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2008_AdrianaAlvesSa.pdf: 2683586 bytes, checksum: 23691b0c8f572a55cb6c82469e6b0425 (MD5) / O tratamento das infecções pelo Trypanosoma cruzi tem sido alvo de muitas
investigações porque a busca da cura da doença de Chaga tem alta relevância
social. Este trabalho teve como objetivo geral avaliar diferentes esquemas
terapêuticos na doença de Chagas experimental. Seus objetivos específicos visaram
a comparar aspectos clínicos, parasitológicos e sobrevivência nos grupos
experimentais e controles, para avaliação do efeito de diferentes esquemas
terapêuticos de tratamento e doses dos fármacos utilizados. Esses parâmetros
foram usados como critério de avaliação dos esquemas de tratamento com drogas
inibidoras de vias metabólicas, envolvidas em divisão e diferenciação celulares, que
poderiam impedir a integração do kDNA do T. cruzi no genoma do hospedeiro.
Grupos de 20 camundongos BALB/c infectados com Trypanosoma cruzi do estoque
Berenice, pesando 20 a 25 g, de ambos os sexos, foram tratados com benzonidazol,
nas fases aguda e crônica da infecção. Formaram-se novos grupos também com 20
animais, que receberam benzonidazol, associados com uma, duas ou três drogas.
As drogas utilizadas foram praziquantel (inibidor de proteína-quinase), ciprofloxacina
(inibidor de topoisomerase) e zidovudina (inibidor da transcriptase reversa). Foi
previamente demonstrado que essas drogas inibem a integração do kDNA no
genoma de célula hospedeira de mamífero in vitro. De acordo com os parâmetros de
avaliação, apenas o grupo de animais tratados na fase crônica da infecção com
benzonidazol associado à ciprofloxacina durante 30 dias teve a parasitemia
negativada, com decréscimo significativo dos títulos de anticorpos e ausência de
amplificação de seqüências de kDNA. O achado sugeriu que o tratamento eliminou a
infecção e preveniu as mutações no genoma do hospedeiro. Nos demais grupos
experimentais os resultados foram similares àqueles obtidos nos grupos tratados
apenas com benzonidazol, pois, não houve negativação das parasitemias e o kDNA
podia ser encontrado no genoma dos camundongos testados. Assim somente a
associação de benzonidazol com ciprofloxacina na concentração ótima testada,
sugeriu a eliminação da infecção, e o kDNA não integrou no genoma dos
camundongos. Nos demais grupos experimentais analisados os resultados obtidos,
sugerem que as drogas administradas não eliminaram as infecções pelo T. cruzi. / The treatment of the T. cruzi infections has been sought by many investigators because
the cure of Chagas disease has high social and economic importance. This work aimed at the
use of various therapeutic formulations to treat the experimental Chagas disease in mice.
Specifically, it was aimed at the clinical, parasitological and survival aspects related to the T.
cruzi infections in experimental and control groups of BALB/c mice. Secondly, this work
aimed at to evaluate therapeutic protocols, using different pharmacological compounds. The
parameters used to evaluate the therapeutic protocol were the elimination of the parasitic
infections and abrogation of the integration of the T. cruzi kDNA minicircle sequences by the
administration of inhibitors of metabolic pathways of cell growth and differentiation. Groups
of 20 mice of both sexes, weighing 20 to 25 g, received the T. cruzi intraperitoneally and were
treated in the acute and chronic phases of the infections. The experimental groups received
benznidazole (0.86 mg/day) alone or in association with one, two or three different inhibitors.
The inhibitors used were: praziquantel (inhibitor of protein-kinases, 0.93 mg/day),
ciprofloxacin (inhibitor of Topoisomerase II, (1.2 mg/day), and zidovudine (inhibitor of
reverse transcriptase, 1.2 mg/day). In a previous study, it was shown that these inhibitors
prevent the integration of kDNA minicircle sequences into the host mammalian cell in vitro.
The drugs were administered by gavage of mice for a period of 15, 30 or 60 days. Following
the parameters set for evaluating the effects of each therapeutic regime, only a group of
chronically infected mice treated with benznidazole and ciprofloxacin for 30 days eliminated
the parasitemia, and showed consistent fall of the specific anti-T. cruzi antibody titers, and
abrogated the integration of the kDNA into the mouse genome. This finding has suggested
that this therapeutic regime was indeed efficient because it abrogated the infection, the
specific antibody titers and the kDNA integrations. However, when half-dose benznidazol and
ciprofloxacin were used the mice the infections sere set free. Also in all the other
experimental groups the results obtained indicated therapeutic failure, because the results
were similar to those obtained with benznidazole alone: the parasitemias were patent and the
kDNA was recovered from infected-treated animals. In summary, the administration of
benznidazole combined with ciprofloxacin to T. cruzi-infected mice eliminated the infection
and kDNA did not integrate into the mouse genome. In relationship to the remaining infectedand
treated groups it was observed therapeutic regimes did not eliminate the infections.
| Identifer | oai:union.ndltd.org:IBICT/oai:repositorio.unb.br:10482/1466 |
| Date | January 2008 |
| Creators | Sá, Adriana Alves de |
| Contributors | Teixeira, Antônio Raimundo Lima Cruz |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/masterThesis |
| Source | reponame:Repositório Institucional da UnB, instname:Universidade de Brasília, instacron:UNB |
| Rights | info:eu-repo/semantics/openAccess |
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