• 1

    Dondorp A, Nosten F, Stepniewska K, Day N, White N, 2005. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 366 :717–725.

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    • Export Citation
  • 2

    Hutagalung R, Htoo H, Nwee P, Arunkamomkiri J, Zwang J, Carrara IV, 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 :211–214.

    • Search Google Scholar
    • Export Citation
  • 3

    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 :390–396.

    • Search Google Scholar
    • Export Citation
  • 4

    Kager PA, Schultz MJ, Zijlstra EE, van den Berg B, van Boxtel CJ, 1994. Arteether administration in humans: preliminary studies of pharmacokinetics, safety and tolerance. Trans R Soc Trop Med Hyg 88 (Suppl 1):S53–S54.

    • Search Google Scholar
    • Export Citation
  • 5

    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 :261–267.

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    • Export Citation
  • 6

    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 :48–55.

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    • Export Citation
  • 7

    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 :65–69.

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    • Export Citation
  • 8

    Hien TT, Turner GD, Mai NT, Phu NH, Bethell D, Blakemore WF, Cavanagh JB, Dayan A, Medana I, Weller RO, Day NP, White NJ, 2003. Neuropathological assessment of artemether-treated severe malaria. Lancet 362 :295–296.

    • Search Google Scholar
    • Export Citation
  • 9

    Hien TT, Day NP, Nguyen HP, Nguyen TH, Pham PL, Dinh XS, Ly VC, Ha V, Waller D, Peto TE, White NJ, 1996. A controlled trial of artemether or quinine in Vietnamese adults with severe falciparum malaria. N Engl J Med 335 :76–83.

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    • Export Citation

 

 

 

 

LETTERS TO THE EDITOR

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  • 1 Shoklo Malaria Research Unit, Mae Sot, Tak Province, Thailand; Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Center for Vaccinology and Tropical Medicine, Churchill Hospital, Oxford, UK
  • 2 Shoklo Malaria Research Unit, Mae Sot, Tak Province, Thailand
  • 3 Shoklo Malaria Research Unit, Mae Sot, Tak Province, Thailand; Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
  • 4 Shoklo Malaria Research Unit, Mae Sot, Tak Province, Thailand; Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Center for Vaccinology and Tropical Medicine, Churchill Hospital, Oxford, UK
  • 5 Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Center for Vaccinology and Tropical Medicine, Churchill Hospital, Oxford, UK

Dear Sir,

Dr. Toovey rings once again the alarm bell on the potential neurotoxicity of the artemisinin derivatives. These drugs are now the cornerstone for the treatment of falciparum malaria, and use throughout the tropics is increasing rapidly, so potentially serious adverse effects are of great concern. Dr. Toovey has suggested previously that coartemether (artemether-lumefantrine) causes irreversible hearing loss and has speculated that artesunate neurotoxicity contributed to fatal outcomes in the recent SEAQUAMAT severe malaria trial in which artesunate reduced the mortality of severe malaria by 35%,1 and he now finds that the negative results from our study of the effects of artemether-lumefantrine on hearing are unconvincing.2

The neurologic lesions observed in animals exposed to large doses of parenteral oil soluble artemether or artemether were localized to certain brain stem nuclei, in particular those involved with hearing and balance.3 The lesions were associated with sustained drug exposure, which is why it was so difficult to produce them with oral drug administration (the artemisinin derivatives are rapidly absorbed and eliminated when given orally). Subsequent extensive clinical and pathologic studies have naturally focused on determining whether similar lesions occur in humans treated with these drugs for malaria. Audiometric testing, with the exception of the study of Dr. Toovey and a single volunteer in Vietnam (who had a reported small drop in hearing threshold of 15–30 db at 12,000 Hz),4,5 has not shown any effect of drug treatment. However, audiometric tests alone are not sufficient to study the potential effects of drugs on auditory function because they explore only the proximal end of the pathway. In our study,2 we measured auditory brainstem responses (ABRs) focusing on waves III–V to detect changes in the neuronal conduction between the caudal pons and the midbrain. This is the segment of the auditory pathway relevant to the location of lesions observed in animals. Our objective was not “.to provide reassurance that artemether lumefantrine was not ototoxic,” but to investigate Dr. Toovey’s allegation that otoxicity was irreversible. In this retrospective case-control study (by definition without baseline measurements), we found no differences in the auditory wavelengths and their latencies between cases exposed to coartemether and the controls who were not. Thus, if artemether-lumefantrine is ototoxic, it is not irreversible. Our results confirm the negative findings of two previous studies, which also combined ABR with audiometry.6,7

Dr. Toovey is also unconvinced by the negative results of the neuropathological study of patients who died of severe malaria in a comparative trial of artemether and quinine.8 However, it should also be noted that more than 100 survivors in this randomized and blinded study, in which patients received a high dose of parenteral artemether, underwent audiometry at discharge from the hospital.9 There was no difference between the two groups. Further prospective audiometric studies are in progress, but the weight of evidence to date increasingly suggests that the artemisinin derivatives are safe and do not affect hearing.

REFERENCES

  • 1

    Dondorp A, Nosten F, Stepniewska K, Day N, White N, 2005. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 366 :717–725.

    • Search Google Scholar
    • Export Citation
  • 2

    Hutagalung R, Htoo H, Nwee P, Arunkamomkiri J, Zwang J, Carrara IV, 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 :211–214.

    • Search Google Scholar
    • Export Citation
  • 3

    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 :390–396.

    • Search Google Scholar
    • Export Citation
  • 4

    Kager PA, Schultz MJ, Zijlstra EE, van den Berg B, van Boxtel CJ, 1994. Arteether administration in humans: preliminary studies of pharmacokinetics, safety and tolerance. Trans R Soc Trop Med Hyg 88 (Suppl 1):S53–S54.

    • Search Google Scholar
    • Export Citation
  • 5

    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 :261–267.

    • Search Google Scholar
    • Export Citation
  • 6

    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 :48–55.

    • Search Google Scholar
    • Export Citation
  • 7

    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 :65–69.

    • Search Google Scholar
    • Export Citation
  • 8

    Hien TT, Turner GD, Mai NT, Phu NH, Bethell D, Blakemore WF, Cavanagh JB, Dayan A, Medana I, Weller RO, Day NP, White NJ, 2003. Neuropathological assessment of artemether-treated severe malaria. Lancet 362 :295–296.

    • Search Google Scholar
    • Export Citation
  • 9

    Hien TT, Day NP, Nguyen HP, Nguyen TH, Pham PL, Dinh XS, Ly VC, Ha V, Waller D, Peto TE, White NJ, 1996. A controlled trial of artemether or quinine in Vietnamese adults with severe falciparum malaria. N Engl J Med 335 :76–83.

    • Search Google Scholar
    • Export Citation
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