A Review of the Studies

Galantamine Combats Alzheimer's and Vascular Dementia
The evidence for this natural herbal product's efficacy is overwhelming
By Will Block

n the September issue of Life Enhancement, we ran an article on galantamine - the 16th in a series - that summarized the highlights of the previous 15. We reviewed the basic facts about: (1) what galantamine is - it's an alkaloid; (2) where it comes from - it's extracted from certain flowers; (3) what it does - it helps prevent and combat the effects of dementia, and also acts as a muscle stimulant; (4) how it does that - that's kind of complicated; and (5) why it's a better alternative to the prescription drugs widely used in the treatment of Alzheimer's disease - it's because galantamine has a unique, dual mode of action that makes it superior to the drugs. We even saw why galantamine can be considered to be a "gift from the gods."*


*If you haven't yet read the September article, now would be a good time to do so. Even if you don't, however, you'll have no trouble following this one, so don't worry about it.


In this article we'll review the most important studies we reported on previously, supporting galantamine's benefits in treating the two principal types of dementia, Alzheimer's disease and vascular dementia. Despite their different origins, these two terrible diseases are strikingly similar in effect and can be difficult to distinguish from each other (they were summarized in the September article as well). Although galantamine is best known for its action against Alzheimer's, it has also proved to be beneficial against vascular dementia, which has recently been found to have even more in common with Alzheimer's than had previously been believed.1


In terms of cognitive function,
galantamine works as well as
the synthetic drugs.


Galantamine Gets Seal of Approval

During the past decade, medical researchers in many countries have conducted several dozen studies to determine the effects of galantamine in halting, or even reversing, the decline in memory and other cognitive functions that afflict patients with dementia. The results have been so positive that in 2001, galantamine was granted FDA approval for sale as a prescription drug. The irony here is that galantamine has a long history of use as a natural herbal product, and it is, fortunately, still available without prescription (and at substantially lower cost) today. Whether by prescription or not, all galantamine molecules are the same and are indistinguishable as to their source.

In any case, the quality of the studies that supported the benefits of galantamine ranged from first-rate to, well, somewhat less than first-rate. That should not surprise anyone. In medical research, as in all fields of endeavor, some people are smarter and more capable, conscientious, and meticulous than others - and it shows in their work. It is just that kind of superior work that other researchers look for when they conduct a meta-analysis of the literature.

Why Is a Meta-Analysis So Useful?

A meta-analysis is a thorough, hard-nosed, expert review of the literature, with the aim of identifying the best-conducted studies in terms of scientific method and overall credibility. The authors then consolidate the results of the best studies to enable them to reach the most valid conclusions, based on as much data as possible, about the subject at hand. Such a meta-analysis has been carried out for galantamine, and the results have confirmed its role as an effective treatment for Alzheimer's disease.2

The authors combed medical journals and monographs, databases of clinical trials, and directories of Ph.D. theses for all available information on galantamine's role as a treatment for Alzheimer's. To ensure that only high-quality research was included in the meta-analysis, they screened the studies for the following factors: (1) the studies had to be randomized, double-blind, placebo-controlled, and unconfounded (i.e., galantamine had to be tested alone, not in combination with any other agent); (2) they had to have covered a treatment period of more than 4 weeks for patients with Alzheimer's disease; and (3) they had to meet tough additional criteria regarding the study protocol and the reporting of data. Of the 33 studies examined, only seven made the grade. *


*This does not necessarily mean that the other 26 studies were of poor quality, only that they did not meet the highest standards to which the best studies are held.


Galantamine's Efficacy Is Confirmed

From the combined results of these seven studies - all of which involved patients with mild to moderate Alzheimer's (none severe) - the authors concluded:

. . . this review shows consistent positive effects for galantamine in trials of 3 months, 5 months, and 6 months duration. . . . there is evidence demonstrating efficacy for galantamine on global ratings, cognitive tests, assessments of ADLs [activities of daily living], and behavior. The magnitude of the effect on cognition is similar to other acetylcholinesterase inhibitors, including donepezil, rivastigmine, and tacrine.

(Donepezil and rivastigmine are the most widely used synthetic drugs for treating Alzheimer's disease; tacrine is rarely used anymore, owing to its severe side effects.)


Galantamine had a positive
therapeutic effect in all key areas
of cognitive and noncognitive
abilities in the demented patients.


In other words, in terms of cognitive function (memory, learning, etc.), galantamine works as well as the synthetic drugs. The dosages most commonly used in these studies were either 24 or 32 mg/day, but the authors concluded that 16 mg/day is probably preferable because its efficacy is equal to that of the higher doses, and it is less likely to cause gastrointestinal (GI) upset, a possible side effect of galantamine. The synthetic drugs can cause GI upset too but may also produce more serious side effects, such as liver toxicity and heart-rate irregularities.

Galantamine Preserves Cognitive Function

Studies have shown that, over the course of one year, there is a clear and significant decline in cognitive function in patients with Alzheimer's disease.3 For a treatment to be regarded as successful, therefore, it is not necessary that it be able to reverse the course of the disease (a tall order). Success is achieved if the treatment can simply halt the decline and maintain baseline levels of cognitive function, i.e., the levels that prevailed when the treatment was begun.

In a recent review article on current treatments for Alzheimer's, the author cites evidence for the success of galantamine in this regard from three randomized, double-blind, placebo-controlled studies of up to 6 months' duration.4 In these studies, galantamine actually went one better than maintaining baseline levels of cognitive function: it significantly improved them. By contrast, in the control groups taking placebo, cognitive function declined significantly, as expected.

The author of the review also describes two 12-month studies in which galantamine treatment (24 mg/day) was again successful, albeit less dramatically so. For the most part, cognitive function remained unchanged over the course of these studies - a definite success, since normally a decline would be expected - but in some measures it showed a less-than-expected decline (modest success), and in others it showed some improvement.

Galantamine Alleviates Caregivers' Burden

The two 12-month studies mentioned above evaluated not just cognitive function but also caregivers' burden, i.e., the practical impact of the disease, in terms of time and effort required, on those charged with caring for the patients. In both studies, the overall caregivers' burden remained unchanged over the course of the study for those in the galantamine group.

By contrast, there was a significant increase (as expected) in the burden on those caring for patients in the control group.

Galantamine Preserves Ability to Function in Daily Living

The author of another review article cites four randomized, double-blind, placebo-controlled studies that encompassed the effects of galantamine on functional ability (as opposed to cognitive function) in Alzheimer's disease.5 In three of these studies, galantamine showed significant benefits on an index called activities of daily living (ADL), as measured by standardized tests. These studies were of 3, 5, and 6 months' duration, and the dosage of galantamine used ranged from 16 to 32 mg/day, with a 24-mg/day dose included in each study.

In the fourth study, no benefits from galantamine were seen after 6 months of treatment (no difference between galantamine and placebo), but when the study was extended to 12 months, it was found that patients receiving 24 mg/day of galantamine had maintained their baseline levels on the ADL scores, whereas those on placebo had suffered a significant decline.

Galantamine Preserves Behavioral Stability

One of these four studies also evaluated behavioral symptoms associated with Alzheimer's disease, and here again, galantamine (16 and 24 mg/day) showed a distinct benefit: maintenance of baseline values on a standardized test over a 5-month period, while the control group showed a significant decline. The researchers also studied the effect of these behavioral patterns on caregivers' burden, and they found (not surprisingly) that a favorable outcome in behavior meant a decreased burden on the caregivers.

Vascular Dementia and Alzheimer's Often Coexist

As mentioned earlier, galantamine has proved to be beneficial against vascular dementia as well as Alzheimer's disease. The underlying cause of vascular dementia is cerebrovascular disease (the brain's equivalent of cardiovascular disease), in which clogged arteries impair blood flow, contribute to high blood pressure, and set the victim up for strokes, which can cause severe damage to brain tissue.

Cerebrovascular disease is common in the elderly and is a risk factor not only for vascular dementia but also for Alzheimer's disease. The two diseases are often found to coexist, to varying degrees, in older people suffering from dementia. Both diseases produce various kinds of pathological changes in the brain that are related to the symptoms of dementia.

Galantamine Combats Vascular Dementia Too

A large-scale clinical trial was carried out recently on the efficacy of galantamine in patients diagnosed with cerebrovascular disease together with probable vascular dementia or Alzheimer's disease.1 In other words, all the patients (592 men and women, average age 75) had cerebrovascular disease and either probable vascular dementia or Alzheimer's (the percentages were roughly half and half). The study was a 6-month, randomized, placebo-controlled, double-blind trial undertaken in ten countries.

Galantamine or placebo was administered orally, twice daily, according to a dose-escalation schedule that culminated in a daily dose of 24 mg after the first 6 weeks of the trial. The patients were evaluated several times, using a number of internationally accepted, standardized test protocols, on measures of cognition, behavioral symptoms, activities of daily living, and global functioning (a clinician's interview-based impressions of change, plus input from the patient's caregiver).


The patients taking galantamine
showed significant improvements
in both types of dementia . . .
they didn't just hold their ground,
they gained some back.


After 6 months, the results showed that galantamine had a positive therapeutic effect in all key areas of cognitive and noncognitive abilities in the demented patients. The improvements noted were of similar size to those seen previously in galantamine studies on patients with Alzheimer's disease.6-8

With Galantamine, Patients Actually Gained Ground

In the study, the patients taking placebo showed a disease progression typical of what would be expected in their respective types of dementia: those with combined Alzheimer's disease and cerebrovascular disease experienced a steady deterioration of function, whereas those with probable vascular dementia did not, because that disease tends to proceed in irregular steps at long intervals.

By contrast, the patients taking galantamine showed significant improvements in both types of dementia, relative to the baseline values measured at the outset of the study. In other words, they didn't just hold their ground, they gained some back. This kind of improvement in the Alzheimer's group is particularly gratifying, because with other anti-Alzheimer's drugs, the best one can usually hope for is to stop losing ground, for about 6 months (after which the drugs start to lose their effectiveness).

Galantamine's Novel Mechanism of Action May Be the Key

Thus, galantamine demonstrated yet again that it is effective (and safe) in the treatment of dementia. In the authors' words:

Galantamine has shown broad, sustained efficacy in patients with mild to moderate Alzheimer's disease, and this efficacy is not compromised by concomitant cerebrovascular disease. The subgroup of patients with probable vascular dementia who were treated with galantamine in this study showed significant improvement in cognition . . . . the results observed with galantamine in our study represent an important finding for this subgroup of patients and provide evidence of efficacy further to those in previous trials with other cholinergic agents. The broad benefits of galantamine may reflect its novel mechanism of action.

The Evidence for Galantamine Continues to Mount

The latest evidence of galantamine's value comes from a randomized, double-blind, placebo-controlled trial to evaluate the efficacy and tolerability of galantamine taken at three different dosages - 18, 24, and 36 mg/day - over a period of 3 months.9 The subjects were 285 patients (males and females over 45 years old, average age 74) divided into four groups: one for each of the three dosages, plus a control group.

All the subjects had mild to moderate Alzheimer's disease, and they were screened to exclude those who had dementia that might be due to any other cause, such as vascular dementia. The researchers evaluated the patients' condition at baseline and again after 6 and 12 weeks, by means of standardized tests of cognitive function and activities of daily living (the latter can be used as indicators for an overall quality-of-life assessment). They found that at all dosages, galantamine significantly improved the patients' condition, with the greatest gains being realized at the intermediate, 24-mg/day dose.

The authors concluded that ". . . the favorable effects of galantamine on patients' quality of life confirm that its effects on cognitive function are clinically relevant." In their opinion, the 24-mg/day dose is optimal for the treatment of Alzheimer's disease, based on both the efficacy and tolerability results, but they point out that 16 mg/day may be adequate for some people.

Galantamine - The Best There Is

That galantamine is a safe and effective agent for combating the effects of dementia is indisputable, and that it is the best such agent seems very likely, based on the growing body of evidence in the scientific literature. Although it's disheartening to realize that no one is immune to the demon of dementia and that our susceptibility to it increases as we age, it's gratifying to know that there is a natural substance - a "gift from the gods" - that can help hold the demon at bay and temper its wrath. Anyone whose memory may be faltering with age might find benefit in the protective power of galantamine.

A Salute to Charlton Heston

Alzheimer's disease is equally tragic for all its victims, be they great or humble, rich or poor, famous or obscure. Still, it's hard for us not to be especially affected by the news of this terrible disease striking those who are highly accomplished and prominent, and who have been "larger than life" in one way or another. One way, certainly, is to have graced the silver screen, as Ronald Reagan did before he entered politics.

Now we have learned that Reagan's old friend Charlton Heston is similarly afflicted, albeit in the very early stages of the disease. With characteristic grace and eloquence, he announced the news of his condition in a speech that was both inspiring and heartbreaking. He will continue to work while he is still able, fighting a battle he knows he cannot win but is determined to prolong for as long as possible. We admire his courage and spirit and wish him - and all the other victims of dementia - the very best that medical science can offer in the way of treatment and hope.

References

  1. Erkinjuntti T, Kurz A, Gauthier S, Bullock R, Lilienfeld S, Damaraju CV. Efficacy of galantamine in probable vascular dementia and Alzheimer's disease combined with cerebrovascular disease: a randomised trial. Lancet 2002 Apr 13;359:1283-90.
  2. Olin J, Schneider L. Galantamine for Alzheimer's disease (Cochrane review). In The Cochrane Library, Issue 2, 2001. Oxford: Update Software.
  3. Stern RG, Mohs RC, Davidson M, et al. A longitudinal study of Alzheimer's disease: measurement, rate, and predictors of cognitive deterioration. Am J Psychiatry 1994;151:390-6.
  4. Tariot PN. Maintaining cognitive function in Alzheimer disease: how effective are current treatments? Alzheimer Dis Assoc Disord 2001;15 Suppl 1:S26-33.
  5. Winblad B. Maintaining functional and behavioral abilities in Alzheimer disease. Alzheimer Dis Assoc Disord 2001;15 Suppl 1:S34-40.
  6. Tariot PN, Solomon PR, Morris JC, Kershaw P, Lilienfeld S, Ding C. A 5-month, randomized, placebo-controlled trial of galantamine in Alzheimer's disease. Neurology 2000;54:2269-76.
  7. Raskind MA, Peskind ER, Wessel T, Yuan W, and the Galantamine USA-1 Study Group. Galantamine in AD: a 6-month, randomized, placebo-controlled trial with a 6-month extension. Neurology 2000;54:2261-8.
  8. Wilcock GK, Lilienfeld S, Gaens E, on behalf of the Galantamine International-1 Study Group. Efficacy and safety of galantamine in patients with mild to moderate Alzheimer's disease: a multicentre randomised controlled trial. Brit Med J 2000;321:1445-8.
  9. Wilkinson D, Murray J, in collaboration with the Galantamine Research Group. Galantamine: a randomized, double-blind, dose comparison in patients with Alzheimer's disease. Int J Geriatr Psychiatry 2001;16:852-7.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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