The proposed research is designed to determine whether therapy of adult cerebral malaria with the combination of the iron chelator, desferrioxamine B, and quinine will lead to faster recovery of full consciousness compared to treatment with artesunate as a single agent. Two potential advances in chemotherapy for cerebral malaria over standard quinine therapy have emerged recently. (i) Derivatives of qhingausu such as artesunate may have an advantage over quinine by a greater speed of action in parasite clearance through an iron-dependent, free artesunate may also interact with iron derived from heme or hemozoin in the cerebral microcirculation to generate free radicals that might promote neurotoxicity and hinder recovery of full consciousness. (ii) The addition of iron chelation with desferrioxamine B to standard quinine therapy for cerebral malaria may both enhance clearance of parasitemia through a direct, stage-specific, shizontocidal effect of iron withholding and also protect against damage to the central nervous system by inhibiting iron-induced peroxidant damage to host cells and subcellular structures. Because of the potential twofold beneficial mechanism of action by iron chelation, including both enhanced parasite clearance and central nervous system protection, we postulate that the combination of desferrioxamine B and quinine may prove to be superior to single agent artesunate in the therapy of cerebral malaria. In clinical studies we found that therapy with artesunate in acute, uncomplicated falciparum malaria cleared parasites and fever faster that mefloquine (P<0.05). By contrast, in complicated malaria, studies by others have produced conflicting evidence as to whether enhanced parasite clearance will lead to faster recovery from coma when artesunate is used to treat cerebral malaria. For quinine led to a two-fold increase in the relative rate of parasite clearance parasitemia (P=0.01) and to a 2.2-fold increase in the relative rate of recovery of full consciousness from deep coma (P=0.03) compared to quinine plus placebo. We now propose a randomized, double-blind, clinical trial in adults with cerebral malaria to compare the effect of the combination of desferrioxamine B and quinine on recovery from coma to the effects of artesunate and of quinine as single agents.
The specific aims are to:
Aim 1 : Determine if, in comparison to artesunate therapy alone, the combination of desferrioxamine B and quinine will speed recovery of full consciousness in adults with cerebral malaria;
Aim 2 : Determine if the combination of desferrioxamine B and quinine will enhance the clearance of P.falciparum from the blood, decrease the incidence of neurologic sequelae and prevent acute medical complications.
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