Ginkgo biloba
– the source of ginkgolides
Fig. 1. Ginkgo biloba L. Photo © H B Juneby.
Hans B. Juneby
Drug Discovery Based on Natural Products, September 2009
Division of Pharmacognosy
Department of Medicinal Chemistry
Uppsala University, Sweden
Contents
1 Introduction ........................................................................................................ 3
2 Monograph on Ginkgo biloba ……..................................................................... 4
2.1 Name ................................................................................................................ 4
2.2 Habitat ............................................................................................................. 4
2.3 Parts used ........................................................................................................ 5
2.4 Active ingredients .......................................................................................... 5
2.5 Pharmacology ................................................................................................. 6
2.6 Interactions ..................................................................................................... 6
2.7 Toxicology ....................................................................................................... 7
2.8 Medicinal use ................................................................................................. 8
2.9 Preparations and dosages ............................................................................ 8
3 References ......................................................................................................... 9
2
1 Introduction
Ginkgo biloba has been used in traditional Chinese medicine for thousands of years. In
the 1960s a standardized ginkgo leaf extract, EGb 761, was introduced in Europe.
This and other similar extracts are concentrated (about 50:1) and standardized to
contain 24% flavonoids and 6% terpene trilactones (ginkgolides and bilobalid). The
recommended dose is 120 – 240 mg per day divided in three doses.
An extract from the leaves of Ginkgo biloba is used in cerebrovascular and peripheral
vascular disorders. Adverse effects include headaches, dizziness, palpitations,
gastrointestinal disturbances, and skin hypersensitivity reactions. Ginkgo is one of
the most widely used plant based medicines in the world. Twenty years ago (1989)
there were already over five million prescriptions a year for gingko biloba extract
(Reynolds, 1993).
The German Regulatory Authority (Commission E) has approved the following indications for the standardized ginkgo extracts:
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Symptomatic relief of organic brain dysfunction
Intermittent claudication
Vertigo (vascular origin)
Tinnitus (vascular origin)
Further research is exploring the use of ginkgo extracts for a number of other
indications, and many studies have already been published in the scientific literature.
Over 3000 scientific research papers on Ginkgo biloba and its active constituents have
been published since 2001, and over 2500 ginkgo related patents were filed during
the same period (Van Beek & Montoro, 2009).
Future uses may be in the areas of arteriosclerosis (Rasetti et al. 1997; Li et al., 2009),
enzyme inhibition (Budzinski et al., 2000) insulin metabolism (Kudolo, 2000), adjunct
cancer therapy (Hauns et al., 2001), mountain/altitude sickness (Roncin et al., 1996;
Gertsch et al, 2002), adjunct schizophrenia therapy (Zhou et al., 1999; Zhang et al.
2001) , sudden deafness (Reisser & Weidauer, 2001), vitiligo (Parsad et al., 2003), etc.
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2 Monograph on Ginkgo biloba
Fig. 2. A typical leaf from Ginkgo biloba. Photo © H B Juneby.
2.1 Name
Ginkgo biloba L. Ginkgo belongs to the family Ginkgoacea in the Ginkgoales order of the
division Gymnospermae, which contains mainly fosil members (Trease & Evans, 1983).
English: Ginkgo, Maidenhair Tree. German: Gingko-baum. Danish: Tempeltrae. Finnish: Neidonhiuspuu, Ginkgo. Norwegian: Ginkgo. Swedish: Kinesiskt tempelträd.
2.2 Habitat
Native to East Asia, where it is extensively cultivated for food (the seeds) and
medicine (the leaves), especially in Japan and Taiwan. It is also cultivated in Europe
and North America for pharmaceutical purposes and as an up to 30 m high ornamental tree with dioecious flowers, which means that there are separate male and
female plants (Trease & Evans, 1983; Sandberg & Bohlin, 1993; Samuelsson, 2004).
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2.3 Parts used
Ginkgo bilobae folium – Ginkgo leaves. Ginkgo bilobae semen – The almond-like ginkgo
seeds, which are edible when separated from their fleshy outer layer.
2.4 Active ingredients
The main active ingredients in the leaves are about 30 different flavonoids, the
terpene trilactone ginkgolides A, B, C, J, M, and bilobalide (Samuelsson, 2004; Jensen,
2007). Small amounts of toxic ginkgol, ginkgolic acid and bilobin are also present,
especially in the fruit pulp (Roth et al., 1994; Der Marderosian & Liberti, 1988).
Fig. 3. The main terpene trilactone structure of the Ginkgolides. From Samuelsson (2004), p. 342.
Used with permission from the publisher (Apotekarsocieteten, Yvonne Andersson, 2009-09-23).
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2.5 Pharmacology
The ginkgolides are glycine and GABA receptor antagonists (Jensen et al. 2007). They
are also potent antagonists against platelet activating factor (PAF), which plays an
important role in a number of conditions, including anaphylaxis, asthma, CNSdisorders, graft rejection, inflammation, ischemia, renal disease and shock. Ginkgo
flavonoids inhibit cyclo-oxygenase and lipoxygenase, which reduces the production
of thromboxane A₂, thereby preventing platelet aggregation, clot formation and
thrombosis. The flavonoids are also free radical scavengers (Samuelsson, 2004).
Many studies have shown that ginkgo has anti-inflammatory, antioxidant, vascular
and cognitive-stimulating effects. Ginkgo is an effective treatment for peripheral
occlusive arterial disease (Schweizer & Hautmann, 1999) and arteriosclerosis (Rasetti
et al. 1997; Li et al., 2009), as well as enhancing coronary blood flow and decreasing
the blood pressure (Mahady, 2002).
Intake of Ginkgo biloba extract for three months increased the pancreatic beta cell
insulin producing function, perhaps by increasing the rate of insulin metabolic
clearance (Kudolo, 2000). Another study looked at acute pancreatitis, which causes a
release of platelet activating factor (PAF), which in turn induces systemic effects that
contribute to circulatory disturbances and multiple organ failure. A special terpenoid
extracted from Ginkgo biloba leaves was used successfully treat acute pancreatitis by
acting as a PAF receptor antagonist (Chen et al., 2008).
According to the NCI Drug Dictionary (2009), EGb761 is “A standardized ginkgo
biloba extract with antioxidant and neuroprotective activities. EGb761 has been
shown to inhibit the proliferation of certain tumor cells in vitro.” Ginkgo extract can
improve the treatment of several types of cancer, including advanced colon cancer
(Hauns et al., 2001).
Other conditions that respond positively to treatment with ginkgo extract include
mountain (altitude) sickness (Roncin et al., 1996; Gertsch et al, 2002). As an adjunct
schizophrenia therapy (Zhou et al., 1999; Zhang et al. 2001). Treat sudden deafness
(Reisser & Weidauer, 2001). Stop the progression of vitiligo (Parsad et al., 2003), etc.
2.6 Interactions
According to Bruhn & Eneroth (2000) there are no reported contraindications or
interactions with other drugs, in spite of the very extensive use of ginkgo in Germany
and France during many years. Burkhard & Lehrl (1991) report on a ginkgo monitoring study with more than 13 500 patients that did not reveal any negative
interactions. Meletis & Jacobs (1999) and Brinker (1998) advice caution in combining
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aspirin (salicylic acid) with ginkgo due to a significantly increased bleeding time and
risk of hemorrhage. This potential interaction has not yet been proven clinically,
which is also true for a possible interaction with warfarin (Miller & Murray, 1998).
There is only one single reported case of a patient taking warfarin in whom bleeding
occurred after starting to take ginkgo (Mathews, 1998).
Ginkgo may potentiate monoamine oxidase inhibitors. It also potentiates papaverine
intracavernosal injection for male impotence and is effective by itself in patients with
arterial erectile dysfunction (Brinker 1998). Ginkgo extract protects liver cells from
damage caused by cyclosporine in vitro (Barth et al., 1991), and it partially reverses
cyclosporine induced reduced kidney function in vitro (Bagnis et al., 1996). Ginkgo
can effectively reverse sexual dysfunction caused by fluoxetine (Prozac) or sertraline
(Zoloft), which are selective serotonin reuptake inhibitor (SSRI) drugs (Lininger,
1999).
2.7 Toxicology
The toxicity of ingested ginkgo alkylphenols has never been conclusively proven, but
in most standardized commercial extracts their content has been limited to less than
5 ppm (Van Beek & Montoro, 2009). One of the alkylphenols, ginkgolic acid, is
irritating to the eyes, the skin and the respiratory system (ChemBlink, 2009). The
extract has not been associated with any serious side effects, but mild reactions have
been reported, including gastrointestinal upset and headache. However, contact with
whole ginkgo plant parts have been associated with severe allergic reactions. There is
a cross-allergenicity between ginkgo fruit pulp and poison ivy. Ginkgolic acid and
bilobin have structural similarities with the allergens of poison ivy and cashew nut
shell oil (Der Marderosian & Liberti, 1988).
Fig. 4. Ginkgolic acid. Reproduced with permission from ChemBlink 2009-09-23.
2.8 Medicinal use
7
The German Regulatory Agency (Commission E) has approved the following
indications for standard extracts of ginkgo: Symptomatic relief of organic brain dysfunction. Intermittent claudication. Vertigo and tinnitus (both of vascular origin). An
extract from the leaves of Ginkgo biloba is used in cerebrovascular and peripheral
vascular disorders (Reynolds, 1993). Ginkgo has a blood vessel dilating action that
may have a positive effect in men with erectile dysfunction (Sohn & Sikora, 1991).
See also the additional information under pharmacology, interactions and toxicology.
2.9 Preparations and dosages
In the 1960s a standardized ginkgo leaf extract, EGb 761, was introduced in Europe.
This and other similar extracts are concentrated (about 50:1) and standardized to
contain 24% flavonoids and 6% terpene trilactones (ginkgolides and bilobalid). The
recommended dose is 120 – 240 mg per day divided in three doses.
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3 References
Bagnis, C. et al. Prevention of cyclosporine nephrotoxicity with a platelet-activating factor
(PAF) antagonist, Nephrol Dial Transplant 1996, 11, 507-13.
Barth, S.A. et al. Influences of Ginkgo biloba on cyclosporine A induced lipid peroxidation in
human liver microsomes in comparison to vitamin E, glutathione and N-acetylcysteine,
Biochem Pharmacol 1991, 41, 1521-26.
Braun, H. & Frohne, D. Heilpflanzen-Lexikon für Ärzte und Apotheker, Gustav Fischer
Verlag: Stuttgart, Germany 1987.
Brinker, F. Herb Contraindications and Drug Interactions, Eclectic Medical Publications:
Sandy, Oregon 1998.
Bruhn, J.G. & Eneroth, P. (Eds.) Naturläkemedelsboken, Boehringer Ingelheim International:
Stockholm 2000.
Budzinski, J.W. et al. An in vitro evaluation of human cytochrome P450 3A4 inhibition by
selected commercial herbal extracts and tinctures, Phytomedicine 2000, 7, 273-282.
Burkhard, G. & Lehrl, S. Verhältnis von Demenzen vom Multiinfarkt und vom Alzheimertyp in ärztlichen Praxen. Diagnostische und therapeutische Konsequenzen am
Beispiel eines Ginkgo biloba Preparates. Münch Med Wschr 1991, 113, (Suppl 1), 9-14.
ChemBlink 2009-09-23, http://www.chemblink.com/products/22910-60-7.htm
Chen, C. et al. Therapy for acute pancreatitis with platelet-activating factor receptor
antagonists, World J Gastroenterol 2008, 14, 4735-4738.
Der Marderosian, A. & Liberti, L. Natural Product Medicine, George F. Stickley:
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Duke, J.A. The Green Pharmacy, Rodale Press Inc: Emmaus, Pennsylvania 1997.
Gertsch, J.H. et al. Ginkgo biloba for the prevention of severe acute mountain sickness (AMS)
starting one day before rapid ascent, High Alt Med Biol 2002, 3, 29-37.
Hauns, B. et al. Phase II study cf combined 5-flourouracil/Ginkgo biloba extract (GBE 761 ONC)
Therapy in 5-flourouracil pretreated patients with advanced colorectal cancer, Phytotherapy Res 2001,
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Hänsel R. et al. Therapie mit Phyto-Pharmaka, Springer-Verlag: Berlin-Heidelberg-New York 1983.
Jensen, A.A. et al. Probing the Pharmacophore of Ginkgolides as Glycine Receptor
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Juneby, H.B. Fytomedicin – en fickhandbok om medicinalväxter, Artaromaförlaget:
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Li, R. et al. Ginkgolide B Suppresses Intercellular Adhesion Molecule-1 Expression
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Mathews, M.K. Association of Ginkgo biloba with intracerebral hemorrhage, Neurology 1998,
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