dinated by various committees of the National Research Council and later the Board for the Co-ordination of Malaria Studies. This massive, national screening program allowed for a systematic exploitation of certain chemical classes of compounds (Clark, 1946). By the 1950s, after primaquine, chloroquine, pyrimethamine, and proguanil had been introduced, the arsenal of antimalarial drugs seemed to be complete and antimalarial drug discovery seemed to lapse on a global basis. Chloroquine resistance was first reported in South America in the early 1960s. Around the same time, chloroquine-resistant malaria was appearing among U.S. forces stationed in southern Vietnam (World Health Organization, 1981).

In 1964, the Army reestablished its antimalarial research program in order to develop new prophylactic and therapeutic drugs for use against resistant parasite strains. The program had a basic science component focused on the biology of the malaria parasite and research on malaria immunology, with the long-range goal of developing a vaccine. The Division of Experimental Therapeutics (formerly the Division of Medicinal Chemistry) at WRAIR was put in charge of a multidisciplinary antimalarial drug development program that combined both in-house and contract research with complementary elements in the pharmaceutical industry (Milhous and Schuster, 1990).

Walter Reed Army Institute of Research

WRAIR has the expertise and laboratory capability to carry a potential antimalarial compound from the chemist's bench, through efficacy testing, toxicity testing, and clinical trials, to registration by the U.S. Food and Drug Administration (FDA). In recent years, the institute has collaborated increasingly with the pharmaceutical industry and WHO to expedite the development process.

While basic and field research activities in malaria are conducted by the National Institutes of Health, United States Agency for International Development, and Centers for Disease Control, WRAIR is the only federal body with a discrete program for development of drugs for treatment of tropical diseases.

Various approaches have been used by WRAIR scientists to identify, design, and synthesize new antimalarial drugs, including empirical screening, screening of plant extracts from traditional medicines, synthesis of analogs to compounds known to have antimalarial (or antimicrobial or anti-tumor) activity, and selective targeting of specific parasite enzymes (so-called rational drug design).

Historically, rodent models of malaria have been the primary tool for identifying drug candidates. Compounds that lack toxicity and demonstrate efficacy in preliminary animal testing are selected for advanced testing in rodent or simian models. During the past 10 years, methods of in



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