ity, better oral bioavailability, and a longer half-life than primaquine. Human testing awaits the filing of an investigational new drug application with FDA. It is of considerable interest that WR 238605 has also shown activity against the opportunistic pathogen Pneumocystis carinii in rodents (Bartlett et al., 1991). Pneumocystis carinii pneumonia is a common and serious infection in AIDS patients. A partner for development of the drug has not yet been selected.

BW566c

This compound is a member of the hydroxynaphthoquinone class of compounds. The antimalarial activity of these compounds was discovered in the 1940s, when they were synthesized and tested as part of an effort to develop a synthetic replacement for quinine. Several drugs in this class, including menoctone, have gone on to human testing, but further development proved unwarranted.

BW566c was identified as an antimalarial candidate at the British drug company Burroughs Wellcome (Gutteridge, 1989). Interest intensified when, like WR 238605, it was found to possess anti-P. carinii activity. It is now in human trials for the treatment of P. carinii pneumonia. Development of BW566c as an antimalarial agent depends on the results of these studies; it is not likely to undergo further research and development if it has only antimalarial potential, since Burroughs Wellcome, like most other pharmaceutical companies, has terminated its antimalarial drug discovery program.

There is some evidence that the hydroxynaphthoquinones act by inhibiting electron transport at ubiquinone-sensitive sites in the parasite mitochondria. This inhibition is coupled to inhibition of the enzyme dihydroorotate dehydrogenase, which is necessary for pyrimidine (and thus nucleic acid) synthesis.

Antibiotics

Antimalarial activity has been found in various fluoroquinoline antibiotics and newer erythromycin derivatives, including azithromycin and roxithromycin. Most research has focused on the quinolones, which are already approved by the FDA for human use. One of these, ciprofloxacin, is now in human trials for malaria. Whether or not these drugs will have advantages over the tetracyclines and clindamycin remains to be seen.

Agents That Reverse Chloroquine Resistance

A wide variety of drugs have been found to restore the potency of chloroquine against resistant strains of P. falciparum in vitro. None of these



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