Making Strides Against Strokes

Researchers are starting to unravel the mystery

The odds weren't good for Ann Yazgoor. Two years ago, Yazgoor suffered a major stroke, and her doctors figured she wouldn't survive. But Yazgoor was lucky. When the stroke hit, she was at Yale-New Haven Medical Center, being examined after what had probably been a minor stroke two days earlier. Doctors quickly gave her some tissue plasminogen activator (TPA), recently approved for busting up blood clots in strokes. Yazgoor is now able to walk and has regained almost full use of her arms. While the stroke left her with impaired vision, Yazgoor is grateful: "I was supposed to be dead."

Unfortunately, tales such as Yazgoor's are rare. In the past few years, a number of experimental stroke drugs have proved ineffective in human trials. TPA is the only one on the market for the treatment of strokes caused by blood clots, but fewer than 5% of patients receive it, in part because it must be given within three hours of the attack. Doctors must also first determine the type of stroke, since TPA can be dangerous for a stroke caused by hemorrhage instead of a clot.

COMPLEX. Scientists have come to realize that stroke is a devilishly complicated cascade of events. But the good news is that they are beginning to decipher the complexity. Researchers are developing a number of treatments aimed at different targets within that cascade so that they can short-circuit the process, making an eventual treatment of the damage caused by stroke feasible. Drugs are being developed to protect brain tissue from being irreversibly damaged from blood deprivation and to prevent the damage that can occur when blood rushes back into certain areas of the brain after stroke. There is research on ways to bust up clots in the brain, with new drugs or lasers. There is even some early work on transplanting cells into the brain to aid recovery.

Because a stroke sets off so many different responses, the search for treatment is that much tougher. Researchers have learned, for example, that simply restoring blood to the damaged part of the brain can cause the body to counterattack with tissue-killing white blood cells. "We had this naive idea that we could find one drug to block this entire cascade," says Dr. Anthony J. Furlan, head of the stroke unit at the Cleveland Clinic Foundation. "Most people think we are going to need some cocktail approach and not one magic drug."

TRIGGERS. New options are desperately needed. Strokes occur when blood is cut off to part of the brain, either because of a clot that blocks blood flow or, in about 15% of cases, from the rupture of a blood vessel, or hemorrhage. The trigger could be an irregular heart beat, high blood pressure, or a number of other factors--that often strike with no warning. The result can be widespread brain-cell death that leaves the patient seriously impaired. The National Stroke Assn. says that about 750,000 Americans suffer strokes each year, and 160,000 die annually. About 4 million Americans live with the consequences of a stroke, costing the U.S. $30 billion annually, the association estimates.

In the past decade, researchers have gained a better understanding of a stroke's destructive force. Areas where brain cells are so damaged by the loss of blood that they can't be saved are referred to as the core of the stroke. Outside of the core, in the so-called penumbra of the stroke, blood flow is severely curtailed, but brain cells can still be salvaged. The drug industry is focusing primarily on finding treatments that can rehabilitate those less damaged cells.

ROUGH ROAD. Progress has not always been straightforward. Take what was thought at the outset to be one of the most promising therapies: blocking one of a cell's entryways, the NMDA (N-methyl-D-aspartate) channel. Certain chemicals released during a stroke cause the channel to open, letting calcium into the cell. Too much calcium can be deadly, though, sending enzymes into action that in effect digest the cell. The hope was that by blocking the NMDA channel, the drugs could ward off cell death.

Great theory, but the reality has proved to be a lot tougher. Cambridge Neuroscience Inc. halted work in 1998 on its NMDA candidate, Cerestat, after trials revealed the drug wasn't showing a benefit. Then, at the American Stroke Assn.'s 25th International Stroke Conference in February, Glaxo Wellcome PLC also reported that its drug wasn't showing effectiveness in an 1,800-patient European trial. Glaxo is still awaiting results from a U.S. trial of the drug involving 1,600 patients.

DELAYS. Part of the problem is the difficulty of designing human trials for stroke drugs. The NMDA-channel drugs worked beautifully in animal studies. But humans often don't get to a hospital for many hours after their stroke, so most of the trials have involved giving the drugs as late as six hours after a stroke. Experts warn that this may simply be too late. "I think that is the most obvious explanation for the failures," says Dr. John R. Marler, associate director for clinical trials at the National Institute of Neurological Disorders & Stroke.

Despite the challenges, drug companies are forging ahead. One promising approach under study is to block calcium entry by controlling the normal electric charge of the cell. When cells become more negatively charged, certain calcium gateways do not open. AstraZeneca is in final testing of the drug clomethiazole, which stimulates a site on brain cells called the GABA-sub-a receptor. Once stimulated, the receptor allows chloride ions to enter the cell, giving it a negative charge. A European trial of clomethiazole was less than definitive, but AstraZeneca is betting a U.S. trial will prove the drug's effectiveness.

Taking a slightly different tack, Bristol-Myers Squibb Co. is in final human testing of a compound that lets positively charged potassium out of the cell, giving it a more negative charge. "In animals, we've seen up to a 30% reduction in resulting volume of tissue death," says Dr. Perry Molinoff, head of preclinical neuroscience at Bristol-Myers.

Both of these compounds are aimed at preserving brain tissue deprived of blood within several hours of a stroke. But there is another danger: When blood comes rushing back to areas where the blood flow had been cut off, it appears to trigger a scramble by the body to repair the tissue. White blood cells rush to the blood-deprived site--which they see as damaged--and begin wiping out the healthy tissue.

Several companies, including Millennium Pharmaceuticals, Pfizer, and startup ICOS, are developing treatments that block the white blood cells from getting at brain tissue. ICOS Corp.'s product, called LeukArrest, is moving into the final phase of human testing. The drug binds to certain receptors on the surface of white blood cells. When those sites are blocked, the white blood cell can't attach to the blood vessel wall, the first step to making its way into the brain.

Perhaps even greater progress could be made if physicians had better tools to break up clots before they cause widespread brain damage. Abbott Laboratories has a new clotbusting drug in development that is being delivered by catheter directly to the brain, in the hope that it will work more quickly than TPA, which is delivered intravenously.

There are other ways to bust a clot, though. Dr. Wayne M. Clark and colleagues at the Oregon Stroke Center in Portland are trying lasers. A catheter with a laser tip is threaded through the patient's blood vessels and aimed at the clot. Light and energy are created only where there is red matter, so the white surface of the blood vessel isn't affected. Only the blood clot is vaporized.

"FORECAST." Just five patients have been treated to date, but Clark is optimistic that the laser technology will soon be moved into a larger trial. Others are looking at mini-vacuums or sound waves to break up clots. Clark says the speed of such mechanical approaches may wind up making them more useful than drugs. "You can get results in seconds, vs. hours," he says.

Much further out is work to harness the brain's own power at fighting stroke. In recent years, researchers have discovered that patients who have had small strokes often suffer less damage from a major stroke than patients who had been stroke-free. Those smaller attacks may actually prep the brain for a future stroke. "That permits the brain to get the weather forecast ahead of the hurricane," surmises Dr. Roger P. Simon, director of neurobiology research for the Legacy Health System in Portland, Ore.

Scientists are searching for the genes that might help battle that storm. Simon, for example, has blocked in rats the action of a gene called BCL2, known to prolong the life of a cell. Simon found the stroke damage in these rats was double in those who did not have the BCL2 gene blocked. If researchers can identify genes that suppress or induce cell death, they might even be able to develop drugs that prevent stroke. That's still many years off. But at least now, scientists have some solid targets to aim for against a formidable foe.