Paracetamol Effect on Oxidative Stress and Renal Function in Severe Malaria
Status:
Completed
Trial end date:
2014-09-21
Target enrollment:
Participant gender:
Summary
Blackwater fever, characterized by intravascular haemolysis and hemoglobinuria, is an
important cause of renal impairment and mortality in severe malaria caused by Plasmodium
falciparum. The largest malaria clinical trials report blackwater incidences of 5-7% in Asian
adults and 4% in African children with severe malaria treated with artesunate or quinine. The
prevalence of blackwater fever in Chittagong, Bangladesh is 15% with associated rates of
renal failure and mortality of 42.9% and 14.2% respectively.
The fundamental characteristic of blackwater fever is the presence of intravascular hemolysis
of both infected and uninfected erythrocytes and release of free haemoglobin. The cytotoxic
free haemoglobin present can cause severe oxidative damage as a result of haem redox cycling
yielding ferric and ferryl heme, which generate radical species that induce lipid
peroxidation and subsequent production of F2-isoprostanes (F2-IsoPs). Evidence suggests that
F2-IsoPs generated by the hemoprotein-catalyzed oxidation of lipids are responsible for the
oxidative damage and vasoconstriction associated with renal injury in haemolytic disorders
and rhabdomyolysis.
A novel mechanism of paracetamol was recently demonstrated, showing that paracetamol is a
potent inhibitor of hemoprotein-catalyzed lipid peroxidation by reducing ferryl heme to its
less toxic ferric state and quenching globin radicals. In a recent proof of concept trial,
paracetamol at therapeutic levels was shown to significantly decrease oxidant kidney injury,
improve renal function and reduce renal damage by inhibiting the hemoprotein-catalyzed lipid
peroxidation in a rat model of rhabdomyolysis-induced renal injury. Since adults with severe
malaria demonstrate increased concentrations of cell-free haemoglobin, and urinary F2-IsoPs,
the investigators hypothesize that this novel inhibitory mechanism of paracetamol may provide
renal protection in this population by reducing the hemoprotein-induced lipid peroxidation.
As there is currently no consensus that exists concerning adequate medical treatment for
blackwater fever, the potential application of this safe and extensively used drug would be
of great benefit.