May 30, 1997

Study of clot-busting stroke drug expanded

Study of clot-busting stroke drug expanded

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Dr. Howard Kirshner

New treatments being studied at Vanderbilt University Medical Center may hold the promise of reducing the permanent damage caused by strokes.

VUMC researchers are taking part in a national trial that expands the amount of time after the onset of a stroke that patients can be administered the investigational drug tPA, a thrombolytic treatment designed to dissolve the blood clots that cause strokes.

The drug is currently approved by the FDA for use on patients within three hours after the onset of a stroke. The current study is designed to widen that window to five hours. VUMC is one of the 50 centers nationwide taking part in the study.

"The statistics are that only 5 percent of patients come into the emergency room in time to get tPA," said Dr. Howard S. Kirshner, professor and vice chairman of Neurology. "With patient education and recognition by families, that could be raised to 25 percent. If we open the window to five hours I believe the number of patients being treated will double."

According to Kirshner, 800 stroke patients are needed to participate in the study, and expanding the time frame of administering tPA will increase the number of study participants.

"Many centers around the country are still having problems getting people to come in within the three-hour time limit. We have not yet had any patients at VUMC," said Kirshner.

The average time it takes stroke patients to get into the emergency room is between 10-12 hours. Many patients do not immediately realize they have had a stroke, Kirshner said.

Another problem is that many people have severe strokes while sleeping. Since the criteria for studies is based on the time since the stroke began, patients often are not seen until 8-9 hours after a stroke.

"For any of the treatments to work we have to have greater awareness that a stroke is an emergency and not just something that happens when people get old," said Kirshner.

Some signs of stroke onset include: numbness, weakness, or paralysis in the face, arm, or leg, especially on one side of the body; sudden blurred or decreased vision in one or both eyes; difficulty speaking or understanding simple statements; or loss of balance or coordination when combined with other signs.

In addition to the thrombolytic treatment using the drug tPA, patients will soon be able to receive a neuroprotective agent called lubeluzole, which blocks the release of nitric acid in the neurons after a stroke.

When a stroke occurs there is an area of the brain that is irreversibly damaged. There are also areas that are not yet permanently damaged, but are releasing chemicals which cause cell death.

One of the chemicals released in these circumstances is glutamate, one of the brain's key signaling molecules. Glutamate overloads living cells after a stroke and causes the release of nitric acid and other chemicals. These chemicals kill the surrounding cells causing additional damage to the brain. This cycle of cell death eventually stops on its own but not until after causing extensive damage to the brain.

Glutamate inhibiting drugs, like lubeluzole, hold great promise at limiting the damage that occurs after a stoke, but so far have been hard to develop.

One of the problems researchers faced in the development of this drug was that many forms of glutamate receptor blockers are hallucinogenic. The prototype, in fact, for the family of glutamate receptor blockers was bencyclodine, commonly known as angel dust.

The drug currently being tested does not cause hallucinations because it acts on a reaction later in the chain of events than the glutamate uptake into the cell.

"In the phase III trials, lubeluzole showed a great deal of promise for the treatment of strokes. We hope that more neuroprotective drugs can be developed and that we can use them in tandem with the thrombolytic drugs like tPA," said Kirshner.