title: Meningeal inflammation increases artemether concentrations in cerebrospinal fluid in Papua New Guinean children treated with intramuscular artemether.
abstract: Although the artemisinin-associated neurotoxicity identified in vitro and in animal studies has not been confirmed clinically, only one adult study has measured cerebrospinal fluid (CSF) concentrations after administration of conventional doses. Potential artemisinin neurotoxicity could be serious in children, especially those with meningitis and, consequently, a compromised blood-brain barrier. We measured CSF/plasma artemether and dihydroartemisinin (DHA) concentrations in 32 Papua New Guinean children with a mean age of 39 months with suspected or proven severe falciparum malaria who underwent a single lumbar puncture after intramuscular artemether administration. CSF artemether concentrations were 0 to 43.5 μg/liter and CSF concentration/plasma concentration ratios were 0 to 38.1%. DHA was measurable in CSF in only two children. The seven children with meningeal inflammation (CSF white cell count > 20/mm(3)) had higher CSF artemether concentration/plasma artemether concentration ratios than those without (median, 6.7% [interquartile ratio, 2.5 to 27.8%]% versus 0.0% [interquartile ratio, 0.0 to 2.5%]; P = 0.002). Meningeal inflammation was associated with a 4.6-fold increase in the CSF artemether concentration/plasma artemether concentration ratio in a population pharmacokinetic model. These data suggest that pharmacovigilance should be heightened when intramuscular artemether is given to severely ill children with evidence of meningeal inflammation.
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia.
authors.forename: Laurens
authors.initials: L
authors.lastname: Manning
authors.forename: Moses
authors.initials: M
authors.lastname: Laman
authors.forename: Madhu
authors.initials: M
authors.lastname: Page-Sharp
authors.forename: Sam
authors.initials: S
authors.lastname: Salman
authors.forename: Ilomo
authors.initials: I
authors.lastname: Hwaiwhanje
authors.forename: Namar
authors.initials: N
authors.lastname: Morep
authors.forename: Peter
authors.initials: P
authors.lastname: Siba
authors.forename: Ivo
authors.initials: I
authors.lastname: Mueller
authors.forename: Harin A
authors.initials: HA
authors.lastname: Karunajeewa
authors.forename: Timothy M E
authors.initials: TM
authors.lastname: Davis
mesh_terms: D000077549:Artemether; D037621:Artemisinins / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007273:Injections, Intramuscular; D016778:Malaria, Falciparum / Q000188:drug therapy; D008297:Male; D008578:Meninges / Q000276:immunology*; D010219:Papua New Guinea; D011446:Prospective Studies
chemical_list: D037621:Artemisinins; C039060:artenimol; D000077549:Artemether