Cardiovascular pharmacotherapy and herbal medicines: the risk of drug interaction (Review)

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Review

Cardiovascular pharmacotherapy and herbal medicines:

the risk of drug interaction

Angelo A. Izzoa,*, Giulia Di Carloa , Francesca Borrellia , Edzard Ernst b

a Department of Experimental Pharmacology, University of Naples ‘‘Federico II’’, via D. Montesano 49, 80131 Naples, Italy bComplementary Medicine, Penninsula Medical School, Universities of Exeter and Plymouth, 25 Victoria Park Road, EX2 4NT, UK

Received 18 April 2003; received in revised form 10 June 2003; accepted 14 June 2003

Available online 21 February 2004

Abstract

Use of herbal medicines among patients under cardiovascular pharmacotherapy is widespread. In this paper, we have reviewed the

literature to determine the possible interactions between herbal medicines and cardiovascular drugs. The Medline database was searched for

clinical articles published between January 1996 and February 2003. Forty-three case reports and eight clinical trials were identified.

Warfarin was the most common cardiovascular drug involved. It was found to interact with boldo, curbicin, fenugreek, garlic, danshen,

devil’s claw, don quai, ginkgo, papaya, lycium, mango, PC-SPES (resulting in over-anticoagulation) and with ginseng, green tea, soy and St.

John’s wort (causing decreased anticoagulant effect). Gum guar, St. John’s wort, Siberian ginseng and wheat bran were found to decrease

plasma digoxin concentration; aspirin interactions include spontaneous hyphema when associated with ginkgo and increased bioavailability if

combined with tamarind. Decreased plasma concentration of simvastatin or lovastatin was observed after co-administration with St. John’s

wort and wheat bran, respectively. Other adverse events include hypertension after co-administration of ginkgo and a diuretic thiazide,

hypokalemia after liquorice and antihypertensives and anticoagulation after phenprocoumon and St. John’s wort. Interaction between herbal

medicine and cardiovascular drugs is a potentially important safety issue. Patients taking anticoagulants are at the highest risk.

D 2004 Elsevier Ireland Ltd. All rights reserved.

Keywords: Cardiovascular pharmacotherapy; Herbal medicines; Drug interaction

1. Introduction

Interest in ‘‘alternative’’ medicine including plant-de-

rived medications is growing. Self-administration of herbal

medicines is among the most popular of alternative therapies

[1,2]. In the US, the market for herbal medicinal products

(usually sold as food supplements or nutraceuticals)

amounted to US$590.9 million [3]. These sales figures

relate only to food stores, drug stores and mass market

and would obviously be larger if buying clubs, convenience

stores, natural food markets, multilevel marketing compa-

nies, health professionals, mail or Internet order had been

considered. The relevance of alternative therapies for car-

diovascular medicine is highlighted by the recent workshop

on the use of herbal medicines in cardiovascular, lung and

blood research sponsored by the US National Heart, Lung,

and Blood Institute [4].

In view of the increasing use of herbal remedies by the

general public and subsequent interest by the authorities, it

is imperative to promote credible research on the safety of

herbal products including the possibility of interactions with

concurrent cardiovascular pharmacotherapy. Providing ac-

curate and clinically relevant advice to patients regarding

the possibility of herb–drug interactions is a challenge for

healthcare practitioners.

Because all herbal medicines are mixtures of more than

one active ingredient, they obviously increase the likelihood

of herb –drug interactions [5]. Moreover, the majority of

people who use herbal products do not reveal this to their

physician or pharmacist [2]. This increases the likelihood

that herb–drug interactions are not identified and resolved

in a timely manner. Nevertheless, recent data indicate that

potentially serious interactions exist between some common

herbal remedies and widely used conventional pharmaceut-

icals [6–16], including those used in the therapy of cardio-

vascular diseases [17–20].

In this article, we review the existing clinical data on

suspected interactions between herbal medicine and con-

0167-5273/$ - see front matter D 2004 Elsevier Ireland Ltd. All rights reserved.

doi:10.1016/j.ijcard.2003.06.039

* Corresponding author. Tel.: +39-81-678439; fax: +39-81-678403.

E-mail address: [email protected] (A.A. Izzo).

www.elsevier.com/locate/ijcard

International Journal of Cardiology 98 (2005) 1–14


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Table 1

Clinical interactions between herbal medicines and conventional cardiovascular drugs

Conventional

drug

Herbal

medicine

Result of

interaction

Possible

mechanism

Pharmacological

comment

Clinical

comment

No. of ca

Interaction with cardiac drugs

Digoxin Gum guar Decreased

plasma digoxin

concentration

Reduced absorption Guar gum reduces

gastric emptying,

which result in a

transient delayed

digoxin absorption.

Similar amount

of digoxin was

found in 24-h urine

whether given with

or without guar gum.

a

Digoxin St. John’s

wort

Decreased

plasma digoxin

concentration

Induction

of P-glycoprotein

Digoxin is a substrate

of P-glycoprotein

which is induced by

St. John’s wort.

St. John’s wort may

reduce efficacy of

digoxin and make a

patient a nonresponder.

a

Digoxin Siberian

ginseng

Increased

plasma digoxin

concentration

Some component

of Siberian ginseng

might impair digoxin

elimination or

interfere with the

digoxin assay.

Siberian ginseng

inhibits the

metabolism of

hexobarbital

in mice.

The patient was

asymptomatic for

digoxin toxicity

despite a level of

2.5 ng/l.

1

Digoxin Wheat bran Decreased

plasma digoxin

concentration

Reduced absorption Bran contains fibers

which can trap

digoxin.

Digoxin levels

were still within

the therapeutic range.

a

Interactions with antihypertensive drugs

Diuretic thiazide Ginkgo Increase in blood

pressure

Not known This interaction is

surprising as Ginkgo

is a peripheralvasodilatator.

If confirmed, the

interaction is

potentially dangerous.

1

Antihypertensives Liquorice Hypokalemia Additive effect

on potassium

excretion

Some antihypertensive

drugs induce

hypokalemia; liquorice

has mineralcorticoid

effects which may

cause potassium

excretion.

Serum potassium

levels should be

monitored closely

in patients who are

predisposed to

cardiac arrhythmias

and who are

concurrently treated

with digitalis

glycosides.

1


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Interactions with antiplatet drugs

Aspirin Ginkgo Spontaneous

hyphema

Additive

inhibition

of platelet

aggregation

Ginkgolides from

ginkgo have

antiplatelet activity

and are PAF receptor

antagonists.

Spontaneous bleeding

from the iris into

the anterior chamber

of the eye is a rare

problem.

1

Aspirin Tamarind Increased

bioavailability

of aspirin

Not known Uncertain a

Interactions with anticoagulants

Warfarin Boldo/

Fenugreek

Increased

anticoagulant

effect

Additive effect

on coagulation

mechanisms

Both boldo and

fenugreek contain

anticoagulant

coumarins.

Risk of bleeding;

given the narrow

therapeutic index of

warfarin, vigilance

is needed.

1

Warfarin Curbicin Increased

anticoagulant

effect

Additive effect

on coagulation

mechanisms

Vitamin E contained

in curbicin can

antagonize the

effect of vitamin

K on coagulation.

Cases of coagulation

disorders related to

vitamin E have

been reported.

2

Warfarin Danshen Increased

anticoagulant

effect

Additive effect

on coagulation

mechanisms

and/or increased

plasma warfarin

concentration

In addition to its

antiplatelet activity,

danshen decreases

warfarin elimination

in rats.

Risk of bleeding;

given the narrow

therapeutic index

of warfarin, vigilance

is needed.

3

Warfarin Devil’s claw Increased

anticoagulant

effect, purpura

Unknown In contrast to NSAIDs,

devil’s claw does not

affect platelet function.

Risk of bleeding;

given the narrow

therapeutic index

of warfarin, vigilance

is needed.

1

Warfarin Dong quai Increased

anticoagulant

effect

Additive effect

on coagulation

mechanisms

Dong quai contains

anticoagulant

coumarins.

Risk of bleeding;

given the narrow

therapeutic index of

warfarin, vigilance

is needed.

2

Warfarin Garlic Increased

anticoagulant

effect; increase

in clotting time

Additive effect

on coagulation

mechanisms

Garlic has antiplatelet

activity.

Garlic treatment has

been associated

with bleeding even in

the absence of

warfarin or other

anticoagulant

treatment.

2


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Table 1 (continued )

Conventional

drug

Herbal

medicine

Result of

interaction

Possible

mechanism

Pharmacological

comment

Clinical

comment

No. of ca

Interactions with anticoagulants

Warfarin Ginkgo Intracerebral

hemorrhage

Additive effect

on coagulation

mechanisms

Ginkgolides from

ginkgo have antiplatelet

activity and are PAF

receptor antagonists.

Spontaneous bilateral

subdural haematomas

associated with

long-term ginkgo

ingestion have been

reported (even in the

absence of

anticoagulants).

1

Warfarin Ginseng Decreased

anticoagulant

effect

Unknown Antiplatelet activity

of ginseng has been

reported but would

not seem to explain

this case of decreased

anticoagulation;

a pharmacokinetic study

in rats did not reveal a

significant interaction

between warfarin and

ginseng.

Potential seriousness

of thrombotic

complications

1

Warfarin Green tea Decreased

anticoagulant

effect

Pharmacological

antagonism

Warfarin produces

anticoagulation

by inhibiting

production of the

vitamin-K dependent

clotting factors.

Green tea contains

vitamin K and

thus antagonize the

effect of warfarin.

Patients receiving

warfarin need

to be routinely

questioned about

their intake of

vitamin K-containing

foods and beverages.

1

Warfarin Lycium Increased

anticoagulant

effect

Unknown The weak inhibition

of Lycium on

hepatic enzyme

could not explain

such interaction.

Risk of bleeding;

given the

narrow therapeutic

index of warfarin,

vigilance is needed.

1

Warfarin Mango Increased

anticoagulant

effect

Hepatic enzyme

inhibition

Mango contains high

amounts of vitamin

A and human studies

have shown that

vitamin A (retinol)

inhibits CYP2C19

enzymes.

Risk of bleeding;

given the narrow

therapeutic index

of warfarin,

vigilance is needed.

13


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Warfarin Papaya Increased

anticoagulant

effect

Unknown Risk of bleeding;

this interaction is

potentially fatal.

1

Warfarin PC-SPES Increased

anticoagulant

effect

Additive effect

on coagulation

mechanisms

PC-SPES contains

anticoagulant

coumarins.

The thromboembolic

side effects of PC-SPES

are potentially fatal;

individuals at risk should

be strongly advised

against using PC-SPES

and warfarin or aspirin.

1

Warfarin Soy Decreasedanticoagulant

effect

Not known The decrease in INR was thought to be

clinically relevant

1

Warfarin St. John’s

wort

Decreased

anticoagulant

effect

Hepatic enzyme

induction

Warfarin is metabolised

by CYP 1A2 in the

liver, which is induced

by St. John’s wort.

Although none

of the patients

developed

thromboembolic

complications,

the decrease in

INR was thought

to be clinically

relevant.

7

Phenprocoumon St. John’s

wort

Increased

‘‘Quick-Wert

test (indicating

decreased

anticoagulant

effect)

Hepatic enzyme

induction

St. John’s wort could

reduce phenprocoum

on plasma levels

throughout hepatic

enzyme induction.

Phenprocoumon

has a narrow

therapeutic window;

possible loss

of activity.

1a

Phenprocoumon Wheat bran Decreased plasma

level of

phenprocoumon;

increase in the

free plasma

phenprocoumon

fraction

Decreased absorption

can explain the

decreased plasma

level; however, the

mechanism of the

increase of free plasma

phenprocoumon

fraction is unknown.

Bran contains fibers

which can trap

phenprocoumon.

In view of the

different effects

on phenprocoumon

pharmacokinetics,

the clinical

significance is

unpredictable.

a


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Conventional

drug

Herbal

medicine

Result of

interaction

Possible

mechanism

Pharmacological

comment

Clinical

comment

No. of ca

Interactions with antilipidaemic drugs

Simvastatin St. John’s

wort

Decreased

plasma

simvastatin

concentration

Hepatic enzyme

induction

Simvastatin is

extensively

metabolised by CYP

3A4 in the intestinal

wall and liver, which

are induced by

St. John’s wort.

a

Lovastatin Oat bran Decreased

lovastatin

absorption

Bran contains fibers

which can trap digoxin.

The decreased

absorption of

lovastatin resulted

to an increase in

LDL levels which

led to the abortion

of the trial. Lovastatin

pharmacokinetics

and LDL returned

normal after bran

discontinuation.

a

Lovastatin Pectin Decreased

lovastatin

absorption

Pectin can trap digoxin. The decreased

absorption of

ovastatin resulted

to an increase in

LDL levels which

led to the abortion

of the trial. Lovastatin

pharmacokinetics

and LDL returned

normal after pectin

discontinuation.

a

a Interaction revealed by a clinical study. Clinical studies are more rigorous than case reports.


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ventional cardiovascular pharmacotherapy. Its aim is to alert

healthcare professionals to the fact that herbal medicines are

not entirely free of risks for cardiovascular patients.

2. Methods

Systematic literature searches were made using Medline

(via PubMed, from January 1966 to February 2003). The

search terms were herbal medicine, botanical medicine,

phytotherapy, drug interaction, adverse effects, side effects,

adverse drug reaction, safety and toxicity. Recent books on

herb– drug interactions or herbalism [21–26] were also

searched for further relevant information. Additional pub-

lications were identified by checking all reference lists and

by searching our files. No language restrictions were im-

posed. All clinical reports on interactions were read and

relevant data were extracted by the first three authors into

predefined tables and validated by the senior author. In vitro

experiments have been excluded.

3. Results

Forty-three case reports (appeared in 21 publications)

and eight clinical studies were located [27–55]. Warfarin

was the most common drug involved (37 cases and 1

clinical trial) [35–50]. Key data from these publications

are summarized in Table 1. Table 2 summarizes chemical

constituents, pharmacological action, clinical evidence and

adverse effects of the herbal medicines interacting with

cardiovascular drugs.

3.1. Interactions with cardiac inotropic drugs

3.1.1. Digoxin

Digoxin is a cardiac glycoside which originates from the

digitalis (foxglove) plant. As other cardiac glycosides, it can

increase the contractility of the heart muscle and is therefore

used in treating heart failure [56].

A single-blind, placebo-controlled study with two paral-

lel groups showed that St. John’s wort reduced digoxin

through levels after 10 days of co-medication [28]. Intestinal

absorption, distribution and renal excretion of digoxin are

mediated by the multiple-drug-resistance gene product P-

glycoprotein, which has been shown to be induced by St.

John’s wort [58,59]. Through this mechanism, St. John’s

wort may reduce efficacy of digoxin and make a patient a

nonresponder, whereas increased toxicity may be anticipat-

ed after withdrawal of the herb.

Increased levels of digoxin have been associated with

ingestion of Siberian ginseng [29]. The patient was asymp-

tomatic for digoxin toxicity despite a level of 5.2 ng/l.

Electrocardiogram, potassium level and serum creatine level

were normal. Digoxin levels decreased upon dechallenge

and increased upon rechallenge. The product was analyzed

for digoxin or digitoxin contamination, but none was found.

It is possible that some component of Siberian ginseng

might interfere with digoxin assay.

A double-blind study in 10 healthy volunteers showed

that guar gum reduced serum digoxin concentration during

the early absorption period [27]. This interaction is very

likely due to the ability of guar gum to reduce gastricemptying [57], which results in a transient delayed digoxin

absorption. Consistently, digoxin levels in 24-h urine were

similar whether subject were given or not guar gum.

A randomized study on 30 geriatric patients showed that

wheat bran (but not ispaghula) reduced digoxin concentra-

tion (probably trapped by fiber contained in wheat bran),

although the levels were still within the therapeutic range

[30]. This interaction has no clinical relevant influence on

therapeutic digoxin.

3.1.2. Interaction with antihypertensives

Ginkgo is a peripheral vasodilator [60]. Surprisingly, an

elderly patient was found to have a further increase in blood

pressure after taking ginkgo while receiving a thiazide

diuretic (not specified in the original paper) for hypertension

[31]. There is no rational pharmacological mechanism to

explain this unusual case.

A case of flaccid quadriplegia due to profound hypoka-

lemia has been reported to be due to ingestion of small

amounts of liquorice contained in a laxative preparation

taken in combination with antihypertensive treatment (not

specified in the original paper) [32]. The interaction could

be due to an additive effect of potassium excretion as both

some antihypertensives and liquorice (which possess min-

eralcorticoid effects) can cause potassium excretion [56,61].

3.2. Interaction with platelet aggregation inhibitor drugs

3.2.1. Aspirin

Aspirin is currently employed in the prophylactic treat-

ment of transient cerebral ischemia, to reduce the incidence

of recurrent myocardial infarction and to decrease mortal-

ity in postmyocardial infarction patients. Aspirin blocks

thromboxane A2 synthesis from arachidonic acid in plate-

lets by irreversibly acetylating and thus inhibiting cyclo-

oxygenase, a key enzyme in prostaglandin synthesis. The

aspirin-induced inhibition of thromboxane A2

synthesis

last for the life of the platelet (approximately 7–10 days)

[56].

A case report demonstrated a patient treated with aspirin

for 5 years experienced bleeding of the eye and blurred

vision after self-medication with ginkgo for 1 week [33].

After stopping ginkgo, there was no recurrence of bleeding

over a 3-month follow-up period. The interaction is likely

due to an additive effect on platelet function as ginkgolide B

from ginkgo is a potent PAF receptor antagonist [62].

A clinical study [34] performed on six healthy volunteers

showed that a tamarind extract incorporated in a traditional

meal increased plasma levels of aspirin and salicylic acid

A.A. Izzo et al. / International Journal of Cardiology 98 (2005) 1–14 7


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Table 2

Herbal medicines interacting with cardiovascular pharmacotherapy: source, main constituent(s), main pharmacological action(s), promoted use, clinical

evidence and adverse events

Herbal medicine

(Common name/

Latin name)

Source Main

constituent(s)

Main

pharmacological

action(s)

Promoted use Clinical

evidence

Adverse events

Boldo/ Peumus boldus Leaves Boldine Choleretic/

cholagogue,diuretic

Indigestion,

constipation,hepatic ailments

Specific studies

not available

Not expected

Curbicina / Serenoa repens/

Cucurbita pepo

a Fatty acids,

phytosterols,

flavonoids,

polysaccharides

Antiandrogenic,

anti-inflammatory

Benign prostatic

hyperplasia

Serenoa repens is

effective in the

treatment of benign

prostatic hyperplasia.

Gastrointestinal

complaints,

constipation,

diarrhea,

decreased libido

Danshen/ Salvia

miltiorrhiza

Roots Tanshinones,

phenolic

compounds

Vasorelaxant,

anti-ischemic,

antiplatelet;

radical scavenger

Angina, myocardial

infarction, ischemic

diseases

Effectiveness not

proven. Most studies

are neither

placebo-controlled

nor blinded.

Specific studies

not available

Dong quai/ Angelica

sinensis

Roots Phytoestrogens,

flavonoids,

coumarins

Estrogenic effects,

anti-inflammatory,

vasorelaxant

Gynecological

disorders,

circulation

conditions

No sufficient

evidence of

effectiveness

Photosensitivity

leading to mild

dermatitis,

bleedingDevils claw/

Harpagophytum

procumbens

Root, tubers Harpagoside Anti-inflammatory,

anti-arrhythmic,

positive inotropic,

negative chronotropic

Musculoskeletal

and arthritic pain

Promising to treat

musculoskeletal

and back pain

Gastrointestinal

symptoms

Fenugreek / Trigonella

foenum-graecum

Seeds Alkaloids,

flavonoids,

saponins

Antilipidaemic,

hypoglycemic,

cholagogue

Diabetes mellitus,

hypercholesterolemia

Promising in

reducing serum

cholesterol levels

Minor

gastrointestinal

symptoms,

allergic reactions

Ginseng/ Panax

ginseng

Roots Triterpene

saponins

known as

ginsenosides

Immunomodulatory,

anti-inflammatory,

antitumor,

hypoglycemic

Loss of energy and

memory; stress

states; male sexual

dysfunction

Not established

for any indications

Insomnia, diarrhea,

vaginal bleeding,

mastalgia, possible

cause of

Stevens–Johnson

syndrome

Garlic/ Allium

sativum

Bulb Alliins Antihypertensive,

antidiabetic,

antiplatelet,

antilipidaemic

Hypercholesterolemia,

prevention of

arteriosclerosis

Small

antihypertensive

and antilipidaemic

effect

Allergic reactions,

nausea, heartburn,

flatulence, breath

and body odor

Ginkgo/ Ginkgo

biloba

Leaves Ginkgolides,

flavonoids

Increase of

microcirculatory

blood flow,

antiplatelet, free

radical scavenging

Circulatory disorders Favorable evidence

for the treatment

of intermittent

claudication, tinnitus

and dementia

(including

Alzheimer’s

dementia)

Gastrointestinal

disturbances,

vomiting, allergic

reactions, pruritus,

headache, dizziness,

nose bleeding

Green tea/ Camellia

sinensis

Leaves Polyphenols,

caffeine

Antimutagenic,

antioxidant,

antilipidaemic,

antitumoral, CNS

stimulant

Prevention of

cancer,

cardiovascular

diseases,

adjuvant treatment

for AIDS

Cautiously positive

as anticancer; strong

inverse associations

of tea intake with

aortic arteriosclerosis

and cardiovascular

risk b.

Insomnia

Guar gum/ Cyamopsis

tetragonolobus

Seeds Galactomannan,

lipids, saponins

Antihyperglycemic,

antilipidaemic

Diabetes, obesity,

hypercholesterolemia

Small effect

cholesterol

levels; ineffective

for obesity

Flatulence, diarrhea,

abdominal

distension, nausea,

hypoglycemic

symptoms

Kava/ Piper

methysticum

Rhizome Kavapyrones Anxiolytic,

anesthetic,

muscle relaxant

Anxiety insomnia Well documented

for the treatment

of anxiety

Stomach

complaints,

restlessness,

mydriasis,

dermatomyositis,

hepatitis

A.A. Izzo et al. / International Journal of Cardiology 98 (2005) 1–148


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(a metabolite of aspirin). The mechanism of such interac-

tion is not known.

3.3. Interaction with anticoagulants

3.3.1. Warfarin

Warfarin owes its action to its ability to antagonize the

cofactor function of vitamin K [56]. Theoretically, increased

anticoagulant effects could be expected when combined

with coumarin-containing herbal medicines (e.g. boldo,

fenugreek and don quai) or with antiplatelet herbs (danshen,

garlic and ginkgo). Conversely, vitamin K-containing herbs

(e.g. green tea) can antagonize the anticoagulant effect of

warfarin [63].Clinical reports indicate over-anticoagulation when com-

bined to boldo, fenugreek, garlic, danshen, devil’s claw,

dong quai, ginkgo, papaya, Lycium and mango and de-

creased anticoagulant effect if co-administered with gin-

seng, green tea, soy and St. John’s wort [35– 50]. Given the

narrow therapeutic index of warfarin, both the effects could

have serious consequences.

A patient treated with warfarin for atrial fibrillation

saw his international normalized ratio (INR) increased

after taking a variety of natural products, including boldo

and fenugreek [35]. When he stopped herbal products, the

INR returned normal after 1 week. The herb–drug inter-

action was observed a second time after both products

were reintroduced a few days later. Both boldo and

fenugreek contain anticoagulant coumarins which, in an

additive or synergistic way, could produce such interac-

tion [64].

Two cases of increased INR were reported after co-

administration of curbicin (a preparation containing saw

palmetto, pumpkin and vitamin E) [36]; the INR normalized

after discontinuation of curbicin. No anticoagulant effect has

been found in the literature associated with the two major

components of curbicin. However, vitamin E has been

shown to antagonize the effect of vitamin K and may lead

to increased risk of bleeding, particularly in patients taking

oral anticoagulants [65].

Three case reports have highlighted the possibility of

interaction between warfarin and danshen, resulting in

increased anticoagulant effect [37–39]. The interaction

could have both a pharmacokinetic (changes in plasma

concentration) and a pharmacodynamic (additive effect on

coagulation mechanisms) basis; in fact, animal studies

indicate that danshen, in addition to its antiplatelet effect

[66], increases the absorption and decreases elimination of

warfarin [67].

A review on traditional remedies and food supplements

briefly mentions the case of purpura associated with con-

comitant use of devil’s claw and warfarin [31]. Due to the paucity of information reported, the likelihood of such

interaction cannot be established; possible mechanisms of

such interaction are not known as very little is known about

the metabolism and distribution of devil’s claw components;

an effect of devil’s claw on platelet function seems unlikely

as this herbal drug, in contrast to aspirin, does not affect

blood eicosanoids production [68].

Two well-documented case reports indicate over-anti-

coagulation following co-administration of warfarin and

dong quai [40,41]. Phytochemical analyses have revealed

in dong quai the presence of natural coumarin derivatives

[69], which can decrease coagulation by replacing vitamin

K as the apoenzyme in an enzyme complex; notably,

warfarin is a synthetic coumarin anticoagulant.

Two cases of increased INR were mentioned in patients

taking garlic previously stabilized on warfarin [42]. A

likely mechanism is an additive effect on coagulant mech-

anisms, as garlic possesses antiplatelet activity [70]. How-

ever, garlic treatment has been associated with bleeding

even in the absence of warfarin or other anticoagulant

treatment [71].

A well-documented case report demonstrated that a

patient under pharmacological treatment with warfarin

(5 years) experienced a left parietal hemorrhage after 2


Herbal medicine

(Common name/

Latin name)

Source Main

constituent(s)

Main

pharmacological

action(s)

Promoted use Clinical

evidence

Adverse events

Wheat bran/ Triticum

aestivum

Seeds Indigestible

carbohydrates

(starch, cellulose,

hemicelluloses),lignin

Stimulates

intestinal

peristalsis

Constipation,

obesity

Ineffective to

treat obesity

Bloating

Data extracted from Refs. [1,21,23].a Curbicin contains Serenoa repens (saw palmetto) fruits, Cucurbita pepo (pumpkin) seeds and vitamin E. b Data from epidemiological studies.c The cholesterol-lowering effect of oat bran is not shared by wheat bran.d PC-PCS is a mixture of eight herbal drugs, namely, Dendrathema morofolium (chrysanthemum), Isatis indigotica (dyer’s woad), Glycyrrhiza glabra

(liquorice), Ganoderma lucidum (reishi), Panax pseudoginseng (san-qui ginseng), Rabdosia rubescens (rubescens), Serenoa repens (saw palmetto) and

Scutellaria bacicalensis (Baikal skullcap).e Pectins are biopolymers with molecular weights of 60000 to 90000. Their basic structural framework is formed by galacturonic acid molecules. Pectins

are present to some degree in all plant products but are particularly abundant in fleshy fruits and storage roots. Rich commercial sources are sugar beet

fragments, apple residue, orange and lemon waste product and carrots.



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months of co-administration with ginkgo [43]. As stated

above, an additive effect on coagulation mechanisms could

be responsible of such interaction [62]. It should be noted

that intracerebral hemorrhage associated with long-term

ginkgo ingestion has been reported, even in the absence of

anticoagulants [72].

A case report of suspected inter action between warfarinand ginseng has been reported [44]. A decrease of INR was

noted, but because the patient took several other drugs

concomitantly (i.e. diltiazem, nitroglycerin and salsalate),

causality is uncertain. Anti platelet activity of ginseng has

been previously noted [73], but, of course, this would not

seem to explain such interaction. A pharmacokinetic study

in rats did not reveal a significant interaction between

warfarin and ginseng [74].

A case of inhibition of the effect of warfarin (decreased

INR) by green tea has been reported [45]. The patient,

which received warfarin for thromboembolic prophylaxis,

began drinking 1/2 to 1 gal of green tea per day about 1

week prior to the decreased INR. Green tea can be a

significant source of vitamin K and thus antagonize the

effect of warfarin [75].

An elevated INR was observed in a Chinese woman

previously stabilized on warfarin [46]; this was likely

caused by a concentrated Chinese herbal tea made from

Lycium fruits (three to four glasses daily), a Chinese herb

considered to have a tonic effect on various organs. In vitro

evaluation showed weak inhibition of warfarin metabolism

by CYP2C9 by the tea of Lycium, suggesting that the

observed interaction may be caused by factors other than

the CYP450 system [46].

A single publication reported 13 male patients whoseINR were found increased after mango fruit ingestion [47].

After identification of mango fruit as a possible cause of

supratherapeutic INR, patients were instructed to stop man-

go ingestion for 2 weeks. The average measured INR in the

13 patients decreased by 17.7% after discontinuation. Re-

challenge with mango fruit in 2 of the 13 patients produced

increased INR. Although the exact mechanism for this

interaction is unknown, there are literature reports suggest-

ing that concomitant administration of warfarin and large

doses of vitamin A (mango contains high amounts of

vitamin A) can cause an increased anticoagulant effect

[76]. Vitamin A (retinol) inhibits hepatic human CYP2C19

and this would lead to a moderate increase in warfarin

concentrations and thus higher INRs [77].

Another plant-based remedy which can interact with

warfarin is papaya [31], the fruit of the papaya tree. A case

has been mentioned briefly where the INR of an antico-

agulated patient was increased after addition of papaya

extract to his prescribed medication [31]. The pharmaco-

logical mechanisms by which papaya may affect coagula-

tion are not known. Nevertheless, this interaction is

potentially fatal. Papaya is contraindicated with warfarin

as it may damage the mucous membranes of the gastroin-

testinal tract, and the resultant bleeding would be increased.

A 79-year-old man with prostate cancer started treatment

with warfarin after he developed deep vein thrombosis

during treatment with PC-SPES (an anticancer herbal mix-

ture) [48]. PC-SPES therapy was stopped, but when it was

subsequently reinitiated, his INR became more difficult to

maintain in the therapeutic range and his warfarin require-

ments decreased. HPLC analysis of PC-SPES revealed the presence of coumarins, which can inhibit vitamin K reduc-

tase in a similar manner to warfarin [78].

A 70-year-old man who was stable on warfarin therapy

developed subtherapeutic INR values after ingesting soy

protein in the form of soy milk [50]. The subtherapeutic

INR values could not be explained by factors known to

reduce the INR such as noncompliance, new medication,

other alternative therapies or increased consumption of

vitamin K. INR values returned to therapeutic concentra-

tions within 2 weeks after discontinuation of the soy milk.

The mechanism of such interaction is not known.

Although not all investigations yielded the same results,

most studies agreed that St. John’s wort activate enzymes

of the cytochrome P450 enzyme system, including CYP

1A2 which is responsible of the metabolisation of warfarin

in the liver [79–81]. Probably via this mechanism, St.

John’s wort increased the metabolism of warfarin; such

mechanism could explain the decrease of the seven cases

of INR associated with concomitant use of warfarin and St.

John’s wort reported by the Swedish Medical Product

Agency [50]. Notably, a clinical study [52] showed that

St. John’s wort decreased the plasma concentration of

phenprocoumon, an anticoagulant chemically related to

warfarin (see below).

3.3.2. Phenprocoumon

Phenprocoumon is an anticoagulant chemically related to

warfarin; as it is the case of warfarin, it could potentially

interact with coumarin- or vitamin K-containing herbal

medicines or with antiplatelet herbs [56].

A case report highlighted the possible reduced efficacy of

phenprocoumon if co-administered with St. John’s wort

[51]. The possibility is strengthen by a clinical study which

showed that 11-day medication of St. John’s wort resulted in

a significant decrease of the area under the curve (AUC) of

the free phenprocoumon compared with placebo [51].

Induction of hepatic enzyme by St. John’s wort is a likely

mechanism which could explain such interaction.

A study on seven healthy volunteers showed that inges-

tion of 35 g wheat bran produced a decreased absorption

rate of phenprocoumon but no decrease in overall bioavail-

ability [53]. In addition, an increase in the free plasma

fraction of phenprocoumon was seen after wheat bran

administration. While the presence of fibers in bran can

easily explain the decreased absorption rate, the increase in

the free plasma fraction cannot be explained by our present

knowledge of wheat bran biological properties. It is note-

worthy that the increase in absorption would predict de-

creased efficacy, while increased free plasma fraction would



12/14

predict increased activity of phenprocoumon; thus, the

clinical significance of such interaction is unpredictable.

3.4. Interaction with antihyperlipidemic drugs

3.4.1. Simvastatin, pravastatin and lovastatin

Simvastatin, pravastatin and lovastatin are inhibitors of HMG-CoA reductase, the rate-limiting step in cholesterol

synthesis. By inhibiting de novo cholesterol synthesis, they

deplete the intracellular supply of cholesterol [56].

A clinical study showed that repeated St. John’s wort

treatment (14 days) decreased plasma concentrations of

simvastatin but not of pravastatin [54]. Because simvastatin

is extensively metabolised by CYP3A4 in the intestinal wall

and liver (which is induced by St. John’s wort) [79– 81], it is

likely that this interaction is partly caused by the enhance-

ment of the CYP3A4-mediated first-pass metabolism of

simvastatin in the small intestine and liver.

A decrease of absorption of lovastatin was observed in

patients who took this lipid-lowering agent concomitantly

with pectin or oat bran [55]. This resulted to an increase in

LDL levels which lead to the abortion of the trial. When

these plant-based preparations were discontinued, lovastatin

pharmacokinetics returned to normal and lipoprotein levels

in plasma normalized as a result. This interaction is likely

due to the ability of pectins or bran fibers to bind or trap

concurrently administered lovastatin.

4. Discussion

Herbal medicines follow modern pharmacological prin-ciples. Hence, herb–drug interactions are based on the same

pharmacokinetic and pharmacodynamic mechanisms as

drug– drug interactions [5]. Herbal medicines may affect

absorption (e.g. guar gum reduces digoxin absorption) [27],

metabolism (e.g. St. John’s wort increases warfarin metab-

olism, causing decreased anticoagulant effect) [50] or ex-

cretion (St. John’s wort increases digoxin renal excretion)

[28] of concurrently administered cardiovascular drugs.

Herb– drug interactions that involve distribution mecha-

nisms have not been reported. Moreover, interactions may

be additive or synergetic, whereby the herbal products

potentiate the action of the conventional cardiovascular

drug (e.g. ginkgo potentiates the antiplatelet effect of

aspirin) [33]. Conversely, the herb may be directly antago-

nistic to the action of the drug (e.g. green tea antagonizes the

anticoagulant effect of warfarin) [45].

Based on the above evidence, there can be little doubt

that interactions between herbal medicines and cardiovas-

cular drugs exist. The real incidence of such interactions is

probably unknown, as is the likelihood that a patient will

have an adverse event when taking two drugs (i.e. herbal

and conventional medicines) with the potential to interact.

Much of the available information about the interaction

between herbal medicines and cardiovascular pharmacother-

apy is gleaned from case reports, although clinical studies

are now also beginning to appear in the literature. Obvious-

ly, case reports have to be interpreted with great caution, as

causality is not usually established beyond reasonable

doubt. To establish causality is, of course, a difficult task.

Rechallenge would be the most straightforward clinical test,

but for obvious reasons, this option is not always available.Hence, even well-documented case reports (and many are

not well documented) can only serve as a critical early

warning system.

In conclusion, interaction between herbal medicine and

cardiovascular drugs is a potentially important safety issue.

Patients under anticoagulant pharmacotherapy are at the

highest risk. Healthcare professionals need to be aware of

potential herb – drug interactions and researcher should

strive to fill the numerous gaps in our present understanding

of this problem.

Acknowledgements

This work was supported by the Enrico and Enrica

Sovena Foundation and SESIRCA (Regione Campania,

Italy).

References

[1] Ernst E, Pittler MH, Stevinson C, White A. The desktop guide to com-

plementary and alternative medicine. An evidence-based approach.

Edinburg: Butterworth Heinemann; 2000.

[2] Eisenberg DM, Davis RB, Ettner SL, Apple S, Wilkey S, Van Rom- pay M, et al. Trends in alternative medicine use in the United States,

1990– 1997: results of a follow-up national survey. JAMA 1998;

280:1569–75.

[3] US sales figures for herbal medicinal products. Fact 2001;6:231.

[4] Lin MC, Nahin R, Gershwin ME, Longhurst JC, Wu KK. State of

complementary and alternative medicine in cardiovascular, lung, and

blood research [executive summary of a workshop]. Circulation 2001;

103:2038–41.

[5] Izzo AA, Borrelli F, Capasso R. Herbal medicine: the risk of drug

interaction. Trends Pharmacol Sci 2002;23:358– 9.

[6] Fugh-Berman A. Herb– drug interactions. Lancet 2000;355:134– 8.

[7] Miller LG. Herbal medicinals. Selected clinical considerations focus-

ing on known or potential drug–herb interactions. Arch Intern Med

1998;158:2200– 11.

[8] Izzo AA, Ernst E. Interactions between herbal medicines and pre-scribed drugs. Drugs 2001;61:2163–75.

[9] Williamson EM. Synergy and other interactions in phytomedicines.

Phytomedicine 2001;8:401 – 9.

[10] Scott GN, Elmer GW. Update on natural product – drug interactions.

Am J Health-Syst Pharm 2002;59:339– 47.

[11] Klepser TB, Klepser ME. Unsafe and potentially safe herbal thera-

pies. Am J Health-Syst Pharm 1999;56:125 – 37.

[12] Smolinske SC. Dietary supplement– drug interactions. J Am Med

Women’s Assoc 1999;54:191 – 5.

[13] Ang-Lee MK, Moss J, Yuan C-S. Herbal medicines and perioperative

care. JAMA 2001;286:208–16.

[14] Barrett B, Kiefer D, Rabago D. Assessing the risks and benefits of

herbal medicine: an overview of scientific evidence. Altern Therap

1999;5:40–9.



13/14

[15] Smolinske SC. Dietary supplement– drug interactions. JAMA 1999;

4:191–2.

[16] Cupp MJ. Herbal remedies: adverse effects and drug interactions. Am

Fam Phys 1999;59:1239–45.

[17] Aggarwal A, Ades PA. Interactions of herbal remedies with prescrip-

tion cardiovascular medications. Coron Artery Dis 2001;12:581– 4.

[18] Wittkowsky AK. Drug interactions update: drugs, herbs, and oral

anticoagulation. J Thromb Thrombolysis 2001;12:67 – 71.

[19] Villegas JF, Barabe DN, Stein RA, Lazar E. Adverse effects of herbal

treatment of cardiovascular disease: what the physician must know.

Heart Dis 2001;3:169– 75.

[20] Chan TY. Interaction between warfarin and danshen (Salvia miltior-

rhiza). Ann Pharmacother 2001;35:501–4.

[21] Schulz V, Hansel R, Tyler VE. Rational phytotherapy. A physicians’

guide to herbal medicine. 4th ed.Heidelberg, Germany: Springer Ver-

lag; 2001.

[22] Johns Cupp M. Toxicology and clinical pharmacology of herbal prod-

ucts. New Jersey: Totowa Human Press; 2000.

[23] Capasso F, Gaginella T, Grandolini G, Izzo AA. Phytotherapy. A

quick reference to herbal medicine. Heidelberg, Germany: Springer

Verlag; 2003.

[24] Herr SM. Herb– drug interaction handbook. 2nd ed.Nassau, NY:

Church Street Books; 2002.

[25] Lininger SW. A – Z guide to drug – herb– vitamin interactions. Rock-

lin (CA): Prima Publishing; 1999.

[26] Meletis CD, Jacobs T. Interactions between drugs and natural medi-

cines. Sandy (OR): Eclectic Medical Publications; 1999.

[27] Huupponen R, Seppala P, Iisalo E. Effect of guar gum, a fibre prep-

aration, on digoxin absorption in man. Eur J Clin Pharmacol 1984;

26:279–81.

[28] Johne A, Brockmolller J, Bauer S, Maurer A, Langheinrich M, Roots

I. Pharmacokinetic interaction of digoxin with an herbal extract from

St John’s wort ( Hypericum perforatum). Clin Pharmacol Ther 1999;

66:338–45.

[29] McRae S. Elevated serum digoxin levels in a patient taking digoxin

and Siberian ginseng. Can Med Assoc J 1996;155:293 – 5.

[30] Nordstrom M, Melander A, Robertsson E, Steen B. Influence of

wheat bran and of a bulk-forming ispaghula cathartic on the bioavail-ability of digoxin in geriatric in-patients. Drug Nutr Interact 1987;5:

67–9.

[31] Shaw D, Leon D, Kolev S, Murray V. Traditional remedies and food

supplements: a 5-year toxicological study (1991– 1995). Drug Saf

1997;17:342–56.

[32] Cumming AAM, Boddy K, Brown JJ. Severe hypokalaemia with

paralysis induc ed by small doses of liquo rice. Postgrad Med J

1980;56:526–9.

[33] Rosenblatt M, Mindel J. Spontaneous hyphema associated with in-

gestion of Ginkgo biloba extract. N Engl J Med 1997;336:1108.

[34] Mustapha A, Yakasai IA, Aguye IA. Effect of Tamarindus indica L.

on the bioavailability of aspirin in healthy human volunteers. Eur J

Drug Metab Pharmacokinet 1996;21:223– 6.

[35] Lambert JP, Cormier A. Potential interaction between warfarin and

boldo-fenugreek. Pharmacotherapy 2001;21:509– 12.[36] Yue QY, Jansson K. Herbal drug and anticoagulant effect with and

without warfarin: possibly related to the vitamin E component. J Am

Geriatr Soc 2001;49:838.

[37] Izzat MB, Yim AP, El-Zufari MH. A taste of Chinese medicine. Ann

Thorac Surg 1998;66:941–2.

[38] Tam LS, Chan Tym Leung WK, Critchley JA. Warfarin interactions

with Chinese traditional medicines: danshen and methyl salicylate

medicated oil. Aust NZ J Med 1995;25:238.

[39] Yu CM, Chan JC, Sanderson JE. Chinese herbs and warfarin poten-

tiation by danshen. J Intern Med 1997;25:337– 9.

[40] Ellis GR, Stephens MR. Untitled (photograph and brief case report).

BMJ 1999;319:650.

[41] Page RL, Lawrence JD. Potentiation of warfarin by dong quai. Phar-

macotherapy 1999;319:870 – 6.

[42] Sunter WH. Warfarin and garlic. Pharm J 1991;246:772.

[43] Matthews MK. Association of Ginkgo biloba with intracerebral hae-

morrhage. Neurology 1998;5:1933.

[44] Janetzky K, Morreale AP. Probable interactions between warfarin and

ginseng. Am J Health-Syst Pharm 1997;54:692–3.

[45] Taylor JR, Wilt VM. Probable antagonism of warfarin by green tea.

Ann Pharmacother 1999;33:426– 8.

[46] Lam AY, Elmer GW, Mohutsky MA. Possible interaction between

warfarin and Lycium barbarum L.. Ann Pharmacother 2001;35:

1199–201.

[47] Monterrey-Rodriguez J. Interaction between warfarin and mango

fruit. Ann Pharmacother 2002;36:940–1.

[48] Davis NB, Nahlik L, Vogelzang NJ. Does PC-SPEs interact with

warfarin? J Urol 2002;167:1793.

[49] Cambria-Kiely JA. Effect of soy milk on warfarin efficacy. Ann

Pharmacother 2002;36:1893– 6.

[50] Yue Q-Y, Bergquist C, Gerden B. Safety of St John’s wort ( Hyper-

ricum perforatum). Lancet 2000;355:576– 7.

[51] Bon S, Hartmann K, Kubn M. Johanniskraut: Ein Enzyminduktor?

Schweiz Apothztg 1999;16:535– 6.

[52] Donath F, Roots I, Langheinrich M, Hubner W-D. Interaction of St

John’s wort extract with phenprocoumon. Eur J Clin Pharmacol

1999;55:A22.

[53] Kitteringham NR, Mineshita S, Ohnaus EE. The effect of wheat bran

on the pharmacokinetics of phenprocoumon in normal volunteers.

Klin Wochenschr 1985;63:537– 9.

[54] Sugimoto K, Ohmori M, Tsuruoka S, Nishiki K, Kawaguchi A, Har-

ada K, et al. Different effects of St John’s wort on the pharmacoki-

netics of simvastatin and pravastatin. Clin Pharmacol Ther 2001;70:

518–24.

[55] Richter WO, Jacob BG, Schwandt P. Interaction between fibre and

lovastatin. Lancet 1999;338:706.

[56] Harvey RA, Champe CA. Pharmacology. Philadelphia: J.B. Lippin-

cott; 1992.

[57] Schonfeld J, Evans DF, Wingate DL. Effect of viscous fiber (guar) on

postpra ndial motor activity in human small bowel. Dig Dis Sci

1997;42:1613–7.

[58] Durr D, Stieger B, Kullak-Ublick GA, Rentsch KM, Steinert HC,Meier PJ, et al. St John’s wort induces intestinal P-glycoprotein/

MDR1 and intestinal and hepatic CYP3A4. Clin Pharmacol Ther

2000;68:598–604.

[59] Hennessy M, Kelleher D, Spiers JP, Barry M, Kavanagh P, Back D,

et al. St John’s wort increases expression of P-glycoprotein: impli-

cations for drug interactions. Br J Clin Pharmacol 2002;53:75–82.

[60] Valli G, Giardina EV. Benefits, adverse effects and drug interactions

of herbal therapies with cardiovascular effects. J Am Coll Cardiol

2002;39:1084–95.

[61] Borrelli F, Izzo AA. The plant kingdom as a source of antiulcer

remedies. Phytother Res 2000;14:581– 95.

[62] Braquet P, Hosford D. Ethnopharmacology and the development of

natural PAF antagonists as therapeutic agents. J Ethnopharmacol

1991;32:135–9.

[63] Heck AM, DeWitt BA, Lukes AL. Potential interactions betweenalternative therapies and warfarin. Am J Health-Syst Pharm 2000;57:

1221–7.

[64] Newall CA, Anderson LA, Phillipson JD. Herbal medicines. A guide

for health-care professionals. London (UK): The Pharmaceutical Press;

1996.

[65] Corrigan JJ Jr, Margens FL. Coagulopathy associated with vitamin E

ingestion. JAMA 1974;230:1300–1.

[66] Wang Z, Roberts JM, Grant PG, Colman RW, Schreiber AD. The

effect of a medicinal Chinese herb on platelet function. Thromb Hae-

most 1982;48:301– 6.

[67] Nanhn Chan K, Lo AC, Yeung JH, Woo KS. The effects of danshen

(Salvia miltiorrhiza) on warfarin pharmacodynamics and pharmaco-

kinetics of warfarin enantiomers in rats. J Pharm Pharmacol 1995;

47:402–6.



14/14

[68] Moussard C, Alber D, Toubin MM, Thevenon N, Henry JC. A drug

used in traditional medicine, Harpagophytum procumbens: no evi-

dence for NSAI-like effect on whole blood eicosanoid production in

human. Prostaglandins Leukot Essent Fat Acids 1992;46:283–6.

[69] Zhu DP. Dong quai. Am J Clin Med 1987;15:117 – 25.

[70] Beretz A, Cazenave JP. Old and new natural products as the source of

modern antithrombotic drugs. Planta Med 1991;57:S68– 72.

[71] German K, Kumar U, Blackford HN. Garlic and the risk of TURP

bleeding. Br J Urol 1996;76:518.

[72] Rowin J, Lewis SL. Spontaneous bilateral subdural hematomas asso-

ciated with chronic Ginkgo biloba ingestion. Neurology 1996;46:

1775–6.

[73] Gillis CN. Panax ginseng pharmacology: a nitric oxide link? Biochem

Pharmacol 1997;54:1–8.

[74] Zhu M, Chan KW, Ng LS, Chang Q, Chang S, Li RC. Possible

influences of ginseng on the pharmacokinetics and pharmacody-

namics of warfarin in rats. J Pharm Pharmacol 1999;51:175– 80.

[75] McKenna DJ, Hughes K, Jones K. Green tea monograph. Altern Ther

Health Med 2000;6:61– 8.

[76] Abramowicz M. Vitamin supplements. Med Lett Drugs Ther 1985;27:

66–8.

[77] Yamazaki H, Shimada T. Effects of arachidonic acid, prostaglandins,

retinol, retinoic acid and cholecalciferol on xenobiotic oxidations

catalysed by human cytochrome P450 enzymes. Xenobiotica 1999;

29:231–41.

[78] Pandha HS, Kirby RS. PC-SPES: phytotherapy for prostate cancer.

Lancet 2002;359:2213 – 4.

[79] Di Carlo G, Borrelli F, Ernst E, Izzo AA. St John’s wort: Prozac from

the plant kingdom. Trends Pharmacol Sci 2001;22:291–6.

[80] Wang Z, Gorski JC, Hamman MA, Huang SM, Lesko LJ, Hall SD.

The effects of St John’s wort ( Hyperic um perforatu m) on human

cytochrome P450 activity. Clin Pharmacol Ther 2001;70:317– 26.

[81] Roby CA, Anderson GD, Kantor E, Dryer DA, Burstein AH. St

John’s wort: effect on CYP3A4 activity. Clin Pharmacol Ther 2000;

67:451–7.


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Cardiovascular pharmacotherapy and herbal medicines: the risk of drug interaction (Review)