• 1

    Kager PA, Schultz MJ, Zijlstra EE, van den Berg B, van Boxtel C, 1994. Arteether administration in humans: preliminary studies of pharmacokinetics, safety and tolerance. Trans R Soc Trop Med Hyg 88 :53–54.

    • Search Google Scholar
    • Export Citation
  • 2

    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
  • 3

    Toovey S, 2006. Effects of weight, age, and time on artemether-lumefantrine associated ototoxicity and evidence of irreversibility. Travel Med Infect Dis 4 :71–76.

    • Search Google Scholar
    • Export Citation
  • 4

    Claessen FA, van Boxtel CJ, Perenboom RM, Tange RA, Wetsteijn JC, Kager PA, 1998. Quinine pharmacokinetics: ototoxic and cardiotoxic effects in healthy Caucasian subjects and in patients with falciparum malaria. Trop Med Int Health 3 :482–489.

    • Search Google Scholar
    • Export Citation
  • 5

    Tange RA, Dreschler WA, Claessen FA, Perenboom RM, 1997. Ototoxic reactions of quinine in healthy persons and patients with Plasmodium falciparum infection. Auris Nasus Larynx 24 :131–136.

    • Search Google Scholar
    • Export Citation
  • 6

    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 :211–214.

    • Search Google Scholar
    • Export Citation
  • 7

    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
  • 8

    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
  • 9

    Toovey S, 2005. Reply to comment on: audiometric changes associated with the treatment of uncomplicated falciparum malaria with co-artemether. Trans R Soc Trop Med Hyg 99 :314–315.

    • Search Google Scholar
    • Export Citation
  • 10

    Toovey S, 2005. Reply to comment on: Audiometric changes associated with the treatment of uncomplicated falciparum malaria with co-artemether. Trans R Soc Trop Med Hyg 99 :316–317.

    • Search Google Scholar
    • Export Citation
  • 11

    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
  • 12

    Schmuck G, Roehrdanz E, Haynes RK, Kahl R, 2002. Neurotoxic mode of action of artemisinin. Antimicrob Agents Chemother 46 :821–827.

  • 13

    White NJ, Dondorp AM, Nosten F, Day NPJ, 2006. Artesunate versus quinine for severe falciparum malaria—authors’ reply. Lancet 367 :111–112.

    • Search Google Scholar
    • Export Citation
  • 14

    Franco-Paredes C, Dismukes R, Nicolls D, Kozarsky PE, 2005. Reply to Newton et al. Clin Infect Dis 41 :1688–1689.

 

 

 

 

 

A CASE-CONTROL AUDITORY EVALUATION OF PATIENTS TREATED WITH ARTEMETHER-LUMEFANTRINE

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  • 1 Royal Free and University College Medical School, London, United Kingdom

Dear Sir,

There are now three reports of human ototoxicity with artemisinin or artemisinin combination treatments (ACTs; Adjei and others, unpublished data).13 All of these studies conducted baseline audiograms before drug exposure and were able to measure hearing threshold shifts in individual subjects and to detect subtle losses in hearing threshold.

One of the studies that conducted baseline audiometry was performed in healthy volunteers.1 An ototoxicity study in subjects with severe malaria, which included baseline audiograms, showed fully reversible shifts in hearing threshold under treatment with quinine.4,5 These facts all point away from malaria and toward artemisinins and ACTs as a cause of hearing loss.

A recently published Thai study had hoped to provide reassurance that artemether-lumefantrine was not ototoxic.6 Given the deficiencies of this Thai study, it is unable to offer such reassurance.

First, the Thai study failed to include any baseline measurements (i.e., pre-drug exposure measurements). This fundamental weakness precludes the Thai study from drawing any conclusions about hearing threshold shifts in individual subjects. This same deficiency was also present in two earlier studies quoted by the Thai report.7,8 The need for baseline audiometry was pointed out in the original Mozambican paper referred to by the Thai paper, as well as in subsequent published correspondence.2,9,10 The two earlier studies quoted in the Thai report also suffered from lack of drug exposure standardization.7,8

Second, the degree of hearing loss reported in both treated subjects and controls in the Thai study is a major confounder. Given the magnitude of the threshold shifts reported in both treated subjects and controls, it is quite possible that any subtle artemether-lumefantrine associated threshold shift would have been obscured and consequently remained undetected.

Third, the long interval between drug exposure and audiometry in the Thai study lays it open to any number of additional confounders. In contrast, all subjects in the Mozambican study lived and worked in the same environment and had post-exposure audiometry conducted before discharge from that environment.

With regard to the necropsy study quoted in the Thai report,11 Schmuck and others12 have shown that artemisinin-induced neurotoxicity does not manifest microscopically before day 7 after exposure, with the total extent of cell injury or death not fully manifest before day 14 after exposure. This crucial, but apparently overlooked, finding must cast doubt on the necropsy study, in which the median time between initiation of artemisinin therapy and death was 76.5 hours (interquartile range, 8–331 hours); the findings of Schmuck and others also call into question a large number of animal artemisinin safety studies.

Recently emerged additional data from the SEAQUA-MAT study also support clinical artemisinin neurotoxicity.13 In this study, malaria patients treated with intravenous artesunate who developed late hypoglycemia were more likely to die than other artesunate recipients; patients treated with quinine who developed late hypoglycemia were not more likely to die than other quinine recipients. This finding is fully compatible with the known mechanism of artemisinin neurotoxicity: severe neuronal energy depletion with collapse of the inner mitochondrial membrane potential and profound ATP depletion in brainstem neurons. Energy-depleted neurons might be hard pressed to survive the additional challenge of hypoglycemia.

Inconvenient as it might be, evidence that currently deployed artemisinins might well be neurotoxic is accumulating14 and needs to be confronted. Given the enthusiasm for, and widespread deployment of, these agents, a careful and thoughtful re-examination of artemisinin neurotoxicity is called for, with studies that are capable of making a meaningful contribution.

REFERENCES

  • 1

    Kager PA, Schultz MJ, Zijlstra EE, van den Berg B, van Boxtel C, 1994. Arteether administration in humans: preliminary studies of pharmacokinetics, safety and tolerance. Trans R Soc Trop Med Hyg 88 :53–54.

    • Search Google Scholar
    • Export Citation
  • 2

    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
  • 3

    Toovey S, 2006. Effects of weight, age, and time on artemether-lumefantrine associated ototoxicity and evidence of irreversibility. Travel Med Infect Dis 4 :71–76.

    • Search Google Scholar
    • Export Citation
  • 4

    Claessen FA, van Boxtel CJ, Perenboom RM, Tange RA, Wetsteijn JC, Kager PA, 1998. Quinine pharmacokinetics: ototoxic and cardiotoxic effects in healthy Caucasian subjects and in patients with falciparum malaria. Trop Med Int Health 3 :482–489.

    • Search Google Scholar
    • Export Citation
  • 5

    Tange RA, Dreschler WA, Claessen FA, Perenboom RM, 1997. Ototoxic reactions of quinine in healthy persons and patients with Plasmodium falciparum infection. Auris Nasus Larynx 24 :131–136.

    • Search Google Scholar
    • Export Citation
  • 6

    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 :211–214.

    • Search Google Scholar
    • Export Citation
  • 7

    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
  • 8

    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
  • 9

    Toovey S, 2005. Reply to comment on: audiometric changes associated with the treatment of uncomplicated falciparum malaria with co-artemether. Trans R Soc Trop Med Hyg 99 :314–315.

    • Search Google Scholar
    • Export Citation
  • 10

    Toovey S, 2005. Reply to comment on: Audiometric changes associated with the treatment of uncomplicated falciparum malaria with co-artemether. Trans R Soc Trop Med Hyg 99 :316–317.

    • Search Google Scholar
    • Export Citation
  • 11

    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
  • 12

    Schmuck G, Roehrdanz E, Haynes RK, Kahl R, 2002. Neurotoxic mode of action of artemisinin. Antimicrob Agents Chemother 46 :821–827.

  • 13

    White NJ, Dondorp AM, Nosten F, Day NPJ, 2006. Artesunate versus quinine for severe falciparum malaria—authors’ reply. Lancet 367 :111–112.

    • Search Google Scholar
    • Export Citation
  • 14

    Franco-Paredes C, Dismukes R, Nicolls D, Kozarsky PE, 2005. Reply to Newton et al. Clin Infect Dis 41 :1688–1689.

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