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PROMISING DEVELOPMENTS BUT NO NEW BREAKTHROUGHS IN ADJUVANT THERAPY IN STROKE REHABILITATION

San Antonio, TX — Cultured stem cells taken from neonatal mice and injected directly into the brains of rats could offer new promise as an adjuvant therapy to enhance poststroke recovery in the rehabilitation setting. But, according to neuroscientists, the studies are highly speculative at this time, and involve only lab animals.

Speaking here at the 27th International meeting of the American Stroke Association in February, Seth Finklestein, MD, said basic fibroblast growth factor (bFGF) is a protein synthesized by cells, which can migrate throughout the brain, taking up position around the site of the infarct, inducing changes in neighboring cells. This growth factor also appears to enhance the growth and proliferation of stem cells.

“It's unclear where these cells go, what they become, and the role they play in the recovery process, but it's an intriguing fact that new cells are being born in the brain on the same side as the brain injury and appear to migrate and differentiate into some of the brain neurons,” said Dr. Finklestein, Head of ViaCell Neuroscience, a division of ViaCell, Inc., in Worcester, MA. Dr. Finkelstein was formerly Associate Professor of Neurology at Harvard Medical School.

STEM CELL EXPERIMENTS

In a study designed to show whether exogenous growth factors and stem cells could be used following stroke, 10 rats with cortical infarcts were injected with one million units of neonatal mouse neural cells, and 10 with a combination of mouse neural cells and 0.5 mcg of bFGF. The cells were injected at approximately 14 sites in the brain.

The mice receiving the combination therapy performed, on average, twice as well as the mice that received only monotherapy on a number of different movement tests. Although very preliminary, the results are reproducible, Dr. Finklestein said.

Dr. Finklestein added that he and fellow investigators “have reason to believe that we can find a stem cell population in umbilical cord blood, and with the right growth factors and the right selection processes, they will be able to transform these stem cells into glial cells and neurons.”

He pointed out that investigators at the University of Michigan have proven that intravenous human umbilical cord blood cells will survive, migrate, and improve functional recovery when injected into the brains of mice that have had a stroke (See Stroke 2001; 32(11): 2682–2688).

RESULTS WITH PIRACETAM

According to Wolf-Dieter Heiss, MD, of the University of Cologne in Germany, 70,000 cases of stroke-related aphasia occur in that country each year, and while many resolve spontaneously, 60 percent are left with some deficit. This represents an important segment of the population who could benefit from adjuvant therapy, he said.

In a study Dr. Heiss conducted with colleagues in Cologne, 24 patients with mild and moderate aphasia received either piracetam (2400 mg twice daily) or placebo, plus speech therapy, over a period of six weeks. Those who received piracetam fared significantly better than those who received the placebo (Stroke 2000; 31: 2112–2116).

They also had a greater increase in brain activation than those who received the placebo, and they improved on more language function tests. But, while piracetam seemed to work in Dr. Heiss's study, other studies did not support his findings.

NEED FOR CAUTION

Larry Goldstein, MD, Associate Professor of Medicine at Duke University in Durham, NC, urged caution in interpreting the data on adjuvant therapies. He said part of the difficulty and danger with adjuvant therapies is that the data comes from isolated studies. For example, much of the current thought about using amphetamines for stroke rehabilitation comes from a single trial done in 1997 that involved a small number of subjects, who were treated with one 10 mg dose of methylphenidate (Archives of Physical Medicine Rehabilitation 1997; 78: 245–250).

Other studies investigating methyl-phenidate have failed to show any benefit when the drug was used as adjuvant therapy, Dr. Goldstein said. Two studies demonstrated some benefit with small sample sizes, but when the raw data were reanalyzed, there were no overall differences in outcomes between the treatment groups (Stroke 2001; 32 (9): 2093–2098); (Stroke 1995; 26 (12): 2254–2259).

No lasting effect of the drug was shown, but nonetheless, a beneficial effect was pronounced, and many clinicians began administering amphetamines to their stroke patients, Dr. Goldstein said, adding it was “a terrible extrapolation of very limited data.”

Subsequent studies investigating methylphenidate failed to show any benefit when the drug was used as adjuvant therapy (Cerebrovascular f 2001; 12(3): 253–257).

“We have to be very careful not to jump to conclusions,” said Dr. Goldstein. “A paper might report a statistically significant benefit from looking at the data in only one way,” said Dr. Goldstein.