Evaluation of emodepside in laboratory models of human intestinal nematode and schistosome infections

Tanja Karpstein,Jennifer Keiser,Valérian Pasche,Cécile Häberli,Anna Neodo,Ivan Scandale

doi:10.1186/s13071-019-3476-x

Abstract

BackgroundHelminthiases are very prevalent worldwide, yet their treatment and control rely on a handful of drugs. Emodepside, a marketed broad-spectrum veterinary anthelminthic with a unique mechanism of action, undergoing development for onchocerciasis is an interesting anthelmintic drug candidate. We tested the in vitro and in vivo activity of emodepside on nematode species that serve as models for human soil-transmitted helminth infection as well as on schistosomes.MethodsIn vitro viability assays were performed over a time course of 72 hours for Trichuris muris, Necator americanus, Ancylostoma ceylanicum, Heligmosomoides polygyrus, Strongyloides ratti, Schistosoma mansoni and Schistosoma haematobium. The drug effect was determined by the survival rate for the larvae and by phenotypical scores for the adult worms. Additionally, mice infected with T. muris and hamsters harboring hookworm infection (N. americanus or A. ceylanicum) were administered orally with emodepside at doses ranging from 1.25 to 75 mg/kg. Expelled worms in the feces were counted until 3 days post-drug intake and worms residing in the intestines were collected and counted after dissection.ResultsAfter 24 hours, emodepside was very active in vitro against both larval and adult stages of the nematodes T. muris, A. ceylanicum, N. americanus, H. polygyrus and S. ratti (IC50 < 4 µM). The good in vitro activity was confirmed in vivo. Hamsters infected with the hookworms were cured when administered orally with 2.5 mg/kg of the drug. Emodepside was also highly active in vivo against T. muris (ED50 = 1.2 mg/kg). Emodepside was moderately active on schistosomula in vitro (IC50 < 8 µM) 24 h post-drug incubation and its activity on adult S. mansoni and S. haematobium was low (IC50: 30–50 µM).ConclusionsEmodepside is highly active against a broad range of nematode species both in vitro and in vivo. The development of emodepside for treating soil-transmitted helminth infections should be pursued.

Highlights

Helminthiases are very prevalent worldwide, yet their treatment and control rely on a handful of drugs
After one day of incubation, emodepside was highly active against adult A. ceylanicum and N. americanus with half maximal inhibitory concentration (IC50) values below 0.005 μM, which were reduced by half over the incubation period (IC50 < 0.0025 μM)
We further investigated the efficacy of emodepside in vivo on rodents infected with T. muris, A. ceylanicum and N. americanus

Summary

Introduction

Helminthiases are very prevalent worldwide, yet their treatment and control rely on a handful of drugs. Helminths affect a fifth of the world population and their associated morbidities include general fatigue, food malabsorption or iron deficiency anemia [1,2,3,4]. They are an important public health issue in low and middle income countries, where they enhance the vicious cycle of poverty notably by reducing school attendance and productivity [5, 6]. The most prevalent helminthiases are schistosomiasis (primarily caused by Schistosoma haematobium, S. japonicum and S. mansoni) that affects more than 250 million people and soil-transmitted helminthiases (STH) that account for more than 1.5 billion infected cases worldwide [2, 4, 6, 7]. Together with the rising risk of drug resistance due to an intense use of the same drugs and the lack of lead molecules in the development pipeline, the discovery of new anthelmintic treatments is urgent [12, 14, 15]

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