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Folium Ginkgo

Definition
Folium Ginkgo consists of the dried whole leaf of Cinkgo biloba L. (Ginkgoaceae).

Synonyms
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, yinhsing.

Description
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.

Plant material of interest: dried leaf
The kernel (nut, seed) is used in Chinese medicine.

General appearance
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.

Organoleptic properties
Ginkgo leaves have a weak characteristic odour.

Microscopic characteristics
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.

Powdered plant material
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 fascicles.

Geographical distribution
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.

General identity tests
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 and bilohalide.

Purity tests
Microbiology

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..

Foreign organic matter
Not more than 5%, of twigs and not more than 2%, of other foreign matter.

Total ash
Not more than 11%.

Pesticide residues.
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.

Heavy metals
Recommended lead and cadmium levels are not more than 10 and 0.3mg/kg. respectively, in thc final dosage fonn of the plant material.

Radioactive residues
For analysis of strontium-90, iodine-131, caesium-134, caesium-137, and plutonium-239, sce WHO guidelines on quality control methods for medicinal plants.

Other purity tests
Acid-insoluble ash, acid-insoluble cxtractive, chemical, and moisture test" to be established in accordance with national requirements.

Chemical assays
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

Certain commercial 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.
        

Dosage forms

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.

Medicinal uses
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 indications.

Uses described in pharmacopoeias and in traditional systems of medicine
None.

Uses described in folk medicine, not supported by experimental or clinical data
As a vermifuge, to induce labour for the treatment of bronchitis, chronic rhinitis, chilblains, arthritis, and oedema.

Pharmacology
Experimental pharmacology

Cerebrovascular insufficiency and peripheral vascular diseases
In vitro studies.  A standardized extract of Ginkgo biloba (100g/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.

The constituents 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.

Vestibular 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.

Positive effects 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 factor (PAF)
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.

Clinical pharmacology
Cerebral insufficiency

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.

Peripheral 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.

After meta-analysis 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.

Vertigo and tinnitus
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 placebo group.

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..

Statistical analysis 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.

Contraindications
Hypersensitivity to G. biloba preparations.

Warnings
No information available.

Precautions
Carcinogenesis, mutagenesis, impairment of fertility
Investigations with G.biloba extracts have shown no effects that were mutagenic, carcinogenic, or toxic to reproduction.

Pregnancy: non-teratogenic effects
The safety of Folium Ginkgo for use during pregnancy has not been established,

Nursing mothers
Excretion of Folium Ginkgo into breast milk and its effects on the ncwhorn have not been established.

Other precautions
No information is available concerning general precautions or drug interactions, drug and laboratory test interactions, teratogenic effects on pregnancy or paediatric use.

Adverse reactions
Headaches, gastrointestinal disturbances, and allergic skin reactions are possible adverse effects.

Posology
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.