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1R. Anton
Traditional use as proof of safety and efficacy
Robert ANTON
Emeritus Professor of the University of StrasbourgMember of national Academies of Pharmacy and Medicine
robert.anton@unistra.fr
Botanical in food supplements, Ministero della Salute
International Conference, Rome, April 18th 2013
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Summary
I. What does tradition means ?
II. Criteria to evaluate the traditional knowledge
III. Evidence coming from the traditional experience
IV. Availability of bibliographic data
V. Limits of the concept of tradition
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1. A long history of use and the modern science
Young girl Papoue from New Guinea
(Photo A. Newman)
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2. Many traditional food supplementsand drugs used in all the world
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I. I
Materia medica: compendium of real clinical observations:
China, Guyana, India, Madagascar, New Caledonia…
3. The tradition is a precious guide
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XVI e century: clinical trial of aerial parts of spirea (Spirea ulmaria, Rosaceae)
antipyretic
salicylic aldehyde glycoside
Hippocrates 500 b.c. (Salix alba, Salicaceae), bark antalgicsalicylic alcohol glycoside
4. A proof of efficacy: history of use and modern science
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Gerhardt : acetylation of salicylic acid (1853) Anti-inflammatory- antirheumatic (prostagladines) (1971) Platelets aggregation inhibition (1985) Colon cancer prevention (1997)
salicylic acid acetylsalicylic acid (aspirin)
OH
COOH
OCOCH3
COOH
hémisynthèse
métabolisme
4. A proof of efficacy: History of use and modern science
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5. Ethical drugs and molecular models
Artemisia (artemisinine), Belladonna (atropine),Camptotheca(camptothecine), Catharanthus (vinblastine), Cinchona(quinine),Coca (cocaine), Colchicum (colchicine), Digitalis(digoxine), Ephedra (ephedrine),Ipeca (emetine), Ochrosia (ellipticine),Papaver (morphine, codeine)…
Taxus baccata Diterpene: Taxol Commercial drug
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Cynara
Gentiana
Cytisus
Spirea
Ficaria
Mélilotus
Passiflora
6. Ambivalent or borderline plants for food supplements
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Summary
I. What does tradition means?
II. Criteria to evaluate the traditional knowledge
III. Evidence coming from the traditional experience
IV. Availablity of bibliographic data
V. Limits of the concept of tradition
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1. Parameters to take into consideration on traditional information
Long history of use (generally many centuries) Collection of all information on practical traditional use Existence of convergence of use in different continents
without primitive contact
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Examples: Convergence of uses in different continents
Example of chinese Panax ginseng C.A. Meyer: adaptogene helping to cope with mental and physical stress.
The canadian or american Panax quinquefolius L.: same chemical profile (ginsenosides), similar conditions of use
Plantago sp. growing in separate regions in the world and used for the same type of symptoms: relative respiratory discomfort.
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1. Parameters to take into consideration on traditional information
Rigourous botanical identification Chemotaxonomic aspects Geographical origin and cultivation methods Part of the plant used Respect of the traditional type of preparation Identification of the type of population concerned Observation on eventual secondary effects Confirmation state with chemical profile in order to
understand the pharmaco-clinical effects
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2. Rigourous identification of raw material
Importance of the complete scientific denomination Example of family, genus and species
Lamiaceae familyLavandula angustifolia Mill., Lavandula latifolia Medik. …
Example of sub species and varieties: Bergamot (Citrus aurantium L. ssp bergamia (Wight & Arnott)
Engler) Bitter orange(Citrus aurantium ssp aurantium L.)
Example of varieties with different compositions:Basilicum (Ocimum basilicum): heterogenicity in terms of
morphologies and chemical profiles (O. basilicum var. basilicum, O. basilicum var. difforme Benth., O. basilicum var glabratum Benth….)
I
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3. Importance of the plant chemotypes
Accuracy of chemotypesExamples- Thymus vulgaris with linalol- Thymus vulgaris with geraniol- Thymus vulgaris with thujanol- Thymus vulgaris with thymol- Thymus vulgaris with carvacrol- Thymus vulgaris with terpineol- Thymus vulgaris with p-myrcene- consequence: different chemical profiles and toxicity
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Aristolochiaceae: all species
contain toxic aristolochic acid
Other plant species from other palnt families also contain diverse aristolochic acids and aristolactames
Forbidden: severe renal and hepatotoxicity (oral route)
4. Importance of the chemotaxonomy
Aristolochic acid
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5. Importance of data for production of the raw material
Geographical origin and multiple extrinsic factors: influence on the secundary metabolism
- environment and growing conditions- mode of cultivation or wild state- temperature, humidity, sunny period- harvesting time ….additional treatments
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6. Importance of the part of the tarditional plant used
Type of organs: differenciation concerning the same speciesExample of Cinnamomum zeylanicum
Bark of young stems
cinnamicaldehyde
Leaves and young
branches eugenol
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7. Traditional forms of botanical preparations
Aqueous extraction (hot water): infusion, decoction (root, seed), maceration (cold water for mucilages)
Dried aqueous forms
Hydro-alcoholic extracts: advantages: extraction of both lipophilic and hydrophilic constituents; presence of glycosides more physiologically active
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10. Numerous qualitative and quantitative analytical techniques: Ginkgo extract: HPLC-TLC…
-
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Summary
I. What does tradition means ?
II. Criteria to evaluate the traditional knowledge
III. Evidence coming from the traditional experience
IV. Availability of bibliographic data
V. Limits of the concept of tradition
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1. Positive contribution of the tradition for efficacy and safety
- 1° Most appropriate method of preparation and efficacy are confirmed by experience and scientific papers
Camellia sinensis : solubility of caffeine only in hot water, not in cold
- 2° Identification and select the particular part of the plant for specific populations: mucilages of Malva sylvestris improve intestinal transit for children. Anthraquinones derivatives (Cassia senna., Rheum palmatum…) are purgative for the same purpose in adults
- 3°Help to use botanical preparations in a safe way and eliminate potential risks: Teucrium chamaedrys.
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Importance of the traditional preparation
Lipophilic diterpenes structure type: neo-clerodane
Presence in the powder but not in the traditional infusion
Teucrium chamaedrys (Lamiaceae)
Acute cytolytic hepatitis
(26 cases)
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2. Positive contribution of the tradition forefficacy and safety
- 4° Identification and select particular part and eliminate toxic components
Borago officinalis: seed: source of fatty acids (linoleic and gamma-linolenic); all the other parts contain strong hepatotoxic pyrrolizidinic alkaloids
Manihot esculenta: root traditional preparation (rasping, drying…): removal of toxic volatile cyanogenic compounds
- 5° Holistic approach with the combination of several botanical products: Gentiana lutea stimulates appetite.
Foeniculum vulgare complete with a spasmolytic activity.
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Summary
I. What tradition means
II. Criteria to evaluate traditional knowledge
III. Evidence coming from the traditional experience
IV. Available bibliographic data
V. Limits of the tradition
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1. Available bibliographical data
• Ancient books can be consulted: Hippocrates, Galen, Paracelsus…some pharmacological and clinical effects can be confirmed
• Chronological ethnobotanical sources of information and references overview are available
• Numerous data bases identify other information e.g. pharmaco-toxicological papers give a justification of the traditional use and exposure estimation
• Important body of documentation during the last 25 years (minimum) is available
• Few clinical trials: coast – no possible patent
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2. EMA and AFSSA concepts (ANSES now)
EMA: status of « traditional drugs »
AFSSA (2003): « Framework for the evaluation of the safety, the effect and the claim foodstuff, made from plants for the human diet »
- The more the preparation differs from the traditional conditions of use, the more additional evidence on safety will be required
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3. Some recommendations of the Council of Europe
• Official mandate: creation of a working group ad-hoc: « Plant based food supplements » of the Committee of experts « Human nutrition»
• References:
Guidelines on the quality, safety and marketing of plant-based food supplements (24.06.2005)
Populations possibly at risk (28.11. 2006)
Homeostasis, a practical tool to distinguish between food supplements and medicines (28.11.2006)
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4. Monographs and reference standard texts
European Pharmacopoeia French Pharmacopeia = Pharmacopée française German Pharmacopoeia = Deutsches Arzneibuch (DAB) English Pharmacopoeia = British Pharmacopoeia (BP) US Pharmacopoeia = United States Pharmacopoeia
(USP) WHO monographs and guidelines ESCOP = European Scientific Cooperation in
Phytotherapy EMA (EMEA) : HMPWP (Herbal Medicinal Products
Working Party) Other references: AFNOR (France), ISO, ICH…. Data bank: COSING…
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6. Examples of standard scientific reference text books
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Summary
I. What does tradition means?
II. Criteria to evaluate the traditional knowledge
III. Evidence coming from the traditional experience
IV. Availability of bibliographic data
V. Limits and respect of the tradition
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1. The alkaloids are generally out of use…a too high degree of toxicity…food supplements are not concerned
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substitution by other chinese plants with a closely denomination
Stephania tetrandra
Aristolochia fangchi
Chinese plants
2. Confusion in vernacular denomination
Nephrotoxicity : Nephrotoxicity : 105 cases : carcinomas105 cases : carcinomas
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substitution of the fruits of Illicium verum (« true » chinese star anise) by Illicium religiosum (« Japan star anise »)
- - low percentage of anethole - but toxic sesquiterpene lactones
e.g.anisatine,neoanisatine
3. Adulteration of traditional plant and preparation
Star anise
Illicium verum(Illicaceae)
convulsions (The Netherlands, Holland, France)
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Traditional drink in the South Pacific islands: Vanuatu, Fidji, New Caledonia
kavapyrones with « anxiolytic» effect
4. Non compliance of the dosage
Piper methysticum(Piperaceae)
kava
Hepatotoxicity
French official decision to stop the distribution(8.01.02)
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5. The large problem of concentration and mixtures
Green tea: hepatitis given with high concentrated hydroalcoholic extract (tannins)
Mixture of anti-rheumatismal asian plants Contamination by synthetic
active products: corticosteroids, phenylbutazone, caffeine, theophylline …A lot of unknown traditional
plant use in Europa
矿产资源丰富。已探明各类矿产82种,占河南省已发现矿产品种的76.6%。其中天然碱、蓝晶石、红柱石储量全国第一;银、铜、锌、铅、石墨、大理石、
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All things are poison and nothing is without poison,
only the dose permits something not to be
poisonous”
Phillip von Hohenheim(Paracelsus, 1493-1541)
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Summary
I. What tradition means
II. Criteria to evaluate traditional knowledge
III. Bibliographic data
IV. Limits of the tradition
Conclusion
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1. An important, ancestral and empirical kowledge…
Observation of tradition must be based on the choice of specific botanicals, of the traditional preparation, on toxicological and on clinical data on human or animal
Tradition – quality – efficacy - safety Tradition knows that « What is natural is not necessarily
good» and that some plants can kill you !
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EMEA: two levels of therapeutical indications, marketing authorization and plants with a therapeutical aim- « traditional use » ( history of use, tradition and galenical form)- « well-established use » (bibliographic pharmacoclinical data available)
Why not for food supplements…in general only intended for the maintain of the homeostasis state….and only for the help concerning minor health troubles?
2. Why tradition is recognized by EMA for herbal remedies and not for food supplements ?
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Cathedral European Parliament
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