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J Am Coll Cardiol, 2002; 39:1083-1095
© 2002 by the American College of Cardiology Foundation
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REVIEW ARTICLE

Benefits, adverse effects and drug interactionsof herbal therapies with cardiovascular effects

Georgianne Valli, MD* and Elsa-Grace V. Giardina, MD, FACC*,*

* Division of Cardiology, Department of Medicine, and the Center for Women’s Health, Columbia University, New York, New York, USA

Manuscript received August 20, 2001; revised manuscript received December 27, 2001, accepted January 11, 2002.

* Reprint requests and correspondence: Dr. Elsa-Grace V. Giardina, Division of Cardiology, Room PH3-346, Department of Medicine, Columbia University, 630 West 168th St., New York, New York 10032, USA.
evg1{at}columbia.edu


   Abstract
Top
 Abstract
Background
 Cardiovascular benefits and...
 Conclusions
 References
 
Because the use of herbal therapies in the U.S. is escalating, it is essential to be aware of clinical and adverse effects, doses and potential drug-herb interactions. A consumer poll in 1998 indicated that one-third of respondents use botanical remedies, and nearly one in five taking prescription medications also used herbs, high-dose dietary supplements or both. An estimated 15 million adults are at risk for potential adverse interactions involving prescription medications and herbs or vitamin supplements, yet most practicing physicians have little knowledge of herbal remedies or their effects. Herbal products are marketed without the proof of efficacy and safety that the Food and Drug Administration (FDA) requires of drugs. The Dietary Supplement and Health Education Act of 1994 allocates responsibility to manufacturers for ensuring safety and efficacy with no specific requirements to submit documentation. Manufacturers may state a product’s physiologic effects but may not make claims for the treatment or cure of specific diseases. Consumers and practitioners have little information about product safety, contraindications, interactions or effectiveness and are reliant on manufacturers to provide accurate labeling. Recently, the growing number of foods with herbs has raised concerns at the FDA, which requires evidence that food additives are safe. Considering that the growing appeal of herbal remedies is likely to continue, physicians, particularly cardiologists, must become familiar with the available cardiovascular information on herbs. This review highlights the existing data on the efficacy, adverse effects and interactions for herbal therapies that impact on the cardiovascular system.

Abbreviations and Acronyms
  CHF
  congestive heart failure
  CNS
  central nervous system
  FDA
  Food and Drug Administration
  HDL
  high-density lipoprotein
  INR
  international normalized ratio
  LDL
  low-density lipoprotein
  LV
  left ventricular
  MI
  myocardial infarction
  NCCAM
  National Center for Complementary and Alternative Medicine
  NYHA
  New York Heart Association
  PAF
  platelet activating factor
  PT
  prothrombin time
  SPICE
  Survival and Prognosis Intervention of Crataegus Extract trial
  TCM
  traditional Chinese medicine

Because the use of herbs and herbal therapies in the U.S. is escalating, it is essential to be aware of clinical and adverse effects, doses and potential drug interactions. Most practicing physicians have little knowledge of herbal treatments or adverse effects (1). A consumer poll in 1998, however, indicated that nearly one-third of respondents use botanical remedies (2). Moreover, of those who take prescription medications, nearly one in five uses herbs, high-dose dietary supplements or both (3), suggesting an estimated 15 million adults are at risk for adverse interactions involving prescription medications and herbs or vitamin supplements. In addition, the growing demand for soft drinks and foods with herbal additives greatly expands public exposure. Sales of such products grew from $20 million to $700 million in the past three years (4).


   Background
Top
 Abstract
 Background
Cardiovascular benefits and...
 Conclusions
 References
 
Herbal products are marketed without proof of efficacy or safety that the Food and Drug Administration (FDA) requires of drugs. The Dietary Supplement and Health Education Act of 1994 assigns responsibility for ensuring safety and efficacy to manufacturers, with no requirement to submit documentation of product testing; it does not set standards for quality control nor require approval before supplements enter the market (5). Manufacturers may not make claims for treatment or cure of a disease but may state a product’s physiologic effects. Consumers have little information to make decisions about safety, adverse effects, contraindications, interactions or effectiveness and must rely on manufacturers to provide ingredients that are accurately labeled (6). Recently, the increasing number of foods containing herbs has raised concerns at the FDA, which requires evidence that food additives are safe; consequently, manufacturers have been warned that the safety of herbal additives must be proven (4).

Many herbal remedies cannot be patented, and manufacturers do not expect to recoup the estimated $350 million to confirm safety and efficacy (7). The National Center for Complementary and Alternative Medicine (NCCAM), established in 1998 at the National Institutes of Health, is mandated to conduct and advocate research into complementary medicines and techniques (8). With a limited budget of $68.7 million for 2000, NCCAM pursues only a few therapies and techniques being practiced (8). Investigating the efficacy of herbal therapy is complex because many contain mixtures of compounds and exist in varied forms (7). Compounds isolated from herbs may have important pharmacologic activity, but data from isolates may understate or overstate actions of the herb, and such compounds are variably present in specific products (9–12). Resources on activity, dosages, toxicities, contraindications and drug interactions of herbal remedies are constrained by limited research and information.

Experience in other countries.   In Germany, the Ministry of Health established the Commission E, a committee of doctors, pharmacists, scientists and herbalists to evaluate the safety, quality and efficacy of herbs (13). Commission E approves new remedies and publishes monographs with recommendations on dose, indications, contraindications, interactions and mechanisms (13). Physician prescriptions for herbs account for more than one-half of sales in Germany, and nearly one-quarter are for cardiovascular conditions (7). The Commission E reports are widely used in the U.S. and published by the American Botanical Council (13). The reference text PDR for Herbal Medicines is substantially comprised of them (14). In China, there are two parallel government-supported systems of medicine (15). Traditional Chinese medicine (TCM) comprises a variety of remedies including herbs, acupuncture, acupressure and other techniques (15). Patients seek care from TCM practitioners, or practitioners trained in Western medicine, and many institutions offer both (16). Research is supported in each system; however, controlled trials are lacking because use of a placebo is considered unethical (15).


   Cardiovascular benefits and adverseeffects of common herbal therapies
Top
 Abstract
 Background
 Cardiovascular benefits and...
Conclusions
 References
 
Several herbs offer potential for cardiovascular conditions including venous insufficiency, intermittent claudication, hyperlipidemia, hypertension and congestive heart failure (CHF) (Table 1). Varied mechanisms, including antioxidant, antiplatelet, fibrinolytic, antiatherosclerotic, antihyperlipidemic, antiarrhythmic and vasodilatory actions, are ascribed to herbs (17). Data from epidemiologic studies support the potential of dietary antioxidants and flavonoids (18–21) present in several herbs (22,23) to improve cardiovascular health. To date, however, clinical trials with antioxidants such as vitamin E, vitamin A and beta carotene fail to show clinical benefit (24–29). Herbal remedies may induce adverse cardiac effects including sympathomimetic activity, hypertension and arrhythmias (Table 2). Many interfere with platelet function, and patients at risk for bleeding or taking antiplatelet drugs should be cautioned about specific herbs. Physicians must be attuned to interactions between herbs and drugs with a narrow therapeutic window, such as warfarin and digoxin (Table 3). Adverse effect data is almost exclusively available as case reports and, as a result, may be vastly underreported.


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  		Table 1 Herbs for Cardiovascular Indications

 

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  		Table 2 Herbs With Adverse Cardiovascular Effects

 

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  		Table 3 Important Cardiovascular Drug Interactions

 
Lack of regulation of quality control and of product standardization makes it difficult to establish safe doses of herbal products. Active compounds may vary 200-fold between manufacturers and batches (30). Additives and contaminants including caffeine, indomethacin and heavy metals, such as lead, mercury and arsenic, have been found in herbal remedies (31–33). Misidentification of plants has led to serious adverse events including renal failure (31). Considering that the growing appeal of herbal remedies is likely to continue, physicians, particularly cardiologists, must become familiar with the available cardiovascular information on herbs. This review highlights the existing data on the efficacy, adverse effects and interactions for herbal therapies that impact on the cardiovascular system.

Danshen (Salvia miltiorrhiza).   Danshen is used in TCM to promote blood flow and treat cardiovascular diseases. It is sold in over-the-counter herbal preparations, prescribed by TCM doctors and administered in Chinese hospitals for angina pectoris (34), acute myocardial infarction (MI) (35) and ischemic and thrombotic disorders (36). In vitro and animal studies suggest it may be vasoactive, scavenge free radicals (37) and inhibit platelet aggregation (38,39). The active compounds in danshen are tanshinones and phenolic compounds (34,36).

Danshen has been studied in China for acute MI and ischemic heart disease (35,40). Most studies are neither placebo-controlled nor blinded, and often use danshen combined with other herbs. A double-blind study of 67 subjects with ischemic heart disease reported symptomatic and electrocardiographic improvement with tanshinone IIA, a compound present in danshen (41). No differences in cardiac contractility, compliance, inotropy, blood viscosity or fibrinogen were found. Danshen has been studied for coronary artery vasodilation, the mechanism underlying its use in angina (42). At low doses, it causes generalized vasodilation and decreases blood pressure (42). At higher doses, however, it causes vasoconstriction in noncoronary arteries (34,42). Case reports link danshen to warfarin potentiation (43,44). Animal studies confirm that danshen decreases warfarin clearance and increases bioavailability (45).

Feverfew (Tanacetum parthenium).   Feverfew is primarily used for migraine prophylaxis (46). It inhibits platelet release of serotonin (47) and may have vasoactive effects (48). The active compound in feverfew, parthenolide, is a sesquiterpene lactone. Other compounds have been investigated for biologic activity, most notably flavonoids for a potential anti-inflammatory effect (49). Feverfew is one of a few herbs for which data on the content of the active compounds in commercial preparations are available (12). Typical daily doses for migraine prophylaxis are 50 to 100 mg of whole or powdered dried leaves, corresponding to 500 µg of parthenolide (12,47).

In vitro studies demonstrate that feverfew and parthenolide inhibit platelet aggregation and platelet and leukocyte release of serotonin (46,50). In vitro vasoactive effects vary with the formulation. Chloroform extracts of fresh leaves inhibit smooth muscle contractility, but extracts of dried leaves elicit a contractile response (48,51). Because chloroform extracts of dried feverfew do not contain measurable amounts of parthenolide, other vasoactive compounds may be present (48). Vasoactive and antiplatelet actions observed in vitro have not been confirmed in clinical trials (46,47,52–55).

The most common side effect is mouth ulcers (46). Feverfew’s inhibition of platelet serotonin release in vitro raises concerns about interaction with antiserotonin migraine prophylactic drugs (56) and potentiation of bleeding with antiplatelet agents. However, serious adverse events or interactions have not been reported.

Garlic (Allium sativum).   Estimated mass-market sales of garlic supplements in 1998 were $84 million (2). Respondents to the third National Health and Nutrition Examination Survey listed garlic more frequently than other dietary supplements (5). It is believed to thin the blood, reduce cholesterol, decrease blood pressure, inhibit atherosclerosis and improve circulation.

Randomized clinical trials have been conducted for antihypertensive, antiatherosclerotic and antiplatelet actions, and intermittent claudication. A recent summary of the data supporting garlic’s potential in modifying cardiovascular risk, while generally supporting its usefulness, also emphasized the lack of knowledge about active compounds and mechanisms of action (57). Though garlic is believed to be beneficial for conditions for which approved drugs are available, such as hyperlipidemia and hypertension, few studies compare it to pharmacologic treatments.

Studies of garlic are plagued by methodologic problems related to active compounds. The active substance is allicin, formed by the action of alliinase on alliin when garlic is crushed (58). Allinase is inactivated by acid pH, heat and extraction in organic solvents (59). Thus, garlic’s effects are dependent on whether it is cooked or in aqueous, oil or organic extracts (58,59). In addition to allicin, other active compounds in garlic include methyl allyl trisulfide, diallyl trisulfide, diallyl disulfide and ajoene (58–60). Its characteristic odor (60) is associated with the active compounds, which limits blinding in clinical trials. Most studies use commercially available dried garlic powder standardized for allicin content, in doses of 300 to 900 mg/day. However, even standardized products may yield different quantities of allicin owing to differences in tablet composition (11). Few trials indicate whether placebo could be differentiated from active treatment.

Garlic is generally safe and well tolerated; however, serious adverse events, including central nervous system (CNS) bleeding (61) and skin burns from topical application (57), have been reported. Effects such as flatulence, dyspepsia, allergic dermatitis and asthma have been described (57). Increases in both the prothrombin time (PT) and international normalized ratio (INR) in subjects previously stable on warfarin have been attributed to garlic (62); however, there is little to substantiate the mechanism of the interaction (63).

Hyperlipidemia
The antihyperlipidemic effect of garlic has been extensively studied. Early trials lacked controls, adequate blinding and dietary monitoring; they were underpowered or did not analyze results based on intention to treat (57,64). Recent trials have produced negative findings, possibly resulting from preparations with reduced bioavailability of allicin (11). Several meta-analyses have summarized data from clinical trials. Each has used different inclusion criteria, yet the results are consistent across analyses: garlic modestly reduces lipids 15 to 25 mg/dl (5% to 15%) (57,64–67).

The earliest meta-analyses included studies with deficiencies (65,66). Warshafsky et al. (65) reported a reduction in serum cholesterol of 23 mg/dl (9% from baseline) (65). Silagy and Neil (66) reported lipid reduction of 12% and provided a subgroup analysis of trials that utilized nonpowder forms (i.e., raw, oil or extract). Lipids were reduced by 15% in this subgroup; however, three of five studies were not double-blind and two were not placebo-controlled. Stevinson et al. (67) selected only randomized, placebo-controlled trials of hypercholesterolemic subjects and reported a reduction of only 15.7 mg/dl (4% to 6% reduction). A subgroup analysis of studies with the highest scores for methodologic quality found no difference between garlic and placebo.

Most recently, Ackermann et al. (57) reported a comprehensive meta-analysis of garlic trials, showing a reduction in cholesterol of 17 mg/dl. Subgroup analyses of trials including only hyperlipidemic subjects and double-blind trials did not differ. In contrast to Silagy and Neil (66), subgroup analysis of trials employing standardized dried garlic powder preparations showed a slightly improved reduction in cholesterol of 19 mg/dl. This analysis also reported a dose duration effect of garlic.

A trial of garlic versus a fibrate drug for hyperlipidemia reported similar efficacy (68). Treatment with dried garlic powder tablets (900 mg/day) reduced total serum cholesterol levels from 282 mg/dl to 210 mg/dl over 12 weeks while bezafibrate (600 mg/day) reduced cholesterol from 287 mg/dl to 208 mg/dl. Both treatments produced parallel reductions in low-density lipoprotein (LDL) and increases in high-density lipoprotein (HDL) cholesterol. There was a trend toward greater reduction in serum triglycerides with bezafibrate (42% vs. 29%).

Hypertension
In vitro evidence suggests garlic reduces blood pressure by inhibiting platelet nitric oxide synthase (69). Many clinical trials, however, find no significant antihypertensive effect despite form, dose or duration of treatment. Studies evaluating hypertensive subjects report a modest reduction in diastolic pressure (70–72). A small, open-label trial reported that large doses of garlic powder (2,400 mg) lowered blood pressure 7/16 mm Hg. Only the diastolic pressure decreased significantly (70). In a placebo-controlled, double-blind study of 47 hypertensive subjects only the diastolic pressure decrease (13 mm Hg) was significant (71). A meta-analysis reported a modest systolic reduction of 7.7 mm Hg and diastolic reduction of 5.0 mm Hg (72), but only two trials involved hypertensive subjects.

Coagulation
Blood-thinning properties are attributed to enhanced fibrinolytic and antiplatelet activity. There is no consensus as to the mechanism of fibrinolytic activity. In vitro and animal studies support several mechanisms for garlic’s antiplatelet effects. Diallyl disulfide and diallyl trisulfide inhibit thromboxane synthesis (58,73), possibly by inhibiting phospholipase-A and mobilizing arachidonic acid (74). Extract of raw garlic contains compounds that inhibit cyclooxygenase (75) and ajoene, a compound in alcohol extracts of garlic, may inhibit binding of fibrinogen to platelet receptors (76). Ajoene, however, is not found in most garlic preparations (59,60).

Garlic’s anticoagulant properties have been linked to reports of bleeding (61,77); however, clinical trials find conflicting results (74,78–82). Dried garlic powder decreased platelet aggregation in three controlled trials (78,80,81). Conversely, no difference was found in platelet aggregation or thromboxane levels in 14 healthy men (82). Several trials describe increased fibrinolytic activity, and two report elevation of tissue plasminogen activator (80,83–85). However, a trial using garlic powder in patients with hyperlipoproteinemia found no change in bleeding time, fibrin split products or clot lysis time (86).

Atherosclerosis
The antiatherosclerotic activity of garlic is attributed to cholesterol lowering, but in vitro and animal studies also support effects independent of lipid levels, possibly by inhibition of lipid peroxidation (87,88). Two clinical trials report benefits in atherosclerotic conditions. In subjects with peripheral arterial occlusive disease, pain-free walking distance improved 46 meters with garlic compared to 31 meters with placebo (81). Though the mean difference in walking distance between groups increased, change in walking distance within each group was not significant (89). Garlic administered for 48 months reduced atherosclerotic plaque at the femoral artery or carotid bifurcation by 5% to 18% (90). Notably, 23% of subjects taking garlic versus 3% on placebo withdrew owing to odor, underscoring the difficulty of blinding in garlic trials.

Ginkgo (Ginkgo biloba).   Ginkgo biloba, the best-selling herbal remedy in the U.S. (2), is derived from the leaves of the maidenhair tree. It is used for cognition and memory as well as cerebrovascular disease, peripheral vascular disease, sexual dysfunction, affective disorders, multiple sclerosis, retinal disorders and hearing loss. The mechanisms by which ginkgo and its constituent compounds improve vascular health include free radical scavenging, antiplatelet actions, anti-inflammatory actions, vasodilation and decreased blood viscosity. Gamma-aminobutyric acid receptor agonism and inhibition of monoamine oxidase-B have also been investigated. Active isolates of ginkgo fall into two classes: flavonoids and terpenoids. An extract standardized for flavonoid and terpenoid content, EGb761, is available. Typical doses are 120 to 160 mg/day (91). Commission E recommends 120 to 240 mg extract two to three times daily for cerebral insufficiency (92). Common side effects are nausea, dyspepsia, headache and allergic skin reactions (91,93). More serious adverse effects, including spontaneous subdural hematomas (94), intracerebral hemorrhage (95) and hyphema (96), as well as warfarin and trazodone interactions, have been described (97,98).

Vascular dementia
Ginkgo may benefit cerebrovascular disease by improving blood flow, reducing ischemia-reperfusion injury or inhibiting platelets (91,99,100). Most trials of ginkgo enroll patients with cognitive impairment due to diverse etiologies (101,102). Few enroll patients with only vascular dementia, and these trials report conflicting results. A double-blind, placebo-controlled trial of acute ischemic stroke showed no benefit with ginkgo (100). Similarly, there was no difference in a trial of 52 subjects with vascular dementia who underwent psychometric testing (103). A trial assessing dizziness, motor activity, speech comprehension and depression reported that only dizziness improved (104). However, two trials have demonstrated improvement in measures of cognition, including the Wechsler Adult Intelligence Scale and Sandoz Clinical Assessment-Geriatric (105,106).

Intermittent claudication
Ginkgo may improve intermittent claudication via vasoregulation, platelet antagonism and protection against postischemic oxidative damage (91,93,107). At least 11 randomized, placebo-controlled trials have been conducted. A meta-analysis of trials of ginkgo for intermittent claudication reported pain-free walking distance increased by 34 meters (93). In eight trials of 415 patients all but one favored ginkgo over placebo, although only four reported confidence intervals that did not include zero. None reported serious adverse events. A meta-analysis of pharmacologic interventions for intermittent claudication similarly concluded that ginkgo improves pain-free walking distance by 32 meters (108). However, this effect was modest compared to pentoxifylline (208 meters) and naftidrofuryl (101 meters).

Antioxidant
Evidence from in vitro and animal experiments supports antioxidant activity (91,109,110). Flavonoids constitute about 25% of EGb761 (92) and have antioxidant and free radical scavenging properties, although the exact mechanism remains unclear (22). In addition, bilobalide and ginkgolides A and B are terpenoid compounds selectively studied for protecting ischemic tissue from reperfusion injury (110–112). Pietri et al. (113) investigated whether short term pretreatment with high-dose ginkgo extract (320 mg/day for five days) decreased reperfusion injury in patients undergoing aortic valve replacement. Markers of oxidative stress and cardiac performance, including cardiac index and left ventricular (LV) stroke work, improved after operation; however, clinical outcomes did not differ.

Platelet antagonism
Ginkgo may inhibit platelets and platelet-induced postischemic inflammatory response by antagonism of platelet activating factor (PAF), which has been implicated in reperfusion injury and cardiac dysfunction in shock (114). Ginkgolide B is a potent inhibitor of PAF in humans (115,116). Other components of ginkgo extract have been identified as inhibitors of phospholipase A2, and thus the production of PAF as well as eicosanoids (107). However, the compounds attributed with antiplatelet effects are present in small amounts in most extracts, and may not produce the same inhibition seen in studies of isolated compounds (117,118).

No controlled trials in humans confirm ginkgo as an antiplatelet agent. A placebo-controlled trial of ginkgo reported no effect on platelet aggregation (119). However, antiplatelet effects have been cited as the mechanism underlying bleeding events. Two cases of CNS hemorrhage occurred with ginkgo, 120 to 160 mg/day (94,95). In both, PT and partial thromboplastin time were normal, but bleeding time was higher and returned to normal after ginkgo biloba was discontinued. A case of hyphema occurred after ingestion of ginkgo and aspirin; however, no coagulation or bleeding measures were reported (96). In another patient, previously stable on warfarin, administration of ginkgo was associated with elevated PT and intracerebral hemorrhage (97).

Ginseng.   Ginseng refers to the root of Panax species. The most commonly examined species are Panax ginseng (Asian ginseng), Panax quinquefolius (American ginseng) and Panax japonicus (Japanese ginseng) (120). The terms "red" and "white" refer to different methods of ginseng preparation, not different species (121). Siberian ginseng, the root of an unrelated species, Eleutherococci, does not contain similar compounds (122). Ginseng is believed to promote vigor, potency, well-being and longevity. In China it is utilized for angina pectoris, MI and CHF. It has been evaluated for many other indications, most notably for use as an antihyperglycemic. It is administered as a whole dried root, extract, tea or capsule. The active compounds are heterogeneous triterpene saponin glycosides, collectively termed ginsenosides. The exact ginsenosides vary by Panax species (120), root age (122) and preparation method (i.e., red or white) (122). The actions of specific ginsenosides vary, and in some instances are inconsistent. Of note, many products that claim ginseng content have no ginsenosides (9,10). Typical doses are 100 to 400 mg of ginseng extract daily. The Commission E monograph recommends a dosage of 1 to 2 g of root daily (92).

Heart failure
Clinical trials in China and Korea have investigated ginseng for cardiac function, although there is no known mechanism and little data from placebo-controlled or blinded studies. An open trial evaluating CHF contrasted, 1) red ginseng, 2) digoxin, and 3) digoxin plus red ginseng, and found that hemodynamic improvement was most marked with combined therapy (123). An open trial of Panax notoginseng plus captopril versus captopril monotherapy in subjects with LV diastolic dysfunction reported improved diastolic relaxation with the combined medications (124). In a double-blind, placebo-controlled trial of coronary heart disease, a mixture of Chinese herbs, including ginseng, found that stroke volume index and cardiac index improved (125).

Hypertension
Ginseng has been shown to have both hypertensive and hypotensive effects in animal studies trials (122). Hypotensive effects are attributed to enhanced synthesis of nitric oxide (122). An open trial of 4.5 g red ginseng daily found systolic blood pressure decreased after eight weeks (126). In contrast, a ginseng-abuse syndrome has been described wherein hypertension, behavioral changes and diarrhea occur (127,128). In an observational study of 133 chronic ginseng users, 22 developed elevated blood pressure (127). Subjects reported using a variety of preparations, including some that contained Siberian ginseng (128), which has been separately linked with hypertension (129). These conflicting effects are attributed to diverse actions of particular ginsenosides (122).

Antioxidant effects
Animal studies suggest that ginseng scavenges free radicals (122). In a placebo-controlled trial of 30 patients undergoing mitral valve surgery, ginseng and ginsenoside Rb were evaluated for protective effects in ischemia and reperfusion injury (130). Both improved postoperative cardiac function; however, ginseng provided greater benefit than the isolate ginsenoside Rb.

An interaction of ginseng with warfarin, in which the INR was reduced to subtherapeutic levels, has been reported (131). However, no mechanistic evidence for the interaction has been provided (63). Interaction with digoxin, or with the digoxin assay and Siberian ginseng (132), has been observed, though this may have been due to a contaminant (133). Some ginseng preparations have been contaminated with germanium, which has led to an account of ginseng-related diuretic resistance and renal failure (134).

Hawthorn (Crataegus species).   Hawthorn is a spiny shrub native to Europe and North America whose leaves, flowers and berries are used for CHF. Flavonoids and oligomeric procyanthins are the active constituents of hawthorn, and an extract standardized for these compounds, WS 1442, is available. Proposed mechanisms of action include antioxidant, inotropic, vasodilatory and antihyperlipidemic actions, as well as decreased capillary permeability (92). Hawthorn extract (160 to 900 mg two to three times a day for six weeks) is approved by Commission E for use in New York Heart Association (NYHA) functional class II CHF (92). This dose corresponds to 30 to 168.7 mg procyanidins or 3.5 to 19.8 mg flavonoids per dose (92).

Both animal and in vitro studies support several potential mechanisms of action. Hawthorn extract reduces reperfusion injury in ischemic rat hearts (135). After exposure to the extract, rat cardiomyocytes show increased inotropy and a prolonged refractory period (136). Hawthorn, in addition, decreases plasma lipids and increases hepatic LDL receptor activity in rats (137,138).

Heart failure
Clinical trials of hawthorn describe decreased symptoms of CHF as well as improved cardiac performance. Several controlled clinical trials report an improved product of systolic blood pressure and heart rate measured at rest and during exercise (pressure heart rate product) (139–141). In an open trial of 1,011 subjects, the ejection fraction increased and arrhythmias decreased (142). Other reports indicate that cardiac work tolerance is enhanced (92). The first large-scale study designed to look at mortality, cardiac events and hospitalization is currently underway (143). The Survival and Prognosis Investigation of Crataegus Extract (SPICE) trial is investigating WS 1442 for CHF in NYHA functional class II and III. This randomized, placebo-controlled, double-blind, international, multicenter trial will enroll 2,300 subjects by 2002. Subjects will receive either 450 mg of WS 1442, standardized to contain 84.3 mg procyanidins, or placebo in addition to standard CHF drugs (digoxin, angiotensin-converting enzyme inhibitors and diuretics) for 24 months.

Hawthorn has few adverse effects and no reported drug interactions (92). Toxicity of WS 1442 has been studied in animals: doses up to 100 times normal produced no toxic effects (144). The claim that hawthorn potentiates digoxin has not been substantiated (145).

Horse chestnut seed (Aesculus hippocastanum).   Commission E has approved horse chestnut seed extract for chronic venous insufficiency (250 to 312 mg extract twice daily) (92). The active compound, aescin, is a mixture of triterpene glycosides (92). Aescin decreases lower extremity edema by decreasing capillary permeability via inhibition of endothelial lysosomal enzymes and preservation of capillary wall glycocalyx (146), and venoconstriction via prostaglandin F2{alpha} (147). Extracts standardized for aescin content are available, and the Commission E recommends 50 mg aescin twice daily (92).

A review of eight placebo-controlled trials for venous insufficiency reported that lower extremity circumference and volume decreased, and leg pain and pruritus improved (148). The most frequent adverse effects were gastrointestinal symptoms, dizziness, headache and pruritus. Trials that compared horse chestnut to hydroxyethylrutosides, a semisynthetic mixture of flavonoid compounds (149), found little difference between treatments (148). In a partially blind study of horse chestnut seed versus compression stockings or placebo, the volume of lower extremity edema decreased 45 ml for each active treatment compared to a 10 ml increase for placebo (150).

Side effects include pruritus, nausea, headache and dizziness (148). There is one reported case of hepatitis from a commercial preparation of horse chestnut extract, Venoplant (151). Venocuran, an herbal preparation that contained horse chestnut, plus phenopyrazone, extracts of white squill, convallaria, oleander and adonis, was removed from the market owing to a systemic lupus-like syndrome (152).

Ma huang (Ephedra sinica).   Ma huang is a natural source of ephedrine and has potent sympathomimetic activity. Herbal remedies and soft drinks used for energy or weight loss often contain ma huang. Its pharmacokinetics and bioavailability are similar to standard doses of ephedrine (153), but the effects are delayed in onset. Between 1997 and 1999, a total of 140 reports of adverse events were related to ma huang (154); 13 caused permanent impairment and 10 resulted in death. Many reports concern healthy young people without known cardiac disease. The majority had new-onset hypertension, and other findings included cerebrovascular accidents, arrhythmias and MI. Several reports link the adverse response of ma huang to concurrent use of caffeine, guarana (a source of caffeine and theophylline [155]) or exercise. A case report of eosinophilic myocarditis possibly associated to ma huang has also been reported (156).

Other herbs.   Dong quai (Angelicae sinensis)
Dong quai, a TCM remedy for menstrual symptoms and the menopause (157), is also used for antiarrhythmic, antithrombotic, antiasthmatic and analgesic effects (157–160). In humans, dong quai has been evaluated for estrogenic effects (161). Quinidine-like effects have been reported in animals (159), but not evaluated in clinical trials. Antithrombotic effects are attributed to coumarin derivatives and ferulic acid contained in the oil of the root (157,159). Ferulic acid may cause platelet dysfunction by inhibiting production of thromboxane A2 (157). In a controlled trial of 96 subjects with new cerebral thrombosis or embolism, there was no difference in improvement rate with dong quai (160). Case reports of warfarin potentiation have been reported, and an interaction is supported by animal studies, which demonstrate alteration of warfarin pharmacodynamics after dong quai (157,158).

Ginger (Zingiber officinale)
Dried ginger powder, 500 to 1000 mg, or fresh ginger, 2 to 4 g, is used for nausea (92,162). Ginger’s alleged vitalizing effect on the heart and blood is attributed to decreased platelet aggregation and inhibition of thromboxane synthesis observed in in vitro studies (162). In vitro antiplatelet activity varies by form (dried, raw, cooked or extract) (163). Clinical studies, however, using raw, cooked or dried ginger do not show an effect on bleeding time, platelet aggregation or thromboxane production (163–165). Compounds isolated from ginger, including shogaol and gingerol, have been studied for positive inotropic and pressor effects (166,167); however, no clinical trials currently support these effects. Neither adverse effects nor drug interactions have been reported (92,162).

Hellebore (Veratrum species)
A variety of hellebore species grow in North America, Europe and Asia and contain active veratrum alkaloids (168). As a source of veratrum alkaloids, hellebore’s use as an antihypertensive was precluded by nausea and vomiting (168). Cardiac arrhythmias also occur, particularly in association with digitalis (168). Hellebore toxicity often results from accidental ingestion, particularly when white hellebore (Veratrum albums) is mistaken for gentian to produce gentian wine (169). Toxicity is associated with vomiting, hypotension and bradycardia, but is rarely fatal (169,170).

Kava (Piper methysticum)
Kava, a member of the black pepper family, is used by aboriginal peoples of the South Pacific as an anxiolytic, and it has been promoted to treat anxiety, depression and muscle tension (171). Sales of kava products in the U.S. were $8 million in 1998, having grown more than 450% from the prior year (2). Kava pyrones, the active compounds in kava (172,173), may inhibit cyclooxygenase and thromboxane synthase (174). A small observational study of an aboriginal community found that HDLs were higher in kava users (175). Adverse effects include rash, elevated hepatic enzymes, pulmonary hypertension and hepatitis (175,176). Kava may also interact with benzodiazepines, inducing coma (177).

Licorice (Glycyrrhiza glabra)
Licorice, an extract of the root of Glycyrrhiza glabra, is used as a sweetening and flavoring agent. It is also used as an herbal remedy for gastritis and upper respiratory tract infections (178–180). Most licorice candies in the U.S. do not contain licorice (181). The active constituent of licorice is glycyrrhizic acid. A metabolite, glycyrrhetinic acid, inhibits renal 11ß-hydroxysteroid dehydrogenase and causes a state of mineralocorticoid excess by impeding the inactivation of cortisol (179). Case reports link licorice to hypertension, hypertensive encephalopathy, pulmonary edema, edema, hypokalemia, arrhythmias, CHF, muscle weakness and acute renal failure (178). Dilated cardiomyopathy resulting from excessive use of licorice and glycyrrhizin for gastritis has been reported (180). Fifty to 100 g of confectionary licorice, or 50 to 300 mg glycyrrhetinic acid, over weeks may cause adverse effects (182,183). A study of 30 healthy, normotensive volunteers reported that 100 g per day of licorice (270 mg glycyrrhizic acid) over four weeks increased systolic blood pressure 6.5 mm Hg and decreased plasma potassium 0.24 mmol/l from baseline (184). Susceptibility to licorice varies greatly; subjects with underlying hypertension and women may be more sensitive (179,184). Adverse effects may take weeks to reverse because of suppression of the renin-angiotensin-aldosterone axis and because glycyrrhetinic acid has a large volume of distribution (179).

Yohimbine (Pausinystalia yohimbe)
Yohimbine is isolated from yohimbe, the bark of the tree Pausinystalia yohimbe, and is used for erectile dysfunction (185). It is a competitive alpha2-antagonist that increases central sympathetic outflow and raises blood pressure, heart rate and norepinephrine levels (186–188). As a result, it may exacerbate elevated blood pressure in hypertensive patients, as well as cause arrhythmias and tremors (186,187). Yohimbine has been evaluated for use in postural hypotension associated with autonomic dysfunction (189). As an alpha2-antagonist, yohimbine opposes the effects of clonidine (186). It also interacts with tricyclic antidepressants, so that pressor effects occur at lower doses, and may potentiate the alpha-adrenergic blocking properties of phenothiazines (190). Adverse reactions include mania (191), bronchospasm (192), a systemic lupus-like syndrome (193) and agranulocytosis (194). The recommended dose is 5.4 mg three times daily; pressor effects are associated with doses of 15 to 20 mg (190).

Other herbal adverse effects and drug interactions
A number of herbs, including oleander, adonis, black Indian hemp (apocynum), black hellebore, lily-of-the-valley (convallaria), squill and strophanthus, contain cardiac glycosides that can potentiate digoxin (195). There are frequent case reports of toxic ingestion of oleander, a common flowering shrub found throughout North America (196–198). Oleander toxicity has been effectively treated with digoxin-specific antibodies (196). St. John’s wort (Hypericum perforatum) decreases serum levels of digoxin through induction of a p-glycoprotein drug transporter (199). In a single-blind, placebo-controlled study, after 10 days of St. John’s wort, digoxin levels were reduced more than 25% (199). Several herbs used for a laxative effect, such as senna, cascara sagrada and buckthorn (200), may augment potassium loss and lead to toxicity in digoxin users. Belladonna, an herb used for gastrointestinal symptoms, is a source of atropine and may cause tachycardia (92).


   Conclusions
Top
 Abstract
 Background
 Cardiovascular benefits and...
 Conclusions
References
 
The growing use of herbal remedies in the U.S. has far exceeded the increase in available information on their benefits, adverse effects and drug interactions. Coherent, easily accessible data on remedies is lacking. English translations of the collected German Commission E monographs represent one of the few references for consumers and practitioners. Such information is critical to physicians who often must counsel patients about herbal alternatives to traditional therapy and address the concern of herb-drug interactions. Although there is little existing data comparing herbal therapy to approved drugs, the SPICE trial is a landmark investigation of an herbal remedy with standard therapy. With only modest evidence-based data, physicians may opt to put off interactive questions or refrain from prescribing herbal remedies. Considering that the escalating appeal of herbal remedies is likely to continue, such a stance is impractical and potentially risky for patients. Rather, another option is that physicians and other health care providers become familiar with the data and advocate for greater research and access to information.


   Footnotes
 
This study was supported in part by grant HL-07046 from the Department of Health and Human Services; grant RR-00645 from the Research Resources Administration; grant P50-AT00090 from the Center for Complementary and Alternative Medicine in Aging, Bethesda, Maryland; and a grant from Linda and Peter Nisselson, New York.


   References
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 Abstract
 Background
 Cardiovascular benefits and...
 Conclusions
 References
 

  1. Wharton R, Lewith G. Complementary medicine and the general practitioner. BMJ. 1986;292:1498–1500[Medline]
  2. Brevoort P. The booming U.S. botanical market: a new overview. Herbal Gram. 1998;44:33–46
  3. Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990–1997. JAMA. 1998;280:1569–1575[Abstract/Free Full Text]
  4. Winter G. F.D.A. warns food companies about herbal additives. The New York Times. June 7, 2001;:C1–C17
  5. Radimer KL, Subar AF, Thompson FE. Nonvitamin, nonmineral dietary supplements: issues and findings from NHANES III. J Am Diet Assoc. 2000;100:447–454[CrossRef][Medline]
  6. Cottrell K. Herbal products begin to attract the attention of brand-name companies. Can Med Assoc J. 1996;155:216–219[Abstract]
  7. Marwick C. Growing use of medicinal botanicals forces assessment by drug regulators. JAMA. 1995;273:607–609[CrossRef][Medline]
  8. Nahin RL, Straus SE. Research into complementary and alternative medicine: problems and potential. BMJ. 2001;322:161–164[Free Full Text]
  9. Cui J, Garle M, Eneroth P, Bjorkhem I. What do commercial ginseng preparations contain (letter). Lancet. 1994;344:134[Medline]
  10. Liberti LE, Marderosian AD. Evaluation of commercial ginseng products. J Pharm Sci. 1978;67:1487–1489[CrossRef][Medline]
  11. Lawson L. Garlic powder for hyperlipidemia—analysis of recent negative results. Q Rev Nat Med. 1998;:187–189
  12. Heptinstall S, Awang DV, Dawson BA, Kindack D, Knight DW, May J. Parthenolide content and bioactivity of feverfew (Tanacetum parthenium (L.) Schultz-Bip.). Estimation of commercial and authenticated feverfew products. J Pharm Pharmacol. 1992;44:391–395[Medline]
  13. Blumenthal M. Introduction. Blumenthal M, Busse WR, Goldberg A, Gruenwald J, Riggins CW, Rister RS. The Complete German Commission E Monographs. Austin, TX: American Botanical Council; 1998. p. 5–80
  14. Fleming T. PDR for Herbal Medicines. Montvale, NJ: Medical Economics; 2000. p. 1–2
  15. Hesketh T, Zhu WX. Health in China. BMJ. 1997;315:115–117[Free Full Text]
  16. Huang KC. The Pharmacology of Chinese Herbs. Boca Raton, FL: CRC Press; 1993. p. 3
  17. Miller LG. Herbal medicinals. Arch Intern Med. 1998;158:2200–2211[Abstract/Free Full Text]
  18. Hertog MGL, Feskens EJM, Hollman PCH, Katan MB, Kromhout D. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet. 1993;342:1007–1011[CrossRef][Medline]
  19. Kushi LH, Folsom AR, Prineas RJ, Mink PJ, Wu Y, Bostick RM. Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. N Engl J Med. 1996;334:1156–1162[Abstract/Free Full Text]
  20. Hertog MG, Kromhout D, Aravanis C, et al. Flavonoid intake and long-term risk of coronary heart disease and cancer in the seven countries study. Arch Intern Med. 1995;155:381–386[Abstract]
  21. Knekt P, Jarvinen R, Reunanen A, Maatela J. Flavonoid intake and coronary mortality in Finland: a cohort study. BMJ. 1996;312:478–481[Abstract/Free Full Text]
  22. Cook NC, Samman S. Flavonoids—chemistry, metabolism, cardioprotective effects, and dietary sources. J Nutr Biochem. 1996;7:66–76[CrossRef]
  23. Howard BV, Kritchevsky D. Phytochemicals and cardiovascular disease. Circulation. 1997;95:2591–2593[Free Full Text]
  24. Rapola JM, Virtamo J, Ripatti S, et al. Randomised trial of {alpha}-tocopherol and ß-carotene supplements on incidence of major coronary events in men with previous myocardial infarction. Lancet. 1997;349:1715–1720[CrossRef][Medline]
  25. The {alpha}-Tocopherol, ß-Carotene Study Group. The effect of vitamin E and ß-carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med. 1994;330:1029–1035[Abstract/Free Full Text]
  26. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334:1150–1155[Abstract/Free Full Text]
  27. Menasché P, Antebi H, Alcindor L-G, et al. Iron chelation by deferoxamine inhibits lipid peroxidation during cardiopulmonary bypass in humans. Circulation. 1990;82(Suppl IV):IV390–396[Medline]
  28. Yau TM, Weisel RD, Mickle DAG, et al. Vitamin E for coronary bypass surgery. J Thorac Cardiovasc Surg. 1994;108:302–310[Abstract/Free Full Text]
  29. Menasché P, Pasquier C, Bellucci S, Lorente P, Jaillon P, Piwnica A. Deferoxamine reduces neutrophil-mediated free radical production during cardiopulmonary bypass in man. J Thorac Cardiovasc Surg. 1988;96:582–589[Abstract]
  30. Harkey MR, Henderson GL, Gershwin ME, Stern JS, Hackman RM. Variability in commercial ginseng products: and analysis of 25 preparations. Am J Clin Nutr. 2001;73:1101–1106[Abstract/Free Full Text]
  31. Fugh-Berman A. Herb–drug interactions. Lancet. 2000;355:134–138[CrossRef][Medline]
  32. Ko RJ. Adulterants in Asian patent medicines. (letter)N Engl J Med. 1998;339:847[Free Full Text]
  33. Ernst E. Harmless herbs? A review of the recent literature. Am J Med. 1998;104:170–178[CrossRef][Medline]
  34. Lei X-L, Chiou GCY. Cardiovascular pharmacology of Panax notoginseng (Burk) F.H. Chen and Salvia miltiorrhiza. Am J Chin Med. 1986;14:145–152[CrossRef][Medline]
  35. Keji C. Certain progress in the treatment of coronary heart disease with traditional medicinal plants in China. Am J Chin Med. 1981;9:193–196[CrossRef][Medline]
  36. Liu G-T, Zhang T-M, Wang B-E, Wang Y-W. Protective action of seven natural phenolic compounds against peroxidative damage to biomembranes. Biochem Pharmacol. 1992;43:147–152[CrossRef][Medline]
  37. Wu Y-J, Hong C-Y, Lin S-J, Wu P, Shiao M-S. Increase of vitamin E content in LDL and reduction of atherosclerosis in cholesterol-fed rabbits by a water-soluble antioxidant-rich fraction of Salvia miltiorrhiza. Arterioscler Thromb Vasc Biol. 1998;18:481–486[Abstract/Free Full Text]
  38. Wang Z, Roberts JM, Grant PG, Colman RW, Schreiber AD. The effect of a medicinal Chinese herb on platelet function. Thromb Haemost. 1982;48:301–306[Medline]
  39. Onitsuka M, Fujiu M, Shinma N, Maruyama HB. New platelet aggregation inhibitors from tanshen. Chem Pharm Bull. 1983;31:1670–1675[Medline]
  40. Qiu R-X, Luo Z-Q, Luo H-C, et al. [Effect of Xinmaitong capsule on damage of lipid peroxidation in coronary heart disease patients with myocardial ischemia] [translated from Chinese]. Chung Kuo Chung Hsi I Chieh Ho Tsa Chih. 1997;17:342–344[Medline]
  41. Shanghai Cooperative Group for the Study of Tanshinone IIA. Therapeutic effect of sodium tanshinone IIA sulfonate in patients with coronary heart disease. J Tradit Chin Med. 1984;4:20–24[Medline]
  42. Lei X-L, Chiou GCY. Studies on cardiovascular actions of Salvia miltiorrhiza. Am J Chin Med. 1986;14(1–2):26–32[CrossRef][Medline]
  43. Chan TYK. Drug interactions as a cause of overanticoagulation and bleedings in Chinese patients receiving warfarin. Int J Clin Pharmacol Ther. 1998;36:403–405[Medline]
  44. Yu CM, Chan JCN, Sanderson JE. Chinese herbs and warfarin potentiation by "danshen". J Intern Med. 1997;241:337–339[CrossRef][Medline]
  45. Chan K, Lo ACT, Yeung JHK, Woo KS. The effects of danshen (Salvia miltiorrhiza) on warfarin pharmacodynamics and pharmacokinetics of warfarin enantiomers in rats. J Pharm Pharmacol. 1995;47:402–406[Medline]
  46. Groenewegen WA, Knight DW, Heptinstall S. Progress in the medicinal chemistry of the herb feverfew. Prog Med Chem. 1992;29:217–238[Medline]
  47. Vogler BK, Pittler MH, Ernst E. Feverfew as a preventive treatment for migraine: a systematic review. Cephalalgia. 1998;18:704–708[CrossRef][Medline]
  48. Barsby RW, Knight DW, McFadzean I. A chloroform extract of the herb feverfew blocks voltage-dependent potassium currents recorded from single smooth muscle cells. J Pharm Pharmacol. 1993;45:641–645[Medline]
  49. Williams CA, Harborne JBN, Geiger H, Robin J, Hoult S. The flavonoids of Tanacetum parthenium and T. vulgare and their anti-inflammatory properties. Phytochemistry. 1999;51:417–423[CrossRef][Medline]
  50. Heptinstall S, White A, Williamson L, Mitchell JRA. Extracts of feverfew inhibit granule secretions in blood platelets and polymorphonuclear leucocytes. Lancet. 1985;1:1071–1074[Medline]
  51. Barsby RW, Salan U, Knight DW, Hoult JRS. Feverfew and vascular smooth muscle: extracts from fresh and dried plants show opposing pharmacological profiles, dependent upon sesquiterpene lactone content. Planta Med. 1993;59:20–25[Medline]
  52. Johnson ES, Kadam NP, Hylands DM, Hylands PJ. Efficacy of feverfew as prophylactic treatment of migraine. BMJ. 1985;291:569–573[Medline]
  53. Murphy JJ, Heptinstall S, Mitchell JRA. Randomised double-blind placebo-controlled trial of feverfew in migraine prevention. Lancet. 1988;2:189–192[Medline]
  54. Palevitch D, Earon G, Carasso R. Feverfew (Tanacetum parthenium) as a prophylactic treatment for migraine: a double-blind placebo-controlled study. Phytother Res. 1997;11:508–511[CrossRef]
  55. De Weerdt CJ, Bootsma HPR, Hendriks H. Herbal medicines in migraine prevention. Phytomedicine. 1996;3:225–230
  56. Wong HCG. Is feverfew a pharmacologic agent. (letter)Can Med Assoc J. 1999;160:21–22[Medline]
  57. Ackermann RT, Mulrow CD, Ramirez G, Gardner CD, Morbidoni L, Lawrence VA. Garlic shows promise for improving some cardiovascular risk factors. Arch Intern Med. 2001;161:813–824[Abstract/Free Full Text]
  58. Ali M, Thomson M, Afzal M. Garlic and onions: their effect on eicosanoid metabolism and its clinical relevance. Prostaglandins Leukot Essent Fatty Acids. 2000;62:55–73[CrossRef][Medline]
  59. Lawson LD, Ransom DK, Hughes BG. Inhibition of whole blood platelet-aggregation by compounds in garlic clove extracts and commercial garlic products. Thromb Res. 1992;65:141–156[CrossRef][Medline]
  60. Agarwal KC. Therapeutic actions of garlic constituents. Med Res Rev. 1996;16:111–124[CrossRef][Medline]
  61. Rose K, Croissant P, Parliament C, Levin M. Spontaneous spinal epidural hematoma with associated platelet dysfunction from excessive garlic ingestion: a case report (letter). Neurosurgery. 1990;26:880–882[CrossRef][Medline]
  62. Sunter W. Warfarin and garlic. Pharm J. 1991;:722
  63. Vaes LP, Chyka PA. Interactions of warfarin with garlic, ginger, ginkgo, or ginseng: nature of the evidence. Ann Pharmacother. 2000;34:1478–1482[Abstract]
  64. Neil HAW, Silagy CA, Lancaster T, et al. Garlic powder in the treatment of moderate hyperlipidemia: a controlled trial and meta-analysis. J R Coll Physicians Lond. 1996;30:329–334[Medline]
  65. Warshafsky S, Kamer RS, Sivak SL. Effect of garlic on total serum cholesterol. A meta-analysis. Ann Intern Med. 1993;119:599–605[Abstract/Free Full Text]
  66. Silagy C, Neil A. Garlic as a lipid lowering agent—a meta-analysis. J R Coll Physicians Lond. 1994;28:39–45[Medline]
  67. Stevinson C, Pittler MH, Ernst E. Garlic for treating hypercholesterolemia. Ann Intern Med. 2000;133:420–429[Abstract/Free Full Text]
  68. Holzgartner H, Schmidt U, Kuhn U. Comparison of the efficacy and tolerance of a garlic preparation vs. bezafibrate. Arzneimittelforschung. 1992;42:1473–1477[Medline]
  69. Das I, Khan NS, Sooranna SR. Potent activation of nitric oxide synthase by garlic: a basis for its therapeutic applications. Curr Med Res Opin. 1995;13:257–263[Medline]
  70. McMahon FG, Vargas R. Can garlic lower blood pressure? A pilot study. Pharmacotherapy. 1993;13:406–407[Medline]
  71. Auer W, Eiber A, Hertkorn E, et al. Hypertension and hyperlipidemia: garlic helps in mild cases. Br J Clin Pract Suppl. 1990;69:3–6[Medline]
  72. Silagy CA, Neil HAW. A meta-analysis of the effect of garlic on blood pressure. J Hypertens. 1994;12:463–468[Medline]
  73. Bordia T, Mohammed N, Thomson M, Ali M. An evaluation of garlic and onion as antithrombotic agents. Prostaglandins Leukot Essent Fatty Acids. 1996;54:183–186[CrossRef][Medline]
  74. Bordia A, Verma SK, Srivastava KC. Effect of garlic (Allium sativum) on blood lipids, blood sugar, fibrinogen and fibrinolytic activity in patients with coronary artery disease. Prostaglandins Leukot Essent Fatty Acids. 1998;58:257–263[CrossRef][Medline]
  75. Ali M. Mechanism by which garlic (Allium sativum) inhibits cyclooxygenase activity. Effect of raw versus boiled garlic extract on the synthesis of prostanoids. Prostaglandins Leukot Essent Fatty Acids. 1995;53:397–400[CrossRef][Medline]
  76. Apitz-Castro R, Badimon JJ, Badimon L. Effect of ajoene, the major anti-platelet compound from garlic, on platelet thrombus formation. Thromb Res. 1992;68:145–155[CrossRef][Medline]
  77. Burnham BE. Garlic as a possible risk for postoperative bleeding. (letter)Plast Reconstr Surg. 1995;95:213[Medline]
  78. Kieswetter H, Jung F, Pindur G, Jung EM, Mrowietz C, Wenzel E. Effects of garlic on thrombocyte aggregation, microcirculation and other risk factors. Int J Clin Pharmacol Ther Toxicol. 1991;29:151–155[Medline]
  79. Harenberg J, Giese C, Zimmerman R. Effect of dried garlic on blood coagulation, fibrinolysis, platelet aggregation and serum cholesterol levels in patients with hyperlipoproteinemia. Atherosclerosis. 1988;74:247–249[CrossRef][Medline]
  80. Legnani C, Frascaro M, Guazzaloca G, Ludovici S, Cesarano G, Coccheri S. Effects of a dried garlic preparation on fibrinolysis and platelet aggregation in healthy subjects. Arzneimittelforschung. 1993;43:119–122[Medline]
  81. Kiesewetter H, Jung F, Jung EM, et al. Effects of garlic coated tablets in peripheral arterial occlusive disease. Clin Invest. 1993;71:383–386[Medline]
  82. Morris J, Burke V, Mori TA, Vandongen R, Beilin LJ. Effects of garlic on platelet aggregation: a randomized placebo-controlled double-blind study. Clin Exp Pharmacol Physiol. 1995;22:414–417[Medline]
  83. Bordia A, Joshi HK, Sanadhya YK, Bhu N. Effect of essential oil of garlic on serum fibrinolytic activity in patients with coronary artery disease. Atherosclerosis. 1977;28:155–159[CrossRef][Medline]
  84. Chutani SK, Bordia A. The effect of fried versus raw garlic on fibrinolytic activity in man. Atherosclerosis. 1981;38:417–421[CrossRef][Medline]
  85. Kiesewetter H, Jung F, Mrowietz C, Pindur G, Heiden M, Wenzel E. Effects of garlic on blood fluidity and fibrinolytic activity: a randomized, placebo-controlled, double-blind study. Br J Clin Pract Suppl. 1990;69:24–29[Medline]
  86. Luley C, Lehmann-Leo W, Moller B, Martin T, Schwartzkopff W. Lack of efficacy of dried garlic in patients with hyperlipoproteinemia. Arzneimittelforschung. 1986;36:766–768[Medline]
  87. Orekhov AN, Grünwald J. Effects of garlic on atherosclerosis. Nutrition. 1997;13:656–663[CrossRef][Medline]
  88. Prasad K, Mantha SV, Kalra J, Lee P. Prevention of hypercholesterolemic atherosclerosis by garlic, an antioxidant. J Cardiovasc Pharmacol Ther. 1997;2:309–320[Medline]
  89. Jepson RG, Kleijnin J, Leng GC. Garlic for peripheral arterial occlusive disease. Cochrane Database Syst Rev. 2000;4:CD000095
  90. Koscielny J, Klubendorf D, Latza R, et al. The antiatherosclerotic effect of Allium sativum. Atherosclerosis. 1999;144:237–249[CrossRef][Medline]
  91. Kleijnin J, Knipschild P. Ginkgo biloba. Lancet. 1992;340:1136–1139[CrossRef][Medline]
  92. German Commission E. Approved herbs. Blumenthal M. The Complete German Commission E Monographs. Austin, TX: American Botanical Council; 1998. p. 73–418
  93. Pittler MH, Ernst E. Ginkgo biloba extract for the treatment of intermittent claudication: a meta-analysis of randomized trials. Am J Med. 2000;108:276–281[CrossRef][Medline]
  94. Rowin J, Lewis SL. Spontaneous bilateral subdural hematomas associated with chronic ginkgo biloba ingestion. Neurology. 1996;46:1775–1776[Free Full Text]
  95. Vale S. Subarachnoid haemorrhage associated with ginkgo biloba. Lancet. 1998;352:36[Medline]
  96. Rosenblatt M, Mindel J. Spontaneous hyphema associated with ingestion of ginkgo biloba extract (letter). N Engl J Med. 1997;336:1108[Free Full Text]
  97. Matthews MK Jr. Association of Ginkgo biloba with intracerebral hemorrhage. (letter)Neurology. 1998;50:1933[Medline]
  98. Galluzzi S, Zanetti O, Binetti G, Trabucchi M, Frisoni GB. Coma in a patient with Alzheimer’s disease taking low dose trazodone and ginkgo biloba. J Neurol Neurosurg Psychiatry. 2000;68:679–680[CrossRef][Medline]
  99. Krieglstein J, Beck T, Seibert A. Influence of extract of ginkgo biloba on cerebral blood flow and metabolism. Life Sci. 1986;39:2327–2334[CrossRef][Medline]
  100. Garg RK, Nag D, Agrawal A. A double-blind placebo-controlled trial of ginkgo biloba extract in acute cerebral ischaemia. J Assoc Physicians India. 1995;43:760–763[Medline]
  101. Kleijnen J, Knipschild P. Ginkgo biloba for cerebral insufficiency. Br J Clin Pharmacol. 1992;34:352–358[Medline]
  102. Hopfenmuller W. Nachweis der therapeutischen wirksamkeit eines ginko biloba-spezialextraktes. Arzneimittelforschung. 1994;44:1005–1013[Medline]
  103. Hartmann A, Frick M. [Effectiveness of a ginkgo special extract on psychometric parameters in patients with vascular dementia] [German]Munch Med Wochenschr. 1991;133:S23–25
  104. Diamond BJ, Shiflett SC. Arch Phys Med Rehabil. 2000;81:668–678[Medline]
  105. Arrigo A, Cattaneo S. Clinical and psychometric evaluation of Ginkgo biloba extract in chronic cerebrovascular diseases. Agnoli A, Rapin JR, Scapagnini V, Weitbrecht WV. Effects of Ginkgo Biloba Extract on Organic Cerebral Impairment. London: John Libbey; 1985. p. 85–90
  106. Halama P, Bartsch G, Meng G. Disorders of brain performance of vascular origin. Randomized double-blind study of the effectiveness of Ginkgo biloba extractFortschr Med. 1988;106:408–412[Medline]
  107. Baek S-H, Yun S-S, Kwon TK, et al. The effects of two new antagonists of secretory PLA2 on TNF, iNOS, and COX-2 expression in activated macrophages. Shock. 1999;12:473–478[CrossRef][Medline]
  108. Moher D, Pham B, Ausejo M, et al. Pharmacological management of intermittent claudication: a meta-analysis of randomised trials. Drugs. 2000;59:1057–1070[CrossRef][Medline]
  109. Pietri S, Maurelli E, Drieu K, Culcasi M. Cardioprotective and anti-oxidant effects of the terpenoid constituents of ginkgo biloba extract (Egb 761). J Mol Cell Cardiol. 1997;29:733–742[CrossRef][Medline]
  110. Liebgott T, Miollan M, Berchadsky Y, Drieu K, Culcasi M, Pietri S. Complementary cardioprotective effects of flavonoid metabolites and terpenoid constituents of Ginkgo biloba extract (EGb 761) during ischemia and reperfusion. Basic Res Cardiol. 2000;95:368–377[CrossRef][Medline]
  111. Janssens D, Remacle J, Drieu K, Michiels C. Protection of mitochondrial respiration activity by bilobalide. Biochem Pharmacol. 1999;58:109–119[CrossRef][Medline]
  112. Zhou L, Zhu X. Reactive oxygen species-induced apoptosis in PC12 cells and protective effect of bilobalide. J Pharmacol Exp Ther. 2000;293:982–988[Abstract/Free Full Text]
  113. Pietri S, Seguin JR, d’Arbigny P, Drieu K, Culcasi M. Ginkgo biloba extract (EGB 761) pretreatment limits free radical-induced oxidative stress in patients undergoing coronary bypass surgery. Cardiovasc Drugs Ther. 1997;11:121–131[CrossRef][Medline]
  114. Montrucchio G, Alloatti G, Camussi G. Role of platelet-activating factor in cardiovascular pathology. Physiol Rev. 2000;80:1669–1699[Abstract/Free Full Text]
  115. Chung KF, Dent G, McCusker M, Guinot P, Page CP, Barnes PJ. Effect of a ginkgolide mixture (BN 52063) in antagonizing skin and platelet responses to platelet activating factor in man. Lancet. 1987;1:248–251[Medline]
  116. Braquet P, Esanu A, Buisine E, Hosford D, Broquet C, Koltai M. Recent progress in ginkgolide research. Med Res Rev. 1991;11:295–355[CrossRef][Medline]
  117. Braquet P. Cedemin, a Gink