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Nitric Oxide May Hold Key to First Treatment for Deadly Form of Malaria, Duke Scientists Report

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DURHAM, N.C. -- Working in the heart of Africa's malaria country, researchers from Duke University Medical Center and the Durham V.A. Medical Center have shattered a misconception about malaria, and in the process discovered a biological link that could lead to an effective treatment for the deadliest form of the disease.

The research team, from Duke and Tanzania, discovered that people with cerebral malaria, the most severe form, have lower levels of the signaling molecule nitric oxide than others with milder forms of the disease. They showed that nitric oxide (NO) in the blood appears to protect the body from the malaria parasite, contrary to expectations, and that it may help stop malaria infection from becoming deadly. The researchers say the finding could lead to a relatively simple therapy that may help save the lives of more than 2 million people, many of them children, who die each year from malaria.

The work, published in the August issue of the Journal of Experimental Medicine, is the most detailed study conducted to date of the role of nitric oxide in children infected with malaria, the researchers said.

"These results suggest that a drug that would increase the level of nitric oxide in the body may be an effective treatment for cerebral malaria," Dr. Brice Weinberg, one of the study's authors and an expert on nitric oxide, said in an interview. "Since inexpensive drugs capable of delivering nitric oxide are currently available and in use for other disorders, testing for use in malaria could progress rapidly."

The work was supported by the Duke Division of Infectious Disease and International Health, American Society of Tropical Medicine and Hygiene, the V.A. research service, the James R. Swiger Hematology Research Fund, and the National Institutes of Health. Malaria is a seemingly random killer. Common in much of Africa and Asia, it infects most everyone living in sub-Saharan Africa. Most fall ill with fever and flu-like symptoms and recover quickly. But some, mostly children and pregnant women, succumb to the deadly form called cerebral malaria.

In cerebral malaria, red blood cells containing the malaria parasite stick to the lining of blood vessels, causing blockage, and decreasing the blood supply to parts of the brain. Up to one- third of children who develop cerebral malaria die, despite treatment. Some of those who recover have lasting damage such as limb weakness and blindness. There is no way of telling who will get cerebral malaria or who will die from it.

"Family members will often bring a child who is already unconscious to the hospital," said Dr. Nicholas Anstey, the study leader and first author. "We treat cerebral malaria with injections of the antimalarial drug quinine, drugs for convulsions, intravenous fluids and supportive care. But mostly, we just have to wait to see if the child will recover. Some will recover seemingly spontaneously, but up to a third will die. Clearly, we need better treatments."

Researchers and infectious disease specialists have proposed several possible reasons why malaria progresses to this deadly form. Some of the most recent studies have focused on the role of NO. Recent research has shown that NO plays many important roles in the body, including regulation of blood pressure, brain function and immune activity.

Based on laboratory studies, some scientists had suggested that NO may help protect the body from malaria at moderate levels, but too much NO production may be harmful and actually contribute to the development of cerebral malaria, Anstey said. But when the Duke team measured levels of NO in the sickest Tanzanian children, they found exactly the opposite result.

Anstey spent a year at the Duke-Muhimbili Clinical Research Laboratory in Dar es Salaam, Tanzania, collecting blood samples from 191 children. Some of the children were healthy, some had a mild malaria infection, while others were extremely ill with cerebral malaria. Anstey worked with Tanzanian doctors Mushtaq Hassanali, Esther Mwaikanbo and Denis Manyenga to assess the children's illnesses and their diets for sources of nitrate, which can affect the scientist's measurements of nitric oxide by-products in the blood. Anstey conducted many of the tests in Tanzania, and brought the samples back to Duke for additional laboratory analysis.

"We were surprised to find that far from being increased in cerebral malaria, NO production was actually decreased," said Anstey, now at Menzies School of Health Research, Darwin, Australia. "Levels were clearly the lowest in children with cerebral malaria."

In contrast, children with the mildest form of infection, with parasites in their blood but no symptoms, had increased NO production, suggesting NO actually protected these children from disease.

"In addition to the important findings about NO and cerebral malaria, this study exposed what is happening with the vast majority of malaria cases that never come to medical attention," said Dr. Donald Granger, a former Duke infectious disease specialist, now at the University of Utah Medical Center. "As physicians, we only see the tip of the iceberg, the cases in which the NO system isn't operating properly and the infection accelerates to cerebral malaria. This study dramatically demonstrates that, as with most common infections, the vast majority occur below the tip of the iceberg. The bulk of cases are 'under water' and are never seen. In a normal course of malaria infection, NO operates normally to suppress the parasite, and the infection resolves itself."

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