Key technical issues of herbal medicines with reference to interaction with other medicines

KEY TECHNICAL ISSUES OF HERBAL MEDICINES WITH REFERENCE TO INTERACTION WITH OTHER MEDICINES

KEY TECHNICAL ISSUES FOR HERBAL MEDICINES WITH REFERENCE TO INTERACTION WITH OTHER MEDICINES KEY TECHNICAL ISSUES OF HERBAL MEDICINES WITH REFERENCE TO INTERACTION WITH OTHER MEDICINES Key technical issues of herbal medicines with reference to interaction with other medicines ISBN 978-92-4-001914-0 (electronic version) ISBN 978-92-4-001915-7 (print version) © World Health Organization 2021 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. 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Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. iii Contents Foreword v Acknowledgements vi Abbreviations vii Glossary viii Executive summary xi 1. Introduction 1 1.1 The herbal medicines/products market and consumption and concomitant use of traditional and complementary medicines with conventional medicines 1 1.2 Objectives, aims and scope 2 1.2.1 Objectives 2 1.2.2 Aims 2 1.2.3 Scope 3 2. Therapeutic aspects of herb–drug interactions 5 2.1 Beneficial and harmful interactions 5 2.1.1 Beneficial interactions 5 2.1.2 Harmful interactions 6 2.2 Types and mechanisms of herb–drug interaction 9 2.2.1 Pharmaceutical interactions 9 2.2.2 Pharmacokinetic interactions 9 2.2.3 Pharmacodynamic interactions 11 2.2.4 Pharmacogenomics and pharmacogenetics 12 2.3 Application of in vitro testing to evaluate herb–drug interactions 12 2.4 Challenges for evaluating and monitoring herb–drug interactions 16 2.4.1 Factors associated with increased risk of herb–drug interactions 16 2.4.2 Complexity of herbal medicines 17 2.4.3 Quality of herbal medicines 17 2.4.4 Patient susceptibility 18 2.4.5 Practitioner competence and training 20 3. Data collection, assessment and dissemination of herb–drug interactions 21 3.1 Herb–drug interaction reports 21 3.2 Pharmacovigilance systems 21 3.3 Types and relevance of herb–drug interaction reporting 22 3.4 Assessing clinical reports and human case studies 24 3.5 Information retrieval 25 3.6 Dissemination of information 26 iv 4. Managing herb–drug interactions 27 4.1 Education and training of health professionals 27 4.1.1 Raising awareness 27 4.1.2 Basic and continuing education 27 4.1.3 Overview of reporting suspected herb–drug interactions 27 4.2 Consumer information and education 29 4.3 Research strategies for herb–drug interactions 30 4.3.1 Research methods 30 4.3.2 Correlation of preclinical studies with clinical outcomes 30 4.3.3 Identification of interactive constituent(s) 31 4.3.4 Combination herbal medicines 31 4.3.5 Overview of research strategies 31 References 33 Annex 1. Summary of interaction reports for well-documented herbs 37 Annex 2. Participants 65 vForeword Many countries are seeking to expand coverage of essential health services, including essential medicines, at a time when the unique health challenges of the twenty-first century are emerging, such as rising consumer expectations for care, soaring costs, and stagnant or reduced budgets. One important part of the efforts to address these challenges is using the resources of traditional and complementary medicine. According to the WHO Global Report on Traditional and Complementary Medicine 2019 (WHO, 2019a), traditional and complementary medicine practices are recognized by the health authorities in 170 World Health Organization (WHO) Member States. The Global Report also shows the growing trend in numbers of countries where policies and regulations on traditional and complementary medicine have been developed and implemented over the past two decades. Combining the use of traditional and complementary medicine with conventional medicine has increased significantly in recent years worldwide, in particular the combined use of herbal and conventional medicines. Interactions between medicines can possibly result in therapeutic failure or adverse events during treatment, and can also affect the outcome of clinical trials if not controlled. Despite increasing recognition of herb–drug interactions (HDIs), there is no standard system for prediction and evaluation – and WHO is receiving increasing numbers of requests from Member States to provide technical and policy support in this area. It is a priority for WHO to enhance the safety, quality and effectiveness of traditional and complementary medicines in achieving the goal of universal health coverage, as documented in the WHO Traditional Medicine Strategy: 2014–2023 (WHO, 2013). In response to the request from Member States, and in implementing the WHO strategy, WHO initiated the development of a technical document on interaction of herbal medicines with other medicines. This document provides information on the critical technical issues related to interactions between herbal medicines and other medicines for health-care professionals, regulators, researchers, pharmacovigilance centres, manufacturers and consumers. WHO encourages Member States to strengthen research, education, international cooperation and pharmacovigilance on HDIs to maximize the benefits and minimize the harmful effects of using herbal medicines, reduce risks, and support health professionals, patients and consumers in making informed and safe decisions. This document will be helpful in promoting the safety, quality and effectiveness of traditional, complementary and integrative medicines and in appropriate integration of traditional and complementary medicines into national health systems. It will also support the implementation of the WHO 13th Programme of Work, in particular integrated, people-centred health services for achieving the goal of universal health coverage. Dr Edward Kelley Director, Department of Integrated Health Services, World Health Organization vi Acknowledgements The World Health Organization (WHO) wishes to express its sincere appreciation to the Regional Government of Lombardy, Italy, for kindly hosting the first WHO working group meeting on key technical issues for herbal medicines with reference to interaction with other medicines in Milan in June 2011, with its financial support; and the National Center for Natural Products Research, School of Pharmacy, University of Mississippi, United States of America, for its generous financial contribution to the second WHO working group meeting in Oxford, Mississippi, United States, in July 2016. WHO also wishes to thank the Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, WHO Collaborating Centre for Traditional Medicine, Beijing, China, for providing financial support and hosting a WHO consultation meeting in October 2019. WHO acknowledges the valuable contribution of Professor Elizabeth Williamson, School of Pharmacy, University of Reading, United Kingdom of Great Britain and Northern Ireland. WHO acknowledges the valuable contribution of Professor Liu Xinin, Member of the WHO Expert Advisory Panel for Traditional Medicine, from the Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, WHO Collaborating Centre for Traditional Medicine, Beijing, China, and his team in preparing the draft document, with advice from Dr Zhang Qi, Head of the Traditional, Complementary and Integrative Medicine Unit, Integrated Health Services Department, WHO, supported by Ms Yukiko Maruyama, Scientist, and Dr Aditi Bana, Technical Officer, from the Traditional, Complementary and Integrative Medicine Unit. Special thanks are extended to Professor Harry HS Fong, Member of the WHO Expert Advisory Panel for Traditional Medicine in the Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, United States, and his colleague Professor Chun-Tao Che, Director, WHO Collaborating Centre for Traditional Medicine, University of Illinois at Chicago, United States, for their untiring assistance in preparation and revision of the draft document. WHO is grateful to all participants in the two working group meetings and the consultative meeting for their work in reviewing the draft document; participants are listed in Annex 2. Thanks are also given to the more than 100 experts in over 30 countries, including WHO Collaborating Centres for Traditional Medicine, and members of the WHO Expert Advisory Panel on Traditional Medicine, who reviewed and provided comments and advice on the draft document. vii Abbreviations CAR constitutive active/and rostane receptor CYP cytochrome P450 HDI herb–drug interaction HIV human immunodeficiency virus INR international normalized ratio P-gp permeability glycoprotein PXR pregnane X receptor WHO World Health Organization viii Glossary Active pharmaceutical ingredient – Substance used in a finished pharmaceutical product intended to furnish pharmacological activity or to otherwise have a direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to have a direct effect in restoring, correcting or modifying physiological functions in humans (WHO, 2011a). Some active pharmaceutical ingredients contain more than one active component responsible for their effects, for example herbal products. Adverse event/experience – Any untoward medical occurrence that may present during treatment with a pharmaceutical product but that does not necessarily have a causal relationship with this treatment (WHO, 2004a). A serious adverse event is any untoward medical occurrence that, at any dose, results in death, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/ incapacity, or is life-threatening. Adverse reaction – Response to a pharmaceutical product that is noxious and unintended and that occurs at doses normally used in humans for prophylaxis, diagnosis or treatment, or for the modification of physiological function (WHO, 2004a). Complementary medicine – Broad set of health-care practices that are not part of that country’s own traditional or conventional medicine and not fully integrated into the dominant health-care system. The term “complementary medicine” is used interchangeably with “traditional medicine” in some countries (WHO, 2013). Cytochrome P450 (CYP) – Group of enzymes involved in food and drug metabolism and found in high levels in the liver. This class consists of more than 50 enzymes, three of the most significant being CYP3A4, CYP2D6 and CYP2C9. Dosage form – Form of the completed pharmaceutical product, such as tablet, capsule, injection, elixir or suppository (WHO, 2011b). Drug/medicine – Any substance or pharmaceutical product for human or veterinary use that is intended to modify or explore physiological systems or pathological states for the benefit of the recipient (WHO, 2011b). Excipient – Any component of a medicine other than the claimed therapeutic ingredient or ingredients (WHO, 2011b). Finished herbal product – Herbal preparation made from one or more herbs (i.e. different herbal preparations from the same herb, or herbal preparations from different plants). Products containing different herbal materials are called “mixture herbal products”. Finished herbal products and mixture herbal products may contain excipients in addition to the active ingredients (WHO, 2017). ix Herb – Crude plant material that may be entire, fragmented or powdered. Herbs include the entire aerial part, leaves, flowers, fruits, seeds, roots, bark, trees (stem or root), tubers, rhizomes and other plant parts (WHO, 2017). Herbal material – Includes, in addition to herbs, other crude plant materials, such as gums, resins, balsams and exudates (WHO, 2017). Herbal medicine – May include herbs, herbal materials, herbal preparations and finished herbal products in a form suitable for administration to humans (WHO, 2017). In some countries, herbal medicines may also contain, by tradition, natural organic or inorganic active ingredients that are not of plant origin (e.g. animal or mineral materials). Herbal preparation – Preparation produced from herbal materials by physical or biological processes, such as extraction (with water, alcohol or supercritical carbon dioxide), fractionation, purification, concentration, fermentation, processing with a natural vehicle, or steeping or heating in alcoholic beverages, honey or other materials. The resulting herbal preparations include comminuted (fragmented) or powdered herbal materials, extracts, tinctures, fatty (fixed) or essential oils, expressed plant juices, decocts, and cold and hot infusions (WHO, 2017). Herbal product – Broad term encompassing herbal medicines and related products. Other terms used include botanical drugs, herbal dietary supplements, herbal drugs, herbal food supplements, herbal functional foods, herbal nutraceuticals, natural health products, phytomedicines, phytopharmaceuticals and phytotherapics. These terms vary widely according to regional and national legislation. Herb-drug interaction (HDI) – Interaction involving a herbal medicine, as defined above, and another medicine. This may be a herb–drug interaction (involving a conventional medicine) or a herb–herb interaction (involving two or more herbal medicines). P-glycoprotein – Multidrug-resistance protein in the cell membrane that pumps many medicines out of cells, reducing their bioavailability. Pharmaceutical interaction/incompatibility Includes complex formation, such as that between proteins and polyphenols or metals, which may reduce solubility of the drug or herbal constituent(s), thus delaying or preventing absorption. It may also involve chemical degradation and render either or both medicines ineffective or toxic. Pharmaceutical product – Any preparation for human or veterinary use that is intended to modify physiological or pathological states for the benefit of the recipient (WHO, 2011b). In the context of this document, pharmaceutical products also include herbal medicinal products. Pharmacodynamic interaction – Occurs when two drugs or more interact as a result of their intrinsic pharmacological effects. The interaction may involve receptor binding and post- receptor effects, resulting in synergistic or antagonistic outcomes. xPharmacogenetics – Study of single or multiple related drug–gene interactions. Pharmacogenomics – Study of genetic variations that influence the response to drugs, encompassing genomics and epigenetics and the effects of multiple genes. Pharmacokinetic interaction –Occurs due to differences in the absorption, distribution, metabolism or excretion of a drug when taken in combination with another drug, compared with the predicted behaviour when taken individually. These differences may cause changes in the concentration of one or both drugs, which may affect treatment outcomes or increase toxicity. Pharmacovigilance – Science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other possible drug-related issue (WHO, 2004a). Polymorphism – Presence of genetic variations, for example changes in cytochrome P450 enzyme and transporter expression profiles, which affects the capacity of an individual to metabolize drugs. Side-effect – Unintended effect of a pharmaceutical product occurring at doses normally used in humans that is related to the pharmacological properties of the drug (WHO, 2004a). Traditional and complementary medicine – Merges the terms “traditional medicine” and “complementary medicine”, encompassing practices, practitioners and products (WHO, 2013). Traditional medicine – Sum total of the knowledge, skill and practices based on the theories, beliefs and experiences indigenous to different cultures, whether explicable or not, used in the maintenance of health and the prevention, diagnosis, improvement or treatment of physical or mental illness (WHO, 2013). xi Executive summary Although there are few sources of reliable data on the number of people taking conventional medicines and traditional or complementary medicines concurrently, the practice of using combinations of herbal medicines and conventional medicines to improve therapeutic outcomes is widespread. Evaluation of herb–drug interaction (HDI) liability is challenging due to variability in herbal product composition, uncertainty of the causative constituents, and often scant knowledge of constituent pharmacokinetics. These limitations are confounded further by the varying perspectives concerning herbal product regulation. Many Member States have requested that the World Health Organization (WHO) provide technical support on how to deal with HDIs correctly. This document is part of a more comprehensive series of documents that provide greater context about the safe and effective use of herbal medicines. The document was initiated in 2011 in Milan, Italy, when the first working group meeting was organized. The document was drafted in May 2015, and then discussed in the second working group meeting in 2016 in Mississippi, United States of America. The first and second global peer reviews were conducted in October 2018 and February 2019, respectively. The final consensus was reached in a WHO consultation meeting in Beijing, China, on 16–18 October 2019. Based on this consensus, the draft was further updated and finalized by a small peer-review group in November 2019. The concepts of beneficial and harmful HDIs are introduced, with documented examples from the published literature. Types of HDI and their mechanisms are outlined, and the relevance of in vitro, general screening and in vivo tests is included. Challenges faced in evaluating and monitoring HDIs, data collection, assessment and dissemination of information are briefly discussed. The education and training of health professionals and consumers are addressed, together with potential research strategies for further investigation of the mechanisms, incidence, monitoring and management of HDIs. The intention of this document is to provide as much concise information as possible, and to give direction and guidance on capitalizing resources to support informed decision-making and maximize the safe concurrent use of herbal medicines and other medicines. It is not the objective of this document to address complex toxicological issues or to act as a guideline for clinical treatment or the use of fixed combinations of herbal medicines. Interactions with diagnostic procedures and with nonpharmaceutical interventions such as surgery are beyond the scope of this report and are not addressed. A selection of reports and case histories of HDIs involving well-documented herbs is collated in Annex 1. An evaluation of the available evidence is provided, and the entries have been reviewed by expert panels over several global reviews. Dr Zhang Qi, Head Unit of Traditional, Complementary and Integrative Medicine, Department of Integrated Health Services, World Health Organization

11. Introduction 1.1 The herbal medicines/products market and consumption and concomitant use of traditional and complementary medicines with conventional medicines Increasing numbers of people use traditional, complementary and integrative medicine in Africa, Asia, Oceania and the Americas (WHO, 2013). Many traditional, complementary and integrative medicine modalities include the use of herbal medicines, although the results from studies on the frequency of herbal medicines use vary too widely to be meaningful due to the survey methods used, vague definitions of “herbal medicines” or “food supplements”, and the notoriously poor response rates achievable with such studies. It can be agreed, however, that the use of herbal medicines is high, increasing, and predominant in certain types of patient, culture and disease states. A 2014 study estimated that 18.8% of respondents were using at least one “plant-based supplement” in Europe (Garcia-Alvarez et al., 2014). In South Africa, over 27 million people have been reported to use herbal medicines and there are an estimated 200 000 traditional healers (Abdullahi, 2011). Up to 60% of South Africans consult these healers, usually in addition to using modern biomedical services (Van Wyk et al., 2009). In Japan, according to a survey in 2011, 89% of doctors prescribe Kampo products in their daily practice (Arai and Kawahara, 2019). Popular use of herbal medicines in Brazil is often due to poor medical and pharmaceutical assistance and the high cost of treatment with conventional medicines (Mazzari and Prieto, 2014). Another indicator of herbal medicines use is the expanding commercial market over the past 50 years. Sales of herbal dietary supplements in the United States of America surpassed US$ 8.8 billion in 2017, an increase of 9.4% from 2017 and the strongest growth since 1998 (Smith et al., 2019). In China, the herbal medicines market was worth US$ 100–120 billion in the period 2014–2016, representing about 30% of the pharmaceutical industry (Dang et al., 2016). Sales of herbal medicines in Brazil in 2014 reached US$ 343.7 million (Carvalho et al., 2018). In South Africa, the herbal product trade has been estimated to contribute over US$ 200 million to the economy (Abdullahi, 2011). Along with the dramatic global rise in herbal medicine use and sales, there has been a parallel increase in the number of people taking conventional medicines and traditional or complementary medicinal products concurrently. Although there are few sources of reliable data on the number of people using combinations of herbal medicines and conventional medicines to improve therapeutic outcomes, it is reasonable to assume this is widespread. Although there are limited data on the number of people taking conventional medicines and traditional or complementary medicines concurrently, the increasing consumption and concomitant expansion of the herbal products market have raised concern among health- care professionals, researchers, regulatory authorities and consumers regarding herb–drug interactions (HDIs). The practice of using combinations of herbal medicines and conventional medicines, whether prescribed or bought over-the-counter, to improve therapeutic 2outcomes, maintain general health, prevent diseases, and treat chronic and refractory diseases such as mental health issues, cardiovascular and cerebrovascular diseases, and tumours, is widespread. According to a British study, the prevalence of taking herbs or dietary supplements concurrently with prescription medicines in elderly people was 33.6% (Agbabiaka et al., 2017). People frequently fail to tell their doctors, and doctors often fail to ask their patients, about use of herbal medicines. The concurrent use of herbal medicines with other medicines can result in therapeutic failure or adverse events, and can also affect the outcomes of clinical trials if not appropriately controlled. Systematic evaluation of HDI liability, as is routine for new medicines under development, necessitates identifying individual chemical constituents of herbal products and characterizing their interaction potential. Despite increasing recognition of HDIs, there is no standard system for prediction and evaluation. Evaluation of HDI liability is challenging due to variability in herbal product composition, uncertainty of the causative constituents, and often scant knowledge of constituent pharmacokinetics. These limitations are confounded by the varying perspectives concerning herbal product regulation. 1.2 Objectives, aims and scope 1.2.1 Objectives The primary objective of this document is to provide information for health-care professionals, regulators, researchers and other stakeholders on key technical issues related to HDIs in order to support health professionals, patients and consumers in making informed decisions to maximize beneficial applications and minimize side-effects of herbal medicines and products. A second objective seeks to encourage health professionals to engage in their jurisdictional pharmacovigilance system, because reporting interactions makes herbal medicines usage safer for all patients; regulators and policy-makers to ensure traditional, complementary and integrative medicine is effectively incorporated into pharmacovigilance systems; and researchers and academics to become familiar with this topic and contribute to the body of scientific knowledge needed to advance the understanding of this important field. It is not the objective of this document to address complex toxicological issues or to provide guidelines for clinical treatment. Interactions with diagnostic procedures and with nonpharmaceutical interventions such as surgery are beyond the scope of this report and are not addressed. 1.2.2 Aims ■ To summarize the issues surrounding HDIs regarding their incidence, and the mecha- nisms and pharmacokinetic and pharmacodynamic principles involved in HDIs. ■ To discuss the challenges in evaluating and monitoring HDIs resulting from issues specific to herbal medicines, such as their complexity, variability in sources and 3production methods (as detailed in other WHO guidelines), and in terms of consu- mer behaviour. ■ To outline strategies for increasing awareness and educating health-care professio- nals and consumers. ■ To create awareness about reporting of HDIs. ■ To promote and facilitate research on HDIs. 1.2.3 Scope There are many examples of combinations of herbs that should or should not be taken together based on empirical knowledge and centuries of observation, but the scientific information available about HDIs is rare. These points are addressed in the individual WHO benchmarks for training in traditional, complementary and integrative medicine publications. For example, Benchmarks for Training in Traditional Chinese Medicine includes a list of combinations that should not be used, except by specialists under “extreme caution” (WHO, 2010a). Benchmarks for Training in Ayurveda explains antagonistic combinations of herbs and foods in terms of their Ayurvedic properties, but interactions between specific herbs are not detailed (WHO, 2010b). In Benchmarks for Training in Unani Medicine, although no specific herbal combinations are given, the importance of recognizing herbal interactions is emphasized (WHO, 2010c). Naturopathy training requires competence in botanical medicines; Benchmarks for Training in Naturopathy states that practitioners should be aware of “the potential interactions between herbal remedies, pharmaceutical products or foods” (WHO, 2010d).

52. Therapeutic aspects of herb–drug interactions Examples from the current literature related to HDIs are shown in Table 1 and Annex 1. Harmful HDIs are the priority in terms of public health and safety; however, herbal medicines may be taken alongside other products not only as part of integrated treatment but also to deliberately exploit beneficial herbal interactions – for example, to improve the bioavailability of a medicine. Research into HDIs is a relatively new field of clinical study, and it is important to acknowledge that not all HDIs are harmful and some can result in positive effects. 2.1 Beneficial and harmful interactions 2.1.1 Beneficial interactions Herb–drug interactions The use of herbal formulae and their positive effects on people receiving chemotherapy was reviewed by Qi et al. (2015). In Japan, many doctors prescribe Kampo medicines to manage cancer-related symptoms and outcomes (Amitani et al., 2015). Chinese herbal medicines have been used successfully in the treatment of various diseases, including drug-resistant enterobacteria infection (Cai et al., 2017). Schisandra sphenanthera Rehder & E.H. Wilson is used in traditional Chinese medicine as a hepatoprotective agent in people undergoing liver transplant who are also being treated with the immunosuppressant tacrolimus. This combination has been shown to reduce diarrhoea and agitation associated with the use of tacrolimus, to increase the oral bioavailability of tacrolimus, and to improve liver function (Jiang et al.2010), and further studies are warranted. Herb–herb interactions The therapeutic efficacy of certain herbal medicines can be augmented by the administration of other herbs through synergistic, additive, chemical or metabolic mechanisms, including increasing biological effects through more than one mechanism or altering absorption and bioavailability. Alternatively, a herbal medicine may reduce the toxicity of another herb, for example by reducing the bioavailability of a specific component. An example of the augmentation of effects is shown by a double-blind, placebo-controlled study on the cognitive performance of healthy adults following administration of Ginkgo biloba L. or Panax ginseng C.A. Mey. or their combination. A sustained improvement of test responses following treatment with the ginkgo–ginseng combination was observed compared with use of the individual herbs (Scholey and Kennedy, 2002), although no mechanism for this synergistic effect was postulated. Black pepper (Piper nigrum L.) is a component of many Ayurvedic formulae such as Trikatu. The constituent piperine enhances the absorption and bioavailability of herbal and conventional medicines, partly by modulating p-glycoprotein and metabolic enzymes (Meghwal and Goswami, 2013). 6The use of specific combinations to attenuate toxicity is documented in ancient classical traditional Chinese medicine texts and was established over many years of observation and empirical evidence from clinical practice. They are known as principles of “mutual detoxification” and “mutual restraint” and refer to the action of removing or restraining (weakening) the toxicity of one ingredient by another ingredient; for example, liquorice rhizome and astragalus root have been used to attenuate the toxicity of Aconiti Praeparata Radix (Liu et al., 2014). There are few human studies comparing combinations with individual herbs in reducing toxicity, but animal studies support the principle. The combination of Ku Shen (Sophora flavescens Aiton) with Gan Cao (Glycyrrhiza uralensis Fisch.) is an established traditional Chinese medicine formula. A study in rats has shown that the absorption of glycyrrhetinic (or glycyrrhetic) acid is reduced and its metabolism increased compared with Gan Cao alone; thus reduced in vivo accumulation of glycyrrhetinic acid may be a mechanism for reducing the sodium- and water- retentive effects of Gan Cao (Shi et al., 2015). 2.1.2 Harmful interactions Herb-drug interactions St John’s wort (Hypericum perforatum L.) was one of the first herbs to be implicated in case reports of drug interactions, and it remains the most commonly cited. The concomitant use of St John’s wort with the anticoagulant warfarin, immunosuppressants (e.g. ciclosporin), antiretrovirals (e.g. indinavir, nevirapine), inotropics (e.g. digoxin) or antineoplastics (e.g. imatinib, irinotecan) may result in reduced plasma concentrations and reduced efficacy of these medicines (Russo et al., 2014). Other herbs have since been reported to be involved in HDIs, but the evidence for many is inconclusive; some examples are given in Table 1. Herb–herb interactions The overall clinical effects of herbal combinations are expected and intended to be the result of complex interactions between components of the mixture. To avoid harmful interactions, multi-herb and fixed formulae are usually produced according to strict rules governing appropriate combinations based on traditional properties (e.g. Tridosha attributes in Ayurveda). In traditional Chinese medicine, specific combinations of herbs have been claimed to be detrimental when taken together; these are described as the “18 incompatible medicaments”, reported to cause adverse reactions when used in combination (see Table 2). Bioavailability enhancers may enhance the effects of other toxic compounds taken at the same time, whether in the same herbal medicine or in a different product, and may need to be considered. 7Table 1. Examples of reported herb–drug interactions 1,2,3 Plant species name and part used Common name Prescribed medicine Reported result of interaction Allium sativum L., bulb Garlic Chlorzoxazone Increased plasma concentration of chlorzoxazone Paracetamol Changes in paracetamol pharmacokinetics Saquinavir Decreased saquinavir blood concentration Angelica sinensis (Oliv.) Diels, root Danggui, Dong quai Warfarin Increased anticoagulant effect Areca catechu L., seed Betel nut Procyclidine Rigidity, bradykinesia, jaw tremors Camellia sinensis (L.) Kuntze, leaf Green tea Folic acid Decreased folate blood concentration Ginkgo biloba L., leaf Ginkgo leave, Yinxingye Omeprazole Decreased omeprazole blood concentration Tolbutamide Decreased tolbutamide blood concentration Talinolol Increased talinolol blood concentration Hibiscus sabdariffa L., flower Hibiscus (roselle) Chloroquine Reduced blood concentration of chloroquine Paracetamol Changes in paracetamol pharmacokinetics Hydrastis canadensis L., root Goldenseal Debrisoquine Decreased debrisoquine urinary recovery ratio Lycium barbarum L., fruit Goji berry, Chinese wolfberry Warfarin Increased anticoagulant effect Mentha piperita L., essential oil Peppermint Felodipine Increased felodipine blood concentration Oenothera biennis L., seed oil Evening primrose Fluphenazine Seizures Panax ginseng C.A. Mey., root and rhizome Ginseng, red or Korean Phenelzine Sleeplessness, tremor, headache Panax quinquefolius L., root Ginseng, American Warfarin Reduced warfarin concentration and anticoagulation effect Piper methysticum G. Forst., root Kava Chlorzoxazone Decreased metabolite/chlorzoxazone serum ratio Salvia miltiorrhiza Bunge, root and rhizome Dan Shen, red sage Warfarin Increased anticoagulant effect Schisandra chinensis (Turcz.) Baill., fruit Magnolia vine fruit Talinolol Increased talinolol blood concentration Silybum marianum (L.) Gaertn., seed Milk thistle Metronidazole Decreased metronidazole blood concentration 1 Table reprinted with permission from Izzo AA, Kim SH, Radhakrishnan R, Williamson EM (2016). A critical approach to evaluating clinical efficacy, adverse events and drug interactions of commonly used herbal remedies. Phytother Res. 30(5):691–700. 2 Data extracted from Izzo AA (2012). Interactions between herbs and conventional drugs: overview of the clinical data. Med Princ Prac. 21:404–28. 3 Well-documented interactions are those revealed by a well-documented case report or multiple case reports and case series (level of evidence 3 out of 5); pharmacokinetic trials in patients or healthy volunteers (level of evidence 4 out of 5); or case report(s) and confirmed by clinical pharmacokinetic trials (level of evidence 5 out of 5) (Izzo 2012). 8Table 2. The 18 incompatible medicaments in traditional Chinese medicine1 Herb Incompatible with Pharmaceutical/ pharmacopoeial name Plant species name Chinese name (Pinyin) Common names Pharmaceutical/ pharmacopoeial name Plant species name Chinese name (Pinyin) Common names Aconiti Radix Aconitum carmichaeli Debeaux Wutou Wolfbane, aconite Fritillariae Bulbus Fritillaria cirrhosa D. Don. Beimu Fritillary Trichosanthis Fructus Trichosanthes kirilowii Maxim.; Trichosanthes rosthornii Harms Gualou Mongolian snakegourd Pinelliae Rhizoma Pinellia ternata (Thunb.) Breit. Banxia Ternate pinellia Ampelopsis Radix Ampelopsis japonica (Thunb.) Makino Bailian Japanese ampelopsis tuber Bletillae Rhizoma Bletilla striata (Thunb.) Reichb. f. Baiji Common ble- tilla tuber Glycyrrhizae Radix et Rhizoma Glycy- rrhiza uralensis Fisch.; Gly- cyrrhiza glabra L.; Glycyrr- hiza inflata Batalin Gan Cao Liquorice, licorice, sweet grass Euphorbiae Pekinen- sis Radix Euphorbia peki- nensis Rupr. Daji Peking spurge Genkwa Flos Daphne genkwa Siebold & Zucc. Yuanhua Lilac daphne flower bud Kansui Radix Euphorbia kansui S.L. Liou ex S.B. Ho Gansui Gansui, Kansui root Sargassi Thallus Sargassum palli- dum (Turner) C. Agardh; Sargas- sum fusiforme (Harvey) Setchell Haizao Seaweed, sargassum Veratri Nigri Radix et rhizoma Veratrum nigrum L. Lilu False hellebore root and rhizome Ginseng Radix et rhizoma Panax ginseng C.A. Mey. Ren Shen Ginseng Salvia Miltiorrhizae Radix Salvia miltiorrhiza Bunge Dan Shen Red root sage Adenophorae Radix Adenophora stricta Miq.; Ade- nophora triphylla (Thunb.) A.DC.; Adenophora tetra- phylla (Thunb). Fisch. Sha Shen Ladybells root Sophorae Flavescen- tis Radix Sophora flaves- cens Ait. Ku Shen Light yellow sophora root Asari Radix et rhizoma Asarum sieboldii Miq. Xixin Manchurian wild ginger Paeoniae Radix Paeonia lactiflora Pall.; P. veitchii Lynch Shaoyao Chinese peony 1 Adapted from Liu XM, Wang Q, Song G, Zhang G, Ye Z, Williamson EM (2014). The classification and application of toxic Chinese materia medica. Phytother Res. 28(3):334–47. 92.2 Types and mechanisms of herb–drug interaction HDIs occur when known or unknown constituents alter the activity of another medicine administered at the same time or within a short timeframe. This action may be synergistic (increased effect) or antagonistic (decreased effect), or a new effect may be produced that would not be expected from use of either medicine alone. The mechanisms of HDIs are defined below; for more information, see European Medicines Agency (2012). HDIs can have a pharmaceutical, pharmacokinetic or pharmacodynamic basis; they can occur during any pharmacokinetic processes or at the site of action. HDIs may interact by more than one mechanism. Figure 1 summarizes the main route by which all drug interactions, including HDIs, occur. A herbal medicine may interact by more than one mechanism; for example, Hypericum perforatum L. may interact with other antidepressants by pharmacodynamic mechanisms to produce a toxic serotonergic syndrome, and by pharmacokinetic processes with ciclosporin to cause transplanted organ rejection by reducing blood levels of the immunosuppressant (Colombo et al., 2014). 2.2.1 Pharmaceutical interactions Pharmaceutical interactions, or incompatibilities, occur when two or more preparations, mixed before administration (e.g. in a liquid medicine), react. This is usually a chemical interaction, such as complex formation between proteins and polyphenols or metals, causing reduced solubility or chemical degradation of the medicine or herbal constituents, and thus may be predictable. Theoretically, the consumption of herbal medicines with probiotics may render the probiotics inactive. The results may be visible in the medicine as colour changes or flocculent precipitates; with herbal medicines, however, colour changes may be masked by natural pigments. 2.2.2 Pharmacokinetic interactions Pharmacokinetic interactions occur when a medicine’s absorption, distribution, metabolism or elimination is altered by the administration of another medicine or herb; they include metabolism-mediated and transporter-mediated interactions. Changes in the gut microflora may alter the bioavailability of orally administered medicines. Absorption interactions Herbal medicines may influence transit time through the gut, which may affect the absorption of a drug. Chemical reactions or complexation may occur in the stomach when two medicines are taken together, which may interfere with the absorption of one or both medicines. Some medicines exist in either ionized or non-ionized form, depending on the pH of the gut and the acid–base dissociation constant (pKa) of the medicine. Non-ionized forms are more lipophilic and more easily absorbed. The regulation of gut pH is important in this context. Smaller, neutral molecules can undergo passive diffusion. 10 The absorption of some medicines is altered if administered together with substances with a high fat content. Some traditional medicines are formulated in an oil base, such as Ayurvedic formulations containing ghee or clarified butter. Distribution interactions Transporter- and metabolic enzyme-mediated interactions include modulating active uptake or efflux of a medicine, and competition for plasma protein binding, thus altering drug transport and bioavailability. P-glycoprotein is a multidrug-resistance protein distributed extensively in the intestinal epithelium, liver, kidney and blood–brain barrier. P-glycoprotein transports many medicines, including tacrolimus, doxorubicin, vinblastine and some protease and reverse transcriptase inhibitors. Activation of P-glycoprotein reduces the bioavailability of these medicines, while inhibition of P-glycoprotein may enhance their bioavailability. Competition for plasma protein transport may alter bioavailability, with consequent transient changes in concentrations of medicines. Metabolic interactions Cytochrome P450 (CYP) enzymes are found in the membranes of the endoplasmic reticulum (microsomes) and mitochondria, hepatocytes and other cell types. About 70–80% of prescribed medicines are metabolized by cytochrome P450 enzymes (Cho and Yoon, 2015). More than 50 isozymes are known, but only 6 are responsible for the metabolism of most drugs, the 3 most significant being CYP3A4, CYP2D6 and CYP2C9. If cytochrome P450 enzyme activity is increased due to increased microsomal enzyme synthesis, the metabolism of other medicines that are substrates for the same enzyme will be increased, leading to reduced therapeutic levels of the first medicine and possible treatment failure. If enzyme activity is reduced, the metabolism of other medicines that are substrates for the same enzyme will be decreased, leading to increased plasma levels of the first medicine and possible induction of toxicity. The outcome of cytochrome P450 inhibition or induction may be more complex than a simple change in plasma levels; for example, unexpected effects may be seen if an active metabolite is produced. Phase II metabolic enzymes include uridine diphosphate-glucuronosyltransferases, sulfo- transferases, N-acetyltransferases and glutathione S-transferases. These enzymes facilitate the attachment of polar and ionizable groups to metabolites generated by phase I metabo- lism and thereby increase their elimination rate. Phase II enzymes are present in the liver and intestine and may be induced or inhibited. Several herbal extracts and compounds have been shown to induce or inhibit phase II enzymes (Mohamed and Frye, 2011), but no clinical cases of interaction have been reported. The constitutive active/and rostane receptor (CAR) and the pregnane X receptor (PXR) are the two major nuclear receptors involved in the regulation of metabolism, distribution and elimination of xenobiotics (Urquhart et al., 2007; Tolson and Wang, 2010). Both play a crucial role in drug interactions and regulate the expression of a wide range of cytochrome P450 enzymes, uridine diphosphate-glucuronosyltransferases and glutathione S-transferases. Some efflux transporters (e.g. P-glycoprotein) and influx transporters (e.g. organic anion- transporting polypeptide 1A2, OAT P1A2) are also regulated by PXR or CAR (Chen et al., 2012; 11 Liu and Li, 2012). Several herbal medicines have now been identified as regulators of PXR (Chang, 2009; Yu et al., 2011). Elimination interactions Renal excretion of drugs comprises three major physiological processes in the kidney: glomerular filtration, tubular secretion and tubular reabsorption. Medicines and metabolites that are tightly bound to plasma proteins are not available for glomerular filtration and are not easily eliminated by this process, but protein binding is not an impediment to medicines that are renally excreted via tubular secretion. In biliary excretion, drugs and their metabolites are transferred to the bile by hepatocytes, delivered via the gallbladder to the intestine, and excreted via the stool. The active drug may also be reabsorbed; this is the enterohepatic cycle. The intestinal flora may hydrolyse conjugated metabolites and free the active drug, allowing it to be reabsorbed. Active transportation is the major mechanism in biliary excretion, and therefore interaction is more likely to be caused by inhibitors or inducers of transporters. 2.2.3 Pharmacodynamic interactions Pharmacodynamic interactions occur when two medicines interact due to their intrinsic pharmacological effects. Many medicines, especially herbal medicines, produce their effects via more than one mechanism and regardless of the route of administration. It is important not to overgeneralize or speculate on interactions based purely on the chemical structures of components of herbal extracts. For example, many case reports cite the coumarin content as a logical reason for an observed cardiovascular interaction. Coumarins are distributed widely in plants, however, and most lack the structural features necessary to inhibit coagulation by depleting vitamin K, as with dicoumarol. Receptor interactions A drug agonist combines with receptors to elicit a pharmacological response, whereas an antagonist blocks this response. A full agonist binds to and activates a receptor to its maximum response. A partial agonist has different affinities for different states of the same receptor or isoforms of the receptor, producing a similar but weaker effect. A drug can act as a full agonist in some tissues and as a partial agonist in other tissues. The outcome of combining two drugs with agonist activity will depend on the doses used, the receptor density, and the relative binding affinity of each drug. An inverse agonist binds to the same receptor as an agonist but dislocates the receptor to its inactive state, thus reducing its intrinsic activity. An inverse agonist thus has opposite actions to those of an agonist – but the effects of both can be blocked by antagonists. Pure antagonists are devoid of action themselves but bind to the receptor, blocking the action of an agonist. They are classified into reversible and non-reversible antagonists. Reversible antagonism can be overcome by increasing the concentration of agonist. Many drugs initially characterized as antagonists are now known to have inverse agonist activity. 12 Organ and system interactions With certain drug combinations, the interaction results in metabolic processes that eventually cause clinical symptoms, some of which are serious. For example, diuretics or strong laxatives such as senna may cause potassium depletion; under such physiological conditions, the toxicity of digoxin is elevated (Wang et al., 2011). 2.2.4 Pharmacogenomics and pharmacogenetics Knowing whether a person has specific genetic variations can help to individualize therapy, reducing the chances of adverse drug events and increasing efficacy, an approach termed “personalized medicine” (Pirmohammed, 2001; WHO, 2002; Scott, 2011; Johnson 2013). The cytochrome P450 enzyme expression profile, including specific genetic variants, influences drug interactions and susceptibility to the drug itself (WHO, 2005; Samer et al., 2013). Pharmacogenomics and pharmacogenetic mechanisms should not be confused with pharmaceutical interactions or chemical incompatibilities, which can be dealt with by a revised system of administration. Mechanisms of HDIs have been well reviewed (e.g. Butterweck and Nahrstedt, 2012; Fasinu et al., 2012; Gurley, 2012; Gurley et al., 2012; Hermann and von Richter, 2012; Posadzki et al., 2013; Chan, 2014; Cho and Yoon, 2015). 2.3 Application of in vitro testing to evaluate herb–drug interactions The same principles for testing the effects of drug-metabolizing enzymes and drug transporter activity apply to herbal medicines as for any other medicines, and the same rigour should be applied when assessing them. The complexity of some herbal medicines, however, means that the overall effects may be difficult to predict. The usual factors that Figure 1. Possible herb–drug interactions: mechanisms and processes CYP, cytochrome P450; P-gp, P-glycoprotein. Absorption Complexation/drug solubility/pKa/gut ph/gut motility Metabolism CYP and other enzymes (oxidases, esterases) Receptor/post- recep for effects Binding/synergirm/ antagonism Distribution P-gp/drug trasporters/protein binding/tissue depot Elimination Biliary (P-gp) and renal excretion (free drug) Organ.system Disease state (e.g. diabetes, kidney failure), biochemical changes (e.g. hypokalaemia) Pharmacodynamic Herb-drug interactions: mechanisms and processes Changes in active drug concentration at target site: potential drug interaction Pharmaceutical/chemical interaction/incompatibility Complexation (e.g polyphenois, proteins, metails), degradation Pharmacokinetic 13 influence an individual’s response to any medicine apply to herbal medicines, but variability in the quality and the chemical constituents of the products must also be considered. There are so many confounding factors associated with screening herbal medicines that some in vitro tests may not be clinically meaningful. In vitro evidence should also include considerations of single-component versus whole-extract effects, intestinal absorption, genetic diversity, enzyme-inducing and enzyme-inhibiting effects offsetting each other, quantitative concentration–response relationships, and metabolic activation issues. Ingested materials are exposed to stomach acid and digestive enzymes, the microbiome, and substantial hepatic first-pass effects that cannot be predicted from in vitro screening tests. Several studies have been criticized for using doses too high to be clinically relevant – for example, at millimolar rather than nanomolar or picomolar levels (Butterweck and Nahrstedt, 2012; Markowitz and Zhu, 2012) – and to date there are no validated approaches to translating in vitro to in vivo extrapolation for HDIs. A medicine may interact with more than one cytochrome P450 or other enzyme and with P-glycoprotein and other drug transporters. Table 3 shows the cytochrome P450, P-glycoprotein and other transporter activity profiles of some commonly used medicinal plants and reports of their clinical interactions. These herbs were selected due to the range of tests that have been performed on their extracts, for comparison with their clinical records of interaction and to illustrate the relevance of the evidence available. They are important for clinically different reasons. Several are used in vulnerable groups of people, such as older people (Ginkgo biloba L., Panax ginseng C.A. Mey.), or for self-medication for minor issues (Valeriana officinalis L. as a sleep aid); others are widely consumed foods and nutritional supplements for health maintenance (Allium sativum L., garlic; Zingiber officinale Roscoe, ginger). Echinacea merits attention as it is often administered to children as an immunostimulant. As shown in Table 3, in vitro evidence frequently does not predict documentable clinical interaction. St John’s wort is the only herb in the list with a battery of preclinical results that would predict an interaction; it potently induces many cytochrome P450 enzymes and strongly induces P-glycoprotein. Conversely, for garlic and ginger, both widely eaten and taken as herbal medicines, the reported cytochrome P450 inhibition does not seem to be detrimental to health – in fact, it is part of their chemopreventive effects – illustrating that cytochrome P450 enzyme induction, especially when combined with P-glycoprotein induction, is so far the best predictor of HDIs. 14 The primary genetic polymorphisms involve CYP2D6, CYP2C19 and CYP2C9. In people who are ultrarapid metabolizers, high activity of polymorphic enzymes may result in treatment failure due to subtherapeutic plasma levels; in people who are poor metabolizers, reduced clearance may lead to overt toxicity (Samer et al., 2013). Thus far, the study of polymorphism has barely been explored in HDIs. 15 Table 3. Cytochrome P450 (CYP) and P-glycoprotein (P-gp) activity of some commonly used herbal medicines, and their interaction reports Plant species name and part used Common name Major constituents CYP involvement P-gp and other transpor- ter effects Clinical interaction reports References Allium sati- vum L., bulb Garlic Sulphides (alliin, allicin, ajoene, allyl disulphides), steroidal glycosides, flavonoids Inhibition of CYP 2C19, 3A4, 3A5 and 3A7 in human and some animal studies Conflicting results (3 studies) Several recorded; cau- sality often not proven; widely used food item; may add to cardiovascu- lar (antiplatelet) effects Hermann and von Richter (2012) Ge et al. (2014) Cho and Yoon (2015) Echinacea spp., root, herb, juice Echinacea Alkylamides (root), caffeic acid derivati- ves, polysaccharides; some differences between species No significant inhibition of CYP2D6 or CYP1A2; weak induction of CYP3AA4 Induction of P-gp via PXR activation No clinical reports; in vivo studies show rela- tive lack of interaction potential Awortwe et al. (2015) Ardjomand and Bauer (2016) Ginkgo biloba L., leaf Ginkgo Diterpene lacto- nes, ginkgolides, bilobalide; biflavone glycosides (ginkge- tin, bilobaletin) Inhibition of CYP1A2, CYP2C9 and CYP2E1 (extract); induction of CYP3A4 (human in vitro studies) Induction of P-gp Several; causality often not proven (vulnerable people); may add to car- diovascular (antiplatelet) effects Ge et al. (2014) Cho and Yoon (2015) Hypericum perforatum L., herb St John’s wort Naphthodianthro- nes (hypericins); phloroglucinols (hyperforins), flavo- nols (hyperoside) Potent induction of CYP3A4, CYP2C9, CYP2C19 and CYP2E1; extracts and hyperforin induce PXR Strong Induc- tion of P-gp via PXR High; many recorded events supported by clinical and mechanistic evidence Ge et al. (2014) Russo et al. (2014) Salvia miltio- rrhiza Bunge, root Dan Shen Diterpenoid quino- nes (tanshinones), phenolic acids (sal- vianolic acids) Inhibition of CYP2C19, CYP2C9, CYP3A2 and CYP3A4 and carboxylesterase Inhibition of P-gp, OAT1 and OAT3 Compound Dan Shen tablets had little influence on phar- macokinetic and pharmacodynamic pro- files of warfarin in most people; potential for interaction with warfarin and with ester prodrugs suggested by animal studies, but no clinical reports Wang and Yeung (2011) Ge et al. (2014) Chua et al. (2015) Lv et al. (2017) Valeriana officinalis L., root Valerian Sesquiterpenes (valerenic acids), monoterpenes, iri- doids (valepotriates) in herb but not most extracts No effect on CYP1A2 or CYP2E1; induction of CYP2D6 and CYP3A4 in vitro but not in vivo Weak induc- tion of P-gp and UGT 1A1 and 2B7 Review suggests no pharmacokinetic inte- raction, but may add to sedative effects Kelber et al. (2014) Zingiber offi- cinale Roscoe, rhizome Ginger Phenolic ginge- rols (dehydrate to shogaols), essen- tial oil (mono- and sesquiterpenes) Individual gingerols inhibit CYP; total extract does not Weak inhi- bition of P-gp (only 6-gingerol) Few recorded; causality often not proven; in vivo studies suggest low inte- raction profile Jiang et al. (2005) Young et al. (2006) Mukkavilli et al. (2015) OAT, organic anion transporter; PXR, pregnane X receptor; UGT, uridine diphosphate-glucuronosyltransferase. 16 2.4 Challenges for evaluating and monitoring herb–drug interactions Over the past 20 years, case reports, case series, and human and animal pharmacokinetic studies have clearly shown that herbal medicines can interact with other medicines, whether prescribed conventional medicines or other herbal medicines. Much of the evidence is of poor quality, however, often with relevant information missing (Izzo et al., 2016). Even with well-documented interaction reports, it may not be possible to establish a causal relationship without further exploratory investigation. Unlike clinical trials accorded to efficacy studies, it is unethical to subject people to a study with potentially harmful interventions and no expected beneficial therapeutic outcome. Therefore, case reports coupled with pharmacokinetic trials usually constitute the highest level of evidence available for HDIs (Izzo, 2012; Posadzki et al., 2013). Many in vivo and in vitro interactions seen under experimental conditions are unlikely to lead to serious clinical consequences, but they must be evaluated in a mechanistic context (Hermann and von Richter, 2012). 2.4.1 Factors associated with increased risk of herb–drug interactions For an HDI to be clinically significant, the therapeutic range of the medicine must be narrow, meaning that a small reduction in pharmacological effect will lead to loss of efficacy or a small increase in pharmacological effect will lead to toxicity. A herbal medicine is unlikely to have these properties, and so the main impact of interaction is on the effects of conventional medicines. For an interaction to be significant, the dose–response curve of the medicine must be steep, such that a small change in plasma concentration leads to a significant change in clinical effect. For many medicines, these conditions are not met because there is an adequate safety margin between effective and toxic plasma levels; this applies to an even greater extent to herbal medicines. Medicines that do meet these conditions, however, such as some antiarrhythmic, antiepileptic, antineoplastic, antithrombotic and immunosuppressant medicines, are susceptible to interactions, and people taking these medicines are usually monitored closely. However, if an individual on any of these medicines presents suddenly with toxic symptoms having previously being stable, it is worthwhile asking whether they have taken any herbal medicines, dietary supplements, or traditional or complementary medicine products recently. Some of the factors associated with an increased risk of interaction are summarized in Table 4. Additional risks are posed by herbal medicines, such as the potential for lifetime exposure and unsupervised consumption (Shipkowski et al., 2018). 17 Table 4. Factors associated with increased risk of herb–drug interaction1 Steep dose–response curve Narrow therapeutic index Route of administration Problematic disposition or pharmacokinetic properties Enzyme inducers or inhibitors used for long-term treatment P-glycoprotein and cytochrome P450 induction or inhibition Susceptibility to genetic polymorphism Simultaneous prescribing by several practitioners Inappropriate self-medication 1 Modified from Chan K (2014). Understanding interactions between Chinese medicines and pharmaceutical drugs in inte- grated healthcare. Chin J Integr Med. 21(2):83–9. 2.4.2 Complexity of herbal medicines Many conventional medicines are intended to elicit a specific response in the body, based on a single target. Conversely, most herbal medicines are complex mixtures of active and inactive compounds or ingredients and act multisystemically. The pharmacokinetics of herbal medicines are often not known, and there may be constituents that affect the transport and bioavailability of other herbal compounds or conventional medicines. Standards and techniques for monitoring drug–drug interactions may not be suitable for investigating HDIs. Furthermore, the evidence regarding the interaction potentials of mixed herbal formulae is almost nonexistent, although manufacturers are now beginning to assess these products. Herbal medicines are rarely produced to the same standards as licensed medicines, unless they are registered as medicines, and the composition of herbal medicines, both qualitatively and quantitatively, is subject to wide variations. 2.4.3 Quality of herbal medicines Herbal medicines are affected by a complex range of factors, leading to variability in their chemical composition and thus their quality, safety and efficacy. Quality improvement may be achieved by implementing control measures for medicinal plant procurement under good agricultural and field collection practices, processing and manufacture of standardized finished herbal medicinal products under good manufacturing practices, and the adoption and implementation of regulatory standards by member states. WHO guidelines and monographs provide helpful information on quality-control measures for herbal medicines (WHO, 1999; WHO, 2003; WHO, 2004c; WHO, 2007a; WHO, 2007b; WHO, 2007c; WHO, 2009; WHO, 2010e; WHO, 2011c; WHO, 2017; WHO, 2018). Botanical sourcing and quality issues The composition of herbal medicines, qualitatively and quantitatively, can vary widely due to intrinsic and extrinsic factors. Intrinsically, species differences and genetic variations, plant organ specificity, ontogeny (stage of development), and diurnal and seasonal variations 18 affect the accumulation of active constituents. Extrinsic factors include environmental factors (e.g. geographical origin, soil), methods of cultivation and field collection (e.g. harvest and post-harvest treatments, drying, transport and storage, preservation, processing and manufacturing processes), inadvertent contamination or substitution, and intentional adulteration. These factors contribute to the quality of botanical materials and the herbal medicinal products prepared from them. Label claims may need to be independently verified for phytochemical content, especially for certain types of product such as those for weight loss, muscle development, and ergogenic and sexual enhancement, where adulteration is particularly rife (Gurley et al., 2018). Processing Before use as a medicine or for the production of finished herbal medicinal products, the harvested plant material first undergoes primary processing to remove soil, foreign materials and unwanted plant parts. The desired plant part may be subjected to only a few simple processing steps, such as cleaning and drying, or it may undergo a series of more complex steps, such as fermenting, roasting, frying, steaming or boiling. The primary purposes of secondary processing are ensuring quality and safety, including the neutralization of toxicity and diminishing side-effects, modification of therapeutic properties, and enhancing efficacy. Examples of herbal materials requiring specific detoxification processing include aconite root (Aconitum sp.), nux-vomica seed (Strychnos nux-vomica L.), gansui root (Euphorbia kansui S.L. Liou ex S.B. Ho), Euphorbia pekinensis Rupr.) and corydalis rhizome (Corydalis yanhusuo (Y.H. Chou & Chun C. Hsu) W.T. Wang ex Z.Y. Su & C.Y. Wu) (Zhao et al., 2010). Processed materials can serve as herbal medicines or as starting materials for manufacturing other herbal products. For further information, see WHO (2018). 2.4.4 Patient susceptibility Genetic factors Different ethnic groups and individual genetic differences among people from the same ethnic origin have genotypic variations that can alter the activity of drug-metabolizing enzymes and increase the likelihood of interactions (see Section 2.2.4). Age and gender Herbal products are used widely by older people (Alsanad et al., 2014; Agabiaka et al. 2017). Metabolic function of the liver and kidney decreases with age, leading to reduced plasma clearance of drugs. Neonates do not have the same range or activity of enzymes for metabolizing drugs; this develops at different rates in individuals over the first two years of life (Lu and Rosenbaum, 2014). These groups of people may be more susceptible to herbal interactions. 19 The influence of gender-related factors means that men and women may experience different HDIs. For instance, during pregnancy or while breastfeeding, women are often discouraged by conventional medical practitioners from taking all but essential medicines (e.g. for epilepsy). However, conventional practitioners may be unaware that some herbs are used explicitly at these times by local tradition, such as raspberry leaf tea (Rubus idaeus L.) during pregnancy, and fenugreek (Trigonella foenum-graecum L.) and fennel (Foeniculum vulgare Mill.) to enhance lactation. There are no known reports of drug interactions or toxicity involving these herbs that have been published to date, and most have “generally recognized as safe” (https://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/) or “qualified presumption of safety” (https://www.efsa.europa.eu/en/topics/topic/qualified- presumption-safety-qps) status, but their use should be closely monitored. Comorbidities The blood concentrations of herbal products and drugs metabolized in the liver or eliminated by the kidneys may be altered if the functioning of these organs is impaired. The most common result is an increase in blood levels, leading to enhanced toxicity and potential for HDIs. People living with cancer are more likely than the general population to take herbal medicines (Alsanad et al., 2014; Poonthananiwatkul et al., 2015). These people are already in a state of impaired health, and so interactions may have severe consequences. In addition, many of the drugs used in chemotherapy have toxic effects even at their usual clinical doses and have a narrow therapeutic index. Many people with cardiovascular disease take warfarin, which has a high potential for interaction with all drugs. People taking warfarin are monitored for anticoagulant effects at regular intervals, depending on their international normalized ratio (INR), a measure of blood clotting time. This has probably reduced the impact of warfarin interactions with herbal medicines. In addition to anticoagulation, many people with cardiovascular disease also take drugs for conditions such as hypertension, arrhythmias, hyperlipidaemia, hypercholesterolaemia or electrolyte imbalance. Many central nervous system drugs are associated with side-effects and the potential for interaction with other medicines. People taking these medicines may not know the possible consequences of taking herbal medicines at the same time as neuroleptics and antidepressants. Hypericum perforatum L. is commonly indicated to treat low mood conditions and has a high interaction potential; people with depression should be asked specifically whether they are considering taking it (Russo et al., 2014). Drug interactions are a common and recurring problem in immunocompromised people (Devanathan et al., 2019), including people living with human immunodeficiency virus (HIV), people living with cancer, and people undergoing transplant and taking certain immunosuppressants. People living with HIV may use herbal remedies and dietary supplements alongside conventional treatments; pharmacokinetic interactions between herbal medicines and antiretroviral drugs may increase the risk of toxicity or antiretroviral treatment failure (Stolbach et al., 2015). 20 2.4.5 Practitioner competence and training Conventionally trained health-care providers should be familiar with the herbal medicines being taken by their patients and the literature describing their known mechanisms of action, therapeutic use, safety and potential for drug interactions. Similarly, traditional or complementary medicine practitioners should have adequate training (WHO, 2010a; WHO, 2010b; WHO, 2010c) and be familiar with the conventional medicines being taken by their patients. Most importantly, both types of practitioner should be able to counsel their patients with regard to the use of herbal medicines alongside conventional medicines and serve as reference sources for all providers. 21 3. Data collection, assessment and dissemination of herb–drug interactions This section contains suggestions for regulators, researchers, clinicians, adverse drug reaction monitors, manufacturers, and other stakeholders concerned with the collection, assessment and dissemination of information on HDIs. The section outlines best current practice for undertaking data collection. The approach is consistent with general pharmacovigilance recommendations for medicines, with additional information required explicitly for herbal medicines. 3.1 Herb–drug interaction reports There is increasing awareness by conventional practitioners that their patients may use herbal and other natural remedies, but globally such awareness is highly variable. Therefore, there is inconsistent documentation in patient records regarding their use of herbal medicines. As a result, HDIs may be missed, information not collated, and no overall reliable statistics for the incidence of clinical HDIs be available. Regulatory authorities should inform health professionals and consumers about safety issues as they arise; in turn, health professionals, consumers, and herbal medicines manufacturers and sponsors should report any suspected potential herbal interactions to the designated authority (see Section 3.2). The type of reporting will vary in different jurisdictional settings. Underreporting of herbal medicines use is exacerbated by the inconsistent classification of herbal medicines in different jurisdictions and countries. Herbal medicines may be classified as herbal or botanical drugs, phytomedicines, therapeutic goods, traditional medicines, complementary medicines, natural health products, functional foods, dietary supplements, biologicals, cosmetics and medical devices, but many herbal medicines are not regulated at all. Some herbal medicines can be purchased directly by consumers without expert counselling on their safe use. The same plant product may be regulated differently within one country (e.g. as a food supplement and as a herbal medicine). These different regulatory approaches affect the identification of interactions and the selection of agency to report to. Consequently, the subsequent action(s), if any, taken by the regulatory and enforcement agencies or jurisdictions may be inconsistent, even if the inherent risks are unchanged. 3.2 Pharmacovigilance systems The WHO Guidelines on Safety Monitoring of Herbal Medicines in Pharmacovigilance Systems (WHO, 2004a) were prepared in the context of the WHO International Drug Monitoring Programme to strengthen national pharmacovigilance capacity regarding herbal medicines. The aim of the Guidelines is to provide technical guidance within existing national drug safety monitoring systems, or, if these systems are not in place, to facilitate their establishment. The Guidelines also provide standard definitions of terms relating to pharmacovigilance and safety monitoring of herbal medicines in order to promote 22 internationally coordinated information exchange. The Guidelines identify challenges posed in the safety monitoring of herbal medicines and propose approaches for overcoming these. Special attention is given to the reporting system for adverse reactions and the analysis of their causes. Currently, the majority of reported adverse events related to the use of herbal medicines are attributable either to poor product quality or to improper use (WHO, 2004a). Although pharmacovigilance systems for monitoring herbal medicines are not in place in many countries, the WHO Collaborating Centre for International Drug Monitoring in Uppsala has been collating reports of adverse events involving herbal medicines from around the world (http://www.who-umc.org/); for example, the pharmacovigilance centre in Morocco reported over 4800 individual herbal case safety reports between 2004 and 2008. In Africa, a survey of 39 countries identified several voluntary and compulsory pharmacovigilance systems (Skalli and Bencheikh, 2015). In Mali, a programme establishing médicaments traditionnels améliorés (“improved traditional medicines”) requires standardization and quality control of the herbal medicines, and submission of a dossier of safety and efficacy, in order to obtain marketing authorization (Wilcox et al., 2012). In Brazil, regulation of herbal medicines, including pharmacovigilance, is established, but only a few reports of herbal interactions have been collected to date. Considering the widespread use of herbal medicines in Brazil, if HDIs occur, they remain unrecognized and unreported (Mazzari and Prieto, 2014). In China, over 310 000 registered reporters, including from hospitals, clinics and pharmaceutical companies, form a network for monitoring and reporting adverse drug reactions for conventional and herbal drugs (National Center for ADR Monitoring, China, 2016). In the European Union, the European Association of Poisons Centres and Clinical Toxicologists collaborates with other agencies (https://www.eapcct.org/). In Indonesia, the National Agency of Drug and Food Control of the Republic of Indonesia has a role in post-marketing surveillance and pre-market evaluation of herbal products. The manufacturer is required to submit a dossier with details of labelling and advice for consumers, including side-effects and possible interactions (WHO, 2019b). In Thailand, there is a list of registered herbal medicines used in hospitals for intensive safety monitoring (Saokaew et al., 2011). In India, pharmacovigilance is covered under the auspices of Ayurveda, Siddha, Unani and homoeopathy (https://www.ayushsuraksha.com/). 3.3 Types and relevance of herb–drug interaction reporting Table 5 summarizes the types of HDI report available and their relevance. Reports for some of the most important herbal medicines are presented in Annex 1 to show how experimental, 23 mechanistic and clinical evidence can be interpreted together to aid clinical decision-making through published literature. Although good clinical studies and case reports form the basis of herbal interaction evidence, animal and in vitro studies may be needed to determine causality of the interaction or to support a mechanism. Animal and in vitro results can be useful for interpreting clinical findings and explaining mechanisms of action, and perhaps predicting potential interactions. However, it is important to consider any metabolic transformations that may occur, and the drug and herb concentrations used experimentally, for their relevance to human clinical doses. The example of Hypericum perforatum L. (Table 3) suggests that for well-documented clinical interactions, experimental studies usually provide supporting evidence that more than one mechanism is involved; where these reinforce each other, such as strong induction of cytochrome P450 enzymes coupled with strong induction of P-glycoprotein, it may result in reduced blood levels of many drugs, causing treatment failure. Collating the evidence of reported HDIs also highlights where research may be focused. Current published evidence mainly concerns herbs of high economic or therapeutic importance, from countries and areas with a more developed tradition and industry (China, European Union, United States). Meta-analyses, which are ideal for evaluating the overall conclusions of several studies, are rarely possible for HDIs because the data sets must be the same to pool the acquired data. The composition (qualitative and quantitative chemical content), formulation and dosage of the herbal medicines being administered in different studies is rarely comparable. A systematic review is therefore usually more appropriate – but this requires a reasonable number of reports to analyse, which is unusual for herbal medicines, and so subjecting such reports to a higher evaluation process is rarely possible. It is even more challenging to assess interactions involving poly-herbal formulae, although an evaluation of the component herbs may allow a tentative identification of the herb causing the interaction. Negative results from clinical studies and in vivo and in vitro tests, which suggest a lack of potential interaction, should always be considered and included in evaluation of a specific herb. 24 Table 5. Types and relevance of herb–drug interaction reporting Type of report Relevance Human, clinical Clinical interaction report confirmed (e.g. by repeated challenge) Highest Clinical report unconfirmed but likely on mechanistic grounds Medium Experimental using human healthy volunteers High Animal In vivo using probe drugs Medium; animal and human cytochrome P450 expression are different Ex vivo using isolated tissue or cells Low; may not consider metabolic transformation In vitro Cell culture, e.g. using human or animal cell lines or microsomal preparations Low; may not consider metabolic transformation or variations in animal and human cytochrome P450 expression 3.4 Assessing clinical reports and human case studies Causality assessment methods were developed for conventional medicines and may be difficult to apply to herbal medicines and HDIs. The basic information required for clinical reports is the same as for all medicines, with additional information specific for herbal medicines. In many published reports, information regarding a herbal medicine is incomplete, with the scientific name of the plant material, the parts used, the extraction type or the dosage regimen not stated. The validity of any report relies on accurate identification of the product or herb, which may be difficult when different common names are used. For example, “ginseng” may refer to several plant species, including Panax ginseng C.A. Mey. (Chinese or Korean ginseng), Panax quinquefolius L., (American ginseng), Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. (Siberian ginseng), or Withania somnifera (L.) Dunal (Indian ginseng) (Shaw et al., 2012). To avoid confusion, the binomial Latin plant name and botanical authority must be cited where known (Chan et al., 2012). Table 6 presents the WHO guidelines on pharmacovigilance for herbal medicines (WHO, 2004a). 25 Table 6. World Health Organization guidelines on information requested for herb–drug interactions1 Where permitted by health information privacy codes, and with appropriate confidentiality, some identification of the patient or consumer in order to avoid duplications and facilitate follow-up Age, sex and brief medical history of the patient or consumer (when relevant); in some countries, ethnicity may need to be specified Details of suspected herbal product if known: species name (Latin binomial and common names of plant), part of the plant used (e.g. herb, root), preparation method, brand or ingredient name, manufacturer, country of origin, batch number, expiry date and provider (supplier or prescriber) Administration details: dose and quantity supplied, dosage form, route, frequency, start and stop dates Indication or reason for use Adverse reaction data: date of onset, including duration from first administration to event, description with symptoms and signs, severity and seriousness, results of clinical investigations and tests, course and outcome, re-challenge with same products where appropriate All other medicines used concurrently or recently (including self-medication), with administration details as above Risk factors where known, e.g. age, impaired renal or hepatic function, previous exposure to herbal medicines concerned, previous allergies, misuse of medicines, social use of drugs Country where report was made and status of reporter (doctor, pharmacist, nurse, other health-care professional, other non-health-care professional) Name and address of reporter (to be considered confidential and to be used only for data verification, completion and case follow-up) 1 Based on WHO (2004). WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems. Geneva: World Health Organization (http://apps.who.int/medicinedocs/en/m/abstract/Js7148e/). If an HDI is suspected, as much data as possible must be recorded so the assessment can be revisited when needed, such as in the light of new information or suspected error in the evaluation. The determination of causality of HDIs should be carried out by qualified individuals experienced in clinical pharmacology and pharmacokinetics, and experts in phytochemistry and pharmacognosy should be recruited to investigate specific aspects of the herbal medicines. 3.5 Information retrieval Many resources are available, including research papers, conference reports, books, review articles and document collections from credible sources. These reports can be identified through systematic surveillance of literature sources, such as the WHO database, international English-language electronic databases (e.g. AMED, CINAHL, IPA, Medicines Complete, NMCD, PubMed), Chinese electronic databases (e.g. CBM, CMCC, CNKI, TCMDS, Wanfang), and other national databases. There are also databases for specific disease targets, such as HIV (http:// www.hiv-druginteractions.org) and hepatitis (http://www.hep-druginteractions.org). Reports of HDIs should be viewed with caution. Speculation based on extrapolation from data associated with an individual constituent of a complex herbal medicine, or those based on large scale in vitro screening exercises or purported mechanisms of action, may not necessarily have clinical significance. The data collected should be evaluated for quality, applicability and clinical relevance in accordance with reporting recommendations for safety monitoring of herbal medicines (WHO, 2004a). 26 3.6 Dissemination of information The provision of valid and validated information on HDIs to decision-makers is essential for the safe use of herbal medicines or concomitant use of herbal and conventional medicines. These stakeholders include national, provincial, state and local health authorities and regulatory agencies, pharmacovigilance centres, poison centres, health professional organizations, health-care providers, other health-care professionals, manufacturers, and patients and consumers. Although it is important that practitioners receive accurate information about HDIs, its dissemination may encounter obstacles similar to those for pharmacovigilance of herbal products (WHO, 2004a). These may include a lack of interest by professional societies and the journals on which practitioners rely for information regarding traditional medicine practices; lack of activity by relevant authorities and health-care professionals regarding reports of herbal interactions; failure to communicate these to patients, consumers, manufacturers and suppliers; conflicts of interest; and inaccurate reporting by media outlets. Communication strategies should be established to effectively reach, or be easily accessible to, all relevant stakeholders (WHO, 2004a). Methods of communication recommended for the safety monitoring of herbal medicines by the WHO (2004a) guidelines include posting on websites, direct mass mailing to providers of herbal medicines and health professionals, briefings to the mass media and patient and consumer associations, education sessions at health professional society meetings, and continuing education of health-care providers. 27 4. Managing herb–drug interactions There are few strategies available for managing HDIs. When health professionals and regulators establish guidelines, the following issues should be considered. 4.1 Education and training of health professionals 4.1.1 Raising awareness Although an increasing number of people consult their health-care professionals before taking herbal medicines, many do not. Before prescribing any medicines that may result in the manifestation of a harmful HDI, health-care professionals are encouraged to ask their patients for full disclosure of all medicines taken, usual diet, recent changes in diet, and conventional and herbal products they may have taken or intend to take. 4.1.2 Basic and continuing education Few, if any, courses on herbal medicines are included in the medical curriculum of conventional health-care practitioners, although in countries with a strong tradition of using herbal medicines, such as China and India, training in herbal medicine should be included in medical universities. In Japan, basic instruction in Kampo medicine is included in the medical and pharmaceutical curriculum; for a health-care professional to prescribe or practise Kampo medicine, they must have completed conventional medicine or pharmacy education. A framework for training traditional medicine practitioners is included in the WHO benchmarks for training herbal practitioners (WHO, 2010a; WHO, 2010b; WHO, 2010c). For health professionals, a curriculum developed by WHO and the International Society for Pharmacovigilance is available to aid planning and conduct training courses in pharmacovigilance (http://isoponline.org/training/pv-curriculum/). 4.1.3 Overview of reporting suspected herb–drug interactions The safety of medicines is usually monitored through spontaneous reporting pharmacovigilance systems. These systems can be used to report suspected adverse reactions to herbal medicines, including HDIs (WHO, 2004a). Standard forms are available for reporting to designated authorities (e.g. pharmacovigilance centres, regulatory authorities, poison centres) by manufacturers of herbal medicines, doctors, pharmacists, nurses and other health professionals and, in some countries, by patients. Many countries (e.g. Australia, Canada, China, Japan, Malaysia, Morocco, New Zealand, Philippines, South Africa, Thailand, United Kingdom, United States) have a reporting system for HDIs. In the United States, health professionals and consumers can report suspected adverse drug reactions of herbal medicines (marketed and consumed as 28 dietary supplements) to the Food and Drug Administration MedWatch scheme. In the United Kingdom, the spontaneous reporting system is referred to as the “yellow card scheme” (because the hard copy of the form is yellow); the Medicines and Healthcare Products Regulatory Agency receives approximately 20  000 yellow card reports every year, of which about 100 concern herbal products (Shaw et al., 2012). Australia has a similar “blue card scheme”. In some countries, such as European Union countries and the United States, poisons control centres, drug information centres and selected consumer organizations can also serve as intake facilities for enquiries on product safety or suspected poisonings, including herbal medicines, and can be useful sources of information on HDIs. The value of these alternative centres in public safety monitoring has been shown in Morocco, for example, where 62% of reports in the poisons control database concerned herbal medicines (Skalli and Bencheikh, 2012). In reporting a suspected HDI, the reporter does not need to confirm any association between the drug and the effect. WHO (2004a, p.23) describes how the degree of certainty of a causal relationship is assigned to one of six categories by the Uppsala Monitoring Centre (Table 7). These criteria were developed with the aim of providing a structured approach to determining the strength of the relationship between a reported event and suspected product. This is a combined assessment that considers the clinical and pharmacological aspects of the case history and the quality of the data reported. Table 7. Causality categories described by the Uppsala Monitoring Centre1 1 Certain A clinical event, including laboratory test abnormality, occurring in a plausible time rela- tionship to medicine administration, and that cannot be explained by concurrent disease or other medicines or chemicals. The response to withdrawal of the medicine (de-cha- llenge) should be clinically plausible. The event must be definitive pharmacologically or phenomenologically, using a satisfactory re-challenge procedure if necessary 2 Probable/likely A clinical event, including laboratory test abnormality, with a reasonable time sequence to administration of the medicine, unlikely to be attributed to concurrent disease or other medicines or chemicals, and that follows a clinically reasonable response on withdrawal (de-challenge). Re-challenge information is not required to fulfil this definition 3 Possible A clinical event, including laboratory test abnormality, with a reasonable time sequence to administration of the medicine, but that could also be explained by concurrent disease or other medicines or chemicals. Information on medicine withdrawal may be lacking or unclear 4 Unlikely A clinical event, including laboratory test abnormality, with a temporal relationship to medicine administration that makes a causal relationship improbable, and in which other medicine, chemicals or underlying disease provide plausible explanations 5 Conditional/ unclassified A clinical event, including laboratory test abnormality, reported as an adverse reaction, about which more data are essential for a proper assessment, or the additional data are under examination 6 Unassessable/ unclassifiable A report suggesting an adverse reaction that cannot be judged because information is insufficient or contradictory, and that cannot be supplemented or verified 1 Source: UMC (2000). Safety monitoring of medicinal products. Uppsala: Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring (https://www.who-umc.org/media/1703/24747.pdf). As a step towards harmonization in medicine regulation in the European Union, three causality categories were proposed by the European Union pharmacovigilance working parties (Table 8). 29 Table 8. Causality categories proposed by the European Union pharmacovigilance working parties1 Category A Reports including good reasons and sufficient documentation to assume a causal relations- hip, in the sense of plausible, conceivable, likely, but not necessarily highly probable Category B Reports containing sufficient information to accept the possibility of a causal relationship, in the sense of not impossible and not unlikely, although the connection is uncertain and may even be doubtful, e.g. because of missing data, insufficient evidence or the possibility of another explanation Category C Reports where causality is, for one or another reason, not assessable, e.g. because of mis- sing or conflicting data 1 Source: WHO (2019b). Essential medicines and health products information portal. Geneva: World Health Organization (http:// apps.who.int/medicinedocs/en/d/Jh2934e/15.html). National pharmacovigilance centres, poison control centres and other designated bodies collecting HDI reports use statistical methods to detect and analyse signals of adverse events for further study or for regulatory action. Usually, a series of similar events rather than a single report is required to generate a signal. The significance of a given signal is dependent upon the seriousness of the event, geographical occurrence (local, national, regional, global), and the quality of the information (WHO, 2002). Published reports documenting HDIs are available from several online databases provided by professional, commercial and nongovernmental organizations and from governmental agencies (e.g. https://nccih.nih.gov/health/providers/digest/herb-drug, https://medlineplus.gov/ druginfo/herb_All.html). The Uppsala Monitoring Centre manages the global WHO database for international drug monitoring (http:/www.who-umc.org/). When an HDI is suspected or confirmed, there should be an expected protocol to be followed by both conventional and traditional practitioners in accordance with the regulation of that country. 4.2 Consumer information and education People may not associate their signs and symptoms with the use of herbal medicines, or may not be aware of the importance of reporting adverse effects. Therefore, individuals should be educated and encouraged to be open with their clinicians about their use of all medicines and supplements. Although the prescriber should report the suspected case, individuals can also report suspected adverse effects in many countries (e.g. Australia, China, European Union countries, India, Indonesia, Morocco). The WHO (2004b) Guidelines suggest that “because of the limited knowledge about interactions between conventional medicines and herbal medicines, this is an area that needs further study”. The Guidelines provide a reference for guiding consumers in choosing a traditional and complementary medicine therapy that is safe and effective. They state that “consumers need to be informed about any potential interactions involved in their therapy”. Relevant information should be provided in a patient information leaflet, which is a requirement in some regions (e.g. Brazil, European Union, Indonesia) but is not mandatory in others. 30 Patient information leaflets and other resources for consumer advice such as websites should include the following, in addition to the usual information concerning indications, contraindications and dosage: ■ If you are feeling unwell, please tell your doctor or another health-care professional that you are taking a herbal medicine with other medicines. ■ Show this leaflet to your doctor or pharmacist so they know what you are taking. ■ Ask whether a report about your case will be made. ■ You can make a report yourself if you think it is important. Consult the authorized website for guidance. 4.3 Research strategies for herb–drug interactions 4.3.1 Research methods Producing evidence to support HDIs would ideally be accomplished by studying the interaction between the herbal medicine as the active pharmaceutical ingredient and the interacting drug. As each herbal product contains hundreds of constituent molecules, and these may vary between batches of the herb, delineating HDIs using standard in vitro and in vivo methods is usually unfeasible. In vivo methods may offer better models than in vitro methods for studying complex mixtures of chemicals, but metabolic differences between animals and humans complicate the interpretation of results. No standard methods are currently available for the study of HDIs, but new methods are being researched (Jackson et al., 2017; Pelkonen et al., 2017). Ethical issues often make human clinical intervention trials difficult to justify, and thus individual case reports and clinical observational studies remain the primary source data for identification of new HDIs and confirming suspected risks. As standard research methods are not available to study HDIs, social science and public health research methods can be used to help understand consumer behaviour and attitudes to assist health regulators and providers in policy development. An emerging strategy for targeting experiments and clinical interventions for herbal medicine research is combining pharmacoepidemiological methods with case–control and cohort studies (Shaw et al., 2012). If herbal interaction signals are detected from spontaneous pharmacovigilance reports (evaluated per pharmacovigilance guidelines; WHO, 2004a), they may serve as a rationale for conducting a case–control study. Clinical studies in tandem with chemical characterization using metabolomics can be applied to identify compounds present in herbal medicines that are responsible for the effect. 4.3.2 Correlation of preclinical studies with clinical outcomes Recent reviews have suggested that although in vitro screening of plant extracts against enzymes responsible for drug metabolism may offer only limited evidence to correlate 31 preclinical results with clinical outcomes, it may provide preliminary data for more in-depth investigations (Brewer and Williams, 2012; Fasinu et al., 2012; Gurley et al., 2012; Izzo, 2012). Table 3 contains a summary of preclinical and experimental tests on specific herbs and the reported clinical interactions for these herbs. It shows that certain in vitro effects are likely to be related to significant interactions. To further understand these interactions, it is important to consider the processes of preparation of the herbal medicine and potential changes in its chemistry. All extracts should be chemically characterized before testing. 4.3.3 Identification of interactive constituent(s) A chemical analysis should be undertaken to identify, if possible, the constituent(s) responsible for the interaction(s). These component(s) may or may not be the same as the active constituents, and bioassays may be useful in assessing the role of the constituent(s) in the interaction. In the event that compounds responsible for the HDI are not necessary for therapeutic activity, then they could be removed. For instance, Hypericum perforatum L. contains hyperforin; this is the main interacting compound but is also an active component (in addition to the hypericins and flavonoids). A hyperforin-free product has been shown to be efficacious (Russo et al., 2014). There are no other well-documented examples of constituents being removed to reduce HDIs. 4.3.4 Combination herbal medicines In addition to investigating the safety of single herbs or medicines, chemical and pharmacological research on herbal formulation is required: in most traditional and complementary medicine systems, mixtures of herbs are used more commonly than single herbs or chemical compounds. The contribution of individual herbs to the overall effect is complex and may involve pharmacodynamic or pharmacokinetic effects. The herbal mixture may be treated as the active pharmaceutical ingredient and tested as an entity. In cases where a component herb is suspected to be the one that causes an HDI, that individual herb must be tested. Fingerprint chemical profiles of the active pharmaceutical ingredient should be recorded and analysed in accordance with WHO guidelines and other pharmacopoeial and relevant standards. 4.3.5 Overview of research strategies Currently, limited guidance or useful information is available for rapid reference on HDIs. Herbal medicines are included in the drug–drug interaction guideline of the European Medicines Agency (2012), but specific guidelines for HDIs have not been developed. There is also a lack of evidence regarding the incidence and severity of herbal interactions. To address these concerns, rigorous research is required to provide support for evaluating clinical reports and making decisions. Most of the research on HDIs has been performed in a limited number of countries. It is crucial to expand research in regions where herbal medicines are used routinely alongside conventional medicines in order to harness knowledge and experience. 32 Although no uniform approach is taken globally, many countries have already established, or even integrated into national health-care systems, regulatory and monitoring programmes to safeguard the use of traditional and complementary medicines in line with national and regional needs. When formulating these initiatives, WHO policies and guidelines should be considered, and existing resources and monitoring schemes exploited. Key areas for attention can be found in the WHO Traditional Medicine Strategy: 2014–2023 (WHO, 2013), which recommends that Member States ensure high-quality traditional medicine products, establish appropriate regulatory frameworks for practitioners and products, and improve the education of practitioners and their patients. 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It is intended simply to illustrate how experimental and clinical evidence can be interpreted together to decide upon the likelihood or causality of an interaction. The herbs were chosen based on a preliminary search to identify the most cited herbs in HDI studies, but the number of citations does not necessarily reflect the likelihood or seriousness of an interaction, since “negative” or “lack of interaction” studies are also included. Further review references are provided for certain herbs where the entries have been truncated. The reports cited in the annex were selected as examples for different medicines involved in the interaction and subjected to a critical evaluation, but inevitably some important studies have been omitted purely due to space constraints. In vitro or in vivo animal studies are included only if they support a mechanism of interaction for a human study. Multi-ingredient herbal formulae, although crucial in the application of most forms of traditional medicine, are not included due to difficulties in ascribing causality to a specific component. The mechanism(s) ascribed to an interaction may have been updated since the earlier reports; our citations are those of the conclusions of the original study. Empty cells in the tables denote that information may have been insufficient or of poor quality or would not meet the purpose of this document, rather than a negative effect. Strategy for search Searches using the keywords “herb–drug interaction” and “herbal interaction” were carried out using PubMed (https://www.ncbi.nlm.nih.gov/pubmed/), Science Direct (http://www. sciencedirect.com/), Google Scholar (https://scholar.google.com/) and NAPRALERT (https:// www.napralert.org).The Chinese literature and databases were also searched without restriction on the study design. After removing duplicates, papers retrieved were reviewed for additional relevant citations. Studies where the full paper was unavailable were excluded as they could not be evaluated properly. A selection of examples of HDI reports in line with the purposes of this document was compiled and reviewed by expert panels in two global reviews. Additional reports suggested by experts during the review process were then added where appropriate. These are summarized in Table A1.1. 38 Table A1.1. Summary of studies included in Annex1 Annex table Herb Number of studies cited Total Human 1 Animal In vitro A1.2 Astragalus spp. (milk vetch) 4 1 3 A1.3 Curcuma longa L. (turmeric) 8 3 3 2 A1.4 Echinacea spp. (coneflower) 8 8 A1.5 Ginkgo biloba L. (maidenhair tree) 19 13 4 2 A1.6 Glycyrrhiza spp. (liquorice) 4 4 1 A1.7 Hypericum perforatum L. (St John’s wort) 26 26 A1.8 Panax ginseng C.A. Mey. (ginseng) 10 8 2 A1.9 Salvia miltiorrhiza Bunge (Dan Shen) 11 3 5 3 A1.10 Schisandra spp. (magnolia vine) 11 3 7 1 A1.11 Silybum marianum (L.) Gaertn. (milk thistle) 6 5 1 A1.12 Zingiber officinale Roscoe (ginger) 3 2 1 Total 110 1 Human studies contain both case reports/series and clinical trials. 39 Ta bl e A1 .2 . As tr ag al us : A st ra ga lu s m on gh ol ic us B un ge /A st ra ga lu s p ro pi nq uu s S ch is ch ki n [= A st ra ga lu s m em br an ac eu s ( Fi sc h. ) B un ge ] ( Le gu m in os ae ); m ilk v et ch – fo ur st ud ie s D ru g de ta ils H er b an d pr od uc t d et ai ls St ud y de ta ils D ru g D os ag e re gi - m en Fo rm Ch em ic al co ns ti tu en ts D os ag e re gi m en Cl in ic al / hu m an In v iv o In vi tr o Sy m pt om s/ ou tc om es H yp ot he si ze d m ec ha ni sm Ev al ua ti on Re fe re nc e D oc et ax el 35 m g/ m 2 / w ee k fo r 3 w ee ks As tr ag al us m on gh ol icu s (J in fu ka ng ) M ul tih er b fo r- m ul a co nt ai ni ng As tr ag al us 75 m l/m 2 /d ay 20 p eo pl e liv in g w ith lu ng c an ce r N o ef fe ct N /A N o in te ra ct io n Ca ss ile th e t a l. (2 00 9) Pi og lit a- zo ne 1. 5 m g/ kg si ng le do se 10 : 1 ra tio de co c- tio n fr om gr an ul es N ot st at ed 2. 8 g/ kg /d ay fo r 7 d ay s Ra t, ty pe 2 di ab et es N o ef fe ct N /A N o in te ra ct io n Yu an e t a l. (2 01 2) Th eo ph y- lli ne 15 m g/ kg As tr ag a- lo si de IV (A G -IV ) Pu re A G -IV 3 m g/ kg IV fo r 7 da ys Ra t Re du ce d cl ea ra nc e of th eo ph yl lin e In hi bi tio n of CY P1 A2 Po te nt ia l in te ra ct io n: in cr ea se d to xi ci ty o f th eo ph yl lin e Zh an g et a l. (2 01 3) M id az ol am 15 m g/ kg Ex tr ac t N ot st at ed 10 m g/ kg Ra t In cr ea se in Cm ax a nd A U C In hi bi tio n of CY P3 A4 Po te nt ia l in te ra ct io n: in cr ea se d ef fe ct of m id az ol am Pa o et a l. (2 01 2) AU C, a re a un de r c on ce nt ra tio n– tim e cu rv e; C m ax , m ax im um p la sm a co nc en tr at io n; C YP , c yt oc hr om e P4 50 ; I V, in tr av en ou s; N /A , n ot a pp lic ab le . Ca ss ile th B R, R iz vi N , D en g G, Y eu ng K S, V ic ke rs A , G ui lle n S, e t a l. (2 00 9) . S af et y an d ph ar m ac ok in et ic tr ia l o f d oc et ax el p lu s a n As tr ag al us -b as ed h er ba l f or m ul a fo r n on -s m al l c el l l un g ca nc er p at ie nt s. Ca nc er Ch em ot he r P ha rm ac ol . 6 5( 1) :6 7– 71 . Pa o LH , H u OY , F an H Y, L in C C, L iu L C, H ua ng P W (2 01 2) . H er b– dr ug in te ra ct io n of 5 0 Ch in es e he rb al m ed ic in es o n CY P3 A4 a ct iv ity in v itr o an d in v iv o. A m J Ch in M ed . 4 0( 1) :5 7– 73 . Yu an Y M , G ao JW , S hi Z , H ua ng P, L u YS , Y ao M C, H ua ng M (2 01 2) . H er b– dr ug p ha rm ac ok in et ic in te ra ct io n be tw ee n ra di x as tr ag al i a nd p io gl ita zo ne in ra ts . J E th no ph ar m ac ol . 1 44 (2 ):3 00 –3 04 . Zh an g YH , Z ha ng Y J, Gu o YL , L i W J, Yu C (2 01 3) . A st ra ga lo sid e IV in hi bi te d th e ac tiv ity o f C YP 1A 2 in li ve r m ic ro so m es a nd in flu en ce d th eo ph yl lin e ph ar m ac ok in et ic s i n ra ts . J P ha rm P ha rm ac ol . 6 5( 1) :14 9– 55 . 40 Ta bl e A1 .3 . C ur cu m a lo ng a L. (C ur cu m a do m es tic a Va l.) (Z in gi be ra ce ae ); tu rm er ic – e ig ht st ud ie s1 D ru g de ta ils H er b an d pr od uc t d et ai ls St ud y de ta ils D ru g D os ag e re gi m en Fo rm Ch em ic al co ns ti - tu en ts D os ag e re gi m en Cl in ic al / hu m an In vi vo In v it ro Sy m pt om s/ ou tc om es H yp ot he si ze d m ec ha ni sm Ev al ua ti on Re fe re nc e Ca rb op la tin , et op os id e, vi nc ris tin e Ca rb op la tin , et op os id e an d vi nc ris tin e as pr ob e dr ug s Cu rc um in Cu rc um in N /A H um an re tin o- bl as to m a ce lls Sy ne rg is tic c yt o- to xi c ef fe ct N ot st at ed Po te nt ia l in te ra ct io n: m ay e nh an ce cy to to xi ci ty Sr ee ni va sa n et a l. (2 01 5) Cl op id og re l, w ar fa rin Cl op id og re l an d w ar fa rin a s pr ob e dr ug s Cu rc um in Cu rc um in 25 , 5 0 or 10 0 m g/ kg fo r 7 d ay s Ra t Co m pe tit iv e in hi - bi tio n of C YP 2C 19 ; ne gl ig ib le e ff ec t o n ot he r C YP e nz ym es In hi bi tio n of CY P2 C1 9 U nc le ar Li u et . ( 20 13 ) D ex tr o- m et ho rp ha n 30 m g si ng le do se Tu rm er ic po w de r, et ha no lic ex tr ac t N /A N ot st at ed 6 m al es In cr ea se in u rin e m et ab ol ic ra tio o f de xt ro m et ho rp ha n/ de xt ro rp ha n In hi bi tio n of CY P2 D 6 U nc le ar Al -J en oo bi e t al . ( 20 15 ) 10 0 μg /m l N /A H um an liv er m ic ro so - m es In hi bi tio n of O - a nd N -d em et hy la tio n of de xt ro m et ho rp ha n Ev er ol im us 0. 5 m g/ kg Cu rc um in Cu rc um in 50 –1 00 m g/ kg Ra t D ec re as e in A U C an d Cm ax o f e ve - ro lim us w ith lo w er bi oa va ila bi lit y In du ct io n of CP 3A 4; in hi bi tio n of P -g p In te ra ct io n: re du ce d ef fic ac y of ev er ol im us H se ih e t a l. (2 01 4) Fl ui nd io ne N ot st at ed Tu rm er ic po w de r in fu si on N ot st at ed 2. 5 g/ da y fo r 5 d ay s 1 w om an ag ed 5 6 ye ar s El ev at io n of IN R N ot st at ed In te ra ct io n: in cr ea se d ris k of b le ed in g D av el uy e t a l. (2 01 4) Lo sa rt an 10 m g/ kg ga va ge Cu rc um in Cu rc um in 10 0 m g/ kg fo r 7 d ay s Ra t In cr ea se d pl as m a co nc en tr at io ns o f lo sa rt an a nd it s m et ab ol ite s In hi bi tio n of P- gp , i nh ib iti on o f CY P3 A4 U nc le ar Li u et a l. (2 01 2) 41 D ru g de ta ils H er b an d pr od uc t d et ai ls St ud y de ta ils D ru g D os ag e re gi m en Fo rm Ch em ic al co ns ti - tu en ts D os ag e re gi m en Cl in ic al / hu m an In vi vo In v it ro Sy m pt om s/ ou tc om es H yp ot he si ze d m ec ha ni sm Ev al ua ti on Re fe re nc e Su lfa sa la zi ne 2 g Cu rc um in ca ps ul es Cu rc um in 2 g 8 m al es In cr ea se d pl as m a le ve ls of su lfa sa la zi ne In hi bi tio n of P -g p In te ra ct io n: in cr ea se d bi oa va ila bi lit y of su lfa sa la - zi ne Ku su ha ra e t al . ( 20 12 ) AU C, a re a un de r c on ce nt ra tio n– tim e cu rv e; C m ax , m ax im um p la sm a co nc en tr at io n; C YP , c yt oc hr om e P4 50 ; I N R, in te rn at io na l n or m al iz ed ra tio ; N /A , n ot a pp lic ab le ; P -g p, P -g ly co pr ot ei n. 1 Fo r f ur th er d et ai ls of th e co m pl ex p ha rm ac ok in et ic s o f t he c ur cu m in oi ds , s ee B ah ra m so lta ni R , R ah im i R , F ar za ei M H (2 01 7) . P ha rm ac ok in et ic in te ra ct io ns o f c ur cu m in oi ds w ith c on ve nt io na l d ru gs : a re vi ew . J E th no ph ar m ac ol . 2 09 :1– 12 . Al -J en oo bi F I, A l-T hu ka ir AA , A la m M A, A bb as FA , A l-M oh iz ea A M , A lk ha rf y KM , A l-S uw ay eh S A (2 01 5) . E ffe ct o f C ur cu m a lo ng a on C YP 2D 6- a nd C YP 3A 4- m ed ia te d m et ab ol ism o f d ex tro m et ho rp ha n in h um an liv er m ic ro so m es a nd h ea lth y hu m an su bj ec ts . E ur J D ru g M et ab P ha rm ac ok in et . 4 0( 1) :6 1– 6. D av el uy A , G én ia ux H , T hi ba ud L , M al la re t M , M ire m on t-S al am é G, H ar am bu ru F (2 01 4) . P ro ba bl e in te ra ct io n be tw ee n an o ra l v ita m in K a nt ag on ist a nd tu rm er ic (C ur cu m a lo ng a) . T he ra pi e. 6 9( 6) :5 19 –2 0. Hs ie h YW , H ua ng C Y, Y an g SY , P en g YH , Y u CP , C ha o PD , H ou Y C (2 01 4) . O ra l i nt ak e of c ur cu m in m ar ke dl y ac tiv at ed C YP 3 A4 : i n vi vo a nd e x- vi vo st ud ie s. Sc i R ep . 4 :6 58 7. Ku su ha ra H , F ur ui e H, In an o A, S un ag aw a A, Y am ad a S, W u C, e t a l. (2 01 2) . P ha rm ac ok in et ic in te ra ct io n st ud y of su lfa sa la zi ne in h ea lth y su bj ec ts a nd th e im pa ct o f c ur cu m in a s a n in v iv o in hi bi to r o f B CR P. Br J P ha rm ac ol . 1 66 :7 93 –8 03 . Li u AC , Z ha o LX , L ou H X (2 01 3) . C ur cu m in a lte rs th e ph ar m ac ok in et ic s o f w ar fa rin a nd c lo pi do gr el in W ist ar ra ts b ut h as n o eff ec t o n an tic oa gu la tio n or a nt ip la te le t a gg re ga tio n. P la nt a M ed . 7 9( 11 ):9 71 –7 . Li u AC , Z ha o LX , X in g J, Li u T, D u FY , L ou H X (2 01 2) . P re -t re at m en t w ith c ur cu m in e nh an ce s p la sm a co nc en tr at io ns o f l os ar ta n an d its m et ab ol ite E XP 31 74 in ra ts . B io l P ha rm B ul l. 35 (2 ):1 45 –5 0. Sr ee ni va sa n S, K ris hn ak um ar S (2 01 5) . S yn er gi st ic e ffe ct o f c ur cu m in in c om bi na tio n w ith a nt ic an ce r a ge nt s i n hu m an re tin ob la st om a ca nc er c el ls lin es . C ur r E ye R es . 4 0( 11 ):1 15 3– 65 . Ta bl e A1 .3 . Cu rc um a lo ng a L. (C ur cu m a do m es tic a Va l.) (Z in gi be ra ce ae ); tu rm er ic – e ig ht st ud ie s1 (C on 't. ) 42 Ta bl e A1 .4 . E ch in ac ea : E ch in ac ea p ur pu re a (L .) M oe nc h. /E ch in ac ea a ng us tif ol ia D C. /E ch in ac ea p al lid a (N ut t.) N ut t. (A st er ac ea e) ; p ur pl e co ne flo w er , na rr ow -le av ed co ne flo w er , p al e co ne flo w er – e ig ht st ud ie s1 D ru g de ta ils H er b an d pr od uc t d et ai ls St ud y de ta ils D ru g D os ag e re gi m en Fo rm Ch em ic al co ns ti - tu en ts D os ag e re gi m en Cl in ic al / hu m an In vivo In vitro Sy m pt om s/ ou tc om es H yp ot he si ze d m ec ha ni sm Ev al ua ti on Re fe re nc e Ca ff ei ne , m id az ol am Ca ff ei ne 2 00 m g, m id az ol am 0. 05 m g/ kg IV Ro ot e xt ra ct Ec hi na ce a pu r- pu re a (N at ur e’ s Bo un ty ) N ot st at ed 40 0 m g 4 tim es /d ay fo r 8 d ay s 12 p eo pl e (6 fe m al e) In cr ea se d sy st e- m ic c le ar an ce o f or al c af fe in e an d IV m id az ol am In du ct io n of CY P1 A2 a nd CY P3 A4 ; n o ef fe ct on o th er e nz ym es Po te nt ia l i nt e- ra ct io n w ith ca ff ei ne a nd m id az ol am G or sk i e t a l. (2 00 4) D ar un av ir, rit on av ir D ar un av ir 60 0 m g/ rit on av ir 10 0 m g 2 tim es / da y fo r 4 w ee ks Ro ot e xt ra ct Ec hi na ce a pu rp ur ea (A rk op ha rm a) N ot st at ed 50 0 m g ev er y 6 h on da ys 1 –1 4 15 p eo pl e liv in g w ith H IV Li tt le o ve ra ll ef fe ct o n da ru na vi r p ha rm a- co ki ne tic s, bu t s om e in di vi du al s s ho w ed de cr ea se in A U C; n o ef fe ct o n rit on av ir In du ct io n of CY P3 A4 Po te nt ia l i nt e- ra ct io n w ith da ru na vi r i n so m e pe op le ; n o in te ra ct io n w ith rit on av ir M ol tó e t a l. (2 01 1) D ig ox in 0. 25 m g Ex tr ac t o f E ch i- na ce a pu rp ur ea al l p ar ts , a nd Ec hi na ce a au gu st ifo lia ro ot St an da rd iz ed 2. 2 m g is ob u- ty la m id es 1 ca ps ul e 3 tim es /d ay fo r 1 4 da ys 18 p eo pl e (9 fe m al e) N o ch an ge in p ha rm a- co ki ne tic s o f d ig ox in N /A N o in te ra ct io n G ur le y et a l. (2 00 8) D oc et ax el 13 5 m g as 60 m in IV in fu si on b ef or e ec hi na ce a D ro ps c on ta in in g 95 % a er ia l p ar ts an d 5% ro ot E ch i- na ce a pu rp ur ea N ot st at ed 20 d ro ps 3 tim es / da y 10 p eo pl e liv in g w ith ca nc er N o ch an ge in p ha rm a- co ki ne tic s o f p ac lit ax el N /A N o in te ra ct io n G oe y et a l. (2 01 3) Et op os id e 50 m g/ m 2 o n da ys 1 –5 o f e ac h cy cl e N ot st at ed N ot st at ed N ot st at ed 1 m al e liv in g w ith lu ng c an ce r Th ro m bo cy to pe ni a re qu iri ng p la te le t tr an sf us io n N ot st at ed Po te nt ia l d ru g in te ra ct io n: in cr ea se in to xi - ci ty o f e to po si de Bo ss ae r e t a l. (2 01 2) Et ra vi rin e 40 0 m g/ da y Ex tr ac t o f r oo t of E ch in ac ea pu rp ur ea N ot st at ed 50 0 m g ev er y 8 h fo r 1 4 da ys 15 p eo pl e liv in g w ith H IV N o ch an ge in a ny ph ar m ac ok in et ic pa ra m et er s N /A N o in te ra ct io n M ol tó e t a l. (2 01 2) 43 D ru g de ta ils H er b an d pr od uc t d et ai ls St ud y de ta ils D ru g D os ag e re gi m en Fo rm Ch em ic al co ns ti - tu en ts D os ag e re gi m en Cl in ic al / hu m an In vivo In vitro Sy m pt om s/ ou tc om es H yp ot he si ze d m ec ha ni sm Ev al ua ti on Re fe re nc e Lo pi na vi r, rit on av ir Lo pi na vi r 40 0 m g or rit on av ir 10 0 m g 2 tim es /d ay fo r 29 .5 d ay s Fr es h liq ui d ex tr ac t 8 : 1 Ec hi - na ce a pu rp ur ea he rb so ft -g el ca ps ul es 2 50 m g St an da rd iz ed al ky la m id es , po ly sa cc ha ri- de s, ci ch or ic ac id 50 0 m g 3 tim es / da y on da ys 1 6– 28 13 p eo pl e (5 fe m al e) N o ef fe ct o n co nc en - tr at io ns o f l op in av ir or rit on av ir Po ss ib le in du c- tio n of C YP 3A 4 by e ch in ac ea co un te ra ct ed by in hi bi tio n by rit on av ir N o in te ra ct io n Pe nz ak e t a l. (2 01 0) W ar fa rin 25 m g Ex tr ac t o f E ch i- na ce a pu rp ur ea an d Ec hi na ce a an gu st ifo lia ro ot (M ed iH er b) St an da rd iz ed 75 m g to ta l al ka m id es 12 75 m g 4 tim es / da y 12 m al es N o ph ar m ac od yn am ic , pl at el et a gg re ga tio n or b as el in e cl ot - tin g ch an ge s; sm al l in cr ea se in c le ar an ce of S -w ar fa rin N /A N o in te ra ct io n Ab du l e t a l. (2 01 0) AU C, a re a un de r c on ce nt ra tio n– tim e cu rv e; C YP , c yt oc hr om e P4 50 ; H IV , h um an im m un od efi ci en cy v iru s; IV , i nt ra ve no us ; N /A , n ot a pp lic ab le . 1 Fo r a re vi ew o f e ch in ac ea in te ra ct io ns , s ee G ur le y BJ , F ife r E K, G ar dn er Z (2 01 2) . P ha rm ac ok in et ic h er b– dr ug in te ra ct io ns (p ar t 2 ): dr ug in te ra ct io ns in vo lv in g po pu la r b ot an ic al d ie ta ry su pp le m en ts a nd th ei r c lin ic al re le va nc e. P la nt a M ed . 7 8( 13 ):1 49 0– 51 4. Ab du l M I, Jia ng X , W ill ia m s KM , D ay R O , R ou fo ga lis B D, L ia uw W S, e t a l. (2 01 0) . P ha rm ac ok in et ic a nd p ha rm ac od yn am ic in te ra ct io ns o f e ch in ac ea a nd p ol ic os an ol w ith w ar fa rin in h ea lth y su bj ec ts . B r J C lin Ph ar m ac ol . 6 9( 5) :5 08 –1 5. Bo ss ae r J B, O dl e B (2 01 2) . P ro ba bl e et op os id e in te ra ct io n w ith E ch in ac ea . J D ie t S up pl . 9 (2 ):9 0– 95 . Go ey A K, M ei je rm an I, R os in g H, B ur ge rs JA , M er gu i-R oe lv in k M , K ee ss en M , e t a l. (2 01 3) . T he e ffe ct o f E ch in ac ea p ur pu re a on th e ph ar m ac ok in et ic s o f d oc et ax el . B r J C lin P ha rm ac ol . 7 6( 3) :4 67 –7 4. Go rs ki JC , H ua ng S M , P in to A , H am m an M A, H ill ig os s J K, Z ah ee r N A, e t a l. (2 00 4) . T he e ffe ct o f e ch in ac ea (E ch in ac ea p ur pu re a ro ot ) o n cy to ch ro m e P4 50 a ct iv ity in v iv o. C lin P ha rm ac ol T he r. 75 (1 ):8 9– 10 0. Gu rle y B J, Sw ai n A, W ill ia m s D K, B ar on e G, B at tu S K (2 00 8) . G au gi ng th e cl in ic al si gn ifi ca nc e of P -g ly co pr ot ei n- m ed ia te d he rb -d ru g in te ra ct io ns : c om pa ra tiv e eff ec ts o f S t J oh n’ s w or t, ec hi na ce a, cl ar ith ro m yc in , an d rif am pi n on d ig ox in p ha rm ac ok in et ic s. M ol N ut r F oo d Re s. 52 (7 ):7 72 –9 . M ol tó J, V al le M , M ira nd a C, C ed eñ o S, N eg re do E , C lo te t B (2 01 2) . H er b– dr ug in te ra ct io n be tw ee n Ec hi na ce a pu rp ur ea a nd e tr av iri ne in H IV -in fe ct ed p at ie nt s. An tim ic ro b Ag en ts C he m ot he r. 56 (1 0) :5 32 8– 31 . M ol tó J , V al le M , M ira nd a C, C ed eñ o S, N eg re do E , B ar ba no j M J, Cl ot et B (2 01 1) . H er b– dr ug in te ra ct io n be tw ee n Ec hi na ce a pu rp ur ea a nd d ar un av ir– rit on av ir in H IV -in fe ct ed p at ie nt s. An tim ic ro b Ag en ts Ch em ot he r. 55 (1 ):3 26 –3 30 . Pe nz ak S R, R ob er ts on S M , H un t J D, C ha ire z C , M al at i C Y, A lfa ro R M , e t a l. ( 20 10 ). Ec hi na ce a pu rp ur ea si gn ifi ca nt ly in du ce s c yt oc hr om e P4 50 3 A ac tiv ity b ut d oe s n ot a lte r l op in av ir– rit on av ir ex po su re in h ea lth y su bj ec ts . P ha rm ac ot he ra py . 3 0( 8) :7 97 –8 05 . Ta bl e A1 .4 . Ec hi na ce a: E ch in ac ea p ur pu re a (L .) M oe nc h. /E ch in ac ea a ng us tif ol ia D C. /E ch in ac ea p al lid a (N ut t.) N ut t. (A st er ac ea e) ; p ur pl e co ne flo w er , na rr ow -le av ed co ne flo w er , p al e co ne flo w er – e ig ht st ud ie s1 (C on 't. ) 44 Ta bl e A1 .5 . G in kg o bi lo ba L .; (G in kg oa ce ae ); m ai de nh ai r t re e, fo ss il tr ee – 1 8 st ud ie s D ru g de ta ils H er b an d pr od uc t d et ai ls St ud y de ta ils D ru g D os ag e re gi m en Fo rm Ch em ic al co ns ti tu en ts D os ag e re gi m en Cl in ic al / hu m an In vi vo In vi tr o Sy m pt om s/ ou tc om es H yp o- th es iz ed m ec ha - ni sm Ev al ua - ti on Re fe r- en ce Am lo di pi ne 1 m g/ kg b ef or e an d af te r ex tr ac t ( G BE ) Ex tr ac t, ta bl et s St an da rd iz ed : gi nk go lid e (G KL ) A 1. 9% , G KL B 4 .6 % , bi lo ba lid e 3. 8% 10 0 m g/ kg /d ay fo r 10 d ay s Ra t Cm ax , A U C an d el i- m in at io n in cr ea se d by e xt ra ct , G KL B , bi lo ba lid e In hi bi tio n of CY P3 A4 U nc le ar W an g et al . ( 20 16 ) An tih or m on e th er ap y An as tr oz ol e, le tr oz ol e, ta m ox ife n; us ua l t re at m en t Ex tr ac t (E G B 76 1) ta bl et 12 0 m g St an da rd iz ed : 2 4% fla vo ne s, 6% te r- pe ne la ct on es 12 0 m g 2 tim es /d ay fo r 3 w ee ks O pe n- la be l cr os so ve r s tu dy : 60 w om en , n = 20 p er g ro up N o di ff er en ce fo r a ny dr ug s; 31 /6 0 re po rt ed no si de -e ff ec ts ; o th er s ci te d na us ea , d ia rr ho ea or h ea da ch e N /A N o in te ra ct io n Va rd y et al . ( 20 13 ) As pi rin 32 5 m g/ da y Ex tr ac t (E G B 76 1) ta bl et 30 0 m g St an da rd iz ed : 2 4% fla vo ne s, 6% te r- pe ne la ct on es 30 0 m g/ da y ve rs us pl ac eb o D ou bl e- bl in d RC T: 5 5 pe op le ag ed ≥ 6 9 ye ar s w ith ri sk fa ct or s fo r c ar di ov as cu - la r d is ea se N o de te ct ab le im pa ct on c oa gu la tio n ov er 4 w ee ks N /A N o in te ra ct io n G ar dn er e t al . ( 20 07 ) At or va st at in 40 m g si ng le do se b ef or e an d af te r ex tr ac t Ex tr ac t ta bl et 12 0 m g St an da rd iz ed (n ot st at ed ) 36 0 m g/ da y fo r 1 4 da ys 16 m al es AU C an d Cm ax re du - ce d; n o ef fe ct o n m ar ke rs o f c ho le st er ol sy nt he sis /a bs or pt io n N /A N o in te ra ct io n G uo e t a l. (2 01 2) Ci lo st az ol 10 0 m g 2 tim es / da y Ex tr ac t (G in ex in ) N ot st at ed 80 m g 2 tim es /d ay fo r 7 d ay s RC T cr os so ve r: 34 m al es N o ch an ge s i n bl ee di ng tim es o r a dv er se e ve nt s N o ef fe ct o n CY P3 A4 o r CY P2 C1 9 N o in te ra ct io n Ki m e t a l. (2 01 4) 45 D ru g de ta ils H er b an d pr od uc t d et ai ls St ud y de ta ils D ru g D os ag e re gi m en Fo rm Ch em ic al co ns ti tu en ts D os ag e re gi m en Cl in ic al / hu m an In vi vo In vi tr o Sy m pt om s/ ou tc om es H yp o- th es iz ed m ec ha - ni sm Ev al ua - ti on Re fe r- en ce Cl op id og re l 7. 5 m g/ kg o n da y 15 Ex tr ac t (E G B 76 1) St an da rd iz ed : 2 4% fla vo ne s, 6% te r- pe ne la ct on es 4 , 2 0 or 10 0 m g/ kg Ra t D os e- de pe nd en t in cr ea se in C m ax a nd AU C of c lo pi do gr el ac tiv e m et ab ol ite Ac tiv at io n of PX R, in hi bi - tio n of P -g p, in du ct io n of m ul tip le C YP en zy m es U nc le ar D en g et a l. (2 01 6) 10 μ M Ra t liv er m ic ro - so m es D on ep ez il 1. 5 m g/ kg /d ay fo r 1 4 da ys Ex tr ac t (E G B 76 1) St an da rd iz ed : 22 –2 7% fl av on es , 5– 7% te rp en e la ct on es 10 0 m g/ kg /d ay fo r 14 d ay s Ra t Ac et yl ch ol in es te ra se , ch ol in e ac et yl tr an s- fe ra se , c ho lin e up ta ke un af fe ct ed N /A N o in te ra ct io n St ei n et a l. (2 01 5) Ef av ire nz Us ua l r eg im en (> 1 0 ye ar s) Ex tr ac t ta bl et N ot st at ed 30 0 m g/ da y fo r 2 m on th s M an a ge d 41 y ea rs li vi ng w ith H IV Tr ea tm en t f ai lu re In du ct io n of CY P2 B6 O ne c as e; po te nt ia l in te ra ct io n N ac ca - ra to e t a l. (2 01 2) Ib up ro fe n 60 0 m g/ da y Ex tr ac t (G in gi um , Bi oc ur ) N ot st at ed 40 m g 2 tim es /d ay M an a ge d 71 y ea rs D ea th d ue to c er eb ra l ha em or rh ag e In hi bi tio n of p la te le t ag gr eg at io n O ne c as e; po te nt ia l in te ra ct io n M ei se l e t al . ( 20 03 ) O m ep ra zo le 40 m g be fo re an d af te r tr ea tm en t Ex tr ac t ta bl et 70 m g St an da rd iz ed : 22 .9 % fl a- vo ne s, 6. 8% te rp en e la ct on es 14 0 m g 2 tim es /d ay fo r 1 2 da ys 18 m al es ge no ty pe d fo r CY P2 C1 9 D ec re as e in ra tio o f AU C om ep ra zo le to 5- hy dr ox y- om ep ra zo le In du ct io n of CY P2 C1 9 Re du ce d pl as m a om ep ra - zo le in po or m et a- bo liz er s Yi n et a l. (2 00 4) Pa cl ita xe l 3. 5 μM H yd ro - ly se d ex tr ac t Q ua nt ifi ed fo r G KL , bi lo ba lid e an d fla vo ne s 10 –1 00 m M te rp en e la ct on es H um an he pa - to cy te s D os e- de pe nd en t in hi bi tio n of 6α -h yd ro xy la tio n of pa cl ita xe l In hi bi tio n of CY P2 C8 M ay re su lt in in cr ea - se d bl oo d le ve ls of pa cl ita xe l Et he rid ge et a l. (2 00 9) Ta bl e A1 .5 . G in kg o bi lo ba L .; (G in kg oa ce ae ); m ai de nh ai r t re e, fo ss il tr ee – 1 8 st ud ie s ( Co n' t.) 46 D ru g de ta ils H er b an d pr od uc t d et ai ls St ud y de ta ils D ru g D os ag e re gi m en Fo rm Ch em ic al co ns ti tu en ts D os ag e re gi m en Cl in ic al / hu m an In vi vo In vi tr o Sy m pt om s/ ou tc om es H yp o- th es iz ed m ec ha - ni sm Ev al ua - ti on Re fe r- en ce Ph en yt oi n Pe rs on ’s us ua l re gi m e Ex tr ac t; al so o th er he rb al m ed ic in es N ot k no w n N ot k no w n M an a ge d 55 y ea rs Fa ta l s ei zu re a ss oc ia te d w ith su bt he ra pe u- tic p la sm a le ve ls of ph en yt oi n In du ct io n of CY P2 C1 9 In te ra ct io n: re du ce d pl as m a le ve ls of ph en yt oi n Ku pi ec an d Ra j (2 00 5) Si m va st at in 40 m g/ da y w ith an d w ith ou t G BE Ex tr ac t ta bl et 12 0 m g St an da rd iz ed : 2 4% fla vo ne s, 6% te r- pe ne la ct on es 12 0 m g 2 tim es /d ay fo r 1 4 da ys , re pe at ed RC T cr os so ve r: 14 m al es Re du ce d AU C an d Cm ax o f s im va st at in , bu t n o ot he r e ff ec t o n ph ar m ac ok in et ic s o r ch ol es te ro l l ev el s Po ss ib le ph ar m ac od y- na m ic e ff ec ts at h ig h do se U nc le ar D ai e t a l. (2 01 3) Ta lin ol ol 10 0 m g be fo re an d af te r G BE tr ea tm en t Ex tr ac t ta bl et 12 0 m g St an da rd iz ed (n ot st at ed ) Si ng le d os e of 1 20 o r 36 0 m g/ da y fo r 1 4 da ys 10 m al es , 3- st ag e se qu en tia l st ud y N o ef fe ct o f s in gl e do se ; 1 4- da y tr ea tm en t in cr ea se d AU C of ta li- no lo l b y 33 % In hi bi tio n of P- gp U nc le ar Fa n et a l. (2 00 9) Va lp ro at e Pe rs on ’s us ua l re gi m e Ex tr ac t, w ith o th er he rb al m ed ic in es N ot k no w n N ot k no w n M an a ge d 55 y ea rs Fa ta l s ei zu re a ss oc ia te d w ith su bt he ra pe u- tic p la sm a le ve ls of va lp ro at e In du ct io n of CY P2 C1 9 In te ra ct io n: re du ce d pl as m a le ve ls of va lp ro at e Ku pi ec an d Ra j (2 00 5) W ar fa rin Pe rs on ’s us ua l re gi m en Pe rs on ’s us ua l do se Va rio us , m ai nl y no t st at ed N /A Li te ra tu re re vi ew w ith st at is tic al pr oc es si ng In cr ea se d ris k of bl ee di ng N ot in ve st ig at ed In te ra ct io n: in cr ea se in w ar fa rin le ve ls St od da rd et a l. (2 01 5) 1. 5 m g/ kg o n da ys 3 –5 Ex tr ac t, G KL B , bi lo ba lid e St an da rd iz ed :2 4. 9% fla vo ne s, 6. 4% G KL , 4. 2% b ilo ba lid e Ex tr ac t 1 g; G KL B 14 0 m g; bi lo ba lid e 10 m g/ kg fo r 5 d ay s M ou se Ex tr ac t/ G KL B d id n ot ca us e bl ee di ng ; e xt ra ct re du ce d w ar fa rin ef fe ct s In du ct io n of m ul tip le C YP en zy m es b y bi lo ba lid e Re du ce d ef fe ct w ith h ig h le ve ls of bi lo ba lid e Ta ki e t a l. (2 01 2) 25 m g Ex tr ac t (E G B 76 1) ta bl et 30 0 m g St an da rd i- ze d: 22 –2 7% fla vo ne s, 5– 7% te rp en e la ct on es 30 0 m g 3 tim es /d ay fo r 7 d ay s 12 m al es N o ef fe ct o n di st rib u- tio n or p ro te in b in di ng of S - o r R -w ar fa rin N on e N o in te ra ct io n Jia ng e t a l. (2 00 5) Ta bl e A1 .5 . G in kg o bi lo ba L .; (G in kg oa ce ae ); m ai de nh ai r t re e, fo ss il tr ee – 1 8 st ud ie s ( Co n' t.) 47 D ru g de ta ils H er b an d pr od uc t d et ai ls St ud y de ta ils D ru g D os ag e re gi m en Fo rm Ch em ic al co ns ti tu en ts D os ag e re gi m en Cl in ic al / hu m an In vi vo In vi tr o Sy m pt om s/ ou tc om es H yp o- th es iz ed m ec ha - ni sm Ev al ua - ti on Re fe r- en ce D ru g pr ob e co ck ta il Ca ff ei ne , om ep ra zo le m id az ol am , to lb ut am id e Ex tr ac t EG B 76 1 St an da rd i- ze d: 22 –2 7% fla vo ne s, 5– 7% te rp en e la ct on es 24 0 m g/ da y fo r 8 d ay s RC T cr os so ve r: 18 p eo pl e N o si gn ifi ca nt e ff ec t, no c lin ic al sy m pt om s N /A N o in te ra ct io n Za do ya n et a l. (2 01 2) AU C, ar ea u nd er co nc en tr at io n– tim e cu rv e; C m ax , m ax im um p la sm a c on ce nt ra tio n; C YP , c yt oc hr om e P4 50 ; N /A , n ot ap pl ic ab le ; P -g p, P -g ly co pr ot ei n; P XR , p re gn an e X re ce pt or ; R CT , r an do m iz ed co nt ro lle d tr ia l. D ai LL , F an L , W u HZ , T an Z R, C he n Y, P en g XD , e t a l. ( 20 13 ). A ss es sm en t o f a p ha rm ac ok in et ic an d ph ar m ac od yn am ic in te ra ct io n be tw ee n sim va st at in an d Gi nk go b ilo ba e xt ra ct s i n he al th y s ub je ct s. Xe no bi ot ic a. 43 (1 0) :8 62 –7 . D en g Y, M o YF , C he n XM , Z ha ng L Z, L ia o CF , S on g Y, X u C (2 01 6) . E ffe ct o f G in kg o bi lo ba e xt ra ct o n th e ph ar m ac ok in et ic s a nd m et ab ol ism o f c lo pi do gr el in ra ts . P hy to th er R es . 3 0( 11 ):1 88 6– 92 . Et he rid ge A S, K ro ll DJ , M at he w s J M (2 00 9) . I nh ib iti on o f p ac lit ax el m et ab ol ism in v itr o in h um an h ep at oc yt es b y Gi nk go b ilo ba p re pa ra tio ns . J D ie t S up pl . 6 (2 ):1 04 –1 0. Fa n L, T ao G Y, W an g G, C he n Y, Z ha ng W , H e YJ , e t a l. (2 00 9) . E ffe ct s o f G in kg o bi lo ba e xt ra ct in ge st io n on th e ph ar m ac ok in et ic s o f t al in ol ol in h ea lth y Ch in es e vo lu nt ee rs . A nn P ha rm ac ot he r. 43 (5 ):9 44 –9 . Ga rd ne r C D, Z eh nd er JL , R ig by A J, N ic ho lu s J R, Fa rq uh ar JW (2 00 7) . E ffe ct o f G in kg o bi lo ba (E gb 76 1) a nd a sp iri n on p la te le t a gg re ga tio n an d pl at el et fu nc tio n an al ys is am on g ol de r a du lts at ri sk o f c ar di ov as cu la r di se as e: a ra nd om iz ed c lin ic al tr ia l. Bl oo d Co ag ul F ib rin ol ys is. 1 8( 8) :7 87 –9 3. Gu o CX , P ei Q , Y in JY , P en g XD , Z ho u BT , Z ha o YC , e t a l. (2 01 2) . E ffe ct s o f G in kg o bi lo ba e xt ra ct s o n ph ar m ac ok in et ic s a nd e ffi ca cy o f a to rv as ta tin b as ed o n pl as m a in di ce s. Xe no bi ot ic a. 4 2( 8) :7 84 –9 0. Jia ng X , W ill ia m s K M , L ia uw W S, A m m it AJ R ou fo ga lis B D, D uk e CC , e t a l. ( 20 05 ). Eff ec t o f g in kg o an d gi ng er o n th e ph ar m ac ok in et ic s a nd p ha rm ac od yn am ic s o f w ar fa rin in h ea lth y s ub je ct s. Br J Cl in P ha rm ac ol . 59 (4 ):4 25 –3 2. Ki m H S, K im G Y, Y eo C W , O h M , G hi m JL , S ho n JH , e t a l. (2 01 4) . T he e ffe ct o f G in kg o bi lo ba e xt ra ct s o n th e ph ar m ac ok in et ic s a nd p ha rm ac od yn am ic s o f c ilo st az ol a nd it s a ct iv e m et ab ol ite s i n he al th y Ko re an su bj ec ts . B r J C lin P ha rm ac ol . 7 7( 5) :8 21 –3 0. Ku pi ec T , R aj V (2 00 5) . F at al se iz ur e du e to p ot en tia l h er b– dr ug in te ra ct io ns w ith G in kg o bi lo ba . J A na l T ox ic ol . 2 9: 75 5– 8. M ei se l C , J oh ne A , R oo ts I (2 00 3) . F at al in tr ac er eb ra l m as s b le ed in g as so ci at ed w ith G in kg o bi lo ba a nd ib up ro fe n. A th er os cl er os is 16 7: 36 7. N ac ca ra to M , Y oo ng D , G ou gh K (2 01 2) . A p ot en tia l d ru g– he rb al in te ra ct io n be tw ee n Gi nk go b ilo ba a nd e fa vi re nz . J In t A ss oc P hy sic ia ns A ID S Ca re (C hi c) . 1 1( 2) :9 8– 10 0. St ei n C, H op fe ld J, L au H , K le in J (2 01 5) . E ffe ct s o f G in kg o bi lo ba e xt ra ct E gb 7 61 , d on ep ez il an d th ei r c om bi na tio n on c en tr al c ho lin er gi c fu nc tio n in a ge d ra ts . J P ha rm P ha rm S ci . 1 8( 4) :6 34 –4 6. St od da rd G J, Ar ch er M , S ha ne -M cW ho rt er L , B ra y B E, R ed d D F, Pr ou lx J, Z en g- Tr ei tle r Q (2 01 5) . G in kg o an d w ar fa rin in te ra ct io n in a la rg e ve te ra ns ’ a dm in ist ra tio n po pu la tio n. A M IA A nn Sy m p Pr oc . 2 01 5:1 17 4– 83 . Ta ki Y, Y ok ot an i K , Y am ad a S , S hi no zu ka K , K ub ot a Y , W at an ab e Y, U m eg ak i K (2 01 2) . G in kg o bi lo ba e xt ra ct at te nu at es w ar fa rin -m ed ia te d an tic oa gu la tio n th ro ug h in du ct io n of h ep at ic c yt oc hr om e P4 50 e nz ym es by b ilo ba lid e in m ic e. P hy to m ed ic in e. 1 9( 2) :17 7– 82 . Va rd y J, D hi llo n HM , C la rk e SJ , O le se n I, Le sli e F, W ar by A , e t a l. (2 01 3) . I nv es tig at io n of h er b– dr ug in te ra ct io ns w ith g in kg o bi lo ba in w om en re ce iv in g ho rm on al tr ea tm en t f or e ar ly b re as t c an ce r. Sp rin ge rp lu s. 2( 1) :12 6. W an g R, Z ha ng H , S un S , W an g Y, C ha i Y , Y ua n Y (2 01 6) . E ffe ct o f g in kg o le af ta bl et s o n th e ph ar m ac ok in et ic s o f a m lo di pi ne in ra ts . E ur J D ru g M et ab P ha rm ac ok in et . 4 1( 6) :8 25 –3 3. Yi n O Q , T om lin so n B, W ay e M M , C ho w A H, C ho w M S (2 00 4) . P ha rm ac og en et ic s a nd h er b– dr ug in te ra ct io ns : e xp er ie nc e w ith G in kg o bi lo ba a nd o m ep ra zo le . P ha rm ac og en et ic s. 14 (1 2) :8 41 –5 0. Za do ya n G, R ok itt a D, K le m en t S D ie ne l A , H oe rr R, G ra m at té T , F uh r U (2 01 2) . E ffe ct o f G in kg o bi lo ba s pe ci al e xt ra ct E gb 7 61 ® on h um an c yt oc hr om e P4 50 a ct iv ity : a c oc kt ai l i nt er ac tio n st ud y in h ea lth y vo lu nt ee rs . E ur J Cl in P ha rm ac ol . 6 8: 55 3– 60 . Ta bl e A1 .5 . G in kg o bi lo ba L .; (G in kg oa ce ae ); m ai de nh ai r t re e, fo ss il tr ee – 1 8 st ud ie s ( Co n' t.) 48 Ta bl e A1 .6 . G ly cy rr hi za : G ly cy rr hi za g la br a L. , G ly cy rr hi za u ra le ns is F is ch . e x D C. , G ly cy rr hi za in fla ta B at al in (L eg um in os ae ); liq uo ric e, li co ric e – fo ur st ud ie s1 D ru g de ta ils H er b an d pr od uc t d et ai ls St ud y de ta ils D ru g D os ag e re gi m en Fo rm Ch em ic al co ns ti tu en ts D os ag e re gi m en Clinical/ human In vivo In vitro Sy m pt om s/ ou tc om es H yp ot he si ze d m ec ha ni sm Ev al ua ti on Re fe re nc e Ci cl os po rin 2. 5 m g/ kg Ex tr ac t Ex tr ac t a nd gl yc yr rh iz in 15 0 m g/ kg on ce , o r o nc e a da y fo r 7 d ay s Ra t D ec re as ed ci cl os po rin bl oo d le ve ls In du ct io n of P -g p an d CY P3 A4 In te ra ct io n: re du ce d bl oo d le ve ls of ci cl os po rin H ou e t a l. (2 01 2) Ka ns ui D rie d he rb Eu ph or bi a ka ns ui S .L . Li ou e x S. B. H o D ec oc - tio n of G ly cy - rr hi za ur al en si s Fi sc h. (G U) N ot st at ed Va ry in g ra tio s Ra t Re du ce d ef fi- ca cy , i nc re as ed to xi ci ty In hi bi tio n of C YP 2C 19 an d in cr ea se d so lu bi lit y of k an su i d ite rp en es In te ra ct io n: m ay re du ce e ff ic ac y an d in cr ea se to xi ci ty o f ka ns ui Sh en e t a l. (2 01 6) M et ho tr ex at e 5 m g/ kg D ec oc - tio n of GU a nd gl yc yr rh i- zi n (G Z) Ch ar ac te riz ed fo r G Z 75 o r 1 50 m g/ kg o f G Z or liq uo ric e de co ct io n (c on ta in in g 75 or 1 50 m g/ kg of G Z) o nc e a da y fo r 7 d ay s Ra t AU C an d m ea n re si - de nc e tim e of m et ho tr ex at e in cr ea se d by G Z an d liq uo - ric e de co ct io n In hi bi tio n of b re as t ca nc er re sis ta nc e pr ot ei n (B CR P) a nd m ul tid ru g re sis ta nc e pr ot ei ns (M RP 2) In te ra ct io n: in cr ea - se d to xi ci ty o f m et ho tr ex at e Li n et a l. (2 00 9) Pe on y ro ot D ec oc tio n of P ae on ia la ct ifl or a Pa ll. ro ot (P R) D ec oc - tio n of GU , d os e ra tio va ry in g Ch ar ac te riz ed fo r G Z Ra t D ec re as ed bi oa va ila bi lit y of p ae on ifl or in Ac tiv at io n of P -g p an d CY P3 A4 ; r at io b et w ee n PR a nd G U cr iti ca l f or ef fe ct U nc le ar Xu e t a l. (2 01 3) AU C, a re a un de r c on ce nt ra tio n– tim e cu rv e; C YP , c yt oc hr om e P4 50 ; P -g p, P -g ly co pr ot ei n. 1 Li qu or ic e an d gl yc yr rh iz in a re kn ow n to ca us e hy pe rt en sio n an d hy po ka la em ia a nd m ay th er ef or e in te ra ct w ith o th er p ot as siu m -d ep le tin g dr ug s, su ch a s d iu re tic s, an d in cr ea se th e ris k o f d ig ox in to xi ci ty . Fo r f ur th er d et ai ls of th e hi gh ly c om pl ex in te ra ct io ns o f l iq uo ric e an d its c on st itu en ts , a nd it s u se in tr ad iti on al fo rm ul ae to m od ify th e eff ec ts o f o th er h er bs , s ee N az ar i, S , R am es hr ad M , H os se in za de h H (2 01 7) . T ox ic ol og ic al e ffe ct s o f G ly cy rrh iz a gl ab ra (l ic or ic e) : a re vi ew . P hy to th er R es . 3 1:1 63 5– 50 ; a nd W an g X, Z ha ng H , C he n L, S ha n L, F an G , G ao X (2 01 3) . L iq uo ric e: a u ni qu e “g ui de d ru g” o f t ra di tio na l Ch in es e m ed ic in e – a re vi ew o f i ts ro le in d ru g in te ra ct io ns . J E th no ph ar m ac ol . 1 50 (3 ):7 81 -9 0. H ou Y C, L in S P, Ch ao P D (2 01 2) . L iq uo ric e re du ce d cy cl os po rin e bi oa va ila bi lit y by a ct iv at in g P- gl yc op ro te in a nd C YP 3 A. F oo d Ch em . 1 35 (4 ) 2 30 7– 12 . Li n SP , T sa i S Y, H ou Y C, C ha o PD (2 00 9) . G ly cy rrh iz in a nd li co ric e sig ni fic an tly a ffe ct th e ph ar m ac ok in et ic s o f m et ho tre xa te in ra ts . J A gr ic F oo d Ch em . 5 7( 5) :18 54 –9 . Sh en J, W an g J, Sh an g EX , T an g YP , K ai J, C ao Y J, et a l. (2 01 6) . T he d os ag e– to xi ci ty –e ffi ca cy re la tio ns hi p of k an su i a nd li co ric e in m al ig na nt p le ur al e ffu sio n ra ts b as ed o n fa ct or a na ly sis . J E th no ph ar m ac ol . 18 6: 25 1– 6. Xu C H, W an g P, W an g Y, Y an g Y, L i D H, L i H F, et a l. ( 20 13 ). Ph ar m ac ok in et ic c om pa ris on s o f t w o di ffe re nt c om bi na tio ns o f S ha oy ao –G an ca o de co ct io n in ra ts : c om pe tin g m ec ha ni sm s b et w ee n pa eo ni flo rin a nd gl yc yr rh et in ic a ci d. J Et hn op ha rm ac ol . 1 49 (2 ):4 43 –5 2. 49 Ta bl e A1 .7 . H yp er ic um p er fo ra tu m L ., (C lu si ac ea e) ; S t J oh n’ s w or t – 2 6 st ud ie s1 ,2 D ru g de ta ils H er b an d pr od uc t d et ai ls St ud y de ta ils D ru g D os ag e re gi m en Fo rm Ch em ic al co ns ti tu en ts D os ag e re gi m en Cl in ic al / hu m an In vivo In vitro Sy m pt om s/ ou tc om es H yp o- th es iz ed m ec ha ni sm Ev al ua ti on Re fe re nc e At or va st at in 10 –4 0 m g/ da y Ex tr ac t (M ov in a) ta bl et 30 0 m g N ot st at ed 60 0 m g/ da y 16 p eo pl e w ith h yp er - ch ol es te - ro la em ia (6 fe m al e) H ig he r b lo od le ve ls of L D L an d to ta l ch ol es te ro l In du ct io n of CY P an d P- gp In te ra ct io n: re du ce d ef fe ct of a to rv as ta tin An dr én e t a l. (2 00 7) Ca rb am az ep in e 10 0 m g 2 tim es / da y fo r 3 d ay s, th en 2 00 m g 2 tim es /d ay fo r 3 da ys , t he n 40 0 m g/ da y fo r 14 d ay s Ex tr ac t t ab le t St an da rd iz ed : 0 .3 % hy pe ric in 30 0 m g 3 tim es / da y 8 pe op le (3 fe m al e) N o di ff er en ce in a ny p ha r- m ac ok in et ic pa ra m et er s N /A N o in te ra ct io n Bu rs te in e t a l. (2 00 0) Ci cl os po rin 12 5– 15 0 m g/ da y H er ba l t ea N ot k no w n “R eg ul ar ly ” (n ot st at ed ) 1 m al e Re du ce d pl as m a le ve ls of c ic lo sp or in In du ct io n of CY P an d P- gp In te ra ct io n: ris k of o rg an re je ct io n ev en at su bt he ra pe u- tic d os es o f S t Jo hn ’s w or t Al sc he r a nd Kl ot z (2 00 3) Pe rs on ’s pr es cr i- be d do se Ex tr ac t ( Ja rs in ) ta bl et 3 00 m g St an da rd iz ed :0 .3 % hy pe ric in , 3 –5 % hy pe rf or in 60 0 m g/ da y 11 p eo pl e un de r- go in g re na l tr an sp la nt Si gn ifi ca nt de cr ea se in bl oo d le ve ls of ci cl os po rin Ba ue r e t a l. (2 00 3) 12 5 m g tw ic e da ily Ex tr ac t ( Ja rs in ) ta bl et 3 00 m g St an da rd iz ed :0 .3 % hy pe ric in , 3 –5 % hy pe rf or in 90 0 m g/ da y 2 pe op le un de r- go in g he ar t tr an sp la nt Ac ut e or ga n re je ct io n Ru sc hi tz ka e t al . ( 20 00 ) Cl oz ap in e Pe rs on ’s us ua l do se Ex tr ac t t ab le t 30 0 m g St an da rd i- ze d: 0. 36 –0 .8 4 m g hy pe ric in , ≥ 9 m g hy pe rf or in 90 0 m g/ da y W om an ag ed 41 y ea rs Re du ce d pl as m a le ve ls of c lo za pi ne In du ct io n of CY P an d P- gp In te ra ct io n: ps yc hi at ric de te rio ra tio n Va n St ra te r e t al . ( 20 12 ) D oc et ax el 13 5 m g IV o ve r 6 0 m in b ef or e an d af te r S t J oh n’ s w or t Ex tr ac t (H yp er i-p la nt ) ta bl et 3 00 m g St an da rd i- ze d: 0. 36 –0 .8 4 m g hy pe ric in , 9 –1 9 m g hy pe rf or in 30 0 m g 3 tim es /d ay fo r 1 4 da ys 10 p eo pl e liv in g w ith ca nc er D ec re as ed do ce ta xe l pl as m a le ve ls In du ct io n of CY P an d P- gp In te ra ct io n: re du ce d pl as m a le ve ls of do ce ta xe l G oe y et a l. (2 01 4) 50 D ru g de ta ils H er b an d pr od uc t d et ai ls St ud y de ta ils D ru g D os ag e re gi m en Fo rm Ch em ic al co ns ti tu en ts D os ag e re gi m en Cl in ic al / hu m an In vivo In vitro Sy m pt om s/ ou tc om es H yp o- th es iz ed m ec ha ni sm Ev al ua ti on Re fe re nc e O ra l ( ho rm on al ) co nt ra ce pt iv es Sy st em at ic re vi ew o f p ub lis - he d st ud ie s be fo re 2 01 6: 4 8 ar tic le s i de nt i- fie d; 4 st ud ie s m et in cl us io n cr ite ria W om en ta ki ng o ra l co nt ra ce p- tiv es In cr ea - se d ris k of br ea kt hr ou gh bl ee di ng In du ct io n of CY P3 A4 a nd CY P2 C9 In te ra ct io n: re du ce d pl as m a le ve ls of h or m o- ne s, le ad in g to co nt ra ce pt iv e fa ilu re Be rr y- Bi be e et al . ( 20 16 ) Et hi ny l oe st ra di ol / di en og es te ro l Ex tr ac t ( H el a- riu m 4 25 ) ta bl et N ot st at ed 17 00 m g/ da y fo r 3 m on th s W om an ag ed 36 y ea rs Pr eg na nc y N ot st at ed Sc hw ar z et a l. (2 00 3) Et hi ny l es tr ad io l/3 -k et o- de so ge st re l Ex tr ac t Z e 11 7) ta bl et 3 00 m g St an da rd iz ed : hy pe ric in 0 .2 % , hy pe rf or in ≤ 0 .2 % 25 0 m g 2 tim es /d ay fo r 1 4 da ys fr om d ay 7 16 fe m al es N o ef fe ct o n ph ar m ac o- ki ne tic s o f ho rm on al co m po ne nt s N /A N o in te ra ct io n w ith lo w h yp er - fo rin e xt ra ct W ill -S ha ha b et al . ( 20 09 ) Ib up ro fe n 40 0 m g be fo re an d af te r S t Jo hn ’s w or t Ex tr ac t t ab le t 30 0 m g St an da rd iz ed :0 .3 % hy pe ric in 30 0 m g 3 tim es /d ay fo r 3 w ee ks 8 m al es M in im al e ff ec ts on ib up ro fe n ph ar m ac ok i- ne tic s N /A N o in te ra ct io n Be ll et a l. (2 00 7a ) Im at in ib 40 0 m g be fo re an d af te r S t Jo hn ’s w or t Ex tr ac t ( Ki ra ) ta bl et 3 00 m g St an da rd iz ed :0 .3 % hy pe ric in 30 0 m g 3 tim es /d ay fo r 2 w ee ks 12 p eo pl e (6 fe m al e) Re du ce d bl oo d le ve ls of im at in ib In du ct io n of CY P3 A4 In te ra ct io n: re du ce d pl as m a le ve ls of im at in ib Fr ye e t a l. (2 00 4) 40 0 m g be fo re an d af te r S t Jo hn ’s w or t Ex tr ac t ( fo rm no t s ta te d) N ot st at ed 30 0 m g 3 tim es /d ay fo r 2 w ee ks 10 p eo pl e M ea n im at in ib AU C de cr ea se d by 3 2% Sm ith e t a l. (2 00 4) Ta bl e A1 .7 . H yp er ic um p er fo ra tu m L ., (C lu si ac ea e) ; S t J oh n’ s w or t – 2 6 st ud ie s1 ,2 (C on 't. ) 51 D ru g de ta ils H er b an d pr od uc t d et ai ls St ud y de ta ils D ru g D os ag e re gi m en Fo rm Ch em ic al co ns ti tu en ts D os ag e re gi m en Cl in ic al / hu m an In vivo In vitro Sy m pt om s/ ou tc om es H yp o- th es iz ed m ec ha ni sm Ev al ua ti on Re fe re nc e In di na vi r 80 0 m g ev er y 8 h fo r 3 d os es be fo re a nd a ft er St Jo hn ’s w or t Ex tr ac t t ab le t 30 0 m g St an da rd iz ed :0 .3 % hy pe ric in 30 0 m g 3 tim es /d ay fo r 2 w ee ks 8 pe op le (2 fe m al e) M ea n in di na vi r AU C de cr ea se d by 5 7% ; m ea n Cm ax d ec re a- se d; T m ax un al te re d In du ct io n of CY P3 A4 In te ra ct io n: re du ce d pl as m a le ve ls of in di na vi r Pi sc ite lli e t a l. (2 00 0) Iri no te ca n 35 0 m g/ m 2 I V w ith a nd w ith ou t St Jo hn ’s w or t Ex tr ac t t ab le t 30 0 m g N ot st at ed 30 0 m g 3 tim es /d ay fo r 1 8 da ys 5 pe op le liv in g w ith ca nc er (3 fe m al e) Re du ct io n in ir in ot ec an co nc en tr at io n In du ct io n of CY P3 A4 In te ra ct io n: re du ce d pl as m a le ve ls of iri no te ca n M at hi js se n et al . ( 20 02 ) M et fo rm in 1 g 2 tim es /d ay fo r 1 w ee k w ith an d w ith ou t S t Jo hn ’s w or t Ex tr ac t c ap su le 24 0– 29 4 m g St an da rd iz ed :9 00 μ g hy pe ric in 24 0– 29 4 m g 2 tim es /d ay fo r 2 1 da ys 20 m al es Im pr ov ed g lu - co se to le ra nc e by e nh an - ci ng in su lin se cr et io n D ec re as ed re na l c le ar an ce Po te nt ia l in te ra ct io n: in cr ea se d ef fe ct of m et fo rm in St ag e et a l. (2 01 5) O xy co do ne 15 m g on d ay 1 4 Ex tr ac t ( Ja rs in ) ta bl et 3 00 m g 0. 3% h yp er ic in , 3– 5% h yp er fo rin St an da rd iz ed : 0 .3 % hy pe ric in , 3 -5 % hy pe rf or in 30 0 m g 3 tim es /d ay fo r 1 4 da ys 12 p eo pl e (6 fe m al e) Re du ce d le ve ls of o xy co do ne ; re du ce d co ld pa in th re sh ol d In du ct io n of CY P3 A4 In te ra ct io n: re du ce d bl oo d le ve ls of ox yc od on e N ie m in en e t a l. (2 01 0) Pr ed ni so ne 20 m g be fo re a nd af te r S t J oh n’ s w or t Ex tr ac t t ab le t 30 0 m g St an da rd iz ed :0 .3 % hy pe ric in 30 0 m g 3 tim es /d ay fo r 2 8 da ys 8 m al es N o ef fe ct o n ph ar m ac o- ki ne tic s o f pr ed ni so ne o r its re ve rs ib le m et ab ol ite pr ed ni so lo ne N /A N o in te ra ct io n Be ll et a l. (2 00 7b ) Re pa gl in id e 1 m g be fo re a nd af te r S t J oh n’ s w or t Ex tr ac t t ab le t 32 5 m g N ot st at ed 32 5 m g 3 tim es /d ay fo r 1 4 da ys 15 p eo pl e N o ef fe ct o n PX R or p ha rm a- co ki ne tic s o f re pa gl in id e N /A N o in te ra ct io n Fa n (e t a l.) 2 01 1 Ta bl e A1 .7 . H yp er ic um p er fo ra tu m L ., (C lu si ac ea e) ; S t J oh n’ s w or t – 2 6 st ud ie s1 ,2 (C on 't. ) 52 D ru g de ta ils H er b an d pr od uc t d et ai ls St ud y de ta ils D ru g D os ag e re gi m en Fo rm Ch em ic al co ns ti tu en ts D os ag e re gi m en Cl in ic al / hu m an In vivo In vitro Sy m pt om s/ ou tc om es H yp o- th es iz ed m ec ha ni sm Ev al ua ti on Re fe re nc e Si m va st at in 10 –4 0 m g/ da y Ex tr ac t (M ov in a) ta bl et 30 0 m g N ot st at ed 30 0 m g 2 tim es / da y 24 p eo pl e w ith h yp er - ch ol es te ro - la em ia (1 0 fe m al e) H ig he r b lo od le ve ls of L D L an d to ta l c ho - le st er ol w ith S t Jo hn ’s w or t N ot st at ed In te ra ct io n: re du ce d ef fe ct of si m va st at in Eg ge rt se n et al . ( 20 07 ) 10 m g/ da y Ex tr ac t c ap le t 30 0 m g St an da rd iz ed :0 .3 % hy pe ric in 30 0 m g 3 tim es / da y 8 he al th y pe op le Lo w er p la sm a si m va st at in co nc en tr at io n In du ct io n of CY P en zy m es an d P- gp In te ra ct io n: re du ce d pl as m a le ve l o f si m va st at in Su gi m ot o et a l. (2 00 1) Ta cr ol im us 0. 1 m g/ kg b ef or e an d af te r S t Jo hn ’s w or t Ex tr ac t t ab le t 30 0 m g St Jo hn ’s w or t t ab le t (3 00 m g/ ta bl et , co nt ai ni ng 4 40 .0 µ g hy pe ric in ) 30 0 m g 3 tim es /d ay fo r 1 8 da ys 10 p eo pl e (8 fe m al e) Av er ag e de cr ea se o f 34 % fo r t ac ro li- m us A U C In du ct io n of CY P3 A4 a nd P- gp In te ra ct io n: re du ce d pl as m a le ve ls of ta cr ol im us H eb er t e t a l. (2 00 4) Ta cr ol im us – m yc op he no la te Pe rs on ’s us ua l do se Ex tr ac t ( Ja rs in ) ta bl et 3 00 m g 0. 3% h yp er ic in , 3– 5% h yp er fo rin St an da rd iz ed : 0 .3 % hy pe ric in , 3 –5 % hy pe rf or in 30 0 m g 2 tim es /d ay fo r 1 4 da ys 10 p eo pl e un de r- go in g re na l tr an sp la nt (4 fe m al e) Si gn ifi ca nt de cr ea se in AU C ta cr o- lim us ; n o ef fe ct o n m yc op he no la te In du ct io n of CY P3 A4 a nd P- gp In te ra ct io n w ith ta cr ol im us : re du ce d pl as m a le ve ls N o in te ra c- tio n w ith m yc op he no la te M ai e t a l. (2 00 3) Ve ra pa m il 24 m g ov er 1 00 m in b y je ju na l pe rf us io n Ex tr ac t (M ov in a) ta bl et 30 0 m g 3– 6% h yp er fo rin St an da rd iz ed : 3 –6 % hy pe rf or in 30 0 m g 3 tim es /d ay fo r 1 4 da ys 8 m al es D ec re as e in bi oa va ila bi - lit y of R - a nd S- ve ra pa m il In du ct io n of fi rs t- pa ss CY P3 A4 m et a- bo lis m In te ra ct io n: re du ce d pl as m a le ve ls of ve ra pa m il Ta nn er gr en e t al . ( 20 04 ) Ta bl e A1 .7 . H yp er ic um p er fo ra tu m L ., (C lu si ac ea e) ; S t J oh n’ s w or t – 2 6 st ud ie s1 ,2 (C on 't. ) 53 D ru g de ta ils H er b an d pr od uc t d et ai ls St ud y de ta ils D ru g D os ag e re gi m en Fo rm Ch em ic al co ns ti tu en ts D os ag e re gi m en Cl in ic al / hu m an In vivo In vitro Sy m pt om s/ ou tc om es H yp o- th es iz ed m ec ha ni sm Ev al ua ti on Re fe re nc e W ar fa rin 25 m g Ex tr ac t ( Bi o- gl an ) t ab le t eq ui va le nt to 1 g he rb St an da rd iz ed : 0. 82 5 m g hy pe ric in , 12 .5 m g hy pe rf or in 1 ta bl et 3 tim es /d ay fo r 2 w ee ks 12 m al es In cr ea se d m et ab ol is m o f R- a nd S -w ar - fa rin , r ed uc ed IN R In du ct io n of C YP 1A 2 an d CY P3 A4 (R -w ar fa rin ), an d CY P2 C9 (S -w ar fa rin ) In te ra ct io n: re du ce d pl as m a le ve ls of w ar fa rin Jia ng e t a l. (2 00 4) Zo lp id em 10 m g fo llo w in g St Jo hn ’s w or t o n da y 1 an d th en 10 m g w ith S t Jo hn ’s w or t a t 14 d ay s Ex tr ac t ( LI 16 ) ta bl et 3 00 m g St an da rd iz ed : 0 .3 % hy pe ric in , 3 –5 % hy pe rf or in 30 0 m g 3 tim es / da y 14 m al es D ec re as ed pl as m a co n- ce nt ra tio n of zo lp id em In du ct io n of CY P3 A4 In te ra ct io n: re du ce d pl as m a le ve ls of zo lp id em H oj o et a l. (2 01 1) AU C, a re a un de r c on ce nt ra tio n– tim e cu rv e; C m ax , m ax im um p la sm a co nc en tr at io n; C YP , c yt oc hr om e P4 50 ; IN R, in te rn at io na l n or m al iz ed ra tio ; IV , in tr av en ou s; LD L, lo w -d en sit y l ip op ro te in ; N /A , n ot a pp lic ab le ; P- gp , P -g ly co pr ot ei n; P XR , p re gn an e X re ce pt or ; T m ax , t im e to m ax im um p la sm a co nc en tr at io n. 1 Th e st ud ie s c ite d co ve r o nl y a se le ct io n of d ru gs a ffe ct ed b y St Jo hn ’s w or t a nd a re n ot in te nd ed to fo rm a c om pr eh en siv e re vi ew . F or fu rt he r r ep or ts , s ee R us so E , S ci cc hi ta no F, W ha lle y BJ , M az zi te llo C, C iri ac o M , E sp os ito S , e t a l. (2 01 4) . H yp er ic um p er fo ra tu m : p ha rm ac ok in et ic s, m ec ha ni sm o f a ct io n, to le ra bi lit y, an d cl in ic al d ru g– dr ug in te ra ct io ns . P hy to th er R es . 2 8: 64 3– 55 . 2 F or re ce nt e vi de nc e on th e ro le o f h yp er fo rin in d ru g in te ra ct io ns , s ee C hr ub as ik -H au sm an n S, V la ch oj an ni s J, M cL ac hl an A J ( 20 19 ). Un de rs ta nd in g dr ug in te ra ct io ns w ith S t J oh n’ s w or t ( Hy pe ric um pe rfo ra tu m L .): im pa ct o f h yp er fo rin c on te nt . J P ha rm P ha rm ac ol . 7 1( 1) :12 9– 38 . Al sc he r D M , K lo tz U (2 00 3) . D ru g in te ra ct io n of h er ba l t ea c on ta in in g St Jo hn ’s w or t w ith c yc lo sp or in e. T ra ns pl In t. 16 : 5 43 –4 . An dr én L , A nd re as so n A, E gg er ts en R (2 00 7) . I nt er ac tio n be tw ee n a co m m er ci al ly a va ila bl e St J oh n’ s w or t p ro du ct (M ov in a) a nd a to rv as ta tin in p at ie nt s w ith h yp er ch ol es te ro le m ia . E ur J C lin P ha rm ac ol . 63 (1 0) :9 13 –1 6. Ba ue r S , S tö rm er E , J oh ne A , K rü ge r H , B ud de K , N eu m ay er H H, e t a l. (2 00 3) . A lte ra tio ns in c yc lo sp or in A p ha rm ac ok in et ic s a nd m et ab ol ism d ur in g tre at m en t w ith S t J oh n’ s w or t i n re na l t ra ns pl an t p at ie nt s. Br J Cl in P ha rm ac ol . 5 5( 2) :2 03 –1 1. Be ll EC , R av is W R, L lo yd K B, S to ke s T J ( 20 07 a) . E ffe ct s o f S t J oh n’ s w or t s up pl em en ta tio n on ib up ro fe n ph ar m ac ok in et ic s. An n Ph ar m ac ot he r. 41 (2 ):2 29 –3 4. Be ll EC , R av is W R, C ha n HM , L in Y J ( 20 07 b) . L ac k of p ha rm ac ok in et ic in te ra ct io n be tw ee n St Jo hn ’s w or t a nd p re dn iso ne . A nn P ha rm ac ot he r. 41 (1 1) :18 19 –2 4. Be rr y- Bi be e EN , K im M J, Te pp er N K, R ile y HE , C ur tis K M (2 01 6) . C o- ad m in ist ra tio n of S t J oh n’ s w or t a nd h or m on al c on tr ac ep tiv es : a sy st em at ic re vi ew . C on tr ac ep tio n. 9 4( 6) :6 68 –7 7. Bu rs te in A H, H or to n RL , D un n T, Al fa ro R M , P isc ite lli S C, T he od or e W (2 00 0) . L ac k of e ffe ct o f S t J oh n’ s w or t o n ca rb am az ep in e ph ar m ac ok in et ic s i n he al th y vo lu nt ee rs . C lin P ha rm ac ol T he r. 68 (6 ):6 05 –1 2. Eg ge rt se n R, A nd re as so n A, A nd ré n L (2 00 7) . E ffe ct s of tr ea tm en t w ith a c om m er ci al ly a va ila bl e St J oh n’ s w or t p ro du ct (M ov in a) o n ch ol es te ro l l ev el s in p at ie nt s w ith h yp er ch ol es te ro le m ia tr ea te d w ith sim va st at in . S ca nd J Pr im H ea lth C ar e. 2 5( 3) :15 4– 9. Fa n L, Z ho u G, G uo D , L iu Y L, C he n W Q , L iu Z Q , e t a l. ( 20 11 ). Th e pr eg na ne X re ce pt or a go ni st S t J oh n’ s w or t h as n o eff ec ts o n th e ph ar m ac ok in et ic s a nd p ha rm ac od yn am ic s o f r ep ag lin id e. C lin P ha rm ac ok in et . 50 (9 ):6 05 –1 1. Fr ye R F, Fi tz ge ra ld S M , L ag at tu ta T F, Hr us ka M W , E go rin M J ( 20 04 ). Eff ec t o f S t J oh n’ s w or t o n im at in ib m es yl at e ph ar m ac ok in et ic s. Cl in P ha rm ac ol T he r. 76 : 3 23 –9 . Go ey A K, M ei je rm an I, R os in g H, M ar ch et ti S, M er gu i-R oe lv in k M , K ee ss en M , e t a l. (2 01 4) . T he e ffe ct o f S t J oh n’ s w or t o n th e ph ar m ac ok in et ic s o f d oc et ax el . C lin P ha rm ac ok in et . 5 3( 1) :10 3– 10 . H eb er t M F, Pa rk JM , C he n YL , A kh ta r S , L ar so n AM (2 00 4) . E ffe ct s o f S t J oh n’ s w or t ( Hy pe ric um p er fo ra tu m ) o n ta cr ol im us p ha rm ac ok in et ic s i n he al th y vo lu nt ee rs . J C lin P ha rm ac ol . 2 00 4; 4 4: 89 –9 4. H oj o Y, E ch iz en ya M , O hk ub o T, Sh im iz u T (2 01 1) . D ru g in te ra ct io n be tw ee n St Jo hn ’s w or t a nd zo lp id em in h ea lth y su bj ec ts . J . C lin P ha rm T he r. 36 (6 ):7 11 –1 5. Jia ng X , W ill ia m s K M , L ia uw W S, A m m it AJ , R ou fo ga lis B D, D uk e CC , e t a l. (2 00 4) . E ffe ct o f S t J oh n’ s w or t a nd g in se ng o n th e ph ar m ac ok in et ic s a nd p ha rm ac od yn am ic s o f w ar fa rin in h ea lth y su bj ec ts . B r J C lin Ph ar m ac ol . 5 7( 5) :5 92 –9 . Ta bl e A1 .7 . H yp er ic um p er fo ra tu m L ., (C lu si ac ea e) ; S t J oh n’ s w or t – 2 6 st ud ie s1 ,2 (C on 't. ) 54 M ai I, St ör m er E , B au er S , K rü ge r H , B ud de K , R oo ts I ( 20 03 ). Im pa ct o f S t J oh n’ s w or t t re at m en t o n th e ph ar m ac ok in et ic s o f t ac ro lim us a nd m yc op he no lic a ci d in re na l t ra ns pl an t p at ie nt s. N ep hr ol D ia l T ra ns pl an t. 18 (4 ):8 19 –2 2. M at hi jss en R H, V er w ei j J , d e Br ui jn P, L oo s W J, Sp ar re bo om A (2 00 2) . E ffe ct s o f S t J oh n’ s w or t o n iri no te ca n m et ab ol ism . J N at l C an ce r I ns t. 94 : 1 24 7– 9. N ie m in en T H, H ag el be rg N M , S aa ri TI , N eu vo ne n M , L ai ne K , N eu vo ne n PJ , O lk ko la K T (2 01 0) S t J oh n’ s w or t g re at ly re du ce s t he c on ce nt ra tio ns o f o ra l o xy co do ne . E ur J Pa in . 1 4( 8) :8 54 –9 . Pi sc ite lli S C, B ur st ei n AH , C ha itt D , A lfa ro R M , F al lo on J (2 00 0) . I nd in av ir co nc en tr at io ns a nd S t J oh n’ s w or t. La nc et . 3 55 (9 20 3) :5 47 –8 . Ru sc hi tz ka F, M ei er P J, Tu rin a M , L üs ch er T F, N ol l G (2 00 0) . A cu te h ea rt tr an sp la nt re je ct io n du e to S ai nt Jo hn ’s w or t. La nc et . 3 55 (9 20 3) :5 48 –9 . Sc hw ar z U I, Bü sc he l B , K irc h W (2 00 3) . U nw an te d pr eg na nc y on se lf- m ed ic at io n w ith S t J oh n’ s w or t d es pi te h or m on al c on tr ac ep tio n. B r J C lin P ha rm ac ol . 5 5( 1) :11 2– 13 . Sm ith P, B ul lo ck JM , B oo ke r B M , H aa s C E, B er en so n CS , J us ko W J ( 20 04 ). Th e in flu en ce o f S t J oh n’ s w or t o n th e ph ar m ac ok in et ic s a nd p ro te in b in di ng o f i m at in ib m es yl at e. P ha rm ac ot he ra py . 2 4: 1 50 8– 14 . St ag e TB , P ed er se n RS , D am ki er P , C hr ist en se n M M , F ed de rs en S , L ar se n JT , e t a l. (2 01 5) . I nt ak e of S t J oh n’ s w or t i m pr ov es th e gl uc os e to le ra nc e in h ea lth y su bj ec ts w ho in ge st m et fo rm in c om pa re d w ith m et fo rm in a lo ne . B r J C lin P ha rm ac ol . 7 9( 2) :2 98 –3 06 . Su gi m ot o K, O hm or i M , T su ru ok a S, N ish ik i K , K aw ag uc hi A , H ar ad a K, e t a l. (2 00 1) . D iff er en t e ffe ct s o f S t J oh n’ s w or t o n th e ph ar m ac ok in et ic s o f s im va st at in a nd p ra va st at in . C lin P ha rm ac ol T he r. 70 (6 ):5 18 –2 4. Ta nn er gr en C , E ng m an H , K nu ts on L , H ed el an d M , B on de ss on U , L en ne rn äs H (2 00 4) . S t J oh n’ s w or t d ec re as es th e bi oa va ila bi lit y of R - a nd S -v er ap am il th ro ug h in du ct io n of th e fir st -p as s m et ab ol ism . C lin Ph ar m ac ol T he r. 75 :2 98 –3 09 . Va n St ra te r A C, B og er s J P (2 01 2) . I nt er ac tio n of S t J oh n’ s w or t ( Hy pe ric um p er fo ra tu m ) w ith c lo za pi ne . I nt C lin P sy ch op ha rm ac ol . 2 7( 2) :12 1– 4. W ill -S ha ha b L, B au er S , K un te r U , R oo ts I, B ra tt st rö m A (2 00 9) . S t J oh n’ s w or t e xt ra ct (Z e 11 7) d oe s n ot a lte r t he p ha rm ac ok in et ic s o f a lo w -d os e or al c on tr ac ep tiv e. E ur J Cl in P ha rm ac ol . 6 5( 3) :2 87 –9 4. 55 Ta bl e A1 .8 . Pa na x gi ns en g C. A. M ey ., (A ra lia ce ae ) G in se ng ; K or ea n/ Ch in es e/ or ie nt al g in se ng – 1 0 st ud ie s1 D ru g de ta ils H er b an d pr od uc t d et ai ls St ud y de ta ils D ru g D os ag e re gi m en Fo rm Ch em ic al co ns ti - tu en ts D os ag e re gi m en Cl in ic al / hu m an In vivo In vitro Sy m pt om s/ ou tc om es H yp o- th es iz ed m ec ha ni sm Ev al ua ti on Re fe re nc e Am lo di pi ne 10 m g/ kg o ra lly a ft er gi ns en g tr ea tm en t St ea m ed gi ns en g ro ot N ot st at ed 0. 5, 1 a nd 2 g/ kg /d ay or al ly fo r 2 w ee ks Ra t In cr ea se d Tm ax ; d ec re a- se d Cm ax ; n o ch an ge in AU C N o ch an ge if a m lo di pi ne ad m in is te re d IV N on e sp ec ifi ed N o in te ra ct io n Ry u et a l. (2 01 4) Im at in ib 40 0 m g/ da y fo r 7 ye ar s Ex tr ac t i n “e ne rg y dr in ks ” N ot st at ed Ta ke n ov er 4 m on th s be fo re e ve nt 1 m an ag ed 26 y ea rs Ac ut e lo bu la r h ep at iti s CY P3 A4 in hi bi tio n In te ra ct io n: im a- tin ib -in du ce d he pa to to xi ci ty Bi lg i e t a l. (2 01 0) La m ot rig in e 15 0 m g 2 tim es /d ay G in se ng / de er a nt le r ve lv et ex tr ac t N ot st at ed Ta ke n ov er 4 m on th s be fo re e ve nt 1 m an ag ed 44 y ea rs D RE SS (d ru g re ac tio n w ith eo si no ph ili a an d sy st em ic sy m pt om s) sy nd ro m e In hi bi tio n of U G T 2B 7 In te ra ct io n: in cr ea se d to xi ci ty o f la m ot rig in e M ye rs e t a l. (2 01 5) Lo pi na vi r/ rit on av ir 40 0 m g/ 10 0 m g 2 tim es /d ay fo r 29 .5 d ay s Ro ot ex tr ac t ca ps ul es St an da rd i- ze d to 5 % gi ns en os id e 50 0 m g 2 tim es /d ay fr om d ay 1 6 fo r 2 w ee ks 13 p eo pl e N o ch an ge in p ha rm a- co ki ne tic p ar am et er s f or ei th er d ru g N /A N o in te ra ct io n Ca ld er ón e t a l. (2 01 4) 56 D ru g de ta ils H er b an d pr od uc t d et ai ls St ud y de ta ils D ru g D os ag e re gi m en Fo rm Ch em ic al co ns ti - tu en ts D os ag e re gi m en Cl in ic al / hu m an In vivo In vitro Sy m pt om s/ ou tc om es H yp o- th es iz ed m ec ha ni sm Ev al ua ti on Re fe re nc e Lo sa rt an 10 m g/ kg Re d gi n- se ng ro ot N ot st at ed 0. 5, 1 a nd 2 g/ kg /d ay fo r 2 w ee ks Ra t N eg lig ib le in flu en ce o n lo sa rt an p ha rm ac ok in et ic s N /A N o in te ra ct io n Ry u et a l. (2 01 5) M id az ol am – fe xo fe na di ne M id az ol am 8 m g an d fe xo fe na di ne 1 20 m g be fo re /a ft er g in se ng tr ea tm en t Po w de - re d ro ot ex tr ac t ca ps ul es St an da rd i- ze d to 5 % gi ns en os id e 50 0 m g 2 tim es /d ay fo r 2 8 da ys 12 p eo pl e, (4 fe m al e) D ec re as e in C m ax a nd A U C of m id az ol am ; n o ef fe ct on fe xo fe na di ne In du ct io n of CY P3 A4 Po ss ib le in te ra ct io n: re du ce d ef fe ct of m id az ol am M al at i e t a l. (2 01 2) Ra lte gr av ir Ra lte gr av ir/ lo pi - na vi r r ito na vi r 40 0 m g/ 40 0 m g/ 10 0 m g 2 tim es /d ay Ly op hi li- ze d ro ot ex tr ac t lo ze ng es 10 00 m g N ot st at ed N ot g iv en 1 m al e liv in g w ith H IV Ac ut e el ev at io n of li ve r en zy m es ; j au nd ic e; w ei gh t lo ss In du ct io n of CY P3 A4 Po ss ib le in te ra ct io n: in cr ea se in ra l- te gr av ir to xi ci ty M at eo - Ca rr as co e t a l. (2 01 2) Ta bl e A1 .8 . Pa na x gi ns en g C. A. M ey ., (A ra lia ce ae ) G in se ng ; K or ea n/ Ch in es e/ or ie nt al g in se ng – 1 0 st ud ie s1 (C on 't. ) 57 D ru g de ta ils H er b an d pr od uc t d et ai ls St ud y de ta ils D ru g D os ag e re gi m en Fo rm Ch em ic al co ns ti - tu en ts D os ag e re gi m en Cl in ic al / hu m an In vivo In vitro Sy m pt om s/ ou tc om es H yp o- th es iz ed m ec ha ni sm Ev al ua ti on Re fe re nc e W ar fa rin 2– 5 m g Ro ot ex tr ac t N ot st at ed 50 0 m g 3 tim es /d ay RC T: 2 5 pe op le w ith is ch ae m ic st ro ke In cr ea se d w ar fa rin IN R, P T an d AU C, b ut n o st at is tic al di ff er en ce N /A N o in te ra ct io n Le e et a l. (2 00 8) Us ua l d os e Ko re an re d gi ns en g ro ot N ot st at ed 1 g/ da y RC T: 2 5 pe op le w ith c ar - di ac v al ve re pl ac e- m en t ( 21 fe m al e) N o si gn ifi ca nt d iff er en ce in IN R N /A Le e et a l. (2 01 0) 25 m g w ith o r w ith ou t 7 d ay s o f pr et re at m en t Ex tr ac t of K or ea n gi ns en g ro ot eq ui va le nt to 0 .5 g , ca ps ul e St an da rd iz ed to 8 .9 3 m g gi ns en os id ea s Rg 1 2 ca ps ul es 3 tim es /d ay fo r 1 w ee k 12 m al es N o ef fe ct o n ph ar - m ac od yn am ic s o r ph ar m ac ok in et ic s o f S - o r R- w ar fa rin N /A Jia ng e t a l. (2 00 4) AU C, a re a un de r co nc en tr at io n– tim e cu rv e; C m ax , m ax im um p la sm a co nc en tr at io n; C YP , cy to ch ro m e P4 50 ; IN R, i nt er na tio na l no rm al iz ed r at io ; IV , in tr av en ou s; LD L, l ow -d en sit y lip op ro te in ; N /A , no t ap pl ic ab le ; P -g p, P -g ly co pr ot ei n; P T, pr ot hr om bi n (b le ed in g) t im e; P XR , p re gn an e X re ce pt or ; R CT , r an do m iz ed c on tro lle d tr ia l; Tm ax , t im e to m ax im um p la sm a co nc en tr at io n; U GT , u rid in e di ph os ph at e- gl uc ur on os yl tr an sf er as e. 1 Fo r f ur th er d et ai ls, se e Ra m an at ha n M R, P en za k SR (2 01 7) . P ha rm ac ok in et ic d ru g in te ra ct io ns w ith P an ax g in se ng . E ur J D ru g M et ab P ha rm ac ok in et . 4 2( 4) :5 45 –5 7. Bi lg i N , B el l K , A na nt ha kr ish na n AN , A ta lla h E (2 01 0) . I m at in ib a nd P an ax g in se ng : a p ot en tia l i nt er ac tio n re su lti ng in li ve r t ox ic ity . A nn P ha rm ac ot he r. 44 (5 ):9 26 –8 . Ca ld er ón M M , C ha ire z C L, G or do n LA , A lfa ro R M , K ov ac s J A, P en za k S R (2 01 4) . In flu en ce o f P an ax g in se ng o n th e st ea dy st at e ph ar m ac ok in et ic p ro fil e of lo pi na vi r-r ito na vi r i n he al th y v ol un te er s. Ph ar m ac ot he ra py . 34 (1 1) :11 51 –8 . Jia ng X , W ill ia m s K M , L ia uw W S, A m m it AJ , R ou fo ga lis B D, D uk e CC , e t a l. (2 00 4) . E ffe ct o f S t J oh n’ s w or t a nd g in se ng o n th e ph ar m ac ok in et ic s a nd p ha rm ac od yn am ic s o f w ar fa rin in h ea lth y su bj ec ts . B r J C lin Ph ar m ac ol . 5 7: 59 2– 9. Le e YH , L ee B K, C ho i Y J, Yo on IK , C ha ng B C, G w ak H S (2 01 0) . I nt er ac tio n be tw ee n w ar fa rin a nd K or ea n re d gi ns en g in p at ie nt s w ith c ar di ac v al ve re pl ac em en t. In t J C ar di ol . 1 9;1 45 (2 ):2 75 –6 . Le e SH , A hn Y M , A hn S Y, D oo H K, L ee B C (2 00 8) . I nt er ac tio n be tw ee n w ar fa rin a nd P an ax g in se ng in is ch em ic st ro ke p at ie nt s. J A lte rn C om pl em en t M ed . 1 4( 6) :7 15 –2 1. M al at i C Y, R ob er ts on S M , H un t J D, C ha ire z C, A lfa ro R M , K ov ac s J A, P en za k SR (2 01 2) . I nfl ue nc e of P an ax g in se ng o n cy to ch ro m e P4 50 (C YP )3 A an d P- gl yc op ro te in (P -g p) a ct iv ity in h ea lth y pa rt ic ip an ts . J C lin Ph ar m ac ol . 5 2( 6) :9 32 –9 . M at eo -C ar ra sc o H, G ál ve z- Co nt re ra s M C, F er ná nd ez -G in és F D, N gu ye n TV (2 01 2) . E le va te d liv er e nz ym es re su lti ng fr om a n in te ra ct io n be tw ee n ra lte gr av ir an d Pa na x gi ns en g: a c as e re po rt a nd b rie f r ev ie w . D ru g M et ab ol D ru g In te ra ct . 2 7( 3) :17 1– 5. M ye rs A P, W at so n TA , S tro ck S B (2 01 5) . D ru g re ac tio n w ith e os in op hi lia a nd sy st em ic sy m pt om s s yn dr om e pr ob ab ly in du ce d by a la m ot rig in e– gi ns en g dr ug in te ra ct io n. P ha rm ac ot he ra py . 3 5( 3) : e 9– 12 . Ry u SH , K im Y S, Ja ng H J, Ki m K B (2 01 5) . N eg lig ib le p ha rm ac ok in et ic in te ra ct io n of re d gi ns en g an d Lo sa rt an , a n an tih yp er te ns iv e ag en t, in S pr ag ue -D aw le y ra ts . J T ox ic ol E nv iro n H ea lth A . 7 8( 20 ):1 22 9– 30 9. Ry u SH , K im JW , K im Y S, L ee S H, C ho Y B, L ee H K, e t a l. (2 01 4) . N eg lig ib le p ha rm ac ok in et ic in te ra ct io n of re d gi ns en g an d an tih yp er te ns iv e ag en t a m lo di pi ne in S pr ag ue -D aw le y ra ts . J T ox ic ol E nv iro n H ea lth A. 7 7( 22 -2 4) :13 72 –8 3. Ta bl e A1 .8 . Pa na x gi ns en g C. A. M ey ., (A ra lia ce ae ) G in se ng ; K or ea n/ Ch in es e/ or ie nt al g in se ng – 1 0 st ud ie s1 (C on 't. ) 58 Ta bl e A1 .9 . Sa lv ia m ilt io rr hi za B un ge . ( La m ia ce ae ); re d sa ge , C hi ne se sa ge – 1 0 st ud ie s1 D ru g de ta ils H er b an d pr od uc t d et ai ls St ud y de ta ils D ru g D os ag e re gi m en Fo rm Ch em ic al co ns ti tu en ts D os ag e re gi m en Cl in ic al / hu m an In vi vo In v it ro Sy m pt om s/ ou tc om es H yp ot he si ze d m ec ha ni sm Ev al ua ti on Re fe re nc e Cl op id og re l 30 0 m g or al ly b ef or e an d af te r tr ea tm en t Ex tr ac t ca ps ul es St an da rd iz ed ta ns hi no ne s 4 ca ps ul es 3 tim es /d ay fo r 7 d ay s 20 m al es Re du ce d pl as m a le ve ls cl op id og re l In du ct io n of P -g p an d CY P3 A4 Po te nt ia l in te ra ct io n Zh ou e t a l. (2 01 8) 30 m g/ kg or al ly W at er ex tr ac t ca ps ul es N ot st at ed 40 0 m g/ kg Ra t N o ef fe ct N /A N o in te ra ct io n Le e et a l. (2 01 1) D oc et ax el 5 m g/ kg IV ; 30 m g/ kg or al ly W at er ex tr ac t ca ps ul es N ot st at ed 40 0 m g/ kg Ra t N o ef fe ct N /A N o in te ra ct io n Fe xo fe na di ne 60 m g be fo re an d af te r tr ea tm en t Et ha no l ex tr ac t St an da rd iz ed ta ns hi no ne s 1 g 3 ti m es / da y fo r 10 d ay s 12 m al es In cr ea se d or al cl ea ra nc e In du ct io n of P -g p In te ra ct io n: re du - ce d fe xo fe na di ne pl as m a le ve ls Q iu e t a l. (2 01 4) M id az ol am 10 m g/ kg IV Ex tr ac t ca ps ul es D an sh en su Ac ut e 50 –2 00 m g/ kg in tr ap er i- to ne al ly fo r 3 da ys Ra t H yp no tic ef fic ac y pr ol on ge d In hi bi tio n of C YP 3A U nc le ar W an g et a l. (2 01 0) Iri no te ca n D ru g pr ob e Ex tr ac t; is ol at ed co m po un ds St an da rd iz ed ta ns hi no ne s N /A En zy m e, ce ll gr ow th as sa ys Re du ce d hy dr ol ys is of e st er ifi ed dr ug s In hi bi tio n of ca rb ox yl es te ra se s U nc le ar H at fie ld e t a l. (2 01 3) Pr op of ol D ru g pr ob e D ih yd ro - ta ns hi no ne I/c ry pt o- ta ns hi no ne N /A N /A H um an li ve r m ic ro so m es In hi bi tio n of gl uc ur on id a- tio n In hi bi tio n of U G T U nc le ar Co ng e t a l. (2 01 3) Ro su va st at in 10 0 m g/ kg D an sh en su D an sh en su 46 m g/ kg Ra t Pl as m a cl ea ra nc e of ro su va st at in re du ce d by > 5 7% In hi bi tio n of tr an s- po rt er p ro te in s o r CY P Po te nt ia l i nt e- ra ct io n: m ay in cr ea se to xi ci ty o f ro su va st at in W en a nd Xi on g ( 2 01 1) 59 D ru g de ta ils H er b an d pr od uc t d et ai ls St ud y de ta ils D ru g D os ag e re gi m en Fo rm Ch em ic al co ns ti tu en ts D os ag e re gi m en Cl in ic al / hu m an In vi vo In v it ro Sy m pt om s/ ou tc om es H yp ot he si ze d m ec ha ni sm Ev al ua ti on Re fe re nc e Th eo ph yl lin e 10 0 m g on da ys 1 a nd 1 5 Ex tr ac t ta bl et eq ui va le nt 1 g ro ot St an da rd iz ed ta ns hi no ne s, m ilt iro ne 4 ta bl et s 3 tim es /d ay fo r 1 4 da ys 12 p eo pl e N o si gn ifi - ca nt e ff ec t on p la sm a th eo ph yl lin e N /A N o in te ra ct io n Q iu e t a l. (2 00 8) W ar fa rin 4 m g Ta ns hi - no ne II A N /A 4 m g Ra t Si gn ifi ca nt de cr ea se in Cm ax a nd p ro - lo ng ed T m ax of w ar fa rin In hi bi tio n of CY P1 A1 , C YP 2C 6 an d CY P2 C1 1 In te ra ct io n: in cr ea se in le ve ls of fr ee w ar fa rin Li u et a l. (2 00 8) 1 m M Ex tr ac t St an da rd iz ed ta ns hi no ne II, sa lv ia no lic ac id s 0. 1 m M H SA bi nd in g In cr ea se d fr ee d ru g co nc en tr at io n D ec re as ed b in di ng to H SA si te I Sh ao e t a l. (2 01 6) Cm ax , m ax im um p la sm a co nc en tr at io n; C YP , c yt oc hr om e P4 50 ; H SA , h um an s er um a lb um in ; I V, in tr av en ou s; N /A , n ot a pp lic ab le ; P -g p, P -g ly co pr ot ei n; T m ax , t im e to m ax im um p la sm a co nc en tr at io n; U GT , ur id in e di ph os ph at e- gl uc ur on os yl tr an sf er as e. 1 So m e st ud ie s s ho w c on fli ct in g re su lts (e .g . f or c lo pi do gr el ). Fo r r ev ie w s o f i nt er ac tin g m ec ha ni sm s, se e Ch en F, L i L , T ia n D D (2 01 7) . S al vi a m ilt io rrh iz a ro ot s a ga in st c ar di ov as cu la r d ise as e: c on sid er at io n of h er b– dr ug in te ra ct io ns . B io m ed R es In t. 98 68 69 4; a nd Z ho u X, C ha n K, Y eu ng JH (2 01 2) . H er b– dr ug in te ra ct io ns w ith D an sh en (S al vi a m ilt io rrh iz a) : a re vi ew o n th e ro le o f c yt oc hr om e P4 50 e nz ym es . D ru g M et ab ol D ru g In te ra ct . 2 7( 1) :9 –1 8. Co ng M , H u CM , C ao Y F, Fa ng Z Z, T an g SH , W an g JR , L uo JS (2 01 3) . C ry pt ot an sh in on e an d di hy dr ot an sh in on e I e xh ib it st ro ng in hi bi tio n to w ar ds h um an li ve r m ic ro so m e (H LM )- ca ta ly ze d pr op of ol g lu cu ro ni - da tio n. F ito te ra pi a. 8 5:1 09 –1 13 . Ha tfi el d M J, Ts ur ka n LG , H ya tt JL , E dw ar ds C C, L em off A , J eff rie s C , e t a l. (2 01 3) . M od ul at io n of e st er ifi ed d ru g m et ab ol ism b y ta ns hi no ne s f ro m S al vi a m ilt io rrh iz a (“D an sh en ”). J N at P ro d. 7 6: 36 − 44 . Le e JH , S hi n YJ , K im H J, O h JH , J an g YP , L ee Y J (2 01 1) . D an sh en e xt ra ct d oe s no t a lte r p ha rm ac ok in et ic s of d oc et ax el a nd c lo pi do gr el , r efl ec tin g its n eg lig ib le p ot en tia l i n P- gl yc op ro te in - a nd c yt oc hr om e P4 50 3A -m ed ia te d he rb –d ru g in te ra ct io ns . I nt J Ph ar m .41 0 (1 –2 ):6 8– 74 . Li u J, W an g XR , C ai Z W , L ee F SC (2 00 8) . E ffe ct o f t an sh in on e IIA o n th e no nc ov al en t i nt er ac tio n be tw ee n w ar fa rin a nd h um an se ru m a lb um in st ud ie d by e le ct ro sp ra y io ni za tio n m as s s pe ct ro m et ry . J A m S oc M as s S pe ct ro m . 1 9( 10 ):1 56 8– 75 . Q iu F, W an g G, Z ha o Y, S un H , M ao G , J iy i A , S un J (2 00 8) . E ffe ct o f d an sh en e xt ra ct o n ph ar m ac ok in et ic s o f t he op hy lli ne in h ea lth y vo lu nt ee rs . B r J C lin P ha rm ac ol . 6 5( 2) :2 70 –7 4. Q iu F, Z en g J, Li u S, H e M , Z hu L , Y e Y, e t a l. (2 01 4) . E ffe ct s o f d an sh en e th an ol e xt ra ct o n th e ph ar m ac ok in et ic s o f f ex of en ad in e in h ea lth y vo lu nt ee rs . E vi d Ba se d Co m pl em en t A lte rn at M ed . 2 01 4: 47 32 13 . Sh ao X , A i N , X u D H, F an X H (2 01 6) . E xp lo rin g th e in te ra ct io n be tw ee n Sa lv ia m ilt io rrh iz a an d hu m an s er um a lb um in : i ns ig ht s fro m h er b– dr ug in te ra ct io n re po rt s, co m pu ta tio na l a na ly sis a nd e xp er im en ta l st ud ie s, Sp ec tro ch im A ct a A M ol B io m ol S pe ct ro sc . 1 61 : 1 –7 . W an g X, L ee W Y, Z ho u X, O r P M , Y eu ng JH (2 01 0) . A p ha rm ac od yn am ic– ph ar m ac ok in et ic (P D –P K) s tu dy o n th e eff ec ts o f D an sh en (S al vi a m ilt io rrh iz a) o n m id az ol am , a m od el C YP 3A p ro be su bs tr at e, in th e ra t. Ph yt om ed ic in e. 1 7( 11 ):8 76 –8 3. W en JH , X io ng Y Q (2 01 1) . T he e ffe ct o f h er ba l m ed ic in e da ns he ns u an d ur so lic a ci d on p ha rm ac ok in et ic s o f r os uv as ta tin in ra ts . E ur J D ru g M et ab P ha rm ac ok in et . 3 6( 4) :2 05 –1 1. Zh ou C H, X u M , Y u HB , Z he ng X T, Zh an g ZF , Z ha ng LT (2 01 8) .E ffe ct s o f D an sh en c ap su le s o n th e ph ar m ac ok in et ic s a nd p ha rm ac od yn am ic s o f c lo pi do gr el in h ea lth y vo lu nt ee rs . F oo d Ch em To xi co l. 11 9: 3 02 –8 . Ta bl e A1 .9 . Sa lv ia m ilt io rr hi za B un ge . ( La m ia ce ae ); re d sa ge , C hi ne se sa ge – 1 0 st ud ie s1 (C on 't. ) 60 Ta bl e A1 .1 0. Sc hi sa nd ra : S ch is an dr a ch in en si s ( Tu rc z. ) B ai ll. /S ch is an dr a sp he na nt he ra R eh de r & E .H . W ils on (S ch is an dr ac ea e) ; m ag no lia v in e, so ut he rn m ag no lia v in e – 11 st ud ie s1 D ru g de ta ils H er b an d pr od uc t d et ai ls St ud y de ta ils D ru g D os ag e re gi m en Fo rm Ch em ic al co ns ti tu en ts D os ag e re gi m en Cl in ic al / hu m an In vi vo In vi tr o Sy m pt om s/ ou tc om es H yp o- th es iz ed m ec ha - ni sm Ev al ua ti on Re fe re nc e Ci cl os po rin 37 .8 o r 1. 89 m g/ kg Ex tr ac t o f Sc hi sa nd ra sp he na nt he ra St an da rd iz ed Sc hi sa nt he rin A 7. 5 m g 0. 25 g /k g Ra t In cr ea se d ci cl os po rin bl oo d le ve ls w ith lo w -d os e Sc hi sa n- dr a sp he na nt he ra ex tr ac t In hi bi tio n of CY P3 A an d P- gp In te ra ct io n: in cr ea se d pl as m a le ve ls of ci cl os po rin Xu e et a l. (2 01 3) 25 m g/ kg Ex tr ac t o f Sc hi sa nd ra ch in en si s St an da rd iz ed 37 .3 0 m g/ g to ta l lig na ns 54 –2 16 m g/ kg Ra t In cr ea se d bl oo d co nc en tr at io n an d lo ng er h al f- lif e of ci cl os po rin La i e t a l. (2 01 5) D ig ox in a nd vi nc ris tin e D ig ox in 0. 5 m g/ kg , vi nc ris tin e 1. 0 m g/ kg Li gn an e xt ra ct St an da rd iz ed Sc hi za nd ro l A , B ; Sc hi sa nt he rin A , B; S ch iz an dr in B 50 0 m g/ kg si ng le d os e or fo r 1 0 da ys Ra t In cr ea se d di go xi n an d vi nc ris tin e AU C In hi bi tio n of P- gp In te ra ct io n: in cr ea se d bl oo d le ve ls of d ig ox in a nd vi nc ris tin e Li an g et a l. (2 01 3) D ig ox in 5 μ M , vi nc ris tin e 5 μM 0. 5, 2 .0 o r 10 .0 g /m l Ca co -2 ce lls In cr ea se d in tr ac el lu la r c on ce n- tr at io n of d ig ox in an d vi nc ris tin e Fe no fib ra te 0. 1% su pp le m en t Ex tr ac t o f Sc hi sa nd ra ch in en si s N ot st at ed 1 g/ kg M ou se In cr ea se d he pa tic lip id - a nd g lu co se - lo w er in g ef fe ct s o f fe no fib ra te N ot st at ed In te ra ct io n: in cr ea se d ef fe ct of fe no fib ra te Zh u et a l. (2 01 5) M id az ol am 15 m g si ng le do se Ex tr ac t o f Sc hi sa nd ra sp he na nt he ra ca ps ul e St an da rd i- ze d 11 .2 5 m g de ox ys ch iz an dr in 3 ca ps ul es 2 tim es /d ay fo r 7 d ay s 12 m al es In cr ea se d or al bi oa va ila bi lit y of m id az ol am In hi bi tio n of CY P3 A4 In te ra ct io n: in cr ea se d ef fe ct of m id az ol am Xi n et a l. (2 00 9) Pa cl ita xe l 30 m g/ kg or al ly , o r 0. 5 m g/ kg IV Ex tr ac t o f Sc hi sa nd ra sp he na nt he ra St an da rd iz ed Sc hi sa nt he rin A 0. 25 g /k g M ou se Pa cl ita xe l e xp os ur e in cr ea se d, b ut n o ce nt ra l n er vo us sy st em to xi ci ty o r ot he r s id e- ef fe ct s In hi bi tio n of P- gp o r C YP In te ra ct io n: in cr ea se d bi oa - va ila bi lit y of pa cl ita xe l Jin e t a l. (2 01 1) 61 D ru g de ta ils H er b an d pr od uc t d et ai ls St ud y de ta ils D ru g D os ag e re gi m en Fo rm Ch em ic al co ns ti tu en ts D os ag e re gi m en Cl in ic al / hu m an In vi vo In vi tr o Sy m pt om s/ ou tc om es H yp o- th es iz ed m ec ha - ni sm Ev al ua ti on Re fe re nc e Ta cr ol im us 2 m g on da ys 1 a nd 1 5 Ex tr ac t o f Sc hi sa nd ra sp he na nt he ra St an da rd i- ze d 11 .2 5 m g de ox ys ch iz an dr in 3 ca ps ul es 2 tim es /d ay fo r 1 3 da ys 12 m al es In cr ea se d AU C an d Cm ax o f t ac ro lim us In hi bi tio n of CY P 3A 4 or P- gp In te ra ct io n: in cr ea se d pl as m a le ve ls of ta cr ol im us Xi n et a l. (2 00 7) 1. 2 m g/ kg Ex tr ac t o f Sc hi sa nd ra sp he na nt he ra ca ps ul e St an da rd i- ze d 11 .2 m g de ox ys ch iz an dr in 15 0 m g/ kg si ng le d os e, or m ul ti- pl e do se s 25 –1 25 0 m g/ kg Ra t In cr ea se d pl as m a co nc en tr at io n of ta cr ol im us fo r s in gl e an d m ul tip le d os es ; ef fe ct is d os e- de pe n- de nt u p to 4 50 m g/ kg In hi bi tio n of P -g p or CY P3 A W ei e t a l. (2 01 3) Ta lin ol ol 10 0 m g w ith or w ith ou t Sc hi sa nd ra ch in en si s Ex tr ac t o f Sc hi sa nd ra ch in en si s ta bl et St an da rd i- ze d 16 .8 5 m g de ox ys ch iz an dr in 30 0 m g 2 tim es /d ay 12 m al es Sc hi sa nd ra c hi ne n- si s i nc re as ed A U C of ta lin ol ol b y 47 % In hi bi tio n of P- gp Po te nt ia l in te ra ct io n: m ay in cr ea se pl as m a le ve ls Fa n et a l. (2 00 9) W ar fa rin 2 m g/ kg IV Ex tr ac t o f Sc hi sa nd ra ch in en si s an d is ol at ed co m po un ds Sc hi za nd ro ls , sc hi za nd rin s 50 0 m g/ kg Ra t In cr ea se d w ar fa rin cl ea ra nc e Ac tiv at io n of PX R by S ch i- za nd ro l B , Sc hi za nd rin s A an d B Po te nt ia l i nt e- ra ct io n: m ay re du ce p la sm a le ve ls M u et a l. (2 00 6) AU C, ar ea u nd er co nc en tr at io n– tim e cu rv e; C m ax , m ax im um p la sm a c on ce nt ra tio n; C YP , c yt oc hr om e P4 50 ; H SA , h um an se ru m al bu m in ; IV , in tr av en ou s; N /A , n ot ap pl ic ab le ; P -g p, P -g ly co pr ot ei n; P XR , p re gn an e X re ce pt or ; T m ax , t im e to m ax im um p la sm a co nc en tr at io n; U GT , u rid in e di ph os ph at e- gl uc ur on os yl tr an sf er as e. 1 H er b– dr ug in te ra ct io ns th at re su lt in a n in cr ea se in th e or al b io av ai la bi lit y of so m e po or ly a bs or be d im po rt an t m ed ic in es , s uc h as im m un os up pr es sa nt s, m ay b e be ne fic ia l b ut sh ou ld b e ex pl oi te d on ly un de r e xp er t c lin ic al su pe rv isi on . Fa n L, M ao X Q , T ao G Y, W an g G, Ji an g F, Ch en Y, e t a l. ( 20 09 ) E ffe ct o f S ch isa nd ra ch in en sis e xt ra ct a nd G in kg o bi lo ba e xt ra ct o n th e ph ar m ac ok in et ic s o f t al in ol ol in h ea lth y v ol un te er s. Xe no bi ot ic a. 3 9( 3) :2 49 –5 4. Jin J, B i H , H u J, Ze ng H , Z ho ng G , Z ha o L, e t a l. (2 01 1) . E ffe ct o f W uz hi ta bl et (S ch isa nd ra sp he na nt he ra e xt ra ct ) o n th e ph ar m ac ok in et ic s o f p ac lit ax el in ra ts . P hy to th er R es . 2 5( 8) :12 50 –5 3. La i Q , W ei J, M ah m oo du rr ah m an M , Z ha ng C , Q ua n S, L i T , Y u Y (2 01 5) . P ha rm ac ok in et ic a nd n ep hr op ro te ct iv e be ne fit s o f u sin g Sc hi sa nd ra c hi ne ns is ex tr ac ts in a c yc lo sp or in e A- ba se d im m un e- su pp re ss iv e re gi m en . D ru g D es D ev el T he r. 9: 49 97 –5 01 8. Li an g Y, Z ho u Y, Z ha ng J, L iu Y , G ua n T, W an g Y, e t a l. (2 01 3) . I n vi tro to in v iv o ev id en ce o f t he in hi bi to r c ha ra ct er ist ic s o f S ch isa nd ra li gn an s t ow ar d P- gl yc op ro te in . P hy to m ed ic in e. 2 0( 11 ):1 03 0– 38 . M u Y, Z ha ng J, Z ha ng S , Z ho u HH , T om a D, R en S , e t a l. (2 00 6) . T ra di tio na l C hi ne se m ed ic in es W u W ei Z i ( Sc hi sa nd ra c hi ne ns is Ba ill ) a nd G an C ao (G ly cy rrh iz a ur al en sis F isc h) a ct iv at e pr eg na ne X re ce pt or a nd in cr ea se w ar fa rin c le ar an ce in ra ts . J P ha rm ac ol E xp T he r. 31 6( 3) :13 69 –7 7. W ei H , T ao X , D i P , Y an g Y, L i J , Q ia n X, e t a l. (2 01 3) . E ffe ct s o f t ra di tio na l C hi ne se m ed ic in e W uz hi c ap su le o n ph ar m ac ok in et ic s o f t ac ro lim us in ra ts . D ru g M et ab D isp o. 4 1( 7) :13 98 –4 03 . Xi n HW , W u XC , L i Q , Y u AR , X io ng L (2 00 9) . E ffe ct s o f S ch isa nd ra sp he na nt he ra e xt ra ct o n th e ph ar m ac ok in et ic s o f m id az ol am in h ea lth y vo lu nt ee rs . B r J C lin P ha rm ac ol . 6 7( 5) :5 41 –6 . Xi n HW , W u XC , L i Q , Y u AR , Z hu M , S he n Y, e t a l. (2 00 7) . E ffe ct s o f S ch isa nd ra sp he na nt he ra e xt ra ct o n th e ph ar m ac ok in et ic s o f t ac ro lim us in h ea lth y vo lu nt ee rs . B r J C lin P ha rm ac ol . 6 4( 4) :4 69 –7 5. Xu e XP , Q in X L, X u C, Z ho ng G P, W an g Y, H ua ng M , B i H C (2 01 3) . E ffe ct o f W uz hi ta bl et (S ch isa nd ra sp he na nt he ra e xt ra ct ) o n th e ph ar m ac ok in et ic s o f c yc lo sp or in A in ra ts . P hy to th er R es . 2 7( 8) :12 55 –9 . Zh u PL , P an S Y, Z ho u SF , Z ha ng Y , W an g XY , S un N , e t a l. (2 01 5) . E ffe ct s of c om bi ne d di et ar y su pp le m en ta tio n w ith fe no fib ra te a nd S ch isa nd ra e fru ct us p ul p on li pi d an d gl uc os e le ve ls an d liv er fu nc tio n in no rm al a nd h yp er ch ol es te ro le m ic m ic e. D ru g D es D ev el T he r. 9: 92 3– 35 . Ta bl e A1 .1 0. Sc hi sa nd ra : S ch is an dr a ch in en si s ( Tu rc z. ) B ai ll. /S ch is an dr a sp he na nt he ra R eh de r & E .H . W ils on (S ch is an dr ac ea e) ; m ag no lia v in e, so ut he rn m ag no lia v in e – 11 st ud ie s1 (C on 't. ) 62 Ta bl e A1 .11 . Si ly bu m m ar ia nu m (L .) G ae rt n. , ( As te ra ce ae ); m ilk th is tle , S t M ar y’ s t hi st le – si x st ud ie s1 D ru g de ta ils H er b an d pr od uc t d et ai ls St ud y de ta ils D ru g D os ag e re gi m en Fo rm Ch em ic al co ns ti - tu en ts D os ag e re gi m en Cl in ic al / hu m an In vi vo In vi tr o Sy m pt om s/ ou tc om es H yp o t he si ze d m ec ha ni sm Ev al ua ti on Re fe re nc e In di na vi r 80 0 m g ev er y 8 h fo r 4 do se s Ex tr ac t ta bl et 30 0 m g St an da rd iz ed si ly m ar in 15 3 m g 17 5 m g 3 tim es /d ay fo r 3 w ee ks 10 p eo pl e (6 m al e) N o ch an ge in ov er al l e xp os ur e of in di na vi r N /A N o in te ra ct io n Pi sc ite lli e t a l. (2 00 2) 80 0 m g ev er y 8 h Ex tr ac t ca ps ul es 45 6 m g St an da rd iz ed si ly m ar in 45 6 m g 3 tim es /d ay on d ay s 2 –3 0 16 p eo pl e N o si gn ifi ca nt ch an ge s N /A M ill s e t a l. (2 00 5) 80 0 m g 3 tim es /d ay on d ay s 1 , 2 , 16 a nd 1 7 Si ly m ar in St an da rd i- ze d re fin ed ex tr ac t 16 0 m g 3 tim es /d ay on d ay s 3 –1 7 10 p eo pl e N o ch an ge in ov er al l e xp os ur e of in di na vi r N /A D iC en zo e t a l. (2 00 3) M id az ol am / ca ff ei ne /t ol - bu ta m id e/ de xt ro - m et ho rp ha n M id az o- la m 1 0 m g, ca ff ei ne 20 0 m g, to lb ut am id e 50 0 m g, de xt ro - m et ho rp ha n 30 m g, pr ob e dr ug s Ex tr ac t (L eg al on 14 0) c ap su - le s 1 75 m g St an da rd i- ze d 14 0 m g si ly m ar in 1 ca ps ul e 3 tim es /d ay 12 p eo pl e N o re le va nt e ff ec t on m aj or C YP ac tiv ity N /A N o in te ra ct io n w ith p ro be d ru gs Ka w ag uc hi -S uz uk i et a l. (2 01 4) M id az ol am M id az ol am 4 m M Ex tr ac t si ly m ar in Si ly bi n A, B ; is os ily bi n A, B N /A H um an m ic ro - so m es In cr ea se d m id az o- la m C m ax a nd A U C In hi bi tio n of CY P3 A4 Po ss ib le : i nc re a- se d ef fe ct o f m id az ol am Br an tle y et a l. (2 01 2) N ife di pi ne 10 m g, 2 do se s Fr ui t ex tr ac t ca ps ul es St an da rd i- ze d 14 0 m g si ly m ar in 28 0 m g 10 h a nd 1. 5 h be fo re ni fe di pi ne 16 m al es N o m ea ni ng fu l ef fe ct o n ha em od y- na m ic p ar am et er s N /A N o si gn ifi ca nt in te ra ct io n Fu hr e t a l. (2 00 7) AU C, a re a un de r c on ce nt ra tio n– tim e cu rv e; C m ax , m ax im um p la sm a co nc en tr at io n; C YP , c yt oc hr om e P4 50 ; N /A , n ot a pp lic ab le . 1 Fo r a re vi ew o f m ilk th ist le in te ra ct io ns , s ee G ur le y BJ , F ife r E K, G ar dn er Z (2 01 2) . P ha rm ac ok in et ic h er b– dr ug in te ra ct io ns (p ar t 2 ): dr ug in te ra ct io ns in vo lv in g po pu la r b ot an ic al d ie ta ry su pp le m en ts a nd th ei r c lin ic al re le va nc e. P la nt a M ed . 7 8( 13 ):1 49 0– 51 4. Br an tle y S J, Gr af T N , O be rli es N H, P ai ne M F ( 20 13 ). A sy st em at ic ap pr oa ch to e va lu at e he rb –d ru g in te ra ct io n m ec ha ni sm s: in ve st ig at io n of m ilk th ist le e xt ra ct s a nd e ig ht is ol at ed co ns tit ue nt s a s C YP 3A in hi bi to rs . D ru g M et ab D isp os . 4 1( 9) :16 62 –7 0. D iC en zo R , S he lto n M , J or da n K, K ov al C , F or re st A , R ei ch m an R , M or se G (2 00 3) . C oa dm in ist ra tio n of m ilk th ist le a nd in di na vi r i n he al th y su bj ec ts . P ha rm ac ot he ra py . 2 3( 7) :8 66 –7 0. Fu hr U , B ec km an n- Kn op p S, Je tt er A , L üc k H, M en gs U (2 00 7) . T he e ffe ct o f s ily m ar in o n or al n ife di pi ne p ha rm ac ok in et ic s. Pl an ta M ed . 7 3( 14 ):1 42 9– 35 . Ka w ag uc hi -S uz uk i M , F ry e RF , Z hu H J, Br in da B J, Ch av in K D, B er ns te in H J, M ar ko w itz J S (2 01 4) . T he e ffe ct s of m ilk t hi st le (S ily bu m m ar ia nu m ) o n hu m an c yt oc hr om e P4 50 a ct iv ity . D ru g M et ab D isp os . 42 (1 0) :16 11 –1 6. M ill s E , W ils on K , C la rk e M , F os te r B , W al ke r S , R ac hl is B, e t a l. (2 00 5) . M ilk th ist le a nd in di na vi r: a ra nd om iz ed c on tro lle d ph ar m ac ok in et ic s s tu dy a nd m et a- an al ys is. E ur J Cl in P ha rm ac ol . 6 1( 1) :1– 7. Pi sc ite lli S C, F or m en tin i E , B ur st ei n AH , A lfa ro R , J ag an na th a S, F al lo on J (2 00 2) . E ffe ct o f m ilk th ist le o n th e ph ar m ac ok in et ic s o f i nd in av ir in h ea lth y vo lu nt ee rs . P ha rm ac ot he ra py . 2 2( 5) :5 51 –6 . 63 Ta bl e A1 .1 2. Zi ng ib er o ffi ci na le R os co e (Z in gi be ra ce ae ); gi ng er – th re e st ud ie s D ru g de ta ils H er b an d pr od uc t d et ai ls St ud y de ta ils D ru g D os ag e re gi m en Fo rm Ch em ic al co ns ti tu en ts D os ag e re gi m en Cl in ic al / hu m an In vi vo In v it ro Sy m pt om s/ ou tc om es H yp o- th es iz ed m ec ha ni sm Ev al ua ti on Re fe re nc e Ph en ac et in , di cl of en ac , bu pr op io n D ru g pr ob e m ix tu re G in ge r ex tr ac t 6 -, 8- , 10 -g in ge ro ls , 6- sh og ao l St an da rd iz ed 50 0 µg / m l g in ge r ex tr ac t, 6- , 8- , 1 0- gi n- ge ro ls , 6- sh og ao l H um an li ve r m ic ro so m es , Ca co -2 c el ls N o si gn ifi ca nt ef fe ct o n CY P N /A N o in te ra ct io n vi a CY P M uk ka vi lli e t al . ( 20 14 ) N ife di pi ne 10 m g/ da y D rie d rh iz om e N ot st at ed 1 g/ da y fo r 1 w ee k 10 p eo pl e w ith ou t a nd 10 p eo pl e w ith hy pe rt en si on Po te nt ia tio n of a nt ip la te - le t e ff ec ts o f ni fe di pi ne N ot st at ed Po te nt ia l in te ra ct io n: en ha nc ed ef fe ct s o f ni fe di pi ne Yo un g et a l. (2 00 6) W ar fa rin 25 m g Ex tr ac t d rie d rh iz om e ca ps ul es e qu i- va le nt to 0 .4 g rh iz om e N ot st at ed 3 ca ps ul es 3 tim es /d ay fo r 7 d ay s 12 m al es N o ef fe ct o n di st rib ut io n or pr ot ei n bi n- di ng o f S - o r R- w ar fa rin N on e N o in te ra ct io n Jia ng e t a l. (2 00 5) CY P, cy to ch ro m e P4 50 ; N /A , n ot a pp lic ab le . Jia ng X , W ill ia m s K M , L ia uw W S, A m m it AJ , R ou fo ga lis B D, D uk e CC , e t a l. ( 20 05 ). Eff ec t o f g in kg o an d gi ng er o n th e ph ar m ac ok in et ic s a nd p ha rm ac od yn am ic s o f w ar fa rin in h ea lth y s ub je ct s. Br J Cl in P ha rm ac ol . 59 (4 ):4 25 –3 2. M uk ka vi lli R , G un da la S R, Y an g C, D on th am se tt y S, C an tu ar ia G , J ad ha v GR , e t a l. (2 01 4) . M od ul at io n of c yt oc hr om e P4 50 m et ab ol ism a nd tr an sp or t a cr os s i nt es tin al e pi th el ia l b ar rie r b y gi ng er b io ph en ol ic s. PL oS O ne . 9 (9 ):e 10 83 86 . Yo un g HY , L ia o JC , C ha ng Y S, L uo Y L, L u M C, P en g W H (2 00 6) . S yn er gi st ic e ffe ct o f g in ge r a nd n ife di pi ne o n hu m an p la te le t a gg re ga tio n: a s tu dy in h yp er te ns iv e pa tie nt s a nd n or m al v ol un te er s. Am J Ch in M ed . 3 4( 4) :5 45 –5 1. 64 65 Annex 2. Participants First World Health Organization working group meeting on key technical issues for herbal medicines with reference to interaction with other medicines, Milan, Italy, 23–25 June 2011 ■ Professor Ahmad Alkofahi, Member of WHO Expert Advisory Panel on Traditional Medicine, Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan ■ Dr Simona Busato, WHO Collaborating Centre for Traditional Medicine, Centre of Research in Medical Bioclimatology, Biotechnologies and Natural Medicine, State University of Milan, Milan, Italy ■ Dr Stephana Carelli, Department of Medicine, Surgery and Dentistry, State University of Milan, Milan, Italy ■ Dr Ana Cecilia Bezerra de Carvalho, Coordinator, Herbal and Homeopathic Medicines, General Office of Drugs, Brazilian Health Surveillance Agency, Brasília, Brazil ■ Dr Frank Ling-fung Chan, Senior Pharmacist, Traditional Chinese Medicine, Chinese Medicine Division, Department of Health, Hong Kong Specialist Administrative Region, China ■ Professor Ki-Ho Cho, Director, WHO Collaborating Centre for Traditional Medicine, East–West Medical Research Institute, Seoul, Republic of Korea ■ Dr Makoto Fujimoto, WHO Collaborating Centre for Traditional Medicine, Department of Japanese Oriental Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan ■ Dr Andrea Geraci, Clinical Research and Drug Experimental Unit, Department of Therapeutic Research and Medicines Evaluation, Italian National Institute of Health, Rome, Italy ■ Dr Takashi Hakamatsuka, Section Chief, Division of Pharmacognosy, Phytochemistry and Narcotics, National Institute of Health Sciences, Ministry of Health, Labour and Welfare, Tokyo, Japan ■ Professor Oliver Yoa-Pu Hu, School of Pharmacy, Defense Medical Center, Taiwan, China ■ Dr Lin-Huang Huang, Chair, Committee on Chinese Medicine and Pharmacy, Department of Health, Taiwan, China ■ Dr Michiho Ito, Associate Professor, Department of Pharmacognosy, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan ■ Dr Konstantin Keller, Member of WHO Expert Advisory Panel on Traditional Medicine, Federal Ministry of Health, Bonn, Germany ■ Dr Olaf Kelber, Head, Preclinical and Clinical Research, Steigerwald Arzneimittelwerk, Darmstadt, Germany ■ Professor Yeong Shik Kim, Director, WHO Collaborating Centre for Traditional Medicine, Natural Products Research Institute, Seoul National University, Seoul, Republic of Korea 66 ■ Dr Robert Kwok-wai Law, Senior Pharmacist, Traditional Chinese Medicine, Chinese Medicine Division, Department of Health, Hong Kong Special Administrative Region, China ■ Professor Liang Aihua, WHO Collaborating Centre for Traditional Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medicinal Sciences, Beijing, China ■ Professor Liu Ping, Director, WHO Collaborating Centre for Traditional Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China ■ Ms Yukiko Maruyama, Scientist, Traditional Medicine, Department for Health System Governance and Service Delivery, World Health Organization, Geneva, Switzerland ■ Dr Basmiah Md Isa, Head, Natural Product Unit, National Pharmaceutical Control Bureau, Ministry of Health, Putrajaya, Malaysia ■ Professor Emilio Minelli, Member of WHO Expert Advisory Panel on Traditional Medicine, Deputy Director, WHO Collaborating Centre for Traditional Medicine, Centre of Research in Medical Bioclimatology, Biotechnologies and Natural Medicine, State University of Milan, Milan, Italy ■ Dr Vural Ozdemir, Associate Professor, Centre of Genomics and Policy, Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, Canada ■ Dr Shanthi Narayan Pal, Technical Officer, Quality Assurance and Safety: Medicines, Department of Essential Medicines and Pharmaceutical Policies, World Health Organization, Geneva, Switzerland ■ Ms Lucia Scrabbi, Planning Unit, Directorate General of Health, Regional Government of Lombardy, Milan, Italy ■ Dr Hyun-kyu Shin, WHO Collaborating Centre for Traditional Medicine, Korea Institute of Oriental Medicine, Daejoen, Republic of Korea ■ Dr Maura Linda Sitanggang, Director, Traditional Medicines, Food Supplements and Cosmetics Evaluation, National Agency for Drug and Food Control, Jakarta, Indonesia ■ Dr Souad Skalli, WHO Collaborating Centre for Strengthening Pharmacovigilance Practices, Pharmacovigilance of Herbal Medicines, Centre Anti Poison et de Pharmacovigilance du Maroc, Rabat, Morocco ■ Dr Michael J. Smith, Member of WHO Expert Advisory Panel on Traditional Medicine, Adjunct Professor, National Center for Natural Product Research, School of Pharmacy, University of Mississippi, University, MS, United States of America ■ Dr Duc Vu, Director, Marketed Biologicals, Biotechnology and Natural Health Products Bureau, Marketed Health Products Directorate, Health Products and Food Branch, Health Canada, Ottawa, Canada ■ Professor Wang Xinhua, Vice President, Guangzhou University of Chinese Medicine, Guangzhou, China ■ Dr Zhang Qi, Coordinator, Traditional Medicine, Department for Health System Governance and Service Delivery, World Health Organization, Geneva, Switzerland ■ Dr Zheng Linyun, Deputy Director, WHO Collaborating Centre for Traditional Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China 67 Second World Health Organization working group meeting on key technical issues for herbal medicines with reference to interaction with other Medicines, Oxford, Mississippi, United States of America, 12–14 July 2016 ■ Professor Ichiro Arai, Department of Kampo Medicine, Nihon Pharmaceutical University, Saitama, Japan ■ Dr Mohammad K. Ashfaq, Principal Scientist, National Center for Natural Product Research, School of Pharmacy, University of Mississippi, University, MS, United States of America ■ Dr Ana Cecilia Bezerra Carvalho, Coordinator, Herbal and Homeopathic Medicines, General Office of Drugs, Brazilian Health Surveillance Agency, Brasilia, Brazil ■ Professor Heather Boon, Dean, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada ■ Dr Amar Gopal Chittiboyina, Senior Research Scientist, National Center for Natural Product Research, School of Pharmacy, University of Mississippi, University, MS, United States of America ■ Mr Kelvin Cheung, WHO Collaborating Centre for Traditional Medicine, Chinese Medicine Division, Department of Health, Hong Kong Special Administrative Region, China ■ Dr Amanda H. Corbett, Clinical Associate Professor, University of North Carolina at Chapel Hill, Eshelman School of Pharmacy, Chapel Hill, NC, United States of America ■ Dr Hubertus Cranz, Director General, Association of the European Self-Medication Industry, Brussels, Belgium ■ Dr Jinhui Dou, Pharmacologist and Pharmacognosist, Botanical Review Team, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States of America ■ Professor Harry Fong, Member of WHO Expert Panel on Traditional Medicine and Professor emeritus, University of Illinois at Chicago, Chicago, IL, United States of America ■ Dr Goh Cheng Soon, Director, Traditional and Complementary Medicine Division, Ministry of Health Malaysia, Kuala Lumpur, Malaysia ■ Dr Hakim Abdul Hannan, Vice Chancellor, Hamdard University, Karachi, Pakistan ■ Dr Michiho Ito, Associate Professor, Department of Pharmacognosy, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan ■ Dr Ikhlas Khan, Assistant Director, National Center for Natural Product Research, School of Pharmacy, University of Mississippi, University, MS, United States of America ■ Dr Shabana Khan, Principal Scientist, National Center for Natural Product Research, School of Pharmacy, University of Mississippi, University, MS, United States of America ■ Professor Yoshinori Kobayashi, Vice-Director General, WHO Collaborating Centre for Traditional Medicine, Oriental Medicine Research Centre, Kitasato University, Tokyo, Japan ■ Professor Liu Xinmin, Member of WHO Expert Advisory Panel on Traditional Medicine, Pharmacology and Toxicology Centre, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, WHO Collaborating Centre for traditional medicine, Beijing, China 68 ■ Dr Vamshi Manda, Research Scientist, National Center for Natural Product Research, School of Pharmacy, University of Mississippi, University, M S, United States of America ■ Professor Stephen Myers, Director, NatMed Research Unit, Division of Research, Southern Cross University, Lismore, Australia ■ Ms Teresa Ngan, Senior Pharmacist, Department of Health, Hong Kong Special Administrative Region, China ■ Professor Tamás Paál, Member of WHO Expert Advisory Panel on Pharmaceutical Preparations, Professor Emeritus, Institute of Drug Regulatory Affairs, University of Szeged; and External Senior Advisor to the National Institute of Pharmacy and Nutrition, Budapest, Hungary ■ Dr Shanthi Pal, Group Lead, Medicines Safety, Safety and Vigilance Team, Department of Essential Medicines and Health Products, World Health Organization, Geneva, Switzerland ■ Professor Olavi Pelkonen, Head of Unit, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland ■ Dr Mauizzati Purba, Director, Indonesian Herbal Medicines, National Agency for Drug and Food Control, Jakarta, Indonesia ■ Dr Ravindra Singh, Assistant Director (Chemistry), Central Council for Research in Ayurvedic Sciences, Ministry of AYUSH, New Delhi, India ■ Dr Souad Skalli, WHO Collaborating Centre for Strengthening Pharmacovigilance Practices, Pharmacovigilance of Herbal Medicines, Centre Anti Poison et de Pharmacovigilance du Maroc, Rabat, Morocco ■ Dr Michael J. Smith, Member of WHO Expert Advisory Panel on Traditional Medicine; and Adjunct Professor, National Center for Natural Product Research, School of Pharmacy, University of Mississippi, University, M S, United States of America ■ Professor Tran Quoc Binh, Director, WHO Collaborating Centre for Traditional Medicine, National Hospital of Traditional Medicine, Hanoi, Viet Nam ■ Dr Ta Thu Thuy, WHO Collaborating Centre for Traditional Medicine, National Hospital of Traditional Medicine, Hanoi, Viet Nam ■ Dr Larry Walker, Director, National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, Mississippi, MS, United States of America ■ Ms Rizka Ayu Kusuma Widjanarko, Indonesian Herbal Medicines, National Agency for Drug and Food Control, Jakarta, Indonesia ■ Professor Elizabeth Williamson, School of Pharmacy, University of Reading, Reading, United Kingdom of Great Britain and Northern Ireland ■ Dr Charles Wu, Pharmacologist, Botanical Review Team, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States of America ■ Dr Zhang Qi, Coordinator, Traditional and Complementary Medicine, Service Delivery and Safety Department, World Health Organization, Geneva, Switzerland 69 World Health Organization consultation meeting on key technical issues for herbal medicines with reference to interaction with other medicines, Beijing, China, 16–18 October 2019 ■ Professor Rabi Narayan Acharya, Head, Department of Dravya Guna, Institute of Postgraduate Teaching and Research in Ayurveda, Gujarat Ayurveda University, Jamnagar, India ■ Professor Ahmad Alkofahi, Member of WHO Expert Advisory Panel on Traditional Medicine, Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan ■ Dr Aditi Bana, Technical Officer, Traditional, Complementary and Integrative medi- cine, Department of Integrated Health Services, World Health Organization, Geneva, Switzerland ■ Peter Chan, Director General, Health Evaluation Directorate, Pest Management Regulatory Agency, Health Canada, Ottawa, Canada ■ Professor Chun-Tao Che, Director, WHO Collaboration Centre on Traditional Medicine, University of Illinois at Chicago, Chicago, IL, United States of America ■ Professor Elaine Elisabetsky, Member of the WHO Expert Advisory Panel on Traditional Medicine, Departamento de Bioquímica, University, São Paulo, Brazil ■ Professor Harry HS Fong, Member of the WHO Expert Advisory Panel on Traditional Medicine, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL, United States of America ■ Dr Neil Travis Gower, Senior Lecturer, Department of Homoeopathy, University of Johannesburg, Germiston, South Africa ■ Professor Yoshinori Kobayashi, Vice-Director General, WHO Collaborating Centre for Traditional Medicine, Oriental Medicine Research Centre, Kitasato University, Tokyo, Japan ■ Professor Liao Yonghong, Director, WHO Collaborating Centre for Traditional Medicine, Department of Pharmaceutical, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Beijing, China ■ Professor Liu Chenghai, Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China ■ Professor Liu Jianxun, Xi Yuan Hospital, China Academy of Chinese Medicinal Sciences, Beijing, China ■ Professor Liu Xinmin, Consultant, Traditional, Complementary and Integrative medi- cine, Department of Integrated Health Services, World Health Organization, Geneva, Switzerland ■ Ms Lu Jianxian, Zhejiang Provincial Institutes for Food and Drug Control, Hangzhou City, China ■ Professor Pulok K. Mukherjee, Director, School of Natural Product Studies, Jadavpur University, Kolkata, India ■ Dr Dal-Seok Oh, East–West Medical Research Institute, Kyung Hee University, WHO Collaborating Centre for Traditional Medicine, Seoul, Republic of Korea ■ Professor Dr Suwijiyo Pramono, Member of the WHO Expert Advisory Panel on Traditional Medicine, Faculty of Pharmacy, Gadjah Mada University, Jogjakarta, Indonesia 70 ■ Professor Rajan Radhakrishnan, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Health Care City, Dubai, United Arab Emirates ■ Professor Rokia Sanogo, Chief, Department of Traditional Medicine, Faculté de Pharmacie, Université de Sciences des Techniques et des Technologies de Bamako, Bamako, Mali ■ Dr Fabio Scano, Officer in Charge, WHO China Office, Beijing, China ■ Professor Shi Shangmei, Director, Division of Chinese Herbal Medicine, China National Pharmacopeia Commission, Beijing, China ■ Professor Souad Skalli, Centre de Recherche Biotechnologies Végétales et Microbiennes, Biodiversité et Environnement, Faculty of Sciences, University Mohammed V, Rabat, Morocco ■ Dr Onusa Thamsermsang, Center for Applied Thai Traditional Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand ■ Ms Manmas Vannabhum, Center for Applied Thai Traditional Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand ■ Professor Wei Jianhe, Deputy Director, WHO Collaborating Centre for Traditional Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Beijing, China ■ Professor Elizabeth Williamson, School of Pharmacy, University of Reading, Reading, United Kingdom of Great Britain and Northern Ireland ■ Professor Wu Zhendou, Deputy Director-General, Department of International Cooperation, National Administration of Traditional Chinese Medicine, Beijing, China ■ Professor Zhang Bengang, Director, WHO Collaborating Centre for Traditional Medicine, Department of Herbal Resources, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Beijing, China ■ Dr Zhang Qi, Coordinator, Traditional, Complementary and Integrative Medicine, Department of Integrated Health Services, World Health Organization, Geneva, Switzerland ■ Professor Zhang Ying, Institute of Basic Medicine, Xi Yuan Hospital, China Academy of Chinese Medicinal Sciences, Beijing, China