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لان ات ۱ ‎Medicines:‏ What You Should Know Mandy Leonard, R.Ph., Pharm.D., BCPS Drug Information Specialist Department of Pharmacy The Cleveland Clinic Foundation

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Objectives Review the reasons why people are using herbal/ alternative medicines. Describe risks from the consumption of herbal/ alternative medicines. Describe briefly changes in law regarding ‏ا الت سام تاق‎ Discuss commonly used dietary supplements, including herbal medicines. Review reputable sources of information regarding herbal/alternative medicines.

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Introduction * Definitions - Food and Drug Administration (FDA) - World Health Organization (WHO) * Homeopathy = * Over 20,000 herbal and other natural products available in the United States. * Economics * Widespread use

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Top-Selling Herbs in Mainstream Market in U.S. 2001 = * Gingko ($46) * Cranberry ۱ ($40) ($11) * Garlic ($39) | ° Black cohosh ($10) * Ginseng ($31) 0 4 )۵ 9( * Soy ($28) * Milk thistle ($ 7) * Saw Palmetto ($25) * Evening primrose ($ 6) ¢ St. John’s wort ($24) * Grape seed ($ 4) * Valerian ($12) 0 (cy ee * Yohimbe ($ 2) ($ in millions; Herbalgram 2002;55:60.)

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Top-Selling Herbs in Mainstream Market in RPT AC) [0 * Ginkgo ($32) ($11) * Echinacea ($32) ‏لك‎ ($ 8) * Soy ($28) ‏اوا تف اننا نا‎ ($ 7) * Saw Palmetto ($23) * Evening primrose ($ 7) * Ginseng ($21) * Kava kava ($ 6) * St. John’s wort ($15) ‏رازن‎ ($ 3) * Black cohosh ($12) ۰ 6۲۵۵9 0 ($ 3) 9 ($ 2) (2003:58:710 صعدولهطعل رعدمنللنه صذ 4)

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Herbal versus Conventional Medication ی 5ع لهدده ی وتو ان ‎effects‏ * Lack of effective treatments/cures

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Herbal versus Conventional 21 210011615 هطو 01 9 safe because derived from nature ‏الى‎ influence * Desire to have control of one’s own health * False claims from manufacturers

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Safety Considerations 0 to 70% of patients do not inform physicians about use of alternative therapies ‏اف‎ ‎- One or more chemical component of the plant BRC SKS MMi eK mC Tien elite ‏نت۱۰‎ ‎- FDA does not require reporting of adverse pure CBIR ‏ا اك ا‎ (MedWatch and SN/AEMS) SCH (MBM a aye Clima MOC MILI betep)

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Safety Considerations ¢ Standardization - Nomenclature and chemical constituents 11 ۳ * Lack of Good Manufacturing Practices (GMPs) * Examples: ginseng, ephedra ا ل القت لل لات - Lack of active ingredient - Contamination

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* Ephedra (ma haung) - Ephedra sinica - Anorexiant, decongestant * Licorice 5 (enyeaiihz-Mellleya=t - 190 ‏مصنعه‌مطوه‎ = - Peptic ulcers - ‏طخدعل ,8115 رعصمتاه] أملدط‎ - High doses - Maximum recommended ای تست ‎(pseudoaldosteronism)‏ - Contraindications - Use no longer than 6 0 ۳ ۷ ne - Drug interactions Sey AD CM erste - Contraindications ‏مصناقده‎ - Drug interactions Se Dec etemm ateaerroriv tiles

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Ephedra * Products containing ephedra account for 64% ۴ of all adverse reactions to herbs in the US * Less than 1% of herbal product sales * FDA announced ban on 12/30/2003 ٠ After Mid-March 2004, illegal to manufacture or sell dietary supplements that contain ‏الالال لتنا‎ ephedrine and related alkaloids ٠ Does not include teas

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Kava (Piper methysticum) Anxiety, stress, sleep disorders (kavapyrones) May be effective for short-term treatment of anxiety (similar to Valium® and Ativan®) Hepatoxicity: liver failure and liver 3 - FDA warning; Canada and some European countries- market removal - Kava dermopathy Use no > 4 weeks; no alcohol/sedating medications; caution when driving or operating ‏لات عت‎

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FDA Proposed Labeling and Manufacturing 2215 * Designing/construction of physical plants * Establishing quality control procedures * Testing manufactured dietary ingredients and ‏1م511‎ 5 = - Five out of 18 soy or red clover-containing products * Only 50 to 80% of declared isoflavones ‏ا ا‎ ¢ Almost 10 times more niacin > - Folic acid * Only 35% of what was stated on label

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or tablet Testine St. John’s Wort In a spot check of retai 1 wert suppleme: varied, according to 4 : tent laborat commissioned & The potency de :

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ConsumerLab.com How to Read a ConsumerLab.com Approved Quality Product Seal: This seal Product met ie is a registered CL’s standards. certification mark. Product was tested CL is independent and for ingredient quality. a consumer-focused. ConsumerLab.com GINKGOBILOBA gore about this product, ingredient, and testing at our web site. You can learn This specific Product was ingredient was laboratory-tested tested. by experts.

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NSF International

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Potential Warfarin-Herb 11100 * Ginger ° Feverfew Seeley Rita - Additive effect - Avoid supplements, but - Monitor or avoid ‏اسه‎ ‎problematic - Increased * Garlic metabolism & ‏ل‎ sii oa decreased effect of Sa Naess 1 ‏حنهته 1۳۲ ا‎ ‏و(‎ - Monitor or avoid should not be problematic

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Consumer Survey * Herbal use, products, and willingness to inform health care practitioners * 794/1300 surveys returned - 42% (n=330): Herbal product use - Common herbal products (aloe, garlic, ginseng, echinacea, and St. John’s wort) - Women (majority) - Higher education (75%) - Herbal users = more prescription medications - Herbal users = negative perception of | ‏ل‎ ‎0

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Laws and Regulations * 1994- Dietary Supplement Health and Education Act (DSHEA) - Definition (dietary supplements not categorized as food additives) ¢ Premarketing approval - Burden of proof that product is adulterated or unsafe rests on the FDA (e.g., ephedra) - “Third-party Literature” * Balanced view of available data - Structure/Function Statements

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Structure/Function Statements * “This product is not intended to diagnose, treat, cure or prevent a 1 ‏"عودع‎ ‎¢ Change in definition of disease ¢ Examples: - ‏59و10 تتتقط ته ددع لع ستسخسصعوطم‎ 4 with aging - Hot flashes Se Sauna lm at icy Herbalgram 2000;48:32-8

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- Distinct chemical component * Work synergistically - Improves blood flow (brain and heart) - Protects against oxidative damage from free radicals (antioxidant) - Inhibits effects of platelet activating factor (PAF)

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“Eyer since she’s been taking ginkgo biloba, she’s been remembering all our old arguments.”

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Ginkgo: Efficacy * Data demonstrate ginkgo leaf extract can Vie mE ROCCE if (roles VLAN ‏وصنصمتامص؟ لهمتع50 0صه صمتامصی؟‎ in patients with multiple types of dementia. * No direct comparisons to conventional medications for dementia. * Modestly improve visual memory and ‏ل ل ل ال‎ demented patients with age-related memory impairment.

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©5015 :0121200 & ع Interactions ۰ pez ffects: = ee ‏رکطمن۲6۵»1‎ ‎gastrointestinal disturbances - Spontaneous bleeding (few case reports) 5 * Drug Interactions: - Anticoagulants (Coumadin®) - Antiplatelets (aspirin, Plavix®, Ticlid®) صتاعط] -

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0210 Dose and را ¢ Standardized: 24% flavone 0176051065 ‏له‎ 690 5 (leaf extract) * Dementia: - 120 to 240 mg ginkgo leaf extract administered orally in two or three divided doses

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Ginkgo: Summary ¢ Mild-to-moderate vasoactive agent * Data promising in Alzheimer’s Disease * Used extensively in Germany ¢ No comparison to standard of care * Well-tolerated (weeks to 1 year) طخت عدم تناع و تتعغصز لاتتعغط-وتحسل ‎٠ CsCl‏ ‎anticoagulants, antiplatelets, and‏ ۹

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Ginseng * Each type of ginseng is unique - Asian or Oriental ginseng (Panax ginseng) - Siberian ginseng (Eleutherococcus senticosus) - American ginseng (Panax quinquefolius) * Active ingredients: Root (panaxosides) ‏الا‎ ‏ل ا للق‎ - Lowers blood pressure * Ginsenoside Rg-1 ۳ VBA CR matt See ‏ل‎

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Panax Ginseng: Efficacy Data demonstrate possibly effective: - Improving abstract thinking, selective memory, and mental arithmetic skills (more effective in conjunction with ginkgo biloba leaf ‏امو قوت‎ - Improving resistance to stress - Controlling blood glucose levels in people with non-insulin dependent diabetes (Type 2) * Possibly ineffective for enhancing athletic performance in healthy, young adults

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Panax Ginseng: Adverse Effects & Drug Interactions ° Adverse Effects: - Nervousness, insomnia, excitation, palpitations, affects blood pressure, lowers blood glucose, alters immune functiom BRGUCC ‏ات‎ berm eC eat mL) * Drug Interactions: - Antidiabetic agents - Warfarin (Coumadin*)

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St. John’s Wort (Hypericum perforatum) *Common forms: capsules, tablets, tinctures= ۰: ‏ال‎ - Flowering tops - Naphthodianthrones (one of many potential active ‏(متمصعص موسرو‎ = + Hypericin - Inhibits MAO, > MAO, ۱ C ICM tla RRO MCHC t ey SEcCSCUK emily taCreLaeteimouaciipec Lately © CocyeybetyiretiCm tility tary ٠ - Catechol-O-methyl-transferase (COMT) 111 ‏ل‎

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St. John’s Wort: Efficacy ¢ For the treatment of mild-to-moderate ‏أقطا عأهوتاكططةهططعل0 وكهل ردمتددوع:1مع0‎ St. John’s wort is: - Superior to placebo - As effective as low-dose tricyclic antidepressants (TCAs; Elavil® and Pamelor®), - Possibly as effective as selective serotonin reuptake inhibitors (SSRIs; Prozac®, Zoloft®, Celexa®, and Lexapro®*)

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St. John’s Wort: PANG ‏ع 5ا0ع1811‎ 101110 Interactions + Adverse Effects: - Sun-exposure: Photosensitivity/Phototoxicity (hypericin component; watch if taking antibiotics) - Insomnia, vivid dreams, headache, dizziness * Drug Interactions: - MAOIs, selective serotonin reuptake inhibitors (SSRIs), Imitrex®, tramadol (Ultram®): Increased serotonin - Cyclosporine (Neoral®): Decreased levels - Warfarin (Coumadin®): Decreased INR (lab test) - Oral contraceptives or hormone replacement therapy: Breakthrough bleeding

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st. John’s Wort: Dose and ۱ RP RELIES ea Late - 0.3% hypericin - 5% hyperforin * Mild-to-moderate depressifj* - 300 mg + Administed orally three times a day - Doses of 1200 mg/day have also been used

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Echinacea (Echinacea angustifolia, pallida, purpurea) * Common Forms: tablet, juice, tea * Purple coneflower * Source: Applicable parts are the roots and above ground parts. ٠ Pharmacologic action [constituent(s)?] ٠ ‏اأتتتقاعة لمستتحتاصة أمعع11ل0م1‎ ‏ار ل ال نا للك‎ - Cytokines, monocytes, natural killer cells

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Echinacea: Efficacy * Echinacea is possibly effective for - Reducing symptoms associated with influenza- like upper respiratory infections such as the common cold and flu. - Evidence suggests reduction in duration and severity of symptoms if started when symptoms are first noticed and used for 7 to 10 days. * Possibly ineffective for preventing the common cold or influenza when taken prophylactically.

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Echinacea: Adverse Effects & Drug Interactions ¢ Adverse Effects: - Allergic reactions * ragweed, daisies, marigolds - Fever, nausea, vomiting, unpleasant taste, and dizziness - Atopy; more likely to experience allergic reaction * Drug Interactions: - Immunosuppressants: Interfere with therapy - Medications used for transplant patients, cancer patients, and patients with multiple sclerosis

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Echinacea: ‏م1005‎ 30 ‏و(‎ 1 1 1 * Wide variety of doses depending on formulation * Difficulty in standardization (echinacoside, alkamide content) ¢ Purpurea herb juice: 6 to 9 mL for 8 weeks * Purpurea crude extract: 2 tablets administered orally three times a day * Tea: 5 to 6 cups on day 1 of symptoms, then 1 cup/day for 5 days

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Echinacea: Summa ¢ Formulation/species that offer mos benefit is unclear. co ¢ E. purpurea pressed j ‏تكلا‎ or E. pallida root extracts at first sign of cold ٠ 11 taken greater than 8 weeks - Reduced immunostimulatory effects? - One week drug holiday (not substantiated) * Well-tolerated (up to 12 weeks)

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Dietary Supplements: Immune- ‏تست‎ AeA * Grape seed extract * Melatonin * Siberian ginseng lacus Alfalfa Panax ginseng ‏ا‎ vhs) Cat’s claw Coenzyme Q10 DHEA Echinacea [ef-ab Tor

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Herbal Use in Patients Undergoing Surgery ¢ Approimately 26% of patients scheduled for surgery use herbal products ~ Cardiovascular instability - Prolongation of anesthesia/sedation - Bleeding - Electrolyte disturbances - Immunosuppression 01

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Discontinuation of Use Before Surgery ¢ Echinacea * Ginseng - ‏مهل ولح‎ - 7 days Be nen Cy errant - Hypoglycemia; Bleeding 0 . 2 huang) - 24 hours - 24 hours Sector - Cardiac cautions * St. John’s Wort ¢ Garlic aa PNT - 7 days ۳ ‏عممتاع هوم مامد‎ ~ Biceding * Valerian ‏هاهه 0 - تایه‎ 0 0 - Bleeding JAMA 2001;2860):219

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Herbal References * Natural Medicines Comprehensive ‏ععوطم]ا2‎ ‎- $92/year (book or web version) - $132/year (book and web version) * The Review of Natural Products - $160/year (bimonthly updates) * The Professional’s Handbook of Complimentary and Alternative Medicine ۳ ‏لك‎

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Natural Medicines Comprehensive _ Database _ NATURAL MEDICINES (/7P>\ ‏ات لیات نت‎ Te J] 00 fags 2272

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۴۲ اك ‎Natural Products‏ Lat a ey ‏رخ نتملا‎ ۹ 2000

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PDR for Herbal Medicines

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American Botanical Council (ABC) Ginseng’s Good Name + Herb Baths + Aromatherapy « St. John’s Works | | ا 7 95 5

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Herbal References * The United States Pharmacopeia and The National Formulary (USP- NF) - $526/edition - 21 botanical monographs (since 1995) * Internet Reference - The Natural Pharmacist (www.tnp.com) * Conditions * Drug Interactions * Review of published articles Peel rte ty

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11121 26 5 * The Herbal Internet Companion - Herbs and Herbal Medicine Online - $20 (ISBN 0-7890-1052-6)

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IBIDS Databasy * International Bibliographic Information on Dietary Supplements - Office of Dietary Supplements (ODS) at the NIH - Published, international, scientific literature * Vitamins, minerals, and botanicals - Over 676,000 unique scientific citations abstracts 111 ‏لان‎ ‎٠ ‏عكدطهغهل 18125 للدظ‎ * Peer-Reviewed Citations Only database * IBIDS Consumer database

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CARDS Database * Computer Access to Research on ‏[ممنا5 كتداع نآ‎ 5 - Office of Dietary Supplements (ODS) at the NIH - Specific mandates from the DSHEA 9 ‏تفت رتیت‎ pertaining to dietary supplements - Free of charge - www.ods.od.nih.gov

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Summary ٠ ‏غ215 تتتهطم 220 ,21115 برسملءأووطم لاع]'‎ about herbal therapy use (documentation) ¢ “Natural” does not mean safe ¢ Herbal-pharmaceutical interactions do Clete i a * Lack of standardization (variability in herbal content and efficacy among manufacturers) * Lack of quality control and regulation (contamination and misidentification)

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Conclusions * Because of lack of efficacy and toxicity information, patients and clinicians should be aware that advice about herbal therapies is not absolute and is a matter 3 of judgment. * Base advice on available knowledge that is congruent with your needs and the OCC MMM mente * Majority of recommendations are NOT evidence-based

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PHARMACY “My husband hasn’t been himself lately. Do you have any pills to keep him that way?”

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