GINKGO: Ginkgo biloba

GINKGO: Ginkgo biloba

Historical Overview

Once common in North America and Europe, ginkgo became extinct over much of its range during the Ice Age, though surviving in China. Three hundred years ago, Englebert Kaempfer, a German surgeon employed by the Dutch East India Company, was the first Westerner to observe and describe the tree. He called it "ginkgo," an eighteenth century phonetic pronunciation of a Japanese name. In 1771, Linnaeus gave it the binomial Ginkgo biloba. The tree was introduced to North America in 1784 in the garden of William Hamilton at Woodlands near Philadelphia (Li, 1956). Ginkgo is widely grown as an ornamental under adverse conditions such as inner city environs.

Over the past 20 years ginkgo has become an increasingly well-known medicinal plant worldwide. Its complex and unique chemistry gives it remarkable resistance to pests and disease, tolerance to adversity, and a storehouse of biologically active compounds. Ginkgo leaf extract, standardized to percentages of the known active constituents, is now among the best-selling phytomedicine in Europe.

The leaves, known as Bai-guo-ye in Traditional Chinese Medicine, have been used for"benefiting the brain," as an astringent to the lungs, to relieve symptoms of asthma and cough, and in the treatment of filariasis (a chronic disease caused by a parasitic nematode) in doses of 4.5-9 g (Yueh, 1987). While mention of the tree itself came much earlier in Chinese literature, ginkgo leaf is first mentioned in Lan Mao's Dian Nan Ben Cao (Pharmaceutical Natural History of Southern Yunnan), published in 1436 during the Ming dynasty. Lan Mao notes external use to treat skin and head sores as well as freckles. Internal use of the leaves is first noted in Liu Wen-Tai's Ben Cao Pin Hui Jing Yao (Essentials of the Pharmacopoeia Ranked According to Nature and Efficacy), an imperial commissioned work recorded in 1505. Liu Wen Tai notes use of the leaves in the treatment of diarrhea (Leung, 1990). Clinical experience in modern China has focused on using tablets or injectable drug forms in the treatment of angina pectoris, chronic bronchitis, and its effect on lowering serum cholesterol levels (Yueh, 1989). An infusion of the boiled leaves is still used in the treatment of frostbite (Michel and Hosford, 1988).

Modern Use

Today ginkgo leaf extracts manufactured in Europe and Asia are used for a wide variety of conditions. Clinical use focuses on the treatment of poor circulation, heart disease, eye disease, ringing in the ear (tinnitus), chronic cerebral insufficiency, accidents involving brain trauma, dementia, and various conditions associated with senility (Drieu, 1985; Warburton, 1988).

Preparations currently available on the world market include dried leaf, tinctures, homeopathic preparations, and various extracts. The leaves are a rich complex of chemical structures. Active constituents include bioflavonoids such as the flavonoid glycosides kaempferol, quercetin, and isorhamnetin; flavones; and organic acids. Novel diterpene lactones, unique to ginkgo, are currently the focus of intensive pharmacological and clinical research. These include the ginkgolides (A, B, C, and M) and bilobalide, a sesquiterpene (Boralle, Braquet, and Gottlieb, 1988).

According to Drieu (1985), the total extract from Ginkgo biloba is active, while single isolated components do not provide the activity of the total extract. This suggests a pharmacological synergism of components rather than a single biologically active compound. As far as we can ascertain, virtually all of the nearly 250 pharmacological and clinical studies published in the last 15 years have involved a specific standardized extract developed and researched in Germany. It is subject to a complex extraction process and standardized to 24 percent flavone glycosides, as well as being further calibrated for, among other constituents, ginkgolides and bilobalide. This specific extract is produced by a German/French consortium (Drieu, 1985, 1988).

The standardized extract of the leaves is beneficial in a broad range of physiological dysfunctions and pathological conditions, including those involved with circulation, blood conditions, metabolism, and immune function (Michel and Hosford, 1988). Pharmacological effects of the extract include free-radical scavenging properties as effective as uric acid, plus the ability to inactivate the formation of radicals not affected by uric acid. The extract inhibits lipid peroxidation of membranes, helping to maintain integrity and permeability of cell walls (Pincemail and Deby, 1988). Chatterjee (1985) reviewed studies showing that the ginkgo extract has vascular-tone regulating properties, an anti-hypoxic effect (hypoxia -- lack of a sufficient supply of oxygen) and experimental inhibitory activity in cerebral edema and neurotoxicity, and also helps to modulate cerebral energy metabolism. In clinical practice the extract has a protective, curative, and modulating effect against a wide spectrum of pathological processes.

Numerous pharmacological and clinical studies of ginkgo leaf extract have demonstrated a positive effect in increasing vasodilation and peripheral blood flow rate in capillary vessels and end-arteries in various circulatory disorders, Reynaud's disease, varicose conditions, post-thrombotic syndrome (Weiss, 1988; Liberti, 1988), chronic cerebral vascular insufficiency (Vorberg, 1985), short-term memory improvement (Hindmarch, 1988), cognitive disorders secondary to depression, dementia (Warburton, 1988), tinnitus (Meyer, 1988), vertigo (Claussen, 1988), obliterative arterial disease of the lower limbs (Bauer, 1984), a protective effect against hypoxia in normal healthy males (Schaffler and Reeh, 1985), and other conditions.

The Ginkgolides

In addition to looking further into specific aspects of Ginkgo Biloba Extract (GBE) itself, future ginkgo research will undoubtedly focus on investigating the activity of individual chemical components, such as the ginkgolides. The ginkgolides, bitter diterpene principles of the leaves and roots, were first isolated in 1932 by Furukawa. The chemical structure of ginkgolides was elucidated and named by Japanese researchers Nakanishi et al. in 1966 (Nakanishi, 1988). They are extremely complex molecules unique to ginkgo and derive from one the most intricate natural molecular frameworks. Using a highly complex multistep procedure, E. Corey et al. (1988), chemists at Harvard University, recently succeeded in completely synthesizing Ginkgolide B (Boralle, Braquet, and Gottlieb, 1988).

The various ginkgolides have different degrees of potency. Ginkgolide B is considered the most active. They are very selective antagonists of platelet aggregation induced by platelet-activating factor (PAF), an inflammatory autacoid. Autacoids, generally synthesized in local tissue sites, mediate local types of tissue response, such as pain perception, blood coagulation, and smooth muscle contraction. PAF is involved in various inflammatory, cardiovascular, and respiratory disorders. The ginkgolides modulate various enzyme systems and ion pumps, all serving to help explain their broad-spectrum therapeutic potential (Michel and Hosford, 1988). Ginkgolides counteract the effects of PAF in human and rabbit blood platelets, both in vitro and ex vivo (Braquet, 1985).

The use of PAF receptor antagonists, such as the ginkgolides, has recently raised hope that they may be used in a wide variety of human diseases. The use of ginkgo leaves for human disease, now known to be affected by PAF antagonists, has a long history. The specific extract of ginkgo leaf has been extensively studied and used for many years in West Germany and France for the treatment of cerebral and peripheral vascular disease. Only rare association of minor and reversible side effects have been observed. Further studies of the ginkgolides in other disease conditions are warranted, given the potential broad role of PAF receptor antagonists (Chung and Barnes, 1988). The ginkgolides should be considered pharmacologically and clinically distinct from GBE. Pure ginkgolides are currently available only to a handful of researchers.

Clinical Studies

Clinical studies indicate use of the well-defined standardized extract in the treatment of common conditions of elderly populations, including dizziness, depression, ringing in the ears (tinnitus), vasoconstriction, short-term memory loss, prevention and treatment of various stages of dementias, improvement in peripheral and cerebral blood flow, a protective effect on the blood-brain barrier, and an anti-radical effect (Braquet, 1988; Weiss, 1988; Liberti, 1988).

Hindmarch (1988) reported on the effects of oral administration of the standardized Ginkgo biloba extract (GBE) on the short term memory of healthy young volunteers (ages 25-40 years). In a double-blind cross-over trial, Hindmarch found that, one hour following a single oral 600 mg dose of GBE, short-term memory parameters were significantly improved compared with controls. According to Hindmarch, the battery of tests indicates a specific activity on central cognitive processes and he proposes the use of GBE in cases and conditions where memory problems are a feature.

Warburton (1988) reviews the results of 20 clinical studies, including two double-blind crossover studies, nine double-blind studies, eight open studies, and one open-multicenter study. The dose used in most of the studies was 120 mg extract GBE per day. A number of studies used 160 mg per day and, in some cases, doses up to 360 mg were administered. Overall, however, Warburton sees no advantage in using doses of 160 mg per day in long-term applications. Estimates of overall efficacy ranged from 44 to 92 percent. He concludes that many categories of elderly patients could benefit from GBE. As well as supporting frequent use in patients suffering from vascular disorders, Warburton considers the data also show that GBE should be useful in dementias generally, including cerebral impairment of organic etiology, and in patients with decreased intellectual function associated with depressed states, given the positive effect of GBE on mood. Warburton also believes that these preparations should be used at the onset of symptoms associated with cerebral deficits, so that patients could lead normal lives, avoiding hospitalization.

Warburton's review indicates GBE was devoid of toxic side effects, except for minor reversible gastric disturbances. In addition to the studies reviewed, he also cites one exhaustive analysis involving 2,855 patients. This reported a higher incidence of mild gastric disturbances (still only 3.7 percent). Other very rare side effects included headache, dizziness, and vertigo, which, as Warburton states, seems paradoxical, "in view of the high level of success of EGb [GBE] in this type of symptom."

More recently, in a multicenter study involving 8,505 patients observed over 6 months, Stalleicken and Ihm (1989) reported the total incidence of adverse effects to be 0.4 percent. These were all of a minor nature and reversible. Gastric upsets were again the most common at 0.1 percent. All of these analyses and studies were done using the German extract described above. Given such data, as well as a long history of use, plus the results of all other studies of the last 15 years, safety seems well established.

A recent retrospective critical review analyzed the quality and methodology of 40 clinical trials (published since 1975) on the use of ginkgo extracts in cerebral insufficiency. The outcome of the trials (all of which reported positive results) were interpreted in relation to their quality. Clinical trials reporting results in healthy volunteers were excluded. For most of the studies the dosage was 120 mg/day of the ginkgo extract (given for at least 4-6 weeks). Of the 40 studies, eight were deemed well-performed. The authors concluded that the results of the evaluation of these ginkgo studies were consistent with the quality of scientific research on a conventional pharmaceutical drug. The authors of this review noted that they both might try ginkgo for symptoms for which the extracts are indicated, given that no clear side effects are reported. However, they stress the need for additional trials, in which double-blindness is checked, a larger number of patients are involved, with better descriptions of randomization procedures, patient characteristics, and more effective measurement of data (Kleijnen and Knipschild, 1992). For additional recent comprehensive reviews on all aspects of ginkgo see Defeudis (1991), and Huh and Staba (1992).

Summary

In summary, Ginkgo biloba, termed a living fossil, has survived for 200 million years. Its longevity can be attributed to its adaptability and resistance to disease which result in part from its complex and unique biochemical products. The leaves, whose use was first recorded in Chinese herbals 500 years ago, have historically been used in China to improve brain function, treat bronchitis, and other ailments. Modern science provides a rational scientific basis for traditional uses of the leaves. Given its long history of safe use as a healthful beverage tea in Asia, and the extensive clinical experience in Europe in the last two decades, this valuable plant-derived product will undoubtedly become more widely known and used in the U.S.

References

Agnoli, A., J. R. Rapin, V. Scapagnini, and W. V. Weitbrecht (eds.). 1985. Effects of Ginkgo Biloba Extract on Organic Cerebral Impairment. London: John Libbey Eurotext, Ltd.

Bauer, U. 1984. Six-month Double-blind Randomized Clinical Trial of Ginkgo Biloba Extracts Versus Placebo in Two Parallel Groups in Patients Suffering from Peripheral Arterial Insufficiency. Arzneim-Forsch. 34: 716-721.

Boralle, N., P. Braquet and O. R. Gottlieb. 1988. Chemical Composition of Ginkgo. In P. Braquet (ed.) 1988. Op. cit. Pp. 9-25.

Braquet, P. 1985. BN 52021 and related compounds: A new series of highly specific PAF-Acether receptor antagonists isolated from Ginkgo biloba. Blood Vessels. 16: 559-572.

Braquet, P. (ed.) 1988. Ginkgolides -- Chemistry, Biology, Pharmacology and Clinical Perspectives. Vol. I. Barcelona, Spain: J. R. Prous.

Chatterjee, S.S. 1985. Effects of Ginkgo Biloba Extract on Cerebral Metabolic Processes. In A. Agnoli, J. R. Rapin, V. Scapagnini, and W. V. Weitbrecht (eds.) 1985. Op. cit. Pp. 5-15.

Chung, K.F. and P.J. Barnes. 1988. Clinical Perspectives of PAF-Acether Antagonists. In P. Braquet (ed.) 1988. Op. cit. Pp. 333-344.

Claussen, C. F. 1988. Diagnostic and Practical Value of Craniocopography in Vertiginous Syndromes. In E. W. Fünfgeld (ed.) 1988. Op. cit. pp. 251-259.

Cory, E. J., M. C. Kang, M. C. Desai, A. K. Ghosh, and I. N. Houpis. 1988. Total Synthesis of Ginkgolide B. J. Am. Chem. Soc. 110: 649-651.

DeFeudis, F. V. 1991. Ginkgo biloba Extract (EGb 761): Pharmacological Activities and Clinical Applications. Amsterdam: Elsevier.

Drieu, K. 1985. Multiplicity of effects of Ginkgo Biloba Extract: Current status and new trends. In A. Agnoli, J.R. Rapin, V. Scapagnini, and W. V. Weitbrecht (eds.). Op. cit. Pp. 63-68.

Drieu, K. 1988. Preparation and Definition of Ginkgo Biloba Extract. In E. W. Fünfgeld (ed.) 1988. Op. cit. pp. 32-36.

Fünfgeld, E. W. (ed.) 1988. Rökan (Ginkgo biloba), Recent Results in Pharmacology, and Clinic. Berlin: Springer-Verlag.

Hindmarch, I. 1988. Activity of Ginkgo Biloba Extract on Short-term Memory. In E. W. Fünfgeld (ed.) 1988. Op. cit. Pp. 321-326.

Huh, H. and E. J. Staba. 1992. The Botany and Chemistry of Ginkgo biloba L. Journal of Herbs, Spices & Medicinal Plants. 1(1/2):91-124.

Kleijnen, J. and P. Knipschild. 1992. Ginkgo biloba for cerebral insufficiency. Br. J. Clin. Pharmac. 34:352-358.

Leung, A. 1990. Personal communication, Feb. 13.

Li, H. L. 1956. A Horticultural and Botanical History of Ginkgo. Morris Arb. Bull. 7:3-12.

Liberti, L. (ed.) 1988. Ginkgo. The Lawrence Review of Natural Products. Feb. 1988.

Meyer, B. 1988. A Multicenter Randomized Double-Blind Study of Ginkgo Biloba Extract Versus Placebo in the Treatment of Tinnitus. In E. W. Fünfgeld (ed.) 1988. Op. cit. Pp. 245-250.

Michel, P. F. and D. Hosford. 1988. Ginkgo Biloba: From "Living Fossil" to Modern Therapeutic Agent. In P. Braquet (ed.) 1988. Op. cit. pp. 1-8.

Nakanishi, K. 1988. Ginkgolides - Isolation and Structural Studies Carded out in the Mid-1960s. In P. Braquet (ed.) 1988. Op. cit. pp. 27-36.

Pincemail, J. and C. Deby. 1988. The Antiradical Properties of Ginkgo Biloba Extract. In E. W. Fünfgeld (ed.) 1988. Op. cit. pp. 71-82.

Schaffler, V. K. and P. W. Reeh. 1985. Double-blind Study of the Hypoxia-protective Effect of a Standardized Ginkgo Biloba Preparation after Repeated Administration in Healthy Volunteers. Arzneim-Forsch. 35: 1283-1286.

Stalleicken, D. and P. Ihm. 1989. Observation of the Course of Cognitive Deficits. Results of a Multicenter Study Involving Psychological Test Operations. Neurologie Psychiatrie. Special Issue 1: 64-69.

Vorberg, G. 1985. Ginkgo Biloba Extract (GBE): A Long-term Study of Chronic Cerebral Insufficiency in Geriatric Patients. Clinical Trials Journal 22:149-157.

Warburton, D. M. 1988. Clinical Psychopharmacology of Ginkgo Eiloba Extract. In E. W. Fünfgeld (ed.)1988. Op. cit. pp. 327-345.

Weiss, R. F. 1988. Herbal Medicine. Beaconsfield, England: Beaconsfield Publishers Ltd.

Yueh, C. H. 1987. Personal communication.

Yueh, C. H. 1989. Personal communication.

American Botanical Council.

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By Steven Foster

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