Activity of OZ78 analogues against Fasciola hepatica and Echinostoma caproni

Abstract

The rapid spread of triclabendazole resistance in veterinary medicine is an important motivation for fasciocidal drug discovery and development. The aim of this study was to characterize the fasciocidal properties of 1,2,4,5-tetraoxane (MT04 and MT14) and 1,2,4-trioxane (ST16 and ST28) analogues of the fasciocidal drug candidate OZ78, an 1,2,4-trioxolane. Dose response relationships were determined against juvenile and adult Fasciola hepatica in rats and Echinostoma caproni in mice. The temporal effects of MT04, MT14, ST16, and ST28 compared to OZ78 on the viability of F. hepatica were tested in vitro. The heat flow of OZ78 and MT04 treated flukes was studied with isothermal microcalorimetry. Finally, surface changes to adult flukes were monitored by scanning electron microscopy (SEM) 18, 24, and 48 h post-treatment of rats with 50 mg/kg MT04. Administration of 50-100 mg/kg of the synthetic peroxides resulted in complete elimination of adult F. hepatica from rats. SEM pictures revealed sloughing and blebbing already 18 h post-treatment with MT04. MT04 (100 mg/kg) cured infections with juvenile F. hepatica, whereas MT14, ST16, and ST28 showed only low to moderate worm burden reductions. At 300 mg/kg, MT14 was the only compound to completely eliminate worms from E. caproni infected mice. MT14 showed the highest activity against juvenile F. hepatica in vitro. MT04 was very active against adult F. hepatica in vitro, which was confirmed by heat flow measurements. In conclusion, we have identified MT04 as another lead compound with potential against F. hepatica, hence further preclinical studies are necessary to determine if MT04 can be considered a drug development candidate.

A comparative study on the impact of two artemisinin derivatives, artemether and artesunate, on the female reproductive system of Fasciola hepatica

“…More recently, they have received a considerable amount of attention as potential fasciolicides. A number of semi-synthetic and fully-synthetic artemisinin derivatives have been tested against Fasciola hepatica, and activity demonstrated under in vitro conditions and in rodent (rat) infections, even against a TCBZ-resistant isolate of F. hepatica (Keiser et al, 2006a(Keiser et al, ,b, 2007Duthaler et al, 2010Duthaler et al, , 2012Zhao et al, 2010;Kirchhofer et al, 2011Kirchhofer et al, , 2012Wang et al, 2011). This activity has not been fully or consistently translated to infections in larger ruminants such as sheep (Keiser et al, 2008(Keiser et al, , 2010aMeister et al, 2013).…”

“…Nevertheless, it is important for the future design and testing of new artemisinin derivatives that there is a better understanding of their action against fluke. There have been few morphological studies and they have concentrated on external surface changes to flukes following treatment (Keiser and Morson, 2008a,b;Halferty et al, 2009;O'Neill et al, 2009O'Neill et al, , 2015Kirchhofer et al, 2011;Duthaler et al, 2012).…”

Comparison of novel and existing tools for studying drug sensitivity against the hookworm Ancylostoma ceylanicum in vitro

“…The noise amplitude curve, following exponential decay, is based on absolute values of the amplitudes of noise obtained for 20 minutes over the entire course of the experiment. The intersection of the sample curve with the background line defines the death of worms (Kirchhofer et al 2011;Manneck et al 2011). The nanocalorimeter offers a greater sensitivity, in the range of 20 nW.…”

“…Isothermal calorimetry measures quantitatively exoand endothermic heat flow of metabolic processes, and has already shown applicability using different helminth models (Braissant et al 2010;Kirchhofer et al 2011;Manneck et al 2011). The endpoint used in this study was the time of death of the worms.…”

History of echinostomes (Trematoda)

“…These authors have performed a number of in vivo (using mice as definitive host) and in vitro studies with E. caproni as the drug discovery tool. They have assessed the anthelmintic properties of different medicinal plants and compounds which have allowed them to define several drug development candidates (Keiser et al, 2006a, b, c;Saric et al, 2008;Keiser 2010;Ferreira et al, 2011;Kirchhofer et al, 2011;Panic et al, 2013). Moreover, these workers have started the study of metabonomics in helminth infections using E. caproni as an experimental model (Saric et al, 2008).…”