compounds have yet been tested in clinical trials. These drugs may act by blocking the active efflux of chloroquine from the parasite, a process that can be measured in vitro (Krogstad et al., 1987). Similar compounds inhibit the efflux of anticancer drugs from resistant tumor cells.

A number of compounds with pharmacokinetics similar to that of chloroquine, including verapamil (and its analogs), desipramine, ketotifen, cyproheptadine, nifedipine, diltiazem, and chlorpromazine, have been tested in animals (Bitonti et al., 1988; Peters, 1990b). All but chlorpromazine have been found wanting because of toxicity, an inability to cure infection, or both (Vennerstrom et al., 1991). The combination of chloroquine and chlorpromazine can cure experimental P. falciparum infections in aotus monkeys (Rossan et al., 1990).

Like chloroquine, chlorpromazine has a long half-life. A great deal of clinical experience has been obtained with this drug. It has a good safety profile at the doses required to treat malaria and is inexpensive. Other phenothiazines should be evaluated for their ability to reverse chloroquine resistance.

If the efficacy of a chloroquine-chlorpromazine combination is supported by field studies, the addition of chlorpromazine or similar drugs to preparations of chloroquine could have tremendous potential for treating falciparum malaria. It should also be determined whether the chloroquine-chlorpromazine combination is useful for chloroquine-resistant P. vivax malaria.

Agents in Preclinical Development

Three classes of compounds are in various stages of pre-human testing. These include analogs of floxacrine, which has unsuitable toxicity; quinazoline folate antimetabolites; and 1,2,4-trioxane derivatives, which are synthetic analogs of artemisinin.

Pharmaceutics and Clinical Pharmacology

The discovery and subsequent development of novel antimalarial drugs have little value unless those compounds reach the people who can benefit from their use. The way drugs are manufactured, packaged, stored, distributed, and marketed is crucial to this end. Although these processes are dependent to some degree on the management of malaria control programs and the infrastructure of malarious countries, they are very much part of the drug development process. These issues are too broad to discuss in detail here, but it is essential to recognize that the development of antimalarial drugs is futile unless those drugs reach the populations that require them: the residents of malarious regions.

Great advances in the use of an antimalarial drug can be expected once



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