Use Of Botanical Dietary Supplements Research Articles

Botanical inhibitors of SARS-CoV-2 viral entry: a phylogenetic perspective

Throughout the SARS-CoV-2 pandemic, the use of botanical dietary supplements in the United States has increased, yet their safety and efficacy against COVID-19 remains underexplored. The Quave Natural Product Library is a phylogenetically diverse collection of botanical and fungal natural product extracts including popular supplement ingredients. Evaluation of 1867 extracts and 18 compounds for virus spike protein binding to host cell ACE2 receptors in a SARS-CoV-2 pseudotyped virus system identified 310 extracts derived from 188 species across 76 families (3 fungi, 73 plants) that exhibited ≥ 50% viral entry inhibition activity at 20 µg/mL. Extracts exhibiting mammalian cytotoxicity > 15% and those containing cardiotoxic cardiac glycosides were eliminated. Three extracts were selected for further testing against four pseudotyped variants and infectious SARS-CoV-2 and were then further chemically characterized, revealing the potent (EC50 < 5 µg/mL) antiviral activity of Solidago altissima L. (Asteraceae) flowers and Pteridium aquilinum (L.) Kuhn (Dennstaedtiaceae) rhizomes.

The Botanical Safety Consortium: A public-private partnership to enhance the botanical safety toolkit

Botanical dietary supplement use is widespread and growing, therefore, ensuring the safety of botanical products is a public health priority. This commentary describes the mission and objectives of the Botanical Safety Consortium (BSC) - a public-private partnership aimed at enhancing the toolkit for conducting the safety evaluation of botanicals. This partnership is the result of a Memorandum of Understanding between the US FDA, the National Institute of Environmental Health Sciences, and the Health and Environmental Sciences Institute. The BSC serves as a global forum for scientists from government, academia, consumer health groups, industry, and non-profit organizations to work collaboratively on adapting and integrating new approach methodologies (NAMs) into routine botanical safety assessments.The objectives of the BSC are to: 1) engage with a group of global stakeholders to leverage scientific safety approaches; 2) establish appropriate levels of chemical characterization for botanicals as complex mixtures; 3) identify pragmatic, fit-for-purpose NAMs to evaluate botanical safety; 4) evaluate the application of these tools via comparison to the currently available safety information on selected botanicals; 5) and integrate these tools into a framework that can facilitate the evaluation of botanicals. Initially, the BSC is focused on oral exposure from dietary supplements, but this scope could be expanded in future phases of work. This commentary provides an overview of the structure, goals, and strategies of this initiative and insights regarding our first objectives, namely the selection and prioritization of botanicals based on putative toxicological properties.

Secoiridoids from Dogwood (Cornus officinalis) Potentiate Progesterone Signaling.

The use of botanical dietary supplements for the alleviation of conditions such as hot flashes, premenstrual syndrome, and fertility is prolific worldwide. Estrogen and progesterone receptors (ER and PR) and their corresponding steroid hormones are critical for the relief of hot flashes and the treatment of patients who develop endometriosis, and these pathways can influence the development of endometrial, ovarian, and breast cancers. However, few studies have investigated or identified the natural product components in herbal supplements that act on the PR. In the current study, a new secoiridoid, demethoxy-cornuside (1), along with six known secoiridoids (2-7) were isolated from the twigs of dogwood (Cornus officinalis) by bioassay-guided isolation with a progesterone response element (PRE)/luciferase (Luc) reporter assay in Ishikawa cells. Four phytoprogestins (1, 2, 6, 7) potentiated the effect of progesterone in the PRE/Luc assay. This study demonstrates that C. officinalis components might potentiate progesterone signaling in the presence of progesterone, which could modify progesterone receptor action in hormone-responsive tissues such as the uterus and mammary gland.

Trends and factors of botanical dietary supplement use among US adults with COPD from 1999 to 2016.

The potential effects of botanical dietary supplements (BDS) in the treatment of asthma have been proposed. However, the evidence of the effects of BDS use among patients with COPD is limited. The objective of our study was to exam the trends and effects of BDS use among US adults with COPD. A serial, cross-sectional study was conducted by using data of the NHANSE from 1999 to 2016 (n = 53,348). COPD (n = 2,580) was identified by using self-reported diagnosis history, and any BDS use was identified in the past 30 days. The prevalence of BDS use was calculated for respondents with and without COPD. Simple linear regression models were applied to test for trends in BDS use. Multiple logistic regression models were used to identify the factors of BDS use and patients' clinical outcomes, including all-cause hospitalization and abnormal hemoglobin levels, associated with BDS use. The results were weighted to represent national estimates. The prevalence of BDS use was greater among participants who had COPD compared to the referent group (mean 16.77% vs. 15.11%, p = 0.044). The trend of BDS use decreased from 1999 through 2016 in COPD group (p = 0.0023), but the trend remained stable in the non-COPD group (P>0.05). Results of multivariate logistic regression models showed that patients with higher family income (≥100% FPL) and graduated from college were more likely to use BDS compared with non-users. BDS use was associated with a lower likelihood of having all-cause hospitalization (adjusted odds ratio = 0.64; 95% CI 0.45-0.92) and abnormal levels of hemoglobin (adjusted odds ratio = 0.67; 95% CI 0.49-0.92) among adult COPD patients, after adjusting for covariates. The overall use of BDS decreased during 1999 through 2016 for US adults with COPD. The potential benefit of these supplemental medications use for clinical outcomes might exist for adult COPD patients.

P175 - Urinary estrogen derivatization and high-resolution LC-MS analysis to determine modulation of estrogen metabolism in women resulting from use of botanical dietary supplements

P175 - Urinary estrogen derivatization and high-resolution LC-MS analysis to determine modulation of estrogen metabolism in women resulting from use of botanical dietary supplements

Adverse event reporting patterns of concomitant botanical dietary supplements with CYP3A4 interactive & CYP3A4 non-interactive anticancer drugs in the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS)

ABSTRACTBackground: To examine the adverse event (AE) reporting patterns for concomitant Botanical Dietary Supplements (BDS) and anticancer drugs.Research design and methods: Using the 2004–2015 U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database, AEs involving commonly used BDS and anticancer drugs (categorized into CYP3A4 interactive and CYP3A4 non-interactive) were examined. Disproportionality analyses using reporting odds ratios (RORs) assessed the relative reporting rates of 1) serious AEs (i.e., mortality and morbidity) with concomitant use of BDS (overall and by type) and anticancer drugs compared to anticancer drugs only; and 2) AEs by specific System Organ Classes (SOCs).Results: A total of 3,264 AEs were reported involving concomitant BDS and CYP3A4 interactives, and 3,885 involving concomitant BDS and non-interactive anticancer drugs. ROR of serious AEs with concomitant all BDS and anticancer drugs compared to anticancer drugs alone showed a potential protective signal (ROR = 0.65, 95% CI = 0.62,0.68), but ROR for açaí and non-interactive anticancer drugs indicated potential risk (ROR = 1.70, 95% CI = 1.01,2.86). Heterogeneity of reporting patterns of AEs related to certain SOCs was observed for use of BDS along with anticancer drugs.Conclusion: This study identified potential protective and risk signals for AEs with concomitant use of BDS and anticancer drugs.

Irilone from Red Clover ( Trifolium pratense) Potentiates Progesterone Signaling.

The use of botanical dietary supplements is becoming increasingly popular for the alleviation of hormonal-based conditions such as hot flashes, premenstrual syndrome, and fertility. Estrogen and progesterone receptors (ER and PR) play an essential role in these processes. However, despite the fact that many therapies used to alleviate gynecological conditions act through PR-mediated mechanisms, few studies have investigated or identified any herbal natural product components that act on this receptor. In the current study, we used a progesterone response element (PRE)-luciferase (Luc) reporter assay to identify four phytoprogestins present in a standardized red clover ( Trifolium pratense) extract. We found that the component irilone (1) potentiated the effect of progesterone in both endometrial and ovarian cancer cell lines. In these cancers, progesterone action is generally associated with positive outcomes; thus the potentiating effect of 1 may provide entirely new strategies for enhancing progesterone signaling as a means of mitigating conditions such as fibroids and endometriosis. Formononetin (3) and biochanin A (4) exhibited mixed agonist activity, while prunetin (2) acted only as an antagonist. Collectively, these results suggest that the effects of red clover extract repeatedly observed in cultured cells and the inverse correlation between risk of various cancers and flavonoid intake may be due, in part, to altered progesterone signaling.

Trends in botanical dietary supplement use among US adults by cancer status: The National Health and Nutrition Examination Survey, 1999 to 2014.

Patients with cancer may use botanical dietary supplements (BDS) in an attempt to manage the side effects of chemotherapy, yet evidence about BDS use among patients with cancer is limited. The authors examined trends in BDS use among US adults according to cancer status and patient characteristics. A serial, cross-sectional study was conducted using data from the National Health and Nutrition Examination Survey from 1999 through 2014 (n = 43,644). Self-reported cancer diagnosis history and any BDS use in the preceding 30 days were determined. The prevalence of BDS use was calculated in each cycle for respondents with and without cancer, both overall and by patient characteristics. Simple linear regression models were applied to test for trends in BDS use at a 2-sided P value < .05. Multiple logistic regression models were performed to identify the patient factors associated with BDS use. The results were weighted to represent national estimates. The prevalence of BDS use was greater among participants who had cancer compared with participants who did not have cancer, but trends remained stable during 1999 through 2014 for both groups. Trends in BDS use declined in patients with cancer who were older (Ptrend = .047), had a low annual family income (Ptrend = .028), and had a lower education level (Ptrend = .004). Among the respondents without cancer, trends in BDS use declined in those who were middle-aged (Ptrend = .025), non-Hispanic whites (Ptrend = .025), those with a lower education level (Ptrend = .011), and those who were not receiving prescription medication (Ptrend = .036). Patient age, sex, race/ethnicity, income, education, and health conditions were associated with BDS use. The overall use of BDS remained stable during 1999 through 2014 for US adults with and without cancer, but it varied by individual characteristics. Cancer 2018;124:1207-15. © 2017 American Cancer Society.

Use of Botanical Dietary Supplements in Infants and Children and Their Effects on Health

&#x0D; &#x0D; Botanical Dietary Supplements (BDS) has an important&#x0D; part in the human diet throughout the history. People, who lived in ancient&#x0D; times, relied on the plants for the treatment of diseases of infants and&#x0D; children. According to World Health Organization, approximately 80 percent of&#x0D; the population who live in developing countries use herbal supplements in order&#x0D; to meet the basic health needs of relies on Botanical Dietary Supplements for infants and children&#x0D; are used for upper respiratory tract infection, lack of appetite,&#x0D; gastrointestinal disorders, sleep disorders, urinary tract disorders,&#x0D; gynecological diseases and skin diseases. Furthermore, not only the medical&#x0D; products but also botanical dietary supplements are used for Attention Deficit&#x0D; Hyperactivity Disorder (ADHD), depression, inflammatory bowel disease, cystic&#x0D; fibrosis, Rheumatoid arthritis, along with chronic diseases like asthma or&#x0D; cancer. The most widely used botanical dietary supplements are echinacea, St.&#x0D; St. John's wort, ginseng and ginkgo biloba. On the other hand, the use of&#x0D; botanical dietary supplements by infants and children not may only cause side&#x0D; effects but also can interact with other drugs used. It should be noted that&#x0D; the dosage of botanical supplements consumption for children also differs from&#x0D; the dosage for adults. In conclusion, this paper explains which botanical&#x0D; dietary supplements can be used by infants and children and their positive and&#x0D; negative effects on health

Motivations for Botanical Use by Socioeconomically Diverse, Urban Adults: Does Evidence Support Motivation?

The study objectives were to characterize botanical dietary supplement (BDS) use and to compare the motivations for botanical supplement (BS) use to the efficacy of the botanical in a socioeconomically and racially diverse urban adult population. Subjects were from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study, a 20-year prospective health disparities study with African American and white adults from Baltimore, Maryland. All study participants completed two dietary recalls and a dietary supplement (DS) questionnaire in Wave 3 (n = 2140). Diet quality was evaluated by the Healthy Eating Index-2010 and the Mean Adequacy Ratio for 17 micronutrients. A comparison of reported motivations to efficacy reported in the literature of single BS was conducted. Approximately 50% (1062/2140) of participants took DS. Of these, 8% (n = 178) reported taking either BS or BDS. It was found that BDS users had better diet quality than DS users as well as nonusers of DS. The top three motivations for BDS users were to improve overall health, to maintain health, and to supplement the diet. There is limited evidence for the efficacy of most BS. Review of the efficacy of the 15 BS reported by ≥5% of the study population revealed beneficial health roles for only fiber, gingko biloba extract EGb 761, and hawthorn berry. To the authors' knowledge, this study is the first to report a better quality diet with BDS use for a racially diverse urban population. Yet, improvement in diet is needed because overall quality did not achieve current recommendations. To improve overall health, it may be beneficial for this population to focus on dietary modifications to reduce the risks associated with chronic diseases. In general, the reported motivations for BS use were not supported by clinical evidence.

Adulterated pharmaceutical chemicals in botanical dietary supplements: novel screening approaches

AbstractThe increased availability and use of botanical dietary supplements (BDS) has been accompanied by an increased frequency of adulteration of these products with pharmaceutical chemicals. These adulterated products are a worldwide problem, and their consumption poses health risks to consumers. The main focus of this paper is to highlight novel screening approaches utilized in the detection of adulterants in BDS marketed for different therapeutic purposes. We summarize spectroscopic methods involving near-infrared, infrared, Raman, and nuclear magnetic resonance spectroscopy as feasible and interesting in-field screening tools for the analysis of suspected products (adulterated or not) before being sent to a laboratory for deeper inspection. In addition, the new approaches based on chromatographic methods such as liquid chromatography-circular dichroism, liquid chromatography-mass spectrometry, thin layer chromatography-surface enhanced Raman spectroscopy, and thin layer chromatography-mass spectrometry are discussed and reviewed. Novel analysis strategies from targeted analysis to post-targeted and non-targeted analysis allowing simultaneous determination of the number of multiclass pharmaceuticals are discussed.

Emerging Scenario on Industrial Use of Bio Resources and Development of Models for Computing Access and Benefit Sharing (ABS) Mechanisms

Objectives: Bio resources are sources for major economies in the world and provide livelihood opportunities for local tribes. Bio resources form part of raw material for herbal products/medicine manufacturing industry. One of the objectives of the Convention on Biological Diversity (CBD) is access and benefit sharing (ABS) arising out of utilization of bio resources. ABS calculation is most debated issue among end user – herbal products / medicine manufacturing industry. Methods and Results: Mechanisms for ABS computation are still evolving in many nations. In order to remove disparity in ABS calculation and bring in transparency, in this article we have presented three models. In the process, we have developed bio resource sustainability grid to map bio resources based on the i) ease of access, ii) regenerability of resources and iii) sustainability. First model describes calculation of ABS according to cost of bio resources, the second model links to proportion of bio resource with proportion of final formulation and the third model provides a formula which is analogous to Drug Price Control Order. Conclusion: With increase in use of botanical dietary supplements, nutraceuticals and emerging research in phytopharmaceuticals as drugs the quantum of usage of bio resources will proportionally increase. In addition to usage, conservation of critical bioresources is responsibility of stakeholders. The ABS computation approaches we have presented here can provide transparent ABS computation. The models can be adopted by other nations BDAs either directly or after minor modifications. The purpose of transparency in ABS calculation is served as both the end user and regulator can calculate the ABS payments without debate. Further, it would supplement the cause of sustainable utilization of bioresources while promoting conservation.

Pharmacokinetic Interactions between Drugs and Botanical Dietary Supplements.

The use of botanical dietary supplements has grown steadily over the last 20 years despite incomplete information regarding active constituents, mechanisms of action, efficacy, and safety. An important but underinvestigated safety concern is the potential for popular botanical dietary supplements to interfere with the absorption, transport, and/or metabolism of pharmaceutical agents. Clinical trials of drug-botanical interactions are the gold standard and are usually carried out only when indicated by unexpected consumer side effects or, preferably, by predictive preclinical studies. For example, phase 1 clinical trials have confirmed preclinical studies and clinical case reports that St. John's wort (Hypericum perforatum) induces CYP3A4/CYP3A5. However, clinical studies of most botanicals that were predicted to interact with drugs have shown no clinically significant effects. For example, clinical trials did not substantiate preclinical predictions that milk thistle (Silybum marianum) would inhibit CYP1A2, CYP2C9, CYP2D6, CYP2E1, and/or CYP3A4. Here, we highlight discrepancies between preclinical and clinical data concerning drug-botanical interactions and critically evaluate why some preclinical models perform better than others in predicting the potential for drug-botanical interactions. Gaps in knowledge are also highlighted for the potential of some popular botanical dietary supplements to interact with therapeutic agents with respect to absorption, transport, and metabolism.

High-Throughput Cytochrome P450 Cocktail Inhibition Assay for Assessing Drug-Drug and Drug-Botanical Interactions.

Detection of drug-drug interactions is essential during the early stages of drug discovery and development, and the understanding of drug-botanical interactions is important for the safe use of botanical dietary supplements. Among the different forms of drug interactions that are known, inhibition of cytochrome P450 (P450) enzymes is the most common cause of drug-drug or drug-botanical interactions. Therefore, a rapid and comprehensive mass spectrometry-based in vitro high-throughput P450 cocktail inhibition assay was developed that uses 10 substrates simultaneously against nine CYP isoforms. Including probe substrates for CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and two probes targeting different binding sites of CYP3A4/5, this cocktail simultaneously assesses at least as many P450 enzymes as previous assays while remaining among the fastest due to short incubation times and rapid analysis using ultrahigh pressure liquid chromatography-tandem mass spectrometry. The method was validated using known inhibitors of each P450 enzyme and then shown to be useful not only for single-compound testing but also for the evaluation of potential drug-botanical interactions using the botanical dietary supplement licorice (Glycyrrhiza glabra) as an example.

Pharmacokinetic interactions between drugs and botanical dietary supplements

The use of botanical dietary supplements has grown steadily over the last 20 years despite incomplete information regarding active constituents, mechanisms of action, efficacy, and safety. An important but under-investigated safety concern is the potential for popular botanical dietary supplements to interfere with the absorption, transport and/or metabolism of pharmaceutical agents. Clinical trials of drug-botanical interactions are the gold standard and are usually carried out only when indicated by unexpected consumer side effects or, preferably, by predictive in vitro studies. For example, Phase I clinical trials have confirmed clinical observations and in vitro studies that St. John's wort (Hypericum perforatum) induces cytochrome P450 3A4/5, whereas Phase I studies did not substantiate in vitro predictions that milk thistle (Silybum marianum) would inhibit CYP1A2, CYP2C9, CYP2D6, CYP2E1, and CYP3A4. Here, we highlight discrepancies between in vitro and in vivo data concerning drug-botanical interactions and critically evaluate why some in vitro models overestimate or sometimes underestimate the potential for drug-botanical interactions. Gaps in our knowledge are also highlighted for the potential of some popular botanical dietary supplements to interact with therapeutic agents with respect to absorption, transport and metabolism.

Mass spectrometric analysis of pharmaceutical adulterants in products labeled as botanical dietary supplements or herbal remedies: a review.

The increased availability and use of botanical dietary supplements and herbal remedies among consumers has been accompanied by an increased frequency of adulteration of these products with synthetic pharmaceuticals. Unscrupulous producers may add drugs and analogues of various classes, such as phosphodiesterase type 5 (PDE-5) inhibitors, weight loss, hypoglycemic, antihypertensive and anti-inflammatory agents, or anabolic steroids, to develop or intensify biological effects of dietary supplements or herbal remedies. The presence of such adulterated products in the marketplace is a worldwide problem and their consumption poses health risks to consumers. Analytical methods that allow rapid and reliable testing of dietary supplements for the presence of synthetic drugs are needed to address such fraudulent practices. Mass spectrometry (MS) and hyphenated techniques such as liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) have become primary tools in this endeavor. The present review critically assesses the role and summarizes the applications of MS in the analysis of pharmaceutical adulterants in botanical dietary supplements and herbal remedies. The uses of MS techniques in detection, confirmation, and quantification of known pharmaceutical adulterants as well as in screening for and structure elucidation of unexpected adulterants and novel designer drugs are discussed.

Chemical profiles of American prickly ash, botanical dietary supplements from the Zanthoxylum genera

Zanthoxylum clava-herculis L. and Zanthoxylum americanum Mill. (Rutaceae) are Native American medicinal plants that are currently popular as botanical dietary supplements. Despite this use, little information on the chemical profiles of these two species or the commercially available products exists. To promote the safe and effective use of botanical dietary supplements, we undertook the chemical characterization of these two species using UPLC-DAD-MS/MS obtained from a high resolution and accurate mass hybrid quadrupole-Orbitrap mass spectrometer. This method is efficient for obtaining structurally rich chemical information. The major constituents of both species were isolated and their structures confirmed using NMR, including the use of variable temperature NMR for herclavin (1). Herein we report, for the first time, the presence of an alkyamide from Northern prickly ash, supporting its traditional use for toothaches.

P04.26. Prevalence of botanical dietary supplement use among Hispanics in the United States: a systematic review

Methods We performed a systematic review of BDS use among adult Hispanics living in the US. Our strategy included electronic database searches (CINAHL, EMBASE, Global Health, CAB Abstracts, and Medline) with keywords: herbal, herb, medicinal plant, botanical and Hispanic or Latino along with a manual search of retrieved references. We included only studies with at least 1% Hispanics, prevalence estimates for Hispanics, and publication dates 1998-2011. We extracted information on study and sample characteristics, and rates of disclosures to clinicians.

The Role of Quality Assurance and Standardization in the Safety of Botanical Dietary Supplements

The importance of complementary and alternative therapies such as botanical dietary supplements continues to increase throughout the world (1). The World Health Organization (WHO) has estimated that the majority of people in developing countries depend on traditional and herbal medicines as their primary source of health care (2). In the United States, 42% of the population have reported using complementary and alternative medicines, especially botanical dietary supplements (3), costing an estimated $5.1 billion per year (4). The marketing and use of dietary supplements has grown rapidly in the United States following the passage of the ‘Dietary Supplement and Health Education Act’ in 1994, which exempts dietary supplements from regulation as drugs providing that they are not marketed for the diagnosis, treatment, cure, or prevention of disease (5). Although the use of botanical dietary supplements has increased substantially during the last two decades, evidence for their efficacy and safety has not been well documented. In the United States for example, botanical dietary supplements are currently exempt from good manufacturing practice, do not require proof of efficacy, and do not require pre-marketing approval by the FDA unless drug-like claims are made. The safety of botanical dietary supplements is the responsibility of the manufacturers, and the role of the FDA in safety assurance is limited to post-marketing monitoring of adverse effects. Since no disease treatment or prevention benefits may be claimed for dietary supplements, they are exempt from FDA regulation, and efficacy studies for these products are relatively rare. Therefore, the safety and efficacy of most botanical dietary supplements lack documentation, which concerns many health care providers and consumers. Possible problems with botanical dietary supplements include contamination with pesticides, herbicides and heavy metals, contamination or adulteration with pharmacologically active medications, use of the incorrect part of the plants (for example, leaves instead of roots), and even misidentification of the plant species incorporated into the product. Since no toxicology studies are required for botanical dietary supplements, there is also concern that interaction might occur between botanicals and conventional pharmaceuticals or that metabolic activation of constituents in the botanical dietary supplement might result in the formation of toxic metabolites. The possibility of overdose is also an issue, since studies to establish maximum tolerated dosages and safe long-term chronic dosages are not required and are rarely carried out. Since botanical dietary supplements may be marketed until proven unsafe through the documentation of adverse effects, the safety of these products is determined primarily through self-regulation by manufacturers. Since consumers expect a consistent and safe product, the agricultural and herbal industries should work together to produce safe products of reproducible quality using basic principles of botany, chemistry and pharmacology. This review addresses basic safety issues concerning botanical dietary supplements. Specific problems that have occurred with respect to safety are described, and solutions to these safety issues are proposed.

Botanical Dietary Supplements Gone Bad

The use of botanical dietary supplements has increased exponentially in the past decade. As outlined in the previous reports, they are often perceived to be safe due to their “natural” origin, long-standing ethnomedical use, and over-the-counter availability. However, unlike pharmaceuticals that must undergo extensive clinical trials prior to FDA approval, dietary supplements have little regulation of either efficacy or safety in the USA (1). There is also growing interest in food products with ‘functional health’ properties, which have only a few regulations worldwide (2). In addition, several of these botanicals are currently extracted using different procedures than they were originally, and over-the-counter availability often leads to over dosing and to severe interactions when taken together with other medications (3-6). In particular, a significant number of these herbal products have been associated with hepatotoxicity (4,7). The ultimate toxin is usually a reactive electrophile or free radical formed by oxidative metabolism. Several examples of botanicals which form reactive intermediates will be discussed in this review.