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ERC

A-HERO Report Summary

Project ID: 614739
Funded under: FP7-IDEAS-ERC
Country: Switzerland

Mid-Term Report Summary - A-HERO (Anthelmintic Research and Optimization)

We have made considerable progress implementing innovations in anthelmintic drug discovery and development during the first phase of this project. Our goal is to make alternative treatments available for soil-transmitted helminthiasis and schistosomiasis and to improve the existing treatments. To facilitate drug discovery work we studied a novel calorimeter to assess the viability on the hookworms and the whipworm Trichuris muris as well as fluorescence markers on schistosomes. We tested a range of libraries against laboratory models for soil-transmitted helminthiasis and schistosomiasis and identified several anthelminthic lead candidates through thorough in vitro and in vivo studies which could serve as starting point for structure-activity relationship studies. In preclinical research we developed and validated a method based on dried-blood spots for praziquantel to facilitate pharmacokinetic studies in rural settings. We also evaluated drug-drug interactions for albendazole-mebendazole and albendazole-oxantel in order to investigate drug combinations for soil-transmitted helminthiasis in clinical trials. With regard to clinical research conducted, we studied the efficacy and safety of ascending dosages (20, 40 and 60 mg/kg) of praziquantel in school-aged and preschool-aged children infected with Schistosoma mansoni and S. haematobium. The S. mansoni study revealed that both 40 and 60 mg/kg praziquantel showed high egg reduction rates in school-aged children, hence our findings support the use of the recommended 40 mg/kg dose of praziquantel as the standard treatment in preventive chemotherapy for S. mansoni infections in this age group. Praziquantel shows lower efficacy in preschoolers suggesting that higher doses are needed to achieve equal clinical benefit. In this study we analysed stool and urine samples and observed that the gut microbiome is impacted by the presence of S. mansoni. The intensity of infection, however, is not linked with increased or decreased dysbiosis. No difference in abundance was related to treatment with praziquantel. In addition, discriminant urinary metabolite profiles were found between infected and non-infected children at baseline as well as according to the dose of praziquantel administered 24 hours after treatment. An ultrasound investigation conducted in the framework of the S. haematobium study found that bladder morbidity is widespread among preschoolers. A significant correlation (p<0.05) was observed between praziquantel treatment and reversal of S. haematobium induced morbidity. Progression of urinary tract pathology decreased with increasing praziquantel dosages. A worsening of morbidity was observed among children in the placebo group. We also tested the antimalarial Synriam and the anthelminthic moxidectin in an exploratory Phase 2 clinical trial. Both drugs show low efficacy against S. haematobium, hence an ancillary benefit is not expected when these drugs are used for treating onchocerciasis and malaria in co-endemic settings. Further studies are needed to confirm that moxidectin and Synriam show moderate egg reduction rates against S. mansoni. Finally, we demonstrated that moxidectin showed similar cure rates as ivermectin against strongyloidiasis in a clinical trial conducted in Lao PDR:

Contact

Stefan Mörgeli, (Senior administrative officer)
Tel.: +41 61 2848320
E-mail
Record Number: 195419 / Last updated on: 2017-03-13
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