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A Strike Against Stroke

New drugs promise to prevent some of the ensuing brain damage
It's a scene that would not play well on a show like ER: a patient comes in complaining of numbness, blurred vision and difficulty speaking. Doctors diagnose a stroke--but instead of racing to perform emergency surgery or a dramatic table top resuscitation, they simply run a few tests and prescribe medication. This less flamboyant way of treating stroke might make for dull television, but it is fast becoming an action-paced area of medicine. Strokes are the third leading killer in the U.S., after heart disease and cancer. And recent studies indicate that the new drug treatments can protect stroke victims from potentially devastating brain damage.

For the past several decades, neurologists had nothing to offer people who had already suffered a stroke. Doctors could recommend preventative measures for high-risk patients, such as lowering blood pressure and reducing body weight. Patients who showed warning signs received anticoagulant drugs, including aspirin, to prevent the blood clots in the brain that cause strokes. But there was no way to help once a stroke occurred. As a result, brain damage from strokes is the leading cause of adult disability in the U.S., afflicting a total of some three million people each year.

In December of 1995, however, stroke and its aftermath started looking more manageable. Researchers at the National Institute of Neurological Disorders and Stroke described encouraging results from advanced clinical trials of a drug known as tissue plasminogen activator, or tPA. In those trials, physicians found that tPA, currently used to treat heart attacks, can also breakup cerebral blood clots, restoring the flow of blood and thereby preventing brain damage. Patients who received the drug within three hours of the onset of a stroke were up to 50 percent more likely than the placebo group to have minimal or no disabilities three months after the event.

Genentech, the maker of tPA, has since requested approval from the Food and Drug Administration to market the substance as a stroke therapy; a decision from the agency could come in the next few months, according to James C. Grotta, a tPA researcher at the University of Texas at Houston. Although the drug is not cheap--about $2,000 a dose--it could keep thousands of patients out of expensive nursing homes and rehabilitation programs.

Other stroke-treatment compounds also show promise. At the meeting of the American Academy of Neurology this spring, research groups announced results from successful, albeit limited, clinical trials of two such drugs, citicoline and aptiganel. Both substances appear to help restore the brain's disrupted chemistry. Citicoline seems to rebuild the membranes of damaged nerve cells. Aptiganel blocks the entry of excess calciumin to brain cells (scientists believe high levels of calcium build up after a stroke, leading to cell death).

Even more drugs intended to alleviate brain damage from strokes may be on their way. At the March meeting of the American Chemical Society, researchers from several drug companies presented new substances that are just now entering clinical trials. Thomas M. Bare of Zeneca Pharmaceuticals reported, for example, preliminary studies of a compound his group has designated ZD9379. This substance suppresses the activity of glutamate, an amino acid that, after a stroke, accumulates in and damages brain cells.

Of course, many promising new drugs never make it through clinical trials. Ciba-Geigy recently ended its human trial of selfotel, stating that the drug was not effective enough at treating stroke to justify continuing the work. Justin A. Zivin of the San Diego Veterans Administration Medical Center, who served as a safety monitor for some of the selfotel trials, believes the study ended in part because of the drug's side effects, which included hallucinations and agitation

Some researchers argue that such neurological side effects may be difficult to avoid. Jay P. Mohr of Columbia Presbyterian Medical Center suggests that perhaps "some behavioral response is necessary to indicate that the drug is working." He compares the side effects of stroke therapies to the hair loss that accompanies chemotherapy. And Elkan R. Gamzu, president of Cambridge NeuroScience, points out that these effects seem to be more unpleasant than dangerous.

Shepherding new drugs though human trials is also hampered by difficulties in dispensing medication at the right time. Doctors must administer tPA between three and six hours after a stroke begins; previous studies suggest that administering tPA too late could cause internal bleeding in the brain. Agents such asciticoline and aptiganel are somewhat less time sensitive; they can be provided effectively as long as 24 hours after the stroke. Yet most victims do not immediately recognize the warning signs, and so do not even check into a hospital until at least 24 hours after the attack.

The rise of chemical treatments is encouraging a new focus on prompt response after a stroke, both by patients and by physicians. Karen Putney, vice president of the National Stroke Association, emphasizes that the main hurdle for treatment is that "patients are not coming in early enough." Maybe improved prospects of recovery will entice them into the emergency room. As Zivin puts it, "neurologists are good at making a diagnosis, but now they will have to become actively involved in making people better."

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