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384 Ashley and Whiteway rapidly to the liver where they invade individual hepatocytes. They then developinto hepatic schizonts, which mature over five to seven days before rupturingto release thousands of merozoites into the blood. These immediately invade redblood cells. This marks the beginning of the asexual life cycle of the “blood stage”parasite. The young trophozoites start as tiny “rings,” which look like signet ringsor stereo headphones under light microscopy. This circulating stage, which lasts 12to 18 hours, is less pathogenic than the more mature trophozoite stages, which inP. falciparum infections cause cytoadherence of the infected erythrocytes. Sequestrationof the parasitized erythrocytes leads to microvascular obstruction and is animportant mechanism in the pathogenesis of severe disease. Mature trophozoitesdevelop into schizonts, which will rupture at the end of the 48-hour asexual cyclereleasing more merozoites. These invade more red cells starting a new cycle andcausing the infection to expand exponentially. The sexual life cycle, which in P.falciparum starts slightly later than the asexual cycle, results from the production ofmale and female gametocytes from asexual parasites. As the switch from asexual tosexual development is density dependent, early effective treatment of falciparummalaria prevents significant gametocytogenesis and therefore interrupts transmission.The gametocytes may persist in the circulation for days or weeks. They are notpathogenic to their host, but they are the source of transmission of malaria, and thusgametocytocidal activity is of public health importance. In P. vivax and P. ovaleinfections, some of the sporozoites inoculated by the mosquito remain dormant inthe liver as hypnozoites, which may cause relapses weeks or months later—evenafter an apparently successful treatment of the blood stage infection.Antimalarial Stage SpecificityThe term blood schizontocide is widely used to describe the action of antimalarialson blood stage parasites, although it is a slight misnomer as maturetrophozoites are more susceptible to the antimalarial drugs and formed schizontsare relatively resistant. Young ring trophozoites are also relatively drug resistant(particularly to quinine and pyrimethamine). CQ acts mainly on the large ringform and mature trophozoite stages of the parasite. Quinine acts principally onthe mature trophozoite stage of parasite development while the antifols act alittle later. The artemisinin derivatives are the most rapidly acting of the knownantimalarials, and they have the broadest time window of antimalarial effect(from ring forms to early schizonts). These compounds prevent maturation ofring stages, thus reducing subsequent cytoadherence and by inference, diseaseseverity. Only the 8-aminoquinolines, primaquine, and tafenoquine are capable ofkilling the hypnozoites of P. vivax and P. ovale, and these are also the onlycompounds, which kill the mature (stage 5) gametocytes of P. falciparum. Theartemisinin derivatives reduce gametocytemia by rapidly reducing the parasitebiomass and also killing immature gametocytes (stages 1 to 4). In contrast, in thetreatment of the other three malarias, all the antimalarial drugs are gametocytocidal(21,22).MECHANISMS OF RESISTANCEStable resistance arises from the selection and spread of parasites with spontaneouschromosomal point mutations or gene duplications, which are independent of drugselection pressure (Table 1). The frequency of naturally occurring viable mutants