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To determine the effect of treatment with Ginkgo biloba extract on objective measures of cognitive function in patients with Alzheimer disease (AD) based on formal review of the current literature. An attempt was made to identify all English and non-English-language articles in which G. biloba extract was given to subjects with dementia or cognitive impairment. Inclusion criteria for the meta-analysis were (1) sufficiently characterized patients such that it was clearly stated there was a diagnosis of AD by either Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, or National Institute of Neurological Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria, or there was enough clinical detail to determine this by our review; (2) clearly stated study exclusion criteria, ie, those studies that did not have stated exclusions for depression, other neurologic disease, and central nervous system-active medications were excluded; (3) use of standardized ginkgo extract in any stated dose; (4) randomized, placebo-controlled and double-blind study design; (5) at least 1 outcome measure was an objective assessment of cognitive function; and (6) sufficient statistical information to allow for meta-analysis. Of more than 50 articles identified, the overwhelming majority did not meet inclusion criteria, primarily because of lack of clear diagnoses of dementia and AD. Only 4 studies met all inclusion criteria. In total there were 212 subjects in each of the placebo and ginkgo treatment groups. Overall there was a significant effect size of 0.40 (P<.0001). This modest effect size translated into a 3% difference in the Alzheimer Disease Assessment Scale-cognitive subtest. Based on a quantitative analysis of the literature there is a small but significant effect of 3- to 6-month treatment with 120 to 240 mg of G. biloba extract on objective measures of cognitive function in AD. The drug has not had significant adverse effects in formal clinical trials but there are 2 case reports of bleeding complications. In AD, there are limited and inconsistent data that preclude determining if there are effects on noncognitive behavioral and functional measures as well as on clinician's global rating scales. Further research in the area will need to determine if there are functional improvements and to determine the best dosage. Additional research will be needed to define which ingredients in the ginkgo extract are producing its effect in individuals with AD.
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SECTION EDITOR: DAVID E. PLEASURE, MD
The Efficacy of Ginkgo biloba on Cognitive Function
in Alzheimer Disease
Barry S. Oken, MD; Daniel M. Storzbach, PhD; Jeffrey A. Kaye, MD
Objective: To determine the effect of treatment with
Ginkgo biloba extract on objective measures of cognitive
function in patients with Alzheimer disease (AD) based
on formal review of the current literature.
Methods: An attempt was made to identify all English and
non–English-language articles in which G biloba extract was
given to subjects with dementia or cognitive impairment.
Inclusion criteria for the meta-analysis were (1) suffi-
ciently characterized patients such that it was clearly stated
there was a diagnosis of AD by either Diagnostic and Sta-
tistical Manual of Mental Disorders, Revised Third Edition,
or National Institute of Neurological Disorders and Stroke–
Alzheimer’s Disease and Related Disorders Association cri-
teria, or there was enough clinical detail to determine this
by our review; (2) clearly stated study exclusion criteria,
ie, those studies that did not have stated exclusions for de-
pression, other neurologic disease, and central nervous sys-
tem–active medications were excluded; (3) use of stan-
dardized ginkgo extract in any stated dose; (4) randomized,
placebo-controlled and double-blind study design; (5) at
least 1 outcome measure was an objective assessment of
cognitive function; and (6) sufficient statistical informa-
tion to allow for meta-analysis.
Results: Of more than 50 articles identified, the over-
whelming majority did not meet inclusion criteria, pri-
marily because of lack of clear diagnoses of dementia and
AD. Only 4 studies met all inclusion criteria. In total there
were 212 subjects in each of the placebo and ginkgo treat-
ment groups. Overall there was a significant effect size
of 0.40 (P,.0001). This modest effect size translated into
a 3% difference in the Alzheimer Disease Assessment
Scale–cognitive subtest.
Conclusions: Based on a quantitative analysis of the lit-
erature there is a small but significant effect of 3- to 6-
month treatment with 120 to 240 mg of G biloba extract
on objective measures of cognitive function in AD. The
drug has not had significant adverse effects in formal clini-
cal trials but there are 2 case reports of bleeding compli-
cations. In AD, there are limited and inconsistent data
that preclude determining if there are effects on noncog-
nitive behavioral and functional measures as well as on
clinician’s global rating scales. Further research in the area
will need to determine if there are functional improve-
ments and to determine the best dosage. Additional
research will be needed to define which ingredients in
the ginkgo extract are producing its effect in individuals
with AD.
Arch Neurol. 1998;55:1409-1415
G
INKGO BILOBA is a living
fossil tree having under-
gone little evolutionary
change over almost 200
million years. While cur-
rently it is essentially extinct in the wild,
it is widely cultivated for its nut as well
as for its leaves. The tree has a high tol-
erance to urban and industrial pollution
and is extremely resistant to insects, bac-
teria, viruses, and fungi. Extracts of the
leaves have been used for 5000 years in tra-
ditional Chinese medicine for various pur-
poses. Medicinal extracts are made from
dried leaves. Studies on the biological ac-
tivity of different components of the ginkgo
leaf began with modern scientific meth-
ods about 20 years ago.
Currently, ginkgo extracts used for
medicinal purposes are usually standard-
ized to contain 24% ginkgo-flavone
glycosides and 6% terpenoids. The
terpenoids include bilobalide and the
ginkgolides A, B, C, M, and J that are
20-carbon cage molecules with six 5-
membered rings. The ginkgolides are an-
tagonists of platelet-activating factor (PAF)
that has numerous biological effects.
1
Be-
sides causing platelet activation and ag-
gregation, PAF produces proinflamma-
tory effects (eg, increasing vascular
permeability), is an extremely potent ul-
cerogen in the stomach, and contracts
smooth muscle, including bronchial
muscle. Platelet-activating factor has a di-
rect effect on neuronal function and long-
NEUROLOGICAL REVIEW
From the Department of
Neurology (Drs Oken and
Kaye) and Center for Research
on Occupational and
Environmental Toxicology
(Dr Storzbach), Oregon Health
Sciences University, and
Portland Veteran Affairs
Medical Center (Dr Kaye),
Portland.
ARCH NEUROL / VOL 55, NOV 1998
1409
©1998 American Medical Association. All rights reserved.
term potentiation.
2,3
An initial report
4
suggested that lis-
sencephaly, a disorder of neural migration and dendritic
branching, was associated with changes in the gene cod-
ing a PAF inactivating enzyme found in cerebral cortex,
PAF acetylhydrolase. This was not confirmed in a later
independent laboratory study.
5
The other major components of ginkgo extract are
the flavonoids that contribute to ginkgo’s antioxidant and
free radical scavenger effects.
6
Ginkgo has been found to
(1) reduce cell membrane lipid peroxidation in experi-
mental spinal cord injury similarly to methylpredniso-
lone
7
; (2) reduce bromethalin-induced cerebral lipid per-
oxidation and edema
8
; (3) protect brain neurons against
oxidative stress induced by peroxidation
9-11
; (4) de-
crease neuronal injury following ischemia or electrocon-
vulsive shock
12
; and (5) reduce subchronic cold stress
effects on receptor desensitization.
13
Other biological effects of G biloba extract have been
observed. It is an inhibitor of monoamine oxidase A and
B.
14
Biological effects in various mammalian species have
been demonstrated in many organs, such as decreasing
retinal neovascularization following injury,
15
altering the
immune system
16
and promoting compensation from ves-
tibular deafferentation.
17
Therapeutically, ginkgo may be biologically plau-
sible to use in Alzheimer disease (AD) for several rea-
sons. While the cause and underlying pathophysiologi-
cal features of AD are unknown, prominent hypotheses
as to the cause center around age-related oxidative in-
jury.
18,19
As described earlier, the flavonoid components
of ginkgo appear to be useful in animal models in pre-
venting some types of oxidative and peroxidative neu-
ronal injury. Another hypothesis of a cause of AD cen-
ters around an inflammatory process.
20,21
Ginkgo being
a PAF antagonist has anti-inflammatory effects. An-
other reason for the plausibility of use of ginkgo in in-
dividuals with AD also relates to its activity as a PAF an-
tagonist. The effect of PAF antagonism directly on brain
function is fairly unexplored.
2,3
Ginkgo has been widely used by naturopathic doc-
tors and other alternative and complementary health care
providers. Alternative or complementary medicine is
widely used in North America with 34% of US adults in-
terviewed in 1990 having used some form of alternative
medicine in the past year.
22
In the United States people
spend an estimated $1.5 billion per year on herbal medi-
cines with projected annual growth of 15%.
23
Germany
is one of the largest herbal users among American or west-
ern European countries with total sales in 1993 of $1.9
billion for plant-based allopathic medicines (half of these
prescribed by physicians) and with 5 million prescrip-
tions for ginkgo in 1988. Clinically, ginkgo extract is
widely used in Europe for treatment of memory disor-
ders associated with aging, including AD and vascular
dementia. It is already widely used in the United States
as an alternative therapy for AD despite the presence of
only 1 American study.
24
Prior to the publication of that
American trial, a conservative estimate at a university
cognitive assessment clinic found 10% of patients using
alternative medicines to improve cognitive function
and an additional 29% to improve general health.
25
A
less conservative estimate comes from another study
26
METHODS
We attempted to identify all randomized placebo-
controlled clinical trials (both English and non–
English language) in which G biloba was adminis-
tered for at least 2 months to patients with dementia
or other cognitive impairment. The search for po-
tentially relevant studies and reviews was per-
formed through MEDLINE using the keywords
“ginkgo” and “gingko [sic].” Trials referenced by ar-
ticles that were found were also screened. Addition-
ally, we had access to a listing of 60 articles with En-
glish summaries from a preliminary Cochrane
Collaboration Review (http://www.cochrane.co.uk)
on the use of ginkgo in dementia and related disor-
ders. This search was done using several databases
including MEDLINE, EMBASE, and PsychLit as well
as references in review articles and textbooks. Addi-
tional search words included brand names for ginkgo
(eg, Tanakan, Tebonin, Rokan, or Ginkoba) and a
standardized extract, EGb 761.
Our goal was to evaluate only those studies that
met minimally acceptable scientific standards. We
therefore used the following criteria for inclusion in
the quantitative review.
• Patients needed to be clearly and sufficiently
characterized such that there was a clearly stated di-
agnosis of AD by either Diagnostic and Statistical
Manual of Mental Disorders, Revised Third Edition or
National Institute of Neurological Disorders and
Stroke–Alzheimer’s Disease and Related Disorders As-
sociation criteria, or there was enough clinical de-
tail to determine this by our review.
Studies needed to clearly state their exclu-
sion criteria, ie, those studies that did not have stated
exclusions for depression, other neurologic disease,
and central nervous system–active medications were
excluded. We did not exclude trials solely for the lack
of neuroimaging studies on all subjects.
The use of standardized ginkgo extract in
any stated dose was required (24% or 25% ginkgo-
flavone glycosides and 6% terpenoids, see above). The
dose could be given by any route of administration.
The study needed to be randomized, placebo-
controlled, and double-blind. Details of the random-
ization procedure were not required.
• At least 1 outcome measure needed to be an
objective assessment of cognitive function.
The studies that met these inclusion criteria are
listed in
Table 1. Studies also needed to include de-
scriptive statistics from which effect sizes
27,28
could
be computed. This only caused the exclusion of 1 ar-
ticle in Table 1 from the quantitative analysis.
Meta-analytic methodology was used to quan-
titatively assess the effects of ginkgo on objective mea-
sures of cognition for all studies that were found to
meet the above-listed criteria. This statistical meth-
odology involves computation of individual effect
sizes
27,28
for each study sample which, after weight-
ing for sample size, becomes a single case to be used
in subsequent analyses. For each evaluated study we
computed the effect size (g statistic) according to the
methodology of Hedges and Olkin.
28
ARCH NEUROL / VOL 55, NOV 1998
1410
©1998 American Medical Association. All rights reserved.
that found 55% of caregivers had used at least 1 alterna-
tive medicine to improve the patient’s memory. Ginkgo
was the major alternative treatment besides vitamins in
those studies.
To help define the efficacy of G biloba in AD, a re-
view of the current literature and a meta-analysis of stud-
ies that met minimally acceptable scientific criteria was
performed.
RESULTS
STUDIES REVIEWED AND INCLUDED
Fifty-seven articles
24,29-84
were identified, of which sev-
eral were review articles. There were dozens of studies
mostly in the French and German literature suggesting
the efficacy of ginkgo for the treatment of memory im-
pairment associated with aging but only a limited num-
ber were properly blinded and placebo-controlled with
well-characterized subjects. Almost all reported posi-
tive effects of ginkgo. The overwhelming majority con-
tained the diagnosis of cerebral insufficiency. However,
the term cerebral insufficiency is vague and overinclu-
sive with criteria that include depressed mood, fatigue,
lack of motivation, dizziness, and tinnitus. Without suf-
ficiently detailed description all articles simply using the
diagnosis of cerebral insufficiency were excluded from
the meta-analysis. Other potentially relevant studies were
excluded for other reasons. Weitbrecht and Jansen
63
stud-
ied patients with primary degenerative dementia but did
not further describe the inclusion or exclusion criteria.
The patients in the study of Chartres et al
36
were receiv-
ing decreasing doses of neuroleptics and tranquilizers.
There was 1 study
85
that otherwise met the inclusion cri-
teria but could not be included in the formal meta-
analysis because of a lack of sufficiently descriptive sta-
tistics. Four studies
24,81,86,87
were identified that met all
criteria (
Table 2). These 4 studies included patients with
mild or moderate dementia severity. Although 2 of these
studies
86,24
reported additionally on patients with vascu-
lar dementia, only groups composed solely of patients
diagnosed as having AD were included in the analysis.
ANALYSIS TECHNIQUES
Of the 4 studies that met criteria, 2 reported means and
SDs.
86,87
For these studies we computed the g statistic based
on pooled SDs.
28
Wesnes et al
87
reported statistical analy-
ses that aggregated their multiple cognitive measures
across multiple assessments. However, we deemed it more
appropriate to calculate the effect size for Wesnes et al
87
by averaging the effect sizes of their multiple cognitive
measures reported for their final assessment (12 weeks).
To provide more comparable treatment duration and in-
crease total sample size, the intention-to-treat sample of
Le Bars et al
24
at 26 weeks was used to calculate the study’s
effect size. As this study reported means and 95% con-
fidence intervals (instead of SDs or SEs), the 95% con-
fidence interval was used to calculate the SE, which in
turn was used to calculate the SD for use in effect size
calculation. Hofferberth
81
reported P values for the Mann-
Whitney U statistic, but did not report means or SDs. The
effect size for the final assessment (12 weeks) was cal-
culated from the reported P value and sample sizes us-
ing the formula reported by Hedges and Olkin.
28
The 4 studies
24,81,86,87
reported analyzable data for 212
patients treated with ginkgo and 212 with placebo. In-
dividual group sample sizes, as shown in Table 2, ranged
from 19 to 104. After appropriate weighting for sample
size,
28
the mean effect size of the 4 samples was 0.41 (95%
confidence interval, 0.22-0.61). This indicates that the
weighted mean effect size was equivalent to a little less
than half of an SD. There was significant variability in
effect sizes (range, 0.1-1.1).
ADVERSE EFFECTS
In a previous review,
31
no serious adverse effects were
noted in any of the older studies and the incidence of sig-
nificant adverse effects was similar in all placebo-treated
Table 1. Studies Satisfying Inclusion Criteria*
Source, y Diagnoses
No. of
Subjects
Analyzed
Study
Duration,
wk
Dropout
Rate, %
Daily
Dose,
mg
Ginkgo
Formulation
Cognitive
Outcome Measures
Other Outcome
Measures
Hofferberth,
81
1994 AD 40 12 ?5 240 EGb 761 SKT, choice reaction time SCAGS, EEG
Le Bars et al,
24
1997 AD (
DSM-III-R
) 207 26 20 120 EGb 761 ADAS-cog CGIC, GERRI
Kanowski et al,
86
1996
AD (
DSM-III-R
) 125 24 30 240 EGb 761 SKT CGI, NAB, EEG
Wesnes et al,
87
1987 AD (dementia with
appropriate medical
and psychiatric
exclusions)
58 12 7 120 Tanakan 10-Item battery including
Benton Visual Retention Test,
Digit Symbol, word
list recall, and reaction time
Quality-of-life scale
Rai et al,
85
1991 AD (dementia with
appropriate medical
and psychiatric
exclusions)
27 24 9 120 Tanakan MMSE, Kendrick Digit
Copying and Object
Learning tasks, digit recall,
and classification task
EEG
*
AD indicates Alzheimer disease; EGb 761, a ginkgo extract (Dr Willmar Schwabe Pharmaceuticals, Karlsruhe, Germany); SKT, Synrom-Kurztest; SCAGS,
Sandoz Clinical Assessment Geriatric Scale; EEG, electroencephalogram;
DSM-III-R, Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition
;
ADAS-cog, Alzheimer Disease Assessment Scale–cognitive subtest; CGIC, Clinical Global Impression of Change; GERRI, Geriatric Evaluation by Relative’s Rating
Instrument; CGI, Clinical Global Impressions; NAB, Nurnberger Alters-Beobachtungsskala; and MMSE, Mini-Mental State Examination. The dropout rate is for
26-week data in the study by Le Bars et al.
24
The study by Rai et al
85
met criteria for inclusion other than lack of sufficient statistics for meta-analysis.
ARCH NEUROL / VOL 55, NOV 1998
1411
©1998 American Medical Association. All rights reserved.
and ginkgo-treated groups. In the studies we reviewed and
the studies in our meta-analysis there were also no sig-
nificant adverse effects. In all these studies doses have
ranged up to 240 mg/d. Ginkgo may prolong the bleed-
ing time and there are 2 case reports of hemorrhage in sub-
jects who were taking ginkgo. A 33-year-old woman had
been taking 120 mg of ginkgo for 2 years prior to devel-
oping bilateral subacute subdural hematomas without a
known history of trauma.
88
Two simultaneously drawn
bleeding times were 15 and 9.5 minutes with the upper
limit for the laboratory being 9 minutes. One month after
stopping ginkgo, 2 simultaneously drawn bleeding times
were both 6.5 minutes. A second case report concerned a
70-year-old man who was taking aspirin daily for 3 years
following coronary artery bypass surgery.
89
He devel-
oped spontaneous bleeding from the iris into the anterior
chamber 1 week after beginning 80 mg/d of Ginkoba, a
ginkgo extract. Another case report
90
concerned a 72-year-
old who developed a small subdural hematoma several
months after beginning ginkgo therapy. A final case re-
port
91
was that of a 78-year-old who had been stable re-
ceiving warfarin for atrial fibrillation for 5 years with a pro-
thrombin time of 16.9 seconds who presented with a left
parietal intracerebral hemorrhage 2 months after begin-
ning ginkgo therapy. These case reports are clearly of con-
cern. However, given the large but unknown number of
people taking ginkgo and the lack of such serious ad-
verse effects reported in any of the published articles to
date totaling several thousand subjects, the incidence of
bleeding complications with administration of ginkgo is
of unknown magnitude and significance.
NEUROPHYSIOLOGY
Several studies on AD have included neurophysiologi-
cal outcome measures. The trial by Kanowski et al
86
per-
formed electroencephalographic frequency analysis in 36
of the subjects (17 ginkgo-treated and 19 placebo-
treated subjects) enrolled at one site and found signifi-
cant improvement in several electroencephalographic vari-
ables in the ginkgo group, including greater dominant
posterior frequency and less theta activity. Hoffer-
berth
81
also found a significant decrease in the theta/
alpha ratio in the active group compared with the pla-
cebo group. Rai et al
85
reported a decrease in slow
frequency activity in the treatment group.
COMMENT
Despite the widespread use of G biloba and more than
50 publications on its use in age-related functional and
cognitive changes, there are only a handful of random-
ized, well-controlled studies of its use in patients with a
diagnosis of AD. We identified only 1 article before 1991
that met inclusion criteria. This is consistent with the study
by Kleijnen and Knipschild
30
who reviewed 40 studies
through 1991 concerning the use of G biloba for demen-
tia and cerebral insufficiency. Among the 40 studies, 8
were chosen to meet certain criteria for a good study (a
subset of our criteria) and were discussed in more detail
in a later article.
31
None of these 8 articles specifically
stated that the diagnosis was AD. A single article among
8 had sufficient description such that the diagnoses were
determined to be probable AD and it is included in our
meta-analysis.
87
The other 7 articles and most of the clini-
cal articles published since, especially the non–English-
language articles, do not have sufficiently stringent in-
clusion criteria with cerebral insufficiency the most
common diagnosis.
While all studies can be criticized for some aspects
of design and analysis, we believe that 4 studies meet rea-
sonable criteria for an adequate clinical trial in AD. There
are some concerns regarding the performance of the stud-
ies as well as the quantitative analysis. The studies var-
ied in length of treatment and daily dose of ginkgo (120
or 240 mg). The correct dose of ginkgo has never been
formally established. While 120- and 240-mg/d doses are
typical among clinical trials, animal studies have used
doses of 100 mg/kg. The dose issue will need to be ad-
dressed in future studies. The dropout rate in the study
of Le Bars et al
24
at 1 year was fairly high. However, to
maintain comparability with the trial durations in the other
studies we used the 6-month intention-to-treat data from
the study of Le Bars et al.
24
The 6-month data did not have
a particularly high dropout rate. The outcome measures
are of variable quality with only 1 using the Alzheimer Dis-
ease Assessment Scale–cognitive subtest (ADAS-cog).
24
However, the Syndom Kurztest is a short neuropsycho-
logical battery with high reliability that is similar to the
ADAS-cog.
92
While the small number of trials is a limitation of
this meta-analysis, the aggregate sample is fairly large.
Despite the heterogeneity among study results, the simi-
larity of effect sizes of the 2 largest studies accounting
for more than 75% of the sample supports a real effect.
Additionally, the fairly low effect size in the study by
Wesnes et al
87
appears to be, at least in part, related to
having to average the effect over their 10 outcome mea-
sures, some of which would be predicted to be insensi-
tive to intervention. Some of the heterogeneity of effect
may be related to dose with the 2 studies using a 240-
mg/d dose producing greater effect sizes. Despite all
the concerns, the administration of standardized G bi-
loba extract appears to have a modest effect on cognitive
function in AD with an effect size of about 0.4. The ef-
fect size is comparable with the donepezil trial by Rog-
Table 2. Studies Satisfying Inclusion Criteria
and With Sufficiently Descriptive Statistics
Source, y
Effect
Size
95%
Confidence
Interval
No. of
Subjects
Taking
Ginkgo
No. of
Subjects
Taking
Placebo
P
Kanowski et al,
86
1996 0.5156 +0.16 to +0.87 61 64 .005
Le Bars et al,
24
1997 0.311 +0.04 to +0.59 104 103 .03
Wesnes et al,
87
1987 0.108 20.44 to +0.65 26 26 .69
Hofferberth,
81
1994 1.117 +0.45 to +1.78 21 19 .001
Overall 0.413 +0.22 to +0.61 212 212 ,.0001
ARCH NEUROL / VOL 55, NOV 1998
1412
©1998 American Medical Association. All rights reserved.
ers et al.
93
Using their ADAS-cog placebo-treatment dif-
ference of 2.5 and 2.9 (5 and 10 mg of donepezil) and
an SD of 6, estimated from their figure 1, the effect size
is 0.42 and 0.48 for the doses.
93
The actual ADAS-cog dif-
ference in the donepezil trial of 2.5 and 2.9 for the 2 doses
is slightly greater than that presented in the study by Le
Bars et al,
24
which also used the ADAS-cog and
observed a difference from placebo of 1.7 in their 26-
week intention-to-treat data. The effect size estimate of
0.4 will be useful for design of future studies. For
example, an independent samples t test would require
about 110 subjects per group to attain a power of 90%
at an effect size of 0.427. Our article does not address
the issue of efficacy of ginkgo in other dementia syn-
dromes, eg, vascular dementia, for which there is some
preliminary positive results in 2 of the studies
24,88
included in our meta-analysis.
The clinical significance of this effect size of about
0.4 is less clear. Not all 4 studies
24,81,86,87
had functional,
behavioral, or global change outcome measures. Since
there was an insufficient number for quantitative analy-
sis on these measures, they are briefly summarized
herein. The study by Kanowski et al
86
reported a signifi-
cant difference in a clinician’s global rating scale but not
in an activities of daily living scale. The study by Le
Bars et al
24
reported no significant difference in the cli-
nician’s global rating scale, but did on the Geriatric
Evaluation by Relative’s Rating Instrument, their func-
tional scale. Hofferberth
81
reported improvement in a
daily function measure (the Sandoz Clinical Assessment
Geriatric Scale). We need further research to determine
whether there is improvement in noncognitive behavior
or daily function since this is critical in evaluating the
use of treatment in AD.
The component of ginkgo extract that produces its
clinical effect is not known. If it turns out that the fla-
vonoid components are producing the clinical effect, then
other antioxidants may prove as effective and safer. For
example, is the effect of ginkgo additive with vitamin E?
Alternatively, if the terpenoid components are produc-
ing the clinical effect, then it needs to be determined which
of the terpenoids is most effective (eg, ginkgolide B). This
aspect of ginkgo is potentially of most interest since the
unique chemical structure of the terpenoids makes it one
of a limited number of good PAF antagonists. The cur-
rently available standardized extracts are only standard-
ized to percentage of flavonoids and terpenoids. The im-
plication of this is that the relative amounts of the
ginkgolide and bilobalide components of the terpenoids
or the various flavonoids may vary across preparations
and even seasons.
94
The individual component chemi-
cals in ginkgo extract, eg, ginkgolide B, are available from
some manufacturers.
The enriched or special extract EGb 761 developed
by Dr Willmar Schwabe Pharmaceuticals, Karlsruhe, Ger-
many, has been used in most of the trials in Table 1. The
patent for extract EGb 761 has expired so other manu-
facturers can use the same extraction process from the
ginkgo leaf. There are no data comparing the efficacy of
different formulations of ginkgo in AD, the so-called phy-
togenerics, even though most are standardized to 24%
flavonoids and 6% terpenoids.
This article is not intended to produce specific
clinical recommendations on the use of ginkgo in indi-
viduals with AD. Only additional high-quality research
can address this issue. In general, physicians should
inquire about alternative therapy use by patients to be
aware of potential drug interactions and to ensure that
the patient feels comfortable discussing alternative
therapies with their nonalternative health care provider.
In general, when considering alternative therapies, cli-
nicians should ensure that patients are actually taking
what is recommended. Some of the products are not
pharmacy grade, do not contain known amounts of the
intended drug, and may contain unknown amounts of
other compounds. If considering the use of ginkgo,
ensure that a standardized extract (24% flavonoids or
ginkgo-flavone-glycosides and 6% terpenoids) is used.
Given its mode of action on PAF and the case reports
of possible hemorrhagic complications, it certainly
seems prudent to be cautious in its use in patients tak-
ing anticoagulants or antiplatelet agents, or with a
bleeding diathesis.
Accepted for publication May 28, 1998.
This study was supported in part by grants AG15171
(Dr Oken) and AG08017 (Dr Kaye), National Institutes of
Health, Bethesda, Md.
The Cochrane Collaboration was invaluable and pro-
vided many of the reference titles along with a structured
English-language summary. Dan Zajdel assisted in the prepa-
ration of the manuscript.
Reprints: Barry S. Oken, MD, Department of Neurol-
ogy, CR120, Oregon Health Sciences University, 3181 SW
Sam Jackson Park Rd, Portland, OR 97201 (e-mail:
oken@ohsu.edu).
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... In animal models [267,269] and in vitro [270], the extract of Gb leaves has been reported to attenuate neuronal damage, in particular that induced by amyloidbeta [271][272][273][274] and even to have beneficial effects on cognition in combination with donepezil in animal models of AD [275,276]. The chemical constituents of Gb comprise flavonoids, terpene lactones, and ginkgolic acids [277] that may explain its favorable effects in experimental studies possibly mediated by antioxidant activities, improvements in microcirculation, modulation of neurotransmitters, enhancement of neuroplasticity, prevention of brain edema, and other neuroprotective actions [268,[278][279][280][281][282][283]. ...
... Ginkgo biloba extracts have been used empirically in the treatment of dementia in humans for several decades [277,284]. However, whether Gb can improve cognitive function and prevent cognitive decline and dementia in clinical studies is as yet a controversial question. ...
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Multiple factors combined are currently recognized as contributors to cognitive decline. The main independent risk factor for cognitive impairment and dementia is advanced age followed by other determinants such as genetic, socioeconomic, and environmental factors, including nutrition and physical activity. In the next decades, a rise in dementia cases is expected due largely to the aging of the world population. There are no hitherto effective pharmaceutical therapies to treat age-associated cognitive impairment and dementia, which underscores the crucial role of prevention. A relationship among diet, physical activity, and other lifestyle factors with cognitive function has been intensively studied with mounting evidence supporting the role of these determinants in the development of cognitive decline and dementia, which is a chief cause of disability globally. Several dietary patterns, foods, and nutrients have been investigated in this regard, with some encouraging and other disappointing results. This review presents the current evidence for the effects of dietary patterns, dietary components, some supplements, physical activity, sleep patterns, and social engagement on the prevention or delay of the onset of age-related cognitive decline and dementia.
... In recent years the scientific evidence for the use of Ginkgo biloba extracts (GBE) has begun to establish its efficacy in several health areas. A main area of interest for GBE research has focused on its beneficial effects for reducing the symptoms of age-related cognitive decline, including mild memory impairment, cerebral insufficiency and dementia including Alzheimer's disease [4][5][6][7][8]. GBE may also protect from the damaging effects of ischaemic events including neuronal degeneration [9,10]. ...
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Background Ginkgo biloba extracts (GBE) have been used in traditional medicines for centuries. GBE has been shown to deliver protective effects against symptoms of age-related cognitive decline. Despite there being standardised extractions for GBE, there is still variability in the absorption and efficacy of different extracts. Following the development of a liposomal GBE (Ginkgosome™), the aim of this study is to investigate the absorption of the liposomal formulation compared to a comparator formulation of equal dose. Methods Thirteen healthy male and female volunteers completed this single equivalent dose, randomised, double-blind crossover study. Plasma concentrations were determined at baseline and at regular intervals over a 24-h period following ingestion of 120 mg of either a liposomal or comparator formulation. Results The liposomal formulation was able to increase plasma concentration of ginkgolide B and C by 1.9 and 2.2-fold compared to the comparator formulation. Conclusion The novel liposomal formulation is safe in humans and demonstrates superior absorption for the supply of GBE constituents compared to a comparator standardised formulation.
... Ginkgo biloba is commonly used as a therapeutic agent for early stage Alzheimer's disease, vascular dementia, peripheral claudication, and tinnitus of vascular origin [107][108][109]. Ginkgo is a neuroprotective agent, antioxidant, free-radical scavenger, membrane stabilizer, and inhibitor of platelet-activating factor [110][111][112][113]. In in vitro studies, ginkgo prevented neuronal death induced by hypoxia, nitric oxide, and cyanide [114][115][116]. ...
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Although facial nerve palsy is not a life-threatening disease, facial asymmetry affects interpersonal relationships, causes psychological stress, and devastates human life. The treatment and rehabilitation of facial paralysis has many socio-economic costs. Therefore, in cases of facial paralysis, it is necessary to identify the cause and provide the best treatment. However, until now, complete recovery has been difficult regardless of the treatment used in cases of complete paralysis of unknown cause and cutting injury of the facial nerve due to disease or accident. Therefore, this article aims to contribute to the future treatment of facial paralysis by reviewing studies on drugs that aid in nerve regeneration after peripheral nerve damage.
... Ginkgo biloba is the oldest living tree species in the world. The standardized Ginkgo biloba extract (GBE) from the dried leaves has neuroprotective effects and is used for the treatment of memory impairment and dementia [83,84]. GBE contains 6% terpenoids, 24% flavonoid glycosides and 5-10% organic acids [85]. ...
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Neurodegenerative disorders including Parkinson’s disease (PD), Huntington’s disease (HD) and the most frequent, Alzheimer’s disease (AD), represent one of the most urgent medical needs worldwide. Despite a significantly developed understanding of disease development and pathology, treatments that stop AD progression are not yet available. The recent approval of sodium oligomannate (GV-971) for AD treatment in China emphasized the potential value of natural products for the treatment of neurodegenerative disorders. Many current clinical studies include the administration of a natural compound as a single and combination treatment. The most prominent mechanisms of action are anti-inflammatory and anti-oxidative activities, thus preserving cellular survival. Here, we review current natural products that are either approved or are in testing for a treatment of neurodegeneration in AD. In addition to the most important compounds of plant origin, we also put special emphasis on compounds from algae, given their neuroprotective activity and their underlying mechanisms of neuroprotection.
... We note that most of the existing research evidence pertaining to tinnitus and flavonoids focuses on flavonoids as a component of Ginkgo biloba supplements [43][44][45][46][47][48][49][50]. However, the main flavonoid compounds found in Ginkgo biloba are quercetin, kaempferol and isorhamnetin which belong to the flavonols subclass [51]. ...
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Purpose Dietary flavonoids are bioactive compounds that have been widely investigated for their associations with vascular health outcomes. As the development of tinnitus has been linked to vascular pathways, dietary flavonoids may have role in the prevention of tinnitus symptoms. This study reports the associations between the intakes of major classes of dietary flavonoids and 10-year incidence of tinnitus. Methods Of the 1753 participants (aged ≥ 50 years) from the Blue Mountains Hearing Study with complete baseline data on tinnitus symptoms and dietary intakes, 536 (31%) cases of tinnitus were identified and excluded from further analysis. Dietary data was collected using a semi-quantitative food frequency questionnaire and intakes of the five major classes of flavonoids were determined using U.S. Department of Agriculture flavonoid databases. Presence of prolonged tinnitus was assessed by a positive response to a single question administered by an audiologist. Results Of the remaining 1217 participants without tinnitus at baseline, 222 (18%) incident cases of tinnitus were identified over 10 years. After age–sex adjustment, participants in the third versus first quartile of proanthocyanidin intake were significantly less likely to develop incident tinnitus by 36% (HR = 0.64; 95% CI 0.43–0.96, Ptrend = 0.04). Following multivariable adjustment, this protective trend was non-significant (HR = 0.60; 95% CI 0.39–0.92; Ptrend = 0.06). Similarly, a non-significant protective trend was observed when comparing the fourth versus first quartile of intake of all flavonoids (OR = 0.61; 95% CI 0.39–0.96). No other associations were observed. Conclusion Our findings do not support the hypothesis that dietary flavonoids are protective against the development of tinnitus over 10 years. The weak significant association observed between proanthocyanidin and incident tinnitus may be a chance finding as there was no significant trend following multivariate adjustments and, therefore, requires further studies to investigate these associations.
... The principal enzyme responsible for the clotting process is thrombin, while plasmin is an enzyme responsible for fibrin and fibrinogen degradation. [6,7] Several synthetic and semi-synthetic drugs such as oral anticoagulants, antiplatelets, or thrombolytics are available for treating various thrombotic disorders (vascular blockage, myocardial or cerebral infarction, venous thromboembolism, and deep vein thrombosis). Most of these drugs exhibit adverse effects like bleeding, severe anaphylactic reactions, overarching safety, and efficacy. ...
... 8 The benefit of Ginkgobiloba is attributed to its two active chemical components, flavonoids and terpenoids. 9 Apart from that Ginkgobiloba has been proved to augment cholinergic system and increase the synaptic plasticity in central nervous system. 10,11 Ascorbic acid is anantioxidant found in citrus fruits and vegetables and strawberries. ...
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... Several scientists have found that ginkgo leaves contain active antioxidant complex compounds. They protect lipids in the cortex of nerve cells and prevent them from being broken down by free radicals [10,11,12]. The United States exports 1,100 tons of dried ginkgo leaves to Europe annually. ...
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This article presents the results of research on the biochemical composition of green and yellowing leaves of 64-year-old bipedal ginkgo ( Ginkgo biloba L. ) seed and pollen trees growing in the Botanical Garden of the Academy of Sciences of Uzbekistan, introduced to Uzbekistan in the last century. Biochemical analyzes recorded the presence of 6 types of vitamins and 44 macro- and micronutrients in the leaves of the ginkgo tree. Vitamin C levels were found to be lower in the seed tree than in the pollen tree. The amount was 35.8 mg/% in the green leaves of the seed tree and 34.4 mg/% in the yellowed leaves. Ginkgo leaves contain important macro-and micronutrients such as Ca, Mg, K, Al, Fe, Cu, Mn, Zn, Mo, Co, I, Se, which are necessary for the vital activity of the human body and normal metabolism. The green leaves of the two-leafed ginkgo pollen tree contained 27577.288 mg/l of calcium, 11562.299 mg/l of potassium, the leaves of the seed tree 13912.903 mg/l of calcium and 7491.462 mg/l of potassium. At the same time, the green leaves of ginkgo contain 3073.807 mg/l – 7977.459 mg/l magnesium, 4353.72-5003.88 mg/l phosphorus, 501.073-515.343 mg/l sodium, 779.750 mg/l– the presence of silicon in the amount of 844.039 mg/l and iron in the amount of 373.023 mg/l – 655.148 mg/l was determined.
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Alternative splicing (AS) is an important genetic regulation mechanism for enhancing the diversity and complexity of the transcriptome and proteome from a limited number of genes. G. biloba is a typical relict tree species with rich medicinal value; the alternative splicing characteristics of the G. biloba genome are intriguing due to its very large proportion of large introns. In this study, the genome-wide landscape of the ginkgo AS pattern was revealed through a comprehensive analysis of multiple tissues across different developmental stages. Intron retention was the dominant AS type in all tissues together with a much lower frequency compared to other plants, and the functional enrichment of different AS type-related genes also showed great differences. In addition, the AS patterns of important secondary metabolites in G. biloba, including flavonoids and terpenoids, were thoroughly analyzed. These results could be beneficial for studies on gene regulation and the synthesis mechanisms of important secondary metabolites in woody plants.
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Despite the shortage of adequate evidence on the safety of herbal products, their practice as an alternative or complementary medicine is gaining popularity worldwide among health practitioners. Evidence shows increasing attention toward the medical herbs as a forerunner for a pharmacological activity to treat different ill patients. One of the severe associations is the coadministration of herbal medicine along with traditional/conventional drugs. Herb–drug interaction becomes the single most essential clinical consequence of the practice. It can impact health and the effectiveness of treatments. Using the structural evaluation process, the confirmation of herb–drug interaction presents a different degree of clinical importance. Various pharmacokinetic and pharmacodynamic mechanisms were proposed for herb–drug interactions, including the alteration/modification in the gastrointestinal function with the subsequent effects on the absorption, distribution, inhibition, and induction of the metabolic enzymes and transporters, and altercation of renal elimination of the drugs and their respective metabolites. This chapter expounds on the risk associated with herb–drug interactions with some classical examples supported with clinical evidence and mechanisms involved. A cross-talk on the regulatory aspects and methods followed for the prediction of herb–drug interactions is also provided.
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Chapter
Typische Symptome des hirnorganisehen Psychosyndroms (HOPS) wie Schwindel, Merkfähigkeits-, Konzentrations- und Orientierungsstörungen sind heute im Rahmen von Therapiestudien zum einen Teil quantitative meßbar, zum anderen Teil subjektiv beobachtbar. In dieser placebokontrollierten Doppelblindstudie mit Ginkgo-biloba-Extrakt EGb 761 (Rökan) an 36 Patienten mit den klassischen Zeichen des HOPS wurde versucht, sich durch Messung des quantifizierten EEG und der sakkadischen Augenbewegungen sowie mittels psychometrischer Tests (Wiener Determinationsgerät, Zahlenverbindungstests) ein objektives Bild vom Einfluß einer solchen Pharmakotherapie zu verschaffen. Rökan wurde nach einer zweiwöchigen Wash-out-Periode über einen Zeitraum von acht Wochen 3mal täglich 40 mg (= 120 mg Tagesdosis) gegeben; das Kontrollkollektiv wurde mit einem äußerlich identischen Placebo behandelt. Die oben zitierten Prüfungen wurden vor und jeweils nach vier und acht Wochen Behandlung durchgeführt, die quantitative Auswertung des EEG fand nur vor und am Ende der Behandlung statt. Aufgenommen wurden ausschließlich Patienten, die bei mindestens zwei dieser vier Prüfungskriterien pathologische Untersuchungsergebnisse aufwiesen. Kranke mit nicht erlaubter Zusatzmedikation, mit akuten Herz-Kreislaufstörungen und Erkrankungen des Verdauungs-und Stoffwechselsystems wurden in dieser Studie nicht berücksichtigt. Bereits nach vierwöchiger Therapie, aber auch nach acht Wochen, ließen sich sowohl im Sakkaden-Test als auch bei den psychometrischen Untersuchungen hochsignifikante Unterschiede gegenüber der Placebo-Behandlung beobachten. Die Sakkaden-Dauer vermindert sich, die Latenz nimmt ab. Parallel dazu und ebenfalls statistisch signifikant unterschiedlich stieg die Zahl der richtigen Antworten am Wiener Determinationsgerät und im Zahlenverbindungstest. Für den Theta-Anteil des Theta-Alpha-Quotienten fand sich eine eindeutige Abnahme. Von Placebo wurden all diese Parameter kaum beeinflußt. Nebenwirkungen waren in beiden Gruppen geringfügig, so daß die Therapie bei allen Patienten problemlos zu Ende geführt werden konnte. Diese randomisiert-doppelblind durchgeführte Studie belegt also eine hochsignifikante Überlegenheit von Rökan, einem hochgereinigten standardisierten Extrakt aus getrockneten Ginkgo-Blättern, gegenüber Placebo und bestätigt bisher positive Erfahrungen auf diesem Indikationsgebiet.
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A physical treatment as therapy for vestibular disorders with the aim to improve the natural compensation mechanisms is proposed. Instead of sedative agents, which inhibit vestibular compensation, a drug which is known to augment cerebral metabolism, Ginkgo biloba, is used. The training itself consisted of some exercises to selectively improve certain vestibulo-ocular, vestibulo-cervical and proprioceptive reflexes. The effect of the training was checked by a vertigo questionnaire and by posturographic body sway measurements in Romberg's test. It could be shown that by training alone (i.e. with placebo) a clear amelioration of vertigo and a significant effect was still higher, if Ginkgo biloba (2 times 40 drops) was given. It seems that the effect of the vestibular training could be supported by combination therapy with Ginkgo biloba.
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This paper reviews and evaluates all the currently available clinical trials on the efficacy of three nootropics. Only randomised, double-blind, placebo-controlled clinical trials were taken into account which produced 44 studies allowing comparison of the patient populations, efficacy and tolerability of Ginkgo biloba special extracts, nimodipine and tacrine. Taking all the studies together, statistically significant results were obtained at three relevant levels of efficacy (psychopathological, psychometric, behavioural) for all three substances. Nine studies produced significant results at all three efficacy levels. One study on Ginkgo biloba and one on tacrine also produced significant results according to the latest measures now demanded (operationalised diagnosis of dementia, inclusion of mild-to-moderate cases, statistical proof at all three levels of efficacy and global clinical evaluation). The clinical efficacy of all three substances has thus been demonstrated.