Ginkgo biloba Extracts in Neurological Disorders Therapy

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Ginkgo biloba Extracts in Neurological Disorders Therapy Clinical Trials I. Irem Tatli Department of Pharmaceutical Botany, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey

O U T L I N E Introduction113

Tardive Dyskinesia

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Medical Uses

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Dosage and Duration

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Meta-Analysis and Systematic Reviews of Ginkgo Clinical Trials

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Normal Cognitive Functioning

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Side Effects and Quality Issues of EGb 761®

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Age-Related Cognitive Impairment

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Age-Related Dementia and Alzheimer’s Disease

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Dementia and Alzheimer’s Disease

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Multiple Sclerosis

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INTRODUCTION Dementia is a clinical syndrome characterized by losses of cognitive and emotional abilities that are sufficient to interfere with daily functioning and quality of life. The American Psychiatric Association, in its Diagnostic and Statistical Manual of Mental Disorders (DSM-IVTR, 2000), defines the diagnostic features of dementia as memory impairment, deterioration of language function (aphasia), impaired ability to execute activities despite intact muscles, senses, and comprehension of the task (apraxia), and disturbances in executive functioning (the ability to think abstractly and to plan, initiate, sequence, monitor, and conclude complex behavior). Dementia can be mild (work and social activities are impaired, but the capacity for independent living remains), moderate (independent living is hazardous, and some supervision Bioactive Nutraceuticals and Dietary Supplements in Neurological and Brain Disease http://dx.doi.org/10.1016/B978-0-12-411462-3.00012-6

Exposure to Ginkgo Leaf Extracts in Clinical Studies122 Conclusion122 References123

is required), or severe (daily living activities are impaired, continuous supervision is required, and the person is largely incoherent or mute). Dementia can be caused by Alzheimer’s disease (AD), vascular disease (VD), human immunodeficiency virus (HIV), head trauma, Parkinson’s disease (PD), Huntington’s disease (HD), Pick’s disease, Creutzfeldt-Jakob disease (CJD), substance abuse, and other medical conditions (Schulz et al., 2000). AD is observed as a gradual and progressive cognitive decline. Diagnosis of AD is often made once other causes of dementia have been ruled out, due to a lack of laboratory markers. Cerebrovascular disease can cause vascular dementia (VaD) diagnosed by characteristic neurological signs or laboratory evidence. Symptoms include transient ischemic attacks (ministrokes), hemipareses, tinnitus (ringing in the ears), dizziness, headache, and anxiety (Schulz et al., 2000).

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© 2015 Elsevier Inc. All rights reserved.

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Ginkgo biloba L. (Ginkgoaceae; Figure 12.1) is a primitive member of the Gymnosperms and is the only living representative of a family which once contained at least six genera of which 200-million-year-old fossils have been found. Ginkgo biloba is a tree with an average height of 20 m originating in East Asia, where it is cultivated for its seeds, which are used as food and for medicinal purposes. Ginkgo biloba is also widely cultivated in Japan, the United States, and Europe both as an ornamental plant and for pharmaceutical purposes. The species is dioecious, and thus female plants are preferred for seed production, but males are preferred as ornamentals because the fruit pulp deteriorates under fruit maturation and produces a remarkable smell from butyric acid. Ginkgolides are diterpenes with a unique structure and are characteristic constituents of the leaves of Ginkgo biloba. Besides the ginkgolides, the leaves also contain a sesquiterpene derivative, bilobalide, and a great number of flavonoids present as mono-, di-, and triglycosides of kaempferol, quercetin, and isorhamnetin (Figure 12.2; Bedir et al., 2002). Nonglycosidic biflavonoids, cathecins, and proanthocyanodins have also been isolated. Flavonoid glycoside esters with coumaric acid are structurally interesting. The leaves also contain potent allergens (ginkgolic acids) that must be removed before an extract can be used as a drug. Another potentially toxic constituent is 4’-O-methylpyridoxine, which occurs mainly in the seeds but which has been found also in some batches of leaves. Excessive consumption of seeds causes convulsions, loss of consciousness, and even death (Samuelsson, 2004).

of the leaves was introduced into Western countries as a herbal remedy for the treatment of diseases appearing with advanced age and with symptoms such as vertigo, tinnitus, headache, impaired short-term memory, hearing loss, decreased vigilance, and mood disturbance. These symptoms are associated with peripheral circulatory insufficiency due to degenerative angiopathy and cerebrovascular insufficiency. Flavonoids and the ginkgolides are regarded as the pharmacologically active principles. The flavonoids inhibit cyclooxygenase and lipoxygenase and could thus decrease production of thromboxane A2, which is a potent platelet aggregator involved in clot formation and subsequent thrombosis. Ginkgo flavonoids are also free radical scavengers and could thus diminish the damage to cell membranes that causes malfunction and death of cells in the brain. The most attention has been given to the ginkgolides, which have potent antagonist activity against plateletactivating factor (PAF). PAF is a phospholipid with an ether linkage to a long-chain fatty alcohol. It plays an important role in several pathological conditions, such as asthma, shock, ischemia, anaphylaxis, graft rejection, 11

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MEDICAL USES

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In China, the medicinal use of Ginkgo leaves has a very long history. The plant is recorded in herbals that are almost 5000 years old as a remedy against asthma and ‘to benefit the brain.’ About 35 years ago, an extract

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FIGURE 12.1  Ginkgo biloba L.

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FIGURE 12.2  Three new compounds from G. biloba L.

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Age-Related Cognitive Impairment

renal diseases, CNS-disorders, and numerous inflammatory conditions. The ginkgolides are highly specific inhibitors of the binding of PAF to its cellular receptors. Ginkgolide B is the most powerful antagonist. PAF stimulates the conversion of phospholipids in cells to arachidonic acid and thus has an influence on the biosynthesis of prostaglandins and leukotriens, which, as mentioned previously, are associated with thrombosis and inflammation especially in connection with cerebral edema. Several clinical trials have been performed that indicate Ginkgo extract could be of benefit in cases of cerebral insufficiency in elderly patients. To be of value, however, these extracts must be standardized with respect to the content of flavonoids and ginkgolides. This is not always the case with the preparations that are available on the market (Samuelsson, 2004). Most of the Ginkgo leaf products on the market are concentrated extracts with a ratio of roughly 50 parts leaf to one part extract. This means that the manufacturing procedure, which uses an acetone–water extraction and several purification steps, yields one kilogram of final product from 50 kilograms of dried Ginkgo leaves. Standardized leaf extract generally contains 22–27% flavonol glycosides, 5–7% terpene lactones (2.8–3.4% ginkgolides A, B, and C, and 2.6–3.2% bilobalide), and less than 5 ppm of ginkgolic acid. Although many Ginkgo constituents are purported to contribute to the herb’s therapeutic effect, some of the constituents have been linked to specific pharmacological actions, such as flavonol glycosides and ginkgolides/bilobalide (Foster and Tyler, 1999; Schulz et al., 2001). Ginkgold® and Ginkoba® are manufactured by Dr. Willmar Schwabe GmbH & Co. in Germany and are remarketed in the United States by Nature’s Way Products, Inc. and Pharmaton Natural Health Products, respectively. These products contain a patented Ginkgo leaf extract called EGb 761® (50:1), which is characterized as containing 24% flavonol glycosides and 6% terpene lactones. EGb 761® is sold in Europe in products named Tanakan®, Rökan®, and Tebonin® Forte (Barrett, 2004). The vast majority of clinical trials on Ginkgo have been conducted on products containing the EGb 761® extract. A total of 27 controlled clinical studies covering indications of cognitive function (normal and agerelated impairment), dementia (including Alzheimer’s disease), multiple sclerosis, and tardive dyskinesia are included.

DOSAGE AND DURATION Dosages range from 80–240 mg of dry extract divided into two or three daily doses, with an average daily recommended dose of 120 mg. The German Commission recommends 120 to 240 mg of extract two to three times

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daily for cerebral insufficiency (Blumenthal et al., 1998). Dosages of Ginkgo as high as 720 mg/d have been used in clinical trials for dementia, memory, and circulatory disorders. Significant improvement on one or more ­outcome measures is associated with dosages between 120–300 mg/d for durations of three to 12 weeks. Treatments lasting four to six weeks are generally needed before positive effects can be expected when Ginkgo is taken for disorders of memory, mood, or physiologic function (Diamond and Bailey, 2013).

NORMAL COGNITIVE FUNCTIONING Four trials that looked at the effect of EGb 761® on cognitive function in normal volunteers reported mixed results. The largest study, including 203 adults over 60 years old without cognitive impairment, did not report any benefit from Ginkoba®, 40 mg three times daily for six weeks, compared to placebo. The study used a battery of tests to measure cognitive function as well as a selfreported memory function questionnaire and a global rating by a companion (Solomon et al., 2002). Another trial included 40 volunteers (55 to 88 years old) who took 120 mg of extract or a placebo for six weeks and reported improvements in speed of mental processing following treatment. Participants receiving treatment judged their memory as improved, but objective memory tests did not reveal any statistical improvement (Mix and Crews, 2000). Two small crossover trials examined the effect of one dose of Ginkgo on reaction time and memory. In both trials, memory improved one hour after administration of 600 mg of extract. One of the trials, with eight women aged 25 to 40 years, reported a selective but marked improvement in working memory (Hindmarch, 1986). The other trial, with 12 females with a mean age of 22 years, failed to replicate the benefit to working memory but did find evidence of improved secondary memory (Warot et al., 1991). Other measurements of reaction time or the activity of the central nervous system in general did not change in either trial.

AGE-RELATED COGNITIVE IMPAIRMENT Five good-quality trials looked at elderly people with cognitive impairment attributed to aging. All trials used cognitive test batteries, four of them computerized. The patients in these trials all satisfied the criteria of ageassociated memory impairment and, in the more extreme trials, mild cognitive impairment. All trials showed statistically significant benefits to one or more aspects of cognitive function, including attention, information processing, and both short- and long-term memory. Four trials ranged in length from three months to one year and used a dose

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of 120 or 160 mg extract per day. Improvement was observed after one month (Israel et al., 1987; Rai et al., 1991; Taillandier et al., 1986; Wesnes et al., 1987). The largest trial (122 subjects) and longest running (one year) reported an increase in the Geriatric Clinical Evaluation score after three months of treatment with continued improvement for the remainder of the year (Taillandier et al., 1986). The fifth trial, which included a series of one-day experiments, showed improvement in a computerized test of information processing completed one hour after taking doses of 320 or 600 mg of extract (Allain et al., 1993). The Ginkgo Evaluation of Memory (GEM) study was initially designed as a five-year, randomized, doubleblind, placebo-controlled trial of Ginkgo biloba, administered in a dose of 120 mg twice per day of EGb 761® for the prevention of dementia (and especially AD) in normal elderly or those with mild cognitive impairment. The study anticipates 8.5 years of participant follow up. Initial power calculations based on estimates of incidence rates of dementia in the target population (women and men, age 75+) led to a 3000-person study, which was successfully recruited at four clinical sites around the United States from September 2000 to June 2002. The primary outcome was incidence of allcause dementia; secondary outcomes included rate of cognitive and functional decline, the incidence of cardiovascular and cerebrovascular events, and mortality. Following screening to exclude participants with incident dementia at baseline, an extensive neuropsychological assessment was performed and participants were randomly assigned to treatment groups. All participants were required to have a proxy who agreed to provide an independent assessment of the functional and cognitive abilities of the participant. Assessments were repeated every six months. Significant decline at any visit, defined by specific changes in cognitive screening scores, led to a repeat detailed neuropsychological battery, neurological and medical evaluation, and magnetic resonance imaging (MRI) scan of the brain. The final diagnosis of dementia was achieved by a consensus panel of experts. Side effects and adverse events were tracked by computer at the central data coordinating center, and unblinded data were reviewed by an independent safety monitoring board. The overall average modified mini mental state examination (3MSE) was 93 (perfect score=100). Scores on the AD assessment scale (possible range of 0–70; lower is less impaired) were also quite low on average, as expected (mean of 6.5, with a standard deviation of 2.7). Finally, as judged by the clinical dementia rating (CDR), which combined the assessment of the participants and the assessment by their proxies, 60% of the participants had a CDR of 0 (no perceived deficits in cognition), whereas almost 40% had a CDR of 0.5, indicative of some impairment of

cognitive function. CDR of 0.5 was regarded by some investigators as possible dementia and was sometimes thought of as mild cognitive impairment (MCI); there were no ‘age corrections’ for CDR. Twelve of the 3072 participants had a CDR of 1.0, which was regarded as indicative of dementia, but these subjects scored well enough in both the screening tests (ADAS and 3MSE) and the detailed neuropsychological battery to gain entry to the study. The outcomes of MCI and the ability of Ginkgo to alter the risk of dementia and MCI and the development or progression of cardiovascular and cerebrovascular disease and their contribution to cognitive impairment were studied. This large cohort exposed to G. biloba should also answer definitively the question of whether the case reports of hemorrhage in persons who took G. biloba represent a true risk of the treatment (De Kosky et al., 2006).

AGE-RELATED DEMENTIA AND ALZHEIMER’S DISEASE In broad terms, an age-dependent degenerative disease is widely used to describe a condition in which the function or structure of affected tissues or organs progressively experience deterioration over time, such as cardiovascular diseases, nervous system dysfunction, immune system decline, and skeletal muscle degeneration. Neurodegenerative disease associated with aging is a disorder resulting from the gradual and progressive loss of neuronal cells, leading to nervous system dysfunction. The disorder is often associated with the deterioration of certain nerve cells in the central or peripheral nervous system; the changes in these cells cause them to function abnormally and eventually die. Amongst a variety of neurodegenerative diseases, AD is the most prevalent and devastating disorder in the growing elderly population. It is estimated that 4.5 million Americans were diagnosed with AD in 2000, with an annual estimated cost of $100 billion. It is predicted that the number will continue to climb and reach 13.2 million by 2050 in the US population. Globally, approximately 24 million people worldwide are living with AD (2014). Clinical signs of AD are characterized by progressive memory loss and cognitive deterioration, usually with an onset after 65 years of age. AD is the most common cause of dementia and accounts for about 70% of patients with dementia in the elderly. Extracellular senile plaques and intracellular neurofibrillary tangles in the brains of AD patients have been identified as pathological hallmarks of AD (Luo and Cao, 2009). The hypothesis that dementia of Alzheimer’s type (DAT) is due to a ‘cholinergic deficit’ at central synapses has led to the development of a new group of drugs for this indication: the cholinesterase (ChE) inhibitors.

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Age-Related Dementia and Alzheimer’s Disease

Thus, EGb 761® is now competing with the ChE inhibitors tacrine, donepezil, rivastigmine, and galantamine. No direct comparative trials have been undertaken, but long-term studies lasting 24 to 56 weeks to demonstrate efficacy have been carried out with both groups of substances in accordance with current EU guidelines. To date, only one psychometric scale has gained general acceptance as the primary criterion of efficacy: The cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog), whose scores range from 0 to 70 (the lower the better). The initial scores of patients in the trials were between 20 and 30; the improvements after six months of treatment (less those seen with placebo) were about two points under Ginkgo extract and two to four points with the ChE inhibitors. However, the relatively small differences are called into question by the occurrence of drug-specific side effects with the ChE inhibitors. Unlike treatment with EGb 761®, up to 90% of the patients given the ChE inhibitors developed nausea and vomiting, so there is a suspicion that methodological reasons in the sense of an ‘unblinding’ of the treatment groups caused the apparent superiority in the intensity of the effect. In addition, the benefits of treatment were rapidly reversed after ending administration of ChE inhibitors, which did not occur to the same extent with EGb 761®. Adverse drug reactions are more than 10 times more common with the ChE inhibitors, and the treatment costs are about five times higher than with EGb 761® (Schulz, 2003). A study was conducted that included elderly adults with either dementia or nondemented, ageassociated memory impairment (AAMI). A total of 214 participants with a mean age of 83 years included 63 with dementia due to AD or vascular origins and 151 with age-related memory loss in the study, which was a 24-week, randomized, double-blind, placebo-­controlled, parallel-group, multicenter trial. The majority of the mini-mental state examination (MMSE) scores were in the range of 12 to 24, signaling moderate impairment. The participants, recruited from 39 homes for the elderly in the Netherlands, were divided into three groups for the initial three months and given 160 or 240 mg of EGb 761® or a placebo (0 mg/d). After 12 weeks, the subjects in the two Ginkgo groups were randomized to continued Ginkgo treatment or placebo treatment. Primary outcome measures in the study were the syndrome Kurz test (SKT; psychometric functioning), the clinical global impression of change (CGI-2; psychopathology, assessed by nursing staff), and the Nuremberg gerontopsychological rating scale for activities of daily living (NAI-NAA; behavioral functioning). One hundred twenty-three patients received Ginkgo (n=79, 240 and 160 mg/d combined) or placebo (n=44) during the 24-week intervention period. No statistically significant differences

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in mean change of scores between Ginkgo and placebo were found. The differences were SKT, +0.4 (90% confidence interval [CI] –0.9–1.7); CGI-2, +0.1 (90% CI –0.3–0.4), and NAI-NAA, –0.4 (90% CI –1.9–1.2). A positive difference is in favor of Ginkgo. Neither the dementia subgroup (n=36) nor the AAMI subgroup (n=87) experienced a significant effect of Ginkgo treatment. The groups taking EGb 761® were randomized again to either continue with Ginkgo or to take a placebo for the rest of the six-month study. The initial placebo group continued to take a placebo. An intention-to-treat analysis showed no effect on neuropsychological testing, clinical assessment of symptoms, depressive mood, self-perceived memory, health, or behavior in either the relatively small group that took Ginkgo (79) or the placebo group (44) for the entire six months. There was no dose–effect relationship and no effect of prolonged Ginkgo treatment. In short, none of the subgroups benefited from Ginkgo compared to placebo. The trial results did not support the view that Ginkgo is beneficial for patients with dementia or AAMI (van Dogen et al., 2000, 2003). One aim was to assess the efficacy of long-term use of EGb 761® for the reduction of incidence of AD in elderly adults with memory complaints. In the randomized, parallel-group, double-blind, placebo-controlled GuidAge clinical trial, adults aged 70 years or older who spontaneously reported memory complaints to their primary-care physician in France were enrolled. Participants in a 1:1 ratio according to a computer-generated sequence were enrolled in a twice per day dose of 120 mg standardized G. biloba extract or a matched placebo. Participants and study investigators and personnel were masked to study group assignment. Participants were followed up for five years by primary-care physicians and in expert memory centers. The primary outcome was conversion to probable AD in participants who received at least one dose of study drug or placebo compared by use of the log-rank test. Between March 2002 and November 2004, ­Vellas et al. (2012) enrolled and randomly allocated 2854 participants, of whom 1406 received at least one dose of Ginkgo biloba extract and 1414 received at least one dose of placebo. After five years, 61 participants in the Ginkgo group had been diagnosed with probable AD compared with 73 participants in the placebo group (hazard ratio [HR] 0.84, 95% CI 0.60–1.18; p=0·306), but the risk was not proportional over time. Incidence of adverse events was much the same between groups: 76 participants in the Ginkgo group died compared with 82 participants in the placebo group (0.94, 0.69– 1.28; p=0.68); 65 participants in the Ginkgo group had a stroke compared with 60 participants in the placebo group (risk ratio 1.12, 95% CI 0.77–1.63; p=0.57). Incidence of other hemorrhagic or cardiovascular events

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also did not differ between groups. Long-term use of standardized Ginkgo biloba extract in this trial did not reduce the risk of progression to AD compared with placebo (Vellas et al., 2012).

DEMENTIA AND ALZHEIMER’S DISEASE EGb 761® has also been tested in a series of randomized, placebo-controlled trials and found effective in the treatment of dementia syndromes, namely AD, VaD, and mixed forms of both (Ihl et al., 2010). In a randomized, double-blind, placebo-controlled study, the efficacy of a Ginkgo leaf extract, administered at 120 mg/d over a period of one to three months, was investigated in 40 patients (average age of 72 years) with mild to moderate primary degenerative dementia. Compared to placebo, the extract significantly improved both psychometric test performance and clinical assessment. After three months of treatment with the extract, a mean improvement of 23.5% compared to baseline was found on the Crichton scale (p<0.0001). The Sandoz Clinical Assessment: Geriatric (SCAG) total score improved by approximately 33% compared to baseline values (p<0.0001). No adverse reactions were reported (­Weitbrecht and Jansen, 1986). Four good-quality trials, two large and two small, found a benefit from treatment with Ginkgo on dementia. The two large, well-conducted, positive trials included a combined total of 293 patients with either AD or VaD. One study used a dose of 240 mg per day and continued for six months. The efficacy of EGb 761® in outpatients with presenile and senile primary degenerative DAT and multi-infarct dementia according to DSM-III-R was investigated in a prospective, randomized, double-blind, placebo-controlled, multicenter study. After a four-week run-in period, 216 patients were included in the randomized 24-week treatment period. These received either a daily oral dose of 240 mg EGb 761® or a placebo. Clinical efficacy was assessed by means of a responder analysis, with therapy response being defined as response in at least two of the three primary variables. The data from the 156 patients who completed the study in accordance with the study protocol were taken into account in the confirmatory analysis of valid cases. The frequency of therapy responders in the two treatment groups differed significantly in favor of EGb 761®, with p<0.005 in Fisher’s Exact Test. The intent-to-treat analysis of 205 patients led to similar efficacy results. Thus, the clinical efficacy of the EGb 761® in dementia of the Alzheimer’s type and multi-infarct dementia was confirmed. The investigational drug was found to be well tolerated (Kanowski et al., 1997). The other study used a dose of

120 mg per day and lasted for one year (Le Bars et al., 1997). In both studies, the treatment groups showed improvement after six months of dosing according to the following scales: SKT (a brief test of cognitive function, memory and attention), CGI (clinician’s interviewbased quantified judgment of the amount of change in overall impairment), ADAS-Cog (a performancebased cognitive test that objectively evaluates memory, language, praxis, and orientation), and Geriatric Evaluation by Relatives Rating Instrument (GERRI, an inventory completed by the caregiver; Kanowski et al., 1997; Le Bars et al., 1997). This well-known Ginkgo study showed a benefit from Ginkgo comparable to c­ urrent pharmacological therapies of choice, for e­xample, Aricept. Subsequently, to facilitate comparison with Ginkgo clinical studies of six months’ duration, a full analysis was carried out of 26-week results from the previously mentioned study. It showed that among the 244 patients (from the initial 309) who completed the 26-week evaluation, the placebo group showed a significant worsening in all domains of assessment compared to baseline values, whereas the Ginkgo group slightly improved on cognitive assessment and daily living/social behavior; ADAS-Cog and GERRI scores were in favor of the Ginkgo leaf extract. In the Ginkgo group, 26% of patients achieved at least a four-point improvement in the ADAS-Cog score compared to 17% in the placebo group. With respect to GERRI scores, 30% of the Ginkgo group improved and 17% worsened, whereas the placebo group showed the opposite trend, as 25% of patients improved and 37% worsened. Thus, compared to placebo, significant benefit from use of the Ginkgo leaf extract was evident after 26 weeks (Le Bars et al., 2000). A reanalysis of the Le Bars and colleagues (2002) study included a stratification of Alzheimer’s patients according to severity of cognitive impairment. The relative changes from baseline depended upon the severity of the disease. Significant improvement compared to baseline according to the ADAS-cog and GERRI was observed in those with mild cognitive impairment (MMSE more than 23). In patients with moderate to severe dementia (MMSE less than 23), there was less deterioration in the EGb 761® group compared to baseline than that observed in the placebo group (Le Bars et al., 2002). The small trial had a combined total of 58 patients with AD who were given 240 mg per day for three months. The studies demonstrated improvement with treatment compared with placebo according to the SKT test (Hofferberth, 1994). To investigate of the effect of EGb 761® treatment (240 mg/d) on the clinical course, 20 outpatients with degenerative DAT were treated with placebo or active drugs for three months. To determine attention and memory, SKT tests were performed. Other psychometric tests (trailmaking test, ADAS, CGI) and

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Dementia and Alzheimer’s Disease

electrophysiological investigations (EEG topography) were also evaluated. Even though in the SKT test the active group (19.67 points) had a weaker baseline level than the placebo group (18.11 points), it experienced an improvement to 16.78 points under treatment with EGb 761®, whereas the placebo group experienced a deterioration to 18.89 points. The differences between the baseline and final values formed the basis for a statistical group comparison, which gave a result favorable to EGb 761® at a significance level of p<0.013. In addition to this psychometric confirmation of efficacy, certain descriptive trends were found at the psychopathological (CGI) and dynamic functional (EEG findings) levels, which can be interpreted as evidence of effectiveness of EGb 761® in mild to moderate dementia and of local effects in the central nervous system. Intergroup differences in the ADAS cognitive and noncognitive subscales did not reach statistical significance, probably because of the small sample size (Maurer et al., 1998). The efficacy of four ChE inhibitors (tacrine, donepezil, rivastigmine, and metrifonate) and EGb 761® in AD were compared. Only patients suffering from Alzheimer’s dementia were included in the studies of ChE inhibitors. Results from studies with ChE inhibitors and EGb 761® after 24 to 30 weeks of randomized treatment were compared. The differences in the effects of the active substance and placebo on cognition were measured on the ADAS-Cog scale, taking into account the different degrees of dementia in the various studies and the dropout rate due to adverse drug reactions. Efficacy, expressed as the delay in symptom progression or the difference in response rate between active substance and placebo, showed no major differences between the four ChE inhibitors and the Ginkgo special extract. Only tacrine exhibited a high dropout rate due to adverse drug reactions. For this reason, the prescription of tacrine to new patients should be critically evaluated. Secondgeneration ChE inhibitors (donepezil, rivastigmine, and metrifonate) and EGb 761® should be considered equally effective in the treatment of mild to moderate Alzheimer’s dementia (Wettstein, 2000). Secondary analyses of a randomized controlled trial were performed to find out whether treatment effects of EGb 761® differed by type of dementia. Three-hundred ninety-five patients aged 50 years or above with dementia with neuropsychiatric features were treated with EGb 761® (240 mg/d) or placebo for 22 weeks. Patients scored between 9 and 23 on the SKT, a cross-culturally validated cognitive test battery. Their total score on the Neuropsychiatric Inventory (NPI) was at least 5. Efficacy was assessed by the SKT test battery (primary outcome measure), the verbal fluency test, the clock-drawing test, the NPI, the Hamilton rating scale for depression (HAMD), and the Gottfries-Bråne-Steen scale (GBS).

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Applying standard research diagnostic criteria, 214 patients were diagnosed with AD (probable AD or possible AD with cerebrovascular disease) and 181 with probable VaD. Under EGb 761® treatment, the SKT total score improved by −3.0±2.3 and −3.4±2.3 points in patients with AD and VaD, respectively, whereas the patients on placebo deteriorated by +1.2±2.5 and +1.5±2.2 points, respectively (p<0.01 for both drug–placebo differences). Significant drug and placebo differences were found for all secondary outcome variables with no major differences between AD and VaD subgroups. The rate of adverse events tended to be higher for the placebo group (Napryeyenko et al., 2009). In the previous studies, it was shown that EGb 761® may have been more efficient when dementia was associated with neuropsychiatric features. To understand whether treatment effects correlated with neuropsychiatric symptom burden at baseline, retrospective analyses of data from a 24-week, randomized, placebo-controlled, double-blind clinical trial of EGb 761® (240 mg once daily) were enforced. A total of 410 outpatients with AD, vascular dementia, or AD with cerebrovascular disease, each associated with neuropsychiatric features, were enrolled. Patients evaluated 5 or above on the NPI, with at least one item score being 3, and between 9 and 23 on the SKT cognitive test battery. Correlations between changes from baseline and NPI baseline scores were significantly different between EGb 761® and placebo groups. The slopes of the regression lines for the active and the placebo groups showed qualitative and statistically significant differences. With increasing NPI baseline scores, there was faster deterioration in the placebo group and thus more net benefit from treatment for the EGb 761® group. Due to faster decline of placebo-treated patients, the net effects of EGb 761® on cognitive and functional abilities were larger in patients with more pronounced symptoms (Ihl et al., 2010). A multicenter, double-blind, randomized, placebocontrolled, 24-week trial with 410 outpatients was conducted to demonstrate the efficacy and safety of a 240 mg, once-daily formulation of EGb 761® in patients with mild to moderate dementia (AD or VaD) associated with neuropsychiatric symptoms. Patients scored 9 to 23 on the SKT cognitive battery and at least 6 on the NPI, with at least one of four key items rated at least 4. Primary outcomes were the changes from baseline to week 24 in the SKT and NPI total scores. The ADCS Clinical Global Impression of Change (ADCSCGIC), verbal fluency test, activities of daily living international scale (ADL-IS), DEMQOL-Proxy qualityof-life scale, and 11-point box scales for tinnitus and dizziness were secondary outcome measures. Patients treated with EGb 761® (n=200) improved by 2.2±3.5 points (mean ± SD) on the SKT total score, whereas those receiving placebo (n=202) changed only slightly

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by 0.3±3.7 points. The NPI composite score improved by 4.6±7.1 in the EGb 761® treated group and by 2.1±6.5 in the placebo group. Both drug/placebo comparisons were significant at p<0.001. Patients treated with EGb 761® also showed a more favorable course in most of the secondary efficacy variables. In conclusion, treatment with EGb 761® at a once-daily dose of 240 mg was safe and resulted in a significant and clinically relevant improvement in cognition, psychopathology, functional measures, and quality of life of patients and caregivers (Herrschaft et al., 2012).

MULTIPLE SCLEROSIS Multiple sclerosis (MS) is a chronic demyelinating neurological disease afflicting young and middleaged adults that results in problems with coordination, strength, cognition, affect, and sensation. To determine whether EGb 761® improved functional performance in individuals with MS, a double-blind, placebocontrolled, parallel group study was designed. The end point was the change between baseline (i.e., preintervention) and follow-up evaluation following a regimen of four tablets per day at 60 mg per tablet for four weeks. Twenty-two individuals with MS were randomly assigned to either the treatment or control condition. Groups did not differ with respect to age, IQ, or education. Half of the subjects received 240 mg per day of EGb 761®, and the other half received placebo. The main outcome measures assessed depression (center for epidemiologic studies of depression scale [CES-D]), anxiety (state-trait anxiety inventory [STAI]), fatigue (modified fatigue impact scale [MFIS]), symptom severity (symptom inventory [SI]), and functional performance (functional assessment of multiple sclerosis [FAMS]). The Ginkgo group had significantly more individuals showing improvement on four or more measures with improvements associated with significantly larger effect sizes on measures of fatigue, symptom severity, and functionality. The Ginkgo group also exhibited less fatigue at follow-up compared with the placebo group. This exploratory pilot study showed that no adverse events or side effects were reported and that Ginkgo exerted modest beneficial effects on select functional measures (e.g., fatigue) among some individuals with MS (Johnson et al., 2006). The final analyses were performed with 12 participants in the Ginkgo intent-to-treat group and nine participants in the placebo group by the same researcher group. The goal was to determine the effect of Ginkgo versus placebo on information processing and executive function and evaluate the relative contributions of fatigue and mood in mediating changes in cognition. There were no significant differences between the Ginkgo and placebo

group on visual–spatial memory and attention/concentration. However, the Ginkgo-treated group showed enhanced processing speed in contrast to the placebo group on the visual threshold serial addition test. The Ginkgo-treated group also emitted fewer verbal intrusions on the ­California verbal learning test than the placebo group. These findings may have been mediated by Ginkgo’s purported central cerebrovascular-modulating properties and neurotransmitter-potentiating activity, resulting in modest increases in the strength of underlying memory, enhanced activation at encoding, and/or more efficient retrieval and executive control. These results may suggest modest benefits in taking Ginkgo, but more convincing evidence awaits future work using larger samples and additional cognitive measures. However, given the prominence of slower processing and dysexecutive function in MS, even modest improvements in executive function may enhance activities of daily living (Diamond et al., 2013).

TARDIVE DYSKINESIA Tardive dyskinesia (TD) has no well-accepted treatments or known pathophysiology, but low brain derived neurotrophic factor (BDNF) may play an important role in its pathophysiology. EGb-761® is a potent antioxidant that has neuroprotective effects mediated through enhancing BDNF levels. It was hypothesized that treatment with EGb-761® would increase serum BDNF levels and reduce TD, particularly among schizophrenia patients who have the BDNF valine 66 to methionine (Val66Met) genotype (Val/Val). Serum BDNF levels and genotyping for the BDNF gene Val66Met polymorphism were assessed in Chinese schizophrenic patients with (n=368) and without (n=563) TD as well as healthy control subjects (n=546). About half of the TD patients (n=157) then participated in a double-blind, randomized, placebo-controlled, 12-week treatment with 240 mg per day of EGb-761®. Serum BDNF levels were measured again post-treatment. Clinical efficacy was determined using the abnormal involuntary movement scale (AIMS). TD patients had lower BDNF levels than the non-TD patients and healthy controls. EGb-761® treatment improved symptoms of TD and increased BDNF levels compared with placebo treatment. Moreover, the improvement of AIMS total score correlated with the increase in BDNF levels. Furthermore, improvement in the AIMS score was greatest in those with the Val/Val allele and lowest with the Met/Met allele. The BDNF system may be implicated in the pathophysiology of TD and its improvement with antioxidant treatment. Patients with the genetic potential for greater BDNF release (Val/Val at 66) may obtain a greater reduction in TD from EGb-761® treatment (Zhang et al., 2012).

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SIDE EFFECTS AND QUALITY ISSUES OF EGb 761®

META-ANALYSIS AND SYSTEMATIC REVIEWS OF GINKGO CLINICAL TRIALS Several meta-analysis and systematic reviews of the clinical literature on Ginkgo have been published. An objective measure of the effect of Ginkgo on cognitive function in patients with AD was attempted in a metaanalysis of randomized, placebo-controlled, doubleblind studies. The four studies that met the inclusion criteria contained a total of 212 subjects treated with Ginkgo and 212 with placebo. Oken et al (1998) found a small but significant effect after three to six months of treatment with 120–240 mg of Ginkgo extract compared to placebo. The modest effect size calculated from reported p-values for cognitive measures and sample size translated into a 3% difference in the ADAS-Cog (Oken et al., 1998). Published one year later, a systematic review of the treatment of dementia with Ginkgo included nine double-blind, randomized, placebo-­controlled trials. It was concluded that the majority of trials support the notion that Ginkgo is efficacious in delaying the ­clinical deterioration of patients with dementia or in bringing about symptomatic improvement (Ernst and Pittler, 1999). An evaluation of the treatment of age-related cognitive impairment or dementia of any type with any Ginkgo extract compared to placebo was undertaken in a meta-analysis including 33 randomized, doubleblind studies. Birks et al. (2002) concluded that, compared to placebo, Ginkgo showed significant benefit for cognition at doses less than 200 mg/d and more so with doses more than 200 mg/d, both for 12 weeks. Benefits in cognition were also found following 24 weeks with any Gingko dose. Activities of daily living also showed a benefit with doses less than 200 mg/d in treatment lasting 12 weeks and of shorter duration (Birks et al., 2002).

SIDE EFFECTS AND QUALITY ISSUES OF EGb 761® As summarized in Table 12.1, common side effects, including headache, nausea, gastrointestinal upset, diarrhea, dizziness, or allergic skin reaction, in the EGb 761® treated group were not different compared with those in the placebo group. It should be noted that EGb 761® could increase bleeding risk for people who take anticoagulant drugs, have bleeding disorders, or undergo surgery or dental procedures (discontinuation 36 hours prior to surgery is recommended by physicians). For example, when taken with aspirin spontaneous hyphema could occur, and when used with Warfarin, intracerebral hemorrhage could result. Interestingly, EGb 761® was found to

TABLE 12.1 Side Effects and Cautions Adverse Effect

Drugs

Headache, nausea, gastrointestinal upset, diarrhea, dizziness, or allergic skin reaction

No significant difference from placebo

Could increase bleeding risk for people who take anticoagulant drugs, have bleeding disorders, or undergo surgery or a dental procedure (discontinue 36 h prior) Alone, no inhibition of blood coagulation or platelet aggregation

With aspirin spontaneous hyphema With warfarin intracerebral hemorrhage

Reduce effectiveness of anticonvulsant for seizure Uncooked Ginkgo seeds contain ginkotoxin which can cause seizures

With carbamazapine or valproic acid, seizure

Luo and Cao, 2009

reduce the effectiveness of anticonvulsants for seizure. Seizure could also be caused by noncooked Ginkgo seeds containing ginkotoxin. As with any natural products, standardization and quality concerns could impact on all studies. The problems of complex herbals could adversely affect assay sensitivity of any clinical trial. Furthermore, standardization of herbs against one active marker group may not necessarily assure standardization of the activity of the extract. In general, phytochemical composition can vary depending on variability in the raw material from which the extract is obtained, for example, harvesting period, drying process, storage conditions, method of extraction, solvent composition, and ratio of raw material to extraction fluid. Based on a survey of 27 U.S. brands (tabs and caps) of EGb 761® tested for content, flavone glycosides varied from 24–36%, terpene lactones ranged from 4–11%, and ginkgolic acid ranged from ∼500–90,000 ppm (should not exceed 5 ppm). Of 14 products tested for dissolution, 10 exhibited > 75% dissolution of glycosides and lactones in 30 minutes, two exhibited about 55–70%, and one about 10% dissolution in 30 minutes. The authors warned that many of the investigated products cannot be considered to be pharmaceutically equivalent to the patented original product by Schwabe (Luo and Cao, 2009). Most studies reporting side effects have been case reports with dosages ranging from 80–150 mg/d for durations from one week to up to one year, with many patients having comorbid conditions and taking other medications. Several case studies report bleeding abnormalities that are potentially attributable to Ginkgo, including reports suggesting that Ginkgo may cause postoperative bleeding. The mechanism of action may involve the constituents ginkgolide, bilobalide, and other components that are PAF-receptor antagonists (Table 12.2; Diamond and Bailey, 2013).

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TABLE 12.2  Drug Interactions Adverse Reaction/Interactions

Drug

Case study: bleeding

Warfarin (Coumadin, Jantoven, Marfarin), ibuprofen (Advil), aspirin, vitamin E

Case study: bleeding

Rofecoxib (Vioxx)

Case studies: bleeding

Antiplatelets and anticoagulants

Seizure in one case report

Antiepileptics

Increased blood pressure in one case report

Thiazides

Mixed results in four pharmacokinetic trials

Midazolam (Versed)

Reduced drug concentration in pharmacokinetic trials

Omeprazole (Losec, Prilosec, Omesec)

Priapism in one case report

Risperidone (Risperdal)

Decreased area under the curve (AUC) in one pharmacokinetic trial

Ritonavir (Norvir)

Mixed results in two pharmacokinetic trials

Tolbutamide (Orinase, Tol-Tab)

Coma in one case report Increased sedative effects

Trazodone (Desyrel, Oleptro)

Decreased AUC

Alprazolam (Xanax, Niravam)

Possible interaction at high doses

Nicardipine (Cardene)

Synergistic effects

Monoamine oxidase inhibitors

Increased effectiveness

Haloperidol (Haldol)

Increased effectiveness

Nifedipine (Adalat, Afeditab CR, Nifediac)

Diamond and Bailey, 2013

EXPOSURE TO GINKGO LEAF EXTRACTS IN CLINICAL STUDIES In human pharmacological studies with Ginkgo leaf extracts, healthy volunteers were exposed to single doses of 360 mg and 600 mg, and 18 elderly subjects with benign memory deficits (mean age of 69 years) received a single dose of 600 mg; no adverse effects were observed in any of these studies. Forty clinical studies involving two different Ginkgo leaf extracts and more than 2000 patients were also reviewed, and no serious side effects were noted. These findings were corroborated by a subsequent review of more than 50 clinical studies involving patients with dementia or cognitive impairment, which revealed no significant adverse effects from the same two extracts. In very rare cases, mild gastrointestinal complaints, headache, and allergic skin reactions have been reported.

A large drug-monitoring study with a Ginkgo leaf extract involved 13 565 patients with vascular-type dementia (40%), Alzheimer’s-type dementia (28%), or mixed forms (32%), of whom 10 815 received 120 mg of the extract daily for a minimum of three months. Adverse events were observed in 183 patients (1.69%), the more important being headache (0.22%), nausea (0.34%), gastrointestinal complaints (0.14%), diarrhea (0.14%), and allergic reactions (0.09%); no cases of therapy discontinuation due to the extract were reported. This finding is consistent with pharmacovigilance data collected systematically in Germany from 1982 to 1994. The rates of adverse effects per million packages sold of a Ginkgo leaf extract preparation were 0.35 for gastrointestinal disturbances, 0.19 for headaches, and 0.8 for allergic reactions. A similar finding was observed in a 12-month clinical study involving 309 patients with dementia who received 120 mg of an extract or a placebo daily. The final analysis revealed that adverse events were equally distributed between the two treatment groups with the exception of gastrointestinal symptoms, which were more often attributed to the active drug group (18 out of 29 events). In contrast, in a clinical study during which 216 patients with dementia received either 240 mg of a Ginkgo leaf extract or placebo daily for 24 weeks, conspicuous differences in adverse events were observed in relation to two WHO-defined organophysical systems; adverse effects in skin and its appendages were observed more frequently in the Ginkgo group, whereas gastrointestinal disorders occurred more often under placebo. No specific substance-related changes were evident in laboratory parameters (ESCOP Monographs, 2003).

CONCLUSION It was implicated that human dosage ranges and reactions to Ginkgo reflect many factors including pharmacology, pharmacokinetics, and pharmacodynamics of individual Ginkgo components in addition to possible synergistic effects. Ginkgo has been studied in numerous controlled trials and has displayed a good safety profile over time. It has shown potential in ameliorating the effects of a variety of disorders and symptoms. Mechanisms of action have been examined and expressed in multiple studies, and possible drug interactions and adverse events continue to be explored in clinical trials. In summary, Ginkgo has the potential to provide a safe alternative and complementary tool for treating a variety of symptoms and disorders. Patient outcomes, safety, and research are optimized when clinicians and researchers are informed with respect to composition, indications,

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