RESISTANCE TO ARTEMISININ OF MALARIA PARASITES (PLASMODIUM-FALCIPARUM) INFECTING ALPHA-THALASSEMIC ERYTHROCYTES IN-VITRO - COMPETITION IN DRUG ACCUMULATION WITH UNINFECTED ERYTHROCYTES

Plasmodium falciparum infecting hemoglobin (Hb)H and/or Hb Constant Sp ring erythrocytes has higher resistance to artemisinin in vitro than w hen infecting normal erythrocytes. This is due to low drug accumulatio n of infected erythrocytes resulting from competition with uninfected variant erythrocytes, which have a higher accumulation capacity than g enetically normal cells. Drug accumulation of the parasite was shown t o be saturable and dependent on metabolic energy. The 50% inhibitory c oncentrations (IC50's) for the parasite in HbH/Hb Constant Spring eryt hrocytes were decreased when normal erythrocytes were added to the inf ected cells, and correspondingly, the IC50's in normal erythrocytes we re increased when HbH/Hb Constant Spring erythrocytes were added to th e infected cells. The changes of IC50 corresponded to the variation in drug accumulation of mixtures of normal and variant erythrocytes of d ifferent compositions. The IC50's for the parasite in variant erythroc ytes were also greatly decreased when the hematocrit of the culture wa s lowered, while the IC50's in normal erythrocytes were independent of the hematocrit. The increase in IC50 values for the parasites infecti ng variant erythrocytes was also related to the decrease in parasite a ccumulation, indicating that drug accumulation capacity of the parasit e also has a role in determining drug sensitivity. Artemisinin sensiti vity therefore is determined by its accessibility to the parasite, whi ch is decreased in infected variant erythrocytes.