1:0,5 e 1:1 em sistemas solventes com diferentes valores de constantes dielétricas, os quais foram secas em evaporador rotativo. As propriedades biofarmacêuticas, tais como solubilidade... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Schistosomiasis is a serious problem of public health in tropical countries. In Brazil, it is caused by Schistosoma mansoni. The treatment is done with praziquantel which is effective against all important schistosomiasis species, which affect the human being, in spite of its high permeability in Gastrointestinal Tract (TGI). This drug has very poorly water solubility, that could limiting its absorption. Due to this limitation, PZQ's bioavailability is very low and your increase is a challenging and an important aspect for the development of formulations. Development of drug release systems has been very used in order to solve the need of improvement of bioavailability of poorly water soluble drugs. Drug release systems allow for greater effectiveness of drugs by reducing their doses and frequency of administration and reduction of adverse effects; increasing adherence to treatments by patients. Many of these strategies have been focused in polymeric matrix systems such as, the hydrogels, which have been widely studied prolong the release of the drug. Dextran is a polysaccharide that is highly hydrophilic, non toxic, safe, stable, biocompatible and biodegradable. The objective of this work is the development of hydrogels, using dextran with molecular weight of 70kDa and 148kDa, and praziquantel as de drug-like model. Hydrogels were prepared and obtained mixing dextran and praziquantel in proportions drug:polymer of 1:0,5 and 1:1 in solvent systems with different values of dielectric constants, which were dried in rotary evaporator. Biopharmaceutical properties, such as solubility and dissolution rate, were analyzed in the design of hydrogels. Characterization assays were performed swelling test, IR spectroscopy and DSC. The tests of swelling rate showed that the hydrogels swell slowly, but faster than the free polymer... (Complete abstract click electronic access below) / Orientador: Maria Palmira Daflon Gremião / Coorientador: Adélia Emilia de Almeida / Banca: Marco Vinìcius Chaud / Banca: Beatriz Stringuetti Ferreira Cury / Mestre

Submitted by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2014-04-02T13:33:04Z No. of bitstreams: 1 Delsilene Borges. Avaliação...2013.pdf: 2874154 bytes, checksum: 062e7af1c2af767178820b1b4d1d1bc7 (MD5) / Made available in DSpace on 2014-04-02T13:33:04Z (GMT). No. of bitstreams: 1 Delsilene Borges. Avaliação...2013.pdf: 2874154 bytes, checksum: 062e7af1c2af767178820b1b4d1d1bc7 (MD5) Previous issue date: 2013 / Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil / Na esquistossomose mansônica o fígado é o órgão alvo das agressões patogênicas, onde as lesões hepáticas caracterizam-se principalmente pela presença de granulomas periovulares e formação de fibrose periportal, além de alterações vasculares responsáveis pela hipertensão dentro do sistema venoso portal. A angiogênese precede a maioria dos casos de fibrose, onde se verifica participação direta das células estreladas hepáticas (CEH) e das células endoteliais sinusoidais (CES) que são estimuladas, principalmente por macrófagos do tipo II (M2) – ativados alternativamente. O tratamento para esquistossomose é feito pelo uso do praziquantel (PZQ), o qual é capaz de promover cura parasitológica e reparo das lesões hepáticas, todavia pouco se sabe sobre os componentes celulares envolvidos na angiogênese durante o reparo do fígado. Este trabalho teve como objetivo estudar o remodelamento das lesões hepáticas pós-tratamento e investigar a participação das CEH, CES e macrófagos M2 no processo de reparo das lesões. Após aprovação pela Comissão de Ética no Uso de Animais (CEUA-CPqGM), protocolo nº 006/2011, 80 camundongos Swiss Webstar foram utilizados, destes 70 foram infectados com 50 cercárias do Schistossoma mansoni e dez permaneceram intactos. Quatro meses após infecção foi realizado tratamento com PZQ (400mg/Kg) em parte dos animais infectados, formando assim três grupos: um controle, um infectado não tratado e outro infectado e tratado. Em diferentes intervalos de tempo foram realizadas três hepatectomias parciais: a primeira com quatro meses de infecção (antes do tratamento); a segunda com seis meses de infecção e dois meses de tratamento; a terceira com oito meses de infecção e quatro de tratamento. Os fragmentos hepáticos coletados foram submetidos a avaliações morfológicas e estudos imuno-histoquímicos para visualização de componentes celulares – macrófagos M2 (Ym1), CEH (α-SMA) e CES (CD31). Análises morfométricas foram realizadas para quantificação do percentual de tecido fibroso e das células imunomarcadas. Nossos resultados demonstraram que após dois meses de tratamento com PZQ foi possível observar reabsorção do tecido fibroso hepático com redução da expressão de macrófagos M2 e CEH. Quatro meses após a quimioterapia verifica-se aumento no número de células endoteliais. Esses resultados sugerem que macrófagos M2 e CEH têm participação ativa na formação do tecido fibroso, exercendo pouca influência na fase involutiva do granuloma. Todavia, a intensa proliferação de CES nos granulomas involutivos, confirma o importante papel da angiogênese no remodelamento das lesões hepáticas. / The liver is a target for pathogenic attacks during schistosomiasis, showing periovular granulomas and the formation of periportal fibrosis, besides vascular changes responsible for hypertension within portal venous system. Angiogenesis precedes most cases of fibrosis, which can be verified the presence of hepatic stellate cells (HSC) and liver sinusoidal endothelial cells (LSEC) stimulated mostly by macrophages type II (M2) – alternatively activated. Schistosomiasis treatment is based on praziquantel (PZQ), which enables parasitological cure and resolution of liver cells. However, knowledge regarding active cell components on angiogenesis during liver regeneration is scarce. Our goal was to study the remodeling of liver injuries during post-treatment phase and investigate the role of HSC, LSEC and macrophages (M2) on the process of resolution of injuries. After the approval of ethical committee for animal research of the CPQGM-FIOCRUZ, record number 006/2011, 80 mice Swiss Webstar were used, which 70 were infected by 50 cercariae of Schistossoma mansoni and ten remained intact. Four months after infection a treatment with PZQ (400mg/Kg) was started in part of infected animals, constituting three different groups: normal, non-treated infected and treated and infected. In different times three partial hepatectomias were made: the first on four months of infection (before treatment); the second with six months of infection and two months of treatment; and the third with eight months of infection and four months of treatment. In all liver fragments collected for morphological evaluations were performed and immunohistochemistry studies were made to visualize macrophages M2 (Yml), HSC (α-SMA) and LSEC (CD31). Morphometric analysis was performed to quantify percentage of fibrosis and the immunostainig cells. Our results show that after two months of PQZ treatment it is possible to observe fibrosis resorption in the liver, with reduction of macrophages M2 expression and HSC. Four months after chemotherapy an increase on the number of LSEC was verified. These results suggest that macrophages M2 and HSC are active on the formation of fibrosis tissue, playing little influence on the evolving phase of the granuloma. Nevertheless, intense proliferation of LSEC observed on involute granulomas confirm the important role for angiogenesis on remodeling of liver injuries.

Made available in DSpace on 2014-06-11T19:25:27Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-06-30Bitstream added on 2014-06-13T19:53:12Z : No. of bitstreams: 1 campos_fs_me_arafcf.pdf: 532601 bytes, checksum: 9fe71fde77ba94b50f7ca2408438a7c7 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A esquistossomose é um sério problema de saúde pública nos países tropicais. No Brasil, é causado pelo Schistossoma mansoni. O tratamento é feito com praziquantel, o qual é eficaz contra todas as espécies importantes de esquistossomos, que afetam os seres humanos, apesar de sua alta permeabilidade no Trato Gastrointestinal (TGI). Este fármaco tem solubilidade muito baixa em água, que pode limitar a sua absorção. Devido a essa limitação, a biodisponibilidade do PZQ é muito baixa e seu aumento é um aspecto importante e desafiador no desenvolvimento de formulações. O desenvolvimento de sistemas de liberação de fármacos tem sido muito utilizada no intuito de solucionar a necessidade de melhora de biodisponibilidade de fármacos. Os sistemas de liberação de fármacos permitem uma maior eficácia dos fármacos com a redução das doses e de sua freqüência de administração e redução dos efeitos adversos; aumentando a adesão aos tratamentos por parte dos pacientes. Muitas dessas estratégias estão sendo focadas nos sistemas matriciais poliméricos como, por exemplo, os hidrogéis, os quais são amplamente estudados por prolongarem a liberação dos fármacos. O dextrano é um polissacarídeo, que é altamente hidrofílico, atóxico, seguro, estável, biocompatível e biodegradável. O objetivo deste trabalho é o desenvolvimento de hidrogéis, utilizando dextrano com massas moleculares de 70kDa e 148kDa, e o praziquantel como fármaco-modelo. Os hidrogéis foram preparados e obtidos misturando dextrano e praziquantel em proporções fármaco:polímero de 1:0,5 e 1:1 em sistemas solventes com diferentes valores de constantes dielétricas, os quais foram secas em evaporador rotativo. As propriedades biofarmacêuticas, tais como solubilidade... / Schistosomiasis is a serious problem of public health in tropical countries. In Brazil, it is caused by Schistosoma mansoni. The treatment is done with praziquantel which is effective against all important schistosomiasis species, which affect the human being, in spite of its high permeability in Gastrointestinal Tract (TGI). This drug has very poorly water solubility, that could limiting its absorption. Due to this limitation, PZQ’s bioavailability is very low and your increase is a challenging and an important aspect for the development of formulations. Development of drug release systems has been very used in order to solve the need of improvement of bioavailability of poorly water soluble drugs. Drug release systems allow for greater effectiveness of drugs by reducing their doses and frequency of administration and reduction of adverse effects; increasing adherence to treatments by patients. Many of these strategies have been focused in polymeric matrix systems such as, the hydrogels, which have been widely studied prolong the release of the drug. Dextran is a polysaccharide that is highly hydrophilic, non toxic, safe, stable, biocompatible and biodegradable. The objective of this work is the development of hydrogels, using dextran with molecular weight of 70kDa and 148kDa, and praziquantel as de drug-like model. Hydrogels were prepared and obtained mixing dextran and praziquantel in proportions drug:polymer of 1:0,5 and 1:1 in solvent systems with different values of dielectric constants, which were dried in rotary evaporator. Biopharmaceutical properties, such as solubility and dissolution rate, were analyzed in the design of hydrogels. Characterization assays were performed swelling test, IR spectroscopy and DSC. The tests of swelling rate showed that the hydrogels swell slowly, but faster than the free polymer... (Complete abstract click electronic access below)

O presente trabalho é uma formulação teórica que permite estudar num modelo estocástico, a influência dos erros de classificação na mensuração da prevalência da esquistossomose mansônica. Os erros de classificação são desagregados e identificados como: falhas de leitura por parte do examinador ou preparo inadequado da lâmina; contingências biológicas que possibilitam o aparecimento de ovos não viáveis e a eliminação de ovos contínua por parte dos indivíduos. É apresentada uma solução geral para o problema, bem como soluções para os casos em que se conhece a distribuição de probabilidades do número de ovos de S.mansoni. Uma solução aproximada e independente da forma e dependente dos dois primeiros momentos da distribuição do número de ovos é sugerida. A influência dos erros de classificação pode quantitativamente ser apreciada, através de um conjunto de tabelas elaboradas com diversos valores dos parâmetros intervenientes no problema. / The present paper is a theoretical approach which will, allow studying the influence - in a stochastic model - of errors in classifying the measurement of the prevalence of Schistosomiasis mansoni. The misclassification errors considered are due to: (A) failure of the examiner in either (1) reading or (2) poor technique. (B) biological contingences which will allow for the appearence of (1) sterile eggs, or (2) discontinuity in the elimination of eggs by the carriers. An exact general solution of the problem is presented, as well as solutions for the particular cases in which the probability distribution of S.mansoni eggs counts in known. An approximate solution is suggested, which is independent from the way in which the number of eggs is distributed, but depends upon the first two moments of the probability distribution of the eggs counts. The influence of misclassification errors can be judged in a quantitative way, by means of a set of tables mande up for the different parametric values of the problem.