Potential Antiplasmodial Activity of Artemether and Miconazole Combination against Plasmodium berghei in Preclinical Murine Malaria Model

Following recent reports of resistance to currently approved artemisinin-based combination therapy (ACT), there is an urgent need for alternative ACT for effective treatment of malaria. Meanwhile, the antimalarial potential of artemether/miconazole combination has not been explored. In this work, we investigated artemether/miconazole combination as a new combo-therapy for malaria caused by chloroquine-sensitive and multidrug-resistant Plasmodium berghei (Pb) in murine models. The antimalarial activity of each drug and their combination [artemether (8mg/kg)/miconazole (2mg/kg)] was investigated using standard protocols for uncomplicated malaria (UM) and severe malaria (SM) in mice infected with chloroquine-sensitive Pb (CPb) and Pb ANKA (PbA), respectively. Hematological parameters (WBC, RBC, PCV and haemoglobin) and lethality of infected mice were assessed. Results revealed that the combination administered peorally (p.o.) gave greater antimalarial activity (p<0.0001) than monotherapies of pure artemether, miconazole and marketed chloroquine (p.o) although the effect was less than that of therapeutic dosage of marketed ACT (artemether-lumefantrine) (4mg/24mg/kg) against CPb. Furthermore, intraperitoneally (i.p.) administered artemether/miconazole combo-therapy gave greater antimalarial activity than artemether and miconazole monotherapies (p<0.0001) and the effect was comparable with commercial i.m. artemether against PbA. Moreover, the combo-therapies had similar effects to conventional antimalarials in preventing Pb-induced alterations in hematological parameters of the malariogenic mice. Results indicate miconazole as a promising repurposable drug with therapeutic potential against drug-sensitive and resistant parasites. Therefore, artemether/miconazole combination could serve as a plausible ACT option for UM and as an alternative to artemisinin derivatives in SM. An on-going research would seek to enhance the observed effects via nanotechnology-based drug delivery systems.