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Experimental drug holds promise for use as post-stroke therapy: study

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TORONTO - Newly reported Canadian research is holding out hope that a treatment for minimizing the damage done by the most common type of stroke could be on the horizon.

A Toronto-based research team is reporting that an experimental drug significantly reduced brain damage and post-stroke impairment when used in macaque monkeys in which strokes were induced.

The report, in the journal Nature, makes no reference to use of the drugs in humans.

But at an international stroke conference in New Orleans in early February, the team presented preliminary data of a Phase II human trial in which the drug was reported to be "quite favourable." Larger and more expensive Phase III trials are needed to gain regulatory approval to bring drugs to market.

The new report, which lays out data from a series of experiments in monkeys, is being greeted with enthusiasm laced with a heavy dose of caution.

Researchers have tried for over half a century to find a drug or therapy to protect the brain from the cascade of damage seen after an ischemic stroke, the type caused by a blockage of blood to the brain. About 85 per cent of strokes are the result of clots blocking blood flow, depriving the brain of oxygen.

More than 1,000 experimental treatments to protect the brain after this type of stroke have been tried in cell culture, in mice and in rats. Time after time hopes have been dashed.

"Everyone has cured rats of stroke. And no one has managed to cure or to help with neuroprotection in human stroke," said Dr. Michael Tymianski, senior author of the paper and principle investigator on this drug, known at this point as Tat-NR2B9c.

In fact, the history of repeated failures in the search for neuroprotector drugs has led some to conclude the human brain is too complex to be shielded in this way.

Currently there is only one treatment available for ischemic stroke. Drugs that break up the clot can minimize the damage done. But clot busters must be used within a small window; if given later than 4 1/2 hours after a stroke they have no effect. That limitation gave rise to the maxim used in describing the urgency of stroke care: Time is brain.

Because clot-busting drugs can only be given after scans show that a stroke was caused by a clot, not a bleed in the brain (the other type of stroke), few people are diagnosed in time to get benefit from this type of therapy.

Dr. Stephen Phillips, a Halifax neurologist who wasn't involved in the study, noted that a national audit of stroke care published last summer showed that only eight per cent of Canadians who experience a stroke manage to get to the hospital and receive a diagnosis in time to be treated with clot-busting drugs.

The need for more treatment options — or for a neuroprotective drug that could enlarge the treatment window for clot busters — is tremendous, said Phillips, a stroke neurologist at Dalhousie University. Stroke is the third leading cause of death in Canada and the leading cause of disability in adults.

In order to bypass the problems seen trying to translate results in rodents to results in humans, Tymianski and colleagues at the Kremil Neuroscience Centre of Toronto Western Research Institute tested their drug in macaques, primates which have complex brains much more similar to human brains than other animal models tested.

In one study, they induced strokes in a group of monkeys, then gave half the animals the drug one hour after the start of the stroke. The animals that received the drug had roughly 70 per cent less brain damage than the monkeys that were not given the drug.

In two other studies, the team tried to see if the drug would work with clot-busting therapy. Monkeys were given strokes, then given the drug or a placebo, followed by clot busters. Two different time schedules were used, but in both, the drug appeared to be protective — even after the normal window for clot busters should have closed.

Tymianski said getting drug company backing — critical to bringing a drug to market — is not easy in this field at this point.

"All these failures in human clinical trials have really taken away the appetite of researchers and of the pharmaceutical industry of trying to develop drugs in this space," he said in an interview.

"So nothing short of efficacy in primates or even humans would suffice as evidence that it's worthwhile developing these drugs. Because rat data just doesn't meet the bar these days."

A company Tymianski formed has taken development of the drug to this point, with a lot of support from the Canadian Stroke Network and Heart and Stroke Ontario. The company, NoNO Inc., is currently in discussions with the pharmaceutical industry, he said.

Phillips described the work as "very elegant" — high praise in science — and said the results do seem encouraging.

But while Phillips said he would like better treatments for the stroke patients he sees, he knows from past experience it is too soon to get too hopeful about these results.

"Because I've been round the block a few times and because I was a participant — and actually a leader in one of these neuroprotective trials — in the past, you know I'll believe it when I see it kind of thing," Phillips said.

"I don't think you can get away from the history of this neuroprotection story. It does play forward."

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