Ginkgo biloba

Scientific Name(s): Ginkgo biloba L. Family: Ginkgoaceae

Common Name(s): Ginkgo , maidenhair tree , kew tree , ginkyo , yinhsing (Japanese silver apricot)

Uses

Ginkgo has been studied extensively in diverse medical conditions. Evidence is lacking to support a protective role in cardiovascular conditions and stroke, and a definitive place in therapy for dementia and schizophrenia, although promising, is yet to be established. The findings from 2 large trials are pivotal in evaluating the efficacy of G. biloba extracts.

Dosing

Standardized ginkgo leaf extracts, such as EGb 761 ( Tebonin forte , Schwabe), have been used in clinical trials for cognitive and circulatory disorders at daily doses of 120 to 240 mg of extract.

Contraindications

Absolute contraindications have not been established.

Pregnancy/Lactation

Evidence is lacking on the safety of ginkgo; preparations should not be used during pregnancy and lactation.

Interactions

Ginkgo interacts with the human cytochrome P450 (CYP-450) system and its isoenzymes, which may affect the metabolism of various drugs. Case reports of various interactions exist; however, consistent data are limited.

Adverse Reactions

Severe adverse reactions are rare; possible reactions include headache, dizziness, heart palpitations, and GI and dermatologic reactions. Ginkgo pollen can be strongly allergenic. Contact with the fleshy fruit pulp may cause allergic dermatitis similar to poison ivy.

Toxicology

A toxic syndrome has been recognized in Asian children who have ingested ginkgo seeds.

Botany

The ginkgo is the world's oldest living tree species. It can be traced back more than 200 million years to fossils of the Permian geologic period and is the sole survivor of the family Ginkgoaceae. Individual trees may live as long as 1,000 years and grow to a height of approximately 38 m. Ginkgo has characteristic fan-shaped leaves. The species is dioecious. Male trees older than 20 years blossom in the spring, and adult female trees produce a plum-like, gray-tan fruit that falls in late autumn. Its fleshy pulp has a foul, offensive odor and can cause contact dermatitis. The edible inner seed resembles an almond and is sold in Asian markets. 1 , 2

History

The ginkgo species almost became extinct during the last ice age that began approximately 2 million years ago. The species survived in China, where it was cultivated as a sacred tree and still decorates Buddhist temples throughout Asia. Ginkgo preparations have been used for medicinal purposes for more than a thousand years. Traditional Chinese physicians used ginkgo leaves to treat asthma and chilblains (inflammation of the small blood vessels in the skin in response to cold but above freezing temperatures). Ancient Chinese and Japanese people ate roasted ginkgo seeds and considered them a digestive aid and preventive agent for drunkenness. In the Western world, ginkgo has been used since the 1960s when technology made it possible to isolate its active compounds. The flavonoids act as free-radical scavengers, and the terpenes (ginkgolides) inhibit platelet-activating factor. Ginkgo is one of the most commonly prescribed medications in Europe, but it is not approved for medical use in the United States where it is sold only as a nutritional supplement. 2 , 3

Chemistry

The main medicinal constituents are found in the ginkgo leaf. These include flavonoids and several terpene trilactones unique to ginkgo (ginkgolides and bilobalide). The 3 major flavonoids of ginkgo are quercetin, kaempferol, and isorhamnetin. Approximately 40 minor flavonoids also have been identified and include catechins, dehydrocatechins (proanthocyanidins), and flavones (eg, ginkgetin, amentoflavone, bilobetin, sciadopitysin). The major terpene molecules unique to ginkgo are ginkgolides A, B, C, J, and M and bilobalide. Other medicinal constituents of ginkgo include shikimic, vanillic, ascorbic, and p-coumaric acids. Other leaf components include the steroids sitosterol and stigmasterol, polyprenols, benzoic acid derivatives, carbohydrates, straight chain hydrocarbons, alcohol, ketones, and 2-hexenol. There is a seasonal variation in the content of active compounds in leaves, with the highest amounts present in autumn. 4 , 5 , 6 , 7 , 8

The seed portion of ginkgo contains carbohydrate (38%), protein (4%), and less than 2% fat. Ginkgotoxin, amino acids, cyanogenetic glycosides, and long-chain phenols, including anacaric acid, bilobol, and cardanol, are also present. Ginkgolic acid and related alkylphenols from the lipid fraction of the fruit pods have been reviewed. The foul-smelling odor of the fleshy portion of the seeds is caused by high concentrations of butanoic and hexanoic acids. 4- O -methylpyridoxine has been isolated from the seeds. 3 , 6 , 8 Biological standardization of ginkgo extracts has been reported. 9

Uses and Pharmacology

The widespread usage of G. biloba extracts in clinical trials make data from animal studies largely redundant. Antioxidant properties have been described for G. biloba extracts and may account for observed protective effects of ginkgo in conditions of oxidative stress. Most studies have been conducted in animal or in vitro models. 10 , 11 , 12 , 13

Alzheimer and other dementias

A place in therapy for ginkgo in the reduction of incidence of dementia in elderly patients, as well as protection from decline in cognitive function, remains unclear.

Findings from trials evaluating ginkgo in dementia conducted up to 2008 have been included in 2 meta-analyses. 14 , 15 A Cochrane trial meta-analysis included 36 trials evaluating primarily EGb 761 versus placebo and found the results lacked consistent evidence of clinically important effects. Some of the trials included in the meta-analysis were of small sample size and treatment duration was less than 3 months. 14 The second meta-analysis included 9 trials with duration of treatment at least 12 weeks, and found a statistically significant improvement of cognition with EGb761 but no difference in “activities for daily living” measures. In a subgroup analysis, ginkgo therapy resulted in improved “activities for daily living” measures in patient participants with Alzheimer disease. 15 In both analyses, adverse events were similar for ginkgo and placebo. 14 , 15

Several small and 2 large clinical trials have been conducted since these meta-analyses. The results from the Ginkgo Evaluation of Memory (GEM) study have been published, and preliminary results are available for the GuidAge study. The GEM study found no effect of ginkgo in reducing the incidence of dementia or preventing decline in cognitive impairment among more than 3,000 enrolled older adult participants with normal to mild cognitive impairment. 16 , 17 Similarly, the incidence of Alzheimer dementia among the total enrolled population of more than 2,800 elderly participants was no different for ginkgo compared with placebo. Results from a planned subgroup analysis suggest a favorable finding for treatment with EGb 761 ginkgo for at least 4 years in preventing conversion to Alzheimer dementia. 18 However, these results are yet to be published in a peer-reviewed journal.

A pharmaceutical company–sponsored clinical study (N = 400) found greater improvements in cognitive and neuropsychiatric measures among people with Alzheimer dementia with neuropsychiatric features treated with 240 mg EGb761 per day over placebo. 19 Another sponsored study, the GINDON trial (N = 96) found similar improvements in cognitive function and neuropsychiatric assessments for all 3 study arms: ginkgo (240 mg/day), donepezil (10 mg/day), and a combination of both (240 mg/10 mg daily). 20

Other CNS conditions

Ginkgo extracts have been studied in clinical trials for conditions including schizophrenia, attention-deficit/hyperactivity disorder, dyslexia, autism, anxiety, and migraine, with varying effects. 21 , 22 , 23 , 24 , 25 As an antioxidant, ginkgo is of interest in schizophrenia, and a meta-analysis has been conducted of 6 quality clinical trials published to date. 26 As add-on therapy in long-term schizophrenia, ginkgo (EGb) performed better than placebo in the management of total and negative symptoms. 26

Cancer

The standardized extract of G. biloba leaves has been examined for treating several forms of cancer. 27 Numerous mechanisms of action have been proposed. 28 , 29

Animal data

Caspase-3 is a key mediator of apoptosis in mammalian cells. EGb 761 induced apoptotic cancer cell death by activating caspase-3 in oral cavity cancer cells in rats. 30 EGb 761 may reduce the risk of stomach cancer by dose-dependent inhibition of gastric mucosal lesions, as demonstrated in animal experiments. 31 , 32 G. biloba had potent antifibrotic activity against bleomycin-induced lung fibrosis in rats. 33

Clinical data

Thirty patients with gastric cancer were treated with 2 oral G. biloba exocarp polysaccharides (GBEP) capsules twice per day for longer than 1 month. An electron gastroscope was used to measure the area of tumors before and after treatment. Inhibitory and effective rates were then calculated. Results show that GBEP capsules reduced the area of tumors by an effective rate of 73%. 34

In one clinical trial, 32 patients with progressive advanced colorectal cancer were treated with ginkgo extract (EGb 761) 350 mg following conventional 5-fluorouracil therapy. Ginkgo improved the efficacy of 5-fluorouracil in colorectal cancer patients. Progression of the cancer occurred in 22 patients, there was no change in 8 patients, and partial responses were seen in 2 patients, for an overall response rate of 6.3%. Results of the combined treatment of EGb 761 and 5-fluorouracil suggest a favorable benefit-risk ratio and an increased median survival time of 9.5 months, which is similar to other second-line combination treatments. 35

One epidemiologic study claims that ginkgolide A and B may be associated with chemoprevention of certain forms of ovarian cancer. 36

G. biloba extract's antioxidant effects were studied in Chernobyl nuclear accident recovery workers with clastogenic factors (CF) evidenced as DNA fragmentation and damage. G. biloba extract was tested on the plasma of salvage personnel, and after 2 months of treatment at 40 mg 3 times per day, plasma CF regressed or completely disappeared. 28 , 37 An anticlastogenic effect was demonstrated for ginkgo versus placebo in patients with Graves disease receiving radioiodine therapy. 38

Cardiovascular disease

The GEM study (N = 3,069 elderly men and women) preplanned an evaluation of cardiovascular outcomes and found no evidence that 240 mg/day of ginkgo as EGb 761 reduced total or cardiovascular mortality or cardiovascular events. 39 A statistically significant positive finding was obtained for ginkgo in peripheral vascular disease; however, the number of events was too small to generalize. 39 Similarly, ginkgo did not reduce blood pressure in hypertensive or normotensive participants in the GEM study. 40 A Cochrane meta-analysis of 14 clinical trials evaluating the role of ginkgo in intermittent claudication found no evidence of a clinically important benefit for patients with peripheral arterial disease. 41 Ginkgo has been evaluated for the prevention of acute mountain sickness with equivocal results. 42 , 43

Diabetes

A limited number of small trials have been conducted by the same pool of researchers. Twenty healthy subjects with normal glucose tolerance blood levels were administered a glucose tolerance test before and after 3 months of therapy with G. biloba 120 mg at bedtime. After 3 months, a significant ( P < 0.001) increase in fasting plasma levels of insulin and C-peptide and C-peptide area under the curve (AUC) was found when measured after 2 hours of 75 g glucose tolerance test. No changes in glucose tolerance were observed. EGb 761 was hypothesized to increase the rate of insulin metabolic clearance. 44 In a follow-up study, EGb 761 increased pancreatic beta cell function in type 2 diabetes patients taking oral hypoglycemic agents in response to glucose tolerance testing. 45 The pharmacokinetic properties of metformin 500 mg once daily were not affected with coadministration of 120 mg of EGb 761 over 3 months. 46 Ingestion of 120 mg of EGb 761 for 3 months did not produce insulin resistance in the non- and prediabetic populations, nor did it exacerbate the disease in the type 2 diabetic subjects. 47

Sexual dysfunction in women

Clinical trials of small sample size have produced varying and equivocal results for the effect of ginkgo in sexual dysfunction in women. 48 , 49 , 50 , 51 A further larger study (N = 99) examined ginkgo versus placebo and compared this with sex therapy alone and in combination with ginkgo. Eight-week administration of ginkgo (300 mg) was found to be no more effective than placebo. 52

Stroke

G. biloba extract is widely used in China to treat short-term ischemic stroke. 53 However, a Cochrane systematic review that included 10 trials with a total of 792 patients and assessed the efficacy of ginkgo found no convincing evidence to support the use of ginkgo for recovery after stroke or improvement in neurological deficit at the end of treatment. 54

Other pharmacological activity

Limited clinical trials or other human studies have been conducted in conditions including glaucoma, 55 , 56 , 57 multiple sclerosis, 58 , 59 viral or postviral respiratory conditions, 60 tinnitus, 61 , 62 premenstrual syndrome, 63 , 64 Raynaud phenomenon, 65 and endothelial function. 66 , 67

Dosage

Standardized ginkgo leaf extracts, such as EGb 761 ( Tebonin forte , Schwabe), have been used in clinical trials for cognitive and circulatory disorders at daily doses of 120 to 240 mg of extract. 16 , 17 , 39 Extracts are usually standardized to 24% flavones and 6% terpene lactones. 16 , 17 Ginkgo is available commercially in several dosage forms, including teas, liquids, colas, capsules, extracts, tablets, sprays, and bars. Pharmacokinetic testing of ginkgo in capsule, drop, and tablet forms has been performed, as well as following IV administration. When administered orally while fasting, bioavailability is high; food did not change the AUC quantitatively but did increase the time to maximum plasma concentration. 68 , 69 , 70

Pregnancy/Lactation

A systematic review found evidence lacking on the safety of ginkgo in pregnancy or during lactation. 71 Based primarily on expert opinion regarding potential antiplatelet activity and reported emmenagogue properties, ginkgo should not be used during pregnancy and lactation. 71 An animal study in pregnant rats treated with 7 to 14 mg/kg/day of ginkgo resulted in reduction in fetal body weights, 72 while another found no embryotoxicity. 73

Interactions

Ginkgo interacts with the human CYP-450 system and its isoenzymes, which may affect the metabolism of various drugs. 74 , 75 , 76 , 77 Case reports of various interactions exist; however, consistent data are limited. 78

Anticoagulant/antiplatelets

Case reports exist of episodes of bleeding with concomitant administration of ginkgo; however, data from large clinical trials suggest such safety concerns are unwarranted. 79 , 80 , 81 , 82

Anticonvulsants (eg, phenytoin, valproic acid and derivatives)

A case report exists of a 55-year-old man who suffered from a fatal breakthrough seizure. 83 Evidence documented subtherapeutic serum levels for both of his anticonvulsants, Depakote and Dilantin . The man was also self-medicating with G. biloba . Both Depakote and Dilantin are metabolized by CYP2C9, so induction of this enzyme by ginkgo may explain their subtherapeutic levels. Ginkgo has also been found to protect against the hepatotoxicity in Depakote -treated patients; the mechanism of action involves ginkgo reducing the overproduction of reactive oxygen species caused by Depakote . 84 , 85

Antihypertensives (eg, nifedipine, propranolol)

G. biloba may inhibit the metabolism of nifedipine, elevating nifedipine plasma concentrations and increasing the pharmacologic and adverse reactions. Compared with giving nifedipine alone, administration of nifedipine 10 mg after 18 days of G. biloba 120 mg/day to 21 healthy volunteers increased nifedipine plasma levels 29% when measured 0.5 hours after nifedipine administration. 86 An animal study documented that pretreatment with EGb 761 decreased plasma concentrations of propranolol by inducing several CYP enzymes. 87

Benzodiazepines (eg, alprazolam, midazolam)

G. biloba may slightly decrease alprazolam plasma concentrations. In 12 healthy volunteers, 14 days of pretreatment with G. biloba extract 60 mg twice daily decreased the AUC of alprazolam 17% when administered as a single oral 2 mg dose. 88 The clearance of midazolam was decreased 26% in an experiment in 10 healthy volunteers who were also administered G. biloba extract 360 mg daily for 28 days. 89

Cyclosporine

Results of an animal study documented decreased oral bioavailability of cyclosporin (62%) and reduced clearance (51%) with ginkgo. 90

Digoxin

An open-label, randomized, crossover study in 8 healthy volunteers who were administered ginkgo 240 mg daily for 2 weeks documented a 21.9% increase in the AUC of digoxin at a dose of 0.5 mg. 91

Haloperidol

Concurrent use of G. biloba and haloperidol may increase the efficacy and decrease extrapyramidal adverse reactions of haloperidol, as documented in a double-blind, placebo-controlled study of 56 patients with long-term, treatment-resistant schizophrenia. 92

Nonsteroidal anti-inflammatory drugs (eg, ibuprofen)

Fatal intracerebral mass bleeding occurred in a 71-year-old man taking concurrent G. biloba and ibuprofen. 93 He had been taking G. biloba extract 40 mg twice daily for at least 30 months before his death, which occurred 4 weeks after starting ibuprofen 600 mg daily.

Proton pump inhibitors (eg, omeprazole)

G. biloba may increase the metabolism of omeprazole, reducing its plasma concentrations and decreasing therapeutic effect. In 12 healthy subjects, administration of omeprazole 40 mg after 12 days of pretreatment with G. biloba extract 140 mg twice daily decreased the ratio of the omeprazole AUC to the 5-hydroxyomeprazole metabolite 68%, compared with taking omeprazole alone. 94 In addition, urinary recovery of the metabolite was reduced.

Selective serotonin reuptake inhibitors (eg, fluoxetine)

Ginkgo may increase the risk of serotonin syndrome when taken with selective serotonin reuptake inhibitors. A case report documents a hypomanic episode after the addition of G. biloba and St. John's wort to a regimen of buspirone and fluoxetine. 95

Sulfonylureas (eg, tolbutamide)

In a study in 10 healthy men taking tolbutamide 125 mg alone and after receiving G. biloba extract 120 mg 3 times daily for 28 days, pretreatment with G. biloba reduced tolbutamide AUC 16% and attenuated the blood-glucose lowering effect of tolbutamide. 96 G. biloba may increase the metabolism (CYP2C9) of tolbutamide. 97

Trazodone

The risk of sedation with trazodone may increase with concurrent ingestion of G. biloba . 97 An 80-year-old woman with Alzheimer disease went into a coma during coadministration of trazodone 20 mg twice daily and G. biloba 80 mg twice daily. The patient was taken to the hospital and immediately regained consciousness following the administration of flumazenil to antagonize the effects of trazodone. The mechanism for this possible interaction is not known.

Adverse Reactions

Adverse reactions reported in large clinical trials using dosages of up to 240 mg/day EGb 761 ginkgo extract for durations of up to 6 years do not differ from placebo groups. 14 , 15 , 16 , 17 A trial evaluating the safety and effectiveness of EGb 761 at dosages of 240 mg/day over 22 weeks found no difference in adverse events for ginkgo compared with placebo. 98

Severe adverse reactions are rare, and case reports include headache, dizziness, heart palpitations, and GI and dermatologic reactions. Injectable forms of ginkgo may cause circulatory disturbances, skin allergy, or phlebitis, and parenteral ginkgo was withdrawn from the market because of the potential for severe adverse reactions. 3

The effect of ginkgo on platelets is unclear; case reports of a risk of increased bleeding appeared in the literature, while clinical trials have found no effect on platelet function. 79 , 80 , 99 Ginkgo use should be used with caution in populations at risk of bleeding.

Ginkgo pollen can be strongly allergenic. Contact with the fleshy fruit pulp can cause allergic dermatitis similar to poison ivy. 3

Toxicology

A toxic syndrome (“Gin-nan” food poisoning) has been recognized in children who have ingested ginkgo seeds. Approximately 50 seeds have produced tonic-clonic seizures and loss of consciousness. 89 , 100 , 101 Seventy reports (between 1930 and 1960) found 27% lethality, with infants being most vulnerable. Ginkgotoxin (4-O-methylpyridoxine), found only in the seeds, was considered responsible for this toxicity. 3 , 6 In animal experimentation with gingko extracts, no mutagenic or teratogenic effects were found. Oral administration of up to 1,600 mg/kg/day in rats did not produce teratogenic effects. Other animal toxicity data are available, including lethal dosing and other studies performed in mice, rats, guinea pigs, rabbits, and dogs. 3 No evidence of embryotoxicity was found for ginkgo extracts in rats given at 4 times the equivalent therapeutic dosage, despite the preparation containing potentially cytotoxic and mutagenic compounds, such as ginkgolic acids and alkylphenols. 73

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