The proposed research project is designed to compare the effect on the pathological manifestations of adult cerebral malaria of two new approaches to therapy; (i) the combination of the iron chelator, desferrioxamine B, and quinine and (ii) the endoperoxide, artesunate, as a single agent. Improved means of treating cerebral malaria are urgently needed because without therapy this disorder is almost inevitably fatal and, even with standard quinine treatment, up to 50% of subjects may die. We have recently evaluated two new approaches to the treatment of cerebral malaria with (i) endoperoxide derivatives of qinghaosu such as artesunate and (ii) the combination of an iron chelator such as desferrioxamine with quinine therapy. Both artesunate and desferrioxamine have antimalarial effects that involve iron but by distinct mechanisms. Our studies in vitro have provide evidence that artesunate acts by using iron (probable derived from the heme) to generate free radicals that damage the intraerythrocytic parasites from the blood. Despite this potential advantage, clinical trails in cerebral malaria have suggested that we swift antiparasitic action of artesunate may not be associated with more rapid recovery of full consciousness, compared to standard therapy with quinine alone. These observations raise the possibility that artesunate may also interact with iron (derived from heme, hemozoin or ferritin) in the stagnant circulation of cerebral microvessels, generating potentially harmful free radicals that might promote neurotoxicity and impede recovery of consciousness. Desferrioxamine seems to have a dual iron-related mechanism of action. The available evidence suggests that desferrioxamine (i) irreversibly damages the intraerythrocytic parasite by forming a complex with intraparasitic iron that deprives critical enzymatic systems in the plasmodium of this essential nutrient and (ii) protects patients against iron-induced peroxidant injury resulting from disordered iron metabolism in cerebral malaria. The combination of desferrioxamine and quinine may have an advantage over standard therapy with quinine alone both because of accelerated clearance of parasites for the blood and because of inhibition of the underlying iron-dependent damage to the host. In the proposed study, detailed pathological examinations at autopsy of adults who die during the Project 1 clinical trial will have three specific aims:
Aim 1 : to examine pathological features of cerebral malaria using autopsy studies with light and electron microscopy and immunohistochemistry;
Aim 2 : to determine the quantitative perivascular distribution of iron around the microvasculature to the brain with the new ultrastructural technique of electron spectroscopic imaging;
Aim 3 : to systematically compare the type, extent and neuroanatomic localization of brain lesions.
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