Activity of OZ78 analogues against Fasciola hepatica and Echinostoma caproni

Kirchhofer, C. and Vargas, M. and Braissant, O. and Dong, Y. and Wang, X. and Vennerstrom, J. L. and Keiser, J.. (2011) Activity of OZ78 analogues against Fasciola hepatica and Echinostoma caproni. Acta tropica : Zeitschrift für Tropenwissenschaften und Tropenmedizin, 118 (1). pp. 56-62.

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Official URL: http://edoc.unibas.ch/dok/A6002097

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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 48h post-treatment of rats with 50mg/kg MT04. Administration of 50-100mg/kg of the synthetic peroxides resulted in complete elimination of adult F. hepatica from rats. SEM pictures revealed sloughing and blebbing already 18h post-treatment with MT04. MT04 (100mg/kg) cured infections with juvenile F. hepatica, whereas MT14, ST16, and ST28 showed only low to moderate worm burden reductions. At 300mg/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
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Klinische Pharmakologie
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Klinische Pharmakologie
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Helminth Drug Development (Keiser)
UniBasel Contributors:Kirchhofer, Carla and Keiser, Jennifer
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Elsevier Science Publ.
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:01 Dec 2017 06:36
Deposited On:08 Nov 2012 16:19

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