A case-control auditory evaluation of patients treated with artemisinin derivatives for multidrug-resistant Plasmodium falciparum malaria.

Abstract

Abstract. The artemisinin derivatives are now used widely in areas with multidrug-resistant Plasmodium falciparum malaria such as Southeast Asia, but concerns remain over their potential for neurotoxicity. Mice, rats, dogs, and monkeys treated with high doses of intramuscular artemether or arteether develop an unusual pattern of focal damage to brain stem nuclei (particularly those involved in auditory processing). To investigate whether a similar toxic effect occurs in patients treated with these compounds, clinical neurologic evaluation, audiometry and early latency auditory evoked responses were measured in a single-blind comparison of 79 patients who had been treated with Ն2 courses of oral artemether or artesunate within the previous 3 years, and 79 age-and sex-matched controls living in a malaria-endemic area on the northwestern border of Thailand. There were no consistent differences in any of these test results between the cases and controls. This study failed to detect any evidence of significant neurotoxicity in patients treated previously with oral artemether or artesunate for acute malaria.Artemisinin derivatives are now used widely for the treatment of Plasmodium falciparum malaria in Southeast Asia. On the western border of Thailand where P. falciparum has developed resistance to nearly all antimalarials, the combination of mefloquine and artesunate was introduced in 1994 as a first-line treatment. 1 More than 3,000 patients with uncomplicated falciparum malaria have been recruited subsequently in prospective studies to optimize antimalarial treatment. Detailed prospective follow-up of these patients, including simple neurologic examinations, has failed to identify any serious adverse effects associated with the 2 most widely used compounds, oral artesunate or artemether. 2 However, animal studies have raised concerns about the potential neurotoxicity of some of the artemisinin derivatives. [3][4][5][6][7][8] These studies showed that rodents, dogs, and monkeys treated with intramuscular arteether or artemether (the 2 oil-soluble derivatives) develop dose-dependent damage to certain brain stem nuclei. Neurologic findings included gait disturbance, loss of spinal, brain stem, and pain responses, and, eventually, death. Pathologic changes in these experimental animals were found even in the absence of any detectable neurobehavioural symptoms. 4,5 The neuropathologic lesions were unusual in that they were confined to the neuronal cells of certain brain stem nuclei, whereas adjacent nuclei were often unaffected. The nuclei affected included those in the auditory relay. 6,7 Despite the lack of reported toxicity in extensive clinical studies to date, 2,9 it remains possible that the artemisinin compounds produce a similar pattern of neurotoxicity in humans. To assess possible toxic effects on the brain stem in patients treated with repeated courses of artemether or artesunate, brain stem auditory evoked responses (BAERs) were measured in a case-control study. These have been used 10 to detect neurotoxici...

Randomized, Prospective, Three-Arm Study to Confirm the Auditory Safety and Efficacy of Artemether-Lumefantrine in Colombian Patients with Uncomplicated Plasmodium falciparum Malaria

“…Two case-control studies in which audiological measurements including ABR were performed in patients exposed to several courses of artemisinin derivatives reported no differences in the test results between cases and controls. 7,24 A more recent case-control study along the Thailand-Myanmar border performed pure-tone threshold and ABR tests in subjects treated with A-L within the previous 5 years and found no evidence of auditory brainstem impairment attributable to A-L. 25 Sim ilarly, a pure-tone threshold and ABR study in a limited number of healthy volunteers with experimentally induced malaria, treated with A-L, found no evidence of a detrimental drug effect on the auditory system. 26 In a randomized study in malaria patients from Ethiopia, pure-tone thresholds revealed statistically significant temporary threshold shift only in the quinine group, but this effect did not appear to be clinically significant.…”

Neuropathologic toxicity of artemisinin derivatives in a mouse model.

“…29,30 Extensive clinical studies that included detailed neurologic testing and specific evaluation of auditory-evoked potentials have also reported no evidence for neurotoxic side effects of artemether. 31,32 Currently, the artemisinin drugs have been used in more than two million people with malaria, of whom more than ten thousand have been included in carefully monitored clinical trials, and no direct evidence for a clinically relevant neurotoxic effect in humans has been reported. The neurotoxicity reported in rodents, dogs, and monkeys has occurred with high doses.…”

Studies of the neurotoxicity of oral artemisinin derivatives in mice.

“…No evidence of neurotoxicity has emerged in extensive clinical studies of the artemisinin derivatives, which have included detailed neurologic testing, and specific evaluation of auditory-evoked potentials. 10 This extensive clinical experience has given rise to increased confidence in the safety of this important class of antimalarial drugs.…”