Stimulated by the recent Transient Receptor Potential (TRP) discussion, the following began as a comment from one of RxISK’s background activists but grew into a post.
RxISK is not about to desert orthodox medicine and turn to herbalism but herbalism may well have a lot to offer. It looks like many traditional remedies actually do act on systems we knew nothing about until recently. If any readers have contacts with serious herbalists it would be good to get their input on some of the issues allopathic drug treatments cause and how herbal preparations might help but also anything that is known about risky interactions between allopathic medicines and herbal preparations.
Daffodils are not strictly a herb but as Kevin Stephens found out they echo recent posts on RxISK. KS became interested because he knew someone with Alzheimer’s, so he took a course in genetics to understand how growing daffodils for medicine could help.
A former shepherd turned software developer and engineering enthusiast, Kevin’s introduction to the world of daffodil farming also came through a chance encounter with biotech expert Professor Trevor Walker.
Daffodil leaves and flower stalks contain crystals of calcium oxalate. This is not unexpected, since some members of almost all plant families, including many crops, synthesise oxalic acid (C2H2O4) as a normal physiological process. Oxalic acid is a strong dicarboxylic acid and the most oxidised organic compound synthesised by plants. The crystals were first seen in plant tissues by Antonie van Leeuwenhoek in the late 1600s as a consequence of his improvements to magnifying lenses. For many years they were thought to form spontaneously, but it is now apparent that the complexity of crystal formation, even extending to morphology, requires a substantial level of genetic and biochemical control.
In daffodils, bundles of needle-shaped calcium oxalate crystals termed raphides are formed. As well as being involved in controlling calcium levels in the tissues, the raphides provide some protection from grazing animals and insects. This extends to people, since an eczematous rash and sores – ‘daffodil picker’s rash – on the hands and arms are a well-documented hazard of the flower bulb industry where ‘cut’ flowers are actually plucked from the base. The rash is partly due to the raphides released into the sap that exudes from broken stems and leaves. Soluble oxalate itself is also toxic to animals through interference with calcium metabolism.
Daffodils also synthesise a wide range of isoquinoline alkaloids. The total level in the bulbs is generally 1-2%, but over 100 individual compounds have been identified among different Narcissus varieties, starting with lycorine identified from N. pseudonarcissus in 1877 by A. W. Gerrard. They are collectively termed the Amaryllidaceae alkaloids, after the taxonomic family to which Narcissus belongs, since the specific chemical structures are unique to that family.
The characteristic features fall into nine principal skeletal subgroups, all containing ring systems derived from the amino acids phenylalanine and tyrosine, and a single nitrogen atom, which can be secondary, tertiary or even quaternary (Figure 1). In addition, all are moderately weak bases (pKa 6 – 9). Biosynthetic pathways were proposed from the 1960s following radiolabelling experiments and isolation of proposed chemical intermediates (Figure 2). However, researchers have yet to isolate and study the relevant Narcissus enzymes.
The alkaloids are undoubtedly why eating all parts of daffodils can cause illness, with symptoms including vomiting, abdominal pain and diarrhoea in animals and people., but fortunately the result is usually a short period of illness without long-term consequences.
Daffodils have been used regularly in folk and traditional medicine, for in addition to the well-documented sickness-inducing properties, extracts can produce numbness, hallucinations, convulsions and cardiac effects, as well as being used for centuries in cancer treatments. Applying juice or aqueous extracts to burns or open wounds can result in numbness and these effects explain why there has been interest in identifying their chemical and pharmacological bases.
Plants are important for new pharmaceuticals because of the complexity of their secondary metabolic compounds. Indeed, one third of the approximately 1000 new pharmaceuticals registered in the past 25 years originated from or were inspired by natural products. The global market in plant-derived drugs in 2008 was estimated to be worth about £12bn from both prescribed and over-the-counter sales.
The best-studied Narcissus alkaloids are lycorine, narciclasine, galanthamine and pretazettine, which have several pharmacological activities, and extraction and purification are favoured because it is challenging to synthesise in large quantities compounds with high levels of stereoselectivity.
Galanthamine, also called galantamine, marketed as Reminyl by pharma company Shire Pharmaceuticals, is particularly interesting because it is approved by the National Institute for Health and Clinical Excellence in the UK as a treatment of early stage and moderate Alzheimer’s dementia. Alzheimer’s currently affects at least 600,000 people in the UK and as many as 35m people worldwide, and incidences will increase dramatically as average life expectancies increase.
Alkaloids are of interest because people with Alzheimer’s appear to have a shortage of the neurotransmitter acetylcholine in their brains. In the 1950s, the Russian pharmacologists M. D. Mashkovsky and R. P. Kruglikova-Lvova discovered that galanthamine could competitively inhibit the enzyme acetylcholine esterase. Further work established that its action was long-acting, selective and reversible, with a number of clinical uses such as recovery from a type of curare-induced anaesthesia and, later, Alzheimer’s disease.
SME Alzeim in Brecon in mid-Wales is leading scientific work, with support from the Welsh Assembly and central governments, to develop the necessary chemical expertise. One attraction of Wales for producing alkaloids is that chemical levels can be enhanced by the stresses of growing the plants in the Welsh mountains. Studies include extensive horticultural trials to identify the most appropriate regimens for alkaloid production – such as varietal, location and climatic combinations – in collaboration with Cambridge and Bangor universities. Highly specialised fertiliser treatments as well as unique harvesting and processing equipment have been developed. Harper Adams University in Shropshire is now also involved.
Much work has also been necessary to develop a new, wet-based industrial scale extraction process with chemical engineers at Manchester University.
The daffodil is destined to be at the centre of intense research activity in the near future in order to realise urgently needed commercial expansion of production not just for generic versions of galanthamine-based oral medicines but also for the development of other drug delivery systems and, eventually, other alkaloids that promise to be of value to medicine.
See Welsh Daffodils