Herbal / Drug Interactions

Herbal / Drug Interactions

اسلاید 1: www.tabaye.ir

اسلاید 2: Herbal / Drug Interactions Gary W. Elmer, R.Ph.,Ph.D.Department of Medicinal Chemistry, elmer@u.washington.edu11/03/06

اسلاید 3: Elmer et al. unpublished

اسلاید 4:

اسلاید 5:

اسلاید 6: Steps for Detecting and Advising on Herbal/Drug InteractionsIs the patient taking any herbal supplements?Does the herbal have efficacy for the intended use?Is the product reliable? (i.e.,what are they REALLY taking?)Is the Rx drug one with a narrow therapeutic margin?

اسلاید 7: Evaluation of Herbal/Drug InteractionsSpeculative or Theoreticale.g. St. John’s Wort and tyramine containing foods due to MAOI effects or evening primrose oil and risk for bleeds with warfarinIn vitro effectse.g. St. John’s Wort and microsomal studies showing inhibition of CYP3A4In vivo - animal studiese.g. Kava and alcoholIn vivo - human case reportse.g. Ginkgo and warfarin bleedsIn vivo - healthy human volunteer studiese.g. indinivir and St. John’s WortIn vivo - clinical studies in patients

اسلاید 8: Important Criteria for Evaluation of a Human Herbal/Drug Interaction ReportReputable standardized product used and carefully described?Product used analyzed for marker compounds?Same batch used throughout study?Doses appropriate?Steady state study to discern CYP induction?Is observation consistent with known mechanisms of action?Is observation consistent with literature observations?Crossover, randomized, placebo controlled human volunteer study with appropriate n?

اسلاید 9:

اسلاید 10: Stevinson et al. Ann Int Med 133:420-429, 2000

اسلاید 11: Spontaneous spinal hemoatoma associated with garlic Rose et al. Neurosurgery 1990;26:880-882.87 year old male2g of garlic per day for “years”presented with weakness and partial paralysisbleeding time of 11.5 min (normal = 3 min)day 3 post surgery bleed time of 5 min (after stopping garlic)Other reports: Garlic and TURP bleeding (German et al. Br J Urology 1995;76:518).Garlic and surgery bleeding (Burnham BE; Plastic Reconstr Surgery 1995;95:213).

اسلاید 12: Piscitelli et al. Garlic and Saquinavir. Clin Infect Dis 2002;34:234-238. N=10 Garlic=GarliPure (Natrol)(BID)

اسلاید 13: Piscitelli et al. Garlic and Saquinavir. Clin Infect Dis 2002;34:234-238. N=9 Garlic=GarliPure (Natrol)(BID)

اسلاید 14: Gurley et al. Clin Pharmacol Ther 2002;72:276-287 n=12; note: used garlic oil prep (500mg TID)

اسلاید 15: Markowitz et al. Clin Pharmacol Ther 2003;74:170, n=14, 3X600mg for 14d (Kwai)

اسلاید 16: Garlic summaryEfficacy: Mild benefit for use in hyperlipidemia Safety: goodDrug interactions: warfarin; possibly aspirin and other antiplatelet adhesion drugs (pharmacodynamic interaction); not with HIV drugs (other 3A4 substrates?) but depends on product (pharmacokinetic interaction)Product selection: Suggest enteric coated tablets standardized to about 4mg allicin yield/tabletDose: equivalent of about 4g (2-3 cloves) of fresh garlic per day i.e. 8-12 mg allicin/d

اسلاید 17: Gurley et al. Clin Pharmacol Ther 2004;76:428-440.CYP 1A2

اسلاید 18: Gurley et al. Clin Pharmacol Ther 2004;76:428-440.800mg BID for 30d (Wild Oats Market)(analyzed)CYP 3A4

اسلاید 19: Gorski et al. Clin Pharmacol Ther 2004;75:89-100N=12 crossover, before and after 400mg QID Echinacea purpurea root extract for 8dA= Cl caffeine (CYP 1A2)B= Cl tolbutamide (CYP 2C9)

اسلاید 20: Gorski et al. Clin Pharmacol Ther 2004;75:89-100N=12 crossover, before and after 400mg QID Echinacea purpurea root extract for 8dOpen circle is echinaceaA= midazolam IV (CYP 3A4)B= midazolam PO (CYP 3A4)

اسلاید 21: EchinaceaSummaryEfficacy: evidence for treatment not preventionSafety: good; rare allergyDrug interactions: Pharmacodynamic: don’t give to patients taking immunosuppressive drugsPharmacokinetic: may inhibit 1A2; may inhibit intestinal 3A4 but induce hepatic; clinical significance unclearProduct selection: want standardized extract containing about 4% phenolicsDose: about 250mg QID for treatment Questions remainingWhich product? Tincture? Tablets? Root extrract? Flowering tops? Pressed juice? E. purpurea? E. augusifolia? E. pallida?

اسلاید 22:

اسلاید 23:

اسلاید 24:

اسلاید 25: Bleeds associated with ginkgo use

اسلاید 26: IsoformType of InhibitionKi (g/ml)CYP1A2Mixed11.20.6Competitive2.1---CYP2A6Mixed21.22.1CYP2C9Competitive9.1---CYP2D6Competitive133.1---CYP3A4Mixed17.02.5Non-linear Regression Ki Values

اسلاید 27: Tolbutamide Human Study (CYP 2C9 probe)-6 Subjects (3 males, 3 females)-Subjects ingested 500mg tolbutamide and collected 6-12 hour urine (Control phase)-Followed by a 2 week wash-out period-Subjects then ingested two 60mg Ginkgo biloba extract tablets 2 times a day for 3 days-The morning of day 4 patients received a 500mg dose of tolbutamide along with the ginkgo and collected 6-12 hour total urine (Ginkgo phase)Tolbutamide dose2 week wash-out periodGinkgo biloba doseTolbutamide dose

اسلاید 28: Control680  323 Ginkgo610  327

اسلاید 29: Diclofenac-Ginkgo Interaction (CYP 2C9 probe)12 healthy non-smoking subjects were recruited (8 males 4 females)50 mg diclofenac potassium (immediate release) was administered every 12 hours for 14 daysOn day 8, 120 mg of Ginkgo biloba extract was added to the diclofenac regimen.On days 7 and 14 plasma collected at times (0, 0.5, 1,2,4,6,8,10, and 12 hrs)12 hour urine collectedDiclofenac 50 mg every 12 hoursGinkgo biloba 120 mg every 12 hoursDay 7 blood drawDay 14 Blood draw

اسلاید 30: Control0.64  0.36Ginkgo0.61  0.33Mohutsky et al. Am J Ther 2006;13:24-31

اسلاید 31: Ginkgo biloba - Diclofenac Tolbutamide Human Studies ConclusionsNo difference was observed in the metabolic ratio between the two arms of the study (tolbutamide alone and tolbutamide + Ginkgo)No difference was seen between the clearances of the two arms of the study ( diclofenac alone and diclofenac + Ginkgo)Ginkgo extract does not appear to interact with CYP2C9 substrates in humans

اسلاید 32: Gurley et al. Clin Pharmacol Ther 2002;72:276-287 n=12 (CYP 3A4) ginkgo-Wild Oats Markets (24% flavone glycosides, 6% ginkgolides)(analyzed)

اسلاید 33: Engelsen et al, Thromb Haemost 2002;87:1075-6. N=21, double blind, crossover. Rx=1 month with 2 week washout. Dose of warfarin did not change.

اسلاید 34: Jiang et al. Br J Clin Pharmacol 2005;59:425-432.N=12 ginkgo for 7d; warfarin alone or in combination with ginkgo or ginger

اسلاید 35:

اسلاید 36: Ginkgo/Drug Interactions other studiesMarkowitz et al. J Clin Psycopharmacol 2003;23:576-581. No effect of multiple dosing of ginkgo on dextromethorphan (2D6) or alprozolam (3A4) pharmacokinetics. n=12Mauro et al. Am J Ther 2003;10:247-251. No effect of multiple dosing of ginkgo on digoxin (Pgp) pharmacokinetics. N=8 crossoverMohutsky et al. Am J Ther in press. No effect of multiple dosing of ginkgo on diclofenac (2C9) or tolbutamide (2C9). N=12 crossoverYin et al. Pharmacogenetics 2004;14:841-850. Induction of 2C19 mediated hydroxylation of omeprazole.

اسلاید 37: Yin et al. Pharmacogenetics 2004;14:841-850. Induction of 2C19 mediated hydroxylation of omeprazole(shaded circle is ginkgo, open circle is baseline)140mg BID x 12d

اسلاید 38: Ginkgo biloba summaryEfficacy: good for dementia and poor peripheral circulatory problemsSafety: good; rare bleeding episodesDrug interactions: no effect on 3A4,2C9 or 2D6 but may induce 2C19; inhibits platelet adhesion; possible pharmacodynamic interaction with “blood thinners” but not common Product selection: look for EGb761 extract Dose: 1-2 60mg tabs, BIDQuestions remaining includeExtent of memory improvement in younger patients?Delay Alzheimer’s and dementia?Help in other circulatory disorders?Synergistic with other drugs and treatments?

اسلاید 39: Soy and Menopausal and Postmenopausal problemsHot flashes- maybe helpsOsteoposis-some evidence for helpSoy Effects on CancersLong consumption of soy associated with lower rates of breast, endometrial and prostate cancers (Asian cultures)Soy and some soy isoflavones have unknown effects on estrogen receptor positive breast cancer but may stimulate growthSoy may slightly inhibit protate cancer growthSoy-Cardiovascular Benefits Favorable effects on cholesterol balance; “heart healthy”Isoflavones inhibit CYP3A4 in vitro

اسلاید 40: herbalBaselineWeek 1 TreatmentWeek 2 TreatmentWeek 3 WashoutWeek 4 StatisticsGinseng 4.4  2.4 3.7  2.2 3.6  1.8 3.7  1.6 NSSoy isoflavones4.9  2.5 5.0  2.0 4.6  2.2 ------- NS6-hydroxycortisol/cortisol ratio (CYP 3A4)From: Anderson and Elmer, Clinical Pharmacology and Therapeutics 43:643-648 (2003).

اسلاید 41: SoyEfficacy: increased soy ingestion may decrease hot flashes and other postmenopausal symptoms; cardiovascular benefits as well. Safety: good but use in breast cancer may be riskyDrug interactions: not with with tamoxifen but effect on CYP3A4 is unlikelyProduct selection: soy or isoflavonesDose: about 20-40g of soy protein has been used. This contains 30-50mg of isoflavones.Questions remaining includeHow much benefit? Safety in breast cancer?

اسلاید 42: “Probable Interaction Between Warfarin and Ginseng” Janetzky and Morreale, Am J. Health-Syst Pharmacy 54:692-693,1997 47 yr old male on warfarin for 10 years with an INR of 3-4 started ginseng (INR= 3.1, 4 weeks prev) INR declined to 1.5 after 3 weeks on ginsengINR increased to 3.3 after stoppingginseng causing CYP induction?

اسلاید 43: Yuan, C.-S. et. al. Ann Intern Med 2004;141:23-27Changes in individual peak international normalized ratio (INR), INR area under the curve (AUC), peak plasma warfarin level, and warfarin AUC in weeks 1 and 4 in American ginseng or placebo groups5mg warfarin for 3d before and after 1g/d ginseng (50mg/d ginsenosides) American ginseng (Panax quinquifolius) n=20

اسلاید 44: Jiang et al. Br J Clin Pharmacol 2004;57:592-599. SJW, ginseng and placebo in triple crossover study. N=12 single dose 25mg warfarin following 7d (ginseng) or 14d (sjw) of herbal; ginseng dose=54mg/d ginsenosides; Korean ginseng (Panax ginseng)

اسلاید 45: Jiang et al. Br J Clin Pharmacol 2004;57:592-599. SJW, ginseng and placebo in triple crossover study. N=12 single dose 25mg warfarin following 7d (ginseng) or 14d (sjw) of herbal; ginseng dose=54mg/d ginsenosides; Korean ginseng (Panax ginseng)

اسلاید 46: herbalBaselineWeek 1 TreatmentWeek 2 TreatmentWeek 3 WashoutWeek 4 StatisticsGinseng 4.4  2.4 3.7  2.2 3.6  1.8 3.7  1.6 NSSoy isoflavones4.9  2.5 5.0  2.0 4.6  2.2 ------- NS6-hydroxycortisol/cortisol ratio (CYP 3A4)From: Anderson and Elmer, Clinical Pharmacology and Therapeutics 43:643-648 (2003).

اسلاید 47: Gurley et al. Clin Phamcol Ther 2002;72:276-287 n=12; Panax ginseng

اسلاید 48: GinsengEfficacy: some evidence for applications in geriatric patients (improved “quality of life”) and in diabetes Safety: good; Drug interactions: no apparent induction of CYP 3A4 but induction of 2C9 (warfarin) with Am ginseng (Panax quinquifolius) but maybe not Korean (Panax ginseng). May precipitate hypoglycemia with insulin or oral hypoglycermics. Product selection: product should be standardized so dose is 4-7% ginsenosides/dQuestions remaining include:What, actually is this stuff good for!

اسلاید 49:

اسلاید 50: Lecrubier et al. Am J Psychiatry 2002;159:1361 n=375

اسلاید 51: Interactions with St. John’s Wort -cyclosporin-Study: 2 case reportscase 1: 61yr had transplant 11mos earlier; cyclosporin, azathioprine, steroids for 11 mos. Unexplained heart failure noted after SJW started.case 2: 63yr had transplant 20mos earlier: same senario as case 1. Ref: Ruschitzka et al. Lancet 355:548-549,2000

اسلاید 52:

اسلاید 53: Markowitz et al. JAMA 290:1500,2003 n=12 14d of SJWCYP 3A4

اسلاید 54: Durr et al. Clin Pharmacol Ther 2000;68:598-604.

اسلاید 55: Summary of SJW Interactions (adapted from Henderson et al. Br J Clin Pharmacol 2002;54:349-346)

اسلاید 56: St. John’s WortSummaryEfficacy: good evidence for mild to moderate depressionSafety: don’t combine with other medications unless under close monitoring; possible photosensitivityDrug interactions: a problem! Is a P450 inducer and a p-glycoprotein inducerProduct selection: want standardized extract containing about 0.3% hypericin or 1-2% hyperforinDose: about 300mg TID for treatmentQuestions remaining includeHow best to use this herbal given that there are drug interaction problems

اسلاید 57: Kava (Kava Kava)Usesmild tranquilizerPrecautionsadditive effect with alcoholdon’t take with other CNS depressants (documented problem when combined with alprazolam, Zoloft) (pharmacodynamic effect)long use may result in rash and discolored skin or allergynot for use in pregnancy or depressionis a local anesthetic32 reports in USA of liver toxicity including some with liver failure

اسلاید 58: “Coma from the health food store: interaction between kava and alprazolam” Ann Int Med 125:940-941,1996 54 yr old male hospitalized in a “lethargic and disoriented state” on alprazolam, cimetidine, terazosin took kava for 3 days alpha pyrones in kava known to bind to GABA receptors (benzodiazepines) apparent additive effect  oversedation

اسلاید 59: Kava-SummarySummaryEfficacy: long historical use of AQUEOUS extract; reasonable evidence for efficacy for mild to moderate anxiety. Safety: hepatotoxicity associated with alcoholic extracts, rash with long use, Drug interactions: not with other anxiolytics or sedatives or liver toxic drugs (acetaminophen)Advice: don’t take Kava until hepatotoxicity risk is sorted out! Questions remaining includeHow effective is this for occasional use?How prevalent is hepatotoxicity?

اسلاید 60: Gurley et al. Clin Pharmacol Ther 2005;77:415-426. N=12Potential Interactions of Goldenseal with CYP2D6 and CYP 3A4 substrates

اسلاید 61: Herbals affecting clotting adapted from Natural Medicine Comprehensive Database and Norred and Brinker, Alt Ther Health Med 2001;7:58-67.Andrographis panuculaBogbeanDevil’ clawginsengPau d’arcoangelicaBoldoDong quaigreen teameadow sweetanisecapsicumErigeronhawthornprickly asharnicaceleryEvening primrose oilhorse chestnut barkpassionflowerAsafoetachamomilefeverfewHuang qipopularBaikal skullcapclove oilfish oilhorseradishquassiaBilberrycoleus rootfenugreekkavared cloverBlack current seeddanshengarliclicoricereishi mushroomBladderwrackdandelion rootgingeronionSha shenBomelainDanshenginkgopapainShinpi barkSweet birch oilTonka bean tumericvitamin Ewintergreen oilwild carrotwild lettucewillowwood ear mushroomwoodruff

اسلاید 62: Herbs with clotting problems reported in humans Ginkgo -case reports of bleeds alone and in combination with aspirin or warfarin but human studies show no effect on CYP or INRGarlic - case reports of increased surgical blood lossSt. John’s wort - induces P450 enzymes leading to reduced drug actionEvening primrose oil - human study showed 40% increase in bleed time but no other reportsBorage seed oil - same as evening primrose oilVitamin E - doses >1200 i.u./d can increase bleed timeCranberry juice case reports of increased INR (salicylic acid? CYP 2C9 inhibition?) but in vivo study showed no change in flurbiprofen (CYP 2C9 substrate) in vivoKava - liver toxicity could increase warfarin effectLycium barbarumcase report of increased INRDanshen - case reports of increased INR with warfarinDong quai - case reports of increased INR with warfarinGinseng - decreased INR with warfarin (Panax quinquifolius)Green tea -case report of decreased INR with warfarin but huge amountCoQ10 - case reports of decreased INR with warfarin but human study showed no effect on INR

اسلاید 63: Table 4a Significant Risk of CAM-drug Adverse Interaction  Potential EventMechanismaNumberb Occurrencesc n=294 with CAM plus conventional med combinations with significant riskRisk of bleedsAspirinGarlic23;25-27PD147 214Ginkgo24;28PD102127WarfarinGarlic25-27PD13 16Ginkgo29PD7 7Ginseng32;33PKd3 3TiclopidineGarlic23;25-27PD46Ginkgo24;30;31;54PD2 3PentoxifyllineGinkgo24;30;31PD3 3Total281 (5.6%)380

اسلاید 64:

اسلاید 65: Seem to have low pharmacokinetic drug interaction potential based on recent studiesGingerValerianMilk thistleSaw palmettoCoQ10glucosamine

اسلاید 66: Glucosamine and type 2 diabeticsRecent study examined the effect of 90d of Cosamin DS or placebo on glycosylated hemoglobin levels in type 2 diabetics. N=38 result: no effectArch Intern Med 2003;163:1587-90

اسلاید 67: Herbals affecting drug management (i.e., herbal/drug interactions)literature analysis (Fugh-Berman and Ernst, Herbal Drug “Interactions and Assessment of Reliability” Br J Clin Pharmacol 2001;52:587-595) 108 reported cases of suspected interactions 69% “unable to be evaluated” 19% possible interactions 13% (14) well documented 11/14 involved warfarin 7/14 involved St. John’s wort

اسلاید 68: From: Lam AY, Mohutsky MA and Elmer GW. Probable herbal/drug interaction between warfarin and a common Chinese herb, Lycium barbarum. Ann Pharmacother 2001;35:1199-1201

اسلاید 69: Top 20 Selling Herbals - Mass Market, 52 weeks ending Jan2,2005 HerbalGram 2005;66:63Product1. garlicproduct dependent Inhibition of 3A4; enhance warfarin effect2. echinacea may inhibit CYP 1A23. saw palmetto 4. ginkgo may induce 2C19 5. soy may block action of tamoxifen6. cranberry 7. ginseng Panax quiquifolius may induce 2C98. black cohoshmay have weak 2D6 induction action9. St. John’s wort definitive interactions; induce 3A4 and Pgp10. milk thistle 11. evening primrose may enhance warfarin effect12. valerian 13. green tea14. bilberryRed indicates risk for drug interactions

اسلاید 70: Top 20 Selling Herbals - Mass Market, 52 weeks ending Jan2,2005 HerbalGram 2003;58:71Product15. grape seed16. horny goat weedenhance warfarin effect and increase BP17. yohimbeaffect BP medications18. horse chestnutmight enhance warfarin effect19. eleutheromight enhance warfarin effect20. ginger multi-herbs52+29na all other12-7.5natotal257Red indicates risk for drug interactionsNote: kava and pycnogenol fell off the top 20 listNote: total herbal sales are estimated at $4.2 billionThe above figures include sales from food stores, drug stores, and mass market retailers but with Wal-Mart figures not included. It does not include warehouse buying clubs, convenience stores, natural foods stores, multilevel marketers, health professional sales, mail order or internet sales.

اسلاید 71: Gary Elmer’s assessment of herbal/drug interaction potential (in rank order of significance)(11/13/06)St. John’s wort – induces CYP and Pgp; don’t take with other drugs unless the drugs have a large therapeutic range and are not “life saving” drugsAmerican ginseng (Panax quinquefolius) – induces CYP2C9; not with warfarin, tolbutamide and other 2C9 substratesGoldenseal – induces CYP3A4 and 2D6. This herbal is not recommended due to lack of efficacy proof and potential interactionsGarlic and ginkgo – don’t take with antiplatelet adhesion drugs or aspirin or with warfarin (risk of bleeds); this is a pharmacodynamic effectGinkgo may induce CYP2C19 so may lower 2C9 substrate Echinacea may induce CYP1A2 so may lower 1A2 substrates

اسلاید 72: References with Good Herbal/Drug Interactions Discussion“Top 100 Drug Interactions” Hansten PD and Horn JD. H&H Publications 2005Natural Medicines Comprehensive Database. Online version updated “daily”. UW Healthlinks http://www.naturaldatabase.com/; $92The Natural Medicines Encyclopedia. free with access subscription ($24/yr) to consumerlab.com www.consumerlab.com

اسلاید 73: Recent ReviewsScott GN and Elmer GW. Update on natural product-drug interactions. Am J Health-Syst Pharm 2002;59:339-347Ernst E. The risk-benefit profile of commonly used herbal therapies: ginkgo, St. John’s wort, ginseng, echinacea, saw palmetto and kava. Ann Intern Med 2002;136:42-53Izzo AA. Herb-drug interactions: an overview of the clinical evidence. Fundam Clin Pharmacol. 2005 Feb;19(1):1-16.Ernst E. Prescribing herbal medications appropriately. J Fam Pract. 2004 Dec;53(12):985-8.

اسلاید 74: What can we do?dialog with NDs and other prescribersrecommend the best productsask patients about herbals they may be takingherbals should not usually be recommended for acute or serious illnessesavoid herbal use with drugs with narrow therapeutic window, esp. warfarin, cyclosporin, digoxin, HIV protease inhibitors, theophylline, carbamazepinestay informed