Narcissus and Daffodil

Pharmacology of Narcissus compounds 347
stimulating the release of adrenocorticotrophic hormone (ACTH) in eight surgical
patients. Again, neostigmine failed to produce this effect. Although a central
action seems likely, the exact mechanism remains obscure.
No changes in liver function tests were observed in these early studies. Reviewing
clinical trials to date, there is virtually no evidence that galanthamine has any liver
toxicity.
As a result of its proposed use in patients with AD, attempts have been made to
characterise the CNS toxicity of galanthamine. Because of a previous observation
that galanthamine was a mild CNS stimulant (Cozanitis and Toivakka, 1971),
the same authors investigated the epileptogenic potential of galanthamine in 18
epileptics controlled with phenytoin (Cozanitis et al., 1973b). Six patients showed
increased abnormal EEG activity with one patient showing marked increases in
spike and paroxysmal wave activity; no seizures were precipitated. EEG changes
indicating CNS stimulation have also been reported in cats (Kostowski and
Gumulka, 1968), but a series of experiments in rabbits indicated that high doses
(1 mg/kg) could suppress epileptic activity induced by instillation of penicillin into
the dorsal hippocampus (Losev and Tkachenko, 1986).
Onset of REM sleep is known to be controlled by cholinergic mechanisms in the
brain stem. Studies have shown that galanthamine reduces the latency of REM
sleep and the overall duration of slow-wave non-REM sleep after single, 10 or 15 mg
doses of galanthamine in healthy volunteers (Rieman et al., 1994). The result is
typical of other cholinergic agents and mimics some of the sleep abnormalities
seen in major depressive disorders. The relevance of this to the use of galanthamine
in AD, where patients can become clinically depressed, is unclear.
Safety data from clinical trials in Alzheimer’s disease
The therapeutic activity of galanthamine, studied in a variety of clinical trials
involving patients with AD, is discussed in the next chapter. Side effects were not
reported uniformly and in some cases it is not clear whether they were omitted
from the report or did not occur. The following side effects have been observed
under clinical trial conditions.
In a small trial involving four Alzheimer’s patients, who received galanthamine
15, 30 and 45mg daily in an escalating regimen over 2–3 months, galanthamine
was well-tolerated at the two lower doses, but only one patient could tolerate
45 mg/day; the others experienced agitation and insomnia (Thomsen et al., 1990a).
Dal-Bianco et al. (1991) described a preliminary study where six Alzheimer’s
patients were given galanthamine (30–50 mg daily) for up to 16 months without
apparent adverse effects. However, this too was a small trial; larger studies show
that at therapeutic doses, cholinergic effects are an annoying problem with galanthamine.
They are usually mild, consisting of nausea and vomiting, which can be
minimised by careful, stepwise upward titration over 1–2 weeks. Conventional
antiemetics such as metoclopramide or domperidone may be useful in short
courses lasting a few days.
In a placebo-controlled trial, 44 patients received galanthamine 20–50 mg/day
in two or three divided doses for 10 weeks (Kewitz and Davis, 1994). The most
common adverse events were nausea (16%) and vomiting (19%). Abdominal pain,
diarrhoea, agitation and dizziness each occurred in 4% of patients. Kewitz et al.