Narcissus and Daffodil

358 D. Brown
A successful cholinergic therapy for AD would have to have the following
properties:
• Ability to cross the blood-brain barrier after oral or parenteral administration.
• Adequate and predictable absorbtion after oral administration.
• Unaffected by first-pass metabolism.
• High affinity for brain acetylcholinesterase.
• Ready reversibility of binding to brain acetylcholinesterase.
• Selectivity for acetylcholinesterase rather than butyrylcholinesterase (present
mainly outside the central nervous system).
• A pharmacokinetic profile allowing once or twice daily dosing.
• Few side effects, and those that do occur should be well characterised and
reversible on drug cessation.
Clinical studies to date indicate that galanthamine fulfils at least some of the
criteria on this wish-list.
CLINICAL TRIALS WITH GALANTHAMINE
Early clinical trials
Galanthamine was evaluated in the treatment of patients with AD in a few small
trials that were essentially pilot studies. Most were non-comparative, open-label,
with low patient numbers making statistical interpretation difficult or impossible.
The results are often available only in abstract form and interesting data, such as
subjective impressions, side effects and withdrawals, are often omitted. Furthermore,
the diagnostic tests used to assess response to therapy have differed from
study to study, making objective comparisons difficult. Table 14.1 contains definitions
of the main tests used in galanthamine trials. Table 14.2 summarises the
main points of galanthamine trials reported so far. Galanthamine is commonly
administered as the hydrobromide salt.
The first study to be published came from Austria (Rainer et al., 1989). The trial
involved ten patients with symptoms indicating Alzheimer-type dementia. Nine
remained evaluable, eight females and one male; the reason for withdrawal of one
patient was not given. The age range of the nine evaluable patients was 61–89
years (mean, 77 years). The mean duration of disease was 2.7 years. Patients were
initiated on 15 mg galanthamine hydrobromide orally, increasing to 30 mg/day
after 1 week and continuing for 7 weeks. While the pre- to post-treatment comparison
did not reach statistical significance in most psychometric and neuropsychiatric
tests, some improvements in clinical symptoms were observed. Patients
showed improvement in some standard psychological tests of cognitive function
and memory conventionally used on AD patients, notably tests of global memory
performance, attention and concentration (six of nine patients) and visual-motor
shape perception, visual memory and attentive concentration (six of nine patients).
There was an improvement in speed but not the degree of performance in some
patients. Three patients experienced improved quality of life and day-to-day
performance. No adverse effects were noted.