CEREBRAL MALARIA--ROLE OF IRON IN PATHOGENESIS &THERAPY

The proposed International Collaboration in infectious Disease Research continues an established, long-term cooperative effort between investigators at Mahidol University, Bangkok, Thailand, the University of Michigan, Ann Arbor, Michigan, and Case Western Reserve University, Cleveland, Ohio in a program of basic and clinical research designed to develop new approaches to the treatment of cerebral malaria. In many parts of the world, cerebral malaria is the most common clinical presentation and cause of death in severe malaria. Improved means of treatment 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 means of treating cerebral malaria with (i) endoperoxide derivatives of qinghpaosu such as artesunate and (ii) the combination of an iron chelator such as desferrioxamine with quinine therapy. These drugs are structurally unrelated to any of the quinoline antimalarials and exhibit no cross- resistance. Both artesunate and desferrioxamine have antimalarial effects that involve iron but by distinct mechanisms. Our studies in vitro have provided evidence that artesunate acts by using iron (probably derived from heme) to generate free radicals that damage the intraerythrocytic parasite. Artesunate may have an advantage over standard therapy with quinine alone because of its more rapid clearance of parasites from blood. 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 from the blood and because of inhibition of the underlying iron-dependent damage to the host. To evaluate the role of iron in pathogenesis and therapy of cerebral malaria, a multidisciplinary collaborative program has been developed at the Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University in Bangkok, Thailand. The specific aims of the component projects are: Project 1: to conduct a prospective, randomized, double-blind clinical trial of the treatment of cerebral malaria with (i) desferrioxamine and quinine, (ii) single agent therapy with artesunate, and (iii) single agent therapy with quinine, Project 2: to assess the effect of artesunate and desferrioxamine on the pathophysiology of cerebral malaria, using autopsy studies with light and EM, immunohistochemistry and elemental analysis;