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Study Finds Drug Helps Some Alzheimer's Patients : Medicine: Tacrine can partially reverse memory loss, reduce dementia for some in early stages, researchers say.


A highly touted but still controversial drug called tacrine can partially reverse memory loss and reduce dementia in some patients with early stages of Alzheimer's disease, a new study has found.

The study results reported today in the Journal of the American Medical Assn. are the strongest yet to suggest that drugs can ease the effects of Alzheimer's, which afflicts at least 2.5 million Americans and perhaps as many as 4 million, most over the age of 65.

More than half of the patients who received the highest doses of tacrine in a trial at 23 medical centers showed improvement in their short-term memory, use of language and ability to carry out simple tasks, according to the study.

"We saw significant improvements in a large number of patients," said Dr. Martin Farlow, a neurologist at Indiana University Medical Center who headed the trial. "The improvement was the equivalent of rolling back the clock by about six months, on average."

He added that the trend of the results suggests that "if tacrine can be given in higher doses, a larger percentage of patients will respond."

Perhaps even more important, USC neurologist Dr. Lon Schneider said, the results are exciting "because they show that the course of the disease can be modified by drugs," providing hope that even better drugs will be developed.

"This has legitimately pumped up the enthusiasm and expectation of clinicians and Alzheimer's families," said Dr. Gene Cohen, acting director of the National Institute on Aging, "but it remains to be seen how useful this drug will be. . . . We're encouraged but we want more data."

The beneficial effects of the drug, also known as THA or by the brand name Cognex, are mitigated by its potential to cause severe liver damage in one out of four patients. The liver damage is reversible if patients stop taking the drug.

"Tacrine is not for everyone," said Dr. Gary W. Small, a psychiatrist at UCLA who credited the drug with a "modest but clinically meaningful effect."

About 4,200 Alzheimer's patients are receiving tacrine under an expanded access program approved by the U.S. Food and Drug Administration.

Alzheimer's disease is characterized by memory loss, disorientation, depression and deterioration of bodily functions. It is ultimately fatal, causing about 100,000 deaths in the United States each year.

The cause of Alzheimer's is still unknown, although a growing body of evidence suggests it is largely genetic in origin. Symptoms are produced by the death of brain cells that secrete acetylcholine, a neurotransmitter essential to many thought processes.

Researchers have been unable to introduce more acetylcholine in the brain to replace what is lost. Many have therefore turned to compounds like tacrine that block the function of enzymes that break down excess acetylcholine, thereby making more of the neurotransmitter available.

Another chemical called velnacrine, which is closely related to tacrine, does the same thing and is also being studied in Alzheimer's patients. Last week, however, the FDA said there is not yet enough information about velnacrine to expand its experimental use in patients.

Tacrine has been highly controversial since 1986, when Dr. William H. Summers and his colleagues at UCLA reported dramatic improvements in mental functions among some patients who took the drug. The UCLA report has subsequently been largely dismissed, however, because of flaws in the design of its experiments.

Similar problems cast doubt on a large clinical trial of tacrine that was reported two weeks ago in the New England Journal of Medicine. Overall, the results of that trial were found to be "clinically trivial," in the words of one critic, but a small proportion of Alzheimer's patients in the trial showed dramatic improvements, USC's Schneider said.

Overall, improvements in mental functioning in the latest study are more apparent, Cohen said, but he cautioned that the patients were studied for only 12 weeks, a relatively short time in the case of a disease in which effects last for the rest of a patient's life. "We need results about what happens when the drug is taken over a longer period of time," he said.

The most serious of tacrine's side effects is an elevation of liver enzyme levels in the blood, indicating that damage is being done to the liver. The potential for this damage is so great that patients receiving tacrine must have weekly tests of liver function, greatly increasing the cost.

But changes in the liver are reversible when tacrine is stopped, Farlow said, and some evidence from the study suggests that the potential for liver damage can be minimized by starting patients at low levels and slowly increasing the doses.

Other side effects included nausea and vomiting, diarrhea, abdominal pain and skin rashes. Nearly one-quarter of the Alzheimer's patients originally enrolled in the study withdrew because of side effects.

In balancing the potential benefits and side effects of tacrine, Cohen said, "clinicians will have to ask if the benefits are sufficiently apparent and if the gains are worth the pain."

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