Research - Ginkgo biloba
Targeted metabolomic profiling of cardioprotective effect ofGinkgo biloba L. extract on myocardial ischemia in rats
Myocardial ischemia (MI) is one of the highest mortality diseases in the world. It is closely associated with metabolism disorders of endogenous substances. Ginkgo biloba L. extract (GBE) is a popular herbal medicine used for prevention and therapy of MI. But its regulation effect on the metabolism disorders caused by MI remains currently unknown.
Our metabolomic profiling study provided insight into endogenous metabolic disorders of MI and cardioprotective mechanisms of GBE.
The rats were preventive administrated of GBE (200 mg/kg, i.g.) for 4 weeks and then subcutaneous injected of isoproterenol to establish MI model. Heart marker enzymes and histopathological examination were adopted to evaluate MI model and effect of GBE. On this base, endogenous metabolites in rat plasma and heart were well profiled using the developed targeted metabolomic profiling platform to comprehensively analyze metabolic pathways and find biomarkers.
A targeted metabolomic profiling platform was developed and only 100 μl biological sample was used to quantify 808 metabolites covering the core network of lipid, energy, amino acid and nucleotide metabolism. Then using this platform, endogenous metabolites of rats undergoing MI model and GBE pre-treatment were well profiled. Orthogonal partial least squares discriminant analysis (OPLS-DA) was used to discriminate between groups and find biomarkers.
The metabolomic profiles of MI model rats pre-protected by GBE were significantly different from those of unprotected. 47 metabolites were found as potential biomarkers and indicated MI would lead to disturbed metabolism due to inflammation, oxidative stress and structural damage; while GBE could effectively restore fatty acid, sphingolipid, phosphoglyceride, glyceride, amino acid and energy metabolism, closely related to its antioxidant, PAF antagonist and hypolipidemic properties.
The cardioprotective effect of GBE can be achieved through the comprehensive regulation of multiple metabolic pathways.
Source : Journal Phytomedicine
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Ethanolic Ginkgo biloba leaf extract prevents renal fibrosis through Akt/mTOR signaling in diabetic nephropathy
- Qian Lu1,
- Wen-Zi Zuo1,
- Xiao-Jun Ji,
- Yue-Xian Zhou,
- Yu-Qing Liu,
- Xiao-Qin Yao,
- Xue-Yan Zhou,
- Yao-Wu Liu,
- Fan Zhang,
- Xiao-Xing Yin
Recently, extract of Ginkgo biloba leaves (GbE) have become widely known phytomedicines and have shown various pharmacological activities, including improvement of blood circulation, protection of oxidative cell damage, prevention of Alzheimer's disease, treatment of cardiovascular disease and diabetes complications. This study was designed to investigate the effects of an ethanolic GbE on renal fibrosis in diabetic nephropathy (DN) and to clarify the possible mechanism by which GbE prevents renal fibrosis.
We investigated the protective effects of GbE on renal fibrosis in STZ-induced diabetic rats. Rats were randomized into six groups termed normal control, diabetes mellitus, low dose of GbE (50 mg/kg/d), intermediate dose of GbE (100 mg/kg/d), high dose of GbE (200 mg/kg/d) and rapamycin (1 mg/kg/d).
After 12 weeks, the rats were sacrificed and then fasting blood glucose (FBG), creatinine (Cr), blood urea nitrogen (BUN), urine protein, relative kidney weight, glycogen and collagen accumulation, and collagen IV and laminin expression were measured by different methods. The amounts of E-cadherin, α-SMA and snail, as well as the phosphorylation of Akt, mTOR and p70S6K in the renal cortex of rats, were examined by western blotting.
Compared with diabetic rats, the levels of Cr, BUN, urine protein, relative kidney weight, accumulation of glycogen and collagen, and expression of collagen IV and laminin in the renal cortex were all decreased in GbE treated rats. In addition, GbE reduced the expression of E-cadherin, α-SMA, snail and the phosphorylation of Akt, mTOR and p70S6K in diabetic renal cortex.
GbE can prevent renal fibrosis in rats with diabetic nephropathy, which is most likely to be associated with its abilities to inhibit the Akt/mTOR signaling pathway.
Source : Journal Phytomedicine
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Protection Efficacy of the Extract of Ginkgo biloba against the Learning and Memory Damage of Rats under Repeated High Sustained +Gz Exposure
Liang-En Chen, Feng Wu, Andong Zhao, Hua Ge, and Hao Zhan
Repeated high sustained positive Gz (+Gz) exposures are known for the harmful pathophysiological impact on the brain of rats, which is reflected as the interruption of normal performance of learning and memory. Interestingly, extract of Ginkgo biloba (EGb) has been reported to have neuroprotective effects and cognition-enhancing effects. In this study, we are interested in evaluating the protective effects of EGb toward the learning and memory abilities. Morris Water Maze Test (MWM) was used to evaluate the cognitive function, and the physiological status of the key components in central cholinergic system was also investigated. Our animal behavioral tests indicated that EGb can release the learning and memory impairment caused by repeated high sustained +Gz. Administration of EGb to rats can diminish some of the harmful physiological effects caused by repeated +Gz exposures. Moreover, EGb administration can increase the biological activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) but reduce the production of malondialdehyde (MDA). Taken together, our study showed that EGb can ameliorate the impairment of learning and memory abilities of rats induced by repeated high sustained +Gz exposure; the underlying mechanisms appeared to be related to the signal regulation on the cholinergic system and antioxidant enzymes system.
Source : Evidence Based Complementary and Alternative Medicine
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Systematic Review of EGb 761® in Dementia with Behavioral and Psychological Symptoms
von Gunten A, Schlaefke S, Überla K.
Efficacy of Ginkgo biloba extract EGb 761® in dementia with behavioural and psychological symptoms: A systematic review. World J Biol Psychiatry. August 27, 2015; [epub ahead of print]. doi: 10.3109/15622975.2015.1066513.
Behavioral and psychological symptoms of dementia (BPSD), also known as neuropsychiatric symptoms, occur in 80-100% of patients with this condition. However, many studies evaluating dementia treatments exclude patients with BPSD. Meta-analyses evaluating the efficacy of EGb 761® (Dr. Willmar Schwabe GmbH & Co. KG; Karlsruhe, Germany), a proprietary ginkgo (Ginkgo biloba, Ginkgoaceae) leaf extract, for the treatment of dementia have produced equivocal conclusions. There are several new studies that assessed patients with BPSD that were not included in the meta-analyses. Hence, this systematic review was conducted to evaluate the safety and efficacy of EGb 761 for the treatment of dementia in patients who have clinically significant BPSD.
The following electronic databases were searched: PubMed (from inception through December 2013), EMBASE (January 2006 through December 2013), and PASCAL (inception through December 2013). Also, the reference sections of systematic reviews were screened and the manufacturer of EGb 761 was queried for unpublished research. The inclusion criteria were as follows: (1) randomized, placebo-controlled, double-blind, clinical trials assessing the effects of oral EGb 761 in patients with Alzheimer's disease (AD), vascular dementia (VaD), or mixed dementia, with a study duration of ≥ 22 weeks; (2) the patients enrolled were diagnosed with dementia according to the Diagnostic and Statistical Manual of Mental Disorders III-R and IV (DSM-III-R, DSM-IV),International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10), National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA), or the National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS/AIREN); (3) had clinically significant BPSD as defined by minimal scores on the Neuropsychiatric Inventory (NPI) or other appropriate rating scales; (4) outcome measures were defined for BPSD and at least two of the three typical domains of assessment, namely, cognition, activities of daily living (ADL), and clinical global assessment (CGA); and (5) methodological quality was adequate (randomization, allocation concealment, and blinding; sample size estimation; numbers and disposition of patients who discontinued the trial prematurely; and statistical analyses were reported and judged adequate).
A total of four trials met the inclusion criteria. The manufacturer of EGb 761 provided the individual patient data from the studies so that the data could be pooled for analysis. The studies took place in Bulgaria (n = 1); Ukraine (n = 2); and Republic of Belarus, Republic of Moldova, and Russian Federation (multinational study, n = 1). In total, there were 1628 patients who were randomly assigned, and 1598 were included in the full analysis set (n = 796, EGb 761 and n = 802, placebo). Dropout rates were low (2-8%) and similar between groups. The mean age for the total population was 66 years. All studies evaluated 240 mg/day EGb 761 for 22-24 weeks. Baseline scores were similar between groups and across studies.
An analysis of covariance model was used to evaluate the effects of EGb 761 compared to placebo for the cognition, BPSD, ADL, and quality-of-life (QoL) domains; an analysis of variance model was used to assess CGA. In the case of the ADL and CGA domains where different outcome measures were used in different trials, the results were standardized within each individual trial to create a dimensionless measure. Treatment effects for the cognition, BPSD, ADL, and QoL domains were presented as standardized least mean squares differences (LMSD), and CGA was expressed as least mean squares. Standardized mean differences (Cohen's D) was used to compare overall effect sizes; standardized effect sizes of 0.2, 0.5, and 0.8 were classified as small, moderate, and large effects, respectively. Statistical significance was assumed with P < 0.05.
The short cognitive performance test (SKT) was used to evaluate cognition in all four trials. Three of the four studies demonstrated that EGb 761 was significantly superior to placebo; the numerical improvement in the fourth study did not reach statistical significance. In the pooled analysis, EGb 761 was significantly better than placebo (P < 0.001). The overall effect size was moderate.
All four of the studies demonstrated that EGb 761 was significantly better than placebo on the NPI total score assessing BPSD and the NPI caregiver distress score measuring BPSD-related caregiver distress. The pooled analysis indicated that EGb 761 was significantly better than placebo (P < 0.001). The overall effect size was moderate.
ADL assessments showed that in all four studies and in the pooled analysis, EGb 761 was significantly better than placebo (P < 0.001). The overall effect size was moderate.
CGAs showed that in three studies EGb 761 was significantly better than placebo; however, in one study there was no significant difference between groups. The pooled analysis revealed that EGb 761 was significantly better than placebo (P < 0.001). The overall effect size was moderate to large.
Only two of the four studies evaluated QoL. In both studies, and in the pooled analysis, EGb 761 was statistically superior to placebo (P < 0.001). The overall effect size was small.
Subgroup analysis of the three diagnostic subpopulations (AD, VaD, and mixed) revealed that EGb 761 was significantly better than placebo for all outcomes, except QoL for patients with VaD. The authors speculate that the lack of effect on QoL in the VaD group may be due to a lack of statistical power in this very small subsample or there may be different determinants of QoL for patients with VaD.
To evaluate whether the benefits were clinically meaningful, response rates and numbers needed to treat (NNTs) were calculated. NNTs of 6-9 are considered clinically meaningful in placebo-controlled trials of psychotropic drugs. In the present analysis, EGb 761 had NNTs of 4-5 for each outcome measure, indicating that it produced a clinically meaningful benefit.
The frequency of adverse events was similar between groups. "There was no clustering of any type of event in the EGb 761 treated patients."
Overall, the effect sizes were moderate for the domains of cognition, BPSD, ADL, and CGA, while the effect on QoL was small. The authors concluded that EGb 761 was statistically and clinically superior to placebo in improving cognitive performance, BPSD, functional abilities, and overall condition. Accordingly, caregiver distress decreased. Limitations are that none of the trials evaluated postponement of nursing home placement, and it is uncertain whether these results can be extrapolated to patients with severe BPSD. Although studies suggest that treatment benefits increase with increasing severity of BPSD, there are no published trials evaluating the efficacy of EGb 761 for the treatment of patients with severe BPSD.
This systematic review is unique and valuable because the authors conducted large-scale pooled analyses of individual patient data. This is opposed to the typical meta-analysis where authors evaluate mean data extracted from a published report. The pooled analyses support the conclusion that 240 mg/day EGb 761 is safe and moderately effective for the treatment of outpatients with dementia and mild to moderate BPSD.
Two of the authors (A. von Gunten and K. Überla) received consultant honoraria from Dr. Willmar Schwabe GmbH & Co. KG, and the third (S. Schlaefke) is a salaried employee of the company.
—Heather S. Oliff, PhD
Source : American Botanical Council, Herbclip
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Meta-Analysis Demonstrates Safety and Efficacy of Defined Ginkgo Extract for Treating Dementia in Elderly
by Amy C. Keller
Reviewed: Gauthier S, Schlaefke S. Efficacy and tolerability of Ginkgo biloba extract EGb 761® in dementia: a systematic review and meta-analysis of randomized placebo-controlled trials. Clin Interv Aging. 2014;9:2065-2077.
Many older adults suffer from Alzheimer’s disease (AD) or other cerebrovascular diseases. The leading clinically tested proprietary ginkgo (Ginkgo biloba, Ginkgoaceae) leaf extract EGb 761® has shown a variety of mechanisms related to treating AD in vivo, including repairing mitochondrial function, modulating neuroplasticity, and increasing dopamine concentrations in only frontal brain areas.
EGb 761 is an acetonic (60% per weight) dry extract of ginkgo leaves standardized to contain 22-27% ginkgo flavonglycosides, 5-7% terpene lactones (2.8-3.4% ginkgolides A, B, and C, and 2.6-3.2% bilobalide), and less than 5 parts per million ginkgolic acids. It is produced by Dr. Willmar Schwabe GmbH & Co. KG of Karlsruhe, Germany.
Processing methods and bioactive compound content are integral to establishing the efficacy and safety of botanicals and may greatly differ among products. This systematic review and meta-analysis investigates clinical trials using the standardized product EGb 761 for the treatment of AD and/or vascular dementia (VaD). The statistical analysis performed in this study was funded by Schwabe; one of the authors (Schlaefke) is an employee of the company.
This study searched the databases PubMed (to December 2012), EMBASE (2006-2011), and PASCAL (to December 2011). Included clinical trials were randomized, placebo-controlled, and double-blind, with a duration of 20 weeks or more. The included trials used EGb 761 for the treatment of AD, VaD, or a combination of the two conditions, according to diagnostic requirements from a variety of internationally recognized sources of criteria. Also, trials must have used two of the three following outcome measures: cognition, activities of daily living (ADL), and clinical global impression. Trials with patients having other mental deficiencies or that incorporated EGb 761 in conjunction with cholinesterase inhibitors (e.g., donepezil [Aricept®] and tacrine [Cognex®]) were excluded.
The study authors located 15 randomized, placebo-controlled, clinical trials of EGb 761; of these, eight were excluded due to failure to meet the inclusion criteria listed above. Patients from the seven included trials were prescribed a dosage of 120 mg (two trials) or 240 mg (six trials) of EGb 761 for 22-26 weeks (one trial tested both dosages). The Jadad Scale, used to evaluate the trial quality (scores range from 1 to 5, with 5 indicating the highest trial robustness), indicated “appropriate”quality, with scores of 3 for two trials and 5 for five trials. From the trials, 2,625 patients were evaluated, with 1,396 taking EGb 761 and 1,229 taking placebo. Females comprised 50% to 86% of the patient population in the studies, and patients ranged from 63 to 79 years old. Physical metrics such as height, weight, body mass index, and cognitive metrics were not different at baseline between treatment and placebo groups.
The seven included trials used two different but overlapping validated cognitive assessment tools. Five of the trials reported significant beneficial effects on cognition for those taking EGb 761 as compared to those in the placebo group (P=0.03). These effects were found to be dose dependent, and those taking 240 mg of EGb 761 had significantly better cognitive performance than those in the placebo group (P=0.04). ADL was measured by four different scales. Those taking EGb 761 scored significantly better as compared to those in the placebo group (P<0.001), and those taking 240 mg had a significantly greater improvement in ADL than those in the placebo group (P=0.001).
In clinical global impression assessments using three different rating scales, those taking EGb 761 rated significantly better than those taking placebo (P=0.01); this was also observed in those taking 240 mg of EGb 761 as compared to those in the placebo group (P=0.007). In general, the odds ratio for cognitive improvement in those taking EGb 761 as compared to placebo was 2.48 (95% confidence intervals [CI]: 1.17, 5.28; P=0.02). The odds ratio for improvement in clinical global impression for EGb 761 treatment as compared to placebo was 3.18 (95% CI: 1.78, 5.67; P<0.0001).
In two of the studies, slightly more patients taking EGb 761 experienced adverse side effects (ASEs) than those taking the placebo; however, in the other five trials, those with ASEs were equally distributed between groups. The relative risk ratio for ASEs with EGb 761 was 0.96 (95% CI: 0.90, 1.01). Likewise, “serious” ASEs were comparable in all trials across the treatment groups. In both treatment and placebo groups, ASEs included headache, dizziness, hypertension, tinnitus, angina pectoris, and respiratory tract infection. The ASEs causing early termination of patient participation in either group were symptoms typical of dementia, including agitation, anxiety, insomnia, or unspecific symptoms such as constipation, nausea, headache, and dizziness.
Overall, the results of this meta-analysis suggest that 240 mg daily intake of EGb 761 is effective in improving cognition, ADL, and clinical global impression in those suffering from AD and/or VaD, with minimal adverse side effects. This phytomedicinal formulation may be a useful adjuvant therapy in those suffering from cognitive decline.
Source : Herbal Gram - American Botanical council
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Ginkgo biloba Extract EGb 761® in Children with ADHD Preliminary Findings of an Open Multilevel Dose-Finding Study
Objectives: The side effects, nonresponse, and prejudices against conventional pharmacological treatments call for complementary or alternative medical treatments (CAM) for ADHD. One possible treatment, at least for cognitive problems, might be the administration of Ginkgo biloba, though evidence is currently rare. This study tests the clinical efficacy of a Ginkgo biloba special extract (EGb 761®) and its correlation with brain electrical activity in children with ADHD combined type according to DSM-IV.
Method: In this open clinical pilot study, EGb 761® was administered to 20 children with ADHD over 3 to 5 weeks. Dosage was increased to a maximum of 240 mg daily if attention problems persisted. Possible drug side effects were assessed using the Side Effect Rating Scale. Efficacy was assessed in a multilevel approach including clinical assessment, quality of life (QoL), as well as performance and preparatory brain-electrical activity evoked during a Continuous Performance Test (Cue-CNV in the CPT).
Results: A very low rate of mild adverse effects occurred during the observation period. Following EGb 761® administration, possible improvements in QoL, ADHD core symptoms as well as CPT performance were detected. Improved core symptoms were positively related to elevated CNV amplitude.
Conclusion: This preliminary evidence suggests that EGb 761® at a maximal dosage of 240 mg daily might be a clinically useful alternative treatment for children with ADHD, but further evidence is required before firm conclusions can be made.
Source : Zeitschrift für Kinder- und Jugendpsychiatrie und Psychotherapie
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The Synergistic Beneficial Effects of Ginkgo Flavonoid and Coriolus versicolor Polysaccharide for Memory Improvements in a Mouse Model of Dementia
Xianying Fang, 1 , 2 Yan Jiang, 1 , 2 Hui Ji, 3 Linguo Zhao, 1 , 2 , * Wei Xiao, 4 , * Zhenzhong Wang, 4 and Gang Ding 4
This study reports the combination of Ginkgo flavonoid (GF) and Coriolus versicolor polysaccharide (CVP) in the prevention and treatment of a mouse model of Alzheimer's disease (AD). GF is a traditional health product, and CVP is the main active ingredient of the medicinal fungus Coriolus versicolor. The Morris water maze test, the Y maze, and the step-through test showed that the combinational use of CVP and GF synergistically improved memory in a mouse model of AD. Based on H&E staining analysis, the combination of CVP and GF decreased the severity of the pathological findings in the brain. Given that the expression of IL-1β, IL-6, and TNF-α was downregulated, the inflammation response in AD mice was considered to be inhibited. The downregulation of GFAP further demonstrated that inflammation was reduced in the brain of AD mice following treatment. Moreover, the expression levels of superoxide dismutase (SOD) and catalase (CAT) were elevated in the brains of treated mice, indicating that oxidation levels were reduced upon the combination treatment. Our results provide new insights into the efficient utilization of traditional medicine for preventing dementia.
Source ; eCAM
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Effect of Ginkgo Biloba Extract on Lipopolysaccharide-induced Anhedonic Depressive-like Behavior in Male Rats
- Kuei-Ying Yeh1,*,
- Sing-Siang Shou1,
- Yi-Xuan Lin1,
- Chao-Cin Chen1,
- Chen-Yen Chiang1 and
- Chien-Yu Yeh2
The peripheral administration of lipopolysaccharide (LPS) induces depressive-like behavior. Anhedonia is a core symptom of depression, defined as a loss of the capacity to experience pleasure. The present study used the sucrose preference test to investigate the influence of Ginkgo biloba extract (EGb 761) on LPS-induced anhedonia in male rats. The animals were randomly divided into four groups: (I) vehicle + saline, (II) vehicle + LPS, (III) EGb 761 + saline, and (IV) EGb 761 + LPS. Saline or LPS (100 µg/kg) was administered intraperitoneally 2 h before the sucrose preference test. Sucrose consumption was recorded 2, 4, 6, 13, and 24 h after 100 µg/kg of LPS or saline injection in the dark phase of the light/dark cycle. Dopamine and serotonin levels in the nucleus accumbens were measured. Our results indicated that the vehicle + LPS group exhibited a significant decrease in sucrose intake compared with the vehicle + saline group. The EGb 761 + LPS group showed more sucrose and food consumption than the vehicle + LPS group. Additionally, compared with the EGb 761 + LPS group, the vehicle + LPS group had less dopamine levels in the nucleus accumbens. Treatment with EGb 761 had no effect on water intake. Our results suggest that EGb 761 may be useful for reducing anhedonic depressive-like behavior.
Source : Phytotherapy Research
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Ginkgo Comparable to Betahistine in Treating Vertigo and Has a Superior Safety Profile
Sokolova L, Hoerr R, Mishchenko T. Treatment of vertigo: A randomized, double-blind trial comparing efficacy and safety of Ginkgo biloba extract EGb 761 and betahistine. Int J Otolaryngol. 2014;2014:682439. doi: 10.1155/2014/682439.
Vertigo (dizziness) associated with cerebrovascular disorders is most commonly treated with drugs that improve cerebral blood flow. According to an international survey, betahistine is the most frequently prescribed medication, followed by piracetam, and then ginkgo (Ginkgo biloba). Research suggests that impaired neuronal plasticity prevents compensation for vestibular disturbances, and EGb 761® (manufactured by Dr. Willmar Schwabe GmbH & Co. KG; Karlsruhe, Germany) has been shown to enhance neuronal plasticity. The purpose of this randomized, controlled, double-blind, multi-center study was to compare the efficacy and safety of ginkgo to that of betahistine in the treatment of patients with vertigo.
Eligible patients (n = 160, ≥ 45 years old) diagnosed according to the International Classification of Diseases, 10th edition (ICD-10) with peripheral vertigo or vertiginous syndrome not otherwise specified were enrolled in this study conducted at 10 outpatient hospital clinics in the Ukraine. Included patients had symptoms of vertigo for ≥ 3 months, scored ≥ 3 on a 1-to-10 numeric analogue scale (NAS) of vertigo severity at screening, and could respond to interview questions and complete questionnaires in Russian or Ukrainian. Included females had a negative pregnancy test and adequate birth control. Excluded patients had specific vertiginous syndromes (e.g., Ménière's disease, Lermoyez syndrome, and benign paroxysmal positional vertigo), vertigo due to specified somatic diseases (except cerebrovascular disease), other severe disorders, contraindications for ginkgo or betahistine, gastrointestinal disorders with uncertain absorption of the active agents, or needed drugs that might interfere with efficacy assessments.
Patients were randomly assigned to receive either 240 mg/day ginkgo extract EGb 761 (60% ginkgo leaf acetone extract standardized to contain 22-27% ginkgo flavonoids, 5-7% terpene lactones, 2.6-3.2% bilobalide, and ˂ 5 ppm ginkgolic acids) or 32 mg/day betahistine dihydrochloride for 12 weeks. Efficacy and safety were evaluated at 4, 8, and 12 weeks. Efficacy was evaluated using: (1) the vertigo NAS; (2) the short form of the Vertigo Symptom Scale, which assesses the frequency and severity of vertigo within the last month; (3) the Sheehan Disability Scale, which evaluates the extent psychological symptoms disrupt a patient's work, social life, and family life; and (4) the Clinical Global Impressions (CGI) Scale. Safety was monitored via measurement of vital signs, physical examination, 12-lead electrocardiogram (ECG), and laboratory tests. There were no significant differences between groups at baseline.
Both groups improved compared to baseline on all measures. There were no significant differences between groups on any measurement, although "numerically, the improvements of patients receiving EGb 761 were slightly more pronounced on all scales." On the CGI, physicians rated 79% of the patients receiving EGb 761 and 70% of the patients receiving betahistine as "much improved" or "very much improved."
Blinded review could not rule out a causal relationship for 6 adverse events (AEs) in 5 patients in the EGb 761 group and 18 AEs in 16 patients in the betahistine group. In the EGb 761 group, both the total number of AEs and the number of patients reporting AEs were lower compared to the betahistine group.
The authors conclude that EGb 761 is at least as effective as betahistine, the world's most frequently prescribed drug in the treatment of vertigo. Although not statistically significant, numerically the EGb 761 group had more pronounced improvements in all outcome measures. And in terms of safety and tolerability, EGb 761 was superior to betahistine.
Despite the fact that there were 80 patients per group, the study did not have sufficient statistical power to prove equivalence between EGb 761 and betahistine. The study had several other limitations: (1) there was no negative control (placebo group) to provide an objective measure of the true effect size of both treatments because it would be unethical to deny treatment to the placebo group; (2) although assessments were conducted at 4 and 8 weeks, the interim data were not reported so the elapsed time till onset of measurable improvements cannot be compared; and (3) there was no follow-up to determine how long the therapeutic benefit lasted after treatment discontinuation. Given comparable efficacy, the latter 2 factors are important considerations when choosing a treatment. The patients were not queried as to whether they would choose to continue the treatment after the trial ended.
Nonetheless, the data are encouraging because EGb 761 compared favorably to the most frequently used drug for vertigo, it had fewer AEs in fewer patients, and might be less expensive than betahistine [Note: Pharmacoeconomics were not discussed in this report]. A larger, sufficiently powered clinical trial is needed to prove equivalence and confirm ginkgo has a superior safety profile to betahistine.
—Heather S. Oliff, PhD
Source : American Botanical Council - Herb Clip
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The Ginkgo biloba Extract EGb 761 Modulates Proteasome Activity and Polyglutamine Protein Aggregation
Marcel Stark and Christian Behl
Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, Duesbergweg 6, 55099 Mainz, Germany
The standardized Ginkgo biloba extract EGb 761 has well-described antioxidative activities and effects on different cytoprotective signaling pathways. Consequently, a potential use of EGb 761 in neurodegenerative diseases has been proposed. A common characteristic feature of a variety of such disorders is the pathologic formation of protein aggregates, suggesting a crucial role for protein homeostasis. In this study, we show that EGb 761 increased the catalytic activity of the proteasome and enhanced protein degradation in cultured cells. We further investigated this effect in a cellular model of Huntington’s disease (HD) by employing cells expressing pathologic variants of a polyglutamine protein (polyQ protein). We show that EGb 761 affected these cells by (i) increasing proteasome activity and (ii) inducing a more efficient degradation of aggregation-prone proteins. These results demonstrate a novel activity of EGb 761 on protein aggregates by enhancing proteasomal protein degradation, suggesting a therapeutic use in neurodegenerative disorders with a disturbed protein homeostasis.
....It was shown that in Alzheimer's Disease the treatment with EGb 761 provides protective effects through a combination of antioxidative , free radical scavenging , antiamyloidogenic , and antiapoptotic properties .
Source : Evidence Based Complementary and Alternative Medicine
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Evidence of Ginkgo Extract Efficacy in Patients with Dementia and as an Adjunct for Treating Patients with Chronic Schizophrenia
By Healther S. Oliff PhD
Reviewed: Brondino N, De Silvestri A, Re S, et al. A systematic review and meta-analysis of Ginkgo biloba in neuropsychiatric disorders: from ancient tradition to modern-day medicine. Evid Based Complement Alternat Med. 2013;2013:1-11. doi: 10.1155/2013/915691.
Ginkgo (Ginkgo biloba, Ginkgoaceae) extract is one of the most popular phytomedicines; however, according to the authors, there has been no systematic review on its effect on neuropsychiatric disorders other than dementia. Hence, the purpose of this report was to conduct a systematic review of ginkgo clinical trials for such disorders.
The authors searched MEDLINE®, Embase™, PsycINFO®, and the Cochrane Database of Systematic Reviews from inception through April 2012. The search terms were gingko biloba, ginkgo, ginko, gingko, bilobalid* [asterisk commands search to locate all terms that start with the preceding word], egb 761, dementia, cognitive impairment, Alzheimer, autism, autistic spectrum disorder, schizophrenia, psychosis, psychotic disorder, delusion, depression, major depression, depressive symptom, anxiety, generalized anxiety disorder, anxious, attention deficit disorder, ADHD, attention deficit, hyperactivity, and addiction. According to the article, “All search terms were searched individually in each database and combined together. The search strategy had no time restriction but was limited to articles in English, Italian, French, Spanish, and German. Additionally, all recovered papers were reviewed for further relevant references.” Study inclusion criteria were randomized, controlled clinical trials; a minimum of 10 patients per group; and treatment for less than six weeks. When possible, the data were pooled for a meta-analysis.
A total of 1,109 studies were identified. Of these, 113 were obtained for additional evaluation, and 18 met the inclusion criteria and were incorporated in this review. There was one randomized, double-blind study of patients with attention deficit hyperactivity disorder, which included 50 children treated with 80 mg/day (for participants weighing < 30 kg) or 120 mg/day ginkgo compared with methylphenidate for six weeks. Methylphenidate — a psychostimulant marketed under several trade names, including Ritalin® — was much more effective than ginkgo, though the latter had significantly fewer adverse side effects.
There was one randomized, placebo-controlled study of patients with autism, which included 47 children who were treated with the antipsychotic drug risperidone (on the market as Risperdal® and generic) in addition to either 80 mg/day (if < 30 kg) or 120 mg/day ginkgo extract or placebo for 10 weeks. There was no significant difference between groups, which means that no added effect for risperidone could be shown for ginkgo extract.
There was one randomized, double-blind, placebo-controlled study in patients with cocaine addiction, which included 44 patients who received either 240 mg/day ginkgo extract, the nootropic piracetam, or placebo for 10 weeks. There was no significant difference among the three groups.
There was one randomized, placebo-controlled study in patients with generalized anxiety disorder (GAD) or adjustment disorder with anxious mood in which participants were treated with 240 mg/day ginkgo, 480 mg/day ginkgo, or placebo for four weeks. There was a significant dose-response improvement in the ginkgo-treated patients compared with placebo-treated patients.
There was one randomized, placebo-controlled study of medicated patients with chronic schizophrenia and tardive dyskinesia who were treated with 240 mg/day ginkgo extract or placebo for 12 weeks. The ginkgo group had a significant improvement in the Abnormal Involuntary Movement Scale but not on secondary outcomes — namely the psychopathological scales — as the placebo group also showed improvements over time.
There were three other randomized, controlled studies in patients with chronic schizophrenia treated with ginkgo extract and either clozapine, haloperidol, or olanzapine (antipsychotic drugs), and these data were pooled for meta-analysis. The studies with clozapine and haloperidol were double-blind and placebo-controlled (n=42 and n=109, respectively), and the third study was olanzapine-controlled (n=29). The pooled analysis favored ginkgo; however, the results had substantial heterogeneity (i.e., when looking at the individual outcome measures, not all outcomes favored ginkgo treatment).
There were 10 studies of dementia; eight placebo-controlled and two donepezil-controlled. (Donepezil [sold as Aricept® and DONEP] is an acetylcholinesterase inhibitor.) Only the eight placebo-controlled studies (which utilized 120 or 240 mg/day ginkgo for 12-52 weeks) could be included in a meta-analysis. All trials used the standardized extract EGb 761® (Dr. Willmar Schwabe GmbH & Co. KG; Karlsruhe, Germany). The methodological quality of the eight studies was judged to be “adequate.” The pooled data showed that the Alzheimer’s Disease Assessment Scale-cognitive subscale and Syndrom-Kurz test outcome measures favored ginkgo treatment. There was also a significant difference in activities of daily living (ADL) standardized change scores between treatment groups when combining different scales: the Alzheimer’s Disease Activities-of-Daily-Living International Scale, Geriatric Evaluation by Relatives Rating Instrument, Gottfries-Bråne-Steen-Activities of Daily Living scale, Nürnberger Alters-Alltagsaktivitäten-Skala, and Nürnberger Alters-Beobachtungsskala. The two studies comparing donepezil and ginkgo showed no significant differences between treatments.
The authors conclude that the general lack of evidence prevents them from drawing conclusions for most neuropsychiatric conditions. However, the meta-analysis of dementia studies shows that ginkgo provides benefits for cognition and ADL. The authors state that the benefits for dementia and schizophrenia were modest and that some studies showed statistical improvements that were not necessarily clinically meaningful. Nonetheless, the authors conclude that despite heterogeneous results, the evidence supports the use of the proprietary standardized ginkgo extract in patients with dementia and as an adjunct therapy for patients with schizophrenia.
Source : HerbalGram. 2013; American Botanical Council
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Ginkgo biloba Extract and Bilberry Anthocyanins Improve Visual Function in Patients with Normal Tension Glaucoma
Seong Hee Shim,1 Joon Mo Kim,1 Chul Young Choi,1 Chan Yun Kim,2 and Ki Ho Park3,4
1Department of Ophthalmology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
2Department of Ophthalmology, Institute of Vision Research, Yonsei University College of Medicine, Seoul, Korea.
3Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea.
4Seoul Artificial Eye Center, Seoul National University Hospital Clinical Research Institute, Seoul, Korea.
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.
Source : Journal of Medicinal Food
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Many Ginkgo Extracts Safe, Says Herbal Science Group - American Botanical Council Clarifies Importance of Ginkgo Toxicology Report
The nonprofit American Botanical Council (ABC) says that clinically tested ginkgo extracts sold as dietary supplements in the United States are safe for most consumers. The ABC statement follows news of the publication of a report by the National Toxicology Program that showed that a special formulation of a Chinese ginkgo extract produced cancers in certain strains of rats and mice in a series of animal toxicology studies performed over two years In the conclusion of the report, the authors wrote, “We conclude that Ginkgo biloba extract caused cancers of the thyroid gland in male and female rats and male mice and cancers of the liver in male and female mice.”1
In February 2012, ABC sent public comments to NTP for the authors of the ginkgo study to consider in revising the draft report.2 The ABC comments were compiled by a committee of medicinal plant science and toxicology experts.
ABC emphasized that the Chinese ginkgo extract manufactured in Shanghai is not consistent with any compendial botanical and chemical standards for quality as set forth in various official pharmacopeias and does not conform to the well-established chemical profiles, quality, and purity of the leading, clinically tested ginkgo extracts produced by the pioneering Willmar Schwabe Pharmaceuticals of Karlsruhe, Germany, and Indena SpA in Milan, Italy. The ginkgo used in the NTP study was manufactured by the Shanghai Xing Ling Science and Technology Pharmaceutical Co., Ltd.
“The ginkgo extract used in this study is different from the high-quality ginkgo extracts used in published clinical trials showing safety and various beneficial activities of ginkgo,” said Mark Blumenthal, founder and executive director of ABC. “That is, the Shanghai ginkgo extract used by NTP does not represent the quality of German ginkgo extract that is the world standard for ginkgo. It is highly unfortunate that NTP chose to use this ginkgo extract as it means that the results of the NTP’s studies are not applicable to the standard-setting ginkgo extracts.”
In addition, ABC noted that the dosage levels administered to the test animals was significantly higher (up to 55-108 times higher) than the levels of ginkgo extract that are normally ingested by consumers (120-240 milligrams per day), as calculated by ABC’s consulting toxicologist.
“At best, what NTP can say is that significantly high doses of this particular Shanghai Chinese ginkgo extract – when added to a corn-oil base – produced cancer in the lab animals,” added Blumenthal.
ABC emphasized that the NTP studies are not intended to imply the potential adverse effect in humans.
“The NTP’s public message, and the resulting media reports, totally miss this point about the actual identity of the ginkgo extract and the high-dosage levels, and will probably cause confusion among consumers and health professionals alike,” added Blumenthal.
“Almost anything will create cancer in rats and mice when it’s fed to them at high doses for two years,” said Bill J. Gurley, PhD, professor of pharmaceutical sciences in the College of Pharmacy at the University of Arkansas School for Medical Sciences, Little Rock. “All toxicologists and pharmacologists are aware of the susceptibility of certain strains of rodents used for research purposes to develop various forms of cancer and other diseases when subjected to various substances.” Dr. Gurley was a co-author of the 2012 ABC public comments letter to NTP.
“This is disappointing, to say the least,” said Rick Kingston, PharmD, president of regulatory and scientific affairs at SafetyCall International in Minneapolis, MN, and professor of pharmacy at the University of Minnesota College of Pharmacy.
“Notwithstanding major design flaws in the study in identifying an appropriate compound to represent available ginkgo in the market,” continued Dr. Kingston, “even the reviewers voiced adamant proclamations that the results in this animal research were not intended for direct extrapolation to humans. For this oversight to not be reconciled by the NTP review group is disconcerting, especially since misinterpretation of the results by well-intentioned, but scientifically unsophisticated media outlets, and possibly even consumer groups, should have been an expected outcome.” Dr. Kingston also was a co-author of the public comments letter from ABC to NTP.
The ABC comments sent to NTP as part of the public comment process also called attention to other anomalies and/or problems with the NTP ginkgo studies as noted in the draft report. These include concerns that the Shanghai ginkgo extract used in the NTP study was from several different production batches, and that the ginkgo extract material used in the study was not analyzed for the presence of potential contaminants.
1. National Toxicology Program. NTP Technical Report on the Toxicology and Carcinogenesis Studies on Ginkgo Biloba Extract (CAS NO. 90045-36-6) IN F344/N Rats and B6C3F1/N Mice. (Gavage Studies). March 2013. Available at: http://ntp.niehs.nih.gov/ntp/htdocs/LT_rpts/TR578_508.pdf.
2. Blumenthal M, Gurley BJ, Kingston R, Low Dog T, Mackay D. American Botanical Council Revised Comment on NTP Draft Toxicology Report on Ginkgo Biloba Extract. Feb. 7, 2012. Available at: http://ntp.niehs.nih.gov/NTP/About_NTP/TRPanel/2012/February/PublicComm/Blumenthal20120125.pdf.
Source : American Botanical Council
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Review and meta-analysis of usage of ginkgo as an adjunct therapy in chronic schizophrenia
Vidhi Singh1, Surendra P. Singh2 and Kelvin Chan3
1MediWare Computer Software Engineering, Wolverhampton, West Midlands, UK
2Mental Health Directorate, Wolverhampton City Primary Care Trust and University of Wolverhampton, Wolverhampton,West Midlands, UK
3University of Wolverhampton, Wolverhampton, West Midlands, UK
This study aimed to review the roles of antioxidants in the pathophysiology of schizophrenia, whether the properties of ginkgo can ameliorate symptoms of this illness, and evaluate available literature to test this assumption. This review is based upon published works on antioxidants and ginkgo. A primary electronic search for meta-analysis on the usage of ginkgo or its derived products in schizophrenia was conducted using Pubmed, Cochrane Library, EMBASE, CINAHL, PsycINFO and AMED. Inclusion criteria were:criteria-based diagnosis of schizophrenia, randomized case assignment, use of ginkgo as an add-on therapy, and assessment using standardized rating scales to measure the state of psychopathology for negative and total symptoms of schizophrenia. Additionally, a detailed review was undertaken to investigate if antioxidants are involved in development of psychotic symptoms in schizophrenia. The six studies that fulfilled the selection criteria were constituted of 466 cases on ginkgo and 362 cases on placebo.They all used the Scale for the Assessment of Negative Symptoms (SANS) to measure negative symptoms,and the Scale for the Assessment of Positive Symptoms (SAPS) or the Brief Psychiatric Rating Scale (BPRS) to measure total symptoms. Difference between ginkgo and control groups from their pre- and post-trials cores and its pooled standard deviation were used to compute standardized mean difference (SMD).Ginkgo as an add-on therapy to antipsychotic medication produced statistically significant moderate improvement (SMD=x0.50) in total and negative symptoms of chronic schizophrenia. Ginkgo as add-on therapy ameliorates the symptoms of chronic schizophrenia. The role of antioxidants in pathogenesis of schizophrenia has also been explored
Source : International Journal of Neuropsychopharmacology (2010),13, 257–271
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Short-Term Effects of Ginkgo biloba Extract on Peripapillary Retinal Blood Flow in Normal Tension Glaucoma
Jong Woon Park,1 Hee Jung Kwon,1 Woo Seok Chung,2 Chan Yun Kim,2 and Gong Je Seong2
Based on the vascular theory of glaucoma pathogenesis, we wanted to evaluate the effect of Ginkgo biloba extract (GBE) on peripapillary blood flow in patients with normal tension glaucoma (NTG).
Thirty patients with NTG were randomly placed in the GBE-treated or control groups. The GBE-treated group received 80 mg GBE orally, twice a day for four weeks, and the control group received a placebo twice a day for four weeks. Complete ocular examinations including visual field, Heidelberg retina flowmeter, and systemic examinations were performed on the first study day and on the day treatment was completed.
After GBE treatment, the mean blood flow, volume, and velocity increased at almost all points, and there was a statistically significant increase in blood flow at almost all points, in comparison to the placebo. Blood volume significantly increased only in the superior nasal and superior temporal neuroretinal rim areas. GBE also significantly increased blood velocity in areas of the inferior temporal neuroretinal rim and superior temporal peripapillary area.
GBE administration appears to have desirable effect on ocular blood flow in NTG patients.
Source : Korean J Ophthalmol. 2011 October; 25(5): 323–328.
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Efficacy and Tolerability of Ginkgo Extract in Treatment of Alzheimer’s Disease and Vascular Dementia
by Heather S. Oliff
Reviewed: Ihl R, Tribanek M, Bachinskaya N; for the GOTADAY Study Group. Efficacy and tolerability of a once daily formulation of Ginkgo biloba extract EGb 761® in Alzheimer’s disease and vascular dementia: Results from a randomised controlled trial. Pharmacopsychiatry. 2012;45(2):41-46. Many studies have demonstrated the safety and efficacy of 240 mg (120 mg 2x/day) of ginkgo (Ginkgo biloba, Ginkgoaceae) special extract EGb 761® (Dr. Willmar Schwabe GmbH and Co. KG Pharmaceuticals; Karlsruhe, Germany). Patient compliance is better when patients are required to take fewer daily doses. Therefore, the manufacturer developed a once-daily 240 mg dose of EGb 761. The once-daily dose was tested and found to be safe and efficacious in a previous trial.1 The goal of the present study was to learn more about efficacy in different types of dementia. This was accomplished by conducting a subgroup analysis of the total population of a randomized, controlled, double-blind, multicenter study.
Since the methods have been described previously, they were mentioned only briefly in this report. Patients were recruited from the outpatient clinic of the Department of Psychiatry of the National Medical University in Kiev, Ukraine, and 19 outpatient clinics of neurological or psychiatric hospitals in Ukraine between April and November 2006. The study included outpatients (n=410, aged ≥ [equal to or greater than] 50 years) with mild to moderate dementia due to probable Alzheimer’s disease (AD), possible AD with cerebrovascular disease (CVD), or vascular dementia (VaD).
Clinical diagnosis of AD was established via the criteria of the National Institute of Neurological and Communicative Disorders and Stroke together with the Alzheimer’s Disease and Related Disorders Association (NINCDS/ADRDA); VaD was established according to the diagnostic criteria published by the National Institute of Neurological Disorders and Stroke together with the Association Internationale pour la Recherche et l’Enseignement en Neurosciences (NINDS/AIREN); and possible AD with CVD was established according to the relevant subsets of those criteria. A recent (≤ [equal to or less than] 1 year old) CT or MRI scan had to be consistent with the clinical diagnosis.
Other inclusion criteria included a score of ≤ 35 on the Test for the Early Detection of Dementia with Differentiation from Depression (TE4D), a total score of 9-23 on the SKT (Erzigkeit’s short syndrome test) cognitive test battery, a total score of ≥ 5 on the 12-item Neuropsychiatric Inventory (NPI), and at least one item score (other than delusion or hallucination) of ≥ 3 on the NPI. Patients were excluded if they had significant psychiatric disorders (e.g., major depression or subsyndromal depression), severe somatic disorders, or were taking a medication that could have influenced the assessment scores. Patients were treated with 240 mg EGb 761 or placebo 1x/day for 24 weeks. The primary outcome measures were the SKT and NPI.
A total of 404 patients were included in the analysis, with 333 patients diagnosed as having AD (probable AD: n=121 and possible AD with CVD: n=212) and 71 patients diagnosed as having VaD. Treatment adherence was 99%. For the SKT total score, both subgroups taking EGb 761 had an improvement from baseline by 1.4 points, which was significantly better than the placebo-treated group (AD, P<0.001 and VaD, P<0.05). For the NPI score, VaD patients treated with EGb 761 responded better to treatment than the patients with AD treated with EGb 761 (4.5 point improvement vs 2.9 points, respectively) (P-value not reported). Also for the NPI score, EGb 761-treated patients with AD and VaD improved significantly more than placebo-treated patients (AD, P=0.001 and VaD, P<0.05). When looking at clinically meaningful improvements (decrease in SKT scores by ≥ 3 points or decrease in NPI by ≥ 4 points), 33% of EGb 761-treated patients with AD compared with 14% of placebo-treated patients with AD had clinical improvement on the SKT (P<0.001), and 43% of EGb 761-treated patients with AD compared with 22% of placebo-treated patients with AD had clinical improvement on the NPI (P<0.001). The number of patients with VaD showing clinical improvement was similar to that in patients with AD, but, due to the small size of the VaD subsample, the ginkgo-placebo difference was not statistically significant (for SKT, EGb 761-treated: 28% vs. placebo-treated: 19%, and for NPI, EGb 761-treated: 54% vs. placebo-treated: 31%).
For all secondary outcome variables (NPI caregiver distress score, the Clinical Global Impression of Change as adapted by the Alzheimer’s Disease Cooperative Study [ADCS-CGIC], the Alzheimer’s Disease Activities of Daily Living International Scale [ADL-IS], and the Verbal Fluency Test), except the dementia quality-of-life scale, there were statistically significant differences between the EGb 761 group and the placebo group in AD as well as in VaD. Quality of life was significantly improved only in AD.
The AD subgroup was further broken down into probable AD and possible AD with CVD. The authors state, “There were no conspicuous differences in efficacy related to vascular pathology.”
According to the authors, the most frequently reported adverse events (AEs) were reported with similar frequency among treatment groups, and there were no major bleeding events (data were not provided).
The authors believe that the study population represents everyday practice. The authors conclude that EGb 761 had “essentially similar” effects in patients with AD and VaD. They also think that the data support the use of EGb 761 for dementia as diagnosed in the primary care setting since EGb 761 had similar efficacy for both populations. The study was sponsored by the manufacturer of EGb 761.
—Heather S. Oliff, PhD
1. Ihl R, Bachinskaya N, Korczyn A, et al. Efficacy and safety of a once-daily formulation of Ginkgo biloba extract EGb 761® in dementia with neuropsychiatric features: A randomized controlled trial. Int J Geriatr Psychiatry. 2011; 26(11):1186-1194.
Source : HerbalGram. 2012; American Botanical Council
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Gingko Biloba - Monograph
"There have been over four hundred scientific studies conducted on proprietary standardized extracts of the leaf of ginkgo in the past 30 years. Ginkgo is the world's most ancient extant tree, originating two hundred million years ago. Primary research was conducted by the W. Schwabe Co. of Karlsruhe, Germany, producer of the proprietary extract EGb 761. Ginkgo extract is a good example of a phytomedicine that must be standardized in order to deliver the intended benefits; the scientific literature does not support the clinical benefits of other dosage forms of crude ginkgo leaf or low-concentration extracts made from the leaf. The dry extract is pharmaceutically prepared to a 35–67:1 ratio of dried leaves to final extract; standardization is carried out to 24% ginkgo flavonol glycosides (based on flavones like quercetin, kaempferol, and isorhamnetin) and 6% terpene lactones (ginkgolides and bilobalide). A comprehensive, almost exhaustive, 401 page book reviewing the chemistry, pharmacology, toxicology, and all clinical studies conducted on EGb761 in various areas of clinical application has been published (DeFeudis, 1998).
Ginkgo biloba extract (GBE) has been popular in Europe and now is popular in the United States and other parts of the world for its neuroprotective properties and ability to aid circulatory problems in the elderly, especially cerebral insufficiency and the consequent cognitive effects, peripheral circulatory impairment, particularly intermittent claudication (poor circulation to the lower legs), and vertigo and tinnitus. New uses for protection against altitude sickness and to mediate erectile dysfunction in males have also been investigated.
Clinical studies demonstrate that daily doses of 120 to 240 mg of GBE can lead to an improvement in the symptoms associated with cerebral insufficiency, such as memory loss, depression, and tinnitus, within 8 to 12 weeks (Vorberg, 1985; Rai et al., 1991). An early review of 20 clinical studies concluded that many categories of elderly patients could benefit from GBE (Warburton, 1988). All of these trials used EGb 761.
In a later critical review of 40 ginkgo trials, the authors looked for evidence of the efficacy of GBE in cerebral insufficiency (Kleijnen and Knipschild, 1992a, 1992b). Four gingko preparations were used in the trials: Tebonin®, Tanakan®, rkan®, and Kaveri®. The first three are different names for EGb 761, the Schwabe product. Kaveri® (LI 1370; Lichtwer Pharma, Germany) is standardized in comparable percentages (25 and 6%). In accordance with German regulatory requirements, both products are purified to contain less than 5 parts per million ginkgolic acids. The standard dose was 120 mg/day for at least four to six weeks. Of the 40 trials, eight were deemed well performed. Shortcomings in the other trials included small patient numbers, inadequate description of randomization procedures, patient characteristics, effect measurement, and data presentation. In no trial was double-blindness checked. Virtually all trials reported positive results, and no serious side effects were reported in any trial. In a comparison of ginkgo with co-dergocrine, registered for the same indication, no marked differences were found in the quality of the evidence of the efficacy of ginkgo in cerebral insufficiency compared with co-dergocrine. The authors concluded that positive results have been reported for ginkgo in the treatment of cerebral insufficiency, but further studies should be conducted for a more detailed assessment of its efficacy.
In a meta-analysis of 11 placebo-controlled, randomized, double-blind trials in aged patients with cerebral insufficiency (Hopfenm ller, 1994), eight comparable trials were examined, most using a daily dose of 150 mg. Seven of the studies confirmed the effectiveness of ginkgo compared to placebo in cerebral insufficiency, while one study was inconclusive. Another double-blind trial tested the efficacy of LI 1370 on 90 patients with cerebral insufficiency caused by old age (Vesper and Hnsgen, 1994). A daily dose of 150 mg was administered for 12 weeks, with the ginkgo group showing significant improvement compared to placebo.
A recent meta-analysis (Oken et al., 1998) systematically reviewed over 50 clinical studies on GBE for treatment of dementia and cognitive functions associated with Alzheimer's disease (AD). Only four studies met the inclusion criteria for the evaluation, because in many of the trials patients did not have a clear diagnosis of dementia and AD. There were 212 patients each in the ginkgo and placebo groups of the four studies. Based on a quantitative analysis of these trials, the researchers concluded that administration of 120 mg to 240 mg GBE (EGb 761, Tanakan®; Ipsen, France) for three to six months had a small but significant effect on objective measures of cognitive function in AD, without significant adverse effects in formal clinical trials.
Until recently, market claims for the application of ginkgo for Alzheimer's disease were viewed as exaggerated and unfounded. However, three studies have suggested potential benefits in this area. Ginkgo has shown therapeutic potential in slowing some of the symptoms associated with early stages of Alzheimer's disease. In a randomized, double-blind, placebo-controlled study of 40 patients with senile dementia of the Alzheimer type, a daily dose of 240 mg of EGb 761 was given to the treatment group (Hofferberth, 1994). Battery tests were administered at baseline, one, two, and three months, with a significant improvement in memory and attention in the ginkgo group after only one month. No side effects were reported, and improvement continued over the three-month study.
Another study also suggests ginkgo's benefits for early stages of Alzheimer's (Kanowski et al., 1996, 1997). A randomized, double-blind, placebo-controlled study of 156 patients with presenile or senile primary degenerative dementia of the Alzheimer's type or multi-infarct dementia was conducted for 24 weeks using EGb 761. Seventy-nine subjects received 240 mg ginkgo extract per day; 77 received placebo. The ginkgo group was observed to have responded at a rate of 28% to three primary variables compared to only 10% for the placebo group. The authors concluded that GBE is "of clinical efficacy in the treatment of outpatients with dementia" of the two types noted.
Of considerable interest was the recent study published in JAMA on ginkgo's effects in preventing symptoms associated with Alzheimer's (Le Bars et al., 1997). This involved a placebo-controlled, double-blind, randomized, multicenter trial with 202 men and women 45 years of age or older, diagnosed with mild to moderately severe dementia. The trial lasted 52 weeks, with 97 subjects given 120 mg per day of EGb 761, and 105 given placebo. Using standardized assessment scales, patients were evaluated at baseline and at three-month intervals for cognitive function, daily living skills, social behavior, and overall impairment. Compared to placebo, the ginkgo group showed either improvement or a delay in progression of the disease with every assessment tool except that used for evaluation of overall impairment. The researchers concluded that EGb 761 was safe and appeared capable of stabilizing and, in a substantial number of cases, improving the cognitive performance and the social functioning of demented patients for six months to one year.
In an editor's note published with the Le Bars study, JAMA senior editor Margaret Winker, M.D., acknowledged that "Few treatments for Alzheimer's disease (AD) have been found to be both effective and acceptable to patients and their caregivers" (Winker, 1997). She noted the increase in popularity of natural substances for various conditions and lamented the lack of controlled clinical trials (presumably focusing on American medical journals) to test these products and the fact that, as natural products, their chemistry of "active ingredients" is variable. Dr. Winker stated that this trial used EGb 761, the chemically defined, standardized extract for treatment of dementia. She pointed out, "While the effect size was modest, EGb 761 reduced patients' cognitive decline and manifestations of dementia rated by the caregiver as compared with placebo, particularly for patients with a diagnosis of AD. The mechanism of action is unclear but it is postulated to be related to the agent's antioxidant properties. Only a single dose was studied, drop-out rates were high, and longer-term follow-up will be important; but this agent is an intriguing addition to the drugs thought to be helpful for patients with AD."
A recent review compared ginkgo with two conventional nootropic (cognitive-activating) medications (Letzel et al., 1996). Forty-four randomized, double-blind, placebo-controlled clinical trials were reviewed in which ginkgo extract, nimodipine, and tacrine were tested. Statistically significant results were obtained at three levels of efficacy (psychopathological, psychometric, and behavioral) for all three substances. The authors compared 25 studies on ginkgo, 9 on nimodipine, and 10 on tacrine. They noted that frequency of adverse events was lowest with ginkgo, confirming the previously established relative safety of ginkgo extract. They also compared study design to new standards set in Germany and the European Community, reporting that progress in the methodology of the studies has improved in the last decade and that "the efficacy of Ginkgo biloba special extract and tacrine has already been demonstrated according to the strictest criteria."
Another recent review investigated the use of ginkgo for dementia (Alzheimer type, multi-infarct dementia, or mixed types) (Ernst and Pittler, 1999). Eighteen double-blind, randomized, placebo-controlled trials were identified by the authors after extensive search on major databases. Nine were excluded, eight because patients were assessed with "cerebral insufficiency" and one due to assessment of cerebro-organic syndome. The authors concluded that the majority of randomized controlled trials support the idea that GBE is "efficacious in delaying the clinical deterioration of patients with dementia or in bringing about symptomatic improvement." The authors noted that none of the current studies were "flawless and ultimately convincing" but that the safety and tolerability profile of ginkgo is "reassuring." They called for more research to answer many questions that remain about ginkgo's efficacy.
A review of controlled studies on GBE in the treatment of intermittent claudication reported on 10 trials, finding most of poor methodological quality. All studies implied gingko was an effective therapy for intermittent claudication. The author recommended further trials with meticulous methodology, including studies on whether ginkgo can be usefully combined with walking exercise (Ernst, 1996). The Commission E reviewed some of these studies and concluded that there was sufficient evidence for approval for this indication. A recent trial on 111 patients with angiographically proven peripheral arterial disease and intermittent claudication was published on EGb 761 (Peters et al., 1998). A significant increase in pain-free walking distance was observed in the group taking 120 mg ginkgo extract over a 24-week study conducted in five centers. However, because Doppler index values did not change to indicate an increase in total circulation to the legs, the authors of this study speculated that the improvement in walking distance may be due to improved nutrition to tissues and microcirculation, rather than changes in macrocirculatory parameters.
The use of GBE (EGb 761) was examined for the treatment of peripheral arterial occlusive disease in a randomized, placebo-controlled, double-blind study. Forty patients suffering from Fontaine stage IIb were given two 80 mg tablets per day and the difference in pain-free walking distance was measured after eight, sixteen, and twenty-four weeks of treatment. By twenty-four weeks, the changes in the mean pain-free walking distance were +47.7% and +14.3% (p=0.021). The study concluded that the tolerability of GBE was good and that it had demonstrated clinical efficacy for peripheral arterial occlusive disease (Blume et al., 1998).
An analysis of twelve placebo-controlled, randomized, double-blind studies (five on GBE, seven on pentoxifylline) found a relative increase in pain-free walking distance of 45% for GBE (EGb 761) and 57% for pentoxifylline, the most-frequently prescribed synthetic treatment for peripheral occlusive arterial disease (Letzel and Schoop, 1992).
A meta-analysis of EGb 761 in the treatment of peripheral arterial disease examined five placebo-controlled trials with similar design and inclusion criteria (Schneider, 1992). In all studies, treatment effect was quantified by the increase of walking distance measured in a standard treadmill exercise. The analysis revealed a highly significant therapeutic effect of EGb 761 for the treatment of peripheral arterial disease, based on a mean increase in walking distance of 0.75 times (of the standard deviation) higher than that achieved by placebo. A daily dose of 120 mg for six months was successful in the treatment of intermittent claudication in 79 patients (Bauer, 1984). The randomized, placebo-controlled, double-blind study found significant improvement in the ginkgo group compared to placebo after 24 weeks.
The results of studies on ginkgo's effectiveness in tinnitus (ringing of the ears) have been mixed. A recent study failed to substantiate ginkgo's efficacy in treating this condition. Eighty patients were given ginkgo in this open trial, with 21 patients reporting improvements. Twenty of the 21 patients reporting improvements were then included in a double-blind, placebo-controlled, crossover study, with discouraging results. Seven patients believed ginkgo effective, seven preferred placebo, and the other six found no difference between placebo and ginkgo. The authors concluded that while statistical group analysis in this study did not support the use of ginkgo for tinnitus, it is possible that GBE has an effect on some patients (Holgers et al, 1994). However, this study was not performed using the GBE EGb 761, and the dose was 29.2 mg of extract per day instead of the usual dose of 120–240 mg per day. The Commission E approved GBE for tinnitus of "vascular and involutive origin."
In a randomized, double-blind, placebo-controlled study on tinnitus, 99 patients were given a 40 mg tablet of GBE (EGb 761), 3 times daily for 12 weeks. Improvement in the sound volume (5 to 10 dB) of the ear with the worst tinnitus was shown after 8 and 12 weeks in the GBE group, while the placebo group remained unchanged. Statistically significant differences were not observed in the other measured parameters: the contralateral ear, click-evoked otoacoustic emissions, subjective assessment of intensity, or hearing loss (Morgenstern and Biermann, 1997).
An interesting study of mountain climbers was conducted in the Himalayas using EGb 761 (Tanakan®) (Roncin et al., 1996). This randomized, controlled study was based on 44 healthy men who had experienced symptoms of altitude sickness on previous climbs. Over a period of eight days, they ascended to a base camp at about 14,700 feet elevation, with periodic ascents to higher points. The daily dose for the ginkgo group was two tablets twice per day (160 mg total). According to the assessment of cerebral symptoms, none of the climbers in the ginkgo group experienced acute mountain sickness (headache, dizziness, shortness of breath, nausea, vomiting), compared to 41% of the placebo group. In the assessment by respiratory parameters, 14% of the ginkgo climbers experienced altitude sickness, compared to 82% in the placebo group. Ginkgo was also rated significantly more effective in preventing cold-related circulatory problems (numbness, tingling, aching, and swelling of extremities), based on evaluations of the functional disabilities and results obtained by plethysmography (measurement extremity circulation). Also, 18% of the ginkgo climbers reported moderate or severe impairment of diuresis, compared to 77% on placebo.
In a somewhat novel application of ginkgo, researchers have studied its benefits in assisting patients suffering from anti-depression-induced sexual dysfunction, caused predominantly by selective serotonin reuptake inhibitors (SSRIs) (Cohen and Bartlik, 1998). The study was conducted in response to a case of a geriatric patient using Ginkgo biloba for memory enhancement who reported improved erections. The open study on 63 subjects found that women (33) were more responsive to the sexually enhancing effects than men (30), with relative success rates of 91% compared to 76% for the men. The ginkgo (product brand not noted) was given at a dosage range of 60 to 120 mg twice daily, within the normal range for the usual applications of ginkgo. The ginkgo reportedly had a positive effect on all four phases of the sexual response cycle: desire, excitement (erection and lubrication), orgasm, and resolution (afterglow). The authors note that the mechanism of action for this application is not yet clear. Postulated mechanisms include enhanced circulation to genitals by inhibition of PAF, direct effect on prostaglandins, known to enhance erectile function, and yet-to-be described norepinephrine receptor-induced effects on the brain.
In sum, there is a considerable degree of evidence from clinical trials to support the present use of GBE for a range of cognitive and peripheral vascular conditions. This conclusion was reinforced by the recent publication of a monograph on ginkgo by the World Health Organization (see Uses, below) (WHO, 1999).
Although most commercial ginkgo products sold as dietary supplements in the United States appear to be standardized to similar parameters (i.e., concentrated 50–1, standardized to 65 terpenes and 24% flavonol glycosides), it is possible that there may be differences in the biological activity of various brands. One study compared three commercial products in humans by measuring dynamic mapping of brain wave activity by computer-aided EEG (Itil and Mortorano, 1995). All three products increased alpha activity and decreased delta, theta, and beta waves. The study demonstrated that one product (Ginkgold®, Nature's Way, Utah; equivalent to EGb 761) was observed in all areas of the brain, while the effects of the others were limited to specific areas: one brand was limited to the temporal area and the other was limited primarily to the frontal area and slightly in the left posterior temporal area. The authors concluded that Ginkgold® produced the most homogeneous central nervous system effects in healthy subjects, with 9 out of 12 showing central nervous system effects correlated with cognitive activating drugs, e.g., tacrine.
In 1994, the Commission E published a negative (unapproved) monograph for various types of ginkgo preparations that did not conform to the parameters for the approved dried standardized preparation (made with acetone and water). These unapproved preparations include crude ginkgo leaf and related preparations, plus non-standardized extracts and fluidextracts from ginkgo leaf made with water and ethanol or methanol. The approved monograph clearly focuses on a specific type of preparation; the two commercial extracts of this type being the preparations on which almost all the scientific and clinical studies on the effectiveness of GBE have been carried out (as noted above). Thus, only the specified acetone-water extract of ginkgo was approved.
In May 1997, the German Federal Institute for Drugs and Medical Devices (BfArM) sent a letter to manufacturers of ginkgo extracts and other preparations regarding the levels of ginkgolic acids in these products. The letter stated that, based on the present level of knowledge, the BfArM considered it necessary to reduce the content of ginkgolic acids in finished ginkgo preparations to a maximum level of five parts per million. If proof of this level cannot be documented, "the registration for these pharmaceuticals will be cancelled since in this case, there is the well-founded suspicion that the pharmaceuticals—when used in accordance with the instructions [in the monographs]—produce damaging effects which exceed a justifiable degree according to the knowledge of medical science" (Thiele, 1997).
Pharmacopeial grade ginkgo leaf, for use in manufacturing the standardized extracts described in this monograph, consists of the dried leaf of Ginkgo biloba L. The raw material may contain no more than 3.0% stems and not more than 2.0% other foreign organic matter. It must contain not less than 0.8% flavonol glycosides as determined by liquid chromatography. Botanical identity must be confirmed by a thin-layer chromatography (TLC) test, as well as macroscopic and microscopic examinations (USP 24–NF19, 1999). Additionally, the British Herbal Pharmacopoeia requires that the dried leaf contain not less than 18% water-soluble extractive (BHP, 1996).
Description A dry extract from the dried leaf of Ginkgo biloba L. manufactured using acetone-water and subsequent purification steps without addition of concentrates or isolated ingredients. The preparation/extract ratio is 35–67:1, on average 50:1. The extract is characterized by: 22–27% flavonone glycosides, determined as quercetin and kaempferol, including isorhamnetin (via HPLC) and calculated as flavones with a molar mass of MMr = 756.7 (quercetin glycosides) and Mr = 740.7 (kaempferol glycosides); 5–7% terpene lactones, of which approximately 2.8–3.4% consists of ginkgolides A, B, and C, as well as approximately 2.6–3.2% bilobalide; below 5 ppm ginkgolic acids. The given ranges include manufacturing and analytical variances.
Chemistry and Pharmacology Ginkgo leaf contains diterpenes including ginkgolide A, ginkgolide B, ginkgolide C (Budavari, 1996), plus ginkgolide J, and the sesquiterpene bilobalide; flavonols, including kaempferol, quercetin, and isorhamnetin; flavones, including luteolin and tricetin; biflavones, mainly bilobetin, ginkgetin, isoginkgetin (Huang, 1999; Leung and Foster, 1996), and sciadopitysin (Gobbato et al., 1996); catechins; proanthocyanidins; sterols (Leung and Foster, 1996); and 6-hydroxykynurenic acid (6-HKA) (Grsel and Reuter, 1998).
According to the Commission E, the following pharmacological effects have been established experimentally:
Improvement of hypoxic tolerance, particularly in the cerebral tissue.
Inhibition of the development of traumatically or toxically induced cerebral edema, and acceleration of its regression.
Reduction of retinal edema and of cellular lesions in the retina.
Inhibition in age-related reduction of muscarinergic cholinoceptors and alpha-adrenoceptors as well as stimulation of choline uptake in the hippocampus.
Increased memory performance and learning capacity.
Improvement in the compensation of disturbed equilibrium.
Improvement of blood flow, particularly in the region of microcirculation.
Improvement of the rheological properties of the blood.
Inactivation of toxic oxygen radicals (flavonoids).
Antagonism of the platelet-activating factor (PAF) (ginkgolides).
Neuroprotective effect (ginkgolides A and B, bilobalide).
The pharmacokinetics have been investigated both in animal experiments and in trials involving humans. An absorption rate of 60% was found in rats for a radioactively labeled extract (as specified under the Description section, above). In humans, after application of an extract specified as above, absolute bioavailability was 98100% for ginkgolide A, 7993% for ginkgolide B, and at least 70% for bilobalide.
Both the acute and the chronic toxicity of an extract as specified under Descriptionis very low; accordingly, the LD50 in the mouse was 7725 mg/kg body weight after oral application and 1100 mg/kg body weight after intravenous application.
Investigations with this extract as specified above showed no effects which were either mutagenic, carcinogenic, or toxic to reproduction (DeFeudis, 1998).
No evaluation was performed on the transferability of the experimental results to extracts other than those investigated.
[Ed. note:This statement refers to the fact that only a few proprietary ginkgo extracts were used in the studies upon which this monograph is based. Whether these results can be extrapolated to other ginkgo extracts is uncertain.]
The vaso- and tissue-protective actions of ginkgo extract include the properties of relaxing blood vessels in spastic conditions, increasing tone of abnormally relaxed vessels, protecting against capillary permeability, inhibiting platelet aggregation and antithrombotic activity, and anti-ischemic and anti-edematous properties. The flavonoids present in GBE may be responsible for the cognitive-enhancing action of ginkgo extract. These flavonoids may enhance the release of catecholamines and other neurotransmitters, inhibit biogenic amine uptake, protect catechol-O-methyltransferase and monoamine oxidase, and protect endothelial-derived relaxing factor mechanisms in the brain (Van Beek et al., 1998).
Uses The Commission E approved the internal use of ginkgo for the following conditions:
(a) For symptomatic treatment of disturbed performance in organic brain syndrome within the regimen of a therapeutic concept in cases of dementia syndromes with the following principal symptoms: memory deficits, disturbances in concentration, depressive emotional condition, dizziness, tinnitus, and headache. The primary target groups are dementia syndromes, including primary degenerative dementia, vascular dementia, and mixed forms of both.
Note:Before starting treatment with ginkgo extract, clarification should be obtained as to whether the pathological symptoms encountered are not based on an underlying disease requiring a specific treatment.
(b) Improvement of pain-free walking distance in peripheral arterial occlusive disease in Stage II according to Fontaine (intermittent claudication) in a regimen of physical therapeutic measures, in particular walking exercise.
(c) Vertigo and tinnitus (ringing in the ear) of vascular and involutional origin.
The World Health Organization reiterated the Commission E approved uses noted above, adding the following specific conditions to peripheral arterial occlusive disease: Raynaud's disease (intermittent blue coloring of extremities due to restricted blood flow with no known direct cause, i.e., idiopathic, other than possible cold or emotion), acrocyanosis (i.e., Crocq's disease: persistently poor circulation to hands and sometimes the feet, resulting in cold, blue, sweaty condition), and post phlebitis syndrome (painful swelling of veins) (WHO, 1999).
Contraindications The Commission E noted hypersensitivity to ginkgo preparations.
The product data sheet of the leading ginkgo preparation (EGb 761) notes that the 120 mg dosage (Tebonin intens 120 mg) should not be used in children under 12. 'Since Ginkgo extracts have not yet been sufficiently investigated in case of depressive mood and headache not occurring in relation with demential syndromes, [this product] may only be applied in these symptoms when taking into consideration all necessary precautionary measures' (Schwabe, 1999).
Side Effects Very seldom cases of stomach or intestinal upsets, headaches, or allergic skin reaction.
Use During Pregnancy and Lactation No restrictions known.
Interactions with Other Drugs Commission E reported that none were known (based on data available before publication of the monograph in July, 1994).
The Tebonin product data sheet notes, 'The effect of platelet-aggregation inhibitors may be enhanced. The case of a spontaneous hyphema after combined intake of a Ginkgo-biloba-containing pharmaceutical and aspirin has been documented' (Schwabe, 1999).
Dosage and Administration Unless otherwise prescribed: 120-240 mg standardized dry extract in liquid or solid pharmaceutical form for oral intake, given in two or three daily doses to treat indication (a) listed above in the Use section. Indications (b) and (c) require 120-160 mg native dry extract, given in two or three daily doses.
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Cohen, A.J. and B. Bartlik. 1998. Ginkgo Biloba for antidepressant-induced sexual dysfunction. J Sex Marital Ther 24(2):139143.
DeFeudis, F.V. 1998. Ginkgo biloba extract (EGb 761): From Chemistry to the Clinic. Weisbaden, Germany: Ullstein Medical Verlagsgesellschaft.
Ernst, E. 1996. [Ginkgo biloba in treatment of intermittent claudication. A systematic research based on controlled studies in the literature] [In German]. Fortschr Med 114(8):8587.
Ernst, E. and M.H. Pittler. 1999. Ginkgo biloba Dementia: A systematic review of double-blind, placebo-controlled trials. Clin Drug Invest 17(4):301308.
Gobbato, S., A. Griffini, E. Lolla, F. Peterlongo. 1996. HPLC quantitative analysis of biflavones in Ginkgo biloba leaf extracts and their identification by thermospray liquid chromatography-mass spectrometry. Fitoterapia 67(2):152158.
Grsel, I. and G. Reuter. 1998. Analysis of 6-hydroxykynurenic acid in Ginkgo biloba and Ginkgo preparations. Planta Med 64:566570.
Hofferberth, B. 1994. The efficacy of EGb 761 in patients with senile dementia of the Alzheimer type: A double-blind, placebo-controlled study on different levels of investigation. Hum Psychopharmacol 9:215222.
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Itil, T. and D. Martorano. 1995. Natural substances in psychiatry (Ginkgo biloba in dementia). Psychopharm Bull 31(1):147158.
Kanowski, S., W.M. Hermann, K. Stephan, W. Wierich, R. Horr. 1997. Proof of the efficacy of the Ginkgo biloba special extract EGb 761 in outpatients suffering from mild to moderate dementia of the Alzheimer's type or multi-infarct dementia. Phytomedicine 4(1):313.
Kanowski, S., W.M. Hermann, K. Stephan, W. Wierich, R. Horr. 1996. Proof of efficacy of the Ginkgo biloba special extract EGb 761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multi-infarct dementia. Pharmacopsychiatry 29:4756.
Kleijnen, J. and P. Knipschild. 1992a. Ginkgo biloba for cerebral insufficiency. Br J Clin Pharmacol 34(4):352358.
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Letzel, H., J. Haan, W.B. Feil. 1996. Nootropics: Efficacy and tolerability of products from three active substance classes. J Drug Dev Clin Pract 8:7794.
Letzel, H. and W. Schoop. 1992. Ginkgo biloba extract EGb 761 and pentoxifylline in intermittent claudicaton: Secondary analysis of clinical efficacy studies. Vasa 21(4):403410.
Leung, A.Y. and S. Foster. 1996. Encyclopedia of Common Natural Ingredients Used in Food, Drugs, and Cosmetics, 2nd ed. New York: John Wiley & Sons, Inc.
Morgenstern, C. and E. Biermann. 1997. Ginkgo biloba special extract EGb 761 in the treatment of tinnitus aurium: Results of a randomized, double-blind, placebo-controlled study. Fortschr Med 115(4):711.
Oken, B.S., D.M. Storzbach, J.A. Kaye. 1998. The efficacy of Ginkgo biloba on cognitive function in Alzheimer disease. Arch Neurol 55(11):14091415.
Peters, H., M. Kieser, U. Holscher. 1998. Demonstration of the efficacy of Ginkgo biloba special extract EGb 761 on intermittent claudicationa placebo-controlled, double-blind multicenter trial. Vasa 27(2):105110.
Rai, G.S., C. Shovlin, K.A. Wesnes. 1991. A double-blind, placebo controlled study of Ginkgo biloba extract (Tanakan) in elderly out-patients with mild to moderate memory impairment. Curr Med Res Opin 12(6):350355.
Roncin, J.P., F. Schwartz, P. D'Arbigny. 1996. EGb 761 in control of acute mountain sickness and vascular reactivity to cold exposure. Aviat Space Environ Med 67(5):44552.
Schneider, B. 1992. Ginkgo biloba extract in peripheral arterial diseases. Meta-analysis of controlled clinical studies. Arzneimforsch 42(4):428436.
Thiele, A. 1997. Averting of drug-induced risks, grade II: pharmaceuticals containing Ginkgo biloba leaves. Communication to Dr. Willmar Schwabe GmbH & Co., May 27.
United States Pharmacopeia, 24th rev. and National Formulary, 19th ed. (USP 24NF19). 1999. Rockville, MD: United States Pharmacopeial Convention, Inc. 24582459.
Van Beek, T.A., E. Bombardelli, P. Morazzoni, F. Peterlongo. 1998. Ginkgo biloba L. Fitoterapia 49(3):195244.
Schwabe. 1999. Tebonin intens 120 mg Data Sheet. Karlsruhe, Germany: Willmar Schwabe Arzneimittel GmbH & Co.
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Vorberg, G. 1985. Ginkgo biloba extract (GBE): A long-term study of chronic cerebral insufficiency in geriatric patients. Clin Trials J 22:149157.
Warburton, D.M. 1988. Clinical psychopharmacology of Ginkgo biloba extract. In: Funfgeld, E.W. (ed.). Rokan (Ginkgo biloba): Recent Results in Pharmacology and Clinic. Berlin-Heidelberg: Springer Verlag. 327345.
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Additional Resources Ahlemeyer, B. and J. Kriglstein. 1998. Neuroprotective Effects of Ginkgo biloba Extract. In: L.D. Lawson and R. Bauer (eds.). Phytomedicines of Europe: Chemistry and Biological Activity. Washington, DC: American Chemical Society. 210220.
Auguer, M. et al. 1994. Advances in Ginkgo biloba Extract Research, Vol. 3. Elsevier: Paris. 3137.
Blume J., M. Kieser, U. Hlscher. 1996. [Placebo-controlled double-blind study on the efficacy of Ginkgo biloba special extract EGb 761 in maximum-level-trained patients with intermittent claudication] [In German]. Vasa 25(3):265274.
Bone, K. 1996. GinkgoRecent Research. Can J Herbalism Spring:2941.
Braquet, P. 1987. The ginkgolides: potent platelet-activating factor antagonists isolated from Ginkgo biloba L.: Chemistry, pharmacology and clinical applications. Drugs of the Future (12):643699.
Brown, D. 1997. Ginkgo Biloba Extract for Age-Related Cognitive Decline and Early-stage DementiaA Clinical Overview. Quarterly Rev Nat Med Summer:9196.
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Chatterjee, S.S. et al. 1985. Effects of Ginkgo Biloba Extract on Organic Cerebral Impairment. London: John Libbey Eurotext, Ltd.
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DeFeudis, F.V. 1991. Ginkgo biloba extract (EGb 761):Pharmacological Activities and Clinical Applications. Elsevier Editions Scientifiques: Paris. 5051.
Della Loggia, R. et al. 1996. Anti-inflammatory activity of some Ginkgo biloba constituents and their phospholipid-complexes. Fitoterapia 67(3):257264.
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Guinot, P., E. Caffrey, R. Lambe, A. Darragh. 1989. Tanakan inhibits platelet-activating-factor-induced platelet aggregation in healthy male volunteers. Haemostasis 19(4):219223.
Haguenauer, J.P., F. Cantenot, H. Koskas, H. Pierart. 1988. Treatment of disturbed equilibrium with Ginkgo Biloba extract: Multicenter double-blind study versus placebo. In: F ngfeld, E.W. (ed.). Rkan (Ginkgo Biloba).Recent Results in Pharmacology and Clinic. New York: Springer Verlag.
Itil, T.M., E. Erlap, E. Tsambis, K.Z. Itil, U. Stein. 1996. Central nervous system effect of Ginkgo Biloba, a plant extract. Am J Therapeutics 3(63):6373.
Itil, T.M., S.H. Kornhauser, I. Ahmed. 1996. Early diagnosis and treatment of memory disturbances. Am J Electromed Jun:8185.
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Jung, F., C. Mrowietz, H. Kiesewetter, E. Wenzel. 1990. Effect of Gingko Biloba on fluidity of blood and peripheral microcirculation in volunteers. Arzneimforsch 40(5):589593.
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Pietri, S., J.R. Seguin, P. d'Arbigny, K. Drieu, M. Culcasi. 1997. Gingko biloba extract (EGb 761) pretreatment limits free radical-induced oxidative stress in patients undergoing coronary bypass surgery. Cardiovasc Drugs Ther 11(2):121131.
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Pincemail, J. et al. 1989. Superoxide anion scavenging effect and superoxide dismutase activity of Ginkgo biloba extract. Experientia 45:708712.
Robben Batre, P. et al. 1996. Phase II study with 5-FU plus Gingko biloba extract (GBE 761 ONC) in 5-FU pretreated patients with advanced colorectal cancer. (Annual Congress of the German and the Austrian Society of Hematology) Ann Hematol 73(2):A73.
Schulz, V., R. Hnsel, V.E. Tyler. 1998. Rational Phytotherapy: A Physicians' Guide to Herbal Medicine. New York: Springer. 38-50.
Scorolli, L. et al. 1997. Evolution of color vision in early diabetic retinopathy treated by Ginkgo biloba extract. Ann Ottalmol Clin Ocul 123(68):245251.
Smith, P.F., K. Maclennan, C.L. Darlington. The neuroprotective properties of Ginkgo biloba leaf: a review of the possible relationship to platelet-activating factor. 1996. J Ethnopharmacol 50(3):131139.
Soholm, B.1998. Clinical improvement of memory and other cognitive functions by Gingko biloba: Review of relevant literature. Adv Ther 15(1):5465.
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This material was adapted from The Complete German Commission E MonographsTherapeutic Guide to Herbal Medicines. M. Blumenthal, W.R. Busse, A. Goldberg, J. Gruenwald, T. Hall, C.W. Riggins, R.S. Rister (eds.) S. Klein and R.S. Rister (trans.). 1998. Austin: American Botanical Council; Boston: Integrative Medicine Communications.
1) The Overview section is new information.
2) Description, Chemistry and Pharmacology, Uses, Contraindications, Side Effects, Interactions with Other Drugs, and Dosage sections have been drawn from the original work. Additional information has been added in some or all of these sections, as noted with references.
3) The dosage for equivalent preparations (tea infusion, fluidextract, and tincture) have been provided based on the following example:
- Unless otherwise prescribed: 2 g per day of [powdered, crushed, cut or whole] [plant part]
- Infusion: 2 g in 150 ml of water
- Fluidextract 1:1 (g/ml): 2 ml
- Tincture 1:5 (g/ml): 10 ml
This monograph, published by the Commission E in 1994, was modified based on new scientific research. It contains more extensive pharmacological and therapeutic information taken directly from the Commission E."
Source Commission E Monography - American Botanical Council
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