Abstract
BackgroundFascioliasis and paragonimiasis are widespread foodborne trematode diseases, affecting millions of people in more than 75 countries. The treatment of choice for these parasitic diseases is based on triclabendazole, a benzimidazole derivative which has been suggested as a promising drug to treat pregnant women and children. However, at the moment, this drug is not approved for human use in most countries. Its potential adverse effects on embryonic development have been scarcely studied, and it has not been assigned a pregnancy category by the FDA. Thus, to help in the process of risk-benefit decision making upon triclabendazole treatment during pregnancy, a better characterization of its risks during gestation is needed.MethodologyThe zebrafish embryo test, a preimplantation and a postimplantation rodent whole embryo culture were used to investigate the potential embryotoxicity/teratogenicity of triclabendazole and its first metabolite triclabendazole sulfoxide. Albendazole and albendazole sulfoxide were included as positive controls.Principal FindingsTriclabendazole was between 10 and 250 times less potent than albendazole in inducing dysmorphogenic effects in zebrafish or postimplantation rodent embryos, respectively. However, during the preimplantation period, both compounds, triclabendazole and triclabendazole sulfoxide, induced a dose-dependent embryolethal effect after only 24 h of exposure in rodent embryos and zebrafish (lowest observed adverse effect concentrations = 10 μM).Conclusions/SignificanceIn humans, after ingestion of the recommended doses of triclabendazole to treat fascioliasis and paragonimiasis (10 mg/kg), the main compound found in plasma is triclabendazole sulfoxide (maximum concentration 38.6 μM), while triclabendazole concentrations are approximately 30 times lower (1.16 μM). From our results it can be concluded that triclabendazole, at concentrations of the same order of magnitude as the clinically relevant ones, does not entail teratogenic potential in vitro during the organogenesis period, but its first metabolite triclabendazole sulfoxide has a high embryotoxic capacity in vitro during the preimplantation stage.
Highlights
Fascioliasis and paragonimiasis are food-borne trematode diseases affecting millions of people worldwide [1]
TCBZ is only approved for veterinary use in most countries, it is included in the World Health Organization model list of essential medicines for use in these two parasitic diseases [4], and it has even been suggested as a promising treatment for Fasciola hepatica infections occurring in pregnant women and children [8]
Most of these other benzimidazoles are teratogenic in animals and have been classified within the Food and Drug Administration (FDA) pregnancy category C
Summary
Fascioliasis and paragonimiasis are food-borne trematode diseases affecting millions of people worldwide [1]. TCBZ is regarded as a safe compound during pregnancy, especially in comparison to other benzimidazoles used to treat parasitic diseases Most of these other benzimidazoles are teratogenic in animals (reviewed in [9]) and have been classified within the Food and Drug Administration (FDA) pregnancy category C (animal reproduction studies have shown an adverse effect on the foetus and there are no adequate and well- controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks). This alleged safety relies on a disproportioned difference of available information among the different benzimidazolic compounds. To help in the process of risk-benefit decision making upon triclabendazole treatment during pregnancy, a better characterization of its risks during gestation is needed
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