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DURHAM, N.C. -- Children with the deadliest types of malaria could potentially be treated with arginine, a simple nutrient that is produced by the body and found in some foods, according to a team of researchers from Duke University Medical Center and around the world.

In a study of 75 African children, the researchers found that youngsters with the lowest levels of arginine suffered from the deadliest consequences of malaria. Hence, the researchers believe that giving arginine supplements to the sickest children might prevent them from dying. More than a million children die of malaria each year, despite the best available treatments.

Results of their study, funded by the Thrasher Research Fund and the NIH, are published in the Feb. 22, 2003, issue of the international medical journal The Lancet.

"Arginine levels were so closely correlated to malaria disease severity that we were able to predict who had the most severe forms of disease based on their arginine levels," said Bert Lopansri, M.D., of the University of Utah Medical Center, lead author of the study.

Arginine is an amino acid that is necessary for the production of nitric oxide, a chemical in the blood that can kill parasites and prevent malaria disease. People who produce too little nitric oxide are at greatest risk of developing the deadliest forms of malaria, the researchers recently demonstrated in the same group of children. (Brice Weinberg, M.D. of Duke and the Durham VA Medical Center was principal investigator of that study, published in the Nov. 9, 2002, issue of The Lancet.)

In the current study, the researchers showed that extremely low arginine levels are also linked to severe malaria and mortality. Researchers from Utah, the Durham VA Medical Center, Duke University Medical Center, the Menzies School of Health Research in Australia, and the Herbert Karuki University in Tanzania have spent a decade studying what factors cause some children with malaria to recover while others become severely ill and die.

The team's recent findings suggest that arginine is a promising treatment option because it is inexpensive, relatively safe and an already-proven method of boosting nitric oxide in people with other illnesses. Arginine is currently used to treat narrowed arteries, extreme cases of high blood pressure and other disorders.

Yet nitric oxide has its risks, cautioned the researchers. It is known to be toxic to the body in high doses or in the wrong organs, said Donald Granger, M.D., of the University of Utah Medical Center. It is also difficult to deliver the correct amounts of nitric oxide using pills, injections or inhalers. However, properly administered arginine treatments can boost nitric oxide levels naturally, at the appropriate levels and in the right places in the body, Granger said.

In turn, higher nitric oxide levels would combat malaria disease by enhancing blood flow, preventing infected red blood cells from adhering to the lining of blood vessels, and decreasing the production of inflammatory chemicals that exacerbate disease, said Weinberg of the Durham VA Medical Center and Duke University Medical Center.

Current anti-malarial drugs work differently, by limiting the malaria parasite's growth within the blood. However, such anti-malarial drugs do not necessarily ameliorate the tissue damage caused by the parasite. As a result, malaria continues to be deadly, with a malaria death occurring every 30 seconds worldwide.

Combining arginine with anti-malarial drugs might better combat deadly malaria because the two drugs' mechanisms of action appear to be quite different, the researchers said.

"Drug resistance to current therapies is growing worse, and even with the best treatments, 20 percent of children with cerebral malaria still die from complications of the disease," said Nicholas Anstey, M.D., a malariologist from the Menzies School of Health Research in Darwin, Australia. "Arginine may have potential as a complementary drug to augment existing anti-malarial drugs, and to prevent complications from malaria."

The two most severe forms of the disease are cerebral malaria and severe anemia. In cerebral malaria, red blood cells containing the malaria parasite adhere to the lining of blood vessels, causing blockages and decreasing blood supply to parts of the brain. Approximately one-fifth of children with cerebral malaria die despite treatment. In severe anemia, parasites consume hemoglobin, destroy red blood cells and block blood formation until the patient is beyond rescue.

"There is an emerging body of evidence demonstrating that arginine is important in a variety of disease states," said Weinberg. "We are excited about the potential for assessing arginine's safety and effectiveness in treating severe malaria."