Narcissus and Daffodil

Narcissus patents 413
extraction (Deurer and Hille, 1994). Another transdermal delivery system containing
pergolide free base or its mesylate or hydrochloride salt is also described (Asmussen
et al., 1997).
An oral sustained release composition, in the form of a tablet or capsule, incorporates
the use of active ingredient particles coated with an enteric protection agent,
polyvinyl pyrrolidone (Fischer et al., 1998).
New galanthamine analogues or derivatives
Benzazepine analogues and diaza-bi cycloalkanes (Davis and Goodman, 1994),
methylapogalanthamine hydrochloride (Czollner et al., 1997) (the latter having
hypotensive properties), 1-aminomethyl-1-phenyl-4-hydroxy-cyclohexane derivatives
said to be analgesic in activity (Abdusamatov, 1963), spiro-benzazepines (also
analgesic and sedative) (Grelan Pharmaceutical KK, 1975) and 6-O-demethylgalanthamine
(Grelan Pharmaceutical Co., 1975) are amongst a whole host of
analogues and other salts (Davis et al., 1995a,b,c; Chaplin et al., 1997a; Christen
et al., 1997) that are claimed to be more potent, or less toxic or more brain-specific
cholinesterase inhibitors, than galanthamine itself. Some of these patents cover not
only the novelty of the molecules, but also method(s) of production.
Specific production patents include means of ‘producing galanthamine derivatives
by condensing and reducing a benzaldehyde derivative and a tyramine derivative,
oxidatively cyclising the protected product and reducing the keto group’
(Czollner et al., 1996) and another by a ring closure method (Grelan Pharmaceutical
Co., 1972).
Use patents
Patents discussed under this heading are often broader in scope than just being
related to galanthamine. Analogues, and even cholinesterase inhibitors in general,
are often also included in these claims.
The original uses of crude concoctions of snowdrop bulbs and, later on, of more
highly purified materials, included an array of neuro-muscular disorders, such as
poliomyelitis and myaesthaenia gravis, as well as more vague neurological conditions.
The discovery of the reduction of levels of choline acetyl transferase in the
brains of Alzheimer’s Disease victims led to the search for compounds that could
cross the blood-brain barrier and boost cholinergic activity in the basal nuclei, hippocampus
and cortex. Tacrine was the first acetyl cholinesterase, to be developed
for such a therapeutic use in Alzheimer’s Disease, but it has a greater affinity for
butyryl than for acetyl cholinesterase, and may lead to raised liver enzyme activity
that can seriously restrict its use. Galanthamine is one of a number of so-called
second generation inhibitors that do not have adverse activity on the liver, readily
pass the blood-brain barrier, and are more specific inhibitors of the acetyl form of
cholinesterase. In addition, galanthamine has nicotinic activities, which could well
differentiate it from other second-generation cholinesterase inhibitors in the
clinic.
The major indication for galanthamine at present is Alzheimer’s Disease. Oral
(10–2000 mg/day), parenteral (0.1 to 4 mg/kg) and intracerebroventricular administration
via an implanted reservoir (0.01–5.0 mg/kg/day) are claimed to improve