Apr. 4, 2003 A drug that quashes the activity of a key brain chemical is the first effective treatment for patients in the later stages of Alzheimer's disease, according to the results of a large multi-center clinical study published in the April 3 issue of the New England Journal of Medicine.
The drug, memantine, slows the mental and physical deterioration of patients with moderate to severe Alzheimer's disease, according to Barry Reisberg, M.D., Professor of Psychiatry at NYU School of Medicine, who led the study. "These patients seem to be declining much less, about half as much as ordinarily expected, over a six-month period," says Dr. Reisberg. "This medication will slow down the otherwise inexorable progress of this disease, and it is remarkably free of side effects. These are very impressive results. It looks like this drug really will have an impact on this disease," he says.
Neil Buckholtz, Ph.D., Chief, Dementias of Aging Branch at the National Institute on Aging says: "This study shows that treatment in the very late stages of Alzheimer's disease can be beneficial in a number of ways, for both patients and caregivers."
It isn't yet known if memantine can slow the disease for more than six months, says Dr. Reisberg. "It may slow the progression for a longer period of time, and we have some evidence that it does, but that remains to be definitively determined," he says. The drug also may be effective in milder forms of the disease, and in combination with other medicines, and studies are underway to assess its other potential uses, he says.
Alzheimer's disease is the most common form of dementia affecting people over age 65. Some four million Americans have the mind-robbing disease, and it is the major reason why people are institutionalized in the United States.
There are no treatments available for slowing the later stages of the disease, when patients are in the most distress. In the moderate to severe stages, patients begin to lose the ability to care for themselves. They have trouble dressing and bathing; many can no longer make a cup or coffee or tea for themselves. "This is the time when there is an increase in behavioral disturbances, and when the burden on caregivers intensifies as they struggle to care for a loved one who is slipping away," says Dr. Reisberg.
Memantine blocks the activity of a brain chemical called glutamate, which excites neurons. In recent years researchers have learned that when neurons become over stimulated because of an abundance of glutamate, the nerve cells can become damaged or die, and this "excitotoxicity" has been linked to death of neurons in the brains of patients with Alzheimer's, says Dr. Reisberg. Nerve cells that respond to glutamate are involved in memory and learning. "Memantine is a completely different chemical way of getting at the disease," he says.
The available treatments for Alzheimer's in the United States, which are effective in the mild to moderate stages of the disease, are aimed at a different chemical system in the brain, called the cholinergic system. These drugs strengthen the activity of neurons that use the brain chemical acetylcholine to transmit their signals.
Dr. Reisberg is Clinical Director of NYU's William and Sylvia Silberstein Aging and Dementia Research and Treatment Center. A longtime Alzheimer's researcher, Dr. Reisberg in the early 1980s developed scales to describe the clinical course of the disease. The scales evolved in part from his observations that the disease essentially reverses the normal pattern of human development, a process that he has called "retrogenesis." So, in the final stages, for example, patients progressively lose their ability to dress and bathe, maintain continence, speak and walk, sit up, smile, and hold up their head. The scales make it possible for clinicians and family members to understand the progressive losses and associated behavioral symptoms of the disease.
The new study was led by Dr. Reisberg and Steven Ferris, Ph.D., Professor of Psychiatry and the Gerald J. and Dorothy R. Friedman Professor of the Alzheimer's Disease Center at NYU School of Medicine. Dr. Reisberg's team coordinated the study, which involved 32 medical centers nationwide and enrolled 252 patients. The mean age of the patients was 76 and 67 percent of the participants were women. All of the patients lived independently in the community and were not institutionalized. All had trouble putting on their clothing and many also had difficulties with bathing, toileting, and continence. All of the patients could still speak to some extent and were still able to walk.
The study was randomized and doubled-blinded, the most rigorous methods available for testing the effects of potential treatments. Over 28 weeks, patients received 10 milligrams of memantine or a dummy (placebo) pill twice a day. A battery of behavioral, cognitive, and functional tests were used to evaluate patients at the beginning and end of the study, and clinicians conducted interviews with caregivers to assess the activities of patients during the study.
Overall, the study found that the patients who were taking the memantine showed significantly less deterioration in cognition and in the ability to perform daily life activities than those taking the dummy pills. The side effects from the drug were minimal. Patients taking the dummy pills experienced more side effects than did those who received memantine, according to the study, and there were no side effects that were likely to be related to the drug.
Memantine is manufactured by Merz Pharmaceuticals, based in Frankfurt, Germany, and it has been used in Germany for more than a decade to treat various neurologic conditions. However, it had never been tested in rigorous clinical trials. Based largely on Dr. Reisberg's study, the drug has recently been approved by European regulatory authorities to treat severe Alzheimer's disease.
In the United States, Forrest Pharmaceuticals, Inc., based in New York City, has licensed the drug from Merz. The Food and Drug Administration, which has not approved the drug for marketing in the United States, is currently reviewing the drug.
A toll free number has been set up for the general public to get information about memantine and Alzheimer's disease. The number is 866-321-5323.
The study was supported by grants from Merz Pharmaceuticals and the National Institute on Aging.
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