Invited Podium Presentations
Interactions - an overview
Ernst Edzard, MD, PhD. FRCP (Edin.), Professor, Complementary Medicine, Peninsula Medical School, Universities of Exeter & Plymouth, UK
Natural medicines have become immensely popular in Western countries. Consumers often assume that natural can be equated with harmless but, in fact, numerous risks have been associated with the use of herbal medicines. One of the most important of these risks relates to herb-drug interactions. It is increased through the facts that the typical herbal medicine user is likely to use prescribed drugs in parallel; that few patients tell their doctors; and that few doctors have sufficient knowledge about herbal medicine. Herb-drug interactions can be pharmacodynamic or pharmacokinetic in nature. Numerous herbal medicines have been implicated and some of the most popular herbs amongst these are St John’s wort, ginkgo biloba, kava. This plethora of possible herb-drug interactions is contrasted by the relative paucity of hard evidence to show that herb-drug interactions are clinically relevant. Most of this evidence today is based on relatively few case reports which rarely allow inference of causality. This discrepancy might be due to several factors: lack of systematic research into herb-drug interactions and under-reporting. It is
Herb-Drug Interactions: Issues and Perspectives
Mark Blumenthal
American Botanical Council and HerbalGram & HerbClip
In the past decade there has been a general increase in the use of herbs, phytomedicines, and herbal supplements in North America, particularly as measured in surveys of consumers in the United States. Although the rates of growth are different for various channels of trade, in general, consumers are consuming more products with pharmacologically active botanical ingredients. There has also been an increase in the use of prescription and over-the-counter conventional drugs. This suggests what would appear to be an inevitable increase in the number of consumers who are ingesting both herbal dietary supplements and OTC and/or Rx drugs simultaneously. Various surveys suggest that about 30-31% of herbal dietary supplement users are also ingesting OTC and/or Rx drugs. This leads to an obvious concern about the potential for these pharmacologically active substances to interact, producing either adverse reactions/interactions, reductions and/or increases in the efficacy of the conventional drugs, or, in some cases, even beneficial interactions.
During the last 5 years, there has been a growing number of publications in medical and pharmacy journals of articles dealing with herb-drug interactions. Some of these papers deal with experimental studies, e.g., in vitro studies that attempt to determine if there is a molecular or mechanistic rationale for a putative herb-drug interaction. Unfortunately, all too often this in vitro data can be misinterpreted as actual evidence of a putative interaction, when in reality many of these in vitro trials may not be directly applicable to human clinical situations, i.e., they may not be clinically relevant.
The body of herb-drug interactions is based on a hierarchy of evidence, from speculative and theoretical, to data from empirical observations, to in vitro data, to animal data based on injected or per oral use of either a whole herb or sometimes an isolated phytochemical constituent from the herb, to a single case report, to results from controlled clinical trials. Thus far, one of the most rational and reliable references for such information is Francis Brinker’s book, Herb Contraindications & Drug Interactions, 3d ed, and its corresponding website, <http://www.eclecticherb.com/emp/updatesHCDI.html>.
Access to reliable data about these interactions is not only of concern to practitioners but also to consumers. While pharmaceutical companies have a responsibility to disclose known interactions of drugs with common foods as well as dietary supplements, such responsibilities are not as clearly defined in legislation and regulation for manufacturers of herbal dietary supplements, at least in the U.S. Common law and business law in the U.S. do require that failure to warn of generally known interactions increases both legal liability of the manufacturer as well as its risks under laws affecting product liability. To assist the public in receiving such information on herb supplement product labels, the American Botanical Council has initiated its Safety Assessment Program wherein ABC conducts peer-reviewed safety assessments of many of the top-selling herbs in the U.S. market, with such information available for use on product labels, websites, etc. to help consumer use herbal products more responsibly and help reduce the incidence of potentially adverse interactions.
Current Understanding of Mechanisms and Clinical Relevance of Food - Drug Interactions: From Inactivation of Drug Metabolism to Inhibition of Drug Transport
David G. Bailey, Department of Medicine, Lawson Health Research Institute, London Health Sciences Centre and University of Western Ontario, London, Ontario, Canada
The public generally considers natural products, like foods and herbal medications, to be safe and advantageous for human health. That these substances are not formally regulated contributes to the popular opinion that they are entirely innocuous, which may not be always true. In some cases, there is the potential for drug interactions, sometimes with adverse clinical outcomes. The focus of this presentation will be grapefruit, which will include the discovery of the original interaction and the multiple possible mechanisms of modulation of biological processes that regulate the disposition of numerous drugs. There will be a discussion of inactivation of drug metabolism mediated by intestinal, compared to hepatic, cytochrome P450 3A4 (CYP3A4), a crucial enzyme estimated to be involved in the elimination of 50% of all drugs. It will address our current understanding of the effect on the intestinal and hepatic efflux transporter, P-glycoprotein. Moreover, recent research findings will be presented on the action on intestinal active uptake of drugs mediated by organic anion transporting polypeptides (OATPs). Where possible, issues addressed for each mechanism will include inter-individual variability and reproducibility in the extent of the pharmacokinetic interaction, influence of age of individual, class of affected drugs (known and predicted), active ingredients in grapefruit and clinical implications (importantly affected medications, potential alternative non-interacting drug, volume and duration-effect relationships) and other similarly acting foods. Finally, consideration will be given to the accuracy of current labelling and cautionary statements based on known scientific information.
Molecular Basis of Herbal-Drug Interactions
Richard B. Kim, Professor of Medicine and Parmacology, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
Herbals products have been widely utilized for centuries to treat a variety of illnesses. For example, extracts of the resin of guggulu tree have been used to treat ailments ranging from obesity to lipid disorders, while the Chinese herbal mixture Yin Zhi Huang has been used to treat neonatal jaundice. However, like drugs, herbal products are increasingly recognized to have unexpected adverse interactions, particularly when combined with drugs. Indeed, ingestion of St John’s wort has been shown to cause induction of drug metabolism and loss of therapeutic efficacy for a number of concomitantly administered drugs. Recent studies clearly suggest many herbal remedies contain constituents that interact with proteins that regulated the expression of drug metabolizing enzymes and transporters called nuclear receptors. Specifically, activation of xenobiotic responsive nuclear receptors such as Pregnane X Receptor (PXR), Constitutive Androstane Receptor (CAR), and Farnesoid X Receptor (FXR) appear to account for both the therapeutic as well as adverse effects of many herbal remedies. Accordingly, a better understanding of nuclear receptor biology may help in identifying herbals likely to cause clinically relevant herbal-drug interactions prior to their widespread use.
Drug interactions with St John’s wort: clinical evidence
Angelo A Izzo, Department of Experimental Pharmacology, University of Naples Federico II, Naples Italy
St John’s wort (SJW, Hypericum perforatum) seems to be effective for mild to moderate depression. As a monotherapy, SJW has an encouraging safety profile. However, there is evidence that taking this remedy can result in pharmacokinetic or pharmacodynamic interactions. The pharmacokinetic interactions that have been identified so far all point towards the fact that herbs induce cytochrome enzymes and P-glycoprotein. SJW has been shown to lower plasma concentration (and/or the pharmacological effect) of a number of drugs including cyclosporin, digoxin, indinavir, nevirapine, simvastatin, tacrolimus, warfarin and oral contraceptives. Pharmacodynamic interactions include serotonergic syndrome when SJW is co-administered with serotonin reuptake inhibitors antidepressants (e.g. the antidepressants sertaline, paroxetine, nefazodone). Much of the available is gleaned from case reports, although clinical studies are now also beginning to appear in the literature. Although some studies report clinically insignificant herb-drug interactions, a number of case reports highlights the fact that such interactions may have serious consequences (e.g. interaction between St John’s wort and cyclosporine).
In conclusion, the potential of drug interactions with SJW is high, particularly with drugs which are metabolized by cytochrome enzymes and/or are substrate of P-glycoprotein. With the widespread use of SJW, the risk of herb-drug interactions could be a growing clinical concern.
Future Focus for Herb-Drug Interaction Studies: Predict, Prepare, and Prevent
Shufeng Zhou, Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore 117543
Herb-drug interactions may arise when herbs are taken concomitantly with therapeutic drugs. There is increasing number of reports on herb-drug interactions, although many of which are from case studies and limited clinical observations. Herb-drug interactions may alter drug clearance, response and toxicity. Timely identification of drugs or herbs that interact with each other in the early stages of drug development and close therapeutic drug monitoring may assist in reducing toxic herb-drug interactions. To minimize these unfavourable interactions and the potential toxicity, it is also important to predict herb-drug interactions. A simple qualitative prediction of the potential for herb-drug interaction may be made based on the properties of drugs and the herbs of interest. Drugs may be subject to herbal interaction if a) they are anticoagulants, sedatives and antidepressants, oral contraceptives, anti-HIV agents, cardiovascular drugs and immunosuppressants; b) they have narrow therapeutic indices; c) they are substrates for cytochrome P450s (CYPs) and/or P-glycoprotein (PgP); and d) they are administered orally and chronically. On the other hand, herbs may be subject to drug interactions if they contain components that inhibit or induce CYPs and/or PgP or contain active components that act on specific drug targets (e.g. enzymes and receptors). The latter may cause synergistic or antagonistic effects. However, quantitative prediction of herb-drug interactions following pharmacokinetic principles may be difficult due to the presence of a number of complicating factors associated with the patients, herbs and drugs. Further studies are needed to determine the relative contribution of these factors in clinically important herb-drug interactions.
Interactions between herbal medicinal products, ‘natural health’ products and other medicines: pharmacovigilance strategies in the United Kingdom and New Zealand
Joanne Barnes, School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
There is an increasing awareness at several levels of the need to develop pharmacovigilance practices for herbal medicinal products (HMPs) and other natural health products (NHPs). Awareness has arisen in part because of the extensive use of these products, including their concurrent use with other (particularly prescription-only) medicines, and in part because of several recent high-profile safety concerns, including herb-drug, herb-food and other interactions, which have had an impact on the public health.1 Many HMPs/NHPs lack formal investigation of their safety (and efficacy) profiles, including their potential for clinically relevant interactions with other medicines. Furthermore, unregulated HMPs/NHPs are widely available, and at least some of these are of poor pharmaceutical quality, which may be important with respect to their potential for interactions with other medicines. Pharmacovigilance for HMPs/NHPs, including detecting interactions with other medicines, is in the early stages of its development. Currently, spontaneous reporting schemes are the main method used for identifying herb-drug interactions but, as with other established pharmacovigilance methods, have important limitations with regard to HMPs/NHPs. Other aspects of pharmacovigilance for HMPs/NHPs, such as acting on and communicating safety concerns, and consumer behaviours, present several unique and additional challenges over those encountered for conventional medicines. These issues, together with pharmacovigilance strategies for HMPs/NHPs interactions in the United Kingdom and New Zealand, will be discussed.
The Role of the Uppsala Monitoring Centre in Safety Monitoring Herbal Medicines
Mohamed H. Farah, WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden
The use of herbal medicines is associated with adverse reactions that affect many people in the world, and important interactions between conventional and herbal medicines have been documented. Serious side effects have occurred around the world due to mislabeling of herbal products. Many problems arise in monitoring the safety of herbal medicines, and we know that accurate identification of herbal products is problematic, but it is essential if concerns associated with the use of herbal medicines are to be understood. A simple mistake made in the correct identification of herb or the incorrect use of a certain part of a plant can have serious or even fatal results. International collaboration is needed for the proper identification of herbal products. There are some procedures which need to be established at country levels. Each country should make an inventory of most used herbal products, recorded by using scientific plant names that are understood all over the world. These should record names of products together with identification of their contents if known. The botanical name for each plant used is the best standard for identification. To facilitate this, the UMC has produced a book called “Accepted scientific names of therapeutic plants and their synonyms” which will be published soon. The principles of monitoring safety are the same for both conventional and herbal medicines, national pharmacovigilance centres already receive reports concerning herbal medicines, and many people use both types of medicines and even take them concurrently. More collaboration between traditional healers-to healthcare professional, academics, industry and medicines regulators. More training for all those involved with herbal medicines are needed. Educating the general public that natural products are not always safe. Encouraging health professionals to ask about natural products patients are taking.
Clinical Risk Management of Herb-Drug Interactions
Peter A.G.M. De Smet, Scientific Institute Dutch Pharmacists, The Hague, and Department of Clinical Pharmacy, University Medical Centre St Radboud, Nijmegen, The Netherlands
Clinical risk management provides a systematic approach for controlling healthcare risks, which comprises risk identification and assessment, development and execution of risk reduction strategies, and evaluation of risk reduction strategies. On the basis of recent literature and Dutch experiences with the clinical risk management of drug-drug interactions in general, it will be explored which strategies should be considered for improving the current risk management of adverse herb-drug interactions. In particular, attention will be given to:
- The need for more systematic recording of herbal products in the same patient records, in which prescription medicines are filed;
- The need for a transparent and reproducible method for deciding which herb-drug interactions should be incorporated in computerised interaction surveillance systems;
- The need for adequate coverage of all the different risk moments of herb-drug interactions;
- The need to increase our knowledge about the risk modifiers that can either increase or decrease the consequences of a herb-drug interaction; [1]
- The need to evaluate, whether the risk minimization strategies that we have designed and implemented actually work effectively and efficiently;
- The need to realise that, at the end of the day, it is the users of herbal products who are in the driver’s seat and that we therefore require effective risk communication strategies to inform these users in well-chosen terms and in a non-condescending manner.[2]
[1] De Smet PAGM. Health risks of herbal remedies: an update. Clin Pharmacol Ther 2004;76:1-17
[2] Several authors. Special issue about risk communication. BMJ 2003;327:27.
Warfarin-herb interactions: fact, fiction, and pharma influence
Adriane Fugh-Berman, MD, Department of Physiology and Biophysics, Georgetown University School of Medicine, Washington DC, USA
This talk will briefly review reported interactions between warfarin and herbs and discuss problems in the quality of adverse event reporting regarding botanicals and dietary supplements. A question has been raised about whether the popularity of botanicals and dietary supplements has aroused competitive interest from pharmaceutical companies. Corporate influence on medical literature about drugs is pervasive; some literature on botanicals and dietary supplements may also be commissioned by pharmaceutical companies. An example of pharmaceutical company influence on a warfarin-herb interactions review will be discussed.
The control of Traditional Medicine and the Risk Communication Strategies of the Health Sciences Authority, Singapore
Chan Cheng Leng, Pharmacovigilance / Information & Research, Centre for Drug Administration, Health Sciences Authority, Singapore
In many drug regulatory regimes, traditional medicines (TMs), which usually contain natural ingredients, vitamins and minerals are generally regarded as having lower inherent risk than western medicines. Due to the growing popularity of such medications and the occasional detection of adulteration and inherent toxicities of these preparations, which may pose serious public health issues, many regulatory agencies are now exploring means to better regulate these medicines. The control of TMs presents a major challenge to regulatory agencies as it is difficult to apply the same standards of regulation as western pharmaceuticals due to the limitations arising from the inherent characteristics and traditional use of these products. In Singapore, the Health Sciences Authority (HSA) oversees the regulation of TMs (e.g. traditional Indian medicines, Chinese proprietary medicines). The controls in place require the dealers (manufacturers, importers, distributors and retailers) of TMs, regardless of their origin, to be responsible for ensuring the safety and quality of the product which include compliance with toxic heavy metal limits and ensuring the absence of synthetic western ingredients or prohibited substances. Based on a risk-management approach, additional controls are imposed on Chinese proprietary medicines (CPMs) which include pre-marketing product listing and licensing of dealers (importers, wholesalers and local manufacturers), in view of their wider usage in the local market and greater number of dealers and products. The presentation will give an overview of the control of TMs in Singapore with special emphasis on CPMs. The principles and rationale behind the control measures will also be briefly discussed. The focus of the presentation will be on the risk communication strategies that are employed by HSA for TM control and the speaker will give the pros and cons of the communication channels that are developed. Case studies involving TMs will be used to illustrate the communication strategies employed by the agency. These include the examples of Slim 10 (a CPM found to be adulterated with nitroso-fenfluramine), and other TMs found adulterated with western pharmaceuticals and non-compliance with heavy metals limit.
Abstract of Poster Presentations
Reporting Adverse Events and Drug Interactions Associated with Natural Health Products: Development of a Theoretical Framework
Rishma Walji. BSc, ND and Heather Boon, BScPhm, PhD
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
Introduction: In Canada, adverse events including drug interactions are voluntarily and spontaneously reported through the Canadian Adverse Drug Reaction Monitoring Program. Under-reporting is a major limitation with any spontaneous reporting system but especially with adverse events and drug interactions associated with natural health products (NHPs).
Purpose: To develop a conceptual framework for active surveillance of adverse events and drug interactions associated with NHPs. The objectives of the framework are to: 1. Identify major factors that influence adverse event incidence in users of NHPs. 2. Highlight important factors affecting a patient’s decision to report an adverse event. 3. Hypothesize inter-relationships between the factors identified.
Methods: A framework was developed from a literature review on active reporting systems for over-the-counter (OTC) and prescription drugs. Risk factors for adverse drug reactions and drug-herb interactions were determined from previous studies. Concepts uniquely pertinent to NHP study were extrapolated from previous literature on NHP users.
Results: An adequate theoretical framework for actively studying NHP adverse event and drug interaction reporting has not been previously established. Adverse event/drug interaction reporting for NHPs is divided into two phases: 1. The occurrence of an adverse event/drug interaction and 2. The decision to report. The first phase is influenced by several factors such as the individual patient’s characteristics, their beliefs and perceptions about NHPs, characteristics of the NHP itself, as well as the method of use of the product. The second phase is influenced by the characteristics of the adverse event/drug interaction itself as well as knowledge of and access to reporting resources. Information sources are important for both phases
Conclusion: This framework will be used to develop an active surveillance model that will be pilot tested as part of R. Walji’s PhD requirements. The project will attempt to test the feasibility of using active consumer surveillance to gather adverse event and drug interaction information on natural health products.
Key words: natural health product; CAM (complementary alternative medicine); active surveillance; post-marketing; adverse event; adverse effect; ADR (adverse drug reaction); side effect; herb-drug interaction; SAR (suspected adverse reaction); pharmacovigilance.
Survey of Community Pharmacist Reporting of Adverse Drug Reactions Associated with Natural Health Products.
Charrois TL1, Hill R2, Vu D3, Foster BC4, Boon H5, Cramer K1, Vohra S1
1 CARE Program, University of Alberta; 2 Adverse Drug Reactions Unit, Therapeutic Goods Administration, Australia; 3 Marketed Health Products Directorate, Health Canada, 4 Therapeutic Products Directorate, Health Canada; 5 Leslie Dan Faculty of Pharmacy, University of Toronto.
Study Objectives: 1) to identify community pharmacist awareness of potential adverse events and/or drug interactions associated with natural health products (NHP) and, 2) to provide information regarding pharmacist reporting of adverse events (AE) / drug interactions with NHPs.
Methods: Survey questions were derived from a literature review of previous surveys, data collected from Health Canada and in consultation with clinicians, pharmacists, policy-makers and researchers. A convenience sample of 321 community pharmacists in Alberta and British Columbia were asked to participate.
Results: 132 pharmacists responded resulting in a response rate of 41% (132/321). A total of 19% of the population had previously reported an AE to Health Canada. When asked specifically about NHP-drug interactions/AE, 47% of pharmacists stated they had seen a potential interaction, however, only 2 of these respondents reported it to Health Canada. Half of these pharmacists discussed the interaction with the patient (52%). The majority (89%) of pharmacists reported being moderately to extremely concerned about NHP-drug interactions/AE. Over 82% reported being moderately to extremely concerned regarding the quality of NHPs, with 91% of respondents indicating their concern was due to lack of standardization.
Conclusions: In terms of adverse events, the majority of pharmacists were very concerned about the potential for interactions. As well, these pharmacists were concerned about the quality of available products. This survey provides evidence to suggest pharmacists are encountering reportable AEs in patients using NHPs, however not reporting these events. This leads us to believe that the current system of passive surveillance is not adequate. Whether this lack of reporting is an issue with regards to knowledge about the reporting system or due to other constraints, is unknown. The majority of pharmacists felt more education on NHPs was needed on this subject (92%).
Interactions between Dietary Fats and Methylmercury Exposure on Serum Biochemistry, Immunoglobulin, and Hematology in Rats
Xiaolei Jin1, Eric Lok1, Kamla Kapal1, Genevieve Bondy1, Cheryl Armstrong1, Rudolf Mueller1, Stan Kubow2, Marnie Taylor1, Laurie H.M. Chan3, and Rekha Mehta1
1 Toxicology Research Division, Food Directorate, HPFB, Health Canada; 2 School of Dietetics and Human Nutrition, McGill University; 3Centre for Indigenous Peoples' Nutrition and Environment (CINE), McGill University.
Objectives: Fish consumption is by far the most important source of human exposure to methylmercury (MeHg), especially in the arctic region. Dietary factors such as selenium and vitamins have been reported to modulate mercury toxicity. In this study, we examined the effects of dietary fats on MeHg-mediated changes in serum biochemistry, immunoglobulin, and hematology in rats.
Methods: Sprague Dawley rats were administered isocaloric diets containing 15% by weight soy oil, seal oil, docosahexaenoic acid (DHA), fish oil, or lard for 28 days. Rats were then gavaged with 0, 1, or 3 mg MeHg/kg body weight (BW) per day and fed on the same diet for 14 consecutive days. Rats were then sacrificed and blood samples were analyzed for hematology. Serum samples were analyzed for clinical biochemistry and immunoglobulin.
Results: A number of significant differences in serum biochemistry, immunoglobulin, and hematology were detected between vehicle controls of different dietary groups. For example, soy oil group had significantly higher serum lactate dehydrogenase-L (LDH-L) level. MeHg at the doses used induced many toxicological changes, most of which were diet-dependent. For example, only in the fish oil group, did 3 mg MeHg/kg BW significantly and dose-dependently decrease IgG level, and only in the lard group, did it increase serum total bilirubin, as compared with their vehicle controls.
Conclusions: Our results suggest that different dietary fats can have different effects on toxicological end points, can impose significant modulating effects on MeHg toxicity, and therefore are important factors to be considered in the risk assessment of MeHg exposure.
Interactions between Diets and Methylmercury Exposure on Markers of Systemic and Organ Oxidative Stress in Rats
Xiaolei Jin, Eric Lok, Kamla Kapal, Marnie Taylor, Rekha Mehta, Laurie H.M. Chan* Toxicology Research Division, Food Directorate, HPFB, Health Canada, Ottawa, Ontario, Canada, and *Centre for Indigenous Peoples' Nutrition and Environment (CINE), McGill University, Montreal, Quebec, Canada
Objectives: Dietary factors were shown to modulate mercury toxicity, however, the underlying mechanisms were not clear. MeHg is known to increase oxidative stress. We therefore measured markers of systemic and organ oxidative stress in rats exposed to MeHg and fed different dietary proteins and fats to determine the effects of MeHg and diets, and their interaction on these markers.
Methods: Male Sprague Dawley rats were maintained on a starch-based, semi-purified basal diet containing 22-26% by weight casein (C), fish meal (FM) or whey (W) or 15% soy oil (SO), docosahexanoic acid (D), seal oil (SE), fish oil (FO), or lard (L) for 28 days. The rats were then gavaged with 0, 1, or 3 mg MeHg/kg body weight (BW) for 14 consecutive days. On the 14th day, 24h urine samples were collected and analyzed for 8-hydroxy-2 -deoxyguanosine (8OHdG) and isoprostane. Liver, kidney, and brain were dissected and analyzed for thiobarbituric acid reactive substances (TBARS), lipidperoxide (LPO), and/or GSH.
Results: Urinary 8-OHdG was significantly higher in rats fed FM than SO or D diet. Urinary isoprostane was significantly higher in rats fed FO or L than other diets. Kidney TBARS was significantly higher in rats fed FO than SO. Brain TBARS was significantly lower in rats fed SO than D, FO, L, or FM diet. Brain LPO was significantly lower in rats fed L than C, SE, SO, FM, or W diet. No differences in kidney LPO and GSH were found between diets. MeHg at 3 mg/kg BW significantly increased urinary 8OHdG and liver TBARS in rats fed L diet, urinary isoprostane in rats fed D, SE, FO, C, or W diet, kidney TBARS in rats fed SO or D diet, and kidney GSH in rats fed SO, SE, or C diet. It significantly decreased brain TBARS in rats fed L diet, and urinary 8OHdG in rats fed FM.
Conclusions: These results suggest that dietary proteins and fats can have significant effects on markers of systemic and/or organ oxidative stress. They can have significant and organ-specific interactions with MeHg on these markers, therefore are important factors to be considered in the risk assessment of MeHg exposure.
Homeopathic Medicines: A Need to Develop Unique Innovative Regulatory Frameworks, Involving Drug, Food and Natural Health Product Interactions.
Leelamma Nielsen 1, Vijay Nielsen 3, Kerissa Illchuk 3, Ron Harris 2
1 President, Canadian Coalition for Homeopathic Medicine (CCHM), Canada; 2 Advisor, Canadian Coalition for Homeopathic Medicine (CCHM), Canada; 3 General Membership, Canadian Coalition for Homeopathic Medicine (CCHM), Canada.
Purpose: The purpose of this abstract is to present the unique properties of homeopathic medicines, in relations to drug, food and natural health product interactions and risk management protocol.
Methods: This abstract is organized into four distinct sections: 1) Philosophy, principles and practice of homeopathy and the impact of current risk management protocol. 2) Diversity of homeopathic medicines: the potential misinterpretation of adverse reactions. 3) Integrating data and information through clinical and research experience of practitioners. 4) Consumer protection and education: pro-active involvement of stakeholders and Health Canada.
Results: The uniqueness and diversity of homeopathic medicines requires certain modification of existing definitions. With co-operation from CCHM, Health Canada and other stakeholders, implementation of the proposed modifications will result in innovative risk management strategies, while ensuring accurate information is received by the consumer.
Conclusions: The dilemma specific to homeopathy is its philosophical stance, influencing the exclusive pharmacological processing. The input from experienced practitioners and clinicians can help in the comprehension and integration of four key points. 1) Understanding and respecting the principles, practice and philosophical interpretation of homeopathy. 2) The large diversity of homeopathic medicines that can potentially result in variable interactions. 3) The knowledge through clinical experience in administrating homeopathic medicines via oral, topical and injection. 4) Collaborating unique, philosophical principles and clinical realities of homeopathy with current risk management protocol, enabling the delivery of innovative and accurate information.
Phytoestrogens versus hormone therapy: representations by French and Quebecois physicians
Catherine Garnier1, Christine Thoër-Fabre,2 Anne-Laure Saives3
Professor at the Université du Québec à Montréal (UQAM), Director of the Groupe d'étude sur l'interdisciplinarité et les représentations sociales (GEIRSO) and the Major Collaborative Research Initiatives program on the medication cycle, SSHRC; 2 Postdoctoral fellow, GEIRSO-UQAM, Major Collaborative Research Initiatives program on the medication cycle, SSHRC 3 Professor, department of Technology Management, UQAM.
The goal of this research, which falls within the field of the socio-anthropology of health, is to compare the representations by French and Quebecois physicians with respect to phytoestrogens and hormone replacement therapy in a context—post Women’s Health Initiative (WHI, Roussouw et al., 2002—in which support for hormone treatments is not unanimous in the scientific community. We have adopted a qualitative approach involving semi-structured interviews, based on the principles of grounded theory (Glaser and Strauss, 1967) and have carried out a constant comparative analysis of the data in order to promote the emergence of thematic categories. The results of the first stage of this research, which was carried out in France, have brought to light the fact that the representations constructed by gynecologists with regard to phytoestrogens have five primary dimensions. The study would appear to suggest that phytoestrogens have come to play a more important role in the treatment of menopausal women since the WHI results were published, and now represent an alternative treatment option for physicians. However, several of the doctors who were met remain fairly reticent about recommending products that do have “drug status.” These results will be compared with those emanating from research we have undertaken with Quebec physicians. This comparative approach should provide a better understanding of how the cultural context and the organizational aspects of professional practice influence the construction of physicians’ representations with respect to phytoestrogens and hormone therapy, as well as the reflexive implication of drug risks.
Phytochemical Study on the Discovered Canadian Rhodiola rosea Chemorace
Filion, V.J.1, Cuerrier, A.2, Archambault, M.2, Rochefort, G.3, and Arnason, J.T.1
1 Centre for Advanced Research in Environmental Genomics , Department of Biology, University of Ottawa, Ottawa, ON, CANADA; 2 University of Montreal, IRBV Institute, Montreal, QC, CANADA; 3 Makivik Corporation, QC, CANADA
Introduction: Rhodiola rosea L. (Crassulaceae) is a medicinal plant used both traditionally and commercially in Eurasian countries. The scientifically documented therapeutic effects of R. rosea include anti-carcinogenic, anti-depressant, immuno-stimulant and adaptogenic properties.
Objectives: The objective of this study was to characterize the presence of the following biologically active phytochemicals: salidroside, tyrosol, rosavin, rosarin and rosin.
Methods: The newly discovered Canadian chemorace was collected in the summer of 2005 in Nunavik, Quebec. Laboratory techniques involve reverse phase HPLC (RP-HLPC) with a diode-array detector (DAD) these were used in order to identify and quantify the five phenylpropanoids glycosides listed above. R. rosea constituents will be further analyzed using Atmospheric Pressure Chemical Ionization (APCI) by mass spectrometry (MS).
Results: Preliminary RP-HPLC results have detected the presence of all five phenylpropanoids glycosides in the Canadian samples. Once we fully characterize the phytochemistry of the Canadian chemorace we intend to confirm the bioactivity of the constituents with bioassay tests.
Conclusions: The results of our study will provide baseline data for the phytochemical authentication of future commercialized Canadian R. rosea natural health products thus insuring quality control.
Safety and Efficacy Assessment of Natural Health Products Derived from Medicinal Plants with Psychological Activity: Some Perspectives of the New Canadian Natural Health Products Regulations
Wijeweera P.
Bureau of Product Review and Assessment, Natural Health Products Directorate, Health Canada, Ottawa, Ontario, Canada.
Objectives: To overview some natural health products (NHPs) derived from medicinal plants that promote mental health and the perspectives of the Natural Health Products Regulations in their safety and efficacy assessment.
Methods: Review.
Conclusions: Some perspectives of the new Natural Health Products Regulations in safety and efficacy assessment of some NHPs that promote mental health and the usage of such NHPs in different medicinal paradigms will be revealed.
The Natural Health Products Regulations, which came into effect in January 2004, provides a new fundamental regulatory framework in assessing safety and efficacy of commercially marketed natural health products in Canada.
The biologically active metabolites synthesized in medicinal plants may play a significant role as readily available sources of therapeutic products. An overview of health products derived from some medicinal plants, which are in use to promote mental health in different medical systems, will be discussed. Recent scientific advancements in understanding health risks and efficacy assessment from policy perspectives will be presented for:
Ashwagandha (Withania somnifera)
Brahmi (Bacopa monniera)
Ginkgo (Ginkgo biloba)
Ginseng (Panax ginseng)
Gotukola (Centella asiatica)
Kava (Piper methysticum)
Passion Flower (Passiflora incarnata)
St. John’s Wort (Hypericum perforatum)
Valerian (Valeriana officinalis)
The poster was previously presented at the Health Canada Science Forum 2005.
Pharmacoenhancing effect of dillapiol in rats: A new drug-sparing agent for the anti-HIV drug saquinavir
Awad, R.1, Foster, B.C.2, Durst, T.3, van Heeswijk, R.P.G.4a, Bourbeau, M.4b, Trudeau, V.L.5 and Arnason, J.T.1
1 Ottawa-Carleton Institute of Biology, University of Ottawa, Ottawa, Ontario, Canada; 2 Therapeutic Products Directorate, Health Canada, Ottawa, Ontario, Canada; 3 Department of Chemistry, University of Ottawa, Ottawa, Ontario, Canada; 4 Clinical Investigation Unit, Division of Infectious Diseases, (a) The Ottawa Hospital, (b) Ottawa Health Research Institute, Ottawa, Ontario, Canada; 5 Centre for Advanced Research in Environmental Genomics (CAREG), University of Ottawa, Ottawa, Ontario, Canada.
Purpose: This study was to determine if purified dillapiol, a naturally occurring active compound in the dill plant Anethum graveolans L., was able to act as an enhancement agent to increase the bioavailability of the HIV-protease inhibitor saquinavir (SQV) in a rat model.
Methods: Purified dillapiol (> 99 %) was obtained through vacuum distillation of Indian dill oil, followed by column chromatography and confirmed by NMR. In the acute animal trials, male han Wistar rats were cannulated and gavaged with 20 mg/kg SQV (control) or with 20 mg/kg SQV + 25 mg/kg dillapiol (treated). Blood samples were collected at six time points over 4 hours and the saquinavir concentration in plasma was analyzed using LC/MS/MS.
Results: Preliminary results show that dillapiol, at the administered dose, was able to increase SQV plasma levels almost three-fold. SQV levels remained significantly higher at the end of the 4 hour test period in treated rats suggesting increased, and maybe delayed absorption in SQV (increase in Cmax).
Conclusions: Dillapiol has promise as an effective pharmacoenhancer of SQV and maybe other HIV protease inhibitors, to replace more toxic drugs. A chronic pharmacokinetic study would assist in determining the longer-term effects of dillapiol on SQV plasma concentrations. A postitive outcome may lead to a modified therapy with potentially decreased toxicity.
This research was presented at the University of Ottawa Biology Research Day, Ottawa, ON. April 2003.
Decision support for menopausal women considering the use of natural health products: A needs assessment with proposed interventions
France Légaré MD PhD, Dawn Stacey RN PhD, Sylvie Dodin MD MSc, Annette O’Connor RN PhD, Monique Richer PhD, Sylvie Tapp BSc
Context: Menopausal middle-aged women are the largest group of natural health products (NHPs) users. Lack of scientific information about the efficacy of most NHPs is recognized as a source of difficulty when making decisions about using NHPs. However, it is unclear if other factors influence women’s decision making regarding the use of NHPs.
Objective: To identify the decision support needs of women regarding the use of NHPs and potential interventions to support effective decision making including roles of various players (e.g., patients, physicians, nurses, community groups, store owners, pharmacists).
Design: Exploratory theory-driven qualitative study.
Setting: Two communities: one Anglophone and one Francophone.
Participants: Women aged 45 to 64 years and purposeful sampling of key informants (e.g., pharmacists, family physicians, gynaecologists, community-based groups, NHP store owners, policy makers).
Instruments: Interview guide, focus group guide, demographic survey.
Main and secondary outcome measures: Content analysis based on the Ottawa Decision Support Framework to identify the most frequent difficult decisions, sources of difficulty, roles of various players in decision making, suggested resources for effective decision support, and strategies for translating NHP evidence for these women.
Results: 6 focus groups and 15 key informant interviews were conducted. The main difficult decisions identified was to use NHPs or not and what product to use. The most frequently identified sources of difficulty when making this decision were: lack of confidence in NHPs, inadequate facts about NHP, costs, doctor's not receptive to discuss, too many to choose from, potential dangers, lack of scientific data. Suggested resources needed to support decision making included a information on options, government guidelines, integrated care approach, training for physicians, public lectures, reliable web site, insurance coverage, telephone advice lines.
Conclusions: Middle-aged women reported experiencing difficulty when making decisions to use NHPs. This presentation will identify priorities for addressing women’s decision support needs and highlight potential roles of the various players and present a prototype of a decision aid for middle-aged women about the use of NHPs.
Synergistic anti-Candida effect of dillapiol in combination with the dialdehyde sesquiterpenes isolated from the newly discovered, Pleodendron costaricense (Costa Rica)
Treyvaud Amiguet, V.1, Petit, P.2, Ta, C.A.1, Nuñez, R.3, Sánchez-Vindas, P.3, Poveda Alvarez, L.3, Smith, M.L.1, Arnason, J.T.1 and Durst, T.2
1 Ottawa-Carleton Institute of Biology, Ottawa, ON, Canada; 2 Department of Chemistry, University of Ottawa, Ottawa, ON, Canada; 3 Herbario Juvenal Valerio Rodriguez, Universidad Nacional, Heredia, Costa Rica.
Purpose: The Canellaceae, a tropical family containing mainly aromatic trees, is well known in African traditional medicine for the antifungal properties of the genus Warburgia. Recently, a new species, named Pleodendron costaricense N. Zamora, Hammel and R. Aguilar, was discovered in Costa Rica. This study investigated the major secondary compounds and their anti-Candida activities. Dillapiol, a member of a group of both natural and synthetic synergists known as polysubstrate mono-oxygenase inhibitors, was combined with the pure dialdehyde sesquiterpenes to optimize the antifungal response.
Methods: The major compounds were isolated and purified from the ethyl acetate extracts (leaves and bark) by chromatography methods and recrystallization. Their structures were identified by uni- and bidimentional nuclear magnetic resonance (NMR) and their molecular masses were determined by Electron Impact Mass Spectrometry (EI-MS). The antifungal activity against Candida albicans wild type (AL-1) was determined by the minimum inhibitory concentration (MIC) values which were recorded as the lowest tested concentration of antifungal activity that resulted in a prominent reduction ( 80%) of fungal growth. Synergistic assays were carried out using the pure dialdehyde isolated sesquiterpenes combined with sub-lethal amount of dillapiol.
Results: The phytochemical analysis revealed a high diversity of terpenes and led to the isolation of four known drimane-type sesquiterpenes (cinnamodial, cinnamosmolide, polygodial and mukaadial) as well as two new sesquiterpenes named parritadial (drimane-type) and pleodendione (eremophilane-type). Cinnamodial, the major secondary compound found in P. costaricense, was the most promising anti-Candida dialdehyde sesquiterpenes (MIC = 62.5 g/mL) and its activity was enhanced by 4-fold in combination with dillapiol. Mukaadial and parritadial showed lower activities (MIC = 1000 g/mL) which were enhanced with dillapiol by 4-fold and by 2-fold, respectively.
Conclusion: The natural compound dillapiol which is well known for its insecticidal synergistic effects, showed a similar anti-Candida synergistic potential with dialdehyde sesquiterpenes isolated from P. costaricense. The mode of action of the antifungal cinnamodial will be investigated to better understand how to optimize its activity.
Botanical Extracts Containing Berberine and Related Alkaloids Interfere with the Activity of Human Cytochrome P450-Mediated Drug-Metabolism
Leduc, R.I.1, Scott, I.M.2, Saleem, A.1, Arnason, J.T.1, Marles, R.3 and Foster, B.C.2
1 Centre for Advanced Research in Environmental Genomics, University of Ottawa, Ottawa, ON, Canada; 2 Therapeutic Products Directorate, Health Canada, Ottawa, ON, Canada; 3 Natural Health Products Directorate, Health Canada, Ottawa, ON, Canada.
Purpose: The study was to characterize the degree of metabolic interference Hydrastis canadensis L. ethanolic extracts as well as ethanolic extracts of other berberine-producing botanicals have on the activity of three human cytochrome P450 (CYP) isozymes. This study addresses the potential health risks and loss of pharmaceutical therapeutic value that may occur when pharmaceutical products are complemented with natural health products (NHPs) containing berberine and related alkaloids.
Methods: High-throughput enzyme inhibition screening assays were used in order to quantify the effect of H. canadensis, Coptis trifolia groenlandica (L.) Salisb., Berberis vulgaris L., Mahonia aquifolium (Pursh) Nutt., Sanguinaria canadensis L. and Eschscholzia californica Cham. extracts against the metabolic activity of CYP3A4, CYP2C19 and CYP19 isozymes. Extracts were prepared in 55% ethanol and filtered prior to screening and quantification. Reverse-phase HPLC was utilized in order to quantify the following alkaloids in each extract: berberine, hydrastine, canadine, californidine, sanguinarine and protopine among others.
Results: The species tested to date are H. canadensis, C. trifolia groenlandica, B. vulgaris and M. aquifolium, all of which exhibited an inhibitory effect against the activity of all three isozymes. Among them, H. canadensis extracts demonstrated the greatest inhibition, followed by C. trifolia groenlandica, B. vulgaris and M. aquifolium. We will also be analyzing S. canadensis and E. californica extracts and comparing their effects on CYP-mediated metabolism to our current results.
Conclusion: NHPs containing berberine and related alkaloids may interfere with human drug and intermediary metabolism in such a way that may decrease the therapeutic value of ingested pharmaceutical drugs.
Quality Control of Ginkgo Products Using Nanospray Tandem Mass Spectrometry
Changqing Liu, Rupasri Mandal, and Xing-Fang Li.
University of Alberta, Edmonton, Alberta, Canada.
Gingko extract is widely used health supplement, and it is also used as a treatment for cerebrovascular, peripheral circulatory disorders, asthma, and coughs. The major active components of ginkgo biloba include terpene trilactones and flavonol glycosides. Ginkgolic acids, another class of compounds in ginkgo, are potentially toxic, which is recommended to limit their concentrations less than 5 g/g. However, the quality control of ginkgo products is difficult because multiple classes of active and toxic compounds are present. Generally, available analytical techniques can analyze only one class of compounds at a time. Quality control is time-consuming and expensive. Therefore, we developed a nanospray mass spectrometry technique (nESI-MS) for simultaneously determination of these three groups of compounds.
We report here a negative ionization nanoelectrospray ionization mass spectrometry (nanoESI-MS) technique that simultaneously detect active components, terpenes and intact flavonol glycosides, and toxic ginkgolic acids in ginkgo products. Unlike the conventional methods that hydrolyze flavonol glycosides to flavonoids for analysis, this technique directly detects intact flavonol glycosides, enabling differentiation of these natural glycosides from the synthetic flavonoids. Thus, it allows the detection of fortification of ginkgo products, alleviating a common problem encountered by the conventional methods. Analysis of 14 commercial ginkgo products using this technique demonstrates large variations and deviation from the well-accepted standardized ginkgo extract. Three products showed evidence of fortification with synthetic surrogates. Two products were found to have toxic ginkgolic acids that exceed the 5 mg/g limit by as much as 60000 fold. These results emphasize the importance of appropriate monitoring of ginkgo product quality. This technique is potentially useful for monitoring of other natural products.
Activity of Arctostaphylos uva-ursi on Cytochrome P450 Family-mediated Metabolism and P-glycoprotein Function in Human Cell Lines.
CH. Yu 1, BM. Chauhan 1, JT. Arnason 1, R.J. Marles 2, A. Krantis1, I. Scott1, BC. Foster 1,3
1 Centre for Research in Biopharmaceuticals and Biotechnology, University of Ottawa, Ottawa, ON, Canada; 2 Natural Health Products Directorate, Health Canada, Ottawa, ON, Canada; 3 Therapeutic Products Directorate, Health Canada, Ottawa, ON, Canada.
Purpose: Interactions between Natural Health Products (NHPs) and drugs may affect their disposition, potentially affecting the safety and efficacy of these or other products. This study was undertaken to characterize the potential effect of Arctostaphylos uva-ursi on drug disposition by examining cytochrome P450 3A4/5/7, 2C19, and CYP19-mediated metabolism, and P-glycoprotein (Pgp)-mediated transport.
Methods: Bulk (3) and capsulated (2) A. uva-ursi was obtained from commercial outlets. The capsules were batched to give a representative sample and herbal material was ground to a common consistency. Aqueous and methanolic extracts (25 mg/mL in dH2O and 5 mg/mL in methanol) were prepared prior to testing. CYP 3A4/5/7, 2C19 and 19-mediated metabolism was determined using in vitro fluorescence bioassays. Aqueous extracts were used to determine the effect on Pgp-mediated uptake of rhodamine 123 into human monocytes (THP-1) and Caco-2 cells. All products were analyzed by HPLC for arbutin, gallic acid, myrcitrin, isoquercetin.
Results: Our data indicates that both aqueous and methanolic extracts of the 5 A. uva-ursi products show high potential to inhibit metabolism, with the exception of the methanolic extracts against 3A4 and 19 which had low to moderate activity. The aqueous extracts of A. uva-ursi showed an inhibitory effect on Pgp at 1 hr and an inductive effect at 18 hrs for both cell lines. With the exception of gallic acid, similar levels of the examined biomarkers were found in the five products.
Discussion: These herbal products have pharmacological properties that may potentially affect drug safety and efficacy. Further studies are warranted against a wider range of cytochrome P450 isozymes and transport proteins to determine if these effects are clinically significant.
Previously presented at the annual meeting of the Canadian Society for Pharmaceutical Sciences 2005