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Galantamine: use in Alzheimer’s

disease and related disorders
Roger Bullock

Galantamine (Reminyl®) has long been used as a traditional medicine and has an
interesting pharmacology as it is both a reversible acetylcholinesterase inhibitor and an
allosteric potentiator of nicotinic cholinergic receptors. The efficacy of galantamine has
been studied in an extensive development program in Alzheimer’s disease, and mixed
and vascular dementia. Randomized, double-blind, placebo-controlled trials of up to
6 months duration and subsequent open-label follow-up studies have produced a broad
CONTENTS
spectrum of beneficial effects on cognitive and noncognitive disease symptoms.
Pharmacology Apparent benefits for caregivers paralleled these, with a potentially reduced burden and
Pharmacokinetics cost. It appears that early and continued treatment maximizes the observed effects, which
Safety & tolerability in translate into economic terms, when applied to cost-effectiveness models. Overall,
clinical studies galantamine has a broad ranging efficacy and tolerability across an increasing range
Clinical efficacy of conditions.
Expert opinion & Expert Rev. Neurotherapeutics 4(2), 153–163 (2004)
five-year view
Key issues Galantamine (Reminyl®, Shire, UK) has long aspects of memory loss (e.g., forgetting names
been used as a traditional medicine and has an and repetitive questions), getting lost in unfa-
References
interesting pharmacology as it is both a reversible miliar environments and deterioration in
Affiliation acetylcholinesterase inhibitor and an allosteric judgement and behavior. In the later stages,
potentiator of nicotinic cholinergic receptors [1]. increasing disorientation and personality
Alzheimer’s disease (AD) is the most common changes occur and eventually gross deficits in
neurodegenerative dementia, estimated to affect all intellectual functions become apparent.
approximately 15 million people worldwide, Patients show a measurably reduced capacity
posing considerable health challenges to both to perform activities of daily living (ADL) that
patients and their families [2,3]. It is a progressive once lost, are usually irreversible [6]. Early on,
condition that is primarily characterized by cog- it is the more complex, instrumental activities
nitive deterioration, reduced functional ability that suffer, but later in the disease basic activi-
and neuropsychiatric symptoms that can mani- ties such as self care and feeding become com-
fest as alterations in behavior [4]. The first symp- promised. The course and occurrence of
toms of AD generally occur after 60 years of age, behavioral symptoms in AD is more variable
although the age of onset may vary between 45 [7]. However, it is suggested that up to 90% of
Kingshill Research Center, and 95 years. Increasingly severe symptoms patients exhibit behavioral and psychological
Department of Old Age Psychiatry, develop as the disease progresses, with death nor- symptoms at some time during the course of
Avon and Wiltshire Mental Health
Trust, Victoria Hospital,
mally occurring within 8–10 years of the initial dementia. In the early stages, these are com-
Swindon, SNI 4HZ, UK diagnosis (range 3–15 years) [5]. This time-frame monly apathy and anxiety, the more obvious
Tel.: +44 179 343 7501 may extend as cases are diagnosed earlier, espe- and difficult behaviors (e.g., agitation and
Fax: +44 179 343 7521 cially as a result of the emerging interest in mild aggression) present during the mid-to-late
roger.bullock@kingshill-research.org cognitive impairment (MCI). stages of disease severity [8].
KEYWORDS: Untreated patients with mild-to-moderate Patients with AD usually become dependent
Alzheimer’s disease, cholinesterase AD show a significant annual cognitive on the care of others, with burden increasing
inhibitor, galantamine, nicotinic,
vascular dementia decline. Early cognitive symptoms include as the disease progresses. Eventually this may

www.future-drugs.com © Future Drugs Ltd. All rights reserved. ISSN 1473-7175 153
Bullock

become such that the sufferer can no longer be managed at also suggests that it has intrinsic antioxidant properties,
home and full-time care (24-h a day supervision) becomes nec- which would add a further protective mechanism to its
essary during the final stages of their life. This is often provided mode of action [11].
in an institutional setting, making the cost of treatment
significantly higher [9]. Pharmacology
Accordingly, noncognitive measures such as evaluating ACh is a neurotransmitter produced in cholinergic neurons
changes in ADL, behavior, caregiver burden, quality of life for release into the synaptic cleft where it subsequently binds
and resource use has become an increasing part of assessing the with both nicotinic and muscarinic ACh receptors. Free ACh
efficacy of AD treatments. Maintaining patients’ functional is hydrolyzed by AChE into its constituents, choline and ace-
abilities and delaying the onset of behavioral symptoms may tate. Inhibition of this process by AChEI is the simplest
lead to an increase in quality of life for both patients and car- method to improve cholinergic transmission. X-ray crystallog-
egiver. This could postpone patient progression to full-time raphy shows that galantamine binds reversibly to the active
care due to consequent reductions in caregiver burden – repre- site of AChE [12]. By this mechanism, galantamine slows the
senting a substantial saving in both direct and indirect health- breakdown of ACh, raising its concentration within the syn-
care costs, especially if the care systems around dementia were aptic cleft. In a healthy volunteer study, the median maximal
sufficiently integrated. Thus, a major goal when considering inhibitory activity of galantamine of red blood cell AChE
the pharmacological treatment of AD, is to produce main- was 39%, 30 min after a single oral 10 mg dose [13]. AChE
tained and clinically relevant benefits across the whole inhibition in patients with AD given galantamine, 5–15 mg,
spectrum of AD domains. three-times daily, for 2–3 months, was between 21 and 41%.
Although it is clear that eventually there are multiple neuro- This inhibition tailed off rapidly with cessation of treatment,
chemical abnormalities in AD, a deficit in central cholinergic with almost no inhibition observed 30 h after the final dose.
function has been established as a core pathophysiological fea- Throughout this study, no significant inhibition of butyryl-
ture [10]. This cholinergic deficit is closely linked to the severity cholinesterase was observed, supporting results from in vivo
of clinical impairments, particularly nicotinic receptor loss [15]. and ex vivo evidence.
Therefore, current symptomatic treatments for AD focus on This establishes galantamine as an AChEI but it appears to
restoration of brain cholinergic function. Three strategies have be a relatively weak one, with an inhibitory concentration of
been investigated: 50% (IC50) of 700 nM, as compared with donepezil (Aricept®,
Eisai, Tokyo, Japan; Pfizer, NY, USA) IC50 15 and rivastigmine
• Increasing the synthesis of acetylcholine (ACh) (using ACh
(Exelon®, Novartis, Basel, Switzerland) IC50 4. Supporting this
precursors, such as choline)
notion is the fact that there is a tenfold lower potency for AChE
• Stimulating cholinergic receptors (with cholinergic agonists inhibition in the brain than that found in human erythrocytes,
such as M1 agonists) whereas tetrahydroaminoacridine (tacrine, Cognex®, Parke-
Davis, NJ, USA) and physostigmine (Antilirium®, Forest Phar-
• Attenuating the degradation of synaptic ACh through
maceuticals Inc., MO, USA) exhibited a similar degree of enzy-
cholinesterase (ChE) inhibition
matic activity in both tissues [14]. Therefore, it would appear
Currently, the most successful strategy in achieving clinically likely that some other mechanism must be driving the efficacy
relevant benefits has been through the use of acetylchonineste- demonstrated in galantamine studies.
rase inhibitors (AChEIs). However, the progressive nature of nAChRs are abundant in the brain, play an important role
AD results in the continued emergence of symptoms irrespec- in brain function and are reduced in AD – to the extent that
tive of ChE inhibitor treatment. This may be at an apparently their loss correlates with the severity of illness, more so than
slower rate than if patients were left untreated but indicates the reduction in ACh activity [15]. This loss is particularly pro-
need for the development of further treatments. However, these found in the hippocampus and neocortex – both being
remain some way off, so hopefully the current therapies, per- involved in the learning and memory tasks that are impaired
haps those with more than one mechanism for enhancing in AD [16]. This loss may also be receptor subtype selective, in
cholinergic neurotransmission, may offer additional benfits to that the α4 nAChR subunit, in particular, is decreased in
those seen with the ‘pure’ AChEIs. these same areas [17]. More recent studies have also reported
Galantamine is the fourth AChEI to be indicated for the reduced levels of both α7 nAChR messenger RNA and pro-
treatment of mild-to-moderately severe AD. Galantamine is tein and decreased α7 nAChR ligand binding in animal
a tertiary alkaloid that was originally extracted from the models of dementia [18].
bulbs of the Amaryllidaceae family (e.g., daffodils). It has nAChRs may represent a suitable target for therapeutic inter-
three chiral centers and occurs in both the S- and R-forms, vention in AD. Blockade of nicotinic receptors with
of which the S-form is naturally occurring. It has a unique mecamylamine (Inversine®, Merck & Co., NY, USA), a selec-
dual cholinergic mechanism, in that as well as inhibiting tive nicotinic antagonist, produces dose-related impairments in
acetylcholinesterase (AChE), it has a potentiating effect on cognition [19]. Conversely, nicotinic agonists have been shown
nicotinic acetylcholine receptors (nAChR). New evidence to improve cognitive and psychomotor function in animal

154 Expert Rev. Neurotherapeutics 4(2), (2004)

 Galantamine

models, healthy volunteers and patients with AD [20]. However, proposition for use in all stages of AD, perhaps more so in early
prolonged use of these agents carries the potential for nAChR AD. Clinical trial results from placebo-controlled MCI studies
desensitization and subsequent development of tolerance [21]. are eagerly anticipated.
Galantamine has a second mechanism of action – it enhances
the activity of the nicotinic receptor. It achieves this by binding Pharmacokinetics
to a site on the α-subunit of the nicotinic receptor that is differ- The pharmacokinetics of galantamine administered via oral,
ent from where acetylcholine binds to open the ion channel intravenous or subcutaneous routes, is well characterized in
(FIGURE 1). Thus, it is not an agonist, as nicotine is – so does not healthy volunteers and patients with AD, as well as in ani-
run any risk of desensitization of the receptor itself [22]. Instead, mal and in vitro experiments [29,30]. After oral administra-
it makes the ion channel within the receptor more efficient. tion, galantamine is rapidly absorbed reaching peak plasma
These receptors occur both post- and presynaptically. Postsyn- concentrations (Tmax) at 0.5–2 h with a high mean absolute
aptic nAChR in the cholinergic system conduct excitatory oral bioavailability of 88.5% and low plasma protein bind-
action potentials. Increasing their efficiency will enhance ordi- ing (~18%) [31,32]. Galantamine has a short plasma half-life
nary cholinergic transmission. Presynaptic receptors are found (t½) of approximately 7 h and linear pharmacokinetics over
throughout the brain and modulate most other transmitter the recommended daily dose range of 8 to 24 mg per day
systems by increasing transmitter release through extra cal- (given twice-daily). No accumulation occurred during
cium influx. This action at the allosteric site may be one 2–6 months of therapy.
mechanism that leads to synaptic plasticity. The alteration of Galantamine is primarily metabolised via cytochrome (CYP)
glutamate, γ-aminobutyric acid and serotonin transmission P450 in the liver, with up to 75% of galantamine doses elimi-
may eventually contribute to influencing the management of nated via hepatic pathways [32]. Thus, reducing the mainte-
the psychological and behavioral aspects of AD [22]. nance dose of galantamine may decrease possible side effects
This effect of galantamine is called allosteric potentiation and when using potent CYP2D6 inhibitors such as paroxetine or
makes it one of a class of compounds called allosteric potentiat- CYP3A4 inhibitors such as ketoconazole (Nizoral®, Janssen-
ing ligands (APLs). Others include physostigmine and codeine Cilag Ltd, NJ, USA) and erythromycin. Currently, no clinically
[22]. Other similar acting compounds are being sought. Evi- meaningful metabolites have been identified. In clinical trials
dence that this effect is not occuring at the acetylcholine site is with AD patients, galantamine maximum concentration
provided by the fact that it is not antagonized by (Cmax) values have been seen to be 30–40% higher than in
mecamylamine – a nicotinic receptor antagonist at the site at healthy young subjects [32]. This may be due to differences in
which ACh binds [23]. This is not like any potential nicotinic renal function, food intake and higher numbers of females in
stimulation seen with donepezil (a pure cholinesterase inhibi- AD studies (all of which may have a small effect on Cmax but
tor). This latter effect is inhibited by mecamylamine, suggest- not the overall area under the curve). Pharmacodynamic inter-
ing that it is simply due to increased ACh in the synapse, rather actions are theoretically possible with drugs that potentiate the
than any alternative action. action of succinylcholine during anaesthesia or with drugs that
The fact that galantamine produces these effects on nAChR affect heart rate. Therapeutic doses of galantamine (12 mg
activity via this allosteric binding site has been confirmed by twice-daily) have not been shown to alter the pharmacokinetics
competitive inhibition experiments using the monoclonal anti- of either digoxin or warfarin, suggesting that these interactions
body FK1, which binds specifically to the APL-binding region are unlikely [32].
on the α-subunit of nAChRs [24]. When
FK1 is present, galantamine binding to
Nicotinic agonist Allosteric potentiating (sensitizing) ligand
nAChRs is blocked and ion channel activity
is reduced [25]. Nicotinic Acetylcholine
Nicotine has been shown to have neuro- agonist
protective features in vitro. Galantamine has Galantamine
now been shown to have similar in vitro
effects – reduced apoptosis, upregulation of
bcl-2 and protection against amyloid toxic-
ity [26–28]. These neuroprotective mecha- Nicotinic Nicotinic
nisms are difficult to demonstrate in clinical receptor receptor
experiments, especially as time is a con-
straint. Attempting to make inferences from
The agent binds to the nicotinic The agent binds to the nicotinic
the published studies that have been receptors at the same binding site receptor at a different binding site as
designed to show symptomatic effects is as Ach – desensitization risk Ach – no desensitization risk
open to criticism. However, the fact that
Figure 1. Allosteric binding of galantamine increases receptor efficiency in the presence of
these protective mechanisms exist, makes
Ach versus nicotinic agonist action that acts in the same way as ACh. ACh: Acetylcholine.
the use of galantamine an attractive

www.future-drugs.com 155
Bullock

Safety & tolerability in clinical studies using galantamine 24 mg [33]. The second 6-month trial was a
During clinical trials, irrespective of length, galantamine dem- global study where placebo (n = 215) was compared with galan-
onstrated good tolerability with no treatment emergent effects tamine 24 mg per day (n = 220) or 32 mg per day (n = 218) [41].
or clinically relevant effects on vital signs and laboratory tests. Longer term (12 months) efficacy has also been assessed in an
Most patients completed treatment (up to 77%), particularly open-label follow-up in two of these trials [43]. All studies were
with slower rates of titration [33,34]. Most patients (98%) also designed to measure all of the recognized important domains of
had coexisting illnesses with 96% taking other medications. AD – cognitive, ADL, behavior and global outcomes. A selec-
Across all studies, the frequency of adverse events was low, with tion of clinical assessments were selected to provide valid and
most being mild in severity. Most occurred at initiation or dur- reliable outcome data.
ing dose-escalation and were transient with no need to alter In these studies, all patients (overall mean age 71.9 years) had
treatment. Cholinergically-mediated side effects were the main mild-to-moderate AD, as defined by an Mini Mental State Eval-
reports (particularly those involving the gastrointestinal system). uation score of between 10 and 24 and a score of more than 11
No muscle cramps or sleep disturbance were reported as in on the Alzheimer’s disease Assessment Scale (ADAS-cog). The
other cholinesterase inhibitors [35–37]. Furthermore, galantamine overall mean ADAS-cog score across all the trials ranged from
appeared to be safe and well-tolerated in patients switched from 24.7 to 29.4. As a result of these entry criteria, background dis-
prior treatment with cholinesterase inhibitors [38,39]. ease characteristics did not differ significantly between any
individual or pooled treatment groups.
Clinical efficacy
Alzheimer’s disease Cognition
Galantamine has been studied in five pivotal double-blind, pla- Cognitive function is the essential measure when assessing
cebo-controlled clinical trials of varying length in AD dementia treatment response in clinical trials. In the galan-
[33,34,40–42]. Two 3-month international studies have compared tamine studies, as in most others, the ADAS-cog was used to
placebo with galantamine 24–32 mg per day. Both showed that measure cognitive abilities and was one of the primary outcome
24 and 32 mg galantamine were effective for cognition, ADL measures [44]. The ADAS-cog scale is more sensitive to a wider
and global measures [40,42]. Another 5-month US study com- range of disease severity and has greater specificity for the key
pared placebo (n = 286) with galantamine 8 mg/day (n = 140), features of cognitive dysfunction in AD than other cognitive
galantamine 16 mg/day (n = 279) and galantamine 24 mg/day assessments [44].
(n = 273) [34]. Two 6-month trials have also been completed. A In all randomized, double-blind studies up to a 6-month
US study compared placebo (n = 213), galantamine 24 mg/day duration, galantamine maintained patients’ cognitive function
(n = 212) and galantamine 32 mg/day (n = 211) after which above baseline. This compares with placebo treated patients,
patients who still met the inclusion criteria were eligible to enter where significant cognitive decline occurred. Galantamine
a 6-month extension study (total study duration 12 months) 16–32 mg/day for 3–6 months resulted in an overall mean

Double-blind
Improvement
-4
Mean (± SE) change from baseline

-3 Open-extension
-2
in ADAS-cog score

-1
§
0
1
2
3
4 Placebo/galantamine 24 mg
5 Galantamine 24 mg/galantamine 24 mg
6 Historical placebo group

7
0 3 6 9 12 Deterioration
Time (months)

Figure 2. 12-month cognitive benefits of Galantamine in Alzhiemer’s disease.

§p < 0.05 versus placebo/galantamine (not statistically different from baseline).
ADAS: Alzhiemer’s Disease Assessment Scale; SE: Standard error. Adapted from [33,60].

156 Expert Rev. Neurotherapeutics 4(2), (2004)

 Galantamine

treatment difference across the five studies Improvement

(galantamine vs. placebo) of 3–4 points on Open
Double-blind extension
the ADAS-cog after up to 6 months of 0
treatment. This difference is generally

Mean (± SEM) change from baseline

accepted as clinically and statistically sig- -2 §
nificant. Change from baseline ADAS-cog Galantamine 24 mg/

in total DAD score

scores with 16 and 24 mg per day were also galantamine 24 mg
-4
consistently significantly different from Pooled placebo data:
placebo at 3 months (p < 0.01) and at 5 -6 galantamine 24 mg/
and 6 months (p < 0.001) [33,34,40]. These placebo and historical
placebo group
improvements in ADAS-cog scores were -8
maintained above baseline with galan- § Not significantly
different from baseline
tamine at both 5 and 6 months (p < 0.001) -10
unlike placebo, where scores fell signifi-
-12
cantly below baseline (FIGURE 2) [33,34]. Anal-
ysis of pooled results from two 6-month
-14
double-blind trials showed that patients
treated with galantamine 24 mg per day Deterioration
either improved or stabilized at approxi-
Baseline 3 6 9 12
mately twice the rate of the placebo-treated
Time (months)
patients. The rates of treatment response at
24 mg per day were 64.8% no change Figure 3. 12-months functional benefit of galantamine in Alzheimer’s disease.
DAD: Disability assessment in dementia; SEM: Sample Evaluation Method. Adapted from [33,60].
from baseline, 32.1% more than 4-point
improvement on the ADAS-cog and
16.7%, more than 7 (all p < 0.001 vs. placebo). Functional assessments showed that measures of ADL were
significantly better during treatment with galantamine than
Global function with placebo. During 3 months of treatment with galan-
The other essential measure in evaluating a drug effect is a scale tamine 24–32 mg/day, there was a significant galan-
that measures change in overall global status. These are tamine–placebo difference in DAD scores from baseline
intended to confirm clinically meaningful overall effects, rather (4.3 points, p < 0.001). These benefits were observed across
than measure small changes that are less likely to have any both instrumental and basic self-care activities. DAD scores
actual clinical relevance. The Clinician’s Interview-Based also showed efficacy at 24 and 32 mg per day in a 6-month
Impression of Change plus caregiver input (CIBIC-plus) is a study (FIGURE 3). In the 5-month US study, mean ADCS–ADL
widely used global assessment of change in AD trials, including scores showed a significantly smaller decrease (i.e., benefit over
galantamine studies. It is conducted independently from other placebo) with galantamine 16 and 24 mg per day (p < 0.001).
assessments, using information from brief interviews with both In addition, no significant changes from baseline were observed
the patient and an informant (e.g., the caregiver) to gain a prac- (p < 0.001) suggesting that patients’ baseline levels of ability
tical description of how the patient manages their daily life and were preserved over the study period.
how this may change during the study [46].
CIBIC-plus outcomes were statistically significantly better in Behavior
all patients treated with galantamine compared with placebo – In the pivotal galantamine studies, effects on behavior were
at any dose over any time period up to 6 months (p < 0.05 in measured using the Neuropsychiatric Inventory (NPI). This is
all cases). Of all the scales used in trials, these findings have a validated and reliable scale that was developed specifically to
most utility with respect to real clinical benefit as they represent assess psychopathology in patients with dementia [49]. The NPI
an independent view of the overall effect of taking a treatment assesses the severity and frequency of commonly seen behavio-
or not, rather than more sensitive testing of selected areas of the ral symptoms, plus the level of caregiver distress these
illness [46]. symptoms cause.
Galantamine appeared to postpone the emergence of behav-
Activities of daily living ioral symptoms during the 5-month study. Patients receiving
The Alzheimer’s Disease Co-operative Study ADL 16 or 24 mg per day maintained baseline levels of behavioral
(ADCS–ADL) inventory and the Disability Assessment in symptoms, unlike placebo-treated patients who experienced a
Dementia (DAD) have been used in galantamine studies to significant increase in behavioral systems (p < 0.01). Change
measure changes in daily functioning [47,48]. Both rely on struc- (improvement) in NPI score from baseline was significantly
tured interviews with caregivers or informants and both assess greater with galantamine 16 and 24 mg per day than with pla-
basic and instrumental ADL. cebo at 5 months (p < 0.05). Among the NPI subitems,

www.future-drugs.com 157
Bullock

aberrant motor behavior, anxiety, disinhibition and hallucina- Long-term data

tions responded best to galantamine. It is also safe when used Long-term placebo-controlled studies are now less ethical in
with atypical antipsychotics, including risperidone (Risperdal®, patients since beneficial therapies exist. As a result, long-term
Organon, NJ, USA) [50]. open-label follow-up is often conducted and compared with
extrapolations from the placebo group. This appears to have
Caregiver burden certain face validity as the average annual decline for untreated
The amount of time spent caring by caregivers was evaluated AD patients is consistently estimated at up to 8 points on the
using a caregiver time questionnaire designed specifically for ADAS-cog scale per year in follow-up studies and models, with
this purpose [51]. This questionnaire addressed two defined var- a slower rate in milder illness [57]. However, interpretation may
iables: time spent assisting patients with ADL and time spent be confounded by high drop-out rates.
supervising patients. In a 6-month international study, the Data, up to 48 months now exists on galantamine. In a
average daily time spent assisting patients increased steadily 12-month US study patients were enrolled in a 6-month
over time with placebo-treated patients, reaching an additional open-label extension phase after completing the initial rand-
23 min by month 6 (p < 0.05) [52]. In contrast, the average time omization. All patients then received galantamine 24 mg per
assisting galantamine-treated patients decreased relative to base- day. The cognitive benefits of galantamine treatment were
line by 15–38 min – meaning caregivers of those on galan- maintained at or above baseline for the whole 12 months
tamine averaged up to 61 fewer minutes a day assisting those where patients had received continuous galantamine treatment
they care for (FIGURE 4). In terms of the daily amount of time for that period [33]. Patients previously on placebo showed
that patients required supervision from caregivers, galantamine improved cognitive function, but differed in that they did not
provided greater benefits than placebo. Supervision time also catch up with the other group and remained statistically worse
increased on placebo relative to baseline – reaching two addi- (p < 0.05) [58,59]. This suggests that the maximal effect is seen if
tional hours per day by month 6 (p < 0.001). There was no sig- treatment is initiated early and maintained at a stable dose.
nificant change in supervision time from baseline with With function, DAD scores were no different statistically
galantamine 24 or 32 mg per day. from baseline in galantamine patients who took the drug for
the 12-month study period [60]. These results were compared
Pooled results from 6-month clinical trials with historic 12-month data from a previous study (sabelu-
The data from the two 6-month placebo-controlled trials zole [formerly Reminyl] in AD). DAD scores in this historic
showed that at 6 months, galantamine 24 mg per day main- data had dropped by 11–13 points at month 12. Galan-
tained patients’ cognitive function above baseline (p < 0.001) tamine-treated patients fared better by 11.4 points (p < 0.001)
when compared with placebo – where significant deteriora- [61]. This was in both instrumental and basic ADL – which is
tion occurred (p < 0.001) [53]. The difference in mean reflected in continued improvement in caregiver time [62].
ADAS-cog scores between galantamine- and placebo-treated These benefits continue after the baseline has been crossed,
patients in the pooled analysis was 3.4–3.9 points – reinforc- with galantamine-treated patients continuing to remain above
ing the clinical relevance. A subgroup analysis of the data the expected decline with respect to cognition and function,
showed this effect was independent of age or sex and not even after 48 months [63]. Since the studies are not controlled,
influenced by baseline disease severity – with patients with it is difficult to infer much, especially concerning any disease
an advanced disease doing as well as those with earlier diag- modification. Drop-out rates are relatively low, so a good pro-
nosis [54,55]. Similarly, patient apolipoprotein-E4 genotype portion of patients appear to have significant and demonstrable
status did not affect these results, unlike some other ongoing benefits.
cholinesterase inhibitors [56].
Comparative studies in AD
Two studies have compared galantamine and donepezil in AD.
60 Double-blind Open-extension
Neither has shown differences in primary end points. A 12-
Change in caregiver

40 Placebo week study showed galantamine to have similar tolerability and

Reminyl ease of use to donepezil, but although performing on the
time (min)

20
24 mg/day ADAS-cog and DAD as well as it had in other clinical trials, it
0
was outperformed by donepezil on these scales [64]. The second
-20
trial lasted 52 weeks with function as the primary outcome
-40 measure [65]. Though function results were the same, in this
-60 instance galantamine was statistically superior on cognition
Baseline 3 6 9 12 (both MMSE [FIGURE 5] and ADAS-cog) and subjective car-
Time (months) egiver burden [65]. In this study, computerized testing of simple
Figure 4. 12-month changes in caregiver assistance with activities reaction time (SRT; a predominantly cholinergic function) was
of daily living with galantamine in Alzheimer’s disease. also similar between the two drugs, whereas galantamine was
statistically superior in choice reaction time (cholinergic plus

158 Expert Rev. Neurotherapeutics 4(2), (2004)

 Galantamine

dopaminergic FIGURE 6) [65]. This is a significant finding as the

2.5
best explanation for these results is that galantamine is affecting Reminyl

Mean MMSE (1 SE) change

2.0 Donepezil
transmitter systems beyond the cholinergic system in this popu-
lation – which is in accordance with animal findings [66]. Thus, 1.5
1.0

from baseline
both drugs boost cholinergic function equally well (SRT), but
galantamine through its nicotinic mechanism has an added 0.5
effect, which should translate clinically as an increase in atten- 0.0
tion. This may have been what the caregivers picked up on in -0.5 0 10 20 30 40 50 60

the subjective burden scale. -1.0

The most important consideration here is whether this repre- -1.5
sents the first demonstration of the allosteric modulation in a -2.0
clinical study. As this mechanism is associated with other dis- -2.5 Weeks
ease modifying findings in vitro, this may offer hope that they
Figure 5. Galantamine and donepezil in Alzheimer’s
are also occurring in vivo [26–28]. This cannot be proven until disease – MMSE.
the tools to demonstrate such phenomena in clinical studies are MMSE: Mini Mental Status Examination; SE: Standard error.
forthcoming, but even without conclusive proof, this may be a Adapted from [65].
relevant consideration when selecting drugs in MCI.
Thus, in terms of mild-to-moderate AD there have been no disease dementia (PDD), which is why a recent Cochrane
proven differences in using galantamine, donepezil or rivastig- review only supports the use of rivastigmine for this condition
mine in head-to-head studies. This is not surprising given that [72]. Some open-label studies have given encouraging results and
at this stage there is already significant pathology to overcome a clinical study in a memory clinic showed that both DLB and
and large numbers will be needed to show small differences. PDD responded as well to cholinesterase inhibitors, including
galantamine, as AD patients [73,74].
Cerebrovascular disease & vascular dementia
Galantamine was studied in a mixed population of both AD Other conditions
with cerebrovascular disease (CVD) and vascular dementia MCI is receiving increasing attention as it seemingly represents
(VaD) to establish whether it would reverse the cholinergic def- a predementia risk state. Large pivotal studies are due to be
icits present. Overall the study was positive with the 24 mg reported using galantamine for treatment of this population in
treatment dose reaching significance over placebo in all usually mid-2004. If positive, they will further reinforce the need to
measured domains [67]. The ADAS effect size was 2.7 points. In assess and treat early.
a subgroup analysis, the AD with CVD results proved very sim- There is no evidence that galantamine has a role in
ilar to the AD studies. However, in the VaD group, galan- fronto–temporal dementia at present. However, the effect that
tamine failed to reach significance over placebo, partly because galantamine exerts on nicotinic receptors is being explored in
it was not powered to do so, but mainly because the placebo other conditions where nicotinic abnormalities have been
group remained stable – as expected clinically. reported. To this end, a study in schizophrenia is under way in
These effects continued up to 12 months with the initial the USA after case reports to support the efficacy and examples
treatment group remaining above baseline and the placebo of use in autistic spectrum disorder have appeared [75–77].
group also moving above and staying better than baseline
(FIGURE 7) [68]. Interim data at 2 years suggests the baseline is Health economics
crossed at 20 months [69]. Costs in AD care are due to health and social care resource uti-
The study was the first to be published in this patient group lization, with drug costs constituting only a small proportion
and while it may not yet mean regulatory approval for treat- [78]. As severity of illness increases, patients with AD make
ment in VaD, it does support the results many have seen in off- increasing use of a wide range of services, with institutional care
license treatment [70]. Larger pivotal studies are currently under proving most costly [79,80]. Economic models are considered
way in VaD alone. What is more interesting is that AD with appropriate to model the costs and how drug treatment may
CVD is probably the most common dementia presenting to affect them. A model for galantamine (the Assessment of
memory clinics – 60% of cases in one study, with pure AD Health Economics in Alzheimer’s Disease [ADHEAD] model)
making up a further 37% [71]. This means that over 90% of has been developed using clinical data from pivotal galantamine
cases coming to a memory clinic may well respond to galan- Phase III studies, taking patient characteristics to predict the
tamine, making it an easy compound to use in specialist and need for full-time care [81].
primary care. UK data entered in to the AHEAD model predicts that only
five patients with mild-to-moderate AD need to be treated with
Dementia with Lewy bodies galantamine at 16 mg to avoid 1 year of full-time care (number
No controlled studies have been conducted with galantamine needed to treat [NNT] = 5.2), while at 24 mg, the NNT
in either dementia with Lewy bodies (DLB) or Parkinson’s reduces to 3.9 patients [82]. An overall saving in treatment costs

www.future-drugs.com 159
Bullock

measuring observed behavior, was shown to good effect when

-600 Donzepezil
looking at choice reaction time in the comparison study with
MSEC (change from predose)

Galantamine
No treatment donepezil. Coupled with the fact that galantamine is only a
-400
weak cholinesterase inhibitor, yet produces similar results to
-200 the other compounds it is classed alongside, it would appear
that being an APL is the key mode of action, and perhaps
0 galantamine should be officially classed as such.
With current opinion favoring the coexistence of AD and
200 CVD in most patients, the demonstration of the efficacy of
galantamine across AD, AD with CVD and VaD means that it is
400 an easy compound to use across this spectrum of patients. Pure
0 6 13 26 52
Weeks VaD is a much rarer entity than once thought. Studies in VaD
Figure 6. Galantamine and donepezil in Alzheimer’s disease – CRT. are forthcoming but even now it is quite reasonable to use galan-
The no-treatment arm is from historic data and represents how tamine in all cases of AD, both pure and with concomitant CVD
untreated Alzheimer’s patients fare on CRT. No placebo was used in the (often called mixed). This should result in overall savings,
study. Adapted from Truyen and Bullock, European Federation of especially in patients still above baseline at 6 months.
Neurological Societies (2003).
CRT: Choice reaction time; MSEC: Millisecond.
As new treatments become available, combinations of ther-
apy will inevitably be tried. Galantamine has no known clini-
is expected in patients who remain above baseline in cognition cally significant interactions with antipsychotics, antidepres-
at 6 months and continue with therapy. In clinical terms, this sants, nonsteroidal anti-inflammatory agents or statins. More
means patients remaining at home longer, with a lesser need for importantly, it appears safe in usage with memantine (Ebixa®,
full-time care and spending less time in nursing homes. There- Lundbeck, Norway, Merz Germany [EU], Forest Laborartories
fore, as with other cholinesterase inhibitors, it appears that pro- Inc., NY, USA [USA]) – a newly licensed compound in Europe
longed treatment with galantamine in AD could produce and the USA for moderate-to-severe AD, with a differing and
healthcare savings. perhaps complementary mode of action [85].
Should galantamine prove to be effective in MCI, it will offer
Expert opinion & five-year view further advantages, starting as early as preclinical dementia
AD and related dementias follow an intractable course, which patients and remaining through to advanced dementia – both
until recent years had very few treatment options. The cholineste- in AD and potentially VaD. The clinical possibility of any
rase inhibitors have changed that position and heralded the start added disease modification that its differing mode of action
of earlier assessment and increasing understanding of these condi- suggests, makes it an attractive choice to use early in these
tions. In clinical studies cholinesterase
Placebo/galantamine
inhibitors produce a moderate symptomatic
Galantamine/galantamine
effect, all with broadly similar results. They –3
offer respite not cure. Currently they are § Improvement
Mean (±SE) change in ADAS-cog

§
classed together as a group, though it would –2
§
appear that they have different modes of
action. This creates the opportunity to –1
from baseline

switch within class should efficacy or

tolerability be an issue [83]. 0
Galantamine has been extensively stud-
ied in AD and related disorders and
1
proved to be an effective and well-toler-
ated symptomatic treatment, with
2 Double-blind phase Open-label phase Deterioration
responders benefiting from several years
of benefit compared with previously
Baseline Week 6 Month 3 Month 6 Month 12
untreated individuals [84]. The improve-
ments seen with galantamine are across Placebo/galantamine (n) (194) (183) (173) (158) (146)
all domains measured including behav- (116)
ior, where multiple transmitter deficits Galantamine/galantamine (n) (388) (354) (319) (285) (275)
are involved. The allosteric potentiation (239)
of nicotinic modulation may help explain Figure 7. 12-month cognitive changes with galantamine in Alzheimer’s disease plus CVD and
how galantamine modifies these other vascular dementia. §p < 0.001 vs. placebo.
ADAS: Alzhiemer’s Disease Assessment Scale; CVD: Cerebrovascular disease; SE: Standard error.
transmitter systems, which though
Adapted from [68].
harder to demonstrate in terms of

160 Expert Rev. Neurotherapeutics 4(2), (2004)

 Galantamine

diseases. Such a profile could further enhance the remaining showing nicotinic receptor abnormalities, such as
quality of life for patients and carers and continue to reduce the schizophrenia, the APL action may open the door to a much
stigma of cognitive decline. Finally, with other conditions wider range of disorders than initially imagined.

Key issues

• Galantamine has shown positive benefits compared with placebo in a range of clinical studies encompassing Alzheimer's and
cerebrovascular disease.
• Dalantamine has two distinct modes of action: cholinesterase inhibition and allosteric modulation at the nicotinic receptor.
• The nicotinic action leads to reduced amyloid toxicity and cell death in vitro and upregulation of certain neuroprotective factors.
• The in vitro findings would suggest that patients on galantamine should experience a prolonged duration of benefit, supported in
part by the results of 4-year open-label data.
• Improved measures of cognition and executive function using galantamine in comparison with donepezil in a controlled study, add
weight to the benefit of the nicotinic mode of action.

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76 Rosse RB, Deutsch SI. Adjuvant Wiltshire Mental Health Trust, Victoria
•• The first long-term comparison study of Hospital, Swindon, SNI 4HZ, UK
galantamine administration improves
two acetylcholinesterase inhibitors, one Tel.: +44 179 343 7501
negative symptoms in a patient with
with and one without nicotinic Fax: +44 179 343 7521
treatment-refractory schizophrenia. Clin.
modulation, which produced cognitive roger.bullock@kingshill-research.org
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