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Chapter 5 : To Destroy Liver Stages: Primaquine and Tafenoquine
From 1947 to 1951, monkeys were used in the search for a safe and effective radical-cure drug, one superior to pamaquine, pentaquine, and isopentaquine. Thirty-four derivatives with diverse origins were screened, and one in particular, SN-13272, prepared by Robert C. Elderfield was especially interesting. Elderfield’s compound was named primaquine. Gram for gram, primaquine was about four times as effective as pamaquine. In the early stages of the American involvement in the war in Vietnam, the U.S. military was faced with increasing numbers of casualties from chloroquine-resistant P. falciparum. Tafenoquine was shown to eliminate the dormant or “sleeping” hypnozoite stages in the livers of P. cynomolgi-infected rhesus monkeys. The pathway from methylene blue to tafenoquine is shown. Tafenoquine is under development jointly by WRAIR and Glaxo-SmithKline Pharmaceuticals as a replacement for primaquine. The mechanism of therapeutic action and toxicity of this 8-aminoquinoline, like those of primaquine, remain incompletely understood despite more than five decades of study. In vitro tests showed that tafenoquine was 5- to 10-fold better at killing asexual stages of P. falciparum than was primaquine. Orally administered tafenoquine was slowly absorbed and, in marked contrast to primaquine, slowly metabolized, with an elimination half-life of 14 days. Hopefully, with Food and Drug Administration (FDA) approval, tafenoquine will be marketed possibly for use by travelers as a single weekly dose.