**Acknowledgements**

PZQ and ARA mono-therapy induced 20% cure rates, while cure rate of 78% was achieved

Combination of PZQ-oxamniquine (OXA) was assayed in randomized, non-blinded, doseranging trials in treatment of Malawi and Zimbabwe schoolchildren with low, moderate, and heavy infection. Cure rates were not available for Malawi children, while it reached 89% with the higher dose (20 and 10 mg/kg for PZQ and OXA, respectively) for children in Zimbabwe. No direct comparisons were reported for PZQ and OXA mono-therapy, and accordingly, synergistic effect was not documented [119-121]. Additionally, opposite to PZQ and ARA,

PZQ and artemether or artesunate in combination resulted in a protection rate of about 80%, slightly higher than PZQ mono-therapy for treatment of schistosomiasis haematobium and japonicum in two field trials [122, 123]. In a field trial in high *S. mansoni* endemicity Senegalese villages, 1- to 60-year-old (median=18 years) patients with moderate *S. mansoni* infection were treated with PZQ, artesunate, or both drugs in combination (35-39 individuals per study arm). Cure rates were 44% for PZQ, 23% for artesunate, and 69% for the drugs combined. Combi‐ nation of PZQ and artesunate appeared clearly synergistic, but the efficacy was obviously lower than for PZQ + ARA [123, 124]. This study revealed that efficacy of artemisinin derivative alone against *S. mansoni* is not evident and, furthermore, was not observed in *S. haematobium* infections [122]. Most importantly, artemether, and artemisin derivatives are used for malaria therapy; artemisinin resistance in *Plasmodium falciparum* is now prevalent across mainland

Southeast Asia, and poses a threat to the control and elimination of malaria [125].

There were no reduction in efficacy of artemether and artesunate in killing PZQ-resistant and PZQ-susceptible *S*. *japonicum* worms in mice treated 7 and 8 or 35 and 36 days post-infection [126]. Opposite findings were observed regarding ARA, as its efficacy was as low as that of PZQ in treating schoolchildren with heavy *S. mansoni* infection, residing in areas where massive PZQ campaigns were applied for 10 consecutive years [55]. This finding implies that *S. mansoni* worms were resistant to mono-therapy with either PZQ or ARA. That has led us to propose that resistance to PZQ and ARA is attributed to continuous PZQ use, eliciting selection for worms with tight upper lipid bilayer, consequent to excessive SM synthesis and content or lower nSMase activity. Progeny of these worms would prevent access of even the 312 Da PZQ molecules, and would be less susceptible to ARA-mediated nSMase activation. Exposure of such worms to PZQ would not lead to their demise, yet likely facilitate ARA-mediated nSMase activation, SM hydrolysis and worm attrition. Exposure of these worms to ARA would lead to nSMase activation that is not lethal, yet sufficient to now allow entry of PZQ to perform its schistosomicidal action. Our proposition was supported by the considerable increase in cure rates in all children treated with PZQ + ARA versus the drugs' mono-therapy. The increase in cure rates was most highly significant (*P*<0.0001) for children with heavy infections were cure rates with either PZQ or ARA alone were 20% and attained 78% with the drugs combined. We shall test this hypothesis via evaluation of the cholesterol/SM content and nSMase activity in worms derived from cercariae obtained from communities of low prevalence/low PZQ use

OXA is effective against *S. mansoni* but not *S. haematobium* [121].

with the drug combination [55, 56].

160 An Overview of Tropical Diseases

*2.3.2. Molecular basis for efficacy*

Experiments related to ARA efficacy and safety in mice and hamsters were supported by the Science and Technology Development Fund, Egypt, grants Nos. 144 and 2073 to R. El Ridi. For clinical trials in Menoufiya and Kafr El Sheikh, funding was provided by DSM North America, Columbia, Maryland.
