Submitted by Jorge Silva (jorgelmsilva@ufrrj.br) on 2017-06-26T18:12:15Z No. of bitstreams: 1 2016 - Fabr?cia Ferreira e Ferreira.pdf: 1846980 bytes, checksum: c127e17162c67e64b719801f92b0c6fc (MD5) / Made available in DSpace on 2017-06-26T18:12:15Z (GMT). No. of bitstreams: 1 2016 - Fabr?cia Ferreira e Ferreira.pdf: 1846980 bytes, checksum: c127e17162c67e64b719801f92b0c6fc (MD5) Previous issue date: 2016-03-23 / Canine demodicosis is an inflammatory skin disease, frequently diagnosed in veterinary clinics, caused by the proliferation of mites of the species Demodex sp. In recent years, important findings about the disease have been reported, mainly aspects related to treatment, with the insertion of new molecules or new treatment regimens. Doramectin is a macrocyclic lactone that has been used empirically by veterinarians, who use different routes, doses and intervals in its administration, with no homogeneus results. This study aimed to evaluate the use of doramectin in the treatment of dogs affected by the generalized form of demodicosis. Of the forty-six dogs diagnosed with the disease during the study, 20 were selected for the study and divided into three groups: Group I ? treated with doramectin at a dose of 600 mcg/kg once a week orally, group II ? treated at a dose of 300 mcg/kg orally every 3 days and group III ? treated at a dose of 600 mcg/kg every 7 days subcutaneously. The animals were treated until three consecutive negative skin scrapings were obtained, with intervals of at least fifteen days between them (parasitological cure). The days required to obtain the parasitological cure were 105, 82 and 100 according to the indicated groups; and their treatment efficiencies were 75, 100 and 83%, respectively. Doramectin was effective in treating generalized demodectic mange in dogs, regardless of the dose, route and interval of administration. However, the best results were obtained in the group treated at a dose of 300 mcg/kg orally every 3 days. There were no reported adverse reactions with the use of macrocyclic lactone. / Demodiciose canina ? uma doen?a inflamat?ria da pele, frequentemente diagnosticada nos consult?rios veterin?rios, causada pela prolifera??o de ?caros da esp?cie Demodex sp. Nos ?ltimos anos, importantes descobertas sobre a doen?a foram reportadas, principalmente os aspectos relacionados ao tratamento, com a inser??o de novas mol?culas ou novos esquemas de tratamento. A doramectina ? uma lactona macroc?clica que vem sendo usada de forma emp?rica por m?dicos veterin?rios, que a utilizam por diferentes vias, doses e intervalos na sua administra??o, com resultados heterog?neos. O objetivo do estudo foi avaliar a utiliza??o da doramectina no tratamento da demodiciose generalizada em c?es. Dos 46 animais diagnosticados com a doen?a, 20 foram selecionados e divididos em tr?s grupos experimentais: grupo I ? tratado com doramectina dose de 600 mcg/kg semanalmente por via oral, grupo II ? tratado na dose de 300 mcg/ kg por via oral a cada 3 dias e o grupo III ? tratado na dose de 600 mcg/kg a cada 7 dias por via subcut?nea. Os animais foram tratados at? a obten??o de tr?s raspados negativos consecutivos com pelo menos 15 dias de intervalo entre eles (cura parasitol?gica). Os dias necess?rios para obten??o da cura parasitol?gica foram 105, 82 e 100 de acordo com os grupos assinalados e as respectivas efic?cias ao tratamento foram 75, 100 e 83%. A doramectina demonstrou ser eficaz no tratamento da demodiciose generalizada em c?es independente da dose, via e intervalo de sua administra??o. Entretanto, os melhores resultados obtidos foram observados no grupo tratado com a dose de 300 mcg/ kg por via oral a cada 3 dias. N?o foram reportadas quaisquer rea??es adversas com a utiliza??o da lactona macroc?clica.

Les infections par les nématodes gastro-intestinaux entrainent des baisses en productions animales et des pertes économiques majeures pour les éleveurs. Les lactones macrocycliques (LMs) sont parmi les antiparasitaires les plus utilisés dans la lutte contre les nématodes gastro-intestinaux en médecine vétérinaire. De part une utilisation intensive, des résistances aux LMs chez les parasites gastro-intestinaux se sont développées au sein des élevages du monde entier mettant en péril l'efficacité thérapeutique de ces molécules. Par ailleurs, le développement de nouveaux antiparasitaires est limité. Ainsi, un des enjeux pour assurer le contrôle de ces parasites est de ralentir les phénomènes de résistance aux LMs afin de prolonger leur efficacité. Le succès d'une telle stratégie repose sur les connaissances précises des mécanismes impliqués dans la résistance. Parmi eux, la modulation des systèmes de détoxification est décrite lors de phénomènes de résistance aux LMs. Au cours de ces travaux, nous avons étudiés la régulation des systèmes de détoxification, en réponse à l'ivermectine chez l'hôte. Nous avons montré, en comparaison à une administration unique, qu'une administration répétée d'ivermectine par voie orale chez la souris est responsable de l'induction de l'expression de certains gènes transporteurs ABC et cytochromes impliqués dans son métabolisme. Ceci entraîne, à la fois, une diminution de la concentration de la molécule parentale et une augmentation de la teneur de son métabolite principal dans le plasma et l'intestin. Ensuite, nous avons étudié l'implication des mécanismes de régulation des systèmes de détoxification, et notamment les récepteurs nucléaires, dans la tolérance à l'ivermectine chez le nématode C.elegans. Nous avons montré que le récepteur nucléaire nhr-a est important pour la tolérance et le développement de la résistance à l'ivermectine. Enfin, nous avons étudié l'impact d'inhibiteurs des transporteurs ABC sur l'efficacité de l'ivermectine. Nous avons mis en évidence la capacité de certains flavonoïdes et de l'ivermectine aglycone à potentialiser l'efficacité de l'ivermectine chez le nématode. Une exposition d'ivermectine induit la surexpression des systèmes de détoxification chez l'hôte. Ceci pourrait être la base des mécanismes moléculaires de la résistance chez le nématode. Cibler les systèmes de détoxification ou les mécanismes de résistance, par des inhibiteurs adaptés, représente une stratégie pertinente pour potentialiser l'efficacité de l'ivermectine. / Infections with gastrointestinal nematodes (GINs) in livestock leads to major losses in production and consequently impact economically farmers. Their intensive use has led to widespread anthelmintic resistance which is nowadays the main threat on the sustainable control of GINs in livestock. The development of new anthelmintic is limited due to the cost of such process. Then, the challenge remains in optimizing the use of existing molecules. Therefore, it is urgent to limit and control MLs resistance in order to extend their efficacy and to avoid therapeutic failure. Resistance mechanisms remain to be elucidated. In that context, we investigated regulatory mechanism of detoxification systems of ivermectin implicated in therapeutic efficacy in host and resistance development in nematode. Therapeutic combinations of ivermectin with flavonoïds have been evaluated to potentiate its efficacy in nematode. We showed that repeated oral administration of ivermectin induced gene expression encoding some ABC efflux transporters and cytochromes involved in its metabolism. Compared with single administration, repeated ivermectin administration lowered plasma, liver and intestine drug concentration, while increasing main metabolite content in plasma and intestine. We have also shown that nuclear receptor nhr-a was important for ivermectin tolerance and ivermectin development of resistance in C. elegans. Finally, we demonstrated the ability of the flavonoïd phloretin to potentiate ivermectin efficacy in the nematode C. elegans. Taken together, these data suggest that induction of detoxification systems impact on ivermectin distribution and targeting their regulation could be an appropriate strategy to potentiate ivermectin efficacy in host and to reverse resistance in nematode.