Made available in DSpace on 2016-04-28T20:16:22Z (GMT). No. of bitstreams: 1 2007- Luciana Rodrigues de Almeida.pdf: 1825503 bytes, checksum: 9ab5871c2a5cc80a95e08f1046a2745c (MD5) Previous issue date: 2007-02-26 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / With the aim to study the therapeutic and prophylactic effects of homeopathic medicines were employed acute and chronic infection models: experimental infection of mice by Trypanosoma evansi and by Trypanosoma cruzi, respectively, as a mice immunization model with T. evansi extract aiming evaluate the homeopathic biotherapic immunomodulatory effects. It were employed the homeopathic medicines: T. evansi biotherapic on T. evansi infection model and immunization, T. cruzi biotherapic and Phosphorus on T. cruzi infection model. Adult male C57BL/6 inbred mice had been divided in experimental groups: Treated with biotherapic before experimental infection and immunization (Bbi); treated with biotherapic post-infection and immunization (Bpi); treated with Phosphorus post T. cruzi infection (Phosphorus); treated with physiologic serum before and post-infection and immunization (Control) and control group not infected. The biotherapics were made from blood of T. evansi and T. cruzi experimentally infected mice. Phosphorus was proposed by correlation between clinical and repertorial images of T. cruzi infection, considering the diathesis of Chaga s Disease. Both were used at 12 DH (Hering s decimal) potency. After infection, mice were monitored at two days intervals, to determine the parasitaemia and infectivity and virulence parasite s parameters. Hematological evaluations were also realized as a serology to IgM and IgG search. In according with the obtained results, it were not observed therapeutic or prophylactic effects due to biotherapic on T. evansi infected mice, that may be attributed to the high virulence and hyper acute course of infection characteristic of this experimental model. The results obtained when mice were treated with biotherapic before and after immunization with T. evansi extract suggests immunomodulatory effect, since it were observed highest lymphocytic response at Bbi (p<0,05), as highest IgG titers at Bpi (p<0,05), when comparated to the control group. On T. cruzi infected mice a significant lower patence period was observed in Bai group (p<0,05), as well a lower rate of mortality, lowest parasitaemias values at 9, 13, 15 (p<0,05), 17 (p<0,05), 22, 24 and 28 days post infection, and a significant growing of lymphocytes (p<0,05) and neutrophils (p<0,05) along the course of infection, regarding Control group. Phosphorus showed longest patent period, higher maximum of parasitaemia value (p<0,05), in relation to Bai and Control group, nevertheless, with 0% of mortality. The histopathological study showed at Bbi less intense inflammatory lesions, being the more intense lesions observed at Phosphorus and Control group, which showed cronification characteristics of inflammatory process. The results indicate immunomodulatory effects of biotherapics, as an effect of Phosphorus on the patogenicity of infection, and should be better investigated. / Com o objetivo de estudar efeitos terap?uticos e profil?ticos de medicamentos homeop?ticos foram empregados modelos de infec??o aguda e cr?nica: infec??o experimental de camundongos por Trypanosoma evansi e por Trypanosoma cruzi, respectivamente, assim como foi, tamb?m, empregado modelo de imuniza??o de camundongos com extrato de T. evansi, objetivando avaliar efeitos imunomodulat?rios de bioter?pico homeop?tico. Foram empregados os medicamentos homeop?ticos: bioter?pico de Trypanosoma evansi no modelo de infec??o por T. evansi e imuniza??o; bioter?pico de Trypanosoma cruzi e Phosphorus na infec??o por T. cruzi. Para tal, camundongos machos adultos da linhagem C57BL/6 foram divididos em grupos experimentais: tratado com bioter?pico antes da infec??o experimental e imuniza??o (Bai); tratado com bioter?pico ap?s infec??o e imuniza??o (Bpi); tratado com Phosphorus ap?s infec??o por T. cruzi (Phosphorus); tratado com soro fisiol?gico antes e ap?s infec??o e imuniza??o (Controle ) e grupo controle n?o infectado (s/ infec.). Os bioter?picos foram preparados a partir do sangue de camundongos experimentalmente infectados por T. evansi e por T. cruzi. O medicamento Phosphorus foi proposto atrav?s da correla??o entre as imagens cl?nicas e repertorial da infec??o por T. cruzi, considerando-se as caracter?sticas diat?sicas da Doen?a de Chagas. Ambos foram empregados na 12? dinamiza??o decimal Hering (12DH). Ap?s infec??o experimental, os animais foram monitorados a cada dois dias para determina??o da parasitemia e de par?metros relacionados ? infectividade e ? virul?ncia da parasita. Foram tamb?m realizadas avalia??es hematol?gicas e sorologia para pesquisa de anticorpos IgM e IgG ap?s-infec??o e imuniza??o. De acordo com os resultados obtidos, n?o foram observados efeitos profil?ticos e/ou terap?uticos decorrentes da administra??o de bioter?pico homeop?tico em camundongos infectados por T. evansi, o que pode ser atribu?do ? elevada virul?ncia e curso hiper agudo caracter?stico deste modelo experimental. Os resultados decorrentes do tratamento com bioter?pico antes e ap?s imuniza??o de camundongos com extrato de T. evansi sugerem efeito imunomodulador, sendo observada resposta linfoc?tica mais precoce e intensa em Bai (p<0,05), assim como maiores t?tulos de IgG em Bpi (p<0,05) em rela??o ao controle. Em camundongos infectados por T. cruzi, observou-se em Bai menor per?odo de pat?ncia (p<0,05), menor percentual de mortalidade e menores valores parasit?micos nos dias 09, 13, 15 (p<0,05), 17(p<0,05), 22, 24 e 28 dias p?s- infec??o, em rela??o ao Controle, al?m de aumento significativo no n?mero de linf?citos (p<0,05) e neutr?filos (p<0,05) ao longo do curso da infec??o. O grupo Phosphorus apresentou maior per?odo de pat?ncia e maior valor de parasitemia m?xima (p<0,05), quando comparados ao Bai e ao Controle, entretanto, registrou-se 0% de mortalidade neste grupo durante o per?odo avaliado. O estudo histopatol?gico revela que o grupo Bai apresentou, em geral, les?es inflamat?rias teciduais menos intensas, sendo as les?es mais intensas observadas em Phosphorus e Controle, o qual apresentou caracter?sticas de cronifica??o do processo inflamat?rio. Os resultados obtidos indicam efeitos imunomoduladores associados ? administra??o de bioter?picos, assim como efeitos do medicamento Phosphorus sobre a patogenia da infec??o por T. cruzi, devendo, assim, ser melhor investigados.

Les maladies tropicales négligées causées par les protozoaires kinétoplastidés du genre Leishmania et Trypanosoma représentent une menace pour près d’un demi-milliard de personnes en zone intertropicale, entrainant jusqu’à 50 000 décès par an. Parmi les molécules en développement clinique pour traiter ces pathologies, le fexinidazole est une prodrogue appartenant à la famille des 5-nitroimidazoles et qui exerce son action anti-infectieuse via une étape de bioactivation catalysée par des nitroréductases (NTR) parasitaires, enzymes dont le co-facteur est une flavine. Afin d’identifier de nouveaux nitrohétérocycles antiparasitaires substrats des NTR, une petite chimiothèque d’imidazo[1,2-a]pyridines synthétisées au laboratoire a subi un criblage in vitro ayant conduit à l’identification d’une molécule Hit, à la fois active sur Leishmania donovani et Trypanosoma brucei brucei. Ce composé a servi de point de départ à un travail de pharmacomodulation, dans un premier temps en position 8 du cycle imidazo[1,2-a]pyridine : l’introduction de groupements variés à l’aide de réactions de couplage pallado-catalysées de Suzuki-Miyaura, Sonogashira et Buchwald-Hartwig ou des réactions de SNAr, a permis de mettre en lumière plusieurs composés « tête de série » au profil biologique nettement amélioré. Dans un second temps, le travail de pharmacomodulation entrepris a été étendu aux positions 2, 3 et 6 du cycle imidazo[1,2-a]pyridine en vue de compléter les données de relations structure-activité, d’étudier en particulier l’impact du potentiel rédox et d’optimiser les paramètres physico-chimiques et pharmacocinétiques in vitro des meilleurs composés. / The kinetoplastids of the Leishmania and Trypanosoma genus are the causative agents of neglected tropical diseases that threaten nearly half a billion people in the intertropical zone, resulting in 50 000 deaths per year. Among the molecules in clinical development to treat these pathologies, fexinidazole is a prodrug belonging to the 5-nitroimidazoles family, which exerts its anti-infectious action via a bioactivation step catalyzed by parasitic nitroreductases (NTR), enzymes whose cofactor is a flavin. In order to identify novel nitroheterocycles as parasitic NTR substrates, a small chemical library of imidazo[1,2-a]pyridines synthesized by our laboratory was screened in vitro, leading to the identification of a Hit molecule active both on Leishmania donovani and Trypanosoma brucei brucei. This compound served as a starting point for a pharmacomodulation work, initially in position 8 of the imidazo[1,2-a]pyridine ring: the introduction of various chemical groups using the pallado-catalyzed coupling reactions of Suzuki-Miyaura, Sonogashira and Buchwald-Hartwig, or SNAr reactions, highlighted several "lead" compounds with a significantly improved biological profile. In a second step, the pharmacomodulation work was extended to positions 2, 3 and 6 of the imidazo[1,2-a]pyridine ring in order to complete the structure-activity relationship data, to study in particular the impact of the redox potential and to optimize the physicochemical and in vitro pharmacokinetic parameters of the best compounds in order to initiate the study of their in vivo activity on a trypanosomiasis mouse model.