Ginkgo Ginkgo Ext

Document Sample
Ginkgo Ginkgo Ext Powered By Docstoc

Species (Family)                                           Seeds
Ginkgo biloba L. (Ginkgoaceae)                             Alkaloids Ginkgotoxin (4-O-methylpyridoxine) ."

Synonym(s)                                                 Amino acids
Fossil Tree, Kew Tree, Maidenhair Tree
                                                           Cyanogenetic glycosides    Allergenic ginkgolic acids .
                                                           Ginkbilobin . (1 )
Part(s) Used
Leaf                                                       Standardised extracts of G . biloba leaves are
                                                           standardised on the content of ginkgo flavonoid
Phormacopoeial and Other                                   glycosides (22-27% ; determined as quercetin,
Monographs                                                 kaempferol and isorhamnetin), and terpene lactones
BHP 1996(G9)                                               (5-7% ; comprising around 2 .8-3 .4% ginkgolides A,
Complete German Commission E(G3)                           B and C, and 2 .6-3 .2% bilobalide, and less than
Martindale 32nd edition (G43)                              5 ppm ginkgolic acids) . (G3,G56)
Mills and Bone (GSO)
PDR for Herbal Medicines 2nd edition (G36)
                                                           Food Use
Ph Eur 2002 (G28)
WHO volume 1 1999 (G63)                                    Ginkgo biloba is not used in foods .

Legal Category (Licensed Products)
                                                           Herbal Use
Ginkgo is not included in the GSL . (G3
                                                           Ginkgo has a long history of medicinal use, dating
Constituents('                                             back to 2800BC . Traditional Chinese medicine used
                                                           the seeds (kernel/nuts) for therapeutic purposes . The
Leaf                                                       seed is used in China as an antitussive, expectorant
                                                           and anti-asthmatic, and in bladder inflamma-
Amino acids 6-Hydroxykynurenic acid (2-carboxy-
                                                           tion ." ,11,G50) In China, the leaves of Ginkgo biloba
4-one-6-hydroxyquinoline), a metabolite of trypto-         were also used in asthma and in cardiovascular
phan .(3-5)                                                disorders,G ) although the leaves have little history
                                                           of traditional use in the West . Today, standardised
Flavonoids Dimeric flavones (e .g. amentoflavone,
                                                           concentrated extracts of G. biloba leaves are mar-
bilobetin, ginkgetin, isoginkgetin, sciadopitysin) ;(6)    keted in several European countries, and are used in
flavonols (e .g . quercetin, kaempferol) and their gly-    cognitive deficiency, intermittent claudication (gen-
cosides(3,7) and coumaroyl esters .                        erally resulting from peripheral arterial occlusive
                                                           disease), and vertigo and tinnitus of vascular origin
                                                           (see Pharmacological Actions, Clinical stu-
                                                           dies) .(G3,G32,G56,G6 )
Terpenoids Sesquiterpenes (e .g . bilobalide), diter-
penes (e .g . ginkgolides A, B, C, J, M, which are
unique cage molecules, (S,9,G48) and triterpenes (e .g.    Dosage
sterols) .
                                                           Cognitive deficiency
Other constituents Benzoic acid, allergenic ginkgolic
acids, 2-hexenal, polyprenols (e .g . di-trans-poly-cis-   Leaf extract 120-240 mg dry extract orally in two or
octadecaprenol), sugars, waxes, (1 a pepride . (10)        three divided doses . (G3)

                                                                                                 Ginkgo          251

Peripheral arterial occlusive disease and                   30 or 60 mg/kg/day, whereas performance was stable
vertigo/tinnitus                                            among young rats (eight weeks old) following EGb
                                                            761 administrationa l EGb 761 200 mg/kg adminis-
leaf extract 120-160 mg dry extract orally in two or
three divided doses . (G3)                                  tered orally to rats aged more than 26 months old led
                                                            to significant improvements in aspects of cognitive
                                                            behaviour . (17) In vivo studies have also shown that
Clinical trials of standardised extracts of G . biloba
leaves (EGb 761, Willmar Schwabe GmbH and LI                oral administration of EGb 761 (50 or 100 mg/kg/day
1370, Lichtwer Pharma GmbH) in patients with                for three weeks) to rats prevented the short-term
cognitive deficiency have generally used oral doses         memory-impairing effects of scopolamine adminis-
ranging from 120 to 240 mg daily, usually for 8-12
                                                            tered intraperitoneally (0 .125 mg/kg)
weeks, although some studies have continued treat-             The anxiolytic effects of a range of doses (0 .01-
ment for up to 24 or 52 weeks. IG56) Clinical trials in     10 mg/kg) of combination preparations containing
peripheral arterial occlusive disease used oral doses of    different mixture ratios of standardised extracts of
120-160 mg extract daily for 3-6 months . (G56)
                                                            ginkgo leaf and ginger root have been tested in rats
                                                            using the elevated plus-maze test . (18) Compared with
                                                            controls, rats treated with the combination prepara-
Pharmacological Actions                                     tion (mixture ratio of ginger extract to ginkgo
                                                            extract, 2.5 : 1 ; 1 mg/kg, intragastrically) spent
In vitro and animal studies                                 increased amounts of time in the open arms of the
There is a vast literature describing basic scientific      maze, whereas the behaviour of rats treated with
research relating to the effects of ginkgo . Several        preparations of a mixture ratio of 1 :1 and 1 :2 .5
pharmacological activities have been documented             did not change.
for ginkgo leaf extracts and/or their constituents .           Several studies have reported that treatment with
These include effects on behaviour, learning and            EGb 761, compared with control, aids recovery of
memory, cardiovascular activities, effects on blood         function following brain injury, as demonstrated by
flow and antioxidant activity . The most important          behavioural tests in rats who had undergone bilateral
active principles of ginkgo extract include the gink o      frontal lobotomy or septohippocampal deafferenta-
flavonoid glycosides and the terpene lactones~ 1)           tion, and in rat models of cortical hemiplegia . (13)
Ginkgo has been described as having polyvalent                 It has been suggested that the effects of EGb 761 in
action, i.e . the combined activity of several of its       the experimental animal models described above may
constituents is likely to be responsible for its            involve aspects of neuronal plasticity, e .g. neuronal
effects . (13)                                              regeneration . (13) Studies in rats have investigated, for
   The pharmacological activities of ginkgo have            example, the effects of EGb 761 administration on
been reviewed,( 1,8,9,13-1 5) and other texts bring         expression of neurotrophins and apolipoprotein E,
together several studies in specific areas, e .g . neuro-   and on behavioural recovery, following entorhinal
protective effects.("' ) A summary of some of the           cortex lesions, and on regeneration of primary olfac-
literature on the in vitro and in vivo (animals) effects    tory neurons following olfactory bulbectomy .
of ginkgo leaf is given below .                             Research investigating the effects of EGb 761 on
                                                            neuronal plasticity has been summarised . (1,13,19)
Effects on behaviour, learning and memory The
effects of a standardised extract of ginkgo leaf (EGb       Cardiovascular and hoemorheological activities Stu-
761) on learning and memory, and on behaviour in            dies investigating the molecular mechanisms that
relation to ageing and in recovery from brain injury,       may contribute to the vasoregulatory (vasodilata-
have been well studied .( 13) Animal models (rats and       tion and vasoconstriction) effects of standardised
mice) designed to test aspects of learning and memory       ginkgo leaf extract (EGb 761) have been
(e .g . acquisition and retention) have documented          described! 13,20) In vitro experiments using isolated
improvements in animals treated with oral, intraper-        rabbit aorta suggested that possible mechanisms
itoneal or subcutaneous EGb 761, compared with              include effects on cyclic-GMP phosphodiesterase,
controls .(131 Studies involving rats reported improve-     prostaglandin 1 2 and nitric oxide (NO) . Ex vivo
ments in acquisition and retention in older (24-            studies using isolated guinea-pig heart showed that
month-old), but not younger (eight-month-old) rats .        EGb 761 led to a concentration-dependent increase in
Other experiments involving rats of different ages          coronary blood flow. In studies involving isolated rat
have found that older rats (12- and 18-months old)          heart and in anaesthetised rabbits, EGb 761 admin-
showed improved performance in an eight-arm radial          istration has been reported to protect against myo-
maze test following oral administration of EGb 761          cardial ischaemia-reperfusion injury ; the antioxidant

252        Ginkgo

and f ee- adical scavenging effects of EGb 761 (see       b onchoconst iction induced by PAF . Ginkgolide B
below) may be impo tant in this ega d .(13) One study     does not appea to inte fe e with cyclooxygenase, but
using isolated at hea ts suggested that the ca dio-       at an ea lie step involving PAF ecepto s and phos-
p otective effects we e due to the te penoid constitu-    pholipase activation . Eosinophil infilt ation occu s in
ents of EGb 761, and that the mechanism was               asthma and in alle gic eactions, the numbe of
independent of di ect f ee adical-scavenging activ-       eosinophils inc easing du ing late phase . Since PAF
ity.~ 1) An in vit o study with endothelial cells sug-    is a potent activato of eosinophil function, it has
gested that the anti-ischaemic activity of EGb 761        been a gued that gink~olide B may inte fe e with the
may be due pa tly to the effects of the constituent       late-phase esponse . (2 )
bilobalide in p otecting mitochond ial activity . (22)       P e-administ ation of ginkgolide B (1-5 mg/kg,
    The effects of ginkgo leaf ext act have been          int avenous) to ats has been epo ted to educe
studied in no mal ats and those with ischaemic            PAF-induced dec eases in diastolic and systolic a te -
b ain damage with middle ce eb al a te y occlu-           ial blood p essu e in anaesthetised no motensive ats ;
sion . (23) O al administ ation of ginkgo ext act         this effect has also been epo ted in this animal model
100 mg/kg was epo ted to inc ease ce eb al blood          when ginkgolide B is administe ed sho tly afte PAF
flow in no mal ats, but the inc ease was less ma ked      administ ation .( 13)
in ats with ce eb al a te y occlusion .                      Ginkgolide B has also been documented to have
    In vit o studies using human blood cells have         some beneficial effects in endotoxic shock; PAF is
documented effects of EGb 761 on seve al haemo-           believed by some to be implicated in shock states . In
 heological pa amete s . (13) Fo example, in vit o,       anaesthetised guinea-pigs, int avenous administ a-
EGb 761 no malised changes in e yth ocyte viscos-         tion of ginkgolide B (1 o 6 mg/kg) p io to injection
ity and in the viscoelastic -p ope ties of the e yth o-   of Salmonella typhimu ium endotoxin educed the
cyte memb ane induced by standa d metabolic               initial apid dec ease in blood p essu e, and int a-
challenge (pH 6 .8 ; 380 mosmol/L) in six human           venous administ ation of ginkgolide B du ing the
blood dono s . In othe in vit o expe iments, EGb          p olonged phase of shock (1 hou afte endotoxin
761 p otected against hyd ogen pe oxide-induced           administ ation) immediately and dose dependently
damage in human e yth ocytes . In studies using            eve sed the dec ease in blood p essu e . (13) Othe
blood f om patients with ci culato y diso de s,           studies have found that ginkgolide B educed a te ial
incubation with EGb 761 was epo ted to dec ease           blood p essu e in the seconda y, but not the ea ly,
e yth ocyte agg egation . In vit o expe iments using      phase following administ ation of Esche ichia coli
human neut ophils have found that EGb 761 at a            endotoxin . (13)
concent ation of 10 tmol/L inhibits elease of
hyd ogen pe oxide f om these cells . The effects of       Antioxidant activity The f ee adical-scavenging
EGb 761 on inhibition of human platelet agg ega-          effects and antioxidant activity of EGb 761 in vit o
tion elicited by substances such as th ombin and          a e well documented . (13) EGb 761 scavenges seve al
collagen have been documented .(13) A study using          eactive oxygen species, includiy hyd oxyl, supe -
blood donated by healthy voluntee s (n=35)                oxide and pe oxyl adicals . (13 .26,2 ) In at ce ebella
 epo ted that a standa dised ext act of ginkgo leaf       neu ons and ce ebella g anule cells, ginkgo ext act
inhibited ADP- and collagen-induced platelet agg e-       was epo ted to p otect against oxidative st ess
gation in platelet- ich plasma, gel-filte ed platelets    induced by hyd o en pe oxide, anothe eactive
and in whole blood in a concent ation-dependent           oxygen species .(28,N) In cultu es of at hippocampal
manne . (24)                                              cells, incubation with EGb 761 p otected against cell
                                                          death induced by Q-amyloid, p otected against toxi-
Platelet-activating facto   antagonism Ginkgolides        city induced by hyd ogen pe oxide, and blocked (3-
have been epo ted to competitively inhibit the bind-      amyloid-induced events, such as accumulation of
ing of platelet-activating facto (PAF) to its mem-         eactive oxygen species . (30) Bilobalide has also been
b ane ecepto . (8,9,25)                                   documented to p otect neu ons against oxidative
   Ginkgolide B antagonises th ombus fo mation            st ess induced by eactive oxygen species in
induced by PAF and, in guinea-pigs, it also induces       vit o . ( 31) Expe iments in ge bils have suggested that
a apid cu ative th ombolysis . A p otective effect is     the neu op otective effects of gingko ext act may be
exe ted by ginkgolides on PAF-induced b oncho-            due to inhibition of nit ic oxide fo mation . (32)
const iction and ai way hype activity in immuno-             Othe studies which have desc ibed neu op otec-
anaphylaxis and in antigen-induced b onchial p ovo-       tive effects of EGb 761 have suggested that anti-
cation tests. O al o int avenous injection of ginkgo-     oxidant activity may be involved! 16) In vit o, a
lide B antagonises ca diovascula impai ments and          standa dised ginkgo leaf ext act was found to inhibit
                                                                                                Ginkgo          253

photo-induced formation of cholesterol oxides in a            Three long-chain phenols, anacardic acid, bilobol
c oncentration-dependent manner . (33)                     and cardanol, isolated from seeds of G . biloba are
    Antioxidant activity has been documented for           active against Sarcoma 180 ascites in mice . (42)
EGb 761 in vivo . In rats, treatment with EGb 761
increased the concentrations of circulating and cel-
                                                           Clinical studies
lular polyunsaturated fatty acids, and reduced ery-
throcyte cell lysis induced by hydrogen peroxide . (34)    Phannocokinetics       Data on the pharmacokinetics of
Also in rats, oral administration of EGb 761 was           standardised extracts of ginkgo leaf have been sum-
reported to increase activity of the enzymes catalase      marised .( 1,iS,Gis,G21) Mean bioavailabilities of gink-
and superoxide dismutase in the hippocampus, stria-        golide A, ginkgolide B and bilobalide following oral
tum and substantia nigrum . (35) Other data collected      administration of ginkgo extract 120 mg to fasting
in this study suggested a decrease in lipid peroxida-      healthy volunteers were 80%, 88% and 79%, respec-
tion in rat hippocampus in EGb 761-treated rats . In       tively . Food intake increased the time taken to reach
another study in rats, EGb 761 (200 mg/kg/day for          peak concentration (suggesting slower absorption),
four weeks) protected against carbon tetrachloride-        but did not affect bioavailability . (1,G18) Peak concen-
induced (1 .5 mLlkg) liver damage, as determined by        trations of ginkgolides A and B and bilobalide
malondialdehyde concentrations (a breakdown pro-           observed in fasting volunteers ranged from 16 .5 to
duct of lipid peroxidation) . (36)                         33.3 ng/mL, and from 11 .5 to 21 .1 ng/mL in volun-
                                                           teers who had consumed food ." Urinary excretion of
 Other activities In vivo studies have suggested that      ginkgolides A and B, and bilobalide, is around 70%,
 EGb 761 may protect against chemically induced            50% and 30%, respectively, of the dose administered
carcinogenesis. In mice, oral administration of EGb        orally . (G18)
761 (150 mg/kg daily for two weeks), compared with
control, was reported to reduce tumour multiplicity ;       Therapeutic effects Most clinical trials of ginkgo
however, the inhibitory effect was not statistically       have explored its effects in the treatment of cogni-
significant. (37) It was also reported that EGb 761-        tive deficiency or cerebral insufficiency,              a
treatment reduced the cardiotoxicity of doxorubicin .      term used to describe a collection of symptoms
    EGb 761 and ginkgolide B have been shown to            thought to arise from an age-related reduction in
inhibit peripheral-type benzodiazepine receptor            cerebral blood flow. These symptoms include for-
(PBR) expression and cell proliferation in the             getfulness, poor concentration, poor perception,
human breast cancer cell line MDA-231, which is            debilitation, dizziness, fatigue, sleep disturbances,
known to be rich in PBR . (38) By contrast, the prolif-    listlessness, depressed mood, headache, mood
eration of MCF-7 breast cancer cells, which are low        swings, restlessness, tinnitus, anxiety, hearing loss
in PBR, was not affected .                                 and disorientation . (43,G56) Several studies have
    In rats, oral administration of standardised ginkgo    tested the effects of standardised ginkgo leaf extracts
leaf extract 300 mg/kg was shown to ameliorate             on cognitive function in patients with Alzheimer's
nephrotoxicity induced by administration of genta-         disease (44) and/or multi-infarct dementia . (45) Both are
micin 80 mg/kg . (39)                                      conditions which share several symptoms (e .g . mem-
    Aqueous extracts of dried ginkgo leaves have been      ory impairment) with cerebral insufficiency . Several
reported to inhibit monoamine oxidases (MAO) A             other trials have explored the effects of ginkgo
and B .(40) A study investigating the effects of biloba-   extracts on cognitive ability in individuals with no
lide on gamma-aminobutyric acid (GABA) concen-             history of significant cognitive impairment. A few
trations and on glutamic acid decarboxylase activity       studies have explored the effects of ginkgo on tinni-
in mouse brain found that GABA concentrations and          tus alone . (46)
glutamic acid decarboxylase activity were signifi-             Clinical research with ginkgo extracts has also
cantly higher in animals treated orally with biloba-       focused on effects in improving pain-free walking
lide 30 mg/kg daily for four days .(4 ') However, there    distance in patients with intermittent claudication/
were no differences between treated and control mice       peripheral arterial occlusive disease . (47,G56) Other
with regard to glutamate concentrations .                  studies have explored the effects of ginkgo in
    Several in vivo studies have documented adaptive       patients with chronic venous insufficiency, antide-
effects for EGb 761 . (20)                                 pressant-related sexual dysfunction, seasonal affec-
    A peptide isolated from the leaves of Ginkgo           tive disorder (SAD), and symptoms of depression .
biloba has been reported to have antifungal activity          Almost all clinical trials of ginkgo have investi-
against several fungi, including Pellicularia sasakii      gated the effects of the standardised ginkgo leaf
and Alternaria alternata . (10)                            extracts EGb 761 and LI 1370 .
254         Ginkgo

 Cognitive deficienc4, dementia in Alzheimer's disease,      an intention-to-treat anal4sis (n = 309), ginkgo reci-
 multi-infarct dementia A revie4 of controlled clin-         pients scored significantl4 better than did placebo
 ical trials of ginkgo in patients 4ith cerebral insuffi-    recipients on the Adas-Cog and the GERRI
 cienc4 identified 40 studies .(43) Generall4, trials        (p=0 .04 and p=0 .004, respectivel4) . A slight 4or-
 tested oral doses of standardised e4tracts of ginkgo        sening on the CGIC 4as observed for both groups.
 leaf of 120 mg dail4 administered for at least four to      The average end-points for the intention-to-treat
 si4 4eeks. Most trials reported significant results or      anal4sis 4ere 38 .6 and 34 .6 4eeks for the ginkgo
 positive (but not statisticall4 significant) trends in      and placebo groups, respectivel4 .
 favour of ginkgo, compared 4ith control . Ho4ever,             A s4stematic revie4 of randomised, double-blind,
 it 4as reported that most trials 4ere of poor metho-        placebo-controlled trials assessing the effects of stan-
 dological qualit4 ; onl4 eight studies 4ere considered      dardised ginkgo leaf e4tracts on cognitive function in
 to be 4ell-conducted . All of these eight studies           patients 4ith Alzheimer's disease, characterised
 reported statisticall4 significant results for ginkgo,      according to recognised criteria, included four stu-
 compared 4ith placebo . Nevertheless, further rando-        dies. (44) These involved oral administration of ginkgo
 mised, double-blind, controlled trials involving larger     e4tract 120 or 240 mg dail4 for 12-26 4eeks, and
 numbers of patients 4ere deemed necessar4. 43)              involved a total of 212 patients each in the ginkgo
 Details of 39 controlled studies of the ginkgo              and placebo groups . A meta-anal4sis of the results of
 e4tracts EGb 761 and LI 1370 have been sum-                 the four studies indicated a modest effect for ginkgo,
 marised . (GS6) All but tWO 148,49) of these studies 4ere   compared 4ith placebo (difference of 3% on the
 conducted before ne4 guidelines for testing the             Adas-Cog) .
 efficac4 of nootropic drugs 4ere developed . (G56)             Another s4stematic revie4 included nine rando-
 Details of the t4o studies that did meet the metho-         mised, double-blind, placebo-controlled trials of
 dological criteria described in the guidelines are given    standardised ginkgo leaf e4tracts in patients 4ith
 belo4 .                                                     dementia of the Alzheimer t4pe and/or multi-infarct
    In a randomised, double-blind, placebo-controlled        dementia . (45) The revie4 included t4o studies
 trial, after a four-4eek placebo run-in period, 216         described above . (48,49) Studies generall4 involved
 patients 4ith mild-to-moderate primar4 degenerative         the administration of oral doses of ginkgo e4tract
 dementia of the Alzheimer t4pe, or multi-infarct            120 or 240 mg dail4 for 6-12 4eeks, although t4o
 dementia, received standardised ginkgo leaf e4tract         studies involved a 24-4eek (48) or 52-4eek(49) admin-
 (EGb 761) 120 mg orall4 t4ice dail4, or placebo, for        istration period . One stud4 involved the administra-
 24 4eeks . (48) At the end of the stud4, data for 156       tion of intravenous infusions of ginkgo e4tract
 patients 4ere eligible for anal4sis . There 4ere sig-       200 mg four times per 4eek for four 4eeks . It 4as
 nificantl4 more responders to treatment (defined as a       reported that, overall, the studies provided evidence
 response to at least t4o of the three primar4 outcome       to support the efficac4 of standardised ginkgo leaf
 measures - a ps4chopathological assessment, an              e4tracts in the s4mptomatic treatment of dementia .
 assessment of cognitive performance and a beha-             Ho4ever, methodological limitations of several of
 vioural assessment of activities of dail4 life) in the      the included studies (e.g . poorl4 defined inclusion and
 ginkgo group, compared 4ith the placebo group               e4clusion criteria and method of randomisation,
 (28% versus 10% of ginkgo and placebo recipients,           treatment period less than si4 months, small sample
 respectivel4; p=0 .005) . The difference 4as also           sizes) 4ere also emphasised . It 4as concluded that
 statisticall4 significant in an intention-to-treat anal4-   further studies are required to establish the benefits of
 sis (23% versus 10% of ginkgo and placebo recipi-           ginkgo in dementia . 5)
 ents, respectivel4; p = 0.005) .                               In a randomised, double-blind, placebo-controlled
    A randomised, double-blind, placebo-controlled           stud4, 60 elderl4 volunteers 4ith mild-to-moderate,
 stud4 involved 327 patients 4ith mild-to-severe             age-related cognitive d4sfunction received oral
 dementia related to Alzheimer's disease or multi-           ginkgo e4tract (GB-8 ; no further details provided)
 infarct dementia . 149) Participants received standar-      40 mg, 80 mg or placebo, three times dail4 for three
 dised ginkgo leaf e4tract (EGb 761) 40mg orall4             months .(50) At the end of the stud4, for the 54
 three times dail4 (n=166), or placebo (n=161), for          patients 4ho completed, it 4as reported that mem-
 52 4eeks, and under4ent a batter4 of assessments at         or4 function (as assessed b4 the Wechsler Memor4
 12, 26 and 52 4eeks . The primar4 outcome measures          Scale) improved significantl4 in the lo4-dose ginkgo
 4ere the Alzheimer's Disease Assessment Scale Cog-          group, compared 4ith baseline values (p = 0 .016), but
 nitive Subscale (Adas-Cog), the Geriatric Evaluation        that there 4as no significant improvement in the
 b4 Relative's Rating Instrument (GERRI) and the             placebo or high-dose ginkgo groups, compared 4ith
 Clinical Global Impression of Change (CGIC) . In            baseline values . A significant decrease in diastolic
                                                                                                 Ginkgo          255

blood pressure, compared with baseline values, was           performance was carried out immediately before and
also reported for the low-dose ginkgo group                  at 1, 2 .5, 4 and 6 hours after ginkgo administration .
(p = 0 .04) . This study, however, had methodological        It was reported that with doses of ginkgo extract of
limitations (e .g. small sample size), and the report of     240 and 360 mg, there was a statistically significant
the study did not include statistical analyses between       improvement in `speed of attention' (a measure of
groups .                                                     reaction time) from 2 .5 hours up to 6 hours (the last
   A more methodologically rigorous randomised,              measurement point) after ginkgo administration .
double-blind, placebo-controlled trial involving                In a randomised, double-blind, placebo-con-
patients with age-related impairment of memory               trolled, crossover study, eight healthy female volun-
and/or concentration assessed the effects of an              teers (mean age 32 years) were given a standardised
alcohol/water extract of fresh leaves of ginkgo              extract of G . biloba leaf at doses of 120, 240 and
(drug extract ratio 1 :4; total flavonoid glycosides         600 mg .(54) One hour after treatment, volunteers
0.20 mg/mL, total ginkgolides 0 .34mg/mL) . ( 51 ) Par-      undertook a series of psychological tests . Memory
ticipants received undiluted ginkgo extract (n = 77),        was found to be significantly improved with G .
diluted ginkgo extract (1 : 1 with placebo) (n = 82), or     biloba leaf 600 mg, compared with placebo .
placebo (n = 82), 40 drops (1 .9mL) three times daily           A randomised, double-blind, placebo-controlled,
for 24 weeks. At the end of the treatment period, a          crossover trial involving 31 volunteers aged 30-59
check for blinding indicated that participants were          years tested the effects of a standardised extract of
unable to identify the treatment they received . There       ginkgo leaf (LI 1370) 50 mg three times daily, 100 mg
were no statistically significant differences between        three times daily, 120 mg each morning, 240 mg each
the three groups in subjective perceptions of memory         morning, and placebo, each taken for two days
and concentration, and in the following objective            followed by a washout period of at least five
measures: the Expended Mental Control Test (a                days .(-5-5) A battery of tests to assess memory and
measure of attention and concentration), and Rey             cognitive and psychomotor performance was carried
test parts 1 and 2 (which measure short-term memory          out 30 minutes before ginkgo administration and
and learning curve, and long-term memory and                 then hourly for 12 hours . It was reported that there
recognition, respectively) . However, a significant          was a `marginally significant' effect of treatment,
difference between groups was observed in the Ben-           compared with placebo, in a test assessing short-
ton test of visual retention-revised (a measure of           term memory, although the p-value given for this
short-term visual memory) - increases in baseline            was greater than 0 .05 (p = 0.053). Post-hoc analyses
scores of 18, 26 and 11% were recorded for the               suggested that ginkgo extract 120 mg each morning
high-dose ginkgo, low-dose ginkgo and placebo                was associated with better performance in this test
groups, respectively (p=0 .0076). (51                        than other doses of ginkgo extract (including ginkgo
   In an open study, 18 elderly patients with `possible      extract 50 mg three times daily) and placebo . There
or probable' Alzheimer's disease were randomised to          were no statistically significant effects of treatment
receive a single oral dose of tacrine 40 mg or a             on immediate and delayed word recall and choice
standardised extract of ginkgo leaf (SeGb ; no further       reaction time.
details provided) 240 mg in two separate sessions                Other studies have assessed the cognitive-enhan-
within three- to seven-day intervals . (52) It was           cing effects of ginkgo extracts in older volunteers . In
reported that both interventions induced pharmaco-           a randomised, double-blind, placebo-controlled trial,
logical effects in the central nervous system (CNS), as      48 cognitively intact individuals aged over 55 years
assessed by quantitative pharmaco-electroencephalo-          received a standardised ginkgo leaf extract (EGb 761)
gram measurements . It should be noted that this was         60 mg three times daily, or placebo, for six weeks . (56)
an uncontrolled study.                                       A battery of neuropsychological tests was carried out
                                                             before treatment and at the end of the study . Ginkgo
Cognitive enhancement in healthy volunteers Ginkgo           extract recipients experienced a significant improve-
has been tested for its cognitive enhancing                  ment in tests assessing speed of processing abilities,
effects in healthy (i .e . cognitively intact) individuals   compared with placebo recipients (p < 0 .03) . How-
in addition to investigations into its effects in patients   ever, no statistically significant differences between
with cognitive deficiency .                                  the ginkgo extract and placebo groups were evident
   In a double-blind, placebo-controlled, cross-over         for tests assessing memory .
study, 20 healthy volunteers aged 19-24 years                    In a questionnaire survey, the effects of adminis-
received a standardised extract of ginkgo leaf               tration of a standardised ginkgo leaf extract (LI
(GKSO1) at doses of 120 mg, 240 mg and                       1370) 120 mg daily for four months on the activities
360 mg.(") A battery of tests used to assess cognitive       of daily living were assessed in volunteers aged 32-97
256                                 Ginkgo

years(mnSD)68                                .9 (8 .4) years ).,57) Volunters                                                                                                            placebointrg us'                                                      .(58) The design of this
wercuitdvaeorlinagze                                                                 . Of 8557                                                                                           study has been criticised .Forexampl,ticns
intalrespod,5028werligbfothesurvy                                                             .                                                                                          did not have face-to-face contact with an investigator
Intoal,10vuers(who ntcurely                                                                                                                                                              atnyimedurgthsy                                                      . (59)
usingaykoprducts)weaiobrndmly                                                                                                                                                                                                    Inardomise,cntlria28ptenswih
aloctedrivgnkoextrac                                                    ;alotherspn-                                                                                                     untreads lofhearingcvdtraenous
dentswralocdthen-ramcotl                                                                                                                                                                 infuso 6%hydrxetlsach(HES),orinta-
group,nlesthyad e thyonlwised                                                                                                                                                            venousadrlgikoextac,fr10dys                                                          . 160) There
to receive ginkgo . It was reported that ginkgo extract                                                                                                                                  wernostaiclygnfatdiercsbwn
recipntsahvdigfcantlybersothane                                                                                                                                                          thewogrupsinmvetharing                                                                  . Further
contrlgupasce ingabltyoperfm                                                                                                                                                                        studienvolgarumbesofparticne
activesofdlying,se-amtofbily                                                                                                                                                                        required . ( 6o )
cope,andvisulogecafrmdnslep                                                                    .
Howevr,fsaleon,thrsulfitdy                                                                                                                                                               Periphalt ocusiveda/ntrmieclau-
shouldbeintrp cauosly                                     .Forexampl,th                                                                                                                          dicotion The effects of standardised extracts of
study was carried out by post, therefore investigators                                                                                                                                   ginkgo have been investigated in patients with Fon-
dinotmeparcinstyme,hsudwa                                                                                                                                                                tainesgIprhealtiocusveda                                                                                                                                                     .
             notrulyadmise,thuywasopen,thcrl                                                                                                                                             This condition is characterised by the onset of pain,
groupdintecvplabotes,ndhrwa                                                                                                                                                                      asreultofxygndicthelgmus,on
             nochek mplian                      .                                                                                                                                                walkingdstcerahnoud30-
                                                                                                                                                                                                 metrs                                                      . (GI ") Therationlfusgikonths
Tinnitus                                                                       and hearinglos                    Tintusadherglo                                                                   conditsfrectinmprovgbldfw                                                                                                                                         .
              aretwofhsymp dentia                                                                                                                                  . IG56) Sevral                                                 Ameta-nlysiofrdme,ubl-ind
              studies have assessed the effects of ginkgo on these                                                                                                                                placebo-ntrdialsofgnkextracfoh
conditsale                                                                                    .                                                                                                   treamnofiteclaudion e
                                                  Asytemaicrvwofndmise,ctrol                                                                                                                      eightsud aesdfctonwalkigds-
              trialsofgnkextracsinucldefiv                                                                                                                                                        tance. t 61 > Thetrialsnvodtf415paiens
              studies - fourstdiecmpagnkoextrcs                                                                                                                                                   whorecivdastnrexactofginkleat
withplacebo,nd stuycomparedgink                                                                                                                                                                   dosef120r6mgdaily,opcebfr6,12
              extracwihonvetaldrugs                                                                                                 .Thretials d                                                  (onetrialch)24weks                                                                                      .Thepoldrsutfm
              thesandrigkoleafxtrcEGb761                                                                                                                                          ;ful            altrisndceatislygnfcatires
              detailsofhrxactsedinhotrsudiea                                                                                                                                                      inpa-frewlkgdistanceforkg-taed
              not given in the review .Therviwconludtha,                                                                                                                                          patients, compared                                                                       with placeborints
              overal,thsudienfprovidencto                                                                                                                                                         (weightdmanfrec(WMD)                                                                                                                 :34metrs                 ; 95%
              suportginkexacs trmenfoitus,                                                                                                                                                        confide trvals(CI)                                                                        : 26-43metrs)                                              .Asimlar
              buthafreinvstgaowrequidtofly                                                                                                                                                        resultwaobindhersultfo ixsudeof
              establih nfts                                                                     .Typical,teswofh                                                                                  godmethlicaquywerpold(WMD                                                                                                                                       : 37
              studiehamolgcfws                                                                                                                   . (46)                                           metrs                                                      ; 95% CI :26-47metrs)                                       .Itisqueonabl
                                                  Adouble-in,ctrdalpubishenc                                                                                                                       whether the extent of these increases in pain-free
              thesymaicrvw,tesdhfcoastndr-                                                                                                                                                         walkingdstcelinayrvt                                                                                                                         . (61)
              threimsdalyfo12weksin dvuals,                                                                                                                                              Chronic                         venous insufceyadvnouslcer                     A
              aged 18-70 years, with tinnitus who were otherwise                                                                                                                         randomise,ubl-ndpaceotrldia
              healty                                                         . (58 ' Participants were recruited via advertise-                                                          asedthprociveftsoacmbin
              mentsplacdihUKntoalpresdinBtsh                                                                                                                                             preparation (Ginkgor Forte) containing a standar -
TintusAocan'publito                                                                                                                                  .Themainout-                        dised extract of ginkgo (2 .3%), troxerutine
               comeasurwpticans'elf- mto                                                                                                                                                 (48 .85%)andheptmiol(48                                     .85%) against venous
               tinus(lodean`hwtroublesm')f,                                                                                                                                              walinjury48femalptinswhcrovenus
               duringafte mn,cariedoutvpsal                                                                                                                                              insufficiency. (62) GinkgorFte625mdaily,or
               questionar delphoncas                                                                                                                              . Participants         placebo,wsgivnfrouweks                                             .Intoal,42
               werpaidhosble(489pair,                                                                                                                                   .e . 978 of      patienscomldhtuy,bonl28wer
               12particnswemahd)nteraomly                                                                                                                                                includethfanlysibecuofprtl
               alocted ivorplaceb                                                                                               . At the end of the study,                               violatns                         .Circulatngedohicl(CE)ount
               thersulindcathgkoextrac(LI1370)                                                                                                                                           wasued mrofinjuythevasclr
               50mgthreisdalyw`nomrefctivhan                                                                                                                                             endothlium(CEcnsareidptns
                                                                                                  Ginkgo          257

with chronic venous insufficiency . 162) After four            gen.(8) After 6 .5 hours, participants were subjected
weeks' treatment, CEC counts decreased signifi-               to a provocation test with acetylcholine so that the
cantly in both the treatment and placebo groups (by            treatment of later stages of an asthma attack could be
 14 .5% and 8 .4%, respectively), compared with base-          assessed . Mixed ginkgolide standardised extract,
line values (p = 0.0021 and p = 0 .0146, respectively) .      40 mg three times daily, or placebo, were given
The mean change in CEC count after four weeks'                 during the three days before the test and a final
treatment was reported to be significantly greater for         single dose of 120 mg of extract was given 2 hours
the treatment group, compared with the placebo                 before the challenge . The results suggested that
group (p = 0.039).                                            ginkgolides were effective in both the early phase
     In another double-blind trial, 213 patients with         and the late phase of airway hyperactivity . (8)
chronic venous or mixed ulcers located at the mal-                 A study involving six patients with a history of
leolus (rounded protuberance on ankle joint) received         exercise-induced asthma assessed the effects of a
ginkgo extract 160 mg daily, or placebo, together              specific PAF antagonist (BN 52063, a standardised
with standard care (elastic stockings, local dressings        mixture of ginkgolides A, B and C, ratio of
and cleansing of ulcers) for 12 weeks ." ) At the end of      40 :40 :20) on the response to isocapnic hyperventi-
the study, ginkgo extract recipients, compared with           lation with dry cold air . (65) Participants were rando-
placebo recipients, showed a significant reduction            mised to receive BN 52063 240 mg orally 2 hours
in ulcer area .                                                before cold air challenge, 2 .4 mg by metered dose
                                                              inhaler 30 minutes before cold air challenge, or
Asthma, PAF antagonism           Intradermal injections of     placebo. It was reported that oral BN 52063 did
    PAF induce a biphasic inflammatory response similar        not reduce bronchoconstriction during challenge . A
    to that observed in sensitised individuals subjected to    significant increase in airways resistance was
    moderate doses of allergen . A single dose of a mixture    observed after inhalation of BN 52063 . In another
    of ginkgolides has been reported to antagonise this        study, six patients with a history of exercise-induced
response . (63) Oral administration of ginkgolides             asthma received BN 52063 120 mg orally twice daily,
resulted in a reduction of eosinophil infiltration in          1 mg by spinhaler three times daily, or placebo, for
    atopic patients given intracutaneous injections of         three days, then, on the test day, 240 mg orally 3
PAF . (63)                                                     hours before exercise challenge, 5 mg by spinhaler 1
       In a randomised, double-blind, crossover study,         hour before challenge, or placebo, respectively . With
    80 and 120 mg capsules containing a standardised           oral treatment, the prolonged reduction in peak
mixture of ginkgolides A, B and C (ratio of                    expiratory flow was significantly attenuated
40 :40 :20) were given as a single oral dose 2 hours           (p < 0.05) . (65)
    before challenge by intradermal PAF/histamine . Both
dose ranges inhibited flare which was maximal after            Antidepressant-related sexual dysfunction Two
5 minutes . Within 15-30 minutes wheal volume was              open, uncontrolled studies have explored the effects
reduced, with the greatest effect being observed for           of ginkgo extract in sexual dysfunction associated
the higher dose treatments . The protection was still         with treatment with antidepressant drugs . (66,67) One
present 8 hours after oral dosing . ) Similar inhibition      of these studies involved 63 men and women who
of PAF was observed for platelet aggregation with              were receiving treatment with selective serotonin
single oral doses of 80 and 120 mg extract which              reuptake inhibitors (SSRIs), venlafaxine, nefazo-
were given 2 hours before blood withdrawal . The              done, bupropion, phenelzine or protriptyline, and
ginkgolide mixture given orally also blocked PAF-             experiencing      sexual    dysfunction,       including
induced airway hyper-responsiveness .                         decreased libido, erectile difficulties, delayed or
       Antagonism of the effects of PAF by a standar-          inhibited orgasm and/or ejaculatory failure . 1661 All
 dised mixture of ginkgolides was assessed in a dou-          participants received ginkgo extract 40 or 60 mg
 ble-blind, placebo-controlled crossover study in six         twice daily, titrated up to a maximum of 120 mg
 healthy subjects aged 25-35 years . (64) Wheal and           twice daily (average daily dose 207 mg), for four
 flare responses to PAF examined 2 hours after inges-         weeks . It was reported that sexual dysfunction was
 tion of 80 mg and 120 mg of ginkgolide mixture were            relieved, as assessed by clinical interview and self-
 inhibited in a dose-related manner . Both doses sig-           report, in 91% and 76% of female and male partici-
  nificantly inhibited PAF-induced platelet aggregation       pants, respectively . An open, prospective pilot study
  in platelet-rich plasma . (64)                              involved 14 patients with sexual dysfunction (severe
       A randomised, double-blind, crossover study             or complete loss of libido, with or without inability to
   involved patients with atopic asthma who were               achieve or maintain erection, failure or delay in
    challenged with their specific dust or pollen anti-        ejaculation, anorgasmia) associated with current
258       Ginkgo

treat                                                                  de                                                   200 mg
but                           .                                        dai   .'' )  Ei              Jo
trip                                . (67) Part                        si                                      120 m
a                                     stan  240 mg                     fr             8 to       35 of the study .
  weeks .                                                              th       As
  stre                                                                 age
  ton At the end of the study,                      . Among the pr                                      .
   12 indi                                                              th
  sign                                                                  mi                             50% o
  anxie                 6 (p < 0 .05)      and                          Ham
   weeks 3 and pat   6 (p < 0 .01 for
   with                   .                                             wi
        One of these studies  (136) has                                 ex               0.05) . Ho
   meth                                                                 be
   report.(68 Owing to their open, uncontrolled designs, si
   neit                                                                 for controls (p < 0.05) . It
   ofgi                                                                                                   g
   dysf                                                                 gr
   ably                                              .                  ci
                                                                        me                                                          .
    Other conditions A                                                  Fu                     Co
    gink                                                                be
    iden                                                                tr                    . The design of the study, together
    20 patie     .(69) The study design did not include wi
    blin                                           . The review co
    conc                                                                ex                                                    .
    vent                                                                   A                                           165 women
    tion                                               .                wi
        In                                                        27 st                                      a        761) 160 mg
    patie                                                               dai                                     16 o
    rece                                                                cy                  5 of the following cycle, for two
    Bilo                                               24 mg            cycles . (72) Both groups experienced improvements in
    terp                  6 mg)                                         sy
     (n=15), or             (n=12), for 10 weeks or until            . gi                                           p
    deve                                                       . (70) we
    All                                                                 im
    December;                                                           th            ass .
    and                                            . Six of the 15         Th                             o
     gink                                     12 plac                   in                                 .
     ents                                                               is
     ging symptoms of SAD ('winter depression') .                       ti                                                      I
     repo                                                               su
     stati                                                              be
     test.                                                              pat Al     .
     differences between groups on the Montgomery-                      ox                .)
     Asbe                                                               tr    82 in
     (for                                                               fo
     carbo                                                              re                      0.25 mg
     toms                                                               gi                  360 mg              12 weeks. (73) At the
     ing, depressed mood) .                                             end of                    Th
     be(e                                                                                                 c
     size                                        .(70)                  be
         An                                                             val                                    o       (SD) : 815 .8
     stan                                                (LI 1370) (697 .8) and                           respectively; p=0.021) .
                                                                                         596 .7 (148 .3), d
     onIn                                                                                                 c
                                                                                                 Ginkgo          259

 (SD) SOD concentrtions fell from 780 .4 (605 .4) t        drdised extrcts of ginkgo lef re well tolerted
bseline to 617 .6 (189 .7) t the end of the study,        when used t recommended doses . (43,G21) Adverse
lthough this decrese ws reported to be sttisticlly     effects re uncommon . A postmrketing surveillnce
non-significnt. A between-group comprison ws             study involving 10 815 ptients who received 
not reported . Men (SD) SOD concentrtions in             stndrdised extrct (LI 1370) of ginkgo lef
group of 30 ge- nd sex-mtched helthy volunteers         reported tht the frequency of dverse effects ws
were 515 .8 (70.4). 73)                                      1 .7% .(G56) Adverse effects reported with stndr-
    he effects of  preprtion comprising Ginkgo          dised extrcts of ginkgo lef re generlly mild, nd
bilob dimeric flvonoids in  1 :2 complex with            include nuse, hedche, gstrointestinl upset nd
phosphtidylcholine (GBDF-Phytosome) on the                 dirrhoe;        llergic     skin     rections     occur
microcircultion of the skin hve been investigted         rrely . (76,G21,G56)
using vrious techniques including, infrred photo-             A systemtic review of nine rndomised, double-
pulse plethysmogrphy, lser doppler flowmetry,             blind, plcebo-controlled trils of stndrdised
high-performnce contct thermogrphy nd compu-            ginkgo lef extrcts in ptients with dementi of the
terised videothermogrphy . (74) In  controlled study,     Alzheimer type nd/or multi-infrct dementi con-
smll numbers of helthy individuls nd volunteers         cluded tht, overll, the frequency of dverse effects
with crocynosis or cellulitis were treted with           reported for ginkgo ws not mrkedly different thn
0.5 mL of  crem (oil-in-wter emulsion) contin-          tht for plcebo . ( " ) he lrgest tril included in this
ing 3 % GBDF-Phytosome or n oil-in-wter emul-             review involved 327 ptients with mild-to-severe
sion of 2% phosphtidylcholine (control).                   dementi relted to Alzheimer's disese or multi-
Prticipnts who received the GBDF-Phytosome pre-           infrct dementi who received stndrdised ginkgo
prtion were reported to experience significnt            lef extrct (EGb 761) 40 mg orlly three times dily
increses in cpillry blood flow nd skin temper-         (n=166), or plcebo (n=161), for 52 weeks . (49) It
ture, compred with bseline vlues, wheres no             ws reported tht there ws no sttisticlly signifi-
significnt chnges were observed for the control           cnt differences between ginkgo nd plcebo in the
group. No between-group comprisons were                    number of prticipnts reporting dverse events, or in
reported . (74) hese preliminry findings suggest tht     the frequency nd severity of dverse events . Of 188
the effects of this preprtion on skin microcircul-       dverse events reported during the study, 97 were
tion my deserve further investigtion .                    reported by ginkgo recipients nd 91 by plcebo
   A phse II (open, uncontrolled) study explored           recipients . However, clinicl trils generlly only
the effects of stndrdised ginkgo lef extrct (EGb        hve the sttisticl power to detect common, cute
761) given in combintion with S-fluorourcil (5-           dverse effects . Similr findings were reported in
F) in 44 ptients with dvnced progressive color-         nother systemtic review/met-nlysis which
ectl cncer who hd previously received 5-F . (75)        included eight rndomised, double-blind, plcebo-
he rtionle for including ginkgo extrct in the           controlled trils of ginkgo extrct for the tretment
regimen ws bsed on its reputed bility to increse        of intermittent cludiction, involving  totl of 415
locl blood flow . hus, it ws hypothesised tht           ptients who received stndrdised extrct of ginkgo
ginkgo extrct might enhnce locl tumour blood            lef t doses of 120 or 160 mg dily, or plcebo, for
flow nd thus improve the distribution of 5-F' . In        up to 24 weeks . (47) Five of the eight studies included
the study, prticipnts received ginkgo extrct             reported (rrely) mild, trnsient dverse events occur-
350 mg in 250 mL sline intrvenously over 30               ring in ginkgo recipients ; the remining three studies,
minutes on dys 1-6, nd 5-F 500 mg/m 2 in                 comprising lmost 50% of the totl number of
250 mL sline intrvenously over 30 minutes on              ptients, did not report ny dverse events .
dys 2-6 . he regimen ws repeted every three                 here re isolted reports of bleeding ssocited
weeks until recurrence of tumour progression . Dt         with ingestion of Ginkgo bilob extrct. One report
from 32 ptients who hd received t lest two              describes  70-yer-old mn who experienced spon-
courses of tretment were eligible for nlysis . Of        tneous bleeding from the iris into the nterior
these ptients, 69% experienced progression of              chmber of the eye one week fter he begn tking
disese, 25% experienced no chnge, nd 6 .3%               stndrdised ginkgo extrct 80 mg dily . '77) A 61-
(n = 2) were in prtil remission . (75)                    yer-old mn who hd tken ginkgo extrct 120 mg
                                                            or 160 mg dily for six months experienced 
Side-effects, oxicity                                      subrchnoid hemorrhge . 1711) Another report
                                                            describes  33-yer-old womn who begn experi-
he sfety nd toxicity of ginkgo hve been                 encing incresingly severe hedches, s well s
reviewed .( I11,G2 ' ) Avilble dt indicte tht stn-   double vision nd nuse nd vomiting, over sev-

260        Ginkgo

eral months . (79) During the course of investigations,    some supporting evidence for the modern
it was revealed that she had been consuming                clinical      uses of standardised         ginkgo leaf
standardised ginkgo extract 120 mg daily for two           extracts . (1,2,8,13,14,16.19,20,76,82,83)
years . Her symptoms improved, although her head-              Also, standardised ginkgo leaf extracts are among
aches were not entirely relieved, after evacuation of      the herbal preparations that have undergone most
bilateral subdural haematomas which were identi-           extensive clinical investigation . The effects of ginkgo
fied following an MRI scan . On stopping ginkgo            extracts in dementia have been tested clinically
extract, her prolonged bleeding time was reduced,          mostly in trials involving patients with cognitive
and on follow-up she was symptom-free . A causal           deficiency, Alzheimer's disease (44) and/or multi-
relationship between ginkgo ingestion and bleeding         infarct dementia . Some high-quality studies invol-
in these cases has not been definitively established .     ving patients with dementia have reported signifi-
    There is a report of acute myoglobinuria in a          cant beneficial effects for standardised ginkgo leaf
29-year-old man who was a regular weight-trainer           extracts . (48,49) However, systematic reviews/meta-
and who had been taking a combination prepara-             analysis of all relevant randomised, double-blind,
tion containing extracts of ginkgo (200 mg), guar-         placebo-controlled trials have reported modest
ana (Paullinia cupana, 500 mg) and kava (Piper             effects for ginkgo extract, compared with pla-
methysticum, 100 mg) . ( S0) The man was admitted          cebo, (44) and have concluded that further high-qual-
to an intensive care unit with severe muscle pain          ity studies are required to establish the benefits of
and blood creatine kinase and myoglobin concen-            ginkgo in dementia . (45) Small randomised, double-
trations of 100500IU/L (normal values : 0-195)             blind, placebo-controlled trials investigating the cog-
and 10 000 ng/mL (normal values : 0-90), respec-           nitive enhancing effects of ginkgo extracts in healthy
tively . Signs and symptoms subsided within six            volunteers have reported conflicting results . Further
weeks. The relevance, if any, of ginkgo ingestion          study is required to determine whether ginkgo
to the man's condition, is unclear .                       extracts are of value in cognitively intact indivi-
    Contact or ingestion of the fruit pulp has pro-        duals. The effects of ginkgo extract in patients with
duced severe allergic reactions including erythema,        tinnitus have not been definitively established by
oedema, blisters and itching . (63) The seed contains      trials carried out to date. A meta-analysis of trials
the toxin 4-O-methylpyridoxine which is reported           of standardised ginkgo leaf extract in peripheral
to be responsible for 'gin-nan' food poisoning in          arterial occlusive disease found that ginkgo signifi-
Japan and China ."' ) The main symptoms are con-           cantly improved pain-free walking distance, although
vulsion and loss of consciousness and lethality is         the clinical relevance of the extent of improvement is
estimated in about 27% of cases in Japan, infants          questionable . (47)
being particularly vulnerable .                               Generally, the intended uses of ginkgo are not
                                                           suitable for self-medication .

Contra-indications, Warnings
The fruit pulp has produced severe allergic reactions
and should not be handled or ingested . The seed           See also General References G3, G5, G18, G21, G29,
causes severe adverse effects when ingested .              G31, G32, G36, G43, GS0, G54, G56, G63 and G64 .
   Ginkgo extract should only be used with caution         1 Van Beek TA et al. Ginkgo biloba L. Fitoterapia
in patients taking anticoagulant or antiplatelet              1998 ; 69 : 195-244.
agents.                                                    2 Van Beek TA, ed . Ginkgo . The Genus Ginkgoa-
                                                              ceae. Amsterdam : Harwood Academic Publishers,
Pregnancy and lactation     No studies appear to have         1998 .
been reported on the effects of G . biloba leaf extracts   3 Victoire C et al . Isolation of flavonoid glycosides
or ginkgolides in pregnant or lactating women . In            from Ginkgo biloba leaves . Planta Med 1988 ; 54 :
view of the many pharmacological actions documen-            245-247 .
ted and the lack of toxicity data, use of ginkgo during    4 Schenne A, Holzl J . 6-Hydroxykynurensaure, die
pregnancy and lactation should be avoided .                  ersre N- haltige Verbindung aus den Blattern von
                                                              Ginkgo biloba . Planta Med 1986 ; 52 : 235-236.
Pharmaceutical Comment                                     5 Nasr C, et al . 2-Quinoline carboxylic acid-4,6 -
                                                             dihvdroxy from Ginkgo biloba. Paper presented at
There is a vast scientific literature describing             the Phytochemical Society of Europe Symposium :
the pharmacological effects of ginkgo leaf extracts           Biologically Active Natural Products, Lausanne,
and their constituents .(S1) These data provide               19S6, p. 9.
                                                                                                    Ginkgo          261

 6   Briancon-Scheid F et al . HPL separation and                   effects of flavonoid metabolites and terpenoid
     quantitative determination of biflavones in leaves             constituents of Ginkgo biloba extract (EGb 761)
     from Ginkgo biloba. Plaizta Med 1983 ; 49: 204-                during ischemia and reperfusion. Basic Res ardiol
     220.                                                            2000 ; 95 : 368-377 .
 7   Vanhaelen M, Vanhaelen-Fastre R. Kaempferol-3-           22   Janssens D et a! . Protection by bilobalide of the
     O-(3-glucoside (astragalin) from Ginkgo biloba .                ischaemia-induced alterations of the mitochondrial
     Fitoterapia 1988 ; 59 : 511 .                                  respiratory activity . Fund lin Pharmacol 2000 ;
 8   Braquet P . The ginkgolides : potent platelet-activat-          14 :193-201 .
     ing factor antagonists isolated from Ginkgo biloba       23    Zhang WR et al. Protective effect of Ginkgo
     L. : hemistry, pharmacology and clinical applica-             extract on rat brain with transient middle cerebral
     tions . Drugs of the Futtire 1987 ; 12 : 643-699 .             artery occlusion . Neurol Res 2000; 22 : 517-521 .
 9   Anonymous . Extract of Ginkgo biloba (EGb 761) .         24    Dutta-Roy AK et al. Inhibitory effect of Ginkgo
     Presse Med 1986; 15 : 1438-1598 .                              biloba extract on human platelet aggregation .
10   Huang X et al . haracteristics and antifungal                 Platelets 1999 ; 10 : 298-305 .
     activity of a chitin binding protein from Ginkgo         25    Hosford D, et al. Natural antagonists of platelet-
     biloba . FEBS 2000 ; 478 : 123-126 .                           activating factor. Phytother Res 1988 ; 2 : 1-17 .
11   Wada K et al. Studies on the constitution of edible      26    Maitra I et al . Peroxyl radical scavenging activity
     medicinal plants . 1 . Isolation and identification of         of Ginkgo biloba extract EGb 761 . Biochem
     4-0-methylpyridoxine, toxic principle from the                 Pharmacol 1995 ; 49 : 1649-1655 .
     seed of Ginkgo biloba L . hem Pharm Bull 1988 ;         27    Lee S-L et al. Superoxide scavenging effect of
     36 : 1779-1782 .                                               Ginkgo biloba extract on serotonin-induced mito-
12   Wang H, Ng TB . Ginkbilobin, a novel antifungal                genesis . Biochem Pharmacol 1998 ; 56 : 527-533 .
     protein from Ginkgo biloba seeds with sequence           28    Oyama Y et al. Ginkgo biloba extract protects
     similarity to embryo-abundant protein . Biochem                brain neurons against oxidative stress induced by
     Biophys Res ommun 2000; 279: 407-411 .                        hydrogen peroxide . Brain Res 1996; 712 : 349-
13   DeFeudis FV. Ginkgo biloba. From hemistry to                  352 .
     linic . Wiesbaden, Germany : Ullstein Medical,          29    Wei T et al . Hydrogen peroxide-induced oxidative
     1998 .                                                         damage and apoptosis in cerebellar granule cells :
14   lostre F, De Feudis FV, eds . ardiovascular                  protection by Ginkgo biloba extract . Pharmacol
     Effects o f Ginkgo biloba Extract (EGb761) .                   Res 2000; 41 : 427-433 .
     Advances in Ginkgo biloba Extract Research, vol          30    Bastianetto S et a!. The ginkgo biloba extract (EGb
     3 . Paris : Elsevier, 1994 : 1-162 .                           761) protects hippocampal neurons against cell
15   Reuter HD. Ginkgo biloba - botany, constituents,               death induced by 0i-amyloid . Eur J Neurosci 2000 ;
     pharmacology and clinical trials . Br J Phytother              12 :1882-1890 .
     1995/6 ; 4: 3-20 .                                       31    Zhou L-J, Zhu X-Z . Reactive oxygen species-
16   hristen Y, ed . Ginkgo biloba Extract (EGb 761)               induced apoptosis in P12 cells and protective
     as a Neuroprotective Agent : From Basic Studies to             effect of bilobalide. J Pharmacol Exp Ther 2000 ;
     linical Trials. Advances in Ginkgo biloba Extract             293 :982-988 .
     Research, vol 8 . Paris: Elsevier, 2001 .                32    alapai G et al. Neuroprotective effects of Ginkgo
17   Winter J . The effects of an extract of Ginkgo                biloba extract in brain ischaemia are mediated by
     biloba, EGb 761, on cognitive behaviour and                    inhibition of nitric oxide synthesis . Life Sci 2000;
     longevity in the rat . Physiol Behav 1998 ; 63 :               67 : 2673-2683 .
     425-433 .                                                33    Rasetti MF et al. Extracts of Ginkgo biloba L.
18   Hasen6rhl RU et al. Dissociation between anxio-                leaves and Vaccinium myrtillus L . fruits prevent
     lytic and hypomnestic effects for combined extracts            photo induced oxidation of low density lipoprotein
     of Zingiber officinale and Ginkgo biloba, as                   cholesterol . Phytomedicine 1996/97; 3 : 335-338 .
     opposed to diazepam . Pharmacol Biochem Behav            34    Drieu K et al . Effect of the extract of Ginkgo
     1998 ; 59 : 527-535 .                                          biloba (EGb 761) on the circulating and cellular
19   hristen Y et al., eds . Effects of Ginkgo biloba              profiles of polyunsaturated fatty acids : correlation
     Extract (EGb 761) on Neuronal Plasticity .                     with the anti-oxidant properties of the extract .
     Advances in Ginkgo biloba Extract Research, vol                Prostaglandins Leukot Essent Fatty Acids 2000 ;
     S . Paris : Elsevier, 1996 .                                   63 :293-300 .
20   Papadopoulos V et a! . Adaptive Effects of Ginkgo        35    Bridi R et al. The antioxidant activity of standar-
     biloba Extract (EGb 761) . Advances in Ginkgo                  dized extract of Ginkgo biloba (EGb 761) in rats .
     biloba Extract Research, vol 6 . Paris : Elsevier,             Phytother Res 2001 ; 15 : 449-451 .
     1997.                                                    36    Bahcecioglu IH et al. Protective effect of Ginkgo
21   Liebgott T et a! . omplementary cardioprotective              biloba extract on l 4 -induced liver damage .

262         Ginkgo

      HepaOol Res 1999 ; 15 : 215-224 .                            Psychopharmacol Bull 1998 ; 34 : 391-397 .
37    Agha AM eO a!. ChemoprevenOive effecO of Ginkgo         53   Kennedy DO eO a! . The dose-dependenO cogniOive
      biloba exOracO againsO benzo(a)pyrene-induced                effecOs of acuOe adminisOraOion of Ginkgo biloba Oo
      foresOomach carcinogenesis in mice : amelioraOion            healOhy young volunOeers . Psychopharmacology
      of doxorubicin cardioOoxiciOy . J Exp Clin Cancer            2000 ; 151 : 416-423 .
      Res 2001 ; 20 : 39-50 .                                 54 Subhan Z, Hindmarsh I . The psychopharmacolo-
38    Papadopoulos V eO al. Drug-induced inhibiOion of             gical effecOs of Ginkgo biloba exOracO in normal
      Ohe peripheral-Oype benzodiazepine recepOor                  healOhy volunOeers. IrOO J Clin Pharmacol Res 1984 ;
      expression and cell proliferaOion in human breasO            4 : 89-93 .
      cancer cells . AnOicancer Res 2000 ; 20 : 2835-2848 .   55   Rigney U eO al. The effecOs of acuOe doses of
39    Naidu MUR eO al. Ginkgo biloba exOracO amelio-               sOandardized Ginkgo biloba exOracO on memory
      raOes genOamicin-induced nephroOoxiciOy in raOs .            and psychomoOor performance in volunOeers .
      PhyOomedicine 2000 ; 7 : 191-197 .                           PhyOoOher Res 1999 ; 13 : 408-415 .
40    WhiOe HL eO al. ExOracOs of Ginkgo biloba leaves        56 Mix JA, Crews WD . An examinaOion of Ohe
      inhibiO monoamine oxidase . Life Sci 1996 ; 58 :             efficacy of Ginkgo biloba exOracO EGb 761 on
      1315-1321 .                                                  Ohe neuropsychological funcOioning of cogniOively
41    Sasaki K eO al . EffecOs of bilobalide on gamma-             inOacO older adulOs. J AlOern ComplemenO Med
      aminobuOyric acid levels and gluOamic acid dec-              2000 ; 6 : 219-229 .
      arboxylase in mouse brain . Eur J Pharmacol 1999;       57   Cockle SM eO a!. The effecOs of Ginkgo biloba
      367:165-173 .                                                exOracO (LI 1370) supplemenOaOion on acOiviOies of
42    IOokawa H eO al . AnOiOumour principles from                 daily living in free living older volunOeers : a
      Ginkgo biloba L . Chem Pharm Bull 1987 ; 35 :                quesOionnaire survey . Hum Psychopharmacol
      3016-3020 .                                                  2000 ; 15 : 227-235 .
43    Kleijnen J, Knipschild P . Ginkgo biloba for            58   Drew S, Davies E. EffecOiveness of Ginkgo biloba
      cerebral insufficiency . Br J Clin Pharmacol 1992 ;          in OreaOing OinniOus : double blind, placebo con-
      34 :352-358 .                                                Orolled Orial . BMJ 2001 ; 322 : 73-75 .
44    Oken BS eO al. The efficacy of Ginkgo biloba on         59   ErnsO E . MarkeOing sOudies and scienOific research
      cogniOive funcOion in Alzheimer disease . Arch               musO be disOincO. BMJ 2001 ; 322 : 1249 .
      Neurol 1998 ; 55 : 1409-1415 .                          60   Bukovics K eO a!. Vergleich von Ginkgo biloba and
45    ErnsO E, PiOOler MH . Ginkgo biloba for demenOia .           6% HES 200/0,5 in der Behandlung des akuOen
      A sysOemaOic review of double-blind, placebo-                H6rsOurzes . J Pharmakol Ther 1999; 2 : 48-56 .
      conOrolled Orials . Clin Drug InvesO 1999 ; 17 :        61   PiOOler MH, ErnsO E . Ginkgo biloba exOracO for Ohe
      301-308 .                                                    OreaOmenO of inOermiOOenO claudicaOion : a meOa-
46    ErnsO E, SOevinson C. Ginkgo biloba for OinniOus: a          analysis of randomised Orials . Am J Med 2000 ;
      review. Clin OOolaryngol 1999 ; 24 : 164-167 .               108 : 276-281 .
47    PiOOler MH, ErnsO E . Ginkgo biloba exOracO for Ohe     62 Janssens D eO al. Increase in circulaOing endoOhelial
      OreaOmenO of inOermiOOenO claudicaOion : a meOa-           cells in paOienOs wiOh primary chronic venous
      analysis of randomized Orials . Am J Med 2000 ;            insufficiency : proOecOive effecO of Ginkor ForO in a
      108 : 276-281 .                                            randomized double-blind, placebo-conOrolled clin-
48    Kanowski S eO al. Proof of efficacy of Ohe Ginkgo          ical Orial . J Cardiovasc Pharmacol 1999 ; 33 : 7-11 .
      biloba special exOracO Egb 761 in ouOpaOienOs           63 Pizzorno JE, Murray MT . A TexObook of NaOural
      suffering from mild Oo moderaOe primary degen-             Medicine . SeaOOle, WA : John BasOyr College Pub-
      eraOive demenOia of Ohe Alzheimer Oype or mulOi-           licaOions, 1985 (looseleaf) .
      infarcO demenOia . PhyOomedicine 1997 ; 4: 3-13 .       64 Chung KF . EffecO of a ginkgolide mixOure (BN
49    Le Bars P eO al. A placebo-conOrolled, double-blind,       52063) in anOagonising skin and plaOeleO responses
      randomized Orial of an exOracO of Ginkgo biloba for        Oo plaOeleO acOivaOing facOor in man. LanceO 1987 ; is
      demenOia . JAMA 1997 ; 278 : 1327-1332 .                     248-251 .
50    WinOher K eO al. EffecOs of Ginkgo biloba exOracO       65   Wilkens JH eO al . EffecOs of a PAF-anOagonisO (BN
      on cogniOive funcOion and blood pressure in elderly          52063) on bronchoconsOricOion and plaOeleO acOiva-
      subjecOs . Curr Ther Res 1998 ; 59 : 881-888 .               Oion during exercise-induced asOhma . Br J Clin
51    BrauOigam MRH eO al. TreaOmenO of age-relaOed                Pharmacol 1990 ; 29 : 85-91 .
      memory complainOs wiOh Ginkgo biloba exOracO : a        66   Cohen AJ, BarOlik B . Ginkgo biloba for anOide-
      randomized double blind placebo-conOrolled sOudy .           pressanO-induced sexual dysfuncOion . J Sex MariOal
      PhyOomedicine 1998 ; 5 : 425-434 .                           Ther 1998; 24 : 139-143 .
52    IOil TM eO al. The pharmacological effecOs of           67   WheaOley D . Ginkgo biloba in Ohe OreaOmenO of
      Ginkgo biloba, a planO exOracO, on Ohe brain of              sexual dysfuncOion due Oo anOidepressanO drugs .
      demenOia paOienOs in comparison wiOh Oacrine .               HiOm Psychopharmacol 1999 ; 14 : 511-513 .
                                                                                              Ginkgo         263

68  Balon R . Ginkgo biloba for antidepressant-induced         fluorouracil/Ginkgo biloba extract (GBE 761
    sexual dysfunction? J Sex Marital Ther 1999 ; 10 :         ONC) therapy in 5-fluorouracil pretreated patients
    1-2 .                                                      with advanced colorectal cancer . Phytother Res
69 Evans JR. Ginkgo biloba extract for age-related             2001 ; 15 : 34-38 .
    macular degeneration (Cochrane review) . In : The      76 DeFeudis FV . Safety of EGb 761-containing
    Cochrane Library, Issue 3, 2001 . Oxford : Update          products . In: DeFeudis FV, ed . Ginkgo biloba
    Software, 2001 .                                           Extract (EGb 761). Pharmacological Activities
70 Lingiaerde 0 et al. Can winter depression be                and Clinical Applications . Amsterdam: Elsevier,
    prevented by Ginkgo biloba extract? A placebo-             1991 .
    controlled trial . Acta Psychiatr Scand 1999 ; 100 :   77 Rosenblatt M, Mindel J . Spontaneous hyphema
    62-66 .                                                    associated with ingestion of Ginkgo biloba extract.
71 Hemmeter U et al . Polysomnographic effects of              N Engl J Med 1997 ; 336 : 1108 .
    adjuvant Ginkgo biloba therapy in patients with        78 Vale S . Subarachnoid haemorrhage associated with
    major depression medicated with trimipramine .             Ginkgo biloba . Lancet 1998 ; 352 : 36 .
    Pharmacopsychiatry 2001 ; 34 : 50-59 .                 79 Rowin J, Lewis SL. Spontaneous bilateral subdural
72 Tamborini A, Taurelle R . Rev Fr Gynecol Obstet             hematomas associated with chronic Ginkgo biloba
    1993 ; 88 : 147. Cited by Bone K . Treatment of            ingestion . Neurology 1996 ; 46 : 1775-1776 .
    congestive symptoms of premenstrual syndrome           80 Donadio V et a! . Myoglobinuria after ingestion of
    with ginkgo . Br J Phytother 1995/96 ; 4 : 46 .            extracts of guarana, Ginkgo biloba and kava .
73 Zhang XY et al. The effect of extract of Ginkgo             Neurol Sci 2000 ; 21 : 124 .
    biloba added to haloperidol on superoxide dis-         81 Houghton PJ . Ginkgo . Pharm J 1994 ; 253 : 122-
    mutase in inpatients with chronic schizophrenia . J        123 .
    Clin Psychopharmacol 2001 ; 21 : 85-88 .               82 Braquet P, ed . Ginkgolides - Chemistry, Biology,
74 Bombardelli E et al. Activity of phospholipid-              Pharmacology and Clinical Perspectives, vol 1 .
    complex of Ginkgo biloba dimeric flavonoids on             Barcelona : JR Prous, 1988 .
    the skin microcirculation . Fitoterapia 1996 ; 67:     83 Braquet P, ed . Ginkgolides - Chemistry, Biology,
    265-273 .                                                  Pharmacology and Clinical Perspectives, vol 2 .
75 Hauns B et al. Phase II study of combined 5-                Barcelona : JR Prous, 1989 .

Shared By:
Tags: Ginkgo, Ginkgo
Description: Ginkgo Ginkgo Ext