Revived drug prevents malaria, skirts drug resistance

September 24, 1999

"Clobbering parasites at two places is greater insurance that you clean them out."

A chemical ranked with the second-string players in the world's continuing contest with malaria has reappeared as a new drug, apparently capable of preventing the disease. Paired with an older, standard drug, it provides protection with an unusually small risk of drug resistance.

In a study in the September American Journal of Tropical Medicine and Hygiene, researchers at Johns Hopkins describe how the drug atovaquone was 100 percent effective in keeping volunteers bitten by mosquitoes carrying Plasmodium falciparum, the parasite responsible for fatal forms of malaria, from developing the disease.

"Atovaquone attacks the parasite at a different point in its life cycle from other drugs -- one that reaches the parasite sooner," says Theresa A. Shapiro, M.D., Ph.D., the clinical pharmacologist who led the Hopkins team. Further, pairing atovaquone with proguanil, an older malaria-fighting drug, "should greatly raise our chances of preventing malaria while avoiding the drug resistance that now plagues its treatment. Clobbering parasites at two places," Shapiro says, "is greater insurance that you clean them out."

Drug resistance occurs when a few parasites in their human hosts manage to survive therapy. The parasites then prosper and dominate as causes of disease. Malaria researchers report that drug-resistant forms of the parasite infest 80 percent of countries with the disease.

Atovaquone's different approach may skirt another stumbling block in malaria prevention: keeping patients on the drugs. With current preventives, travelers must take them weeks after a visit to a malaria-carrying country. "With atovaquone, travelers should be able to take their last dose as they leave," says Shapiro.

In the study, 12 volunteers were started on atovaquone -- at either a high or a low dose -- while four volunteers received a placebo drug. All were then exposed to and bitten by five mosquitoes heavily infected with the malaria parasite. "If you plan to expose people to falciparum malaria, especially on an outpatient basis," says Shapiro, "you'd better know what you're doing. We carefully screened for volunteers who knew what was going on, who understood their consent papers, who knew the risks they were taking and who realized the importance of being 100 percent compliant in their follow-up visits. We needed people who went into this with their eyes open."

The volunteers reported daily to a Hopkins clinic for three weeks, then somewhat less frequently for another eight weeks, getting blood tests for the parasite as well as an interview geared to pick up symptoms.

The blood tests included new methods sensitive to human red blood cells carrying parasites as well as conventional microscopic searches for the parasites in blood. As a more precise check, the researchers also used PCR (polymerase chain reaction) assays sensitive to parasite DNA.

After two weeks, the four volunteers not on atovaquone developed malaria, while those on the drug had no signs of infection. (The daily blood tests caught the malaria at its earliest stages in the four with the disease; they were promptly put on standard drug therapy and declared disease-free three days later. Follow-up testing a year later showed no disease.)

Further, says Shapiro, failure of the parasites to survive the lowest dose of atovaquone is one of several signs that the drug attacks the parasites early on, when they move into the liver in the first stage in their life cycle. Other drugs typically act later, only after the parasites have reproduced in the liver 30,000-fold, migrated into red blood cells and entered the bloodstream as the blood cells rupture.

Atovaquone, whose chemical structure is unusual, belongs to a class of anti-malarials called hydroxy-naphthoquinones originally readied during World War II. Most of the drugs in that group proved too toxic or too quickly broken down in the body. "They lost out when more benign and easily synthesized drugs such as chloroquine appeared," Shapiro says. But atovoquone, an offshoot developed later in the 1970s, had promise because it was the least toxic.

It crawled on a slow track until recently, when drug companies resurrected it as a therapy for the Pneumocystis infections that give AIDS patients pneumonia. "Atovoquone is a survivor," says Shapiro. "Now here it is again."

The research was funded by Glaxo Wellcome, an NIH grant and the Burroughs Wellcome Fund. Glaxo Wellcome is preparing to donate the combined form of atovaquone and proguanil to a non-profit foundation that will distribute the drug, with tight restrictions, in malaria-endemic countries. "If you have a new approach to drug resistance," says Shapiro, "you can't squander it. You can't throw the drug around carelessly. We've seen what happens when we do that."

Other Hopkins researchers in the study are Channa D. Ranasinha, M.D.(a postdoctoral fellow no longer at Hopkins), Nirbhay Kumar, Ph.D., and Patricia Barditch-Crovo, M.D.
The article is in the American Journal of Tropical Medicine 60(5), 1999, pp.831-836. Photographs are available showing parasites breaking out of red blood cells, of humans being inoculated by mosquitoes.

Related Web sites: This site tells the status of malaria worldwide, and gives statistics and current therapies.

Johns Hopkins Medicine

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