Neurotoxicity of artemisinin derivatives

Abstract

To the Editor—We wish to draw attention to a recent letter published in this journal by Toovey [1] regarding the alleged neurotoxicity of the artemisinin derivatives. The letter was in response to a reply by Newton et al. [2] to a case reported by Franco-Paredes et al. [3]. This letter makes reference to our congress presentation [4], but Toovey has changed the title of our abstract and has overstretched our data. The title of our abstract was “Amodiaquine-Artesunate versus Artemether-Lumefantrine: Efficacy and Safety for Single or Repeat Episodes of Uncomplicated Malaria in Ghanaian Children,” but it was referenced in Toovey's letter as “Clinical Neurotoxicity of Artemisinin Drugs in Malaria Treatment.” Furthermore, the conclusion of our abstract stated, “no differences in audiometric thresholds, electrocardiographic intervals, or laboratory parameters were noted” (p. S38). It is, therefore, incorrect for Toovey to state, in support of his viewpoint, that findings from our study support the conclusion of irreversible ototoxicity after treatment with artemisinin derivatives [1]. The proceedings of a separate symposium on this topic at the 4th Multilateral Initiative on Malaria Congress have not been published.

We do not consider the issues surrounding the potential neurotoxicity of the artemisinin derivatives during routine clinical use to be resolved, and we do not rule out the possibilities that the artemisinin derivatives may have a narrower therapeutic index than assumed, that they may be associated with neuro- or ototoxicity under certain circumstances (as reported in adults working in a construction site who were treated with coartemether [5]), or that individual cases of abnormal neurological findings reported after treatment with artemisinin derivatives may be drug related [3; 6–8].

The call for a “re-examination of the safety of artemisinins in current clinical use, rather than the uncritical attribution of clinically observed abnormalities to the disease itself” (p. 1214) [1] is relevant, but the evidence currently available in the published literature [9–12] does not support the conclusion of irreversible ototoxicity, and evidence ascribing ototoxicity to artemisinins during routine clinical use [5] is not convincing enough to influence the current implementation of programs.

What may be important at this stage is to conduct studies that could overcome the methodological limitations of previous reports and could shed further light on the controversies surrounding this issue, before the stage of ubiquitous use of these drugs is reached. Initiation of pharmacovigilance programs in parallel with the current deployment of artemisinin combination therapies in endemic areas would be highly desirable.