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.
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.
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
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.
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.