O antígeno B (AgB) é uma proteína polimérica de aproximadamente 160 kDa secretada durante a fase larval dos parasitos do gênero Echinococcus. Sua função provavelmente está relacionada com a evasão da resposta imune do hospedeiro, e tem sido relatado que seus genes apresentam alta diversidade de seqüências, mesmo dentro de um único metacestóide de E. granulosus. Em E. multilocularis o AgB é codificado por uma família multigênica composta por pelo menos cinco genes. Neste trabalho nós avaliamos o efeito do sistema imune dependente de célula T sobre a diversificação somática dos genes do antígeno B em metacestóides de E. multilocularis obtidos de camundongos secundariamente infectados com microcistos: uma linhagem proficiente e outra não proficiente quanto à resposta imune celular (BALB/c e nude, respectivamente). Os animais foram sacrificados após um ou dois meses de infecção para coleta da massa parasitária e extração do RNA. Após a síntese do cDNA foram feitas PCRs específicas para quatro genes (EmAgB1, EmAgB2, EmAgB3 e EmAgB4) e o produto desta reação foi clonado. Os clones resultantes foram analisados quanto à presença de polimorfismo através de PCR-SSCP e os alelos descobertos foram seqüenciados. A diversidade alélica foi calculada através do Índice de Diversidade de Shannon e desvios da neutralidade foram testados através do Teste D de Tajima e através do Teste Exato de Fisher, que detecta excesso de mutações não-sinônimas em relação às mutações sinônimas. Um teste adicional, que calcula a probabilidade (através da distribuição binomial) de ocorrência das mutações não-sinônimas, foi realizado. Comparando a diversidade encontrada nos genes do AgB não encontramos evidências de que a pressão imposta pelo sistema imune esteja relacionada com a diversidade de seqüências encontrada em nosso estudo. O gene EmAgB2 apresentou Índices de diversidade mais elevados (principalmente quando coletado do camundongo BALB/c após um mês de infecção) e também apresentou maior quantidade de indels. Apenas um dos alelos encontrados em nossa amostragem foi compartilhado por parasitos coletados de diferentes camundongos, sugerindo que os alelos possam ter surgido após a infecção dos camundongos. O Teste D de Tajima resultou em valores negativos em todas as análises. Entretanto, nem o Teste Exato de Fisher nem a análise da probabilidade binomial encontraram excesso de mutações não sinônimas para qualquer dos genes analisados. Portanto, nossos dados indicam que os genes do AgB durante a fase de metacestóide evoluem segundo o modelo neutro e o valor D de Tajima negativo pode ser explicado devido a rápida proliferação celular do metacestóide após a infecção secundária. / The Antigen B (AgB) is a polymeric protein secreted during the larval stage of the Echinococcus flatworms. The AgB is involved with the evasion of host immune response and its genes show high variability, even inside a single E. granulosus metacestode. To date, five AgB genes have been reported in the E. multilocularis genome. In this work we analyzed the AgB diversification in E. multilocularis recovered from secondarily infected mice. Two different mouse strains were infected with microcysts of E. multilocularis: BALB/c and nude, which are T-Cell immune response proficient and non-proficient, respectively. The mice were necropsed one or two months post infection and the parasite mass was collected for RNA extraction. Following the cDNA synthesis, each AgB gene (EmAgB1, EmAgB2, EmAgB3 and EmAgB4) was amplified in a specific PCR and the products of these reactions were cloned. The polymorphism present in each AgB gene was assessed by PCR-SSCP and the variant alleles were sequenced. The allele diversity for each gene was calculated by the Shannon Diversity Index and neutrality departures were tested by Tajima’s D Test, and Fisher’s Exact Test, which evaluates the excess of non-synonymous over synonymous substitutions. An additional test, which estimates the binomial probability of occurrence of nonsynonymous mutations, was also performed. We did not find association between the AgB diversity and the immune response of the host. The EmAgB2 gene showed the largest diversity index among the four genes (especially when collected from BALB/c at first month post infection) and it also presented a large quantity of alleles containing indels. The parasites collected from different mice do not share AgB alleles (with a single exception), and suggest that the new alleles could have arisen after the mice infection. The Tajima’s D Test resulted in negative values in all analyses. However, both Fisher’s Exact Test and the binomial probability analysis did not detect excess of non-synonymous mutation in our samples. Therefore, our data suggest that AgB genes evolve by the neutral model during the metacestode stage, and the negative Tajima’s D value could be explained by the fast cellular proliferation of the metacestode after secondary infection.

A forma larval de Echinococcus granulosus (metacestóide) é o agente causador da hidatidose cística, zoonose endêmica no Rio Grande do Sul. Essa parasitose caracteriza-se pelo crescimento de uma massa cística preenchida de líquido hidático que causa compressão em órgãos e tecidos vizinhos. O antígeno B (AgB) é um dos maiores componentes do líquido hidático. Apesar da função do AgB ser mal conhecida, alguns indícios sugerem que ele está envolvido na interação parasito/hospedeiro. Sabe-se que os genes de contingência em microparasitas (protozoários e bactérias) são os responsáveis pela evasão da resposta imune do hospedeiro, e estão localizados, freqüentemente, na região sub-telomérica dos cromossomos. A localização sub-telomérica poderia estar relacionada com a alta variabilidade encontrada na família multigênica do AgB, uma vez que tais regiões costumam estar mais sujeitas à mutação. No presente trabalho procuramos verificar a proximidade dos genes de AgB dos telômeros através de experimentos de Southern blot utilizando a técnica de TRF (Telomere Restriction Fragment) onde o DNA genômico de E. granulosus e E. multilocularis foi clivado com seis diferentes enzimas de restrição e hibridizado com um inserto que possui o motivo telomérico C3TA2 (caracterizado para E. granulosus) e re-hibridizado com produtos de PCR dos genes AgB, ambos marcados com fluoresceína. Os nossos resultados permitiram a identificação de heterogeneidade no tamanho dos telômeros de E. granulosus. Ainda, utilizamos um PCR extra longo (XL-PCR) com primers específicos para os genes de AgB e um primer contendo o motivo telomérico de E. granulosus. Foram obtidos amplicons de aproximadamente 1600 pb para AgB2 , AgB3 e AgB4, e de 1300 e 3500 pb para AgB3. Não foram obtidos amplicons para AgB1. Com base nos dados obtidos neste trabalho, sugerimos que os genes AgB2, AgB3 e AgB4 estão localizados próximos a um motivo telomérico, mas ainda não podemos definir a precisa localização dos genes nos cromossomos. / The larval stage of Echinococcus granulosus (metacestode) causes the cystic hydatic disease, an endemic zoonosis from the state of Rio Grande do Sul. The disease is characterized by the growth of a cyst filled with liquid (hydatic fluid), leading to the compression of the neighbouring organs and tissues. Although the biological role of antigen B (AgB) is still uncertain, several clues show that it is involved in the parasite/host interaction. Contingency genes are known to be responsible for the evasion of host imune response in microparasites, and are frequently localized in chromosome sub-telomeric regions. A sub-telomeric localization could be related to the high variability found in the AgB multigene family, since these regions are usually more prone to mutations. In the present work we tried to verify the proximity of AgB genes to the telomeres with Southern blot experiments using the TRF (Telomeric Restriction Fragment) technique, where the genomic DNA from 35 E. granulosus and 5 E. multilocularis isolates were digested with 6 different restriction enzimes and hybridized with an insert containg the E. granulosus telomeric motif (C3TA2) and re-hybridized with PCR products derived from AgB genes, both labeled with fluorescein. Our results show heterogenity in the E. granulosus telomere size. Furthermore, we used an extra long PCR (XL-PCR) with specific primers for AgB genes and a primer containing the E. granulosus telomeric motif. We obtained amplicons with about 1600 bp for AgB2, AgB3 and AgB4, and with 1300 and 3500 bp for AgB3. No amplicons were obtained using AgB1 specific primers. Based on these data, we suggest that the E. granulosus AgB2, AgB3 and AgB4 genes are localized in the vincinity of telomeric motifs, but we are still unable to define the precise localization of the genes at chromosomes.

The fundamental basis of the project concentrates upon an interactive manoeuvre involving Modern Continental Philosophy and the Postmodern Visual Arts. The primary components that structure the thesis conduct a Deleuzoguattarian "process” of action to produce a series of mechanisms designed to “open-up" a space in which to manifest a range of interpretations/translations that follow the developmentary trajectory of designated specific areas of art production. The primary aims concern the advance of the action to communicate an innovative/original set of expositions with a view to both “animate" and enhance these designated perspectives. The structural framework of the project tracks through “passages'/lines of flight” that occur/result from the impact of the Deleuzoguattarian mechanisms upon chosen material - "Introduction" (Primary) sets forth some guiding themes (how to think knowledge without the presumption of the neutral interchangeability of the subject?). “Tours of the Black Clock" (Dark) elaborates the Nietzschean background that informs the philosophical basis of the complete project. “Electrolite” (Spin the Black Circle), “Where Angels Play" (In a Network of Lines that Intersect), “Not to Touch the Earth” (Elephant Stone) “Across” (Out of Time) are sections designed to trace a number of alternative pathways through the major texts of the Deleuzoguattarian enterprise. “Becoming X" (Impact) initiates a secondary movement of experimentation. “Animal Nitrate" (The Image of Chance) effects “an encounter" with the work of painter Francis Bacon via the Deleuze text(s) “Logique de la Sensation" (1981), “Time and Again" (New Damage) introduces and articulates a number of instances from Deleuzian film-theory “The Fountainhead” (Vision Machines) is the main section of the project which evolves a detailed process analysing the paintings of American painter David Salle “The Mirror of Enigmas" (Numbers in the Dark) traces related Deleuzeoguattarian themes through the films of David Lynch, maintaining as a background an examination of Postmodern American culture/society. “Breaking into Heaven" (Elegia) returns to the more specific analysis of the late paintings of David Salle and uses the mechanics elaborated in Deleuze's book “Le Pli”. “Final Cut”/”Last Exit”/”Memorial Beach" is an attempt at a series of concluding remarks within the project divisions are resolved within a comprehensive Deleuzoguattarian structural system - evolving to be primarily defined in terms of two “active" processes/movements which engage theory and explanation, practice and application respectively, being therefore both a philosophical /academic debate while incorporating a high-level of “creative" experimentation. The first sections of the project detail an extensive series of explanatory “pathways/journeys” through the texts of Deleuze and Guattari with a view to indicating measures that can be deployed/utilized in a Deleuzoguattarian process of art/cultural analysis. Constructing the architectural pattern/”anatomy” of a series of interpretative surfaces to reflect the dimensions of the cultural material approached. The sections in the second part of the project enact a number of experimental designs, dispatching Deleuzoguattarian mechanisms in the body of the chosen cultural material. An interpretative surface is never under the influence of a single differentiated flow it constitutes the mutual boundary of numerous adjacent flows. The same interpretative surface is therefore available to be understood in as many different ways as there are adjacent flows along its fractural surface. This project is essentially a speculative enterprise, a philosophical experiment whose aim is to enhance, enlarge and intensify our “knowledge" of the area defined, through a synthesis, here labelled as a “Deleuzoguattarian process of Art analysis”. For Deleuze, thought creates what it thinks, as perception creates what it perceives (and therefore does not relate to it). The philosophical concept does not refer to the lived, but consists through its own creation, in setting up an event that surveys ("survole“) the whole of the lived no less than every state of affairs Deleuzoguattarian philosophy does not establish a relationship “between” philosophy and other disciplines, other ways of making sure, but eliminates this relationship to the advantage of a type of “greater philosophy” Thought/Philosophy thinks the sufficient reason of the actual in this manner. For Nietzsche, whose enterprise constitutes (I have suggested) the base/departure for the Deleuzoguattarian program, “the world" we know lies in our interpretation of it. However, the task of interpretation is not to discover “truth" but to “create" it. According to Nietzsche, there is no “world-in-itself, no unconditioned and stable entities that await our discovery, but a dynamic and turbulent “becoming" in which the forms we perceive are not separate from our interpretations of them Because we are ourselves part of this becoming, there is no vantage point from which it is possible to gain the absolute/unconditioned knowledge that we have imbued with the idea of “truth”. The exercise merely becomes self-reflective. However, despite this skepticism, Nietzsche realizes that the game of truth is unavoidable, so therefore he, and In consequence we, departing/initiating the pathways through this project, have to cast in the role of the philosopher who knows what he invents and invents while he knows. In Postmodern Art no style dominates. Alternatively we experience endless improvisations and variations on themes, parody/playfulness. Postmodern artists are unabashedly eclectic and call attention to it, combining traditions borrowing from rituals and myths. All the world's cultural symbols are now available in the public domain - “SANTA CLAUS IS ON THE CROSS". The Deleuzoguattarian process of art delineated is a play with the game of “truth” and not an explanation of a “whole" a description of the network of the "dynamic”/fluid nature of our transitional relationship to it. It is the flow of energy that encompasses what Deleuze/Nietzsche refer to as “the whole" A flow invokes the dynamic/fluid nature of becoming, while energy/activity implies a potentiality - the inherent capacity and growth actuated by the will to power. The flows of energy are manifested into differentiated flows within flows, “Ad infinitum” and powered by the parameters of state space - a potential i.e field defined by the characteristics of the subject flows associated Nothing exists in isolation Differentiation exists only via relations to other flows in a dynamic/non linear network of resistances.

My PhD is entitled Sub-Versions of Reading. The thesis is concerned with critical refractions such as reading, interpretation, criticism, commentary ... activities which resemble each other in that they do not resemble that from which they derive; thus derived rather than original, secondary rather than primary, their status is also deemed second-rate. My aim has been both to reread their inferior plight and rewrite this plight through the theoretical insights culled from recent literary theory. I therefore compare two theoretical frameworks, one hermeneutic, the other post-structural both of which have contributed, each in different ways, towards a theorization of reading. Following this, I come to argue that the kind of Unitarian, totalizing hermeneutic approach, which seeks to reduce the original text's polysemantic possibilities, unlike a post-structuralist strategy which renders the "original” indeterminable and unleashes the isotropisms of textuality, can make no real critical difference to empower the refractor, be it the reader, critic or translator. Thus my argument finally uses translation, as the very site, that 'impossible place' where the multiple discourses on reading, re-reading, misreading, (un)readabl1ty, reading/as/writing connect, and where the (sub)version of translation can be theorized differently. Here, theories can be seen to multiply, and in multiplying, they not merely transform the "state" of translation (as a re/writing) but also the state of "theory" (as a multiplication of theorems).

The present dissertation discusses the relationship between cultural constructions of climate and practical attempts at regulating the latter’s perceived influence on human beings in the ‘long’ seventeenth century—a time of crucial historical and intellectual changes. Drawing upon a broad range of printed and manuscript sources written in various languages (including travel accounts, missionary letters, scientific papers, political treatises, and medical writings), the research presented here reconstructs the long-term success of classical ‘climate theories’ and the concrete behaviours that these theories inspired in early modern Europe and the American colonies. By investigating the various strategies that were used to cope with, and capitalize on, the perceived influence of climate, the dissertation challenges common characterizations of climate theory as a form of determinism. After a preliminary chapter about the origins, transmission, and circulation of climate theory in its multiple and conflicting forms, the following chapters each explore a different way of negotiating climatic influence in the ‘long’ seventeenth century, notably diet and lifestyle (Chapter 2), geographical displacement (Chapter 3), and environmental engineering (Chapter 4). The ‘Epilogue’ then briefly looks at post-seventeenth-century developments before drawing some general conclusions about the historical evolution and cultural significance of early-modern climate theories. Situating itself at the intersection of several disciplinary fields (including intellectual history, reception studies, and the history of medicine and science), this dissertation examines, on the one hand, the interplay of environmental ideas and practices in specific historical contexts; and, on the other hand, the acquisition, transmission, and circulation of environmental knowledge at, and across, different socio-cultural levels. It thus raises questions of tradition and innovation, consistency and diversity, ‘learned’ and ‘popular’ culture, investigating the ways in which epistemic paradigms are formed and transformed across time and space.

This thesis explores issues in aesthetics with reference to Bergson. The first chapter outlines and assesses Bergson's interesting and subtle theory of humour, which emphasises the necessary lack of sympathy in humour, and its generalising, external methodology. In doing so it explores the different ways the motif of 'something encrusted on the living' functions on various levels. This is ultimately found to be an interesting account which has many merits. The second chapter then begins to outline the theoretical structure of Bergson's account of humour in terms of vertical and horizontal movement. This leads to an account of Bergson's critique of 'ordinary' conceptual language and a consideration of other alternatives, including metaphor. The third chapter discusses Bergson's notion of intuition and levels of interpretation - assessing what, if any, relation there is between Russian Formalism and Bergson's own understanding of poetry. The notion of levels helps to define Bergson's anti-modernism, when modernism is understood as the self-referential exposure of the art work's own conditions of possibility. The fourth chapter examines several art forms. Music is discussed in some detail with particular attention being paid to the distinction between rhythm and melody, notions of repetition, creativity and difference. A comparison it then made between Bergson's thoughts on evolution and melodic creativity. This discussion is of importance not only for the light it casts on aesthetic issues, but also because music, or more specifically melody, is often given as an example of the heterogeneous continuity of duration. The thesis also examines painting, particularly in relation to duration, comparing it with photography. Bergson's arguments against cinema are then discussed. The thesis also examines how the role of sympathy functions in artistic production generally. Finally Bergson's ability to distinguish between art and philosophy is examined referring back to notions of self-reflexivity in art.

The notions of 'meaning' and 'historicity', of the manner in winch they inform or reflect conceptions of collective or ‘social’ being and of individuality, and of the ways in which these dimensions are primordially experienced by human beings. This investigation concerns primarily the phenomenological and hermeneutic traditions and especially Heidegger’s formulation of the notion of historicity as correlative to the 'event' of truth understood in terms of an interplay between disclosure and concealment (aAf)0eia) and Gadamer's understanding of 'meaning and historicity’ as an indispensable couplet for both philosophical hermeneutics and the social sciences. Nevertheless the present inquiry does not content itself with an exploration of the notions of 'meaning' and historicity' within the confines of the phenomenological-hermeneutic tradition, but rather attempts to attain a more adequate grasp of those concepts by a critical Juxtaposition of Heidegger and Gadamer with accounts that have the 'social' as their point of departure. Thus, Heidegger’s formulations on historicity are not only examined in relation to his 'immediate' legacy of German thought -especially Hegel and Nietzsche- but are also contrasted with conceptions of history pertaining to the Marxist tradition and especially Castoriadis’ conception of the social-historical. In effect, the contrast between 'historicity' and the workings of 'actual' history has arguably prevented a genuine dialogue between the Marxist and the phenomenological camps. Far from being concerned with a synthesis of those traditions or from being preoccupied with justifying either of them I have attempted to show that a combined reading of both is indispensable for the disclosure of the essential dimensions of historical experience. Castoriadis' emphasis on the ‘magmatic’ character of unconscious significations and his grounding of social-historical 'instituting' on the unconscious, together with Heidegger's attempt to link the primordial experience of history with myth have given me occasion to dissociate the very notion of 'meaning' from that of 'rationality'. This should not be interpreted as a rejection of rationality or as an -at bottom- ethical invocation of a return to a pre-Critical philosophical position but rather as an attempt to indicate the primordial manner in which history is accessible in experience and which arguably precedes any thematic theorizing of the historical realm. I have finally attempted to show the antinomies inherent in any attempt to grasp ‘rationally’ the social-historical by a detailed exploration of Gadamer's ambivalent conception of tradition’ and 'prejudice'. Gadamer’s conception of the ‘fusion of horizons’ gave me occasion to reflect further on the manner in which history and truth are made correlatively accessible in thought, in experience, and in historical praxis.

Heritage was defined as “what we value”, or “what we wish to pass on to future generations”, that is to say, heritage is not only a product of the past but also a valuable process in a culture (Deacon, 2003). Furthermore, the relationship between nature and culture is a defining problem for recent debates over the meanings of heritage after The 1972 UNESCO Convention. There is a centuries-old aesthetic discourse in Western culture that treats natural landscapes as objects of beauty, and this has influenced designations of natural heritage beyond human occupants, with the result that they are often considered desirable to conserve with traditional management practice (West & Ndlovu, 2010). The main standard for identifying heritage sites in the Western tradition, particularly Britain, France and Germany during the 19th Century, has formed a tangible perspective which is architectural style and historical significance including different views of power and dominance of particular civilisation (Jokilehto, 1990; Smith & Akagawa, 2009). Recently, recognising the significance of garden heritage has brought awareness of the crucial inputs needed to manage still existing garden heritage and to understand what we already have lost. Garden heritage is a vague term, embodying cultural landscape and tangible landscape. Managing garden heritage is a very important issue in passing our heritage to future generations. The main purpose of this study is to fully integrate the principles of management for intangible garden heritage connecting fabric and intangible assets within the Byeolseo garden which is a unique traditional form of the Korean garden. This study is based on the use of complementary research methods to address the relationship between local government perspectives and international ‘best practice’ concerning garden heritage values with their tangible and intangible aspects. How people establish value of garden heritage was main question that drove this study. As the detachment between local communities and their garden heritage site and the vanish of gardener and head gardener, this study aimed to re-connect between them with strategy for understanding garden heritage sites that respects the public perception of garden heritage. The cases of Byeolseo garden shows that people generally understand garden heritage in terms of significances. This study classifies six significances of gardens, but public perception of garden heritage should be formed by complex of these significances rather than individual significance, which is mostly found to be unclear to the public in South Korea. Therefore, this study encourage that the importance of the public appreciation of garden heritage sites depend on understanding their significance.

Orientador: Fábio Simões de Vicente / Banca: Agnaldo Aparecido Freschi / Banca: Tomaz Catunda / Resumo: O processo sol-gel permite a produção de materiais Híbridos Orgânicos/Inorgânicos para aplicações em óptica e fotônica. Materiais Híbridos de Sílica/orgânico unem propriedades da Sílica e dos polímeros orgânicos e permitem a incorporação de diversas moléculas orgânicas na matriz, possibilitando a obtenção de materiais fotoativos avançados. Destas moléculas destacam-se os corantes lasers, como a Rodamina-B, que possui comprimento de onda de emissão bem definido e alta eficiência quântica. Neste trabalho preparamos materiais híbridos de sílica/orgânico via processo sol-gel utilizando como precursores os alcóxidos de silício 3-glicidoxipropiltrimetoxisilano (GPTS) e tetraetilortosilicato (TEOS). Amostras ainda na fase de sol foram dopadas com Rodamina-B em concentrações variando de 0,01 a 5 mmol/L. A fluorescência das amostras foi caracterizada mostrando dependência entre as características da emissão e a concentração de dopante. Os espectros de fluorescência sofrem um deslocamento para a região do vermelho com o aumento da concentração do dopante, enquanto a intensidade de emissão apresenta maior valor para a amostra com concentração de 0,5 mmol/L. Também foram determinados os coeficientes de absorção óptica, que apresentaram comportamento linear com a concentração. A partir das amostras (sol) foram produzidos xerogéis com concentrações de Rodamina-B de 0,0386 a 19,3 mmol/L. Os espectros de fluorescência destes xerogéis também apresentaram deslocamento para a região do vermelho... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Organic-Inorganic Hybrid Materials prepared by sol-gel process have applications in different areas such as optics and photonics. Silica/organic hybrid materials combine the properties from the silica and the organic polymers and can be doped with organic molecules with different optical properties, allowing preparation of advanced photoactive materials. In the wide range of photoactive organic materials one of interest is the Rhodamine-B, a laser dye which presents tunable emission and high quantum yield. In this work we have produced hybrid silica/organic samples derived from 3-glycidoxypropyltrimethoxysilane (GPTS) and tetraethylorthosilicate (TEOS) by sol-gel process. Silica/organic sols were doped with Rhodamine-B concentrations ranging from 0.01 to 5 mmol/L. The fluorescence spectra of the samples were characterized and a relationship between emission characteristics and dopant concentration has been observed. A red shift in the wavelength emission was observed, as the dopant concentration increased and the maximum emission intensity was achieved for the sample with concentration of 0.5mmol/L. Were determined the optical absorption coefficients that showed a linear relation with the concentration. The sol samples were dried and xerogels were obtained and the new concentrations of Rhodamine-B in the solid matrix were determined, ranging from 0.0386 to 19.3 mmol/L. The fluorescence spectra of the xerogels were characterized, showing a red shift as the dopant concentration increased and the maximum emission intensity was achieved for the xerogel with concentration of 6.56 mmol/L. The optical absorption coefficients of these xerogels showed a linear behavior with the dopant concentration. Random laser action for the xerogel with concentration of 19.3 mmol/L was measured using an pulsed laser (532 nm, 8ns), ... (Complete abstract electronic access below) / Mestre

Orientadora : Profª. Drª. Astrid Wiens Souza / Coorientador : Prof. Dr. Roberto Pontarolo / Dissertação (mestrado) - Universidade Federal do Paraná, Setor de Ciências da Saúde, Programa de Pós-Graduação em Ciências Farmacêuticas. Defesa: Curitiba, 16/12/2016 / Inclui referências : f. [38-45;69-72;90-96;130-132] / Área de concentração: Insumos, medicamentos e correlatos / Resumo: A anfotericina B é um antifúngico de amplo espectro utilizado principalmente, no manejo de infecções fúngicas invasivas (IFI). Está disponível no mercado nas formulações convencional e lipídicas (lipossomal, dispersão coloidal e complexo lipídico). A formulação convencional apresenta valor de aquisição, atualmente, no Brasil, mil vezes inferior ao das formulações lipídicas, no entanto, também apresenta eventos adversos graves, dentre eles, a nefrotoxicidade, que pode levar o paciente a realização de diálise ou mesmo a óbito. Neste contexto, é importante utilizar ferramentas como as disponíveis na Avaliação de Tecnologias em Saúde, a fim de, estudar os riscos e benefícios destas tecnologias, considerando, tanto sua eficácia, segurança e tolerabilidade, quanto os custos envolvidos no tratamento e no manejo dos eventos adversos. Assim, os objetivos deste trabalho foram: avaliar e comparar evidências de eficácia, segurança e tolerabilidade das formulações de anfotericina B em pacientes com suspeita e/ou confirmação de IFI; realizar um levantamento das evidências de custo-efetividade, no uso de antifúngicos sistêmicos para o tratamento e/ou profilaxia em pacientes com suspeita ou confirmação de IFI; e, realizar uma análise de custo-efetividade das formulações de anfotericina B. Inicialmente foi realizada uma revisão sistemática (RS) de ensaios clínicos randomizados (ECR), nas bases de dados; Medline, Scielo, Scopus e Web of Science. Os estudos incluídos tiveram dados de eficácia (cura), segurança (eventos adversos e morte) e tolerabilidade (descontinuação) coletados, para posterior realização de análise estatística: meta-análise, pelo software Review Manager. Na sequência, foi realizada uma busca sistemática de estudos farmacoeconômicos em pacientes com IFI, utilizando as bases de dados: Medline, Scopus e Web of Science. Por fim, conduziu-se a realização do modelo de custo-efetividade, desenvolvido como árvore de decisão, utilizando o software TreeAge. Foram considerados, para a elaboração do modelo, os desfechos de cura, morte e nefrotoxicidade com posterior tratamento medicamentoso ou dialítico. Os parâmetros adotados na construção do modelo foram: perspectiva do Sistema Único de Saúde (SUS), custos diretos médicos, horizonte temporal de três e seis semanas, de acordo com o tempo máximo de utilização dos medicamentos prevista em bula. Na primeira RS foram encontrados 5682 ECR, dos quais, 25 contemplaram os critérios de inclusão (n = 2996). Os principais resultados evidenciam que as formulações de anfotericina B apresentam perfil de eficácia muito similar, no entanto, diferem estatisticamente no que concerne a segurança, sendo que, as formulações lipídicas apresentam menores taxas de eventos adversos, incluindo: nefrotoxicidade, febre, calafrios e vômito. Na RS acerca dos modelos farmacoeconômicos, pôde-se verificar que, não há na literatura nenhuma avaliação farmacoeconômica entre as formulações de anfotericina B entre si. Enfim, no modelo de custo-efetividade construído, a formulação convencional de anfotericina B se mostrou mais custo efetiva, seguido das formulações lipossomal e complexo lipídico, respectivamente. Por fim, sugere-se que, a qualidade de vida seja incorporada à presente análise farmacoeconômica, a fim de, avaliar mais profundamente as consequências dos eventos adversos, principalmente, nefrotoxicidade com tratamento dialítico, na vida dos pacientes. Palvras-chave: Anfotericina B. Nefrotoxicidade. Resivão-sistemática. Meta-análise. Custo-efetividade. / Abstract: Amphotericin B is a broad spectrum antifungal, used mainly, to treat invasive fungal infections (IFI). It's available in different formulations: conventional and lipid-based (liposomal, lipid complex and colloidal dispersion). Conventional formulation, in Brasil, costs one thousand more than the lipid-based ones, although, it also presents severe adverse events, like nephrotoxicity, an important adverse event which can lead patient to dialysis or even death. In this context, it's important to assess, though Healht Tecnology Assessment, the risks and benefits of these technologies, considering, as its efficacy, safety, tolerability, as the costs involved in the treatment and in the management of adverse events. Thus, the objectives of this study were: to value and to compare the evidences of efficacy, safety and tolerability of amphotericin B formulations, in patients with confirmed or suspect IFI; to conduct a survey of cost-effectiveness evidence on systemic antifungal used to treat or prevent IFI; and, to perform a cost-effectiveness analysis of amphotericin B formulations. First it was conducted the systematic review (SR) of randomized controlled trials (RCT), in the fallowing databases: Medline, Scielo, Scopus and Web of Science. Included studies had data on efficacy (cure), safety (adverse events) and tolerability (discontinuation) collected, for the statistical analysis conducted as meta-analysis in software Review Manager. In sequence it was done the systematic search of the pharmacoeconomic studies with patients with IFI, using the following databases: Medline, Scopus and Web of Science. Finally, the cost-effectiveness analysis was conducted. It was used the analytic-tree decision model performed using TreeAge software. The outcomes used to construct the model were: cure, death and nephrotoxicity with medical treatment or treatment with dialysis. It was considered, to perform this analysis, the perspective of the Brasilian Public Healht System, only direct medical costs and a time-horizon of three and six weeks, according to the drug leaflet. The first SR found 5682 RCT, which 25 fit the inclusion criteria (n=2.996). Main results show that the amphotericin B formulations presents similar efficacy profile, although they differ, statistically in safety. The lipid-based formulations presets less adverse events, such as: nephrotoxicity, fever, chills and vomiting. The SR about the pharmacoeconomic models, could show that there isn't, in the literature, a pharmacoeconomic evaluation among amphotericin B themselves. Lastly, the cost-effectiveness model showed that the conventional amphotericin B formulations is more cost-effective, followed by the liposomal and lipid complex formulations, respectively. Finally, we suggest that quality of life should be incorporated in this pharmacoeconomic analysis, in order to, assess, more deeply, the consequences of adverse events, mainly, nephrotoxicity, with consequent dialysis, in patient's life. Key-words: Amphoptericin B. Nephrotoxicity. Systematic-review. Meta-analysis. Cost-effectiveness.