Plants> <Folium Ginkgo>
Folium Ginkgo consists of the dried whole leaf of Cinkgo biloba L. (Ginkgoaceae).
Pterophyllus salisburiensis Nelson, Salisburia adiantifolia Smith, Salisburia
macrophylla C. Koch.
Selected vernacular names
Eun-haeng, gin-nan, ginkgo, ginkgo balm, ginkgo leaves, ginkyo, ginan,
ichor, it yo, kew tree, maidenhair tree, pei-wenr temp]e balm, yin guo,
A mono typic dioecious plant that is the only living representative of
the Ginkgoales. It has a grey bark, reaches a height of 35 m and
a diameter of 3-4 m sometimes up to 7 m), and has fall-like leaves that
are deciduous, alternate, lengthily petiolate, bilobate, base wedge-shaped,
6-9cm broad (sometimes up to 15-20cm), turning yellow in autumn. Venation
dichotomously branching, seemingly parallel, Staminate and ovulate strobili
borne on separate trees; staminate strobili in consisting of naked pairs
of anthers in catkin-like clusters; ovulate strobili in the form of long,
slender, fused stalks bearing a single naked ovule which is fertilized
by motile sperm cells, developing into 2 seeds. Seeds yellow when mature,
foul-smelling, drupe-like, the middle layer of integument becoming hard
or stone-like, the outer layer fleshy.
material of interest: dried leaf
The kernel (nut, seed) is used in Chinese medicine.
The leaves are green, grey-yellow, brown or blackish; the upper side of
aleaf may be somewhat darker than the underside. The leaves are
fan-shaped, long-petioled and have two lobes with forked veins radiating
from the petiole end.
Ginkgo leaves have a weak characteristic odour.
Young leaves have abundant trichomes that become confined to the petiole
base as the leaf ages. While the leaves have no midrib, dichotomous venation
with regular, numerous branching parallel veins arises from two vascular
strands within the petiole. Stomata occur almost exclusively on the lower
surface of the leaf. The epidermis of the upper and underside of the leaf
consists of undulated, irregular, mostly long extended cells. in the cross-section,
the epidermal cells appear nearly isodiametric and from above appcar to
be slightly undulated, with the upper cells appearing larger. The outer
walls of thc epidermal cells are covered with a more or less thin layer
of cuticlc. In the arca of vascular bundles there are remarkable long
extended narrow cells with slightly undulated walls. Numerous druses of
calcium oxalate occur ncar thc vascular bundles.
The colour of the powder agrees with that of the leaves. The powder shows
fragments of the epidermis with wavelike indentations irregular in form
with generally elongated cells; large stomal openings of the anisocytic
type; markedly elongated, narrow cells with only weakly undulatcd walls
in the vascular areas and without marked indentations. The equifacial
mesophyll compriscs excretory vesicles, secretory cells, and idioblasts,
as well as intermittent calcium oxalate druses, in the region of the vascular
Native to China, but grown as an ornamental shade tree in Australia, south-cast
Asia, Europe, Japan, and the United States of America. It is commercially
cultivated in France and the United States of America.
Macroscopic and microscopic examinations. Thin-layer chromatographic analysis
for the presence of the characteristic flavonoids, ginkgolidcs. and bilobalide;
high-performance liquid chromatographic analysis for flavonoids, ginkgolides,
and bilobalide; and gas-liquid chromatographic evaluation of ginkgolides
The test for Salmonella spp. in Folium Ginkgo should be negative. The
maximum acceptable limits of other microorganisms are as follows. For
preparation of decoction: aerobic bacteria-not more than 10- / g; fungi-not
more than 10 5/g; Escherichia coli-not more than 10 2/g. Preparations
for internal use: aerobic bacteria-not more than 10 5/g or ml; fungi-not
more than 10-4/g or ml; enterobacteria and certain Gram-negative bacteria-not
more than 10 3/g or ml; Escherichia coli--0/g or ml..
Not more than 5%, of twigs and not more than 2%, of other foreign matter.
Not more than 11%.
To be established in accordance with national requirements. Normally,
the maximum residue limit of aldrin and dieldrin in Folium Ginkgo is not
more than 0.05mg/kg. For other pesticides, see WHO guidelines on
quality control methods for medicinal plants, and guidelines for predicting
dietary intake of pesticide residues.
Recommended lead and cadmium levels are not more than 10 and 0.3mg/kg.
respectively, in thc final dosage fonn of the plant material.
For analysis of strontium-90, iodine-131, caesium-134, caesium-137, and
plutonium-239, sce WHO guidelines on quality control methods for medicinal
Acid-insoluble ash, acid-insoluble cxtractive, chemical, and moisture
test" to be established in accordance with national requirements.
Flavonoids not less than 0.5 %, calculated as flavonol glycosides or 0.2-0.4%
calculated as aglycones; also contains ginkgolides (0.06 - 0.23%) and
bilobalide (up to 0.26%.
Qualitative and quantitative
determination of flavonoid glycosides is carried out after hydrolysis
to the aglycones kaempferol, quereetin, and isorhamnetin. The qualitative
presence or absence of biflavones is determined by high-performance liquid
chromatography; and qualitative and quantitative determination of the
diterpene ginkgolides and sesquiterpcne bilobalide by high-perfonnance
liqllid chromatography or gas-liquid chromatography
products used for clinical and experimental biological studies, e.g. EGb
761 and LI 1370, do not contain biflavones.
Major chemical constituents
Folium Ginkgo contains a wide variety of phytochemicals, including
alkanes, lipids, sterols, benzenoids, carotenoids, phenylpropanoids, carhohydrates,
flavonoids, and terpenoids. The major constituents are flaavonoids of
which mono-, di-, and tri-glycosides and coumaric acid esters that are
based on the flavonols kaempferol and quercctin dominate. Lesser quantities
of glycosides are derived from isorhamnetin, myricetin, and 3methylmyricetin.
Non-glycosidic biflavonoids, catechins, and proanthocyanidins arc also
present. Characteristic constituents of this plant material are the uniquc
diterpene lactones ginkgolides A, B, C, J, and M and the sesquitcrpene
lactone bilobalide. Representative structures of the major and characteristic
constituents arc presented below.
Standardized extracts (dry cxtract., from dried leaves, extracted with
acetone and water, drug extract ratio 35-67: 1) contain 22-27" flavone
glycosides and ,'5-7% terpene lactones, of which approximately 2.8-3.4%
consists of ginkgolides A, B, and C and 2.6-3.2% bilobalide. The
level of ginkgolic acids is below 5mg/kg. Coated tablets and solution
for oral administration are prepared from standardized purifeid extracts.
Uses suported by clinical data
Extracts as dcscribcd abuvl' (Dosge forms) have been used for symptomatic
treatment of mild to moderate cerobrovascular insufficiency (demential
syndromes in primary dgenerative dementia, vascular dementia, and mixed
forms of both) with the following symptoms: mmory deficit, disturbance
in concentration, depressive emotional condition, dizziness, tinnituus,
and headache. Such extracts are also used to improve pain-free walking
distance in people with peripheral arterial occlusive disease such as
intermittent claudication, Raynaud discase. acrocyanosis, and post-phlebitis
syndromc. and to treat inner ear disorders such as tinnitus and vertigo
of vascular and involutive origin, Extracts and doses other than those
described in Dosage forms and Posology are used for similar but milder
described in pharmacopoeias and in traditional systems of medicine
described in folk medicine, not supported by experimental or clinical
As a vermifuge, to induce labour for the treatment of bronchitis, chronic
rhinitis, chilblains, arthritis, and oedema.
Cerebrovascular insufficiency and peripheral vascular diseases
In vitro studies. A standardized extract of Ginkgo biloba (100µg/ml)
did not produce isometrically recordable contractions in isolated rabbit
aorta but did potentiate the contractile effect of norepinephrine.
Higher concentrations (EC 50 = 1.0mg/ml) produced a concentration-dependent
contraction that could be antagonized by the a-adrenoceptor-blocking agent
phentolamine. Both cocaine and desipramine, inhibitors of catecholamine
re-uptake, potentiated the contractile effect of norepinephrine but inhibited
the contractile effects of a standardized extract of G. biloba and tyramine.
The results of these experiments indicate that the contractile
action of G. biloba may be due to the release of catecholamines from endogneous
tissue reserves, and this activity may explain some of the therapeutic
effects of the drug in humans (e.g. improvement in cerebrovascular and
peripheral vasuclar insufficiency). On the basis of experiments
comparing the effects of an extract of G. biloba phentolamine, propranolol,
gallopamil, theophylline, and papaverine on the biphasic contractile response
of norepinephrine in isolated rat aorta, researchers concluded that G.
biloba had musculo-tropic action similar to that of papaverine.
This activity was previously reported for the flavonoids quercetin, kaemperol,
and is isorhamnetin, isolated from the leaves of G. biloba. The
flavonoids and papaverine both inhibit3.5-cyclic-GMP phosphodiesterase,
whcih in turn induces endothelium-dependent relaxation in isolated rabbit
aorta by potentiating the effects of endothelium-derived relaxing factors.
In vitro studies
have demonstrated that G. biloba extracts scavenge free radicals.
Ginkgo biloba extracts have been reported to reduce free radical lipid
peroxidation induced by NADPH-Fe systems in rat microsomes, and to protect
human liver microsomes from lipid peroxidation caused by ciclosporin A.
The extract also inhibits the generation of reactive oxygen radicals in
human leukocytes treated with phorbol myristate acetate. The antioxidant
action of G. biloba extract may prolong the half-life of endothelium
derived relaxing factor by scavenging superoxide anions. Both the
flavonoid and terpenoid constitutents of G. biloba appear to aid
the free-radical scavenging activity of the drug.
Ginkgo biloba extract
protected against brain tissue hypoxic damage in vitro. The ginkgolides
and bilobalide were responsible for the anithypoxic activity of the extract.
Ginkgolides A and B have been shown to protect rat hippocampal neurons
against ischaemic damage, which may be due to their ability to act as
antagonists to receptors for platelet-activating factor (PAF).
In vivo studies.
Oral administration of G. biloba extract protected rats against induced
cerebral ischaemia. Intravenous perfusion of a G. biloba extract
prevented the development of multiple cerebral infarcion in dogs injected
with fragments of an autologous clot into a common carotid artery.
These data suggest that G. biloba extract, administered after clot formation,
may have some beneficial effects on acute cerebral infarction or ischaemia
caused by embolism . Other experiments demonstrated that animals
treated with G. biloba extract survived u nder hypoxic conditions
longer than did untreated controls. Longer survival was due not
only to significant improvements in cerebral blood flow, but also to an
increase in the level of glucose and ATP. Other studies have shown
that a G. biloba extract devoid of ginkgolides but containing bilobalide
had protective activity when administered intraperitoneally to mice with
induced hypobaric hypoxia. Intravenous infusion of G. biloba extract
significantly increased pial arteriolar diameter in cats and improved
cerebral blood flow in rats. The active constituents of G.biloba responsible
for increasing cerebral blood flow appeared to be the non.flavonoid
compounds; ginkgolide B may be responsible for this action owing to its
PAF-antagonist activity. Furthermore, intravenous administration of a
standardized G. biloba extract and ginkgolide B to rats showed that the
extract, but not ginkgolide B, decreased the brain's use of glucose.
of G. biloba responsible for its anti-ischaemic activity remain undefined.
The flavonoids, ginkgolides, and bilobalide have all been suggested, but
it is possible that other constituents may be responsible.
An extract of G.biloba
was effective in the in vivo treatment of cerebral oedema, a condition
of excessive hydration of neural tissues owing to damage by neurotoxic
agents (such as triethyltin) or trauma, Bilobalide appeared to playa significant
role in the anti oedema effect. Oral or subcutaneous administration of
an extract of G. biloba to rats with acute and chronic phases of adriamycin-induced
paw inflammation partially reversed the increase in brain water, sodium,
and calcium and the decrease in brain potassium associated with sodium
arachidonate-induced cerebral infarction.
Mice treated with
a standardized extract of G. biloba (100 mg/kg, orally for 4-8 weeks)
showed improved memory and leaming during appetitive operant conditioning.
and auditory effects
Ginkgo biloba extract improved the sum of action potentials in the cochlea
and acoustic nerve in cases of acoustically produced sound trauma in guinea-pigs.
The mechanism reduced the metabolic damage to the cochlea. Oral or parenteral
administration of a standardized G. biloba extract to mice (2 mg/kg) improved
the ultrastructure qualities of vestibular sensory epithelia when the
tissue was fixed by vascular perfusion. Improvement was due to the effects
of the drug on capillary permeability and general microcirculation.
on vestibular compensation were observed after administration of G. biloba
extract (50 mg/kg intraperitoneally) to rats and cats that had undergone
unilateral vestibular neurectomy.
Antagonism of platelet-activating
The ginkgolides, and in particular ginkgolide B, are known antagonists
of P AF. P AF is a potent inducer of platelet aggregation, neutrophil
degranulation, and oxygen radical production leading to increased microvascular
permeability and bronchoconstriction. Intravenous injections of PAF induced
transient thrombocytopenia in guinea-pigs, which was accompanied by non-histamine-dependent
bronchospasm. Ginkgolide B has beelil shown to be a potent inhibitor of
P AF-induced thrombocytopenia and blionchoconstriction . P AF or ovalbumin-induced
bronchoconstriction in sensitized guinea-pigs was inhibited by an intravenous
injection ofginkgolide B (1-3mgl kg) 5 minutes prior to challenge.
Cerebral insufficiency is an inexact term to describe a collection of
symptoms associated with dementia. In dementia owing to degeneration with
neuronal loss and impaired neurotransmission, decline of intellectual
function is associated with disturbances in the supply of oxygen and glucose.
In clinical studies G. biloba effectively managed symptoms of cerebral
insufficiency including difficulty in concentration and memory, absent-mindedness,
confusion, lack of energy, tiredness, decreased physical perfomlance,
deprcssive mood, anxiety, dizziness, tinnitus, and headache. Several mechanisms
of action of G. biloba have been described: effects on blood circulation
such as the vasoregulating activity of arteries, capillaries, veins (increased
blood flow); rheological effects (decreased viscosit:>', by P AF-receptor
antagonism); metabolic changes such as increased tolerance to anoxia;
beneficial influence on neurotransmitter disturbances; and prevention
of damage to membranes by free radicals. Treatment of humans with G. biloba
extract has been shown to improve global and local cerebral blood flow
and microcirculation to protect against hypoxia, to improve blood rheology,
including inhibition of platelet aggregation, to improve tissue metabolism,
and to reduce capillary permeability.
A critical review
of 40 published clinical trials (up to the end of 1990) using an orally
administered G. biloba extract in the treatment of cerebral insufficiency
concluded that only eight of the studies were well performed. Almost all
trials reported at least a partially positive response at dosages of 120-160mg
a day (standardized extract) and treatment for at least 4-6 weeks. In
a comparison of G. biloba with published trials using co-dergocrine (dihydroergotoxine),
a mixture of ergoloid mesilates used for the same purpose, both G. biloba
extract and co-dergocrine sho'Ned similar efficacy. A direct comparison
of 120mg of G. biloba standardized extract and 4.5mg co-dergocrine showed
similar improvements in both groups after 6 weeks.
A meta-analysis of
11 placebo-controlled, randomized double-blind studies in elderly patients
given G. biloba extract (150 mg orally per day) for cerebral insufficiency
concluded that eight studies were well performed. Significant differences
were found for all analysed single symptoms, indicating the suiperiority
of the drug in comparison with the placebo. Analysis of the total score
of clinical symptoms indicated that seven studies confirmed the effectiveness
of G. biloba extract, while one study was inconclusive.
arterial occlusive disease
The effectiveness of G. biloba extract in the treatment of intermittent
claudication (peripheral arterial occlusive disease Fontaine stage II),
as compared with a placebo, was demonstrated in placebo-controlled, double-blind
clinical trials by a statistically significant increase in walking distance.
Sixty patients with peripheral arterial occlusive disease in Fontaine
stage IIb who were treated with the drug (120-160mg for 24 weeks) and
underwent physical training also clearly increased their walking distance.
Out of 15 controlled
trials (up to the end of 1990) only two were of acceptable quality. The
results of both studies were positive and showed an increase in walking
distance in patients with internlittent claudication after 6 months, and
an improvement of pain at rest in patients treated with 200mg of G. biloba
extract for 8 weeks.
of five placebo-controlled clinical trials (up to the end of 1991) of
G. biloba extract in patients with peripheral arterial disease, investigators
concluded that the extract exerted a highly significant therapeutic effect.
Ginkgo biloba extracts have been used clinically in the treatment of inner
ear disorders such as hearing loss, vertigo, and tinnitus. In a placebo-controlled,
double-blind study of 68 patients with vertiginous syndrome of recent
onset, treatment with G. biloba extract (120-160mg daily, for 4-12 weeks)
produced a statistically significant improvement as compared with the
The results of clinical
studies on the treatment of tinnitus have been contradictory. At least
six clinical studies have assessed the effectiveness of G.biloba extract
for the treatment of tinnitus. Three studies reported positive results.
One multicentre, randomized, double-blind, 13-month study of 103 patients
with tinnitus showed that all patients improved, irrespective of the prognostic
factor, when treated with Ginkgo biloba extract (160mg/day for 3 months).
Three other clinical trials reported negative outcomes..
of an open study (80 patients) without placebo, coupled with a double-blind,
placebo-controlled part (21 patients), demonstrated that a concentrated
G. biloba extract (29.2mg/day for 2 weeks) had no effect on tinnitus.
Hypersensitivity to G. biloba preparations.
No information available.
Carcinogenesis, mutagenesis, impairment of fertility
Investigations with G.biloba extracts have shown no effects that were
mutagenic, carcinogenic, or toxic to reproduction.
The safety of Folium Ginkgo for use during pregnancy has not been established,
Excretion of Folium Ginkgo into breast milk and its effects on the ncwhorn
have not been established.
No information is available concerning general precautions or drug interactions,
drug and laboratory test interactions, teratogenic effects on pregnancy
or paediatric use.
Headaches, gastrointestinal disturbances, and allergic skin reactions
are possible adverse effects.
Dried extract (as described in Dosage fornls), 120-240 mg daily in 2 or
divided doses (2); 40mg extract is equivalent to 1.4-2.7 g. leaves. Fluid
extract (1: 1), 0.5ml. 3 times a day.