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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