Narcissus and Daffodil

334 D. Brown
with neostigmine the activity of galanthamine against human erythrocyte, human
serum and dog skeletal muscle cholinesterases was 400–1000 times less potent
(Boissier and Lesbros, 1962), although functional studies demonstrated a potency
reduction of only 10–20 times, suggesting that galanthamine may be able to potentiate
the actions of acetylcholine also. The pharmacological explanation of this
remains obscure. When the relative potencies of galanthamine, neostigmine and
pyridostigmine in reversing pancuronium-induced muscle paralysis were studied
in anaesthetised rats, galanthamine was 30 times less potent than neostigmine and
12 times weaker than pyridostigmine (Cozanitis et al., 1981). The dose-response
curve for galanthamine was shallower than those of the other two drugs, indicating
some as yet unexplained differences in mode of action. Comparative in vitro
studies have shown that human erythrocyte anticholinesterase inhibition by galanthamine
is essentially reversible, whereas that of tacrine, a rival treatment for
Alzheimer’s disease, is not (Tonkopii et al., 1976). In these early experiments,
tacrine was considerably more potent than galanthamine against animal acetylcholinesterase,
but in more recent studies, galanthamine was longer acting against
mouse brain acetylcholinesterase in vivo (Sweeney et al., 1989; Tonkopii and
Padinker, 1995).
Galanthamine also inhibits human erythrocyte anticholinesterase selectively,
having a much smaller effect (from 60 to 100 times less) on butyrylcholinesterase
both in vitro and in vivo (Thomsen and Kewitz, 1990). This property may be
important, as more potent inhibition of the latter might increase toxicity in the
form of neurological side effects – notably prolonged neuromuscular and respiratory
distress – particularly if the baseline activity of this enzyme is already
depressed by liver disease or a hereditary defect (Pacheco et al., 1995) or the drug
is administered long-term, as is likely in Alzheimer’s disease (Thomsen and
Kewitz, 1990). This observation is also relevant to the selection of drugs for the
treatment of Alzheimer’s disease, where it is known that physostigmine inhibits
both acetyl- and butyrylcholinesterase, while tacrine may have more effect on the
latter than on the former (Thomsen et al., 1991b). Inhibition of erythrocyte anticholinesterase
may also be used to relate pharmacological activity to therapeutic
effect, and thus optimise therapy in Alzheimer’s disease. For example, a therapeutic
window of dosing that stabilises erythrocyte acetylcholinesterase activity at 30–36%
of baseline has been proposed (Becker et al., 1991).
Directly relevant to experimental findings in animals is the observation that the
pro-cholinergic activity of galanthamine was considerable in both human, postmortem
brain tissue – particularly in the frontal cortex compared with the hippocampus
– and in fresh cortex samples obtained from operations to remove brain
tumours (Thomsen et al., 1991a). In these experiments, tacrine was three times as
potent as galanthamine and physostigmine some 200 times more effective. In spite
of these differences, the oral daily doses required to achieve equivalent cognitive
benefit are approximately 30 and 160 mg/day for galanthamine and tacrine,
respectively.
Galanthamine has also been shown to inhibit acetylcholinesterase in human
volunteers and patients with Alzheimer’s disease (Thomsen and Kewitz, 1990;
Thomsen et al., 1990a, 1991b), although the peripheral (erythrocyte) activity was ten
times that of the brain activity. Baraka and Harik (1977) found that galanthamine
(0.5 mg/kg, intravenous (IV)) reversed scopolamine-induced central anticholinergic