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Oral Activated Charcoal Prevents Experimental Cerebral Malaria in Mice and in a Randomized Controlled Clinical Trial in Man Did Not Interfere with the Pharmacokinetics of Parenteral Artesunate

de Souza, JB; Okomo, U; Alexander, ND; Aziz, N; Owens, BMJ; Kaur, H; Jasseh, M; ... Walther, M; + view all (2010) Oral Activated Charcoal Prevents Experimental Cerebral Malaria in Mice and in a Randomized Controlled Clinical Trial in Man Did Not Interfere with the Pharmacokinetics of Parenteral Artesunate. PLOS ONE , 5 (4) , Article e9867. 10.1371/journal.pone.0009867. Green open access

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Abstract

Background: Safe, 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 Findings: We 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 IFN gamma(+) 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/Significance: oAC 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.

Type: Article
Title: Oral Activated Charcoal Prevents Experimental Cerebral Malaria in Mice and in a Randomized Controlled Clinical Trial in Man Did Not Interfere with the Pharmacokinetics of Parenteral Artesunate
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0009867
Publisher version: http://dx.doi.org/10.1371/journal.pone.0009867
Language: English
Additional information: © 2010 de Souza et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. British Medical Research Council (#G0400786 to PMK; http://www.mrc.ac.uk/index.htm), the Medical Research Council Laboratories (UK) core funding to the MRC Gambia Unit, a North Shore-LIJ Faculty Award to LU, the NIGMS, and the North Shore-LIJ GCRC (#1MO1RR018535; http://www.feinsteininstitute.org/Feinst​ein/GCRC). BO is supported by a MRC Postgraduate Studentship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Keywords: SEVERE FALCIPARUM-MALARIA, TUMOR-NECROSIS-FACTOR, CELL DEFORMABILITY, IMMUNE-RESPONSE, KENYAN CHILDREN, EXPRESSION, QUININE, RECEPTOR, TANZANIA, HOST
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/120618
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