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Antimicrobial Agents and Chemotherapy, September 2009, p. 3770-3776, Vol. 53, No. 9
0066-4804/09/$08.00+0     doi:10.1128/AAC.00452-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Combination Chemotherapy against Clonorchis sinensis: Experiments with Artemether, Artesunate, OZ78, Praziquantel, and Tribendimidine in a Rat Model{triangledown}

Jennifer Keiser,1* Shu-Hua Xiao,2 Thomas A. Smith,3 and Jürg Utzinger3

Department of Medical Parasitology and Infection Biology, Swiss Tropical Institute, P.O. Box, CH-4002 Basel, Switzerland,1 National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, Shanghai 200025, People's Republic of China,2 Department of Public Health and Epidemiology, Swiss Tropical Institute, P.O. Box, CH-4002 Basel, Switzerland3

Received 6 April 2009/ Accepted 26 June 2009

Caused by the Chinese liver fluke Clonorchis sinensis, clonorchiasis is of growing public health importance. Treatment and control of the disease rely on a single drug, praziquantel, and little information regarding combination chemotherapy is available. 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 a 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 body weight of artesunate, for example, reduced worm burden by 50% and 95%, respectively. Artemether and OZ78 (12.5 to 50 mg/kg) showed dose-dependent killing of worms but no significant drug interactions when given with 150 mg/kg praziquantel, suggesting independent additive effects. In contrast, artesunate and tribendimidine (12.5 to 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 various 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.

* Corresponding author. Mailing address: Department of Medical Parasitology and Infection Biology, Swiss Tropical Institute, P.O. Box, CH-4002 Basel, Switzerland. Phone: 41 61 284-8218. Fax: 41 61 284-8105. E-mail: jennifer.keiser{at}unibas.ch

{triangledown} Published ahead of print on 6 July 2009.

Antimicrobial Agents and Chemotherapy, September 2009, p. 3770-3776, Vol. 53, No. 9
0066-4804/09/$08.00+0     doi:10.1128/AAC.00452-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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