All the jokes about “snail mail” notwithstanding, the postal service is an amazingly efficient enterprise that handles mountains of letters and packages (and junk) with such reliability that we seldom give a thought as to whether or not our mail will be delivered. We assume that it will be, because it almost always is.

The logistics and infrastructure of mail delivery boggle the mind. Think of the myriad people and things and actions required for the transfer of just one letter from you to Cousin Charlie in another state. Think of the innumerable industries whose goods and services are required to make those things and actions possible. And think of the billions of pieces of mail delivered every day, even to the remotest parts of the world. If just one key factor went wrong with that system, . . . .

If your mind starts to go, will you notice?
By now you’ve realized that mail delivery is a crude metaphor for the human mind, the complexity of which makes the global postal network seem like a connect-the-dots picture by comparison. The mere act of reading and understanding the words on this page evokes whirlwinds of electrical activity and biochemical reactions in your brain - all needed for such subtle tasks as image analysis, pattern recognition, abstract thought, and memory storage (you are planning to cherish the memory of this article forever, aren’t you?). And boggling your mind, which you did just moments ago, probably maxes out some of your circuits, with all neurons firing.

“Firing” is an apt term. We speak of the firing of neurons (nerve cells) when bits of information are transmitted from one such cell to the next. The ammunition consists of neurotransmitter molecules - infinitesimal “guided missiles” that zip across the synaptic junctions (the gaps between nerve endings), thereby completing that part of the circuit. What kind of information is transmitted, and how reliably it’s transmitted, depends not only on the neural circuit being activated but also on the kind of missile being fired and the kind of target it seeks. If anything in this system becomes deficient, well, some of the light bulbs upstairs may start to flicker.

The irony is, you might not even notice it, because if your thinking capacity is slightly impaired, you just might not be thinking clearly enough to recognize the problem - and unrecognized problems tend to get worse. How’s that for a vicious spiral?

Acetylcholine is much more than a neurotransmitter
One way out of the spiral is by ensuring that your body has sufficient choline to produce abundant acetylcholine, a vital brain neurotransmitter that you’ve always taken for granted, just like the mail. But just as mail delivery slows down if the trucks run out of gas, your mind slows down if it’s running low on acetylcholine (ACh for short). Actually, the analogy goes beyond that - and in a surprising way. Just as an organized society can’t function without the materials and expertise needed to build its infrastructure (including the roads on which the mail travels), your body can’t function without the acetylcholine needed for the proper functioning of its cells.

How’s that, you say? Acetylcholine is the quintessential neurotransmitter - that’s what “cholinergic function” is all about. It’s not significantly active in non-neuronal systems, right? Not right, say some German pharmacologists who have reviewed the world’s scientific literature to see what roles acetylcholine may play in non-neuronal function, i.e., in bodily organs or systems other than the central or peripheral nervous systems. Here is their eye-opening conclusion, in their own words (”phylogenetically” pertains to the evolutionary history of life on earth):1

. . . it becomes evident that the non-neuronal cholinergic system represents a most widely expressed and highly effective system created by nature to regulate or modulate basic cell functions. . . . It is fascinating to revise the role of acetylcholine in biological systems by discriminating between non-neuronal and neuronal ACh. The non-neuronal cholinergic system, phylogenetically an extremely old system, is more widely distributed in biological systems than the neuronal system. The majority of human cells synthesize acetylcholine . . . We postulate that a picture will emerge showing that ACh plays an important role in the regulation of cellular homeostasis, comparable with its dominant role within the nervous system.

The scientists are saying, in short, that we have long been overlooking a fundamentally important aspect of acetylcholine’s role in our physiology - a role that runs deeper and broader than we imagined.

Acetylcholine helps maintain homeostasis
Before getting to some of the evidence supporting the authors’ conclusion, let’s look at its implications. Homeostasis is one of the key concepts of biology. It is the process by which an organism, or an organ, or a single cell, maintains equilibrium by adjusting its physiological processes to compensate for the effects of disruptive outside forces, such as changes in temperature or chemical composition, or assault by hostile microorganisms. Since homeostasis is necessary for the proper functioning, and ultimately the survival, of our cells, it’s fair to say that anything, such as acetylcholine, that plays an important role in that process is very important indeed. This suggests the obvious: that any nutritional precursor to such a vital compound - in this case, choline - should be high on our priority list.

An intriguing clue regarding the importance of acetylcholine is its ubiquity in nature. Although we think of it primarily as a neurotransmitter, ACh is found, more than any other such type of molecule, in a wide variety of creatures - including those that do not even have a nervous system. It has been detected in bacteria and in primitive organisms, such as blue-green algae, yeasts, fungi, protozoa, worms, and sponges. It has also been discovered in some primitive plants.

Acetylcholine is vital for cellular function
All of this suggests that acetylcholine has played a vital role in the evolutionary history of life on earth, going back an astounding 3 billion years or so, and that this role, far from originating for purposes of neurotransmission, was much more basic than that, having to do with fundamental aspects of cellular development and function. When neuronal tissue did finally evolve in living things (marine organisms and mollusks) about 500 to 400 million years ago, it may be that these cells merely took advantage of an already sophisticated, built-in cholinergic system and adapted it to their newfound need for neurotransmission.

The German authors cite evidence of a role of acetylcholine in such diverse non-neuronal cellular functions as mitosis (cell division), cell differentiation, organization of the cytoskeleton (the internal structural framework of the cell), cell-cell contact, secretion, absorption (of nutrients such as choline and amino acids), membrane development (especially choline-containing phospholipids); and metabolism.

Epithelial cells are espcially important
Acetylcholine appears to be synthesized in the majority of human cells, the authors report. A particularly important role of ACh in humans is in the function of epithelial cells. These are smooth, tightly packed cells that constitute the membranous lining, inside and outside, of most organs. They form the primary protective barrier against assault by potentially harmful substances, such as bacteria, viruses, and fungi, in their immediate environment. Epithelial cells are thus extremely important in maintaining homeostasis. They appear to be directly involved in regulation of the immune response, such as the release of antibodies to attack and destroy microbial invaders.

Acetylcholine activity has been detected in epithelial cells of the human airway, the alimentary tract, the kidneys, the urogenital tract, the eyes, the placenta, and the skin, as well as in glandular tissue of the female breast. And it has been observed that the vast majority of epithelial cells contain both nicotinic and muscarinic receptors, the same kinds of specialized molecular receptors that are activated by ACh in the nervous system. That cannot be a coincidence.

Galantamine boots acetylcholine
Nor can it be a coincidence that there is also widespread activity throughout the body of acetylcholinesterase (AChE), the enzyme that nature designed to attack and destroy acetylcholine. The purpose is to preserve a proper physiological balance (an example of homoeostasis), but AChE sometimes gets the upper hand and depletes our ACh too much, thereby upsetting the balance. Because ACh deficiency is characteristic of Alzheimer’s disease and other age-related cognitive impairments, the primary treatment is administration of agents that inhibit the action of AChE. One such agent is galantamine, a compound extracted from the snowdrop and daffodil, among other plants.

Note that, in the previous paragraph, we did not say AChE depletes our “stores” of acetylcholine. That’s because we don’t have any stores of this vital molecule. ACh appears to be continuously released by cells - and wherever there is ACh, there is also AChE (inside the cells as well as outside), which is so efficient in its appointed task that the acetylcholine can never get very far from its “home cell” before being gobbled up. This prevents it from being a true hormone (hormones are substances that can travel far from their point of origin before exerting their effects), but it has been called a “local hormone” because of the kinds of effects it has on its own turf.

Galantamine delivers
The nutrient choline, in addition to being a precursor to acetylcholine, is an essential “building block” in the construction of various types of cell membranes. It is believed that there is an interplay between these two functions, i.e., that either one may “target” the resources of the other in order to meet its needs. In any case, supplementing with choline is an excellent way to ensure that our bodies have ample access not only to good cell-building material but also to the acetylcholine they need for so many vital functions - non-neuronal as well as neuronal, as we now know. Important as well is Pantothenic acid (vitamin B5), a cofactor for choline.

Galantamine indirectly boosts the available amounts of ACh, but it goes a step further, in a way that most other AChE inhibitors do not. Galantamine modulates nicotinic receptors (one of the two kinds of ACh receptors mentioned earlier) in such a way as to make them more sensitive - more receptive, in a sense - to ACh, thus boosting the efficacy of ACh and making galantamine that much more valuable as “brain food” forage-related cognitive impairments, and especially in the treatment of Alzheimer’s disease.2

So if you’re feeling somewhat less like the finely tuned, high-performance biological machine that you ought to be, don’t go postal. Go get Galantamine instead. When combined with choline and vitamin B5, special delivery of nutrients helps your mind and your body function better. And when the mailman comes with the package, don’t let your dog bite him.

References

1. Wessler I, Kirkpatrick CJ, Racke K. The cholinergic ‘pitfall’: acetylcholine, a universal cell molecule in biological systems, including humans. Clin Exp Pharm Physiol 1999;26:198-205.
2. Maelicke A, Samochocki M, Jostock R, Fehrenbacher A, Ludwig J, Albuquerque EX, Zerlin M. Allosteric sensitization of nicotinic receptors by galantamine, a new treatment strategy for Alzheimer’s disease. Biol Psychiatry 2001;49:279-88.
3. Coyle J, Kershaw P. Galantamine, a cholinesterase inhibitor that allosterically modulates nicotinic receptors: effects on the course of Alzheimer’s disease. Biol Psychiatry 2001;49:289-99.

In a recent issue of FEBS Letters (Federation of European Biochemical Societies), researchers at Israel’s respected Weizmann Institute published an elucidation of the mechanism by which galantamine - a compound extracted from the common snowdrop (Galanthus nivalis) - blocks the action of a key brain enzyme involved in Alzheimer’s disease.1 The researchers studied galantamine in detail and found that it seems to achieve the same effect as drugs such as Aricept® or tacrine, but that it may go well beyond them.

The aging cholinergic system is imbalanced
Adding insult to injury, all the while that the release of acetylcholine (ACh) is being compromised by degenerating nerve cells, the enzyme acetylcholinesterase (AChE) is cleaving acetylcholine molecules in two at the rate of about 20,000 molecules per AChE molecule per second. Even if AChE activity declines with age, as seems to be the case, the real issue is the balance between acetylcholine production, release, and breakdown. For example, if ACh breaks down faster than it’s produced and released, or if its production and release are substantially diminished, even if the rate of breakdown is not, then in these cases (and others), the result is a cholinergic dysfunction (cholinergic means pertaining to actions mediated by acetylcholine), and one’s memory declines.3

The decline of acetylcholine production and release is relevant not only to Alzheimer’s disease but also to dementia and other age-related memory impairments (ARMIs). Because Alzheimer’s and other cognitive impairments steal away the “light” of memory, they may be thought of as “ARMIs of the night.”

Galantamine slows acetylcholine depletion
Using x-ray crystallography, the Weizmann Institute researchers found that galantamine binds to AChE in such a way as to destroy its ability to cleave ACh, thus putting the brakes on the depletion of these vital, memory-enhancing messenger molecules. By preserving more ACh molecules, galantamine permits the better maintenance of memory function.

Moreover, as the researchers found, galantamine does something else that none of the drugs or other herbs used to treat cholinergic decline do: it binds to acetylcholine receptors (proteins on the surface of the nerve cell that are activated by acetylcholine), thus directly stimulating neuronal function. More recent research indicates that this involves nicotinic receptors, in particular. This is a class of specialized ACh receptors that are activated by nicotine (which is known to enhance cerebral blood flow and cognitive and psychomotor functions),* but also by various other substances, among which galantamine is one of the most potent.

Nicotinic receptors play an important role in memory and learning, and their progressive loss is one of the distinctive neuroanatomical symptoms of Alzheimer’s. Another symptom is the buildup of a deleterious substance called amyloid. It is significant that the stimulation of nicotinic receptors may be associated with an inhibition of amyloid, thus perhaps helping to preserve or recover memory.4

Galantamine is a mind-body phytonutrient
In terms of biological evolution, acetylcholine is an ancient compound, having occurred very early in the lower species of life, both plant and animal.5 It is thought that non-neuronal (vegetative) acetylcholine first appeared in the Precambrian era, as far back as 3 billion years ago. Its appearance in animals is dated to approximately 500-400 million years ago, in the Paleozoic era.

Clearly, acetylcholine has played an important role in the evolution of living things, including us. This role is not confined, however, to the realm of the mind - nor, therefore, is that of galantamine, acetylcholine’s “protector.”

In lower animals as well as in humans, acetylcholine is the “universal neurotransmitter” for the neuronal activation of muscle fibers. Small wonder, then, that larger amounts of it can yield benefits for the body, as has been reported in the scientific literature. Thus it is especially interesting to note that when galantamine was rediscovered by European scientists in the 1950s, it was found to be in folk-medicine use for neuromuscular relief, not for memory enhancement.

In the 1960s, the snowdrop (a flowering plant) was discovered to be in use in Italy for muscular soreness.6 Indeed, its earliest modern clinical use was for anesthesiology.7 Since then, it has been used for a variety of neurological, ophthalmological, gastroenterological, cardiological, and physiotherapeutic purposes, as well as for intensive care and resuscitation.

Galantamine crosses the blood-brain barrier freely8 and has not been found to accumulate in tissue.9 Side effects are rare, especially compared with drugs used for Alzheimer’s disease, such as tacrine.

Sexual enhancement too
Although there is little evidence for the continuous use of galantamine as a restorative of lost or declining cognitive functions in European systems of folk medicine, other phytonutrients do have a long history, such as Melissa officinalis, Salvia elegans, and Artemisia absinthium.10 These have also been known to activate nicotinic receptors. Nevertheless, studies of galantamine in clinical usage indicate that it is one of the most extraordinary of these phytonutrients in terms of its scope. Studies have shown it to be valuable for psychogenic impotence, or psychologically caused sexual dysfunction. One study found that 30 days of treatment with 10 mg of galantamine taken three times daily resulted in stabilizing erectile function and eliminating premature ejaculation in 108 of 170 men, a 64% success rate.11

Galantamine - Gift from the Gods
The modern rediscovery of galantamine alluded to in the accompanying article led eventually to a startling hypothesis regarding the Odyssey, Homer’s epic celebration of heroic memory. Our current knowledge of pharmacology and ethnobotany suggests that the “drug” delivered by Hermes, the messenger of the gods, to Odysseus to enable him to rescue his crew of sailors from the mind-numbing spell that the sorceress Circe had put them under was probably galantamine! The spell, in Homer’s description, bore the earmarks of atropine (from jimsonweed).

Atropine is an anticholinergic, a substance that disrupts the brain’s acetylcholine-mediated messaging system, resulting in cognitive dysfunction and memory impairment. The ideal antidote to such a drug would be an acetylcholinesterase inhibitor, and Homer’s description of Hermes’ gift from the gods points to galantamine, which was well suited to the purpose.

How uplifting it is to think that Homer’s imperishable words could convey to us, over the millennia since he composed them, the hidden messages that have allowed modern scientists to deduce some of the pharmacological knowledge of the ancients. Looking back on them, we think, “They still had so much to learn.” But then, so do we.

* These benefits of nicotine are no where near enough to compensate for the harm it causes from smoking. Nicotine is a deadly poison.

References:

1.  Greenblatt HM, Kryger G, Lewis T, Silman I, Sussman JL. Structure of acetylcholinesterase complexed with (-)-galanthamine at 3-Å resolution. FEBS Lett 1999 Dec 17;463(3):321-6.

2.  Callahan LM, Chow N, Cheetham JE, Cox C, Coleman PD. Analysis of message expression in single neurons of Alzheimer’s disease brain. Neurobiol Aging 1998 Jan-Feb;19(1 Suppl):S99-105.

3.  Beeri R, Andres C, Lev-Lehman E, Timberg R, Huberman T, Shani M, Soreq H. Transgenic expression of human acetylcholinesterase induces progressive cognitive deterioration in mice. Curr Biol 1995 Sep 1;5(9):1063-71.

4.  Galantamine improves memory and learning ability in Alzheimer’s patients. July 20, 1998. http://www.pslgroup.com/dg/8F5D6.htm

5.  Wessler I, Kirkpatrick CJ, Racke K. The cholinergic “pitfall”: acetylcholine, a universal cell molecule in biological systems, including humans. Clin Exp Pharmacol Physiol 1999 Mar;26(3):198-205.

6.  Venturi VM, Piccinin GL, Taddei I. Pharmacognostic study of self-sown Galanthus nivalis (var. gracilis) in Italy. Boll Soc Ital Biol Sper 1965 Jun 15;41(11):593-7.

7.  Paskov DS, Stoyanov KA, Saev SK, Tenev KA, Mincheva ML. Clinical experience with Nivalin as anticholinesterase drug in anaesthesiological practice. Proc First Eur Congr Anesthesiol, Vienna, Sep 3-9, 1962.

8.  Cozanitis DA. Galanthamine hydrobromide, a longer acting anticholinesterase drug, in the treatment of the central effects of scopolamine (Hyoscine). Anaesthesist 1977 Dec;26(12):649-50.

9.  Thomsen T, Kewitz H. Selective inhibition of human acetylcholinesterase by galanthamine in vitro and in vivo. Life Sci 1990;46(21):1553-8.

10.  Wake G, Court J, Pickering A, Lewis R, Wilkins R, Perry E. CNS acetylcholine receptor activity in European medicinal plants traditionally used to improve failing memory. J Ethnopharmacol 2000 Feb;69(2):105-14.

11.  Ludianskii EA. On the use of anticholinesterase agents in the treatment of neurological diseases. Sov Med 1964 Mar;27:84-7

Erkinjuntti T, Kurz A, Gauthier S, Bullock R, Lilienfeld S, Damaraju CV.

Department of Clinical Neurosciences,
Helsinki University Central Hospital, Helsinki, Finland.
timo.erkinjuntti@hus.fi

ABSTRACT

BACKGROUND: Vascular dementia is the second commonest form of dementia, and vascular factors contribute to the development of dementia in many patients with Alzheimer’s disease. Galantamine amplifies the acetylcholine response by inhibiting acetylcholinesterase and modulating nicotinic receptors. It has shown broad, sustained benefits in patients with Alzheimer’s disease. We investigated the effects of galantamine in patients with a diagnosis of probable vascular dementia or Alzheimer’s disease combined with cerebrovascular disease.

METHODS: Eligible patients were randomly assigned galantamine 24 mg/day (n=396) or placebo (n=196) in a multicentre, double-blind, 6-month trial. Primary endpoints were cognition (Alzheimer’s disease assessment scale, cognitive subscale [ADAS-cog]) and global functioning (clinician’s interview-based impression of change plus caregiver input [CIBIC-plus]). Secondary endpoints included assessments of activities of daily living and behavioural symptoms. Patients were monitored for adverse events. Analyses were on the basis of observed case or last observation carried forward.

FINDINGS: Galantamine showed greater efficacy than placebo on ADAS-cog (galantamine change -1.7 [SE 0.4] vs placebo 1.0 [0.5]; treatment effect 2.7 points; p<0.0001) and CIBIC-plus (213 [74%] vs 95 [59%] patients remained stable or improved, p=0.0001). Activities of daily living and behavioural symptoms were also significantly improved compared with placebo (p=0.002 and p=0.016, respectively). Galantamine was well tolerated.

INTERPRETATION: Galantamine showed a therapeutic effect on all key areas of cognitive and non-cognitive abilities in this group of dementia patients.

Olin J, Schneider L

Adult and Geriatric Treatment and Preventative Interventions Branch,
National Institute of Mental Health, NIMH, Room 7160, MSC 9635,
6001 Executive Blvd., Bethesda, Maryland 20892-9635, USA.
jolin@mail.nih.gov

ABSTRACT

BACKGROUND: Galantamine (also called galanthamine, marketed as Reminyl (Janssen)) was isolated from several plants, including daffodil bulbs, but is now synthesized. Galantamine is a specific, competitive, and reversible acetylcholinesterase inhibitor. It is also an allosteric modulator at nicotinic cholinergic receptor sites potentiating cholinergic nicotinic neurotransmission. A small number of early studies showed mild cognitive and global benefits for patients with Alzheimer’s disease (AD), and recently several multicenter clinical trials have been published with positive findings. Galantamine has received regulatory approval in 29 counties: Argentina, Australia, Canada, Czechia, the European Union (except for The Netherlands), Iceland, Korea, Mexico, Norway, Poland, Singapore, South Africa, Switzerland, Thailand, and the United States.

OBJECTIVES: The objective of this overview is to assess the clinical effects of galantamine in patients with probable AD, and to investigate potential moderators of an effect.

SEARCH STRATEGY: The trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 4 July 2001 using the terms galantamine and Reminyl. The Specialized Register at that time contained records from the following databases: CCTR/Central:April 2001 (issue 2); Medline: 1966 to June 2001; Embase: 1980 to April 2001; PsycLit: 1887 to April 2001; Cinahl: 1982 to March 2001; SIGLE (Grey Literature in Europe): 1980 to December 2000; ISTP (Index to Scientific and Technical Proceedings): to May 2000; INSIDE (BL database of Conference Proceedings and Journals): to June 2000; Aslib Index to Theses (UK and Ireland theses): 1970 to June 2001; Dissertation Abstract (USA): 1861 to June 2001; ADEAR (Alzheimer’s Disease Clinical Trials Database): to June 2001; National Research Register (including the MRC Clinical Trials Directory): April 2001 (issue 2) Alzheimers Society Trials Database: to June 2001; Glaxo-Wellcome Trials Database: to June 2001; Centerwatch Trials Database: to December 2000. Published reviews were inspected for further sources. Additional information was collected from an unpublished investigational brochure for galantamine.

SELECTION CRITERIA: Trials selected were randomized, double-blind, parallel-group, and unconfounded comparisons of galantamine with placebo for a treatment duration of greater than 4 weeks in subjects with AD.

DATA COLLECTION AND ANALYSIS: Data were extracted independently by the reviewers and pooled where appropriate and possible. The pooled odds ratios (95%CI) or the average differences (95%CI) were estimated. Intention-to-treat and observed cases data were both reported, if the data were available to be reported. Outcomes of interest include the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog), clinical global impression of change (CIBIC-plus or CGIC), Alzheimer’s Disease Cooperative Study/Activities of Daily Living (ADCS-ADL), Disability Assessment for Dementia scale (DAD) and Neuropsychiatric Inventory (NPI). Potential moderating variables of a treatment effect included trial duration and dose.

MAIN RESULTS: Seven trials were identified that met criteria for entry, with six being Phase II or III industry-sponsored multicenter trials. Two were of 12 weeks duration; one of 13 weeks, one of 5 months; one of 29 weeks; and two of 6 months duration. Trials of 5 months or more were aggregated together in the analyses as ‘6 months.’ Overall, galantamine showed significant treatment effects at daily doses of 16-32 mg/d for trials of 3- to 6-months duration. For global ratings, trials of 3 months duration with doses of 24-32mg/d (Odds Ratio (OR) 2.3; 95%CI 1.3 - 3.9) and 36mg/d (OR 3.3; 95%CI 1.2 - 9.3) were statistically significant in favor of treatment. For trials of 6 months duration (5-months to 29 weeks), only doses of 8mg/d failed to be statistically significant (16mg: OR 2.25; 95% CI 1.6 - 3.3; 24mg: OR 2.0; 95%CI 1.5 -2.5; 32mg: OR 1.9; 95%CI 1.4 - 2.5). For cognitive function over 6 months duration: at 16mg/d, improvements measured -3.3 points (k=1; 95%CI -4.4 - -2.1) on weighted mean difference on the ADAS-Cog scale; -3.5 points at 24mg/d (k=3; 95%CI -4.3 - -2.8), and -4.0 points at 32mg/d (k=2; 95%CI -5.0 - -3.0). The single 3 month trial with ADAS-Cog data also showed statistically significant improvement. Both observed cases (WMD 3.8; 95%CI 0.3 - 7.3) and intent to treat analyses using the Disability Assessment of Dementia scale gave statistically significant results in favor of treatment for daily doses of 32mg for 6 months duration (as did the single 3 month trial of 24-32mg/d treatment that used this scale) The small number of trials available for analysis, however, limited the power of subgroup analyses to detect differences. Galantamine consistently failed to show statistically significant treatment effects at doses of 8mg/day. Galantamine’s adverse effects appear similar to those of other cholinesterase inhibitors, in that it tends to produce gastrointestinal effects acutely and with dosage increases. Overall, subjects treated with galantamine at doses of 24-32 mg/d were more likely to discontinue participation in most trials compared to subjects treated with lower doses or placebo, but in the one trial with a slower rate of titration the discontinuation rate was not significantly greater than placebo for the 16 mg/day dose.

REVIEWER’S CONCLUSIONS: Patients in these trials were similar to those seen in earlier antidementia AD trials, and consisted primarily of mildly to moderately impaired outpatients. Galantamine’s effects on more severely impaired subjects has not yet been assessed. Nevertheless, this review shows consistent positive effects for galantamine for trials of 3 months, 5 months and 6 months duration. In addition, although there was not a statistically significant dose-response effect, doses above 8mg/d were, for the most part, consistently statistically significant. Thus, there is evidence demonstrating efficacy for galantamine on global ratings, cognitive tests, assessments of ADLs and behavior. This magnitude for the cognitive effect is similar to other cholinesterase inhibitors including donepezil, rivastigmine, and tacrine. Galantamine’s safety profile is similar to other cholinesterase inhibitors with respect to cholinergically mediated gastrointestinal symptoms. No information is available on adverse events that occurred less than 5% of the time. It appears that doses of 16 mg/d were best tolerated in the single trial where medication was titrated over 4 week periods, and because this dose showed statistically indistinguishable efficacy with higher doses, it is probably most preferable initially.

Albuquerque EX, Santos MD, Alkondon M, Pereira EF, Maelicke A

Department of Pharmacology and Experimental Therapeutics,
University of Maryland School of Medicine,
Baltimore MD 21201, USA.
ealbuque@umaryland.edu
Alzheimer Dis Assoc Disord 2001 Aug;15 Suppl 1:S19-25

ABSTRACT

Impaired cholinergic function in the central nervous system is an early feature of Alzheimer disease (AD). Currently, cholinergic deficit is usually corrected by increasing the amount of acetylcholine in the synapse by inhibiting acetylcholinesterase (AChE). One of the most consistent cholinergic deficits in AD is the reduced expression of nicotinic acetylcholine receptors (nAChR) in the brain. Since these receptors are essential for learning and memory, restoring nicotinic cholinergic function is a promising approach to treating AD. Allosteric modulation of nAChR is a novel approach, which circumvents development of tolerance through long-term use of conventional nicotinic agonists. Allosteric modulators interact with receptor-binding sites distinct from those capable of recognizing the natural agonist. Positive allosteric modulation of nAChR activity has no effect on conductance of single channels; instead, by facilitating channel opening, it potentiates responses evoked by the interaction of the natural agonist with presynaptic and postsynaptic nAChR. Allosteric modulation of nAChR activity could therefore potentially produce a significant benefit in AD. One such allosteric modulator is galantamine. In addition to increasing nAChR activity, galantamine also inhibits AChE. This novel, dual mechanism of action distinguishes galantamine from many other AChE inhibitors. Galantamine has been shown to improve cognitive and daily function for at least 6 months in placebo-controlled trials, and to maintain these functions at baseline levels for at least 12 months in a 6-month open-label extension study. Galantamine has positive effects on nAChR expression, which are likely to contribute to its sustained efficacy in the treatment of AD patients.

Tariot PN

Department of Psychiatry,
University of Rochester Medical Center
New York, USA. Pierre_Tariot@URMC.Rochester.edu
Alzheimer Dis Assoc Disord 2001 Aug;15 Suppl 1:S26-33

ABSTRACT

Cognitive impairment, a core feature of Alzheimer disease (AD), is highly correlated with functional decline and caregiver time. Over 12 months, patients with mild-to-moderate AD deteriorate by 5-6 points from baseline on the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog). Stabilizing cognitive decline is, therefore, an important treatment outcome in AD. Cognitive deficits are thought to result in part from central cholinergic impairment, which provides the rationale for the enhancement of cholinergic neurotransmission as a treatment approach for AD. Acetylcholinesterase (AChE) inhibition has, to date, produced the most promising outcomes in clinical trials. Galantamine appears to be novel among marketed agents in that it inhibits AChE and modulates cholinergic nicotinic receptors, perhaps increasing neurotransmission via both mechanisms. Long-term effects of AChE inhibitors and galantamine on ADAS-cog scores of patients with mild-to-moderate AD have been studied in placebo controlled trials as well as open-extension studies that followed randomized, double-blind studies for up to 6 months. Conventional AChE inhibitors (rivastigmine and donepezil) have maintained ADAS-cog baseline scores for up to 40 weeks in open extension studies, and Mini-Mental State Examination (MMSE) scores for up to 52 weeks in a placebo-controlled study. The mean ADAS-cog score of galantamine -treated patients did not change from baseline at 12 months (6 months double-blind study followed by 6 months open-label extension), suggesting that cognitive function had been maintained. These results suggest that cholinergic treatments, including galantamine, may stabilize cognitive decline of AD patients. This outcome is likely to make an important difference to patients and caregivers.

Winblad B

Karolinska Institutet,
Alzheimer Disease Research Center
Huddinge Hospital, Sweden.
bengt.winblad@neurotec.ki.se
Alzheimer Dis Assoc Disord 2001 Aug;15 Suppl 1:S34-40

ABSTRACT

Limitations associated with conventional acetylcholinesterase inhibitors have led to interest in therapies with more than one mode of action. Galantamine is a novel treatment for Alzheimer disease with a dual mode of action. The mechanisms involved may result in better long-term cognitive function, and may specifically affect behavioral symptoms. Three acetylcholinesterase inhibitors available in the USA, donepezil, rivastigmine and tacrine, have demonstrated improvements in activities of daily living. However, data are mixed and much is questionable because of the outcome measures used. Galantamine showed evidence of functional benefit in three pivotal Phase III studies of up to 6 months’ duration. Furthermore, galantamine stabilized instrumental and basic activities of daily living in an open-label 12-month study. This long-term maintenance of functional ability would be expected to be an important benefit for patients and carers. Open-label studies have suggested that donepezil and tacrine might have beneficial effects on behavioral symptoms. In a 5-month pivotal study, galantamine significantly slowed the progression of behavioral symptoms in patients with mild-to-moderate Alzheimer disease. These behavioral benefits were associated with reduced caregiver distress and translated into reduced caregiver time. These benefits would be expected to make an important difference to the quality of life of patients and caregivers.

Pearson VE

Department of Pharmacy
The Johns Hopkins Hospital
Baltimore, MD, USA. vpearso@jhmi.edu
Ann Pharmacother 2001 Nov;35(11):1406-13

ABSTRACT

OBJECTIVE: To review the historic, pharmacologic, pharmacokinetic, therapeutic, and toxicologic features of galantamine, a new acetylcholinesterase inhibitor, and to assess its role in the treatment of Alzheimer disease symptoms.

DATA SOURCES: A search of articles was conducted using MEDLINE, TOXLINE, and the literature database Psychinfo, from 1966 to June 1999. The manufacturers, Janssen and SoPharm (Bulgaria), were contacted to obtain relevant preclinical data. Published textbooks of meeting symposia were also reviewed.

STUDY SELECTION: Studies with animals and humans addressing preclinical pharmacology, human studies on pharmacokinetics, open clinical trials, and controlled studies were evaluated.

DATA EXTRACTION: Relevant data were extracted from published studies and meeting abstracts only.

DATA SYNTHESIS: Galantamine has an extensive record of activity as a reversal agent for neuromuscular blockade. Galantamine is also effective in the treatment of mild to moderate Alzheimer disease symptoms. Its efficacy versus similar Alzheimer treatment agents has yet to be determined. Adverse effects are gastrointestinal in nature and usually appear during the first weeks of therapy.

CONCLUSIONS: Galantamine is a useful agent for the treatment of Alzheimer disease and for the reversal of neuromuscular blockade. It acts as both an acetylcholinesterase inhibitor and a nicotinic receptor agonist.

Maelicke, A

Institute of Physiological Chemistry and Pathobiochemistry,
Johannes Gutenberg University Medical School, Mainz, Germany.
Int J Clin Pract Suppl 2001 May;(120):24-8

ABSTRACT

There is considerable evidence indicating that, as in Alzheimer’s disease, the central cholinergic system is impaired in vascular dementia (VaD). Using lessons learned from Alzheimer’s disease research, it has been proposed that enhancement of the cholinergic system is a rational approach to treating the symptoms of VaD. Galantamine’s dual mode of action may provide a greater chance of success in treating patients with Alzheimer’s disease through enhanced efficacy on the cognitive, functional and behavioural aspects of dementia. Trials are currently underway to see if this broad spectrum of efficacy extends to patients with Alzheimer’s disease with cerebrovascular disease (’mixed’ dementia) or VaD, as well as other conditions, and the results are eagerly awaited.

Maelicke, A

Laboratory of Molecular Neurobiology,
Johannes-Gutenberg University Medical School
Mainz, Germany. alfred.maelicke@uni-mainz.de
Clin Ther 2001;23 Suppl A:A8-12

Abstract

Galantamine, the most recently approved acetylcholinesterase inhibitor (AChEI) for use in the United States, has allosteric modulating activity at nicotinic receptors and inhibits acetylcholinesterase. This dual mechanism of action may make galantamine an attractive option for patients with Alzheimer’s disease who have not benefited from their current therapy; thus, methods for switching patients from donepezil or rivastigmine to galantamine are needed. Protocols for switching patients from one AChEI to another must consider both the time required for washout of the first drug and the rate of dose escalation of the second drug. Both issues depend on the pharmacodynamics, pharmacokinetics, and pharmacology of the drugs under consideration. Because the common property of the drugs considered here is their acetylcholinesterase inhibitory activity, it seems reasonable to keep this activity at or below the activity achieved by the first drug at all times. In addition, the patient’s condition should be monitored to avoid deterioration resulting from subtherapeutic drug concentrations during the switch. The switching protocol proposed here has been based on an analysis of mean plasma concentrations of donepezil following administration of a single dose and on the established pharmacokinetics of galantamine.