Treating Alzheimer's Disease with daffodils

Challenge: A natural source for the treatment of Alzheimer's disease

Natural inspiration: Daffoidil (Narcissus pseudonarcissus), Snowdrop (Galanthus nivalis)

 

Fields of daffodils growing in the heart of the Black Mountains, Wales may soon yield a cost effective drug, galantamine, for use in the treatment of the early stage of Alzheimer’s disease.  Galantamine is not synthetic compound but rather an extract of the Daffodils growing in the Black Mountains, Wales © Alzeimhumble daffodil (Narcissus pseudonarcissus) or snowdrop (Galanthus nivalis). 

 

Although these plants have been used as traditional medicine since ancient times it has only recently become a commercial proposition.  In the Odyssey, Homer is thought to have described Odysseus as using the snowdrop to clear his mind1. “...The root was black, while the flower was as white as milk; the gods call it Moly...”2.  Galantamine was first extracted from the snowdrop in the early 1950’s after a Bulgarian pharmacologist saw remote villagers rubbing their forehead with the plant leaves and bulbs.  It was first officially approved for use as a drug in Bulgaria in 19582.

 

Galantamine is present in the leaves and bulbs of all species and varieties of daffodils and is considered to protect the plant from grazing animals and microbial infection3.  However, galantamine is found at varying levels in different daffodil varieties3 with only certain varieties containing significant amounts to be useful on a commercial scale4.  Galantamine levels in the plant also vary with environmental conditions and with stage of growth4.  Trials to assess this variation in different varieties of daffodil began in Wales in 2006.  Results showed that galantamine was generally found in much higher levels in the daffodils grown at 1,400 feet in the Black Mountains compared with the same varieties planted in Pembrokeshire at sea level5.  Subsequently, Alzeim, a company that researches, develops, and produces drugs for the treatment of Alzheimer's disease, from Talgarth near Brecon, have planted 120 acres (48ha) of carefully selected daffodil varieties in the Black Mountains of Powys with a view to bringing this product into commercial production in Wales6

A field trial of different varieties of daffodil © Alzeim

 

 

Ten tons of daffodil bulbs are required to produce one kilogram of galantamine7 and with the current bulb prices at £600 a ton7 this is good news not only for the Welsh economy but farmers in the Welsh hills.  This new crop could help farmers not only diversify production but improve their income and financial security.  The potential is significant given the projected market growth for drugs of this nature. 

 

 

 

Extent and impact of dementia

In the UK today there are over 820,000 people living with dementia; in total some 25 million people – 42% of the UK population – are affected by dementia, either through friends or family.  An estimated 163,000 new cases of dementia occur in England and Wales each year – one every 3.2 minutes, and one in three of the over 65’s will die with some form of dementia.  With an aging population these figures are forecast to rise dramatically in the near future8

 

Dementia occurs in every country of the world; it affects 1 in 20 people over the age of 65 and 1 in 5 over the age of 80.  Globally there are an estimated 35.6 million people with dementia and this is forecast to rise to over 115 million by 20509.  Sixty percent of people with dementia live in developing countries.  While the rate of dementia is expected to double between 2001 and 2040 in developed nations, it is forecast to increase by more than 300 percent in India, China and South Asia10.  The most common type of dementia is Alzheimer’s disease. 

 

These are sobering statistics but also represent real people.

 

Economics of dementia

According to the Alzheimer’s Disease Institute, the total estimated worldwide cost of dementia in 2010 was US$604 billion11Dementia costs the UK economy £23 billion per year, that is, nearly twice the cost of cancer (£12 billion per year), almost three times the cost of heart disease (£8 billion per year) and more than four times the cost of strokes (£5 billion)8.  Every dementia patient costs the economy an average £27,647 per year8.  To this must be added the incalculable cost to families not to mention the individual affected.

 

Combined government and charitable investment in dementia research, however, is hardly comparable to its cost.  Annually it amounts to only £50 million, less than a tenth of that spent on cancer research (£590 million) and less than a third of that spent on heart disease at £169 million per year and about double that directed to stroke research, £23 million8.

 

Alzheimer’s disease treatment - Galantamine

With so many people suffering from dementia demand for treatment is growing.  In fact the market for Alzheimer’s drugs in the United States, France, Germany, Italy, Spain, the United Kingdom and Japan alone is projected to triple from US$4.9 billion in 2009 to US$13.3 billion in 201012.  In 2001 galantamine had worldwide sales on the order of US$45 million16 representing around 12% of the Alzheimer medication market.  The world market price per kilogram of galantamine is roughly the same as that for gold17

 

Although no drug currently is able to prevent or cure the disease, one drug that has proved effective in the treatment of the symptoms of Alzheimer’s is galantamine.  Galantamine is an acetylcholinesterase inhibitor, that is, it reduces the rate that the chemical acetylcholine is broken down in the brain13.  This chemical is the molecular messenger that helps brain cells communicate with each other more efficiently and is essential for memory and thought13, 14.  

 

Historically, natural galantamine has been available from sources in Eastern Europe and lately China, where it is extracted from the bulbs of flowering plants in the Amaryllidaceae family, including daffodils (N. pseudonarcissus) and the common snowdrop (G. nivalis)5.  It is currently used in over 70 countries worldwide15 with use approved in Europe in 2000.  However, the extraction process is expensive, due to the relatively low levels of the alkaloid galantamine found in the plants.  This has meant that the branded medicines containing galantamine, such as Razadyne® (formerly Reminyl), and MemeronTM, have not been made widely available as a treatment for early-stage sufferers5.  Given its relatively high cost in the UK it is currently available on prescription only in Scotland.  However, Alzeim hope that, with their cheaper extraction and production methods along with locally sourced galantamine, the much-needed extra quantities of the drug will become available at lower prices.  The hope is that NICE – The National Institute of Clinical Excellence approve the drug on cost benefit grounds.  This will enable many more patients to benefit from this treatment18. Daffodil (Narcissus pseudonarcissus) © Cathy Gardner

 

Biodiversity

The wild daffodil (Narcissus pseudonarcissus) is native throughout Western Europe, including England and Wales, Germany, France, Spain and Portugal.  John Gerard, writing in the 16th century, stated that it grew “almost everywhere through England”19 occurring naturally in a range of habitats, including ancient broadleaved woodlands, riverbanks, roadside verges, pastures and orchards19, 20

 

There are 36 species of Narcissus which are divided into 2 sub-genera (Hermione and Narcissus) and 11 sections.  Over 30,000 cultivars of the daffodil are named in the Royal Horticultural Society (RHS) Daffodil Registration Database, around 26,000 of which are considered to be unique20.  

 

While wild daffodils were commonly picked and sold during the 18th century, this casual ‘picking’ had little impact on wild populations as the bulbs remained in the soil.  However, during the 19th century intensification of agricultural practices, changes in land use, over collection of bulbs20 and hybridisation with cultivars19 saw the wild populations decline dramatically throughout England and Wales.  Distribution in the wild is now sadly patchy in England21 and uncommon in Wales.22

 

Wild daffodils regenerate both by seed and by development of clonal bulbs around the parent.  Both these methods are necessary for survival, the second enabling regeneration when cold weather prevents insect pollination, as well as when seedling mortality is high as is common in open areas15.

 

Although the wild daffodil is not threatened with extinction throughout its range, four other species,(N. bujei, N. alcaracensis, N. longispathus and N. radinganorum), all native to Spain, are rated as Endangered by the IUCN20

 

In 1981 the wild daffodil was Flower of the Year and subjected to a national awareness campaign in Germany23.  Since then targeted management has been put into place in order to stabilise populations24.

 

With the growing dementia population and naturally variability in galantamine levels between species, conservation of Narcissus species is of great importance.  Galantamine is one of a number of alkaloids found in the daffodil family.  Many of these are currently subject to research as potential treatments for a variety of diseases and ailments.  Historically, preparations made from daffodils have been used to treat burns, joint pain, strains, wounds and pulmonary congestion25 so research could lead to the discovery and development of a variety of additional medical treatments.

 

Images

Daffodils in Black Mountains, Wales - Alzeim

Field trials of daffodils - Alzeim

Daffodil – Cathy Gardener

 

References:

  1. Memeron   Accessed December 2010
  2. Homer The Odyssey  Book X  The Internet Classics Accessed December 2010
  3. Morris, P,  Brookman, J and Theodorou M  (2006) Sustainable production of the natural product, galanthamine  Defra Ref: NF0612  Tecnical Annex 1  Accessed December 2010
  4. Cambria Magazine  (2008) Daffodil help for Alzheimer’s  Interview with Prof.J.T. Walker of Alzeim Ltd., Talgarth   Accessed December 2010
  5. Farmers Guardian (2006) Hope for Alzheimer sufferers using uplands-grown daffodils  Accessed December 2010
  6. BBC News (2010) Drug’s company welcomes Alzheimer’s boost  Accessed December 2010
  7. Leapman, M (1995)  Drug hopes rest on a host of daffodils The Independent Online
  8. Alzheimer’s Research Trust (2010) Dementia Statistics  Accessed December 2010  
  9. The Global Impact of Dementia Alzheimer’s Disease International  Accessed December 2010  
  10. Ferri et al (2005) Global prevalence of dementia: a Delphi consensus study. The Lancet 366, 2112-2117
  11. World Alzheimer's Report 2010 The Global Economic impact of dementia Alzheimer’s Disease International  Accessed December 2010
  12. Tayler L (2010)  Alzheimer’s drug market set to more than triple Pharma Times online  Accessed December 2010
  13. Galantamine Medline plus  Accessed December 2010
  14. Agora Health Ltd  (2003) Galantamine Provides a Natural Remedy In The Treatment Of Alzheimer’s
  15. Takeda Pharmaceutical Co  (2010)  About Agreement Reached to Co-market R113675 (Galantamine Hydrobromide), a Treatment for Alzheimer’s Disease  Accessed December 2010
  16. Lundbeck Belgium, Alzheimer's disease Accessed December 2010
  17. Daily Mail  (2009)  Why Welsh daffodils may hold the key to beating Alzheimer's disease Daily Mail Online
  18. Aled Blake (2010) How a crop of Welsh daffodils is destined to ease the plight of dementia sufferers.  Wales Online  Accessed January 2011
  19. Gloucester Wildlife Trust ( 2010)  The Wild Daffodil in Northwest Gloucestershire  Accessed December 2010
  20. Kew  Plants and Fungi: Narcissus pseudonarcissus (daffodil) Kew Online
  21. Natural England Wild Daffodil - Narcissus pseudonarcissus  Accessed December 2010
  22. Countryside Council for Wales Wales’ ancient roots  Accessed December 2010  
  23. Stiftung Naturschutz Hamburg und Stiftung zum Schutze gefährdeter Pflanzen  Accessed December 2010
  24. Federal Ministry for the Environment, Nature Conservation and Nuclear Safety (BMU) (2009)  Report on the State of Nature by the German Federal Government for the 16th electoral term pp10
  25. Health Care  Daffodil Herb - Dosage and Useful Properties  Online Health Care  Accessed December 2010