Activity of OZ78 analogues against Fasciola hepatica and Echinostoma caproni

Carla Kirchhofer, Mireille Vargas, Olivier Braissant, Yuxiang Dong, Xiaofang Wang, Jonathan L. Vennerstrom, Jennifer Keiser

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

The rapid spread of triclabendazole resistance in veterinary medicine is an important motivation for the discovery and development of novel fasciocidal drugs. 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, a 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.

Original languageEnglish (US)
Pages (from-to)56-62
Number of pages7
JournalActa Tropica
Volume118
Issue number1
DOIs
StatePublished - Apr 2011

Keywords

  • Echinostoma caproni
  • Fasciola hepatica
  • In vitro studies
  • In vivo studies
  • Microcalorimetry
  • Synthetic peroxides

ASJC Scopus subject areas

  • Parasitology
  • veterinary (miscalleneous)
  • Insect Science
  • Infectious Diseases

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