Ginkgo biloba: a living fossil

Abstract

In 1998, Americans spent about 4 billion dollars on botanical medicines (1Brody JE, Americans gamble on herbs as medicines. The New York Times. 1999:D1.Google Scholar, 2Canedy D. Real medicine or medicine show? Growth of herbal sales raises issues about value. The New York Times. 1998:D1–D4.Google Scholar) and Ginkgo biloba ranked first among herbal medications sold in health food stores (3Brevoort P. The booming US botanical market—a new overview.Herbalgram. 1998; 44: 33-46Google Scholar). Ginkgo biloba, whose medicinal uses were described in the Chinese Materia Medica more than 2,000 years ago, is used most frequently to treat memory and cognitive impairment, for which it has moderate efficacy with minimal side effects (4Hofferberth B. The efficacy of EGb 761 in patients with senile dementia of the Alzheimer type a double-blind, placebo-controlled study on different levels of investigation.Human Psychopharmacol. 1994; 9: 215-222Crossref Scopus (137) Google Scholar, 5Kanowski S. Hermann W.M. Stephan K. et al.Proof of efficacy of the Ginkgo biloba special extract EGb 761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multi-infarct dementia.Pharmacopsychiatry. 1996; 29: 47-56Crossref PubMed Scopus (371) Google Scholar, 6Kleijnen J. Knipschild P. Ginkgo biloba for cerebral insufficiency.Br J Clinl Pharmacol. 1992; 34: 352-358Crossref PubMed Scopus (323) Google Scholar, 7Kleijnen J. Knipschild P. Ginkgo biloba.Lancet. 1992; 340: 1136-1139Abstract PubMed Scopus (552) Google Scholar, 8Le Bars P.L. Katz M.M. Berman N. et al.A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia.JAMA. 1997; 271: 985-991Google Scholar, 9Oken B.S. Storzbach D.M. Kaye J.A. The efficacy of Ginkgo biloba on cognitive function in Alzheimer disease.Arch Neurol. 1998; 55: 1409-1415Crossref PubMed Scopus (548) Google Scholar). Some patients also use ginkgo to treat symptoms of claudication, a condition for which the German Federal Health Agency considers it to be effective (10Fetrow C, Avila J. Professional’s Handbook of Complementary and Alternative Medicines. 1999, Springhouse. 281.Google Scholar).Ginkgo biloba comes from the leaves of the ginkgo tree, one of the oldest living plant species. Dating back more than 200 million years, it is often referred to as “a living fossil.” Because its leaves resemble the maidenhair fern, it is also known as the maidenhair tree. Unrelated to any other living plant species, it grows throughout China, Korea, Japan, Europe, and the United States. Ginkgo trees can be up to 100 feet tall, 50 feet in circumference, and can live for as long as 1000 years. After the nuclear bomb was detonated in Hiroshima, they were the first plants to re-grow and were free of signs of genetic mutation. Partly because of their hardiness, the trees are frequently planted in large cities such as New York and Tokyo.The ginkgo leaf contains many active ingredients, including flavonol and flavone glycosides, diterpene lactones, ginkgolides, sesquiterpenes, iron-based superoxide dismutase, p-hydroxybenzoic acid, ascorbic acid, and catechin. The crude drug formulation of ginkgo is obtained from the dried green leaves. An acetone-water mixture is used to extract and concentrate the active constituents and remove toxic compounds such as ginkgolic acids. The German government has approved a standardized form of ginkgo leaf extract (Egb761) which contains 22% to 27% flavonoid glycosides, 5% to 7% terpene lactones, and < 5 parts per million of ginkgolic acids. The flavonoid glycosides are considered to be a major active ingredient in the extract, and manufacturers commonly standardize their product to a flavonoid glycosides content of 24%. Ginkgolic acids are potentially allergenic and toxic; they share similar properties to the urushiols that are found in mango rind, cashew nut shells, and the sumac-poison ivy family.How might this living fossil help patients with dementia or peripheral arterial disease? A common pathway for both diseases may be improved tissue perfusion and increased tolerance of hypoxia. The flavonoid glycosides seem to have antioxidant activity, and they may reduce endothelial cell injury due to free radical oxidation, thereby reducing the progression of atherosclerosis (11Rong Y. Geng Z. Lau B. Ginkgo biloba attenuates oxidative stress in macrophages and endothelial cells.Free Rad Biol Med. 1995; 20: 121-127Crossref Scopus (81) Google Scholar, 12Marcocci L. Packer L. Droy-Lefaix M.T. et al.Antioxidant action of Ginkgo biloba extract EGb 761.Methods Enzymol. 1994; 234: 462-475Crossref PubMed Scopus (454) Google Scholar). Flavonoids may also protect hypoxic tissue. In the early phases of brain ischemia, massive release of free fatty acids and the accumulation of platelet activating factor result in the production of free radicals that are extremely neurotoxic. Ginkgolide B, a terpene, is a platelet-activating factor antagonist and may provide some of the neuroprotective and antithrombotic properties attributed to ginkgo (13Beek T.A. Morazzoni E.B. Peterlongo F. Ginkgo biloba.Fitoterapia. 1998; 3: 195-244Google Scholar, 14Reuter H.D. Ginkgo biloba-botany, constituents, pharmacology, and clinical trials.Br J Phytotherapy. 1996; 4: 3-20Google Scholar, 15Koltai M. Platelet activating factor. A review of its effects, antagonists and possible future clinical implications (Part II).Drugs. 1991; 42: 174-204Crossref PubMed Scopus (107) Google Scholar). Additional suggested mechanisms include reduced capillary fragility and decreased erythrocyte aggregation activity (13Beek T.A. Morazzoni E.B. Peterlongo F. Ginkgo biloba.Fitoterapia. 1998; 3: 195-244Google Scholar, 16Ernst E. Matrai A. Hamorheologische in-vitro Effekte von Ginkgo biloba.Herz Kreislauf. 1986; 18: 350-360Google Scholar). Finally, the flavonoid glycosides and ginkgolide B may inhibit other events, which include platelet aggregation, platelet adherence, and oxidized lipoprotein formation, that lead to atherosclerosis and vascular injury.In this issue of The Green Journal, Pittler and Ernst report the results of their meta-analysis of the use of Ginkgo bilobaextract for patients with intermittent claudication (17Pittler M.H. Ernst E. The efficacy of Ginkgo biloba extract for intermittent claudication. A meta-analysis of randomized clinical trials.Am J Med. 2000; 108: 276-281Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar). Peripheral arterial disease affects about 1 in 8 elderly patients (18Criqui M.H. Fronek A. Barrett-Connor E. et al.The prevalence of peripheral arterial disease in a defined population.Circulation. 1985; 71: 510-515Crossref PubMed Scopus (944) Google Scholar), although not all have intermittent claudication (19Fowkes F.G.R. Epidemiology of atherosclerotic arterial disease in the lower limbs.Eur J Vasc Surg. 1988; 2: 283-291Abstract Full Text PDF PubMed Scopus (132) Google Scholar). While the majority of nondiabetic patients with this condition remain stable, approximately 10% to 15% have progressive disease, and some require amputation. Therapeutic interventions are targeted at reducing cardiovascular risk factors, especially tobacco smoking, and promoting regular exercise with the goal of increasing exercise tolerance. Pharmacologic treatment has been less successful; in particular, vasodilators have not proven effective. Current options approved by the Food and Drug Administration (FDA) include pentoxifylline and cilostazol.It can be difficult to determine the efficacy of therapies for intermittent claudication. Proper evaluation requires using objective measures such as exercise performance and hemodynamic measurements, as well as subjective measures that include questions about walking impairment, physical activity, and general health status (20Hiatt W.R. Hirsch A.T. Regensteiner J.G. Brass E.P. Clinical trials for claudication assessment of exercise performance, functional status, and clinical end points.Circulation. 1995; 92: 614-621Crossref PubMed Scopus (254) Google Scholar). In the meta-analysis reported in this issue of The Green Journal, Pittler and Ernst used pain-free and maximal walking distance as their primary outcomes. There is controversy about which of these two measurements provides a better assessment of clinical status. Recently, Muller-Beuhl and colleagues evaluated a cohort of 150 patients to determine which of these two parameters was more closely associated with angiographic findings and functional status. They found no correlation between either parameter and angiographic findings. However, maximal walking distance was the best predictor of overall functional status (21Muller-Buhl U. Kirchberger I. Wiesemann A. Relevance of caludication pain distance in patients with peripheral arterial occlusive disease.Vasa. 1999; 28: 25-29Crossref PubMed Scopus (27) Google Scholar). Pittler and Ernst identified studies that used constant-load exercise testing. However, there is substantial within-subject and between-subject variation in this test, and performance improves with repetitive testing. A graded treadmill test, such as the Bruce protocol, appears to give more useful results (22Gardner A.W. Skinner J.S. Cantwell B.W. Smith L.K. Progressive versus single-stage treadmill tests for evaluation of claudication.Med Sci Sports Exercise. 1991; 23: 402-408Crossref PubMed Scopus (430) Google Scholar). Results from constant and graded treadmill testing, therefore, are not comparable and should be evaluated separately (20Hiatt W.R. Hirsch A.T. Regensteiner J.G. Brass E.P. Clinical trials for claudication assessment of exercise performance, functional status, and clinical end points.Circulation. 1995; 92: 614-621Crossref PubMed Scopus (254) Google Scholar).How can the main findings of this meta-analysis—that Ginkgo biloba improved pain-free walking by 34 meters when compared with placebo—be applied in practice? Although ginkgo was well tolerated and less expensive than the two FDA-approved drugs, clinicians will remain reluctant to recommend this herbal medicine to their patients. Why? First, as the authors point out, the effect was modest, especially as compared with exercise programs. Second, clinicians prefer to use products that have only one active ingredient and better-defined mechanisms of action. In addition, with the passing of the 1994 Dietary Supplement Health and Education Act, herbal products are not required to undergo screening by the FDA for safety, effectiveness, or product quality. This act permits manufacturers to claim that their products enhance “normal structure and function,” without submitting evidence to the FDA or any other regulatory body. Therefore, unlike regulated drugs, the burden of proof rests with the FDA to disprove health claims made by the manufacturers. For the pharmaceutical-herbal companies, this permits direct access to consumers. Companies also save about $500 million and 17 years on research and development for each product. However, unregulated sale of these products may result in exposure to heavy-metal toxicity, adulterants, variable dosing, and even incorrect herb identification (23Ernst E. Harmless herbs? A review of the recent literature.Am J Med. 1998; 104: 170-178Abstract Full Text Full Text PDF PubMed Scopus (525) Google Scholar, 24Foundation HR. Herb Safety Report. Herb Research Foundation: Boulder, CO. 1997:1–18.Google Scholar, 25De Smet P. The safety of herbal products. Essentials of Complementary and Alternative Medicine. Jonas W and Levin J, eds. New York: Lippincott Williams and Wilkins. 1999:108–136.Google Scholar).It is no wonder that clinicians are reluctant to recommend herbal products. Even when an herbal medication is shown to be safe and effective in clinical trials, there is no guarantee that the over-the-counter formulations will be comparable. Herbal products should be regulated for safety and product quality so that clinicians who wish to prescribe them will be able to apply the results of research without fear of doing harm to patients. In 1998, Americans spent about 4 billion dollars on botanical medicines (1Brody JE, Americans gamble on herbs as medicines. The New York Times. 1999:D1.Google Scholar, 2Canedy D. Real medicine or medicine show? Growth of herbal sales raises issues about value. The New York Times. 1998:D1–D4.Google Scholar) and Ginkgo biloba ranked first among herbal medications sold in health food stores (3Brevoort P. The booming US botanical market—a new overview.Herbalgram. 1998; 44: 33-46Google Scholar). Ginkgo biloba, whose medicinal uses were described in the Chinese Materia Medica more than 2,000 years ago, is used most frequently to treat memory and cognitive impairment, for which it has moderate efficacy with minimal side effects (4Hofferberth B. The efficacy of EGb 761 in patients with senile dementia of the Alzheimer type a double-blind, placebo-controlled study on different levels of investigation.Human Psychopharmacol. 1994; 9: 215-222Crossref Scopus (137) Google Scholar, 5Kanowski S. Hermann W.M. Stephan K. et al.Proof of efficacy of the Ginkgo biloba special extract EGb 761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multi-infarct dementia.Pharmacopsychiatry. 1996; 29: 47-56Crossref PubMed Scopus (371) Google Scholar, 6Kleijnen J. Knipschild P. Ginkgo biloba for cerebral insufficiency.Br J Clinl Pharmacol. 1992; 34: 352-358Crossref PubMed Scopus (323) Google Scholar, 7Kleijnen J. Knipschild P. Ginkgo biloba.Lancet. 1992; 340: 1136-1139Abstract PubMed Scopus (552) Google Scholar, 8Le Bars P.L. Katz M.M. Berman N. et al.A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia.JAMA. 1997; 271: 985-991Google Scholar, 9Oken B.S. Storzbach D.M. Kaye J.A. The efficacy of Ginkgo biloba on cognitive function in Alzheimer disease.Arch Neurol. 1998; 55: 1409-1415Crossref PubMed Scopus (548) Google Scholar). Some patients also use ginkgo to treat symptoms of claudication, a condition for which the German Federal Health Agency considers it to be effective (10Fetrow C, Avila J. Professional’s Handbook of Complementary and Alternative Medicines. 1999, Springhouse. 281.Google Scholar). Ginkgo biloba comes from the leaves of the ginkgo tree, one of the oldest living plant species. Dating back more than 200 million years, it is often referred to as “a living fossil.” Because its leaves resemble the maidenhair fern, it is also known as the maidenhair tree. Unrelated to any other living plant species, it grows throughout China, Korea, Japan, Europe, and the United States. Ginkgo trees can be up to 100 feet tall, 50 feet in circumference, and can live for as long as 1000 years. After the nuclear bomb was detonated in Hiroshima, they were the first plants to re-grow and were free of signs of genetic mutation. Partly because of their hardiness, the trees are frequently planted in large cities such as New York and Tokyo. The ginkgo leaf contains many active ingredients, including flavonol and flavone glycosides, diterpene lactones, ginkgolides, sesquiterpenes, iron-based superoxide dismutase, p-hydroxybenzoic acid, ascorbic acid, and catechin. The crude drug formulation of ginkgo is obtained from the dried green leaves. An acetone-water mixture is used to extract and concentrate the active constituents and remove toxic compounds such as ginkgolic acids. The German government has approved a standardized form of ginkgo leaf extract (Egb761) which contains 22% to 27% flavonoid glycosides, 5% to 7% terpene lactones, and < 5 parts per million of ginkgolic acids. The flavonoid glycosides are considered to be a major active ingredient in the extract, and manufacturers commonly standardize their product to a flavonoid glycosides content of 24%. Ginkgolic acids are potentially allergenic and toxic; they share similar properties to the urushiols that are found in mango rind, cashew nut shells, and the sumac-poison ivy family. How might this living fossil help patients with dementia or peripheral arterial disease? A common pathway for both diseases may be improved tissue perfusion and increased tolerance of hypoxia. The flavonoid glycosides seem to have antioxidant activity, and they may reduce endothelial cell injury due to free radical oxidation, thereby reducing the progression of atherosclerosis (11Rong Y. Geng Z. Lau B. Ginkgo biloba attenuates oxidative stress in macrophages and endothelial cells.Free Rad Biol Med. 1995; 20: 121-127Crossref Scopus (81) Google Scholar, 12Marcocci L. Packer L. Droy-Lefaix M.T. et al.Antioxidant action of Ginkgo biloba extract EGb 761.Methods Enzymol. 1994; 234: 462-475Crossref PubMed Scopus (454) Google Scholar). Flavonoids may also protect hypoxic tissue. In the early phases of brain ischemia, massive release of free fatty acids and the accumulation of platelet activating factor result in the production of free radicals that are extremely neurotoxic. Ginkgolide B, a terpene, is a platelet-activating factor antagonist and may provide some of the neuroprotective and antithrombotic properties attributed to ginkgo (13Beek T.A. Morazzoni E.B. Peterlongo F. Ginkgo biloba.Fitoterapia. 1998; 3: 195-244Google Scholar, 14Reuter H.D. Ginkgo biloba-botany, constituents, pharmacology, and clinical trials.Br J Phytotherapy. 1996; 4: 3-20Google Scholar, 15Koltai M. Platelet activating factor. A review of its effects, antagonists and possible future clinical implications (Part II).Drugs. 1991; 42: 174-204Crossref PubMed Scopus (107) Google Scholar). Additional suggested mechanisms include reduced capillary fragility and decreased erythrocyte aggregation activity (13Beek T.A. Morazzoni E.B. Peterlongo F. Ginkgo biloba.Fitoterapia. 1998; 3: 195-244Google Scholar, 16Ernst E. Matrai A. Hamorheologische in-vitro Effekte von Ginkgo biloba.Herz Kreislauf. 1986; 18: 350-360Google Scholar). Finally, the flavonoid glycosides and ginkgolide B may inhibit other events, which include platelet aggregation, platelet adherence, and oxidized lipoprotein formation, that lead to atherosclerosis and vascular injury. In this issue of The Green Journal, Pittler and Ernst report the results of their meta-analysis of the use of Ginkgo bilobaextract for patients with intermittent claudication (17Pittler M.H. Ernst E. The efficacy of Ginkgo biloba extract for intermittent claudication. A meta-analysis of randomized clinical trials.Am J Med. 2000; 108: 276-281Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar). Peripheral arterial disease affects about 1 in 8 elderly patients (18Criqui M.H. Fronek A. Barrett-Connor E. et al.The prevalence of peripheral arterial disease in a defined population.Circulation. 1985; 71: 510-515Crossref PubMed Scopus (944) Google Scholar), although not all have intermittent claudication (19Fowkes F.G.R. Epidemiology of atherosclerotic arterial disease in the lower limbs.Eur J Vasc Surg. 1988; 2: 283-291Abstract Full Text PDF PubMed Scopus (132) Google Scholar). While the majority of nondiabetic patients with this condition remain stable, approximately 10% to 15% have progressive disease, and some require amputation. Therapeutic interventions are targeted at reducing cardiovascular risk factors, especially tobacco smoking, and promoting regular exercise with the goal of increasing exercise tolerance. Pharmacologic treatment has been less successful; in particular, vasodilators have not proven effective. Current options approved by the Food and Drug Administration (FDA) include pentoxifylline and cilostazol. It can be difficult to determine the efficacy of therapies for intermittent claudication. Proper evaluation requires using objective measures such as exercise performance and hemodynamic measurements, as well as subjective measures that include questions about walking impairment, physical activity, and general health status (20Hiatt W.R. Hirsch A.T. Regensteiner J.G. Brass E.P. Clinical trials for claudication assessment of exercise performance, functional status, and clinical end points.Circulation. 1995; 92: 614-621Crossref PubMed Scopus (254) Google Scholar). In the meta-analysis reported in this issue of The Green Journal, Pittler and Ernst used pain-free and maximal walking distance as their primary outcomes. There is controversy about which of these two measurements provides a better assessment of clinical status. Recently, Muller-Beuhl and colleagues evaluated a cohort of 150 patients to determine which of these two parameters was more closely associated with angiographic findings and functional status. They found no correlation between either parameter and angiographic findings. However, maximal walking distance was the best predictor of overall functional status (21Muller-Buhl U. Kirchberger I. Wiesemann A. Relevance of caludication pain distance in patients with peripheral arterial occlusive disease.Vasa. 1999; 28: 25-29Crossref PubMed Scopus (27) Google Scholar). Pittler and Ernst identified studies that used constant-load exercise testing. However, there is substantial within-subject and between-subject variation in this test, and performance improves with repetitive testing. A graded treadmill test, such as the Bruce protocol, appears to give more useful results (22Gardner A.W. Skinner J.S. Cantwell B.W. Smith L.K. Progressive versus single-stage treadmill tests for evaluation of claudication.Med Sci Sports Exercise. 1991; 23: 402-408Crossref PubMed Scopus (430) Google Scholar). Results from constant and graded treadmill testing, therefore, are not comparable and should be evaluated separately (20Hiatt W.R. Hirsch A.T. Regensteiner J.G. Brass E.P. Clinical trials for claudication assessment of exercise performance, functional status, and clinical end points.Circulation. 1995; 92: 614-621Crossref PubMed Scopus (254) Google Scholar). How can the main findings of this meta-analysis—that Ginkgo biloba improved pain-free walking by 34 meters when compared with placebo—be applied in practice? Although ginkgo was well tolerated and less expensive than the two FDA-approved drugs, clinicians will remain reluctant to recommend this herbal medicine to their patients. Why? First, as the authors point out, the effect was modest, especially as compared with exercise programs. Second, clinicians prefer to use products that have only one active ingredient and better-defined mechanisms of action. In addition, with the passing of the 1994 Dietary Supplement Health and Education Act, herbal products are not required to undergo screening by the FDA for safety, effectiveness, or product quality. This act permits manufacturers to claim that their products enhance “normal structure and function,” without submitting evidence to the FDA or any other regulatory body. Therefore, unlike regulated drugs, the burden of proof rests with the FDA to disprove health claims made by the manufacturers. For the pharmaceutical-herbal companies, this permits direct access to consumers. Companies also save about $500 million and 17 years on research and development for each product. However, unregulated sale of these products may result in exposure to heavy-metal toxicity, adulterants, variable dosing, and even incorrect herb identification (23Ernst E. Harmless herbs? A review of the recent literature.Am J Med. 1998; 104: 170-178Abstract Full Text Full Text PDF PubMed Scopus (525) Google Scholar, 24Foundation HR. Herb Safety Report. Herb Research Foundation: Boulder, CO. 1997:1–18.Google Scholar, 25De Smet P. The safety of herbal products. Essentials of Complementary and Alternative Medicine. Jonas W and Levin J, eds. New York: Lippincott Williams and Wilkins. 1999:108–136.Google Scholar). It is no wonder that clinicians are reluctant to recommend herbal products. Even when an herbal medication is shown to be safe and effective in clinical trials, there is no guarantee that the over-the-counter formulations will be comparable. Herbal products should be regulated for safety and product quality so that clinicians who wish to prescribe them will be able to apply the results of research without fear of doing harm to patients.