Abstract
BackgroundSafe, cheap and effective adjunct therapies preventing the development of, or reducing the mortality from, severe malaria could have considerable and rapid public health impact. Oral activated charcoal (oAC) is a safe and well tolerated treatment for acute poisoning, more recently shown to have significant immunomodulatory effects in man. In preparation for possible efficacy trials in human malaria, we sought to determine whether oAC would i) reduce mortality due to experimental cerebral malaria (ECM) in mice, ii) modulate immune and inflammatory responses associated with ECM, and iii) affect the pharmacokinetics of parenteral artesunate in human volunteers.Methods/Principal FindingsWe found that oAC provided significant protection against P. berghei ANKA-induced ECM, increasing overall survival time compared to untreated mice (p<0.0001; hazard ratio 16.4; 95% CI 6.73 to 40.1). Protection from ECM by oAC was associated with reduced numbers of splenic TNF+ CD4+ T cells and multifunctional IFNγ+TNF+ CD4+ and CD8+ T cells. Furthermore, we identified a whole blood gene expression signature (68 genes) associated with protection from ECM. To evaluate whether oAC might affect current best available anti-malarial treatment, we conducted a randomized controlled open label trial in 52 human volunteers (ISRCTN NR. 64793756), administering artesunate (AS) in the presence or absence of oAC. We demonstrated that co-administration of oAC was safe and well-tolerated. In the 26 subjects further analyzed, we found no interference with the pharmacokinetics of parenteral AS or its pharmacologically active metabolite dihydroartemisinin.Conclusions/SignificanceoAC protects against ECM in mice, and does not interfere with the pharmacokinetics of parenteral artesunate. If future studies succeed in establishing the efficacy of oAC in human malaria, then the characteristics of being inexpensive, well-tolerated at high doses and requiring no sophisticated storage would make oAC a relevant candidate for adjunct therapy to reduce mortality from severe malaria, or for immediate treatment of suspected severe malaria in a rural setting.Trial RegistrationControlled-Trials.com ISRCTN64793756
Highlights
Severe malaria encompasses a broad range of clinical syndromes resulting mainly from infection with Plasmodium falciparum, and is estimated to be responsible for the death of 0.5–1.0 million African children every year [1]
Results oAC protects mice from cerebral malaria To test the hypothesis that oral administration of activated charcoal (AC) might have a beneficial effect on the outcome of severe malaria, we used the model of experimental CM (ECM) caused by Plasmodium berghei ANKA (PbA) infection in C57BL/6 mice
5/5 mice treated with diluent alone died from ECM at d7 p.i., whereas 0/5 mice treated with Actidose-AquaH - derived AC died by day 9 p.i. and 3/5 survived beyond day 10 (x21 = 9; p = 0.003)
Summary
Severe malaria encompasses a broad range of clinical syndromes resulting mainly from infection with Plasmodium falciparum, and is estimated to be responsible for the death of 0.5–1.0 million African children every year [1]. In addition to the neurological syndrome of cerebral malaria (CM), death from severe malaria in children may result from severe anaemia and/or respiratory distress leading to metabolic acidosis. Cheap and effective adjunct therapies preventing the development of, or reducing the mortality from, severe malaria could have considerable and rapid public health impact. In preparation for possible efficacy trials in human malaria, we sought to determine whether oAC would i) reduce mortality due to experimental cerebral malaria (ECM) in mice, ii) modulate immune and inflammatory responses associated with ECM, and iii) affect the pharmacokinetics of parenteral artesunate in human volunteers
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