Galantamine, a cholinesterase inhibitor that allosterically modulates nicotinic receptors: effects on the course of Alzheimer’s disease
Introduction
Alzheimer’s disease (AD) has become a major public health issue (Jeste et al 1999). In the United States, AD is estimated to cost more than $100 billion annually in direct and indirect costs Ernst and Hay 1994, Schumock 1998; the aging of our population will escalate this cost. The economic burden of AD together with the impact of the illness on patients, family members, and other caregivers makes the search for effective long-term treatments a high priority.
The median survival for patients with AD is approximately 8 years from the onset of symptoms (Barclay et al 1985). During this time, patients invariably exhibit functional as well as cognitive decline (Gauthier et al 1997). The majority of patients will also develop behavioral disturbances (Teri et al 1989). These noncognitive aspects of the illness often cause a change in patients’ level of care: independent living gives way to dependence on family members or assisted living, and often to skilled care or placement in a nursing home Brodaty et al 1993, The Canadian Study of Health and Aging 1994, Teri et al 1989.
Central cholinergic deficits are thought to contribute to the development of cognitive impairment as well as some of the behavioral symptoms associated with AD Bartus et al 1982, Coyle et al 1983, Cummings and Kaufer 1996. Symptomatic pharmacotherapy for AD has therefore been directed at enhancing cholinergic neurotransmission in the central nervous system (CNS). To date, the most successful pharmacologic strategy has been the inhibition of acetylcholinesterase (AChE), the enzyme responsible for catabolizing acetylcholine (ACh) in the synaptic cleft. Three cholinesterase inhibitors—donepezil, rivastigmine, and tacrine—are currently available in the United States for the treatment of AD. These treatments improve cognitive and global function in randomized controlled studies of 6 months duration Corey-Bloom et al 1998, Knapp et al 1994, Rogers et al 1998b, Rosler et al 1999. Results from either open-label studies or retrospective analyses suggest that donepezil and tacrine have beneficial effects on behavioral symptoms Kaufer et al 1996, Mega et al 1999, Raskind et al 1997; prospective, double-blind data are required to confirm these findings.
Since the nature of AD is progressive, treatments that slow the decline in cognitive and daily function and delay the development of behavioral symptoms are desirable. Galantamine is a novel treatment for AD, which inhibits AChE (Bores et al 1996) and modulates nicotinic ACh receptors (nAChRs) (Schrattenholz et al 1996). The main focus of this review is on the results of pivotal phase III studies to assess galantamine’s effects on the course of AD.
Section snippets
Pharmacology of galantamine
Galantamine increases the availability of ACh in the cholinergic synapse by competitively inhibiting AChE, the enzyme responsible for its breakdown Bores et al 1996, Thomsen et al 1991a. Galantamine has more than a 10-fold selectivity for AChE relative to butyrylcholinesterase (Thomsen and Kewitz 1990), which is in contrast to nonselective agents such as tacrine and physostigmine (Thomsen et al 1991b). The inhibition of AChE ceases within 24 hours of discontinuing galantamine (Thomsen and
Preclinical evidence
Several lines of evidence indicate that galantamine has cognitive-enhancing effects. In particular, Sweeney and colleagues Sweeney et al 1988, Sweeney et al 1989, Sweeney et al 1990 have shown that galantamine attenuates cognitive deficits in mice. In these studies, galantamine has been shown to be highly specific for AChE and to have a relatively long duration of action (Sweeney et al 1988). In mice with selective excitotoxic lesions of the nucleus basalis that produced substantial cortical
Patients
Patients who were included in galantamine studies had:
- •
A diagnosis of probable AD according to the National Institute of Neurologic and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association criteria (McKhann et al 1984).
- •
Mild to moderate dementia, which was confirmed by a Mini-Mental State Examination (MMSE) (Folstein et al 1975) score of 11–24 and a score of ≥12 on the Cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) at
Galantamine: effects on cognitive decline
In all four phase III studies, galantamine produced significant benefits on cognitive function relative to a placebo for both OC and ITT analyses (Table 3). In the 5-month study and both 6-month studies, the placebo groups experienced a significant decline in cognitive function relative to baseline (1.8–2.4 points on ADAS-cog, p < .05) Raskind et al 2000, Tariot et al 2000b, Wilcock et al in press. In contrast, patients in the galantamine 16-, 24-, and 32-mg/day groups maintained a significant
Conclusions
Cholinesterase inhibition has been the traditional approach to treating the symptoms of AD. Recently, nAChRs have received considerable attention as potential therapeutic targets for the treatment of AD. Activation of presynaptic nAChRs has been shown to augment the release of a number of neurotransmitters that are deficient in patients with AD, including ACh, monoamines, and glutamate Albuquerque et al 1997, Levin and Simon 1998. Moreover, there is evidence to suggest that activation of nAChRs
Acknowledgements
Aspects of this work were presented at the symposium “Nicotine Mechanisms in Alzheimer’s Disease,” March 16–18, 2000, Fajardo, Puerto Rico. The conference was sponsored by the Society of Biological Psychiatry through an unrestricted educational grant provided by Janssen Pharmaceutica LP.
References (69)
- et al.
Dopamine and nicotinic receptor binding and the levels of dopamine and homovanillic acid in human brain related to tobacco use
Neuroscience
(1998) - et al.
“Mini-mental state”A practical method for grading the cognitive state of patients for the clinician
J Psychiatr Res
(1975) - et al.
Stimulation of alpha4beta2 nicotinic acetylcholine receptors inhibits beta-amyloid toxicity
Brain Res
(1998) - et al.
Influence of kinetics of nicotine administration on tolerance development and receptor levels
Pharmacol Biochem Behav
(1987) - et al.
A long-acting cholinesterase inhibitor reverses spatial memory deficits in mice
Pharmacol Biochem Behav
(1988) - et al.
Galanthamine, an acetylcholinesterase inhibitorA time course of the effects on performance and neurochemical parameters in mice
Pharmacol Biochem Behav
(1989) - et al.
Selective inhibition of human acetylcholinesterase by galanthamine in vitro and in vivo
Life Sci
(1990) - et al.
In vitro effects of various cholinesterase inhibitors on acetyl- and butyrylcholinesterase of healthy volunteers
Biochem Pharmacol
(1991) - et al.
Properties of neuronal nicotinic acetylcholine receptorsPharmacological characterization and modulation of synaptic function
J Pharmacol Exp Ther
(1997) - et al.
Choline and selective antagonists identify two subtypes of nicotinic acetylcholine receptors that modulate GABA release from CA1 interneurons in rat hippocampal slices
J Neurosci
(1999)