Improved protocols using sodium artesunate for the treatment of experimental cerebral malaria

Artemether and artesunate are effective antimalarial drugs in rescue therapies of Plasmodium berghei ANKA (PbA)-infected mice with experimental cerebral malaria (ECM), with a superiority for artemether among the single daily dosing schemes. The present study aimed to optimize the efficacy of artesunate treatment protocols using two daily dosing or slow continuous delivery schemes. PbA-infected mice were treated with four different artesunate protocols on day 5 post-infection (5 dpi). Protocol G4 (single intraperitoneal (IP) loading dose of 20 mg/kg followed by continuous delivery for 3 days with osmotic pumps) was superior to the other artesunate groups, with a 97.2% ± 0.86 reduction of parasitemia in 24 h, but recrudescence ensued in 50% of treated animals. Protocol G1 (loading dose of 40 mg/kg followed by 20 mg/kg twice a day for 5 days) led to a 90.5% ±5.39 decrease in parasitemia 24 h after the first dose without recrudescence. A variant of the G1 protocol, with two doses of 40 mg/kg in the first day, resulted in a survival rate of 42% in ECM-rescuing experiments, with ~30% decreases in hematocrit, hemoglobin, and red blood cell count 24 h after the first dose. Infected mice on 5 dpi showed severe thrombocytopenia (196 ± 118.3 platelets/μL; uninfected controls: 1,291 ± 256.4 platelets/μL), and artesunate treatment had little impact on these numbers 24 h after the first dose. In conclusion, two daily doses IP or via slow continuous delivery improve the efficacy of artesunate treatments compared to single-daily dose schemes and are suitable for ECM adjunctive therapy studies.