Narcissus and Daffodil

Pharmacology of Narcissus compounds 345
sleep disturbances as a potential benefit of the drug. Nausea was the most common
side effect, reversible on drug withdrawal.
TOXICOLOGY AND TOXICITY OF GALANTHAMINE
Toxicological data derived from animals appear to be of limited use in predicting
safety in the intended human population, but some data are of interest. The
reader is referred to reviews on this topic for further information (Harvey, 1995;
Mucke, 1997).
Animal toxicology
Acute toxicity is manifested mainly as exaggerated cholinergic effects that may be
reversed with atropine. Death occurs through respiratory depression, whereas
cardiac function is relatively unaffected. An acute LD 50 of 5.2 mg/kg was determined
in mice after IV administration (Friess et al., 1961). The latter may have been an
underestimate, as a value of almost double this was obtained when galanthamine
was co-administered with 4-aminopyridine, a drug that enhances the release of
acetylcholine from nerve terminals (Micov and Georgiev, 1986). A chronic toxicological
study of the combination, with galanthamine doses up to 2 mg/kg daily,
produced no remarkable changes in blood or major organs (Micov and Georgiev,
1986). As expected, the oral LD 50 was higher than the IV value, at 18.7 mg/kg
(Umarova et al., 1965). Chronic oral doses (0.5 mg/kg/day) were shown to reduce
respiratory volume and to desynchronise EEG patterns in rabbits, but not in other
species, at this low dose. Maternal and embryo-toxicity were observed in rats and
rabbits at doses of 10% of the LD 50 (Paskov, 1986).
Toxicity in man
As an inhibitor of acetylcholinesterase, one might expect cholinergic side effects
to be a feature of the side effect profile of galanthamine. Indeed, these have been
reported following human consumption when narcissus bulbs have been mistaken
for onions, or the leaves and flowers have been eaten (Vigneau et al., 1984). Early
reports of successful use in anaesthesia to reverse neuromuscular junction blocking
agents mentioned few autonomic side effects – which is probably a reflection
on their anecdotal and enthusiastic nature. More recent and carefully controlled
studies confirm the suspicion that autonomic effects are indeed to be expected,
but that these are dose related. Altered electrocardiogram (ECG), blurred vision,
hypersalivation, nausea, vomiting and dizziness have been noted in conscious
volunteers given 20 mg doses. Interestingly, galanthamine produced mild eosinophilia
after injection. According to the authors, this might explain the local tissue
reaction noted on injection of the drug (Cozanitis and Toivakka, 1971). No
changes in blood sugar were observed in conscious volunteers (Cozanitis and
Toivakka, 1971; Riemann et al., 1994) and in patients after surgery (Cozanitis
et al., 1973b). At a relatively high dose of 25 mg, three out of nine surgical patients
had sufficient bradycardia to require reversal with atropine (De Angelis and Walts,
1972).