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.
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.


RESULTS
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 IFNgamma(+)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
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.


BACKGROUND
Controlled-Trials.com ISRCTN64793756.
de Souza
J Brian
JB
Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
Okomo
Uduak
U
Alexander
Neal D
ND
Aziz
Naveed
N
Owens
Benjamin M J
BM
Kaur
Harparkash
H
Jasseh
Momodou
M
Muangnoicharoen
Sant
S
Sumariwalla
Percy F
PF
Warhurst
David C
DC
Ward
Stephen A
SA
Conway
David J
DJ
Ulloa
Luis
L
Tracey
Kevin J
KJ
Foxwell
Brian M J
BM
Kaye
Paul M
PM
Walther
Michael
M
D000284:Administration, Oral; D000328:Adult; D000818:Animals; D000962:Antimalarials; D037621:Artemisinins / Q000493:pharmacokinetics*; D000077332:Artesunate; D002606:Charcoal / Q000494:pharmacology / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007263:Infusions, Parenteral; D016779:Malaria, Cerebral / Q000188:drug therapy / Q000401:mortality / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010962:Plasmodium berghei / Q000187:drug effects; D015996:Survival Rate
D000962:Antimalarials; D037621:Artemisinins; D002606:Charcoal; D000077332:Artesunate