Date post: | 06-Apr-2018 |
Category: |
Documents |
Upload: | michael-thomsen |
View: | 217 times |
Download: | 0 times |
of 29
8/3/2019 HerbDrug Interaction Article Thomsen 6 March 2007
1/29
Herb-Drug Interaction
By Michael Thomsen, Hanni Gennat and Dr Mathias Schmidt
Michael Thomsen
HerbResearch International
29 Macfarlane St
Sth. Hobart TAS 7004
Australia
Tel: 61 3 6223 5332
Fax: 61 3 6223 4842
Email: [email protected]
Introduction
Herbal products need to be assessed for safety and efficacy. A comprehensive safety
profile should also contain information about proven and potential interaction between
pharmaceutical preparations (i.e., drugs) and herbal preparations. A herb-drug interaction
can be defined as a pharmacologic or clinical response to the coadministration of a
traditional drug or pharmaceutical preparation and an herbal product. Concurrent use of
herbs may magnify or oppose the effect of the traditional drugs; some herb-drug
interactions may be clinically insignificant, others may have serious consequences. As
more practitioners prescribe, and more consumers choose to use, herbal preparations, the
possibility of a herb-drug interaction increases. Serious consideration of concomitant
medication needs to be given in order to promote the safe use herbal products within the
community.
The search for information relating to herb-drug interactions is a challenge for health
service researchers, educators and practitioners, and readily accessible information is
lacking. Unfortunately, the majority of information about herb-drug interactions comes
from theoretical suspicions, animal or in-vitro data and anecdotal case reports which
frequently lack pertinent information or are conflicting. Very little information is derived
from well-designed clinical studies and controlled trials. Thus, the relevance of such
information in terms of clinical relevance is questionable. An additional complication is
8/3/2019 HerbDrug Interaction Article Thomsen 6 March 2007
2/29
that the documentation of herb-drug interactions is an evolving process, and will continue
to be as the use of herbal preparations increases. To guide practitioners through this
process, documentation of herb-drug interactions using consistent and reliable guidelines
and protocol are required. This will allow practitioners to consider an alternative
treatment that is unlikely to produce undesirable interaction.
Types of Herb-Drug Interactions
Drug metabolism can be divided into two categories: Phase I reactions (biotransformation
into polar metabolites) and Phase II reactions (conjugation). With respect to herb-drug
interaction, Phase I metabolism is more relevant as it can occur during drug absorption,
before the drug reaches the systemic circulation. This presystemic clearance (or first-pass
metabolism) determines the fraction of the oral dose that will reach the systemic
circulation (i.e., the fraction of the dose that is bioavailable). Cytochrome P450
(CYP450) is the major drug metabolizing enzyme system for Phase I reactions and is
found in the greatest concentrations in the liver and gut wall. The many fates of Phase 1
(P450) metabolites includes: inactivity; equal activity; greater activity; toxicity, or;
activation of a prodrug.
Humans have 17 families of CYP450 genes; 3 of these families are dedicated tometabolizing (i.e., CYP 1, 2 and 3). Drug metabolism (Phase I) is largely mediated by
CYP3A (~50%) and CYP2D6 (~30%), with CYP1A2, 2C9/10, 2C19 and 2E1 accounting
for approximately equal percentages of the remaining 20%. Clinically, the important
aspects of CYP450 drug metabolism to be considered are: induction, inhibition and
genetic polymorphism.
Inducer drugs can decrease the therapeutic levels of substrates by increasing the P450enzyme concentration, or increasing the rate of metabolism of the inducing drug, or other
drugs taken concurrently. An herb-drug interaction may result in increased inactivation of
protease inhibitors and decreased effectiveness of a HIV cocktail, if taken with St Johns
wort, via CYP3A4. Inhibitors can increase the potential for toxicity from substrates by
blocking P450 enzymes that metabolize other drugs, and increasing the serum
8/3/2019 HerbDrug Interaction Article Thomsen 6 March 2007
3/29
concentration of a second drug. Pharmacogenetics concerns genetic polymorphisms that
exist for many drugs, which may explain some idiosyncratic reactions.(Agins 2006)
There are three basic types of drug interactions: 1. interactions that increase the toxicityof one or more drugs in the system; 2. interactions that diminish the therapeutic benefit of
one or more drugs in the system; 3. interactions that enhance, stimulate or complicate the
existing disease process. Herb-drug interactions primarily concern blood
coagulation/clotting, drug metabolism and the central nervous system. Interactions
between herbs and medications can be caused by either pharmacodynamic or
pharmacokinetic mechanisms.
Pharmacodynamic interactions can occur when a herbal product produces additive
(synergistic) or antagonist (competitive) activity in relation to a pharmaceutical drug with
no change in the plasma concentration of either herbal product or drug.(Boullata 2005),
i.e., the two drugs affect a common system. Pharmacodynamic interactions are related to
the pharmacologic activity of the interacting agents and can affect organ systems,
receptor sites, or enzymes. Although the pharmacodynamic interactions may be fairly
predictable based on the knowledge of the mechanisms of both substances, the strength of
the effect is unknown and there is therefore uncertainty about the clinical relevance. This
is further confounded by the fact that individual responses frequently occur.
Herbs with a similar action to a drug should be used cautiously as additive effects may
occur, e.g., herbs with antiplatelet activity should be used with caution during
antiplatelet/anticoagulant drug therapy and perioperatively. Similarly, prescribing kava
(Piper methysticum) or valerian (Valeriana officinalis) with benzodiazepines due to
potential CNS depressive effects, herbal diuretics with pharmaceutical diuretics, or
antidepressants with St. Johns wort (Hypericum perforatum) should be undertaken with
caution, and monitoring of patients is essential.
8/3/2019 HerbDrug Interaction Article Thomsen 6 March 2007
4/29
Antagonistic interactions occur when one drug compromises the effect of another. An
example is when a stimulant herb, such as guarana (Paullinia cupana) which contains a
high level of caffeine, is administered with a sedative-hypnotic or when immune
stimulating herbs such as astragalus (Astragalus membranaceus) or echinacea (Echinacea
sp.) are given with immunosuppressive drugs or when bitter herbs, e.g., gentian
(Gentiana lutea), is used with antacids to improve digestion. In addition, herbs with the
potential to cause organ toxicity may cause further risk of toxicity when drugs with
similar toxicity are administered concurrently, such as when the hepatotoxic herbal
comfrey (Symphytum officinale) is given with large and prolonged doses of
acetaminophen.(MacKinnon 2005)
Pharmacokinetic interactions occur when an herbal preparation changes the absorption
(via pH of stomach), distribution (via competition for protein binding), metabolism, or
excretion (one preparation slows the elimination of another) of a drug that results in
altered levels of the drug or its metabolites. Most of the current evidence of
pharmacokinetic drug interactions involves metabolizing enzymes and drug transporters
and most herb-drug interactions are related to metabolism by the CYP450 system or by
the effect of a herbal on the efflux drug transporter P-glycoprotein (PgP).(MacKinnon
2005) Most of the cases documented to date have concerned St. Johns wort.
In contrast, herbs such as cayenne (Capsicum spp.), coleus (Coleus forskohlii) or long
pepper (Piper longum) may increase drug absorption or availability and should be used
with caution. Absorption of drugs can be impaired when herbs that contain
hydrocolloidal fibers, gums, and mucilage are taken together. These herbals can bind to
drugs that can prevent absorption and, subsequently, reduce systemic
availability.(MacKinnon 2005) As an example, there have been case reports of reducedlithium serum concentrations taken concurrently with psyllium (Plantago ovata), which
inhibits the absorption of lithium.(Perlman 1990)Likewise, herbal laxatives such as aloe
latex (Aloe barbadensis), cascara (Rhamnus purshiana), rhubarb (Rheum palmatum), and
senna (Cassia spp.) can cause loss of fluids and potassium, and can potentially increase
the risk of toxicity with digoxin.(MacKinnon 2005)
8/3/2019 HerbDrug Interaction Article Thomsen 6 March 2007
5/29
St Johns wort a cautionary tale
A detailed Medline search revealed a total of 32 drugs reported to interact with herbal
medicines in humans. These drugs include anticoagulants (warfarin, aspirin and
phenprocoumon), sedatives and antidepressants (midazolam, alprazolam and
amitriptyline), oral contraceptives, anti-HIV agents (indinavir, ritonavir and saquinavir),
cardiovascular drug (digoxin), immunosuppressants (cyclosporine and tacrolimus) and
anticancer drugs (imatinib and irinotecan). Most of them are substrates for CYP450s
and/or P-glycoprotein (PgP), many of which have narrow therapeutic indices.(Yang et al.
2006)
Most of these reports concerns the interaction with St. Johns wort. In the past 3 years,
more than 50 papers have been published regarding interactions between St. John's wort
and prescription drugs. Co-medication with St Johns wort has been documented as
decreasing plasma concentrations of a number of drugs, including amitriptyline,
cyclosporine, digoxin, indinavir, irinotecan, warfarin, phenprocoumon, alprazolam,
dextrometorphane, simvastatin, and oral contraceptives. This is not surprising as
sufficient evidence from interaction studies and case reports indicate that St Johns wort isa potent inducer of CYP450 enzymes (particularly CYP3A4) and/or PgP.(Madabushi et
al. 2006)
Recent studies could show that the degree of enzyme induction by St Johns wort
correlates strongly with the amount of hyperforin found in the product. Hyperforin is a
potent inductor of PgPs and CYP3A4.(Durr et al. 2000;Moore et al. 2000;Watkins et al.
2003;Wentworth et al. 2000) and in vitro studies suggest that this is the compound mostlyresponsible for triggering the interactions.
8/3/2019 HerbDrug Interaction Article Thomsen 6 March 2007
6/29
The content of hyperforin varies from plant to plant according to cultivation method and
harvesting time, however depending on the extraction method and processing hyperforin
can be concentrated in pharmaceutical extracts in varying amounts.(Wurglics et al. 2001)
Some German extracts are artificially enriched in hyperforin and tablet preparations
contain significant amounts, whereas normal extracts contain only traces of hyperforin.
There is reason to believe that traditional hypericum extracts which are low in hyperforin,
do not cause a significant reduction in serum levels of drugs metabolized through the PgP
and CYP450/3A4 systems. The level of interaction of St John's wort and digoxin varies
has been found to depend on the particular extract, especially the level of hyperforin.
(Mueller et al. 2004;Mueller et al. 2006) Products that contain insubstantial amounts of
hyperforin (
8/3/2019 HerbDrug Interaction Article Thomsen 6 March 2007
7/29
Although the active compounds have not yet been identified, St Johns wort appears to be
efficacious in the treatment of mild to moderate depression. It is assumed that the overall
clinical effect is caused by synergies between several constituents.(Butterweck et al.
2003;Vandenbogaerde et al. 2000;Verotta 2003) In other words, for St. Johns wort, the
total extract is considered to be the active ingredient. Hence, full-spectrum extract of St.
Johns wort, with a low, un-enhanced level of hyperforin, is not only efficacious; it is also
less likely to cause significant drug interactions.
St Johns Wort is the most studied herb in terms of interaction with pharmaceutical
preparations. It should not be taken concurrently with other antidepressants, with
coumarin-type anticoagulants, the immunosuppressants cyclosporine and tacrolimus,
protease and reverse transcriptase inhibitors used in anti-HIV treatment or with certain
antineoplastic agents. Fortunately the use of these drugs, with the exception of warfarin,
is rare and in all cases, the use of St. Johns Wort can easily be avoided,(Schulz 2006)
particularly if better labelling of herbal products is instigated.
Several other herbs have been tested since it was established that certain preparations of
St. Johns wort induces CYPP450 and PgP. Most of them have not been found to have a
significant effect. Although milk thistle (Silybum marianum), echinacea (Echinacea spp.)
and goldenseal (Hydrastis canadensis) have been found to inhibit CYP P450 enzymes in
vitro, the effect on antiviral drugs concentrations for example, has been found to be
clinically insignificant.(Lee, Andrade, & Flexner 2006)
The Chinese herb schisandra (Schisandra chinensis) has been shown to have a strong
inhibitory effect on CYP3A4. A recent study evaluated the inhibitory effects of
schisandra fruit and shoseiryuto (a traditional Japanese herbal medicine containing eight
herbal medicines including schisandra fruit) on rat CYP3A activity in vitro, and the effect
of shoseiryuto on pharmacokinetics of nifedipine in rats, in comparison with those of
grapefruit juice, a well-characterized natural CYP3A inhibitor. Shoseiryuto and its herbal
constituents, schisandra fruit, ephedra herb and cinnamon bark exhibited in vitro
inhibitory effect of CYP3A. Although shoseiryuto inhibited rat CYP3A activity in vitro
8/3/2019 HerbDrug Interaction Article Thomsen 6 March 2007
8/29
with a degree comparable to grapefruit juice, shoseiryuto did not significantly affect a
plasma concentration profile of nifedipine in rats as grapefruit juice did. These results
indicate that in vivo experiments using the extract of herbal medicine prepared with the
same dosage form as patients take are necessary to provide proper information about
herbdrug interaction.(Makino, Mizuno, & Mizukami 2006)
One clinical study examined the potential interaction between the drug digoxin and
hawthorn (Crataegus monogyna), a herbal extract used in the treatment of cardiovascular
disorders, and found that hawthorn had no effect on the pharmacokinetic profile of
digoxin.(Tankanow et al. 2003) Additionally, a randomized, placebo-controlled study
found that hawthorn was a beneficial adjunctive treatment in type 2 diabetic patients
taking prescription drugs without causing any adverse drug interactions. There was a
significant group difference in mean diastolic blood pressure reductions in the hawthorn
group compared to the placebo group. No herb-drug interaction was found and minor
health complaints were reduced from baseline in both groups. (Walker et al. 2006)
Saw palmetto (Serenoa repens)(Markowitz et al. 2003a) and ginkgo (Ginkgo
biloba)(Markowitz et al. 2003b) have been shown not to alter CYP450, 2D6 and 3A4 in
healthy volunteers, as assessed by the test drugs tested for each herb, dextromethorphan
(CYP2D6) and alprazolam (CYP3A4).
Herb-drug interaction reporting and evaluation
There is justified concern regarding potential herb-drug interactions. Any reporting of
adverse or beneficial effects must be subject to true scientific rigour; otherwise the true
nature of potential adverse events may be misleading and under reported.
There are several limitations to the current adverse event reporting system, including
limited availability of medical records for the reported adverse events, lack of product
8/3/2019 HerbDrug Interaction Article Thomsen 6 March 2007
9/29
ingredient information for the substances involved in the adverse event, and limited
information on the product by the manufacturers.(MacKinnon 2005)
It is estimated that less than 40% of users of CAM disclose use to theirphysician.(MacKinnon 2005) However, the prevalence of clinically significant
interactions between herbals and medications is unknown. Additionally, patients may not
inform health care providers of suspected interactions, or they do not attribute the
reaction to the natural product. American authorities estimate that 50% of adult
Americans use at least one prescription medication and 7% of adults take 5 or more
prescription drugs. Among prescription drug users, 16% also take herbal
supplements.(Kaufman et al. 2002) In Australia, it is estimated that about 50% of patients
frequently use a combination of a CAM product and pharmaceutical drugs. Like in the
US, patients are reluctant to disclose the use of CAM products to mainstream health
professionals. The attitude of mainstream health professionals towards CAM and
patients relationship with their health professional influenced patients decisions to
discuss their CAM use with mainstream health professionals, especially during the initial
phase of trying a CAM preparation. The reasons given by patients for not disclosing
CAM use to their mainstream health professionals were anticipation of a negative
response, belief that CAM use is a patients own healthcare issue, and a perception that
disclosure of CAM use is not relevant.(Bensoussan & Lewith 2004)
All too often, analytical verification of the composition of herbal medicine(s) is not
conducted by the researchers reporting the drug-interaction. This is an important
consideration, given that the relative composition of herbal constituents varies greatly due
to agricultural, harvesting and post-harvesting processes and because there is no agreed
standardisation profile of St. Johns wort extracts. The botanical identity of medicinal
plant must be established, especially where the origin of particular plants is unknown ordifficult to control. On closer examination of undesired drug effects attributed to the
intake of herbal remedies, discrepancies regarding the listing of the single compounds are
frequently found. It is often found retrospectively that adverse effects attributed to a
certain plant were not likely to have been caused by the herbal preparation, but as the
result of an intentional or accidental substitution with other plants, or by a contamination
8/3/2019 HerbDrug Interaction Article Thomsen 6 March 2007
10/29
of the listed components with; a more toxic plant, a toxin (e.g. mould toxins or heavy
metals), or even with a chemically defined drug.(Awang 1996;Corrigan D 2001;Fugh-
Berman 2000)
If there is no such identification of herbal preparations, the unsubstantiated correlation of
toxic effects with the wrong plant will, in the future, lead not only to erroneous scientific
citations, but also to unsubstantiated warnings for patients and practitioners and official
claims for the labeling of side effects or drug-interactions on packages and leaflets
demanded by the health authorities.
Consistency is required when reporting herb-drug interactions, to ensure that this process
is performed in the most scientifically rigorous way possible, in order to determine the
true effect. Without further pathophysiological or biochemical investigation into the
specific reaction, proper evaluation cannot take place, and a conclusion cannot be made
as to the exact mechanism of herb-drug interaction. When reporting herb-drug
interactions, information regarding the plant parts used, the extraction medium, the
amount of drug taken and the method of preparation should be provided. In addition other
causes including past medical history, the use of recreational drugs or dietary factors
should be thoroughly investigated and considered.
Currently, herbal products in the US are regulated by the Dietary Supplement Health and
Education Act (DSHEA) of 1994. Under DSHEA, information regarding herbal-drug
interactions is prohibited on the label. Currently, manufacturers of dietary supplements
are not required to follow good manufacturing practices (GMPs) for drugs, but are
required to abide by the regulations of GMPs for food. The FDA is currently finalizing its
rule for GMPs specific for dietary supplements.(MacKinnon 2005)
The Australian Therapeutic Goods Administration (TGA) recognizes the importance of
including potential drug interaction on the label, however, the warnings are generally
8/3/2019 HerbDrug Interaction Article Thomsen 6 March 2007
11/29
non-specific. Consumers are advised to consult a health professional. Therapeutic
products are produced under pharmaceutical GMP in Australia.
Contaminants or undisclosed pharmaceuticals and intentional or unintentional herbsubstation may actually be responsible for suspected herbal-drug interactions. Testing of
the quality of more than 1,200 dietary supplement products by the independent laboratory
ConsumerLab found that one in four products lacked the labeled ingredients or had other
serious problems, such as unlisted ingredients or contaminants. This creates a problem
when evaluating the validity of herb-drug interactions.(MacKinnon 2005)
The lack of available clinical data for many herbal products also serves as a barrier for
post-marketing safety assessment of herbal products. The evidence of herb-drug
interactions is often based on presumed pharmacological activity, data derived from in
vitro orin vivo animal studies, or anecdotal single case reports and case series, and
making decisions on this type of data is inconclusive and inadequate. Clinical
investigations are needed to validate in vitro herb-drug interactions.(MacKinnon 2005)
Interpretation and evaluation of the data confounds the establishment of clear clinical
guidelines. How should the evidence be weighed? What is the degree of certainty about
the drug interaction? Is the interaction definite, probable, possible, conditional or
doubtful? And what is the clinical relevance? Is the effect representative of a consistent
effect, or is the interaction a conditional response, a rare response or idiosyncratic? And
is the dose of the drug and/or herb clinically relevant? In many instances, articles warn of
dangerous interaction without actually providing much in terms of proof of their
statements. In a recent review, Butterweck and colleagues demonstrated that beliefs about
herb-drug interactions are mainly theoretical considerations, and not clinically observed
facts.(Butterweck et al. 2004) Herb-drug interactions do occur but equally, alcohol,
cigarette smoking and common foods such as broccoli and grapefruit juice may causeinteractions.
Other examples include the use of feverfew (Tanacetum parthenium), which may
decrease platelet aggregation and therefore affect antithrombotic (e.g., aspirin) or
anticoagulant (e.g., warfarin) medications. Similarly, herbal preparations such as ginkgo
8/3/2019 HerbDrug Interaction Article Thomsen 6 March 2007
12/29
may increase the risk of hypotension in patients taking antihypertensive drugs, due to the
addititive effect of lowering blood pressure. Alternately, licorice (Glycyrrhiza glabra)
and ginseng may decrease the effectiveness of antihypertensive drugs, due to the nature
of their constituents. Herbs such as valerian and kava are purported to increase CNS
depression in patients taking antipsychotics or antiepileptic medications.
Ginger (Zingiber officinale) is often cited as having antiplatelet activity, however, there is
no evidence of an interaction of ginger with warfarin.(Stenton, Bungard, & Ackman
2001;Vaes & Chyka 2000), and ginger has been shown not to alter prothrombin times in
pooled human plasma collected from male volunteers between the ages of 18-57
years.(Jones, Miederhoff, & Karnes 2001) A standardized ginger extract has been shown
to have no significant effect on coagulation parameters or on warfarin-induced changes in
blood coagulation in rats.(Weidner & Sigwart 2000) However, an interaction between
ginger and the anticoagulant drug phenprocoumon has been reported.(Kruth et al. 2004)
Since ginger does not posses anticoagulant activity, it is possible that the interaction was
caused by ginger having a pharmacokinetic effect on phenprocoumon as evidence by an
elevated international normalized ratio (INR) of up to 10 and episodes of epistaxis. The
INR returned to normal levels when the ginger tea was discontinued.
In a systematic review of published case reports, case series, and clinical trials of herb-
drug interactions found that out of 108 reported cases of suspected interactions, 69%
were unable to be evaluated, 19% deemed to be possible interactions and only 13% were
well documented using a 10-point scoring system. Eleven out of 14 cases involved
warfarin and 7 out of 11 involved St. Johns wort.(Fugh-Berman & Ernst 2001)
A recent report estimated that herb-anticancer drug interactions are responsible for
substantially more unexpected toxicities of chemotherapeutic drugs and possible under-
treatment seen in cancer patients and that the knowledge of induction of drug-
metabolizing has identified herb capable of causing interactions with anticancer drugs:kava, vitamin E, quercetin, ginseng, garlic, beta-carotene, and echinacea.(Meijerman,
Beijnen, & Schellens 2006) However, there are no any actual case reports or clinical
studies actuallyprovingthat these herbs are causing significant anti-cancer drug
interactions, therapeutic failure or increased toxicity. Again, the concerns are mainly
theoretical. On the contrary, there are in vivo and clinical reports suggesting that such
8/3/2019 HerbDrug Interaction Article Thomsen 6 March 2007
13/29
natural compounds may reduce the toxicity of chemotherapeutic agents and/or enhance
their therapeutic effect.(HemaIswarya & Doble 2006;Kachnic et al. 1997;Kang et al.
2002;Kiyohara et al. 1995;Melchart et al. 2002;Sakamoto et al. 1991;Sugiyama et al.
1994;Sugiyama et al. 1995;Sugiyama, Ueda, & Ichio 1995)
In a recent article, Holden and colleagues(Holden, Joseph, & Williamson 2005),
identified echinacea and other herbs as dangerous for patients taking arthritis medication.
The authors state that devils claw (Harpagophytum procumbens), ginkgo (Ginkgo
biloba) and garlic (Allium sativum) may have antiplatelet or anticoagulant effects, which
could potentially exacerbate the risk of gastrointestinal bleeding from non-steroidal anti-
inflammatory drugs or corticosteroids, except one case report, which discusses a rare and
unusual event of excessive garlic ingestion causing a spontaneous spinal epidural
haematoma, which would not be considered typical. The other references were
experimental studies or theoretical discussions. The authors concluded that 11% of
patients were taking remedies that might interact with conventional drugs. This statement
is misleading, as the concomitant intake of herbs and conventional drugs is not equivalent
to observation or reporting of herb-drug interactions.
Holden and colleagues assume that with the UK drug legislation changes and the transfer
of uncontrolled food supplements into registered drugs, an overwhelming number of
adverse event reports will surface. While underreporting is likely from the uncontrolled
marketing of food supplements, the expectation of a flood of adverse effect reports seems
exaggerated. In countries such as Switzerland and Germany the herbs in question have
long been registered drugs, and subject to pharmacovigilance with little cause for
concern.
Evidence for Herbal-Drug Interactions
Serious herb-drug interactions are most likely to occur with drugs that have a narrow
therapeutic dosage index such as lithium, digoxin, theophylline and warfarin. Warfarin is
known to interact with many drugs and can result in potentially fatal consequences if
8/3/2019 HerbDrug Interaction Article Thomsen 6 March 2007
14/29
bleeding complications arise or subtherapeutic levels occur. Herbs that decrease platelet
aggregation, inhibit platelet-activating factor, or contain salicylates may increase the risk
for bleeding. Interactions between warfarin and these herbs should be considered
theoretical at the moment,(MacKinnon 2005) however practitionersshould use these
herbs with caution when combined with antiplatelet or anticoagulant therapy.
Many herbs contain coumarins which has led many authors to warn against interaction
with warfarin. However, coumarins need be converted to dicoumarol to have any direct
anticoagulant activity. This conversion only occurs when the fresh plant is improperly
stored leading to the conversion of coumarins to dicoumerol by fungal activity. Some
herbs also contain appreciable amounts of vitamin K, and consumption may antagonize
warfarin therapy. Drinking significant amounts of green tea should be avoided in patients
receiving warfarin, although smaller amounts may not produce any appreciable clinical
reduction in INR values.(MacKinnon 2005)
Dong quai (Angelica sinensis) has been shown to affect the pharmacodynamics but not
the pharmacokinetics of warfarin in rabbits. The root extract did not increase prothrombin
time independently, but significantly lowered prothrombin time values 3 days after co-
treatment with single dose warfarin. Treatment with dong quai did not produce any
siginificant differences in steady state concentrations of warfarin.(Lo et al. 1995) It has
also been reported that a 46-year-old African-American woman with atrial fibrillation
stabilized on warfarin experienced a greater than 2-fold elevation in prothrombin time
and INR after taking dong gui concurrently for 4 weeks. No identifiable cause was
ascertained for the increase except dongquai. The patient's coagulation values returned to
acceptable levels 1 month after discontinuing the herb.(Page & Lawrence 1999) These
reports indicate that dong quai should be used caution in patients on chronic warfarintherapy.
In a randomized, placebo-controlled study in healthy young volunteers, American
ginseng (Panax quinquefolium) antagonized the effect of warfarin. The effect was overall
modest, but most subjects had a reduction in INR values warfarin area under the curve,
8/3/2019 HerbDrug Interaction Article Thomsen 6 March 2007
15/29
with some individuals having substantial changes while taking American ginseng.(Yuan
et al. 2004) However, due to the quality of this study, the mechanism of the interaction
cannot be properly evaluated, thus making the significance of the results difficult to
assess.(Jiang, Blair, & McLachlan 2006)
The fruits and seeds of ginkgo have been used in traditional Chinese medicine for
millenia in the treatment of lung congestion. It is however the dried leaf extract which is
mainly used today, manufactured using acetone-water and subsequent purification steps
without addition of concentrates or isolated ingredients. The extract ratio is 35-67:1
(average 50:1). The extract contains 22-27% flavone glycosides and 5-7% terpene
lactones (ginkgolides and bilobalide) and a level of ginkgolic acids below 5 ppm. Ginkgo
is used mostly for memory impairment, dementia, tinnitus, and intermittent claudication.
Adverse effects of ginkgo are usually mild, transient, reversible, and include
gastrointestinal symptoms, headache, nausea and vomiting. Potentially serious adverse
effects are bleeding, including subdural haematoma.(Izzo & Ernst 2001)
Drug interaction of ginkgo with warfarin is widely suspected, primarily based on
extensive in vitro data,and the theoretical potential for a pharmacodynamic interaction.
Ginkgo has also been found to significantly decrease platelet aggregation in healthy
subject and in type 2 diabetics taking ginkgo.(Kudolo, Dorsey, & Blodgett 2002)
However, controlled in vivo studies using EGb761, the most widely investigated
standardized extract ofGinkgo biloba, have found no significant independent effect on
platelet function and coagulation(Bal Dit, Caplain, & Drouet 2003) or additive effects on
coagulation parameters in patients receiving warfarin.(Engelsen, Nielsen, & Hansen
2003)
Furthermore, a recent study investigating herb-drug interactions with warfarin found very
little evidence of significant interaction. Serum warfarin concentration and response
(prothrombin complex activity) data from healthy subjects who received a single warfarin
dose (25 mg) and either St John's wort, Asian ginseng (Panax ginseng), ginkgo, or ginger
were examined. Coadministration of St John's wort significantly increased warfarin
8/3/2019 HerbDrug Interaction Article Thomsen 6 March 2007
16/29
clearance, whereas treatment with Asian ginseng produced only a moderate increase in
warfarin clearance. Ginkgo and ginger did not affect the pharmacokinetics of warfarin in
healthy subjects. None of the herbs studied had a direct effect on warfarin
pharmacodynamics.(Jiang, Blair, & McLachlan 2006) The discrepancy between the in
vitro data and the lack of an interaction based on in vivo studies is likely to be a
consequence of the pharmacokinetics of the ginkgo constituents.
A few rare case reports suggest a possible connection between ginkgo and excessive
bleeding. A 78-year-old woman who had been taking warfarin for five years after
coronary bypass surgery suffered a left parietal haemorrhage after using a ginkgo product
for two months.(Matthews, Jr. 1998) No change was noted in her prothrombin time. The
intracerebral bleeding was attributed to the antiplatelet effects of ginkgo. However,
patients should be cautioned about potential interactions of ginkgo and drugs with
antiplatelet or anticoagulant effects.
In another reported case, a 33-year-old woman was diagnosed with bilateral subdural
hematomas after almost two years of ingesting ginkgo, in a dosage of 60 mg twice daily.
Her other medications were acetaminophen and an ergotamine-caffeine preparation,
which she used briefly. While she was taking ginkgo, her bleeding times were 15 and 9.5
minutes. Within 35 days after she stopped taking the ginkgo product, her bleeding times
were normal (3 to 9 minutes).(Rowin & Lewis 1996)
Herb-drug interaction in perspective
There is justified concern regarding potential herb-drug interactions. While there are
many articles discussing potential herb-drug interactions, there are very few actual cases.
Perhaps herb-drug interactions are under-reported. Perhaps they are actually quite rare
events. More clinical studies are needed to establish the clinical relevance and
significance of suspected herb-drug interactions.
8/3/2019 HerbDrug Interaction Article Thomsen 6 March 2007
17/29
It seems prudent to be vigilant when prescribing herbal preparations for patients taking
any prescription medications, particularly the elderly, patients with impaired renal or
liver function, or taking critical drugs, (e.g., anti-HIV drugs, chemotherapy), and in
patients on drugs with a narrow therapeutic window (e.g., anti-rejection drugs, digoxin,
lithium and warfarin) and in patients suffering from serious and chronic diseases.
Additionally, clinical medical and natural practitioners alike, should be aware of common
pitfalls, including failure to: consider the effects of dose on the outcome of the
interaction; appreciate the time-course of drug interactions; consider the effects of
sequence of administration and; consider the pharmaceutical, herbal or dietary habits of
the patients. Practitioners should also be aware of making assumptions regarding: similar
magnitude of drug interactions among patients; separating doses to circumvent absorption
interactions, and: routes of administration interacting in the same way. On a practical
note, always recognize the potential for interactions at the level of metabolism when
prescribing. It may also be advantageous to include the patients family medical history,
and to update their drug history on a continual basis.(Agins 2006)
Any reporting of adverse or beneficial effects, however, must be subject to true scientific
rigour; otherwise the true nature of potential adverse events may be misleading and under
reported.
The following herb-drug interaction table outlines the most common and important herb-
drug interactions. It is not a complete reference and should be used as a guide only.
Drug Interaction Chart
Drug Sample
Trade name
Botanical
name
Common
name
Interaction
Alprazolam
(benzodiazapines)
Xanax Piper
methysticum
Kava GABA receptor
stimulation
Avoid. Co-
prescription
may increase
sedation.
Aspirin Aspro,
Solprin,
Astrix, Cartia
Ginkgo biloba Ginkgo Decreased platelet
aggregation
Avoid. Co-
prescription
may increase
8/3/2019 HerbDrug Interaction Article Thomsen 6 March 2007
18/29
bruising and
bleeding.
Betablockers and
other hypotensive
medication
Enalapril,
Peridopril,
Atenolol,
amlodipine
Glycyrrhiza
glabra
Liquorice Long-term use may
elevate blood
pressure
Avoid.
Carbamazepine Tegretol Hypericum
perforatum
St. Johns wort St. Johns wort
may decrease
serum levels.
Avoid.
Carbimazole
(antithyroid
medication)
Neo-
mercazole
Fucus
vesiculosus
Bladderwrack Bladderwrack
contains iodine.
Avoid.
Cortisone,
prednisolone
Cortate,
Presolone,
Solone
Glycyrrhiza
glabra
Liquorice May decrease
metabolism and
therefore potentiate
the effect.
Use with
caution.
Hypericum
perforatum
St. Johns wort St. Johns wort
decreases serum
level.
Avoid.
Echinacea spp. Echinacea Opposite activity. Avoid.
Cyclosporin and
other
immunosuppressive
drugs
Neoral,
Cicloral,
Cysporin
Andrographis
paniculata
Andrographis Opposite activity. Avoid.
Hypericum
perforatum
St. Johns wort St. Johns wort
decreases serum
level.
Avoid.
Crataegus spp. Hawthorn May increase
cardiac effects of
digoxin (possibly
without increasing
the toxicity).
Use with
caution.
Monitor
digoxin
dosage.
Digoxin Lanoxin,
Sigmaxin
Glycyrrhiza
glabra
Liquorice Potassium
depletion may
increase digoxin
toxicity
Avoid.
Haloperidol Serenace Ginkgo biloba Ginkgo May potentiate
effect of
heloperidol.
Use with
caution.
HIV Protease Indinavir Hypericum St. Johns wort St. Johns wort Avoid.
8/3/2019 HerbDrug Interaction Article Thomsen 6 March 2007
19/29
inhibitors and non-
nucleoside
transcriptase
inhibitors
perforatum decreases serum
indinavir.
Imatinib mesylate Glivec
(anticancer
drug)
Hypericum
perforatum
St. Johns wort St. Johns wort
may increase
metabolism of
imatinib
Avoid.
Levodopa Madopa,
Sinemet
Piper
methysticum
Kava Kava may decrease
the effectiveness of
levodopa, because
of dopamine
antagonism.
Avoid. May
reduce the
effectiveness
of levodopa in
the treatment
of
symptoms of
Parkinsons
disease.
Oral contraceptives Diane-35 Hypericum
perforatum
St. Johns wort St. Johns wort
decreases serum
levels.
Clinical
significance
unknown.
Phenprocoumon Anticoagulant Hypericum
perforatum
St. Johns wort St. Johns wort
decreases serum
phenprocoumon.
Avoid.
Phenelzine
monoamine
oxidase inhibitor
Nardil Panax ginseng Korean
ginseng
Inhibits cAMP
phosphodiesterase
activity
Avoid.
Concomitant
use may result
in manic-like
symptoms
Selective Serotonin
Reuptake Inhibitors
Prozac Hypericum
perforatum
St. Johns wort Similar action. Avoid.
Sodium valproate Epilim,
Valpro
Ginkgo biloba Ginkgo Ginkgo has been
shown to reduce
the effects of
sodium valproate
in mice.
Avoid.
Theophylline Nuelin Hypericum
perforatum
St. Johns wort St. Johns wort
decreases serum
theophylline.
Use with
caution.
8/3/2019 HerbDrug Interaction Article Thomsen 6 March 2007
20/29
Glycyrrhiza
glabra
Liquourice Increase in
potassium
excretion.
Avoid.Thiazide
(potassium
depleting diuretic)
Accuretic,
Amizide
Cassia senna
and other
laxative herbs
Senna and
other laxative
herbs
May cause further
potassium
depletion.
Avoid.
Thyroxine sodium Eutroxsig,
Oroxine
Lycopus spp. Bugleweed Interaction
unknown.
Avoid
Angelica
sinensis
Dong quai May decrease
platelet
aggregation.
Use with
caution.
Patients should
be monitored
for
prothrombin
and INR
values.
Allium sativa Garlic May decrease
platelet
aggregation.
Use with
caution.
Patients should
be monitored
for
prothrombin
and INR
values.
Cucurma longa Turmeric May decrease
platelet
aggregation.
Use with
caution.
Patients should
be monitored
for
prothrombin
and INR
values.
Warfarin Coumadin,
Marevan
Coleus
forskolhii
Coleus May decrease
platelet
aggregation.
Use with
caution.
Patients should
be monitored
for
prothrombin
and INR
values.
8/3/2019 HerbDrug Interaction Article Thomsen 6 March 2007
21/29
Ginkgo biloba Ginkgo May decrease
platelet
aggregation.
Use with
caution.
Patients should
be monitored
for
prothrombin
and INR
values.
Hypericum
perforatum
St. Johns wort May increase pro-
thrombin time and
international
normlized ratio
(INR) values.
Avoid.
Panax ginseng Korean
ginseng
May decrease
plateletaggregation.
May increase pro-
thrombin time and
international
normlized ratio
(INR) values.
Use with
caution.Patients should
be monitored
for
prothrombin
and INR
values.
Salix spp. Willow bark May decrease
platelet
aggregation.
Use with
caution.
Patients should
be monitored
for
prothrombin
and INR
values.
Salvia
miltiorrhiza
Dan Shen May decrease
platelet
aggregation.
Use with
caution.
Patients should
be monitored
forprothrombin
and INR
values.
8/3/2019 HerbDrug Interaction Article Thomsen 6 March 2007
22/29
Vaccinium
myrtillus
Bilberry May decrease
platelet
aggregation.
Use with
caution.
Patients should
be monitored
for
prothrombin
and INR
values.
Zingiber
officinale
Ginger May decrease
platelet
aggregation.
Use with
caution.
Patients should
be monitored
for
prothrombin
and INR
values.
References
Agins, A. P. Cytochrome P450 and Beyond. Lecture notes. 2006.
Ref Type: Generic
Awang, D. V. 1996, "Siberian ginseng toxicity may be case of mistaken identity",
CMAJ., vol. 155, no. 9, p. 1237.
Bal Dit, S. C., Caplain, H., & Drouet, L. 2003, "No alteration in platelet function or
coagulation induced by EGb761 in a controlled study", Clin.Lab Haematol., vol. 25, no.
4, pp. 251-253.
Bensoussan, A. & Lewith, G. T. 2004, "Complementary medicine research in Australia: a
strategy for the future", Med.J.Aust., vol. 181, no. 6, pp. 331-333.
8/3/2019 HerbDrug Interaction Article Thomsen 6 March 2007
23/29
Boullata, J. 2005, "Natural health product interactions with medication",
Nutr.Clin.Pract., vol. 20, no. 1, pp. 33-51.
Butterweck, V., Christoffel, V., Nahrstedt, A., Petereit, F., Spengler, B., & Winterhoff,
H. 2003, "Step by step removal of hyperforin and hypericin: activity profile of different
Hypericum preparations in behavioral models",Life Sci., vol. 73, no. 5, pp. 627-639.
Butterweck, V., Derendorf, H., Gaus, W., Nahrstedt, A., Schulz, V., & Unger, M. 2004,
"Pharmacokinetic herb-drug interactions: are preventive screenings necessary and
appropriate?",Planta Med., vol. 70, no. 9, pp. 784-791.
Corrigan D 2001, "Adverse Reports - some first principles. l 2001; 1.", The European
Phytojournal, vol. 1, no. 2, pp. 1-6.
Durr, D., Stieger, B., Kullak-Ublick, G. A., Rentsch, K. M., Steinert, H. C., Meier, P. J.,
& Fattinger, K. 2000, "St John's Wort induces intestinal P-glycoprotein/MDR1 and
intestinal and hepatic CYP3A4", Clin.Pharmacol.Ther., vol. 68, no. 6, pp. 598-604.
Engelsen, J., Nielsen, J. D., & Hansen, K. F. 2003, "[Effect of Coenzyme Q10 and
Ginkgo biloba on warfarin dosage in patients on long-term warfarin treatment. A
randomized, double-blind, placebo-controlled cross-over trial]", Ugeskr.Laeger, vol. 165,
no. 18, pp. 1868-1871.
Fugh-Berman, A. 2000, "Herb-drug interactions",Lancet, vol. 355, no. 9198, pp. 134-
138.
Fugh-Berman, A. & Ernst, E. 2001, "Herb-drug interactions: review and assessment of
report reliability",Br.J.Clin.Pharmacol., vol. 52, no. 5, pp. 587-595.
HemaIswarya, S. & Doble, M. 2006, "Potential synergism of natural products in the
treatment of cancer",Phytother.Res., vol. 20, no. 4, pp. 239-249.
Holden, W., Joseph, J., & Williamson, L. 2005, "Use of herbal remedies and potential
drug interactions in rheumatology outpatients",Ann.Rheum.Dis., vol. 64, no. 5, p. 790.
8/3/2019 HerbDrug Interaction Article Thomsen 6 March 2007
24/29
Izzo, A. A. & Ernst, E. 2001, "Interactions between herbal medicines and prescribed
drugs: a systematic review",Drugs, vol. 61, no. 15, pp. 2163-2175.
Jiang, X., Blair, E. Y., & McLachlan, A. J. 2006, "Investigation of the effects of herbal
medicines on warfarin response in healthy subjects: a population pharmacokinetic-
pharmacodynamic modeling approach",J.Clin.Pharmacol., vol. 46, no. 11, pp. 1370-
1378.
Johne, A., Brockmoller, J., Bauer, S., Maurer, A., Langheinrich, M., & Roots, I. 1999,
"Pharmacokinetic interaction of digoxin with an herbal extract from St John's wort
(Hypericum perforatum)", Clin.Pharmacol.Ther., vol. 66, no. 4, pp. 338-345.
Jones, S. C., Miederhoff, P., & Karnes, H. T. 2001, "The development of a human tissuemodel to determine the effect of plant-derived dietary supplements on prothrombin
time.",Journal of Herbal Pharmacotherapy, vol. 1, no. 1, pp. 21-34.
Kachnic, L. A., Kaufman, D. S., Heney, N. M., Althausen, A. F., Griffin, P. P., Zietman,
A. L., & Shipley, W. U. 1997, "Bladder preservation by combined modality therapy for
invasive bladder cancer",J.Clin.Oncol., vol. 15, no. 3, pp. 1022-1029.
Kang, J., Lee, Y., No, K., Jung, E., Sung, J., Kim, Y., & Nam, S. 2002, "Ginseng
intestinal metabolite-I (GIM-I) reduces doxorubicin toxicity in the mouse testis",
Reprod.Toxicol., vol. 16, no. 3, pp. 291-298.
Kaufman, D. W., Kelly, J. P., Rosenberg, L., Anderson, T. E., & Mitchell, A. A. 2002,
"Recent patterns of medication use in the ambulatory adult population of the United
States: the Slone survey",JAMA, vol. 287, no. 3, pp. 337-344.
Kiyohara, H., Matsumoto, T., Takemoto, N., Kawamura, H., Komatsu, Y., & Yamada, H.
1995, "Effect of oral administration of a pectic polysaccharide fraction from a kampo
(Japanese herbal) medicine "juzen-taiho-to" on antibody response of mice",Planta Med.,
vol. 61, no. 5, pp. 429-434.
8/3/2019 HerbDrug Interaction Article Thomsen 6 March 2007
25/29
Kruth, P., Brosi, E., Fux, R., Morike, K., & Gleiter, C. H. 2004, "Ginger-associated
overanticoagulation by phenprocoumon",Ann.Pharmacother., vol. 38, no. 2, pp. 257-
260.
Kudolo, G. B., Dorsey, S., & Blodgett, J. 2002, "Effect of the ingestion of Ginkgo biloba
extract on platelet aggregation and urinary prostanoid excretion in healthy and Type 2
diabetic subjects", Thromb.Res., vol. 108, no. 2-3, pp. 151-160.
Lee, L. S., Andrade, A. S., & Flexner, C. 2006, "Interactions between natural health
products and antiretroviral drugs: pharmacokinetic and pharmacodynamic effects",
Clin.Infect.Dis., vol. 43, no. 8, pp. 1052-1059.
Lo, A. C., Chan, K., Yeung, J. H., & Woo, K. S. 1995, "Danggui (Angelica sinensis)affects the pharmacodynamics but not the pharmacokinetics of warfarin in rabbits",
Eur.J.Drug Metab Pharmacokinet., vol. 20, no. 1, pp. 55-60.
MacKinnon, K. Herbal-Drug Interactions. InetCE . 1-6-2005. 1-3-2007.
Ref Type: Electronic Citation
Madabushi, R., Frank, B., Drewelow, B., Derendorf, H., & Butterweck, V. 2006,
"Hyperforin in St. John's wort drug interactions",Eur.J.Clin.Pharmacol., vol. 62, no. 3,
pp. 225-233.
Makino, T., Mizuno, F., & Mizukami, H. 2006, "Does a kampo medicine containing
schisandra fruit affect pharmacokinetics of nifedipine like grapefruit juice?",
Biol.Pharm.Bull., vol. 29, no. 10, pp. 2065-2069.
Markowitz, J. S., Donovan, J. L., DeVane, C. L., Taylor, R. M., Ruan, Y., Wang, J. S., &
Chavin, K. D. 2003a, "Multiple doses of saw palmetto (Serenoa repens) did not alter
cytochrome P450 2D6 and 3A4 activity in normal volunteers", Clin.Pharmacol.Ther.,
vol. 74, no. 6, pp. 536-542.
Markowitz, J. S., Donovan, J. L., Lindsay, D. C., Sipkes, L., & Chavin, K. D. 2003b,
"Multiple-dose administration of Ginkgo biloba did not affect cytochrome P-450 2D6 or
3A4 activity in normal volunteers",J.Clin.Psychopharmacol., vol. 23, no. 6, pp. 576-581.
8/3/2019 HerbDrug Interaction Article Thomsen 6 March 2007
26/29
Matthews, M. K., Jr. 1998, "Association of Ginkgo biloba with intracerebral
hemorrhage",Neurology, vol. 50, no. 6, pp. 1933-1934.
Meijerman, I., Beijnen, J. H., & Schellens, J. H. 2006, "Herb-drug interactions in
oncology: focus on mechanisms of induction", Oncologist., vol. 11, no. 7, pp. 742-752.
Melchart, D., Clemm, C., Weber, B., Draczynski, T., Worku, F., Linde, K.,
Weidenhammer, W., Wagner, H., & Saller, R. 2002, "Polysaccharides isolated from
Echinacea purpurea herba cell cultures to counteract undesired effects of chemotherapy--
a pilot study",Phytother.Res., vol. 16, no. 2, pp. 138-142.
Moore, L. B., Goodwin, B., Jones, S. A., Wisely, G. B., Serabjit-Singh, C. J., Willson, T.
M., Collins, J. L., & Kliewer, S. A. 2000, "St. John's wort induces hepatic drugmetabolism through activation of the pregnane X receptor",Proc.Natl.Acad.Sci.U.S.A,
vol. 97, no. 13, pp. 7500-7502.
Mueller, S. C., Majcher-Peszynska, J., Uehleke, B., Klammt, S., Mundkowski, R. G.,
Miekisch, W., Sievers, H., Bauer, S., Frank, B., Kundt, G., & Drewelow, B. 2006, "The
extent of induction of CYP3A by St. John's wort varies among products and is linked to
hyperforin dose",Eur.J.Clin.Pharmacol., vol. 62, no. 1, pp. 29-36.
Mueller, S. C., Uehleke, B., Woehling, H., Petzsch, M., Majcher-Peszynska, J., Hehl, E.
M., Sievers, H., Frank, B., Riethling, A. K., & Drewelow, B. 2004, "Effect of St John's
wort dose and preparations on the pharmacokinetics of digoxin", Clin.Pharmacol.Ther.,
vol. 75, no. 6, pp. 546-557.
Page, R. L. & Lawrence, J. D. 1999, "Potentiation of warfarin by dong quai",
Pharmacotherapy, vol. 19, no. 7, pp. 870-876.
Perlman, B. B. 1990, "Interaction between lithium salts and ispaghula husk",Lancet, vol.
335, no. 8686, p. 416.
Rowin, J. & Lewis, S. L. 1996, "Spontaneous bilateral subdural hematomas associated
with chronic Ginkgo biloba ingestion",Neurology, vol. 46, no. 6, pp. 1775-1776.
8/3/2019 HerbDrug Interaction Article Thomsen 6 March 2007
27/29
Sakamoto, S., Kudo, H., Kuwa, K., Suzuki, S., Kato, T., Kawasaki, T., Nakayama, T.,
Kasahara, N., & Okamoto, R. 1991, "Anticancer effects of a Chinese herbal medicine,
juzen-taiho-to, in combination with or without 5-fluorouracil derivative on DNA-
synthesizing enzymes in 1,2-dimethylhydrazine induced colonic cancer in rats",
Am.J.Chin Med., vol. 19, no. 3-4, pp. 233-241.
Schulz, V. 2006, "Safety of St. John's Wort extract compared to synthetic
antidepressants",Phytomedicine., vol. 13, no. 3, pp. 199-204.
Stenton, S. B., Bungard, T. J., & Ackman, M. L. 2001, "Interactions between warfarin
and herbal products, minerals, and vitamins: A pharmacist's guide", Canadian Journal of
Hospital Pharmacy, vol. 54, no. 3, pp. 184-190.
Sugiyama, K., Ueda, H., & Ichio, Y. 1995, "Protective effect of juzen-taiho-to against
carboplatin-induced toxic side effects in mice",Biol.Pharm.Bull., vol. 18, no. 4, pp. 544-
548.
Sugiyama, K., Ueda, H., Ichio, Y., & Yokota, M. 1995, "Improvement of cisplatin
toxicity and lethality by juzen-taiho-to in mice",Biol.Pharm.Bull., vol. 18, no. 1, pp. 53-
58.
Sugiyama, K., Ueda, H., Suhara, Y., Kajima, Y., Ichio, Y., & Yokota, M. 1994,
"Protective effect of sodium L-malate, an active constituent isolated from Angelicae
radix, on cis-diamminedichloroplatinum(II)-induced toxic side effect",
Chem.Pharm.Bull.(Tokyo), vol. 42, no. 12, pp. 2565-2568.
Tankanow, R., Tamer, H. R., Streetman, D. S., Smith, S. G., Welton, J. L., Annesley, T.,
Aaronson, K. D., & Bleske, B. E. 2003, "Interaction study between digoxin and a
preparation of hawthorn (Crataegus oxyacantha)",J.Clin.Pharmacol., vol. 43, no. 6, pp.637-642.
Vaes, L. P. & Chyka, P. A. 2000, "Interactions of warfarin with garlic, ginger, ginkgo, or
ginseng: nature of the evidence",Ann.Pharmacother., vol. 34, no. 12, pp. 1478-1482.
8/3/2019 HerbDrug Interaction Article Thomsen 6 March 2007
28/29
Vandenbogaerde, A., Zanoli, P., Puia, G., Truzzi, C., Kamuhabwa, A., De Witte, P.,
Merlevede, W., & Baraldi, M. 2000, "Evidence that total extract of Hypericum
perforatum affects exploratory behavior and exerts anxiolytic effects in rats",
Pharmacol.Biochem.Behav., vol. 65, no. 4, pp. 627-633.
Verotta, L. 2003, "Hypericum perforatum, a source of neuroactive lead structures",
Curr.Top.Med.Chem., vol. 3, no. 2, pp. 187-201.
Walker, A. F., Marakis, G., Simpson, E., Hope, J. L., Robinson, P. A., Hassanein, M., &
Simpson, H. C. 2006, "Hypotensive effects of hawthorn for patients with diabetes taking
prescription drugs: a randomised controlled trial",Br.J.Gen.Pract., vol. 56, no. 527, pp.
437-443.
Watkins, R. E., Maglich, J. M., Moore, L. B., Wisely, G. B., Noble, S. M., Davis-Searles,
P. R., Lambert, M. H., Kliewer, S. A., & Redinbo, M. R. 2003, "2.1 A crystal structure of
human PXR in complex with the St. John's wort compound hyperforin",Biochemistry,
vol. 42, no. 6, pp. 1430-1438.
Weidner, M. S. & Sigwart, K. 2000, "The safety of a ginger extract in the rat",
J.Ethnopharmacol., vol. 73, no. 3, pp. 513-520.
Wentworth, J. M., Agostini, M., Love, J., Schwabe, J. W., & Chatterjee, V. K. 2000, "St
John's wort, a herbal antidepressant, activates the steroid X receptor",J.Endocrinol., vol.
166, no. 3, p. R11-R16.
Woelk, H. 2000, "Comparison of St John's wort and imipramine for treating depression:
randomised controlled trial",BMJ, vol. 321, no. 7260, pp. 536-539.
Wurglics, M., Westerhoff, K., Kaunzinger, A., Wilke, A., Baumeister, A., Dressman, J.,
& Schubert-Zsilovecz, M. 2001, "Batch-to-batch reproducibility of St. John's wort
preparations",Pharmacopsychiatry, vol. 34 Suppl 1, p. S152-S156.
Yang, X. X., Hu, Z. P., Duan, W., Zhu, Y. Z., & Zhou, S. F. 2006, "Drug-herb
interactions: eliminating toxicity with hard drug design", Curr.Pharm.Des, vol. 12, no.
35, pp. 4649-4664.
8/3/2019 HerbDrug Interaction Article Thomsen 6 March 2007
29/29
Yuan, C. S., Wei, G., Dey, L., Karrison, T., Nahlik, L., Maleckar, S., Kasza, K., Ang-
Lee, M., & Moss, J. 2004, "Brief communication: American ginseng reduces warfarin's
effect in healthy patients: a randomized, controlled Trial",Ann.Intern.Med., vol. 141, no.
1, pp. 23-27.