Brain attack: progress is slow in finding better ischemic-stroke therapies

Science News,  July 14, 2007  by Andreas von Bubnoff

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About a year ago, E. Gail Anderson Holness was in church when she suddenly felt lightheaded. At first, the then-49-year-old minister, motivational speaker, and Washington, D.C.-based writer didn't think that the episode was serious, even though she'd had headaches for several days. She was healthy, after all, and she ran 4 miles almost every day.

"Because I am an athlete, I could not understand what was happening to me," she says. "I said, 'Just let me go home.'" But when her speech became slurred and the left side of her face started to droop, a friend convinced her to go to the hospital.

Anderson Holness had had an ischemic stroke, the type caused by a blocked blood vessel in the brain. The stroke killed some of her brain tissue by cutting it off from its oxygen and nutrient supplies.

About 600,000 people suffer ischemic strokes each year in the United States. The other kind of stroke, which occurs when blood spills into the brain, affects 100,000 people a year. With more than a million survivors facing varying degrees of permanent damage, strokes are the leading cause of serious, long-term disability in the country.

Still, there is currently only one drug treatment approved by the Food and Drug Administration for use at the time an ischemic stroke occurs. That drug is tissue plasminogen activator (tPA), given intravenously to dissolve blood clots. FDA approved the famous "clot buster" in 1996.

Treatment with tPA saves many patients--as it did Anderson Holness--by opening obstructed blood vessels in their brains. But the drug has severe limitations. Doctors have to first do a computerized tomography scan to make sure that the person isn't experiencing a bleeding stroke, which tPA would make worse. And the clot-busting drug must be administered within 3 hours of the onset of a stroke--which isn't always possible because many delays occur on the way to emergency treatment. After 3 hours, the risk of bleeding outweighs the potential benefit of tPA, at least according to current medical judgment. The potential complications have made emergency room physicians reluctant to give tPA, says Costantino Iadecola, chief of the division of neurobiology at Weill Cornell Medical College in New York City.

As a result, less than 5 percent of ischemic-stroke patients in the United States get treated with tPA. "Very few patients can benefit from the only treatment we have available for stroke," Iadecola says. "There is a tremendous interest to develop new treatments."

Indeed, trials of many treatments are under way. Some test alternative clot busters that may be less likely than tPA to provoke bleeding. Other studies focus on drugs that keep brain cells from dying once a stroke has occurred. Some researchers are using genetics to look for yet more such neuroprotective compounds to test.

Other scientists are trying combinations of drugs because each drug typically targets just one or a few of the many processes that lead to brain-cell death after a stroke.

All in all, researchers have come up with a number of approaches that have shown promise in animal studies. Even so, making such treatments work in people has proved to be a stubborn problem.

BUSTING OUT Given that clot busting is the only approved and effective treatment for ischemic stroke, some researchers are trying to expand on it. For example, Anand Vaishnav of the University of Kentucky Medical Center in Lexington and his stroke team advise doctors at rural hospitals on whether tPA will help or hurt a particular stroke patient.

Many doctors are insufficiently trained or too conservative to use the drug, Vaishnav explains. "We'll give them the green signal to give tPA" when it's appropriate, he says. After a preliminary study, Vaishnav concludes that a national telemedicine system, which would provide instant expert advice to any location, could increase the proportion of ischemic-stroke patients getting tPA to 10 or even 20 percent.

Other doctors are starting to extend the time following a stroke during which tPA can be used, using brain imaging to show that a person still has salvageable tissue in the damaged area. Last year, a team led by researchers at Stanford University published a study suggesting that such patients can benefit from tPA treatment up to 6 hours after a stroke.

Still others are using ultrasound to make tPA more effective, In a small clinical study published in 2004, Andrei Alexandrov, now at the University of Alabama at Birmingham, found that applying ultrasound through the skull triples the effectiveness of tPA in dissolving ischemic-stroke clots. The sound waves agitate the stagnant blood in the blood vessels affected by the stroke, Alexandrov says, allowing tPA to better reach and penetrate the blood clot. "It's like a spoon that stirs sugar in a cup of tea," he says.

More recently, Alexandrov has been working with ImaRx Therapeutics of Tucson, Ariz., which makes tiny, gas-filled bubbles by enclosing minute quantities of perfluoropropane in fatty shells that are similar to cell membranes in humans. Administered intravenously, the bubbles aren't dangerous, he says, because perfluoropropane is chemically inert and present in only small amounts. But when the bubbles reach the site of stroke damage, ultrasound vibration makes them oscillate or even explode. This further agitates the stagnant blood around a clot, Alexandrov says. In February, he told the International Stroke Conference in San Francisco of early success combining tPA, ultrasound, and gas bubbles to dissolve clots in stroke patients.