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Efeitos de Medicamentos Homeop?ticos e Bioter?picos em Camundongos Experimentalmente Infectados por Trypanosoma evansi (STEEL, 1885) BALBIANI, 1988 e Trypanosoma cruzi CHAGAS, 1909 / Effects of homeopathic medecine s and biotherapics on Trypanosoma evansi (STEEL, 1885) BALBIANI, 1988 and Trypanosoma cruzi experimentally infected mice CHAGAS, 1909Almeida, Luciana Rodrigues de 26 February 2007 (has links)
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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.
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Synthèse et étude des relations structure-activité de nouvelles 3-nitroimidazo (1,2-a) pyridines anti-kinétoplastidés / Synthesis and structure-activity relationships study of new anti-kinetoplastid 3-nitroimidazo[1,2-a]pyridinesFersing, Cyril 11 July 2018 (has links)
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.
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