Ginkgo for Intermittent Claudication
Ginkgo for Intermittent Claudication
August 2001; Volume 4; 85-89
By Christine M. Stoltz, MD
Since the early days of medicine, physicians and patients alike have appreciated the importance of "good" circulation. Nowadays, patients are familiar with the consequences of "bad" circulation, including coronary artery disease, cerebrovascular disease, and peripheral vascular disease.
An early symptom of peripheral vascular disease, intermittent claudication (IC) is associated with atherosclerosis of the aorta and arteries of the lower extremities. IC is characterized by muscular pain during exercise that can progress to pain at rest, ulcers, and gangrene. Traditional IC therapy has emphasized reducing the progression of atherosclerosis. Common interventions include exercise, smoking cessation, low-fat diets, and control of comorbid conditions such as diabetes, hypertension, and hyperlipidemia. Adjunct pharmacologic therapy for mild-to-moderate IC may include antiplatelet therapy with aspirin, but pentoxifylline and cilostazol also are used.
Ginkgo biloba, which has received attention as an antioxidant and memory enhancer, has been used for a variety of medical conditions characterized by impaired circulation. Several studies have shown that it may be useful in the management of IC.
Historical Perspective
The ginkgo or maidenhair tree is estimated to be about 200 million years old, and was brought to the United States from China in the late 1700s.1 Derived from dried leaves, Ginkgo biloba extract has been used in traditional Chinese medicine to improve brain and respiratory function. Over the past decade, ginkgo has become increasingly popular for treatment of dementia, cognitive insufficiency, and IC. In 1998, ginkgo was the top-selling medicinal herb in the United States.2
Pharmacokinetics/Composition
The major constituents of Ginkgo biloba extracts are flavone glycosides (specifically quercetin, kaempferol, and isorhamnetin) and terpene lactones (ginkgolides A, B, and C; and bilobalide). Most studies use standardized extracts of EGb 761, which contains 24% ginkgo flavone glycosides and 6% terpene lactones. Gastrointestinal absorption in rats appears to be about 60%. Bioavailability following an oral dose of EGb 761 in humans is 98-100% for ginkgolide A, 79-93% for ginkgolide B, and 70% or more for bilobalide.3
Mechanism of Action
The flavone glycoside components of EGb 761 are believed to act as antioxidants and mild inhibitors of platelet aggregation. Terpene lactones are thought to be neuroprotective because they increase glucose and oxygen utilization, improve perfusion, and generally stimulate cognitive function.
In Vitro and Animal Studies
Several lines of evidence have suggested that ginkgo may modulate the endothelial microenvironment. It has been implicated as a free-radical scavenger, inhibitor of platelet-activating factor, and mediator of nitric oxide metabolism, erythrocyte aggregation, and nuclear transcription factors. Using a bovine endothelial cell model, Wei and colleagues showed ginkgo’s free-radical scavenging capability,4 which was consistent with other studies of its antioxidant activity.5,6 Wei et al also found that ginkgo inhibited nuclear factor kappa-B, which is thought to be an important regulator of vascular pathophysiology.4
Other groups have focused on alterations in nitric oxide production. Although generally regarded as a vasodilator, both high and low levels of nitric oxide have been observed in atherosclerosis. Using a human endothelial cell line, Cheung et al found dose-dependent attenuation of nitric oxide production following treatment with EGb 761.7 This appeared to be caused by a decrease in an inducible isoform of nitric oxide synthetase.7
Additional areas of research have explored ginkgo’s antiplatelet effects. Using a rabbit model, Akiba et al showed that EGb 761 inhibited platelet aggregation in response to oxidative stress,8 which may be relevant at the endothelial level in preventing thrombus formation. In addition, although some groups have proposed that ginkgolide B inhibits platelet-activating factor,9 others have challenged this notion.10
Despite their biologic plausibility, the clinical importance of these in vitro effects is unknown.
Clinical Studies
The most recent meta-analysis of randomized, double-blind, placebo-controlled trials (RDBCTs) of IC was conducted by Pittler and Ernst.11 Using systematic literature searches and unpublished data solicited from manufacturers, they identified eight RDBCTs that evaluated the effects of ginkgo, using pain-free walking distance as a primary outcome measure. In these trials, a total of 415 patients with IC (as defined by the Fontaine criteria) received 120-160 mg/d of Ginkgo biloba extract or placebo for 6-24 weeks. Three of the trials used the standardized extract, EGb 761.
Studies were analyzed independently by two reviewers and were given a quality score based on study design, description of withdrawals and dropouts, and randomization strategy (maximum score = 5). Of the eight studies used in the analysis, one had a perfect quality score (5),12 five studies scored 4,13-17 and two studies scored 3.18,19 (See Table 1. Click here.) Seven studies showed that Ginkgo biloba was more effective than placebo, though only four of these achieved statistical significance.
When subject to statistical pooling, an increase in pain-free walking distance was noted in subjects treated with ginkgo as compared to placebo. The difference was approximately 34 m (95% confidence interval: 24- 43 m). This improvement is of unclear clinical relevance. This result was consistent with the findings from the largest trial19 and was consistent across studies in subgroup analysis.
In comparison, separate studies have shown that an exercise program can increase pain-free walking distances by 88-190% (i.e., up to 139 m).11 Nonetheless, until larger RDBCTs are performed, this meta-analysis probably is the best available evidence of ginkgo’s efficacy in the treatment of IC.
Adverse Effects and Drug Interactions
When used in standard doses, ginkgo generally is well tolerated. However, its use should be avoided in persons with known hypersensitivity to ginkgo preparations. Occasional rash, minor gastrointestinal disturbances, and headache have been described.3
The greatest concern, however, is the potential for bleeding, especially when ginkgo is coadministered with anticoagulants or antiplatelet agents. Several case reports have documented this untoward effect. For example, a spontaneous hyphema occurred in a patient using Ginkgo biloba 40 mg bid and aspirin 325 mg/d.20 Intracerebral bleeding was reported in an elderly woman taking both warfarin and ginkgo.21 In addition, bilateral subdural hematomas occurred in a young woman who had taken Ginkgo biloba 60 mg bid. This was associated with a prolonged bleeding time, which normalized upon discontinuation of the herb.22 A spontaneous intracerebral hemorrhage also was reported in an elderly woman taking Ginkgo biloba 50 mg bid for approximately six months.23 Subarachnoid hemorrhage occurred in a 61-year-old male taking Ginkgo biloba 40 mg 3-4 times daily.24
Concurrent use of ginkgo with other anticoagulants (e.g., heparins and heparinoids), antiplatelet agents, and nonsteroidal anti-inflammatory drugs should be avoided because coadministration may increase the risk of bleeding. Use with other herbs and supplements that can increase the risk of bleeding (e.g., garlic, ginseng, and vitamin E) also should be avoided. Like other antiplatelet agents, ginkgo use should be discontinued prior to surgical procedures. Although the exact lead time for stopping Ginkgo biloba before surgery is unknown, 10-14 days probably is appropriate in most cases.
In addition, ginkgo’s reversible inhibition of monoamine oxidase (MAO) in rat models has led to concern about potential interactions with antidepressants, but this has not been evidenced. Using positron emission tomography, a small study of 10 healthy humans failed to demonstrate alterations in MAO A and MAO B.23 Insufficient data are available on ginkgo’s safety in children and pregnant or lactating women.
Formulation and Dosage
Depending on the manufacturing process used, there may be variation in the composition of ginkgo preparations. The average oral dose is 120 mg of dried extract in 2-3 divided doses daily.26 Although more expensive than exercise or aspirin, ginkgo generally is less costly than pentoxifylline or cilostazol. (See Table 2.)
| Table 2 | ||
| Approximate costs of medical therapies used for intermittent claudication | ||
| Therapy | Dose | Cost per Day |
| Ginkgo biloba | 120 mg | $0.36-0.84 |
| Aspirin | 325 mg qd | $0.08 |
| Pentoxifylline (generic) | 400 mg tid | $1.87 |
| Cilostazol | 100 mg bid | $3.83 |
| Source: Pharmacy and on-line mail-order firms | ||
The formulation most commonly used in the United States and in many clinical trials is EGb 761. As with any herbal supplement, there may be batch-to-batch variation in product, although most manufacturers standardize their extract to 24% ginkgo flavone glycosides and 6% terpene lactones.
Conclusion
At this time, there is tentative evidence to suggest that Ginkgo biloba may be a useful adjunct to exercise and lifestyle modification in the treatment of mild-to-moderate IC. Data are lacking about its efficacy compared to other commonly used therapies and about the safety of long-term use. Further randomized, controlled studies are needed to evaluate its effectiveness and how it may compare with other lifestyle and pharmacologic therapies for peripheral vascular disease.
Recommendation
Patients who are interested in using Ginkgo biloba should consider using the standardized extract, EGb 761. Because of potential for bleeding, patients should avoid taking ginkgo in combination with anticoagulants, antiplatelet agents, nonsteroidal anti-inflammatory drugs, and herbs that increase bleeding risk. Like other antiplatelet agents, it should be discontinued prior to surgical procedures. Until larger studies are available, coadministration with MAO inhibitors also should be avoided. At this time, the use of Ginkgo biloba for IC should be combined with other effective therapeutic modalities such as exercise and smoking cessation.
Dr. Stoltz is Instructor of Medicine, Division of General Internal Medicine, Presbyterian Medical Center, University of Pennsylvania Health System in Philadelphia.
References
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August 2001; Volume 4; 85-89
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