08-Evaluation of Herbal-Drug Interactions.ppt.Convertor

cardiovascular benefits as well.

Safety: good but use in breast cancer may be risky

Drug interactions: not with withtamoxifen but effect on CYP3A4 is unlikely Product selection: soy or isoflavones

Dose: about 20-40g of soy protein has been used. This contains 30-50mg of isoflavones. Questions remaining include

How much benefit? Safety in breast cancer? 44

“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 ginseng INR increased to 3.3 after stopping ginseng causing CYP induction? 45

Yuan, C.-S.et. al. Ann Intern Med 2004;141:23-27

Changes 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 groups

5mg warfarin for 3d before and after 1g/d ginseng (50mg/d ginsenosides) American ginseng (Panaxquinquifolius) n=20 46

Jiang et al. Br J ClinPharmacol 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) 47

Jiang et al. Br J ClinPharmacol 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) 48

herbal Baseline Week 1

Treatment Treatment WaWeek 2

Week 3

We

Ginseng 4.4 ? 2.4 3.7 ? 2.2 3.6 ? 1.8 3.7

Soy isoflavones

4.9 ? 2.5 5.0 ? 2.0 4.6 ? 2.2 -----

6?-hydroxycortisol/cortisol ratio (CYP 3A4)

From: Anderson and Elmer, Clinical Pharmacology and Therapeutics 43:643-648 (2003). 49

Gurley et al. ClinPhamcolTher 2002;72:276-287 n=12; Panax ginseng 50

Ginseng

Efficacy: 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 (Panaxquinquifolius) but maybe not Panax ginseng. May precipitate hypoglycemia with insulin or oral hypoglycermics.

Product selection: product should be standardized so dose is 4-7% ginsenosides/d Questions remaining include:

What, actually is this stuff good for! 51

Lecrubier et al. Am J Psychiatry 2002;159:1361 n=375 52

Interactions with St. John’s Wort -cyclosporin-

Study: 2 case reports

case 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 53 54

Markowitz et al. JAMA 290:1500,2003 n=12 14d of SJW CYP 3A4 55

Durr et al. ClinPharmacolTher 2000;68:598-604. 56

Summary of SJW Interactions

(adapted from Henderson et al. Br J ClinPharmacol 2002;54:349-346) 57

St. John’s Wort Summary

Efficacy: good evidence for mild to moderate depression

Safety: don’t combine with other medications unless under close monitoring; possible photosensitivity

Drug interactions: a problem! Is a broad spectrum P450 inducer and a p-glycoprotein inducer. Product selection: want standardized extract containing about 0.3% hypericin or 1-2% hyperforin

Dose: about 300mg TID for treatment Questions remaining include

How best to use this herbal given that there are drug interaction problems 58 59

Gurley et al. ClinPharmacolTher 2005;77:415-426. N=12

Potential Interactions of Goldenseal with CYP2D6 and CYP 3A4 substrates 60

Herbals affecting clotting

adapted from Natural Medicine Comprehensive Database and Norred and Brinker, Alt Ther Health Med 2001;7:58-67.

Andrographispanucula Bogbean Devil’ claw ginseng Pau d’arco angelica Boldo Dong quai green tea meadow sweet anise capsicum Erigeron hawthorn prickly ash arnica celery Evening primrose oil horse chestnut bark passionflower Asafoeta chamomile feverfew Huang qi popular Baikal skullcap clove oil fish oil horseradish quassia Bilberry coleus root fenugreek kava red clover Black current seed danshen garlic licorice reishi mushroom Bladderwrack dandelion root ginger onion Shashen Bomelain Danshen ginkgo papain Shinpi bark

Sweet birch oil Tonka bean turmeric vitamin E wintergreen oil wild carrot wild lettuce willow wood ear mushroom woodruff 61

Herbs with clotting problems reported in humans

Ginkgo and garlic and St. John’s wort- see earlier notes

Evening primrose oil - human study showed 40% increase in bleed time but no other reports

Borage seed oil - same as evening primrose oil Vitamin E - doses >1200 i.u./d can increase bleed time Cranberry juice case reports of increased INR (salicylic acid? CYP 2C9 inhibition?) but in vivo study showed no change in flurbiprofen (CYP 2C9 substrate) in vivo

Lyciumbarbarum case report of increased INR Danshen - case reports of increased INR with warfarin Dong quai - case reports of increased INR with warfarin

American Ginseng - decreased INR with warfarin (Panaxquinquifolius) Green tea - case report of decreased INR with warfarin but huge amount CoQ10 - case reports of decreased INR with warfarin but human study showed no effect on INR Glucosamine- increased INR cases with warfarin Chondroitin- increased INR cases with warfarin 62

From: Lam AY, Mohutsky MA and Elmer GW. Probable herbal/drug interaction between warfarin and a common Chinese herb, Lyciumbarbarum. Ann Pharmacother 2001;35:1199-1201 63

Table 4a Significant Risk of CAM-drug Adverse Interaction n=5052 (16,173 interviews)

Potential Event Mechanisma Numberb Occurrencesc

Risk of bleeds Aspirin no. patients all occurrences Garlic23;25-27 PD 147 214 Ginkgo24;28 PD 102 127 Warfarin Garlic25-27 PD 13 16 Ginkgo29 PD 7 7 Ginseng32;33 PKd 3 3 Ticlopidine Garlic23;25-27 PD 4 6 Ginkgo24;30;31;54 PD 2 3 Pentoxifylline Ginkgo24;30;31 PD 3 3 Total 281 (5.6%) 380