Screening the Pathogen Box for Identification of New Chemical Agents with Anti-Fasciola hepatica Activity

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ABSTRACT

Fascioliasis is an infectious parasitic disease distributed globally and caused by the liver fluke Fasciola hepatica or F. gigantica. This neglected tropical disease affects both animals and humans, and it represents a latent public health problem due to the significant economic losses related to its effects on animal husbandry. For decades, triclabendazole has been the unique anti- Fasciola drug that can effectively treat this disease. However, triclabendazole resistance in fascioliasis has more recently been reported around the world, and thus, the discovery of novel drugs is an urgent need. The aim of this study was to investigate the fasciocidal properties of 400 compounds contained in the Pathogen Box. The first stage of the screening was carried out by measuring the fasciocidal activity on metacercariae at a concentration of 33 μM each compound (the standard dose). Subsequently, the activities of the most active compounds ( n = 33) at their 50% inhibitory concentration (IC ₅₀) values against metacercariae were assayed, and the results showed that 13 compounds had IC ₅₀s of ≤10 μM. The second stage queried the activities of these compounds at 33 μM against adult flukes, with seven of the compounds producing high mortality rates of >50%. Four hit compounds were selected on the basis of their predicted nontoxic properties, and the IC ₅₀ values obtained for adult worms were <10 μM; thus, these compounds represented the best fasciocidal compounds tested here. A cytotoxicity assay on four types of cell lines demonstrated that three compounds were nontoxic at their most active concentration. In conclusion, three hit compounds identified in this proof-of-concept study are potential candidates in the discovery of new fasciocidal drugs. Further studies are warranted.

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Fascioliasis and other plant-borne trematode zoonoses.

S Mas-Coma, M D Bargues, M. A. Valero (2005)

Fascioliasis and other food-borne trematodiases are included in the list of important helminthiases with a great impact on human development. Six plant-borne trematode species have been found to affect humans: Fasciola hepatica, Fasciola gigantica and Fasciolopsis buski (Fasciolidae), Gastrodiscoides hominis (Gastrodiscidae), Watsonius watsoni and Fischoederius elongatus (Paramphistomidae). Whereas F. hepatica and F. gigantica are hepatic, the other four species are intestinal parasites. The fasciolids and the gastrodiscid cause important zoonoses distributed throughout many countries, while W. watsoni and F. elongatus have been only accidentally detected in humans. Present climate and global changes appear to increasingly affect snail-borne helminthiases, which are strongly dependent on environmental factors. Fascioliasis is a good example of an emerging/re-emerging parasitic disease in many countries as a consequence of many phenomena related to environmental changes as well as man-made modifications. The ability of F. hepatica to spread is related to its capacity to colonise and adapt to new hosts and environments, even at the extreme inhospitality of very high altitude. Moreover, the spread of F. hepatica from its original European range to other continents is related to the geographic expansion of its original European lymnaeid intermediate host species Galba truncatula, the American species Pseudosuccinea columella, and its adaptation to other lymnaeid species authochthonous in the newly colonised areas. Although fasciolopsiasis and gastrodiscoidiasis can be controlled along with other food-borne parasitoses, fasciolopsiasis still remains a public health problem in many endemic areas despite sustained WHO control programmes. Fasciolopsiasis has become a re-emerging infection in recent years and gastrodiscoidiasis, initially supposed to be restricted to Asian countries, is now being reported in African countries.

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Global burden of human food-borne trematodiasis: a systematic review and meta-analysis.

Thomas Fürst, Jennifer Keiser, Jürg Utzinger (2012)

Food-borne trematodiases are a group of neglected tropical diseases caused by liver, lung, and intestinal parasitic fluke infections. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD 2010 study) and a WHO initiative, we assessed the global burden of human food-borne trematodiasis, as expressed in disability-adjusted life years (DALYs) for the year 2005. We systematically searched electronic databases for reports about human food-borne trematodiasis without language restriction, between Jan 1, 1980, and Dec 31, 2008. We used a broad search strategy with a combination of search terms and parasite and disease names. The initial search results were then screened on the basis of title, abstract, and, finally, full text. Relevant quantitative and qualitative data on human prevalence, morbidity, and mortality of food-borne trematodiasis were extracted. On the basis of available information on pathological and clinical appearance, we developed simplified disease models and did meta-analyses on the proportions and odds ratios of specified sequelae and estimated the global burden of human food-borne trematodiasis. We screened 33,921 articles and identified 181 eligible studies containing quantitative information for inclusion in the meta-analyses. About 56·2 million people were infected with food-borne trematodes in 2005: 7·9 million had severe sequelae and 7158 died, most from cholangiocarcinoma and cerebral infection. Taken together, we estimate that the global burden of food-borne trematodiasis was 665,352 DALYs (lower estimate 479,496 DALYs; upper estimate 859,051 DALYs). Furthermore, knowledge gaps in crucial epidemiological disease parameters and methodological features for estimating the global burden of parasitic diseases that are characterised by highly focal spatial occurrence and scarce and patchy information were highlighted. Despite making conservative estimates, we found that food-borne trematodiases are an important cluster of neglected diseases. Swiss National Science Foundation; Institute for Health Metrics and Evaluation. Copyright © 2012 Elsevier Ltd. All rights reserved.