A New Treatment for Patients with Alzheimer Disease
G. Tong, MD, PhD
Jody Corey-Bloom, MD, PhD
Department of Neurosciences,
University of California San Diego, CA, USA.
Introduction
Alzheimer disease (AD), the most common form of dementia in the elderly, is characterized clinically by multiple cognitive deficits, including memory loss, visuospatial impairment, disorientation and language dysfunction. These features are often accompanied by behavioural and mood changes. A definitive diagnosis of AD can only be made by biopsy or autopsy. The major neuropathological features of AD are neuritic plaques and neurofibrillary tangles.
Cholinergic neurotransmission in the central nervous system (CNS) plays a key role in memory, attention, learning and other cognitive processes. Although other neurotransmitter deficiencies (e.g., noradrenaline, dopamine, serotonin and glutamate) have been noted, the cognitive impairments seen in AD patients have been largely attributed to decreased cholinergic neurotransmission. AD, in part, is characterized by the loss of neurons in basal forebrain cholinergic cells, especially in the nucleus basalis of Meynert, which projects to the cerebral cortex and hippocampus.1 The activity of choline acetyltransferase (ChAT), the presynaptic synthetic enzyme for acetylcholine (ACh), has also been shown to be decreased by 50-90% in the brains of AD patients.2 In addition, changes in other cholinergic markers have been reported, including a decline in nicotinic acetylcholine receptors (nAChRs) and a reduction in presynaptic muscarinic activity.3
Although there is currently no cure for AD, symptomatic treatment has focused on the restoration of CNS cholinergic function. The so-called 'cholinergic hypothesis' has led to the rational design of drugs to enhance cholinergic neurotransmission with strategies that include augmentation of ChAT, administration of ACh precursors and/or cholinergic receptor agonists and inhibition of acetylcholinesterase (AChE). To date, only the last approach, which results in decreased elimination of ACh from the synaptic cleft, has been shown to improve functioning in AD patients, albeit moderately.4
Three compounds are available commercially for the treatment of mild to moderate AD: donepezil (Aricept®), rivastigmine (Exelon®) and more recently, galantamine (Reminyl®) (Table 2). Like donepezil and rivastigmine, galantamine shows an improved tolerability profile. Importantly, neither galantamine, rivastigmine nor donepezil are associated with hepatotoxicity.
Chemistry and Pharmacokinetics
Galantamine, a tertiary alkaloid, is a selective, reversible, competitive inhibitor of AChE that enhances CNS cholinergic functions through two mechanisms: inhibition of AChE and potentiation of nAChRs.5-7 Originally extracted from bulbs of the snowdrop and several Amaryllidaceae plants, galantamine has long been used in the clinical setting to reverse neuromuscular blockade induced by tubocurarine-like muscle relaxants. It selectively inhibits AChE rather than butyrylcholinesterase. In addition, galantamine interacts directly with nAChRs to potentiate their action allosterically. The direct effects of galantamine on nAChRs may be of clinical relevance, as activation of presynaptic nAChRs increases the release of ACh and other neurotransmitters, e.g. glutamate, which are involved in memory and learning.
Galantamine is rapidly absorbed following oral administration. It shows linear pharmacokinetics in the dosage range of 4 to 16 mg taken twice daily. In preclinical studies, administration of 10 mg oral galantamine with food delayed the rate, but not the extent, of absorption. Mean maximum plasma drug concentration values in the fasting and fed state were reached in 1.1 and 2.6 hours, respectively. The biological elimination half-life was about 7 hours. The plasma protein binding was relatively low at 18%. Levels in the brain were 2 to 3 times higher than in plasma. The major route of metabolism of galantamine is mediated by cytochrome (CYP) P450 isoenzymes CYP2D6 and CYP3A4, with about 75% of galantamine metabolized. Approximately 18 to 22% of galantamine is