Orientador: Jorge Vega / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-07-20T18:10:06Z (GMT). No. of bitstreams: 1 Baptista_CeliaRegina_M.pdf: 10046267 bytes, checksum: 9f4cdc2c74acd2b3cc7ebea8e3d6983b (MD5) Previous issue date: 1995 / Resumo: Com o objetivo de estudar o efeito quimioterápico de Virazole (1-ß-Dribofuranosil -1,2,4 - triazol-3 - carboxamida) in vitro sobre vírus de plantas, dois modelos de estudo foram realizados. No primeiro utilizou-se calos de videira Vitis vinifera, Seibel 2, infectados com o vírus do enrolamento da folha da videira (VEFV), e calos de fumo Nicotiana tabacum "TNN" e Gomphrena globosa L. infectados com o vírus do anel do pimentão (VAP). No segundo, foi utilizado um modelo aplicado, visando a obtenção de plantas de limoeiro Galego Citrus aurantifolia (Christm.) Swing) livres do vírus da tristeza dos citros "citrus tristeza virus" (CTV). Os objetivos específicos foram: 1) Testar o efeito do Virazole em calos cultivados in vitro, comparando: a) diferentes tipos de vírus (closterovirus e tobravirus) e b) efeito do. Virazole sobre um mesmo vírus em duas espécies de plantas hospedeiras. 2) Avaliar a possibilidade do uso de Virazole para obtenção de plantas cítricas livres do CTV por minienxertia realizada in vitro. Os resultados mostraram que o Virazole inibiu a multiplicação dos 3 vírus em estudo (VEFV, VAP e CTV), pertencentes a dois grupos distintos: closterovirus (VEFV e CTV) e tobravirus (V AP). A utilização de calos infectados com vírus e tratados com Virazole in vitro, mostrou ser um modelo de estudo eficiente para avaliar o efeito desse composto quimioterápico sobre vírus de planta. A indexação serológica; das amostras coletadas a cada subcultura dos calos permitiu acompanhar a evolução do conteúdo de vírus no decorrer de várias subculturas sucessivas. Os resultados mostraram de modo geral, que a quantidade de vírus presente varia muito pouco nas culturas de calos mantidas em ausência de Virazole. As concentrações mais baixas utilizadas não inibiram a multiplicação dos vírus, ao passo que concentrações mais altas do produto provocaram uma diminuição progressiva da concentração de vírus a cada subcultura até que as partículas virais não foram mais detectadas nos testes serológicos. O desenvolvimento da cultura foi afetado por concentrações altas de Virazole, sendo que algumas concentrações foram fitotóxicas, dependendo da planta e do tecido tratado. Em calos de videira infectados com VEFV o significativa a replicação do vírus. A inibição foi proporcional Virazole inibiu de maneira à concentração do produto utilizada. À 50 ppm não foram detectadas partículas virais nos testes serológicos. O Virazole atuou rapidamente em diminuir a concentração do VEFV à um nível baixo em calos em proliferação, porém, um longo período de incubação foi necessário para obter completa supressão dos vírus. Esses resultados são consistentes com a possibilidade de que a atividade antiviral do Virazole se manifesta por sua ação na síntese de novas partículas mais do que uma inativação direta dos vírus existentes. O Virazole foi capaz de inibir a multiplicação do V AP em calos de fumo, mas não em calos de G. globosa. Em fumo a concentração de 200 ppm eliminou os vírus presentes nos calos, enquanto que em calos de G. globosa o Virazole não foi efetivo em nenhuma das concentrações testadas. Possivelmente essas plantas apresentam vias metabólicas alternativas para a replicação do RNA viral ( e não aquela inibida pelo Virazole). A eficiência do Virazole em eliminar o V AP foi também dependente do estágio de desenvolvimento dos tecidos tratados. O Virazole inibiu a multiplicação de vírus quando pedaços de folhas foram utilizados como explantes, porém, ocorreu pouca ou nenhuma inibição quando células de calos não organizados foram tratadas com Virazole. O Virazole inibiu a multiplicação do CTV à concentração de 200 ppm. Essa inibição foi verificada pela ausência de sintomas específicos do vírus da tristeza nas plantas obtidas. As plantas cresceram tão bem quanto as plantas sadias. O Virazole não foi efetivo à 100 ppm. Nessa concentração o vírus provocou paralisação do crescimento das plantas e as folhas apresentaram sintomas de palidez das nervuras, específicos da doença. Esses resultados foram confirmados por ELISA e "Western-blot". Com bases nesses resultados, conclui-se que o Virazole é um quimioterápico eficiente para a obtenção de plantas livres de vírus, dependendo da espécie vegetal, do vírus envolvido e das condições de tratamento / Mestrado / Fisiologia Vegetal / Mestre em Ciências Biológicas

No description available.

Ribavirin, a synthetic nucleoside, was found to inhibit the replication of Rous sarcoma viruses (RSV) and subsequent cell transformation in chick embryo fibroblasts (CEF). It also blocked the transformation of normal rat kidney (NRK) cells infected with temperature-sensitive mutants of RSV. The action of Ribavirin was found to be reversible as removal of the drug from the NRK cells reversed the effects on cell transformation. Ribavirin appears to have a static effect on cell growth of both NRK and CEF cells. In addition, guanosine, xanthosine and inosine altered the effect of Ribavirin on cell growth.

published_or_final_version / abstract / toc / Medicine / Master / Doctor of Medicine

Thesis (D.P.H.)--University of Michigan.

Dissertation (D.P.H.)--University of Michigan.

The current treatment for hepatitis C virus (HCV) infection – combination therapy with pegylated interferon and ribavirin – elicits sustained responses in only ~50% of the patients treated. Greater cumulative exposure to ribavirin increases response to interferon-ribavirin combination therapy. A key limitation, however, is the toxic sideeffect of ribavirin, hemolytic anemia, which often necessitates a reduction of ribavirin dosage and compromises treatment response. Maximizing treatment response thus requires striking a balance between the antiviral and hemolytic activities of ribavirin. Current models of viral kinetics describe the enhancement of treatment response due to ribavirin. Ribavirin-induced anemia, however, remains poorly understood and precludes rational optimization of combination therapy. Here, we develop a new mathematical model of the population dynamics of erythrocytes that quantitatively describes ribavirin-induced anemia in HCV patients. Based on the assumption that ribavirin accumulation decreases erythrocyte lifespan in a dose-dependent manner, model predictions capture several independent experimental observations of the accumulation of ribavirin in erythrocytes and the resulting decline of hemoglobin in HCV patients undergoing combination therapy, estimate the reduced erythrocyte lifespan in patients and describe inter-patient variations in the severity of ribavirin-induced anemia. Further, model predictions estimate the threshold ribavirin exposure beyond which anemia becomes intolerable and suggest guidelines for the usage of growth hormones. A small fraction of the population (~30%) with polymorphisms in the ITPA gene shows protection from ribavirin-induced anemia. The optimum dosage of ribavirin that can be tolerated is then dependent on the ITPA polymorphisms. Coupled with a previous population pharmacokinetic study, our model yields a facile formula for estimating the optimum dosage given a patient’s weight, creatinine clearance, pretreatment hemoglobin levels, and ITPA polymorphism. The reduced lifespan we predict is in agreement with independent measurements from breath tests as well as estimates derived from in vitro studies of ATP depletion. The latter estimates also agree with the extent of ATP depletion due to ribavirin that we predict from a detailed analysis of the nucleoside metabolism in erythrocytes. Our model thus facilitates in conjunction with models of viral kinetics the rational identification of treatment protocols. Our formula for optimum dose presents an avenue for personalizing ribavirin dosage. By keeping anemia tolerable, the predicted optimal dosage may improve adherence, reduce the need for drug monitoring, and increase response rates.

alpha-Interferon (alpha IFN) ist derzeit die Grundlage jeder Behandlung der chronischen Hepatitis C. Zu den unerwünschten Effekten von alpha-IFN gehört die Entwicklung psychiatrischer Nebenwirkungen, die sich häufig als Depressivität äussern. Deren Häufigkeit, Schweregrad und Behandlungsbedarf wurden jedoch bisher nur unzureichend erforscht. 66 Patienten mit chronischer Hepatitis C wurden in einer Pilotstudie mit alpha-IFN als Monotherapie (3x3 MU/ Woche) oder in Kombination mit Ribavirin (1000-1200 mg/ Woche) behandelt. Sämtliche Patienten wurden vor, während und nach der Therapie hinsichtlich ihrer Depressivität beurteilt. Dies geschah sowohl im persönlichen Gespräch als auch mit Hilfe der Selbstbeurteilungsinstrumente ADS (Allgemeine Depressions Skala) und BDI (Beck Depressions Inventar). Die Ausgangsdepressivität der Hepatitispatienten entsprach dem gesunden Eichkollektiv. Im Gesamtdurchschnitt stieg die Depressivität innerhalb der ersten drei Behandlungsmonate um 5,15 (+/-8,94) Punkte auf der ADS und um 3,85 (+/-6,94) Punkte im BDI an. Weniger als ein Drittel der Patienten erlebte keine Zunahme der Depressivität. Patienten, die vor Therapiebeginn eine geringe Depressivität aufwiesen, beschrieben eine stärkere Zunahme depressiver Symptome als Patienten, die initial als depressiv beurteilt wurden. Letztere blieben während des Therapieverlaufs jedoch weiterhin depressiver als die anfangs nicht-depressiven Patienten. Vier Patienten wurden wegen schwerster depressiver Nebenwirkungen stationär psychiatrisch behandelt. Es wurde kein signifikanter Zusammenhang zwischen Ausgangsdepressivität und Behandlungserfolg festgestellt. Um stark gefährdete Patienten frühzeitig zu erkennen, wird vorgeschlagen, sowohl ADS als auch BDI vor und während der Therapie zu verwenden. Anhand eines ADS-Grenzwertes von > 17 vor und >= 30 während der Behandlung konnten 75% derjenigen Patienten, die im Verlauf der Therapie mit alpha-IFN schwerste depressive Symptome entwickelten, identifiziert werden. / Interferon-alpha (alpha-IFN) is presently the mainstay of the treatment of chronic hepatitis C. Side effects include a range of psychiatric symptoms, most frequently the development of depressive symptoms. Their incidence, severity and necessity for therapeutic intervention has not yet been sufficiently studied. 66 patients with chronic hepatitis C were enrolled in a pilot study and treated with either alpha-IFN alone (3x3 MU/ week) or in combination with Ribavirin (1000-1200 mg/ week). All patients went through repeated evaluations concerning their depressive symptoms before, during, and after treatment. Apart from individual interviews with the psychosomatic staff, the psychometric instruments used were the ADS (Allgemeine Depressions Skala, the German version of the Center for Epidemiological Studies Depression Scale, CES-D) and the BDI (Beck Depression Inventory). The initial depression score of the hepatitis C patients was comparable to that of a healthy population. On average, depression scores increased by 5,15 points (+/-8,94) on the ADS and 3,85 points (+/-6,94) on the BDI during the first 3 months of treatment. Less than a third of all patients did not show an increase of depressive symptoms. Patients with an initially low depression score experienced a greater increase of depressive symptoms than patients initially diagnosed as depressive. Nevertheless, the latter patients remained more depressive throughout the study period. Four patients developed severe depressions that necessitated admission to a psychiatric clinic. There was no significant correlation between the initial depression score and the treatment response. In order to recognize those patients at high risk for the development of severe depressions at an early stage, the author proposes the use of ADS and BDI both before and during treatment with alpha-IFN. Using a cut-off score of more than 17 points on the ADS before, and >=30 points during treatment, 75% of all patients developing severe depressions during treatment with alpha-IFN could be identified.

Background: Injecting drug users (IDUs) represent considerable group of patients infected with hepatitis C virus (HCV). HCV treatment is an effective tool for reduction of HCV transmissions among IDUs. Nevertheless treatment rate among IDUs is rather insufficient. Treatment uptake, provision and adherence as well as its efficacy in IDUs are determined by number of specific factors. Aims: Mapping an extent of the provision of HCV treatment to IDUs in the Czech Republic, rules and practices for the admission of IDUs into HCV treatment and its provision, describing relevant factors related to drug use. Material and methods: From January to March 2011, a questionnaire survey among centres for treatment of viral hepatitis in the Czech Republic was conducted. 76 identified centres were addressed, of which 45 (59%) responded, and 40 (53%) filled in an online questionnaire. Results: Estimated number of centres treated HCV with combination of pegylated interferon α and ribavirin in the Czech Republic in 2010 was 61, 39 of them treated IDUs. Estimated 780 persons were treated, of whom 370 were (mostly ex-) IDUs. Reported treatment uptake in IDUs was 60% on average (range 0-90%). Treatment is completed by 80% of IDUs on average (0-100%) according to clinicians. Most clinicians reported no difference in the treatment...

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