clinical drug interactions with medicinal herbs

22
Evid Based Integrative Med 2005; 2 (4): 207-228 REVIEW ARTICLE 1176-2330/05/0004-0207/$34.95/0 © 2005 Adis Data Information BV. All rights reserved. Clinical Drug Interactions with Medicinal Herbs Andreas Johne and Ivar Roots Institut f ¨ ur Klinische Pharmakologie, Charit´ e, Campus Mitte, Universit¨ atsmedizin Charit´ e, Berlin, Germany Contents Abstract ............................................................................................................... 207 1. Methods ........................................................................................................... 208 2. Results ............................................................................................................. 208 2.1 Devil’s Claw .................................................................................................... 208 2.2 Echinacea ..................................................................................................... 208 2.3 Evening Primrose ................................................................................................ 210 2.4 Garlic .......................................................................................................... 214 2.5 Ginkgo ........................................................................................................ 216 2.6 Goldenseal .................................................................................................... 219 2.7 Hawthorn ...................................................................................................... 219 2.8 Kava .......................................................................................................... 220 2.9 Milk Thistle ...................................................................................................... 221 2.10 Peppermint Oil ................................................................................................ 221 2.11 Saw Palmetto ................................................................................................. 222 2.12 Valerian ...................................................................................................... 222 3. Conclusion ......................................................................................................... 223 The problem of herb-drug interactions is being increasingly recognised. However, except for hypericum Abstract (Hypericum perforatum L.; St John’s wort), data on drug interactions with other herbs are still inconclusive, although research has started to fill in the gaps, and knowledge is being gained about this important safety issue. This review summarises clinical data on interactions between drugs and herbal medicines, which were compiled using the following databases: MEDLINE via PubMed, Web of Science ® (from their inception until March 2005) and the Cochrane Library (until 2005, issue 1). Clinical data on herb-drug interactions, observed in case reports, case series or clinical trials, were included. Results are described for the following herbs: Devil’s claw (Harpagophytum procumbens D.C.), echinacea, evening primrose (Oenothera biennis L.), garlic (Allium sativum L.), ginkgo (Ginkgo biloba L.), goldenseal (Hydrastis canadensis L.), hawthorn, kava (Piper methys- ticum Forst.), milk thistle (Silybum marianum [L.] Gaertn.), peppermint, saw palmetto (Serenoa repens [Bartel] Small) and valerian. Information on herb-drug interactions is discussed through use of in vivo and experimental data, and conclusions are drawn when possible. Adverse effects of drugs are a significant hazard for patients complexity is even more pronounced when herbs are suspected to be involved in a drug interaction. and lead to approximately 6% to 10% of all hospital admissions in Great Britain and the US, respectively. [1,2] An estimated 17% of Mechanisms that underlie herb-drug interactions are compara- these adverse effects are related to drug interactions. [1] Therefore, ble with those known for drug-drug interactions. The main prob- knowledge of drug interactions is mandatory for the safe prescrip- lem in establishing causality between the use of a herbal medicinal tion of drugs. However, because of their complex nature, drug and a subsequent drug interaction is caused by the large variability interactions may often be overlooked in a clinical setting. This of herbal preparations. Interactions observed with one preparation

Upload: ivar-roots

Post on 11-Dec-2016

223 views

Category:

Documents


3 download

TRANSCRIPT

Page 1: Clinical Drug Interactions with Medicinal Herbs

Evid Based Integrative Med 2005; 2 (4): 207-228REVIEW ARTICLE 1176-2330/05/0004-0207/$34.95/0

© 2005 Adis Data Information BV. All rights reserved.

Clinical Drug Interactions with Medicinal HerbsAndreas Johne and Ivar Roots

Institut fur Klinische Pharmakologie, Charite, Campus Mitte, Universitatsmedizin Charite, Berlin, Germany

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2071. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2082. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208

2.1 Devil’s Claw . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2082.2 Echinacea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2082.3 Evening Primrose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2102.4 Garlic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2142.5 Ginkgo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2162.6 Goldenseal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2192.7 Hawthorn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2192.8 Kava . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2202.9 Milk Thistle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2212.10 Peppermint Oil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2212.11 Saw Palmetto . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2222.12 Valerian . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222

3. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223

The problem of herb-drug interactions is being increasingly recognised. However, except for hypericumAbstract(Hypericum perforatum L.; St John’s wort), data on drug interactions with other herbs are still inconclusive,although research has started to fill in the gaps, and knowledge is being gained about this important safety issue.This review summarises clinical data on interactions between drugs and herbal medicines, which were compiledusing the following databases: MEDLINE via PubMed, Web of Science® (from their inception until March2005) and the Cochrane Library (until 2005, issue 1). Clinical data on herb-drug interactions, observed in casereports, case series or clinical trials, were included. Results are described for the following herbs: Devil’s claw(Harpagophytum procumbens D.C.), echinacea, evening primrose (Oenothera biennis L.), garlic (Alliumsativum L.), ginkgo (Ginkgo biloba L.), goldenseal (Hydrastis canadensis L.), hawthorn, kava (Piper methys-ticum Forst.), milk thistle (Silybum marianum [L.] Gaertn.), peppermint, saw palmetto (Serenoa repens [Bartel]Small) and valerian. Information on herb-drug interactions is discussed through use of in vivo and experimentaldata, and conclusions are drawn when possible.

Adverse effects of drugs are a significant hazard for patients complexity is even more pronounced when herbs are suspected tobe involved in a drug interaction.and lead to approximately 6% to 10% of all hospital admissions in

Great Britain and the US, respectively.[1,2] An estimated 17% of Mechanisms that underlie herb-drug interactions are compara-these adverse effects are related to drug interactions.[1] Therefore, ble with those known for drug-drug interactions. The main prob-knowledge of drug interactions is mandatory for the safe prescrip- lem in establishing causality between the use of a herbal medicinaltion of drugs. However, because of their complex nature, drug and a subsequent drug interaction is caused by the large variabilityinteractions may often be overlooked in a clinical setting. This of herbal preparations. Interactions observed with one preparation

Page 2: Clinical Drug Interactions with Medicinal Herbs

208 Johne & Roots

cannot be generalised to occur with all formulations of the herb in and low back pain.[83] Extracts of Devil’s claw are prepared fromquestion. Also, interactions between the multiple components the peripheral tubers of the plant, which contain several iridoidwithin one herbal extract may add to the complexity of this glycosides including the key component harpagoside.[84]

problem.[3] Harpagophytum extracts are generally well tolerated. However,similar to other bitter herbs, gastrointestinal adverse effects, suchInteractions between herbal medicinals and drugs came toas dyspeptic symptoms or nausea, may occur.[83]prominence with the first studies involving hypericum (Hypericum

perforatum; St John’s wort) extracts.[4-6] In vitro and in vivo A toxicological review, which evaluated reports on clinicalresearch identified hyperforin as the main component of hyper- problems associated with the use of traditional and herbal reme-icum, which explained most but not all of the interactions of this dies and food supplements that had been forwarded to the Nationalherb with concomitantly given drugs.[7,8] Interactions with hyper- Poison Information Service of the UK between 1991 and 1995,icum have already been summarised extensively.[9-11] Therefore, listed one case of purpura in a patient who received warfarin inthis review focuses on other herbs, used predominantly in Western combination with Devil’s claw.[21] Unfortunately, more detailedcountries, for which the information on drug interactions is less information is lacking. Harpagophytum extracts have been foundconclusive. to influence leukotriene biosynthesis in vitro and ex vivo, while no

effect was observed on ex vivo thromboxane biosynthesis.[85]

1. Methods Furthermore, human arachidonic acid metabolism was demon-strated to be unaffected by Devil’s claw.[86] Based on these find-

All articles describing herb-drug interactions in humans wereings, a link between Devil’s claw intake and haemorrhage appears

included. In vitro and animal studies were only taken into accountto be unlikely.

if they helped to elucidate a possible herb-drug interaction ob-served in humans. Data were retrieved from MEDLINE via

2.2 EchinaceaPubMed, Web of Science® (both until March 2005) and theCochrane Library (until 2005, issue 1) by using the key words

Echinacea (coneflower) is indigenous to North America and‘herb’, ‘herbal’, ‘dietary supplement’ and ‘phytotherapy’, in com-has long been used medicinally by Native Americans.[87] Thebination with ‘drug interactions’, ‘safety’ and ‘toxicity’. As agenus echinacea encompasses nine species, of which Echinaceasecond step, database queries were performed with the colloquialangustifolia D.C., E. pallida (Nutt.) and E. purpurea (L.) Moenchas well as the official names of the herbs that had been identified.are generally employed for the prevention and treatment of upperBibliographies of included papers were scanned for further refer-respiratory tract infections.[88-90] The monograph of the Germanences. In addition, we used our own files for information on theCommission E recommends the use of alcoholic extracts madesubject. Previous review articles on herb-drug interactions werefrom the root of E. pallida and juices pressed from the aerial partsalso searched for relevant information.[12-19]

of E. purpurea.[91] However, marketed products often combinedifferent echinacea species as well as extracts from different parts2. Resultsof the plants. The diversity of echinacea preparations is considera-

Although many of the reports cited in this article lack crucial ble and may account for inconsistencies between clinical studydocumentation either on the quality of the herbal product or on results.[92-94]

temporal relations, concomitant drug use or medical history, we Generally, echinacea preparations are well tolerated. However,have refrained from excluding low-quality data. Nevertheless, the severe cases of allergic reactions have been reported, which maylimitations of the original data, which often made the establish- be a potential problem for first-time users of the herb as cross-ment of a distinct herb-drug interaction relationship difficult, were reactivity between echinacea and other environmental allergenstaken into account.[20] Thus, we ranked data from clinical studies has been identified.[95] Furthermore, echinacea should not be takenhighest. Accordingly, clinical information on herb-drug interac- with other immunomodulating drugs, although this recommenda-tions is given in two separate tables. Case reports are given in table tion is only based on theoretical considerations.[15]

I, while prospective clinical studies investigating herb-drug inter-In vitro studies have suggested an influence of echinacea on

actions are listed in table II.drug-metabolising enzymes, such as cytochrome P450 (CYP)2C19, CYP2D6 and CYP3A4,[96,97] and on P-glycoprotein-medi-

2.1 Devil’s Clawated drug transport.[98] An open-label trial investigated the effects

Devil’s claw (Harpagophytum procumbens D.C.) is used as a of an 8-day multiple dose treatment with a standardised E. pur-mild analgesic and anti-inflammatory remedy for joint diseases purea root extract on single-dose pharmacokinetics of caffeine,

© 2005 Adis Data Information BV. All rights reserved. Evid Based Integrative Med 2005; 2 (4)

Page 3: Clinical Drug Interactions with Medicinal Herbs

Clinical Herb-Drug Interactions 209

Table I. Case reports of herb-drug interactions

Herb (preparation)a Dose per day Age Sex Co-medication Effect Reference(duration) (y)

Devil’s claw (unspecified) ? ? ? Warfarin Purpura 21

Evening primrose oil (unspecified) ? 46 Female Phenothiazine EEG changes, epilepsy 22

Evening primrose oil (unspecified) ? 45 Male Phenothiazine EEG changes, epilepsy 22

Evening primrose oil (unspecified) ? 29 Male Phenothiazine, penicillin EEG changes, epilepsy 22

Evening primrose oil + vitamins 4g (12wk) 43 Male Fluphenazine Grand-mal seizure 23(Efamol™/Efavite™)

Evening primrose oil + vitamins 4g (14wk) 50 Male Fluphenazine, Grand-mal seizure 23(Efamol™/Efavite™) chlorpromazine

Evening primrose oil (unspecified) ? ? ? Anaesthetics (unspecified) Seizure 21

Garlic + karela (curry dish) ? 40 Female Chlorpropamide Chlorpropamide dose ↓ 24

Garlic pearls and tablets ? 2 patients ? Warfarin INR ↑ 25(unspecified) (unknown

age)

Garlic tablets (unspecified) 600mg (12d) 82 Male Fluindione, enalapril, INR ↓ 26furosemide, pravastatin

Garlic tablets (unspecified) ≈2g fresh garlic 43 Female Ritonavir, stavudine, Severe nausea and vomiting 27didanosine

Garlic – raw 10–12 cloves 52 Male Ritonavir, zidovudine, Severe gastrointestinal 27didanosine adverse effects

Ginkgo biloba (unspecified) ? 9 patients ? Antithrombotic and Bleeding events 28(unknown anticoagulative drugsage)

G. biloba (unspecified) 120mg (2y) 33 Female Paracetamol Bilateral subdural 29(acetaminophen), haematomaergotamine/caffeine

G. biloba (unspecified) + Siberian 253.4mg (for 69 Male Lisinopril, glibenclamide, Subdural haematoma 30ginseng (Eleutheroccus senticosus) yearsb) rofecoxib+ fish oil + vitamin E (tocopherol) +multivitamin

G. biloba (unspecified) 80mg (1wk) 70 Male Aspirin (acetylsalicylic acid) Hyphema 31

G. biloba (unspecified) ? 59 Male Aspirin (further drugs not Prolonged postoperative 32specified) bleeding; vitreous

haemorrhage

G. biloba (Gingium™, Biocur, 80mg (2.5y) 71 Male Ibuprofen Fatal intracerebral bleeding 33Germany)

G. biloba (unspecified) ? (2mo) 78 Female Warfarin Intracerebral haemorrhage 34

G. biloba (unspecified) ? Elderly Female Thiazide diuretic Blood pressure ↑ 21

G. biloba (EGb 761™, Dr. Willmar 160mg (2d) 80 Female Donepezil, bromazepam, Coma 35Schwabe GmbH, Germany) tocopherol, trazodone

G. biloba (unspecified) 120mg (2wk) 78 Male Valproic acid, temazepam, Generalised tonic-clonic 36aspirin, ramipril seizures

G. biloba (unspecified) 120mg (12d) 84 Female Valproic acid, aspirin, Status epilepticus 36rivastigmine, thioridazine

Continued next page

© 2005 Adis Data Information BV. All rights reserved. Evid Based Integrative Med 2005; 2 (4)

Page 4: Clinical Drug Interactions with Medicinal Herbs

210 Johne & Roots

Table I. Contd

Herb (preparation)a Dose per day Age Sex Co-medication Effect Reference(duration) (y)

Kava (Kavasporal™ forte, Muller 2 capsules per 76 Female Levodopa, benserazide Extrapyramidal symptoms, 37Goppingen GmbH, Germany) day (10d) ‘off periods’ ↑

Kava (unspecified) + Hypericum ? (10d) 45 Female Levodopa, bromocriptine, Extrapyramidal symptoms 38perforatum (hypericum; St John’s pramipexolewort) + bladderwrack + minerals +vitamins

Kava (unspecified) ? (3d) 54 Male Alprazolam, cimetidine, Lethargy, disorientation 39terazosin

Saw palmetto (Curbicin™, Pharbio 5 tablets (6d) 61 Male Warfarin, simvastatin INR ↑ 40Medical International AB, Sweden)

Valerian (unspecified) 1 tablet (6mo) 39 Female Hypericum, loperamide Delirium 41

Valerian (unspecified) 2 tablets (single 38 Male Fluoxetine Delirium 42dose)

a Details on preparations as provided in the references.

b As specified by authors.

EEG = electroencephalography; INR = international normalised ratio; ↓ indicates decrease; ↑ indicates increase; ? indicates unspecified.

tolbutamide, dextromethorphan and midazolam (intravenous and toid arthritis[102] and mastalgia.[103] Although evening primrose oiloral) in 12 healthy volunteers.[43] The drugs administered are increases the serum concentration of gamolenic acid in healthymarkers for the enzymatic activity of CYP1A2, CYP2C9, volunteers, it had no effect on concentrations of secondary meta-CYP2D6 and CYP3A4. E. purpurea root extract significantly bolic products such as dihomo-γ-linolenic acid and arachidonicdecreased the oral clearance of caffeine by 25%, indicating an acid.[104]

inhibitory influence on the activity of CYP1A2. Changes in the Evening primrose oil was also given to schizophrenic patientskinetics and metabolism of tolbutamide and dextromethorphan in order to normalise prostaglandin E1, a subsequent metabolicwere small and of little clinical relevance. Interestingly, co-medi-

product of gamolenic acid, which was shown to be reduced incation with echinacea increased the clearance of midazolam by

schizophrenia.[105] However, Vaddadi[22] described one female and34% only if midazolam was given intravenously (and not after oral

two male patients with the primary diagnosis of schizophrenia,dosing). These results suggest differential effects of the

whose symptoms worsened when they started taking eveningE. purpurea extract on hepatic and intestinal CYP3A4 activities.

primrose oil in combination with phenothiazine antipsychotics.However, a recent clinical study did not find significant effects

Interestingly, concomitant therapy also disclosed EEG changesof a 28-day multiple-dose treatment with a different E. purpurea

indicating temporal lobe epilepsy. Therefore, the diagnosis ofextract on the activities of CYP1A2, CYP2D6, CYP2E1 and

schizophrenia was questioned and drug therapy was switched toCYP3A4 determined by the use of caffeine, debrisoquine,the antiepileptic agent carbamazepine, whereupon all three pa-chlorzoxazone and midazolam, respectively.[44] The inconsisten-tients improved. However, grand-mal seizures were also observedcies of study results are possibly due to differences in the composi-in two patients during a clinical trial investigating the antipsychot-tion of echinacea preparations.ic efficacy of phenothiazine antipsychotics in combination with amedicinal product containing evening primrose oil and vita-2.3 Evening Primrosemins.[23] The first patient, a 43-year-old man with no history ofepilepsy, had a seizure 12 weeks after intake of evening primroseSeeds of the evening primrose (Oenothera biennis L.) plant areoil and fluphenazine. The second patient experienced a grand-malused to produce oily preparations, which are rich in unsaturatedseizure after concomitant intake of fluphenazine, chlorpromazinefatty acids such as gamolenic acid (γ-linolenic acid). Alterations inand evening primrose oil. It was assumed that evening primrose oilthe biosynthesis of gamolenic acid are suspected to be involved inmay have further reduced the seizure threshold, which is a knownthe pathophysiologies of several diseases.[99,100] Accordingly, sub-adverse effect of the antipsychotic medication. However, onestitution of fatty acids by use of evening primrose oil showedtabularly listed case report also described a patient who exper-promising effects in the treatment of atopic dermatitis,[101] rheuma-

© 2005 Adis Data Information BV. All rights reserved. Evid Based Integrative Med 2005; 2 (4)

Page 5: Clinical Drug Interactions with Medicinal Herbs

Clinical Herb-Drug Interactions 211

Table II. Prospective clinical studies investigating herb-drug interactions

Herb (preparation)a Dose (per Duration Study design Subjects Co-medication Effect Referenceday) (days) (n)

Echinacea purpurea root 1600mg 8 Open-label 12 Caffeine CL/F (25% ↓) 43extract (Nature’s Bounty Tolbutamide CL/F (11% ↓)Inc., USA) Dextromethorphan CL/F ↔

Midazolam (IV/PO) CL (IV, 34% ↑)CL/F (PO, ↔)

E. purpurea (Wild Oats 1600mg 28 Open-label 12 17DMX/caffeine Ratio ↔ 44Market, Inc., USA) 6-OH-chlorzoxazone/ Ratio ↔

chlorzoxazone

4-OH-debrisoquine/debrisoquine Ratio ↔1-OH-midazolam/midazolam Ratio ↔

Garlic capsules (garlic 10mg (≈1g 3 Open-label, 10 Ritonavir AUC (17% ↓, NS) 45powder) fresh garlic) crossover

Garlic (GarliPure™, 1200mg 24 Open-label 9 Saquinavir (Fortovase®) AUC (51% ↓) 46Maximum Allicin, NatureInc., USA)

Garlic (GarliPure™) 1200mg 21 Open-label 10 Erythromycin breath test, 14C metabolised/h ↔ 47saquinavir AUC ↔

Garlic (Kwai™, Lichtwer 3600mg 14 Open-label 14 Dextromethorphan/dextrorphan Ratio ↔ 48Pharma, USA)

Alprazolam AUC ↔

Garlic oil (Wild Oats 1500mg 28 Open-label 12 6-OH-chlorzoxazone/ Ratio (39% ↓) 49Market Inc., USA) chlorzoxazone

17DMX/caffeine Ratio ↔4-OH-debrisoquine/debrisoquine Ratio ↔1-OH-midazolam/midazolam Ratio ↔

Garlic component-diallyl 0.2 mg/kg Single Open-label 8 6-OH-chlorzoxazone/ Ratio ↓ 50sulfide bodyweight dose chlorzoxazone

Garlic (aged garlic extract, 10mL 3mo Open-label 16 Paracetamol (acetaminophen) Minor changes in 51Wakunaga of America Ltd, plasma concentrationsUSA) of paracetamol and

metabolites

Ginkgo biloba extract 240mg 7 Double-blind, 50 Aspirin (acetylsalicylic acid) No additional effect on 52(EGb 761™, Dr. Willmar placebo- bleeding time orSchwabe GmbH, Germany) controlled, coagulation

crossover parameters

G. biloba (Bio-Biloba™, 100mg 4wk Double-blind, 21 Warfarin INR ↔ 53Pharma Nord ApS, placebo-Denmark) controlled,

crossover

G. biloba (Aihoupu Co., 90mg 30 Open-label 14 Donepezil Concentration ↔ 54Japan) Mini Mental State

Examination Scale ↔

G. biloba (Tanakan™, 400mg 13 Open-label, 24 Phenazone (antipyrine) Elimination half-life ↔ 55IPSEN, France) parallel

Continued next page

© 2005 Adis Data Information BV. All rights reserved. Evid Based Integrative Med 2005; 2 (4)

Page 6: Clinical Drug Interactions with Medicinal Herbs

212 Johne & Roots

Table II. Contd

Herb (preparation)a Dose (per Duration Study design Subjects Co-medication Effect Referenceday) (days) (n)

G. biloba (unspecified) 120mg 18 Open-label 22 Nifedipine Cmax (29% ↑) 56

G. biloba (EGb 761) 280mg 12 Open-label 12 Caffeine, chlorzoxazone, N-acetyltransferase 2 57dapsone, debrisoquine, activity ↓, CYP1A2mephenytoin activity ↔, CYP2D6

activity ↔

G. biloba (Wild Oats 240mg 28 Open-label 12 6-OH-chlorzoxazone/ Ratio ↔ 49Market Inc., USA) chlorzoxazone

17DMX/caffeine Ratio ↔4-OH-debrisoquine/debrisoquine Ratio ↔1-OH-midazolam/midazolam Ratio ↔

G. biloba (Leiner Health 240mg 7 Open-label, 8 Digoxin AUC ↔ 58Company, USA) crossover

G. biloba (EGb 761) 240mg 14 Open-label 12 Alprazolam AUC (17% ↓) 59Dextrometorphan/dextrorphan Ratio ↔

G. biloba 280mg 12 Open-label 18 Omeprazole/ AUC ratio 60(Remembrance™, Herbs 5-hydroxyomeprazole (25–58% ↓)Product Ltd, Hong Kong) Omeprazole/omeprazole sulfone AUC ratio ↔

6β-hydroxycortisol/cortisol Ratio ↔

G. biloba (Ginkgolon-24™, 240mg Single Open-label 8 Nifedipine AUC ↔ 61Tokiwa Phytochemical Co., doseLtd, Japan)

G. biloba (unspecified) 360mg 28 Open-label 10 Tolbutamide AUC (16% ↓) 62Midazolam AUC (25% ↑)

G. biloba (unspecified) 240mg Single Crossover, 11 Flurbiprofen CL/F ↔ 63dose placebo-

controlled

Goldenseal (Goldenseal 2280mg 14 Crossover 10 Indinavir CL/F ↔ 64Root, Nature’s Way, USA) Cmax ↔

Goldenseal (Wild Oats 2700mg 28 Open-label 12 4-OH-debrisoquine/debrisoquine Ratio (~40% ↓) 65Market Inc., USA) 1-OH-midazolam/midazolam Ratio (~40% ↓)

17DMX/caffeine Ratio ↔6-OH-chlorzoxazone/ Ratio ↔chlorzoxazone

Hawthorn (WS 1442, Dr. 900mg 21 Open-label, 8 Digoxin AUC ↔ 66Willmar Schwabe crossoverPharmaceuticals,Germany)

Kava (aqueous kava Unspecified Long-term Open-label 6 17DMX/caffeine Ratio (50% ↑) 67extract) use Mephenytoin/4-OH-mephenytoin Ratio ↔

4-OH-debrisoquine/debrisoquine Ratio ↔6-OH-chlorzoxazone/ Ratio ↔chlorzoxazone

1-OH-midazolam/midazolam Ratio ↔

Continued next page

© 2005 Adis Data Information BV. All rights reserved. Evid Based Integrative Med 2005; 2 (4)

Page 7: Clinical Drug Interactions with Medicinal Herbs

Clinical Herb-Drug Interactions 213

Table II. Contd

Herb (preparation)a Dose (per Duration Study design Subjects Co-medication Effect Referenceday) (days) (n)

Kava (Wild Oats Market 2000mg 28 Open-label 12 17DMX/caffeine Ratio ↔ 65Inc., USA) 4-OH-debrisoquine/debrisoquine Ratio ↔

6-OH-chlorzoxazone/ Ratio ↔chlorzoxazone

1-OH-midazolam/midazolam Ratio ↔

Kava (Antares™ 120, 240mg 14 Double-blind, 18 Bromazepam Slight increase in 68Krewel Meuselbach GmbH, crossover sedative effectsGermany)

Kava (aqueous kava 1g per kg Single Placebo- 40 Alcohol (ethanol) Pronounced 69extract) bodyweight dose controlled, impairment in cognitive

parallel performance tests

Kava (WS 1490, Dr. 300mg 8 Double-blind, 40 Alcohol (0.5% constant blood No additive effects on 70Willmar Schwabe GmbH, placebo- levels) cognitive performanceGermany) controlled, and vigilance

parallel

Milk thistle (Legalon™, Dr. 210mg 28 Open-label 16 Aminopyrin Plasma half-life ↔ 71Madaus & Co., Germany) Phenylbutazone Plasma half-life ↔

Milk thistle (Thisilyn™, 525mg 21 Open-label 10 Indinavir AUC ↔ 72Nature’s Way, USA) C8 (25% ↓)

Milk thistle (General 480mg 14 Open-label 10 Indinavir AUC ↔ 73Nutrition Corp., USA)

Milk thistle (Kare and Hope 1368mg 29 Open-label, 14 Indinavir AUC ↔ 74Inc., USA) parallel

Milk thistle (Wild Oats 350mg 28 Open-label 12 17DMX/caffeine Ratio ↔ 44Market Inc., USA) 6-OH-chlorzoxazone/ Ratio ↔

chlorzoxazone

4-OH-debrisoquine/debrisoquine Ratio ↔1-OH-midazolam/midazolam Ratio ↔

Milk thistle (unspecified) ? 14 Open-label 16 Digoxin AUC ↔ 75

Milk thistle (Silybon™, 140mg 9 Open-label 12 Metronidazole AUC (28% ↓) 76Micro Labs Ltd, India) OH-Metronidazole AUC (29% ↓)

Peppermint oil (gelatine 600mg Single Open-label, 12 Felodipine AUC (30% ↑) 77capsules) dose crossover Dehydrofelodipine/felodipine Ratio ↔

Peppermint oil (gelatine 600mg Single Open-label, 12 Simvastatin AUC (30% ↑) 78capsules) dose crossover

Saw palmetto 320mg 14 Open-label 12 Dextromethorphan/dextrorphan Ratio ↔ 79(ProstActive™, Dr. Willmar Alprazolam AUC ↔Schwabe GmbH, Germany)

Saw palmetto (Wild Oats 320mg 28 Open-label 12 17DMX/caffeine Ratio ↔ 44Market, Inc. USA) 6-OH-chlorzoxazone/ Ratio ↔

chlorzoxazone

4-OH-debrisoquine/debrisoquine Ratio ↔1-OH-midazolam/midazolam Ratio ↔

Continued next page

© 2005 Adis Data Information BV. All rights reserved. Evid Based Integrative Med 2005; 2 (4)

Page 8: Clinical Drug Interactions with Medicinal Herbs

214 Johne & Roots

Table II. Contd

Herb (preparation)a Dose (per Duration Study design Subjects Co-medication Effect Referenceday) (days) (n)

Valerian (Valmane™, Kali 250–300mg Single Open-label 8 Alcohol No additive effects on 80Chemie AG, Germany) dose cognition and vigilance

Blood concentration ↔

Valerian (unspecified) 100mg Single Double-blind, 48 Propranolol No additive drug 81dose placebo- effects on cognition

controlled, and vigilancecrossover

Valerian (Dr. Willmar 1000mg 14 Open-label 12 Dextromethorphan/dextrorphan Ratio ↔ 82Schwabe GmbH, Germany) Alprazolam AUC ↔

Cmax (24% ↑)

Valerian (Vitamer Inc., 375mg 28 Open-label 12 17DMX/caffeine Ratio ↔ 65USA) 4-OH-debrisoquine/debrisoquine Ratio ↔

6-OH-chlorzoxazone/ Ratio ↔chlorzoxazone

1-OH-midazolam/midazolam Ratio ↔

a Details on preparations as provided in the references.

AUC = area under the plasma concentration-time curve; C8 = plasma concentration 8 hours after drug administration; CL = clearance, CL/F = totalclearance/bioavailability; Cmax = maximum plasma concentration; CYP = cytochrome P450; INR = international normalised ratio; IV = intravenous; NS =not statistically significant; PO = oral; Ratio = ratio between probe drug and its metabolite; ↔ indicates no change; ↓ indicates decrease; ↑ indicatesincrease; ? indicates unspecified.

ienced a seizure that was related to the combined intake of evening gastrointestinal symptoms, allergic reactions and orthostatic hypo-primrose oil and unspecified anaesthetic medications.[21] tension in rare cases.[109] Garlic has also been reported to reduce

Further investigations are needed to provide information on the blood glucose levels.[24] After eating a particular type of curry, richcentral nervous effects of evening primrose oil preparations alone in garlic and karela (Momordica charantia L.), a 40-year-oldor in combination with medications known to reduce the seizure diabetic woman showed an unexpectedly low urinary glucosethreshold. concentration, which led to a reduction in her dose of chlor-

propamide, an oral antidiabetic sulfonylurea.[24] Results of clinical2.4 Garlic studies investigating the influence of garlic on serum glucose

levels are conflicting, but can hardly explain effects observed inGarlic (Allium sativum L.) may be considered a prototypical

the case report. While two studies found garlic preparations to benutraceutical because it is used as a spice, a functional food and as

mildly hypoglycaemic,[111,112] others observed no relevant influ-a traditional herbal medicine. Cloves of garlic are medicinally

ence on either the serum glucose levels in non-diabetic pa-applied in form of dehydrated powders, oily preparations or aque-

tients[113,114] or on levels of glycosylated haemoglobin or serumous-alcoholic extracts of fresh or aged garlic. However, differ-

insulin levels of diabetic patients.[115,116] Karela, on the other hand,ences in processing and formulation also account for large varia-

has been used traditionally as an antidiabetic agent in India.[117]tions in the chemical composition of commercially available garlic

Studies in humans have demonstrated hypoglycaemic effects ofproducts.[106-108] Constituents of garlic can roughly be divided intokarela, which might better explain the curry-chlorpropamide inter-two main groups: sulphur-containing ingredients (e.g. alliin) andaction.[118]

non-sulphur ingredients. The latter include the alliin-splitting en-The protective effects of garlic against atherosclerosis havezyme alliinase, which cleaves alliin to allicin. Allicin is chemically

partly been attributed to its influence on blood haemostasis. Garlicunstable and degrades to various organosulphur compounds,components have been demonstrated to affect eicosanoid metabo-which are not only responsible for the characteristic odour oflism and platelet aggregation in vitro.[119] Effects on platelet aggre-garlic but also regarded as main contributors to the beneficialgation[120-124] and fibrinolytic activity[114,125] have also been identi-effects of garlic.[109]

fied in humans. However, results of clinical studies are inconsis-Garlic has become popular because of its lipid-lowering andmild antihypertensive capacities.[110] Adverse effects of garlic are tent. In single cases copious ingestion of garlic cloves or intake of

© 2005 Adis Data Information BV. All rights reserved. Evid Based Integrative Med 2005; 2 (4)

Page 9: Clinical Drug Interactions with Medicinal Herbs

Clinical Herb-Drug Interactions 215

garlic tablets was associated with severe bleeding events.[126-128] USA)1 in nine healthy volunteers.[46] Interestingly, even after 14Interestingly, bleeding times were significantly prolonged in two days of abstinence from garlic, AUC values for saquinavir reachedof the three patients, suggesting an inhibitory effect on platelet only 65% of previous baseline levels. These study results suggestaggregation.[126,128] Moreover, alterations of the blood coagulation that multiple-dose treatment with garlic powder preparations acti-parameter international normalised ratio (INR) were observed vates drug metabolism via CYP3A4 and/or drug transport via thewhen garlic preparations were combined with oral vitamin K MDR1 gene product P-glycoprotein, because both factors deter-antagonists. Thus, doubling of the INR was attributed to the intake mine the pharmacokinetics of HIV protease inhibitors. However,of either garlic pearls or tablets in two patients receiving constant two further clinical studies, which also used powdered extracts ofwarfarin treatment. However, this very scanty report did not garlic, did not confirm these findings.[47,48] Jacek et al.[47] (2004,provide further information on garlic products and patients.[25] In only abstract available) observed no influence of a 21-day treat-contrast, reduced drug efficacy of the vitamin K antagonist fluin- ment with garlic (GarliPure™) in ten healthy volunteers on eitherdione had been observed in an 82-year-old patient after intake of single-dose kinetics of saquinavir or the erythromycin breath test,garlic tablets.[26] Twelve days after the patient started to take which had been used to determine CYP3A4 activity. Accordingly,600 mg/day of an unspecified garlic preparation the INR fell a 14-day treatment with another powdered garlic extract (Kwai™,below therapeutic levels. Despite an increase in the dose of fluin- Lichtwer Pharma, USA) was found to have no effect on single-dione, INR levels remained low but returned to therapeutic levels dose kinetics of alprazolam (CYP3A4 substrate) or the metabo-within 4 days after discontinuation of garlic. Other concomitant lism of dextromethorphan (CYP2D6 substrate).[48]

medications had not been changed. The question remains whether powdered garlic preparationsaffect drug metabolism via CYP3A4. The impact of garlic on P-Blood coagulation parameters were rarely monitored in clinicalglycoprotein also remains to be determined in vivo, particularly asstudies with garlic. In one study, a slight and insignificant decreasein vitro data showed an influence on transport activity.[136,137]in prothrombin time had been observed after 4 weeks of treatmentNevertheless, the considerable variation of organosulphur com-with dried garlic extract,[129] whereas blood coagulation parame-pounds in garlic powder preparations is enough to explain differ-ters remained unchanged in another two studies.[125,130] Theseences in study results.[106]results may raise questions regarding a pharmacodynamic reason

for the interaction seen between warfarin, fluindione and garlic. The drug interaction potential of an oily preparation of garlichas been tested in a clinical trial.[49] This open-label study investi-Animal data, on the other hand, suggest that garlic influencesgated the influence of a multiple-dose treatment of a garlic oilvarious phase I and phase II enzymes, which are involved in theextract (Wild Oats Market, Inc., USA) on the plasma concentra-metabolism of drugs and xenobiotics.[131-135] Furthermore, one intion and metabolite formation of selected probe drugs, which arevitro study demonstrated an influence of fresh and various kinds ofused to determine activities of CYP2E1, CYP1A2, CYP2D6 andprocessed garlic on CYP2C9, CYP2C19, CYP3A4, CYP3A5 andCYP3A4.[49] The cocktail of probe drugs, consisting of chlorzox-CYP3A7 through use of human liver microsomes.[136] Therefore,azone, caffeine, debrisoquine and midazolam, was given to 12inhibition of drug metabolism by garlic tablets and raw garlic washealthy volunteers before and after 28 days of garlic treatment.assumed to be the reason for gastrointestinal toxicity in twoAdministration of garlic oil resulted in a reduction of CYP2E1patients receiving HIV triple therapy.[27] Adverse events in aactivity as deduced from a decrease in the formation of the43-year-old woman and a 52-year-old man were ascribed to anmetabolite 6-OH-chlorzoxazone from chlorzoxazone. No signifi-increase in concentration of the HIV protease inhibitor ritonavir.cant effect on the activities of CYP1A2, CYP2D6 or CYP3A4 wasHowever, clinical studies, which investigated the influence ofobserved. Similar effects on CYP2E1 activity were also seen ingarlic on the pharmacokinetics and metabolism of drugs, came toanother open-label study.[50] Eight healthy volunteers received aopposing results. An open-label study of ten healthy volunteerssingle dose of chlorzoxazone together with a single dose of thefound that a 3-day treatment with two soft gelatine capsules ofgarlic oil component diallyl sulfide. Again, the formation ofgarlic powder twice daily led to a slight but statistically insignifi-6-OH-chlorzoxazone was reduced, indicating an inhibitory influ-cant reduction in the single-dose area under the concentration-timeence of diallyl sulfide on CYP2E1 activity.curve (AUC) of ritonavir.[45] Another clinical study observed a

statistically significant decrease in the saquinavir steady-state CYP2E1 is involved in the metabolic activation of chemicalAUC of 51% after 24 days of treatment with a garlic powdered carcinogens. Its inhibition could explain some of the cancerextract (GarliPure™, Maximum Allicin Formula, Nature Inc., chemopreventive effects of garlic.[138] In vitro data also suggests

1 The use of trade names is for product identification purposes only and does not imply endorsement.

© 2005 Adis Data Information BV. All rights reserved. Evid Based Integrative Med 2005; 2 (4)

Page 10: Clinical Drug Interactions with Medicinal Herbs

216 Johne & Roots

that organosulphur compounds in garlic affect various detoxifying induces platelet aggregation and mediates allergic inflammatoryphase II metabolising enzymes.[138] A clinical study addressing processes.[146]

this issue investigated the impact of a multiple-dose treatment with Adverse events such as gastrointestinal symptoms, headachean aged garlic extract (Wakunaga of America, Ltd, USA) on and allergic reactions are rare with ginkgo intake.[109] However, asingle-dose pharmacokinetics of paracetamol (acetaminophen) in pharmacovigilance study, which documented drug-induced ad-16 healthy volunteers.[51] Metabolism of paracetamol is mainly verse events in a German city population over a 5-year period,based on glucuronidation and sulfation, but is also influenced by observed ten patients with bleeding events associated with gink-oxidation via CYP2E1. Single-dose kinetics of paracetamol were go.[28] Nine of these patients had taken ginkgo together with eitherdetermined prior to the treatment period, during the treatment after an antithrombotic or anticoagulative medication. Moreover, case1, 2 and 3 months, and 1 month after garlic intake had been reports described 12 patients who experienced bleeding related tostopped. Only minor changes in paracetamol pharmacokinetics ginkgo intake. In six of these patients, intake of ginkgo alone hadwere observed. However, slight increases in the plasma concentra- been linked to the development of subdural haematoma, subarach-tions of glucuronide and sulfate metabolites of paracetamol were noid haemorrhage, cerebral haemorrhage, enhanced postoperativeconsidered relevant by the authors. bleeding, hyphema and retrobulbar haemorrhage.[147-152]

Results of clinical studies indicate that the influence of garlic Further case reports describe bleeding events in patients whoon human drug metabolism varies with its processing and formula- took ginkgo in combination with other medications. A bilateraltion. Oily preparations may have an inhibitory effect on the subdural haematoma was observed in a 33-year-old woman whoactivity of CYP2E1. Whether powdered extracts influence the had taken an unspecified ginkgo preparation 60mg twice daily formetabolic activity of CYP3A4 and drug transport via P-glycopro- 2 years.[29] Her symptoms started with headache and steadilytein cannot yet be decided. In addition to the possible influence on increased in severity over a 3-month period. Additionally, she hadthe pharmacokinetics of other drugs, physicians should pay atten- taken paracetamol and, briefly, ergotamine/caffeine tablets, co-tion to potential interactions between garlic and medications that medications that are not known to influence platelet aggregation orinfluence bleeding. blood coagulation. Bleeding time was prolonged to 15 minutes and

normalised after ginkgo was withdrawn. Because there was nohistory of trauma or inherited bleeding disorders, ginkgo remained2.5 Ginkgothe most likely explanation for her bleeding. A subduralhaematoma was also diagnosed in a 69-year-old man after a headGinkgo (Ginkgo biloba L., Maidenhair tree) is the oldest livinginjury.[30] Because of diabetes mellitus, hypertension and arthritis,species of tree, having been on Earth for more than 190 millionthe patient received glibenclamide, lisinopril and rofecoxib. Twoyears.[139] The ginkgo tree is extremely hardy and equally resistantmonths after evacuation of the first haematoma, a computerisedto harmful insects and microorganisms as well as to urban andtomography scan revealed three new subdural haematomas. Theindustrial pollution. Although ginkgo was introduced into Westernpatient admitted that he was taking herbal supplements for yearsmedicine only a few decades ago it has become one of the moston a daily basis, including ginkgo (253.4mg), Siberian ginsengpopular phytomedicines. Currently, ginkgo is the second best-(the roots of Eleutheroccus senticosus) [162mg], fish oil, tocoph-selling herbal supplement in the US.[140]

erol (vitamin E) and multivitamins. His bleeding time was pro-Clinical studies support the use of ginkgo leaf extracts forlonged to 17.5 minutes and returned to normal when supplementcognitive impairment and dementia as well as intermittent claudi-intake was stopped. Thrombocytopenia and bleeding tendencycation.[141,142] According to the German Commission E mono-have been reported for glibenclamide but only in single cases.[153]graph, concentrated (35–67 : 1) leaf extracts of ginkgo biloba shallThe cyclo-oxygenase-2 inhibitor rofecoxib does not posses an-contain 22–27% flavone glycosides, 5–7% terpene lactones and notiplatelet effects.[154] Nevertheless, the combination of prescribedmore than 5 ppm of ginkgolic acids, constituents with knowndrugs, vitamins and herbs does not allow the conclusion thatallergic potency.[91,143,144] Although the total extract is supposed toginkgo was the cause of bleeding.exert the therapeutic effects, some pharmacological actions are

probably related to specific constituents or groups of components. Four case reports have also described bleeding in patients whoFor example, radical scavenger and antioxidant effects have been received ginkgo in combination with drugs known to inhibit eitherattributed to the flavonoidic fraction.[139] Terpenoids, such as platelet aggregation or blood coagulation. A 70-year-old maleginkgolides and bilobalides, have demonstrated characteristic patient who had been taking aspirin (acetylsalicylic acid) [325 mg/neuroprotective properties.[145] Ginkgolide B has been shown to be day] for 3 years because of coronary artery bypass suffered from aa potent inhibitor of the platelet-activating factor (PAF), which spontaneous hyphema 1 week after he had started taking 40mg of a

© 2005 Adis Data Information BV. All rights reserved. Evid Based Integrative Med 2005; 2 (4)

Page 11: Clinical Drug Interactions with Medicinal Herbs

Clinical Herb-Drug Interactions 217

concentrated G. biloba extract (Ginkoba™) twice daily.[31] G. drug action. However, it is worth noting that an animal studyobserved additive effects on bleeding time when G. biloba extractbiloba, but not aspirin, was withdrawn and bleeding did not recur(EGb 761) and ticlopidine were administered together.[155]during the 3-month follow-up period. Prolonged postoperative

bleeding following liver transplantation was also reported in a 59- The effects of G. biloba on human platelet aggregation are stillyear-old male patient.[32] Although prothrombin and partial throm- not fully understood.[156] G. biloba inhibits PAF-induced plateletboplastin time were within normal limits, the patient experienced aggregation[157] but it does not affect spontaneous platelet aggrega-peri-hepatic bleeding, which necessitated laparotomy for evacua- tion.[158,159] On the other hand, ginkgo may influence haemorrhe-tion of the haematomas. Three weeks after transplantation he ology by inhibiting erythrocyte aggregation and by enhancingcomplained of visual blurring, which was caused by a vitreous vasodilatation and microcirculation.[158,160] The latter studies indi-haemorrhage. It turned out that the patient had consumed an cate that at least part of the clinical efficacy of ginkgo may beunknown amount of G. biloba, both prior to transplantation and related to its vasoactive and rheological effects. It seems logicalduring his recovery in hospital. He also received aspirin 81 mg/ that the majority of bleeding events observed in case reportsday but no anticoagulative medication. More detailed information occurred in patients who had consumed ginkgo for several monthson co-medication was not given by the authors. Another case to years.[29,30,33,34,147-149,152] Conversely, most of these patients werereport described the development of a fatal intracerebral mass of an older age and it has to be kept in mind that the incidence of,bleeding in a 71-year-old man with an uneventful medical histo- in particular, cerebral haemorrhage significantly increases withry.[33] He had been taking G. biloba (Gingium™, Biocur, Germa- age.[161]

ny) for more than 2 years because of occasional dizziness. Howev- A toxicology review by the National Poison Information Ser-er, 4 weeks prior to his death he had started taking ibuprofen vice of Great Britain reported the case of an elderly female patient(600mg) because of osteoarthritic hip pain. In another case, a 78- who received an unspecified thiazide diuretic for relief of highyear-old woman who had been stabilised on warfarin for 5 years blood pressure.[21] The patient started taking G. biloba, which,because of coronary-artery bypass was diagnosed with an intracer- paradoxically, resulted in a further increase in blood pressure. Theebral haemorrhage after having taken an unspecified G. biloba elevation persisted for a few weeks until both G. biloba and theextract for 2 months.[34] However, her co-morbidity comprising diuretic were withdrawn and blood pressure returned to pre-hypertension, a prior myocardial infarction, atrial fibrillation and treatment levels. In contrast to this case report, clinical studiessick sinus syndrome makes it difficult to definitely attribute her have not shown an effect on blood pressure,[158] but have demon-symptoms to ginkgo intake. strated antihypertensive effects[162] or anti-oedematous activity of

G. biloba extracts.[163]In response to these case reports, prospective herb-drug interac-tion studies were carried out investigating concomitant treatment Although G. biloba extracts are widely used in the treatment ofwith G. biloba and either aspirin or warfarin. In a double-blind, dementia syndromes, side effects involving the CNS have rarelyplacebo-controlled, four-treatment crossover study, 50 healthy been reported. An 80-year-old woman with Alzheimer’s diseasevolunteers received either placebo or G. biloba extract (EGb 761; experienced coma 3 days after her therapy (donepezil,120mg twice daily) or aspirin (500 mg/day) or G. biloba plus bromazepam and tocopherol) had been changed to G. bilobaaspirin (EGb 761 240mg + aspirin 500mg) for 7-day periods extract and trazodone.[35] At the emergency department, her comaseparated by wash-out periods of 3 weeks. Parallel treatment with responded well to a treatment with flumazenil, an antagonist of theginkgo did not enhance the effects of aspirin on bleeding time, benzodiazepine receptor, suggesting that GABA has a role in thisspontaneous aggregation and aggregation induced by adenosine herb-drug interaction. Indeed, results from an animal study indi-diphosphate, arachidonate and PAF.[52] The possible interaction cate that bilobalide may increase GABA levels in mice brains.[164]

between ginkgo and warfarin was also investigated in a double- However, clinical studies that proved the efficacy of G. biloba asblind crossover study in 24 patients stabilised on warfarin.[53] add-on therapy to antidepressive and antipsychotic medication didPatients received a 4-week treatment with either one tablet of not observe comparably severe adverse effects. In a randomised,G. biloba per day (100mg; Bio-Biloba™, Pharma Nord ApS, parallel-group, placebo-controlled study G. biloba extractDenmark) or coenzyme Q10 or placebo in addition to their usual (EGb 761) was given to 20 patients in conjunction with an-warfarin dose. None of the study medications showed an influence tidepressive medication (tri- and tetracyclic antidepressants,on the warfarin-stabilised INR in the 21 patients who completed trazodone in one case) in order to improve therapy-resistant de-the study. Moreover, no adjustment of warfarin dose was needed. pression.[165] Only gastrointestinal symptoms were observed inThus, two prospective interaction studies could not reveal an two patients after G. biloba had been coadministered for 8 weeks.influence of G. biloba extracts on antiplatelet or anticoagulant Three open-label studies and one double-blind, placebo-controlled

© 2005 Adis Data Information BV. All rights reserved. Evid Based Integrative Med 2005; 2 (4)

Page 12: Clinical Drug Interactions with Medicinal Herbs

218 Johne & Roots

trial investigated whether G. biloba was able to alleviate an- ginkgo leaf extracts, was shown to elevate GABA levels in micetidepressant-induced sexual dysfunction symptoms.[166-169] In two brains.[164] Nevertheless, when G. biloba extract was given toof these trials, not a single adverse event was recorded in 63 and 22 mice, the activity of convulsants such as picrotoxin and strychninepatients who had received G. biloba for 4 weeks in combination increased,[176] and antiepileptic effects of valproate andwith various selective serotonin reuptake inhibitors (SSRIs) as carbamazepine were reduced.[177] A possible interaction betweenwell as bupropion, venlafaxine, nefazodone, phenelzine or pro- G. biloba and valproate was also observed in two patients with atriptyline (Vivactil).[166,168] The third study reported gastric irrita- history of epilepsy.[36] A 78-year-old man presented with general-tion in 2 of 12 patients.[167] During the 6-week study period, G. ised tonic-clonic seizures 2 weeks after he had started taking G.biloba extract had been combined mainly with SSRIs.[167] Kang et biloba tablets (120 mg/day). The patient was stabilised on val-al.[169] observed two cases of headache and one case of gastrointes- proate (1200 mg/day). He had not experienced seizures for thetinal disturbances in a group of 19 patients who had received G. preceding 18 months. Other medication (temazepam, aspirin andbiloba extract and either fluoxetine, paroxetine or nortriptyline for ramipril) were taken without change. After ginkgo had been8 weeks.[169] Fourteen of these patients also received withdrawn, the patient remained seizure-free for a follow-up peri-benzodiazepines as adjuvant treatment. A double-blind placebo- od of 8 months. The second patient, an 84-year-old woman,controlled study conducted by Zhang et al.[170] investigated the presented with status epilepticus 12 days after G. biloba tabletsinfluence of G. biloba as add-on therapy to haloperidol in patients (120 mg/day) had been prescribed. She had been free fromwith treatment-resistant schizophrenia. There were no differences seizures for the preceding 2 years. Apart from valproate (1600 mg/between the placebo and G. biloba groups when side effects were day), she had been constantly taking aspirin, rivastigmine andcompared by use of the Treatment Emergent Symptom Scale thioridazine for the last 5 months. The patient remained seizure-(TESS). Furthermore, a 30-day treatment with G. biloba extract free during a 4-month follow-up after G. biloba intake had beendid not alter the pharmacokinetics or pharmacodynamics of stopped. In both cases, G. biloba treatment was time-connected todonepezil, an acetylcholinesterase inhibitor used in the treatment the development of epileptic seizures, possibly as a result of aof dementia syndromes.[54] None of the seven clinical trials that pharmacodynamic antagonism of ginkgo and valproate. However,investigated co-medication of G. biloba with various antidepres- as the patient’s valproate plasma concentrations are unknown, asants, haloperidol or donepezil reported serious adverse events. pharmacokinetic interaction cannot be ruled out.Thus, coma, as observed in one case, may be considered a rare Several clinical studies have investigated the influence ofevent associated with ginkgo extract co-medication. G. biloba extracts on various drug-metabolising enzymes, mainly

G. biloba has also been suggested to cause epileptic seizures. through the use of probe drugs, which allow identifying changes inAccording to the US FDA Special Nutritional Adverse Event the activity of individual enzymes. One of these enzymes,Monitoring System, seizures were associated with G. biloba prep- CYP3A4 is of special interest as it is involved in the metabolism ofarations in three patients as well as with multi-ingredient prepara- about 50% of all drugs.[19] However, results from clinical studiestions including ginkgo in another four patients.[171] that tried to assess effects of ginkgo on CYP3A4 activity are

Vomiting, irritability and convulsion have long been inconsistent. Inhibition of CYP3A4 activity deduced from a 29%recognised as signs of ginkgo seed poisoning in Japan.[172] Ginkgo increase in the maximum plasma concentration (Cmax) ofseeds are eaten as a food in China, Korea and Japan, being edible nifedipine was found in 22 healthy volunteers receiving an 18-daywhen baked, cooked or roasted. Two case reports of seizures have multiple-dose medication with an unspecified G. biloba extract.[56]

been published in the English literature, involving a 2-year-old girl Similarly, a 2-fold increase in nifedipine Cmax was observed inand a 36-year-old woman who had ingested around 50 and 70 two of eight subjects taking single doses of 240mg G. bilobapieces of roasted and cooked ginkgo seeds, respectively.[172,173] extract (Ginkgolon-24™, Tokiwa Phytochemical Co., Ltd, Japan)Following investigation, one of the constituents of ginkgo seeds, together with 10mg of nifedipine.[61] However, the influence of G.4′-O-methylpyridoxine (MNP) was identified as being neurotoxic. biloba on nifedipine pharmacokinetics became insignificant whenTiny quantities of MNP can also be found in ginkgo leaves, ginkgo the analysis was performed for all study participants. In addition,leaf extracts and boiled seeds.[174] MNP is a derivative of pyridox- midazolam plasma concentrations significantly increased after 28ine (vitamin B6) and competes with pyridoxine activity.[175] Pyri- days of treatment with an unspecified ginkgo extract in ten healthydoxine functions as a co-factor of glutamic acid decarboxylase, an volunteers, indicating reduced activity of CYP3A4.[62] In contrastenzyme necessary for the synthesis of GABA. Thus, MNP may to these study results, increased activity of CYP3A4 was observedprecipitate seizures by decreasing GABA concentrations in the in another clinical trial that found a mild but statistically signifi-CNS.[172,173] On the other hand, bilobalide, another constituent of cant decrease in alprazolam concentrations after 14 days of treat-

© 2005 Adis Data Information BV. All rights reserved. Evid Based Integrative Med 2005; 2 (4)

Page 13: Clinical Drug Interactions with Medicinal Herbs

Clinical Herb-Drug Interactions 219

ment with G. biloba extract (EGb 761) in 12 healthy volunteers.[59] 2.6 GoldensealFurthermore, two clinical studies were not able to demonstrate an

Goldenseal (Hydrastis canadensis L.) is indigenous to Northinfluence of multiple doses of G. biloba extracts on CYP3A4America, where roots and rhizomes of the plant were traditionallyactivity through use of omeprazole sulphone and 6β-hydroxycor-employed for various kinds of infectious diseases, gastric com-tisol as well as midazolam as phenotypic markers.[49,60]

plaints or menstrual disorders.[180] The main active components ofSeveral clinical studies also investigated the influence of gink-

goldenseal are thought to be alkaloids such as berberine andgo on other drug-metabolising enzymes. A statistically significant

hydrastine.[181] While there is a lack of published data on thedecrease in tolbutamide concentration was observed after 28 days

clinical efficacy and safety of the crude drug, clinical studies usingof treatment with an unspecified G. biloba extract, pointing to an

berberine demonstrated modest effects in the treatment of diar-increase in the activity of CYP2C9.[62] However, no effect on

rhoea.[180] Moreover, drug interactions were predicted by in vitroCYP2C9 could be identified in a clinical trial that investigated the

studies showing an influence of goldenseal root extract on variouseffect of ginkgo on the kinetics of flurbiprofen.[63] A rise in the

CYP enzymes.[96,182,183] In addition, berberine has been found toactivity of CYP2C19 was found in 18 healthy volunteers, which

alter the activity of the drug transporter P-glycoprotein.[184,185] Onwas ascertained through comparison of ratios between

the basis of this, a clinical trial was initiated investigating theomeprazole/5-hydroxyomeprazole before and after 12 days of

influence of a 14-day treatment with goldenseal root extract onmultiple doses with a G. biloba extract (Remembrance™, Herbs

indinavir, which is a known substrate for both CYP3A4 and P-Product Ltd, Hong Kong).[60] Changes in the metabolism of caf-

glycoprotein.[64] No significant effects on single-dose pharmacoki-feine after 12 days of medication with G. biloba extract EGb 761

netics of indinavir were observed in ten healthy volunteers. Inpointed towards a reduction in the activity of the N-acetyltransfer-

contrast, a recently published clinical study by Gurley et al.[65] thatase 2.[57] No clinically relevant effects of G. biloba treatment were

used debrisoquine and midazolam as probe drugs observed afound for CYP1A2, CYP2D6 and CYP2E1.[49,57,59] Accordingly,

strong inhibitory influence of a 28-day multiple-dose treatmentno effect on the elimination half-life of phenazone (antipyrine)

with a goldenseal extract on CYP2D6 and CYP3A4 activities.was observed in 24 healthy volunteers following a 13-day intake

However, CYP1A2 (caffeine) and CYP2E1 (chlorzoxazone) ac-of G. biloba (400 mg/day, Tanakan™, IPSEN, France).[55]

tivities were not altered by goldenseal in the 12 healthy volunteersPhenazone is thought to be metabolised by CYP1A2 as well as

enrolled in that study.[65]

CYP2C and CYP3A. Furthermore, multiple doses of G. bilobaextract (Leiner Health Products, USA) did not alter single-dose

2.7 Hawthornconcentrations of digoxin in a clinical study involving eighthealthy volunteers, indicating no influence of ginkgo on drug Hawthorn, a member of the Rosacea family, is a fruit-bearingtransport via P-glycoprotein.[58] The diversity that exists in clinical thorny shrub with a long tradition of use for cardiovascular disor-results relates to differences in ginkgo extracts used in the clinical ders and dyspeptic complaints in Western and Eastern medicine.trials. In vitro studies showed varying influences of different Leaves, flowers and fruits of the white blooming Crataegus mono-ginkgo components and fractions of ginkgo extracts on several gyna Jacquin and C. oxyacantha L. are mainly used as crude drugsCYP enzymes. In particular, the flavonoidic fraction of G. biloba for hawthorn preparations.[109] Animal experiments have shownextract was found to alter CYP enzyme activity,[178] and, among pharmacological effects, such as positive inotropic activity, vaso-others, flavone aglycones and amentoflavone were shown to be the dilation or antiarrhythmic properties, which may be related tomost potent inhibitors of single enzymes in vitro.[179] Considering flavonoids and proanthocyanidins, the active principles of haw-the potential influence of ginkgo on the concentration of other thorn extracts.[186,187] Clinical data favour the use of certain haw-drugs, case reports with oral anticoagulants, trazodone or val- thorn preparations for heart failure-related symptoms.[188] Haw-proate can also be explained by pharmacokinetic interactions with thorn extracts are generally well tolerated. No additional toxicitydifferent ginkgo preparations. was observed when hawthorn extracts were combined with ACE

Because of the divergent results of clinical studies, the influ- inhibitors, calcium channel antagonists or diuretics in clinicalence of G. biloba extracts on the pharmacokinetics of co-medi- studies testing efficacy of the herbal medication.[189,190] Neverthe-cated drugs remains to be defined. However, physicians are ad- less, there is some concern about the concurrent use of hawthornvised to consider possible bleeding tendencies, especially in pa- with further cardiovascular medication, especially with cardiactients who use G. biloba extracts on a long-term basis. The glycosides.[12] A combination of crataegus extract with 0.125mgpotential of ginkgo to precipitate seizures should also be taken into digoxin (Crataelanat™) was found to be clinically useful in 126account, although further information is needed regarding this. heart failure patients.[191] However, comprehensive information on

© 2005 Adis Data Information BV. All rights reserved. Evid Based Integrative Med 2005; 2 (4)

Page 14: Clinical Drug Interactions with Medicinal Herbs

220 Johne & Roots

the safety of this herb-drug combination was not provided in this tional aqueous kava extract inhibited the activity of CYP1A2,study. Recently, an open-label study investigated the potential whereas the activities of the other CYP enzymes, CYP2C19,pharmacokinetic interaction between hawthorn extract (WS 1442) CYP2D6, CYP2E1 and CYP3A4, were not affected.[67] However,and digoxin.[66] Concurrent administration of hawthorn for 21 days a second clinical trial could not corroborate these results fordid not alter multiple-dose concentrations of digoxin in eight CYP1A2 in 12 healthy volunteers.[65] Metabolism and kinetics ofhealthy volunteers.[66] Remaining safety questions will probably the probe drugs caffeine, debrisoquine, chlorzoxazone andbe answered by a large ongoing outcome study, which allows the midazolam were not influenced by a 28-day treatment with anconcurrent use of hawthorn extract with digitalis glycosides, di- unspecified kava extract, indicating that kava had no influence onuretics, ACE inhibitors and β-adrenoceptor antagonists (β-block- the activities of CYP1A2, CYP2D6, CYP2E1 and CYP3A4.[65]

ers).[192] Interestingly, kava extracts and traditionally used kava have alsobeen shown to differentially influence the activities of CYP en-zymes in vitro.[205]

2.8 KavaUntoward neurological manifestations after kava intake have

also been reported.[37,38,206] Ingestion of large amounts of kava, butThe kava (Piper methysticum Forst.) shrub is native to thealso of standardised extracts, led to extrapyramidal side effects inSouth Pacific region and has a long history of recreational andsix patients.[37,38,206] One of these patients, a 76-year-old womanceremonial use. Standardised extracts are made from the largebeing treated with levodopa and benserazide for idiopathic parkin-kava rhizome and have gained widespread use in Westernsonism, experienced a pronounced increase in the duration andmedicine for the treatment of mild anxiety.[193] Kavapyrones (alsonumber of ‘off-periods’ 10 days after a kava extract (Kavasporal™called kavalactones) such as kavain and methysticin are thought toforte, Muller Goppingen GmbH, Germany) had been added to herbe the active constituents.[109] ‘Kava dermopathy’, an ichthy-therapeutic regimen.[37] She returned to her normal pattern ofosiform skin rash, as well as adverse effects in the nervous system,fluctuations 2 days after kava had been withdrawn. Anotherliver and lung have been observed after heavy consumption of45-year-old female patient, who had been taking a mixture ofkava in an Aboriginal community.[194] Two postmarketing surveil-minerals, vitamin B complex and herbs such as H. perforatum andlance studies with 4049 and 3029 participants reported low inci-Fucus vesiculosus (bladderwrack), showed bradykinesia, rigiditydences of adverse effects (1.5% and 2.3%, respectively), with mildand tremor 10 days after she had added one capsule of an unspeci-gastrointestinal symptoms or allergic reactions representing thefied kava extract per day to her dietary supplements.[38] Althoughlargest proportion.[109] However, case reports on seriousshe was treated with levodopa and dopamine agonists such ashepatotoxic effects have prompted national authorities of severalbromocriptine and pramipexole, extrapyramidal symptoms re-countries to reassess kava products and to withdraw marketingmained. When her kava intake became known, a therapeutic trialauthorisation,[195] although this decision is not beyond dispute.[196]

with the anticholinergic agent biperiden was initiated and herResearch aimed at discovering the reasons for the hepatotoxici-condition improved. Biperiden was also used successfully in aty of kava has also dealt with the potential influence of humanmale patient for relief of dystonic reactions associated with thedrug-metabolising enzymes.[197] For instance, inherited deficiencyintake of a standardised kava extract (Laitan™).[37] These casefor CYP2D6 has been hypothesised as an individual susceptibilityhistories suggest that kava is a central dopaminergic antagonist.factor for hepatotoxic adverse effects of kava in two patients.[198]

Indeed, binding of kavalactones to dopamine D2 receptors wasDeficiency in CYP2D6 activity is less frequent in Asian andshown in vitro.[207] Furthermore, dose-dependent effects of kavaPolynesian populations, which might explain why hepatotoxicityextract and specific kavalactones on dopamine concentrationshas very rarely been observed in the traditional use of kava.[199]

have been found in the nucleus accumbens of the rat.[208] However,However, no cytotoxic metabolites were detected whenin contrast to the clinical reports, an observational case studykavalactones and kava extract were exposed to cell lines expres-observed an attenuation of antipsychotic-induced extrapyramidalsing various CYP enzymes known for its potential to formside effects due to co-medication with a standardised kava extracthepatotoxic metabolites.[200] Conversely, the influence of kava on(WS 1490, Laitan™) in 42 patients.[209]the activities of drug-metabolising enzymes has also been investi-

gated. Several in vitro studies have suggested that kava and Psychotropic effects of kava have also been related to thekavalactones alter the activities of CYP enzymes CYP1A2, inhibition of voltage-gated Na+ and Ca2+ channels,[210,211] whereasCYP2C9, CYP2C19, CYP2D6 and CYP3A4.[201-204] Recently, a sedative effects are thought to be related to its action on theclinical study involving six healthy long-term kava consumers GABAA-receptor complex.[212] Kava extract has demonstratedfrom New Caledonia showed that long-term ingestion of a tradi- anxiolytic effects comparable with low-dose bromazepam and

© 2005 Adis Data Information BV. All rights reserved. Evid Based Integrative Med 2005; 2 (4)

Page 15: Clinical Drug Interactions with Medicinal Herbs

Clinical Herb-Drug Interactions 221

oxazepam,[213] but may be distinct from benzodiazepines in its of drug-metabolising enzymes,[71] most of the clinical studieseffects on EEG-recordings and reaction time.[214] A 54-year-old could not substantiate this finding. In the first published humanman was hospitalised in a lethargic and disoriented state 3 days study, Leber and Knauff[71] (1976) observed no influence of aafter he had added kava to his therapeutic regimen consisting of 28-day multiple-dose treatment with silymarin extract (Legalon™)alprazolam, cimetidine and terazosin.[39] His alcohol levels were on the half-lives of aminopyrine and phenylbutazone in 16 healthynegative and he denied overdosing with kava or alprazolam. It is volunteers.[71] Similarly, the pharmacokinetics of the HIV proteasepossible that kava and benzodiazepines may have additive effects. inhibitor indinavir were not altered by multiple-dose treatmentHowever, when a clinical study of 18 healthy volunteers compared with different silymarin extracts in three clinical studies.[72-74] Inthe efficacy of a kava-bromazepam combination with those of one study, trough plasma concentrations of indinavir tended to bebromazepam and kava extract (Antares™ 120, Krewel lower when silymarin was coadministered, but these changes wereMeuselbach GmbH, Germany) alone, the sedative superiority of small and probably of minor clinical consequence.[72] A recentthe combination was modest: only 14 volunteers reported in- study testing the pharmacokinetics and metabolism of the probecreased tiredness while taking a kava-bromazepam combination drugs caffeine (CYP1A2), debrisoquine (CYP2D6), chlorzox-compared with 11 volunteers during treatment with bromazepam azone (CYP2E1) and midazolam (CYP3A4) found no relevantalone.[68] Nevertheless, interactions with other agents influencing changes after healthy volunteers (n = 12) had been treated with athe GABAergic system, such as alcohol, may be assumed.[215] milk thistle extract for 28 days.[44] In addition, the pharmacokinet-Indeed, symptoms of heavy kava intake can be mistaken for ics of digoxin, used as a probe drug for P-glycoprotein activity,alcohol over-consumption.[216,217] In mice, the hypnotic effects of were not altered after 14 days of treatment with an unspecifiedalcohol were considerably intensified when a large quantity was milk thistle extract in 16 healthy volunteers.[75] These clinical dataadministered together with kava.[218] A pronounced impairment in are in contrast to results from in vitro studies that showed altera-cognitive performance was also observed in healthy volunteers tions in the activity of various drug-metabolising enzymesreceiving an aqueous extract of kava in combination with alcohol, CYP2C9, CYP2D6, CYP2E1, CYP3A4 and UGT1A6/9 as well aswhereas intake of kava alone had virtually no influence on test P-glycoprotein drug transport by silymarin.[222-225] Only oneresults.[69] However, another parallel-group study did not observe clinical study observed an influence of silymarin extract on theadditive effects of a standardised kava extract (WS 1490) when pharmacokinetics of metronidazole, which is metabolised bycombined with alcohol.[70] CYP2C9 and CYP3A4.[76] Steady-state plasma concentrations of

metronidazole and those of its active metabolite (hydroxy-me-The potential influence of kava on dopaminergic activitytronidazole) were significantly lowered after the 12 healthy volun-should be taken into account. Furthermore, the combination withteers had taken multiple doses of a silymarin extract (Silybon™)other centrally acting agents may be ill-advised. The mechanismsfor 9 days.for hepatic toxicity are still unclear and further studies are needed

to investigate possible interrelations between different kava prepa-2.10 Peppermint Oilrations and drug-metabolising enzymes.

Peppermint (Mentha X piperita L.) is a sterile hybrid between2.9 Milk Thistle spearmint (M. spicata) and water mint (M. aquatica). The most

important variety of M. piperita is Mitcham mint, which was firstMilk thistle [Silybum marianum (L.) Gaertn.] is traditionally cultivated in England about 200 years ago.[109] Peppermint oil,

used for dyspeptic complaints and for the prevention and treatment produced by steam distillation of the dried herb, contains menthol,of liver diseases.[219] Extracts are made from the ripe fruits of milk menthone and a variety of menthol esters. Binding of menthol to athistle and contain the active principle silymarin, which is a specific thermosensitive ion channel elicits the cool sensation thatmixture mainly of three flavonolignanes – silybin (silibinin), is known from peppermint use.[226] Moreover, menthol blockssilydianin and silychristin.[220] Silymarin has been shown to be calcium channels in vitro, which may explain its spasmolytichelpful in the treatment of alcoholic liver disease and mushroom activity.[227,228] Topically applied, peppermint oil is used in coldpoisoning with Amanita phalloides (death cap mushroom).[219,221] and cough preparations and for the treatment of headaches.[229,230]

In general, milk thistle extracts are well tolerated and gastrointesti- However, peppermint oil must not be administered close to thenal symptoms are the adverse effects most frequently observed. Its nostrils of newborns and small children as it may cause ap-influence on xenobiotics and drug-metabolising enzymes has been noea.[231,232] Internally, peppermint oil capsules are used for irrita-widely studied in order to elucidate its anti-toxic actions. Howev- ble bowel disease and functional dyspepsia.[233] Because of itser, while animal studies showed significant changes in the activity influence on gastric emptying and intestinal motility, peppermint

© 2005 Adis Data Information BV. All rights reserved. Evid Based Integrative Med 2005; 2 (4)

Page 16: Clinical Drug Interactions with Medicinal Herbs

222 Johne & Roots

oil may affect the pharmacokinetics of concomitantly given Recently, the interaction potential of saw palmetto extracts onthe pharmacokinetics of other drugs was also investigated in twodrugs.[234-236] Indeed, delayed absorption of caffeine was observedprospective clinical trials.[44,79] A 14-day multiple-dose treatmentafter concomitant intake of menthol 100mg in a clinical study.[237]

with a standardised S. repens extract (ProstActive™, Dr. WillmarFurthermore, in vitro studies using microsomal enzymes fromSchwabe GmbH, Germany) did not change single-dosehumans and rats suggests an influence of peppermint oil andpharmacokinetics of dextromethorphan (CYP2D6) and alprazo-peppermint tea on the drug-metabolising enzymes CYP1A2,lam (CYP3A4) in 12 healthy volunteers.[79] These results wereCYP2E1 and CYP3A.[77,238,239] Administration of peppermint oilconfirmed by a second clinical study with 12 healthy volun-to rats increased the oral bioavailability of ciclosporinteers.[44] Again, multiple-dose treatment with S. repens extract for(cyclosporine) almost 3-fold.[239]

28 days did not change kinetics and metabolism of single doses ofThe in vivo interaction potential of peppermint oil was tested incaffeine, chlorzoxazone, debrisoquine and midazolam. These re-two crossover studies in healthy volunteers.[77,78] Subjects receivedsults indicate that saw palmetto may not change thesingle doses of felodipine (10mg) and simvastatin (40mg) eitherpharmacokinetics of drugs metabolised via CYP1A2, CYP2D6,alone or in combination with single doses of peppermint oilCYP2E1 or CYP3A4.(600mg gelatine capsules). Peppermint oil increased the AUCs of

felodipine and simvastatin by 30%. It is probable that these effects2.12 Valerianare related to inhibition of CYP3A4 by the herbal medicinal. The

clinical data indicate a potential influence of peppermint oil on theAqueous and aqueous-alcoholic extracts of the dried root ofpharmacokinetics of other drugs and necessitates further studies to

valerian species are taken as mild sedatives and sleep aids. Theirclearly appraise effects caused by its co-medication.main chemical constituents are valepotriates and volatile oil com-ponents such as valerenic acid.[244] Valepotriates, highly prevalent

2.11 Saw Palmettoin Mexican valerian (Valeriana edulis Nutt. ex Torr.), have beenshown to be cytotoxic in vitro.[245] However, as they decompose

The ripe, dark red berries of the American dwarf palm [Serenoa during storage[246] only trace amounts of valepotriates have beenrepens (Bartel) Small, Sabal serulata] are widely used in the found in valerian tea preparations.[247] Nevertheless, valepotriatestreatment of benign prostatic hyperplasia.[240] Lipophilic extracts were suggested to be the possible cause of hepatotoxicity in fourof the powdered fruits are rich in fatty acids and plant sterols.[241]

patients using herbal mixtures including valerian.[248] In contrast,Several mechanisms, including anti-androgenic and anti-inflam- no liver damage was observed in another 23 patients who hadmatory actions as well as inhibition of growth factors have been taken an overdose of a hypnotic containing valerian.[249,250] Valer-proposed to mediate the clinical effects of S. repens extracts.[242]

enic acid, on the other hand, is used for standardisation of valerianTherapy with saw palmetto has few adverse effects, one of extracts as it is unique to the most commonly used valerian species

them being mild gastrointestinal symptoms.[240] However, severe Valeriana officinalis L.[244] Valerenic acid has been shown tointraoperative bleeding was observed in a 53-year-old male patient inhibit enzyme-induced breakdown of GABA in vitro.[251] In addi-who received saw palmetto, and no other medication, prior to tion, the extract of V. officinalis L. as a whole inhibits the uptake ofsurgery.[243] While coagulation parameters were within normal GABA from synaptosomes and increases hippocampal GABAlimits in this patient, bleeding time was prolonged to 21 minutes release.[252] Although the mechanisms that underlay the sedativeand normalised 5 days after intake of saw palmetto was discontin- and hypnotic effects of valarian remain inconclusive, positiveued. In contrast, alteration of blood coagulation occurred in a effects on sleep structure and sleep perception were observed in

insomniac patients after 2–4 weeks of treatment.[253,254] Distinct61-year-old male patient receiving warfarin and simvastatin.[40]

from other sedatives, onset of action is delayed with valerianAfter he had started taking Curbicin™ (Pharbio Medical Interna-extracts, which may explain their low risk of promoting dependen-tional AB, Sweden), a mixture containing S. repens, Curcubitacy.[109] There is only one case report that describes symptomspepo and tocopherol, his INR increased from 2.4 to 3.4. The INRresembling benzodiazepine withdrawal in a 58-year-old patientreturned to normal 1 week after he stopped intake of Curbicin™.who had been taking valerian extracts (0.5–2g five times a day) forThe same report mentions another 71-year-old patient whose INRmany years.[255]increased after taking Curbicin™ alone. However, changes in

coagulation parameters of both patients were related to tocopherol, Delirium-like symptoms have been reported in two patientsas there is a possible antagonism between vitamin K and tocopher- who took valerian extracts in combination with centrally actingol. agents. A 39-year-old woman with a history of depression and

© 2005 Adis Data Information BV. All rights reserved. Evid Based Integrative Med 2005; 2 (4)

Page 17: Clinical Drug Interactions with Medicinal Herbs

Clinical Herb-Drug Interactions 223

migraine headaches experienced a brief episode of acute delirium Overall, valerian can be considered to be a safe herb. However,possible interactions with psychotropic agents should be kept inafter she initiated loperamide in addition to a herbal combinationmind.of hypericum extract and valerian root extract.[41] Her symptoms

of disorientation, agitation and confusion resolved within 2 days3. Conclusionfollowing therapy with charcoal, thiamine, naltrexone and

lorazepam. Another case report described a 38-year-old maleConsumers and physicians tend to underestimate the safety risk

patient treated with fluoxetine 20 mg/day for alcohol-inducedof herbs and are not alert to possible adverse effects associated

mood disorder.[42] After taking two gel tablets of an unspecified with its use.[265] On the other hand, reports of adverse eventsvalerian extract the patient described a feeling of loss of control of associated with herbal remedies often provoke a flood of similarhis left arm. His delirium-like symptoms disappeared without reports. Therefore, risk assessment of herbal medicines is evenfurther therapy within 24 hours. Serotonergic action was influ- more handicapped by a reporting bias than are other drugs.[266]

enced in both patients either by hypericum extract or by fluoxe- Adverse effects due to herbal medication were often only observedtine, which could have contributed to the symptoms of agitation in single cases, indicating that a possible individual disposition hasand delirium.[256,257] It should be noted that loperamide itself may to be taken into account. Nevertheless, clinical studies remain thecause acute delirium[258] as may the heavy or long-term consump- mainstay for the evaluation of herb-drug interactions. Results fromtion of alcohol.[259] However, a clinical study involving eight in vitro studies may also be used as a guide for further research;healthy volunteers could not find an additive interaction between however, they are not always predictive and need to be confirmed

by in vivo studies.[267] Clinical research does, however, have toalcohol and valerian preparations containing concentrated valepo-adhere to the special requirements with herbal preparations. Intriates.[80] Furthermore, alcohol blood concentrations were notparticular, variability of the herbal constituents in different ex-influenced by the co-medication. In addition, no additive psychictracts or preparations has to be considered. Ultimately, research oneffects were observed in 48 healthy volunteers receiving a combi-herb-drug interactions will help to restore confidence in valuablenation of valerian extract and propranolol.[81] Although an animaland generally well tolerated uses for herbal medicines.study suggests that valerian potentiates sedative effects of barbitu-

rates,[260] only one case report has described a comatose state in aAcknowledgements76-year-old female patient after intoxication with a barbiturate and

valerian combination.[261] However, valerian seems to be quite We are highly indebted to Dr Gabriele Laschinski for her assistance withthe preparation of the manuscript. The authors have no conflicts of interest. Noharmless when taken alone, even in significant doses. An 18-year-sources of funding were used to assist in the preparation of this review.old female patient who had taken 40–50 capsules of a valerian

extract (Nature’s Way Inc., USA) in a suicide attempt presentedwith fatigue, abdominal pain, chest tightness and tremor; her References

1. Pirmohamed M, James S, Meakin S, et al. Adverse drug reactions as cause ofsymptoms resolved within 24 hours.[262] When intravenously ad-admission to hospital: prospective analysis of 18 820 patients. BMJ 2004; 329:

ministered, valerian extracts led to severe but reversible symptoms 15-92. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions inin two patients, who both recovered remarkably quickly within

hospitalized patients: a meta-analysis of prospective studies. JAMA 1998; 279:12–24 hours.[263,264]

1200-53. Williamson EM. Synergy and other interactions in phytomedicines. PhytomedicineThe pharmacokinetic interaction potential of valerian extracts

2001; 8: 401-9has been studied in two clinical trials.[65,82] In the first study, 4. Johne A, Brockmoller J, Bauer S, et al. Pharmacokinetic interaction of digoxin with

an herbal extract from St John’s wort (Hypericum perforatum). Clin Pharmacolkinetics and metabolism of dextromethorphan and alprazolamTher 1999; 66: 338-45

were used to evaluate CYP2D6 and CYP3A4 activities before and 5. Piscitelli SC, Burstein AH, Chaitt D, et al. Indinavir concentrations and St John’swort. Lancet 2000; 355: 547-8after 14 days of treatment with valerian extract (Dr. Willmar

6. Johne A, Schmider J, Brockmoller J, et al. Lowered plasma levels of amitriptylineSchwabe GmbH, Germany).[82] While there was no effect onand its metabolites upon co-medication with an extract from St. John’s wort

CYP2D6 activity, a slight but clinically insignificant increase in (Hypericum perforatum). J Clin Psychopharmacol 2002; 22: 46-547. Wentworth JM, Agostini M, Love J, et al. St John’s wort, a herbal antidepressant,the alprazolam Cmax was observed. A second clinical trial was

activates the steroid X receptor. J Endocrinol 2000; 166: R11-6unable to identify a significant influence of a 28-day multiple-dose 8. Mai I, Bauer S, Perloff ES, et al. Hyperforin content determines the magnitude of

the Saint John’s wort-cyclosporine drug interaction. Clin Pharmacol Ther 2004;treatment with an unspecified valerian extract on the activities of76: 330-40

CYP1A2 (caffeine), CYP2D6 (debrisoquine), CYP2E1 (chlorzox-9. Henderson L, Yue QY, Bergquist C, et al. St John’s wort (Hypericum perforatum):

azone) and CYP3A4 (midazolam) in 12 healthy volunteers.[65] drug interactions and clinical outcomes. Br J Clin Pharmacol 2002; 54: 349-56

© 2005 Adis Data Information BV. All rights reserved. Evid Based Integrative Med 2005; 2 (4)

Page 18: Clinical Drug Interactions with Medicinal Herbs

224 Johne & Roots

10. Johne A, Roots I. Adverse drug effects and interactions: what is the current 41. Khawaja IS, Marotta RF, Lippmann S. Herbal medicines as a factor in delirium.thinking about the use of St. John’s wort? [in German]. Pharm Unserer Zeit Psychiatr Serv 1999; 50: 969-702003; 32: 242-6 42. Yager J, Siegfreid SL, DiMatteo TL. Use of alternative remedies by psychiatric

patients: illustrative vignettes and a discussion of the issues. Am J Psychiatry11. Mannel M. Drug interactions with St John’s wort: mechanisms and clinical1999; 156: 1432-8implications. Drug Saf 2004; 27: 773-97

43. Gorski JC, Huang SM, Pinto A, et al. The effect of echinacea (Echinacea purpurea12. Miller LG. Herbal medicinals: selected clinical considerations focusing on knownroot) on cytochrome P450 activity in vivo. Clin Pharmacol Ther 2004; 75:or potential drug-herb interactions. Arch Intern Med 1998; 158: 2200-1189-10013. Fugh-Berman A. Herb-drug interactions. Lancet 2000; 355: 134-8

44. Gurley BJ, Gardner SF, Hubbard MA, et al. Assessment of botanical supplementa-14. Ernst E. Interactions between synthetic and herbal medicinal products. Part 2: ation on human cytochrome P450 phenotype: citrus aurantium, echinacea, milksystemic review of the direct evidence. Perfusion 2000; 13: 60-70thistle, saw palmetto. Clin Pharmacol Ther 2004; 76: 428-4015. Ang-Lee MK, Moss J, Yuan CS. Herbal medicines and perioperative care. JAMA

45. Gallicano K, Foster B, Choudhri S. Effect of short-term administration of garlic2001; 286: 208-16supplements on single-dose ritonavir pharmacokinetics in healthy volunteers.16. Izzo AA, Ernst E. Interactions between herbal medicines and prescribed drugs: aBr J Clin Pharmacol 2003; 55: 199-202systematic review. Drugs 2001; 61: 2163-75

46. Piscitelli SC, Burstein AH, Welden N, et al. The effect of garlic supplements on the17. Bhattaram VA, Graefe U, Kohlert C, et al. Pharmacokinetics and bioavailability ofpharmacokinetics of saquinavir. Clin Infect Dis 2002; 34: 234-8herbal medicinal products. Phytomedicine 2002; 9: 1-33

47. Jacek H, Rentsch KM, Steinert HC, et al. No effect of garlic extract on saquinavir18. Ioannides C. Pharmacokinetic interactions between herbal remedies and medicinalkinetics and hepatic CYP3A4 function measured by the erythromycin breathdrugs. Xenobiotica 2002; 32: 451-78test [abstract]. Pharmacol Ther 2004; 75: P8019. Zhou S, Gao Y, Jiang W, et al. Interactions of herbs with cytochrome P450. Drug

48. Markowitz JS, Devane CL, Chavin KD, et al. Effects of garlic (Allium sativum L.)Metab Rev 2003; 35: 35-98supplementation on cytochrome P450 2D6 and 3A4 activity in healthy volun-20. Fugh-Berman A, Ernst E. Herb-drug interactions: review and assessment of reportteers. Clin Pharmacol Ther 2003; 74: 170-7reliability. Br J Clin Pharmacol 2001; 52: 587-95

49. Gurley BJ, Gardner SF, Hubbard MA, et al. Cytochrome P450 phenotypic ratios21. Shaw D, Leon C, Kolev S, et al. Traditional remedies and food supplements: afor predicting herb-drug interactions in humans. Clin Pharmacol Ther 2002; 72:5-year toxicological study (1991-1995). Drug Saf 1997; 17: 342-56276-87

22. Vaddadi KS. The use of gamma-linolenic acid and linoleic acid to differentiate50. Loizou GD, Cocker J. The effects of alcohol and diallyl sulphide on CYP2E1between temporal lobe epilepsy and schizophrenia. Prostaglandins Med 1981;

activity in humans: a phenotyping study using chlorzoxazone. Hum Exp Tox-6: 375-9icol 2001; 20: 321-7

23. Holman CP, Bell AFJ. A trial of evening primrose oil in the treatment of chronic51. Gwilt PR, Lear CL, Tempero MA, et al. The effect of garlic extract on humanschizophrenia. J Orthomolecular Psychiatry 1983; 12: 302-4

metabolism of acetaminophen. Cancer Epidemiol Biomarkers Prev 1994; 3:24. Aslam M, Stockley IH. Interaction between curry ingredient (karela) and drug

155-60(chlorpropamide). Lancet 1979; I: 607

52. Tebonin® Fachinformation. Karlsruhe, Germany: Dr Willmar Schwabe GmbH &25. Sunter WH. Warfarin and garlic [letter]. Pharm J 1991; 246: 722

Co., 2004. (Data on file)26. Pathak A, Leger P, Bagheri H, et al. Garlic interaction with fluindione: a case

53. Engelsen J, Nielsen JD, Winther K. Effect of coenzyme Q10 and Ginkgo biloba onreport. Therapie 2003; 58: 380-1

warfarin dosage in stable, long-term warfarin treated outpatients: a randomised,27. Laroche M, Choudri S, Gallicano K, et al. Severe gastrointestinal toxicity with double blind, placebo- crossover trial. Thromb Haemost 2002; 87: 1075-6

concomitant ingestion of ritonavir and garlic [abstract]. Can J Infect Dis 1998; 954. Yasui-Furukori N, Furukori H, Kaneda A, et al. The effects of Ginkgo biloba

Suppl. A: 471Pextracts on the pharmacokinetics and pharmacodynamics of donepezil. J Clin

28. Haase G, Riethling AK, Drewelow B. Serious ADR associated with Ginkgo biloba Pharmacol 2004; 44: 538-42[abstract]. Eur J Clin Pharmacol 2002; 58: S95

55. Duche JC, Barre J, Guinot P, et al. Effect of Ginkgo biloba extract on microsomal29. Rowin J, Lewis SL. Spontaneous bilateral subdural hematomas associated with enzyme induction. Int J Clin Pharmacol Res 1989; 9: 165-8

chronic Ginkgo biloba ingestion. Neurology 1996; 46: 1775-6 56. Smith M, Lin KM, Zheng YP. An open trial of nifedipine-herb interactions:30. Hoffman T. Ginko, Vioxx and excessive bleeding: possible drug-herb interactions: nifedipine with St. John’s wort, ginseng or Ginkgo biloba. Clin Pharmacol Ther

case report. Hawaii Med J 2001; 60: 290 2001; 69: P8631. Rosenblatt M, Mindel J. Spontaneous hyphema associated with ingestion of 57. Sun H, Zuo Z, Yin OQ, et al. A “high-throughput” cocktail method for screening

Ginkgo biloba extract. N Engl J Med 1997; 336: 1108 the effect of herbal product on liver isozyme activities: experience with Ginkgo32. Hauser D, Gayowski T, Singh N. Bleeding complications precipitated by unrecog- biloba. Clin Pharmacol Ther 2002; 71: P100

nized Gingko biloba use after liver transplantation. Transpl Int 2002; 15: 377-9 58. Mauro VF, Mauro LS, Kleshinski JF, et al. Impact of Ginkgo biloba on the33. Meisel C, Johne A, Roots I. Fatal intracerebral mass bleeding associated with pharmacokinetics of digoxin. Am J Ther 2003; 10: 247-51

Ginkgo biloba and ibuprofen. Atherosclerosis 2003; 167: 367 59. Markowitz JS, Donovan JL, Devane CL, et al. Multiple-dose administration of34. Matthews Jr MK. Association of Ginkgo biloba with intracerebral hemorrhage. Ginkgo biloba did not affect cytochrome P-450 2D6 or 3A4 activity in normal

Neurology 1998; 50: 1933-4 volunteers. J Clin Psychopharmacol 2003; 23: 576-8135. Galluzzi S, Zanetti O, Binetti G, et al. Coma in a patient with Alzheimer’s disease 60. Yin OQ, Tomlinson B, Waye MM, et al. Pharmacogenetics and herb-drug interac-

taking low dose trazodone and gingko biloba. J Neurol Neurosurg Psychiatry tions: experience with Ginkgo biloba and omeprazole. Pharmacogenetics 2004;2000; 68: 679-80 14: 841-50

36. Granger AS. Ginkgo biloba precipitating epileptic seizures. Age Ageing 2001; 30: 61. Yoshioka M, Ohnishi N, Koishi T, et al. Studies on interactions between functional523-5 foods or dietary supplements and medicines: IV. Effects of Ginkgo biloba leaf

37. Schelosky L, Raffauf C, Jendroska K, et al. Kava and dopamine antagonism. extract on the pharmacokinetics and pharmacodynamics of nifedipine inJ Neurol Neurosurg Psychiatry 1995; 58: 639-40 healthy volunteers. Biol Pharm Bull 2004; 27: 2006-9

38. Ballesteros S, Adan S, Ramon MF, et al. Severe adverse effect associated with kava 62. Uchida S, Yamada H, Li XD, et al. Effects of Ginkgo biloba extract onkava [abstract]. J Toxicol Clin Toxicol 2001; 39: 312 pharmacokinetics and pharmacodynamics of tolbutamide and midazolam [ab-

stract]. Clin Exp Pharmacol Physiol 2004; 31: A219-2039. Almeida JC, Grimsley EW. Coma from the health food store: interaction betweenkava and alprazolam. Ann Intern Med 1996; 125: 940-1 63. Greenblatt DJ, von Moltke LL, Perloff ES, et al. Effect of ginkgo on CYP2C9: in

vitro and in vivo studies. Clin Pharmacol Ther 2005; 77: P4840. Yue QY, Jansson K. Herbal drug curbicin and anticoagulant effect with andwithout warfarin: possibly related to the vitamin E component. J Am Geriatr 64. Sandhu RS, Prescilla RP, Simonelli TM, et al. Influence of goldenseal root on theSoc 2001; 49: 838 pharmacokinetics of indinavir. J Clin Pharmacol 2003; 43: 1283-8

© 2005 Adis Data Information BV. All rights reserved. Evid Based Integrative Med 2005; 2 (4)

Page 19: Clinical Drug Interactions with Medicinal Herbs

Clinical Herb-Drug Interactions 225

65. Gurley BJ, Gardner SF, Williams DK, et al. Effect of goldenseal, black cohosh, 89. Melchart D, Linde K, Fischer P, et al. Echinacea for preventing and treating thekava kava, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4 common cold. Cochrane Database Syst Rev 2000; (2): CD000530phenotypes [abstract]. Clin Pharmacol Ther 2005; 77: P36 90. Barrett B. Medicinal properties of Echinacea: a critical review. Phytomedicine

2003; 10: 66-8666. Tankanow R, Tamer HR, Streetman DS, et al. Interaction study between digoxinand a preparation of hawthorn (Crataegus oxyacantha). J Clin Pharmacol 2003; 91. Blumenthal M. The complete German commission E monographs, therapeutic43: 637-42 guide to herbal medicines. Austin (TX): American Botanical Council, 1998

67. Russmann S, Barguil Y, Wenk M, et al. Traditional aqueous kava extracts inhibit 92. Osowski S, Rostock M, Bartsch HH, et al. Pharmaceutical comparability ofCYP4501A2 in humans [abstract]. Clin Pharmacol Ther 2004; 75: P83 different therapeutic Echinacea preperations [in German]. Forsch Komple-

mentarmed Klass Naturheilkd 2000; 7: 294-30068. Herberg KW. Safety-related performance after intake of kava-extract, bromazepamand their combination [in German]. Z Allgemeinmed 1996; 72: 973-7 93. Perry NB, Burgess EJ, Glennie VL. Echinacea standardization: analytical methods

for phenolic compounds and typical levels in medicinal species. J Agric Food69. Foo H, Lemon J. Acute effects of kava, alone or in combination with alcohol, onChem 2001; 49: 1702-6subjective measures of impairment and intoxication and on cognitive perform-

ance. Drug Alcohol Rev 1997; 16: 147-55 94. Gilroy CM, Steiner JF, Byers T, et al. Echinacea and truth in labeling. Arch InternMed 2003; 163: 699-70470. Herberg KW. Effect of kava-special extract WS 1490 combined with ethyl alcohol

on safety-relevant performance parameters [in German]. Blutalkohol 1993; 30: 95. Mullins RJ, Heddle R. Adverse reactions associated with echinacea: the Australian96-105 experience. Ann Allergy Asthma Immunol 2002; 88: 42-51

71. Leber HW, Knauff S. Influence of silymarin on drug metabolizing enzymes in rat 96. Budzinski JW, Foster BC, Vandenhoek S, et al. An in vitro evaluation of humanand man. Arzneimittelforschung 1976; 26: 1603-5 cytochrome P450 3A4 inhibition by selected commercial herbal extracts and

tinctures. Phytomedicine 2000; 7: 273-8272. Piscitelli SC, Formentini E, Burstein AH, et al. Effect of milk thistle on the97. Strandell J, Neil A, Carlin G. An approach to the in vitro evaluation of potential forpharmacokinetics of indinavir in healthy volunteers. Pharmacotherapy 2002;

cytochrome P450 enzyme inhibition from herbals and other natural remedies.22: 551-6Phytomedicine 2004; 11: 98-10473. DiCenzo R, Shelton M, Jordan K, et al. Coadministration of milk thistle and

98. Dresser GK, McDonald W, Kim RB, et al. Evaluation of herbal products asindinavir in healthy subjects. Pharmacotherapy 2003; 23: 866-70potential inhibitors of MDR1 [abstract]. Clin Pharmacol Ther 2004; 75: P7974. Mills E, Wilson K, Clarke M, et al. Milk thistle and indinavir: a randomized

99. Manku MS, Horrobin DF, Morse NL, et al. Essential fatty acids in the plasmacontrolled pharmacokinetics study and meta-analysis. Eur J Clin Pharmacolphospholipids of patients with atopic eczema. Br J Dermatol 1984; 110: 643-82005; 61 (1): 1-7

100. Horrobin DF, Manku MS. Premenstrual syndrome and premenstrual breast pain75. Gurley BJ, Hubbard MA, Barone G, et al. Assessment of milk thistle and black(cyclical mastalgia): disorders of essential fatty acid (EFA) metabolism. Pros-cohosh supplementation on digoxin pharmacokinetics [abstract]. Clintaglandins Leukot Essent Fatty Acids 1989; 37: 255-61Pharmacol Ther 2005; 77: P49

101. Morse PF, Horrobin DF, Manku MS, et al. Meta-analysis of placebo-controlled76. Rajnarayana K, Reddy MS, Vidyasagar J, et al. Study on the influence of silymarinstudies of the efficacy of Epogam in the treatment of atopic eczema: relation-pretreatment on metabolism and disposition of metronidazole. Arzneimittelfor-ship between plasma essential fatty acid changes and clinical response. Br Jschung 2004; 54: 109-13Dermatol 1989; 121: 75-9077. Dresser GK, Wacher V, Wong S, et al. Evaluation of peppermint oil and ascorbyl

102. Little C, Parsons T. Herbal therapy for treating rheumatoid arthritis. Cochranepalmitate as inhibitors of cytochrome P4503A4 activity in vitro and in vivo.Database Syst Rev 2001; (1): CD002948Clin Pharmacol Ther 2002; 72: 247-55

103. Hardy ML. Herbs of special interest to women. J Am Pharm Assoc (Wash) 2000;78. Dresser GK, Wacher V, Ramtoola Z, et al. Peppermint oil increases the oral40: 234-42bioavailability of felodipine and simvastatin [abstract]. Clin Pharmacol Ther

2002; 71: P67 104. Martens-Lobenhoffer J, Meyer FP. Pharmacokinetic data of gamma-linolenic acidin healthy volunteers after the administration of evening primrose oil (Epogam).79. Markowitz JS, Donovan JL, Devane CL, et al. Multiple doses of saw palmettoInt J Clin Pharmacol Ther 1998; 36: 363-6(Serenoa repens) did not alter cytochrome P450 2D6 and 3A4 activity in

normal volunteers. Clin Pharmacol Ther 2003; 74: 536-42 105. Joy CB, Mumby-Croft R, Joy LA. Polyunsaturated fatty acid supplementation forschizophrenia. Cochrane Database Syst Rev 2003; (2): CD00125780. Mayer B, Springer E. Psychoexperimental studies on the effect of a valepotriate

combination as well as the combined effects of valtratum and alcohol [in 106. Lawson LD, Wang ZJ, Hughes BG. Identification and HPLC quantitation of theGerman]. Arzneimittelforschung 1974; 24: 2066-70 sulfides and dialk(en)yl thiosulfinates in commercial garlic products. Planta

Med 1991; 57: 363-7081. Kohnen R, Oswald WD. The effects of valerian, propranolol, and their combina-tion on activation, performance, and mood of healthy volunteers under social 107. Amagase H, Petesch BL, Matsuura H, et al. Intake of garlic and its bioactivestress conditions. Pharmacopsychiatry 1988; 21: 447-8 components. J Nutr 2001; 131: 955S-62S

82. Donovan JL, DeVane CL, Chavin KD, et al. Multiple night-time doses of valerian 108. Lawson LD, Wang ZJ. Low allicin release from garlic supplements: a major(Valeriana officinalis) had minimal effects on CYP3A4 activity and no effect problem due to the sensitivities of alliinase activity. J Agric Food Chem 2001;on CYP2D6 activity in healthy volunteers. Drug Metab Dispos 2004; 32: 49: 2592-91333-6 109. Schulz V, Hansel R, Tyler VE. Rational phytotherapy: a physicians’ guide to

83. Gagnier JJ, Chrubasik S, Manheimer E. Harpagophytum procumbens for osteoar- herbal medicine. 4th ed. Berlin: Springer Verlag, 2001thritis and low back pain: a systematic review. BMC Complement Altern Med 110. Ackermann RT, Mulrow CD, Ramirez G, et al. Garlic shows promise for improv-2004; 4: 13 ing some cardiovascular risk factors. Arch Intern Med 2001; 161: 813-24

84. Wegener T. Die Teufelskralle (Harpagophytum procumbens DC.) in der Therapie 111. Kiesewetter H, Jung F, Pindur G, et al. Effect of garlic on thrombocyte aggrega-rheumatischer Erkrankungen. Z Phytother 1998; 19: 284-94 tion, microcirculation, and other risk factors. Int J Clin Pharmacol Ther Toxicol

1991; 29: 151-585. Loew D, Mollerfeld J, Schrodter A, et al. Investigations on the pharmacokineticproperties of Harpagophytum extracts and their effects on eicosanoid biosyn- 112. Li G, Shi Z, Jia H, et al. A clinical investigation on garlicin injectio for treatment ofthesis in vitro and ex vivo. Clin Pharmacol Ther 2001; 69: 356-64 unstable angina pectoris and its actions on plasma endothelin and blood sugar

levels. J Tradit Chin Med 2000; 20: 243-686. Moussard C, Alber D, Toubin MM, et al. A drug used in traditional medicine,Harpagophytum procumbens: no evidence for NSAID-like effect on whole 113. Jain AK, Vargas R, Gotzkowsky S, et al. Can garlic reduce levels of serum lipids?blood eicosanoid production in human. Prostaglandins Leukot Essent Fatty A controlled clinical study. Am J Med 1993; 94: 632-5Acids 1992; 46: 283-6 114. Bordia A, Verma SK, Srivastava KC. Effect of garlic (Allium sativum) on blood

87. Borchers AT, Keen CL, Stern JS, et al. Inflammation and Native American lipids, blood sugar, fibrinogen and fibrinolytic activity in patients with coronarymedicine: the role of botanicals. Am J Clin Nutr 2000; 72: 339-47 artery disease. Prostaglandins Leukot Essent Fatty Acids 1998; 58: 257-63

88. Bauer R. Echinacea drugs: effects and active ingredients [in German]. Z Arztl 115. Sitprija S, Plengvidhya C, Kangkaya V, et al. Garlic and diabetes mellitus phase IIFortbild (Jena) 1996; 90: 111-5 clinical trial. J Med Assoc Thai 1987; 70 Suppl. 2: 223-7

© 2005 Adis Data Information BV. All rights reserved. Evid Based Integrative Med 2005; 2 (4)

Page 20: Clinical Drug Interactions with Medicinal Herbs

226 Johne & Roots

116. Mansell P, Reckless JP, Lloyd J. The effect of dried garlic powder tablets on serum 142. Pittler MH, Ernst E. Ginkgo biloba extract for the treatment of intermittentlipids in non-insulin dependent diabetic patients. Eur J Clin Res 1996; 8: 25-6 claudication: a meta-analysis of randomized trials. Am J Med 2000; 108:

276-81117. Grover JK, Yadav S, Vats V. Medicinal plants of India with anti-diabetic potential.J Ethnopharmacol 2002; 81: 81-100 143. Jaggy H, Koch E. Chemistry and biology of alkylphenols from Ginkgo biloba L.

Pharmazie 1997; 52: 735-8118. Basch E, Gabardi S, Ulbricht C. Bitter melon (Momordica charantia): a review ofefficacy and safety. Am J Health Syst Pharm 2003; 60: 356-9 144. Kressmann S, Muller WE, Blume HH. Pharmaceutical quality of different Ginkgo

biloba brands. J Pharm Pharmacol 2002; 54: 661-9119. Ali M, Thomson M, Afzal M. Garlic and onions: their effect on eicosanoidmetabolism and its clinical relevance. Prostaglandins Leukot Essent Fatty 145. Maclennan KM, Darlington CL, Smith PF. The CNS effects of Ginkgo bilobaAcids 2000; 62: 55-73 extracts and ginkgolide B. Prog Neurobiol 2002; 67: 235-57

120. Rahman K, Billington D. Dietary supplementation with aged garlic extract inhibits 146. Chung KF, Dent G, McCusker M, et al. Effect of a ginkgolide mixture (BN 52063)ADP-induced platelet aggregation in humans. J Nutr 2000; 130: 2662-5 in antagonising skin and platelet responses to platelet activating factor in man.

Lancet 1987; I: 248-51121. Steiner M, Lin RS. Changes in platelet function and susceptibility of lipoproteins tooxidation associated with administration of aged garlic extract. J Cardiovasc 147. Gilbert GJ. Ginkgo biloba [letter]. Neurology 1997; 48: 1137Pharmacol 1998; 31: 904-8 148. Vale S. Subarachnoid haemorrhage associated with Ginkgo biloba. Lancet 1998;

122. Bordia A, Verma SK, Srivastava KC. Effect of garlic on platelet aggregation in 352: 36humans: a study in healthy subjects and patients with coronary artery disease. 149. Benjamin J, Muir T, Briggs K, et al. A case of cerebral haemorrhage: can GinkgoProstaglandins Leukot Essent Fatty Acids 1996; 55: 201-5 biloba be implicated? Postgrad Med J 2001; 77: 112-3

123. Kiesewetter H, Jung F, Jung EM, et al. Effect of garlic on platelet aggregation in 150. Fessenden JM, Wittenborn W, Clarke L. Gingko biloba: a case report of herbalpatients with increased risk of juvenile ischaemic attack. Eur J Clin Pharmacol medicine and bleeding postoperatively from a laparoscopic cholecystectomy.1993; 45: 333-6 Am Surg 2001; 67: 33-5

124. Legnani C, Frascaro M, Guazzaloca G, et al. Effects of a dried garlic preparation on 151. Schneider C, Bord C, Misse P, et al. Spontaneous hyphema caused by Ginkgofibrinolysis and platelet aggregation in healthy subjects. Arzneimittelforschung biloba extract [in French]. J Fr Ophtalmol 2002; 25: 731-21993; 43: 119-22 152. Fong KC, Kinnear PE. Retrobulbar haemorrhage associated with chronic Gingko

125. Jain RC. Effect of garlic on serum lipids, coagulability and fibrinolytic activity of biloba ingestion. Postgrad Med J 2003; 79: 531-2blood. Am J Clin Nutr 1977; 30: 1380-1 153. Israeli A, Matzner Y, Or R, et al. Glibenclamide causing thrombocytopenia and

126. Rose KD, Croissant PD, Parliament CF, et al. Spontaneous spinal epidural hemato- bleeding tendency: case reports and a review of the literature. Klin Wochenschrma with associated platelet dysfunction from excessive garlic ingestion: a case 1988; 66: 223-4report. Neurosurgery 1990; 26: 880-2 154. Weaver AL. Rofecoxib: clinical pharmacology and clinical experience. Clin Ther

127. German K, Kumar U, Blackford HN. Garlic and the risk of TURP bleeding. Br J 2001; 23: 1323-38Urol 1995; 76: 518 155. Kim YS, Pyo MK, Park KM, et al. Antiplatelet and antithrombotic effects of a

128. Burnham BE. Garlic as a possible risk for postoperative bleeding. Plast Reconstr combination of ticlopidine and Ginkgo biloba ext (EGb 761). Thromb ResSurg 1995; 95: 213 1998; 91: 33-8

129. Harenberg J, Giese C, Zimmermann R. Effect of dried garlic on blood coagulation, 156. Koch E. Inhibition of platelet activating factor (PAF)-induced aggregation offibrinolysis, platelet aggregation and serum cholesterol levels in patients with human thrombocytes by ginkgolides: considerations on possible bleeding com-hyperlipoproteinemia. Atherosclerosis 1988; 74: 247-9 plications after oral intake of Ginkgo biloba extracts. Phytomedicine 2005; 12:

130. Luley C, Lehmann-Leo W, Moller B, et al. Lack of efficacy of dried garlic in 10-6patients with hyperlipoproteinemia. Arzneimittelforschung 1986; 36: 766-8 157. Guinot P, Caffrey E, Lambe R, et al. Tanakan inhibits platelet-activating-factor-

131. Siess MH, Le Bon AM, Canivenc-Lavier MC, et al. Modification of hepatic drug- induced platelet aggregation in healthy male volunteers. Haemostasis 1989; 19:metabolizing enzymes in rats treated with alkyl sulfides. Cancer Lett 1997; 120: 219-23195-201 158. Jung F, Mrowietz C, Kiesewetter H, et al. Effect of Ginkgo biloba on fluidity of

132. Sheen LY, Chen HW, Kung YL, et al. Effects of garlic oil and its organosulfur blood and peripheral microcirculation in volunteers. Arzneimittelforschungcompounds on the activities of hepatic drug-metabolizing and antioxidant 1990; 40: 589-93enzymes in rats fed high- and low-fat diets. Nutr Cancer 1999; 35: 160-6 159. Bal Dit Sollier C, Caplain H, Drouet L. No alteration in platelet function or

133. Guyonnet D, Siess MH, Le Bon AM, et al. Modulation of phase II enzymes by coagulation induced by EGb761 in a controlled study. Clin Lab Haematol 2003;organosulfur compounds from allium vegetables in rat tissues. Toxicol Appl 25: 251-3Pharmacol 1999; 154: 50-8 160. Mehlsen J, Drabaek H, Wiinberg N, et al. Effects of a Ginkgo biloba extract on

134. Fujita K, Kamataki T. Screening of organosulfur compounds as inhibitors of forearm haemodynamics in healthy volunteers. Clin Physiol Funct Imaginghuman CYP2A6. Drug Metab Dispos 2001; 29: 983-9 2002; 22: 375-8

135. Wu CC, Sheen LY, Chen HW, et al. Differential effects of garlic oil and its three 161. Nilsson OG, Lindgren A, Stahl N, et al. Incidence of intracerebral and subarach-major organosulfur components on the hepatic detoxification system in rats. J noid haemorrhage in southern Sweden. J Neurol Neurosurg Psychiatry 2000;Agric Food Chem 2002; 50: 378-83 69: 601-7

136. Foster BC, Foster MS, Vandenhoek S, et al. An in vitro evaluation of human 162. Jezova D, Duncko R, Lassanova M, et al. Reduction of rise in blood pressure andcytochrome P450 3A4 and P-glycoprotein inhibition by garlic. J Pharm Pharm cortisol release during stress by Ginkgo biloba extract (EGb 761) in healthySci 2001; 4: 176-84 volunteers. J Physiol Pharmacol 2002; 53: 337-48

137. Arora A, Seth K, Shukla Y. Reversal of P-glycoprotein-mediated multidrug 163. Lagrue G, Behar A, Kazandjian M, et al. Idiopathic cyclic edema: the role ofresistance by diallyl sulfide in K562 leukemic cells and in mouse liver. capillary hyperpermeability and its correction by Ginkgo biloba extract [inCarcinogenesis 2004; 25: 941-9 French]. Presse Med 1986; 15: 1550-3

138. Yang CS, Chhabra SK, Hong JY, et al. Mechanisms of inhibition of chemical 164. Sasaki K, Hatta S, Haga M, et al. Effects of bilobalide on gamma-aminobutyrictoxicity and carcinogenesis by diallyl sulfide (DAS) and related compounds acid levels and glutamic acid decarboxylase in mouse brain. Eur J Pharmacolfrom garlic. J Nutr 2001; 131: 1041S-5S 1999; 367: 165-73

139. DeFeudis FV, Drieu K. Ginkgo biloba extract (EGb 761) and CNS functions: basic 165. Schubert H, Halama P. Primar therapieresistente depressive Verstimmung altererstudies and clinical applications. Curr Drug Targets 2000; 1: 25-58 Patienten mit Hirnleistungsstorrungen: Wirksamkeit der Kombination von

Ginkgo-biloba-Extrakt EGb 761 mit Antidepressiva. Geriat Forsch 1993; 3:140. Blumenthal M. Herbs continue slide in mainstream market: sales down 14 percent.45-53HerbalGram 2003; 58: 71

141. Birks J, Grimley EJ, Van Dongen M. Ginkgo biloba for cognitive impairment and 166. Cohen AJ, Bartlik B. Ginkgo biloba for antidepressant-induced sexual dysfunction.dementia. Cochrane Database Syst Rev 2002; (4): CD003120 J Sex Marital Ther 1998; 24: 139-43

© 2005 Adis Data Information BV. All rights reserved. Evid Based Integrative Med 2005; 2 (4)

Page 21: Clinical Drug Interactions with Medicinal Herbs

Clinical Herb-Drug Interactions 227

167. Wheatley D. Ginkgo biloba relieves sexual dysfunction due to antidepressant 194. Mathews JD, Riley MD, Fejo L, et al. Effects of the heavy usage of kava ondrugs. Eur Neuropsychopharmacol 1999; 9: S253-4 physical health: summary of a pilot survey in an aboriginal community. Med J

Aust 1988; 148: 548-55168. Ashton AK, Ahrens K, Gupta S, et al. Antidepressant-induced sexual dysfunctionand Ginkgo biloba. Am J Psychiatry 2000; 157: 836-7 195. From the Centers for Disease Control and Prevention. Hepatic toxicity possibly

associated with kava-containing products: United States, Germany, and Swit-169. Kang BJ, Lee SJ, Kim MD, et al. A placebo-controlled, double-blind trial ofzerland, 1999-2002. JAMA 2003; 289: 36-7Ginkgo biloba for antidepressant-induced sexual dysfunction. Hum

Psychopharmacol 2002; 17: 279-84 196. Bauer R, Kopp B, Nahrstedt A. Relevant hepatotoxic effects of kava still need to beproven: a statement of the society for medicinal plant research. Planta Med170. Zhang XY, Zhou DF, Zhang PY, et al. A double-blind, placebo-controlled trial of2003; 69: 971-2extract of Ginkgo biloba added to haloperidol in treatment-resistant patients

with schizophrenia. J Clin Psychiatry 2001; 62: 878-83 197. Anke J, Ramzan I. Kava hepatotoxicity: are we any closer to the truth. Planta Med171. Gregory PJ. Seizure associated with Ginkgo biloba? [letter]. Ann Intern Med 2001; 2004; 70: 193-6

134: 344 198. Russmann S, Lauterburg BH, Helbling A. Kava hepatotoxicity. Ann Intern Med172. Kajiyama Y, Fujii K, Takeuchi H, et al. Ginkgo seed poisoning. Pediatrics 2002; 2001; 135: 68-9

109: 325-7 199. Clouatre DL. Kava kava: examining new reports of toxicity. Toxicol Lett 2004;173. Miwa H, Iijima M, Tanaka S, et al. Generalized convulsions after consuming a 150: 85-96

large amount of gingko nuts. Epilepsia 2001; 42: 280-1 200. Zou L, Harkey MR, Henderson GL, et al. Kava does not display metabolic toxicity174. Arenz A, Klein M, Fiehe K, et al. Occurrence of neurotoxic 4′-0-methylpyridoxin in a homogeneous cellular assay. Planta Med 2004; 70: 289-92

in Ginkgo biloba leaves, medications and Japanese ginkgo food. Planta Med 201. Mathews JM, Etheridge AS, Black SR. Inhibition of human cytochrome P4501996; 62: 548-51 activities by kava extract and kavalactones. Drug Metab Dispos 2002; 30:

175. Wada K, Ishigaki S, Ueda K, et al. An antivitamin B6, 4′-methoxypyridoxine, from 1153-7the seed of Ginkgo biloba L. Chem Pharm Bull (Tokyo) 1985; 33: 3555-7 202. Unger M, Holzgrabe U, Jacobsen W, et al. Inhibition of cytochrome P450 3A4 by

176. Manocha A, Pillai KK, Husain SZ. Effect of Ginkgo biloba on chemoshock in extracts and kavalactones of Piper methysticum (Kava-Kava). Planta Medmice. Ind J Pharmacol 1997; 29: 198-200 2002; 68: 1055-8

177. Manocha A, Pillai KK, Husain SZ. Influence of Ginkgo biloba on the effect of 203. Raucy JL. Regulation of CYP3A4 expression in human hepatocytes byanticonvulsants. Indian J Pharmacol 1996; 28: 84-7 pharmaceuticals and natural products. Drug Metab Dispos 2003; 31: 533-9

178. Gaudineau C, Beckerman R, Welbourn S, et al. Inhibition of human P450 enzymes 204. Zou L, Henderson GL, Harkey MR, et al. Effects of kava (kava-kava, ‘Awa,by multiple constituents of the Ginkgo biloba extract. Biochem Biophys Res Yaqona, Piper methysticum) on c-DNA-expressed cytochrome P450 enzymesCommun 2004; 318: 1072-8 and human cryopreserved hepatocytes. Phytomedicine 2004; 11: 285-94

179. von Moltke LL, Weemhoff JL, Bedir E, et al. Inhibition of human cytochromes 205. Cote CS, Kor C, Cohen J, et al. Composition and biological activity of traditionalP450 by components of Ginkgo biloba. J Pharm Pharmacol 2004; 56: 1039-44 and commercial kava extracts. Biochem Biophys Res Commun 2004; 322:

180. Mahady GB, Chadwick LR. Goldenseal (Hydrastis canadensis): is there enough 147-52scientific evidence to support safety and efficacy? Nutr Clin Care 2001; 4: 206. Spillane PK, Fisher DA, Currie BJ. Neurological manifestations of kava intoxica-243-9 tion. Med J Aust 1997; 167: 172-3

181. Edwards DJ, Draper EJ. Variations in alkaloid content of herbal products contain-207. Dinh LD, Simmen U, Bueter KB, et al. Interaction of various Piper methysticum

ing goldenseal. J Am Pharm Assoc 2003; 43: 419-23cultivars with CNS receptors in vitro. Planta Med 2001; 67: 306-11

182. Foster BC, Vandenhoek S, Hana J, et al. In vitro inhibition of human cytochrome208. Baum SS, Hill R, Rommelspacher H. Effect of kava extract and individual

P450-mediated metabolism of marker substrates by natural products.kavapyrones on neurotransmitter levels in the nucleus accumbens of rats. Prog

Phytomedicine 2003; 10: 334-42Neuropsychopharmacol Biol Psychiatry 1998; 22: 1105-20

183. Chatterjee P, Franklin MR. Human cytochrome P450 inhibition and metabolic-209. Boerner RJ, Klement S. Attenuation of neuroleptic-induced extrapyramidal sideintermediate complex formation by goldenseal extract and its methylenediox-

effects by Kava special extract WS 1490. Wien Med Wochenschr 2004; 154:yphenyl components. Drug Metab Dispos 2003; 31: 1391-7508-10

184. Lin HL, Liu TY, Lui WY, et al. Up-regulation of multidrug resistance transporter210. Friese J, Gleitz J. Kavain, dihydrokavain, and dihydromethysticin non-competi-expression by berberine in human and murine hepatoma cells. Cancer 1999; 85:

tively inhibit the specific binding of [3H]-batrachotoxinin-A 20-alpha-benzoate1937-42to receptor site 2 of voltage-gated Na+ channels. Planta Med 1998; 64: 458-9

185. Maeng HJ, Yoo HJ, Kim IW, et al. P-glycoprotein-mediated transport of berberine211. Gleitz J, Friese J, Beile A, et al. Anticonvulsive action of (+/–)-kavain estimatedacross Caco-2 cell monolayers. J Pharm Sci 2002; 91: 2614-21

from its properties on stimulated synaptosomes and Na+ channel receptor sites.186. Rigelsky JM, Sweet BV. Hawthorn: pharmacology and therapeutic uses. Am JEur J Pharmacol 1996; 315: 89-97Health Syst Pharm 2002; 59: 417-22

212. Jussofie A, Schmiz A, Hiemke C. Kavapyrone enriched extract from Piper187. Vierling W, Brand N, Gaedcke F, et al. Investigation of the pharmaceutical andmethysticum as modulator of the GABA binding site in different regions of ratpharmacological equivalence of different hawthorn extracts. Phytomedicinebrain. Psychopharmacology (Berl) 1994; 116: 469-742003; 10: 8-16

213. Woelk H, Kapoula O, Lehrl S, et al. Treatment of anxiety patients. Double-blind188. Pittler MH, Schmidt K, Ernst E. Hawthorn extract for treating chronic heart failure:study: kava special extract WS 1490 versus benzodiazepine [in German]. Zmeta-analysis of randomized trials. Am J Med 2003; 114: 665-74Allg Med 1993; 69: 271-7

189. Weikl A, Assmus KD, Neukum-Schmidt A, et al. Crataegus special extract WS214. Geβner B, Cnota P. Untersuchungen der Vigilanz nach Applikation von Kava-1442: assessment of objective effectiveness in patients with heart failure

Kava-Extrakt, Diazepam oder Plazebo. Z Phytother 1994; 15: 30-7(NYHA II) [in German]. Fortschr Med 1996; 114: 291-6215. Davis KM, Wu JY. Role of glutamatergic and GABAergic systems in alcoholism. J190. Tauchert M. Efficacy and safety of crataegus extract WS 1442 in comparison with

Biomed Sci 2001; 8: 7-19placebo in patients with chronic stable New York Heart Association class-III216. Rotblatt MD. Cranberry, feverfew, horse chestnut, and kava. West J Med 1999;heart failure. Am Heart J 2002; 143: 910-5

171: 195-8191. Wolkerstorfer H. Treatment of heart disease with a digoxin-crataegus combination217. Perez J, Holmes JF. Altered mental status and ataxia secondary to acute Kava[in German]. Munch Med Wochenschr 1966; 108: 438-41

ingestion. J Emerg Med 2005; 28: 49-51192. Holubarsch CJ, Colucci WS, Meinertz T, et al. Survival and Prognosis: Investiga-218. Jamieson DD, Duffield PH. Positive interaction of ethanol and kava resin in mice.tion of Crataegus extract WS 1442 in congestive heart failure (SPICE):

Clin Exp Pharmacol Physiol 1990; 17: 509-14rationale, study design and study protocol. Eur J Heart Fail 2000; 2: 431-7193. Pittler MH, Ernst E. Kava extract for treating anxiety. Cochrane Database Syst Rev 219. Saller R, Meier R, Brignoli R. The use of silymarin in the treatment of liver

2003; (1): CD003383 diseases. Drugs 2001; 61: 2035-63

© 2005 Adis Data Information BV. All rights reserved. Evid Based Integrative Med 2005; 2 (4)

Page 22: Clinical Drug Interactions with Medicinal Herbs

228 Johne & Roots

220. Wagner H, Diesel P, Seitz M. The chemistry and analysis of silymarin from 244. Houghton PJ. The scientific basis for the reputed activity of valerian. J PharmSilybum marianum Gaertn [in German]. Arzneimittelforschung 1974; 24: Pharmacol 1999; 51: 505-12466-71 245. Bounthanh C, Bergmann C, Beck JP, et al. Valepotriates, a new class of cytotoxic

221. Enjalbert F, Rapior S, Nouguier-Soule J, et al. Treatment of amatoxin poisoning: and antitumor agents. Planta Med 1981; 41: 21-820-year retrospective analysis. J Toxicol Clin Toxicol 2002; 40: 715-57

246. Bos R, Hendriks H, Scheffer JJC, et al. Cytotoxic potential of valerian constituents222. Beckmann-Knopp S, Rietbrock S, Weyhenmeyer R, et al. Inhibitory effects of and valerian tinctures. Phytomedicine 1998; 5: 219-25

silibinin on cytochrome P-450 enzymes in human liver microsomes. Pharmacol247. Shohet D, Wills RBH, Stuart DL. Valepotriates and valerenic acids in commercialToxicol 2000; 86: 250-6

preparations of valerian available in Australia. Pharmazie 2001; 56: 860-3223. Venkataramanan R, Ramachandran V, Komoroski BJ, et al. Milk thistle, a herbal

248. MacGregor FB, Abernethy VE, Dahabra S, et al. Hepatotoxicity of herbal reme-supplement, decreases the activity of CYP3A4 and uridine diphosphoglucuro-dies. BMJ 1989; 299: 1156-7nosyl transferase in human hepatocyte cultures. Drug Metab Dispos 2000; 28:

1270-3 249. Chan TY, Tang CH, Critchley JA. Poisoning due to an over-the-counter hypnotic,Sleep-Qik (hyoscine, cyproheptadine, valerian). Postgrad Med J 1995; 71:224. Zuber R, Modriansky M, Dvorak Z, et al. Effect of silybin and its congeners on227-8human liver microsomal cytochrome P450 activities. Phytother Res 2002; 16:

632-8 250. Chan TY. An assessment of the delayed effects associated with valerian overdose.225. Zhang S, Morris ME. Effect of the flavonoids biochanin A and silymarin on the P- Int J Clin Pharmacol Ther 1998; 36: 569

glycoprotein-mediated transport of digoxin and vinblastine in human intestinal 251. Riedel E, Hansel R, Ehrke G. Inhibition of gamma-aminobutyric acid catabolismCaco-2 cells. Pharm Res 2003; 20: 1184-91 by valerenic acid derivatives [in German]. Planta Med 1982; 46: 219-20

226. Jordt SE, McKemy DD, Julius D. Lessons from peppers and peppermint: the252. Ortiz JG, Nieves-Natal J, Chavez P. Effects of Valeriana officinalis extracts on

molecular logic of thermosensation. Curr Opin Neurobiol 2003; 13: 487-92[3H]flunitrazepam binding, synaptosomal [3H]GABA uptake, and hippocam-

227. Hawthorn M, Ferrante J, Luchowski E, et al. The actions of peppermint oil and pal [3H]GABA release. Neurochem Res 1999; 24: 1373-8menthol on calcium channel dependent processes in intestinal, neuronal and

253. Donath F, Quispe S, Diefenbach K, et al. Critical evaluation of the effect ofcardiac preparations. Aliment Pharmacol Ther 1988; 2: 101-18valerian extract on sleep structure and sleep quality. Pharmacopsychiatry 2000;

228. Hills JM, Aaronson PI. The mechanism of action of peppermint oil on gastrointesti-33: 47-53

nal smooth muscle: an analysis using patch clamp electrophysiology and254. Dorn M. Efficacy and tolerability of Baldrian versus oxazepam in non-organic andisolated tissue pharmacology in rabbit and guinea pig. Gastroenterology 1991;

non-psychiatric insomniacs: a randomised, double-blind, clinical, comparative101: 55-65study [in German]. Forsch Komplementarmed Klass Naturheilkd 2000; 7:229. Eccles R. Menthol: effects on nasal sensation of airflow and the drive to breathe.79-84Curr Allergy Asthma Rep 2003; 3: 210-4

255. Garges HP, Varia I, Doraiswamy PM. Cardiac complications and delirium associ-230. Gobel H, Fresenius J, Heinze A, et al. Effectiveness of Oleum menthae piperitaeated with valerian root withdrawal. JAMA 1998; 280: 1566-7and paracetamol in therapy of headache of the tension type [in German].

Nervenarzt 1996; 67: 672-81 256. Lindenmayer JP. The pathophysiology of agitation. J Clin Psychiatry 2000; 61:5-10231. Javorka K, Tomori Z, Zavarska L. Protective and defensive airway reflexes in

premature infants. Physiol Bohemoslov 1980; 29: 29-35 257. van der Mast RC, Fekkes D. Serotonin and amino acids: partners in delirium232. Wyllie JP, Alexander FW. Nasal instillation of ‘Olbas Oil’ in an infant. Arch Dis pathophysiology? Semin Clin Neuropsychiatry 2000; 5: 125-31

Child 1994; 70: 357-8 258. Schwartz RH, Rodriquez WJ. Toxic delirium possibly caused by loperamide. J233. Pittler MH, Ernst E. Peppermint oil for irritable bowel syndrome: a critical review Pediatr 1991; 118: 656-7

and metaanalysis. Am J Gastroenterol 1998; 93: 1131-5259. Chang PH, Steinberg MB. Alcohol withdrawal. Med Clin North Am 2001; 85:

234. Dalvi SS, Nadkarni PM, Pardesi R, et al. Effect of peppermint oil on gastric 1191-212emptying in man: a preliminary study using a radiolabelled solid test meal.

260. Leuschner J, Muller J, Rudmann M. Characterisation of the central nervousIndian J Physiol Pharmacol 1991; 35: 212-4depressant activity of a commercially available valerian root extract. Arzneimit-

235. Micklefield GH, Greving I, May B. Effects of peppermint oil and caraway oil ontelforschung 1993; 43: 638-41

gastroduodenal motility. Phytother Res 2000; 14: 20-3261. Waked M, Bismuth C, Capron F, et al. Lipid pneumonia discovered in a case of236. Goerg KJ, Spilker T. Effect of peppermint oil and caraway oil on gastrointestinal

epiphenomenal drug poisoning [in French]. Presse Med 1991; 20: 178motility in healthy volunteers: a pharmacodynamic study using simultaneous262. Willey LB, Mady SP, Cobaugh DJ, et al. Valerian overdose: a case report. Vetdetermination of gastric and gall-bladder emptying and orocaecal transit time.

Hum Toxicol 1995; 37: 364-5Aliment Pharmacol Ther 2003; 17: 445-51

237. Gelal A, Guven H, Balkan D, et al. Influence of menthol on caffeine disposition 263. Wells SR. Intentional intravenous administration of a crude valerian root extractand pharmacodynamics in healthy female volunteers. Eur J Clin Pharmacol [abstract]. J Toxicol Clin Toxicol 1995; 33: 5422003; 59: 417-22 264. Mullins ME, Horowitz BZ. The case of the salad shooters: intravenous injection of

238. Maliakal PP, Wanwimolruk S. Effect of herbal teas on hepatic drug metabolizing wild lettuce extract. Vet Hum Toxicol 1998; 40: 290-1enzymes in rats. J Pharm Pharmacol 2001; 53: 1323-9

265. Barnes J, Mills SY, Abbot NC, et al. Different standards for reporting ADRs to239. Wacher VJ, Wong S, Wong HT. Peppermint oil enhances cyclosporine oral herbal remedies and conventional OTC medicines: face-to-face interviews with

bioavailability in rats: comparison with D-alpha-tocopheryl poly(ethylene gly- 515 users of herbal remedies. Br J Clin Pharmacol 1998; 45: 496-500col 1000) succinate (TPGS) and ketoconazole. J Pharm Sci 2002; 91: 77-90

266. Ernst E. Challenges for phytopharmacovigilance. Postgrad Med J 2004; 80: 249-50240. Wilt T, Ishani A, MacDonald R. Serenoa repens for benign prostatic hyperplasia.

267. Butterweck V, Derendorf H, Gaus W, et al. Pharmacokinetic herb-drug interac-Cochrane Database Syst Rev 2002; (3): CD001423tions: are preventive screenings necessary and appropriate? Planta Med 2004;241. Habib FK, Wyllie MG. Not all brands are created equal: a comparison of selected70: 784-91components of different brands of Serenoa repens extract. Prostate Cancer

Prostatic Dis 2004; 7: 195-200

242. Buck AC. Is there a scientific basis for the therapeutic effects of serenoa repens inCorrespondence and offprints: Dr Andreas Johne, Institut fur Klinischebenign prostatic hyperplasia? Mechanisms of action. J Urol 2004; 172: 1792-9Pharmakologie, Charite, Campus Mitte, Universitatsmedizin Charite,243. Cheema P, El-Mefty O, Jazieh AR. Intraoperative haemorrhage associated with theSchumannstr. 20/21, Berlin, 10098, Germany.use of extract of saw palmetto herb: a case report and review of literature. J

Intern Med 2001; 250: 167-9 E-mail: [email protected]

© 2005 Adis Data Information BV. All rights reserved. Evid Based Integrative Med 2005; 2 (4)