title: Impact of Extended Duration of Artesunate Treatment on Parasitological Outcome in a Cytocidal Murine Malaria Model.
abstract: Artemisinin-based combination therapies are a key pillar in global malaria control and are recommended as a first-linePlasmodium falciparumtreatment. They rely upon a rapid 4-log-unit reduction in parasitemia by artemisinin compounds with a short half-life and the killing of remaining parasites by a partner compound with a longer half-life. Current treatment guidelines stipulate giving three 24-h-interval doses or six 12-h-interval doses over a 3-day period. Due to the short half-life of artesunate and artemether, almost all of the resulting cytocidal activity is confined within a single 48-h asexualP. falciparumcycle. Here, we utilized a luciferase reporter,Plasmodium bergheiANKA, in a cytocidal model in which treatment was initiated at high parasitemia, allowing us to monitor a greater than 3-log-unit reduction in parasite density, as well as 30-day survival. In this study, we demonstrated that increasing the artesunate duration from spanning one asexual cycle to spanning three asexual cycles while keeping the total dose constant results in enhanced cytocidal activity. Single daily artesunate doses at 50 mg/kg of body weight over 7 days were the minimum necessary for curative monotherapy. In combination with a single sub-human-equivalent dose of the partner drug amodiaquine or piperaquine, the three-asexual-cycle artesunate duration was able to cure 75% and 100% of mice, respectively, whereas 0% and 33% cures were achieved with the single-asexual-cycle artesunate duration. In summary, cytocidal activity of the artemisinin compounds, such as artesunate, can be improved solely by altering the dosing duration.
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
authors.forename: Leah A
authors.initials: LA
authors.lastname: Walker
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA dsulliv7@jhmi.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Sullivan
mesh_terms: D000655:Amodiaquine / Q000627:therapeutic use; D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D000077549:Artemether; D037621:Artemisinins / Q000627:therapeutic use*; D000077332:Artesunate; D004195:Disease Models, Animal; D005260:Female; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D011804:Quinolines / Q000627:therapeutic use; D010879:Piperazines
chemical_list: D000655:Amodiaquine; D000962:Antimalarials; D000077549:Artemether; D037621:Artemisinins; D000077332:Artesunate; D011804:Quinolines; C034759:piperaquine; D010879:Piperazines
keywords: antimalarial agents; artemisinin; pharmacodynamics