Why the pharmaceutical industry poured so much into this strategy is easy to explain. Why it has been such a failure is less so.
The market for a successful brain-protecting drug could be huge. Stroke is the third leading cause of death, behind heart disease and cancer. It is also the leading cause of serious, long-term disability. The disease causes a heartbreaking variety of breakdowns: loss of speech, paralysis, confusion, emotional instability and more. It all depends on what part of the brain is destroyed.
About 20% of strokes arise from a broken blood vessel inside the head. However, the brain-protecting drugs are intended for the far more common ischemic strokes, the kind resulting from a blockage in the brain's blood supply.
Typically this happens when a blood clot shuts off the flow in the tree of arteries that branches through the brain. Deprived of oxygen, a core of brain tissue begins to die within minutes.
Beyond this dying center is a larger ring of brain cells called the penumbra. Its oxygen supply is diminished but not severed, since some blood dribbles in from other directions. The penumbra is threatened but alive, at least for a while.
Unfortunately, these brain cells also often die in the hours and days that follow, killed by a chemical firestorm called the ischemic cascade. The dying cells in the stroke's core discharge large amounts of message-carrying amino acids, such as glutamate.
Ordinarily the release of this stuff is tightly regulated, but high levels are a disaster. They poison the already weakened cells of the penumbra, in part by prompting them to let in large amounts of calcium. Starved of oxygen, the cells lack the energy to pump the calcium back out. The calcium, in turn, activates a spate of destructive enzymes. One step after another eventually ends in cell death.
The damage doesn't end there. In hours or days, the blood clot that started the stroke dissolves and disappears. Blood rushes back into the penumbra. This launches another misguided cascade of events as the returning white blood cells set off harmful inflammation.
It is an awesomely complex and terrible chain reaction, eating up brain well beyond the locale of the initial stroke. The brain-protecting drugs are logically designed to intercede at various points in the process. Some try to block the cells' intake of calcium. Others are intended to defuse the returning white blood cells.
"There have been many drug candidates that go beyond the simple idea of reopening blood vessels and address these downstream mechanisms," says Dr. Robert McBurney of Cambridge Bioscience. "They show spectacular effects in animals. They simply have not been translated into success in clinical trials."
Why not? The question prompts much soul-searching among those who design and conduct clinical trials--the big human experiments like the ones discussed in New Orleans. While some worry that the entire strategy of brain protection is flawed, most stroke experts say other reasons can at least partly explain the failure:
* Rat strokes are not like human strokes.
The rat is the classic test subject for developing brain-protecting drugs, and all the drugs work well in these animals. But people's brains are in many ways different. .
Moreover, lab rats are genetically identical. They are in great physical shape. They get strokes in exactly the same spots in their brains. And they get treated immediately. None of this is true for people.
"We use young and healthy rats to prove a point in the lab, but most strokes happen in old people with a lot of other diseases," notes Dr. Alejandro Fortesa of the University of Miami.
* The time window is open too wide.
Drug companies hoped to find medicines that could be given to people who wander into the emergency room many hours after their strokes. So drug studies took in people 24 and even 48 hours after the start of symptoms.
"Now we realize that therapies have to be delivered lickety-split," says Dr. Dennis Choi of Washington University, president of the Society for Neuroscience.
This probably means administering them within at most six hours--or even three hours--of the onset of symptoms.
* Maybe a drug works for some strokes but not others.
Ischemic strokes come in many types. Some result from clots that travel up from the heart, others when a fatty lump bursts open on an artery wall. Some block big arteries, others small ones. And the resulting damage ranges from mild to catastrophic.
"We have become slaves of the dichotomy that a drug works or doesn't work," says Dr. Camilo Gomez of the University of Alabama at Birmingham. "In fact, it may just work for some. By lumping all stroke patients together, we dilute our chance of proving it."
A few brain-protecting drugs are still in testing. One of the largest experiments, with 2,700 patients, will see if infusing $1 worth of ordinary magnesium does any good.
Another is Bristol-Myers Squibb's BMS-204352, a calcium regulator being tested on about 3,000 patients worldwide. Company officials hope for a drug so effective, so simple, so safe that it will be given in the ambulance to anyone suspected of having suffered a stroke.
Still, they know the odds.
"It's fair to say we recognize this is a very high-risk project," said Perry Molinoff, a company vice president.
The risks have become so high, in fact, that some doctors fear drug makers will give up entirely, especially if the remaining batch of big experiments turns out badly. Still, many are still optimistic that a brain-protecting drug is possible."
"If a neuroprotective agent is found, it will revolutionize stroke therapy." says Dr. Elzbieta Wirkowski of Winthrop-University Hospital in Mineola, N.Y. "But the search has to go on."
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