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PLANTS-GINKGO BILOBA

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Ginkgo biloba is an ornamental tree commonly planted throughout the US. Human injury may result from ingestion or skin and eye contact with the fruit pulp, or through Ginkgo biloba extracts which are currently being investigated in Europe for their vasodilatory effects. This management will deal with both the plant itself and the extracts.

Specific Substances

    1) Ginkgo tree
    2) Ginkgo biloba
    3) Maidenhair tree
    4) Oriental Plum tree
    5) Silver apricot

Available Forms Sources

    A) USES
    1) GINKGO BILOBA LEAF EXTRACT - Has been used experimentally in Europe to treat diabetic patients, hearing disorders caused by vascular insufficiency, vertigo, Raynaud's disease, acrocyanosis, and post-phlebitis syndrome (Anon1985; Vorberg, 1985; Bauer, 1984).
    a) A review of clinical trials shows inconsistent results in the efficacy of ginkgo extract in treating cognitive impairment and dementia(Birks et al, 2002).
    b) 40 mg of Ginkgo biloba extract was beneficial in 31 patients who had mild to moderate memory impairment (Rai et al, 1991).
    c) Ginkgo biloba leaf extract 40 mg is available as Rokan(R) in Germany, sold by Intersan Institut fur Pharmazeutische und Klinische, Forschung GmbH, Ettlingen, West Germany (Vorberg, 1985). It also has been marketed under the name Tebonin(R), and the name Tanakan (IPSEN Laboratories) (Tallevi & Kurz, 1991).
    2) SEED KERNEL: The seed kernel is usually roasted before eaten. They are sold uncooked, canned, and candied. .
    3) Dermal exposure to fruit may result from gathering fruits or from children playing with fallen fruit (Tomb et al, 1988).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: The leaf extract has been used to treat cognitive impairment, memory loss, and dementia with mixed results. It has also been used to treat diabetic patients, hearing disorders due to vascular insufficiency, vertigo, and Raynaud's disease.
    B) PHARMACOLOGY: LEAF EXTRACT: Mechanism of action is not well understood, but it may exert sympathomimetic action. Primary chemicals include flavonoids (may have a role in antiinflammatory activity) and terpene lactones (bilobalide and ginkgolides). A ginkgolide mixture has been shown to antagonize platelet activating factor.
    C) TOXICOLOGY: FRUIT PULP: The direct irritant action and the allergenic sensitizing action of the fruit pulp is likely due to the presence of anacardic acids, phenols and resorcinols. Allergens (ginkolic acid and bilobol) found in the fleshy seed layer can cross-react with allergens in poison ivy and cashew nuts. The uncooked fruit pulp can produce a local hypersensitivity reaction similar to that of urishiol in poison ivy. Other parts of the plant have not been as well evaluated.
    D) EPIDEMIOLOGY: Exposures are uncommon. Toxicity is likely to be mild.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EVENTS: Dermatitis is likely to occur following contact with the plant. It can be irritating to mucous membranes and, if ingested or placed in the eye, it might cause periorbital edema, cheilitis, eye irritation, stomatitis, and rectal irritation. In sensitized patients, it can produce pruritus ani. Nausea and vomiting may occur after ingesting the leaf extract or the seeds.
    2) RARE: Ginkgo biloba extract has been associated with prolonged bleeding time after chronic use. This is thought to be due to inhibition of platelet-activating factor. However, randomized, placebo-controlled, double-blind study found no change in coagulation parameters, including bleeding time, with acute use. Cerebral hemorrhage has occurred in a few adults following chronic therapy.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Events are anticipated to be similar to adverse events and include nausea and vomiting following ingestion of the leaf extract or the seeds. Local hypersensitivity (dermatitis) and eye irritation is likely following contact with the fruit pulp.
    2) SEVERE TOXICITY: There have been infrequent reports of seizure activity in adults and children following large ingestions of seed kernels.
    0.2.4) HEENT
    A) FRUIT PULP: Contact with the juice of the fruit may cause conjunctivitis. Ingestion of as little as 2 pieces of uncooked fruit has caused perioral erythema and stomatitis.
    B) LEAF EXTRACT: Headache has been reported in some individuals receiving Ginkgo biloba extract.
    0.2.5) CARDIOVASCULAR
    A) LEAF EXTRACT: Ginkgo may cause vasodilatation of capillaries, arteries, and veins, and has shown an increase in cerebral blood flow in human studies.
    0.2.7) NEUROLOGIC
    A) Seizures have been observed in children after large ingestions of Ginkgo seed kernels. This is thought to be due to 4-methoxypyridoxine, a competitive antagonist of pyridoxine, which is needed for GABA synthesis.
    0.2.8) GASTROINTESTINAL
    A) FRUIT PULP: Tenesmus and rectal burning have been reported from eating the fruit. Allergically-sensitive patients may exhibit pruritus ani.
    B) LEAF EXTRACT: Nausea and gastrointestinal upset have been reported as side effects in patients using Ginkgo extract therapeutically.
    C) SEEDS: Vomiting and seizures have been reported after ingestion of a large number of seeds.
    0.2.13) HEMATOLOGIC
    A) LEAF EXTRACT has been shown to inhibit platelet aggregation and may result in spontaneous bleeding following chronic use.
    0.2.14) DERMATOLOGIC
    A) FRUIT PULP: Contact dermatitis has been associated with the fruit pulp. Cross-reactivity exists between the fruit pulp, poison ivy, and poison oak.
    0.2.20) REPRODUCTIVE
    A) When tested in sheep, Ginkgo extract increased uterine artery blood flow, but had little effect on maternal blood flow or amniotic pressure.

Laboratory Monitoring

    A) Toxic levels of ginkgo biloba have not been established. No specific laboratory tests are needed unless otherwise clinically indicated.
    B) Monitor fluid and electrolyte balance in patients with significant vomiting and/or diarrhea.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive; severe toxicity is not anticipated in most cases. Dehydration may develop in patients with significant vomiting and diarrhea. If symptoms are significant, administer IV fluids, and monitor fluid balance and electrolytes.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) SEIZURES: Large ingestions of ginkgo seed kernels have produced seizures in adults and children. Initially treat with benzodiazepines. In patients unresponsive to standard therapy (ie, benzodiazepines), pyridoxine may reverse the CNS effects observed after a large ingestion of ginkgo seed kernels. The exact dose of pyridoxine is not well established. BLEEDING RISK: There have been rare reports of bleeding, including cerebral hemorrhage with chronic use. Ginkgo therapy may inhibit platelet aggregation; monitor for bleeding in patients on chronic therapy or at risk for increased bleeding.
    C) DECONTAMINATION
    1) PREHOSPITAL: ORAL: Due to the irritant effects of the fruit pulp, emesis is not recommended. DERMAL: Wash exposed areas with water; avoid scratching to keep the irritant chemical from spreading to another site. OCULAR: Irrigate exposed eyes with copious amounts of room temperature water for at least 15 minutes.
    2) HOSPITAL: ORAL: Ingestion of the fruit pulp is irritating to the gastrointestinal tract and toxicity is generally self limited. Activated charcoal should only be considered after ingestions of a large number of seeds.DERMAL: Wash exposed areas with water; avoid scratching. Treatment is based on the severity of symptoms; topical corticosteroids may be necessary. Symptoms may take 7 to 10 days to resolve. OCULAR: Irrigate exposed eyes with copious amounts of room temperature water for at least 15 minutes. Conjunctivitis has been reported in some cases following exposure to the fruit pulp.
    D) AIRWAY MANAGEMENT
    1) Airway management is unlikely to be necessary following mild or moderate exposure. Airway support may be indicated in patients that develop seizures or CNS depression.
    E) ANTIDOTE
    1) There is no known antidote.
    F) ENHANCED ELIMINATION
    1) There is no available information; hemodialysis is not indicated.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic children with a minor ingestion of the fruit pulp of the Ginkgo biloba tree or a "taste" ingestion of the ginkgo biloba extract can be can be monitored at home with adult supervision. Following dermal contact, remove exposed clothing and rinse skin with water and flush eyes with copious amounts of water as needed.
    2) OBSERVATION CRITERIA: Children with persistent minor symptoms (ie, diarrhea, vomiting) or alteration in CNS function or seizure activity (adult or child) need to be evaluated in a healthcare setting.
    3) ADMISSION CRITERIA: Patients should be admitted, if symptoms persist or fail to respond to therapy (ie, seizure activity).
    4) CONSULT CRITERIA: Consult a toxicologist or poison center if the diagnosis is unclear.

Range Of Toxicity

    A) TOXICITY: A toxic dose has not been determined.
    B) ACUTE: Seizures have developed in toddlers who ingested 15 to 50 seeds, and in an adult who ingested 60 seeds. Two pieces of uncooked fruit has caused perioral erythema and catharsis. Contact with the pulp seeds has resulted in vesicular dermatitis.
    C) CHRONIC USE: Cerebral hemorrhage has been reported in a few adults following chronic ginkgo biloba administration.

Clinical Effects

Summary Of Exposure

    A) USES: The leaf extract has been used to treat cognitive impairment, memory loss, and dementia with mixed results. It has also been used to treat diabetic patients, hearing disorders due to vascular insufficiency, vertigo, and Raynaud's disease.
    B) PHARMACOLOGY: LEAF EXTRACT: Mechanism of action is not well understood, but it may exert sympathomimetic action. Primary chemicals include flavonoids (may have a role in antiinflammatory activity) and terpene lactones (bilobalide and ginkgolides). A ginkgolide mixture has been shown to antagonize platelet activating factor.
    C) TOXICOLOGY: FRUIT PULP: The direct irritant action and the allergenic sensitizing action of the fruit pulp is likely due to the presence of anacardic acids, phenols and resorcinols. Allergens (ginkolic acid and bilobol) found in the fleshy seed layer can cross-react with allergens in poison ivy and cashew nuts. The uncooked fruit pulp can produce a local hypersensitivity reaction similar to that of urishiol in poison ivy. Other parts of the plant have not been as well evaluated.
    D) EPIDEMIOLOGY: Exposures are uncommon. Toxicity is likely to be mild.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EVENTS: Dermatitis is likely to occur following contact with the plant. It can be irritating to mucous membranes and, if ingested or placed in the eye, it might cause periorbital edema, cheilitis, eye irritation, stomatitis, and rectal irritation. In sensitized patients, it can produce pruritus ani. Nausea and vomiting may occur after ingesting the leaf extract or the seeds.
    2) RARE: Ginkgo biloba extract has been associated with prolonged bleeding time after chronic use. This is thought to be due to inhibition of platelet-activating factor. However, randomized, placebo-controlled, double-blind study found no change in coagulation parameters, including bleeding time, with acute use. Cerebral hemorrhage has occurred in a few adults following chronic therapy.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Events are anticipated to be similar to adverse events and include nausea and vomiting following ingestion of the leaf extract or the seeds. Local hypersensitivity (dermatitis) and eye irritation is likely following contact with the fruit pulp.
    2) SEVERE TOXICITY: There have been infrequent reports of seizure activity in adults and children following large ingestions of seed kernels.

Heent

    3.4.1) SUMMARY
    A) FRUIT PULP: Contact with the juice of the fruit may cause conjunctivitis. Ingestion of as little as 2 pieces of uncooked fruit has caused perioral erythema and stomatitis.
    B) LEAF EXTRACT: Headache has been reported in some individuals receiving Ginkgo biloba extract.
    3.4.3) EYES
    A) CONJUNCTIVITIS: Contact with the juice of the fruit, either by direct splash, or indirectly by hand contact, may cause conjunctivitis (Saito, 1929).
    B) HYPHEMA: A 70-year-old man on aspirin therapy (325 mg daily for 3 years) developed recurrent blurred vision approximately one week after beginning ginkgo biloba extract tablets twice daily. Upon exam, hyphema was noted with no other abnormalities. The herbal product was stopped with no further bleeding noted on follow-up (Rosenblatt & Mindel, 1997).
    3.4.6) THROAT
    A) ERYTHEMA: Ingestion of as little as 2 pieces of the fruit has caused perioral erythema including swollen lips, and erythema of buccal mucosa, tongue, and throat (Becker & Skipworth, 1975).

Cardiovascular

    3.5.1) SUMMARY
    A) LEAF EXTRACT: Ginkgo may cause vasodilatation of capillaries, arteries, and veins, and has shown an increase in cerebral blood flow in human studies.
    3.5.2) CLINICAL EFFECTS
    A) CEREBROVASCULAR ACCIDENT
    1) Ginkgo preparations have been studied for effect on cerebral blood flow (CBF) in human and animal experiments. CBF was increased in 70% of human patients evaluated in one study. The effect was age related, with a 20% increase noted in those 30- to 50-years-old and up to 70% in those 50- to 70-years-old (Saponaro, 1973).
    2) Similar cardiovascular effects were monitored using a xenon-133 tracer technique (Agnoli, 1973). The average vasodilation in human studies has been 40% (Anon1985). The clinical significance of these findings is not known.

Neurologic

    3.7.1) SUMMARY
    A) Seizures have been observed in children after large ingestions of Ginkgo seed kernels. This is thought to be due to 4-methoxypyridoxine, a competitive antagonist of pyridoxine, which is needed for GABA synthesis.
    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) Headache has been reported in individuals receiving Ginkgo biloba extract (Anon1985).
    B) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 2-year-old boy developed vomiting and afebrile general tonic convulsions, 4 hours after eating approximately 50 roasted gingko nuts. A large number of nuts were found in his vomited matter and the 4-O-methoxypyridoxine levels in his serum and urine were elevated. Following treatment with diazepam and pyridoxal phosphate, he recovered completely (Hasegawa et al, 2006).
    b) Ingestion of large amounts of ginkgo seeds by small children or infants has resulted in coma and seizures. The toxin is thought to be 4-O-methylpyridoxine, a competitive antagonist of pyridoxine, which is needed for GABA synthesis (Wada et al, 1988; Kajiyama et al, 2002).
    c) After ingesting 15 to 60 ginkgo biloba seeds, 5 patients developed vomiting and general tonic-clonic seizures. Following treatment with diazepam and vitamin B6, all patients recovered completely (Hori et al, 2004; Huh & Staba, 1992).
    C) CEREBRAL HEMORRHAGE
    1) CASE REPORT: A 38-year-old healthy woman developed a frontal right hematoma and subarachnoid hemorrhage after taking ginkgo biloba (240 mg/d) and thiamine (900 mg/d) chronically for 4 years for leg pain. She developed a sudden onset of left sided weakness and slurred speech approximately 12 hours prior to admission. Upon admission, blood glucose was 146 mg/dL; no other laboratory values were reported. A brain CT confirmed the presence of the bleed. Cerebral angiography was normal along with a normal MRI (ie, absence of a sinus vein thrombosis or other abnormalities). She partially recovered her strength. Ginkgo biloba was discontinued. At follow-up 6 weeks later, the cerebral angiography remained normal. An idiosyncratic event could not be ruled out in this case (Pedroso et al, 2011).
    2) CASE REPORT: A 61-year-old man developed headache, back-pain, nausea, and sleepiness while taking ginkgo biloba 40 mg tablets 3 to 4 times a day for more than 6 months. Although CT exam was normal, a lumbar puncture confirmed the diagnosis of subarachnoid hemorrhage. The extract was stopped without further bleeding (Vale, 1998).

Gastrointestinal

    3.8.1) SUMMARY
    A) FRUIT PULP: Tenesmus and rectal burning have been reported from eating the fruit. Allergically-sensitive patients may exhibit pruritus ani.
    B) LEAF EXTRACT: Nausea and gastrointestinal upset have been reported as side effects in patients using Ginkgo extract therapeutically.
    C) SEEDS: Vomiting and seizures have been reported after ingestion of a large number of seeds.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and gastrointestinal upset have been reported with therapeutic use of ginkgo biloba extract; however, discontinuation of the extract was unnecessary (Vorberg, 1985).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 2-year-old boy developed vomiting and afebrile general tonic convulsions 4 hours after eating approximately 50 roasted gingko nuts. A large number of nuts were found in his vomitus and the 4-O-methoxypyridoxine levels in his serum and urine were elevated. Following treatment with diazepam and pyridoxal phosphate, he recovered completely (Hasegawa et al, 2006).
    b) After ingesting 15 to 60 ginkgo biloba seeds, 5 patients developed vomiting and general tonic-clonic seizures. Following treatment with diazepam and vitamin B6, all patients recovered completely (Hori et al, 2004; Huh & Staba, 1992).
    B) TENESMUS
    1) Rectal burning has been reported with ingestion of as little as 2 pieces of the fruit pulp (Becker & Skipworth, 1975).

Hematologic

    3.13.1) SUMMARY
    A) LEAF EXTRACT has been shown to inhibit platelet aggregation and may result in spontaneous bleeding following chronic use.
    3.13.2) CLINICAL EFFECTS
    A) PLATELET AGGREGATION
    1) Ginkgo biloba extract has been associated with prolonged bleeding time after chronic use (Yagmur et al, 2005). This is thought to be due to inhibition of platelet-activating factor. However, a randomized, placebo-controlled, double-blind study found no change in coagulation parameters, including bleeding time with acute use (Kohler et al, 2004).
    B) CASE REPORT
    1) Case reports have linked chronic use of Ginkgo extract to hemorrhagic complications such as subdural hemorrhage, hyphema, and subarachnoid hemorrhage (Rowin & Lewis, 1996; Vale, 1998; Rosenblatt & Mindel, 1997a). Basic science research casts doubt on whether standard doses of ginkgo extract have sufficient quantities of ginkolides to cause bleeding (Koch, 2005). Placebo-controlled trials using Ginkgo have not shown an increase in adverse events.
    2) A 61-year-old man developed headache, back-pain, nausea, and sleepiness while taking ginkgo biloba 40 mg tablets 3 to 4 times a day for more than 6 months. Bleeding time was increased to 6 minutes (normal 1 to 3) with a normal blood count. A lumbar puncture confirmed the diagnosis of a subarachnoid hemorrhage. The extract was stopped without further bleeding (Vale, 1998).

Dermatologic

    3.14.1) SUMMARY
    A) FRUIT PULP: Contact dermatitis has been associated with the fruit pulp. Cross-reactivity exists between the fruit pulp, poison ivy, and poison oak.
    3.14.2) CLINICAL EFFECTS
    A) DERMATITIS
    1) The fruit pulp is capable of producing primary irritation and allergic contact dermatitis (Sowers et al, 1965; Bolus, 1939; Saito, 1929). The skin reaction generally subsides within 7 to 10 days (Huh & Staba, 1992).
    2) CASE REPORT: A burning sensation of the forearms, followed 2 days later by swelling, erythema, and vesicular lesions which became generalized to the face, neck, and thighs was seen in a 25-year-old who handled the fresh fruit (Tomb et al, 1988).
    3) The intact fruit does not induce dermatitis. The concentration of phenols and resorcinols in the leaves is so small that the leaves generally are not allergenic (Mitchell et al, 1981). However, patch test with the leaves are occasionally reactive in a few sensitized patients (Nakamura, 1985).
    4) CASE REPORTS: Sowers et al (1965) reported contact dermatitis in several girls who had gingko splashed on their legs.
    5) SEED PULP: A streaky vesicular dermatitis was also described in young girls who came in contact with the crushed seed pulp which acted as both a primary irritant and as an allergen (McGovern & Barkley, 1999). The rash had the general appearance of poison ivy (Toxicodendron radicans).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) Allergens found in the fleshy seed layer appear to be ginkgolic acid and bilobol (Kawamura, 1928; Carrier et al, 1990) and can result in a vesicular rash similar to poison ivy (McGovern & Barkley, 1999).
    a) These substances will cross-react with allergens in poison ivy (Benezra et al, 1985) and cashew nut (Mitchell & Rook, 1979a).

Reproductive

    3.20.1) SUMMARY
    A) When tested in sheep, Ginkgo extract increased uterine artery blood flow, but had little effect on maternal blood flow or amniotic pressure.
    3.20.3) EFFECTS IN PREGNANCY
    A) ANIMAL STUDIES
    1) When tested in sheep, Ginkgo extract increased uterine artery blood flow, but had little effect on maternal blood flow or amniotic pressure (Anon1985).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Toxic levels of ginkgo biloba have not been established. No specific laboratory tests are needed unless otherwise clinically indicated.
    B) Monitor fluid and electrolyte balance in patients with significant vomiting and/or diarrhea.
    4.1.2) SERUM/BLOOD
    A) TOXICITY
    1) Toxic levels of ginkgo biloba have not been established.
    4.1.4) OTHER
    A) OTHER
    1) DERMAL
    a) A 10% ginkgo fruit in acetone solution is recommended for patch testing concentrations of fruit pulp greater than this may be a primary irritant (Tomb et al, 1988).

Methods

    A) CHROMATOGRAPHY
    1) An HPLC method has been developed using 0.3 to 1 g of leaves that will quantitate the amount of ginkgolide A, B, C, and bilabolide, in Ginkgo leaves (van Beek et al, 1990).
    2) Although the ginkgolides can be detected using thin-layer chromatography, the detection levels vary considerably with the various methods employed (Tallevi & Kurz, 1991).
    3) Reverse phase-high performance liquid chromatography (RP-HPLC) with diode-array detection is used to determine flavonoid content in the leaves (Lobstein et al, 1991; Sticher, 1993). It is not used clinically.
    a) Hasler & Meier (1993) have also described a RP-HPLC method to determine the quantification of flavonoids, and a method to measure terpenes by gas chromatography after silylation. Their work has also included the means to determine the amount of ginkgolides in extract based on biological methods to ascertain the pharmacological effect of ginkgolides (Hasler & Meier, 1993).
    4) Loggia et al (1993) described a HPLC method to determine the antiinflammatory activity of ginkgo biloba flavonoids. In vivo antiinflammatory activity was measured on mice following a topically-induced chemical dermatitis. The results indicated a dose-dependent effect of G. biloba biflavones (Loggia et al, 1993).
    5) One study deproteinized serum 4-O-methylpyridoxine (MPN) (a toxin found in Ginkgo biloba seeds) and directly introduced it onto an HPLC column using an ion-pair reagent in the mobile phase. This method was used to determine both the serum levels of MPN in 5 patients with Ginkgo biloba seed poisoning and the levels of free-form MPN in such seeds obtained in 8 regions of Japan. The authors suggested that this method is faster and has superior analytical sensitivity over the conventional methods, which require solid-phase extraction (Hori et al, 2004). In one case of intoxication, the concentration of 4-O-methylpyridoxine was determined using the same HPLC method (Hasegawa et al, 2006).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients should be admitted, if symptoms persist or fail to respond to therapy (ie, seizure activity).
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic children with a minor ingestion of the fruit pulp of the Ginkgo biloba tree or a "taste" ingestion of the ginkgo biloba extract can be monitored at home with adult supervision. Following dermal contact, remove exposed clothing and rinse skin with water and flush eyes with copious amounts of water as needed.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a toxicologist or poison center if the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Children with persistent minor symptoms (ie, diarrhea, vomiting) or alterations in CNS function or seizure activity (adult or child) need to be evaluated in a healthcare setting.

Monitoring

    A) Toxic levels of ginkgo biloba have not been established. No specific laboratory tests are needed unless otherwise clinically indicated.
    B) Monitor fluid and electrolyte balance in patients with significant vomiting and/or diarrhea.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS/NOT RECOMMENDED
    1) Due to the irritant effect of the fruit pulp, emesis is not recommended.
    6.5.2) PREVENTION OF ABSORPTION
    A) Ingestion of the fruit pulp is irritating to the gastrointestinal tract and toxicity is generally self limited. Activated charcoal should only be considered after ingestions of a large number of seeds.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive. Severe toxicity is not anticipated in most cases.
    2) There have been rare reports of increased bleeding time and a few reported cases of cerebral hemorrhage following chronic long-term therapy of ginkgo biloba.
    B) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Monitor the patient for dehydration secondary to vomiting and diarrhea. If symptoms are severe, monitor fluid and electrolytes.
    C) SEIZURE
    1) SUMMARY
    a) Large amounts of ingested ginkgo seed kernels may produce coma and seizures in infants or small children. This is thought to be due to the heat-stable antipyridoxine substance, 4-O-methylpyridoxine (Huh & Staba, 1992; Kajiyama et al, 2002).
    2) PYRIDOXINE
    a) Pyridoxine may reverse these CNS effects in severe cases. It appears reasonable and safe to administer pyridoxine to a patient having seizures refractory to standard therapy after a large ingestion of ginkgo seed kernels. The dose of pyridoxine is not well established, but a 2-year old girl did not have any further seizures after receiving a 2 mg/kg dose of pyridoxine and 0.3 mg/kg of diazepam (Kajiyama et al, 2002).
    b) A 2-year-old boy developed vomiting and afebrile general tonic convulsion 4 hours after eating approximately 50 roasted gingko nuts. Following treatment with diazepam (0.4 mg/kg IV) and pyridoxal phosphate (8 mg/kg IV), he recovered completely (Hasegawa et al, 2006).
    c) After ingesting 15 to 60 ginkgo biloba seeds containing 4-O-methylpyridoxine (a toxin found in ginkgo biloba seeds, also known as an antipyridoxine substance), 5 patients developed vomiting and general tonic-clonic seizures. Following treatment with diazepam and vitamin B6, all patients recovered completely (Hori et al, 2004; Huh & Staba, 1992).

Eye Exposure

    6.8.1) DECONTAMINATION
    A) Conjunctivitis has been reported if the eyes have been exposed to the irritant substance either directly or indirectly.
    B) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) SUMMARY
    1) Exposed areas of skin should be washed. Exposed clothing should be washed before it is worn again. Decontamination of the skin with water using a soft sponge or wash cloth should be conducted as quickly as possible.
    6.9.2) TREATMENT
    A) DERMATITIS
    1) It is important to discourage the patient from scratching the affected area. Scratching the affected area may transport the irritant to an unexposed site. Excoriation may result in secondary infection.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) SUMMARY
    1) There is no available information. Hemodialysis in unlikely to be necessary.

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose has not been determined.
    B) ACUTE: Seizures have developed in toddlers who ingested 15 to 50 seeds, and in an adult who ingested 60 seeds. Two pieces of uncooked fruit has caused perioral erythema and catharsis. Contact with the pulp seeds has resulted in vesicular dermatitis.
    C) CHRONIC USE: Cerebral hemorrhage has been reported in a few adults following chronic ginkgo biloba administration.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) LIQUID - The recommended dose of ginkgo daily is equivalent to 300 milligrams of the dried leaf (Houghton, 1994). It is available as an extract in a liquid form, which commonly contains 24% flavonoids and 6% terpenoids with a recommended daily dose of extract of 150 mg daily in three divided doses.
    2) TABLET - The suggested dosage of the standardized ginkgo biloba extract (24% ginkgo flavone glycosides and 6% total terpene lactones) is 120 to 160 milligrams/day (Anon , 2000). In the United States, ginkgo biloba extract is sold in tablet form containing 40 milligrams of extract with the recommended dosage of 1 tablet 3 times daily with meals.

Minimum Lethal Exposure

    A) SUMMARY
    1) Seizures have been observed in children after large ingestions of ginkgo seed kernels. This is thought to be due to 4-methoxypyridoxine, a competitive antagonist of pyridoxine, which is needed for GABA synthesis. A review of cases shows fatalities reported in ranges from 15 to 574 seeds (Kajiyama et al, 2002).
    2) In times of little food, infants have been fed ginkgo seed kernels. Coma and seizures have developed, with a 25% mortality, but no sequelae after recovery (Wada et al, 1988).

Maximum Tolerated Exposure

    A) SUMMARY
    1) Two pieces of uncooked fruit has caused perioral erythema and catharsis in an adult. Contact with the fruit pulp, which contains anacardic acids, phenols, and resorcinols, which may cause dermatitis (Becker & Skipworth, 1975). Contact with the pulp seeds has resulted in contact dermatitis in children (McGovern & Barkley, 1999).
    2) GINKGO EXTRACT: Each seed has approximately 80 mcg of 4-methoxypyridoxine (Kajiyama et al, 2002).
    B) CASE REPORTS
    1) ADULT
    a) A 38-year-old healthy woman developed a frontal right hematoma and subarachnoid hemorrhage after taking ginkgo biloba (240 mg/d) and thiamine (900 mg/d) for 4 years for leg pain. She developed a sudden onset of left sided weakness and slurred speech. A brain CT confirmed the presence of the bleed; cerebral angiography and MRI were normal. Bleeding time was not reported. She partially recovered her strength (Pedroso et al, 2011).
    b) A 61-year-old was diagnosed with subarachnoid hemorrhage and a bleeding time of 6 minutes (normal range: 1 to 3 minutes) while taking gingko biloba 40 mg tablets 3 to 4 times a day. The extract was stopped with no further bleeding (Vale, 1998).
    c) A 38-year-old woman developed vomiting and a single tonic-clonic seizure after ingesting 60 ginkgo biloba seeds. Following treatment with diazepam and vitamin B6, she recovered completely (Hori et al, 2004; Huh & Staba, 1992).
    2) PEDIATRIC
    a) Toddlers aged 1 to 2 years developed vomiting and seizures after ingesting between 14 and 50 seeds. The all recovered after treatment with diazepam and pyridoxine (Hori et al, 2004).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) A 2-year-old boy developed vomiting and afebrile general tonic convulsion 4 hours after eating approximately 50 roasted gingko nuts. The 4-O-methoxypyridoxine levels in his serum and urine were elevated (serum: 37 nanograms/milliliter (ng/mL) on admission and 157 ng/mL after 12 hours; urine: 397 ng/mL at 18 hours after admission and 20 ng/mL at 38 hours). Following treatment with diazepam and pyridoxal phosphate, he recovered completely (Hasegawa et al, 2006).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)MOUSE:
    1) GINKGO EXTRACT: 7725 mg/kg (Duke, 1985)
    B) LD50- (ORAL)RAT:
    1) GINKGO EXTRACT: greater than 10,000 mg/kg (Duke, 1985)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) LEAF EXTRACT
    1) The mechanism of action of Ginkgo leaf extract is not well understood, but is thought to exert sympathomimetic action. Although it is thought to be an inhibitor of COMT its lack of CNS effects indicates this effect may be of minimal importance (Anon1985).
    2) The primary chemicals of interest are flavonoids and terpene lactones (bilobalide and ginkgolides) (Sticher, 1993)(Sticher, 1993). Ginkgolides are C (20) cage molecules with 6 rings containing 5 carbons each (Huh & Staba, 1992). A more detailed discuss of Ginkgo constituents is available in Sticher (1993).
    3) It has a slight spasmolytic effect similar to papaverine. Hellegouarch et al (1985) performed experiments on both arterial and venous preparations and concluded the mechanism of action of Ginkgo leaf extract includes direct action on alpha-adrenoceptors. known of their properties (Kraus & Franz, 1989).
    4) Ginkgo biloba extract is thought to protect intestinal mucosa against ischemic damage by reducing neutrophil infiltration and lipid peroxidation. This conclusion is based on studies done on rats (Otamiri & Tagesson, 1989).
    5) A ginkgolide mixture (BN 52063) has been shown to antagonize platelet activating factor in man (Chung et al, 1987).
    6) Ginkgo biloba contains dimeric flavonoids that may have role in antiinflammatory activity (Loggia et al, 1993).
    B) FRUIT PULP
    1) The primary irritants and allergic sensitizers in the fruit pulp are C13, C15, and C17 alkenyl phenols, resorcinols, and anacardic acids similar to those found in the cashew (Anacardium occidentale). The ginkgo is allergenically cross-reactive in patients sensitized to plants in the botanical family Anacardiaceae, which includes poison ivy and poison oak. The fresh fruit pulp, with seed kernels removed, contains 3.1% anacardiac acids (w/w). Of these, 10.1% are C13-substituted, 67.9% C15, and 22.0% C17. The 5-alkenyl resorcinols (cardol, bilobol) constitute 0.53% of the pulp; only a trace of 3-alkenyl phenols (Cardanol, ginkgol) are present. 6-Alkenyl-2,4-dihydroxybenzoic acid (4-hydroxyanacardic acid) has been reported only in immature fruit (Morimoto, 1968; Mitchell & Rook, 1979; Gellerman, 1976; Benezra et al, 1985).

Toxicologic Mechanism

    A) The direct irritant action and the allergenic sensitizing action of the fruit pulp may be ascribed to anacardic acids, phenols, and resorcinols (Furukawa, 1934-35; (Morimoto, 1968; Gellerman, 1976; Adawadkar & El Sohly, 1981).
    B) The pharmacology of other components of the plant, notably in the heart wood, the sesquiterpene bilabanone, or in the roots, the diterpenoid ginkgolides, have not been assessed.

Physicochemical

Physical Characteristics

    A) GINKGO BILOBA EXTRACT is a white crystalline, tasteless compound which has an acid reaction (Saito, 1929).

Molecular Weight

    A) Not applicable. Ginkgo biloba contains multiple molecules.

References

General Bibliography

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