ANAHEIM, Calif., Feb. 8 -- First came drugs to break apart clots that can cause a stroke when they block an artery carrying blood to the brain. Now researchers are developing a new family of drugs called neuroprotectants designed to minimize the disabling damage to brain tissue that can occur downstream from the clot, caused by the loss of blood flow that characterizes these ischemic strokes.
A test of one such drug was reported here today at a conference on stroke sponsored by the American Heart Association. Patients treated with lubeluzole (trade name: Prosynap) showed greater recovery in their ability to function after a stroke than those who received an inert substance, or placebo, said James Grotta, M.D., professor of neurology at the University of Texas Medical School at Houston. People in the drug-treated group also had a lower incidence of death, but not one that was statistically significant.
"There are two major strategies for treating somebody with a stroke caused by an obstructed artery," Grotta said. "The first is obviously to remove the obstruction." Several clot-dissolving drugs, including tissue plasminogen activator (TPA), can reduce deaths from clot-induced heart attacks. However, TPA has not proved useful in lowering stroke deaths, although studies indicate it can significantly reduce disability in stroke survivors, if itªs administered within a few hours after the artery blockage occurs, he added.
"The second strategy is to protect cells downstream from the blockage from damage," Grotta said. "When an artery is blocked, the fate of the tissue depends on the depth of blood-flow reduction and the duration."
An ischemic stroke, resulting from obstructed blood flow vital to the brain, creates a "whole cascade" of biochemical steps that ultimately lead to cell death if not reversed, the researcher said.
"In an area where the blood flow is essentially zero, nerve cells will live only a few minutes before the cascade kills them," Grotta explained. "Where the flow is reduced to 25 percent of normal, tissue may survive for three hours, or maybe even longer. What a neuroprotectant does is protect nerve cells by interfering with this cascade at one or more sites to reduce the damage from the inadequate blood flow."
Researchers from 83 medical centers in the United States and Canada participated in a randomized, double-blind, placebo-controlled trial of 721 people diagnosed with moderate to severe ischemic stroke. In such a trial, people randomly receive either the drug under study or a medically inert substance called a placebo; neither the study subjects nor the researchers know who gets which until the end of the study. The study included 376 men and 345 women, ranging in age from 19 to 95 years of age, with a mean age of 71.
Treatment began within six hours after the onset of symptoms, with 368 patients receiving lubeluzole and another 353 getting placebo. Lubeluzole was continuously infused through a vein in the arm, starting with an initial dose of 7.5 milligrams (mg) in the first hour, followed by 10 mg per day over the next five days.
Artery blockage was confirmed by CT scans as the cause of strokes in 700 patients. The researchers used these 700 patients in their primary analysis and excluded the remaining 21. The team followed the study participants for three months to see what happened to them.
A pilot study in Europe had indicated that lubeluzole could reduce deaths in ischemic stroke, a finding not confirmed in this phase III trial. "There was a strong trend to lubeluzole, but it was not quite statistically significant," Grotta said. After 12 weeks, 20.9 percent of the lubeluzole patients had died, compared with 25.4 percent of those in the placebo group.
The scientists also looked at the functional outcome of patients. "After all, if you're biologically preserving the brain regions [with lubeluzole], you wouldn't expect to see that much effect on mortality, but you would expect to see a difference in the amount of neurologic deficit," Grotta said.
And the study found that the drug-treated patients showed significantly less disability from their strokes than those who got the placebo. Using the National Institutes of Health Stroke Scale, a means of numerically assessing the degree of disability resulting from a stroke, Grotta and his colleagues found that "lubeluzole patients improved significantly more than did placebo patients" over the 12-week follow-up period.
On a test that measured a patient's daily living activities, 46.8 percent of the lubeluzole group rated independent or mildly disabled, vs. 40.1 percent of those among the placebo group. "There were a number of other functional outcomes scales that we looked at, but the bottom line was that they were all significantly better in the lubeluzole patients as compared to the placebo patients," Grotta said.
Lubeluzole proved "extremely safe" as a stroke treatment. "There was really no significant difference in the number of serious adverse reactions or in the numbers of patients withdrawing from the therapy between the lubeluzole and placebo patients," Grotta said.
He and his colleagues plan to begin a multicenter study later this year to test the effectiveness of a combination of lubeluzole and TPA against ischemic stroke.
Ludwig Hantson, Ph.D., and Tom Wessel, M.D., of the Janssen Research Foundation, Titusville, N.J., and Beerse, Belgium, co-authored the report with Grotta.