Michael Heinrich is professor of
pharmacognosy at the Centre for Pharmacognosy and Phytotherapy, School
of Pharmacy, University of London
|
During the darkest days of the year, when nature seems to be asleep, waiting
for the brightness of spring brings back memories of times past, most notably,
of one’s childhood.
In some people, however, memories, particularly of the immediate past,
are distorted because of dementia. According to the Alzheimer’s Association,
approximately two-thirds of all cases of dementia in the elderly are caused
by Alzheimer’s disease. Alzheimer’s disease is a neurodegenerative
disorder affecting major brain areas, such as the cortex and limbic system.
It often begins with symptoms like short-term memory loss, but it is not
just memory that is affected. The disease continues with more widespread
cognitive and emotional dysfunction, resulting in substantial and long-lasting
disability over the approximate seven to 10 years from diagnosis to eventual
death. Although Alzheimer’s disease usually has no effect on motor
or sensory functions, some atypical clinical presentations (eg, spastic
paraparesis) are occasionally found.
Alzheimer’s disease generally affects 3 per cent of people aged 65–74
years, 19 per cent of those aged 75-84 years and 47 per cent of those aged
85 years and over. According to the World Health Organization, around 35
million people in industrialised countries will suffer from Alzheimer’s
disease by 2010, the number of patients rising with increasing life expectancy.
Why touch on such a depressing topic during this festive period? There
is a surprising link between a treatment for this debilitating disease
and our waiting for the first ambassadors of spring: snowdrops. Galantamine,
a medicine used today to treat Alzheimer’s disease, occurs naturally
in several members of the amaryllis family (Amaryllidaceae). The alkaloid
was first isolated from snowdrop (Galanthus spp, most notably G
woronowii).
The idea for developing a drug from these species seems to be based on
the local use of one of them in a remote part of Europe. Today, galantamine
it is obtained from other members of the same plant family, like daffodil
(Narcissus spp) and snowflake (Leucojum spp), as well as being made synthetically.
Galanthus species are native to many parts of Europe including the south-eastern
European countries, the eastern parts of Turkey and the Caucasus mountain
range but, overall, little has been published about the use of galantamine.
Ethnopharmacology
The study of local and traditional knowledge is an area of scientific
enquiry today commonly called ethnobiology. If the knowledge relates specifically
to medicinal plants, the subject is called ethnopharmacology. As a specifically
labelled field of research, ethnopharmacology has had a relatively short
history. The term was first used in 1967, in the title of a book on hallucinogens: ‘Ethnopharmacologic
search for psychoactive drugs’. However, the concept of developing
drugs from plants used in traditional and local medical systems is much
older and broader. Information about such use is based on a researcher
living in a community, introducing the people to his or her research
interests, eating their food and sharing their joys and fears. The goal
of such research may well be to find new drugs but, often, the ethnopharmacologist
is more interested in the local development of these resources. This
kind of research is, generally, hypothesis driven and based on a series
of well-established field and laboratory methods. It is often conducted
in tropical countries, but may well be conducted in temperate regions
of the world.1
Although in some cases, direct links between a local and a biomedical
use exist, in others the relationship is more complex. All too often
our information
about such local or traditional use is limited. In the case of galantamine,
we are faced with a difficult detective story, which leaves us with many
unresolved riddles. Traditional use of galantamine
Little sound evidence for the traditional use of the Galanthus species
exists. Snowdrop was possibly used in ancient Greece. In 1983, Plaitakis
and Duvoisin hypothesised that that Homer’s “moly” might
have been the snowdrop (G nivalis).2 In his epic poem, The
Odyssey, Homer
described moly and its use by Odysseus as an antidote against Circe’s
poisonous drugs. Thus the Greek description of moly might represent the
oldest recorded use of Galanthus, but the evidence is scanty. Jumping
to the 16th century and to the classical medico-botanical texts of the
renaissance (ie, by Fuchs, Bock, Brunfels, Turner and Gerard), we note
that they do not mention G nivalis. In Köhler’s ‘Arzneipflanzen’ of
1889, practically no medical use is given for species of Galanthus, Leucojum or Narcissus.
Later, in the first half of the 20th century, at the height of interest
in developing local European medicinal plants into medicines, the German
pharmacognosist Madaus does not mention Galanthus or Leucojum and only
discusses N pseudonarcissus, giving some isolated uses that have no direct
association with the central nervous system. Although more archival and
ethnopharmaceutical research is needed, it seems certain, that Galanthus and other genera of the Amaryllidaceae were not commonly used European
medicines until after the 1939–45 war.
According to unconfirmed reports, in 1950s, a Bulgarian pharmacologist
noticed the use of the common snowdrop growing in the wild — people
rubbed it on their foreheads to ease nerve pain. British pharmacognosist
E. J. Shellard recalls a presentation in 1965 by “a Russian pharmacognosist
reporting about a peasant women living at the foot of the Caucasian mountains
who, when young children developed symptoms of an illness which, as he
described them, was
obviously poliomyelitis, gave them a decoction of the bulbs of the Caucasian
snowdrop (G woroncwii Los) [sic] and the children completely recovered
without showing any signs of paralysis.”3 This
remains one of the few second-hand accounts on the local use of snowdrop
and it has not been
possible to trace further relevant and detailed ethnobotanical literature.
In the first pharmacological publication in the early 1950s on galantamine
no reference is made to the traditional use of snowdrop in the Caucasian
region by the Russian authors.
Development into a drug for Alzheimer’s
Most of the early investigations on galantamine were conducted in Bulgaria
and the USSR during the iciest period of the Cold War. In the early 1950s
the Russian pharmacologist Mashkovsky worked with galantamine isolated
from G woronowii. Mashkovsky and Kruglikova-Lvova, in 1951,
used an ex
vivo system of striated muscles (frog straight abdominal and leech
dorsal muscle) and smooth muscles (isolated rabbit small intestine and
guinea
pig uterus) to prove its acetylcholinesterase (AChE) inhibiting properties
and antagonisation of curare-induced effects. This was the first published
work that demonstrated the AChE-inhibiting properties of galantamine.
Chemical structure of galanthamine |
The
following year, the chemical structure of galantamine was established
(the alkaloid has a tertiary nitrogen atom) and published, again based
on material isolated from G woronowii. In 1955, Mashkovsky published
a second paper on the cholinesterase-inhibiting properties of galantamine.
He does not indicate the source of the galantamine but, most probably,
used galantamine isolated from G woronowii, as before.
In 1957, galantamine was isolated from the leaves of G nivalis L.
Again, its cholinesterase-inhibiting properties were investigated as was
its action
against curare. At this time the focus was on alleviating the symptoms
of polio-myelitis — a common and debilitating illness that affected
many young people. In the same year, results from the study of summer snowflake
(L aestivum) showed it to be a rich source of galantamine and
this was to become the main source.
Galantamine was produced in the form of a hydrobromide salt and, since
1958, has been commercially available (Nivalin) as an injection and, since
1984, in tablet form.4 Initially, Nivalin
was used in anaesthesiology to antagonise the effects of non-depolarising
muscle relaxants but was then
rapidly introduced in other areas of medicine, such as neurology, ophthalmology,
gastroenterology, intensive care and resuscitation, cardiology and physiotherapy.
Snowdrop and related species have now been used internally for approximately
40 years for the reversal of neuromuscular blockade and for the treatment
of neurological conditions such as post-polio paralysis and myasthenia
gravis.2 When researchers demonstrated that
galanthamine penetrated the blood-brain barrier, its effects on the CNS
became of interest. Limited
medical experience, particularly in treating neuromuscular (especially
myopathic) and CNS disturbances using the Bulgarian preparation (Nivalin),
has been reported. Production
In 1960, galantamine-producing species were identified that are easier
to cultivate and the full chemical synthesis pathway was published. This
was a biomimetic laboratory process (with a yield of below 1 per cent),
which had been designed as proof of structure rather than for industrial
production.
Detailed research in the West only started in the 1980s when the new
indication (for Alzheimer’s disease) became the central focus of preclinical
and clinical work. However, the use of snowdrop, snowflake, and daffodil
as the only source of galantamine was wholly unsustainable. After its initial
launch in western countries, galantamine remained as a critical resource.
It was only available at prices around $40,000 per kg until Sanochemia
Pharmazeutika, a company based in Austria, developed a method to synthetically
and commercially produce the compound in 1997. Later, galantamine was co-developed
by Shire Pharmaceuticals and the Janssen Research Foundation for Alzheimer’s
disease. They launched galantamine as Reminyl. This was the third drug
licensed in the UK specifically for Alzheimer’s disease and is based
on galantamine extracted from Narcissus spp. Overall, good clinical evidence
is available — some studies show moderate efficacy up to one year
in improving both cognitive functioning and normal living activities in
patients with Alzheimer’s disease. An appropriate dosing regimen
has been developed and the drug can generally be considered to be well
tolerated.4,5
Conclusion
Snowdrop provides a telling story of the
development of a new pharmaceutical from a natural product — a true
success story for pharmacognosy. However, many question
remain unanswered. It seems snowdrops were (or are) used in some remote
parts of Europe but it remains unclear why research into the drug was initiated.
Is this a purely academic question? I do not think so.
Many parts of the world are changing fast and, as a consequence, knowledge
about local and traditional resources is rapidly lost. The practice of
ethnobotany and ethnopharmacy is crucial in helping us to document such
knowledge, which, maybe many years after the initial start of the research
on a topic, might become useful.1 Just as importantly,
research ethics now rightfully demand, that we share the financial benefits
of such successful research with the people who have given us the local
knowledge.
Snowdrops and all the other ambassadors of spring remind us of the intrinsic
optimism of nature, which rejuvenates every year, and it is so appropriate
that a little spring flower gave us one of the main medicines to treat
dementia. ACKNOWLEDGEMENT I am grateful to H. L. Teoh, who compiled many of the
clinical data on galantamine and to Rumen Nikolov (Sopharma, Sofia) for
providing unpublished data and to some early publications in Bulgarian
and Russian. Access to the Pharmaprojects database granted to the School
of Pharmacy, London, for teaching and research purposes is gratefully acknowledged.
References
1. Heinrich M, Barnes J, Gibbons S, Williamson E.M. Fundamentals of pharmacognosy
and phytotherapy. London: Churchill Livingston: 2004.
2. Plaitakis A, Duvoisin RC. Homer’s moly identified as Galanthus
nivalis L: physiologic antidote to stramonium poisoning. Clinical Neuropharmacology
1983;6:1–5.
3. Shellard E.J. Alkaloids from snowdrops. The Pharmaceutical Journal
2000;264:883.
4. Heinrich M, Teoh H.L. Galanthamine from snowdrop — the development
of a modern drug against Alzheimer’s disease from local Caucasian
knowledge. Journal of Ethnopharmacology 2004;92:147–62.
5. Erkinjunti T, Kurz A, Gauthier S, Bullock R, Lilienfeld S, Venkata
Damaraju CR. Efficacy of galantamine in probable vascular dementia and
Alzheimer’s
disease combined with cerebrovascular disease: A randomised trial. Lancet
2002;359:1283–90. |
The
Pharmaceutical Journal