What is Ginkgo biloba extract used for?

Medical Uses
Ginkgo biloba extract has a variety of biological activities. In animal studies, Ginkgo biloba extract appears to reduce glucose utilization in brain areas that regulate somatosensory processing and alertness, inhibit stress-induced corticosteroid release, and prevent age-related changes in the mouse hippocampus. Other animal studies have shown that Ginkgo biloba extract can inhibit nitric oxide, cause vasodilation, reversibly inhibit brain monoamine oxidase A and B, and may scavenge free radicals, which may be mediators of lipid peroxidation and cell damage in Alzheimer's disease. Other studies have found that Ginkgo biloba extract has antioxidant effects and can inhibit acetylcholinesterase.

Cardiovascular and cerebrovascular disease treatment drugs
Ginkgo biloba extract is currently a commonly used traditional Chinese medicine for the treatment of cardiovascular and cerebrovascular diseases. The active ingredients are mainly ginkgo flavonoids and ginkgo diterpenoids. Among them, the ginkgo flavonoid glycosides mainly include quercetin, kaempferol, and isorhamnetin. The ginkgo diterpenoids mainly include ginkgolides A, B, C, J, M and bilobalide.
Ginkgo leaf extract has antioxidant, cardiovascular, anti-inflammatory and anti-tumor activity. It can dilate cardiovascular and arterial blood vessels, and also has a good protective effect on microvessels, effectively preventing blood vessel blockage. It has a good preventive and therapeutic effect on symptoms such as hyperlipidemia, hypertension, and diabetes, and indirectly reduces the incidence of common eye diseases (cataracts, glaucoma, vitreous opacities, retinopathy, diabetic eye diseases and other common eye diseases). It can effectively purify blood, strengthen blood vessels, prevent and treat cardiovascular diseases, and is effective for brain disorders, anti-aging, and cancer prevention. In the past 10 years, American consumers have been taking ginkgo leaf products as health foods to prevent stroke and coronary heart disease. According to a recent report in the American Medical Journal, researchers from the Department of Medicine at Oregon State University in the United States found in a clinical study lasting more than 3 years that long-term oral ginkgo leaf preparations for people over 65 years old can effectively prevent memory deterioration and Alzheimer's disease.
Extraction method
According to incomplete statistics, the current international standard ginkgo leaf extract is EGb761 produced according to the patented process of Schwabe in Germany. It has a brown-yellow powder appearance and a slight ginkgo leaf fragrance. Ginkgo leaf extract is a product extracted from the leaves of Ginkgo biloba L. as raw materials. The commercial extract is usually standardized to contain 24% flavonol glycosides and 6% ginkgo terpene lactones.
There are many methods reported in the literature on the production process of ginkgo leaf extract, mainly acetone extraction-lead salt precipitation method, ethanol extraction-macroporous resin adsorption separation method, supercritical carbon dioxide extraction method, alcohol extraction-extraction-chromatographic separation method, etc. The most widely used method in China is ethanol extraction-resin separation method.
At present, the most widely used method at home and abroad is organic solvent extraction. Since other organic solvents are toxic or volatile, ethanol is generally used as an extractant. Zhang Yonghong et al. showed through experiments that the optimal conditions for extracting flavonoid compounds from ginkgo leaves are 70% ethanol as the extracting solution, extraction temperature 90℃, solid-liquid ratio of 1:20, extraction times of 3 times, and reflux for 1.5h each time.
1. Ethanol extraction-macroporous resin adsorption separation method
Pick out impurities and moldy leaves, wash, chop, extract with 70% ethanol reflux, separate the extract, filter, recover ethanol under reduced pressure, centrifuge to remove residue, dilute with appropriate amount of pure water, add to macroporous adsorption resin column, elute with water until the eluate is clear and light in color, then elute with a certain concentration of ethanol, collect the eluate, concentrate under reduced pressure, and dry under vacuum.
2. Acetone extraction-lead hydroxide precipitation method
Ginkgo leaves are extracted with 60% acetone, filtered after cooling, extracted with carbon tetrachloride, butanone is added and mixed, acetone-butanone phase is separated and precipitated, solid ammonium sulfate is added to the ketone phase and stirred, solid matter is filtered out, filtrate is evaporated under reduced pressure to a concentration of 20%-60% solids, and diluted with 50% denatured ethanol to a concentration of 10% solids. Add lead hydroxide suspension and filter out the precipitate. The filtrate is concentrated to half volume under reduced pressure, and then ammonium sulfate and butanone are added to the concentrate under stirring. After stirring, a butanone-ethanol phase is precipitated; the butanone-ethanol phase is separated from the aqueous phase, and then butanone is added to the aqueous phase, stirred, and a butanone-ethanol phase is precipitated, which is merged into the above butanone-ethanol phase. Ammonium sulfate is added under stirring, and the precipitated aqueous phase is separated after mixing, and the butanone-ethanol phase is dried with sodium sulfate, evaporated to dryness under reduced pressure, and the denatured viscous residual liquid is dissolved with denatured ethanol, and the precipitate is separated after standing for 12 hours, evaporated under reduced pressure, and dried under vacuum.
Pharmacological effects
As early as the early 1960s, ginkgo leaf extract was used to treat cerebrovascular diseases and nervous system diseases abroad, and its efficacy was significant and had no side effects. Ginkgo extract has a strong antioxidant effect, can remove excess free radicals in the body, prevent lipid peroxidation in the body, dilate coronary vessels, increase cerebral blood flow, enhance the antagonistic effect of platelet activating factor, and can treat vascular aging, cerebrovascular insufficiency and other nervous system diseases. In addition, it can also improve the body's immunity and delay aging.
1. Effects on the cardiovascular system
Ginkgo leaf extract can inhibit the activity of angiotensin-converting enzyme (ACE) in normal human serum, thereby inhibiting arteriolar contraction, dilating blood vessels, and increasing blood flow. Ginkgo biloba extract or ginkgo biloba lactone is a highly specific PAF receptor blocker. Ginkgo leaf extract or ginkgo biloba lactone can inhibit platelet activating factor (PAF) and cyclooxygenase or lipoxygenase. Ginkgo leaf extract is well tolerated and antagonizes platelet aggregation caused by PAF, but has no effect on aggregation caused by ADP.
2. Effects on the central nervous system
Ginkgo leaf extract affects the endocrine system and the interaction between the immune system and the central nervous system by inhibiting the action of PAF, which can promote brain circulation metabolism and improve memory function. In addition to improving the lack of memory damage caused by NaNO2, its anti-hypoxia effect may be related to its increase in cerebral blood flow and improvement of brain energy metabolism during hypoxia. Ginkgo biloba lactone B can be used in the clinical treatment of stroke.
3. Effects on the digestive system
Ginkgo biloba extract can significantly improve gastric and intestinal ulcers caused by PAF and endotoxin in rats, and can partially inhibit ethanol damage to the stomach. It has a potential therapeutic effect on liver cirrhosis. Ginkgo biloba lactone B may have a role in the treatment of acute pancreatitis.
4. Effects on the respiratory system
Ethanol extract of ginkgo biloba has a direct relaxant effect on tracheal smooth muscle. Inhalation of atomized ginkgo biloba extract not only inhibits bronchoconstriction, but also inhibits the reduction of white blood cells and eosinophils caused by PAF. Ginkgo biloba extract is of great significance in inhibiting and treating bronchial hyperresponsiveness.
5. Anti-aging effect
Ginkgo biloba flavonoids, isoginkgo biloba flavonoids, ginkgosides and quercetin in ginkgo biloba all have the effect of inhibiting lipid peroxidation, especially quercetin has a stronger inhibitory activity.
7. Effects in transplant rejection and other immune responses
Ginkgo biloba extract can prolong the survival time of transplanted skin, ectopic heart xenotransplantation, and orthotopic liver xenotransplantation. Ginkgo leaf extract can inhibit the natural killer cell activity of the human body against KC526 target cells, and can also prevent the natural killer cell activity caused by interferon.
8. Anti-tumor effect
The crude extract of green leaves of Ginkgo biloba, i.e. the fat-soluble part, can inhibit EB virus. Heptadecene salicylic acid and bilo-betin both have strong inhibitory activity; total flavonoids of Ginkgo biloba can increase the thymus weight and SOD activity level of tumor-bearing mice, and mobilize the body's intrinsic anti-tumor ability; quercetin and myricetin can inhibit the occurrence of carcinogens.
9. Antioxidant effect
Ginkgo leaf extract can directly remove lipid free radicals, lipid peroxidation free radicals and alkyl free radicals, and terminate the free radical chain reaction chain. At the same time, it can also participate in regulating and improving the activity of antioxidant enzymes such as superoxide dismutase and glutathione peroxidase. The antioxidant effect of flavonoids in EGB even exceeds that of vitamins, and has anti-free radical attack properties in vitro.

Pharmacokinetics
1. Pharmacokinetics of flavonoids
Ginkgo flavonoids are mainly absorbed in the form of aglycones. The glycosides or aglycones of ginkgo flavonoids are almost undetectable in plasma and urine. They mainly exist in the form of glucuronic acid conjugates or sulfate conjugates of aglycones. At the same time, there are also literature reports that ginkgo flavonoid aglycones can be detected in plasma or urine after hydrolysis. The different conclusions may be caused by the sensitivity of the analytical instruments and methods, but it also reveals that the bioavailability of ginkgo flavonoid components is low.
Ginkgo flavonoid glycosides are metabolized in the body in two main sites: one is the liver, where a series of reactions occur under the action of liver CYP450 to generate more water-soluble metabolites that are excreted from the body; the other is the intestine, where they are hydrolyzed into aglycones under the action of intestinal flora. In contrast to the activation of CYP3A enzymes by ginkgo terpenoids, ginkgo flavonoids inhibit the activity of CYP3A enzymes, which is a problem that needs to be strictly paid attention to in future experimental processes and clinical medication. Quercetin and kaempferol can cause the activities of CYP1A1, CYP1A2, CYP3A4, etc. in rat and human liver microsomes to decrease.
2. Pharmacokinetics of terpene lactones
During the phase I metabolism of ginkgo terpene lactones, the effects of different lactones on CYP450 enzymes are tissue-specific, and different compounds have different effects on them. Ginkgo lactone A can induce the expression of CYP3A23, and ginkgo lactones A and B have no transcriptional induction effect on CYP3A4; bilobalide can induce the expression of CYP3A4 and CYP2B1. The effect of ginkgo terpene lactones on the CYP450 enzyme system may be the basis of its pharmacological activity. Compared with phase I metabolism, similar to ginkgo flavonoids, in vitro studies have shown that the metabolism of ginkgo terpenoids is also mainly phase II metabolism. Ginkgolide A and bilobalide have significant induction effects on phase II metabolic enzymes (UGT) glutathione-S-transferase and lipoamide dehydrogenase in rats, while ginkgolide B and C have no significant effect on them at the same dose.
Side effects
The LD50 of ginkgo leaf extract is (1202.5±141.3)μg/g for intravenous administration, equivalent to (7.8±0.9)g/Kg of crude drug; (17.9±1.0)g/kg for oral administration, equivalent to (116.4±6.5)g/kg of crude drug. Dogs were injected with 10 to 40 times the commonly used clinical dose of drugs for one week, and nausea, vomiting, diarrhea, loss of appetite, etc. were observed. Tissue sections showed hypersecretion of the small intestinal mucosa, enhanced intestinal peristalsis of anesthetized dogs and rabbits, and local blood vessels hardened after injection.
Both ginkgo biloba and ginkgo biloba have hemolytic effects, and ginkgo biloba has an anesthetic effect on the central nervous system of frogs. When rabbits were injected intravenously with 0.2g/kg of ginkgo biloba, there was a short-term pressor effect, followed by a drop in blood pressure, difficulty breathing, and convulsions and death of the animal; flavonols have no effect on the blood coagulation system at normal doses, and larger doses can hinder blood coagulation. The LD50 of isoginkgo biloba flavonoids injected into the tail vein of mice is 242mg/kg. The symptoms of acute poisoning include rapid breathing, prostrate motionlessness, and death from respiratory paralysis.
Ginkgo biloba acid has a hemolytic effect. When the flavonoid compounds of ginkgo are used at 100 to 1000 times the therapeutic dose, they can cause a moderate decrease in blood pressure, faster breathing, and slower heart rate in guinea pigs.

Drug Interactions
Ginkgo and its monomer components such as quercetin, kaempferol and isorhamnetin have inhibitory effects on CYP3A4, CYP2C9, CYP2B6, etc., while its monomer components such as ginkgolide A, B and bilobalide have inductive effects on CYP1A2, CYP2B1/2, CYP3A2, CYP2C19, UGT1A1, etc., and are P-glycoprotein substrates. Combination with drugs is prone to drug interactions, and the effects are complex, so it needs to be widely paid attention to.
In recent years, there have been reports of individual cases of bleeding caused by taking ginkgo leaf preparations or using them in combination with other anticoagulants. Ginkgo leaf extract inhibits PAF and causes bleeding, among which ginkgolide B is considered to be the most important component for inhibiting PAF. However, there are no corresponding controlled studies. The composition and amount of ginkgo leaf products currently available on the market vary greatly. The relevant dose and specific amount of ginkgolide B and bleeding are still unknown. In addition, there may be other ingredients in the product that can cause bleeding. Therefore, further research is needed in this area. Therefore, according to the current research results, cases of bleeding caused by ginkgo leaf extract preparations should be reported to doctors to attract sufficient attention. And try to avoid the use of ginkgo leaf extract preparations with anticoagulants such as aspirin and warfarin.

Application areas
1. Food and health care products industry
The flavonoids in ginkgo leaves have antioxidant properties and can be added to oils and pastries as antioxidants. The total flavonoids are mostly yellow and have a wide solubility. They are both water-soluble and fat-soluble, so the total flavonoids can act as a colorant. Ginkgo leaves are processed into ultrafine powder and added to food. Ginkgo leaves are ultrafinely crushed and added to pastries, biscuits, noodles, candies, and ice cream at 5% to 10%, and then processed into ginkgo leaf foods with health benefits.
Ginkgo leaf extract is used as a food additive in Canada and has been approved as an over-the-counter drug in Germany and France. Ginkgo leaves are included in the United States Pharmacopoeia (24th edition). Ginkgo leaf extract can be used as a dietary supplement in the United States. There are more than 30 kinds of ginkgo products in the world, and the main dosage forms include: ginkgo leaf tablets, ginkgo oral liquid, ginkgo lactone injection, ginkgo biloba injection, ginkgo ketone ester pills, compound ginkgo leaf granules, ginkgo leaf extract, etc. From 2009 to 2011, the sales and DDDs ranking of ginkgo leaf preparations ranked the top three among commonly used cardiovascular Chinese medicines.
Ginkgo leaves contain a small amount of proanthocyanidins and urushiol acids, which are still toxic to the human body. When ginkgo leaves are used as raw materials for food processing, they must be specially treated to reduce the content of proanthocyanidins and urushiol acids. However, within the current dosage range, there is no acute and chronic toxicity and no teratogenic effect. The Ministry of Health approved ginkgo leaf extract as a new food additive in 1992. In recent years, total flavonoids from ginkgo leaves have been widely used in the food industry, and the research and development of ginkgo leaves has broad prospects.
2. Daily chemical industry
The combination of Ginkgo leaf extract and skin absorption accelerator can also prevent the irritation caused by adhesives used in external ointments and patches, which can be emulsions, ointments, creams, sols and plasters. The skin care products containing GBE on the market mainly include anti-aging cleansers, shower gels, lipsticks, eye creams, etc. GBE can also be used in the production of hair growth and hair care products. Chen Yan and others even added Ginkgo leaf extract to toothpaste, and according to their research, it has a certain anti-caries effect.