Clot clout.

Drug dives
While busting clots remains the key tactic in the pharmaceutical attack on stroke, the blood stoppage can start a deadly chemical spiral that damages the brain even after blood flow is restored.

1. Blood flow stops

2. Cell makes excess glutamate, a
neurotransmitter

3. Anaerobic respiration makes lactic acid

4. Damaging free radicals formed

5. Cell fills with electrolytes and swells

6. Cell dies

The deadly "ischemic cascade" starts with the release of extra neurotransmitters and the concentration of calcium in the cell. The cascade may continue killing nerve cells, or neurons, for hours after blood flow resumes.

The various steps in the ischemic cascade offer tempting targets for medicines that might preserve neurons -- the so-called "neuroprotective" approach to stroke. Indeed, so many drugs interfere with the cascade in animals that, five years ago, neuroprotection for people seemed only a matter of time.

That was then. Now, drugs that help animals don't seem to help humans. The latest bad news came in January, when the drug citicoline failed a large clinical test sponsored by Interneuron Pharmaceuticals. Call it a beautiful theory run aground on the shoals of a nasty fact.

Citicoline is marketed for treating stroke in Japan and Europe, and seems to help neurons survive in three ways, says William Boni, Interneuron's vice-president for communications: preventing the accumulation of toxic fatty acids, helping rebuild cell membranes, and stimulating production of a chemical that communicates between nerve cells.

Square one
Although the drug did not improve a test of brain function that was the trial's goal, significantly more citicoline patients had complete or nearly complete restoration of brain function. (Curiously, more than 50 percent of patients got better on their own, or due to the placebo effect, complicating the evaluation of the real drug's real effects). Still, the trial was a major setback for the idea of protecting neurons from damage after stroke, and Interneuron and its partners have not decided whether to continue testing citicoline.

Felberg says the general failure of neuroprotective drugs indicates they should be given earlier, to a more select group of patients, and that lower standards for success may be appropriate. He suggests that combinations of drugs may work better by blocking several steps in the ischemic cascade. "The situation is similar to a battle where waves of enemies are surging forward," he wrote with colleagues (see "NeuroprotectionŠ" in the bibliography). "If only one wave is halted, the other reinforcements will still overwhelm."

If neural protection won't work, has anyone tried the vacuum cleaner? Seriously ...