Do We Need Plant Food Supplements? A Critical Examination of Quality, Safety, Efficacy, and Necessity for a New Regulatory Framework.

Given the expanding market of plant food supplements (PFSs) not undergoing any pre-marketing authorization, the overall quality, safety and efficacy of PFSs were subjected to a critical examination. Although many high-quality PFSs exist on the legal market, quality concerns are in general justified. Besides economic adulteration, active ingredients dramatically differing from label claims and among products were reported in several studies. In addition, PFSs sold via the Internet may be intentionally adulterated with undeclared prescription drugs. Compared to PFSs with only one single herb, PFSs containing herbal mixtures were more involved in moderate and severe clinical courses. Although prohibited by regulation, misleading labels on PFSs are common. Above all, only vague evidence for the efficacy of PFSs exists. Notwithstanding the unproven efficacy and insufficient safety assessment, PFSs represent a relevant source for consumers to get access to herbal preparations in the United States and meanwhile also in Europe, as launching of licensed/registered European herbal medicinal products (HMPs) has steadily decreased. However, being non-vitamin, non-mineral products, PFSs are neither food nor drugs. In terms of protecting public health and providing the consumer with high-quality, effective, and safe PFSs, possibilities are shown how to deal with the many challenges of PFSs. Last but not least, suggestions are made for assigning PFSs a separate regulatory category being less regulated compared to HMPs but more strictly regulated compared to food laws including implementation of good manufacturing practices and a scientific pre-marketing review process by an expert commission.

Benefits and Limitations of DNA Barcoding and Metabarcoding in Herbal Product Authentication.

INTRODUCTION: Herbal medicines play an important role globally in the health care sector and in industrialised countries they are often considered as an alternative to mono-substance medicines. Current quality and authentication assessment methods rely mainly on morphology and analytical phytochemistry-based methods detailed in pharmacopoeias. Herbal products however are often highly processed with numerous ingredients, and even if these analytical methods are accurate for quality control of specific lead or marker compounds, they are of limited suitability for the authentication of biological ingredients. OBJECTIVE: To review the benefits and limitations of DNA barcoding and metabarcoding in complementing current herbal product authentication. METHOD: Recent literature relating to DNA based authentication of medicinal plants, herbal medicines and products are summarised to provide a basic understanding of how DNA barcoding and metabarcoding can be applied to this field. RESULTS: Different methods of quality control and authentication have varying resolution and usefulness along the value chain of these products. DNA barcoding can be used for authenticating products based on single herbal ingredients and DNA metabarcoding for assessment of species diversity in processed products, and both methods should be used in combination with appropriate hyphenated chemical methods for quality control. CONCLUSIONS: DNA barcoding and metabarcoding have potential in the context of quality control of both well and poorly regulated supply systems. Standardisation of protocols for DNA barcoding and DNA sequence-based identification are necessary before DNA-based biological methods can be implemented as routine analytical approaches and approved by the competent authorities for use in regulated procedures. © 2017 The Authors. Phytochemical Analysis Published by John Wiley & Sons Ltd.

What risks do herbal products pose to the Australian community?

Traditional herbal products are widely used in Australia to treat a broad range of conditions and diseases. It is popularly believed that these products are safer than prescribed drugs. While many may be safe, it is worrying that the specific effects and harmful interactions of a number of their components with prescription medications is not well understood. Some traditional herbal preparations contain heavy metals and toxic chemicals, as well as naturally occurring organic toxins. The effects of these substances can be dire, including acute hepatic and renal failure, exacerbation of pre-existing conditions and diseases, and even death. The content and quality of herbal preparations are not tightly controlled, with some ingredients either not listed or their concentrations recorded inaccurately on websites or labels. Herbal products may also include illegal ingredients, such as ephedra, Asarum europaeum (European wild ginger) and endangered animal species (eg, snow leopard). An additional problem is augmentation with prescription medications to enhance the apparent effectiveness of a preparation. Toxic substances may also be deliberately or inadvertently added: less expensive, more harmful plants may be substituted for more expensive ingredients, and processing may not be adequate. The lack of regulation and monitoring of traditional herbal preparations in Australia and other Western countries means that their contribution to illness and death is unknown. We need to raise awareness of these problems with health care practitioners and with the general public.

[Analysis of difficult problems on European Union laws and regulations of traditional herbal medicinal products].

Registration of Chinese patent medicine in European Union (EU) is of great significance to the internationalization of traditional Chinese medicine as EU market acts as an important position in the global botanical market. In retrospect, the domestic studies on EU regulations of traditional herbal medicinal products have been conducted for more than 10 years, but there is still some cognitive bias and lack of research. In this paper, a review of the relevant research progress and the main misunderstanding problems about Directive 2004/24/EC, like the centralized and decentralized supervision system of traditional herbal medicinal products in the EU, marketing authorization procedures for traditional herbal medicinal products, Community Herbal Monograph and List Entries, would be systematically analyzed, so as to provide reference for the registration of Chinese patent medicine in EU.

[European Union regulatory and quality requirements for botanical drugs and their implications for Chinese herbal medicinal products development].

This paper introduces regulatory pathways and characteristic quality requirements for marketing authorization of herbal medicinal products in the European Union（EU）, and the legal status and applications of "European Union list of herbal substances, preparations and combinations" and "European Union herbal monographs". Also introduced are Chinese herbs that have been granted the EU list entry, those with EU herbal monographs, and registered EU traditional herbal medicinal products with Chinese herbs as active ingredients. Special attention is paid to the technical details of three authorized EU herbal medicinal products (Veregen, Sativex and Episalvan) in comparison with Andrographis paniculata extract HMPL-004 that failed the phase Ⅲ clinical trial for ulcerative colitis. The paper further emphasizes the importance of enriching active fractions of herbal extracts and taking regulatory and quality considerations into account in early stage of botanical drug development.

Innovation in Phytotherapy: Is a New Regulation the Feasible Perspective in Europe?

Classical multicomponent preparations mostly derived from traditional usages in Western and Eastern phytotherapy have been under-evaluated for a long time as potential new pharmaceutical products. The regulatory scenario, in particular at the European level, has only recently considered these aspects proposing harmonized guidelines for the pharmaceutical registration of traditional herbal products. Nevertheless, a specific regulation for innovative products based on the combination of precious knowledge arising from traditional usages and modern scientific advancements is still missing. In this paper, we propose a critical review of the current situation with the specific aim of contributing to create a more favorable regulatory environment for the pharmaceutical registration of new and innovative herbal medicinal products.

Herbal Medicine in Mexico: A Cause of Hepatotoxicity. A Critical Review.

In Mexico, herbal products are commonly used as therapeutic tools. The analysis of several publications reveals that there are dozens of different herbs and herbal products used for different reasons, some of which have been implicated in causing toxic liver disease. However, methodological aspects limit the attribution of causality, and the precise incidence and clinical manifestations of herb-induced liver injury have not been well characterized. This review outlines the history of traditional herbal medicine in Mexico, critically summarizes the mechanisms and adverse effects of commonly used herbal plants, and examines the regulatory issues regarding the legal use of these products.

Assessing herbal products with health claims.

Herbs, herbal extracts, or phytochemicals are broadly used as foods, drugs, and as traditional medicines. These are well regulated in Europe, with thorough controls on both safety and efficacy or validity of health claims. However, the distinction between medicines and foods with health claims is not always clear. In addition, there are several cases of herbal products that claim benefits that are not scientifically demonstrated. This review details the European Union (EU) legislative framework that regulates the approval and marketing of herbal products bearing health claims as well as the scientific evidence that is needed to support such claims. To illustrate the latter, we focus on phytoecdysteroid (PE)-containing preparations, generally sold to sportsmen and bodybuilders. We review the limited published scientific evidence that supports claims for these products in humans. In addition, we model the in silico binding between different PEs and human nuclear receptors and discuss the implications of these putative bindings in terms of the mechanism of action of this family of compounds. We call for additional research to validate the safety and health-promoting properties of PEs and other herbal compounds, for the benefit of all consumers.

Evolution of European Union legislation of herbal medicinal products and its transposition to national legislation in 1965-2007: case Finland.

OBJECTIVES: The study aim was to explore the progress of legislation relating to herbal medicinal products in the European Union and compare it with the corresponding progress of the legislation in Finland in 1965-2007. METHODS: The study was carried out using content analysis. Data were searched from publicly available European Union directives and national acts. All definitions and safety-related requirements for herbal medicinal products were identified. The transposition of safety-related requirements into the national legislation was studied. RESULTS: Medicinal products from plant origins have been part of the European Union legislation since 1965. Most plant-based products have not initially been regarded as medicinal products but rather as some kind of medicine-like products. The official definition of herbal medicinal products was introduced in Directive 2004/24/EC and implemented into the Finnish legislation with the terminology to recognise herbal medicinal products as part of medicinal products. The current safety-related requirements of medicinal products concern analogously herbal medicinal products. CONCLUSIONS: Herbal medicinal products have had different definitions in pharmaceutical legislation over the study period in the European Union and Finland. The current definition places herbal medicinal products more clearly under the medicinal products' legislation. Safety-related requirements are now practically identical for all medicinal products. Transposition of the European Union legislation into the national legislation in Finland is apparent.

[Research on distribution of patents' holders for Chinese herbal compounds in treating cardiovascular and cerebrovascular based on cluster analysis].

To discuss the distribution of patents' holders for Chinese herbal compounds in treating cardiovascular and cerebrovascular, the patents' holders for Chinese herbal compounds in treating cardiovascular and cerebrovascular were cluster analyzed by means of simple statistics and cluster analysis. Clustering variables were composed of patent applications, patent maintained number, related papers' quantity, etc. Chinese herbal compound patents' holders were divided into four categories according to their different scientific research and patent strength. It is the magic weapon for Chinese herbal compound patents' holders that have scientific research patents' transforming and make coordination of patent protection and scientific innovation.

[Establish research model of post-marketing clinical safety evaluation for Chinese patent medicine].

The safety of Chinese patent medicine has become a focus of social. It is necessary to carry out work on post-marketing clinical safety evaluation for Chinese patent medicine. However, there have no criterions to guide the related research, it is urgent to set up a model and method to guide the practice for related research. According to a series of clinical research, we put forward some views, which contained clear and definite the objective and content of clinical safety evaluation, the work flow should be determined, make a list of items for safety evaluation project, and put forward the three level classification of risk control. We set up a model of post-marketing clinical safety evaluation for Chinese patent medicine. Based this model, the list of items can be used for ranking medicine risks, and then take steps for different risks, aims to lower the app:ds:risksrisk level. At last, the medicine can be managed by five steps in sequence. The five steps are, collect risk signal, risk recognition, risk assessment, risk management, and aftereffect assessment. We hope to provide new ideas for the future research.

Association of blood lead and mercury with estimated GFR in herbalists after the ban of herbs containing aristolochic acids in Taiwan.

OBJECTIVE: This study was undertaken to explore the association of estimated glomerular filtration rate (GFR) with exposure to aristolochic acids (ALAs) and nephrotoxic metals in herbalists after the ban of herbs containing ALAs in Taiwan. METHODS: This cross-sectional study recruited a total of 138 herbalists without end-stage renal disease or urothelial carcinoma from the Occupational Union of Chinese Herbalists in Taiwan in 2007. Aristolochic acid I (ALA-I) was measured by ultra-high-pressure liquid chromatography/ tandem mass spectrometry (UHPLC-MS/MS) and heavy metals in blood samples were analysed by Agilent 7500C inductively coupled plasma-mass spectrometry. Renal function was assessed by using a simplified Modification of Diet in Renal Disease Study equation to estimate GFR. RESULTS: Blood lead was higher in herbal dispensing procedures (p=0.053) and in subjects who self-prescribe herbal medicine (p=0.057); mercury was also higher in subjects living in the workplace (p=0.03). Lower estimated GFR was significantly associated with lead (ß=-10.66, 95% CI -18.7 to -2.6) and mercury (ß=-12.52, 95% CI -24.3 to -0.8) with a significant interaction (p=0.01) between mercury and lead; however, estimated GFR was not significantly associated with high ALA-I level groups, arsenic and cadmium after adjusting for other confounding factors. CONCLUSIONS: We found that lower estimated GFR was associated with blood lead and mercury in herbalists after the ban of herbs containing ALAs in Taiwan. The ALA-I exposure did not show a significant negative association of estimated GFR, which might due to herbalists having known how to distinguish ALA herbs after the banning policy. Rigorous monitoring is still needed to protect herbalists and the general population who take herbs.

[Combining herbs with medication--risks vs. chances].

Traditional herbal medicine is driven by the use of plants or parts of plants, which have undergone minimal processing in order to treat disease and improve health. The article: "Traditional Immunosuppression--Lei Gong Teng in Modern Medicine", published in this issue of "Harefuah", raises the importance of integrating herbal medicine within the existing medical system. However, there are various limitations on integrating herbology in official frameworks, such as bureaucratic and legislative restrictions concerning the safety and efficacy of the herbs. This allows the marketing of many plants without a prescription requirement or professional advice. Another limitation relates to therapists, some of whom have not undergone proper training and may recommend the improper use of plants, resulting in a problematic combination with drugs in some cases. Regulation is necessary in order to better serve both the public and doctors. Regulation will define who is allowed to work with herbs and this will create a secure integration of herbs into the formal medical world.

[Traditional immunosuppression--Lei Gong Teng in modern medicine].

Although the origin of many common modern medicines that are routinely being used nowadays in healthcare is in medicinal plants and fungi, herbal medicine as a standalone profession is no longer included in the curricula of most Western medical schools. The medicinal plant Lei Gong Teng [also known as Thunder God Vine, Tripterygium Wilfordii Hook f., that is core to traditional Chinese herbal medicine, was praised for its possible anti-inflammatory properties in ancient traditional scripts that date back thousands of years. Yet, modern interest in its proven immune-modulatory properties serves as a vivid example to the bridge that is being built, gradually but constantly, between the tradition of healing arts and the world of modern therapeutics. In this review we summarize the main findings from an increasing number of clinical and laboratory studies published in top peer-reviewed medical journals that verify the traditional indications for which Lei Gong Teng was used medicinally. Based on these findings, and the risk-benefit profile of the plant's debarked root, we conclude that Lei Gong Teng and its active metabolites should be included in the Israeli herbal pharmacopeia.

The European role on traditional herbal medicinal products and traditional plant food supplements.

Herbs are used in Europe as medicinal products, food, food supplements, and related products. This paper will discuss the concepts of Traditional Herbal Medicines and Traditional Plant Food Supplements, defined in European legislation under differing legal frameworks, regarding Traditional Plant Food Supplements (including Claims Regulation) and the role of the European Food Safety Authority in health claims.

Regulation of medicinal plants for public health--European community monographs on herbal substances.

The European legislation on medicinal products also addresses the medicinal use of products originating from plants. The objective of the legislation is to ensure the future existence of such products and to consider particular characteristics when assessing quality, efficacy, and safety. Two categories are defined: i) herbal medicinal products can be granted a marketing authorisation; and ii) traditional herbal medicinal products can be granted a registration based on their longstanding use if they are complying with a set of provisions ensuring their safe use. The Committee on Herbal Medicinal Products (HMPC) was established at the European Medicines Agency (EMA) to provide monographs and list entries on herbal substances and preparations thereof. Meanwhile, approx. 100 monographs have been published, which define a current scientific and regulatory standard for efficacy and safety of herbal substances and herbal preparations used in medicinal products. This harmonised European standard will facilitate the availability and adequate use of traditional herbal medicinal products and herbal medicinal products within the European Union. Consequent labelling shall also enable patients and health care professionals to differentiate medicinal products from other product categories like cosmetics, food supplements, and medical devices.

[Research progress on current pharmacokinetic evaluation of Chinese herbal medicines].

In order to prove safety and efficacy, herbal medicines must undergo the rigorous scientific researches such as pharmacokinetic and bioavailability, before they are put on the market in the foreign countries. Botanical Drug Products promulgated by the US FDA could guide industry sponsors to develop herbal drugs, which was also an important reference for investigating Chinese herbal medicines. This paper reviews and discusses novel approaches for how to assess systemic exposure and pharmacokinetic of Chinese herbal medicines, which were in line with FDA guidance. This mainly focus on identifying pharmacokinetic markers of botanical products, integral pharmacokinetic study of multiple components, Biopharmaceutics drug disposition classification system, and population pharmacokinetic-pharmacodynamic study in herb-drug interaction.

[Dissection of differences and similarities of botanical drugs in European Union, US and Canada].

Because of the unique nature and treatment concept of traditional Chinese medicines (TCMs), TCMs have been respected again since 70s of last century. The regulatory agencies of some developed countries (the FDA, EMA and Health Canada etc) have published new guidance/guidelines/directives in recent years, such as the botanical drug product guidance of the FDA, the evidence for quality of finished natural health products guidance of the Health Canada and the guideline on quality of herbal medicinal products/ traditional herbal medicinal products of the EMA etc. All of the regulatory agencies are willing to scientifically evaluate the herbal medicines and accept it as therapeutic product. This paper analyzed the history of herbal medicine regulation and the similarities and differences of the regulatory requirements of the European Union, the United States and Canada, proposed possible future direction of the international development of Chinese medicine from the perspective of global regulatory affairs.

Medicinal plants and their preparations in the European market: Why has the harmonization failed? The cases of St. John's wort, valerian, ginkgo, ginseng, and green tea.

BACKGROUND: Botanical ingredients based on plants, algae, fungi or lichens have become widely available on the European Union market offering numerous preparations with considerable differences in classification. They are under the categories of food supplements, herbal medicinal products, cosmetics or medical devices. PURPOSE: The aim of the present work is to highlight how the European regulations concerning the different categories of botanicals can lead to different commercial choices such as time/cost for product development, application for a marketing authorisation, permitted indication (medical or health claim), and as a consequence, the same botanical products are sold in European Union as herbal medicinal products, food supplements, cosmetics or medical devices. Five different widely used botanicals, namely St. John's wort, valerian, ginkgo, ginseng, and green tea were selected to better explain the failure of harmonization through European Union. METHODS: A search of PubMed, ScienceDirect, European Medicines Agency and European commission web sites for medical devices and cosmetics, and European Food Safety Authority websites were conducted and the available information on regulation of herbal medicinal products, food supplements, medical devices and cosmetics in the European Union was collected. In addition, a market survey of all the sold botanical products in Europe was analysed by consultation of the medicines, medical devices, cosmetic and food agencies websites of the European countries. RESULTS: The current European legislation needs implementation and follow up because in the different countries the legal positions of the botanical products varied and it is possible to find the same product classified in the different categories, namely registered medicinal product including prescription only medicine, traditional herbal medicinal product, well established herbal medicinal products or food supplement, or medical device, or homoeopathic/anthroposophical medical product, cosmetic. CONCLUSIONS: There is an urgent need of harmonization, together with the implementation of interoperable vigilance databases, to avoid borderline options.