Narcissus and Daffodil

348 D. Brown
(1994) go on to mention some patients with light-headedness, agitation and sleep
disturbances (incidences were not reported), but there were no withdrawals due
to adverse effects. Liver function tests and serum creatinine remained normal
throughout.
DERIVATIVES OF GALANTHAMINE
As discussed previously, galanthamine is not an ideal drug; cholinergic side effects
such as nausea and vomiting occur in significant number of patients at doses
accepted as therapeutic. Consequently, there has been a degree of research interest
in developing compounds with fewer side effects, and reports of semi- or
wholly synthetic galanthamine derivatives are beginning to appear. The complete
chemical synthesis of galanthamine was achieved and reported almost 40 years
ago (Barton and Kirby, 1960) and an economic production process has recently
been developed which should reduce the cost and guarantee a supply of parent
compound with a consistent level of purity (Holton et al., 1998). Bores and Kosley
(1996) provide an extensive review of attempts to improve upon the safety,
efficacy and pharmacokinetic profile of galanthamine through the synthesis of
analogues. Preclinical assessment of the 6-ester derivatives of 6-demethylgalanthamine
showed most promise, particularly the adamantyl ester (see Figure 13.1).
This compound, like other 6-ester derivatives appears to act as a prodrug. After
oral administration and absorption, rapid hydrolysis takes place, presumably by
non-specific blood and tissue esterases, yielding the potent acetylcholine esterase
inhibitor, 6-demethylgalanthamine – see Figure 13.2 (Bores et al., 1996). This
appears to be five times as potent as galanthamine at inhibiting mouse brain
acetylcholinesterase (Han et al., 1991, 1992), and compared with galanthamine it is
a more selective inhibitor of acetylcholinesterase rather than butyrylcholinesterase.
Galanthamine had better overall bioavailability than any of the ester
analogues, including the adamantyl ester, in rats; but the adamantyl ester was
judged to have the most favourable pharmacokinetics (i.e., slower onset and
sustained levels of 6-demethylgalanthamine, combined with the greater potency of
the latter towards acetylcholinesterase). The compound also had a higher oral
therapeutic index, higher brain levels and greater activity in vivo, as demonstrated
by greater efficacy at causing hypothermia (Bores et al., 1996). The authors
concluded that because of its composite profile, including duration of action, oral
therapeutic index and pharmacokinetics, the adamantyl ester was the best therapeutic
candidate for the treatment of AD. This hypothesis awaits confirmation
from experiments with the compound in higher species and man.
PRETAZETTINE
Compounds in Narcissus species have joined the long line of phytochemicals that
have been investigated for their anti-tumour activity. Several early reports, most of
them originating from a single research group in Honolulu, mention a compound
isolated from the bulbs of Narcissus tazetta called pretazettine (Furusawa et al.,
1976a). This agent is one of many that have been investigated for their ability to