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Ginkgo

Botanical Name: Ginkgo biloba L.
Pharmacopoeial Name: Ginkgo folium
Common Names: Ginkgo, maidenhair tree.

Summary Table
herb description

Family

Ginkgoaceae.

Habitat and Cultivation

Sole survivor of an ancient botanical taxon (Ginkgoales), the ginkgo tree is now widely cultivated as an urban ornamental because of its pollution resistance. Considered a “native” to China, large commercial plantations in the temperate areas of the United States and Western Europe provide most crude herb for medicinal extracts.

Parts Used

Leaf.

Common Forms

  • Dried Leaf:   Powdered.

  • Tincture, Fluid Extract:   50% ethanol.

  • Standardized Dry Extract:   22% to 27.0% flavonoids and 5.0% to 7.0% terpene ginkgolides. Dry extract preparations usually stipulate maximum permitted levels of ginkgolic acid (<5 ppm).

herb in clinical practice

Overview

Ginkgo leaf extract is unusual in that its current use originates entirely from European pharmacological studies in the 1960s rather than a long history of traditional use. Notably, many secondary sources incorrectly claim ginkgo has been used for centuries; the fruit or nut, not the leaf, is the traditional medicine in Chinese herbal practice. Positive clinical trials demonstrating efficacy of ginkgo leaf extract for Alzheimer's disease and other age-related dementias have helped position it as a consistent top-10 best seller throughout Europe and North America in recent years. In the United States, retail sales of ginkgo surpassed $36 million in 2002, and in the same year an estimated 1.375 billion daily single treatments of ginkgo were prescribed in Germany alone. This constitutes a substantial volume of post-marketing surveillance data, which generally confirms the minimal toxicity and adverse effect profile of the extract. Adverse effect incidence corresponds to the low levels noted in clinical trials (<1.5%).

The chemistry of ginkgo leaf extract is complex and includes several unique terpenoid compounds. Research has centered on these compounds’ pharmacology, including inhibition of platelet aggregation by ginkgolide B, which is an unusually high-affinity ligand for the platelet aggregation (platelet-activating) factor (PAF) receptor. However, the known pharmacodynamics of the herb are generally considered a synergistic result of multiple constituents, including flavonol glycosides and oligomeric proanthocyanidins, as well as the terpenoids. Almost all the clinical research has been conducted with the concentrated (50:1) standardized Ginkgo biloba extracts, EGb 761 and LI 1370. Partly because of interest in potential antiplatelet therapeutic agents, several studies have employed isolates of the diterpene trilactones, either ginkgolide B (BN 52021) alone or a combination of ginkgolides A, B, C, and J (BN 52063); however, these data may have limited application to whole-leaf dry extract. In turn, botanical practitioners often use hydroethanolic liquid extracts of whole leaf when preparing blended individual prescriptions. Such extracts have been poorly investigated compared to the standardized dry-extract material, to which they should not be regarded as therapeutically equivalent. Ginkgo folium has therapeutic monographs by the German Commission E (1998) 1 and World Health Organization (WHO, 1999) 2 and subsequent monographs (2003) by the European Scientific Cooperative on Phytotherapy (ESCOP) 3 and American Herbal Pharmacopoeia . 4 Longer works by DeFeudis 5 and van Beek 6 provide more comprehensive and in-depth reviews of the extensive literature.

Historical/Ethnomedicine Precedent

Traditional Western therapeutic indications for ginkgo leaf are absent because of its historically recent incorporation into the materia medica, although seeds have been used in Chinese medicine for centuries.

Known or Potential Therapeutic Uses

Altitude sickness, asthma, Alzheimer's disease and multi-infarct dementia; cerebral insufficiency and associated impairments of memory, learning, attention, and cognitive function (enhancement of these functions in healthy and in aging adult populations, as well as after head trauma); depression, dysmenorrhea, hypoxia; neuroprotection, ischemic protection (cardiac, cerebral, renal), and neurorestoration of disease and iatrogenic nerve damage; macular degeneration, neurosensory deficits including tinnitus, cochlear hearing impairment, oxidative stress, peripheral vascular disorders including intermittent claudication and Raynaud's disease; reduced retinal blood flow, vertigo.

Key Constituents

  • Terpenes:   Ginkgolides A, B, C, and J (diterpene trilactones); bilobalide (sesquiterpene).

  • Flavonoids:   Glycosides of quercitin, kaempferol, and isorhamnetin; (+)-catechin, (−)-epicatechin, (−)-epigallocatechin, and (+)-gallocatechin; oligomeric and polymeric procyanidins.

Phenolic acids, including ginkgolic acid; essential oil.

Therapeutic Dosing Range

  • Fluid Extract:   1:1, 3.0 to 8.0 mL/day.

  • Standardized Extract:   120 to 240 mg/day in divided doses.

Note: Unless otherwise stated in this monograph, ginkgo leaf and ginkgo leaf extract refer to the standardized solid extract preparations that have formed the basis of almost all studies of ginkgo leaf.

interactions review

Strategic Considerations

The consensus of the authoritative botanical monographs is that there are no established interactions between ginkgo leaf (or its standardized extracts) and prescription drugs. Some secondary sources suggest that interaction with anticoagulants is theoretically possible. 3,4From the conventional side, Stockley ' s Drug Interactions cites several herbs that interact with anticoagulants, but does not include ginkgo. 7 Given the widespread use of ginkgo and its multisystem actions, classified by DeFeudis 5 into four broad categories (vasoregulation, cognition-enhancement, stress alleviation, gene regulation), the range of possible interactions may be larger and more complex than suggested by the current literature and reports.

The literature is uneven in quality, leading to interpretive problems. Botanical monographs have distinguished between effects of traditional forms of ginkgo leaf preparations (and the properties of the 50:1 standardized extracts) and effects of isolated constituents (e.g., terpenoid ginkgolides). Conventional sources frequently fail to distinguish form, dose, and duration of administration of ginkgo extracts in their reporting; often also misspelling the name of the herb as “gingko.” 8-16Despite the low quality of reports, some trends emerge when reviewing secondary literature.

A tendency of ginkgo extract alone to induce spontaneous bleeding (i.e., in healthy individuals) is often assumed in mainstream reports of ginkgo interactions; this is controversial. Relative to its high level of use, very few reports of spontaneous bleeding are actually attributable to ginkgo use. 16-19The poor standard of adverse event reporting of ginkgo-associated bleeds has been criticized both in journal correspondence and in several review articles. 20,21The apparent consensus of the reports on bleeding is that although ginkgo leaf extracts may have been associated with some hemorrhagic episodes, particularly ophthalmic neurovascular bleeds, causality is not established, and the general risk is probably overstated. At least three trials in healthy volunteers have failed to demonstrate any significant effect of ginkgo on platelet and coagulation parameters in healthy humans. 22-24Larger-scale trials are needed to investigate potential hematological effects of the extract, particularly in older populations. Several reports of postoperative bleeding are described later in the discussion of surgery.

Coadministration of ginkgo extracts with drugs affecting hemostasis presents questions with no simple evidence-based answers at present. Careful individual assessment and monitoring, with case-by-case therapeutic choices, remain the best practice. Given that the herb has been confirmed by meta-analysis of clinical trials to be effective for peripheral arterial disease, the precise populations that may choose gingko self-prescription may also be those more at risk of potential interactions because of their use of prescription drugs affecting hemostasis. (See further discussion later in the sections on interactions involving antiplatelet agents and warfarin.)

A number of the beneficial interactions of ginkgo listed later relate to its anti-ischemic, antioxidant, neuroprotective/neuroreparative, and chemoprotective effects. Typically, these interactions involve reduction of drug-induced toxicities, such as nephrotoxicity or neurotoxicity, through multiple mechanisms. these protective effects against drug toxicities most likely apply to numerous medications other than those for which preliminary evidence already exists; see doxorubicin, cyclosporine, gentamicin, and haloperidol later. Integrative oncological applications for ginkgo may include radiation sensitization as well as chemoprotection. 25 The role of ginkgo extracts in integrative oncological protocols is a new area of study. 5,26

Pharmacokinetics

There are some pharmacokinetic data on ginkgo extracts in both animal models and humans. Bioavailability of both the triterpene lactones and flavonol glycosides is high, with figures up to eighty per cent for some ginkgolide fractions. The flavonol glycosides are rapidly absorbed, but are extensively metabolized in humans, whilst the terpenoids are excreted unchanged, with overall half-life of about six hours. 27-30There is animal and human evidence that the extract constituents can cross the blood-brain barrier. 31-33The ginkgo flavonoids quercitin, kaempferol, and isorhamnetin are themselves substrates of P-glycoprotein (P-gp). 34

Effects on Drug Metabolism and Bioavailability

Until recently, the question of whether Ginkgo biloba extracts significantly affect drug-metabolizing systems had not been systematically investigated. Initial data from in vitro studies was typically inconclusive or conflicting, but results of more recent in vivo human trials now suggest minimal effects of the herb on cytochrome P450 (CYP450) activity.

Gurley et al. 35,36studied the effects of ginkgo in both young adults and, interestingly, older populations (60-76 years) using the probe–drug cocktail methodology they helped establish as a standard technique for evaluating CYP450 induction and inhibition effects. They found no significant effects of ginkgo extracts on CYP450 1A2, 3A4, 2E1, or 2D6. This corroborates the previous results of Duche et al., 37 as well as Markowitz et al., 38 who found no in vivo effect of ginkgo on CYP2D6 or CYP3A4. A negative study with donepezil (Aricept) and ginkgo coadministration in human volunteers failed to find any effects of ginkgo on the pharmacokinetics of the cholinesterase inhibitor. 39 Donepezil is metabolized by 2D6 and 3A4 and is conjugated by uridine glucuronosyltransferase (UGT) enzymes. Two different trials with separate probe substrates have demonstrated a lack of effect on CYP2C9, the warfarin S-enantiomer–metabolizing enzyme. 40,41This corroborates Jiang et al., 24 who found a lack of pharmacokinetic interaction between warfarin and ginkgo 24 (see warfarin discussion later). A subsequent in vivo trial did detect effects of ginkgo administration on phenotyped variants of CYP2C19 using omeprazole as a substrate; however, this drug is also a potent inhibitor of 2C19, so the general applicability of these results is problematic. 42 At this stage, the possibility of 2C19 interactions remains to be corroborated.

Reliable case reports suggestive of pharmacokinetic interactions between ginkgo and prescription drugs mediated by CYP450 effects are unavailable. Meanwhile, in vitro studies on ginkgo and CYP450 using various models, including rodent and human hepatocytes as well as recombinant enzymes, continue to provide prospective data for in vivo investigations. however, the in vitro models do not correlate well with in vivo data. 43-47

The issue of possible ginkgo effects on drug transporters has not been well studied to date. Absence of any observed effect of the herb on digoxin levels suggests a probable lack of effect on P-gp. 48 Certain ginkgo flavonoids such as quercitin and kaempferol, which are ubiquitous ingredients, have been shown to inhibit P-gp in vitro, as well as being substrates for P-gp themselves. 49,50

herb-drug interactions
Anesthesia, General
Antiplatelet Thromboprophylactics
Acetylsalicylic acid (acetosal, acetyl salicylic acid, ASA, salicylsalicylic acid; Arthritis Foundation Pain Reliever, Ascriptin, Aspergum, Asprimox, Bayer Aspirin, Bayer Buffered Aspirin, Bayer Low Adult Strength, Bufferin, Buffex, Cama Arthritis Pain Reliever, Easprin, Ecotrin, Ecotrin Low Adult Strength, Empirin, Extra Strength Adprin-B, Extra Strength Bayer Enteric 500 Aspirin, Extra Strength Bayer Plus, Halfprin 81, Heartline, Regular Strength Bayer Enteric 500 Aspirin, St. Joseph Adult Chewable Aspirin, ZORprin); combination drugs: ASA and caffeine (Anacin); ASA, caffeine, and propoxyphene (Darvon Compound); ASA and carisoprodol (Soma Compound); ASA, codeine, and carisoprodol (Soma Compound with Codeine); ASA and codeine (Empirin with Codeine); ASA, codeine, butalbital, and caffeine (Fiorinal). Clopidogrel (Plavix), Ticlopidine (Ticlid) Extrapolated, based on similar properties: Cilostazol (Pletal), dipyridamole (Permole, Persantine); combination drug: ASA and extended-release dipyridamole (Aggrenox, Asasantin).
Potential or Theoretical Adverse Interaction of Uncertain Severity

Probability: 3. Possible
Evidence Base: Mixed

Effect and Mechanism of Action

A theoretical pharmacodynamic convergence exists between the inhibitory effects of ginkgo leaf dry extracts on platelet aggregation and the antiplatelet effects of drugs affecting primary hemostasis at the platelet level. The significance of the interaction is unknown but appears to be both overstated and controversial. It may also be regarded as a “contraindication” rather than an interaction, depending on circumstances.

The presumed mechanism is a suggested convergence on platelet disabling by various pathways. Acetylsalicylic acid (aspirin/ASA) is a well-documented antiplatelet agent acting through inhibition of cyclooxygenase production of thromboxane A 2 (TXA 2 ). Ticlopidine (Ticlid) interacts with glycoprotein IIb/IIIa to inhibit fibrinogen binding to activated platelets and has been used to prevent thrombosis when aspirin is poorly tolerated. After reports of hematological adverse effects associated with ticlopidine, clopidogrel (Plavix) is currently the preferred antiplatelet agent in such cases. As with ticlopidine, clopidogrel is an irreversible antiplatelet drug operating through adenosine diphosphate (ADP) receptor antagonism.

Research

Experimental evidence indicates that the components of ginkgo leaf extract can cause in vitro and ex vivo inhibition of platelet aggregation, probably through several mechanisms. These include increase in endogenous aggregation inhibitors such as nitric oxide (NO) and prostaglandin I 2 (PGI 2 ), as well as direct inhibition of PAF. 51 However, the evidence for clinically significant effects of ginkgo extracts on platelet aggregation in humans is not available. In fact, Koch 52 showed that the concentrations of ginkgolides required to inhibit human (vs. rabbit) aggregation induced by PAF were more than 100 times greater than the levels demonstrated by pharmacokinetic measurements in humans after normal dosing at 120 to 240 mg EGb 761 daily. In other words, inhibition of PAF (itself a weak aggregatory factor) requires such high concentrations of ginkgolides that clinical effects of ginkgo consumption on platelet aggregation mediated by PAF seem improbable.

Preclinical investigations by European manufacturers of their ginkgo leaf extracts, as part of the toxicological and related regulatory requirements for medicinal product licensing, have been accessed and reported indirectly by DeFeudis 5 and in the 2003 American Herbal Pharmacopoeiamonograph of the dry extract. 4 Unpublished preclinical studies by Schwabe apparently failed to find any effect of EGb 761 on bleed times at 240 mg/day for 7 days in healthy volunteers, either alone or in combination with acetyl salicylate. The Beaufort-IPSEN-Pharma group sponsored a double-blind trial with 32 healthy volunteers and found no effect on bleed time or other hemostatic parameters after administration of 120 to 480 mg/day for 2 weeks.

A small preclinical study in France administered EGb at three dose levels (120, 240, and 480 mg/day) to 23 normal males for 2 weeks and found no effect on platelet function or coagulation. 23 Another study with healthy volunteers examined the effect of ginkgo extract administration on peripheral microcirculation in normal volunteers with a variety of red blood cell (RBC) and platelet parameters. No effect on platelet aggregation was noted, but a significant increase in RBC aggregation was found. 53 A study with 50 healthy volunteers found no significant effects on coagulation or clotting parameters after 240 mg/day EGb 761 versus placebo for 7 days in a crossover design trial. 22 The same study group continued the investigation into a second phase using the same subjects and assays and found no discernible effect of ginkgo when combined with aspirin, this time versus ASA alone in the same crossover design.

A brief report compared the arterial antithrombotic effect of EGb 761 and aspirin in an animal model using laser-induced emboli. Both aspirin and EGb 761 pretreatment reduced the number and duration of emboli compared with controls. They were not significantly different from each other in antiembolic effect. 54 A rodent study found a potentiation of the effect of ticlopidine by coadministering ginkgo in thrombosis-induced rats, such that 50 mg/kg ticlopidine with 40 mg/kg oral ginkgo was equivalent to 200 mg/kg ticlopidine in inhibition of ADP-dependent platelet aggregation. 55

Jiang et al. 24 conducted an open-label trial (12 healthy male volunteers) and examined a range of pharmacokinetic and hemostasis parameters after administration of ginger or ginkgo, alone or with warfarin (see later section). Aggregation, international normalized ratio (INR), warfarin enantiomer concentrations in plasma and urine, and warfarin enantiomer binding were all measured at day 1 and day 7. The dose of ginkgo was two tablets of EGb 761 standardized 24/6 three times daily for 1 week. Ginkgo had no significant effect on clotting status or the pharmacokinetics and pharmacodynamics of warfarin.

Reports

Only one report of bleeding associated with aspirin and ginkgo concurrent administration is available. A case of hyphema (retinal bleed) reported in a 70-year-old man with a history of coronary bypass and 3 years of aspirin use at 325 mg/day. One week after commencing standardized ginkgo at 40 mg twice daily, he had a spontaneous bleed in the anterior chamber of the right eye. This resolved on cessation of ginkgo, and there was no recurrence after cessation. 17 This case was classified as a “possible” interaction by Fugh-Berman and Ernst. 20

Although not involving aspirin, in a related report a 71-year-old man in Germany had taken 40 mg ginkgo extract twice daily for 30 months and started to take 600 mg ibuprofen daily for osteoarthritic pain. After 4 weeks of concurrent use, the patient was found comatose and died the next day from a massive intracerebral bleed. The authors suggest that TXA 2 -dependent platelet aggregation was inhibited by the ibuprofen, and that this combined with the antiplatelet effect of ginkgo. Concurrent medications were not recorded. 56

Integrative Therapeutics, Clinical Concerns, and Adaptations

The frequent suggestions in both professional and consumer literature that the ginkgo-aspirin combination is responsible for significant incidence of major hemorrhagic adverse events are unsubstantiated at this time. A single report and the failure to demonstrate any effects of the combination on bleed times in preclinical studies suggest that potential clinical problems associated with interaction are considerably overstated. Recent trial evidence demonstrating no effects of EGb 761 alone on hemostasis in healthy volunteers suggests that the potential interaction should probably be reclassified as “speculative.” 22 However, pending large-scale trials, prudence may warrant a degree of caution.

The mechanism of prophylaxis of cerebrovascular accident (CVA, stroke) by antiplatelet agents is poorly understood. Certain individuals may exhibit “aspirin resistance”; 57,58 one study suggested the incidence may be as high as 40%. 59 Also, any prophylactic benefit of aspirin may be caused by secondary rather than primary mechanisms, because hyperactivity of the anucleated platelet is predetermined to a degree at the megakaryocyte level during hematopoiesis. 60,61

Given the favorable profile of ginkgo extract effects on ischemic reperfusion injury, as well as the demonstrated neuroprotective and neuroreparative properties, there is a supportable argument for the benefits of ginkgo leaf extract as a prophylactic for stroke in healthyelderly populations. For those subpopulations with definite indications for prophylactic ASA administration, the combination with ginkgo is unlikely to disrupt hemostasis and may permit the lower dose range of aspirin to be administered, thereby reducing the incidence and severity of gastric mucosal damage. Definitive consensus on the dose of ASA required for effective thromboprophylaxis is not available, but the lower dose of 75 mg/day may suffice in combination with concurrent ginkgo extract use, with less potential gastric mucosal irritation and damage than the higher doses of ASA monotherapy. 62,63 Recent epidemiological evidence suggests that the 75-mg dose of ASA is responsible for the largest number of drug/adverse drug reaction (ADR)–related hospital admissions in the United Kingdom. 64 In this light, the recent (animal) evidence that ginkgo exerts ulceroprotective and cytoprotective effects against inflammation and duodenal ulcers is particularly relevant. 65,66

Cisplatin and Related Platinum Chemotherapy Compounds
Cyclosporine
Doxorubicin and Related Anthracycline Chemotherapy
Fluorouracil
Fluoxetine and Related Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants
Gentamicin and Related Aminoglycoside Antibiotics
Haloperidol and Related Antipsychotics
Surgery
Trazodone
Warfarin and Related Oral Vitamin K Antagonist Anticoagulants
theoretical, speculative, and preliminary interactions research, including overstated interactions claims
Anticonvulsant Medications
Monoamine Oxidase (MAO) Inhibitors
Oral Hypoglycemic Agents and Insulin
Thiazide Diuretics
Citations
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