Narcissus and Daffodil

Pre-synapse
Synaptic cleft
Clinical trials of galanthamine 357
Post-synapse
Figure 14.1 Schematic representation of the action of galanthamine.
➀ Acetylcholine is synthesised and released by pre-synaptic tissue and diffuses across
the synaptic cleft ➁.
➂ In health, sufficient acetylcholine reaches post-synaptic tissue, where it interacts
with receptors to ensure effective nerve transmission. In Alzheimer’s disease, according
to the cholinergic hypothesis, acetylcholine levels are reduced and transmission is
less effective.
➃ Receptor binding is reversible; released acetylcholine diffuses back into the synaptic
cleft and is degraded by pre-synaptic acetylcholinesterase ➄, producing choline ➅,
which is recycled to produce more acetylcholine.
Galanthamine binds reversibly with acetylcholinesterase, inhibiting the catabolism of
acetylcholine, which is then free to replenish and sustain more effective levels in the
synaptic cleft ➆.
Based on this hypothesis, the aim should be to restore intrasynaptic levels of
acetylcholine in AD patients to those seen in health. Various ways of doing this are
reviewed elsewhere (Mucke, 1997; Bartus et al., 1985; Coyle et al., 1983). The
method which holds most promise and therefore has found most favour is to prevent
catabolism of existing intrasynaptic acetlycholine by inhibiting the enzyme
responsible – acetylcholinesterase. A number of anticholinesterase drugs have
been investigated: physostigmine (plus two longer acting derivatives, heptylphysostigmine
and phenserine), tetrahydroaminoacridine (tacrine), velnacrine, metrifonate,
donepezil and rivastigmine, the last two having been licensed in the UK for
AD in 1997 and 1998, respectively. None of them, including galanthamine, is
ideal. For example, tacrine, a well-researched drug with which galanthamine is
often compared, has met with a modicum of success, but the frequency of side
effects, notably hepatotoxicity (Davies and Powchik, 1995), restricts its use and
mandates special patient monitoring.
Early trials with galanthamine were at best inconclusive and of an anecdotal
nature, but several centres are now working with galanthamine in thoroughly
designed clinical trials, which should give us a clearer idea of the therapeutic
potential of the drug in this distressing disease.