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1.  Does Ginkgo biloba reduce risk of cardiovascular events? 
Background
Cardiovascular disease (CVD) was a preplanned secondary outcome of the Ginkgo Evaluation of Memory (GEM) Study. The trial previously reported that Ginkgo biloba (G. biloba) had no effect on the primary outcome, incident dementia.
Methods and Results
The double-blind trial randomized 3069 participants over 75 years of age to 120 mg of G. biloba EGb 761 twice daily or placebo. Mean follow up was 6.1 years. The identification and classification of CVD was based on methods used in the Cardiovascular Health Study. Differences in time to event between G. biloba and placebo were evaluated using Cox proportional hazards regression adjusted for age and gender. There were 355 deaths in the study, 87 due to coronary heart disease with no differences between G. biloba and placebo. There were no differences in incident myocardial infarction (n=164), angina pectoris (n=207) or stroke (151) between G. biloba and placebo. There were 24 hemorrhagic strokes, 16 on G. biloba and 8 on placebo (not significant). There were only 35 peripheral vascular disease (PVD) events, 12 (0.8%) on G. biloba and 23 (1.5%) on placebo (p=0.04 exact test). Most of the PVD cases had either vascular surgery or amputation.
Conclusion
There was no evidence that G. biloba reduced total or CVD mortality or CVD events. There were more PVD events in the placebo arm. G. biloba cannot be recommended for preventing CVD. Further clinical trials of PVD outcomes might be indicated.
doi:10.1161/CIRCOUTCOMES.109.871640
PMCID: PMC2858335  PMID: 20123670
anticoagulation; peripheral vascular disease; cardiovascular disease; stroke; trials
2.  Ginkgo biloba and risk of cancer: Secondary Analysis of the Ginkgo Evaluation of Memory (GEM) Study 
Purpose
Evidence from in vitro and in vivo studies suggests that Ginkgo biloba has cancer chemopreventive properties, but epidemiological evidence is sparse. We analyzed cancer as a secondary endpoint in the Ginkgo Evaluation of Memory (GEM) Study, the largest randomized, double-blind, placebo-controlled clinical trial of Ginkgo supplementation to date.
Methods
A total of 3,069 GEM participants 75+ years of age were randomized to twice-daily doses of either 120mg Ginkgo extract (EGb 761) or placebo and followed for a median 6.1 years. We identified hospitalizations for invasive cancer by reviewing hospital admission and discharge records for all reported hospitalizations over follow-up. Using an intention-to-treat approach, we compared the risk of cancer hospitalization between participants assigned to treatment and those assigned to placebo.
Results
During the intervention, there were 148 cancer hospitalizations in the placebo group and 162 in the EGb 761 group (Hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.87–1.36; p=0.46). Among the site-specific cancers analyzed, we observed an increased risk of breast (HR, 2.15; 95% CI, 0.97–4.80; p=0.06) and colorectal (HR, 1.62; 95% CI, 0.92–2.87; p=0.10) cancer, and a reduced risk of prostate cancer (HR, 0.71; 95% CI, 0.43–1.17; p=0.18).
Conclusions
Overall, these results do not support the hypothesis that regular use of Ginkgo biloba reduces the risk of cancer.
doi:10.1002/pds.1979
PMCID: PMC2917376  PMID: 20582906
Ginkgo biloba; randomized controlled trial; breast cancer; prostate cancer; complimentary and alternative medicine
3.  Ginkgo biloba for Prevention of Dementia: A Randomized Controlled Trial 
Context
Ginkgo biloba is widely used for its potential effects on memory and cognition. To date, adequately powered clinical trials testing the effect of G biloba on dementia incidence are lacking.
Objective
To determine effectiveness of G biloba vs placebo in reducing the incidence of all-cause dementia and Alzheimer disease (AD) in elderly individuals with normal cognition and those with mild cognitive impairment (MCI).
Design, Setting, and Participants
Randomized, double-blind, placebo-controlled clinical trial conducted in 5 academic medical centers in the United States between 2000 and 2008 with a median follow-up of 6.1 years. Three thousand sixty-nine community volunteers aged 75 years or older with normal cognition (n=2587) or MCI (n=482) at study entry were assessed every 6 months for incident dementia.
Intervention
Twice-daily dose of 120-mg extract of G biloba (n=1545) or placebo (n=1524).
Main Outcome Measures
Incident dementia and AD determined by expert panel consensus.
Results
Five hundred twenty-three individuals developed dementia (246 receiving placebo and 277 receiving G biloba) with 92% of the dementia cases classified as possible or probable AD, or AD with evidence of vascular disease of the brain. Rates of dropout and loss to follow-up were low (6.3%), and the adverse effect profiles were similar for both groups. The overall dementia rate was 3.3 per 100 person-years in participants assigned to G biloba and 2.9 per 100 person-years in the placebo group. The hazard ratio (HR) for G biloba compared with placebo for all-cause dementia was 1.12 (95% confidence interval [CI], 0.94–1.33; P=.21) and for AD, 1.16 (95% CI, 0.97–1.39; P=.11). G biloba also had no effect on the rate of progression to dementia in participants with MCI (HR, 1.13; 95% CI, 0.85–1.50; P=.39).
Conclusions
In this study, G biloba at 120 mg twice a day was not effective in reducing either the overall incidence rate of dementia or AD incidence in elderly individuals with normal cognition or those with MCI.
doi:10.1001/jama.2008.683
PMCID: PMC2823569  PMID: 19017911
4.  Ginkgo biloba for Preventing Cognitive Decline in Older Adults 
Context
The herbal product Ginkgo biloba is taken frequently with the intention of improving cognitive health in aging. However, evidence from adequately powered clinical trials is lacking regarding its effect on long-term cognitive functioning.
Objective
To determine whether G biloba slows the rates of global or domain-specific cognitive decline in older adults.
Design, Setting, and Participants
The Ginkgo Evaluation of Memory (GEM) study, a randomized, double-blind, placebo-controlled clinical trial of 3069 community-dwelling participants aged 72 to 96 years, conducted in 6 academic medical centers in the United States between 2000 and 2008, with a median follow-up of 6.1 years.
Intervention
Twice-daily dose of 120-mg extract of G biloba (n=1545) or identical-appearing placebo (n=1524).
Main Outcome Measures
Rates of change over time in the Modified Mini-Mental State Examination (3MSE), in the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog), and in neuropsychological domains of memory, attention, visual-spatial construction, language, and executive functions, based on sums of z scores of individual tests.
Results
Annual rates of decline in z scores did not differ between G biloba and placebo groups in any domains, including memory (0.043; 95% confidence interval [CI], 0.034-0.051 vs 0.041; 95% CI, 0.032-0.050), attention (0.043; 95% CI, 0.037-0.050 vs 0.048; 95% CI, 0.041-0.054), visuospatial abilities (0.107; 95% CI, 0.097-0.117 vs 0.118; 95% CI, 0.108-0.128), language (0.045; 95% CI, 0.037-0.054 vs 0.041; 95% CI, 0.033-0.048), and executive functions (0.092; 95% CI, 0.086-0.099 vs 0.089; 95% CI, 0.082-0.096). For the 3MSE and ADAS-Cog, rates of change varied by baseline cognitive status (mild cognitive impairment), but there were no differences in rates of change between treatment groups (for 3MSE, P=.71; for ADAS-Cog, P=.97). There was no significant effect modification of treatment on rate of decline by age, sex, race, education, APOE*E4 allele, or baseline mild cognitive impairment (P>.05).
Conclusion
Compared with placebo, the use of G biloba, 120 mg twice daily, did not result in less cognitive decline in older adults with normal cognition or with mild cognitive impairment.
Trial Registration
clinicaltrials.gov Identifier: NCT00010803
doi:10.1001/jama.2009.1913
PMCID: PMC2832285  PMID: 20040554
5.  Investigation of herb-drug interactions with ginkgo biloba in women receiving hormonal treatment for early breast cancer 
SpringerPlus  2013;2:126.
Women receiving treatment for breast cancer commonly ingest herbal medicines. Little is known about the potential for herb-drug interactions in this population. The aim of this study is to investigate the effect of ginkgo biloba co-administration on the pharmacokinetics of tamoxifen, anastrozole and letrozole. This was a prospective open-label cross-over study in 60 women with early stage breast cancer taking either tamoxifen, anastrozole or letrozole (n=20/group). Participants received ginkgo biloba (EGb 761) for 3 weeks (120 mg twice daily). Trough concentrations of drugs were measured before and after ginkgo biloba treatment using LC-MS/MS. Toxicities were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events. Trough concentrations before and after treatment with ginkgo biloba were not significantly different for tamoxifen (93.5 ± 29.0, 86.5 ± 25.3 ng/mL; p=0.16), letrozole (91.1 ± 50.4, 89.6 ± 52.14 ng/mL; p=0.60) or anastrozole (29.1 ± 8.6, 29.1 ± 7.6 ng/mL; p=0.97). Ginkgo biloba was well tolerated, with no difference in toxicity during ginkgo biloba. Co-administration of ginkgo biloba does not significantly affect the pharmacokinetics of tamoxifen, anastrozole or letrozole. There was no difference in the toxicity profile of hormone therapy with ginkgo biloba use in women with early stage breast cancer.
doi:10.1186/2193-1801-2-126
PMCID: PMC3625417  PMID: 23596562
Anastrozole; Ginkgo biloba; Herb-drug interaction; Letrozole; Tamoxifen
6.  Assessment of health claims, content, and safety of herbal supplements containing Ginkgo biloba  
Food & Nutrition Research  2010;54:10.3402/fnr.v54i0.5221.
Background
European Regulation 1924/2006 states that all health claims made on foods need to be substantiated scientifically.
Objective
To apply the PASSCLAIM criteria for the scientific substantiation of health claims on foods to herbal supplements containing Ginkgo biloba. Evaluation of three selected claimed health effects for G. biloba (improvement of blood circulation, improvement of symptoms of old age, and improvement of memory) was achieved through review of publicly available scientific data. A total of 35 human intervention studies were evaluated. Commercially available products claimed to contain mainly G. biloba (N=29) were randomly sampled in the Netherlands and analyzed for their content on ginkgo extract. Also, a toxicological risk assessment was performed.
Results
The three selected health claims investigated could not be substantiated. This was mainly because of a lack of data from studies in healthy volunteers. In most studies results performed with a 24% standardized G. biloba extract were described. However, our chemical analysis showed that 25 of the 29 sampled products did not contain the required minimum 24% standardized extract. Moreover, in most preparations the content of substances typical for G. biloba did not conform to what was declared on the label. Since toxicity data for G. biloba are very limited, a safety limit could not be established.
Conclusions
Evidence is lacking for three health claims of herbal products with G. biloba. Neither safety nor efficacy can be guaranteed at the recommended daily dose. The multidisciplinary approach described in this paper provides good insight into issues that are relevant for the evaluation of health claims for herbal food supplements.
doi:10.3402/fnr.v54i0.5221
PMCID: PMC2950792  PMID: 20927202
Ginkgo biloba; health claims; substantiation; botanicals; content; safety
7.  A double-blind, randomized clinical trial of dietary supplementation on cognitive and immune functioning in healthy older adults 
Background
Declining cognitive function is relatively common and increasingly prevalent. Studies have shown that different nutrients (e.g., Ginkgo biloba and vitamin E) appear to be effective at improving memory and concentration, while less is known about their effect on immunity.
Methods
This study investigated the effect of Ginkgo Synergy® plus Choline (n = 33) and OPC Synergy® plus Catalyn® (n = 31) versus placebo (n = 33) in a 6-month, randomized, double-blind trial on cognitive and immune functioning among English-speaking, non-smoking, healthy older adults. The Stroop Color and Word Test, Trail Making Test A and B, Controlled Oral Word Association, Hopkins Verbal Learning, Mini-Mental State Exam, and Digit Symbol were administered at baseline and 3 and 6 months follow-up to assess cognitive functioning. Cytokines and growth factors were measured at baseline and 6 months to assess inflammation and immune functioning. Data were analyzed with linear mixed modeling.
Results
No serious adverse events were noted in this study. According to time on the Trail Making Test-B, the Ginkgo Synergy® plus Choline arm showed improvement from baseline to 3 months follow-up (mean difference = 24.2; SE = 6.4; 95% CI: 8.6, 39.7; p = 0.01). On the Controlled Oral Word Association Trial-S, the scores significantly increased for the Ginkgo Synergy® plus Choline arm from baseline to 6 months follow-up (mean difference = 2.1; SE = 0.8; 95% CI: 0.2, 3.9; p < 0.05) and for the OPC Synergy® plus Catalyn® arm from baseline to 3 months follow-up (mean difference = 2.1; SE = 0.8; 95% CI: 0.2, 4.0; p < 0.05). Epidermal growth factor significantly decreased from baseline to 6 months follow-up for the Ginkgo Synergy® plus Choline arm (mean difference = 120.7; SE = 28.4; 95% CI: 62.6, 178.8; p < 0.001).
Conclusions
Our study showed isolated and modest effects of a Ginkgo biloba plus choline-based formula on cognitive and immune functioning among healthy older adults with no history of significant cognitive deficits. Our trial was registered with clinicaltrials.gov (ID: NCT01672359). This study was supported by a grant from Standard Process, Inc.
doi:10.1186/1472-6882-14-43
PMCID: PMC3916807  PMID: 24495355
Cognitive functioning; Immune functioning; Ginkgo biloba; Choline; Dietary supplement; Older adults; Trail making test; Controlled oral word association; Epidermal growth factor
8.  Personality and medication non-adherence among older adults enrolled in a six-year trial 
British journal of health psychology  2011;16(Pt 1):151-169.
Objectives
Personality factors parsimoniously capture the variation in dispositional characteristics that affect behaviours, but their value in predicting medication non-adherence is unclear. We investigated the relationship between five-factor model personality factors (Conscientiousness, Neuroticism, Agreeableness, Extraversion, and Openness) and medication non-adherence among older participants during a six-year randomized placebo-controlled trial (RCT).
Design
Observational cohort data from 771 subjects aged ≥72 years enrolled in the Ginkgo Evaluation of Memory study, a RCT of Ginkgo biloba for prevention of dementia.
Methods
Random effects logistic regression analyses examined effects of NEO Five-Factor Inventory scores on medication non-adherence, determined via pill counts every 6 months (median follow-up 6.1 years) and defined as taking <80% of prescribed pills. Analyses adjusted for covariates linked with non-adherence in prior studies.
Results
Each 5 year increment in participant age was associated with a 6.7% greater probability of non-adherence (95% confidence interval, CI [2.4, 11.0]). Neuroticism was the only personality factor associated with non-adherence: a 1 SD increase was associated with a 3.8% increase in the probability of non-adherence (95% CI [0.4, 7.2]). Lower cognitive function was also associated with non-adherence: a 1 SD decrease in mental status exam score was associated with a 3.0% increase in the probability of non-adherence (95% CI [0.2, 5.9]).
Conclusions
Neuroticism was associated with medication non-adherence over 6 years of follow-up in a large sample of older RCT participants. Personality measurement in clinical and research settings might help to identify and guide interventions for older adults at risk for medication non-adherence.
doi:10.1348/135910710X524219
PMCID: PMC3126620  PMID: 21226789
9.  Randomised, double blind, placebo controlled comparison of ginkgo biloba and acetazolamide for prevention of acute mountain sickness among Himalayan trekkers: the prevention of high altitude illness trial (PHAIT) 
BMJ : British Medical Journal  2004;328(7443):797.
Objective To evaluate the efficacy of ginkgo biloba, acetazolamide, and their combination as prophylaxis against acute mountain sickness.
Design Prospective, double blind, randomised, placebo controlled trial.
Setting Approach to Mount Everest base camp in the Nepal Himalayas at 4280 m or 4358 m and study end point at 4928 m during October and November 2002.
Participants 614 healthy western trekkers (487 completed the trial) assigned to receive ginkgo, acetazolamide, combined acetazolamide and ginkgo, or placebo, initially taking at least three or four doses before continued ascent.
Main outcome measures Incidence measured by Lake Louise acute mountain sickness score ≥ 3 with headache and one other symptom. Secondary outcome measures included blood oxygen content, severity of syndrome (Lake Louise scores ≥ 5), incidence of headache, and severity of headache.
Results Ginkgo was not significantly different from placebo for any outcome; however participants in the acetazolamide group showed significant levels of protection. The incidence of acute mountain sickness was 34% for placebo, 12% for acetazolamide (odds ratio 3.76, 95% confidence interval 1.91 to 7.39, number needed to treat 4), 35% for ginkgo (0.95, 0.56 to 1.62), and 14% for combined ginkgo and acetazolamide (3.04, 1.62 to 5.69). The proportion of patients with increased severity of acute mountain sickness was 18% for placebo, 3% for acetazoalmide (6.46, 2.15 to 19.40, number needed to treat 7), 18% for ginkgo (1, 0.52 to 1.90), and 7% for combined ginkgo and acetazolamide (2.95, 1.30 to 6.70).
Conclusions When compared with placebo, ginkgo is not effective at preventing acute mountain sickness. Acetazolamide 250 mg twice daily afforded robust protection against symptoms of acute mountain sickness.
doi:10.1136/bmj.38043.501690.7C
PMCID: PMC383373  PMID: 15070635
10.  Effectiveness of Ginkgo biloba in treating tinnitus: double blind, placebo controlled trial 
BMJ : British Medical Journal  2001;322(7278):73.
Objective
To determine whether Ginkgo biloba is effective in treating tinnitus.
Design
Double blind, placebo controlled trial using postal questionnaires.
Participants
1121 healthy people aged between 18 and 70 years with tinnitus that was comparatively stable; 978 participants were matched (489 pairs).
Intervention
12 weeks' treatment with either 50 mg Ginkgo biloba extract LI 1370 three times daily or placebo.
Main outcome measures
Participants' assessment of tinnitus before, during, and after treatment. Questionnaires included items assessing perception of how loud and how troublesome tinnitus was. Changes in loudness were rated on a six point scale. Changes in how troublesome were rated on a five point scale.
Results
There were no significant differences in primary or secondary outcome measures between the groups. 34 of 360 participants receiving active treatment reported that their tinnitus was less troublesome after 12 weeks of treatment compared with 35 of 360 participants who took placebo.
Conclusions
50 mg Ginkgo biloba extract LI 1370 given 3 times daily for 12 weeks is no more effective than placebo in treating tinnitus.
PMCID: PMC26593  PMID: 11154618
11.  Effects of Ginkgo biloba in dementia: systematic review and meta-analysis 
BMC Geriatrics  2010;10:14.
Background
The benefit of Ginkgo biloba has been discussed controversially. The aim of this review was to assess the effects of Ginkgo biloba in Alzheimer's disease as well as vascular and mixed dementia covering a variety of outcome domains.
Methods
We searched MEDLINE, EMBASE, the Cochrane databases, CINAHL and PsycINFO for controlled trials of ginkgo for Alzheimer's, vascular or mixed dementia. Studies had to be of a minimum of 12 weeks duration with at least ten participants per group. Clinical characteristics and outcomes were extracted. Meta-analysis results were expressed as risk ratios or standardized mean differences (SMD) in scores.
Results
Nine trials using the standardized extract EGb761® met our inclusion criteria. Trials were of 12 to 52 weeks duration and included 2372 patients in total. In the meta-analysis, the SMDs in change scores for cognition were in favor of ginkgo compared to placebo (-0.58, 95% confidence interval [CI] -1.14; -0.01, p = 0.04), but did not show a statistically significant difference from placebo for activities in daily living (ADLs) (SMD = -0.32, 95% CI -0.66; 0.03, p = 0.08). Heterogeneity among studies was high. For the Alzheimer subgroup, the SMDs for ADLs and cognition outcomes were larger than for the whole group of dementias with statistical superiority for ginkgo also for ADL outcomes (SMD = -0.44, 95% CI -0.77; -0.12, p = 0.008). Drop-out rates and side effects did not differ between ginkgo and placebo. No consistent results were available for quality of life and neuropsychiatric symptoms, possibly due to the heterogeneity of the study populations.
Conclusions
Ginkgo biloba appears more effective than placebo. Effect sizes were moderate, while clinical relevance is, similar to other dementia drugs, difficult to determine.
doi:10.1186/1471-2318-10-14
PMCID: PMC2846949  PMID: 20236541
12.  Ginkgo biloba Extract for Patients with Early Diabetic Nephropathy: A Systematic Review 
Objectives. To evaluate the effectiveness and safety of a Ginkgo biloba extract for patients with early diabetic nephropathy. Methods. Randomised controlled trials (RCTs) conducted on adults with early diabetic nephropathy which used Gingko biloba extract were included. The major databases were searched, and manufacturers of Gingko biloba products were contacted for information on any published or unpublished studies. Two authors independently extracted the data from the included studies. Data analysis was conducted using Review Manager 5.0 software. Results. Sixteen RCTs were included. Ginkgo biloba extract decreased the urinary albumin excretion rate (UAER), fasting blood glucose (FBG), serum creatinine (SCR), and blood urea nitrogen (BUN). The extract also improved hemorheology. The methodological quality in the included studies was low. The explicit generation of the allocation sequence was described in only 6 trials. None of the included trials were confirmed to use blinding. Three studies had observed adverse events. One study using angiotensin-converting enzyme inhibitor (ACEi) reported mild cough in both groups. No serious adverse effects were reported. Conclusions. Gingko biloba extract is a valuable drug which has prospect in treating early diabetic nephropathy, especially with high UAER baseline level. The safety for early diabetic nephropathy is uncertain. Long-term, double-blinded RCTs with large sample sizes are still needed to provide stronger evidence.
doi:10.1155/2013/689142
PMCID: PMC3595672  PMID: 23533513
13.  Ginkgo biloba Extract and Bilberry Anthocyanins Improve Visual Function in Patients with Normal Tension Glaucoma 
Journal of Medicinal Food  2012;15(9):818-823.
Abstract
Ginkgo biloba
extract (GBE) and anthocyanins are considered beneficial for various vascular diseases. This study was performed to evaluate the effect of GBE and anthocyanins on visual function in patients with normal tension glaucoma (NTG) based on the vascular theory of mechanisms of glaucomatous optic nerve damage. Retrospective analysis was carried out by a chart review of 332 subjects (209 men and 123 women) who were treated with anthocyanins (n=132), GBE (n=103), or no medication (control, n=97). Humphrey Visual Field (HVF) test, logarithm of the minimal angle of resolution best-corrected visual acuity (logMAR BCVA), intraocular pressure, blood pressure, and fasting blood glucose were determined before and after treatment. Complete ocular and systemic examinations were performed. The mean follow-up duration was 23.82±9.84 (range, 12–59) months; the mean anthocyanin treatment duration was 24.32±10.43 (range, 6–53) months, and the mean GBE treatment duration was 23.81±10.36 months (range, 6–59) months. After anthocyanin treatment, the mean BCVA for all eyes improved from 0.16 (±0.34) to 0.11 (±0.18) logMAR units (P=.008), and HVF mean deviation improved from −6.44 (±7.05) to −5.34 (±6.42) (P=.001). After GBE treatment, HVF mean deviation improved from −5.25 (±6.13) to −4.31 (±5.60) (P=.002). A generalized linear model demonstrated that the final BCVA was not affected by demographic differences among the groups. These results suggest that anthocyanins and GBE may be helpful in improving visual function in some individuals with NTG.
doi:10.1089/jmf.2012.2241
PMCID: PMC3429325  PMID: 22870951
anthocyanins; antioxidants; bilberry; gingko
14.  Effect of Ginkgo Biloba on the Pharmacokinetics of Raltegravir in Healthy Volunteers 
Antimicrobial Agents and Chemotherapy  2012;56(10):5070-5075.
Medicinal herbs may cause clinically relevant drug interactions with antiretroviral agents. Ginkgo biloba extract is a popular herbal product among HIV-infected patients because of its positive effects on cognitive function. Raltegravir, an HIV integrase inhibitor, is increasingly being used as part of combined antiretroviral therapy. Clinical data on the potential inhibitory or inductive effect of ginkgo biloba on the pharmacokinetics of raltegravir were lacking, and concomitant use was not recommended. We studied the effect of ginkgo biloba extract on the pharmacokinetics of raltegravir in an open-label, randomized, two-period, crossover phase I trial in 18 healthy volunteers. Subjects were randomly assigned to a regimen of 120 mg of ginkgo biloba twice daily for 15 days plus a single dose of raltegravir (400 mg) on day 15, a washout period, and 400 mg of raltegravir on day 36 or the test and reference treatments in reverse order. Pharmacokinetic sampling of raltegravir was performed up to 12 h after intake on an empty stomach. All subjects (9 male) completed the trial, and no serious adverse events were reported. Geometric mean ratios (90% confidence intervals) of the area under the plasma concentration-time curve from dosing to infinity (AUC0-∞) and the maximum plasma concentration (Cmax) of raltegravir with ginkgo biloba versus raltegravir alone were 1.21 (0.93 to 1.58) and 1.44 (1.03 to 2.02). Ginkgo biloba did not reduce raltegravir exposure. The potential increase in the Cmax of raltegravir is probably of minor importance, given the large intersubject variability of raltegravir pharmacokinetics and its reported safety profile.
doi:10.1128/AAC.00672-12
PMCID: PMC3457394  PMID: 22802250
15.  The Hawthorne Effect: a randomised, controlled trial 
Background
The 'Hawthorne Effect' may be an important factor affecting the generalisability of clinical research to routine practice, but has been little studied. Hawthorne Effects have been reported in previous clinical trials in dementia but to our knowledge, no attempt has been made to quantify them. Our aim was to compare minimal follow-up to intensive follow-up in participants in a placebo controlled trial of Ginkgo biloba for treating mild-moderate dementia.
Methods
Participants in a dementia trial were randomised to intensive follow-up (with comprehensive assessment visits at baseline and two, four and six months post randomisation) or minimal follow-up (with an abbreviated assessment at baseline and a full assessment at six months). Our primary outcomes were cognitive functioning (ADAS-Cog) and participant and carer-rated quality of life (QOL-AD).
Results
We recruited 176 participants, mainly through general practices. The main analysis was based on Intention to treat (ITT), with available data. In the ANCOVA model with baseline score as a co-variate, follow-up group had a significant effect on outcome at six months on the ADAS-Cog score (n = 140; mean difference = -2.018; 95%CI -3.914, -0.121; p = 0.037 favouring the intensive follow-up group), and on participant-rated quality of life score (n = 142; mean difference = -1.382; 95%CI -2.642, -0.122; p = 0.032 favouring minimal follow-up group). There was no significant difference on carer quality of life.
Conclusion
We found that more intensive follow-up of individuals in a placebo-controlled clinical trial of Ginkgo biloba for treating mild-moderate dementia resulted in a better outcome than minimal follow-up, as measured by their cognitive functioning.
Trial registration
Current controlled trials: ISRCTN45577048
doi:10.1186/1471-2288-7-30
PMCID: PMC1936999  PMID: 17608932
16.  Alleviating neuropsychiatric symptoms in dementia: the effects of Ginkgo biloba extract EGb 761®. Findings from a randomized controlled trial 
Purpose:
To examine the effects of Ginkgo biloba extract EGb 761® on neuropsychiatric symptoms of dementia.
Patients and methods:
Randomized, controlled, double-blind, multicenter clinical trial involving 410 outpatients with mild to moderate dementia (Alzheimer’s disease with or without cerebrovascular disease, vascular dementia), scoring at least 5 on the Neuropsychiatric Inventory (NPI), with at least one item score of 3 or more. Total scores on the SKT cognitive test battery (Erzigkeit’s short syndrome test) were between 9 and 23. After random allocation, the patients took 240 mg of EGb 761® or placebo once daily for a period of 24 weeks. Changes from baseline to week 24 in the NPI composite and in the SKT total score were the primary outcomes. The NPI distress score was chosen as a secondary outcome measure to evaluate caregivers’ distress.
Results:
The NPI composite score improved by −3.2 (95% confidence interval −4.0 to −2.3) in patients taking EGb 761® (n = 202), but did not change (−0.9; 0.9) in those receiving placebo (n = 202), which resulted in a statistically significant difference in favor of EGb 761® (P < 0.001). Treatment with EGb 761® was significantly superior to placebo for the symptoms apathy/indifference, sleep/night-time behavior, irritability/lability, depression/dysphoria, and aberrant motor behavior. Caregivers’ distress evaluation revealed similar baseline pattern and improvements.
Conclusion:
Treatment with EGb 761®, at a once-daily dose of 240 mg, was safe, effectively alleviated behavioral and neuropsychiatric symptoms in patients with mild to moderate dementia, and improved the wellbeing of their caregivers.
doi:10.2147/NDT.S18741
PMCID: PMC3090284  PMID: 21573082
Alzheimer’s disease; vascular dementia; patients; caregivers; Ginkgo biloba; EGb 761®
17.  A randomized placebo-controlled trial of Ginkgo biloba for the prevention of cognitive decline 
Neurology  2008;70(19 Pt 2):1809-1817.
Objective
To assess the feasibility, safety, and efficacy of Ginkgo biloba extract (GBE) on delaying the progression to cognitive impairment in normal elderly aged 85 and older.
Methods
Randomized, placebo-controlled, double-blind, 42-month pilot study with 118 cognitively intact subjects randomized to standardized GBE or placebo. Kaplan-Meier estimation, Cox proportional hazard, and random-effects models were used to compare the risk of progression from Clinical Dementia Rating (CDR) = 0 to CDR = 0.5 and decline in episodic memory function between GBE and placebo groups.
Results
In the intention-to-treat analysis, there was no reduced risk of progression to CDR = 0.5 (log-rank test, p = 0.06) among the GBE group. There was no less of a decline in memory function among the GBE group (p = 0.05). In the secondary analysis, where we controlled the medication adherence level, the GBE group had a lower risk of progression from CDR = 0 to CDR = 0.5 (HR = 0.33, p = 0.02), and a smaller decline in memory scores (p = 0.04). There were more ischemic strokes and TIAs in the GBE group (p = 0.01).
Conclusions
In unadjusted analyses, Ginkgo biloba extract (GBE) neither altered the risk of progression from normal to Clinical Dementia Rating (CDR) = 0.5, nor protected against a decline in memory function. Secondary analysis taking into account medication adherence showed a protective effect of GBE on the progression to CDR = 0.5 and memory decline. Results of larger prevention trials taking into account medication adherence may clarify the effectiveness of GBE. More stroke and TIA cases observed among the GBE group requires further study to confirm.
doi:10.1212/01.wnl.0000303814.13509.db
PMCID: PMC2639649  PMID: 18305231
18.  Statins, Risk of Dementia and Cognitive Function: Secondary Analysis of the Ginkgo Evaluation of Memory Study (GEMS) 
Goal
To examine whether lipid lowering medications (LLMs) and especially statin drugs can delay cognitive decline and dementia onset in individuals with and without Mild Cognitive Impairment (MCI) at baseline.
Methods
Longitudinal, observational study of 3,069 cognitively healthy elderly, ages 75 years and older, who were enrolled in the Ginkgo Evaluation of Memory Study. Primary outcome measure was the time to adjudicated all-cause dementia and Alzheimer dementia (AD). Secondary outcome measure was the change in global cognitive function over time measured by 3MSE and ADAS-cog scores.
Findings
Among participants without MCI at baseline current use of statins was consistently associated with a reduced risk of all cause dementia (HR 0. 79, 95% confidence interval, 0.65–0.96, p=0.021) and AD (HR 0.57, 95% confidence interval, 0.39–0.85, p= 0.005). In participants who initiated statin therapy lipophilic statins tended to reduce dementia risk more than nonlipophilic agents. In contrast there was no significant association between LLM use (including statins), dementia onset or cognitive decline in individuals with baseline MCI. However, in individuals without MCI at baseline there was a trend for a neuroprotective effect of statins on cognitive decline.
Conclusions
Statins may slow the rate of cognitive decline and delay the onset of AD and all cause dementia in cognitively healthy elderly individuals whereas individuals with MCI may not have comparable cognitive protection from these agents. However, the results from this observational study need to be interpreted with caution and will require confirmation by randomized clinical trials stratifying treatment groups based on MCI status at baseline.
doi:10.1016/j.jstrokecerebrovasdis.2010.11.002
PMCID: PMC3140577  PMID: 21236699
Cognitive function; 3HMG-ACoA reductase inhibitors; Mild Cognitive Impairment; dementia
19.  Examining Brain-Cognition Effects of Ginkgo Biloba Extract: Brain Activation in the Left Temporal and Left Prefrontal Cortex in an Object Working Memory Task 
Ginkgo Biloba extract (GBE) is increasingly used to alleviate symptoms of age related cognitive impairment, with preclinical evidence pointing to a pro-cholinergic effect. While a number of behavioral studies have reported improvements to working memory (WM) associated with GBE, electrophysiological studies of GBE have typically been limited to recordings during a resting state. The current study investigated the chronic effects of GBE on steady state visually evoked potential (SSVEP) topography in nineteen healthy middle-aged (50-61 year old) male participants whilst completing an object WM task. A randomized double-blind crossover design was employed in which participants were allocated to receive 14 days GBE and 14 days placebo in random order. For both groups, SSVEP was recorded from 64 scalp electrode sites during the completion of an object WM task both pre- and 14 days post-treatment. GBE was found to improve behavioural performance on the WM task. GBE was also found to increase the SSVEP amplitude at occipital and frontal sites and increase SSVEP latency at left temporal and left frontal sites during the hold component of the WM task. These SSVEP changes associated with GBE may represent more efficient processing during WM task completion.
doi:10.1155/2011/164139
PMCID: PMC3166615  PMID: 21941584
20.  Fibrinolytic effects of Ginkgo biloba extract 
A multitude of factors are involved in regulating the blood coagulation homeostatic processes in the body, which may ultimately lead to thromboemboli and thrombosis. The resolution of blood clots after healing is as important as clot formation at the site of a vascular lesion. This is accomplished by fibrinolytic drugs such as streptokinase (SK) and urokinase.
It must be noted that administration of SK may be accompanied by the lysis of blood clots in unwanted sites, and complications such as general lytic conditions, severe hemorrhaging, reduced serum fibrinogen and allergies can occur. Anti-SK antibodies neutralize the effects of SK. Studies on natural compounds and medicinal herbs with fewer side effects have been ongoing. In the present study, the fibrinolytic effect of Ginkgo biloba, an herb grown in Iran, was investigated.
A polyphenolic method was used to obtain Ginkgo extract from its leaves. The fibrinolytic effects of SK (positive control) were compared with those of Ginkgo extract using a fluorometry method.
In producing a labelled clot, fibrinogen was labelled with the fluorescent agent fluorescein isothiocyanate and precipitated in the presence of Ca2+. SK (100 U/mL to 1000 U/mL) and Ginkgo extract were added to labelled fibrin in a plasma environment at dilutions of 1, 1:10, 1:100 and 1:1000 (volume/volume). The fluorescence of the solution was measured between 15 min and 60 min later.
A linear relationship was observed between the fluorescence measured and SK concentrations ranging from 300 U/mL to 700 U/mL. Ginkgo extract displayed a remarkable effect in resolving the clot. As Ginkgo extract remained in the environment, fluorescence increased notably, showing a time-dependent relationship.
Overall, the results indicate that the effects of Ginkgo extract on the fibrinolytic system are similar to those of SK; hence, this herbal extract can be used as a complement to or a substitute for SK. Additionally, it is proposed that the effects of the active ingredients of Ginkgo extract should be studied in animals. Further studies are warranted for evaluating the possible side effects and toxicity of Ginkgo extract in human subjects.
PMCID: PMC2716226  PMID: 19641664
Fibrinolytic; Ginkgo; Streptokinase
21.  Ginkgo biloba does not improve cognitive function in MS 
Neurology  2012;79(12):1278-1284.
Objective:
To determine whether Ginkgo biloba extract (ginkgo) improves cognitive function in persons with multiple sclerosis (MS).
Methods:
Persons with MS from the Seattle and Portland VA clinics and adjacent communities who scored 1 SD or more below the mean on one of 4 neuropsychological tests (Stroop Test, California Verbal Learning Test II [CVLT-II], Controlled Oral Word Association Test [COWAT], and Paced Auditory Serial Addition Task [PASAT]) were randomly assigned to receive either one 120-mg tablet of ginkgo (EGb-761; Willmar Schwabe GmbH & Co, Germany) or one placebo tablet twice a day for 12 weeks. As the primary outcome, we compared the performance of the 2 groups on the 4 tests at exit after adjusting for baseline performance.
Results:
Fifty-nine subjects received placebo and 61 received ginkgo; 1 participant receiving placebo and 3 receiving ginkgo were lost to follow-up. Two serious adverse events (AEs) (myocardial infarction and severe depression) believed to be unrelated to the treatment occurred in the ginkgo group; otherwise, there were no significant differences in AEs. The differences (ginkgo − placebo) at exit in the z scores for the cognitive tests were as follows: PASAT −0.2 (95% confidence interval [CI] −0.5 to 0.1); Stroop Test −0.5 (95% CI −0.9 to −0.1); COWAT 0.0 (95% CI −0.2 to 0.3); and CVLT-II 0.0 (95% CI −0.3 to 0.3); none was statistically significant.
Conclusions:
Treatment with ginkgo 120 mg twice a day did not improve cognitive performance in persons with MS.
Classification of evidence:
This study provides Class I evidence that treatment with ginkgo 120 mg twice a day for 12 weeks does not improve cognitive performance in people with MS.
doi:10.1212/WNL.0b013e31826aac60
PMCID: PMC3440446  PMID: 22955125
22.  Effect of Ginkgo Biloba (EGb 761) on Treadmill Walking Time Among Adults with Peripheral Artery Disease: A Randomized Clinical Trial 
PURPOSE
Medical therapies for treatment of peripheral artery disease (PAD) are limited. Ginkgo biloba has been reported to increase maximal and pain-free walking distance among patients with (PAD); however, the evidence is inconsistent. The objective of this study was to compare the effects of 300 mg/d of Ginkgo biloba (EGb 761) vs. placebo on treadmill walking time and related cardiovascular measures among subjects with PAD.
METHODS
A double-blind, placebo-controlled, parallel design trial with a 4 month duration was employed. Subjects were 62 adults, age 70 ± 8 years (mean, SD), with claudication symptoms of PAD. The primary study outcomes were maximal and pain free walking time on a treadmill. Secondary outcomes included flow mediated vasodilation (FMVD), a measure of antioxidant status as assessed by determining antibody levels to epitopes of oxidized LDL, and questionnaires addressing walking impairment and quality of life.
RESULTS
Maximal treadmill walking time increased by 20±80s and 91±242s in the placebo and EGb 761 groups, respectively (P=0.12). Pain-free walking time increased by 15±31s and 21±43s, respectively (P=0.28). No significant differences were detected between groups for any of the secondary outcomes.
CONCLUSIONS
In older adults with PAD, Ginkgo biloba produced a modest but insignificant increase in maximal treadmill walking time and flow-mediated vasodilation. These data do not support the use of Ginkgo biloba as an effective therapy for PAD, although a longer duration of use should be considered in any future trials.
doi:10.1097/01.HCR.0000327184.51992.b8
PMCID: PMC2748261  PMID: 18628657
Ginkgo biloba; peripheral artery disease; claudication; treadmill time
23.  The ameliorative effect of ascorbic acid and Ginkgo biloba on learning and memory deficits associated with fluoride exposure 
Interdisciplinary Toxicology  2013;6(4):217-221.
Chronic exposure to fluoride causes dental and skeletal fluorosis. Fluoride exposure is also detrimental to soft tissues and organs. The present study aimed at evaluation of the effect of Ginkgo biloba and ascorbic acid on learning and memory deficits caused by fluoride exposure. Male Wistar rats were divided into five groups (n=6). Group 1 control. Groups 2 to 5 received 100 ppm of sodium fluoride over 30 days. Groups 3, 4 and 5 were further treated for 15 days receiving respectively 1% gum acacia solution, 100 mg/kg body weight ascorbic acid, and 100mg/kg body weight Ginkgo biloba extract. After 45 days, all animals were subjected to behavioural tests. The results showed that fluoride affected learning and memory. Fluoride causes oxidative stress and neurodegeneration, thereby affecting learning and memory. Ascorbic acid and Ginkgo biloba were found to augment the reversal of learning and memory deficits caused by fluoride ingestion.
doi:10.2478/intox-2013-0032
PMCID: PMC3945761  PMID: 24678261
fluoride; ascorbic acid; Ginkgo biloba; learning and memory deficits
24.  Diuretic Use is Associated with Better Learning and Memory in Older Adults in the GEM Study 
Background
To investigate the association between diuretics, angiotensin-converting-enzyme inhibitors (ACE-I) and angiotensin 2 receptor blockers (AT2RB) and cognitive function.
Methods
This post-hoc analysis of the randomized controlled Ginkgo Evaluation of Memory Study trial focuses on 3069 non-demented community dwelling participants over the age of 75. At basline visit detailed information about medication use was collected and five cognitive domains were assessed. Multivariable linear regression analyses were used to assess cross-sectional associations between medication use and cognitive function.
Results
36% reported history of hypertension and 51% antihypertensive medication use, with 17% reporting diuretic, 11% ACE-I, and 2% AT2RB use. Potassium-sparing diuretic use (N=192) was associated with better verbal learning and memory measured by California Verbal Learning Test (CVLT), compared to no antihypertensive medication users (β=.068, P =.01; β =.094, P <.001) and other antihypertensive medication users (β=.080, P =.03; β=.153, P <.001). Use of ACE-I or AT2RB was not associated with better cognitive function.
Conclusion
Results warrant further investigation into possible protective effects of potassium-sparing diuretics and the role of potassium in mitigating cognitive decline.
doi:10.1016/j.jalz.2011.03.010
PMCID: PMC3341535  PMID: 22465175
Cognitive function; Diuretic; Angiotensin converting enzyme inhibitor; Angiotensin receptor blocker
25.  Antiproliferative effect of the Ginkgo biloba extract is associated with the enhancement of cytochrome P450 1B1 expression in estrogen receptor-negative breast cancer cells 
Biomedical Reports  2013;1(5):797-801.
Ginkgo biloba is a dioecious tree and its extract is a complex mixture that has been used for thousands of years to treat a variety of ailments in traditional Chinese medicine. The aim of this study was to present our observations on the inhibitory effects of different Ginkgo biloba extracts on human breast cancer cell proliferation and growth. Our results demonstrated that treatment of MCF-7 and MDA-MB-231 human breast cancer cells with Ginkgo biloba leaves and ginkgo fruit extract inhibited cell proliferation. It was also observed that this inhibition was accompanied by the enhancement of cytochrome P450 (CYP) 1B1 expression in MDA-MB-231 cells. In addition, treatment with ginkgo fruit extract resulted in a higher CYP1B1 expression in MDA-MB-231 cells compared to treatment with the Ginkgo biloba leaves extract. Our results suggested that the inhibitory effects of the Ginkgo biloba extract on estrogen receptor-negative breast cancer proliferation and the induction of CYP1B1 expression may be exerted through an alternative pathway, independent of the estrogen receptor or the aryl hydrocarbon receptor pathway.
doi:10.3892/br.2013.150
PMCID: PMC3916983  PMID: 24649031
breast cancer; Ginkgo biloba; cytochrome P450 1B1; estrogen receptor

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