International Journal of Cardiology 98 (2005) 1 14 www.elsevier.

com/locate/ijcard

Review

Cardiovascular pharmacotherapy and herbal medicines: the risk of drug interaction

Angelo A. Izzo a,*, Giulia Di Carlo a, Francesca Borrelli a, Edzard Ernst b
b a Department of Experimental Pharmacology, University of Naples Federico II, via D. Montesano 49, 80131 Naples, Italy Complementary Medicine, Penninsula Medical School, Universities of Exeter and Plymouth, 25 Victoria Park Road, EX2 4NT, UK

Received 18 April 2003; received in revised form 10 June 2003; accepted 14 June 2003 Available online 21 February 2004

Abstract Use of herbal medicines among patients under cardiovascular pharmacotherapy is widespread. In this paper, we have reviewed the literature to determine the possible interactions between herbal medicines and cardiovascular drugs. The Medline database was searched for clinical articles published between January 1996 and February 2003. Forty-three case reports and eight clinical trials were identified. Warfarin was the most common cardiovascular drug involved. It was found to interact with boldo, curbicin, fenugreek, garlic, danshen, devils claw, don quai, ginkgo, papaya, lycium, mango, PC-SPES (resulting in over-anticoagulation) and with ginseng, green tea, soy and St. Johns wort (causing decreased anticoagulant effect). Gum guar, St. Johns wort, Siberian ginseng and wheat bran were found to decrease plasma digoxin concentration; aspirin interactions include spontaneous hyphema when associated with ginkgo and increased bioavailability if combined with tamarind. Decreased plasma concentration of simvastatin or lovastatin was observed after co-administration with St. Johns wort and wheat bran, respectively. Other adverse events include hypertension after co-administration of ginkgo and a diuretic thiazide, hypokalemia after liquorice and antihypertensives and anticoagulation after phenprocoumon and St. Johns wort. Interaction between herbal medicine and cardiovascular drugs is a potentially important safety issue. Patients taking anticoagulants are at the highest risk. D 2004 Elsevier Ireland Ltd. All rights reserved.
Keywords: Cardiovascular pharmacotherapy; Herbal medicines; Drug interaction

1. Introduction Interest in alternative medicine including plant-derived medications is growing. Self-administration of herbal medicines is among the most popular of alternative therapies [1,2]. In the US, the market for herbal medicinal products (usually sold as food supplements or nutraceuticals) amounted to US$590.9 million [3]. These sales figures relate only to food stores, drug stores and mass market and would obviously be larger if buying clubs, convenience stores, natural food markets, multilevel marketing companies, health professionals, mail or Internet order had been considered. The relevance of alternative therapies for cardiovascular medicine is highlighted by the recent workshop on the use of herbal medicines in cardiovascular, lung and blood research sponsored by the US National Heart, Lung, and Blood Institute [4].

* Corresponding author. Tel.: +39-81-678439; fax: +39-81-678403. E-mail address: aaizzo@unina.it (A.A. Izzo). 0167-5273/$ - see front matter D 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2003.06.039

In view of the increasing use of herbal remedies by the general public and subsequent interest by the authorities, it is imperative to promote credible research on the safety of herbal products including the possibility of interactions with concurrent cardiovascular pharmacotherapy. Providing accurate and clinically relevant advice to patients regarding the possibility of herb drug interactions is a challenge for healthcare practitioners. Because all herbal medicines are mixtures of more than one active ingredient, they obviously increase the likelihood of herb drug interactions [5]. Moreover, the majority of people who use herbal products do not reveal this to their physician or pharmacist [2]. This increases the likelihood that herb drug interactions are not identified and resolved in a timely manner. Nevertheless, recent data indicate that potentially serious interactions exist between some common herbal remedies and widely used conventional pharmaceuticals [6 16], including those used in the therapy of cardiovascular diseases [17 20]. In this article, we review the existing clinical data on suspected interactions between herbal medicine and con-

Table 1 Clinical interactions between herbal medicines and conventional cardiovascular drugs Conventional drug Herbal medicine Result of interaction Decreased plasma digoxin concentration Possible mechanism Reduced absorption Pharmacological comment Guar gum reduces gastric emptying, which result in a transient delayed digoxin absorption. Digoxin is a substrate of P-glycoprotein which is induced by St. Johns wort. Siberian ginseng inhibits the metabolism of hexobarbital in mice. Bran contains fibers which can trap digoxin. Clinical comment Similar amount of digoxin was found in 24-h urine whether given with or without guar gum. St. Johns wort may reduce efficacy of digoxin and make a patient a nonresponder. The patient was asymptomatic for digoxin toxicity despite a level of 2.5 ng/l. Digoxin levels were still within the therapeutic range. No. of cases Comment on report reliability Not applicablea Ref A.A. Izzo et al. / International Journal of Cardiology 98 (2005) 114

Interaction with cardiac drugs Digoxin Gum guar

[27]

Digoxin

St. Johns wort

Decreased plasma digoxin concentration Increased plasma digoxin concentration

Induction of P-glycoprotein

Not applicablea

[28]

Digoxin

Siberian ginseng

Digoxin

Wheat bran

Decreased plasma digoxin concentration

Some component of Siberian ginseng might impair digoxin elimination or interfere with the digoxin assay. Reduced absorption

The report is well documented; the level of digoxin decreased upon dechallenge and increased upon rechallenge. Not applicablea

[29]

[30]

Interactions with antihypertensive drugs Diuretic thiazide Ginkgo Increase in blood pressure

Not known

Antihypertensives

Liquorice

Hypokalemia

Additive effect on potassium excretion

This interaction is surprising as Ginkgo is a peripheral vasodilatator. Some antihypertensive drugs induce hypokalemia; liquorice has mineralcorticoid effects which may cause potassium excretion.

If confirmed, the interaction is potentially dangerous. Serum potassium levels should be monitored closely in patients who are predisposed to cardiac arrhythmias and who are concurrently treated with digitalis glycosides.

The report contains inadequate information.

[31]

The report contains inadequate information.

[32]

Interactions with antiplatet drugs Aspirin Ginkgo

Spontaneous hyphema

Additive inhibition of platelet aggregation

Ginkgolides from ginkgo have antiplatelet activity and are PAF receptor antagonists.

Spontaneous bleeding from the iris into the anterior chamber of the eye is a rare problem. Uncertain

Aspirin

Tamarind

Increased bioavailability of aspirin

Not known

The report provides some evidence for interaction. However, ginkgo taken on its own has been suspected to cause brain hemorrhage. Not applicablea

[33]

[34]

Interactions with anticoagulants Warfarin Boldo/ Fenugreek

Increased anticoagulant effect

Additive effect on coagulation mechanisms

Both boldo and fenugreek contain anticoagulant coumarins. Vitamin E contained in curbicin can antagonize the effect of vitamin K on coagulation. In addition to its antiplatelet activity, danshen decreases warfarin elimination in rats. In contrast to NSAIDs, devils claw does not affect platelet function.

Warfarin

Curbicin

Increased anticoagulant effect

Additive effect on coagulation mechanisms

Risk of bleeding; given the narrow therapeutic index of warfarin, vigilance is needed. Cases of coagulation disorders related to vitamin E have been reported. Risk of bleeding; given the narrow therapeutic index of warfarin, vigilance is needed. Risk of bleeding; given the narrow therapeutic index of warfarin, vigilance is needed. Risk of bleeding; given the narrow therapeutic index of warfarin, vigilance is needed. Garlic treatment has been associated with bleeding even in the absence of warfarin or other anticoagulant treatment.

Interaction confirmed by rechallenge

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Warfarin

Danshen

Increased anticoagulant effect

Warfarin

Devils claw

Increased anticoagulant effect, purpura

Additive effect on coagulation mechanisms and/or increased plasma warfarin concentration Unknown

Although neither of the two patients has been re-exposed to curbicin, the causal relation is quite strong. Reports provide reliable evidence for an interaction.

[36]

[37 39]

The report contains inadequate information.

[31]

Warfarin

Dong quai

Increased anticoagulant effect

Additive effect on coagulation mechanisms

Dong quai contains anticoagulant coumarins.

Reports provide reliable evidence for an interaction.

[40,41]

Warfarin

Garlic

Increased anticoagulant effect; increase in clotting time

Additive effect on coagulation mechanisms

Garlic has antiplatelet activity.

The report contains inadequate information.

[42]

(continued on next page)

Table 1 (continued) Conventional drug Herbal medicine Result of interaction Intracerebral hemorrhage Possible mechanism Additive effect on coagulation mechanisms Pharmacological comment Ginkgolides from ginkgo have antiplatelet activity and are PAF receptor antagonists. Clinical comment Spontaneous bilateral subdural haematomas associated with long-term ginkgo ingestion have been reported (even in the absence of anticoagulants). Potential seriousness of thrombotic complications No. of cases Comment on report reliability The report contains reasonable documentation of interactions. Ref

Interactions with anticoagulants Warfarin Ginkgo

[43]

A.A. Izzo et al. / International Journal of Cardiology 98 (2005) 114

Warfarin

Ginseng

Decreased anticoagulant effect

Unknown

Warfarin

Green tea

Decreased anticoagulant effect

Pharmacological antagonism

Warfarin

Lycium

Increased anticoagulant effect

Unknown

Warfarin

Mango

Increased anticoagulant effect

Hepatic enzyme inhibition

Antiplatelet activity of ginseng has been reported but would not seem to explain this case of decreased anticoagulation; a pharmacokinetic study in rats did not reveal a significant interaction between warfarin and ginseng. Warfarin produces anticoagulation by inhibiting production of the vitamin-K dependent clotting factors. Green tea contains vitamin K and thus antagonize the effect of warfarin. The weak inhibition of Lycium on hepatic enzyme could not explain such interaction. Mango contains high amounts of vitamin A and human studies have shown that vitamin A (retinol) inhibits CYP2C19 enzymes.

The report is well documented; however, the patient took several other drugs concomitantly.

[44]

Patients receiving warfarin need to be routinely questioned about their intake of vitamin K-containing foods and beverages.

The report is well documented.

[45]

Risk of bleeding; given the narrow therapeutic index of warfarin, vigilance is needed. Risk of bleeding; given the narrow therapeutic index of warfarin, vigilance is needed.

The report contains adequate information.

[46]

13

The interaction was determined as probable based on the Naranjo probability scale. Rechallenge in 2 of the 13 patients confirmed such interaction.

[47]

Warfarin

Papaya

Warfarin

PC-SPES

Increased anticoagulant effect Increased anticoagulant effect

Unknown

Additive effect on coagulation mechanisms

PC-SPES contains anticoagulant coumarins.

Warfarin

Soy

Decreased anticoagulant effect

Not known

Risk of bleeding; this interaction is potentially fatal. The thromboembolic side effects of PC-SPES are potentially fatal; individuals at risk should be strongly advised against using PC-SPES and warfarin or aspirin. The decrease in INR was thought to be clinically relevant

The report contains inadequate information. The report contains adequate information. However, PC-SPES, administered alone, can cause transient severe bleeding diathesis. An objective causality assessment in this case revealed that INR decline was in the range of possible to probable. These cases are reported in a single publication, which contains insufficient information; however, a clinical study showed that St. Johns wort decreased the plasma concentration of phenprocoumon (which is chemically related to warfarin). The report provides some evidence for interaction. Moreover, a clinical study confirm such an interaction. Not applicablea

[31]

[48]

A.A. Izzo et al. / International Journal of Cardiology 98 (2005) 114

Warfarin

St. Johns wort

Decreased anticoagulant effect

Hepatic enzyme induction

Warfarin is metabolised by CYP 1A2 in the liver, which is induced by St. Johns wort.

Although none of the patients developed thromboembolic complications, the decrease in INR was thought to be clinically relevant.

[50]

Phenprocoumon

St. Johns wort

Phenprocoumon

Wheat bran

Increased Quick-Wert test (indicating decreased anticoagulant effect) Decreased plasma level of phenprocoumon; increase in the free plasma phenprocoumon fraction

Hepatic enzyme induction

St. Johns wort could reduce phenprocoum on plasma levels throughout hepatic enzyme induction. Bran contains fibers which can trap phenprocoumon.

Phenprocoumon has a narrow therapeutic window; possible loss of activity. In view of the different effects on phenprocoumon pharmacokinetics, the clinical significance is unpredictable.

1a

[51,52]

Decreased absorption can explain the decreased plasma level; however, the mechanism of the increase of free plasma phenprocoumon fraction is unknown.

[53]

(continued on next page)

Table 1 (continued) Conventional drug Herbal medicine Result of interaction Possible mechanism Hepatic enzyme induction Pharmacological comment Simvastatin is extensively metabolised by CYP 3A4 in the intestinal wall and liver, which are induced by St. Johns wort. Bran contains fibers which can trap digoxin. Clinical comment No. of cases Comment on report reliability Not applicable Ref

Interactions with antilipidaemic drugs Simvastatin St. Johns Decreased wort plasma simvastatin concentration

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Lovastatin

Oat bran

Decreased lovastatin absorption

Lovastatin

Pectin

Decreased lovastatin absorption

Pectin can trap digoxin.

The decreased absorption of lovastatin resulted to an increase in LDL levels which led to the abortion of the trial. Lovastatin pharmacokinetics and LDL returned normal after bran discontinuation. The decreased absorption of ovastatin resulted to an increase in LDL levels which led to the abortion of the trial. Lovastatin pharmacokinetics and LDL returned normal after pectin discontinuation.

There is a strong evidence for such interaction.

[55]

Not applicable

[55]

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

A.A. Izzo et al. / International Journal of Cardiology 98 (2005) 114

ventional cardiovascular pharmacotherapy. Its aim is to alert healthcare professionals to the fact that herbal medicines are not entirely free of risks for cardiovascular patients.

2. Methods Systematic literature searches were made using Medline (via PubMed, from January 1966 to February 2003). The search terms were herbal medicine, botanical medicine, phytotherapy, drug interaction, adverse effects, side effects, adverse drug reaction, safety and toxicity. Recent books on herb drug interactions or herbalism [21 26] were also searched for further relevant information. Additional publications were identified by checking all reference lists and by searching our files. No language restrictions were imposed. All clinical reports on interactions were read and relevant data were extracted by the first three authors into predefined tables and validated by the senior author. In vitro experiments have been excluded.

for digoxin or digitoxin contamination, but none was found. It is possible that some component of Siberian ginseng might interfere with digoxin assay. A double-blind study in 10 healthy volunteers showed that guar gum reduced serum digoxin concentration during the early absorption period [27]. This interaction is very likely due to the ability of guar gum to reduce gastric emptying [57], which results in a transient delayed digoxin absorption. Consistently, digoxin levels in 24-h urine were similar whether subject were given or not guar gum. A randomized study on 30 geriatric patients showed that wheat bran (but not ispaghula) reduced digoxin concentration (probably trapped by fiber contained in wheat bran), although the levels were still within the therapeutic range [30]. This interaction has no clinical relevant influence on therapeutic digoxin. 3.1.2. Interaction with antihypertensives Ginkgo is a peripheral vasodilator [60]. Surprisingly, an elderly patient was found to have a further increase in blood pressure after taking ginkgo while receiving a thiazide diuretic (not specified in the original paper) for hypertension [31]. There is no rational pharmacological mechanism to explain this unusual case. A case of flaccid quadriplegia due to profound hypokalemia has been reported to be due to ingestion of small amounts of liquorice contained in a laxative preparation taken in combination with antihypertensive treatment (not specified in the original paper) [32]. The interaction could be due to an additive effect of potassium excretion as both some antihypertensives and liquorice (which possess mineralcorticoid effects) can cause potassium excretion [56,61]. 3.2. Interaction with platelet aggregation inhibitor drugs 3.2.1. Aspirin Aspirin is currently employed in the prophylactic treatment of transient cerebral ischemia, to reduce the incidence of recurrent myocardial infarction and to decrease mortality in postmyocardial infarction patients. Aspirin blocks thromboxane A2 synthesis from arachidonic acid in platelets by irreversibly acetylating and thus inhibiting cyclooxygenase, a key enzyme in prostaglandin synthesis. The aspirin-induced inhibition of thromboxane A2 synthesis last for the life of the platelet (approximately 7 10 days) [56]. A case report demonstrated a patient treated with aspirin for 5 years experienced bleeding of the eye and blurred vision after self-medication with ginkgo for 1 week [33]. After stopping ginkgo, there was no recurrence of bleeding over a 3-month follow-up period. The interaction is likely due to an additive effect on platelet function as ginkgolide B from ginkgo is a potent PAF receptor antagonist [62]. A clinical study [34] performed on six healthy volunteers showed that a tamarind extract incorporated in a traditional meal increased plasma levels of aspirin and salicylic acid

3. Results Forty-three case reports (appeared in 21 publications) and eight clinical studies were located [27 55]. Warfarin was the most common drug involved (37 cases and 1 clinical trial) [35 50]. Key data from these publications are summarized in Table 1. Table 2 summarizes chemical constituents, pharmacological action, clinical evidence and adverse effects of the herbal medicines interacting with cardiovascular drugs. 3.1. Interactions with cardiac inotropic drugs 3.1.1. Digoxin Digoxin is a cardiac glycoside which originates from the digitalis (foxglove) plant. As other cardiac glycosides, it can increase the contractility of the heart muscle and is therefore used in treating heart failure [56]. A single-blind, placebo-controlled study with two parallel groups showed that St. Johns wort reduced digoxin through levels after 10 days of co-medication [28]. Intestinal absorption, distribution and renal excretion of digoxin are mediated by the multiple-drug-resistance gene product Pglycoprotein, which has been shown to be induced by St. Johns wort [58,59]. Through this mechanism, St. Johns wort may reduce efficacy of digoxin and make a patient a nonresponder, whereas increased toxicity may be anticipated after withdrawal of the herb. Increased levels of digoxin have been associated with ingestion of Siberian ginseng [29]. The patient was asymptomatic for digoxin toxicity despite a level of 5.2 ng/l. Electrocardiogram, potassium level and serum creatine level were normal. Digoxin levels decreased upon dechallenge and increased upon rechallenge. The product was analyzed

A.A. Izzo et al. / International Journal of Cardiology 98 (2005) 114

Table 2 Herbal medicines interacting with cardiovascular pharmacotherapy: source, main constituent(s), main pharmacological action(s), promoted use, clinical evidence and adverse events Herbal medicine (Common name/ Latin name) Boldo/Peumus boldus Source Main constituent(s) Boldine Main pharmacological action(s) Choleretic/ cholagogue, diuretic Antiandrogenic, anti-inflammatory Promoted use Clinical evidence Specific studies not available Serenoa repens is effective in the treatment of benign prostatic hyperplasia. Adverse events

Leaves

Curbicina/Serenoa repens/ Cucurbita pepo

Fatty acids, phytosterols, flavonoids, polysaccharides Tanshinones, phenolic compounds

Indigestion, constipation, hepatic ailments Benign prostatic hyperplasia

Not expected

Danshen/Salvia miltiorrhiza

Roots

Vasorelaxant, anti-ischemic, antiplatelet; radical scavenger Estrogenic effects, anti-inflammatory, vasorelaxant

Angina, myocardial infarction, ischemic diseases

Dong quai/Angelica sinensis

Roots

Phytoestrogens, flavonoids, coumarins Harpagoside

Devils claw/ Harpagophytum procumbens Fenugreek/Trigonella foenum-graecum

Root, tubers

Seeds

Alkaloids, flavonoids, saponins Triterpene saponins known as ginsenosides

Anti-inflammatory, anti-arrhythmic, positive inotropic, negative chronotropic Antilipidaemic, Diabetes mellitus, hypoglycemic, hypercholesterolemia cholagogue Immunomodulatory, anti-inflammatory, antitumor, hypoglycemic

Gynecological disorders, circulation conditions Musculoskeletal and arthritic pain

Gastrointestinal complaints, constipation, diarrhea, decreased libido Effectiveness not Specific studies proven. Most studies not available are neither placebo-controlled nor blinded. No sufficient Photosensitivity evidence of leading to mild effectiveness dermatitis, bleeding Promising to treat Gastrointestinal musculoskeletal symptoms and back pain Promising in reducing serum cholesterol levels

Ginseng/Panax ginseng

Roots

Garlic/Allium sativum

Bulb

Alliins

Ginkgo/Ginkgo biloba

Leaves

Ginkgolides, flavonoids

Antihypertensive, antidiabetic, antiplatelet, antilipidaemic Increase of microcirculatory blood flow, antiplatelet, free radical scavenging

Green tea/Camellia sinensis

Leaves

Polyphenols, caffeine

Antimutagenic, antioxidant, antilipidaemic, antitumoral, CNS stimulant

Guar gum/Cyamopsis tetragonolobus

Seeds

Galactomannan, lipids, saponins

Antihyperglycemic, antilipidaemic

Kava/Piper methysticum

Rhizome

Kavapyrones

Anxiolytic, anesthetic, muscle relaxant

Minor gastrointestinal symptoms, allergic reactions Loss of energy and Not established Insomnia, diarrhea, memory; stress for any indications vaginal bleeding, states; male sexual mastalgia, possible dysfunction cause of Stevens Johnson syndrome Allergic reactions, Hypercholesterolemia, Small nausea, heartburn, prevention of antihypertensive flatulence, breath arteriosclerosis and antilipidaemic and body odor effect Gastrointestinal Circulatory disorders Favorable evidence disturbances, for the treatment vomiting, allergic of intermittent claudication, tinnitus reactions, pruritus, headache, dizziness, and dementia nose bleeding (including Alzheimers dementia) Prevention of Cautiously positive Insomnia as anticancer; strong cancer, inverse associations cardiovascular diseases, of tea intake with aortic arteriosclerosis adjuvant treatment and cardiovascular for AIDS riskb. Diabetes, obesity, Small effect Flatulence, diarrhea, hypercholesterolemia cholesterol abdominal levels; ineffective distension, nausea, for obesity hypoglycemic symptoms Stomach Anxiety insomnia Well documented for the treatment complaints, of anxiety restlessness, mydriasis, dermatomyositis, hepatitis

A.A. Izzo et al. / International Journal of Cardiology 98 (2005) 114 Table 2 (continued) Herbal medicine (Common name/ Latin name) Liquorice/Glycyrrhiza glabra Source Main constituent(s) Glycyrrhizinic acid Main pharmacological action(s) Expectorant, anti-inflammatory, anti-ulcer, aldosterone-like effects Analgesic; anti-inflammatory; antioxidant; laxative Antilipidaemic, anti-atherosclerotic Promoted use Clinical evidence Liquorice is an effective anti-ulcer; however, its use has declined. Specific studies not available Adverse events

Roots

Gastric ulcer, catarrhs, cancer prevention, inflammation Constipation (also used as a food and as a source of vitamins) Hypercholesterolemia, prevention of atherosclerosis Indigestion, obesity

Adverse effect consistent with adrenocorticotropic actions Not expected

Mango/Mangifera indica

Fruits

Vitamins A and C; fibers

Oat branc/Avena sativa

Seeds

Fibers

Papaya/Carica papaya

Fruits

d PC-SPESd/Dendrathema morofolium/Isatis indigotica/Glycyrrhiza glabra/Ganoderma lucidum/Panax pseudoginseng/Rabdosia rubescens/Serenoa repens/Scutellaria bacicalensis Pectinse fleshy fruits and storage roots of many plantse

Proteolytic, amylolytic, lipolytic activity Polysaccharides, Immunostimulant, phytosterols, fatty cytotoxic acids, flavonoids

Papain (enzyme)

Promising in reducing cholesterol and LDL blood levels Specific studies not available Lack of randomized clinical studies

Not expected

Not expected

Prostate cancer

Reduced libido, hot flashes, diarrhea, dyspepsia, leg cramps, gynaecomastia, nipple tenderness, pulmonary emboli, vein thrombosis Not expected

Antidiarrheal

Diarrhea

Siberian ginseng/ Eleutherococcus senticosus

Roots

Eleutherosides

Immunomodulatory, anti-inflammatory, antitumor, hypoglycemic

Loss of energy and memory; stress states, male sexual dysfunction

Pectins-based home remedies are useful in the treatment of diarrhea. Not established for any indications

Soy/Glycine max

Beans

Phytoestrogens

Hepatoprotective, anti-osteoporosis

Treatment of menopausal symptoms; prevention of heart diseases and cancer

St. Johns wort/ Hypericum perforatum

Aerial parts

Hypericin, hyperforin, flavonoids

Antidepressant, antiretroviral

Depression

Tamarind/Tamarindus indica

Fruits

Sugars, mucilages

Stimulates intestinal peristalsis

Constipation (also used as a food)

Promising for treating menopausal symptoms; case-control studies suggest a link between soy phytoestrogen consumption and reduced risk of breast and other cancers. Effective for mild to moderate depression; not suited for major depression Effective laxative

Diarrhea, dizziness, hypertension, pericardial pain, tachycardia, insomnia, extrasystoles, headaches Occasional gastrointestinal effects, i.e. stomach pain, flatulence, loose stool and diarrhea

Gastrointestinal symptoms

Not expected

(continued on next page)

10 Table 2 (continued) Herbal medicine (Common name/ Latin name) Wheat bran/Triticum aestivum Source

A.A. Izzo et al. / International Journal of Cardiology 98 (2005) 114

Main constituent(s) Indigestible carbohydrates (starch, cellulose, hemicelluloses), lignin

Main pharmacological action(s) Stimulates intestinal peristalsis

Promoted use

Clinical evidence Ineffective to treat obesity

Adverse events

Seeds

Constipation, obesity

Bloating

Data extracted from Refs. [1,21,23]. a Curbicin contains Serenoa repens (saw palmetto) fruits, Cucurbita pepo (pumpkin) seeds and vitamin E. b Data from epidemiological studies. c The cholesterol-lowering effect of oat bran is not shared by wheat bran. d PC-PCS is a mixture of eight herbal drugs, namely, Dendrathema morofolium (chrysanthemum), Isatis indigotica (dyers woad), Glycyrrhiza glabra (liquorice), Ganoderma lucidum (reishi), Panax pseudoginseng (san-qui ginseng), Rabdosia rubescens (rubescens), Serenoa repens (saw palmetto) and Scutellaria bacicalensis (Baikal skullcap). e Pectins are biopolymers with molecular weights of 60 000 to 90 000. Their basic structural framework is formed by galacturonic acid molecules. Pectins are present to some degree in all plant products but are particularly abundant in fleshy fruits and storage roots. Rich commercial sources are sugar beet fragments, apple residue, orange and lemon waste product and carrots.

(a metabolite of aspirin). The mechanism of such interaction is not known. 3.3. Interaction with anticoagulants 3.3.1. Warfarin Warfarin owes its action to its ability to antagonize the cofactor function of vitamin K [56]. Theoretically, increased anticoagulant effects could be expected when combined with coumarin-containing herbal medicines (e.g. boldo, fenugreek and don quai) or with antiplatelet herbs (danshen, garlic and ginkgo). Conversely, vitamin K-containing herbs (e.g. green tea) can antagonize the anticoagulant effect of warfarin [63]. Clinical reports indicate over-anticoagulation when combined to boldo, fenugreek, garlic, danshen, devils claw, dong quai, ginkgo, papaya, Lycium and mango and decreased anticoagulant effect if co-administered with ginseng, green tea, soy and St. Johns wort [35 50]. Given the narrow therapeutic index of warfarin, both the effects could have serious consequences. A patient treated with warfarin for atrial fibrillation saw his international normalized ratio (INR) increased after taking a variety of natural products, including boldo and fenugreek [35]. When he stopped herbal products, the INR returned normal after 1 week. The herb drug interaction was observed a second time after both products were reintroduced a few days later. Both boldo and fenugreek contain anticoagulant coumarins which, in an additive or synergistic way, could produce such interaction [64]. Two cases of increased INR were reported after coadministration of curbicin (a preparation containing saw palmetto, pumpkin and vitamin E) [36]; the INR normalized after discontinuation of curbicin. No anticoagulant effect has been found in the literature associated with the two major components of curbicin. However, vitamin E has been shown to antagonize the effect of vitamin K and may lead

to increased risk of bleeding, particularly in patients taking oral anticoagulants [65]. Three case reports have highlighted the possibility of interaction between warfarin and danshen, resulting in increased anticoagulant effect [37 39]. The interaction could have both a pharmacokinetic (changes in plasma concentration) and a pharmacodynamic (additive effect on coagulation mechanisms) basis; in fact, animal studies indicate that danshen, in addition to its antiplatelet effect [66], increases the absorption and decreases elimination of warfarin [67]. A review on traditional remedies and food supplements briefly mentions the case of purpura associated with concomitant use of devils claw and warfarin [31]. Due to the paucity of information reported, the likelihood of such interaction cannot be established; possible mechanisms of such interaction are not known as very little is known about the metabolism and distribution of devils claw components; an effect of devils claw on platelet function seems unlikely as this herbal drug, in contrast to aspirin, does not affect blood eicosanoids production [68]. Two well-documented case reports indicate over-anticoagulation following co-administration of warfarin and dong quai [40,41]. Phytochemical analyses have revealed in dong quai the presence of natural coumarin derivatives [69], which can decrease coagulation by replacing vitamin K as the apoenzyme in an enzyme complex; notably, warfarin is a synthetic coumarin anticoagulant. Two cases of increased INR were mentioned in patients taking garlic previously stabilized on warfarin [42]. A likely mechanism is an additive effect on coagulant mechanisms, as garlic possesses antiplatelet activity [70]. However, garlic treatment has been associated with bleeding even in the absence of warfarin or other anticoagulant treatment [71]. A well-documented case report demonstrated that a patient under pharmacological treatment with warfarin (5 years) experienced a left parietal hemorrhage after 2

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11

months of co-administration with ginkgo [43]. As stated above, an additive effect on coagulation mechanisms could be responsible of such interaction [62]. It should be noted that intracerebral hemorrhage associated with long-term ginkgo ingestion has been reported, even in the absence of anticoagulants [72]. A case report of suspected interaction between warfarin and ginseng has been reported [44]. A decrease of INR was noted, but because the patient took several other drugs concomitantly (i.e. diltiazem, nitroglycerin and salsalate), causality is uncertain. Antiplatelet activity of ginseng has been previously noted [73], but, of course, this would not seem to explain such interaction. A pharmacokinetic study in rats did not reveal a significant interaction between warfarin and ginseng [74]. A case of inhibition of the effect of warfarin (decreased INR) by green tea has been reported [45]. The patient, which received warfarin for thromboembolic prophylaxis, began drinking 1/2 to 1 gal of green tea per day about 1 week prior to the decreased INR. Green tea can be a significant source of vitamin K and thus antagonize the effect of warfarin [75]. An elevated INR was observed in a Chinese woman previously stabilized on warfarin [46]; this was likely caused by a concentrated Chinese herbal tea made from Lycium fruits (three to four glasses daily), a Chinese herb considered to have a tonic effect on various organs. In vitro evaluation showed weak inhibition of warfarin metabolism by CYP2C9 by the tea of Lycium, suggesting that the observed interaction may be caused by factors other than the CYP450 system [46]. A single publication reported 13 male patients whose INR were found increased after mango fruit ingestion [47]. After identification of mango fruit as a possible cause of supratherapeutic INR, patients were instructed to stop mango ingestion for 2 weeks. The average measured INR in the 13 patients decreased by 17.7% after discontinuation. Rechallenge with mango fruit in 2 of the 13 patients produced increased INR. Although the exact mechanism for this interaction is unknown, there are literature reports suggesting that concomitant administration of warfarin and large doses of vitamin A (mango contains high amounts of vitamin A) can cause an increased anticoagulant effect [76]. Vitamin A (retinol) inhibits hepatic human CYP2C19 and this would lead to a moderate increase in warfarin concentrations and thus higher INRs [77]. Another plant-based remedy which can interact with warfarin is papaya [31], the fruit of the papaya tree. A case has been mentioned briefly where the INR of an anticoagulated patient was increased after addition of papaya extract to his prescribed medication [31]. The pharmacological mechanisms by which papaya may affect coagulation are not known. Nevertheless, this interaction is potentially fatal. Papaya is contraindicated with warfarin as it may damage the mucous membranes of the gastrointestinal tract, and the resultant bleeding would be increased.

A 79-year-old man with prostate cancer started treatment with warfarin after he developed deep vein thrombosis during treatment with PC-SPES (an anticancer herbal mixture) [48]. PC-SPES therapy was stopped, but when it was subsequently reinitiated, his INR became more difficult to maintain in the therapeutic range and his warfarin requirements decreased. HPLC analysis of PC-SPES revealed the presence of coumarins, which can inhibit vitamin K reductase in a similar manner to warfarin [78]. A 70-year-old man who was stable on warfarin therapy developed subtherapeutic INR values after ingesting soy protein in the form of soy milk [50]. The subtherapeutic INR values could not be explained by factors known to reduce the INR such as noncompliance, new medication, other alternative therapies or increased consumption of vitamin K. INR values returned to therapeutic concentrations within 2 weeks after discontinuation of the soy milk. The mechanism of such interaction is not known. Although not all investigations yielded the same results, most studies agreed that St. Johns wort activate enzymes of the cytochrome P450 enzyme system, including CYP 1A2 which is responsible of the metabolisation of warfarin in the liver [79 81]. Probably via this mechanism, St. Johns wort increased the metabolism of warfarin; such mechanism could explain the decrease of the seven cases of INR associated with concomitant use of warfarin and St. Johns wort reported by the Swedish Medical Product Agency [50]. Notably, a clinical study [52] showed that St. Johns wort decreased the plasma concentration of phenprocoumon, an anticoagulant chemically related to warfarin (see below). 3.3.2. Phenprocoumon Phenprocoumon is an anticoagulant chemically related to warfarin; as it is the case of warfarin, it could potentially interact with coumarin- or vitamin K-containing herbal medicines or with antiplatelet herbs [56]. A case report highlighted the possible reduced efficacy of phenprocoumon if co-administered with St. Johns wort [51]. The possibility is strengthen by a clinical study which showed that 11-day medication of St. Johns wort resulted in a significant decrease of the area under the curve (AUC) of the free phenprocoumon compared with placebo [51]. Induction of hepatic enzyme by St. Johns wort is a likely mechanism which could explain such interaction. A study on seven healthy volunteers showed that ingestion of 35 g wheat bran produced a decreased absorption rate of phenprocoumon but no decrease in overall bioavailability [53]. In addition, an increase in the free plasma fraction of phenprocoumon was seen after wheat bran administration. While the presence of fibers in bran can easily explain the decreased absorption rate, the increase in the free plasma fraction cannot be explained by our present knowledge of wheat bran biological properties. It is noteworthy that the increase in absorption would predict decreased efficacy, while increased free plasma fraction would

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predict increased activity of phenprocoumon; thus, the clinical significance of such interaction is unpredictable. 3.4. Interaction with antihyperlipidemic drugs 3.4.1. Simvastatin, pravastatin and lovastatin Simvastatin, pravastatin and lovastatin are inhibitors of HMG-CoA reductase, the rate-limiting step in cholesterol synthesis. By inhibiting de novo cholesterol synthesis, they deplete the intracellular supply of cholesterol [56]. A clinical study showed that repeated St. Johns wort treatment (14 days) decreased plasma concentrations of simvastatin but not of pravastatin [54]. Because simvastatin is extensively metabolised by CYP3A4 in the intestinal wall and liver (which is induced by St. Johns wort) [79 81], it is likely that this interaction is partly caused by the enhancement of the CYP3A4-mediated first-pass metabolism of simvastatin in the small intestine and liver. A decrease of absorption of lovastatin was observed in patients who took this lipid-lowering agent concomitantly with pectin or oat bran [55]. This resulted to an increase in LDL levels which lead to the abortion of the trial. When these plant-based preparations were discontinued, lovastatin pharmacokinetics returned to normal and lipoprotein levels in plasma normalized as a result. This interaction is likely due to the ability of pectins or bran fibers to bind or trap concurrently administered lovastatin.

apy is gleaned from case reports, although clinical studies are now also beginning to appear in the literature. Obviously, case reports have to be interpreted with great caution, as causality is not usually established beyond reasonable doubt. To establish causality is, of course, a difficult task. Rechallenge would be the most straightforward clinical test, but for obvious reasons, this option is not always available. Hence, even well-documented case reports (and many are not well documented) can only serve as a critical early warning system. In conclusion, interaction between herbal medicine and cardiovascular drugs is a potentially important safety issue. Patients under anticoagulant pharmacotherapy are at the highest risk. Healthcare professionals need to be aware of potential herb drug interactions and researcher should strive to fill the numerous gaps in our present understanding of this problem.

Acknowledgements This work was supported by the Enrico and Enrica Sovena Foundation and SESIRCA (Regione Campania, Italy).

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4. Discussion Herbal medicines follow modern pharmacological principles. Hence, herb drug interactions are based on the same pharmacokinetic and pharmacodynamic mechanisms as drug drug interactions [5]. Herbal medicines may affect absorption (e.g. guar gum reduces digoxin absorption) [27], metabolism (e.g. St. Johns wort increases warfarin metabolism, causing decreased anticoagulant effect) [50] or excretion (St. Johns wort increases digoxin renal excretion) [28] of concurrently administered cardiovascular drugs. Herb drug interactions that involve distribution mechanisms have not been reported. Moreover, interactions may be additive or synergetic, whereby the herbal products potentiate the action of the conventional cardiovascular drug (e.g. ginkgo potentiates the antiplatelet effect of aspirin) [33]. Conversely, the herb may be directly antagonistic to the action of the drug (e.g. green tea antagonizes the anticoagulant effect of warfarin) [45]. Based on the above evidence, there can be little doubt that interactions between herbal medicines and cardiovascular drugs exist. The real incidence of such interactions is probably unknown, as is the likelihood that a patient will have an adverse event when taking two drugs (i.e. herbal and conventional medicines) with the potential to interact. Much of the available information about the interaction between herbal medicines and cardiovascular pharmacother-

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