Narcissus and Daffodil

340 D. Brown
were internationally inaccessible. Western research conducted at this time merely
paralleled and often duplicated the eastern European effort, rather than building
upon it. Add to this the fact that early preparations of galanthamine were obtained
by liquid carbon dioxide extraction of plant tissue and were therefore only available
in small and often unreliable quantities of uncertain purity. Although a full synthesis
of galanthamine was published in 1960 (Barton and Kirby, 1960), full-scale industrial
synthesis was shown to be possible at a much later date, implying that a supply
of predictable and reproducible purity was not used in early trials.
Historically, the considerable interest in galanthamine is illustrated by the fact
that patents have been filed for its use in conditions as diverse as nicotine addiction,
alleviation of benzodiazepine side effects, male erectile dysfunction, chronic
fatigue syndrome, bipolar and panic disorders and acute mania (Mucke, 1997).
There is a rational basis to many of the therapeutic uses to which galanthamine
has been put. They may be divided into those, where, reversal of excessive anticholinergic
activity is required, and those where, cholinergic activity is deficient.
Uses of galanthamine where reversal of excessive
anticholinergic activity is required
Reversal of drug-induced paralysis in anaesthetics
The ability of galanthamine to reverse tubocurarine-induced muscle paralysis was
discovered almost half a century ago (Mashkovskii, 1955). The drug has been used
extensively to reverse the effects of curare and other muscle relaxants after surgery
in eastern European countries, but published reports are largely anecdotal (see
review by Paskov, 1986). Use has been rare in the West, where reports are fewer
but better documented (Mayrhofer, 1966; Wislicki, 1967; Cozanitis, 1971; Baraka
and Cozanitis, 1973). Typically, an intravenous dose of galanthamine is given to
induce spontaneous respiration and awakening. Sometimes a second dose may be
given, 5–10 minutes after the first. It is claimed that galanthamine has fewer cholinergic
side effects than neostigmine, thus reducing the need for compensatory
atropine, and that galanthamine speeds recovery from respiratory depression
caused by morphine analgesia, but these effects are not fully substantiated.
For example, Cozanitis (1971) reported the successful use of galanthamine
given intravenously in graded doses to a maximum of 20 mg in 40 surgical
patients, to reverse the effects of alcuronium, pancuronium, gallamine and
tubocurarine. The recovery rate was slower than that usually seen with neostigmine;
atropine was not necessary. Side effects included increased pulse rate in
most patients, increased salivation, dizziness and injection site reactions in some
patients. Galanthamine was judged to be approximately 20 times less potent than
neostigmine (Baraka and Cozanitis, 1973).
Uses of galanthamine where cholinergic activity is deficient
Research effort in this area has focused almost exclusively on investigating galanthamine
as a potential treatment for Alzheimer’s disease (AD). Phase 2 and Phase 3
clinical trials with galanthamine in this indication are reviewed in the following
chapter of this volume.