drug does. In endemic areas, the worst treatment results are seen in young children who have little immunity. In contrast, although their degree of immune protection cannot be quantitated or assumed, older children or adults in high-transmission areas may do surprisingly well with failing drugs because much of their therapeutic response stems from immunity rather than antimalarial drug action.

In severe falciparum malaria, the stage at which an antimalarial drug acts is especially important since the ultimate goal of treatment is to halt parasite maturation to late-stage, cytoadherent parasites (i.e., mature schizonts that attach to endothelial cells lining small blood vessels), which are primarily responsible for life-threatening complications. The artemisinin derivatives are advantageous because they prevent parasites from maturing to these more pathological stages, whereas quinine and quinidine do not affect parasites until they have already cytoadhered. The antifols act even later in the cycle, and are not recommended for severe malaria (Yayon et al., 1983; ter Kuile et al., 1993). None of the drugs will prevent rupture of infected erythrocytes and reinvasion once a schizont has formed. Young ring forms (i.e., early asexual parasites) also are relatively drug resistant, especially to quinine and pyrimethamine.

Artemesinin derivatives offer the broadest antimalarial action against the range of developmental stages, and the most rapid in vivo activity (ter Kuile et al., 1993; White, 1997). These compounds (and, to a lesser extent, chloroquine) prevent ring stages from maturing, hastening their clearance, and preventing end-organ pathology that would otherwise occur if cytoadherence progressed unchecked (Chotivanich et al., 2000).

MECHANISMS OF ACTION AND DRUG RESISTANCE

Antifolate Drugs

Pyrimethamine, and biguanides such as cycloguanil interfere with folic acid synthesis, inhibiting the parasite enzyme known as dihydrofolate reductase-thymidilate synthase (DHFR). Sulfonamides act at the previous step in the folic acid pathway, inhibiting the parasite enzyme dihydropteroate synthase (DHPS). There is marked synergy between these two classes of drugs when they are taken together. However, resistance to pyrimethamine in P. falciparum developed within a few years of its introduction (Peters, 1987) due to point mutations in the DHFR gene, which cause 100- to 1,000-fold reduced affinity of the enzyme complex to the drug. Progressive mutations in the DHFR gene of P. falciparum further decreased efficacy. Triple mutant infections are relatively resistant to antifolate treatment; with a fourth mutation within the malaria parasite, antifolate drugs become completely ineffective.



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