tance seriously compromises the therapeutic options for malaria infections acquired in many parts of the world. The choice of a drug should be guided at least in part by an understanding of the drug sensitivities of the parasites in the locality in which the infection originated. Typically, quinine, mefloquine, or halofantrine can be used to cure falciparum malaria that is resistant to pyrimethamine and chloroquine. In areas where artemisinin or artemether is available, these drugs generally seem to be effective. As a last line of defense, prolonged courses of tetracyclines can be useful. However, these antibiotics are slower acting than other antimalarial drugs and, when used alone, are not satisfactory for treating severe disease. For the several areas of the world plagued by strains of multidrug-resistant P. falciparum, only very restricted treatment options exist. As these strains spread, the effectiveness of antimalarial drugs will continue to erode.

Available Antimalarial Drugs
Causal Prophylactics

Primaquine The 8-aminoquinoline class of antimalarial drugs, of which primaquine is the most studied, were derived from methylene blue in one of the earliest efforts in medicinal chemistry. The discovery of methylene blue's antimalarial activity by Guttman and Ehrlich in 1891 is sometimes considered to mark the advent of modern chemotherapy (Carson, 1984).

In 1926, the world's first synthetic antimalarial agent, pamaquine, was produced in Germany. A close structural analog of primaquine, this compound proved too toxic for clinical use. Primaquine was subsequently developed during a massive screening program for new antimalarial drugs instituted by the U.S. Army during World War II.

The use of primaquine was somewhat hampered by its limited supply, but this situation has been resolved. The utility of primaquine therapy is also limited because it has a relatively low therapeutic index. That is, the dose required to produced a cure is only slightly lower than the amount considered toxic in humans. Prominent side effects include gastrointestinal distress, methemoglobinemia, and in patients with a genetic deficiency in the enzyme glucose-6-phosphate dehydrogenase, oxidant stress-induced hemolytic anemia. Changes in the drug's formulation may reduce the incidence or severity of these reactions.

The mechanism of action of primaquine against malaria liver-stage parasites and gametocytes has not been determined. Metabolism of primaquine by the host is thought to be necessary for drug activity, and most investigations have focused on the ability of primaquine metabolites to generate active oxygen species that kill the parasite (Bates et al., 1990). Though



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