Narcissus and Daffodil

Clinical trials of galanthamine 365
good indicator of 3-year outcome. No clinically significant disturbances in blood
biochemistry or liver function tests were observed.
SUMMARY
The results of early trials of galanthamine compare well with those of later studies,
but one should remember that today’s criteria for classification of patients with
AD are much more precise. It has been estimated that early inclusion criteria may
have been only 85% specific for AD (Wade et al., 1987). Most of the early studies
reported here are really no more than pilots, and leave much to be desired; however,
they were conducted by three, independent research groups and the results attracted
sufficient attention to prime the planning of more extensive and sophisticated trials.
Such trials are at present ongoing and results have not yet been published.
One reason why the anticholinesterase approach is only partially successful in
AD is the multifactorial nature of the neuropharmacological deficits seen in the
disease (Perry, 1987). As AD appears to be a disorder involving deficits in a
number of neurotransmitters, it seems logical to assume, and on the basis of the
evidence, correct, that the strategy of acetylcholine preservation slows the progression
of the disease but does not halt it. Secondly, a multifactorial approach,
involving several pharamcological interventions at once (for example, combined
strategies to boost levels of noradrenaline, serotonin, gamma-aminobutyric acid,
somatostain and corticotrophin releasing factor, all of which have been shown to
be deficient in AD), may hold more promise.
From the trial data so far, it would appear that there is a sub-group of patients
who respond well to galanthamine, and in whom the cholinergic deficit is a major
component of their disease.
The side effect profile of galanthamine appears favourable, particularly when
compared with tacrine, where hepatotoxicity is a particular worry (Knapp et al.,
1994; Wagstaff and McTavish, 1994) and metrifonate, where clinical trials have
recently been suspended because of concerns about muscle weakness (personal
communication, Bayer UK). Anticholinergic side effects, particularly nausea and
vomiting, may be a problem, and measures to minimise these, such as slow
upward titration of the initial dose and co-administration of antiemetics, should be
investigated further.
Galanthamine is approved by the Austrian authorities for use in AD. However,
there remains at present a lack of controlled, double-blind trials of sufficient quality
and length to define clearly the role of this interesting agent. Head-to-head
comparisons with other agents such as tacrine have not been performed, and
more information is also required on long-term use, dose response, use in old age
(where renal and hepatic impairment are common), and potential interactions
with other drugs used in co-morbid conditions (such as Parkinson’s disease, agitation,
anxiety, aggression and depression).
In terms of pharmaceutical development, a once-daily dosage form would be a
useful advance, having obvious applications in elderly or forgetful patients and at
least one transdermal, controlled release patch is under development (Morierty,
1995). An alternative is to synthesise galanthamine analogues with extended halflife
and improved efficacy.