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JAC Advance Access published online on July 1, 2003
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkg319
© 2003 by The British Society for Antimicrobial Chemotherapy
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© 2003 The British Society for Antimicrobial Chemotherapy

Original article

Hydroxychloroquine is much less active than chloroquine against chloroquine-resistant Plasmodium falciparum, in agreement with its physicochemical properties

David C. Warhurst 1 *, Jonathan C. P. Steele 1 , Ipemida S. Adagu 1 , John C. Craig 2 , and Christopher Cullander 2

1 Pathogen Molecular Biology and Biochemistry Unit, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel St., London WC1E 7HT, UK
2 Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143-00446, USA

* Corresponding author. E-mail: david.warhurst{at}lshtm.ac.uk.

Received 6 September 2002 ; revised 6 February 2003 ; accepted 6 May 2003

Abstract

The 4-aminoquinoline drug hydroxychloroquine (HCQ) is reported to be as active as chloroquine (CQ) against falciparum malaria, and less toxic. Existing prophylactic regimens for areas where there is CQ-resistant malaria recommend CQ with proguanil as an alternative where none of the three preferred regimens (atovaquone-proguanil, doxycycline or mefloquine) is thought suitable. In such cases, toxicity is likely when CQ-proguanil is administered to persons being treated for autoimmune disease with daily HCQ. The question therefore arises whether in such circumstances HCQ could effectively replace the CQ component of the prophylactic combination. We confirmed similar activity of CQ and HCQ against CQ-sensitive Plasmodium falciparum, but found that whereas HCQ in vitro was 1.6 times less active than CQ in a CQ-sensitive isolate, it was 8.8 times less active in a CQ-resistant isolate. The result can also be predicted from an analysis of the physicochemical properties of CQ and HCQ. To give limited protective effect similar to 300 mg CQ base weekly against CQ-resistant P. falciparum would demand daily doses of HCQ above the recommended safe level. These observations contraindicate the use of HCQ in prophylaxis or treatment of CQ-resistant falciparum malaria. Where CQ-proguanil prophylaxis is the only option available in a patient on high-dose HCQ treatment, visiting a CQ-resistant area, replacement of the anti-inflammatory regimen by a daily CQ course at a suitable dose should be considered.

Keywords: hydroxychloroquine, chloroquine, amodiaquine, drug-resistance, enantiospecificity
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