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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
Interaction Likely but Uncertain Occurrence and Unclear Implications

Probability: 6. Unknown
Evidence Base: Inadequate

Effect and Mechanism of Action

Anesthetic-induced sleeping time may be altered by pretreatment with ginkgo. The mechanism of action is unknown.

Research

Ginkgo leaf extracts are known to cross the physiological intact blood-brain barrier (BBB) in a rodent model. A shortening effect on narcosis-induced sleeping times was demonstrated when a single intraperitoneal dose of EGb 761 at 25 and 50 mg/kg body weight or ginkgolide B at 1 and 5 mg/kg was administered before sodium barbital–induced narcosis. 31 Ginkgolide A was ineffective. A similar study also found shortening of sleeping time after intraperitoneal administration of hexobarbital, α-chloralose, and urethane in mice. 32 However, these researchers found that ginkgolide A isolate and bilobalide isolate could reproduce the shortening effects of the whole-leaf extract. A human study using quantitative electroencephalographic (EEG) data established that a single 240-mg dose of EGb 761 induced a significant increase in EEG activity 3 hours later, corresponding to that associated with “cognitive activator drugs.” This suggests effective penetration of the human BBB. 33

Clinical Implications and Adaptations

In the absence of reports, and given the small number of rodent studies, this interaction cannot be characterized clearly at this time. The pharmacological evidence for a mechanism is circumstantial, but the prospect that EGb 761 extracts may cross the intact BBB and interact with medications affecting neurotransmission is finite. More research is required to understand the effects of ginkgo extracts on increasing brain activity in opposition to anesthesia.

Given the additional possibility of antiplatelet effects on primary hemostasis during surgical procedure (see surgery), elective surgery patients should be carefully questioned regarding disclosure of self-administered herb use and advised to refrain from ginkgo consumption before surgery, to prevent possible interactions with anesthetics.

Antiplatelet Thromboprophylactics
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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