THE CHEMOTHERAPY OF RODENT MALARIA .39. ULTRASTRUCTURAL-CHANGES FOLLOWING TREATMENT WITH ARTEMISININE OF PLASMODIUM-BERGHEI INFECTION IN MICE, WITH OBSERVATIONS OF THE LOCALIZATION OF [H-3]-DIHYDROARTEMISININE IN P-FALCIPARUM INVITRO

Ultrastructural changes were followed in Plasmodium berghei after the treatment of the mouse host with a single 10 mg kg-1 dose of artemisinine (qinghaosu). After 30 minutes, changes in the limiting and other membranes of the parasite were seen, together with alterations in ribosomal organization and endoplasmic reticulum. No changes were noted in digestive vacuoles or pigment, but nuclear membrane blebbing developed after one hour and segregation of the nucleoplasm after three hours. Further degenerative changes with disorganization and death occurred from eight hours onwards. The morphological changes in ribosomes and endoplasmic reticulum correlate in time with the depression in protein synthesis observed in P. falciparum in vitro. Similarly, the onset of nucleoplasmic segregation correlates with the development of nucleic acid synthesis inhibition. Tritiated reduced drug was shown to be localized in parasite membranes, indicating that changes in membrane integrity might precede the early depression of protein synthesis. Membrane association of artemisinine may be related to its amphipathic characteristics and similarity in some respects to a sterol.