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Gout Drug May Relieve Sickle Cell Pain

Inhibits enzyme linked to circulatory problems, study says

MONDAY, Dec. 17, 2001 (HealthDayNews) -- A drug designed to treat gout may relieve some of the painful complications of sickle cell disease.

New research suggests that the drug, allopurinol, inhibits an enzyme linked to the circulatory disorder that commonly occurs in people with sickle cell disease.

Although human trials have yet to begin, the findings, which are published in the Dec. 18 issue of the Proceedings of the National Academy of Sciences, offer hope to the estimated 72,000 Americans living with the disease.

Sickle cell disease is an inherited disorder that causes red blood cells (hemoglobin) to become crescent- or sickle-shaped. The distortion makes it more difficult for these oxygen-carrying cells to maneuver through blood vessels, causing blockages and tissue damage.

People with sickle cell disease face such complications as anemia, pain, delayed growth, infections and stroke. If "sickled" cells become trapped in the lung, they can cause an excruciating and potentially lethal condition called acute chest syndrome.

Most of the people who get the disease are of African, Mediterranean or Middle Eastern heritage, and most survive only into their 40s. There is no known cure, although several advances have been reported in animals. Just last week, scientists reported that they cured sickle cell disease in mice.

Senior investigator Bruce Freeman's earlier studies had focused on damaging forms of oxygen metabolism, or oxygen radicals. The body uses certain vitamins and enzymes to protect it against these radicals.

In sickle cell disease, nitric oxide is inactivated by these oxygen radicals, interfering with the ability of blood vessels to readily move blood to tissues that need oxygen.

But in genetically engineered mice that served as an animal model for the disease in humans, Freeman and his colleagues at the University of Alabama at Birmingham found that increased activity of an enzyme called xanthine oxidase (XO) is linked to greater production of these toxic forms of oxygen.

The XO enzyme comes from damaged liver cells in sickle cell patients. "It gets released into the circulation and sticks to the blood vessel wall," says Freeman, an anesthesiology professor.

Allopurinol reduces the body's production of uric acid, which in high amounts leads to gout. According to Freeman, the drug also appears to inhibit the XO enzyme completely.

"It's no longer active in terms of its ability to consume the substrate and generate the products that it normally does, with one of those products being toxic forms of oxygen," Freeman says.

The findings raise the potential for a new approach to sickle cell treatment, says Jack Lancaster, a professor of physiology and medicine at the Louisiana State University Health Sciences Center in New Orleans, who is familiar with the research.

"This opens up a whole new avenue in the development of therapies," Lancaster says. "This enzyme, when it's in circulation, does no good. If we can design a drug to inhibit that enzyme in circulation, then theoretically this should have a great benefit."

The University of Alabama researchers are currently trying to organize a large-scale human study of the effect of allopurinol on blood flow in people who have sickle cell disease.

The researchers are optimistic about the future study, partly because previous studies showed that the XO enzyme is elevated in people who have high cholesterol and hardening of the arteries and that allopurinol increased their blood flow and decreased their blood pressure.

"That same response in the sickle cell patients is something that we'd like to see," Freeman says.

"These people walk around with chronic pain all the time, and that's an awful thing," Lancaster adds. "This opens up a whole new area of potential therapy, and I think it's really very exciting."

What to Do: For more information on sickle cell disease, visit the Web sites for the Sickle Cell Disease Association of America, the National Heart, Lung and Blood Institute or the Joint Center for Sickle Cell and Thalassemic Disorders.

SOURCES: Interviews with Bruce A. Freeman, Ph.D., professor, department of anesthesiology, University of Alabama at Birmingham; Jack R. Lancaster, Jr., Ph.D., professor of physiology and medicine, Louisiana State University Health Sciences Center, New Orleans; Dec. 18, 2001, Proceedings of the National Academy of Sciences
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