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: michael.thomsen@herbresearch.com.au

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

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 to metabolizing (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 P450 enzyme 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

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 toxicity of 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.

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 reduced lithium 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)

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 is a 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 mostly responsible for triggering the interactions.

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 (<1%) have been shown not to produce clinically significant enzyme induction.(Madabushi, Frank, Drewelow, Derendorf, & Butterweck 2006) A hyperforinrich extract has been shown to decrease digoxin serum levels though an activation of the metabolic PgP transporter system, whereas an extract virtually free of hyperforin did not exhibit this effect.(Johne et al. 1999)

Similarly, no effect on hormonal blood levels was found on concomitant intake of St. Johns wort and oral contraceptives. The latter are metabolized through the CYP450/3A4 system. It would appear that St. Johns wort extracts with a low hyperforin content do not induce interactions at the two examined metabolizing enzyme systems (PgP transporter system and CYP450/3A4).

Some evidence suggests that hyperforin may contribute to the antidepressant activity of St Johns wort. However, clinical studies using St Johns wort preparations with a low hyperforin amount (<1%) clearly demonstrated the superiority of this plant extract over placebo and its equivalence to imipramine and fluoxetine in the treatment of mild to moderate forms of depression(Madabushi, Frank, Drewelow, Derendorf, & Butterweck 2006;Woelk 2000) indicating that the herb may be used to treat depression, without causing significant herb-drug interactions.

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

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

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 their physician.(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 or difficult 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

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;FughBerman 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

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 herb substation 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 or in 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 cause interactions. 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

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 herbdrug 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 undertreatment seen in cancer patients and that the knowledge of induction of drugmetabolizing 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 actually proving that 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

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 antiinflammatory 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

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 cotreatment 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 warfarin therapy. 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,

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 of Ginkgo 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

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.

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 herbdrug interactions. It is not a complete reference and should be used as a guide only.

Drug Interaction Chart

Drug Sample Trade name Alprazolam (benzodiazapines) Xanax Botanical name Piper methysticum Common name Kava GABA receptor stimulation Avoid. Coprescription may increase sedation. Aspirin Aspro, Solprin, Astrix, Cartia Ginkgo biloba Ginkgo Decreased platelet aggregation Avoid. Coprescription may increase Interaction

bruising and bleeding. Betablockers and other hypotensive medication Enalapril, Peridopril, Atenolol, amlodipine Carbamazepine Tegretol Hypericum perforatum St. Johns wort St. Johns wort may decrease serum levels. Carbimazole (antithyroid medication) Cortisone, prednisolone Cortate, Presolone, Solone Glycyrrhiza glabra Liquorice May decrease metabolism and therefore potentiate the effect. Cyclosporin and other immunosuppressive drugs Neoral, Cicloral, Cysporin Echinacea spp. Andrographis paniculata Digoxin Lanoxin, Sigmaxin Hypericum perforatum St. Johns wort St. Johns wort decreases serum level. Crataegus spp. Hawthorn May increase cardiac effects of digoxin (possibly without increasing the toxicity). Glycyrrhiza glabra Liquorice Potassium depletion may increase digoxin toxicity Haloperidol Serenace Ginkgo biloba Ginkgo May potentiate effect of heloperidol. HIV Protease Indinavir Hypericum St. Johns wort St. Johns wort Avoid. Use with caution. Use with caution. Monitor digoxin dosage. Avoid. Avoid. Echinacea Andrographis Hypericum perforatum St. Johns wort St. Johns wort decreases serum level. Opposite activity. Opposite activity. Avoid. Avoid. Avoid. Use with caution. Neomercazole Fucus vesiculosus Bladderwrack Bladderwrack contains iodine. Avoid. Avoid. Glycyrrhiza glabra Liquorice Long-term use may elevate blood pressure Avoid.

inhibitors and nonnucleoside transcriptase inhibitors Imatinib mesylate Glivec (anticancer drug)

perforatum

decreases serum indinavir.

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. Avoid.

Phenprocoumon

Anticoagulant

Hypericum perforatum

St. Johns wort

St. Johns wort decreases serum phenprocoumon.

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 Sodium valproate

Prozac

Hypericum perforatum

St. Johns wort

Similar action.

Avoid.

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.

Thiazide (potassium depleting diuretic)

Accuretic, Amizide

Glycyrrhiza glabra

Liquourice

Increase in potassium excretion.

Avoid.

Cassia senna and other laxative herbs Thyroxine sodium Eutroxsig, Oroxine Warfarin Coumadin, Marevan Angelica sinensis Lycopus spp.

Senna and other laxative herbs Bugleweed

May cause further potassium depletion. Interaction unknown.

Avoid.

Avoid

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.

Coleus forskolhii

Coleus

May decrease platelet aggregation.

Use with caution. Patients should be monitored for prothrombin and INR values.

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 prothrombin time and international normlized ratio (INR) values.

Avoid.

Panax ginseng

Korean ginseng

May decrease platelet aggregation. May increase prothrombin time and international normlized ratio (INR) values.

Use with caution. Patients should be monitored for prothrombin and INR values. Use with caution. Patients should be monitored for prothrombin and INR values.

Salix spp.

Willow bark

May decrease platelet aggregation.

Salvia miltiorrhiza

Dan Shen

May decrease platelet aggregation.

Use with caution. Patients should be monitored for prothrombin and INR values.

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

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