Drug Interaction of Herbal and Western Medicines

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۱/۷۱۷/۷۸۷ ۲ 

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Drug Interaction of Herbal and Western Medicines oo0 oo000 Prof. Oliver Yoa-Pu Hu, Ph.D. Dean Research, Development and Continuing Education National Defense Medical Center Taipei, Taiwan, R.O.C. 

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@ Outline ™ Current Status of Herbal or Traditional Medicines in Eastern and Western World ™ Adverse Events and Drug-Interaction Caused by Herbal or Traditional Medicines ™ Evidences Based Drug-Interaction Caused by Herbal or Traditional Medicines ™ Conclusions and Suggestions EHFG 5-8, Oct. 2005 

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مد Current Status of Herbal or Traditional Medicines in Eastern and Western World 

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+: Insurance Paid for Herbal Medicines ™ German health insurance paid $283 million in reimbursements for prescribed ginkgo, St. John’s wort, mistletoe, saw palmetto, ivy, hawthorn, stinging nettle root, myrtol, phytosterols, and cucurbita in 2003. ™ French health insurance paid $91 million in partial reimbursements for ginkgo, saw palmetto, and pygeum prescriptions with a total value of $196 million in 2002. NEJM 352:12, 2005 EHFG 5-8, Oct. 2005 5 

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422, The-Counter Herbal Medicines in 2003 2.06 billion Germany France 1.13 billion lealy 548 million Poland 252 million United Kingdom IE] 212 million Spain [I] 170 million Belgium [I] 127 million Switeerland [J] 93 million Austria [J] 88 milion Distribution of the $4.96 Billion European Market for Over-the-Co Herbal Medicines in 2003. TeNaterande [Tei mien sera:wan Herbal Medicines market was 4.0 billion in 2002 C2ech Republic [J] 75 million “Sales of Over-the-Counter Herbal Medicines (8) NEJM 352:12, 2005 EHFG 5-8, Oct. 2005 6 

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@ Herbal Medicines in US ™ In a 1990 survey of 1,539 adults, 33.8% of respondents used herbal medicines or nutritional supplements. ™ By 1997, the number had increased to 42.1%, with most people paying the cost out-of-pocket. ™ Approximately 40% of patients who use alternative therapies do not disclose this information to their doctor. AM J Ophthalmol! 138:639, 2004 EHFG 5-8, Oct. 2005 

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مد Adverse Events and Drug- Interaction Caused by Herbal or Traditional Medicines 

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Reference ‘Da (1992); Haar oa, (DD; 1993) Kang eta (1994) Catvene-Lavier ‏اه و‎ 1996), Citi ‘and Yeh (1999): Colao et al 199% 1999); Helay et al (1957) Jeong (1998) Livet al, (1999) BaAbbas ot a. (1999) )2001 امه و ‎Wang al, ECO)‏ ‎Let al (1985‏ « Isoforms by Herbal Constituents (I) ARR ivan? ALR activation? AR activation ARR binding? AR binding? AR ativan? AR scivation ‘AMR asain? ‘ab binding? Asay system Riawive Rinvivo M& Heals Rain vivo M hepatoma cll ine 0 ( Min vivo من Min vivo Hin stro Min vivo ممما انوم ‎‘Agonist‏ ‎‘Agonist‏ Antagonist Antagonist ‘Agonist Agonist ‘Agonist ‏يسم‎ bal constiuens “ale DAD, DAS Pipsine lavonnid gusset, ‏یویر‎ ‎۳ ‎favene) مالم اه م0 ‎(Green a blck ea exact‏ زوجم شم اه امه ‎(irom Zizyphi‏ ‎Trucs)‏ 57 مدز Gian evra, (cominued) = Crude methanolic extract; DAD = Diallyl disulfide; DAS = Diallyl sulfide; H = Human; M = Mouse; PH 18 tocytes; PXR = Pregnane X receptor; R = Rat; SJW = St. John’s wort. 5, 2003 Drug Metabolism Reviews 3: ct. 2005 

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« Isoforms by Herbal Constituents (II) 57 Traction iors ‏را‎ Induction Assay system mechani Reference Tada ‏موی‎ Wa vie ‏مهن لا‎ — Wang @ al 6001 ‏مه‎ Gate DAD. DAS Agmist — Rinvivo ‘Sheen ea 1999) peri ‏ما نم‎ Kang etal (1994) FMaconcide(Havanone, Agonist Rin vivo ‏امه داوس‎ (1956) ‘avons lange) eledein Antagonist Mbepstoma cell ine AMR activation? Seong (1998) ‏سا‎ ‏سید مه‎ HHepatceyes ‏ی نت13‎ et 1, (2001) ‘conn = Crude methanolic extract; DAD = Diallyl disulfide; DAS = Diallyl sulfide; H = Human; M = Mouse; PH = Primar stocytes; PXR = Pregnane X receptor; R = Rat; SJW = St. John’s wort. Drug Metabolism Reviews 35:35, 2003 10 EHFG 5-8, Oct. 2005 

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42: Isoforms by Herbal Constituents (III) or ‏متس‎ ‏سنجمه مره یر | هس‎ Reference ‏انارت‎ Gare DAD, DAS alll Antagonist -Rinvivo Dus (1992); Haber ea matt slide (1994:1985) Piping Agonist Riavivo Kang atl. 1998), Oleswolis acid Angonist Min vivo AR binding? ——_ Jeong (1999) CYPIA —SIWCNE,Iyperfin Agonist ‏وا‎ PRR sctivaon —Wansvert et (2000). Moe eh (2300), Wang eal. 2001); Roby etal 2000) Gate DAS, DAD, diab ‏امه‎ Rinvivo Wuetal. 2002) tise Licorice exact Agonist ‏ما‎ XR zctivaion? Pein e1 ab (1998) ‏مور‎ = Crude methanolic extract; DAD = Dially! disulfide; DAS = Diallyl sulfide; H = Human; M = Mouse; PH = Ptimar tocytes; PXR = Pregnane X receptor; R = Rat; SJW = St. John’s wort. Drug Metabolism Reviews 35:35, 2003 EHFG 5-8, Oct. 2005 11 

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#2. Known Pharmacokinetic Herb-Drug Interactions (1) Effect Increase the plasma AUC and Cmax (human) Increase the oral bioavailability (human) Increase the AUC and Cmax Decrease the clearance and apparent volume of distribution (rat) Interaction Drug Phenytoin, propranolol, theophylline, Curcumin (from Curcuma longa) Felodipine, terfenadine, saquinavir, cyclosporine, midazolam, triazolam, verapamil, lovastatin, cisapride, astemizole R- and S- Warfarin Drug Metabolism Reviews 35:35, 2083 Herb Piperine Grape fruit juice Danshen (from the root of Salvia miltiorrhiza) EHFG 5-8, Oct. 2005 

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85:35 3 13 #2. Known Pharmacokinetic Herb-Drug Interactions (II) Effect Decrease the elimination Increase the Cmax fourfold Reduce the bioavailability significantly Decrease the blood concentration (human) Enhance plasma clearance Increase the AUC Decrease the AUC Decrease the plasma عونمم لاصو موز Interaction Drug Tolbutamide Diazepam Ampicillin Alcohol Prednisolone Prednisolone Tolbutamide Herb Dong quai (from Angelica dahurica) Khat (Catha edulis) Ginseng Licorice Xiao Chai Hu Tang EHFG 5-8, Oct. 2005, 

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4: between Herbs and Conventional Drugs (I) Conventional Herb Drug Comments ‘Acetylsalicylic | Ginkgo combined with acetylsalicylic acid, acid rofecoxib, or warfarin has been associated with bleeding reactions. 1 Rofecoxib Ginkgo leaf Coma was reported in a patient with Warfarin Alzheimer’s disease who took ginkgo leaf Trazodone with trazodone. Since hawthorn may exert digitalis-like Hawthorn. | igitalis inotropic effects, it is prudent to monitor leaf or 0 ‏تس‎ glycosides persons taking this herb in addition to digitalis glycosides closely. NEJM 347:2046, 2092 EHFG 5-8, Oct. 2005 

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15 4: between Herbs and Conventional Drugs (II) Comments ‘A phototoxic reaction occurred in a patient simultaneously exposed to 5-aminolevulinic acid and St. John’s wort; in clinical studies, pretreatment with St. John’s wort decreased the area under the curve for amitriptyline (and its active metabolite nortriptyline), digoxin, indinavir, midazolam, phenprocoumon, and the active metabolite of simvastatin (simvastatin hydroxy acid); case reports have associated St. John’s wort with reduced levels of cyclosporine (sometimes with transplant rejection), tacrolimus, and theophylline; with increased oral clearance of nevirapine; with intermenstrual bleeding or altered menstrual bleeding in users of oral contraceptives; and with reduced effects of phenprocoumon and warfarin; lethargy and grogginess were reported in a patient taking it Jphy’ paroxetine, and the serotonin on pa gab do Conventional Drug 5-Aminolevulinic acid Amitriptyline Cyclosporine Digoxin Indinavir Midazolam Nefazodone Nevirapine Oral contraceptives Paroxetine Phenprocoumon Sertraline Simvastatin Tacrolimus ee ae Herb St. John’s wort HFG 5-8, Oct. 2005 

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4: between Herbs and Conventional Drugs (III) Conventiona Herb | Drug Comments Gastrointestinal toxic effects in patients taking garlic and ritonavir. Ritonavir AUC for saquinavir decreased by 51 percent in Garlic | ‏وچ‎ patients taking garlic for 20 days; it returned to bulb ۳ 65 percent of base line after a 10-day washout Warfarin ‏ار‎ ‎An increased clotting time in two patients taking warfarin and garlic. Alprazolam a Kava Pee Lethargy and disorientation were reported in a Cimetidine rhizome patient receiving this triple-drug regimen. Terazosin NEJM 347:2046, 2092 EHFG 5-8, Oct. 2005 

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مد Evidence Based Drug- Interaction Caused by Herbal or Traditional Medicines and Food 

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مد @ simvastatin ™ HMG-CoA reductase inhibitor ™ As a substrate for both CYP3A4 and P-gp ™ Bioavailability < 5% EHFG 5-8, Oct. 2005 

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Liver Microsomes with Herbal and Food Constituents (PC: ketoconazole) SUN Drei doe oom Ones (cence sinus ect) EHFG 5-8, Oct. 2005 

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‎OL MULMIEVIO ON 1Otdi‏ بانات ند ری ‎Simvastatin Absorption on Female‏ ‎SD Rats by Oral‏ ‎ ‎ ‎sinwastatic acid (ng/mL) ‎ ‎*12.3 g of green-tea leaf contain 20 mg of 5 ‎EHFG 5-8, Oct. 2005 ‎ ‎ ‎ 

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a إلى آنا دیا تا ‎Mi LPeliain Ol‏ Simvastatin Simvastatin 50 mg/kg in DMSO and HUCHE015 20 mg/kg in B/A 57.0 13 48.8 38.1 14 10 DMSO Parameter (Unit) Control (B) with HUCHEO15 (A) ‏سس‎ (ng/mL) 203.1 +33.2 (49.1) 115826 +290.4 (7.55 © ‘Trex (hr) 0.8 +0.1 (50.3) 1.0 +0.0 (0.0) AUCo+(hmng/mL) 312.1 + 64.5 (62.0) 15239.6 + 986.3 ‏ول‎ ۲ AUCa (aong/mL) 506.6 +132.9(78.7) — 18675.4 + 1176.7 (18.9)90 k (1/h) 0.47 +0.11 (72.7) 0.64 +0.03 (13.3) Tr (hy) 2.1 +04 (58.4) 1.9 +0.1 (15.8) MRT (hr) 1.3 +0.1 (23.1) 1.3 +0.0(5.0) Data=mean +S.E.(%CV)]_ *{] p<0.05] **{] pL.01; n=9 *12.3 g of green-tea leaf contain 20 mg of HUCHEO15 EHFG 5-8, Oct. 2005 

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مد @ Fuvastatin ™ HMG-CoA reductase inhibitor ™ Specifically and extensively metabolized by CYP2C9 ™ Oral bioavailability: 20-30% EHFG 5-8, Oct. 2005 

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Administered Fluvastatin with or @ Fluvastatin in SD Rats after Orally without Herbal Constituents = > a4 1 E 2 ۱ & 1 8 £ 0 ۳ 3 3 3 8 © aap a> mad ace acta ‘ewe (wis) *The herbal constituents is HUCHEO070 that is very rich in Eupatorium odoratum. The dose is 9.3 EHFG 5-8, Oct. 2005 = 

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26 suis Rats after Orally Administered Fluvastatin with or without Herbal % 24 09 20 24 09 12 04 04 28 Constituents PK Fluvastatin (4) (unity 1 parameter control, a-7 with CHEO70, Crna {ngimL) 63.14 © 10.36 141.40 15.76" 1 thn) 47417 42411 AUC, (hetngimL) 710.57 + 55 1389,20 + 166.14" ‏ملا ومو تا ...لاه‎ + 8 2281.00 + 386.56" k ۳ 0.074 + 0.005 0.065 + 0.009 Ta (ae) 9,740.65 11.3 + 3 0۷۳ (mL/minkg) 29.12 + 4.05 12.33 42.10 ‏۲سا‎ (mL/kg) 2484664 2472123 ۰۰ 4 9" ‏ایا ما۸‎ 1515602 28646 4289644 12379.8 MRTivr 0 1582+ 6 173 7 PK = pharmacokinetic, Data = mean + SE, *: p<0.05, **: P<0.01 EHFG 5-8, Oct. 2005 

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25 مد @ Nalbuphine ™ Narcotic analgesics ™ «-agonist, u-antagonist 5 Advantage: low tolerance{] addiction and respiratory depression Drawback: short duration ™ Mainly Metabolized by UGT2B7 ™ Oral bioavailability less than 5% EHFG 5-8, Oct. 2005 

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22. Nalbuphine in SD Rats after Oral © Nalbuphine with or without Herbal Nalbuphine (ng/ml Time(h) 1e HUCHE035 is very rich in Artemisia capillaris and the dose is 4.5 mg/kg. +The EHFG 5-8, Oct. 2005, 

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27 £, PK Parameters for SD Rats after Oral Nalbuphine with or without Herbal BIA 326 0.26 100 10 093 064 014 13 Constituents PK parameters: Without HUCHEO35 (A) With HUCHE035 (B) Com (ng/mL) * 79+18 (2582 +906, Tose (rnin) 9736 2525 AUCo(mintngL) ** 214+88 218.2 +67.6 AUCou (tintngL)* 24.4 +89 244.1 +695 6 imin) 0.0027 + 0.0007 0.0027 + 0.0006 ta (min) 332 +62, 310 +59 MRT (min) 496 +90 316 +103 ‏)کت‎ ** 584 +25 0.83 +0.36 VIF (Likg) * 2919 +863, 3774 +170 Dafa =mean + SE; * p<005;** p<001 EHFG 5-8, Oct. 2005 

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2. Conclusions and @ suggestions (1) ™ Evidences from in vitro and in vivo studies has indicated that the constituents of herbal preparation, even food, interact with various drug metabolic enzymes extensively. ™ High throughput screening assays combine with jn vivo or clinical study will be a useful strategy to examine the herb- drug interactions EHFG 5-8, Oct. 2005 

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2. Conclusions and @ suggestions (IT) ™ Medical and pharmaceutical communities had been slow to respond to this important issue = Government, industry and medical societies should vigorously examine the possible drug interaction with the most commonly used herbal drugs = Drug Insert should clearly indicate the clinically significant drug interaction with commonly used herbs, dietary supplements, healthy food and traditional medicines EHFG 5-8, Oct. 2005 29 

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مد 

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4: Problems Caused from Herbal Medicines = Potential adulterants and contaminations that can affect the quality of herbal remedies © Plants containing belladonna or pyrrolizidine alkaloids, microorganisms, aflatoxins, bacterial endotoxin, pesticides, fumigation agents, toxic metals and Drugs = Potential adverse effects of herbal remedies and their major constituents © Cardiotoxicity: aconire root ruber © Hepatoxicity: certain herbs rich in anthranoids and protoberberine alkaloids, green-tea leaf © Neurotoxicity or convulsions: Kava rhizome © Renal toxicity: B-Aescin (saponin mixture from horse- chestnut seed) NEJM 347:2046, 2002 EHFG 5-8, Oct. 2005 31 

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Poswible Side Effects or Drag Interactions ‎wali,‏ کم له له هه او آس ت نآ هه سه رب ‎cen‏ ات ‏1 ‎rae nae‏ »سل سوه للع دم بسا مسلط سا سوم ‎ ‎5 ‏وا زج مسا تیم اس سک‎ a age Tica ‏رل متس‎ Zac iad gps ap et piney cam Sal ‎Toy ‏لجيه يلسا سمه‎ pica thal alee arab a Winingmnies Fay Sos nas dct ADS ghig dg es ‎Tavs tng pls pcahady aig aves ‏ها‎ ‎Tyas talaga hal ling ‏اه باه مره‎ eo ‏+ و ها تساه همه وله هل مهتم ۳ ‎lng opal‏ هه مد رب ‎beng rn ar ae‏ سن يبا ‎taeda argh bed po‏ ‎waged ahem‏ موز ‎‘Nien has ei nas air pig ncaa ras ‎yume sis i in ‏مج ربا‎ the rapes ef Pon Se Canes ‏سطاء م‎ slob ‏مادا با‎ tke nse lh cin yp renin ‎ ‎ ‎Ta aged ny ona BA el peor ge ao ‏او سا مه گس و‎ ‏سح‎ ‏سم دق هه‎ IDS dry) Py ‏هه هرهلد‎ roel Ney eva ‏سح‎ rebel det ‏شسود‎ bec ‎(eg a ۳ atc cre ya ee ‘Nye ing oly peta aig in isting ivi Vaya ‎‘Aad hd een ev yin omega hn ‏وج رو جع‎ oe bln Wi ‏سمي العامة رسا ماه موسر عومسم نجلا امبسح‎ ‏سا سم ‎Tea ems aml ge lad ‏دس لس تیا‎ ‎Tain sy occa cam apes pn sof ren bei ‎ ‎wg ae ad apa‏ ودقا مام ‎Ta beatg Sneed shes hentia ‎Faraday macs eat lt ‏لس ‎Sv ing a ela‏ ‎Tasco psa anna ae ‏تدم‎ ‎ ‎Tareas raion erm ‏د ‏تا ‏سمه ايه تت بدن ‏ات ‎ints‏ ‎ ‏التي ,مد هيد كد يهار ‎(hadi pace nd la lg. own tao ch ng and tse nie eam poi ‎Name of Herb ‏ممما‎ ‎Fpl nitty Fesager ‎CL, BD aad CHE Gari ‎Ginger ‏منود مولة و ‏آسساه ‎Kava-kava‏ ‎Tiere ‎Sie palmetto Se Toba wort ‎Talerian ‎Titan ‎ ‎ ‎ ‎ ‎ ‎ ‎ ‎ ‎ ‎ ‎ ‎ ‎ ‎ ‎ 

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1 019611121 ۶۸0۱۸۱, 011 0 Contaminants that Can Affect the Quality of Herbal Remedies ‎POTENTIAL ADULTERANTS AND CONTAMINANTS,‏ .1 متعم ‎THAT CAN AFFECT THE QUALITY OF HERBAL REMEDIES.*‏ ‎‘Tyre oF Aoutrenanr ‘oR Gontanuant ExaMnes ‎Bowanicals Adisolochia, digitalis, colchicum, rauwolia, plans ‘outing belladonna or pyrolizicine alll ‎Microorganisms Seapiylococcus aureus, Escherichia cali certs S13), ‏رورم رسمه ,ها ای موه هی‎ ‎Microbial oxins Adarosins, bactnal endoroxins ‎organic phosphates, carbamate‏ ۱[ مهس ‎Insecticides and herbicides, dichiocararmace tung‏ ‎‘ide, iazin herbicides‏ ‎Fumigation agents Euhylens oxide, methsl bromide, phosphine ‎‘Tosic merals ead, cadmium, meteury, arsenic ‎Drugs Analgesic and ansiinflammatory drugs (¢., amino: pphenuzone, phensibucazone, indomethacin), crt: Someroids, benzoxtiazepines; warfirin, fenfaranine, ‏مه‎ ‎ ‎“Daca ave ftom De Smet and De ۹۳۵7 ‎Replacement of Sepenie raved (angi) wih the roe of Arte cide ng (gong Began sing cre sh che con | ‏اس سس سبح ملد اس لس جرب‎ ‏حح سا سس اس اس اس سای‎ Cac! ‏للع ا‎ ingredient ‏مه وی سس ا ا‎ 1/7014 3407:2042 ‏وس‎ ۳ eRe aS ‎ 

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eS eS eee « Herbal Remedies and Their Major Constituents ES Pee ‘Ta@Le 2, POTENTIAL. ADVERSE EFFECTS OF HERRAL REMEDIES AND THEIR MAIOR CONSTITUENIS.* Neuronoiciey or convulsions Aconite root ruber Moses macronbizn 00% wert ‘Anemisia specks ech in santonin ‘Essential off rich in ascaridole Essential oi if in cuione Ginkgo s604 or leat “He rich in colicine “ers rch in postopsoconin Indian eae her Kiva thizome't مد ‎vomica‏ سل ‎Pennytosa oi ‎Stari ‎“Ellow jesamine dhizome ‎Renal soxcity ‎(saponin miseure om‏ متام ‎inorse-chesiauesced‏ ‏عمل موی ‎its coer ‎Certain etends ‏علا‎ ‎Chopars eat or stemt ‎‘Chinese yew" ‎“erie rich in aristolochic aids ‎oor‏ درز ‏ع از ‎cucumber‏ و ‎Sine fie ‎ ‎ ‎ ‎NEJM 347:2046, 2002 4 ‎Cardioconsiey ‎Aconite rooe tuber ‏کیت ماه مس وداج ‎cbs ih in colchicine ‏ديام ‎10 50 ‎Mahone ‎Pokemest lator wor ‎Scorch hroomt ‎Sguiring cucumber ‎Meparounicity ‏ملام وساي ماع ‎Cerri herb‏ ‎(Coren herbecich it prosaber eine alka ‎(Chaparral Tea oe seam ‎Germander species ‎Greens eatt ‎Elbe sich in coumacin ‎ibs rit in posophiowoxin ‎Herbs rich in te proliznine alkalis ‎mpi reo ‎Kava shizome ‎Kombucha ‎Malang ‎Penayasl ‎‘Shale ‎Sor pitrocseogenst ‎EHFG 5-8, Oct. 2005 

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EMeCts OF ot. JONM S ۱ Constituents on the Activity of Various CYPs | ‎TCHR Mesias‏ ممع ‎Contin Tier‏ سنوی ‎ ‎aor + 7 ‎spate, ۲ Sia Gea ‏“سم و كك‎ ‎Rees 1 ee Fon ‎{igi 1 Sin ‎bine ee‏ + مه ‎yy en + Dae 18 44 Competitive‏ ‎wh jp GEREN‏ +1 مسج ‎Qiecetn + ‏ین‎ a ‏ان و سوه عسي كر ما و ۶ و ‎ous‏ اه 1 ‎OF‏ مه ‎Foret 1+ 1 ‎oh 1 1 ‎3 1 Shee 0 ‎| i ‎fee 1 1: ‎Sine‏ 1 م سسکا ی لا 1 مس عست اذل د و 1 توا ‎ Bivem ۷‏ +1 سم ‏مر 07 + ‎Bice‏ ‏مس 7 اعد لاط 1 و ‏5 +1 سم ‎Competitive‏ لد هه لك + ۱ ‎SARE‏ اه مه مج م۳ ‎tener‏ سس ‏7 0 0 1 سسيية ‎Compete‏ _ 1 تن ‎ ‎TH = Tafa yang CME Grade rican xs ous dona 5181 ‏هرس ها معط‎ (CYP=Recinbimual CYP. POD = Pheracetn Osada, St >| ‎Sepestia ty dyes THB Teserone oy dye ‎ ‎ ‎Drug Metabolism Reviews 35:35, 290 EHFG 5-8, Oct. 2005 ‎ 

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2: Isoforms by Herbal Constituents (I) Tati (192); Haber eal 94 19895) )1984( اد پا (Canin Laie al (1996; Coo tnd Ye (199): Con ea. (198, 1999) Helsby tal (1997) )0997 للد وا ‎ong (1998)‏ BuAbbes ct al, 1995) Abn ea. (1996) Vemetal (2001) Waxg ea. 2001) 1955 اه ‘Wang ta. (200) Shea etl. (199), Kang eta. (1983) CasivencLavie etal 096) Kong (1998) ‎‘Abn etal. (1996)‏ الات اه مت ‏ساسم ‏ملسف ‏تن ار انس ان ‎ARR asivatoa‏ ‎AAR bing? ‎An ining? ARR ativan? ‎ABR activation ‘AAR scan? ‎‘AUR ‏شا‎ ‎AMR ativan? ‎Drug Metabolism Reviews 35:35, 2003 36 ‏ی ‎3303 ‎Rinvive ‎Ma Heal Rat in vio ‎Mad cols ‎hepatoma ool ie (eae tele) Rinvivo Rinvivo Mino Hin sito Minviso Rinvivo ‏ممع‎ ‏اما ل سمسوية 3 ۳ ‎Rinvivo‏ ‎vate ‎eae ‏سوه‎ ‏موه‎ ‎NE ‎Antagonist ‏سوم ‎Agonist‏ ‎NE‏ ‏ید ‏سیر ‎Augen‏ ‎‘Apmis‏ ‏سسوم ‏اتيم ‎Antagoniat ‎NE ‎Agonist ‎ovr ‎CYPIAI Garie DAD, DAS ‎patie ‎won (quer, ‘emg dosnt, ‘unger, apigeni, ‏ی‎ ‏0 ‏یی ‏تالم ‎(heen of Mack es exact ‎agi aid ‏ساوسو ‏مضه ‏القع مساو ‎۳ ‎pie ‎Flavonoids (Basen, vine angen) ‏تالم ‎ ‏هه ‎acid‏ یلا ‏سور عبت نمست ‎EHFG 5-8, Oct. 2005 ‎ ‎ ‎ ‎ ‎ ‎