Herbal Psychopharmacology

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Herbal Psychopharmacology James W. Jefferson, MD Clinical Professor of Psychiatry University of Wisconsin School Of Medicine and Public Health Revised August 2007 

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1. Which of the following was responsible for herbal products “flooding” the U.S. market in recent years? ۹ Federal Food, Drug and Cosmetic Act ۱: Kefauver-Harris Amendment C. Dietary Supplement Health and Education Act D. Nutrition Labeling and Education Act ۱ Food and Drug Modernization Act 

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2. Which of the following has been most closely associated with hepatotoxicity? ۰ Ginkgo Kava Saw palmetto St. John’s wort Valerian ۲ 9 ۶ 8 

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3. Which of the following is the clinically most important effect of St. John’s wort on the cytochrome P450 (CYP) system? ۳ 1A2 inhibition ‏و‎ 2D6 inhibition C 2C9 induction D. 2E1 induction 3 3A4 induction 

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4. St. John’s wort has been most extensively studied for the treatment of which of the following disorders? ۰ Bipolar Posttraumatic stress 58 Cc. ۵ ۱ Major depressive ۳ Social anxiety 

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5. A placebo-controlled, double-blind study found Ginkgo biloba to be ineffective for treating antidepressant- induced sexual dysfunction. A. True B. False 

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Objectives ¢Understand the ramifications of DSHEA ¢ Appreciate the current efficacy status of herbals for treating ‏عتتامتطءع:53م2‎ 25 ¢Be aware of the potential effects of herbals on drug metabolism 

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Outline Historical Overview - DSHEA and its Ramifications Valerian ۹ Clinical Studies 1۰. Drug Interactions Ginkgo A. Clinical Studies ۱:1 Drug Interactions Cc. Bleeding ۱8 ۹۳ 

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Outline (Cont’d.) Kava ۹ Clinical Studies 9. Hepatotoxicity 0. Drug Interactions St. John’s Wort ۹ Clinical Studies B Mechanism of Action (Os Side Effects D Drug Interactions ۱2 

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Outline (Cont’d.) Other Herbals A. Uses 1 Drug Interactions ‏لا‎ 5 0122 ‏اأتتتظعم‎ ‎7 Orange Cc. Pomegranate aCe OTN A eLery 8 VII. 111۰ 

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*Historical overview *DSHEA (1994) *Clinical efficacy *Drug interactions *Words of warning 

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Herbs and plants are medical jewels gracing the woods, fields and ۱۳۱ ‏بن‎ ‎۱۱۱۱۱۵۰ ‏رت‎ ‎and few minds understand. Through this want of observation and knowledge the world suffers immense loss Linnaeus 1707-1778 

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Progress? °1938: Food, Drug and Cosmetic Act - Proof of safety °1962: Kefauver-Harris Amendment - Proof of efficacy - Required reporting of adverse events °1994: Dietary Supplement Health and Education ate abo) 5 |e eee ‏م ناث‎ signed by President Clinton) 

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Dietary Supplement Health and Education Act (1994) *Removed supplements from food additive regulations *Burden of proof on FDA *No federal regs for purity, etc. *No mandatory reporting of 

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Since then, these products have flooded the market, subject only to the scruples of their manufacturers. Angell and Kassirer, NEJM 9/17/98 

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“In the United States, the public spends almost $4 billion yearly on supplements, with little or no data on what they can expect.” Lewis and Strom. Ann Int Med 136:617- 618, 2 In 2003, Americans spent nineteen billion dollars on dietary supplements Specter M. The New Yorker, Feb 2, 2004, pp 64-75 

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50 Ginseng Preparations *Analyzed for ginsenosides ¢Content varied from 1.9% to9% (4.7 fold difference) ۰6 (12%) had none Cui et al: Lancet 7/9/94 

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Asian Patent Medicines from California Herbal Stores * Undeclared pharmaceuticals - ephedrine, chlorphenarimine, ۱۱۵۲۱۷۱۲۵6۲05۲6۲, / ۸ ia) * Heavy metal contamination - lead, arsenic, mercury ¢ 32% of 260 medicines California Dept. of Health Services, NEJM 9/17/98 

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Tongkat Ali Power Plus: A Natural Remedy to Improve Sexual Health and Libido ¢“Our products are natural herbal powder made in a more convenient- to-use form capsules” BUT *Analysis of 15 capsules found sildenafil, 59 mg/capsule. 10 of the 15 also contained tadalafil, 1.4 mg/capsule Kenyon et al. J Clin Pharmacology 2006;46:1379-1381 

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FDA Issues Dietary Supplements Final Rule * To require good manufacturing practices (GMPs) for supplements * To ensure quality production, no contaminants, accurate labeling ٠ Effective August 24, 2007, but witha long phase-in * Does not address efficacy and safety ‏55و‎ (7 

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Valerian (Valeriana officinalis) 

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Valerian (Valeriana officinalis) *Galen - the Phu plant (dried roots stink) ‎°U.S. Pharmacopoeia 1820-‏ 1942 یا ۵ ارات عطغ) ‎*WWII - for shell shock *Rat-catchers bait ‎eCatciarctacy 

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Valerian in Psychiatry ار - Better than placebo in 6/7 double-blind studies - Slow onset (2-3 weeks) 2 - Only open-label reports * Well tolerated (mild hangover?) * Does odor defeat the blind? Krystal and Ressler. CNS Spectrums 10/01 

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Valerian for Insomnia * Internet-based, 4-week, double- 1 ‏ات‎ °6.4 mg valerenic acids hs (odor masked) *Valerian (n=135) = placebo (n=135) Jacobs et al., Medicine 2005;84:197-207 

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Valerian for Insomnia: Systematic Review and Meta- Analysis * 16 randomized, placebo-controlled trials, ۱۲213 * Methodologic problems in most, and preparations, doses, durations varied considerably Ce Mee CHIE (cmoauC Coa mete RM AIT LARC Coat Hel might improve sleep quality” ۱ ‏ات‎ ‎Bent et al. Am J Medicine 2006;119:1005-1012 

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Valerian-Drug Interactions (14 days, healthy vol., n=12) *No clinically significant effects on CYP2D6 (dextromethorphan) or 3A4 (alprazolam) ¢ Alprazolam C,,,, T 20% (AUC, T,,. unchanged) Jonovan et al. Drug Metab Dispos 2004;32:1333-1336 

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Valerian and CYP450 Inhibition (28 days, healthy subjects, n=12) *No significant effect CYP1A2, 2D6, 2E1, 3A4 Gurley et al., Clin Pharmacol Ther 2005;77:415-426 

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Valerian and CYP450 Inhibition *So far, so good * Clinical studies-very limited data -only in 24 healthy volunteers 

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Ginkgo (Ginkgo biloba) 

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Ginkgo Biloba Tree (Maidenhair Tree) * Oldest living tree species ۱۳۸۱۱۱ ۱۱۱۱۱۱۰ ‏توت‎ ‎* Lives up to 1000 years * Grows up to 122 feet * Durable Se Jiao Le AA) Hiroshima =- popular in NYC 

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Ginkgo Biloba Components ٠ 2121:0121 15 - Kaempferol - Querectin - Isorhamnetin - Myricetin * Terpene lactones - Ginkgolides - Bilobalide ‏ی‎ 

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Ginkgo Biloba for Dementia *Inconsistent data ¢Further research needed * Cholinesterase inhibitors preferred Kurz and Van Baelen, Dement Geriatr Cogn Disord 2004;18:217-226 Diamond et al., Drugs Aging 2003;20:981-998 

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Extract of Ginkgo Biloba in ۱3۵ 0.10 0.08 GERRI uy cos ۳ Xs} acs 2 Placebo 9 = 000 ‏الس سس سس سس سس سس سس سس هس‎ - EGb ‏كت‎ 0 0 Improved ‏شب‎ 005 as 10 0 0 0 0 5 Baseline 12 26 39 52 Weeks Le Bars et al: JAMA 278:1327-1332, 1997 

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Ginkgo Biloba vs. Placebo on Cognitive Performance in Multiple Sclerosis 12-week, double-blind, n=38 * Dose: 120 mg twice daily * Results: Overall, no statistically significant improvement in cognitive function Lovera et al. Multiple Sclerosis 2007;13:376-385 

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Ginkgo/Ginseng Combination and Cognitive Function *Healthy, middle aged volunteers (n=256) °14 week, double-blind, placebo * Significant improvement on Index of Memory Quality (7.5%) Wesnes et al. NCDEU Poster 81, June 2000 

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Ginkgo for Memory Enhancement (6 week, double-blind, n = 230) *Volunteers, over 60 years old °40 mg t.id. versus placebo *No benefit, but well tolerated Solomon et. al. JAMA 288:835-840, 2002 

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Ginkgo Biloba: No Robust effect on Cognitive Abilities or Mood in Healthy Young or Older ۳۰۳۱۱۱۱۵ * 12-week, double-blind, placebo- controlled, n=93 older, n=104 young adults * Dose: 120 mg/day Burns et al. Human Psychopharmacol Clin Exp 2006;21:27-37 

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Ginkgo Biloba Extract EGb 761 for Generalized Anxiety Disorder (n=82) and Adjustment Disorder with Anxious Mood (n=25) ¢ 4-week, double-blind, placebo-controlled * Dose: 240 mg or 480 mg/day * Results (HAM-A |): EGb 761 > placebo (both ‏(5ع005‎ * Response: 480 mg 44%, 240 mg, 37%, placebo 22% Woelk et al. J Psychiatric Research 2007;41:472-480 

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Ginkgo Biloba for Antidepressant-Induced Sexual Dysfunction (n=37) °240 mg/day EGb761 vs. placebo *8 week, double-blind * Ineffective! Kang et al. Human Psychopharmacol 2002;17:279-284 

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Ginkgo Biloba-Drug Interactions * Donepezil (2D6, 3A4 substrate)* - 30-days, 90 mg/day, n=14 - no effect * Nifedipine (3A4 substrate)** - simultaneous, single dose, n=12 - no effect overall - blood levels doubled in 2 * Omeprazole (2C19, 3A4 substrate)* - 12-day, 280 mg/day, n=18 - CYP2C19 induction ~ ‏م60‎ AUC *Yasui-Furukori et al., J Clin Pharmacol 2004;44:538-542 **Yoshioka et al., Biol Pharm Bull 2004;27:2006-2009 ‏ی‎ et al., Pharmacogenetics 2004;14:841-850 

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Ginkgo Biloba-Drug Interactions (28-day, normal vol., n=12) *Dose: 60 mg gid *No effect on phenotypic ratios: CYP1A2, 2D6, 2E1, 3A4 3urley et al., Clin Pharmacol Ther 2002;72:276-287 

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Ginkgo Biloba-Drug Interactions (14-day, normal volunteers, n=12) * Dose: 120mg bid (EGb 761) ¢ 2D6 (dextromethorphan) - 0۵ 1 ¢ 3A4 (alprazolam) -17% | AUC Markowitz et al., J Clin Psychopharmacol 2003;23:576-581 

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Ginkgo Biloba Effects on 2C9 and 3A4 (14-day, normal volunteers, n=10) * Dose: 360 mg/day (EGb 761) for 28 33 * 2C9 (tolbutamide): 16% | AUC ¢ 3A4 (midazolam): 25% 1AUC * Statistically significant, but clinical significance unclear Uchida et al. J Clin Pharmacol 2006;46:1290-1298 

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Ginkgo Biloba and CYP450 SSSI MTOM AO RICOD Cc MOM OL Tb virB et tes induction of 2C19, little or no effect on 1A2, 2D6, 2E1, 3A4 (small sample sizes) ¢ In vitro inhibition of 1A2, 2C9, 3A4 but only by certain constituents * Rat data do not extrapolate well to humans 

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Ginkgo Biloba and Bleeding * Subdural hematoma (2 cases) * Subarachnoid hemorrhage (1 case) * Intracerebral bleed (1 case) * Vitreous hemorrhage (1 case) * Spontaneous hyphema (1 case) SPN CVA) ‏فاك‎ yAU ODIO MRC Te) wet on warfarin, etc. 

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Kava (Piper methysticum) 

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Kava ٠ ‏1ك لإطاعم2 عواصط‎ (intoxicating pepper) * South Pacific ceremonial and social drink *A stress and anxiety reducing herbal superstar? 

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Kava Drinking "It gives a pleasant, warm and cheerful, but lazy feeling, sociable, though not hilarious or loquacious; the reason is not obscured." Hocart, 1929 

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Kava (Piper methysticum) ۵ 15 - anxiolytic/sedative - muscle relaxant - analgesic © ‏ا‎ ‎٠ 002220116215 )125:212610265( - methysticin See MVEA - dihydrokavain - and others 

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Kava for Anxiety ¢ Effective in 7 double-blind ‏تك القت‎ ٠ 11612-22215515 013 25 - Kava > placebo by 10 points Pittler bs or" ۳۳ sychopharmacol Feb 2000 

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Kava for GAD at Duke (4 week, double-blind, n = 35) * Kava Pure (140 mg — 280 mg KI/day) * Kava = Placebo on all measures * High Anxiety: Placebo > Kava * Low Anxiety: Kava > Placebo Connor and Davidson. Int Clin Psychopharm 17:185-188, 2002 

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Be BCs Tie 0) AS) od 8 hd 0 Aw) 0 DO od Disorder (pooled analysis of 3 small, double-blind, placebo-controlled studies) *Sample: Kava, n=28, placebo, n=30, ۱ XR, n=6 * Dose: 140 mg > 280 mg kavalactones/day) * Results: Kava not effective (significant effects favored placebo) Connor et al Int Clin Psychopharmacol 2006;21:249-253 

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Kava for Anxiety ¢ Internet-based, 4-week, double- blind, placebo-controlled °100 mg total kavalactones tid * Kava (n=121) = placebo (=135) Jacobs et al., Medicine 2005;84:197-207 

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Kava Hepatotoxicity * 78 cases associated with kava (causal ?) ¢ 11 liver transplants ۰ 4 ‏عطاجع0‎ ‎۱ ‏ال‎ ‎Canada; FDA advisory in US * Mechanism: drug interactiqn ?, ‏ی‎ ‎idiosyncrasy ???? Clouatre DL. Toxicol Lett 2004;150:85-96 

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Kava and CYP450 Inhibition (28 days, healthy subjects, n=12) *CYP2E1 - 40% inhibition *CYP1A2 - no effect °CYP2D6 - no effect *CYP3A4 - no effect Gurley et al., Clin Pharmacol Ther 2005;77:415-426 

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Chronic Kava Drinkers Abstain for 30 days «m=6) * Caffeine metabolic ratio doubled ¢ Probes for 2C19, 2D6, 2E1, 3A4 not affected * Kava drinking inhibits 1A2 Russmann et al., Clin Pharmacol Ther 2005;77:453-454 

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Kava-Drug Interactions * CYP450 potency similar to grapefruit juice? (3A4 inhibition in vitro, but not in vivo) * Potentiation of CNS-depressants (ALP/Kava coma) ¢ Antiplatelet activity * MAO-B inhibition *No clinical drug interaction studies thus far nke and Ramzan, J Ethnopharmacol 2004;93:153-168 

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St. John's Wort (Hypericum perforatum) 

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Bioactive Constituents of Saint John's Wort ¢ Phenylpropanes ¢ Flavonol glycosides ٠١ Bioflavones ¢ Proanthocyanidins ¢ Xanthones * Phloroglucinols (hyperforins) ¢ Naphthodianthrones Nahrstedt and Butterweck: Pere NOs: ACT D) 

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St. John’s Wort for Depression (meta-analysis of double-blind ‏ل 1 نل‎ MDD - minimal benefit Non-MDD - possible benefit ¢ Versus standard antidepressant - 14 studies - similar efficacy ° “Current evidence...is inconsistent and confusing” Linde et al. Br J Psychiatry 2005;186:99-107 

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SJW vs Sertraline and Placebo in MDD (8 week, double-blind, n=340)* *Entry: HAM-D,, = 20 *Dose: SJW 900-1500 mg (mean max 1299 mg) Sertraline 50-100 mg (mean max 75 mg) * Response: SJW=sertraline=placebo on طامط ‎primary outcome measures‏ dson et al. JAMA 2002;287:1807-1814 *NCCAM and NIMH funded 

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St. John’s Wort vs. Sertraline and Placebo in MDD (A Research Surprise) * Detectable plasma hyperforin —-GIO wow! waive to 7 —Ohvebo your: positive to 2 ¢Did not influence overall outcome Vitiello et al., J Clin Psychopharmacol 2005;25:243-249 

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St. John’s Wort for Depression - 2005 * Moderate Depressive Disorder (n=241)* “Not inferior to sertraline” * Major Depression (n=251)** “At least as effective as paroxetine” ¢ Major Depression (n=163)*** SJW = fluoxetine = placebo ¢ Mild-Mod MDD (n=135)**** SJW > fluoxetine; SJW trend> PBO *Gastpar et al., Pharmacopsychiatry 2005;38:78-86 **Szegedi et al., Br Med J 2005;330:503-506 *Bjerkenstedt et al., Eur Arch Psychiatry Clin Neurosci ۳ Fava et al., J Clin Psychopharmacol 2005;25:441-447 (Oct) 

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St. John’s Wort for Depression: Cochrane Database Review, Feb 255 * Total of 37 trials, 26 compared to placebo, 14 to standard antidepressants ¢ “current best evidence from placebo Coo we Oem Ohmi CMCC ۶ hypericum in patients with major depression” SROiiec MUCK MNase confusing Linde et al. Cochrane Database of Systematic Reviews, published online April 20, 2005 

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Hypericum Extract STW3-VI vs Citalopram and Placebo in MDD (6-week, double-blind, n=388) ¢Entry: HAM-D,, 20-24 ‘Dose: Extract 900 mg/day Citalopram 20 mg/day ¢ Efficacy (HAM-D J): Extract=Citalopram>placebo* * Response: Extract 52%, citalopram 56%, placebo 39% 5 jastpar et al. Pharmacopsychiatry 2006;39:66-75 LO Ee 

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St. John's Wort Mechanisms of Action ? ¢ 5-HT, NE, DA uptake inhibition (equipotent) * GABA receptor binding * MAO inhibition - very weak * Protein kinase C inhibition ٠ Interleukin-6 suppression * NMDA-receptor antagonism 

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Hyperforin in Rat Locus Coeruleus Increases Extracellular ۰ ‏نومه‎ * Norepinephrine 9001© 9 Kaehler et al: Neuroscience Letters 20:199-202, 1999 

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St. John’s Wort, Antidepressant Drugs and the ‏لمان اذا‎ *5 patients (ages 64 to 84) sertraline (4), nefazodone (1) ٠ 2-4 days on SJW nausea (5), vomiting (3), anxiety (3), restlessness (2), epigastric pain (1), confusion (1) و Lantz et al. J Geriatr Psychiatry Neurol 12:7-10, 1999 

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ل ا ۱ ‎Adults‏ (i.v. or p.o., n=30) ٠*١ ‏لمتلتاصة ملل‎ 20117 *Severe phototoxicity 41 Gulick et al: Ann Int Med 130:510-514, 1999 

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“T now have several anecdotal reports of (St. John’s wort) causing breakthrough bleeding in women on (oral contraceptives)” C. Cracchiolo: Currents Affect Illness 17:11, 1998 

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St. John’s Wort and BC ti *Induces ethinyl estradiol and norethindrone metabolism Vt breakthrough bleeding *Reports of unplanned pregnancy Hall et al., Clin Pharmacol Ther 2003;74:525-535, 

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St. John’s Wort/Drug Interactions * CYP 1A2 - Induced (?) * CYP 2B6 - Induced * CYP 2C9, 2C19--Induced * CYP 2E1 - Induced * CYP 3A4 - Induced (esp. intestinal) * P-Glycoprotein - Induced (nitial Inhibition) 

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P-Glycoprotein ¢A transmembrane efflux pump ¢*Located in intestine, liver, kidney, brain *Decreases drug absorption, increases drug secretion *Chemotherapy resistant cancer cells 

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Pregnane X Receptor (PXR) ¢Nuclear receptor * Activated by diverse xenobiotics ¢ Stimulates transcription of CYP3A and P-glycoprotein genes * Activated by hyperforin, but not by hypericin Moore et al., Proc Nat Acad Sci 2000;97:7500-7502 

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St. John’s Wort and Digoxin * Induction of P-glycoprotein * Digoxin C,,,, | 37%, AUC | 25% (Hyperforin-rich preparation) ¢*Marked variability with dose and formulation Mueller et al., Clin Pharmacol Ther 2004;75:546-557 

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St. John’s Wort Increases Warfarin Clearance Vl S-warfarin (2C9) Vl R-warfarin (1A2, 3A4) VL INR (international normalized ratio VL Anticoagulant effect Jiang et al., Br J Clin Pharmacol 2004;57:592-599 

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St. John’s Wort and Alprazolam ¢SJW - 300 mg tid for 14 days Alprazolam - 2 mg single dose ¢ Alprazolam (CYP3A4 substrate) AUC 1x2 Clearance tf x 2 T,, 12.4 > 6.0 hours Markowitz et al., JAMA 2003;290:1500-1504 

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St. John’s Wort and Carbamazepine (Healthy volunteers, n=8) *CBZ x 14 days, CBZ + SJW (300 mg tid) x 14 days *No change in CBZ clearance *Why?? (CBZ induces SJW?) Burstein et al., Clin Pharmacol Ther 2000;68:605-612 

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ohn’s Wort and Methadone (CYP3<A4 subs Eich-Héchi et al., Pharmacopsychiatry 2003;36:35-37 

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HMG-CoA Reductase Inhibitors (Statins) 1-۶ 2C19 non-P450 Atorvastatin* Fluvastatin ۱ AeA AY (Cervistatin*) 2C9 1100 /11 Laer) Simvastatin عماخاه‌طحاعه عستا۸* 

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St. John’s Wort and Statins (n=16 healthy males, double- blind, placebo-controlled) ¢ Simvastatin (3A4) - | AUC about 50% ¢ Pravastatin (non-P450) - no change Sugimoto et al., Clin Pharmacol Ther 2001;70:518-524 

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و ار در سس ‎Cen LSD‏ یب کت« ۱ 1 0 1 2 3 4 5 Cee Time (h) ۳ ۱ 3 لين ل اننا 

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Effect of St. John’s Wort on Cyclosporine Blood Level انیب هی ها یسب ی يي ‎enone =)‏ ا ۵ یی ۱ 0 5 ‏مت‎ ee ۱ aarti د ايم ‎a‏ وگ ‎oe‏ و يلو 0 ‎Jul 9Feb 98۱5۲ 99۲ 9913۷ 9‏ 9 م9813 عمصه9 9813 ططع98 ررم 000 0 00 Ruschhitzka et al. Lancet. 2000;355:548-549 

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St. John’s Wort Decreases Cyclosporine Blood Levels in Kidney Transplant Patients (n=30) *Mean trough level 47% *Range of decrease 33-62% Breidenbach et al. Transplantation 5/27/00 

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ا و( ‎Cyclosporine AUC‏ (renal transplant patients, n=10) *St. John’s Wort 900 mg/day -High HYF 152% -Low HYF No change Mai et al., Clin Pharmacol Ther 2004;76:330-340 

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Hyperforin Content in SJW (8 Commercial Preparations) *Range: 0.01% to 1.89%* °A 189-fold difference! ac 7 De Los Reyes and Koda. Am J Health-Syst Pharm 2002;59:545-547 

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St. John’s Wort CYP3A Induction Varies From Product to Product أمسعغصم (1لآ11) ستدمتتعموط مغ لمعلصت[] ‎٠‏ * Midazolam (CYP3A substrate) AUC decreased 79%- HYF 41 ۲ 48%- HYF 12 mg/day 21%- HYF 0.13 mg/day Mueller et al. Eur J Clin Pharmacol 2006;62:29-36 Madabushi et al. Eur J Clin Pharmacol 2006;62:225-233 

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Odds and Ends 

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Saw Palmetto (Serenoa repens) OM oa ROLL Kem Leys VAs) *Healthy subjects (14 days, n=12) CYP2D6 - no effect CYP3A4 - no effect Markowitz et al., Clin Pharmacol Ther 2003;74:536-542 

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Ginsengs ¢ American (Panax quinquefolius)* 4 Warfarin level and effect * Asian (Panax ginseng)** No effect - 1A2, 2D6, 2E1, 3A4 * Siberian (Eleutheroccus senticosus) No effect - 2D6, 3A4*** t digoxin level (n=1)**** *Yuan et al., Ann Intern Med 2004;141:23-27 **Anderson et al., J Clin Pharmacol 2003;43:643-648 **Donovan et al., Drug Metab Dispos 2003;31-519-522 McRae S., Can Med Assoc J 1996;155:293-295 

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Milk Thistle (Silybum marianum) °GI, liver, gall bladder 21۲0۳۵166 *Human hepotocyte culture* CYP3A4 - inhibition UGT_ _ - inhibition * Healthy subjects (n=10)** Indinavir (3A4) - no effect *Venkataramanan et al., Drug Metab Dispos 2000;28:1270-1273 *Piscitelli et al., Pharmacotherapy 2002;22:551-556 

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HveIiavva Vuripypuitca (coughs, colds, bronchitis, etc) (12 healthy subjects) * CYP1A2 - inhibition * CYP2C9 - little effect * CYP2D6 - no effect *CYP3A intestinal - inhibition hepatic - induction Orski et al., Clin Pharmacol Ther 2004;75:89-100 

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Garlic (Alltum sativum L.) (14 health ۲ subjects, 14 days) * Antibacterial, antiparasitic, antilipidemic, antihypertensive, immunostimulant ¢ Dextromethorphan (CYP2D6) - No change * Alprazolam (CYP3A4) - No change Markowitz et al., Clin Pharmacol Ther 2003;74:170-177 

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Garlic (10 healthy subjects, 39 days) * Saquinavir (CYP3A4) AUC 151% * P-glycoprotein induction? Piscitelli et al., Clin Infect Dis 2002;34:234-238 

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Angelica dahurica * Chinese herbal - allergy and cold *Inhibits metabolism (rats) - tolbutamide (2C) - nifedipine (3A) - bufurol (2D1) - testosterone (2C11) Ishihara et al., J Pharm Pharmacol 2000;52:1023-1029 

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Goldenseal (Hydrastis canadensis) °“A cure-all type herb” °28 days, healthy subjects, n=12 CYP2D6 - strong inhibition CYP3A4 - strong inhibition Gurley et al., Clin Pharmacol Ther 2005;77:415-426 

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FastOne Dietary Supplement * Kola nut, grape, green tea, ginkgo biloba * CYP1A2 induced ~200% in 3 days in humans (n=4) -more potent than smoking - carcinogenic potential? Ryn and Chung, Food and Chemical Toxicol 2003;41:861-866 

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And Now the Juices 

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Grapefruit Juice *Inhibits CYP3A4 (gut wall), 1A2, 2A6, 2B6 Cyclosporine levels tT 300% * Lovastatin peak conc. T 12-fold ¢Felodpine peak conc. t 500% (bp and rate effects double) ¢Saquinavir AUC Tt 220% 

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Buspirone and Grapefruit Juice اوه Buspirone (ng/ml) (صط) عستم ‎ja et al. Clin Pharmacol Ther 12/98‏ 

صفحه 102:
Grapefruit Juice Also Inhibits * P-glycoprotein (P-gp) * Organic Anion-Transporting Polypeptide (OATP) -A and -B (as does orange juice, but less potent) Satoh et al., Drug Metab Dispos 2005;33:518-523,2005 

صفحه 103:
Seville (Sour) Orange Juice * It does inhibit CYP3A4, but apparently not P- glycoprotein Penzak et al. J Clin Pharmacology 2001:41:1059-1063 

صفحه 104:
Orange Juice Decreases Atenolol Absorption (n=10 volunteers) 200 ml tid - juice or water *Ciax | 49%, AUC | 40% ¢Inhibition of OATP? Lilja et al., Eur J clin Pharmacol 2005;61:337-340 

صفحه 105:
Pomegranate Juice (Punica granatum) * Rats: intestinal 3A inhibition Carbamazepine AUC 1x 1.5 * Human liver microsomes: CPY2C9 inhibition انامه 0۲۵3۸ دده أعع]1ه 3210 :26111121615 ممست ‎٠‏ ‎(midazolam clearance)‏ Hidaka et al., Drug Metab Disp 2005;33:644-648 Nagata et al. Dug Metab Distribution 2007;35:302-305 Farkas et al. J Clin Pharmacology 2007;47:286-294 

صفحه 106:
PDR for Herbal Medicines Ath edition, 2007 Thomson Healthcare 

صفحه 107:
Alternative Medicine Foundation www.amfoundation.org * Evidence based research resource for professionals * Reliable consumer information *HerbMed - interactive evidence- ۱ 7 

صفحه 108:
QuackWatch www.quackwatch.com 

صفحه 109:
1. Which of the following was responsible for herbal products “flooding” the U.S. market in recent years? ۹ Federal Food, Drug and Cosmetic Act ۱: Kefauver-Harris Amendment C. Dietary Supplement Health and Education Act D. Nutrition Labeling and Education Act ۱ Food and Drug Modernization Act 

صفحه 110:
2. Which of the following has been most closely associated with hepatotoxicity? ۰ Ginkgo Kava Saw palmetto St. John’s wort Valerian ۲ 9 ۶ 8 

صفحه 111:
3. Which of the following is the clinically most important effect of St. John’s wort on the cytochrome P450 (CYP) system? A. 1A2 inhibition 2D6 inhibition 2C9 induction 2E1 induction 3A4 induction ج و و ۲ 

صفحه 112:
4. St. John’s wort has been most extensively studied for the treatment of which of the following disorders? ۳ (9 Posttraumatic stress 13] Cc. ۹۵ D Major depressive ۳ Social anxiety 

صفحه 113:
5. A placebo-controlled, double-blind study found Ginkgo biloba to be ineffective for treating antidepressant- induced sexual dysfunction. A. True B. False 

صفحه 114:
Conclusions * Limited, often conflicting, clinical data (best with St. John’s wort) * Marked variability in active ingredients * Often undeclared ingredients * More regulation necessary * More research necessary 

صفحه 115:
Answers to Pre & Post Lecture Exams و سيك إلى نت ضح 2ه