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LETTER TO THE EDITOR

Dear Sir:

We appreciate the comments of Chippaux and others in response to our work pertaining to the antischistosomal properties of artemisinin and its derivatives in laboratory studies and clinical trials,¹ and particularly our recent article assessing the efficacy of artemether in preventing patent Schistosoma haematobium infections.²

First, all our research adhered to protocols that were subject to institutional reviews by the respective boards of the Swiss Tropical Institute and the Center Suisse de Recherches Scientifiques, and were signed by a clinical coordinator and a project manager from the World Health Organization/TDR that subsequently granted financial support. Ethical clearance was obtained from the Ministry of Public Health, Côte d’Ivoire. Written informed consent was sought from parents or legal guardians of all 440 participating schoolchildren.

Second, the primary objective of our work was to establish whether repeated orally administered artemether at a dose of 6 mg/kg once every four weeks had a significant effect on S. haematobium incidence and infection intensity. Addressing this objective necessitated an epidemiologic setting that is well characterized in terms of its overall endemicity and rapid re-infection rates of S. haematobium, i.e., Taabo, in south central Côte d’Ivoire.³

Third, we are well aware that artemether dose regimens used in our studies to curtail the development of adult schistosomes that sequentially cause morbidity are different from those currently recommended for malaria chemotherapy (e.g., three daily doses of 4 mg/kg of artemether in combination with a single or split dose of mefloquine on day 2 or 3).⁴ In our study, we addressed this issue by monitoring malaria parasites and concurrent administration of sulfadoxine-pyrimethamine to parasite-positive subjects.² Importantly, there is no evidence of clinically relevant resistance to any of the artemisinin derivatives, although these compounds have been administered to millions of malaria patients.⁵ Among other reasons, this is explained by their very short elimination half-lives.^5,6

Fourth, Chippaux and others correctly note that the protective efficacy of 0.25 (95% confidence interval = 0.08–0.38) is low; therefore, artemether alone is unlikely to interrupt transmission of S. haematobium. However, infection intensity, microhematuria, and macrohematuria were all reduced by >50%, which in turn is relevant for morbidity control. We have emphasized that the protective efficacy against this schistosome species is considerably lower than those previously observed against S. japonicum and S. mansoni.

Finally, and most importantly, we do not propose "a new control strategy," but rather discuss the potential of artemether "as an additional tool for integrated schistosomiasis control." Artemisinins might prove invaluable for well-defined high-risk groups, i.e., construction workers in water resource development projects or flood relief workers.¹ In addition, current evidence suggests that combination chemotherapy for treating schistosomiasis, using praziquantel together with an artemisinin derivative (or another compound with a similar mechanism of action), is beneficial and results in elevated cure and egg reduction rates.⁷

1. Utzinger J, Xiao SH, N’Goran EK, Bergquist R, Tanner M, 2001. The potential of artemether for the control of schistosomiasis. Int J Parasitol 31: 1549–1562.
2. N’Goran EK, Utzinger J, Gnaka HN, Yapi A, N’Guessan NA, Kigbafori SD, Lengeler C, Chollet J, Xiao SH, Tanner M, 2003. Randomized, double-blind, placebo-controlled trial of oral artemether for the prevention of patent Schistosoma haematobium infections. Am J Trop Med Hyg 68: 24–32.
3. N’Goran EK, Utzinger J, N’Guessan AN, Müller I, Zamblé K, Lohourignon KL, Traoré M, Sosthène BA, Lengeler C, Tanner M, 2001. Reinfection with Schistosoma haematobium following school-based chemotherapy with praziquantel in four highly endemic villages in Côte d’Ivoire. Trop Med Int Health 6: 817–825.
4. World Health Organization, 1998. The Use of Artemisinin and its Derivatives as Anti-Malarial Drugs: Report of a Joint CTD/ DMP/TDR Informal Consultation. Geneva: World Health Organization.
5. Meshnick SR, 2002. Artemisinin: mechanisms of action, resistance and toxicity. Int J Parasitol 32: 1655–1660.
6. Hastings IM, Watkins WM, White NJ, 2002. The evolution of drug-resistant malaria: the role of drug elimination half-life. Philos Trans R Soc Lond B Biol Sci 357: 505–519.
7. Utzinger J, Keiser J, Xiao SH, Tanner M, Singer BH, 2003. Combination chemotherapy of schistosomiasis in laboratory studies and clinical trials. Antimicrob Agents Chemother 47: 1487–1495.

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