New Drug Therapies Delay Effects of Alzheimer's Disease
By Press Release by the National Institute on Aging •
April 23, 1997
Selegiline (or Eldepryl) and alpha-tocopherol (or Vitamin E) may slow important functional signs and symptoms of Alzheimer's disease by about 7 months, according to a report by scientists at 23 Alzheimer's Disease Cooperative Study (ADCS) sites across the U.S. The two drugs delayed important milestones, such as entry into nursing homes, for people with moderately severe Alzheimer's disease, and decreased their loss of daily activities, including bathing, dressing, and handling money, by about 25 percent. Department of Health and Human Services Secretary Donna E. Shalala called the finding "very good news. Each piece of the Alzheimer's disease puzzle that falls into place moves us one step closer to relieving the burden of this devastating disease."
Findings from the study, the longest clinical trial to date testing drugs for slowing the progression of Alzheimer's disease, are reported in the April 24, 1997, The New England Journal of Medicine. Mary Sano, Ph.D., of Columbia University College of Physicians and Surgeons, principal investigator for this study, Leon J. Thal, M.D., University of California at San Diego, principal investigator of the ADCS, and colleagues reported the findings on behalf of scientists at the ADCS sites. The National Institute on Aging (NIA), part of the National Institutes of Health at the Department of Health and Human Services, funded this study as part of the ADCS, a consortium of 35 research centers.
"We looked at the signs and symptoms of Alzheimer's disease that can worsen over time and found that in patients taking these drugs, these signs occurred later," said Sano. "Physicians may want to think about using either selegiline or Vitamin E in patients with moderately severe disease, like those in our study. The drugs may benefit certain patients by delaying some aspects of the deterioration that comes with the disease. Of course, potential side effects and drug interactions need to be considered as well," she added.
Beyond their significance for today's patients, the findings are important in understanding the factors involved in the symptoms of Alzheimer's disease. Researchers exploring the idea that oxidative damage may play a role in Alzheimer's disease theorize that drugs such as selegiline and alpha-tocopherol keep oxidative damage of brain cells at bay, and therefore may be effective in reducing symptoms of the disease.
"This study reinforces the thinking that oxidative damage plays a role in Alzheimer's disease, and we are actively pursuing this line of research," says Neil Buckholtz, Ph.D., acting chief of the dementias of aging branch at the NIA. "Now that we have seen an effect in this group of patients, we will need to look further to determine whether these types of drugs can actually delay the development of symptoms much earlier in the course of the disease."
The clinical trial examined the effects of the two drugs in 341 patients. The participants were divided into four groups, including those receiving placebo, those receiving 10 milligrams of selegiline per day, those taking 2,000 IU (international units) of Vitamin E per day, or people taking a combination of both drugs. Both selegiline, a drug widely used to treat Parkinson's disease, and Vitamin E are currently available.
Using novel, more functional measures of the disease's progression than have been used to study the disease in the past, the researchers assessed the patients every 3 months for 2 years, marking four important milestones in the progression of the disease -- death, institutionalization, loss of the ability to perform basic daily activities, and progression to severe dementia.
The scientists found a significant delay after treatment with either drug, in an analysis that combined all four milestones. With selegiline, when compared to placebo, it took 215 days longer to reach any one of the four milestones. With Vitamin E, the delay was about 230 days. The combination of the drugs showed less of an effect, with a delay of only 145 days.
Looking at the milestones separately, the treatment groups did somewhat better in most categories compared with those receiving a placebo. The results were not statistically significant except for a 13 percent reduction in entry into a nursing home among people taking Vitamin E during the period of the study. On one important, commonly used measure of function in everyday activities, the Blessed Dementia Scale, people in the three treatment groups showed about 25 percent less deterioration of abilities such as eating, dressing, or cooking than those not receiving the drug therapies.
While the measurements of the disease's progression in practical terms showed that the drugs were having a positive effect, there was no improvement in cognition. Measurements of cognition tested memory, attention, language, and comprehension. More research will be needed to see whether the positive findings on function were the result of other improvements in health, such as cardiovascular effects, that are associated with antioxidants, rather than being the direct consequence of antioxidant action on the brain. Two drugs already approved for treatment of Alzheimer's disease, tacrine and donepezil, have been shown to improve cognition by about 6 months. The demonstrated benefits of selegiline and Vitamin E on the functional milestones occurred over a 2-year period.
Scientists were surprised that people taking the combination of the drugs did not do as well or better than those taking either selegiline or Vitamin E separately. From laboratory studies, they had expected the drugs to have an additive effect, since each works in a different way to prevent oxidative damage. The unexpected results in humans highlights how important it is to do controlled clinical trials to test ideas from the laboratory, the researchers emphasized.
While heartened by the finding that either selegiline or Vitamin E moderates some of the signs of Alzheimer's disease, scientists still were cautious about recommending immediate, widespread application of either drug. First, they noted, the study involved patients with moderately severe disease, and more research needs to be conducted to see how the drugs might affect patients at different stages of the disease. Also, use of selegiline could be have potential side effects and interactions with other drugs. In addition, the dosage of Vitamin E used in this study was substantially higher than that typically taken by people as a daily vitamin supplement. Vitamin E may be associated with increased risk of bleeding in certain individuals.
Alzheimer's disease patients and their families should consult their physicians on whether these drugs or tacrine (brand name Cognex) or donepezil (brand name Aricept) may be appropriate for a particular individual. The study reflects progress in the ADCS, set up 6 years ago to facilitate research on treatments for Alzheimer's disease. "The study reported today highlights one important aspect of the program, testing drugs or substances that are already on the market but that may prove useful in delaying decline among Alzheimer's disease patients," Thal noted. Observational studies indicate that estrogen or anti-inflammatory agents, for example, may also have some positive benefits on Alzheimer's disease, Thal said, and scientists in the ADCS are testing these two substances and others in controlled trials to determine if they really do offer a benefit.
Questions and Answers: Selegiline and a-tocopherol in the
Treatment of Alzheimer's Disease
What did this study examine?
The National Institute on Aging's (NIA's) Alzheimer's Disease Cooperative Study tested the effectiveness of a-tocopherol (also known as vitamin E) and selegiline (also known as Eldepryl) in slowing the progression of Alzheimer's disease. Researchers were interested in these drugs because both are anti-oxidants -substances that counteract oxidative damage. The progressive loss of brain cells that occurs in Alzheimer's disease may be related to oxidative damage. Besides acting as an anti-oxidant, selegiline also increases the supply of dopamine and catecholamines, important brain chemicals whose levels are reduced in Alzheimer's disease.
What were the results?
Taking selegiline, vitamin E, or a combination of the two drugs delayed by about 7 months the time it took for patients to reach one of four milestones: death, institutionalization (moving to a nursing home), loss of the ability to perform activities of daily living, or progression to severe dementia. In one commonly used measure of everyday activities, patients in the three treatment groups showed 25 percent less deterioration in activities such as eating and dressing.
What recommendations come from this study?
The researchers believe it is now reasonable for doctors to consider the use of either selegiline or vitamin E in patients with moderately severe Alzheimer's disease. Today, no other treatments have shown a similar ability to delay important milestones in Alzheimer's disease.
What are the possible side effects or problems of these treatments?
In this study, the selegiline and vitamin E were tolerated well with few side effects. However, with both treatments, there are potential problems as reported in other research. Selegiline, which has been studied very carefully over a long period of time, should not be taken with certain other drugs, specifically anti-depressants or narcotics. Reported side effects of selegiline include fainting, nausea, dizziness, confusion, vivid dreams, and sometimes, low blood pressure. Vitamin E is less well-studied, especially at high doses. As a result, neither the long-term effects nor the potential hazards of such high doses are known. Vitamin E may be associated with increased bleeding in certain people, and some studies have suggested that it should not be used with anti-coagulant medications.
Why were there no advantages to combination therapy?
The researchers tested a combination of selegiline and vitamin E because these drugs seemed to work in different ways in animal and cellular models of AD. These laboratory data strongly suggested that they would have an additive effect. However, in this study, people taking the two drugs did no better than those taking either selegiline or vitamin E alone. These findings may indicate that selegiline and vitamin E both affect Alzheimer's disease in similar ways and, thus, there is no advantage to taking both of them. The results show how important it is to do well-controlled studies in people to determine the effects of drugs and, in particular, combinations of drugs. While laboratory studies may give us an idea of what will work, only controlled studies in humans can tell us if these ideas are correct.
Should people in earlier or later stages of the disease also consider therapy with vitamin E or selegiline? What about taking them for prevention?
This study only addressed patients with moderately severe disease. We do not know whether people in other stages of Alzheimer's disease would benefit from these drugs. The only drugs approved by the Food and Drug Administration (FDA) as safe and effective in treating some symptoms of Alzheimer's disease are tacrine (brand name Cognex) and donepezil (brand name Aricept). There is no evidence that any drug, including vitamin E and selegiline, prevents Alzheimer's disease.
Will vitamin E from a drug store work and what dose should be used?
Vitamin E, though relatively safe, may pose problems for some people. It may be associated with increased risk of bleeding in some people, especially those with bleeding problems. In addition, the study used much higher doses of vitamin E than are typically found in vitamin supplements. High doses of vitamin E and its interaction with other drugs have not been well studied. It is very important to check with a doctor before starting any drug or supplement treatment.
How can someone with Alzheimer's disease get selegiline?
Selegiline is a prescription drug approved by the FDA to treat Parkinson's disease. It is not approved for Alzheimer's disease in the U.S. The decision to take any drug must include weighing benefits and risks. If a doctor concludes that a patient's condition is similar to that of the patients in this study and that the risks of selegiline are not serious for that patient, the doctor may choose to prescribe it. Selegiline must be taken under a doctor's supervision, in part because of its potential side effects as discussed above.
Are vitamin E and selegiline better than drugs currently on the market for Alzheimer's disease—tacrine and donepezil? Should patients take anti-oxidants instead of, or in combination with, these drugs, especially if the current treatment is not working?
This study was not designed to show whether vitamin E and selegiline are better than tacrine and donepezil, which both work by increasing the supply of a brain chemical called acetyl-choline. The research shows that the two kinds of drugs affect different symptoms. In this study, vitamin E and selegiline reduced problems with everyday activities such as bathing and dressing, delayed institutionalization, and slowed the advance to severe dementia over a 2-year period. However, they did not improve memory or cognition, which is seen with tacrine and donepezil. In addition, patients in this study had a more advanced stage of Alzheimer's disease than most patients who have benefited from tacrine and donepezil. There is no evidence that anti-oxidants, such as vitamin E and selegiline, have additive effects when combined with drugs that work on acetylcholine. While it may seem that the combination should not be harmful, no one knows. Only carefully controlled studies in patients can answer that question.
How long will selegiline and vitamin E work? Are there any adverse effects when you stop taking them?
The study showed that 2 years of treatment had a measurable effect. We do not know if the effect would be the same if people stopped treatment or if they continued treatment for a longer or shorter period of time. Researchers did not study what would happen if someone stopped treatment. However, there have been no reports of serious adverse effects from stopping the treatment.
How long should it take before we see results? What results should we see?
Any improvements may not be apparent. These drugs have only been shown to delay the effects of disease. The patient will not be getting better, but he or she will be able to maintain basic functional activities longer.
Will these drugs help patients with other dementias?
We do not know. Other studies have examined these drugs in patients with Huntington's disease and Parkinson's disease, but have found no improvements in cognition or effect on dementia in these diseases.
What further research is needed?
Research is needed to test the effectiveness of anti-oxidants in both the earlier and later stages of Alzheimer's disease. More work needs to be done to determine if these drugs can provide an added benefit when used in combination with other medications to treat dementia.
Source: National Institute on Aging
April 23, 1997
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