Galantamine Succeeds Where Others May Have Failed

Galantamine Is the Enemy of Memory Loss

Galantamine Succeeds Where
Others May Have Failed

Its efficacy is unaffected by previous treatments that were discontinued
By Will Block

o succeed where others have failed is a goal shared by adventurers, entrepreneurs, scientists, and others for whom the status quo is inadequate or boring, and who dare to be different in order to improve it. For such people, good enough is not good enough. They want better, and more. What if Edison had been satisfied with gas lamps? As George Carlin has said, “When Thomas Edison worked late into the night on the electric light, he had to do it by gas lamp or candle. I’m sure it made the work seem that much more urgent.”

In the world of medicine, there are many urgent priorities, one of which is to defeat Alzheimer’s disease and other forms of dementia—diseases that used to be lumped under one term: senility. Although an outright defeat of this terrible, debilitating condition is not yet in sight, scientists continue to seek chemical weapons (drugs or nutritional supplements) to use against Alzheimer’s, which is by far the most prevalent form of dementia. Their battle may not have the pyrotechnic excitement of “shock and awe,” but it is sustained and relentless, and it has already yielded some victories they can be proud of.

Galantamine Boosts Acetylcholine Levels

Probably the greatest victory to date has been the discovery and use of the dual mode of action of galantamine, a natural chemical compound that is extracted from various flowers, notably the snowdrop, daffodil, and spider lily. Evidence from clinical trials shows that galantamine is the most effective of the three anti-Alzheimer’s agents currently in use (the other two are the synthetic drugs donepezil and rivastigmine; yet another drug, tacrine, is available but is rarely used anymore because of its severe side effects).*


*Another exciting discovery is the role played by the antioxidant vitamin E in protecting and preserving cognitive function in aging people, even in those with Alzheimer’s. See “Vitamin E Keeps Your Brain Razor-Sharp” and the sidebar (“Vitamin E Protects Brain Function”) to “Galantamine Is Food for Thought” in the November 2002 and May 2003 issues, respectively, of Life Enhancement.


Although the cause of Alzheimer’s disease is unknown, we do know that its symptoms are due in part to a deficiency of the neurotransmitter acetylcholine in certain parts of the brain. This deficiency slowly robs Alzheimer’s victims of their memory and other cognitive functions, causes behavioral problems, and impairs their ability to perform even simple activities of daily living, such as bathing, dressing, and cooking. It can also rob them of several years of their life (see “Preventing Dementia Can Boost Life Expectancy” in Life Enhancement, June 2001).

Like donepezil and rivastigmine, galantamine is an acetylcholinesterase inhibitor. This means that it inhibits the action of an enzyme, acetylcholinesterase, that tends to reduce acetylcholine levels in the brain. In short, galantamine helps to boost acetylcholine levels, which is definitely desirable for Alzheimer’s patients. It may also be desirable (although there is not yet proof of this) for the millions of people who have the age-related condition known as mild cognitive impairment (MCI). This condition goes beyond the normal forgetfulness that comes with age, but it falls short of qualifying as dementia; it represents a transition zone between health and disease. Although MCI does not necessarily lead to Alzheimer’s disease, it is a very strong risk factor for Alzheimer’s (see “Galantamine May Help with Mild Cognitive Impairment” in Life Enhancement, February 2003).

Galantamine’s Dual Mode of Action Keeps It Going

The main reason why galantamine is the most effective agent against Alzheimer’s disease is that it not only does what donepezil and rivastigmine do, it also does something they do not do: it modulates nicotinic receptors on brain cells. These are vitally important molecular sites that are responsive to acetylcholine and certain other molecules, including nicotine (hence the name). Galantamine modulates these receptors in such a way as to preserve both their numbers and their functional integrity, both of which tend to deteriorate in Alzheimer’s disease. With donepezil and rivastigmine, which do not retard this deterioration, the efficacy of the drug gradually decreases, and the symptoms of the disease inevitably become worse.


“This post hoc analysis suggests
that galantamine may be
beneficial in patients who have
discontinued treatment
with conventional acetyl-
cholinesterase inhibitors.”


Because of galantamine’s dual mode of action, it can remain effective for longer periods of time, an inestimable advantage when time is the enemy. Like the Energizer Bunny, galantamine keeps on going even when the other agents have lost their “juice.” This does not mean, however, that galantamine works indefinitely (even the Energizer Bunny eventually tires). It has, however, shown long-term benefits in combating Alzheimer’s disease by halting its progression and even, sometimes, bringing about improvements in several important areas: cognitive function (including memory), behavior, and the activities of daily living (ADL).

Study Uses Gradual Buildup of Galantamine Dosage

One of the best-conducted studies demonstrating these benefits of galantamine was carried out in the United States by Dr. Pierre N. Tariot, of the University of Rochester, and colleagues.1 It was a randomized, placebo-controlled, double-blind clinical trial to study the safety and efficacy of galantamine in patients with mild to moderate Alzheimer’s disease. The patients, 978 men and women, were randomly divided into four groups: one group received placebo, and the other three received 8 mg/day, 16 mg/day, or 24 mg/day of galantamine, for 5 months.

The higher target dosages were reached gradually over a 4-week period, because galantamine sometimes causes mild side effects (chiefly stomach upset) when it is initially taken at too high a level. This problem is easily avoided by starting with a low dosage and increasing it gradually to give the body time to adjust (for more on this, see the sidebar, "Dose Escalation May Be Wise").

Dose Escalation May Be Wise

You’ve heard of altitude sickness. Mountain climbers who are susceptible to its debilitating (and potentially lethal) effects must ascend slowly to give their bodies time to adjust to the low oxygen levels. The same kind of gradual adaptation is sometimes necessary with drugs, and even with nutritional supplements.

Although galantamine is well tolerated by most people, some people take awhile to get used to it, so building up the dosage gradually is the best approach. Doctors call this dose escalation. (Today’s trivia item: the scientific study of medicine dosages is called posology—and no, that p is not a typo.) Galantamine’s side effects, which occur in a small percentage of people, are primarily mild to moderate gastrointestinal upsets, such as nausea, and are usually short-lived.

Significantly, these effects tend to occur more frequently when the patient first starts to take galantamine, especially if the initial dosage is relatively high. Thus it makes sense to start at a low dosage and build up slowly, over a month or two, to the commonly used dosages of 16 or 24 mg/day. As the body adjusts to its new molecular guest, the chances of side effects diminish sharply.

This practice is well accepted in all countries where galantamine has been introduced. The important thing is not to give up on galantamine if some side effects should occur (which, in the great majority of people, they won’t anyway). Just slow down, take it easy, and let Mother Nature take her own sweet time. She always knows best.

Galantamine’s Observed Benefits Lead to Provocative Question

The results of the study, like those of several similar “gold-standard” studies of galantamine, showed distinct improvements in cognitive function, behavior, and ADL.2 Good results were obtained with 16 mg/day, and somewhat better results with 24 mg/day. That’s gratifying, of course, but an interesting question now arises: Would galantamine work as well in patients who had been previously treated for Alzheimer’s disease with some other acetylcholinesterase inhibitor as it would in patients who had had no such prior treatment?

Tariot et al. did not address this question, but the records from their study showed that 446 of the 978 patients (46%) had, in fact, been treated with other acetylcholinesterase inhibitors before the galantamine trial began;* the other 532 patients (54%) had had no such prior treatment. So now the question is: Did the presence of those previously treated patients in the total study group drag down the average improvements brought about by galantamine from what they would have been if none of the patients had been previously treated? In other words, could such prior treatment in some way have acted as a “spoiler” for future treatment with galantamine?


*Unfortunately, the records did not show which acetylcholinesterase inhibitors had previously been used, or for what length of time, or why they were discontinued (probably undesirable side effects or declining efficacy). In any case, admission to the galantamine trial included the requirement that the patient had taken no such agents for at least 60 days before the trial began.


But wait—we can also ask this question from the opposite perspective: Would galantamine have shown the improvements that it did show without the presence of those previously treated patients in the total study group? In other words, could such prior treatment in some way have set up the future treatment with galantamine to look good in the final results? Inquiring minds want to know!

Galantamine’s Benefits Are Not Affected by Previous Treatment

Tariot et al. could subsequently have gone back over their data to separate the results for the two groups in question—previously treated and previously untreated—and thus answer these questions, but for whatever reason, they didn’t. So another research group did, using what is called a post hoc analysis of the Tariot data.3 And let’s cut to the chase: they found no difference in either the efficacy or the side effects of galantamine in the two patient groups in question. In their own words,

This post hoc analysis suggests that galantamine may be beneficial in patients who have discontinued treatment with conventional acetylcholinesterase inhibitors. Thus, our data suggest that discontinuation of prior cholinesterase inhibitor treatment does not preclude the possibility of future effective treatment with galantamine.

That’s gratifying to know, because it means that previous treatment with other acetylcholinesterase inhibitors does not impair galantamine’s subsequent effectiveness, nor does galantamine’s effectiveness depend on previous treatment with other acetylcholinesterase inhibitors. (And let us not forget that galantamine, as we have seen, is more than just an acetylcholinesterase inhibitor anyway, so it has a leg up on donepezil and rivastigmine in that regard.)

Of course, inquiring minds want to know whether all this would work in reverse, so to speak, i.e., whether the results would be the same if some other acetylcholinesterase inhibitor were being evaluated, with galantamine having been used as the previous treatment. That’s an even more intriguing question, in a way, because now we’re talking about the “setup” being the dual-mode action of galantamine, with the “follow-up” being the single-mode action of donepezil or rivastigmine. Would either of these drugs fare as well as galantamine did in the post hoc analysis of the Tariot study? We don’t know, because there are currently no data that could provide an answer.

Galantamine: No Shock, but Awe

Meanwhile, the best answer to the problem of mild to moderate Alzheimer’s disease still seems to be galantamine, and it may also be the best answer for those who have, or wish to prevent, the Alzheimer’s precursor, mild cognitive impairment. MCI can attack you so stealthily that you may not even realize it. Thankfully, Mother Nature has provided a natural weapon, galantamine, with which to fight back. Although it delivers no shock, it may inspire awe.

References

  1. 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.
  2. Olin J, Schneider L. Galantamine for Alzheimer’s disease (Cochrane review). In The Cochrane Library, Issue 2, 2001. Oxford: Update Software.
  3. Mintzer JE, Kershaw P. The efficacy of galantamine in the treatment of Alzheimer’s disease: comparison of patients previously treated with acetylcholinesterase inhibitors to patients with no prior exposure. Int J Geriatr Psychiatry 2003;18:292-7.

Dual-Action Galantamine

Galantamine provides a heralded dual-mode action for boosting cholinergic function: it inhibits the enzyme acetylcholinesterase, thereby boosting brain levels of acetylcholine, and it modulates the brain's nicotinic receptors so as to maintain their function. The recommended daily serving ranges from a low of 4 to 8 mg of galantamine to begin with to a maximum of 24 mg, depending on the individual's response.

For an added measure of benefit, it is a good idea to take choline, the precursor molecule to acetylcholine, as well as pantothenic acid (vitamin B5), an important cofactor for choline. Thus it is possible to cover all bases in providing the means to enhance the levels and effectiveness of your acetylcholine.


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

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