Since 2000, pharmaceutical companies have introduced two new drugs for treating Alzheimer's disease: galantamine (Reminyl) and rivastigmine (Exelon). Like their predecessors, tacrine (Cognex) and donepezil (Aricept), the new drugs have been shown in clinical trials to slow the decline in memory and thinking caused by Alzheimer's disease. But are Reminyl and Exelon just "me too" drugs that do the same thing as older drugs, but in a slightly different way?
Preliminary research suggests they may not be. Laboratory experiments and a limited number of clinical trials with Alzheimer's patients suggest that Reminyl and Exelon may offer some extra punch in the battle against Alzheimer's disease. But the accent needs to be on "may." Although it is generally accepted that all four Alzheimer's drugs are effective, it remains unclear whether any of them is more effective than the others.
How do they work?
Alzheimer's medications raise the level of a brain chemical called acetylcholine that certain brain cells (neurons) need to function properly. They do this by blocking an enzyme called cholinesterase, which normally recycles "used" acetylcholine between neurons.
This increases the amount of acetylcholine in the brain, which appears to counteract some of the effects of Alzheimer's disease on memory and thinking. "They all can improve behavior and physical functioning and for that reason the medical profession agrees that they're warranted," says Robert M. Palmer, M.D., a geriatrician at The Cleveland Clinic in Cleveland, Ohio.
The effect is modest-an average of 4 points of improvement on a 70-point scale of cognitive function. That said, those modest effects can be important on a personal level. Taking the drug upon diagnosis may allow a person with Alzheimer's to participate more fully in day-to-day activities, such as attending family gatherings and cooking and cleaning. This means a person with the disease could continue to function longer without the need for a full-time caregiver or admission to a nursing facility.
Staking a claim
The manufacturers of Reminyl and Exelon are working double-time to convince doctors to prescribe their products rather than Aricept, the leading medication right now. The most convincing way would be to conduct a large "head-to-head" clinical trial to directly compare the effects of the competing drugs. That hasn't happened yet, so most doctors are content to dispense Aricept. "There's really no convincing evidence that any one drug is superior in its effectiveness," Palmer says.
However, laboratory and animal research suggests that slight differences in the way the drugs work, compared to the older cholinesterase inhibitors, may offer certain extra benefits to patients. For example, the manufacturer of Reminyl, Janssen Pharmaceutica, maintains that its product has a duel mechanism of action that may increase its effect on the brain.
Reminyl: sensitizing the brain?
Like the other cholinesterase inhibitors, Reminyl helps to maintain a higher level of acetylcholine in the brain for a longer period of time. Laboratory experiments suggest that Reminyl may also increase the sensitivity of neurons to acetylcholine. So not only is there more acetylcholine available, but Reminyl may boost the response of the brain to it. "It is Reminyl alone that has this second mechanism of action," asserts Sean Lillienfeld, M.D., a neurologist and senior Janssen researcher based in the company's U.S. headquarters in Titusville, New Jersey.
Right now, it's not known what the alleged duel action of Reminyl means for patients. Lillienfeld says that evidence is accumulating that Reminyl may be more effective than the other drugs. However, in the absence of head-to-head trials, that remains a matter of speculation.
Exelon: broader action?
Novartis, the manufacturer of Exelon, has also identified an aspect of its drug that could, hypothetically, offer extra benefits to patients. Exelon appears to block a form of the cholinesterase enzyme that becomes more important in the brain chemistry of Alzheimer's later in the progression of the disease. As a result, patients may benefit more over the long run from Exelon, even if in the short term the drug is no more effective than the others.
But again, there is no evidence from human clinical trials that Exelon does, in fact, have any special benefit compared to its competitors. "Theoretically that might be an advantage," notes Palmer, "but it remains to be seen if it actually means anything at all."
New uses
Besides trying to prove that the new Alzheimer's drugs work better, research is also underway to justify their use for additional brain diseases and conditions. A study published in the April 13, 2002, issue of the British medical journal Lancet suggests that Reminyl may help people with vascular dementia-a condition caused by small strokes in the brain that has symptoms similar to those of Alzheimer's disease.
Clinical trials are also underway to see if cholinesterase inhibitors can help people with mild cognitive impairment (MCI), whose impairments in memory and thinking are noticeable but not severe enough for a diagnosis of Alzheimer's disease. Studies show that over a period of five to 10 years, most people with MCI go on to develop full-blown Alzheimer's. The hope is that starting someone with MCI on cholinesterase inhibitors will prevent or delay the progression to Alzheimer's.
Trials are also underway to establish whether the cholinesterase inhibitors are effective in later stages of Alzheimer's. Right now, the drugs are typically prescribed for mild to moderate stages of the disease, although patients are usually kept on the medications as long as they can continue to benefit from them.
Watchful waiting
It will be years before all these questions are worked out, if at all. In the meantime, the good news for patients is that early diagnosis and treatment of Alzheimer's disease can buy them precious extra time to live a relatively normal, functional life. Recent changes in Medicare policy also mean that more people with Alzheimer's can benefit from helpful measures that don't come from a pill bottle. Physical therapy, for example, can help a person with Alzheimer's to maintain the ability to move around freely and avoid disabling falls.
Although it's difficult to distinguish between the Alzheimer's drugs in terms of their effect on symptoms, they differ in other ways that can and do influence doctors' prescribing decisions. These are convenience of dosing, side effects, and potential for interactions with other drugs.
Convenience of Dosing: The leading Alzheimer's medication today is Aricept, mainly because it's easier to use: patients only have to take it once a day, either in the morning or evening. Reminyl and Exelon, in contrast, must be taken twice daily. Cognex is the least convenient: it must be taken in four equal doses. When a patient reacts badly to Aricept, does not respond to the drug, or does not respond well enough to justify the routine side effects, a doctor will typically try Exelon or Reminyl instead.
Side Effects: The types of side effects caused by the drugs are similar. When people first start taking a cholinesterase inhibitor, they may experience gastrointestinal symptoms such as bloating, nausea, diarrhea, and vomiting. This may subside with time as the person's body becomes accustomed to the drug. To minimize such adverse effects, doctors increase the dosage gradually over a period of weeks.
Cognex appears to have the highest rate of side effects. In clinical trials, only 25 percent of patients were able to stay on the highest, most effective dose of Cognex (160 milligrams per day).
In clinical trials, Exelon appeared to have a higher rate of side effects than Reminyl or Aricept, but not quite as high as Cognex. This may be because the drug is absorbed into the bloodstream more rapidly than the other drugs, which could trigger nausea and other side effects if the dose is not increased gradually enough. However, since large, head-to-head trials have not been conducted to compare the drugs directly, we don't really know if Exelon is less tolerable than Reminyl or Aricept.
Drug Interactions: Because of the way it's broken down in the liver, Exelon may be less apt to interact with other medications that older adults with Alzheimer's disease are likely to be taking. These include anti-inflammatory painkillers such as ibuprofen (Advil) and aspirin, most antibiotics, and ACE inhibitors-an important class of blood pressure medications. "There's is a theoretical risk for drug interactions with the other three Alzheimer's drugs, but right now very little or no risk with Exelon," says Robert M. Palmer, M.D., a geriatrician at The Cleveland Clinic in Cleveland, Ohio.
For the latest on Alzheimer's treatment and resources available in your area, contact the Alzheimer's Disease Education and Referral Center (ADEAR) at 800-438-4380 or www.alzheimers.org.
Further Reading:
Alzheimer's Early Stages: First Steps In Care and Treatment, by Daniel Kuhn and David A. Bennett. (Hunter House, 1999 (1st edition) , 274 pp., $14.95). This guidebook focuses on the medical aspects of the disease and includes a comparison of the normal aging pattern of the brain and the effects of Alzheimer's. Discusses long-term planning, relationships, communication, and how to stay healthy while caring for someone with Alzheimer's.
- "Guidance on the use of donepezil, rivastigmine, and galantamine for the treatment of Alzheimer's disease," by the National Institute for Clinical Excellence (NICE). (Technology Appraisal Guidance No. 19, January 2001. Available online: www.nice.org.uk
- "Efficacy of galantamine in probable vascular dementia and Alzheimer's disease combined with cerebrovascular disease: a randomized trial," by Timo Erkinjuntti, et al. (Lancet, April 13, 2002, Volume 359, pp. 1283-1290.
- "Galantamine for Alzheimer's disease (Cochrane Review)," by J. Olin and L. Schneider. (Cochrane Database Systematic Review 2001; 4: CD001747.)
- "Practice parameter: management of dementia (an evidence-based review)," by the Quality Standards Subcommittee of the American Academy of Neurology. (Neurology, 2001, Volume 56, pp. 1154-1166.)
- "Use of acetylcholinesterase inhibitors in Alzheimer's disease," by Shehram Moghul and David Wilkinson. (Expert Reviews in Neurotherapeutics, 2001, Volume 1, Number 1, pp. 61-69.) Available online: www.future-drugs.com
