Aucun titre de diapositive

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Robert ANTON Annelise LOBSTEIN  Herbal
ingredients in food supplements the French
experience CNRS / UMR 7081 Faculty of Pharmacy
Strasbourg anton_at_pharma.u-strasbg.fr
AESGP, The future of herbal (medicinal) products
and food supplements 7-8 October 2003
Brussels
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To clarify the reflexion which plants are
concerned ?
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1. Origin of the biomolecules

• Biodiversity
• estimation  300 to 500,000 species
• 10 000 different substances for each species
• Two divergent metabolisms
• Primary metabolism  sugars, lipids, proteins,
  oligo-elements, vitamins
• nutritional aspect
• Secondary metabolism terpens, alkaloids,
  polyphenols, steroids coumarins, saponins
• prevention and therapeutical aspects

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2. Sources of pharmaceutical drugs for major
pathologies

• Examples of plants
• Taxus Catharanthus
  Papaver

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3. Chemical homogenous groups of well defined
molecules

• Phytosterols and hypercholesterolemia
• Isoflavonoids and menopause
• Fibers and prevention of intestinal cancer
• Polyphenolic and carotenoid compounds as
  anti-ageing (free radical scavengers)
• Clinical efficacy to be proved

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4. Botanicals as drugs and/or dietary supplements
Guarana
Allium
Matricaria
Ginseng
Coffea
Tea
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5. Position of botanicals at the interface of
nutrition and therapeutics

• Crataegus oxyacantha
• As functional food
• calming for the heart
• As phytomedicine
• for cardiac erethism in the adult
• (healthy heart)

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5. Position of botanicals at the interface of
nutrition and therapeutics

• Valeriana officinalis
• As functional food
• promote sleeping
• As phytomedicine
• neurosedative

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6. Some other examples

• Total or specific extracts (global activity)

Cassia
Ginkgo
Ruscus
Serenoa
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II. Herbal remedies from traditional medicinal
plants
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Official requirements for herbal remedies in
France

• French Agency for the Safety of Drugs Agence
  Française de Sécurité Sanitaire des Produits de
  Santé
• AFSSAPS
• Notice to applicants for marketing
  authorization
• Cahiers de lAgence n3, 1999

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2. Respect of the European definition of the drug

• Herbal remedies from traditional medicinal plants
  
• Medicinal products containing exclusively plant
  material and vegetable drug preparations for
• Health prevention
• in order to correct, restore or modify
  physiological functions
• Treatment to cure human disease

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3. Exact position of the phytomedicines

• DRINK REMEDY
  POISON
• NUTRITION THERAPY
  TOXICOLOGY
• non toxic plants
  molecular models
• in pharmacology
• total or purified extracts isolated compounds
• (global activity) (morphine, digoxine,
  taxol)
• herbal drugs, OTC ethical drugs
• health prevention treatment
• Minor pathologies Major pathologies

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4. Initial imperative aims

• To avoid anarchy on the market
• To define a high level of pharmaceutical quality
• To respect major criteria
• quality, safety, efficacy
• To observe optimal benefit / risk ratio
• To preserve a pharmaceutical tradition

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5. Useful important guidelines and results of
selection

• History of use
• Types of preparations and final products
• Selection of 196 atoxic plant species
• 31 laxative plants
• Precise finished products
• Infusions
• Standardized extracts
• Concentrated fractions

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6. Analytical documentation

• Quality (highest level)
• Botanical identity and origin
• Knowledge of manufacturing process
• Qualitative and quantitative control of starting
  material, intermediate and final products
• Stability test on the finished product (ICH
  standards)
• Reference monographs (HPLC or GC profiles)
• New standards
• radioactivity level, pesticide residues,
  microbiological cleanliness

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7. Toxicological documentation

• Total exemption for
• Herbal drugs for tea (infusion)
• Aqueous extracts
• Hydroalcoholic extracts (lt 30 alcohol)
• Tinctures of traditional use
• Further toxicological information required for
• Non traditional tinctures
• Hydroalcoholic extracts (gt 30 alcohol)
• Non traditional powders of whole plants

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8. Clinical documentation

• only justification and proofs,
• except for authorized therapeutic indications
• dosage correlated with traditional form (herbal
  tea)

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9. List of indications for minor pathologies

• 1. cardiac erethism
• 2. circulatory disorders - capillary fragility -
  hemorrhoids
• 3. wounds - acne - itching of the scalp -
  emollient and antipruritic - burns - buttock
  erythema
• 4. toothache
• 5. gastrointestinal system - colitis - diarrhoea
• 6. painful menstruations
• 7. gallbladder ailments
• 8. colds - influenza

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9. List of indications for minor pathologies

• 9. appetite - weightgain - asthenia - weight
  reducer
• 10. headache
• 11. sleep disorders and neurotonic states
• 12. eye irritation
• 13. cough - bronchitis - cold
• 14. minor articular pains
• 15. mouth-wash
• 16. renal system adjuvant in urinary
  infections - prostate

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10. List of authorized drugs in combination

• Examples
• cardiac erethism / neurosedative
• spasmodic colitis / diarrhoea
• renal elimination / diet
• aperitive / asthenia
• cough / bronchitis
• antalgy / articular ache
• renal elimination / urinary infection

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11. Information for the consumer and the new
Directive

• Packaging package insert dosage form
• Labelling with the mention this drug is
  traditionally used in
• Directive of the European Parliament and of the
  Council modifing the directive 2001/83/CE
  concerning traditional medicines from plants
•  traditional medical uses 
•  well established therapeutical uses 

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III.Situation of herbal food supplements
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1. Food supplements and modern life

• increasing market and public demand
• particular life styles wellness comfort
  pleasure
• taking charge of health prevention
• more scientific understanding on health benefits
  of natural products impact

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2. Present major problems

• lack of precise regulation and particularly
  health claims
• free accessibility to diverse commercial products
  in Europe
• diversity of terminology 
  supplement
  functional food nutraceutical health care
  product ...
• absence of guidelines 
• danger  misleading and safety of use
• No preliminary marketing authorization

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3. Implication of official texts

• Décret n 79-480 (15/06/1979) free distribution
  of 34 plants
• Arrêté Royal Belge (21/11/1997) 
• manufacturing and distribution of foodstuff or
  preparations derived from plants 
• a list of more than 200 species 
• Viscum album, Vinca minor, Ruscus aculeatus, ...
• Directive 258/97/CE 
• novel foods only nutritional aspects for exotic
  food usually not consumed in the EC

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3. Implication of official texts

• Directive 2002/46/EC of EP and of the Council
  (10/05/2002) 
• Definition of food supplements 
•  concentrated sources of nutrients and other
  substances with nutritional or physiological
  effects, alone or in combination
•   dose forms  capsules, pastilles, tablets,
  pills, sachet of powder, ampoules, drops ... 

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4. Necessity of an up-to-date safety assessment
for increasing security recent examples

• Teucrium chamaedrys (Lamiaceae)
• neo-clerodane lipophilic diterpenes
• acute cytolytic hepatitis

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4. Necessity of an up-to-date safety assessment
for increasing security recent examples

• Plants with pyrrolizidinic alkaloids (Asteraceae)
• Unsaturated and
  alkylated necine
  compounds
• Hepatotoxicity veino-occlusive disease

Senecio
Borago
Tussilago
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4. Necessity of an up-to-date safety assessment
for increasing security recent examples

• Chinese plants
• Substitution of two plants
• Nephrotoxicity

Stephania tetrandra
Aristolochia fangchi
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4. Necessity of an up-to-date safety assessment
for increasing security recent examples

• Partial substitution of Chinese star anise
  (Illicium verum) by Illicium religiosum
• - small content of anethole
• - toxic sesquiterpene lactones (anisatine,
  neoanisatine)
• follicle with asymmetrical mericarps and
  terminal hooks
• convulsions
  (Netherlands, France)
• decision of AFSSAPS (26.11.2001) stoppage of
  marketing authorization

Illicium verum (Illicaceae)
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4. Necessity of an up-to-date safety assessment
for increasing security recent examples

• Kava root
• Traditional drink from South Pacific
• Anxiolytic kavapyrones
• Hepatotoxicity

Piper methysticum (Piperaceae)
Decision of AFSSAPS (08.01.2002) use forbidden
for one year
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5. Physiological interactions between botanicals
and drugs

• St Johns Wort
• Antidepressive plant
• Molecular interactions with diverse drugs
  (ciclosporine, theophylline, digoxine,
  anticonceptionals, anti-AIDS drugs)

Hypericum perforatum (Hypericaceae)
French opinion as exclusive drug AFSSAPS
(27.01.2001)
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5. Physiological interactions between botanicals
and drugs

• Ginkgo extract
• PAF inhibition by ginkgolides
• risk with anticoagulants

Ginkgo biloba (Ginkgoaceae)
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IV. Search for a compromise some aspects of
the reflexion of AFSSA
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Concept on a strategy a proposition of
decision tree

• Differentiation based on the interest of
  physiological applications and pathological aims
• Elimination of plants with potential toxicity
• secondary effects
• Interactions with drugs
• risk associated with the use of galenic forms
• present pharmacovigilance data
• Traditional uses over 30 years confirmed with
  pharmacological properties of isolated chemical
  constituents
• High level of quality of the raw material and the
  finished product

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2. Procedure for evaluating the safety of the
plant, its components and the finished product

• In terms of the plant
• identification,
• nature of the organ
• origin
• harvest period
• industrial processes
• contaminants of external origin
• In terms of the extraction method
• nature of the solvent
• extraction parameters
• new extraction methods (supercritical CO2)
• traditional tinctures

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2. Procedure for evaluating the safety of the
plant, its components and the finished product

• Exposure and conditions for consumption or use
• unexpected side effects (allergic reactions)
• consumer survey and intake simulation
• Constitution of data reference of available
  knowledge
• in vitro and in vivo pharmacotoxicological and
  clinical studies
• pharmacovigilance
• methods for establishing a dose without unwanted
  side effects
• Importance of the difference between traditional
  conditions of use of the plant and conditions of
  use for the finished product
• the greater the difference between the finished
  product and traditional dietary use, the greater
  attention should be paid to the collection of
  data demonstrating the absence of risk and the
  physiological value

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3. A guide for the constitution of an industrial
dossier

• Quality control of the finished product
• part I administrative information and summary
• part II scientific and technical documentation
• part III specifications and controlimportant
  stages and quality standards required
• plant material and agricultural processes
• raw material
• industrial processes
• intermediate products
• finished product
• Post-marketing monitoring and reevaluation

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4. Evaluation of the physiological effect

• Physiological effect on generally normal
  functions of the body without pathological impact
  ? separation of the physiological and
  pathological states
• Distinction between prevention (drug) and
  reduction of a major risk factor (food
  supplements)
• Problem of the ingested dose
• Demonstrating the effect 3 situations
• totums and traditional extractsknowledge
  established from traditional data linked with
  experimental data on the totum and/or on isolated
  constituents
• chemically defined isolated moleculesdemonstratio
  n of the beneficial effects
• other extracts with various degrees of
  selectivity higher level of rigour if the use
  is different from its traditional uses

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5. Claim evaluation and indications considered
as physiological tools

• Definition of a special level of claim, based on
  European tradition and experimental data
  (pharmacological, physiological, clinical and
  epidemiological if they exist) for totum and
  traditional extracts over a minimum 30-years
  period
• Indications considered as physiological
• cardiac erethism in adults (healthy heart)
• cutaneous capillary fragility
• pain associated with digestive problems
• choleretic and cholagogue and problems of hepatic
  origins
• appetite stimulant and functional asthenia
• weight loss and weight gain
• neurotonic state and minor sleep problems
• elimination of water from the kidneys
• treatment of constipation (except from anthracene
  plants)

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6. Therapeutical indications for pathological aims

• veinous insufficiency (haemorrhoids )
• treatment of mild diarrhoea
• painful periods and joint pain
• analgesic (cephalagia, dental pain)
• fevers and influenza
• acute benign bronchial infections and coughing
• micturition problems of prostate origin
• mild, temporary depression
• occasional constipation (stimulant laxative)

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7. Examples of claims at the interface to be
discussed

• Menopause state
• Transport sickness
• Immunostimulation
• .

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8. Clear labelling presentation and advertising

• Transparency for the consumer to avoid
  misunderstanding
• Names of plants and composition of the
  preparation
• Portion recommended for daily consumption
• Warning not to exceed the stated recommended
  daily dose
• Storage out of the reach of young children
• Compulsory statement on the labelling and any
  publicity the effect is traditionally
  recognised and the effectiveness has not been
  clinically demonstrated

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9. Present problems to solve

• Differentiating between prevention
  (pharmaceuticals) and reduction of risks (dietary
  supplements)
• Elaborating positive and negative lists of plants
• Determining dosage in relation with efficacy
• Accepting some selective or concentrated extracts
  essential oils, supercritical extracts
• Admitting some plant associations

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CONCLUSION
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• Framework for the evaluation of the safety, the
  effect and the claim of foodstuff, made from
  plants, for the human diet AFSSA, February 2003
• An example of strategy also discussed now at the
  Council of Europe committee of experts on
  nutrition food safety and consumer health
• A necessity to establish clear rules for the
  manufacturer, the official authorities and in
  order to assume a safe consumption
• Dosis makes the poison (Paracelsius)