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Review
Cardiovascular pharmacotherapy and herbal medicines:
the risk of drug interaction
Angelo A. Izzoa,*, Giulia Di Carloa, Francesca Borrellia, Edzard Ernstb
aDepartment of Experimental Pharmacology, University of Naples Federico II, via D. Montesano 49, 80131 Naples, ItalybComplementary 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,
devils claw, don quai, ginkgo, papaya, lycium, mango, PC-SPES (resulting in over-anticoagulation) and with ginseng, green tea, soy and St.
Johns wort (causing decreased anticoagulant effect). Gum guar, St. Johns 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. Johns
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. Johns 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$590.9 million [3]. These sales figures
relate only to food stores, drug stores and mass market
and would obviously be larger if buying clubs, convenience
stores, natural food markets, multilevel marketing compa-
nies, health professionals, mail or Internet order had been
considered. The relevance of alternative therapies for car-
diovascular medicine is highlighted by the recent workshop
on the use of herbal medicines in cardiovascular, lung and
blood research sponsored by the US National Heart, Lung,
and Blood Institute[4].
In view of the increasing use of herbal remedies by the
general public and subsequent interest by the authorities, it
is imperative to promote credible research on the safety of
herbal products including the possibility of interactions with
concurrent cardiovascular pharmacotherapy. Providing ac-
curate and clinically relevant advice to patients regarding
the possibility of herbdrug interactions is a challenge for
healthcare practitioners.
Because all herbal medicines are mixtures of more than
one active ingredient, they obviously increase the likelihood
of herb drug interactions [5]. Moreover, the majority of
people who use herbal products do not reveal this to their
physician or pharmacist [2]. This increases the likelihood
that herbdrug interactions are not identified and resolved
in a timely manner. Nevertheless, recent data indicate that
potentially serious interactions exist between some common
herbal remedies and widely used conventional pharmaceut-
icals[616],including those used in the therapy of cardio-
vascular diseases[1720].
In this article, we review the existing clinical data on
suspected interactions between herbal medicine and con-
0167-5273/$ - see front matterD 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: aaizzo@unina.it (A.A. Izzo).
www.elsevier.com/locate/ijcard
International Journal of Cardiology 98 (2005) 114
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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. Johns
wort
Decreased
plasma digoxin
concentration
Induction
of P-glycoprotein
Digoxin is a substrate
of P-glycoprotein
which is induced by
St. Johns wort.
St. Johns 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 Devils claw Increased
anticoagulant
effect, purpura
Unknown In contrast to NSAIDs,
devils 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 INRwas thought to be
clinically relevant
1
Warfarin St. Johns
wort
Decreased
anticoagulant
effect
Hepatic enzyme
induction
Warfarin is metabolised
by CYP 1A2 in the
liver, which is induced
by St. Johns wort.
Although none
of the patients
developed
thromboembolic
complications,
the decrease in
INR was thought
to be clinically
relevant.
7
Phenprocoumon St. Johns
wort
Increased
Quick-Wert
test (indicating
decreased
anticoagulant
effect)
Hepatic enzyme
induction
St. Johns 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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Table 1 (continued)
Conventional
drug
Herbal
medicine
Result of
interaction
Possible
mechanism
Pharmacological
comment
Clinical
comment
No. of ca
Interactions with antilipidaemic drugs
Simvastatin St. Johns
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. Johns 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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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
StevensJohnson
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
Alzheimers
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
riskb.
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
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Table 2 (continued)
Herbal medicine
(Common name/
Latin name)
Source Main
constituent(s)
Main
pharmacological
action(s)
Promoted use Clinical
evidence
Adverse events
Liquorice/Glycyrrhiza
glabra
Roots Glycyrrhizinic
acid
Expectorant,
anti-inflammatory,
anti-ulcer,
aldosterone-likeeffects
Gastric ulcer,
catarrhs, cancer
prevention,
inflammation
Liquorice is an
effective anti-ulcer;
however, its use
has declined.
Adverse effect
consistent with
adrenocorticotropic
actions
Mango/Mangifera
indica
Fruits Vitamins A
and C; fibers
Analgesic;
anti-inflammatory;
antioxidant; laxative
Constipation
(also used as a
food and as a
source of vitamins)
Specific studies
not available
Not expected
Oat branc/Avena sativa Seeds Fibers Antilipidaemic,
anti-atherosclerotic
Hypercholesterolemia,
prevention of
atherosclerosis
Promising in
reducing
cholesterol and
LDL blood levels
Not expected
Papaya/Carica papaya Fruits Papain (enzyme) Proteolytic,
amylolytic,
lipolytic activity
Indigestion, obesity Specific studies
not available
Not expected
PC-SPESd/Dendrathema
morofolium/Isatis
indigotica/Glycyrrhiza
glabra/Ganoderma
lucidum/Panax
pseudoginseng/Rabdosia
rubescens/Serenoa
repens/Scutellaria
bacicalensis
d Polysaccharides,
phytosterols, fatty
acids, flavonoids
Immunostimulant,
cytotoxic
Prostate cancer Lack of
randomized
clinical studies
Reduced libido,
hot flashes,
diarrhea, dyspepsia,
leg cramps,
gynaecomastia,
nipple tenderness,
pulmonary emboli,
vein thrombosis
Pectinse fleshy fruits
and storage
roots of many
plantse
e Antidiarrheal Diarrhea Pectins-based
home remedies
are useful in the
treatment of
diarrhea.
Not expected
Siberian ginseng/
Eleutherococcus
senticosus
Roots Eleutherosides Immunomodulatory,
anti-inflammatory,
antitumor,
hypoglycemic
Loss of energy
and memory;
stress states,
male sexual
dysfunction
Not established
for any
indications
Diarrhea,
dizziness,
hypertension,
pericardial pain,
tachycardia,
insomnia,
extrasystoles,
headaches
Soy/Glycine max Beans Phytoestrogens Hepatoprotective,
anti-osteoporosis
Treatment of
menopausal
symptoms;
prevention of
heart diseases
and cancer
Promising for
treating
menopausal
symptoms;
case-control
studies suggest
a link between
soy phytoestrogen
consumption and
reduced risk of
breast and other
cancers.
Occasional
gastrointestinal
effects, i.e.
stomach pain,
flatulence, loose
stool and diarrhea
St. Johns wort/
Hypericum
perforatum
Aerial parts Hypericin,
hyperforin,
flavonoids
Antidepressant,
antiretroviral
Depression Effective for mild
to moderate
depression; not
suited for major
depression
Gastrointestinal
symptoms
Tamarind/Tamarindus
indica
Fruits Sugars,
mucilages
Stimulates
intestinal
peristalsis
Constipation
(also used as
a food)
Effective
laxative
Not expected
(continued on next page)
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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, devils claw,
dong quai, ginkgo, papaya, Lycium and mango and de-
creased anticoagulant effect if co-administered with gin-
seng, green tea, soy and St. Johns 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 herbdrug 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 [3739]. 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 devils claw and warfarin [31]. Due to thepaucity 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 devils claw components;
an effect of devils 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
Table 2 (continued)
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 fromRefs. [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 (dyers 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 coagulationmechanisms 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 suspectedinteraction 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. Antiplatelet 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
duringtreatment 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 thepresence of coumarins, which can inhibitvitamin 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. Johns wort activate enzymes
of the cytochrome P450 enzyme system, including CYP
1A2 which is responsible of the metabolisation of warfarin
in the liver [7981]. Probably via this mechanism, St.
Johns 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.
Johns wort reported by the Swedish Medical Product
Agency [50]. Notably, a clinical study [52] showed that
St. Johns 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. Johns wort
[51].The possibility is strengthen by a clinical study which
showed that 11-day medication of St. Johns 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. Johns 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
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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 ofHMG-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. Johns wort
treatment (14 days) decreased plasma concentrations of
simvastatin but not of pravastatin[54].Because simvastatin
is extensively metabolised by CYP3A4 in the intestinalwall
and liver (which is induced by St. Johns 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, herbdrug 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. Johns wort increases warfarin metab-
olism, causing decreased anticoagulant effect) [50] or ex-
cretion (St. Johns 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).
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