Arterolane maleate/Piperaquine Phosphate

Control of schistosomiasis relies on a single drug, praziquantel (PZQ). Given the rising concerns about the potential emergence of PZQ-resistant strains, it has now become necessary to search for novel therapeutics. However, the current pace for anti-schistosomal drug discovery is slow; hence, repositioning of existing approved drugs can offer a safe, rapid and cost-effective solution. The anti-malarial synthetic artemisinin-derivatives trioxolanes demonstrated anti-schistosomal efficacies against the three major species infecting humans and, unlike PZQ, showed activities against both juvenile and adult worm stages. The 1,2,4-trioxolane/OZ277 (arterolane maleate) in combination with a partner drug: piperaquine phosphate was recently developed as an anti-malarial drug and manufactured by Ranbaxy (India) as Synriam™ (SYN). Herein, the in vivo activities of SYN were investigated in a mouse model of Schistosoma mansoni (S. mansoni), compared to PZQ. We show that a single fixed dose of 240mg/kg SYN (40mg/kg arterolane and 200mg/kg piperaqine) induced significant protective effects in mice, in terms of reduction in worm and tissue egg burdens, which were evident against all schistosome developmental stages. Extensive alterations in the tegument and subtegumental tissues of SYN-exposed worms were revealed by both scanning and transmission electron microscopes. Progressive decrease in worm activity and occurrence of death were noticed in vitro upon exposure to the drug - more pronounced in the presence of haemin. This report provides the first evidence of the efficacy of a combination of 1,2,4-trioxolane and piperaquine against S. mansoni in mice. Being effective against young stages, SYN could be used to prevent early Schistosoma infection.