Lily of the Valley Day – the eternal question of dose in determining toxicology and therapeutic effect
On May 1st some of us celebrate Lily of the Valley Day. This holiday is popular especially in France, known as La Fête du Muguet. On this day, the French give bouquets of lilies of the valley to each other. Lily of the valley, Latin name Convallaria majalis, is a plant with small white flowers and a strong scent. All parts of the plant are toxic, with children being particularly susceptible to poisoning. Fatal poisonings in children have been described repeatedly after eating a few berries or drinking water from a vase containing a bouquet of lilies of the valley. If ingested, the plant can lead to serious illness and even death. On the other hand, for centuries lily of the valley has also been known for its medicinal potential. Thus, “Everything is poison and nothing is poison. Only the dose makes a substance not a poison” (latin: Dosis facit venenum) – poisonous substances from plants act as medications when used in small doses. Today, knowing the right dose is a factor that differentiates a poison from a remedy, lily of the valley extract is used as an active ingredient in medicinal products used in the treatment of heart failure and cardiac rhythm disorders, as it contains cardiac glycosides that increase the output force and the rate of heart contractions by acting on the cellular sodium-potassium ATPase pump.
While enjoying spring and awakening nature, do not forget to look after your companions both, kids [1] and animals [2], and protect them from ingestion of plants like lily of the valley. It should be borne in mind that Convallaria majalis is not the only poisonous plant from human surrounding. Plenty of them might be found in house gardens, parks, with worth mentioning e.g.:
- European yew (Taxus baccata),
- oleander (Nerium oleander),
- rhododendrons and azaleas (Rhododendron spp.),
- firethorn (Pyracantha spp.),
- golden chain/rain (Laburnum ssp.),
- poinsettia (Euphorbia pulcherrima),
- Sago palm (Cycas revoluta),
- castor bean (Ricinus communis) and many others.
Herbal products
The history of herbal products and herbal medicines is deeply intertwined with the history of human civilization itself. Substances of herbal origin have been used for thousands of years by various cultures around the world for medicinal purposes. From these days, lots of medicinal products have plant origin. Certainly one of the most known example in this field is the discovery of aspirin (acetylsalicylic acid). According to history, the substance was first found in the bark of a willow tree [3]. In 1897 dr. Felix Hoffman, a German chemist at Friedrich Bayer and Co, produced pure stable acetylsalicylic acid. His discovery was the first time a drug had been made synthetically and was the birth of both aspirin and the pharmaceutical industry. Nowadays, aspirin is a well-known and widely used worldwide active substance that even has its own foundation [4]. Since willow bark has been used as an analgesic and antipyretic, acetylsalicylic acid has new and broader indications, including in cardiovascular disease.
A characteristic feature of plant medicines is that they do not exist in pure form, but are accompanied by numerous natural chemical compounds. Some commonly used herbal medicinal products include:
- Ginseng radix – for symptoms of asthenia such as fatigue and weakness;
- Ginkgo folium – for the improvement of (age-associated) cognitive impairment;
- John’s Wort (Hypericum perforatum) – to alleviate symptoms of depressive disorders;
- Chamomile flos – for gastrointestinal disorders;
- Arnica flos – for the relief of bruises, sprains and localized muscular pain.
Medicinal products may contain one or more herbal substances or one or more herbal preparations, or its combination [5]. A herbal substance is defined as a whole, fragmented or cut plants (but also algae, fungi, lichen) usually in dried form, but sometimes fresh. The examples of herbal substances are Melissa leaf, Mentha leaf or Calendula Officinalis flower. If herbal substances were subjected to further processing, such as extraction, fractionation, purification, concentration, fermentation etc. they are called herbal preparations. These include comminuted or powdered herbal substances, tinctures, extracts, essential oils, expressed juices and processed exudates [5]. Examples of herbal preparation can be Pelargonium Root Liquid Extraction Preparation, Valeriana Root Tincture or liquid formulations of a few herbs used for digestive problems. Examples of products with several herbal preparations in one product might be the products used for treatment of uncomplicated inflammations of the paranasal sinuses composed of gentian root (Gentiana lutea L.), primula flowers (Primula veris L.), sorrel herb (Rumex crispus L.), elder flower (Sambucus nigra L.) and verbena herb (Verbena officinalis L.). Sometimes the purification steps provide an almost pure synthetic-like substance.
Regulatory overview of herbal medicinal products
Herbal medicinal products can be registered in different types of application. Among them the original application, well-established use and traditional herbal medicinal products are the most popular choices. Information on options for registration of medicinal products can be found on our blog in the article describing how to choose the right type of application. Helpful information about the requirements for the registration can be also found in EMA’s documents. European Union monograph comprises the scientific opinion of the Committee on Herbal Medicinal Products (HMPC) on safety and efficacy data concerning a herbal substance and preparations thereof intended for medicinal use [6]. The HMPC evaluates scientifically all available information on a given herbal preparation including non-clinical and clinical data but also documented long-standing use and experience in the EU and, if available, outside the EU. Community herbal monographs are divided into two columns: the left column describes the well-established use requirements while the right column the traditional use requirements. The HMPC gradually develops also the European Union list entries, which are legally binding on applicants and national competent authorities in the Member States, as opposed to herbal monographs. Draft list entries are developed by the HMPC, but the final list entries are adopted and published by the European Commission. Thus, if applicants for traditional use registration can demonstrate that their proposed product and related claims in the application comply with the information contained in the EU list, national competent authorities cannot require additional data to assess the safety and the traditional use of the product. Currently, there are 14 final EU list entries adopted by the European Commission [7], for example Mentha x piperita L., aetheroleum with accepted 3 following indications:
1) Traditional herbal medicinal product used for the relief of symptoms in coughs and colds,
2) Traditional herbal medicinal product used for the symptomatic relief of localised muscle pain,
3) Traditional herbal medicinal product used for the symptomatic relief of localised pruritic conditions in intact skin [8].
Traditional herbal medicinal products registration requirements
Traditional herbal medicinal products [5] are herbal medicinal products for human use that fulfill the conditions laid down in Article 16a(1) of Directive 2001/83/EC, and The European Directive on Traditional Herbal Medicinal Products, i.e. Directive 2004/24/EC, which have indications exclusively appropriate to traditional herbal medicinal products which are designed for use without the supervision of a medical practitioner (oral, external and/or inhalation preparation) and are exclusively for administration in accordance with a specified strength and posology.
The presence in the herbal medicinal product of vitamins or minerals is allowed but their action can only be ancillary to that of the herbal active ingredients regarding the specified claimed indication(s).
The traditional herbal medicinal products can be registered by a simplified registration procedure which allows the registration without requiring particulars and documents on tests and trials on the safety and efficacy, provided that there is sufficient evidence of the medicinal use of the product throughout a period of at least 30 years, including at least 15 years in the EU. The efficacy of the herbal medicinal product is considered plausible on the basis of long-standing use and experience. Non-clinical tests are not necessary, however, even a long tradition does not exclude the possibility that there may be concerns with regard to the product’s safety, and therefore the competent authorities are entitled to ask for all data necessary for its assessment.
Also for safety reasons, no derogation is made with regard to the necessary physico-chemical, biological and/or micro-biological tests required in the quality part of the application dossier, because the quality aspect of the herbal medicinal product is independent of its traditional use. Products should comply with the quality standards found in relevant European Pharmacopoeia monographs and/or those in the pharmacopoeia of a Member State.
From patients` point of view it is easy to identify traditional herbal medicinal products, as the patient information leaflet (section 1) and the summary of product characteristics (section 4) should clearly state that the product is a traditional herbal medicinal product intended for use for the specified indications arising exclusively from its long-term use.
There are various reasons why patients may be interested in the usage of herbal medicines. Some people simply use them because they enjoy phytotherapy. However, for some patients it might be an important factor in the decision that herbal medicines may meet Halal requirements [9].
Unlimited possibilities
As mentioned at the beginning, glycosides from the poisonous lily of the valley have found their indication in the treatment of heart disease. As another example, alkaloids from the poison yew are used to treat breast and ovarian cancer in the form of the paclitaxel active substance. The kingdom of plants constitutes a vast storehouse of countless substances. Many of them are already well-recognized, some are known to be toxic and there are still plenty of them waiting to be discovered or determined in terms of medical indications to be used. Knowledge of the dose-response relationship enables the usage of the drug by ensuring its efficacy and safety. The power of nature should not be underestimated, and so the medicinal plants. Not without exception, herbal medicinal products should be administered like other medicines, consciously and according to the doctor’s advice or the information in the package leaflet.
- Ghorani-Azam A, Sepahi S, Riahi-Zanjani B, Alizadeh Ghamsari A, Mohajeri SA, Balali-Mood M. Plant toxins and acute medicinal plant poisoning in children: A systematic literature review. J Res Med Sci. 2018 Mar 27;23:26.
- Cortinovis C, Caloni F. Epidemiology of intoxication of domestic animals by plants in Europe. Vet J. 2013 Aug;197(2):163-8.
- https://theconversation.com/hippocrates-and-willow-bark-what-you-know-about-the-history-of-aspirin-is-probably-wrong-148087
- https://www.aspirin-foundation.com/
- https://www.ema.europa.eu/en/human-regulatory-overview/herbal-medicinal-products/herbal-medicinal-products-questions-answers
- https://www.ema.europa.eu/en/medicines/field_ema_web_categories%253Aname_field/Herbal/field_ema_herb_outcome/european-union-list-entry-256
- https://www.ema.europa.eu/en/search?f%5B0%5D=ema_search_categories%3A85&f%5B1%5D=herbal_outcome%3A256
- European Union list entry on Mentha x piperita, aetheroleum. EMA/HMPC/679997/2013.
- https://gabi-journal.net/the-incorporation-of-the-halal-management-system-hms-by-the-pharmaceutical-industry.html?utm_source=BenchmarkEmail&utm_campaign=GJ_2023-3_anmt_V24A26-21&utm_medium=email