title: Treatment of murine cerebral malaria by artemisone in combination with conventional antimalarial drugs: antiplasmodial effects and immune responses.
abstract: The decreasing effectiveness of antimalarial therapy due to drug resistance necessitates constant efforts to develop new drugs. Artemisinin derivatives are the most recent drugs that have been introduced and are considered the first line of treatment, but there are already indications of Plasmodium falciparum resistance to artemisinins. Consequently, drug combinations are recommended for prevention of the induction of resistance. The research here demonstrates the effects of novel combinations of the new artemisinin derivative, artemisone, a recently described 10-alkylamino artemisinin derivative with improved antimalarial activity and reduced neurotoxicity. We here investigate its ability to kill P. falciparum in a high-throughput in vitro assay and to protect mice against lethal cerebral malaria caused by Plasmodium berghei ANKA when used alone or in combination with established antimalarial drugs. Artemisone effects against P. falciparum in vitro were synergistic with halofantrine and mefloquine, and additive with 25 other drugs, including chloroquine and doxycycline. The concentrations of artemisone combinations that were toxic against THP-1 cells in vitro were much higher than their effective antimalarial concentration. Artemisone, mefloquine, chloroquine, or piperaquine given individually mostly protected mice against cerebral malaria caused by P. berghei ANKA but did not prevent parasite recrudescence. Combinations of artemisone with any of the other three drugs did completely cure most mice of malaria. The combination of artemisone and chloroquine decreased the ratio of proinflammatory (gamma interferon, tumor necrosis factor) to anti-inflammatory (interleukin 10 [IL-10], IL-4) cytokines in the plasma of P. berghei-infected mice. Thus, artemisone in combinations with other antimalarial drugs might have a dual action, both killing parasites and limiting the potentially deleterious host inflammatory response.
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: W Armand
authors.initials: WA
authors.lastname: Guiguemde
authors.affiliation: Department of Pathology and Bosch Institute, The University of Sydney, Sydney, Australia.
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Hunt
authors.affiliation: Department of Pathology and Bosch Institute, The University of Sydney, Sydney, Australia.
authors.forename: Jintao
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Annael
authors.initials: A
authors.lastname: Marciano
authors.affiliation: Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Haynes
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Clark
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
authors.affiliation: Department of Pathology and Bosch Institute, The University of Sydney, Sydney, Australia Department of Microbiology and Molecular Genetics, The Kuvin Center for the Study of Infectious and Tropical Diseases, The Hebrew University of Jerusalem, Jerusalem, Israel golenser@md.huji.ac.il.
authors.forename: Jacob
authors.initials: J
authors.lastname: Golenser
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology; D004318:Doxycycline / Q000494:pharmacology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D006801:Humans; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016779:Malaria, Cerebral / Q000188:drug therapy* / Q000276:immunology / Q000469:parasitology; D015767:Mefloquine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D021261:Parasitic Sensitivity Tests; D010616:Phenanthrenes / Q000494:pharmacology; D010962:Plasmodium berghei / Q000187:drug effects* / Q000502:physiology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000502:physiology
chemical_list: D000962:Antimalarials; D037621:Artemisinins; C556062:IL10 protein, mouse; D010616:Phenanthrenes; D016753:Interleukin-10; D015847:Interleukin-4; C514498:artemisone; D002738:Chloroquine; D004318:Doxycycline; C023768:halofantrine; D015767:Mefloquine