title: Neuroauditory toxicity of artemisinin combination therapies-have safety concerns been addressed?
abstract: Although artemisinin-based combination therapies (ACTs) are widely viewed as safe drugs with a wide therapeutic dose range, concerns about neuroauditory safety of artemisinins arose during their development. A decade ago, reviews of human data suggested a potential neuro-ototoxic effect, but the validity of these findings was questioned. With 5-10 years of programmatic use, emerging artemisinin-tolerant falciparum malaria in southeast Asia, and the first calls to consider an increased dose of artemisinins, we review neuroauditory safety data on ACTs to treat uncomplicated falciparum malaria. Fifteen studies reported a neurological or auditory assessment. The large heterogeneity of neuro-ototoxic end points and assessment methodologies and the descriptive nature of assessments hampered a formal meta-analysis and definitive conclusions, but they highlight the persistent lack of data from young children. This subgroup is potentially most vulnerable to any neuroauditory toxicity because of their development stage, increased malaria susceptibility, and repeated ACT exposure in settings lacking robust safety monitoring.
authors.forename: Virginia
authors.initials: V
authors.lastname: Ramos-Martín
authors.forename: Carmen
authors.initials: C
authors.lastname: González-Martínez
authors.forename: Ian
authors.initials: I
authors.lastname: Mackenzie
authors.forename: Joachim
authors.initials: J
authors.lastname: Schmutzhard
authors.forename: Cheryl
authors.initials: C
authors.lastname: Pace
authors.forename: David G
authors.initials: DG
authors.lastname: Lalloo
authors.forename: Dianne J
authors.initials: DJ
authors.lastname: Terlouw
mesh_terms: D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage / Q000009:adverse effects*; D037621:Artemisinins / Q000008:administration & dosage / Q000009:adverse effects*; D001304:Auditory Diseases, Central / Q000209:etiology* / Q000469:parasitology; D002675:Child, Preschool; D004334:Drug Administration Schedule; D004351:Drug Resistance; D005260:Female; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D008875:Middle Aged; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000469:parasitology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000502:physiology
chemical_list: D000962:Antimalarials; D037621:Artemisinins; C031327:artemisinin