Toxicological Assessment of Herbal and Traditional Herbal Medicinal Products: New DevelopmentsOlaf KelberHead, Medical Science and Clinical ResearchSteigerwald Arzneimittelwerk GmbH, Darmstadt, Germany
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Overview / Content
New Developments, Literature Overview From ICH to Tradition: New European Regulations in Toxicology The European Herbal Medicines Directive Could it have saved the lives of Romeo and Juliet?(Routlege PA, Drug safety : an international journal of medical toxicology and drug experience; VOL: 31 (5); p. 416-8 /2008)
The New HMPC Genotoxicity Guideline Which studies to conduct?
News from Herbal GenotoxicityThe Example of the Collaborative Genotoxicity Study Project of the Kooperation Phytopharmaka – a surprising success
Perspectives
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New developments - Literature Overview
New developments - view of the scientific literature
Search in DIMDI(All toxicological databases)
Query: herb? toxic? medic?from 2008-2009
Total No. 483 hits
Manual Check for relatedness 90 hits
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New developments - Literature Overview
Search in DIMDI, results:
Low number of papers, no dynamic field of research
Detallied view necessary
Theme Toxicology, general
Hepato-toxicity
Other ARs Heavy Metal toxicity
Sum
Number 36 28 19 7 90
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New developments - Literature Overview
Search in DIMDI, results:
Toxicology, general
- Preclinical and clinical toxicological studies - Includes reviews (e.g. on ginger), in vitro studies - Mainly Indian Medicine, TCM - Also products for veterinary use (dogs, chickens)
Theme Toxicology, general
Hepato-toxicity
Other ARs Heavy Metal toxicity
Sum
Number 36 28 19 7 90
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New developments - Literature Overview
Search in DIMDI, results:
Hepatotoxicity
- Mainly reviews, only few case reports or studies - Incl. TCM, Indian Medicine, Nutraceuticals, Slimming Aids, Contaminated products (e.g. by Bacteria), Insufficiently defined products and reactions
Theme Toxicology, general
Hepato-toxicity
Other ARs Heavy Metal toxicity
Sum
Number 36 28 19 7 90
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New developments - Literature Overview
Search in DIMDI, results:
Other Adverse Reactions
- Incl. reviews covering also chemically defined preparations
- Preparations from TCM, Korea, Singapore, Ayurveda - Incl. Nutraceuticals (e.g. caffeine intoxication), Kava, Aristolochic acid, Black cohosh, Pyrroizidine alkaloids
Theme Toxicology, general
Hepato-toxicity
Other ARs Heavy Metal toxicity
Sum
Number 36 28 19 7 90
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New developments - Literature Overview
Search in DIMDI, results:
Heavy Metal Toxicity
- Mainly reviews of contaminations - Preparations from India and the US
Theme Toxicology, general
Hepato-toxicity
Othter ARs Heavy Metal toxicity
Sum
Number 36 28 19 7 90
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New developments - Literature Overview
Search in DIMDI, results:
Summary
- Mainly reviews
- Mainly Non-European preparations
- No new trends or surprises
Theme Toxicology, general
Hepato-toxicity
Other ARs Heavy Metal toxicity
Sum
Number 36 28 19 7 90
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EU Commission Overview of risk assessment methodologies, Opinion paper published January 2009
New developments - Europe
Critical assessment of methods
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New developments - Europe
Also thematizes limitations of methods
EU Commission Overview of risk assessment methodologies, Opinion paper published January 2009
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From ICH to Tradition
The ICH Toxicity Guidelines
Framework for the study of NCEs Created for the development of NCEs Substances with unknown risk profile Toxicological studies precede the studies
“first in man” resp. the market launch
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From ICH to Tradition
ICH Guidelines
Safety Guidelines
S1 Carcinogenicity
S2 Genotoxicity
S3 Toxico-/Pharmacokinetics
S5 Reproductive Toxicity
S7 Pharmacology
S8 Immunotoxicology
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From ICH to Tradition
ICH Guideline M 3:
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From ICH to Tradition
Example for a toxicological assessment plan for a WEU preparation: High use of resources and time (e.g. 7 years),
no adequate improvement of benefit-risk ratio
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From ICH to Tradition
THMPs and WEU HMPs
Long-standing experience of use in the popu-lation
Often clinical studies, covering clinical endpoints (including acute and chronic tolerability in man)
Substances with (more or less) well known pharmacological and toxicological profile
Toxicological studies follow the use “first in man” resp. the market launch.
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The EU Herbal Medicines Directive
Aim: Enable free trade within the EU
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The EU Herbal Medicines Directive
Aim: Protection of public health
CONFERENCE PAPER Drug Safety 2008:31(5):416-418
The European HerbalMedicines Directive Could it Have Saved the Lives of Romeo and Juliet?
Philip A. Routledge
Department of Pharmacology, Therapeutics and Toxicology, Wales College of Medicine, Heath Park, Cardiff, UK .
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The EU Herbal Medicines Directive
Aim: Protection of public health
Conclusion: No, as in this case, not lack in toxicological data, but lack in communication was causative for death.
CONFERENCE PAPER Drug Safety 2008:31(5):416-418
The European HerbalMedicines Directive Could it Have Saved the Lives of Romeo and Juliet?
Philip A. Routledge
Department of Pharmacology, Therapeutics and Toxicology, Wales College of Medicine, Heath Park, Cardiff, UK .
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The EU Herbal Medicines Directive
Report on the experience acquired (from 29.9.2008)
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The EU Herbal Medicines Directive
Report on the experience acquired (from 29.9.2008)
Genotoxicity data on a case-by case basis
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The HMPC Genotoxicity Guideline
In effect 01.12.2008
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The HMPC Genotoxicity Guideline
Scope:“For many herbal substances/preparations, contained in well established or traditional herbal medicinal products (HMPs), an adequate safety profile may be confirmed by their documented history of medicinal use. However, the complete lack of some specific non-clinical studies (e.g. genotoxicity studies) may present a safety concern because important questions relating to product safety would remain unanswered.”
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The HMPC Genotoxicity Guideline
“Pragmatic framework on how to assess the potential genotoxicity of HMPs”,
Stepwise test strategy:
1. Ames test
2. In case of positive results: mammalian cell assay
3. In case of another positive result: in vivo genotoxicity tests.
Negative results progressing to the nexttest step is not required.
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The HMPC Genotoxicity Guideline
Step 1: The Ames Test
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The HMPC Genotoxicity Guideline
Step 2: The Mouse Lymphoma Assay
Assay in L5178Y mouse lymphoma cells
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The HMPC Genotoxicity Guideline
Step 3: The In Vivo Test
Mouse lymphoma assay in bone marrow or peripheral blood cells
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The HMPC Genotoxicity Guideline
Summary
• Pragmatic approach
• Tests not contributing to a risk reduction in the patient are minimized
• In case of lack of specific concern still without relevant benefit for the patient
• Still a considerable burden in case of herbs of low economic importance
Importance of a collaborative approach
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The HMPC Concept Paper on Genotoxicity Testing
Bracketing andMatrixing as approach to collaborativeresearch
Testing of extremes of extraction solvent polarity for covering the whole range of preparations
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Genotoxicity Testing: Collaborative Approach
Example:
Genotox Project initiated by
Kooperation PhytopharmakaBonn, Germany
Scientific Society active in the field of herbal medicines
www.koop-phyto.org
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Genotoxicity Testing: Collaborative Approach
Aim of the project:- To provide pharmaceutical companies with
state of the art genotoxicity data for registration of Herbal and Traditional Herbal Medicinal Products
- To provide an economic way of conducting trials, using the advantages of a bracketing and matrixing concept in a collaborative approach
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Genotoxicity Testing of Koop. Phyto.
Bracketing and matrixing concept:Example: Hops (Humuli lupuli strobuli)
Extracts tested:polar Water
Methanol 45 %Ethanol 90 %
unpolar HeptaneThese solvents cover the whole range of polarity. Extrapolation to the whole range of extracts Extrapolaton also to drug powder preparations
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Genotoxicity Tests of Koop. Phyto.
- Coordinated collaborative approach
- Conduction in cooperation with GLP certified toxicological laboratories
- Methods according to all current guidelines (including OECD, ICH, EMEA)
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Genotoxicity Tests of Koop. Phyto.
Step 1: Ames test- Bacterial reverse mutation test, developed by
Bruce Ames, Univ. of California, Berkeley, 1970ff.- Salmonella typhimurium strains with defects in
gene(s) involved in histidine synthesis Growth depends on external histidine
- Mutations lead to accidental repair of defect gene Histidine independent growth
- Mammalian hepatic metabolism is mimicked with S9 Mix (enzyme fraction from rat liver)
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Genotoxicity Tests of Koop. Phyto.
Ames testOECD Guideline 471: Conduction in 5 different strainsdiffering in susceptibility to different mutagens
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Genotoxicity Tests of Koop. Phyto.
Ames testFigure: Counting of colonies using the Petri Viewer Mk2 (Perceptive Instruments) and the software program Ames Study Manager
Control: Negative Positive
TA 100
TA 1535
E. coli
Photographs: A
. Sokolow
ski,H
arlan R
CC
, Ro
ßd
orf, G
erman
y
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Genotoxicity Tests of Koop. Phyto.
Step 1: Ames test- For several herbal preparations, positive results
in Ames tests could not be reproduced in mammalian cell assays or in vivo assays
- These false positive results have been attributed mainly to the quercetin content of these herbal preparations
- Therefore the usefulness of the Ames test for testing herbal preparations has been questioned.
(Okpanyi S.N. et al., Arzneim.-Forsch./Drug. Res. 1990, 40 (II)): 851-855)
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Genotoxicity Tests of Koop. Phyto.
Herbal drugs tested:- Artichoke- Bittersweet- Stinging nettle- Marshmallow- Gingko- Ginseng- Hops- St. John´s wort- Garlic- Caraway- Pumpkin oil- Pine oil
- Milk thistle- Melissa- Mistle- Passiflora- Primrose- Rosmary- Horse Chestnut- Liquorice- Thyme- Whitethorn leaves and flowers- Whitethorn fruits- Devils claw
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Genotoxicity Tests of Koop. Phyto.
Results, example:
Negative results for a St. John´s wort extract.
Validated by inde-pendent testing in a second laboratory.
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Genotoxicity Tests of Koop. Phyto.
Conclusions:The project has broadened the knowledge about the safety of important herbs used in Europe and allows to meet current regulatory requirements.
The project unexpectedly has also shown that the safety profile of some herbs, previously under discussion, has to be re-rated as safe when tested by modern validated methods.
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Perspectives
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Perspectives
Harmonization with the US?Wu et al., Food Chem Toxicol 2008, 46:2606-2610
2008: FDA authorizes its first HMP (Veregen®)
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Perspectives
Harmonization with the US?Wu et al., Food Chem Toxicol 2008, 46:2606-2610
Demands of FDA in large parts identical with ICH guidelines for NCEs
From an European perspective, adequate acceptance of traditional or well established use is questionable
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Perspectives
New developments in the assessment of toxicological data and case reports?• Dose as a key issue• Critical consideration of pharmaceutical quality• Priority for clinical data and in vivo toxicological data, use of in vitro data only where adequate• Approach of transparent pragmatism, respecting traditional and well established use also in sub- groups of patients (e.g. children), and by physicians
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Thank you for your attention!
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