Interaction Likely but Uncertain Occurrence and Unclear Implications

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.

Potential or Theoretical Adverse Interaction of Uncertain Severity

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

	Beneficial or Supportive Interaction, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

Preliminary

Effect and Mechanism of Action

Platinum compounds have well-documented neurological and renal toxicities. Pretreatment, coadministration, and posttreatment use of ginkgo extracts with platinum chemotherapy may exert protection against drug toxicities. The interaction is unsupported by human evidence.

Research

Two preliminary experimental studies have investigated whether the established neuroprotective and renal-protective properties of ginkgo might be active against platinum toxicity. One rodent study demonstrated that pretreatment with ginkgo reduced cisplatin ototoxicity, as measured by compound action potential–determined auditory threshold and reduced hair cell damage on scanning electron microscopy, compared with cisplatin alone. Blood urea nitrogen (BUN) and creatinine levels were also lower in the pretreatment group, and histological renal damage was lower than in the nonginkgo group. Finally, rates of tumor growth were unaffected by ginkgo-pretreatment versus cisplatin-alone animals inoculated with squamous cell carcinoma SCC-158 line. ⁶⁷ Another study examined the effects of coadministration (rather than pretreatment) with ginkgo and cisplatin in mice. Sensory nerve conduction velocity and the growth of dorsal root ganglia neurons in culture were superior in the ginkgo coadministration group. ⁶⁸

Integrative Therapeutics, Clinical Concerns, and Adaptations

In both animal studies, oral ginkgo dose was moderately high, approximately 100 mg/kg. Assuming known interspecies pharmacokinetic scaling algorithms, this is approximately equivalent to a daily human dose of 1000 mg, which is higher than the normal therapeutic range for ginkgo extracts. However, acute toxicity of ginkgo is low, and the interaction is plausible. Thrombocytopenia should be monitored because the antiplatelet effects of high doses of ginkgo have not been studied. However, human studies are needed to determine the effectiveness of ginkgo against platinum-induced toxicity.

	Beneficial or Supportive Interaction, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

Preliminary

Effect and Mechanism of Action

Nephrotoxicity is the principal adverse effect of cyclosporine. Ginkgo may significantly ameliorate cyclosporine-induced nephrotoxicity. In addition, acute rejection responses in cyclosporine-immunosuppressed patients may lead to ischemic damage to the graft organ. Ginkgo offers an additional degree of protection from such damage, which is also mediated in part through PAF.

Research

Cyclosporine is known to increase PAF. Rodent studies with ginkgolide B in cyclosporine-immunosuppressed animals have shown that the hemodynamic renal damage induced by the drug can be reversed by BN 52021 administration. ⁶⁹ A rodent study of skin allograft in mice found that whole-leaf ginkgo extract could reproduce the effect of BN 52021 in prolonging allograft survival, although the effect was less than with the ginkgolide B isolate. ⁷⁰ Animal studies have also suggested a protective effective for cardiac allografts and against cardiac ischemic-reperfusion injury. ^71,72 A Japanese in vitro study of the interaction between cyclosporine and BN 52021 in human monocytes from asthma patients suggested that the two agents may be synergistic in reducing inflammatory cytokine production. ⁷³ Another in vitro study, using human liver microsomes, found that EGb 761 abolished cyclosporine-induced lipid peroxidation. ⁷⁴

A double-blind pilot study ( n=20) examined the effects of pretreatment with BN 52021 both in renal graft donors before harvesting and in recipients before grafting, versus placebo. Immunosuppression was with cyclosporine and prednisone. Posttransplant renal failure was 33% in the placebo group and 0% in the BN 52021 group, who also had better serum creatinine values after transplantation than the controls. ⁷⁵

Integrative Therapeutics, Clinical Concerns, and Adaptations

The pharmacological data, although mostly experimental, suggest several potential benefits from the concurrent administration of ginkgo with cyclosporine in immunosuppressed graft patients. The mechanisms underlying improved graft survival and protection against ischemic-reperfusion injury are likely multifactorial. Renal graft patients must confront the paradox that cyclosporine, as well as tacrolimus, is nephrotoxic. Naturopathic physicians and other practitioners of botanical medicine have incorporated ginkgo, along with related renal-protective herbs, into protocols for protective support of renal graft patients. ⁷⁶ Cyclosporine being a substrate of CYP3A4 should not cause concern in that the pharmacokinetic effects of ginkgo on this enzyme are not considered significant. ^36,37 This infrequently discussed interaction could be of great potential value to renal allograft patients, whether using cyclosporine or unrelated immunosuppressants. ⁷⁷ On a cautionary note, one transplant team reported undisclosed use of ginkgo as being responsible for postoperative bleeding after a hepatic transplant. ¹³

	Potential or Theoretical Beneficial or Supportive Interaction, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

Preliminary

Effect and Mechanism of Action

Doxorubicin is known to induce dose-related cumulative cardiotoxicity (short term and long term). This may be reduced by concurrent ginkgo administration.

Research

Few studies have directly examined the possibility that ginkgo and its constituents may ameliorate anthracycline-associated cardiopathy. One rodent study examined the effects of concurrent EGb 761 and doxorubicin administration in mice, one group of which was also pretreated with ginkgo before induction of gastric tumors with benzo(a)pyrene. The ginkgo-pretreated animals had a lower tumor incidence and had higher hepatic glutathione and glutathione- S-transferase levels. Concurrent doxorubicin and oral EGb 761 did not additively increase the antitumor effect, compared with doxorubicin alone, but reduced cardiotoxic markers, both histological damage and lipid peroxidation levels. ⁷⁸ Another study examined the effects of EGb 761 on various parameters of doxorubicin cardiotoxicity in otherwise-normal animals. The EGb-treated animals had significantly lower mortality, ascites, myocardial lipid peroxidation, normalization of antioxidant enzymes, reversal of electrocardiographic (ECG) changes, and minimal ultrastructural damage of the heart, compared with doxorubicin alone. ¹⁵ In unrelated studies, ginkgo has been shown to ameliorate the adverse effects of bleomycin. ^79,80 Antioxidant protectant effects have also been shown for other drugs, including acetaminophen and vancomycin. ^81,82

Integrative Therapeutics, Clinical Concerns, and Adaptations

Doxorubicin is one of the most widely used antineoplastic agents, but its effectiveness is limited by well-documented cardiotoxic adverse effects, which can manifest decades after cessation of treatment. ⁸³ The pathogenetic mechanisms of anthracycline cardiotoxicity are not fully understood, although the ultimate clinical presentation is indistinguishable from typical congestive heart failure. Although an early toxicity may be observed, shortly after commencement of administration (especially in elderly patients), the symptoms of progressive heart failure can appear months or even years after conclusion of the treatment, and the cardiomyopathy initially may be quite asymptomatic. Several possible cardiac protection agents have been examined, but none has been found effective, including vitamin E and N-acetyl cysteine. The iron-chelating agent dexrazoxane (Zinecard) reduces cardiotoxicity but has been associated with possible reduction in antitumor effects; part of the doxorubicin toxicity may be caused by FeII-dox-complex free-radical formation. ⁸⁴

Based on the preliminary animal evidence, and considering the known pharmacology of ginkgo, patients receiving doxorubicin may benefit from a cardioprotection protocol incorporating ginkgo extracts, together with related herbal agents such as hawthorn and nutritional supplements such as coenzyme Q10 and acetyl-carnitine. Further studies are required to examine the potential benefits of this interaction.

Interaction Possible but Uncertain Occurrence and Unclear Implications

Inadequate

Effect and Mechanism of Action

A possible effect of EGb 761 on fluorouracil administration in combination with immediate ginkgo pretreatment has been proposed. This may enhance distribution of the chemotherapeutic agent to tumor sites and reduce side effects.

Research

Ginkgo and 5-FU have been concomitantly administered on colorectal patients ⁸⁵ and pancreatic cancer patients. ⁸⁶ These studies used a parenteral preparation (EGb 761 ONC) as a 30-minute intravenous-push pretreatment before administration of 5-FU (500 mg/m ² /day) for 6 days. These were effectively phase II trials. No adverse effects of the combination were noted, and some improvement was recorded in two patients, with a cessation of cancer progression in several who had previously failed the 5-FU. Quality-of-life parameters and median survival times were not altered. The authors suggest further combination investigation may be warranted. The present studies suggest that the combination is safe and does not lead to increased toxicity.

Integrative Therapeutics, Clinical Concerns, and Adaptations

Although the data are preliminary, corresponding to a phase II trial, the effects of ginkgo extracts as a combination agent in chemotherapy not only have the potential to ameliorate drug-induced toxicities (see Doxorubicin), but also may have anticancer effects. This is a promising topic for integrative oncology that requires research and clinical investigation. ⁸⁷

	Beneficial or Supportive Interaction, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

Mixed

Effect and Mechanism of Action

Sexual dysfunction is a well-documented adverse effect of SSRI antidepressant therapy. Ginkgo leaf extract may be useful in ameliorating such adverse effects by various mechanisms, including NO-dependent vasorelaxation.

Research

A small number of studies have investigated this possible beneficial interaction, but the evidence is mixed. In a negative study, Kang et al. ⁸⁸ found an unusually large placebo effect in a 2-month double-blind randomized controlled trial of SSRI-induced sexual dysfunction after ginkgo administration in increasing doses up to 240 mg/day for 8 weeks total. There was no difference between the EGb 761 and control groups, both reporting significant decrease in symptoms of dysfunction. An open trial of men and women using a variety of antidepressant medications with an unspecified ginkgo extract for 4 weeks at an average dose of 209 mg/day reported effectiveness in reducing SSRI-related symptoms, more so in women ( n= 33) than men ( n= 30). ⁸⁹ The study was subsequently criticized for methodological weaknesses and inadequate statistical analysis by more than one correspondent. ^90,91 A small ( n= 22), positive study by Ashton et al. ⁹² found a slight but incomplete reversal of SSRI-induced sexual dysfunction in men and women after higher-dose ginkgo administration, although the extract product details were not disclosed.

Report

A single case report exists of a woman taking fluoxetine who experienced relief from fluoxetine-induced genital anesthesia after concurrent administration of EGb 761, 180 to 240 mg/day for 2 weeks. ⁹³

Integrative Therapeutics, Clinical Concerns, and Adaptations

This interaction is plausible but cannot be regarded as firmly substantiated. However, the prevalence of SSRI-related sexual dysfunction and excellent safety and toxicological profile of ginkgo leaf extract, whether alone or in combination, may prompt integrative practitioners to conduct an empirical trial with affected patients. Circumstantial support for this approach derives from the known antidepressant effects of ginkgo and its general effectiveness in combination with a variety of antidepressant medications. ⁹⁴

	Potential or Theoretical Beneficial or Supportive Interaction, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

Mixed

Effect and Mechanism of Action

Gentamicin and the aminoglycoside antimicrobials have well-documented adverse effects of ototoxicity and nephrotoxicity. Concurrent administration of ginkgo leaf extract may modulate these toxicities, through multiple mechanisms.

Research

The same researchers who examined protective effects of ginkgo leaf extract against Adriamycin-induced cardiotoxicity (see Doxorubicin) also performed a rodent study to investigate the effects of ginkgo on gentamicin-induced nephrotoxicity. After 2 days of pretreatment with EGb 761 (300 mg/kg op) and 8 days of concurrent administration with 80 mg/kg gentamicin, serum markers of kidney function and histopathology in Wistar rats demonstrated significant protective effects for the ginkgo-combination versus gentamicin-alone group. ⁹⁵ Another animal study examined neurosensory cochlear damage induced by gentamicin using both electrosensory and histopathological criteria in guinea pigs. Pretreatment with ginkgo extract reduced the level of acute toxic changes. ⁹⁶ However, in conflict with these studies, another rodent study of ototoxicity induced by the related aminoglycoside alizarin (amikacin, Amikin) suggested that ototoxicity may be increased by concurrent administration of EGb 761 and alizarin versus alizarin alone. ⁹⁷

Integrative Therapeutics, Clinical Concerns, and Adaptations

This potential interaction is an extrapolation from the known neuroprotective and neuroreparative effects of ginkgo extracts. Protection against the neurosensory toxicity and nephrotoxicity of gentamicin is a plausible beneficial interaction with some evidence from animal experiments, but clinical reports and studies are not available. The rodent studies are also open to methodological criticism, particularly the high dosage levels of EGb 761 used, which do not readily translate to normal human dose schedules for the extract.

Based on current data, concurrent administration of gentamicin or aminoglycoside and ginkgo cannot be recommended without qualification. However, if clinical symptoms of cochlear toxicity or vestibular toxicity persist after cessation of aminoglycoside therapy, subsequent ginkgo leaf extract administration likely would be beneficial in helping reverse the symptoms, although in some cases, certain forms of damage (i.e., to hair cells) may be irreversible. Nephrotoxicity caused by aminoglycosides is considered more reversible than ototoxicity, although the evidence from other forms of drug-induced nephrotoxicity would support the use by extrapolation of ginkgo leaf extract in this context. Until further data are available, firm clinical directions about this interaction are not possible.

	Potential or Theoretical Beneficial or Supportive Interaction, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

Inadequate

Effect and Mechanism of Action

Haloperidol is a heterocyclic antipsychotic drug associated with adverse effects of akathisia and tardive dyskinesia common to the thorazine group of neuroleptics. A beneficial reduction in adverse effects and an increase in drug efficacy, possibly associated with antioxidant activity of the ginkgo extract, may take place with concomitant administration.

Research

A double-blind trial with refractory schizophrenia patients ( n= 109) compared haloperidol, 25 mg/day, alone to the same dose of haloperidol with EGb 761, 360 mg/day, for 12 weeks. Both groups showed some improvement in psychobehavioral scores, although the ginkgo group improved more than the haloperidol-only group. Extrapyramidal symptoms were significantly reduced in the combination group. ⁹⁸ In two related studies, the same authors repeated these findings and also measured the levels of superoxide dismutase (SOD) before and after treatment with the combination; SOD levels were maintained in the ginkgo group more than the controls. The improvements in psychobehavioral assessment scores were positively correlated with SOD levels. ^99,100

Integrative Therapeutics, Clinical Concerns, and Adaptations

The initial studies by one group of researchers provide an intriguing insight into the possible benefits of combining ginkgo with antipsychotic drugs. The prominent extrapyramidal adverse effects of these agents have long been a cause for concern, particularly during long-term neuroleptic administration, during which tardive dyskinesia symptoms may become irreversible. This has caused some controversy in psychiatric circles, with critics such as Breggin ¹⁰¹ and others suggesting that the modus operandiof the neuroleptics in psychotic patients is “brain disabling” by causing cellular damage at the neuronal level.

Although the newer neuroleptic drugs have less severe adverse effects than haloperidol and the thorazine-related heterocyclics, the problem remains significant. The possibility that the established neuroprotective and neuroreparative effects of ginkgo leaf extracts may minimize drug toxicity deserves further investigation. Until more data are available, this must be classed as a “theoretical but plausible” beneficial interaction.

	Potentially Harmful or Serious Adverse Interaction—Avoid
	Biomodal or Variable Interaction, with Professional Management
	Potential or Theoretical Beneficial or Supportive Interaction, with Professional Management

Inadequate

Effect and Mechanism of Action

Perioperative administration of ginkgo leaf is suggested to increase the likelihood of surgery-related and postoperative bleeding. Ginkgo leaf concentrated extracts have inhibitory effects on platelet aggregation in vitro and ex vivo. Antiplatelet activity may operate not only through inhibition of PAF, but also through other aggregation inducers such as thrombin, ADP, collagen, and arachidonic acid. However, clinically significant in vivo antiplatelet effects have not been established in vivo.

Research

Epidemiological and survey data suggest that consumption of herbal and dietary supplements among preoperative patients is common. ¹¹ Failure to disclose herbal medicine usage may be as high as 70% of patients. ¹⁰ Norred et al. ¹⁰² surveyed 500 elective surgery patients, of whom 51% used herbal and nutritional products in the 2 weeks before surgery. Of surveyed patients, 24% consumed 50 different herbs; classification by potential adverse effects revealed that 27% of surgical patients consumed natural pharmacological agents that may inhibit coagulation, affect blood pressure (12%), cause sedation (9%), have cardiac effects (5%), or alter electrolytes (4%). Direct studies of ginkgo use in the preoperative scenario are unavailable.

Reports

Several case reports of excessive postoperative bleeding are available, varying in quality from low to unassessable. Fessenden et al. ¹² reported a case after laparoscopic cholecystectomy in a patient using an unidentified “gingko” (sic) peparation. ¹² The patient was apparently also taking a “multivitamin,” the ingredients of which were not disclosed. The report is impossible to evaluate due to lack of information about the form and dose of the herb.

A report by Norred and Finlayson ¹⁰³ of postsurgical bleeding following mastectomy after use of high doses of ginkgo extract (375 mg four times daily) involved polypharmacy and thus confounds simple interpretation. The patient was also taking vitamin E (800 IU/day for 10 years) and ginseng (300 mg four times daily for 6 weeks), along with bilberry, astragalus, and several prescription medications, although none that directly affects coagulation. ¹⁰³ Although a typical “real life” scenario, the case report is difficult to evaluate, particularly the role of ginkgo extract in the adverse event.

Bebbington et al. ¹⁰⁴ also reported a case of apparently persistent postoperative bleeding after a hip arthroplasty. The 77-year-old woman was concurrently taking aspirin and “simple anti-inflammatories.” Allegation of ginkgo use (120 mg/day) was made by a relative, and the authors attribute the excessive bleeding to the herb. Given the concurrent use of ASA and unspecified anti-inflammatory medications, any single causal attribution seems unwarranted.

Destro et al. ¹⁰⁵ report two similar histories of 50-year-old women undergoing plastic surgery who both experienced diffuse perioperative bleeding and subsequent bilateral hematoma after their rhytidoplasty and blepharoplasty procedures. Medical history, concurrent medications, and validation of ginkgo involvement were not given, although apparently both cases were “linked by chronic auto medication with a commercial extract of ginkgo.”

Yagmur et al. ¹⁰⁶ made a better-documented report of postoperative bleeding with thorough assessments of various coagulation parameters. A 75-year-old woman was taking an 80-mg/day dose of a commercial preparation for more than 1 year before an ambulatory procedure that was followed by extensive bleeding. Postoperative aggregation tests showed a decreased level of aggregation in response to collagen, although ADP, adrenaline, and ristocetin stimuli all resulted in normal aggregation. The patient discontinued the ginkgo postoperatively. Bleed times in response to collagen were reduced from 228 seconds to 168 seconds at 10 days after cessation of the ginkgo.

Clinical Implications and Adaptations

Dire warnings about the dangers of postoperative bleeding with concomitant use of ginkgo extracts are controversial. Norred and Brinker ¹⁰⁷ noted that given the established reluctance of patients to disclose herbal medication usage, overzealous admonitions to “discontinue all herbs prior to surgery” may have the effect of further encouraging clandestine herb use by surgical patients, thus hindering patient communication and rapport and compromising patient safety.

Patient safety mandates a preoperative screening for herb-nutrient-drug interactions as a required element of admission. Ginkgo should be included in advisories to elective surgery patients about potential adverse effects of herbs and nutritional supplements on hemostasis, particularly older women undergoing plastic surgery involving ocular areas, based on the limited case reports. The potential interaction should be presented as a possibility that can be sensibly averted by avoiding ginkgo leaf extract consumption preoperatively. However, the stress-alleviating aspects of ginkgo could also be of therapeutic benefit in the postoperative period, and the acute stress of surgery may be ameliorated by ginkgo administration. ^87,108

Interaction Likely but Uncertain Occurrence and Unclear Implications

Inadequate

Effect and Mechanism of Action

Trazodone, an antidepressant 5-hydroxytryptamine (5-HT ² ) receptor blocker, can cause heavy sedation at antidepressant doses of approximately 400 mg/day. Concurrent ginkgo use could potentiate sedation. The interaction cannot be considered established.

Report

An 80-year-old patient with Alzheimer's disease taking nonsedative doses (20 mg at night) of trazodone commenced ginkgo (form unspecified) at 80 mg twice daily. After 3 days the patient became comatose and was revived by 1 mg of intravenous flumazenil. Both the ginkgo and the trazodone were being used at low levels; concurrent medications were not disclosed. The authors suggest that because of the flumazenil response, benzodiazepine mechanisms were involved (since flumazenil is often used to reverse benzodiazepine-induced intoxication). ⁹ This single report is insufficient basis to consider the interaction between trazodone and ginkgo extract as established. From the known pharmacodynamics of trazodone, concurrent ginkgo must have been potentiating trazodone effects by at least twentyfold because the patient was taking a nonsedating dose. Some sources include this report under a heading of “possible interactions with benzodiazepines,” which is also difficult to justify. ⁴

Research

Current research data do not help elucidate the mechanism or likelihood of this interaction. In vitro effects on neuronal transmission and activity remain poorly understood and are undoubtedly complex, as well as unknown in vivo. ^109,110 Also, the antidoting mechanism of flumazenil and its principal active metabolite 1-methyl-chlorophenyl-piperazine (mCPP) on benzodiazepines is not fully understood, although it may be independent of the benzodiazepine site. ¹¹¹ Extrapolations from the available data to support the interaction report are speculative.

Clinical Implications and Adaptations

These are unclear at this time. For older patients (>75 years) using central nervous system drugs, cautious commencement of ginkgo administration would be prudent. Titration of ginkgo dose toward the desired end-dose range can be made gradually over weeks while monitoring for adverse effects.

Potential or Theoretical Adverse Interaction of Uncertain Severity—Avoid

Mixed

Effect and Mechanism of Action

Theoretical pharmacodynamic convergence occurs between the inhibitory effects of ginkgo leaf dry extracts on platelet aggregation and the hypoprothrombinemic effects of warfarin. The interaction is theorized to increase overall risk of bleeding, although no compelling evidence exists for the clinical occurrence of the interaction, and a single isolated report is contradicted by limited available trial evidence, which suggests the risk may be overstated.

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, including increase in endogenous aggregation inhibitors such as NO and 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 mixed.

As discussed under Clopidogrel, preclinical investigations by European manufacturers of their ginkgo leaf extracts for medicinal product licensing have been reviewed by DeFeudis ⁵ and in the American Herbal Pharmacopoeiamonograph. ⁴ Schwabe (the German producers of EGb 761) failed to find any effect on bleed times at 240 mg EGb 761 daily for 7 days in healthy volunteers, either alone or in combination with acetyl salicylate. The Beaufort-IPSEN-Pharma group's double-blind trial with 32 healthy volunteers found no effect on bleed time or other hemostatic parameters after 2 weeks of 120 to 480 mg/day.

In the French study cited earlier (see Clopidogrel), EGb at 120, 240, or 480 mg/day in 23 normal males for 2 weeks had no effect on platelet function or coagulation. ²³ A trial of 50 healthy volunteers found no significant effect of ginkgo on clotting and bleed time parameters when administered alone for 7 days, versus placebo in a crossover design. ²² Another study with healthy volunteers examined the effect of ginkgo extract on peripheral microcirculation and found no effect on platelet aggregation but a significant increase in RBC aggregation. ⁵³

A small clinical study examined the effects of ginkgo on INR in warfarin-anticoagulated patients. The small crossover trial examined the effects of ginkgo leaf dry extract (100 mg/day orally) and coenzyme Q10 on INR values in 14 outpatients (average age, 64.5 years) maintained on warfarin anticoagulation. INR was not affected, and the mean warfarin dose remained unchanged. ¹¹²

Also as previously discussed, Jiang et al. ²⁴ conducted a open-label trial with 12 healthy male volunteers and examined pharmacokinetic and hemostasis parameters after administration of ginger or ginkgo, alone or with warfarin. Aggregation, INR, warfarin enantiomer concentrations in plasma and urine, and warfarin enantiomer binding were measured at days 1 and 7. The ginkgo dose was two tablets of EGb761 standardized 24/6 three times daily for 1 week. Neither ginger nor ginkgo produced any significant effect on clotting status or on the pharmacokinetics and pharmacodynamics of warfarin.

Report

A single report is available that associates concurrent warfarin and ginkgo use with intracerebral hemorrhage. A 78-year-old woman with a history of dementia, myocardial infarction, hypertension, and atrial fibrillation had used warfarin for 5 years since a coronary bypass procedure. She also had a pacemaker. Sudden-onset apraxia was followed by a computed tomography (CT)–based diagnosis of left parietal hemorrhage; her prothrombin time (PT) was 16.9 and partial thromboplastin time (PTT) 35.5. Ginkgo use was discovered (dose, form, and regimen unstated) for the preceding 2 months. Anticoagulation reversed after cessation of warfarin and ginkgo, without vitamin K administration; however, the patient remained apraxic. ¹¹³ Fugh-Berman and Ernst ²⁰ characterized this case as “possible,” but a single-point score above “unevaluable.”

Clinical Implications and Adaptations

The 4-hydroxycoumarin compound warfarin is the most widely used anticoagulant drug in the Western world. It is known for a high variability in interindividual and intraindividual response. The primary individual factors affecting response variability are age and polymorphisms of CYP450 2C9. ¹¹⁴ The incidence of warfarin-related bleeding complications is difficult to estimate because of methodological issues surrounding data collection and interpretation. Recent calculations suggest that improved anticoagulation control has reduced the serious ADR category of “major bleeds, non-fatal” incidence to approximately 2.5% to 8.0%, with a “minor bleed” incidence of about 15% per year. Fatal bleed estimates vary from 1% to 4.8% annually. ⁶³ Warfarin interacts with a wide range of drugs, including antibiotics, central nervous system agents, and cardiac drugs, as well as dietary substances, many of which increase anticoagulation. ¹¹⁵

All this confounds the already-complex situation of determining the medical appropriateness, form, and level of anticoagulation, especially in older individuals with multiple risk factors for bleeding, such as unstable INR, comorbidities (especially bleeding related), polypharmacy (especially with NSAIDs), advanced age, and difficulty in compliance with requirements of coagulation control.

From an integrative perspective, the patient populations who might benefit most from the neuroprotective and antiischemic effects of ginkgo, such as older (>75 years) individuals with a history of dementia or cerebral ischemia, are also much more likely to be anticoagulated with warfarin. ¹¹⁶ Because no way currently exists to identify those who might be at risk of a ginkgo-induced adverse event, let alone a warfarin-ginkgo interaction, integrative practitioners are arguably confronted by a more complex choice than their conventional care counterparts. This includes whether to switch to different forms of antithrombotic therapy, including strategies based on natural agents such as garlic and nattokinase, to gain benefits from ginkgo administration against possible ischemic damage. (Use of warfarin alternatives is normally restricted to those who have a demonstrated intolerance for the drug.) A case-by-case evaluation, coupled with vigilant monitoring, is essential. Recently available laboratory tests that examine genetic parameters of hypercoagulability, as well as soluble fibrin monomer and dimer, can provide useful information in this regard.

Carbamazepine (Carbatrol, Tegretol), clonazepam (Klonopin), clorazepate (Tranxene), divalproex semisodium, divalproexan sodium (Depakote), ethosuximide (Zarontin), ethotoin (Peganone), felbamate (Felbatol), fosphenytoin (Cerebyx, Mesantoin), levetiracetam (Keppra), mephenytoin, mephobarbital (Mebaral), methsuximide (Celontin), oxcarbazepine (GP 47680, oxycarbamazepine; Trileptal), phenobarbital (phenobarbitone; Luminal, Solfoton), phenytoin (diphenylhydantoin; Dilantin, Phenytek), piracetam (Nootropyl), primidone (Mysoline), sodium valproate (Depacon), topiramate (Topamax), trimethadione (Tridione), valproate semisodium, valproic acid (Depakene, Depakene Syrup), vigabatrin (Sabril), zonisamide (Zonegran).

Some secondary reviewers recommend avoidance of ginkgo with anticonvulsants because of the presence of a “neurotoxin” in the seed and the extracts. ^117,118 This refers to a specific anti–vitamin B ⁶ compound, 4′- O-methylpyridoxine (MPN), present only in the seeds and thought to be responsible for causing convulsions after intoxication following seed (nut) consumption in China and Japan. ¹¹⁹ Levels of MPN in ginkgo leaf (1-5 µg per leaf) are much lower than in seed (80 µg per seed), and neurotoxic effects, including convulsions, occur at oral levels of 11 mg/kg (LD ⁵⁰ of 50 mg/kg) in guinea pigs. The amount of MPN in a typical human therapeutic daily dose of EGb 761 would be about 10 to 50 µg/day, suggesting that intoxication and interaction are unlikely. ⁴ Van Beek has reviewed MPN toxicity in depth. ⁶ Clinical reports of MPN intoxication from ginkgo leaf consumption are absent. A recent speculative case report alleging fatal ginkgo-induced seizures, possibly from MPN intoxication or pharmacokinetic interaction with valproate and phenytoin, was unreliable. The authors failed even to confirm the use of the herb, much less mention dose, frequency of administration, and so on, while including comments about ginkgo nut toxicity and suggesting unproven pharmacokinetic interactions with anticonvulsants through CYP450 2C9 induction. ¹²⁰

MAO-A inhibitors:Isocarboxazid (Marplan), moclobemide (Aurorix, Manerix), phenelzine (Nardil), procarbazine (Matulane), tranylcypromine (Parnate).

MAO-B inhibitors:Selegiline (deprenyl, L-deprenil, L-deprenyl; Atapryl, Carbex, Eldepryl, Jumex, Movergan, Selpak); pargyline (Eutonyl), rasagiline (Azilect).

Evidence from in vitro and ex vivo rodent studies on MAO-A and MAO-B inhibitory activity does not suggest central MAO inhibition by ginkgo. A human study using radiolabeled L-deprenyl and clorgyline (which inactivate MAO-A and -B isoforms, respectively) after 1 month of pretreatment with 60 mg EGb 761 twice daily in 10 normal subjects showed no effect on MAO activity in any brain region imaged by positron emission tomography (PET). ¹²¹ Peripheral MAO inhibition is not precluded by these studies.

Buformin (Andromaco Gliporal, Buformina), chlorpropamide (Diabinese), glimepiride (Amaryl), glipizide (Glucotrol, Glucotrol XL), glyburide (glibenclamide; Diabeta, Glynase, Glynase Prestab, Micronase, Pres Tab), insulin (animal-source insulin: Iletin; human analog insulin: Humanlog; human insulin: Humulin, Novolin, NovoRapid, Oralin), metformin (Dianben, Glucophage, Glucophage XR); combination drugs: glipizide and metformin (Metaglip), glyburide and metformin (Glucovance); phenformin (Debeone, Fenformin), tolazamide (Tolinase), tolbutamide (Orinase, Tol-Tab).

Data are conflicting on the possible effects of ginkgo on pancreatic beta-cell activity, as well as on oral hypoglycemic agents. In a study on the effects of EGb 761 in patients with non-insulin-dependent diabetes mellitus (NIDDM, diet and medication controlled), Kudolo ¹²² suggests that hyperinsulinemic (insulin-resistant) patients should avoid EGb 761 because of an increase in insulin level on an oral glucose tolerance test (OGTT). Kudolo et al. ¹²³ performed a later study that found no effect of EGb 761 on pancreatic beta-cell activity. A Japanese group performed several rodent studies that suggest possible biphasic effects of ginkgo extracts on 2C9, the p450 enzyme that metabolizes sulfonylurea and “glitazone” oral hypoglycemic agents. ^46,124 The relevance of these data to humans is unknown. Suggestions of clinically significant interactions between oral hypoglycemics and ginkgo extracts are not warranted by the available data at this time.

Bendroflumethiazide (bendrofluazide; Naturetin), combination drug: bendrofluazide and propranolol (Inderex); benzthiazide (Exna), chlorothiazide (Diuril), chlorthalidone (Hygroton), cyclopenthiazide (Navidrex), combination drug: cyclopenthiazide and oxprenolol hydrochloride (Trasidrex); hydrochlorothiazide (Aquazide, Esidrix, Ezide, Hydrocot, HydroDiuril, Microzide, Oretic); combination drugs: hydrochlorothiazide and amiloride (Moduretic); hydrochlorothiazide and captopril (Acezide, Capto-Co, Captozide, Co-Zidocapt); hydrochlorothiazide and enalapril (Vaseretic); hydrochlorothiazide and lisinopril (Prinzide, Zestoretic); hydrochlorothiazide and losartan (Hyzaar); hydrochlorothiazide and metoprolol (Lopressor HCT); hydrochlorothiazide and spironolactone (Aldactazide); hydrochlorothiazide and triamterene (Dyazide, Maxzide); hydroflumethiazide (Diucardin), methyclothiazide (Enduron), metolazone (Zaroxolyn, Mykrox), polythiazide (Renese), quinethazone (Hydromox), trichlormethiazide (Naqua).

A paradoxical report in a secondary source suggests that a hypertensive patient receiving a thiazide diuretic took ginkgo (unspecified) and experienced a rise in blood pressure, which was reversed only by cessation of both agents. ¹²⁵ Given the vasorelaxant effects of ginkgo extracts, this interaction appears improbable, and the report is not reinforced by any other data at this time.