Methylene blue for malaria in Africa: results from a dose-finding study in combination with chloroquine

The increasing resistance of Plasmodium falciparum to existing safe and affordable drugs such as chloroquine (CQ) and pyrimethamine-sulfadoxine severely threatens the available options for malaria control in sub-Saharan Africa (SSA) [1]. To maximise efficacy and to minimise resistance development, malaria combination therapy has become a new paradigm [2]. Although a small number of new malaria drugs including artemisinin derivates have been developed in recent years, these are usually too expensive for unsubsidised use in SSA.Methylene blue (MB) has already been used some 100 years ago against malaria but it disappeared when CQ and other drugs entered the market [3]. MB, a specific inhibitor of P. falciparum glutathione reductase, has the potential to reverse CQ resistance and it prevents the polymerization of haem into haemozoin similar to 4-amino-quinoline antimalarials [4]. It has recently been shown that the combination MB-CQ is safe in adults and children with and without G6PD deficiency [5-7]. However, oral MB given twice daily (4 mg/kg/day) together with a standard dose of CQ over three days was not effective in the treatment of uncomplicated malaria in young children of Nouna town in Burkina Faso in 2003. The day 14 CF rate was 53.7%, 95% CI 37.4–69.3, in the CQ control arm [7]. The aim of the present study was to assess the safety and efficacy of higher and more frequent MB doses in combination with CQ in a comparable study population in the same area.A single centre uncontrolled trial with three dose levels was conducted during the rainy season 2004 at the district hospital of Nouna in north-western Burkina Faso, an area of intense malaria transmission [8]. Febrile children from Nouna town were invited to the hospital for examination and treatment. Inclusion criteria were age 6–59 months, uncomplicated malaria (axillary temperature ≥ 37.5°C and ≥ 2.000 P. falciparum asexual parasites per μl blood), haemoglobin ≥ 8 g/dl, absence of severe malaria and other