Interaction of artemisinins with oxyhemoglobin Hb-FeII, Hb-FeII, carboxyHb-FeII, heme-FeII, and carboxyheme FeII: significance for mode of action and implications for therapy of cerebral malaria.

In line with the enhancement of antimalarial activities of the current clinical artemisinins against parasites cultured under CO, the artemisinins are unaffected in vitro by carboxyhemoglobin (CO-Hb-Fe(II)) or CO-heme-Fe(II), but are competitively decomposed by Hb-Fe(II) or heme-Fe(II). In the latter case, the heme studies are greatly facilitated by solubilization of the heme in aqueous medium by use of arginine. None of the Hb species has an appreciable effect on artemisone, or on other aminoartemisinins, and antimalarial activities are either less affected or remain essentially unchanged against parasites cultured under standard microaerophilic conditions or under CO. The findings not only indicate that artemisinins do not require Hb-Fe(II) or heme-Fe(II) for promotion of antimalarial activity, but are also important in relation to the therapy of severe/complicated or cerebral malaria.