Abstract
The toxicity of plants containing certain pyrrolizidine alkaloids has long been recognized in grazing animals and humans. Genotoxicity and carcinogenicity data from
in vitro
and
in vivo
...(animal) studies were published over the last few decades for some of the 1,2-unsaturated pyrrolizidine alkaloids, leading to regulatory action on herbal medicinal products with pyrrolizidine alkaloid-containing plants more than 30 years ago. In recent years, it has become evident that in addition to herbal medicinal products containing pyrrolizidine alkaloid-containing plants, these products may also contain pyrrolizidine alkaloids without actually including pyrrolizidine alkaloid-containing plants. This is explained by contamination by accessory herbs (weeds). The national competent authorities of the European member states and the European Medicines Agency, in this case, the Committee on Herbal Medicinal Products, reacted to these findings by setting limits for all herbal
medicinal products. This review article will briefly discuss the data leading to the establishment of thresholds and the regulatory developments and consequences, as well as the current discussions and research in this area.
In the Member States of the European Union (EU), a harmonized legislation on medicinal products has been enforced, which specifically defines herbal medicinal products and traditional herbal ...medicinal products. The scope was to create a regulatory environment that takes into account the particular characteristics of herbal medicinal products. The harmonization of standards is intended to harmonize assessment and facilitate access to the market in different Member States. The standards defined by the EU herbal monographs of the Committee on Herbal Medicinal Products (HMPC) and the quality requirements laid down in the European Pharmacopoeia represent an excellent model of multinational harmonization of the regulatory environment for herbal and traditional medicines. It has also been demonstrated that this framework is at least partially applicable for herbal and traditional medicines from traditional Chinese medicine (TCM) to gain access to the EU market. Moreover, the HMPC provides specific guidance documents and pilot projects on monographs on the safety and efficacy of Chinese herbal drugs. In the European Pharmacopoeia, the number of quality monographs of herbal drugs with an origin in TCM is continuously growing. These developments indicate that globalization of traditional medicines is an ongoing process. Communication and cooperation between regulators, the scientific community, and interested stakeholders will set the stage for the convergence of diverse regulatory environments. This will contribute to worldwide availability of traditional medicines based on appropriate standards.
Erste Publikationen zum Vorkommen von PA-Kontaminationen in Kräutertees erfolgten im Jahr 2013. Kurze Zeit später folgten dann auch Berichte über eine Kontamination von pflanzlichen Arzneimitteln mit ...PA. Daraufhin forderten verschiedene nationale Zulassungsbehörden und der Ausschuss für pflanzliche Arzneimittel der Europäischen Arzneimittelagentur die Zulassungsinhaber von pflanzlichen Arzneimitteln in Europa dazu auf, Risikobewertungen und Maßnahmen zur Risikominimierung in Bezug auf Pyrrolizidinalkaloide durchzuführen. Sowohl nationale Behörden als auch der HMPC führten Grenzwerte für PA als Kontaminanten ein. Zusätzlich hatte der HMPC sich dafür eingesetzt, dass das Europäische Arzneibuch eine geeignete PA-Bestimmungsmethode im Bereich der Spurenanalytik entwickelt. Diese liegt im Moment als Entwurf zur öffentlichen Kommentierung vor.
Each application for authorisation of a medicinal product must be accompanied by the particulars and documents referred to in Directive 2001/83/EC on the Community code relating to medicinal products ...for human use. Details on the documentation needed for traditional herbal medicinal products (THMP) are given in article 16c of the above mentioned Directive. It is pointed out that a bibliographic review of safety data together with an expert report and additional data, if necessary, are required.
The Committee on Herbal Medicinal Products (HMPC) provides in its “Guideline on the use of the CTD format in the preparation of a registration application for traditional herbal medicinal products” (EMA/HMPC/71049/2007 Rev. 1) guidance on how to present the information and the dossier needed for an application. There, in agreement with the Directive 2001/83/EC, a bibliographical review of safety data is required within the “Non-clinical Overview”. However, it is assumable that for such products, with a long tradition of usage bibliographical information relating to non-clinical safety are available, even if incomplete or not in accordance with today׳s state of the art. In the “Guideline on non-clinical documentation for herbal medicinal products in applications for marketing authorisation (bibliographical and mixed applications) and in applications for simplified registration” (EMEA/HMPC/32116/2005) it is reflected how to deal with such an incomplete set of data for traditional herbal medicinal products and crucial information are highlighted.
This article will focus on the explanation of the requirements needed for the non-clinical safety evaluation of THMPs and some detailed explanations of the performance and interpretation of the mutagenicity studies.
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•Information concerning knowledge about usage of (traditional) herbal medicinal products in pregnancy was reviewed.•The outcome mirrors the different basic perspectives of the involved bodies and ...might lead to contradictory recommendations for patients or health care professionals.•A discussion should be started how to use available knowledge (even if of different quality) and experience to adjust regulatory decisions on a case-by-case basis, if possible.
This review aims to highlight recent approaches concerning usage of (traditional) herbal medicinal products in pregnancy and to discuss appropriate strategies to handle limited information. Therefore, published monographs of the Committee on Herbal Medicinal products (HMPC) and selected publicly funded webpages, medicinal handbooks, publications and industry and health care organisations webpages were evaluated.
While within the monographs of the HMPC a rather conservative approach could be found (mainly because of lacking nonclinical and/or clinical studies), all other sources display a wide variety of information or assessments, thereby often giving contradictory recommendations.
However, some experience with the usage of herbal substances/preparations exists in daily clinical practise without clinical trials or observational studies and some herbal substances/preparations are also used as food/food supplements/cosmetics/medical devices. Discussions should be started how to use that knowledge and experience to adjust regulatory decisions on a case-by-case basis, if possible.
► Thujone (e.g. in absinthe) has a long-term reputation as a neurotoxicant. ► α-Thujone is rapidly acting modulator of the GABAA-receptor. ► Thujone occurs widely in essential oils of medicinal and ...botanical plants. ► Analytical techniques are available to detect α- and β-thujone in various matrices. ► Regulatory status needs re-assessment based on focussed investigations.
Thujone, a major component of the notoriously famous absinthe drink, is neurotoxic, although the current view rather downgrades its risk to humans. In animal studies, thujone inhibits the gamma-aminobutyric acid A (GABAA) receptor causing excitation and convulsions in a dose-dependent manner, although there are uncertainties about the doses required in humans. Toxicity of thujone has been extensively studied. Neurotoxicity is the principal toxic outcome in acute and chronic studies. There is some equivocal evidence of carcinogenicity in rats. Metabolism of thujone has been elucidated both in vitro and in vivo in several species and in vitro in human liver preparations. CYP2A6 is the principal metabolic enzyme, followed by CYP3A4 and, to a lesser extent, CYP2B6. CYP-associated metabolism may give rise to some potential pharmacogenetic and metabolic interaction consequences. Although the data base for determining exposure limits is of variable usefulness, the best estimates for allowable daily intakes via herbal preparations and diet are of the order of 3–7mg/day. There are still important gaps in the knowledge required to assess thujone toxicity, the most important ones being human dose-concentration-effect relationships including the elucidation of bioavailability, and the actual toxicological consequences of potential pharmacogenetic variations and environmental factors.
Medicinal plants and traditional medicines have been used worldwide since ancient times. Currently, there is neither a globally consented terminology nor a harmonized regulatory approach. ...Nevertheless, it is common sense that quality, efficacy and safety should be assessed following scientific standards, addressing particulars and considering an adequate level of risk management. A global market for traditional medicines is emerging, if not already existing. Therefore, a constructive communication about regulatory systems for herbal and traditional medicinal products should be enforced. Best practice standards might be developed according to current scientific knowledge in order to improve mutual acceptance of data, sets of monographs and assessments. Overall, a convergence of the diverse regulatory systems might save resources and lead to an adequate availability of herbal and traditional medicinal products to the patients without neglecting public health.
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Abstract
This paper reports on the major contributions and results of the 2nd International Workshop of Pyrrolizidine Alkaloids held in September 2020 in Kaiserslautern, Germany. Pyrrolizidine ...alkaloids are among the most relevant plant toxins contaminating food, feed, and medicinal products of plant origin. Hundreds of PA congeners with widespread occurrence are known, and thousands of plants are assumed to contain PAs. Due to certain PAsʼ pronounced liver toxicity and carcinogenicity, their occurrence in food, feed, and phytomedicines has raised serious human health concerns. This is particularly true for herbal teas, certain food supplements, honey, and certain phytomedicinal drugs. Due to the limited availability of animal data, broader use of
in vitro
data appears warranted to improve the risk assessment of a large number of relevant, 1,2-unsaturated PAs. This is true, for example, for the derivation of both toxicokinetic and toxicodynamic data. These efforts aim to
understand better the modes of action, uptake, metabolism, elimination, toxicity, and genotoxicity of PAs to enable a detailed dose-response analysis and ultimately quantify differing toxic potencies between relevant PAs. Accordingly, risk-limiting measures comprising production, marketing, and regulation of food, feed, and medicinal products are discussed.
An assessment of genotoxicity is a precondition for marketing authorization respectively registration of herbal medicinal products (HMPs), as well as for inclusion into the ‘Community list of herbal ...substances, preparations and combinations thereof for use in traditional herbal medicinal products’ established by the European Commission in accordance with Directive 2001/83/EC as amended, and based on proposals from the Committee on Herbal Medicinal Products (HMPC).
In the ‘Guideline on the assessment of genotoxicity of herbal substances/preparations’ (EMEA/HMPC/107079/2007) HMPC has described a stepwise approach for genotoxicity testing, according to which the Ames test is a sufficient base for the assessment of genotoxicity in case of an unequivocally negative result. For reducing efforts for testing of individual herbal substances/preparations, HMPC has also developed the ‘guideline on selection of test materials for genotoxicity testing for traditional herbal medicinal products/herbal medicinal products’ (EMEA/HMPC/67644/2009) with the aim to allow testing of a standard range of test materials which could be considered representative of the commonly used preparations from a specific herbal drug according to a ‘bracketing/matrixing’ approach.
The purpose of this paper is to provide data on the practical application of this bracketing and matrixing concept using the example of Valerianae radix, with the intention of facilitating its inclusion in the “Community list”. Five extraction solvents, representing the extremes of the polarity range and including also mid-range extraction solvents, were used, covering the entire spectrum of phytochemical constituents of Valerianae radix, thereby including polar and non-polar constituents. Extracts were tested in the Ames test according to all relevant guidelines. Results were unequivocally negative for all extracts. A review of the literature showed that this result is in accordance with the available data, thus demonstrating the lack of a genotoxic potential.
In conclusion the two guidelines on genotoxicity provide a practically applicable concept. Valerianae radix has no genotoxic potential, supporting its use in HMPs and its inclusion in the Community list.
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