Narcissus and Daffodil

Clinical trials of galanthamine 363
Berzewski et al. (1994) reported in abstract a multi-centre, international,
placebo-controlled trial involving 141 patients with mild or moderate probable AD
(according to NINCDS criteria) who were started on a 3-week, single blind dose
titration phase of 20 mg galanthamine daily. Doses were titrated upwards in 10 mg
steps, every 3 days until individual best-doses were reached, aiming for inhibition
of erythrocyte cholinesterase by at least 40% of pre-therapy baseline. The upper
dose limit was 50 mg/day. These patients showed a mean dose-related improvement
of 5.14 ± 0.53 ADAS-Cog points, which is similar to that reported by Wilcock
et al. (1993). Patients were then randomised to continue galanthamine at a personal
best dose or switched to placebo for the next 10-week, double-blind phase.
The results were encouraging. At the end of the study, those on galanthamine had
improved by a further 1.66 ADAS-Cog points, but those on placebo had deteriorated
by an average of 1.40 points. The MMSE scores showed a similar trend, with
modest improvements during the optimisation phase (mean increase: 1.72 points)
which rose to 2.50 points at the end of the trial. The placebo group dropped an
average of 1.70 points below baseline. Standard neuropsychiatric tests reflecting
drug effects in both cognitive and global evaluation scales showed the same
favourable trend in 72% of patients treated with galanthamine – particularly the
assessment of clinical global impression (effectiveness, tolerance and acceptance by
the patient). Cholinergic side effects were mild, transient and dose-related. For
example, the incidence of nausea and vomiting was 21, 29 and 63% in subgroups
of patients taking average galanthamine doses of 29.4, 34.7 and 37.9 mg/day.
Other cholinergic side effects were diarrhoea and abdominal cramps (4% each),
weight loss (1.2%) and anorexia (3%). The study failed to demonstrate a statistically
significant relationship between dose and cognitive improvement, although a
trend was evident.
Kewitz et al. (1994) reported a multi-centre, placebo-controlled, double-blind
trial of the safety and efficacy of galanthamine in 95 patients, aged 60–87 years,
with mild to moderate primary degenerative dementia. These patients had
demonstrated a primary response to galanthamine under single blind conditions.
Galanthamine was started at 10 mg twice a day and was increased to a
maximum of 50 mg/day during the 3 weeks of dose optimisation. While there
were no significant changes between performance on placebo and galanthamine
in terms of performance on the ADAS-Cog scale (–0.81 for placebo, +1.33 for
galanthamine), there was a significant improvement in the physicians’ global
evaluation demonstrating significantly less deterioration in patients receiving
galanthamine. Nausea and vomiting were the most common side effects, occurring
usually at the start of therapy and tending to resolve with continued treatment.
Light-headedness, agitation and sleep disturbances were also noted. No
alterations in blood chemistry or liver function were noted. Some withdrawals
due to gastrointestinal symptoms were noted, but these were not quantified in
this abstract.
Wilcock and Wilkinson (1997) reported the interim results of an on-going,
randomised, double-blind study. After an initial adjustment phase lasting up to 14
days, 235 patients with mild to moderate AD, as judged by the NINCDS criteria,
received placebo or 22.5, 30.0 or 45.0 mg/day of galanthamine, in three divided
doses with food. Therapeutic effects were measured by the ADAS-Cog scale and
the CIBIC Plus scale (global Clinician Interview Based Impression of Change