Ginkgo biloba

Common Names: Ginkgo, Maidenhair tree, Ginkgo tree

Clinical Names: Ginkgo biloba

Summary

botanical name: Ginkgo biloba

common names: Ginkgo, Maidenhair tree.

overview of interactions:
• herb possibly affecting drug class toxicity: Major Anesthetics

• herb positively affecting drug class performance and toxicity: SSRI's

• herb possibly affecting drug class toxicity: Thiazide Diuretics

• herb affecting positively drug performance and toxicity: Fluoxetine (Prozac®)

• herb affecting drug performance and toxicity: Ticlopidine (Ticlid®)

• herb affecting drug toxicity: Warfarin (Coumadin)

• herbal synergy: Herb Group: Cardiovascular: Platelet Interactors

AHPA Botanical Safety Rating: 2d




Clinical

botanical name: Ginkgo biloba

common names: Ginkgo tree, Maidenhair tree.

parts used: Leaves (when turning yellow).

qualities: Bitter, neutral.

affinities: Blood vessels, especially arteries and capillaries; brain.

actions: Antihypoxic (increases peripheral and cerebral blood flow), antioxidant, cardiovascular tonic, cerebrovascular trophorestorative, Platelet Activating Factor (PAF) antagonist, vasodilator.

dosage:
• Standardized Extracts: 120-240 mg. daily (40-80mg.three times daily.) Manufacturers preparations may vary, most are standardized to contain 6% terpene lactones and 24% flavone glycosides.
• Tincture (1:2) 2 - 5 ml. three times daily.

therapy:
• Alzheimer's, anxiety, cerebrovascular insufficiency (post trauma; stroke recovery; difficulty in concentrating and memory problems), dementia, depression, tinnitus.
• Atherosclerosis, diabetic vasculopathies, hypertension, impotence, intermittent claudication, macular degeneration, peripheral vascular disease, Raynaud's.
• The broad spectrum of pharmacological activities of Gingko, including antioxidant action, free radical scavenging, neuroprotection, lipid peroxidation protection, arterial and venous relaxation, PAF inhibition, cortisol reduction and effects on neuronal plasticity and apoptosis make it useful for an extremely wide range of chronic degenerative conditions, particularly ischemic conditions related to the aging process where its affinity for neuronal tissue which is especially susceptible to free radical damage makes it a multi-function remedy.
(Clostre F. Ann Pharm Fr 1999 57 Suppl 1 1S8-88.)

AHPA Botanical Safety Rating: 2d

toxicity:
• In a review of studies involving over 9000 patients tolerance was excellent and side effects minimal. Commonest problems were gastrointestinal upset, dizziness and headache.
(De Foudis FV. 1991. 143-146.)
• In order to obtain a therapeutically effective concentration of flavonoids from hydroethanolic Ginkgo extracts, a dose of up to 1 oz. tincture per day may be required; this dosage level may contain tannins in concentrations sufficient to cause gastrointestinal distress.
(Bergner P. Medical Herbalism 1990;2:(1) 5-6.)
• Handling of the fresh fruit may cause contact dermatitis due to its phenolic compounds. The fruit pulp and raw nut are toxic if ingested, causing nausea, diarrhea and GI distress.
(Leung AY, Foster 1996. 390-391; Tomb RR, et al. Contact Dermatitis 1988.Oct;19(4):281-283.)

contraindications:
• There are no known contraindications. Caution is required in patients with pre-existing coagulopathies or those taking anticoagulant medication. See: drug interactions.
• Possible association with intracerebral hemorrhage.
(Matthews MK. Neurology 1998 Jun;50(6):1933-1934.)

constituents:
• Flavonoids: Flavonol glycosides, including quercitin, kaempferol, biflavones.
• Diterpenes: Terpene lactones, ginkgolides A, B, C, J, M.
• Sesquiterpene: Bilobalide.
• Other: Organic acids, tannins.

pharmacology:
• Almost all research on Ginkgo has been performed with a German standardized extract known as EGb 761 or GBE which is analytically controlled to 6% terpene lactones and 24% flavone glycosides.
(Snow J. Prot J Bot Med 1996.2 (1) 9-15.)

• Vasodilatation: Ginkgo increases circulation to both the brain and to the extremities and supports increased circulation in both large arteries and capillaries as well as affecting venous tissue. One mechanism of action is through an effect on nitric oxide pathways.
(Arnould T, et al. J Cardiovasc Pharmacol 1998 Mar;31(3):456-463; Jung F, et al. Arzneimittelforschung 1990 May;40(5):589-593); Chen X, et al.Clin Exp Pharmacol Physiol 1997 Dec;24(12):958-959.)

• Platelet Activating Factor Inhibition: Both GBE and the ginkgolide constituents, particularly Ginkgolide B have been shown in numerous animal and clinical studies to be effective PAF inhibitors.
(Akiba S, et al. Biochem Mol Biol Int 1998, 46.6:1243-248.)

• Antioxidant: numerous in vitro and in vivo studies using GBE have confirmed in vitro and in vivo antioxidant activity of Gingko.
(al-Zuhair H, et al. Pharmacol Res 1998 Jul;38(1):65-72. Lugasi A, et al. Phytother Res 1999 13.2:160-162.)

• Neuroprotection: GBE extracts show protective activity against free radical induced neuronal damage. In addition GBE reduced neuronal damage caused by verapamil.
(Ni Y, et al.Neurosci Lett, 1996 214;2-3:115-118; Zhu L, et al. J Basic Clin Physiol Pharmacol 1997 8(4):301-314.)

clinical trials:
• Cerebral insufficiency: Numerous clinical studies have evaluated the efficacy of GBE in cerebral insufficiency with positive results. A metastudy of 40 clinical trials concluded that only 8 studies were well conducted, although the authors concluded in favor of using GBE in cerebral insufficiency.
(Kleijnen J, Klipschild P. Lancet 1992;340:1136-1139.)

• Alzheimer's: A randomised double blind study of 40 Alzheimer's patients found significant improvement of symptoms compared to placebo after one month of 240 mg per day GBE, without side effects.
(Hofferberth B. Human Psychopharmacology, 1994;9:215-212.)

• Peripheral vascular problems: A meta-analysis of trials using GBE for intermittent claudication reported highly significant effects of the extract. GBE had significant anti-ischemic effects in patients with occlusive arterial disease. Several trials have demonstrated effectiveness of GBE in erectile impotence, partcularly impotence caused by SSRI therapy.
(Cohen AJ, Bartlik B.J Sex Marital Ther 1998 Apr;24(2):139-143; Ellison JM, DeLuca JP. J Clin Psychiatry 1998 Apr;59(4):199-200 [Letter].Mouren X, et al. Angiology 1994.45: 413-417; Rowin J. Neurology 1996. Jun;46(6):1775-1776; Schneider B. Arzneim. Forsch. 1992.42:428-436.)

• Other: Significant reduction in Hamilton Scale depression measurements against placebo after 8 weeks treatment.
(Schubert H, Halama P. Geriatr. Forsch.1993, 3:45-53.)

commentary:
The fruit of Ginkgo has a bitter non-edible pulp and contains a seed (nut) which is boiled or roasted and used and food and medicine in China. Ginkgo nut has a long history of use in Chinese medicine as an expectorant, and for urinary disorders such as frequency and eneuresis. Only the leaf is used in Western herbal medicine. The fruit pulp and raw seed are toxic.
(Leung AY, Foster S. 1996. 390-391.)



Interactions

herb possibly affecting drug class toxicity: Major Anesthetics

• preoperative protocols: Murphy discussed cases of patients who had been taking herbs prior to surgery and how this had influenced the course of events, particularly the postponing of the procedure. She emphasized the importance of the perioperative team members asking patients about their use of herbal remedies during assessments of medication use. McLeskey et al found that 170 of 979 (17.4%) of presurgical patients were taking herbal products. Median age of herb users and non-users was 62 years. Of the patients taking these agents, 55% took only one product, 45% took multiple products. In decreasing order, the most commonly utilized herbs among this group were: Gingko biloba (32.4%), garlic (26.5%), ginger (26.5%), ginseng and St. John's Wort (14%). Nutraceuticals most widely used were glucosamine (17%), chromium picolinate (17%) and chondroitin (12%). John B. Neeld, Jr, MD, President of the American Society of Anesthesiologists, has suggested that patients should stop taking herbal medications at least two to three weeks before surgery. Neeld and others have specifically cautioned against feverfew (Tanacetum parthenium) as potentially affecting PT time and increasing risk of bleeding, and St. John's Wort (Hypericum perforatum) and kava-kava (Piper methysticum) as prolonging the sedative effect of anesthesia due to a presumed MAOI-like action. While numerous anecdotal reports and hypotheses as to mechanisms of action have circulated, no clinical research, published case reports or substantive pharmacological analysis has confirmed these claims of adverse effects or interactions.
(Murphy JM. AORN J. 1999 Jan;69(1):173-5, 177-178, 180-183; McLeskey CH, et al. Annual Meeting of American Society of Anesthesiologists. October 1999; Voelker R. JAMA, 281(20).May 26, 1999.1882.)

herb positively affecting drug class performance and toxicity: SSRI's

• research: In an open trial, Ginkgo extract was found to be 84% effective in treating antidepressant-induced sexual dysfunction predominately caused by selective serotonin reuptake inhibitors. Women were more responsive to the sexually enhancing effects of Ginkgo biloba than men.
(Cohen AJ, Bartlik B.J Sex Marital Ther 1998 Apr;24(2):139-143.)

herb possibly affecting drug class toxicity: Thiazide Diuretics

• report: One case has been reported in which an elderly patient taking the combination of a thiazide diuretic and Ginkgo biloba developed elevated blood pressure, which returned to normal when both substances were discontinued. This reaction is paradoxical in light of the known pharmacological actions of the two agents which would more likely be predicted to cause a hypotensive crisis.
(Shaw D, et al. Drug Saf 1997.Nov; 17 (5): 342-356.)

herb positively affecting drug performance and toxicity: Fluoxetine (Prozac®)

• reports: One anecdotal report noted that fluoxetine-induced genital anesthesia was relieved by Ginkgo biloba extract.
(Ellison JM, DeLuca JP. J Clin Psychiatry 1998 Apr;59(4):199-200; Rowin J, Lewis SL. Neurology 1996.Jun;46(6):1775-1776.)

• herbal concern: Individuals who bruise easily might find that such tendency is increased due to the increased circulation in the extremities.

herb affecting drug performance and toxicity: Ticlopidine (Ticlid®)

• research: One animal study suggests that Ginkgo (GBE) extracts potentiate the antiplatelet and antithrombotic effects of effects of Ticlopidine when orally administered. The doses used were an order of magnitude larger than therapeutic dose range in humans.
(Kim YS, et al. Thromb Res 1998.Jul 1;91(1):33-38.)

• herbal concern: The clinical implications of this potential interaction are as of yet unclear. Individuals who have been prescribed ticlopidine should refrain from taking Ginkgo unless specifically coordinated with the prescribing physician and closely monitored.

herb affecting drug toxicity: Warfarin (Coumadin)

• mechanism: Extracts of Ginkgo exhibit PAF inhibitory activity. The terpene fraction, particularly ginkgolide B is thought to be the principal PAF inhibitory component. While PAF antagonists do not operate directly on the clotting cascade, at least two reports of Ginkgo use associated with hemorrhagic episodes (see below) have noted increased PT/PTT times which normalized on cessation of Ginkgo consumption. This suggests the possibility of an additive effect on coagualibility through an unknown synergistic mechanism, since PAF antagonism alone should not affect coagulation times.

• reports: Reports of problematic interactions between Ginkgo and coumadin are rare but remain more than a theoretical concern. Ginkgo inhibits platelet adhesion and can increase any tendency toward bleeding. Case reports of Ginkgo being associated with neurovascular bleeding include one of hyphema, one of subdural hemorrhage and one of subarachnoid hemorrhage. In these reports Ginkgo use was self-prescribed and not disclosed to the physician until after the hemorrhagic episode. Ginkgo alone may cause bleeding. Aspirin was a concurrent medication in one report. The Rowin report mentions concurrent acetaminophen and caffeine/ergotamine consumption. The only report of hemorrhage involving a warfarin stabilized patient was that of Matthews, who did not reveal the dose or nature of Ginkgo preparation involved.
(Kleijnen J, Knipschild P. Lancet 1992;340:1136-1139; Mathews MK. Neurology 1998 Jun;50(6):1933-1934; Rosenblatt M, Mindel J. New Engl J Med 1997 Apr 10;336(15):1108; Rowin J, Lewis SL. Neurology 1996 Jun;46(6):1775-1776; Skogh M. Lancet. 1998 Oct 3;352(9134):1145-1146.)

• herbal concern: Vigilant monitoring of PT/INR values with individuals using warfarin who consume Ginkgo extracts is essential.

herbal synergy: Herb Group: Cardiovascular: Platelet Interactors

• mechanism: Gingko extracts should be considered to additively affect coaguability if combined with other herbs that also affect coagulation such as Allium sativum (Garlic).


Please read the disclaimer concerning the intent and limitations of the information provided here.
Do not rely solely on the information in this article.

The information presented in Interactions is for informational and educational purposes only. It is based on scientific studies (human, animal, or in vitro), clinical experience, case reports, and/or traditional usage with sources as cited in each topic. The results reported may not necessarily occur in all individuals and different individuals with the same medical conditions with the same symptoms will often require differing treatments. For many of the conditions discussed, treatment with conventional medical therapies, including prescription drugs or over-the-counter medications, is also available. Consult your physician, an appropriately trained healthcare practitioner, and/or pharmacist for any health concern or medical problem before using any herbal products or nutritional supplements or before making any changes in prescribed medications and/or before attempting to independently treat a medical condition using supplements, herbs, remedies, or other forms of self-care.



References

al-Zuhair H, el-Fattah AA, el-Sayed,MI. The effect of meclofenoxate with ginkgo biloba extract or zinc on lipid peroxide, some free radical scavengers and the cardiovascular system of aged rats. Pharmacol Res 1998 Jul;38(1):65-72.
Abstract: Aged rats are highly prone to many physiological changes such as blood pressure and heart rate. These changes could be due to modification in membrane phospholipid composition of their blood vessels. Lipid peroxide in vivo has been identified as a basic deteriorative reaction in cellular mechanisms of aging in human. The effect of a nootropic drug, meclofenoxate (MF) or its combination with extract of ginkgo biloba (EGb-761) or zinc (Zn) on malondialdehyde (MDA) product as an index of endogenous lipid peroxidation; phospholipid; glutathione (GSH) and protein thiols (PrSHs) contents as well as superoxide dismutase (SOD) activity in blood, brain, heart and liver of 24-month-old male rats was investigated. Aged rats were treated with MF once daily at oral doses of 100 mg kg-1 body wt. alone or with either EGb at a dose of 150 mg kg-1 body wt. or Zn at 10.5 mg kg-1 body wt. for 4 weeks. This study showed that aging caused a higher increment in MDA level of brain and heart than liver and plasma accompanied with reduction in brain and heart phospholipid contents as well as alteration of the antioxidant systems as compared to 4-month-old rats. Treatment of aged rats with MF alone or combined with either EGb or Zn caused improvement in the measured free radical scavengers especially in brain and heart tissues. Our results also showed that both EGb and Zn induced a significant potential effect of MF action on blood pressure and heart rate. The results were explained in the light of the antioxidant properties of EGb and Zn. Thus it is concluded that EGb and Zn have a beneficial role with MF in diminishing cumulative oxidative changes in aging.

Akiba S, Kawauchi T, Oka T, Hashizume T, SatoT. Inhibitory effect of the leaf extract of Ginkgo biloba L. on oxidative stress-induced platelet aggregation. Biochem Mol Biol Int 1998, 46.6:1243-248.
The effect of the leaf extract of Ginkgo biloba L. on platelet aggregation induced by oxidative stress was studied. The extract caused a dose-dependent inhibition of platelet aggregation stimulated with tert-butyl hydroperoxide (t-BHP) and Fe2+. Similar inhibitory activity was observed when platelets were exposed to H2O2 and Fe2+. Synergistic aggregation induced by a combination of t-BHP and Fe2+ or H2O2 and Fe2+ in association with suboptimal concentration of collagen or U46619, was prevented by the extract. However, the extract failed to inhibit aggregation in response to collagen, thrombin or U46619. Ginkgolides A, B and C inhibited platelet-activating factor-induced aggregation, but not oxidant-induced aggregation. These data suggest that the suppressive effect of the extract is specific on platelet aggregation stimulated by oxidative stress, and that this effect is involved in the mechanism related to its protective effect upon cerebral or myocardial injuries

Arnould T, Michiels C, Janssens D, Berna N, Remacle J. Effect of Ginkor Fort on hypoxia-induced neutrophil adherence to human saphenous vein endothelium. J Cardiovasc Pharmacol 1998 Mar;31(3):456-463.
Abstract: This study was performed to evaluate the effects of Ginkor Fort, a venotropic drug composed of Ginkgo biloba extract, troxerutine, and heptaminol, on neutrophil adherence to the endothelium of saphenous veins. When saphenous veins were incubated 2 h in hypoxic conditions, they showed a five- to sixfold increase in neutrophil adherence to the endothelium. Ginkor Fort at 0.3 mg/ml was able to inhibit this increase by 69%. These results were confirmed by observations in scanning electron microscopy. Ginkor Fort also inhibited the subsequent activation of these neutrophils, as evidenced by the inhibition of superoxide anion release. The biochemical mechanism of this inhibition of neutrophil adherence was studied on endothelial cells in culture. We observed that Ginkor Fort was able to inhibit the different steps of the activation of endothelial cells by hypoxia: the activation of phospholipase A2 and the decrease in adenosine triphosphate (ATP) content. By preventing the first step of the activation cascade, the decrease in ATP content, Ginkor Fort blocks the subsequent increase in neutrophil adherence as well as neutrophil activation. The biochemical mechanism evidenced in this work might explain the beneficial effect of this drug in the treatment of patients with chronic venous insufficiency.

Barth SA, Inselmann G, Engemann R, Heidemann HT. Influences of Ginkgo biloba on cyclosporine A included lipid peroxidation in human liver microsomes in comparison to vitamin E, glutathione and N-acetylcysteine. Biochem Pharmacol 1991 May 15;41(10):1521-1526.
Abstract: The in vitro effect of cyclosporin A (CsA) on lipid peroxidation in human liver microsomes was investigated, and efforts were made to prevent the resulting toxic effect of CsA. Microsomes were prepared from human liver resection material and incubated with CsA (0, 10, 30, 100, 300, 1000 micrograms/mL) for one hour (pH 7.4, 37 degrees, 95% O2, 5% CO2). Subsequently the resulting concentrations of malondialdehyde equivalents (MDA) were determined, a breakdown product of lipid peroxidation. Furthermore the duration of incubation was varied (0, 15, 30, 60, 90 min) using a CsA concentration of 300 micrograms/mL. CsA was shown to stimulate MDA-formation to up to 10-fold of the control value in both a time and concentration dependent manner. The dosage dependent experiment stated above was repeated, adding alpha-tocopherol (vitamin E, 1 mM), reduced glutathione (GSH, 1 mM), N-acetylcysteine (0.1, 0.3, 1, 3 mM), and Ginkgo biloba extract (Gbe, 15, 50, 150 micrograms/mL), respectively, to the medium of incubation. Vitamin E, a potent radical scavenger, proved to inhibit lipid peroxidation almost totally. Both GSH and N-acetylcysteine were also able to prevent lipid peroxidation, suggesting that the antioxidant effect of GSH might be caused by its thiol group and does not depend on the integrity of the whole molecule. Gbe inhibited CsA induced lipid peroxidation in a concentration dependent manner. This effect of Gbe was diminished yet not totally abolished when FeCl3 was added to the medium of incubation, whereas N-acetylcysteine even slightly enhanced CsA stimulated lipid peroxidation in the presence of iron. These results suggest that Gbe might be able to prevent radical mediated damage to human membranes caused by CsA.

Bensky, Gamble A, Kaptchuck T. Chinese Herbal Medicine: Materia Medica. Revised Edition. Seattle: Eastland Press, 1993.

Bergner P. Ginkgo biloba. Medical Herbalism 1990;2:(1) 5-6.

Blumenthal M, Busse WR, Goldberg A, et al, eds. The Complete Commission E Monographs: Therapeutic Guide to Herbal Medicines. Boston, MA: Integrative Medicine Communications, 1998.

Chen X, Salwinski S, Lee TJ. Extracts of Ginkgo biloba and ginsenosides exert cerebral vasorelaxation via a nitric oxide pathway. Clin Exp Pharmacol Physiol 1997 Dec;24(12):958-959.
Abstract: 1. Extracts from the leaves of Ginkgo biloba (EGb) and ginsenosides (GS) have been reported to be effective at increasing vascular relaxation. In the present study, the actions of EGb and GS on the vascular functions of porcine basilar arteries were investigated in vitro using tissue bath techniques. 2. Both EGb and GS relaxed the basilar artery in a concentration-dependent and partly endothelium-dependent manner. However, EGb appeared to be more potent than GS. Relaxation induced by transmural nerve stimulation (TNS) was significantly enhanced by EGb (7.5, 15 and 30 micrograms/mL) and GS (20, 40 and 80 micrograms/mL) in both endothelium-intact and -denuded basilar arteries. Enhanced TNS-induced relaxations were abolished by 0.3 mmol/L N-L-arginine. 3. The present study demonstrates that nitric oxide plays a primary role in TNS-induced relaxation as well as in EGb- and GS-enhanced relaxation within the cerebral vasculature. In addition, our data support the potential of these compounds as therapeutic strategies in cerebral ischaemia and other related vascular dysfunctions.

Clostre F.[Ginkgo biloba extract (EGb 761). State of knowledge in the dawn of the year 2000.] Ann Pharm Fr 1999 57 Suppl 1 1S8-88. [Article in French]
Abstract: EGb 761 is a standardized extract of dried leaves of Ginkgo biloba containing 24% ginkgo-flavonol glycosides, 6% terpene lactones such as ginkgolides A, B, C, J and bilobalide. Its broad spectrum of pharmacological activities allows it to be in adequacy to the numerous pathological requirements--hemodynamic, hemorheological, metabolic-- which occur in cerebral, retinal, cochleovestibular, cardiac or peripheral ischemia. Moreover, EGb 761 has direct effects against necrosis and apoptosis of neurons and improves neural plasticity as evidenced in vestibular compensation. At the molecular and the cellular levels, some evidence obtained with animal models indicates that EGb 761 can interact as a free radical-scavenger and a inhibitor of lipid peroxidation with all, or nearly all reactive oxygen species; maintains ATP content by a protection of mitochondrial respiration and preservation of oxidative phosphorylations; exerts arterial and venous vasoregulator effects involving the release of endothelial factors and the catecholaminergic system. Moreover, EGb 761 regulates ionic balance in damaged cells and exerts a specific and potent Platelet-activating factor antagonist activity. Numerous well-controlled clinical studies, realized in Europe and in USA, have revealed that EGb 761 is an effective therapy for a wide variety of disturbances of cerebral function, ranging from cerebral impairment of ischemic vascular origins (i.e. multi infarct dementia), early cognitive decline to mild-to- moderate cases of the more severe types of senile dementias (including Alzheimer's disease) or mixed origins (i.e. psychoorganic origin). Improvement of signs and symptoms have been demonstrated for cognitive functions, particularly for memory loss, attention, alertness, vigilance, arousal and mental fluidity. Some clinical studies have showed that EGb 761 treatment may improve the capacity of geriatric patients to cope with the stressful demands of daily life. The explanation is a dual stress-alleviating action of EGb 761: its facilitates behavioral adaptation to stress and may decrease the excess of cortisol release to stress. Moreover, EGb 761 shows a specific neuroprotective effects to hippocampic cells. Regarding the visual system, experimental studies have shown that EGb 761 can inhibit or reduce the functional retinal impairments resulting from ischemia- reperfusion, photo-degeneration, diabetic or proliferative retinopathy. Clinical studies have revealed that EGb 761 may be useful in treating visual activity impairments and damages to the visual field associated with chronic cerebrovascular insufficiency, senile macular degeneration and diabete mellitus. Regarding the vestibular and auditory systems, experimental and clinical studies have shown the efficacy of EGb 761 in treating hypoacusis, tinnitus, vertigo, dizziness and other symptoms of vestibulocochlear disorders. At least, adequatly controlled studies in patients with peripheral arterial occlusive disease have provided good evidence for therapeutic efficacy in intermittent claudication. The future of EGb 761 is undoubtedly in the promise in slowing the progression of Alzheimer's disease. Indeed, two recent american clinical studies have shown the efficacy and safety of EGb 761 in patients with mild to severe Alzheimer's disease and multi-infarct dementia. In clinical terms, progression of symptoms was delayed by approximately 6 months. Actually new clinical studies are undertaken in USA and Europe. At the dawn of the third millenium (the Sixth for Ginkgo biloba) we propose a state of art about it.

Cohen AJ, Bartlik B.Ginkgo biloba for antidepressant-induced sexual dysfunction.J Sex Marital Ther 1998 Apr;24(2):139-143.
Abstract: In an open trial ginkgo biloba, an extract derived from the leaf of the Chinese ginkgo tree and noted for its cerebral enhancing effects, was found to be 84% effective in treating antidepressant-induced sexual dysfunction predominately caused by selective serotonin reuptake inhibitors (SSRIs, N = 63). Women (n = 33) were more responsive to the sexually enhancing effects of ginkgo biloba than men (N = 30), with relative success rates of 91% versus 76%. Ginkgo biloba generally had a positive effect on all 4 phases of the sexual response cycle: desire, excitement (erection and lubrication), orgasm, and resolution (afterglow). This study originated from the observation that a geriatric patient on ginkgo biloba for memory enhancement noted improved erections. Patients exhibited sexual dysfunction secondary to a variety of antidepressant medications including selective serotonin reuptake inhibitor (SSRIs), serotonin and nonrepinephrine reuptake inhibitor (SNRIs) monoamine oxidase inhibitor (MAOIs), and tricyclics. Dosages of ginkgo biloba extract ranged from 60 mg qd to 120 mg bid (average = 209mg/d). The common side effects were gastrointestinal disturbances, headache, and general central nervous system activation. The article includes a discussion of presumed pharmacologic mechanisms, including effects on platelet activating factor, prostaglandins, peripheral vasodilatation, and central serotonin and norepinephrine receptor factor modulation.

Cohen-Salmon C, Venault P, Martin B, Raffalli-Sebille MJ, BarkatsM, Clostre F, Pardon MC, Christen Y, Chapouthier G. Effects of Ginkgo biloba extract (EGb 761) on learning and possible actions on aging. J Physiol Paris 1997 Dec;91(6):291-300.
Abstract: A study of the effect of Ginkgo biloba extract (EGb 761) has shown enhancing effects on training in adult and aged Swiss mice. An analysis of inbred mice has confirmed this sensitivity to EGb 761, but depending on the strains, with different effects at different ages. The most interesting results are related to improvements in performances observed with aged mice of the DBA/2J strain. The results obtained with inbred strains in the study of the mossy fibers of the hippocampus make it possible to suggest a link between the improvements in training and the histological structure of the hippocampus. This possibility, which can be confirmed by further studies, is presented here.

D'Arcy PF. Adverse reactions and interactions with herbal medicines, part 1, adverse reactions. Adverse Drug Reactions and Toxicological Review 10 (Winter 1991) 189-208.

De Foudis FV. Ginkgo biloba extract (EGb761): Pharmacological Activities and Clinical Applications. Elsevier Paris 143-146, 1991.

Demott K. St. John’s wort tied to serotonin syndrome. Clinical Psychiatry News 1998;26:28.

Ellison JM, DeLuca JP Fluoxetine-induced genital anesthesia relieved by Ginkgo biloba extract. J Clin Psychiatry 1998 Apr;59(4):199-200. (Letter)

Garg RK, Nag D, Agrawal A. A double blind placebo controlled trial of ginkgo biloba extract in acute cerebral ischaemia. J Assoc Physicians India 1995 Nov;43(11):760-763.

Hofferberth B.The efficacy of EGb761 in patients with senile dementia of the Alzheimer type a double blind placebo controlled study on different levels of investigation. Human Psychopharmacology,1994.9:215-212.

Horr R, Kieser M.[Ginkgo biloba special extract EGb 761--an anti-dementia drug]. Fortschr Med 1998 Jan 30;116(3):39-40. [Article in German]

Hsu H. Oriental Materia Medica, Taiwan, R.O.C.: OHAI 1986.
 
Huang KC. The Pharmacology of Chinese Herbs, Ann Arbor, MI: CRC Press 1993.

Jung F, Mrowietz C, Kiesewetter H, Wenzel E. 1990 Effect of Ginkgo biloba on fluidity of blood and peripheral microcirculation in volunteers. Arzneimittelforschung May;40(5):589-593.
Abstract: In a randomized placebo controlled single-blind cross-over study of n = 10 apparently healthy subjects the influence of Ginkgo biloba (Kaveri) on blood fluidity and cutaneous microcirculation was studied. Microcirculation was measured before and every 30 min for 4 h after administration of Ginkgo biloba; fluidity of blood was determined before and after 1, 2 and 4 h. Significant changes in blood pressure or heart rate were found neither during Ginkgo phase nor placebo phase. Haematocrit, plasma viscosity, erythrocyte rigidity, thrombocyte and leukocyte count as well as thrombocyte aggregation and the number of circulating thrombocyte aggregates were also not influenced by the Ginkgo nor the placebo solution. In contrast a remarkable influence on the erythrocyte aggregation was observed: comparing two samples a significant decrease by 15.6% (p less than 0.001) with regard to the initial value was observed after 2 h. The blood flow in the nail fold capillaries also increased significantly by about 57% (p less than 0.004) 1 h after administration.

Kanowski S, Herrmann WM, Stephan K, Wierich W, Horr R.Proof of efficacy of the ginkgo biloba special extract EGb 761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multi-infarct dementia. Pharmacopsychiatry 1996 Mar;29(2):47-56.
Abstract: The efficacy of the ginkgo biloba special extract EGb 761 in outpatients with presenile and senile primary degenerative dementia of the Alzheimer type (DAT) and multi-infarct dementia (MID) according to DSM-III-R was investigated in a prospective, randomized, double-blind, placebo-controlled, multi-center study. After a 4-week run-in period, 216 patients were included in the randomized 24-week treatment period. These received either a daily oral dose of 240 mg EGb 761 or placebo. In accordance with the recommended multi-dimensional evaluation approach, three primary variables were chosen: the Clinical Global Impressions (CGI Item 2) for psychopathological assessment, the Syndrom-Kurztest (SKT) for the assessment of the patient's attention and memory, and the Nurnberger Alters-Beobachtungsskala (NAB) for behavioral assessment of activities of daily life. Clinical efficacy was assessed by means of a responder analysis, with therapy response being defined as response in at least two of the three primary variables. The data from the 156 patients who completed the study in accordance with the study protocol were taken into account in the confirmatory analysis of valid cases. The frequency of therapy responders in the two treatment groups differed significantly in favor of EGb 761, with p < 0.005 in Fisher's Exact Test. The intent-to-treat analysis of 205 patients led to similar efficacy results. Thus, the clinical efficacy of the ginkgo biloba special extract EGb 761 in dementia of the Alzheimer type and multi-infarct dementia was confirmed. The investigational drug was found to be well tolerated.

Kiesewetter H, Jung F, Mrowietz C, Wenzel E. Hemorrheological and circulatory effects of Gincosan. Int J Clin Pharmacol Ther Toxicol 1992.Mar;30(3):97-102.
Abstract: Gincosan is a combined preparation containing 60 mg ginkgo biloba and 100 mg ginseng, standardized of 24% ginkgo flavone glycosides and 4% ginsenosides. Hemorrheological and circulatory effect as well as blood pressure behavior after the administration of gincosan were studied in an acute trial on 10 voluntary subjects with a mean age of 26 years. Systolic blood pressure decreased significantly both for the large-dose (120 mg ginkgo biloba +200 mg ginseng) and low-dose administration (60 mg ginkgo biloba +100 mg ginseng). Diastolic blood pressure and heart rate decreased only in the high dosage group. The pathologically increased spontaneous platelet aggregation is reduced by both dosages. Erythrocyte velocity in nail fold capillaries increased significantly only in the high dosage group. The parallel group comparison of the high dosage and placebo group showed that they differ only significantly concerning the erythrocyte rigidity, erythrocyte velocity in nail fold capillaries and spontaneous platelet aggregation. A trend towards a decrease in the systolic blood pressure is revealed (p less than 0.1).

Kim YS, et al., Antiplatelet and antithrombotic effects of a combination of ticlopidine and Ginkgo biloba extract. Thromb Res 1998.Jul 1;91(1):33-38.
Abstract: The antiplatelet and antithrombotic effects of the oral combination treatment of ticlopidine and Ginkgo biloba extract (EGb 761) were studied in normal and thrombosis-induced rats. The ex vivo inhibitory effect on ADP-induced platelet aggregation of a small dose of ticlopidine (50 mg/kg/day) in combination with EGb 761 (40 mg/kg/day) was comparable to a larger dose of only ticlopidine (200 mg/kg/day). Bleeding time was also prolonged by 150%. Thrombus weight was also consistently decreased by a combination of ticlopidine and EGb 761 in an arterio-venous shunt model at two doses of ticlopidine (50 mg/kg) plus EGb 761 (20 mg/kg) and ticlopidine (50 mg/kg) plus EGb 761 (40 mg/kg). A combinatory treatment in acute thrombosis model in mice also showed a higher recovery than a single treatment.

Kleijnen J, Klipschild P. Ginkgo biloba. Lancet 1992.340:1136-1139.

Koltringer P, Langsteger W, Klima G, Reisecker F, Eber O. [Hemorheologic effects of ginkgo biloba extract EGb 761. Dose-dependent effect of EGb 761 on microcirculation and viscoelasticity of blood]. Fortschr Med 1993 Apr 10;111(10):170-172. [Article in German]
Abstract: Method: In a randomized open clinical trial involving 42 patients with pathological visco-elasticity values, the effect of a single intravenous injection of 50, 100, 150 or 200 mg of the Ginkgo biloba extract EGb 761, commercially available as Tebonin p.i. on the microcirculation of the skin (Doppler flowmetry) and the visco-elasticity of whole blood was investigated. Results: A dose-dependent significant increase in the microcirculation was found. In the case of visco-elasticity, this dose-dependence was less marked. The present study thus confirms the positive effect of EGb 761 on the microcirculation and whole-blood visco-elasticity in patients with pathological visco-elasticity values, already found in earlier studies, and shows it to be dependent on the dose employed.

Lagrue G, Behar A, Kazandjian M, Rahbar K. [Idiopathic cyclic edema. The role of capillary hyperpermeability and its correction by Ginkgo biloba extract]. Presse Med 1986 Sep 25;15(31):1550-1553. [Article in French]
Abstract: Idiopathic cyclic oedema is a frequent and often unrecognized condition in young women. It is characterized by water and sodium retention with secondary hyperaldosteronism due to capillary hyperpermeability. Treatment is not easy. It includes spironolactone, sometimes sympathomimetics and hygienic-dietetic measures. Thiazide diuretics and laxatives must be avoided. Correcting the capillary defect is of paramount importance. This defect is detected and measured by Landis' labelled albumin test. The authors have tried Ginkgo biloba extract administered either orally or by intravenous infusion. Full correction of the biological anomaly was obtained in 10 cases in which Landis' test was performed before and after oral treatment, and in the 5 cases treated by intravenous infusion.

Le Bars PL, et al. A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. North American EGb Study Group. JAMA 1997.Oct 22;278(16):1327-1332.
Abstract: A 52-week, randomized double-blind, placebo-controlled, parallel-group, multicenter study. Mildly to severely demented outpatients with Alzheimer disease or multi-infarct dementia, without other significant medical conditions. The Ginkgo product used, Egb, was determined to be safe and appeared capable of stabilizing and, in a substantial number of cases, modestly improving the cognitive performance and the social functioning of demented patients for 6 months to 1 year.

Leung AY, Foster S. Encyclopedia of Common Natural Ingredients Used in Food, Drugs and Cosmetics. Second Edition. New York: John Wiley and Sons, .390-391, 1996.

Lugasi A, Horvahovich P, Dworschak E.Additional information to the in vitro antioxidant activity of Ginkgo biloba L Phytother Res 1999 13.2:160-162.
The in vitro antioxidant and free radical scavenging activity of the ethanol extract from Ginkgo biloba L. was examined in different systems. The extract showed hydrogen-donating ability, reducing power, copper-binding property, free radical scavenging activity in a H2O2/.OH- luminol system and it could prevent the autoxidation of linoleic acid. All these properties are involved in the overall antioxidant activity of Ginkgo biloba which makes it suitable for the prevention of human disease in which free radicals play an important role.

Matthews MK Jr. Association of Ginkgo biloba with intracerebral hemorrhage. Neurology 1998 Jun;50(6):1933-1934. (Letter)

Maurer K, Ihl R, Dierks,T, Frolich L. Clinical efficacy of Ginkgo biloba special extract EGb 761 in dementia of the Alzheimer type. J Psychiatr Res 1997.Nov;31(6):645-655.
Abstract: A double-blind, randomized, placebo-controlled parallel-group design in 20 outpatients. The duration of treatment was 3 months. In addition to the psychometric confirmation of efficacy, certain descriptive trends were found at the psychopathological and dynamic functional levels, which were interpreted as evidence of effectiveness of Ginkgo biloba special extract EGb 761 in mild to moderate dementia and of local effects in the central nervous system.

McLeskey CH, Meyer TA, Baisden CE, Gloyna DF, Roberson CR. The incidence of herbal and selected nutraceutical use in surgical patients. Annual Meeting of American Society of Anesthesiologists (ASA) October 1999.
Abstract: An estimated 60 million American adults are reported to use herbal products. Consumers assume, because these products are natural, they are harmless. However, reports of allergic reactions, adverse effects and drug-herb interactions are surfacing. Following IRB approval, a questionnaire was given to 979 presurgical patients. Subjects were asked to indicate the amount and duration of products taken. Age and surgical procedure were noted. 170 surgical patients (17.4%) reported taking such products. Median age of herb users and non-users was 62 years. Of the patients taking these agents, 55% took only one product, 45% took multiple products. In decreasing order, the most commonly utilized herbs among this group were: gingko biloba (32.4%), garlic (26.5%), ginger (26.5%), ginseng and St. John's Wort (14%). Nutraceuticals most widely used were glucosamine (17%), chromium picolinate (17%) and chondroitin (12%). Over 40 herbs were listed as occasionally taken. Females represented 63% of herbal users and 54% of non-users (p=0.05). 19.3% of female patients took one or more of these products vs. 14.5% of male patients. Neurosurgical, gynecologic and orthopedic surgical patients' use of herbals was slightly higher than other surgical groups at 21%, 21% and 20%. Recently one-third of the American public has been identified as users of herbal products. Our lower incidence may result from reluctance of patients to admit taking such products or lack of understanding among patients regarding drug intake and contents of these products. Anesthesia providers, surgeons, and patients should be aware that these medications may not be harmless and are in increasing use. Adverse effects and drug-herbal interactions may suggest alterations in an anesthetic plan.

Murphy JM. Preoperative considerations with herbal medicines. AORN J.1999 Jan;69(1):173-5, 177-178, 180-183.

Skogh M. Extracts of Ginkgo biloba and bleeding or haemorrhage. Lancet. 1998 Oct 3;352(9134):1145-1146.

Mouren, X et al. Study of the anti-ischemic action of EGb761 in the treatment of peripheral arterial occlusive disease by TcPo2 determination. Angiology 1994.45: 413-417.

Ni Y, et al. Preventive effect of Ginkgo biloba extract on apoptosis in rat cerebellar neuronal cells induced by hydroxyl radicals. Neurosci Lett, 1996 214;2-3:115-118.
Abstract: The ability of oxidative stress to induce apoptosis, and the effect of Ginkgo biloba extract (EGb761) on this induction were studied in primary cultured rat cerebellar neuronal cells. Cells were exposed to hydroxyl radicals by treating them with 20-50 microM hydrogen peroxide (H2O2) and 100 microM ferrous sulfate. Hydroxyl radical treatment fragmented the DNA in a manner typical of apoptosis cells, producing a ladder pattern of 200 base pair increments on 1% agarose gel electrophoresis. Pretreatment of cells with 100 micrograms/ml EGb reduced hydroxyl radical induced cells apoptosis (determined by flow cytometry) and DNA fragmentation. The results indicate that hydroxyl radicals induce apoptosis in rat cerebellar neuronal cells and this induction can be prevented by EGb.

Pietri S, Seguin JR, d'Arbigny P, Drieu K, Culcasi M. .Ginkgo biloba extract (EGb 761) pretreatment limits free radical-induced oxidative stress in patients undergoing coronary bypass surgery. Cardiovasc Drugs Ther 1997.Apr;11(2):121-131.
Abstract: A growing body of evidence supports the trigger role of free radicals in the delayed functional and metabolic myocardial recovery following cardiopulmonary bypass (CPB) in humans, thus opening the field to specific therapies. This clinical study was designed to evaluate, in 15 patients undergoing aortic valve replacement, whether the extent of CPB- and reperfusion-induced lipid peroxidation, ascorbate depletion, tissue necrosis, and cardiac dysfunction is reduced by orally administered EGb 761, a Ginkgo biloba extract with potent in vitro antiradical properties. Patients received either EGb 761 (Tanakan, 320 mg/day, n = 8) or a matching placebo (n = 7) for 5 days before surgical intervention. Plasma samples were obtained from the peripheral circulation and the coronary sinus at crucial stages of the operation (i.e., before incision, during ischemia, and within the first 30 minutes post-unclamping), and up to 8 days postoperatively. Upon aortic unclamping, EGb 761 inhibited the transcardiac release of thiobarbituric acid-reactive species (p < 0.05), as assessed by high-performance liquid chromatography, and attenuated the early (5-10 minute) decrease in dimethylsulfoxide/ascorbyl free radical levels, an electron spin resonance index of the plasma ascorbate pool (p < 0.05). EGb 761 also significantly reduced the more delayed leakage of myoglobin (p = 0.007) and had an almost significant effect on ventricular myosin leakage (p = 0.053, 6 days postoperatively). The clinical outcome of recovery of treated patients was improved, but not significantly, compared with untreated patients. Our results demonstrate the usefulness of adjuvant EGb 761 therapy in limiting oxidative stress in cardiovascular surgery and suggest the possible role of highly bioavailable terpene constituents of the drug.

Pirotzky E, Colliez P, Guilmard C, Schaeverbeke J, Braquet P. Cyclosporine-induced nephrotoxicity: Preventive effect of a PAF-acether antagonist, BN 52063. Transplant Proc 1988 Jun;20(3 Suppl 3):665-669.

Rosenblatt M, Mindel J. Spontaneous hyphema associated with ingestion of Ginkgo biloba extract. New Engl J Med 1997.336:1108.

Rowin J, Lewis SL.Spontaneous bilateral subdural hematomas associated with chronic Ginkgo biloba ingestion. Neurology 1996 Jun;46(6):1775-1776.

Satyan KS, Jaiswal AK, Ghosal S, Bhattacharya SK.Anxiolytic activity of ginkgolic acid conjugates from Indian Ginkgo biloba. Psychopharmacology (Berl) 1998 Mar;136(2):148-152.
Abstract: Ginkgolic acid conjugates (GAC) (6-alkylsalicylates, namely n-tridecyl-, n-pentadecyl-, n-heptadecyl-, n-pentadecenyl- and n-heptadecenylsalicylates) isolated from the leaves of Indian Ginkgo biloba Linn., (IGb) were tested for their putative role in anxiety in rats. Elevated plus maze, open-field behaviour, novelty-induced feeding latency and social interaction were the rodent behavioural models used in this study. GAC (0.3 and 0.6 mg/kg, each, p.o.) on single acute administration, showed dose-related changes in the behaviour. GAC (0.6 mg/kg) and DZ augmented open arm entries, the open arm/closed arm entries ratio and increased time spent in the open arm on the elevated plus maze. In the open field, GAC (0.6 mg/kg) and DZ significantly increased ambulation and reduced the immobility time. EGb 761 showed a similar profile. GAC (0.6 mg/kg) and DZ significantly attenuated the increased latency to feed in novel environment. By contrast, EGb 761 and Ginkocer further augmented feeding latency. None of the drugs tested showed any significant effect in the social interaction test. GAC showed consistent and significant anxiolytic activity in all the variables investigated. By contrast, EGb 761 and Ginkocer, which are devoid of GAC, did not evoke significant activity. However, increased rearing and decreased immobility time only in open field behaviour shown by EGb 761 may be due to some antianxiety activity of a lesser degree. Our observations suggest that GAC may be the active constituents of Ginkgo biloba responsible for the anxiolytic activity.

Schneider B.[Ginkgo biloba extrakt bei peripheren arteriellen verschlubkrankheiten] Article in German. Arzneim. Forsch. 1992.42:428-436.

Shaw D, Leon C, Kolev S, et al. Traditional remedies and food supplements: a 5-year toxicological study (1991-1995). Drug Saf 1997.Nov; 17 (5): 342-356.

Snow J. 1996. Ginkgo biloba Monograph. Protocol Journal of Botanical Medicine. 2 (1) 9-15.

Tomb RR, Foussereau J, Sell Y. Mini-epidemic of contact dermatitis from ginkgo tree fruit (Ginkgo biloba L.) Contact Dermatitis 1988.Oct;19(4):281-283.
Abstract: 3 cases of contact dermatitis from ginkgo fruit are reported. Swelling of the prepuce can be the only clinical sign of intolerance, as was observed in 1 case. Diagnosis of contact dermatitis to ginkgo fruit should be made in cities where female ginkgo trees grow, in Chinese, Japanese and South-East Asian subjects, who are aware of the ginkgo nut's culinary qualities within the fruit, as well as in children who play with the fallen fruits as "marbles".

Vale S, Subarachnoid heamorrhage associated with Ginkgo biloba Lancet.1998 Jul4;352(9121):36.

Voelker R. Herbs and Anesthesia. JAMA, 281(20).May 26, 1999.1882.

Wesnes KA, Faleni RA, Hefting NR, et al. The cognitive, subjective, and physical effects of a ginkgo biloba/panax ginseng combination in healthy volunteers with neurasthenic complaints. Psychopharmacol Bull 1997;33(4):677-683.
Abstract: We evaluated the effects of a Ginkgo biloba/ginseng combination on cognitive function in this 90-day, double-blind, placebo-controlled, parallel-group study. Sixty-four healthy volunteers (aged 40 to 65 years), selected on the basis of fulfilling the ICD-10 F48.0 criteria for neurasthenia, were assigned randomly to four equal dosing groups, receiving 80, 160, or 320 mg of the combination b.i.d. or placebo. Assessments were performed on the day before dosing, and again at Days 1, 30, and 90 at 1 hour after the morning dose and 1 hour after the afternoon dose. The assessments included the Cognitive Drug Research (CDR) computerized assessment system, the Vienna Determination Unit, cycle ergometry, and various questionnaires. The treatments were well tolerated by all volunteers. On Day 90 at 1 hour post morning dosing, dose-related improvements were seen on the CDR tests, the 320 mg dose being significantly superior to placebo. These effects, however, were reversed 1 hour after the afternoon dose, possibly suggesting that a longer inter-dosing interval would be preferable. The 80-mg dose produced a significant benefit on the ergometry assessment of heart rate at maximum load. There were also several supporting changes from other assessments, including an advantage of 320 mg over placebo on the global score from the Symptom Checklist-90-revised (SCL-90-R) at Day 90.

Zhu L, et al. Neuron degeneration induced by verapamil and attenuated by EGb761. J Basic Clin Physiol Pharmacol 1997 8(4):301-314.
Abstract: Calcium channel blockers are used as neuroprotective agents, as glutamate antagonists. However, it has been found that calcium channel blockers may compromise neuronal survival after long-term exposure. To explore the mechanisms of the toxicity of calcium channel blockers on neurons, we studied the morphological characteristics and biochemical changes of cultured cortical neurons treated with verapamil, a calcium channel blocker. We now report that cerebral cortical cultures exposed to verapamil for 48 h undergo neuronal degeneration in both concentration-dependent and time-dependent fashion, possibly partially through the activation of apoptosis. On the other hand, it was found that Ginkgo biloba extract (EGb761) attenuated verapamil-induced neuronal injury, suggesting the possibility of using verapamil combined with EGb761 clinically. Furthermore, both B-50 immunoactivity (BIA) and the concentration of intracellular calcium in single neurons ([Ca2+]i) decreased after a 48-h exposure to verapamil, suggesting that the mechanisms of verapamil-induced degeneration may be associated with the disruption of intracellular calcium homeostasis and the inhibition of normal axonal elongation.