Volume 91, Issue 1
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



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.

[open-access] This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Article metrics loading...

The graphs shown below represent data from March 2017
Loading full text...

Full text loading...



  1. Novartis, 2012. Novartis Malaria Initiative. Available at: http://malaria.novartis.com/malaria-initiative/treatment/first-in-class-treatment/index.shtml. Accessed October 23, 2013. [Google Scholar]
  2. Brewer TG, Peggins JO, Grate SJ, Petras JM, Levine BS, Weina PJ, Swearengen J, Heiffer MH, Schuster BG, , 1994. Neurotoxicity in animals due to arteether and artemether. Trans R Soc Trop Med Hyg 88 (Suppl 1): S33S36.[Crossref] [Google Scholar]
  3. Genovese RF, Newman DB, Li Q, Peggins JO, Brewer TG, , 1998. Dose-dependent brainstem neuropathology following repeated arteether administration in rats. Brain Res Bull 45: 199202.[Crossref] [Google Scholar]
  4. Genovese RF, Newman DB, Petras JM, Brewer TG, , 1998. Behavioral and neural toxicity of arteether in rats. Pharmacol Biochem Behav 60: 449458.[Crossref] [Google Scholar]
  5. Nontprasert A, Pukrittayakamee S, Dondorp AM, Clemens R, Looareesuwan S, White NJ, , 2002. Neuropathologic toxicity of artemisinin derivatives in a mouse model. Am J Trop Med Hyg 67: 423429. [Google Scholar]
  6. Nontprasert A, Pukrittayakamee S, Prakongpan S, Supanaranond W, Looareesuwan S, White NJ, , 2002. Assessment of the neurotoxicity of oral dihydroartemisinin in mice. Trans R Soc Trop Med Hyg 96: 99101.[Crossref] [Google Scholar]
  7. Petras JM, Kyle DE, Gettayacamin M, Young GD, Bauman RA, Webster HK, Corcoran KD, Peggins JO, Vane MA, Brewer TG, , 1997. Arteether: risks of two-week administration in Macaca mulatta. Am J Trop Med Hyg 56: 390396. [Google Scholar]
  8. Petras JM, Young GD, Bauman RA, Kyle DE, Gettayacamin M, Webster HK, Corcoran KD, Peggins JO, Vane MA, Brewer TG, , 2000. Arteether-induced brain injury in Macaca mulatta. I. The precerebellar nuclei: the lateral reticular nuclei, paramedian reticular nuclei, and perihypoglossal nuclei. Anat Embryol (Berl) 201: 383397.[Crossref] [Google Scholar]
  9. Erickson RI, Defensor EB, Fairchild DG, Mirsalis JC, Steinmetz KL, , 2011. Neurological assessments after treatment with the antimalarial beta-arteether in neonatal and adult rats. Neurotoxicology 32: 432440.[Crossref] [Google Scholar]
  10. Cook J, Frick KD, Baltussen R, Resnikoff S, Smith A, Mecaskey J, Kilima P, Jamison DT, Breman JG, Measham AR, Alleyne G, Claeson M, Evans DB, Jha P, Mills A, Musgrove P, , 2006. Loss of vision and hearing. , eds. Disease Control Priorities in Developing Countries. Washington, DC: The International Bank for Reconstruction and Development/The World Bank Group. [Google Scholar]
  11. Bernard PA, Pechere JC, Hebert R, , 1980. Altered objective audiometry in aminoglycosides-treated human neonates. Arch Otorhinolaryngol 228: 205210.[Crossref] [Google Scholar]
  12. Fausti SA, Flick CL, Bobal AM, Ellingson RM, Henry JA, Mitchell CR, , 2003. Comparison of ABR stimuli for the early detection of ototoxicity: conventional clicks compared with high frequency clicks and single frequency tonebursts. J Am Acad Audiol 14: 239250. [Google Scholar]
  13. Mitchell CR, Ellingson RM, Henry JA, Fausti SA, , 2004. Use of auditory brainstem responses for the early detection of ototoxicity from aminoglycosides or chemotherapeutic drugs. J Rehabil Res Dev 41: 373382.[Crossref] [Google Scholar]
  14. Alaerts J, Luts H, Wouters J, , 2007. Evaluation of middle ear function in young children: clinical guidelines for the use of 226- and 1,000-Hz tympanometry. Otol Neurotol 28: 727732.[Crossref] [Google Scholar]
  15. Youngs R, Weir N, Tharu P, Bohara RB, Bahadur D, , 2011. Diagnostic otoscopy skills of community ear assistants in western Nepal. J Laryngol Otol 125: 2729.[Crossref] [Google Scholar]
  16. Toovey S, Jamieson A, , 2004. Audiometric changes associated with the treatment of uncomplicated falciparum malaria with co-artemether. Trans R Soc Trop Med Hyg 98: 261267.[Crossref] [Google Scholar]
  17. Kissinger E, Hien TT, Hung NT, Nam ND, Tuyen NL, Dinh BV, Mann C, Phu NH, Loc PP, Simpson JA, White NJ, Farrar JJ, , 2000. Clinical and neurophysiological study of the effects of multiple doses of artemisinin on brain-stem function in Vietnamese patients. Am J Trop Med Hyg 63: 4855. [Google Scholar]
  18. McCall MB, Beynon AJ, Mylanus EA, van der Ven AJ, Sauerwein RW, , 2006. No hearing loss associated with the use of artemether-lumefantrine to treat experimental human malaria. Trans R Soc Trop Med Hyg 100: 10981104.[Crossref] [Google Scholar]
  19. Hutagalung R, Htoo H, Nwee P, Arunkamomkiri J, Zwang J, Carrara VI, Ashley E, Singhasivanon P, White NJ, Nosten F, , 2006. A case-control auditory evaluation of patients treated with artemether-lumefantrine. Am J Trop Med Hyg 74: 211214. [Google Scholar]
  20. Carrasquilla G, Baron C, Monsell EM, Cousin M, Walter V, Lefevre G, Sander O, Fisher LM, , 2012. Randomized, prospective, three-arm study to confirm the auditory safety and efficacy of artemether-lumefantrine in Colombian patients with uncomplicated Plasmodium falciparum malaria. Am J Trop Med Hyg 86: 7583.[Crossref] [Google Scholar]
  21. Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA, , 2011. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 343: d5928.[Crossref] [Google Scholar]
  22. Viswanathan MAM, Berkman ND, Chang S, Hartling L, McPheeters LM, Santaguida PL, Shamliyan T, Singh K, Tsertsvadze A, Treadwell JR, , 2012. Assessing the Risk of Bias of Individual Studies in Systematic Reviews of Health Care Interventions. Agency for Healthcare Research and Quality Methods Guide for Comparative Effectiveness Reviews. Available at: http://effectivehealthcare.ahrq.gov/ehc/products/322/998/MethodsGuideforCERs_Viswanathan_IndividualStudies.pdf. Accessed December 11, 2013. [Google Scholar]
  23. Adjei GO, Kurtzhals JA, Rodrigues OP, Alifrangis M, Hoegberg LC, Kitcher ED, Badoe EV, Lamptey R, Goka BQ, , 2008. Amodiaquine-artesunate vs artemether-lumefantrine for uncomplicated malaria in Ghanaian children: a randomized efficacy and safety trial with one year follow-up. Malar J 7: 127.[Crossref] [Google Scholar]
  24. Maiteki-Sebuguzi C, Jagannathan P, Yau VM, Clark TD, Njama-Meya D, Nzarubara B, Talisuna AO, Kamya MR, Rosenthal PJ, Dorsey G, Staedke SG, , 2008. Safety and tolerability of combination antimalarial therapies for uncomplicated falciparum malaria in Ugandan children. Malar J 7: 106.[Crossref] [Google Scholar]
  25. Ndiaye JL, Faye B, Gueye A, Tine R, Ndiaye D, Tchania C, Ndiaye I, Barry A, Cisse B, Lameyre V, Gaye O, , 2011. Repeated treatment of recurrent uncomplicated Plasmodium falciparum malaria in Senegal with fixed-dose artesunate plus amodiaquine versus fixed-dose artemether plus lumefantrine: a randomized, open-label trial. Malar J 10: 237.[Crossref] [Google Scholar]
  26. Van Vugt M, Angus BJ, Price RN, Mann C, Simpson JA, Poletto C, Htoo SE, Looareesuwan S, White NJ, Nosten F, , 2000. A case-control auditory evaluation of patients treated with artemisinin derivatives for multidrug-resistant Plasmodium falciparum malaria. Am J Trop Med Hyg 62: 6569. [Google Scholar]
  27. Gurkov R, Eshetu T, Miranda IB, Berens-Riha N, Mamo Y, Girma T, Krause E, Schmidt M, Hempel JM, Loscher T, , 2008. Ototoxicity of artemether/lumefantrine in the treatment of falciparum malaria: a randomized trial. Malar J 7: 179.[Crossref] [Google Scholar]
  28. Frey SG, Chelo D, Kinkela MN, Djoukoue F, Tietche F, Hatz C, Weber P, , 2010. Artesunate-mefloquine combination therapy in acute Plasmodium falciparum malaria in young children: a field study regarding neurological and neuropsychiatric safety. Malar J 9: 291.[Crossref] [Google Scholar]
  29. Gorga MP, Johnson TA, Kaminski JR, Beauchaine KL, Garner CA, Neely ST, , 2006. Using a combination of click- and tone burst-evoked auditory brain stem response measurements to estimate pure-tone thresholds. Ear Hear 27: 6074.[Crossref] [Google Scholar]
  30. Sowunmi A, , 1997. Clinical study of cerebral malaria in African children. Afr J Med Med Sci 26: 911. [Google Scholar]
  31. McPherson B, Holborow CA, , 1985. A study of deafness in West Africa: the Gambian Hearing Health Project. Int J Pediatr Otorhinolaryngol 10: 115135.[Crossref] [Google Scholar]
  32. Dunmade AD, Segun-Busari S, Olajide TG, Ologe FE, , 2007. Profound bilateral sensorineural hearing loss in Nigerian children: any shift in etiology? J Deaf Stud Deaf Educ 12: 112118.[Crossref] [Google Scholar]
  33. Schmutzhard J, Kositz CH, Lackner P, Dietmann A, Fischer M, Glueckert R, Reindl M, Stephan K, Riechelmann H, Schrott-Fischer A, Schmutzhard E, , 2010. Murine malaria is associated with significant hearing impairment. Malar J 9: 159.[Crossref] [Google Scholar]
  34. Fusetti M, Eibenstein A, Corridore V, Hueck S, Chiti-Batelli S, , 1999. Mefloquine and ototoxicity: a report of 3 cases. Clin Ter 150: 379382. [Google Scholar]
  35. Wise M, Toovey S, , 2007. Reversible hearing loss in temporal association with chemoprophylactic mefloquine use. Travel Med Infect Dis 5: 385388.[Crossref] [Google Scholar]
  36. Ding D, Qi W, Yu D, Jiang H, Han C, Kim MJ, Katsuno K, Hsieh YH, Miyakawa T, Salvi R, Tanokura M, Someya S, , 2013. Addition of exogenous NAD+ prevents mefloquine-induced neuroaxonal and hair cell degeneration through reduction of caspase-3-mediated apoptosis in cochlear organotypic cultures. PLoS ONE 8: e79817.[Crossref] [Google Scholar]
  37. Kotak VC, Pendola LM, Rodriguez-Contreras A, , 2012. Spontaneous activity in the developing gerbil auditory cortex in vivo involves GABAergic transmission. Neuroscience 226: 130144.[Crossref] [Google Scholar]
  38. Nevin RL, , 2012. Limbic encephalopathy and central vestibulopathy caused by mefloquine: a case report. Travel Med Infect Dis 10: 144151.[Crossref] [Google Scholar]
  39. US Food and Drug Administration, 2013. Drug Safety Communication (Mefloquine Hydrochloride). Available at: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM362232.pdf. Accessed March 13, 2014. [Google Scholar]
  40. World Health Organization, 2010. Guidelines for the treatment of malaria, second edition. Geneva: World Health Organization. [Google Scholar]
  41. Abdulla S, Sagara I, Borrmann S, D'Alessandro U, Gonzalez R, Hamel M, Ogutu B, Martensson A, Lyimo J, Maiga H, Sasi P, Nahum A, Bassat Q, Juma E, Otieno L, Bjorkman A, Beck HP, Andriano K, Cousin M, Lefevre G, Ubben D, Premji Z, , 2008. Efficacy and safety of artemether-lumefantrine dispersible tablets compared with crushed commercial tablets in African infants and children with uncomplicated malaria: a randomised, single-blind, multicentre trial. Lancet 372: 18191827.[Crossref] [Google Scholar]
  42. Medicine OCfEB, 2009. Oxford Centre for Evidence Based Medicine-Levels of Evidence. Available at: http://www.cebm.net/?o=1025. Accessed December 9, 2013. [Google Scholar]
  43. WorldWide Antimalarial Resistance Network (WWARN) DP Study Group, 2013. The effect of dosing regimens on the antimalarial efficacy of dihydroartemisinin-piperaquine: a pooled analysis of individual patient data. PLoS Med 10: e1001564.[Crossref] [Google Scholar]
  44. Olusanya BO, Swanepoel de W, Chapchap MJ, Castillo S, Habib H, Mukari SZ, Martinez NV, Lin HC, McPherson B, , 2007. Progress towards early detection services for infants with hearing loss in developing countries. BMC Health Serv Res 7: 14.[Crossref] [Google Scholar]
  45. Cunningham M, Cox EO, , 2003. Hearing assessment in infants and children: recommendations beyond neonatal screening. Pediatrics 111: 436440.[Crossref] [Google Scholar]
  46. Benjamin J, Moore B, Lee ST, Senn M, Griffin S, Lautu D, Salman S, Siba P, Mueller I, Davis TM, , 2012. Artemisinin-naphthoquine combination therapy for uncomplicated pediatric malaria: a tolerability, safety, and preliminary efficacy study. Antimicrob Agents Chemother 56: 24652471.[Crossref] [Google Scholar]
  47. Ambler MT, Dubowitz LM, Arunjerdja R, Hla EP, Thwai KL, Viladpainguen J, Singhasivanon P, Luxemburger C, Nosten F, McGready R, , 2009. The neurological assessment in young children treated with artesunate monotherapy or artesunate-mefloquine combination therapy for uncomplicated Plasmodium falciparum malaria. Malar J 8: 207.[Crossref] [Google Scholar]
  48. Carrara VI, Phyo AP, Nwee P, Soe M, Htoo H, Arunkamomkiri J, Singhasivanon P, Nosten F, , 2008. Auditory assessment of patients with acute uncomplicated Plasmodium falciparum malaria treated with three-day mefloquine-artesunate on the north-western border of Thailand. Malar J 7: 233.[Crossref] [Google Scholar]

Data & Media loading...

  • Received : 02 Dec 2013
  • Accepted : 13 Apr 2014
  • Published online : 02 Jul 2014

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error