Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-04-03T13:51:17Z No. of bitstreams: 1 elisabethcamposdeandrade.pdf: 1614173 bytes, checksum: 02bbfb073bbecc90f3e7f67d2c386c90 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-04-03T19:01:36Z (GMT) No. of bitstreams: 1 elisabethcamposdeandrade.pdf: 1614173 bytes, checksum: 02bbfb073bbecc90f3e7f67d2c386c90 (MD5) / Made available in DSpace on 2017-04-03T19:01:36Z (GMT). No. of bitstreams: 1 elisabethcamposdeandrade.pdf: 1614173 bytes, checksum: 02bbfb073bbecc90f3e7f67d2c386c90 (MD5) Previous issue date: 2009-03-26 / FAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais / As parasitoses intestinais são um importante problema de saúde pública principalmente nos países subdesenvolvidos ou em desenvolvimento. Embora o parasitismo intestinal seja amplamente reconhecido como relevante no contexto epidemiológico de diversas comunidades, os estudos sobre o assunto são ainda insuficientes, principalmente no Brasil. Em vista da dificuldade de diagnóstico específico das parasitoses, muitas vezes são realizados tratamentos empíricos com mais de uma droga. O objetivo principal do presente estudo foi avaliar a efetividade e segurança do uso de nitazoxanida no tratamento de poliparasitoses comparado à terapêutica tradicional ofertada pelo serviço público. Além deste objetivo, foi possível investigar a prevalência e os fatores associados às parasitoses intestinais na população de Colônia do Paiol, uma comunidade quilombola, na Zona da Mata, Minas Gerais. Na comunidade analisada, procedeuse um estudo transversal por censo, sendo que dos 425 moradores, 391 (92%) foram avaliados através de questionário estruturado e exame coproparasitológico. Os resultados mostraram uma alta positividade (63,8%), sendo as espécies patogênicas mais freqüentes Ascaris lumbricoides (22,4%) e Trichuris trichiura (17,9%). O poliparasitismo ocorreu em 36,5% dos investigados. O ensaio clínico, controlado, duplo cego, randomizado avaliou 65 indivíduos em dois grupos de tratamento. A taxa de cura foi de 32,4% e 38,7% com a nitazoxanida e com o tratamento convencional, respectivamente, mas esta diferença não foi estatisticamente significativa (p=0,599). A ocorrência de vômito (p= 0,031) esteve associada ao tratamento convencional e de urina esverdeada ao uso de nitazoxanida (p=0,002). Os outros efeitos adversos foram independentes da droga. Houve diferença estatisticamente significativa em relação à cor da pele e a taxa de cura para ambos os tratamentos. A menor eficácia efetividade foi apresentada pelos indivíduos de cor preta. São necessários outros estudos para esclarecer a baixa efetividade nos casos de poliparasitismo, assim como, reavaliar as práticas preventivas e terapêuticas, com o uso de novas drogas e de agentes de largo espectro, podendo a nitazoxanida ser uma droga alternativa neste contexto. Agrega-se às novas possibilidades terapêuticas, a necessidade de políticas públicas que garantam qualidade de vida, através de saneamento básico, educação para saúde e acesso ao sistema público de saúde, minimizando as iniqüidades na sociedade. / Intestinal parasitism is an important public health concern, chiefly in underdeveloped or developing countries. Although widely recognized as a relevant community epidemiological issue, intestinal parasitism has not been sufficiently studied in Brazil. Because specific diagnosis is difficult and generally cumbersome, empiric treatment, sometimes with more than one drug, is frequently employed. The main aim of this study was the assessment of the effectiveness and safety of nitazoxanide for the treatment of intestinal polyparasitism, as compared to traditional therapy provided by the public service. The study also investigated the prevalence of and factors associated with intestinal parasitism in the population of Colônia do Paiol, a quilombola community from the Zona da Mata, Minas Gerais, Brazil. A census-based cross-sectional study used a structured questionnaire and stool examination to assess 391 people (92%) of the 425 inhabitants of the community. The frequency of intestinal parasitism was as high as 63.8%, with predominance of Ascaris lumbricoides (22.4%) and Trichuris trichiura (17.9%). Polyparasitism occurred in 36.5% of those investigated. A double-blind randomized controlled trial assessed 65 individuals in two treatment groups. Cure rates were 32.4% and 38.7% with nitazoxanide and conventional treatment, respectively, but the difference was not statistically significant (p = 0.599). Vomiting (p = 0.031) was associated with conventional treatment and greenish urine with nitazoxanide use (p = 0.002). Other untoward effects were independent of which drug was used. There was a statistically significant difference concerning skin color and cure rates for both treatments. Dark-skinned subjects had lower cure rates. Further studies are necessary to clarify the reasons for the low effectiveness found in these cases of polyparasitism, and to reevaluate preventive and therapeutic approaches with new and broad-spectrum drugs, nitazoxanide being an option in this context. In addition to new therapeutic approaches, there is a clear need to develop public policies that, through the provision of basic sanitation, health education and access to the public health system, assure quality of life and minimize inequity.

Healthy, natural pastures is very valuable for biodiversity in the form of both plants and animals. An efficient use of pastures helps to preserve biodiversity, but grazing animals needs to be de-wormed to keep them healthy and to prevent harmful parasites spread on the pasture. The awareness about the environmental impact of the frequent use of deworming agents is low among the public. Some people are unaware that the absorption in horses of anthelmintics is incomplete, which make the circumstances about enviromental effect important to investigate further. The scientific evidence in this area is limited and more studies and trials are needed to deepen the knowledge about the effects of anthelmintics in the environment. Our report includes a compilation of studies conducted on anthelmintics and equine parasites, as well as an experiment which was conducted at the University of Halmstad biogaslaboratory April 2014. Anthelmintics have been shown to have negative impact on the manure ecosystem and especially against manure living fauna. Deworming routines has changed over the years as the equine industry has developed. Nevertheless, there’s still a lack of concrete approach to deworming.

Les lactones macrocycliques (LM) sont des anthelminthiques (AH) à effet paralysant très utilisés chez les animaux et les humains contre les nématodes parasites. Cependant, leur succès thérapeutique est compromis par la résistance croissante aux LM, qui pourrait être en partie dû aux ABC transporteurs P-glycoprotéines (Pgps) sélectionnés et surexprimés chez les nématodes résistants aux LM. Dans ce travail, nous avons étudié plus précisément la P-glycoprotéine 13 du parasite de petits ruminants, Haemonchus contortus. Son orthologue chez le modèle nématode C. elegans, Cel-Pgp-13, est exprimé dans les amphides, structures qui ont été associées à la sensibilité aux AH chez C. elegans et H. contortus. Pour prédire la capacité des Pgps de nematode à transporter des drogues, incluant des LM et autres AH, nous avons développé un modèle de docking in silico. Nous avons utilisé la structure cristallographique de C. elegans Pgp-1 (Cel-Pgp-1), et nous avons montré la liaison avec une forte affinité de plusieurs ligands décrits comme activateurs de sa fonction ATPasique. Nous avons aussi décrit une forte affinité des LM, et un site spécifique de liaison de ces composés à Cel-Pgp-1. Cette approche représente un outil important pour prédire les interactions entre AH, et pour concevoir rationnellement de nouveaux inhibiteurs compétitifs des Pgps de nématode, dans le but d'améliorer les stratégies thérapeutiques. Sur la base de cette approche, nous avons prédit la structure 3D de Hco-Pgp-13 à partir du cristal de Cel-Pgp-1 afin d'étudier son intéraction avec des substrats potentiels, en particulier les LM. Nous avons trouvé des affinités similaires pour différents composés précédemment testés sur Cel-Pgp-1. In vitro, la mesure de l'activité ATPasique montre que l'actinomycine D est un substrat de Hco-Pgp-13. Nos données démontrent la présence possible d'un domaine de reconnaissance multispécifique sur ce transporteur de parasite. La détermination par immunofluorescence de l'expression de Hco-Pgp-13 a montré une distribution tissulaire large indiquant que Hco-Pgp-13 pourrait jouer un role important dans le transport de substrats endogènes et/ou exogènes. En conclusion, ce travail permet de mieux comprendre le rôle des Pgps de nématodes dans le transport de médicaments AH, tant au niveau de l'organisme modèle C. elegans que du nématode parasite H. contortus. Cette étude suggère la conservation de la fonction de tranporteur ABC multidrogue dans ces espèces. La localisation de Hco-Pgp-13 sur les structures amphidiales, et son éventuelle implication dans la résistance aux médicaments et à la survie de H. contortus à l'exposition à des composés AH, restent à préciser. / Macrocyclic lactones (ML) are paralyzing anthelmintics used in animals and humans against parasite nematodes. However, their therapeutic success is compromised by the spread of ML resistance. This might be at least partly due to P-glycoproteins (Pgps) ABC transporters that are selected and overexpressed in ML-resistant nematodes. Deciphering the role of the 10 Pgps expressed in the parasite of small ruminants Haemonchus contortus is thus of major importance to guaranty anthelmintic (AH) efficacy of various drugs. Here we focused on Hco-Pgp-13 due to the expression in the amphids of its closest ortholog in the model nematode C. elegans. Indeed, the amphids represent a putative entry route of drugs to reach AH targets in the nervous system and have been linked to AH susceptibility in C. elegans and H. contortus. In order to predict the capacity of nematode Pgps to transport drugs, including ML and otherAH, we have developed an in silico drug docking model. We have used C. elegans Pgp-1 (Cel-Pgp-1) crystal structure and have showed a high affinity binding of several ligands that have been shown to be activators of its ATPase function. ML were also found to bind with high affinity to Cel-Pgp-1, on a specific binding site. This approach provides a valuable tool to predict drug-drug interactions and to rationally design new competitive inhibitors of nematode Pgps, in order to improve anthelmintic therapeutics. We then predicted a putative 3D structure of Hco-Pgp-13 based on the recently released crystal of Cel-Pgp-1, with which it presented a high homology. This allowed the study of the interaction of Hco-Pgp-13 with potential substrates, in particular ML. We found similar affinities for various drugs previously tested on Cel-Pgp-1, supporting the good homology of these two proteins. Together with in vitro ATPase assay experiments that confirmed the substrate status of actinomycin D, this indicates a possible multispecifc recognition capacity of this parasitic transporter. The determination of Hco-Pgp-13 localization using immunohistochemistry showed a wide tissue expression consistent with a critical role for Hco-Pgp-13 in endogenous and/or exogenous substrate transport. In conclusion, this work provides insights into the role of nematode Pgps in transporting AH drugs, both at the level of the model organism C. elegans and of the parasitic nematode H. contortus. This suggests a high homology of function conserved between ABC tranporters in these species. The localization of such protein on amphidial structures and its possible involvement in drug resistance and survival of H. contortus to exposure to AH compounds remain to be precised.