Final Report Summary - A-HERO (Anthelmintic Research and Optimization)
This project has allowed to implemented innovations in anthelmintic drug discovery and development. To facilitate drug discovery work we studied a novel calorimeters 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 preclinical studies. In preclinical research we developed and validated a method based on dried-blood spots and Mitra for praziquantel to facilitate pharmacokinetic (PK) 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 safety and PK 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. Our findings support the use of the recommended 40 mg/kg dose of praziquantel as the standard treatment in preventive chemotherapy in children. A significant correlation (p<0.05) was observed between praziquantel treatment and reversal of S. haematobium induced morbidity using ultrasound. No exposure response relationship was observed. We analysed stool and urine samples and observed that the gut microbiome is impacted by the presence of S. mansoni. 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. Moxidectin and tribendimidine are ideal anthelminthic alternative treatments. We demonstrated that moxidectin showed similar cure rates as ivermectin against strongyloidiasis in a clinical trial conducted in Lao PDR and that an albendazole-moxidectin combination reveals broad spectrum of activity against soil-transmitted helminthiasis. For the first time a PK study and dose-finding study was conducted with tribendimidine in hookworm infected children. A 400-mg dose of tribendimidine yielded the highest efficacy and was well tolerated. The identified Emax models correlating dADT exposure to egg reduction and cure rates showed shallow curves, indicating that increasing exposure only leads to a small increase in efficacy.