Interactions of mefloquine with praziquantel in the Schistosoma mansoni mouse model and in vitro

Objectives: Mefloquine has interesting antischistosomal properties, hence it might be an attractive partner drug for combination treatment with praziquantel. The aim of this study was to evaluate activities of mefloquine/praziquantel combinations against Schistosoma mansoni in vitro and in vivo. Methods: Dose-response relationships were established following exposure of adult S. mansoni to mefloquine, praziquantel and fixed dose combinations of mefloquine/praziquantel in vitro. S. mansoni-infected mice were treated orally with selected doses of single drugs and drug combinations 7 weeks post-infection. Results: We calculated in vitro LC50 values of 0.024 and 1.9 mu g/mL for praziquantel and mefloquine, respectively. Mefloquine/praziquantel combinations showed synergistic effects, with combination index (CI) values <1 when adult S. mansoni were simultaneously incubated with both drugs in vitro. Reduced viabilities were also observed when schistosomes were first exposed to mefloquine followed by praziquantel in vitro. ED(50)s of 62 mg/kg and 172 mg/kg were determined for mefloquine and praziquantel against adult S. mansoni in vivo, respectively. Combinations of praziquantel (50 or 100 mg/kg) followed the next day by mefloquine (50 or 100 mg/kg) treatment revealed only moderate total worm burden reductions of 47.8%-54.7%. On the other hand, when both drugs (100 mg/kg each) were either given simultaneously or mefloquine was given prior to praziquantel, high total and female worm burden reductions of 86.0%-93.1% were observed. For the later treatment regimen, synergistic effects (CI<1) were calculated when mefloquine and praziquantel were combined using a fixed dose ratio based on their ED(50)s. Conclusions: Combinations of mefloquine and praziquantel may have clinical utility in the treatment of schistosomiasis.