Safe and sound? Testing anti-malarial drug combinations in African children

Sulfadoxine-pyrimethamine (SP) is the first choice drug for uncomplicated falciparum malaria in much of Africa. But increasing resistance means it might not remain useful for long. Research involving Liverpool University and the London School of Hygiene and Tropical Medicine looked at the safety of an alternative drug combination, chlorproguanil-dapsone (CD), in five African countries.

The high cost of some effective anti-malarial drugs limits their widespread use in developing countries. By contrast, CD comes as a fixed-ratio tablet and is available to the public sector at low cost: less than US$0.50 for a three-day adult treatment pack.

Researchers compared the safety and efficacy of CD and SP as treatment for uncomplicated falciparum malaria. The study involved 1 850 children between the ages of 12 and 120 months: 400 each in Tanzania, Kenya, Malawi and Nigeria and 250 in Gabon. The children received either 2.0 mg/kg chlorproguanil and 2.5 mg/kg dapsone by mouth daily for three days, or 1.25 mg/kg pyrimethamine and 25 mg/kg sulfadoxine as a single dose.The results show that:

• CD is more effective than SP – 96 % of patients given CD and 89 % of those given SP showed acceptable clinical improvement and laboratory results by day 14.Overall, 46 % and 50 % of patients taking CD and SP, respectively, had adverse events, but there were no deaths. Most of the serious problems were more likely to be related to malaria than to the treatment.194 patients had signs and symptoms that might be related to treatment. This was more common with CD (11 %) than with SP (7 %). The most common side-effects were red blood cell disorders and gastrointestinal problems.
• Haemoglobin in the CD group was significantly lower than in the SP group, especially at day seven, but this was reversible.

Africa urgently needs new affordable anti-malarial drugs, either for use alone or in combination with artemisinin. The researchers conclude that CD has a greater efficacy than SP in Africa, with few serious side-effects. It is a useful option where SP is failing due to resistance. A fixed-ratio combination of CD and artesunate (CDA) is also being developed.

Regulation authorities in the UK and many African countries have approved the use of CD. When a new drug is launched in the European Union or USA, fewer than 3 000 people will normally have received it in trials. Very rare side-effects may have been missed, so the effects of using the drug are followed through ‘pharmacovigilance’ programmes. Similar surveillance will be necessary in Africa to ensure there are no major problems with CD. Pharmacovigialnce data on CD will inform the development of CDA, which is just finishing clinical Phase-II, and will start Phase-III during 2005.

Contributor(s): Peter WinstanleySource(s):
‘Comparison of chlorproguanil-dapsone with sulfadoxine-pyrimethamine for the treatment of uncomplicated falciparum malaria in young Africa children: double-blind randomised controlled trial’, The Lancet 363: 1843-1848, by A. Alloueche, et al., 2004 More information.

Funded by: GlaxoSmithKline; WHO; UK Department for International Development; Wellcome Trust id21 Research Highlight: 29 September 2004

Further Information:
Peter Winstanley
Department of Pharmacology and Therapeutics
University of Liverpool
Liverpool
UK

Email: p.a.winstanley@liverpool.ac.ukUniversity of Liverpool, UK

London School of Hygiene and Tropical Medicine, UK

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'Resisting the inevitable? Combining drugs to tackle malaria'

Artemether-lumefantrine: is it effective for treating uncomplicated malaria?'

'Value for money: cost-effective options for malaria control'

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