Arteether resistance reversal by ketoconazole/fluconazole in rodent malaria parasite Plasmodium vinckei

Artemisinin and its derivative arteether (ART) are fast acting antimalarial drugs against chloroquine-resistant. There are several partner drugs that are identified as a potential drug for artemisinin combination therapy (ACT) to develop as the antimalarial drug. Limited studies have been carried out in ART drug combination that may have more promising as ACT for resistant Plasmodium parasite. Here, we are the first to show the ART drug resistance reversal in Plasmodium vinckei by using antifungal azole compounds ketoconazole (KTZ) and fluconazole (FCZ). Our previous study has shown that higher antioxidant enzyme, glutathione, and less hemozoin may be correlated with ART resistance in P. vinckei (PvAR). We further hypothesized that glutathione and heme catabolism may be interfered by KTZ and FCZ, resulting in an increased efficacy of ART in PvAR parasite. The results of present study demonstrate synergetic effect of KTZ and FCZ against PvAR parasite, since none of the mice developed infection up to day 10 after combination with ART. These results further showed that ED90 of ART was reduced from 17.23 to 2.19 and 2.56 mg/kg when used in combination with KTZ and FCZ, respectively. Resultant, activity enhancement index (AEI) of ART is significantly increased to 8.60 and 6.73 with partner agents. These studies propose the possibility of ART drug combination that may be helpful in prolonging the life of drug and a promising lead to reduce the chance of resistance development of artemisinin and its derivative.