GBE:Ginkgo Biloba P.E.Flavone4143724% Lactone414376%HPLC Description
Ginkgo Biloba P.E. No.030.Flavone4143724% Lactone414376%HPLCNo.031.Type141914Ginkgo Acid <1ppm
No.032.Type241914Ginkgo Acid <5ppm
No.033.Type341914Ginkgo Acid <10ppm
Ginkgo biloba extract (GBE) and two ingredients, bilobalide and ginkgolide B, are presented to the CSWG as part of a review of botanicals being used as dietary supplements in the United States. Herbal products represent the fastest growing segment of the vitamin, mineral supplements, and herbal products industry, an industry expected to top $6 billion in sales by 2001. GBE is an extremely popular herbal supplement; sales in 1996, the last year figures were available, exceeded $100 million.
Indications are that one in three adults in the United States are now taking dietary supplements. Sweeping deregulation of botanicals now permits GBE to be sold as a dietary supplement to a willing public eager to "improve brain functioning" or "promote radical scavenging activity."
GBE was selected for review for several reasons. First, GBE is a well defined product, and it or its active ingredients, the ginkgolides, especially ginkgolide B, and bilobalide, have clearly demonstrated biological activity. Second, GBE can be consumed in rather large doses for an extended period of time. Third, some ingredients in GBE are known mutagens; in one case, a suspected high dose carcinogen, quercetin, is intentionally concentrated from the ginkgo leaf to manufacture the final product.
Ginkgo biloba extract
SELECTION STATUS
ACTION BY CSWG: 4/28/98
Studies requested:
- Toxicological evaluation, including 90-day subchronic study
- Carcinogenicity
- Mechanistic studies
Priority: High
Rationale/Remarks:
- Potential for widespread exposure through use as a dietary supplement.
- Test extract standardized to 24% flavone glycosides and 6% terpene lactones.
- Mechanistic studies should explore the relative contribution of each active ingredient and the possible synergism among these ingredients.
Ginkgolide B
SELECTION STATUS
ACTION BY CSWG: 4/28/98
- Toxicological evaluation, including 90 day subchronic study
- Micronucleus assay
Priority: High (for comparison with GBE)/Moderate (for other tests)
Rationale/Remarks:
- Commercially available active component of GBE
- Unique chemical structure
- NCI will conduct - Ames Salmonella assay
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CHEMICAL IDENTIFICATION
Ginkgo biloba extract (GBE)
CAS Registry Number: None
Chemical Abstracts Service Name: None
Definition: Standardized, concentrated extract of ginkgo leaves containing 24% ginkgo flavone glycosides and 6% terpene lactones
Trade Names: Egb 761; Ginkgold; Kaveri; LI 1370; rökan; Tanakan; Tebonin;
Structural Class: Botanical; phytopharmaceutical
Standardized ingredients of GBE
Common Name: Quercetin
CAS Registry Number: 117-39-5
Chemical Abstracts Service Name: 4H-1-Benzopyran-4-one, 2-(3,4-dihydroxyphenyl)- 3,5,7-trihydroxy- (9CI)
Structure, Molecular Formula and Molecular Weight:
C15 H10 O7 Mol. wt.: 338.3
Common Name: Kaempferol
CAS Registry Number: 520-18-3
Chemical Abstracts Service Name: 4H-1-Benzopyran-4-one, 3,5,7-trihydroxy-2-(4- hydroxyphenyl)- (9CI)
Structure, Molecular Formula and Molecular Weight:
C15 H10 O6 Mol. wt.: 286.2
Common Name: Isorhamnetin
CAS Registry Number: 480-19-3
Chemical Abstracts Service Name: 4H-1-Benzopyran-4-one, 3,5,7-trihydroxy-2-(4- hydroxy-3-methoxyphenyl)- (9CI)
Structure, Molecular Formula and Molecular Weight:
C15 H12 O6 Mol. wt.: ~314
Common Name: Ginkgolides (mixed); ginkgolide A; ginkgolide B
CAS Registry Number: 15291-77-7; 15291-75-5; 15291-75-5
Chemical Abstracts Service Name: Not available
Structure, Molecular Formula and Molecular Weight:
C20 H24 O10 (Ginkgolide B) Mol. wt.: 424.4 (Ginkgolide B)
R1 R2 R3
Ginkgolide A OH H H
Ginkgolide B OH OH H
Ginkgolide C OH OH OH
Ginkgolide J OH H OH
Ginkgolide M H OH OH
Common Name: Bilobalide
CAS Registry Number: 33570-04-6
Chemical Abstracts Service Name: 4H,5aH,9H-Furo(2,3-b)furo(3',2':2,3)cyclopenta (1,2-c)furan-2,4,7(3H,8H)-trione, 9-(1,1-dimethylethyl)-10,10a-dihydro-8,9-dihydroxy-, (5aR-(3aS*,5aa,8b,8aS*,9a,10aa))- (9CI)
Structure, Molecular Formula and Molecular Weight:
C15H18O8 Mol. wt.: 326.3
Chemical and Physical Properties:
Description: Ginkgo seed has been listed as a source of medicine since the early Chinese herbals. The leaf has been recommended for medicinal uses as early as 1509 and is still used in the form of teas. The focus of this report is a standardized leaf extract first manufactured and marketed in Europe as a medicine for cardiovascular disease and now available in the United States as a dietary supplement (Huh & Staba, 1992; Salvador, 1995).
Technical Products and Impurities: GBE preparations contain 24% flavone glycosides (quercetin, kaempferol, isorhamnetin) and 6% terpene lactones (ginkgolides, bilobalide), various organic acids, and other constituents (Salvador, 1995). Ginkgolide B accounts for about 0.8% of the total extract, and bilobalide accounts for about 3% of the extract (Vasseur et al., 1994). The first standardized GBE was Egb 761, also called Tebonin, Tanakan, and rökan (Kleijnen & Knipschild, 1992a). In the United States, Nature's Way has exclusive distribution rights to Egb 761 and markets this product under the tradename Ginkgold (Anon, 1992).
Many other companies in Asia, Europe, or the United States manufacture or distribute GBE and dietary supplements containing GBE. GBE is also used in combination products to provide "special nutrients for the brain" (Anon., 1998a). Because herbal remedies are not held to the same standards of purity and efficacy as medications in the United States, tremendous variability of the same product can occur between manufacturers and from batch to batch (Martin, 1997).
GBE is available from the following bulk distributers and manufacturers: ATZ Chemical, Inc., ACTA Pharmacal, American Ingredients, Inc., Arrow Chemical Inc., Charles Bowman & Co., CPB International, Inc., China Tech, Inc., Eby Sales, Inc., ExtractsPlus, Fabrichem, Inc., G.C.I. Nutrients, Kingschem, Inc., M.M.P., Inc., Mini Star International, Inc., Morse Chemical, Inc., Motherland Herb-Pharm Inc., Pharmline, Inc., QBI, RIA International, and Schweizerhall, Inc. Ginkgo extract is available from American Ingredients, Inc., Bio-Botanica Inc., Blue California Co., Botanical Products International, Inc., Extracts Plus, Mini Star International, Inc., Motherland Herb-Pharm Inc., and Vege-Tech Co. Ginkgo biloba P.E. is available from Amaz Industries, Inc., American Ingredients, Inc., Anmar International Ltd., Ashland Chemical Company, Eby Sales, Inc., ExtractsPlus, Flavine International Inc., R.W. Greeff & Co., L.L.C., Herbarium, Inc., M.W. International, Inc., Maypro Industries, Inc., Mini Star International Inc., Motherland Herb-Pharm Inc, Starwest Botanicals, Inc., and Stauber Performance Ingredients, Inc. (McCoy, 1998). It could not be ascertained without calling each company which ones produce standardized extract.
(-)-Bilobalide (95% pure) and ginkgolide B (90% pure) are available in research quantities from Sigma (1997).
EXPOSURE INFORMATION
Production and Producers: The ginkgo tree is ancient, the only living representative of the order of Ginkgoales, a species that flourished 150 million years ago during the Mesozoic era, reaching its greatest development during the Jurassic and Cretaceous periods (Salvador, 1995). The ginkgo tree is now cultivated extensively in Asia, Europe, North America, New Zealand, and Argentina (Huh & Staba, 1992).
Modern pharmacological research into the active constituents of ginkgo leaves began in the late 1950s. Spearheaded by the phytopharmaceutical company Dr. Willmar Schwabe GmbH, twenty years of research resulted in a standardized, concentrated extract of ginkgo leaves. The 27 step extraction process requires fifty pounds of leaves to yield one pound of extract and takes up to two weeks to complete. Most critical to the extraction process and final product is the standardization of ginkgo flavone glycosides and terpene lactones. The 24% ginkgo flavone glycosides content of GBE constitutes a carefully measured balance of quercetin, kaempferol, and isorhamnetin. The group of constituents unique to GBE, however, are the terpene lactones which constitute 6% of the final extract (Brown, 1996).
In the United States, GBE is marketed to consumers as an herbal supplement. There are four primary distribution channels: drug stores, supermarkets, mass merchandisers, and specialty vitamin shops and nutrition centers (Heller, 1997). The Internet is also becoming an increasingly important distribution channel. Some typical consumer products are listed below in Table 1.
Table 1. Some dietary supplements containing Ginkgo biloba extract
Company/Product Name Product Description
LifePlus/Food for Thought Tablets containing 50 mg Ginkgo biloba Concentrate and 9 other ingredients
Ultimate Health Inc. Ginkgo biloba 60 mg (extract 24%)
Vitamin Connection Nature's Way GINKGOLD tablets, 60 mg
Vitamin Connection Jarrow Formula's Ginkgo biloba 50:1 tablets, 60 mg
Dynamic Fitness Capsules containing Ginkgo biloba (extract 24%), 60 mg
Nutra-Source PR-1235 Tablet containing Ginkgo biloba (leaf) 60 mg. (50:1 extract, 24% flavonoids, 6% terpene lactones; superoxide dismutase activity 5.8 x 10 to the 5th power/unit/gram)
Reach4Life Tablets containing 30 mg Ginkgo biloba (24-25% ginkgo
heterosides)
Source: Anon., 1998a-d; Nutrasource, 1998; Vitamin Connection, 1998
Production/Import Levels: The US market for retail sales of vitamins, mineral supplements, and herbals is volatile and expanding. Herbal supplements are the major catalysts for the growth in this market. Sales of vitamins, mineral supplements, and herbal products were $4.4 billion for the year ending July 1997 (Eder, 1997) and are expected to climb to $6.5 billion by 2001 (Heller, 1997).
Drug stores account for almost half the total food/drug/mass category volume of $2.1 billion, but this distribution channel is losing market share to supermarkets and mass merchandisers. Supermarket sales of vitamins, including herbal supplements, reached $586 million for the year ending in November 1997, up from $507 million the previous year. In 1996, mass merchandisers attained sales of $575 million, up 26% from the previous year. None of these figures include the nearly equal annual take of specialty vitamin shops, nutrition centers, and other distribution channels (Heller, 1997).
Herbal sales in discount stores totaled $77 million in 1996, a sales increase of 62% from the previous year in a market estimated to be valued at $227 million for that year (Troy, 1997). In 1995, Ginkgo biloba was the number four selling product in health food stores in the United States (Biotek USA, 1998). Sales of Ginkgo biloba in the United States exceeded $100 million in 1996 (Springen & Crowley, 1997).
Between July 19, 1996 and December 30, 1997, the Piers Imports database listed the following imports: 433,719 lb. ginkgo powders or leaves; 68,547 lb. tea; 21,922 lb. dried leaf powder; 17,339 lb. ginkgo tablets; 3,970 lb. crude natural drugs and herbs, and 476 lb. leaves extract. In the same period, approximately 31,000 lb. of ginkgo nuts were also imported (Dialog, 1998).
The European market for herbal medicines is more mature than the US market. Total sales of herbal medicines in the European Union represent approximately one-half of the yearly sales of herbs worldwide. More than 70% of general practitioners in Germany prescribe phytopharmaceuticals; many are covered by national health care insurance. This has led to a phytopharmaceutical market in Germany estimated at $3 billion annually. In Germany, more than 5 million prescriptions are written for GBE each year, with sales in 1993 amounting to $280 million (Brown, 1996; Croom & Walker, 1995).
Neither Ginkgo biloba nor GBE are listed in EPA's Toxic Substances Control Act (TSCA) Inventory.
Use Pattern: Treatment with Ginkgo biloba can be traced to the origins of Chinese medicine 2,800 years ago. In the modern Chinese pharmacopeia, leaves and fruit are still recommended for treating heart and lung problems. The nut, called Pak Ko, is recommended to expel phlegm, stop wheezing and coughing, urinary incontinence and spermatorrhea. The raw seed is said to be anticancerous. It is said to help bladder ailments, menorrhea, uterine fluxes, and cardiovascular ailments. The powdered leaf is inhaled for ear, nose, and throat disorders like bronchitis and chronic rhinitis. Locally applied boiled leaves are used for chilblains. The plant has also been used to treat conditions that may have poor circulation as a common symptom, such as brain function impairment, hearing loss, vertigo and tinnitus (Salvador, 1995).
Current interest in Ginkgo biloba relates to potential medical applications of the plant extracts. The major active component of GBE was considered, until 1983, to be a flavonoid complex that removed free radicals in the peripheral and/or cerebral vascular systems. More recent evidence suggests that the ginkgolides may be more important bioactive ingredients in the leaf extract, as they are platelet activating factor (PAF) antagonists. An increase in PAF occurs in asthma, graft rejection and in immune disorders that induce toxic shock. Ginkgolide B and related diterpenes inhibit the binding of PAF to receptors on the cell surface of some human leukocytes. Patents have been submitted for the use of ginkgolide B and structurally related PAF antagonists to treat or prevent PAF - O-alkyl-acetylglycero-phosphorylcholine (acether) disorders (Huh & Staba, 1992).
In Germany, GBE is licensed for the treatment of cerebral dysfunction, as supportive treatment for hearing loss due to cervical syndrome, and for peripheral arterial circulatory disturbances with intact circulatory reserve (intermittent claudication) (Kleijnen & Knipschild, 1992a).
Like other botanicals, GBE is marketed in the United States as a dietary supplement. Although many botanicals are used to treat or prevent diseases, manufacturers and distributors are prohibited under the Dietary Supplement Health & Education Act of 1994 to include such uses on direct product labeling (Martin, 1997).
Human Exposure: There is potential for ingestion of GBE to a widespread consumer population, since this product is readily available without prescription at a cost highly competitive with prescription medications.
The recommended dose of GBE is 120 to 160 mg daily for persons with intermittent claudication and 240 mg daily for cerebrovascular insufficiency, early stage Alzheimer's disease, resistant depression, and impotence (Brown, 1996).
No listing for Ginkgo biloba or GBE was found in the National Occupational Exposure Survey (NOES). NOES was conducted by the National Institute for Occupational Safety and Health (NIOSH) between 1981 and 1983.
Environmental Occurrence: No information was found in the available literature on potential environmental pollution from the manufacture of GBE or dietary supplements containing GBE. Contact with whole ginkgo plants has been associated with severe allergic reactions, including erythema and edema, similar to response to poison ivy (Salvador, 1995).
Regulations: No standards or guidelines have been set by NIOSH or OSHA for occupational exposure to or workplace allowable levels of Ginkgo biloba or GBE. Ginkgo biloba was not in the American Conference of Governmental Industrial Hygienists (ACGIH) list of compounds for which recommendations for a threshold limit value (TLV) and biological exposure index (BEI) are made.
Herbal remedies, including GBE, are considered by the FDA to be dietary supplements. Under the Dietary Supplement Health and Education Act of 1994, they can be sold legally if they are not labeled or accompanied by any therapeutic or health claims. Herbal remedies can be labeled with descriptions of their role in affecting physiological structure or function, but must be labeled with a disclaimer that the product has not been evaluated by the FDA for cure, prevention, or treatment of a disease (Martin, 1997).
For dietary supplements like GBE on the market before October 15, 1994, the Dietary Supplement Health and Education Act requires no proof of safety. A dietary supplement is considered unsafe only if it presents a significant or unreasonable risk of illness or injury under conditions of use recommended or suggested in labeling, or if no conditions of use are suggested or recommended in the labeling, under ordinary conditions of use (Croom & Walker, 1995).
