Timing is everything for artemisinin action

In Cambodia, the same region where chloroquine resistance developed in the 1950s, a significant delay in the Plasmodium falciparum parasite clearance rates to artemisinins has been persistently observed over the past 5 y, raising the specter of artemisinin “resistance” (1). The parasites in this region have imprints of genetic selection associated with the delay in parasite clearance rates measured by serial patient blood films (2⇓–4). However, the traditional continuous inhibition concentration 50% (IC50) drug assays measured directly with parasites from patient’s blood indicate no significant difference in IC50s (1, 5). In PNAS, Klonis et al. (6) expand upon our knowledge of intraerythrocytic action of artemisinins, in a tour de force of P. falciparum in vitro culture work, by exposing three laboratory isolates to short 1-, 2-, 4-, or 6-h pulses of artemisinins every hour throughout the 48-h life cycle to determine pulse drug IC50. An important unique finding is that an early ring stage that is less than 8-h-old is hypersensitive to artemisinins, and that intrinsic differences preexist among decades-old laboratory P. falciparum isolates not thought to be exposed to the artemisinin drugs before isolation. In an earlier report by Klonis et al. (7), as well as a report by ter Kuile et al. (8), the timing of artemisinin action had been demonstrated to coincide with the onset of hemoglobin ingestion during the late-ring or early trophozoite stages. This experimental window of artemisinin duration of action during the 48-h P. falciparum erythrocyte life cycle is longer than quinoline drugs, such as quinine, mefloquine, or lumefantrine, which inhibit heme crystallization (8). Many malariologists believe artemisinins work after iron activation to induce carbon-centered radical damage of nearby proteins for low 1- to 10-nM inhibition of Plasmodium trophozoite stages, …