Combination chemotherapy against Clonorchis sinensis : experiments with artemether, artesunate, OZ78, praziquantel, and tribendimidine in the rat model

Caused by the Chinese liver fluke Clonorchis sinensis, clonorchiasis is of growing public health importance. Treatment and control of the disease relies on a single drug - praziquantel - and little information is available regarding combination chemotherapy. Here, we evaluated the in vivo efficacy of praziquantel combined with artemether, artesunate, OZ78, and tribendimidine, as well as an artesunate-tribendimidine combination against C. sinensis in the rat model. Data from previous experiments were included and negative binomial regression analyses were carried out to determine dose-response relationships and to study the effect of drug combination. All drugs given in monotherapy were efficacious in killing the worms; doses of 16 and 70 mg/kg of artesunate, for example, reduced worm burden by 50% and 95%, respectively. Artemether and OZ78 (12.5-50 mg/kg) showed dose-dependent killing, but no significant drug interactions when given with 150 mg/kg praziquantel, suggesting independent additive effects. In contrast, artesunate and tribendimidine (12.5-50 mg/kg) showed synergistic interactions with 150 mg/kg praziquantel. When low doses of 3.1 and 6.25 mg/kg OZ78 and artemether, respectively were combined with praziquantel (150 mg/kg) an increased worm survival - above the level observed with praziquantel monotherapy - was noted. A similar antagonism was seen when praziquantel (75 mg/kg) was combined with several of the companion drugs at varying doses. In conclusion, in vivo efficacy of praziquantel, the artemisinins, OZ78, and tribendimidine against C. sinensis is confirmed, and combination chemotherapy with praziquantel produces synergistic and antagonistic effects depending on the doses administered. Further preclinical investigations are warranted